The synthesis and chemistry of 3-diazo-piperidin-2-one

Article abstract of DOI:10.1016/S0040-4020(02)00278-8

The efficient synthesis of 3-diazo-piperidin-2-one, from L-ornithine, in two steps is reported. The chemistry of this new cyclic α-diazoamide was explored and allows the rapid access to a wide range of 3-substituted piperidin-2-one derivatives.

Full text of DOI:10.1016/S0040-4020(02)00278-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3137±3143
The synthesis and chemistry of 3-diazo-piperidin-2-one
²
Ian S. Hutchinson, Stephen A. Matlin and Antonio Metep
Department of Chemistry, Warwick University, Coventry CV4 7AL, UK
Received 6 December 2001;accepted 8 March 2002
AbstractÐThe ef®cient synthesis of 3-diazo-piperidin-2-one, from l-ornithine, in two steps is reported. The chemistry of this new cyclic
a-diazoamide was explored and allows the rapid access to a wide range of 3-substituted piperidin-2-one derivatives. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
in excellent yield by dehydration over alumina in re¯uxing
toluene.4 Diazotisation of 4 was attempted under a variety of
conditions but it was found to occur most ef®ciently
by applying a modi®cation of the method described by
Takamura et al. for a-amino-esters.5 Thus, treatment of 4
with a slight excess of iso-amyl nitrite in chloroform with a
catalytic amount of acetic acid led to 3-diazo-piperdine-2-
one 2, an orange crystalline solid, isolated in 60% yield
(Scheme 1).
Diazo compounds are versatile chemical intermediates that
have found a wide range of useful applications in organic
synthesis.1 We recently introduced the nitromethylene
moiety as a new stabilizing group for diazo compounds
and reported on the chemistry of the new diazo derivative,
3-diazo-2-(nitromethylene)piperidine 1.2 As part of that
study, we required 3-diazo-piperidin-2-one 2 and were
surprised to ®nd that it was not known in the literature
(Fig. 1). In fact simple cyclic a-diazoamides, as a class,
have received only limited attention in the literature with
only a few examples being described.3
Optimisation of the reaction conditions established chloro-
form to be a better solvent than either DCM or benzene.
Compound 2 was found to be very sensitive to the acetic
acid used to catalyse the reaction. Thus, if more than
0.15 mol% of acetic acid, or reaction times greater than
15 min, were used then lower overall yields resulted. The
We now wish to report the synthesis of the novel cyclic
a-diazoamide 2 and describe some of its chemistry which
allows very rapid access to a wide range of 3-substituted
piperidin-2-ones.
2. Results
3-Amino-piperidin-2-one 4 was prepared from l-ornithine 3
Scheme 1. (a) Alumina, toluene, re¯ux, 1.5 h;(b) iso-amyl nitrite, CHCl3,
AcOH(cat), 15 min.
Figure 1.
Keywords: diazoamide;piperidin-2-one;carbene insertion;cyclopropana-
tion;ole®nation;pyrazoline.
Corresponding author. Present address: AstraZeneca R&D Charnwood,
p
Medicinal Chemistry, Bakewell Road, Loughborough LE11 5RH, UK.
Tel.: 144-1509644251;fax: 144-1509645507;
e-mail: antonio.mete@ astrazeneca.com
Present address: Department for International Development, 94 Victoria
Street, London SW1E 5JL, UK.
²
Scheme 2. (a) HCl, dioxane, re¯ux, 1 h;(b) ROH, Rh(II) acetate.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00278-8

3138
I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
Table 1. Metal-catalysed insertion of 2 into O±H bonds
Ra
Catalyst
Time (h) T (8C) Yield (%) Compound
Me
Me
Me
Et
Rh2(OAc)4
CuSO4
1
0.5
4
2
4
1
5
5
25
25
55
25
25
83
45
25
25
35
82
30
10
81
52
52
53
68
66
22
5b
5b
5b
5c
5d
5e
5f
5g
5h
5i
Cu(acac)2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
iso-Pr
tert-Bu
Bn
Phb
(p-Cl)Bnb Rh2(OAc)4
8
Rh2(OAc)4 10
Hc
a
Reactions carried out in the alcohol as solvent.
2 equiv. of alcohol used in DCM as solvent.
Water used in THF as solvent.
b
c
Scheme 4. (a) Methyl methacrylate, room temperature, 4 h;(b) dioxan,
re¯ux, 20 min;(c) methyl acrylate or methyl vinyl ketone or acrolein,
room temperature, 0.5 h;(d) 1,2-dichlorobenzene, re¯ux, 20 min.
product 2 was stable to puri®cation by silica gel chroma-
tography, was crystallised from cyclohexene and could be
stored at 08C for up to 6 months without signi®cant decom-
position. The structure of 2 was con®rmed by the usual
analytical methods. In particular, IR spectroscopy showed
a strong absorbance at 2088 cm21 for the diazo group and
CI-MS showed a molecular ion (M11ˆ126).
leading to 3-hydroxy-piperidin-2-one 5i in an isolated
yield of only 22%.
The rhodium-catalysed cyclopropanation of 2 with electron-
rich double bonds was found to proceed smoothly and in
good isolated yields, with both cyclic and acyclic enol
ethers (Scheme 3).
The scope and synthetic utility of the chemistry of this new
cyclic a-diazoamide was explored. The results of insertion
reactions into H±X bonds are summarised above (Scheme 2
and Table 1).
With ethyl vinyl ether, compound 6 was obtained in 66%
yield as a mixture of diastereomers, which proved insepar-
able by silica gel chromatography. However, the reaction
with dihydrofuran produced the single diastereisomer 7 in
45% yield. The relative stereochemistry of the product was
established by NMR spectroscopy using 2D COSY and nOe
experiments. For compound 7 no nOe was observed
between the protons at the 4 position of the piperidin-2-
one ring and the two protons of the cyclopropyl ring.
