The synthesis of 3-diazo-2-nitromethylenepiperidine

Article abstract of DOI:10.1016/S0040-4039(00)02323-6

The synthesis of 3-diazo-2-nitromethylenepiperidine, in six steps from 2-piperidone, is reported. This is the first compound described which contains the 3-diazo-1-nitropropene function. The title compound is stable enough to be isolated and characterised in gram quantities using standard organic chemistry techniques and was used to prepare some 5-aza-spiro[2.5]octane and 4,5,6,7-tetrahydro-1H-pyrazolo-[4,3-b]pyridine derivatives.

Full text of DOI:10.1016/S0040-4039(00)02323-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1773–1776
The synthesis of 3-diazo-2-nitromethylenepiperidine
Ian S. Hutchinson, Stephen A. Matlin† and Antonio Mete*
Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
Received 11 December 2000; accepted 19 December 2000
Abstract—The synthesis of 3-diazo-2-nitromethylenepiperidine, in six steps from 2-piperidone, is reported. This is the first
compound described which contains the 3-diazo-1-nitropropene function. The title compound is stable enough to be isolated and
characterised in gram quantities using standard organic chemistry techniques and was used to prepare some 5-aza-spiro[2.5]octane
and 4,5,6,7-tetrahydro-1H-pyrazolo-[4,3-b]pyridine derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
Diazo compounds are of great utility in organic synthe-
sis. In general, the most widely used are the more stable
derivatives. These are stabilised by possessing one or
more electron-withdrawing groups adjacent to the
diazo function. The electron-withdrawing groups most
commonly encountered include ketones, carboxylic
acids, esters and amides.1 We were interested in estab-
lishing if any other electron-withdrawing functions
could be used to afford stable diazo-containing com-
pounds. We chose to investigate the nitroethylene
group as it is found in a number of important bioactive
molecules such as histamine H2-antagonists2 and
nitromethylene insecticides.3 In this paper we describe
the preparation and some chemical reactions of 3-
diazo-2-nitromethylenepiperidine 1, the first reported
compound to possess a diazo function stabilised by a
nitroethylene group. Additionally we report the novel
transformation of a dibromomethylene group to a
hydrazone in one step.
The synthetic route to 1 is outlined in Scheme 1.
2-Piperidone 2 was heated in dimethyl sulphate at 55°C
to afford 2-methoxy-3,4,5,6-tetrahydropyridine 3 in
88% yield. Reaction of 3 with nitromethane at 100°C
for 18 h (with continual removal of the methanol
produced
by
distillation),
gave
the
2-
nitromethylenepiperidine 4 in 57% yield.4 Treatment of
4 with NBS in carbon tetrachloride at reflux led to the
Scheme 1. (a) Me2SO4, 55°C, 20 h; (b) MeNO2, 100°C, 18 h; (c) NBS, CCl4, rt, 2 h, then reflux, 1 h; (d) NBS, CCl4, rt, 2 h then
reflux, 1 h; (e) NH2NH2·H2O, EtOH, rt, 20 h; (f) HgO, KOH (cat), CHCl3, −5°C, 10 min.
* Corresponding author. Present address: AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, LE11 5RH, UK.
Tel.:+44(0)1509644251; fax:+44(0)1509645507; e-mail: antonio.mete@astrazeneca.com
Present address: Director, Human Resource Development Division, Commonwealth Secretariat, Marlborough House, Pall Mall, London SW1Y
†
5HX, UK.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02323-6

