Synthesis of 1-Azaspiroundecane ring system via Thorpe-Ziegler annulation of 2-Cyano-2-(4-Cyano-Tethered) Arylpiperidines

Article abstract of DOI:10.1055/s-2002-31904

An efficient stereocontrolled route to the spiro[5.5]undecan framework of the histrionicotoxin alkaloids, employing anodic cyanation and Thorpe-Ziegler cyclization as key steps, is described. In the process of gaining information concerning the hydrolysis of the cyanoenamine function in 8, an unexpected intramolecular Friedel-Crafts type reaction provided the aza-fluorene 10.

Full text of DOI:10.1055/s-2002-31904

LETTER
895
Synthesis of 1-Azaspiroundecane Ring System via Thorpe–Ziegler Annulation
of 2-Cyano-2-(4-Cyano-Tethered) Arylpiperidines
S
ynthesis of 1-A
z
i
aspirou
c
ndecane
R
h
ingSystem ard Malassene,a Loic Toupet,b Jean-Pierre Hurvois,*a Claude Moineta
a
Laboratoire d’Electrochimie, UMR 6509, Institut de Chimie, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
b
Groupe Matière Condensée et Matériaux, Université de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Fax +33(223)235967; E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr
Received 21 February 2002
center after several chemical transformations.8 The pur-
poses of this study were two-fold. Firstly, to widen the
scope of our electrochemical methodology aimed at the
synthesis of new -aminonitrile systems and their subse-
Abstract: An efficient stereocontrolled route to the 1-aza-
spiro[5.5]undecan framework of the histrionicotoxin alkaloids, em-
ploying anodic cyanation and Thorpe–Ziegler cyclization as key
steps, is described. In the process of gaining information concerning
the hydrolysis of the cyanoenamine function in 8, an unexpected in- quent utilization for further chemical purposes; secondly,
tramolecular Friedel–Crafts type reaction provided the aza-fluorene
to evaluate if, in a final step, the unprecedented applica-
tion of the Thorpe–Ziegler9 annulation procedure to the
10.
Key-words: spiro compounds, stereoselective synthesis, lithiation,
annulation, nitriles
above mentioned systems could provide an efficient entry
into the 1-azaspiro[5.5]undecan ring system.
It is now well reported that -aminonitriles can serve both
as an -aminocarbanion and an imine or an iminium ion
precursor.10 In the first mode of reactivity, the acidic pro-
ton can be removed in the presence of bases to generate a
nitrile-stabilized carbanion which, in turn, can be alkylat-
ed with a great variety of electrophiles.11 The high yields
and diastereoselectivities generally observed in this se-
quence prompted us to undertake a rapid investigation
concerning the propensity of our metallated -cyanoam-
ines to form a new C-C bond to the nitrogen atom. Sev-
eral bifunctional -aminonitriles were thus prepared
(Equation and Table). The lithiation procedures were car-
ried out after the dissolution of the requisite aminonitrile
212 in THF, employing a 2 M solution of LDA in THF–n-
heptane, at temperatures ranging from –30 °C to –20 °C.
After one hour of stirring, the electrophiles were added to
the cold solutions before warming to ambient tempera-
ture.
The 2-spiropiperidine framework has been found in large
number of alkaloids isolated from skin extracts of the Co-
lumbian ‘poison-arrow’ frog Dendrobates Histrionicus.1
The unique biological activities2 of the naturally occur-
ring histrionicotoxin 1 or its saturated congener, perhy-
drohistrionicotoxin 1a (Figure) has stimulated the
development of numerous approaches for the rapid and
stereoselective construction of their heterocyclic core.3,4
1, HTX, R1 =
R1
R2 =
R2
N
H
1a, PHTX, R1 = n-C4H9
R2 = n-C5H11
HO
Figure
R
N
CN
N
CN
However, the creation of a new spiro carbon center in the
position to the nitrogen atom remains one of the major
difficulties found in all these studies. In this context, -
aminonitriles5 occupied an important position in that they
are considered as a valuable source of carbanions ideally
suited for the creation of hindered quaternary centers.6 As
a part of our ongoing program aimed at the electrochemi-
cal synthesis of various -aminonitriles, we became at-
tracted to the preparation of piperidine ring systems
substituted at the 2,2 position of the nitrogen atom.7 Sev-
eral studies have shown that such systems appears to be
valuable precursors for the creation of a new spiro carbon
Ph
Ph
rac-3a-g
rac-2
Equation
An additional two hours of stirring at that temperature and
work-up, afforded the expected adducts 3a–f from good to
excellent yields (Table, entries 1-6). Conversely, using
undecyl bromide as a bulky electrophile (entry 7), the re-
action was half completed, and led to the recovery of the
starting material 2 together with the undecyl derivative
3g. This drawback was overcome by a prolonged reaction
time (up to 18 h) at ambient temperature to yield 3g as a
sole product. Reaction with benzaldehyde (entry 4) pro-
vides substitution products as a mixture of syn and anti
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0895,0898,ftx,en;G04902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