However, a nOe was observed between the protons at the
4 position of the piperidin-2-one and two of the tetrahydro-
furan protons. These observations are consistent with
the tetrahydrofuran ring being fused to the cyclopropyl
ring in a trans relationship to the amide bond. Formation
of this product can be rationalised on steric grounds. The
reaction of 2 with furan proceeds in an analogues fashion
with the single diastereoisomer 8 being isolated in 60%
yield.
As mentioned above, 2 was found to be very sensitive to
acetic acid;however, it reacted cleanly with hydrogen
chloride in dioxane to give 3-chloro-piperidin-2-one 5a in
68% yield.6 Rhodium-catalysed insertion into the O±H
bond of alcohols to give the 3-alkoxy-piperidin-2-ones
5b±h was found to proceed in yields ranging from 52±
82%.7 Catalysis of this reaction by copper(II) salts was
also investigated, but was found to afford only low yields
of the desired products. The results in Table 1 show that the
rhodium-catalysed reactions with methanol and ethanol are
both fast and ef®cient, whereas with the more sterically
hindered alcohols, the reactions require longer times and
give lower yields.8 Insertion into water was less ef®cient
It is known that the rhodium-catalysed reaction of furan with
diazo compounds can lead to dieneals resulting from ring
opening of the furan.9 The crude reaction mixture which led
to the formation of 8, was analysed by proton NMR spectro-
scopy. This did indeed detect the presence of two minor side
products bearing aldehyde protons. However, they made up
less than 10% of the reaction mixture and proved unstable to
puri®cation by silica gel chromatography and were not
isolated and characterised.
Table 2. 1,3-Dipolar additions of 2 to electron-de®cient ole®ns
R
R0 Product 9 (yield) Product 10 (yield) Product 11 (yield)
OMe Me 9a (67%)
11a (99%)
11b (75%)
OMe
Me
H
±
±
±
10b (95%)
10c (91%)
10d (69%)
Scheme 3. (a) Ethyl vinyl ether, Rh(II) acetate, room temperature, 1 h;
(b) dihydrofuran, Rh(II) acetate, room temperature, 12 h;(c) furan, Rh(II)
acetate, room temperature, 40 min.

I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
3139
3. Experimental
3.1. General
1H NMR spectra were recorded at 250 MHz (BruÈker
ACF250) or at 400 MHz (BruÈker WH400). 13C NMR
spectra were recorded at 61.42 MHz (BruÈker ACF250).
Mass spectra were recorded on a Kratos MS80 spectro-
meter. Chemical ionisation (CI) mass spectra used ammonia
or methane as reagent gas. Infra red were recorded on a
Perkin±Elmer 1720X Fourier transform spectrometer.
Column chromatography was performed using silica gel
60 (230±400 mesh, Merck).
Scheme 5. (a) X±Ph±CHO, MeReO3, P(Ph)3, THF, room temperature,
7±12 h.
3.1.1. 3-Amino-piperidin-2-one 4. l-Ornithine hydro-
chloride 3 (100 g, 0.59 mol) was added to a stirred solution
of sodium hydroxide pellets (23.8 g, 0.59 mol) in water
(100 ml) at 258C. After 15 min, this solution was added to
a stirred mixture of alumina (300 g) and toluene (1 l) and
heated under re¯ux for 1.5 h. The water produced during the
reaction was collected in a Dean±Stark trap. The reaction
mixture was allowed to cool and the alumina was ®ltered off
and washed with 10% MeOH/CH2C12 (300 ml). The ®ltrate
and washings were combined and the solvent removed
under vacuum to leave 4 as a white crystalline solid,
61.1 g (90%). Mp 35±378C;IR (nujol) nmax (cm21) 3340,
The 1,3-dipolar addition of 2 to electron-de®cient ole®ns
was found to be a very facile and high yielding process
(Scheme 4). The outcome of the reaction was the same
irrespective of whether a rhodium catalyst was present in
the reaction mixture.
The 1-pyrazoline 9a was isolated when methyl methacrylate
was reacted with 2. However, the 2-pyrazolines 10b±d were
isolated from the reaction of 2 with methyl acrylate, methyl
vinyl ketone and acrolein, respectively. Presumably 10b±d
are formed via 1-pyrazoline intermediates which undergo a
facile 1,3 H-transfer. The 1-pyrazoline 9a extruded nitrogen
on heating at 1108C to afford the cyclopropyl derivative 11a
in good yield. 2-Pyrazolines, generally require higher
temperatures to undergo this reaction, and indeed 10b
needed to be heated at 1808C to extrude nitrogen and form
the cyclopropane 11b (Table 2).10
1
3261, 3197, 1646, 1491, 1377, 1349, 1303, 999, 940; H
NMR (CDCl3, 400 MHz) d 7.0 (1H, bs, N±H), 3.2 (2H,
m, CH2N), 3.2 (1H, dd, Jˆ3.8, 3.9 Hz, CH±NH2), 1.5±2.1
(4H, m, CH2CH2), 1.75 (2H, bs, NH2);MS m/z (int) 115
(M11, 100), 99 (10), 70 (96), 58 (30), 42 (42). Anal. found:
C 52.51, H 8.66, N 24.25%;calcd for C 5H10N2O: C 52.63, H
8.77, N 24.56%.