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I. S. Hutchinson et al. / Tetrahedron Letters 42 (2001) 1773–1776
formation of 3-bromo-2-nitromethylenepiperidine 5 in
81% yield from 4. This compound could be converted
to the hydrazone 7 by treatment with four equivalents
of hydrazine. However we obtained a yield of only ca.
10% which was too low to make it an attractive step in
the route to our target 1. This reaction is analogous to
that reported by Hauptmann et al. for a-bromoke-
tones.5 The monobromo derivative 5 was subjected for
a second time to the bromination protocol described
above to afford 3,3-dibromo-2-nitromethylenepipe-
ridine 6 in 71% yield. Treatment of 6 with four equiva-
lents of hydrazine in ethanol at 25°C for 20 h led to
spectrum of the 8a and 8b mixture had no peak for a
diazo group. The 1H NMR (CDCl3) had no vinylic
proton resonance and one N-H proton signal at l 5.0
indicating it was not intramolecularly H bonded to the
nitro group (as is observed for compounds 1 and 4–7
and confirmed in X-ray studies of 4 which show that
the nitro group is cis to the ring nitrogen).7 Addition-
ally a very broad N-H proton was observed at l
1
11.5–14.0 for the pyrazole N-H. When the H NMR
spectrum was run in DMSO-d6 both the N-H signals
became sharper and each separated into two distinct
peaks. These peaks coalesced at 80°C indicating 8a and
8b are two compounds in equilibrium.
3-hydrazono-2-nitromethylenepiperidine
7
in 37%
yield.6 Oxidation of 7 with yellow mercuric oxide at
−5°C in the presence of a catalytic amount of KOH led
to the rapid formation of the 3-diazo-2-nitromethylene-
piperidine 1 in 74% isolated yield.
The isomerisation of 1 to 8a and 8b has not precluded
the study of some of the chemistry of this new diazo
derivative (Scheme 3). Thus 1 was found to undergo
smooth 1,3-dipolar addition to methyl acrylate to
afford the spirocyclic pyrazoline 9 in 60% yield. This
pyrazoline was found to extrude nitrogen when heated
in 1,2-dichlorobenzene at 180°C for 15 min to give a 3:1
mixture of the 5-aza-spiro[2.5]octane derivatives 10 and
11 in a combined yield of ca. 65% which were separable
Compound 1 was stable to purification by flash chro-
matography and was a yellow crystalline solid which
could be stored in a freezer at −20 to −30°C for up to
6 months without significant decomposition.6 At ambi-
ent temperature it was stable enough for all the usual
analytical characterisation to be performed, to confirm
its structure. In particular CI-MS afforded a molecular
ion (M+1=169) and a characteristic M−28 peak at 141
(for loss of N2) and the IR spectrum showed a strong
absorbance at 2070 cm−1 for the diazo group.
by
silica
gel
chromatography.6
The
5-aza-
spiro[2.5]octane system has received limited attention in
the literature to date, with only a few simple derivatives
having been described in some recent patents.8
Carbene insertion reactions have only been briefly
explored so far. Thus rhodium(II) acetate decomposi-
tion of 1 in methanol leads to the expected insertion
product 12 albeit in only 15% yield.9 A major side
product in this reaction was found to be the ketone 13.
The mechanism of formation of this ketone has yet to
be established. However, when 1 was decomposed in a
variety of solvents which could act as oxygen donors
(e.g. DMSO, acetone, nitrobenzene) the ketone deriva-
tive 13 was the main product isolated in yields ranging
from 54 to 70%. The reaction of 1 with ethyl vinyl ether
in the presence of rhodium(II) acetate failed to give the
expected cyclopropyl product but yielded only ketone
13 in ca. 30% yield.
Additional proof of the structure of 1 was provided by
the observation that a solution of 1 in chloroform
underwent a slow rearrangement to a tautomeric mix-
ture of the 4,5,6,7-tetrahydro-pyrazolo-[4,3-b]pyridine
derivatives 8a and 8b in quantitative yield.6 Scheme 2
outlines a possible mechanism for the rearrangement,
which was complete after 36
h at 25°C. This
intramolecular reaction was not unexpected as in
molecule 1 the nucleophilic end of the nitroenamine
function is favourably positioned to react with the
electrophilic end of the diazo group. The structures of
8a and 8b were deduced from CI-MS which gave the
same molecular ion (M+1=169) as for the diazo com-
pound 1, but no peak at 141 for loss of N2. The IR
Scheme 2. (a) CHCl3, rt, 36 h.

I. S. Hutchinson et al. / Tetrahedron Letters 42 (2001) 1773–1776
1775
Scheme 3. (a) Methyl acrylate, 25°C, 5 h; (b) 1,2-dichlorobenzene, 180°C, 15 min; (c) Rh(II) acetate, MeOH, rt, 30 min; (d) Rh(II)
acetate, DMSO, rt, 30 min.
Further details of these and other chemical reactions of
this novel class of diazo derivative will be described in
future papers.
m), 2.3 (2H, t, J=6.9 Hz), 1.7–1.8 (2H, m); 13C NMR
(DMSO-d6, 60 MHz) l 154, 130, 103, 40, 21, 19; CIMS
m/z 171(M+1); anal. found: C, 42.2; H 5.9; N, 32.2% calcd
for C6H10N4O2: C, 42.4; H, 5.9; N, 32.9%. Compound 1:
orange-red solid; mp 105–107°C; IR (CHCl3) wmax 3200,
3140, 2070, 1580, 1390, 1365, 1166, 1094, 970, 880 cm−1
;
Acknowledgements
1H NMR (CDCl3, 300 MHz) l 10.4 (1H, bs), 6.6 (1H, s),
3.4 (2H, m), 2.75 (2H, t, J=6.3 Hz), 2.0 (2H, m); CIMS
(NH3) m/z 186 (M+18), 169 (M+1), 158, 141 (M−28); anal.
found: C, 42.98; H, 4.79; N, 32.95% calcd for C6H8N4O2:
C, 42.86; H, 4.76; N, 33.33%. Compound 8 (mixture of 8a
and 8b): red solid; mp 142–146°C; IR (Nujol) wmax 3182,
We would like to thank EPSRC for financial support
(I.S.H.).
1
3095, 1609, 1495, 1456, 1375, 1337, 1321, 1230, 1186; H
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1161 cm−1; H NMR (CDCl3, 400 MHz) l 10.9 (1H, bs),
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1
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1.95 (1H, dd, J=6.2, 8.1), 1.75 (1H, t, J=6.2), 1.27 (1H,
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1776
I. S. Hutchinson et al. / Tetrahedron Letters 42 (2001) 1773–1776
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