896
R. Malassene et al.
LETTER
Table Alkylation of -Aminonitrile 2 and 4
e
e
CH3
CH3
Entry Electrophile
Product
Time
(h)
Yielda,b
(%)
e
R
N
CN
N
CN
a
1
2
3
4
CH3I
3a, R= CH3
1
2
2
2
90
97
a
Ph
Ph
n-C3H7Br
n-C5H11Br
C6H5CHO
3b, R = n-C3H7
3c, R = n-C5H11
rac-4
rac-5a-d
95
3d, R = C6H5CHOH
syn/anti: 43/57
100
5
6
Cl(CH2)4Br
allylBr
3e, R = (CH2)4Cl
3f, R = Allyl
2
1
95
95
90
90
88
92
95
R
X
e
H3C
H3C
N
R
X
N
7
n-C11H23Br
CH3I
3g, R = n-C11H23
5a, R = CH3
18
2
e
C
CN
Ph
Ph
a
N
8
Li
A
B
9
n-C3H7Br
n-C5H11Br
Cl(CH2)4Br
5b, R = n-C3H7
5c, R = n-C5H11
5d, R = (CH2)4Cl
2
R
X
10
11
2
Scheme 1
2
a Yields are of isolated products
electrophile to produce the energetically favored reactant
like transition state B. Hence, the alkylation procedure
proceeded with retention of configuration at C-2.
b All new compounds had satisfactory elemental analysis, and the 1H,
13C NMR and mass spectra were consistent with the proposed struc-
tures.
The dinitriles 6 and 7 were readily prepared by heating 3e
and 4d (DMSO, 70 °C) with a two-fold excess of sodium
cyanide in the presence of a catalytic amount (5 mol%) of
tetrabutylammonium iodide.19 Evidence for the incorpo-
ration of the cyano group to the molecules was provided
isomers in nearly equal amounts. Upon chromatographic
purification, one of the diastereomers crystallized, and a
further X-ray diffraction performed on a single crystal re-
vealed that both the alcohol and the cyano functions were
in a syn configuration.13
1
by the analysis of the H NMR spectrum of 620 and 7 in
which triplet signals (2 H) attributed to the terminal CH2
groups were found at = 2.20. Similarly, the 13C NMR
spectrum displayed two quaternary CN signals in the re-
gion = 119–121.
The stereochemical outcome of the lithiation-alkylation
procedure has been investigated using the trans -amino-
nitrile 412 as substrate. The procedure was similar to that
reported for the synthesis of 3a–g and afforded the expect-
ed adducts 5a–d in good yields (Table, entries 8–11). We
As a useful method of assembling medium to large sized-
rings,21 we decided to make use of the Thorpe–Ziegler an-
nulation procedure to construct the aza-spiroundecan ring
system. In our case, dinitriles 6 and 7 were ideally suited
for such a cyclization since only the less hindered primary
cyanide reacts with the base to produce the terminal ni-
trile-stabilized carbanion. Furthermore, it was felt that the
angular cyano group was considered as an integral part of
the final compound (future C-7). Traditionally, dinitriles
derivatives were cyclized with alkoxide bases,22 but
catalytic23 or radical24 cyclization methods using iridium
hydride complexes or the couple Bu3SnH–AIBN, respec-
tively, have been recently reported. After few attempts,25
we rapidly observed that Thorpe–Ziegler products 8 and 9
(Scheme 2) could be readily obtained, employing LDA (1
equiv) as a base and THF as the solvent. The IR spectrum
of 8 showed a characteristic absorption at 2185 cm–1 sug-
gesting that the nitriles groups were transformed into the
requisite enaminonitrile function. Further evidence for the
formation of the cyanoenamine moiety was provided by
the analysis of the 13C NMR spectrum of 8 in which the
quaternary sp2 hybridized carbons C-7 and C-8 were
found at = 161.75 and = 74.90, respectively.
were pleased to find that in all cases both the 1H and 13
C
NMR spectra revealed the presence of a single diaster-
eomer (de 99%). Cyano-stabilized carbanions constitute
an important class of intermediates as underscored by a
series of reviews.14 Despite their broad utilization in
chemistry, the exact nature of such species has remained
an open question.15 Therefore, during the last decade, the
structural aspect of various stabilized carbanions has be-
come a subject of growing interest.16 In this context, lithi-