Recently, the ole®nation reaction of diazo compounds with
aldehydes, catalysed by metals, has been described.11±13 We
investigated the reaction of 2 with both aromatic and alkyl
aldehydes catalysed by methyl trioxorhenium.11 The reac-
tion proceeds smoothly with aromatic aldehydes to form the
ole®ns as a ,3:1 (E/Z) mixture (Scheme 5). For 4-nitro-
benzaldehyde, the two geometric isomers could be sepa-
rated by chromatography to afford 12a and 13a in 15 and
46% isolated yield, respectively. The products using benz-
aldehyde, 12b and 13b, and 4-chlorobenzaldehyde, 12c and
13c, could not be separated by chromatography and were
isolated as mixtures in moderate combined yields of 30±
40%.14 This reaction failed or gave very low yields, in our
hands, when aliphatic aldehydes were used. Other, more
recently described catalysts have yet to be tried and may
well lead to better yields and stereo-control in this
reaction.12,13
3.1.2. 3-Diazo-piperidin-2-one 2. 3-Amino-piperidin-2-
one 4 (1.6 g, 14 mmol) was dissolved in chloroform
(30 ml). iso-Amyl nitrite (2.31 g, 18 mmol) and glacial
acetic acid (0.126 g, 2.1 mmol) were added with vigorous
stirring. The resulting solution was re¯uxed for 15 min,
cooled in ice and washed with an ice-cold saturated solution
of NaHCO3 (10 ml). The organic layer was separated, dried
over anhydrous Na2SO4 and the solvent removed under
vacuum. The red solid was puri®ed by column chroma-
tography (SiO2: 20% MeOH/CH2C12), crystallised from
cyclohexene to give 2 as bright orange needles, 1.07 g
(60%). Mp 117±1208C;IR (nujol) nmax (cm21) 3268,
1
3172, 2088 (CvN2), 1635, 1378, 1354, 1320; H NMR
(CDC13, 250 MHz) d 6.5 (1H, bs, N±H), 3.25 (2H, m,
CH2N), 2.7 (2H, t, Jˆ6.3 Hz, CH2), 1.9 (2H, m, CH2); 13C
NMR (CDCl3, 60 MHz) d 167 (CvO), 53 (CvN2), 41
(CH2N), 21 (CH2), 20 (CH2);MS m/z (int) 125 (M1, 85),
96 (12), 68 (90), 53 (41), 41 (100);CI-MS m/z 126 (M11).
Anal. found: C 47.96, H 5.66, N 33.28%;calcd for
C5H7N3O: C 48.00, H 5.60, N 33.60%.
In summary, 3-diazo-piperidin-2-one 2 has been synthesised
and is a new derivative in the rare class of cyclic a-diazo-
amides. It is a relatively stable diazo derivative which can
be easily handled and conveniently stored at 08C for long
periods. It undergoes a wide range of diazo group chemistry
in good to excellent yield and allows rapid access to a
number of novel and known 3-substituted piperidin-2-one
derivatives. It may prove to be a very versatile intermediate
for the synthesis of a wide range of nitrogen-containing
heterocycles and some of its applications towards such
goals are currently being explored.
3.1.3. 3-Chloro-piperidin-2-one 5a. 3-Diazo-piperidin-2-
one 2 (2 g, 0.016 mol) was dissolved in dry dioxan (5 ml)
and added dropwise with vigorous stirring to a solution of
4 M HCl in dioxan (50 ml). The yellow colour of the diazo
compound faded and after 1 h the solvent was removed
under vacuum to leave a pale yellow solid which was recrys-
tallised from diethyl ether to give 5a as a white crystalline
solid, 1.45 g (68%). Mp 116±1188C;IR (nujol) nmax (cm21
)

3140
I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
3255, 1648, 1378, 1327, 1177, 812; 1H NMR (CDCl3,
250 MHz) d 8.0 (1H, bs, N±H), 4.4 (1H, t, Jˆ4.95 Hz,
CH), 3.4 (2H, m, CH2N), 1.9±2.2 (4H, m, CH2CH2);MS
m/z (int) 135 (M1, 23), 133 (65), 97 (43), 84 (68), 82 (100),
68 (42), 62 (69), 58 (68), 55 (89), 43 (34), 41 (45);CIMS m/z
134 (M11). Anal. found: C 44.87, H 6.11, N 10.38, Cl
3.2.5. 3-Benzyloxy-piperidin-2-one 5f. White needles,
yield: 53%. Mp 88±918C;IR (nujol) nmax (cm21) 3272,
1661, 1496, 1454, 1334, 1102, 1028; H NMR (CDCl3,
400 MHz) d 7.2±7.4 (5H, m, Ph), 6.9 (1H, bs, N±H), 4.8
(2H, 2£d, Jˆ11.8 Hz, OCH2), 3.8 (1H, t, Jˆ6.5 Hz, OCH),
3.2±3.35 (2H, m, CH2N), 1.7±2.0 (4H, m, CH2CH2);MS m/
z (int) 99 (100), 91 (97), 84 (11), 71 (11), 51 (14), 43 (36), 41
(32);CI-MS m/z 206 (M11). Anal. found: C 70.51, H 7.38,
N 6.42%;calcd for C 12H15NO2: C 70.24, H 7.32, N 6.83%.
1
26.86%;calcd for C H8NOCl: C 44.94, H 5.99, N 10.49,
5
Cl 26.69%.
3.2. Procedure A. Rhodium-catalysed insertion into the
O±H bond of alcohols used as reaction solvent (Table 1)
3.3. Procedure B. Rhodium-catalysed insertion into the
O±H bond of alcohols with DCM as reaction solvent or
into O±H bond of water with THF as solvent (Table 1)
Rhodium(II) acetate (10 mg) was added to a stirred solution
of 3-diazo-piperidin-2-one 2 (2 mmol) in the alcohol
(15 ml) at 258C and the mixture left to stand for 1±4 h.
When the evolution of nitrogen had ceased, the solvent
was removed under vacuum and the residue dissolved in
CC14 (20 ml). The rhodium catalyst was ®ltered from the
solution, the solvent was removed under vacuum and the
residue crystallised from diethyl ether.
Rhodium(II) acetate (10 mg) was added to a stirred solution
of 3-diazo-piperidin-2-one 2 (2 mmol) and the alcohol (or
water) (10 mmol) in methylene chloride (or THF) (15 ml).
The solution was stirred at 25±458C for 5±10 h. The reac-
tion mixture was loaded onto a silica gel column and eluted
with CH2Cl2, to remove excess alcohol. The product was
isolated by elution with 20±50% MeCN/CH2C12 and
crystallised.
3.2.1. 3-Methoxy-piperidin-2-one 5b. White waxy solid,
yield: 82%. Mp 35±378C;IR (nujol) nmax (cm21) 3272,
1670, 1335, 1204, 1102; H NMR (CDCl3, 250 MHz) d
3.3.1. 3-Phenoxy-piperidin-2-one 5g. Crystallised from
acetone to give white needles, yield: 68%. Mp 156±
1588C;IR (nujol) nmax (cm21) 3286, 1665, 1635, 1334,
1
7.7 (1H, bs, N±H), 3.75 (1H, dd, Jˆ7.3, 4.9 Hz, OCH),
3.6 (3H, s, OCH3), 3.35 (2H, m, CH2N), 1.7±2.2 (4H, m,
CH2CH2);MS m/z (int) 99 (100), 70 (61), 58 (57), 43 (46),
41 (53);CI-MS m/z 130 (M11). Anal. found: C 55.89, H
8.74, N 10.64%;calcd for C H11NO2: C 55.81, H 8.53, N
6
10.85%.
1
1318, 1237, 1202, 1072; H NMR (CDCl3, 400 MHz) d
7.3 (2H, dd, Jˆ7.3, 8.7 Hz, arom), 7.1 (1H, bs, N±H), 7.0
(2H, dd, Jˆ8.7, 1 Hz, arom), 6.95 (1H, t, Jˆ7.3 Hz, arom),
4.7 (1H, dd, Jˆ5.3, 7.5 Hz, OCH), 3.25±3.4 (2H, m, CH2N),
1.8±2.2 (4H, m, CH2CH2);MS m/z (int) 191 (17), 98 (28),
94 (67), 77 (40), 70 (100), 55 (61), 51 (37), 43 (78), 41 (62);
CI-MS m/z 192 (M11). Anal. found: C 69.40, H 6.83, N
7.02%;calcd for C 11H13NO2: C 69.11, H 6.81, N 7.33%.
3.2.2. 3-Ethoxy-piperidin-2-one 5c. White solid, yield:
81%. Mp 57±598C;IR (nujol) nmax (cm21) 3198, 3083,
1680, 1336, 1312, 1116; H NMR (CDCl3, 250 MHz) d
1
6.2 (1H, bs, N±H), 3.8 (1H, dd, Jˆ4.8, 7.2 Hz, OCH),
3.65 (2H, q, Jˆ7 Hz, OCH2), 3.3 (2H, m, CH2N), 1.7±2.1
(4H, m, CH2CH2), 1.2 (3H, t, Jˆ7 Hz, CH3);MS m/z (int) 99
(100), 98 (72), 84 (13), 70 (57), 57 (21), 43 (18), 41 (13);CI-
MS m/z 144 (M11). Anal. found: C 58.74, H 9.32, N 9.57%;
calcd for C7H13NO2: C 58.74, H 9.09, N 9.79%.
3.3.2. 3-(p-Chlorobenzyloxy)-piperidin-2-one 5h. White
)
solid, yield: 66%. Mp 104±1068C;IR (nujol) nma1x (cm21
3191, 1674, 1467, 1377, 1309, 1183, 1109, 810; H NMR
(CDCl3, 250 MHz) d 7.3 (4H, m, Ph), 6.0 (1H, bs, N±H),
4.8 (2H, 2£d, Jˆ12.1 Hz, OCH2), 3.8 (1H, dd, Jˆ6.7, 5.0
Hz, OCH), 3.3 (2H, m, CH2N), 1.9±2.1 (4H, m, CH2CH2);
13C NMR (CDCl3, 60 MHz) d 172 (CvO), 138 (Cquat),
133 (C±Cl), 129 (Carom), 128 (Carom), 74 (CH), 72
(CH2O), 42 (CH2N), 28 (CH2), 19 (CH2);MS m/z (int)
125 (65), 99 (100), 98 (70), 89 (26), 84 (16), 71 (12), 43
(29), 41 (19);CI-MS m/z 240 (M11). Anal. found: C 60.48,
H 5.69, N 5.73%;calcd for C 12H14ClNO2: C 60.25, H 5.86,
N 5.86%.
3.2.3. 3-isoPropoxy-piperidin-2-one 5d. Pale yellow waxy
)
solid, yield: 52%. Mp 46±498C;IR (nujol) nmax (cm21
3202, 3079, 1669, 1495, 1375, 1322, 1312, 1268, 1146,
1
1089; H NMR (CDCl3, 220 MHz) d 7.1 (1H, bs, N±H),
4.1 (1H, septet, Jˆ7.8 Hz, CH(CH3)2), 3.9 (1H, dd, Jˆ6.8,
4.4 Hz, OCH), 3.35 (2H, m, CH2N), 1.7±2.1 (4H, m,
CH2CH2), 1.25 (6H, d, Jˆ7.8 Hz, CH(CH3)2);MS m/z
(int) 99 (62), 98 (27), 70 (30), 55 (35), 43 (100), 41 (35);
CI-MS m/z 158 (M11). Anal. found: C 61.54, H 9.64, N
3.3.3. 3-Hydroxy-piperidin-2-one 5i. White needles, yield:
22%. Mp 134±1368C;IR (nujol) nmax (cm21) 3308, 3206,
1652, 1456, 1319, 1261, 1118, 1096; H NMR (CDCl3,
1
8.53%;calcd for C H15NO2: C 61.15, H 9.55, N 8.92%.