ated -aminonitriles occupied an important position in
chemistry due to their broad range of applications includ-
ing the synthesis of natural or biologically active com-
pounds. The structure of metallated -aminonitriles has
been recently determined by Enders and coworkers.17 It
has been clearly demonstrated by X-ray and by spectro-
scopic methods that nitrile anions should be considered as
complex aggregates with charge delocalization over the
ketene imine moiety. Under our reaction conditions, it
seems likely that deprotonation of 4 yielded the interme-
diate species A (Scheme 1) which, in a second step is at-
tacked from the equatorial direction (e)18 by the entering
Synlett 2002, No. 6, 895–898 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 1-Azaspiroundecane Ring System
897
In summary, we have developed a new and concise ap-
proach for the construction of 1-azaspirocycles featuring
anodic cyanation and Thorpe-Ziegler cyclization as key-
steps. A C-4 methyl-substituted piperidine derivative was
a convenient substrate to study the stereochemical out-
come of the lithiation-alkylation procedure. Our first at-
tempts aimed at the hydrolysis of the -cyanoenamine
function afforded the unreported aza-fluorene 10, which
displays interesting fluorescent properties which are cur-
rently under investigations. Although a limited number of
examples have been studied, the overall sequence de-
scribed in this paper should represent a straightforward
route from piperidine derivatives to the corresponding
spiro systems.
4
NH2
CN
( )4
i
ii
3e
CN
6
7
9
N
N
CN
Ph
Ph
rac-8 (87%)
rac-6 (95%)
CH3
CH3
CN
NH2
ii
i
( )4
CN
CN
4d
N
N
Ph
Ph
rac-7 (85%)
rac-9 (80%)
Scheme 2 (i) NaCN (2 equiv), DMSO, n-Bu4NI (5 mol%), 70 °C,
12 h; (ii) LDA, THF, –78 °C to r.t., 2 h.
Acknowledgement
R. M. thanks the MENRT for a grant.
Both the spiro derivatives 8 and 9 were crystallized from
a mixture of diethyl ether and petroleum ether. An X-ray
diffraction performed on single crystals obtained in this
way definitively ascertained the spirocyclic structure of 8
and 9.13 This study also indicates that the 4-Me group and
the cyanoenamine function were in a trans disposition.
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N
H
Ph
C
rac-10 (90%)
Scheme 3 (i) t-BuOH, HCl (15%), 83 °C, 50 min.
Firstly, this intramolecular condensation should be con-
sidered as a Friedel–Crafts type reaction with the proto-
nated cyanoimine C – or a synthetic equivalent – acting as
key intermediate. Secondly, although protonated amines
are considered as deactivating – I groups, and direct meta
substitution, the proximity of both the reactive centers
constitute the driving force of that condensation.
Synlett 2002, No. 6, 895–898 ISSN 0936-5214 © Thieme Stuttgart · New York

898
R. Malassene et al.
LETTER
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of the data can be obtained free of charge on application to
The Director CCDC, 12 Union Road, Cambridge CB2 IEZ,
UK [fax: int. code+44(1221)336033, e-mail:
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t, J = 6.5 Hz), 2.95 (1 H, dm, J = 12.0 Hz), 3.12 (1 H, tm, J
= 12.0 Hz), 7.15–7.35 (5 H, m). 13 C NMR (50 MHz,
CDCl3): 17.34, 22.25, 23.16, 25.69, 26.20, 36.03, 38.13,
53.35, 61.52, 119.81, 120.64, 127.03, 127.52, 129.58,
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(25) A solution (20 mL, THF) of 6 (0.5 g, 1.87 mmol) was cooled
to –30 °C and treated dropwise (by syringe) with a 2 M
solution of LDA (0.94 mL, 1.87 mmol). The solution was
allowed to warm to –20 °C and maintained at that
temperature for 1 h, before being stirred at r.t. for 3 h. The
reaction mixture was quenched with water and extracted
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Synlett 2002, No. 6, 895–898 ISSN 0936-5214 © Thieme Stuttgart · New York