9
250 MHz) d 6.7 (1H, bs, N±H), 4.1 (1H, dd, Jˆ6.3,
9.3 Hz, OCH), 4.0 (1H, bs, O±H), 3.3 (2H, m, CH2N),
1.6±2.3 (4H, m, CH2CH2);MS m/z (int) 99 (7), 87 (17),
57 (43), 55 (26), 44 (100), 43 (62), 41 (60);CI-MS m/z
116 (M11). Anal. found: C 52.6, H 8.1, N 12.6%;calcd
for C5H9NO2: requires C 52.17, H 7.83, N 12.17%.
3.2.4. 3-tert-Butoxy-piperidin-2-one 5e. Reaction carried
out at re¯ux to give a white crystalline solid, yield: 52%. Mp
105±1108C;IR (nujol) nmax cm21 3202, 3085, 1675, 1366,
1328, 1178, 1108, 1025; 1H NMR (CDCl3, 220 MHz) d 6.7
(1H, bs, N±H), 3.95 (1H, dd, Jˆ6.3, 5.9 Hz, OCH), 3.3
(2H, m, CH2N), 1.6±2.0 (4H, m, CH2CH2), 1.25 (9H, s,
C(CH3)3);MS m/z (int) 156 (30), 143 (19), 116 (100), 98
(40), 71 (42), 57 (90), 41 (32);CI-MS m/z 172 (M11). Anal.
3.3.4. 5-Aza-1-ethoxy-4-oxo-spiro[2.5]octane 6. A solu-
tion of 3-diazo-piperidin-2-one 2 (0.2 g, 1.6 mmol) in
ethyl vinyl ether (20 ml) was treated with rhodium(II)
acetate (10 mg). The reaction was stirred at 258C for 1 h,
found: C 63.41, H 9.96, N 8.02%;calcd for C H17NO2: C
9
63.16, H 9.94, N 8.19%.

I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
3141
then the solvent was removed under vacuum and the residue
was puri®ed by silica gel column chromatography eluted
with acetonitrile to give the product as a white crystalline
turned colourless, the solvent was removed under vacuum
and the residue recrystallised from diethyl ether/pentane to
give white needles, 2.3 g (67%). Mp 94±978C;IR (nujol)
nmax (cm21) 3198, 3058, 1733, 1658, 1445, 1373, 1346,
solid 0.18 g (66%). Mp 106±1088C;IR (nujol) nmax (cm21
)
1
1
3182, 1660, 1435, 1336, 1194, 1129, 1082, 821; H NMR
(CDCl3, 250 MHz) d 6.8 (1H, bs, N±H), 3.65 (1H, dd, Jˆ
4.4, 7 Hz, CH±O), 3.6 (2H, q, Jˆ7 Hz, OCH2), 3.4 (2H, m,
CH2N), 1.8±2.0 (4H, m, CH2CH2), 1.5 (1H, t, Jˆ7 Hz, CH),
1.2 (3H, t, Jˆ7 Hz, CH3), 0.7 (1H, t, Jˆ4.4 Hz, CH); 13C
NMR (CDCl3, 60 MHz) d 174 (CvO), 67 (OCH2), 64
(OCH), 42 (CH2N), 25 (Cspiro), 24 (CH2), 23 (CH2), 21
(CH2), 15 (CH3);MS m/z (int) 169 (M1, 8), 140 (100),
112 (72), 84 (16), 77 (9), 69 (31), 55 (19), 41 (56);CI-MS
m/z 170 (M11). Anal. found: C 64.11, H 9.03, N 8.32%;
calcd for C9H15NO2: C 63.88, H 8.93, N 8.28%.
1302, 1274, 1170, 1143, 840; H NMR (CDCl3, 250 MHz)
d 7.0 (1H, bs, N±H), 3.8 (3H, s, OCH3), 3.3±3.5 (2H, m,
CH2N), 1.8±2.2 (4H, m, CH2CH2), 2.05 (1H, d, Jˆ12.9 Hz,
CH2), 1.9 (1H, d, Jˆ12.9 Hz, CH2), 1.5 (3H, s, CH3); 13C
NMR (CDCl3, 60 MHz) d 171 (CvO), 169 (CvO), 98
(Cquat), 98 (Cspiro), 53 (OCH3), 43 (CH2N), 38 (CH2), 33
(CH2), 23 (CH3), 20 (CH2);MS m/z (int) 197 (M228, 31),
165 (46), 137 (100), 109 (24), 79 (16), 67 (20), 41 (20);
CI-MS m/z 198 (M22811). Anal. found: C 53.39, H 6.75,
N 18.46%;calcd for C 10H15N3O3: C 53.33, H 6.66, N 18.67%.
3.3.8. 1,2,7-Triaza-3-methoxycarbonyl-6-oxo-spiro[4.5]-
dec-2-ene 10b. 3-Diazo-piperidin-2-one 2 (1 g, 8 mmol)
was dissolved in methyl acrylate (50 ml) and stirred at
258C for 30 min. The product crystallised out of the reaction
mixture, was ®ltered and washed with chloroform (15 ml) to
afford a white solid, 1.6 g (95%). Mp 160±1618C;IR (nujol)
nmax (cm21) 3212, 3046, 1730, 1644, 1581, 1493, 1342,
3.3.5. 30-Aza-2-oxa-20-oxo-spiro[bicyclo[3.1.0]hexane-
6,l0-cyclohexane] 7. Rhodium(II) acetate (10 mg) was
added to a solution of 3-diazo-piperidin-2-one 2 (0.25 g,
2 mmol) in dihydrofuran (10 ml) and the reaction was
stirred for 12 h at 258C. The solvent was then removed
under vacuum and the residue was passed down a silica
gel column eluted with 5% hexane/THF to afford the
product. This was recrystallised from diethyl ether/pentane
to give a white crystalline solid 0.15 g (45%). Mp 135±
1408C;IR (nujol) nmax (cm21) 3228, 3187, 1651, 1485,
1
1328, 1285, 1261, 1138, 1099, 789; H NMR (DMSO-d6,
250 MHz) d 8.8 (1H, bs, N±H), 7.7 (1H, bs, N±H), 3.7 (3H,
s, OCH3), 3.3 (1H, d, Jˆ16.8 Hz, CH2), 3.2 (2H, m, CH2N),
2.65 (1H, d, Jˆ16.8 Hz, CH2), 1.6±1.9 (4H, m, CH2CH2);
13C NMR (DMSO-d6, 60 MHz) d 171 (CvO), 163 (CvO),
136 (CvN), 68 (Cspiro), 51 (OCH3), 41 (CH2N), 41 (CH2),
34 (CH2), 19 (CH2);MS m/z (int) 183 (M228, 34), 153 (100),
140 (78), 121 (92), 108 (78), 96 (35), 81 (32), 43 (42);CI-MS
m/z 212 (M11). Anal. found: C 51.00, H 6.24, N 19.72%;
calcd for C9H13N3O3: C 51.18, H 6.20, N 19.89%.
1
1417, 1366, 1335, 1253, 1148, 1122, 1096, 1048, 820; H
NMR (CDCl3, 400 MHz) d 6.0 (1H, bs, N±H), 4.2 (1H, dd,
Jˆ8.4, 18 Hz, OCH), 4.1 (1H, d, Jˆ6 Hz, CH), 3.9 (1H, dt,
Jˆ8.9, 4.4 Hz, OCH), 3.35 (2H, m, CH2N), 2.45 (1H, dd,
Jˆ1.24, 7.3 Hz, OCH), 2.25 (1H, m, CH), 1.8±2.0 (3H, m,
CH2, CH), 1.65 (2H, m, CH2); 13C NMR (CDCl3, 60 MHz)
d 172 (CvO), 75 (OCH2), 69 (OCH), 42 (CH2N), 30
(Cspiro), 29 (CH), 24 (CH2), 22 (CH2), 19 (CH2);MS m/z
(int) 167 (M1, 47), 152 (14), 138 (28), 124 (19), 110 (42),
83 (100), 67 (28), 41 (35);CI-MS 168 (M 11). Anal. found:
C 64.52, H 7.93, N 8.14%;calcd for C 9H13NO2: C 64.67, H
7.78, N 8.38%.
3.3.9. 1,2,7-Triaza-3-methylcarbonyl-6-oxo-spiro[4.5]-
dec-2-ene 10c. 3-Diazo-piperidin-2-one 2 (0.11 g, 0.88
mmol) was dissolved in DCM (2 ml) and added, with
stirring, to methyl vinyl ketone (10 ml) at 258C. After
30 min the product crystallised from the reaction mixture,
was ®ltered and washed with methylene chloride (5 ml) to
give white crystals, 0.157 g (91%). Mp 200±2018C;IR
(nujol) nmax (cm21) 3227, 1659, 1634, 1557, 1429, 1385,
3.3.6. 30-Aza-2-oxa-20-oxo-spiro[bicyclo[3.1.0]hexane-
6,10-cylohex-3-ene] 8. Rhodium(II) acetate (15 mg) was
added to a solution of 3-diazo-piperidin-2-one 2 (0.27 g,
2.1 mmol) in furan (25 ml). The reaction mixture was stirred
at 258C for 40 min and then the solvent removed under
vacuum. The residue was puri®ed by silica gel column
chromatography eluted with 5% IPA/MeCN to afford the
product as an orange crystalline solid 0.25 g (60%). Mp
1328C dec;IR (nujol) nmax (cm21) 3183, 3037, 1643,
1594, 1488, 1421, 1332, 1257, 1146, 960; 1H NMR
(CDCl3, 250 MHz) d 6.9 (1H, bs, N±H), 6.4 (1H, d, Jˆ
2.5 Hz, OCH), 5.2 (1H, t, Jˆ2.6 Hz, CH), 4.8 (1H, d, Jˆ
5.7 Hz, OCH), 3.35 (2H, m, CH2N), 2.9 (1H, dd, Jˆ5.7,
2.7 Hz, CH), 1.8 (2H, m, CH2), 1.4 (2H, m, CH2); 13C
NMR (CDCl3, 60 MHz) d 174 (CvO), 148 (OCH), 102
(CvCH), 71 (OCH), 42 (CH2N), 36 (CH), 22 (CH2), 17
(CH2), 16 (Cspiro);CI-MS m/z 166 (M11). Anal. found:
C 65.61, H 6.63, N 8.24%;calcd for C 9H11NO2: C 65.43, H
6.71, N 8.48%.
1
1342, 1286, 1256, 1103, 996, 632; H NMR (DMSO-d6,
250 MHz) d 9.1 (1H, bs, N±H), 7.7 (1H, bs, N±H), 3.2
(2H, m, CH2N), 3.18 (1H, d, Jˆ16.7 Hz, CH2), 2.55 (1H,
d, Jˆ16.7 Hz, CH2), 2.25 (3H, s, CH3), 1.75±1.9 (4H, m,
CH2CH2); 13C NMR (DMSO-d6, 60 MHz) d 193 (CvO),
171 (CvO), 145 (CvN), 68 (Cspiro), 41 (CH2N), 40
(CH2), 32 (CH2), 25 (CH3), 19 (CH2);MS m/z (int) 137
(82), 124 (65), 78 (82), 63 (100), 43 (49);CI-MS m/z 196
(M11). Anal. found: C 55.35, H 6.64, N 21.48%;calcd for
C9H13N3O2: C 55.38, H 6.67, N 21.54%.
3.3.10. 1,2,7-Triaza-3-formyl-6-oxo-spiro[4.5]dec-2-ene
10d. 3-Diazo-piperidin-2-one 2 (0.19 g, 1.52 mmol) was
dissolved in acrolein (10 ml) and stirred for 20 min at
258C. The product crystallised from the reaction mixture,
was ®ltered and washed with chloroform (5 ml) to give a
white crystalline solid, 0.19 g (69%). Mp 178±1828C;IR
(nujol) nmax (cm21) 3164, 1668, 1550, 1491, 1343, 1284,
1246, 1127, 1114, 1003, 850; 1H NMR (DMSO-d6,
250 MHz) d 9.8 (1H, bs, N±H), 9.5 (1H, s, CHO) 7.8
(1H, bs, N±H), 3.2 (2H, m, CH2N), 3.15 (1H, d, Jˆ
16.7 Hz, CH2), 2.65 (1H, d, Jˆ16.7 Hz, CH2), 1.6±1.9
3.3.7. 1,2,7-Triaza-3-methoxycarbonyl-3-methyl-6-oxo-
spiro[4.5]dec-1-ene 9a. 3-Diazo-piperidin-2-one 2 (1.9 g,
15.2 mmol) was dissolved in methyl methacrylate (20 ml)
and stirred for 4 h at 258C. When the yellow solution had

3142
I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
(4H, m, CH2CH2); 13C NMR (DMSO-d6, 60 MHz) d 185
(CvO), 170 (CvO), 146 (CvN), 69 (Cspiro), 41
(CH2N), 38 (CH2), 34 (CH2), 19 (CH2);FAB-MS m/z (int)
182 (M11, 94), 154 (20), 93 (100), 75 (41), 44 (36). Anal.
found: C 52.89, H 6.15, N 22.98%;calcd for C 8H11N3O2: C
53.04, H 6.08, N 23.20%.
(CDCl3, 60 MHz) d 165 (CvO), 146 (C±NO2), 143
(Carom), 134 (Carom), 133 (Carom), 129 (CvC), 122
(CvC), 42 (CH2), 32 (CH2), 23 (CH2);MS m/z (int) 232
(M1, 52), 231 (98), 185 (27), 128 (17), 97 (25), 85 (46), 71
(57), 57 (100), 43 (69);CI-MS m/z 233 (M11). Anal. found:
C 61.90, H 5.33, N 11.89%;calcd for C 12H12N2O3: C 62.06,
H 5.21, N 12.06%.
3.3.11. 5-Aza-1-methoxycarbonyl-1-methyl-4-oxo-spiro-
[2.5] octane 11a. 1,2,7-Triaza-3-methoxycarbonyl-3-methyl-
6-oxo-spiro[4.5]dec-1-ene 9a (2.25 g, 0.01 mol) was dis-
solved in dioxan (70 ml) and heated under re¯ux for
20 min. The solvent was removed under vacuum and the
residue recrystallised from diethyl ether/pentane to give
the product as white needles, 1.95 g (99%). Mp 112±
1138C;IR (nujol) nmax (cm21) 3193, 3077, 1715, 1669,
1457, 1445, 1315, 1298, 1148, 848; 1H NMR (CDCl3,
250 MHz) d 7.2 (1H, bs, N±H), 3.7 (3H, s, OCH3), 3.35
(2H, m, CH2N), 1.7±2.0 (4H, m, CH2CH2), 1.6 (1H, d,
Jˆ4.8 Hz, CH2), 1.45 (1H, d, Jˆ4.8 Hz, CH2), 1.4 (3H, s,
CH3); 13C NMR (CDCl3, 60 MHz) d 173 (CvO), 171
(CvO), 52 (OCH3), 41 (CH2N), 33 (Cspiro), 32 (Cquat),
26 (CH2), 22 (CH2), 20 (CH2), 15 (CH3);MS m/z (int) 197
(M1, 24), 165 (38), 137 (84), 98 (18), 79 (18), 57 (36), 41
(29);CI-MS m/z 198 (M11). Anal. found: C 60.80, H 7.60,
N 6.95%;calcd for C 10H15NO3: C 60.91, H 7.61, N 7.11%.
The second compound eluted off the column was the
(E)-isomer of the title compound 13a, which was isolated
as a pale yellow solid, 0.215 g (46%). Mp 125±1268C;IR
(nujol) nmax (cm21) 3382, 3190, 1668, 1622, 1510, 1421,
1340, 1107, 993; 1H NMR (CDCl3, 250 MHz) d 8.2 (2H, d,
Jˆ8.55 Hz, H arom), 7.8 (1H, s, vCH), 7.5 (2H, d, Jˆ
8.55 Hz, H arom), 6.3 (1H, bs, N±H), 3.4 (2H, m, CH2N),
2.8 (2H, m, CH2), 1.9 (2H, m, CH2);MS m/z (int) 232 (M1,
40), 231 (80), 202 (19), 185 (23), 97 (30), 71 (62), 43 (81);
CI-MS m/z 233 (M11). Anal. found: C 61.72, H 5.20, N
11.82%;calcd for C 12H12N2O3: C 62.06, H 5.21, N 12.06%.
3.3.14. 3-Benzylidene-piperidin-2-one 12b and 13b.
3-Diazo-piperidin-2-one 2 (0.25 g, 2 mmol) was dissolved
in THF (15 ml) and added dropwise to a solution of benz-
aldehyde (0.212 g, 2 mmol), triphenylphosphine (0.52 g,
2 mmol) and methyl trioxorhenium (15 mg, 3 mol%) in
THF (20 ml). The reaction mixture was stirred at room
temperature for 12 h and then the solvent removed under
vacuum. The residue was puri®ed by preparative tlc (SiO2:
50% MeCN/CHC13) to afford the product as a mixture of
(E) and (Z) isomers as a pale yellow waxy solid, 0.13 g
(34%). Mp 71±758C;IR (nujol) nmax (cm21) 3270, 3182,
1668, 1635, 1461, 1414, 1321, 1109, 909; 1H NMR (CDCl3,
250 MHz) d 7.2±7.8 (6H, m, 5H arom, vCH), 6.3 (1H, bs,
N±H), 3.2 (2H, m, CH2N), 2.72 (2H, t, Jˆ6.4 Hz, CH2),
1.85 (2H, m, CH2);MS m/z (int) 187 (M1, 13), 97 (54),
83 (46), 68 (83), 41 (89);CI-MS m/z 188 (M11). Anal.
found: C 77.30, H 6.87, N 7.30%;calcd for C 12H13NO: C
77.01, H 6.95, N 7.49%.
3.3.12. 5-Aza-1-methoxycarbonyl-4-oxo-spiro[2.5]octane
11b. 1,2,7-Triaza-3-methoxycarbonyl-6-oxo-spiro[4.5]dec-
2-ene 10b (0.2 g, 0.95 mmol) was suspended in dichloro-
benzene (5 ml) and heated under re¯ux for 20 min. Most of
the solvent was removed under vacuum and the remaining
oil subjected to silica gel column chromatography eluted
with 25% MeOH/DCM to give the product as an off-white
solid, 0.13 g (75%). Mp 70±728C;IR (nujol) nmax (cm21
)
3191, 3050, l737, 1657, 1493, 1381, 1356, 1335, 1203,
1
1177, 953; H NMR (CDCl3, 250 MHz) d 6.7 (1H, bs,
N±H), 3.7 (3H, s, OCH3), 3.35 (2H, m, CH2N), 2.4 (1H,
dd, Jˆ6.7, 8.7 Hz, CH), 1.8±2.0 (4H, m, CH2CH2), 1.6 (1H,
dd, Jˆ3.8, 8.7 Hz, CH2), 1.2 (1H, dd, Jˆ3.8, 6.7 Hz, CH2);
13C NMR (CDCl3, 60 MHz) d 171 (CvO), 171 (CvO), 52
(OCH3), 43 (CH2N), 29 (Cspiro), 27 (CH), 25 (CH2), 22
(CH2), 21 (CH2);MS m/z (int) 183 (M1, 18), 151 (36), 123
(100), 96 (25), 83 (44), 67 (16), 41 (25);CI-MS m/z 184
(M11). Anal. found: C 59.41, H 7.20, N 7.51%;calcd for
C9H13NO3: C 59.02, H 7.10, N 7.65%.
3.3.15. 3-(4-Chloro-benzylidene)-piperidin-2-one 12c
and 13c. 3-Diazo-piperidin-2-one 2 (0.25 g, 2 mmol) was
dissolved in THF (15 ml) and added dropwise to a solution
of 4-chlorobenzaldehyde (0.3 g, 2 mmol), triphenylphos-
phine (0.52 g, 2 mmol) and methyl trioxorhenium (25 mg,
5 mol%) in THF (20 ml). The reaction mixture was stirred at
room temperature for 10 h and the solvent removed under
vacuum. The residue was puri®ed by preparative tlc (SiO2:
20% CHCl3/MeCN) to afford the title compound, a mixture
of (E) and (Z) isomers, as a pale yellow waxy solid, 0.17 g
(38%). Mp 58±608C;IR (nujol) nmax (cm21) 3185, 1670,
1630, 1481, 1439, 1321, 1222, 1109, 910; 1H NMR (CDCl3,
250 MHz) d 7.7 (2H, d, Jˆ8.5 Hz, H arom), 7.5 (2H, d,
Jˆ8.5 Hz, H arom), 7.2 (1H, s, vCH), 6.3 (1H, bs,
N±H), 3.3 (2H, m, CH2N), 2.6 (2H, t, Jˆ6.2 Hz, CH2),
1.9 (2H, m, CH2);MS m/z (int) 222 (M1, 12), 186 (15),
158 (11), 125 (82), 97 (68), 68 (15), 43 (9);CI-MS m/z 223
(M11). Anal. found: C 65.21, H 5.42, N 5.99%;calcd for
C12H12ClNO: C 65.01, H 5.45, N 6.32%.
3.3.13. 3-(4-Nitro-benzylidene)-piperidin-2-one 12a and
13a. 3-Diazo-piperidin-2-one 2 (0.25 g, 2 mmol) was dis-
solved in THF (15 ml) and added dropwise to a solution of
4-nitrobenzaldehyde (0.3 g, 2 mmol), triphenylphosphine
(0.52 g, 2 mmol) and methyl trioxorhenium (18 mg, 3.6
mol%) in THF (20 ml). The reaction mixture was stirred
at room temperature for 7 h and then the solvent removed
under vacuum. The residue was passed down a silica gel
column eluted with 50% MeCN/DCM. The ®rst compound
eluted off the column was the (Z)-isomer of the title
compound 12a, isolated as a pale yellow crystalline solid,
0.072 g (15.5%). Mp 120±1228C;IR (nujol) nmax (cm21
)
3199, 1669, 1632, 1513, 1463, 1421, 1343, 1312, 1107;
1H NMR (CDCl3, 250 MHz) d 8.1 (2H, d, Jˆ8.6 Hz, H
arom), 7.55 (2H, d, Jˆ8.6 Hz, H arom), 6.7 (1H, s,
vCH), 6.4 (1H, bs, N±H), 3.4 (2H, t, Jˆ5.95 Hz, CH2N),
2.65 (2H, t, Jˆ6.3 Hz, CH2), 2.0 (2H, m, CH2); 13C NMR
Acknowledgements
We would like to thank EPRSC for ®nancial support (I. S. H).

I. S. Hutchinson et al. / Tetrahedron 58 (2002) 3137±3143
3143
7. Miller, D. J.;Moody, C. J. Tetrahedron 1995, 51, 10811±
10843.
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