Facile synthesis of α,α′ disubstituted N-hydroxypyrrolidines and N-hydroxypiperidines via double 1,4-addition of hydroxylamine

Article abstract of DOI:10.1016/j.tetlet.2006.03.064

A versatile synthesis of α and α′ disubstituted N-hydroxypiperidine and N-hydroxypyrrolidine by consecutive double 1,4-addition of hydroxylamine on the corresponding bis α,β-unsaturated diester is described. This reaction takes place an environmentally friendly (ethanol/water) system and at room temperature.

Full text of DOI:10.1016/j.tetlet.2006.03.064

Tetrahedron Letters 47 (2006) 3191–3193
Facile synthesis of a,a0 disubstituted N-hydroxypyrrolidines and
N-hydroxypiperidines via double 1,4-addition of hydroxylamine
*
´ ´
Frederic C. Bargiggia and William V. Murray
Johnson & Johnson Pharmaceutical Research and Development L.L.C., 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA
Received 27 February 2006; revised 8 March 2006; accepted 9 March 2006
Available online 29 March 2006
Abstract—A versatile synthesis of a and a0 disubstituted N-hydroxypiperidine and N-hydroxypyrrolidine by consecutive double 1,4-
addition of hydroxylamine on the corresponding bis a,b-unsaturated diester is described. This reaction takes place an environmen-
tally friendly (ethanol/water) system and at room temperature.
Ó 2006 Elsevier Ltd. All rights reserved.
N-Hydroxypiperidines and N-hydroxypyrrolidines are
commonly used intermediates in organic synthesis.1
There are several reports of the Michael addition of
hydroxylamine to a,b-unsaturated carboxylate.2,3 Diaz
and co-workers have shown that hydroxylamine can
simultaneously add to an a,b and a0,b0 bis unsaturated
ketones to afford the corresponding N-hydroxypiperi-
dine.4a Yamamura and Otto reported that 1,4-thiazin-
anes can be generated by double 1,4-addition to a
2,4-bis(methoxycarbonyl)-1,5-diaryl-3-thia-1,4-pentadi-
ene.4b To the best of our knowledge, the 1,4-addition to
a bis a,b-unsaturated diester to afford an N-hydroxy-
piperidine or an N-hydroxypyrrolidine has not been
reported (Fig. 1).
While glutaraldehyde 2a is commercially available,
succinaldehyde 2b can be prepared by heating 2-5-di-
methoxyfuran 1 in 2 M hydrochloric acid.5 These dial-
dehydes (2a and 2b) are each treated with 2.2 equiv of
(triphenyl-k5-phosphanylidene)-acetic acid ethyl ester
to afford the octa-2,6-dienedioic acid diethyl ester 3a
or nona-2,6-dienedioic acid diethyl ester 3b in 56%
(from the 2,5 dimethoxy-furane) and 71% yields, respec-
tively (Scheme 1).
Previous reports show that additions of hydroxylamine
to a,b-unsaturated esters are most efficient in protic sol-
vents in the presence of a weak base such as triethyl-
amine or sodium carbonate.3 We found that the
overnight treatment of the diethyl ester (3a or 3b) with
hydroxylamine at room temperature, in 90/10 ethanol
water without any base affords the corresponding N-
hydroxypyrrolidine (4a cis and 4a trans) or the corre-
sponding N-hydroxypiperidine (4b cis and 4b trans) in
good yield (60–80%).5 This double 1,4-addition proceeds
Bis a,b-unsaturated diesters are readily accessible in a
few steps. Octa-2,6-dienedioic acid diethyl ester 3, or
nona-2,6-dienedioic acid diethyl ester 30, can be synthe-
sized from the succinaldehyde or glutaraldehyde.
O
O
O
OR
OR
OH
OR
OH
OR'
O
N
H
NH2OH
N
O
OEt
OEt
OMe
O
n
n
n
n=1, 2
R=Alkoxy
H
H
n=1 3a 56% (2 steps)
n=2 3b 71%
OR'
OR'
a
b
O
n
n
O
O
1
OMe
O
Figure 1.
n=1 2a
n=2 2b
O
*
Scheme 1. Reagents and conditions: (a) for n = 1 only: HCl 2 N; (b)
Pu3CHCO2Et 2.2 equiv CH2Cl2 rt.
Corresponding author. Tel.: +1 908 704 4375; fax: +1 908 722
3420; e-mail: wmurray@prdus.jnj.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.064

3192
F. C. Bargiggia, W. V. Murray / Tetrahedron Letters 47 (2006) 3191–3193
O
The precursor can be prepared from the (1-carboxy-
methyl-cyclohexyl)-acetic acid 5, which is reduced in
high yields to the corresponding diol by treatment with
lithium aluminium hydride in THF. This diol is oxidized
to the dialdehyde using Swern conditions and then con-
verted in the diester 6 by a double Wittig-Horner reac-
tion (52% yield for two steps). When treated with
hydroxylamine, the double addition proceeds to the 4-
spiropiperidine 7 in 73% yield.5 Again, the cis isomer
is the major isomer for the reasons described previously
(Scheme 3).
CO2Et
OH
CO2Et
OH
OEt
OEt
NH2OH
N
N
+
EtOH/H2O 9/1
Reflux
n
n
n
CO2Et
CO2Et
n=1 4a cis (70%)
n=2 4b cis (69%)
n=1 4a trans (22%)
n=2 4b trans (<5%)
n=1 3a
n=2 3b
O
Scheme 2.
to a mixture of the cis and trans pyrrolidines with the cis
isomer predominating (Scheme 2).
We felt it would be interesting to study the behaviour of
a double 1,4-addition in the systems that contain, at
least, one ketone. We were curious if the 1,2 addition
would compete with the tandem 1,4 additions. We pre-
pared the 1:2 mixture of diester (3a or 3b) and formyl-
monoester (8a or 8b) by addition of 0.5 equiv of (tri-
phenyl-k5-phosphanylidene)-acetic acid ethyl ester to
the bisaldehyde (2 or 2b). The monoaldehyde can be iso-
lated by chromatography. The a,b-unsaturated ketone
(9a or 9b) can be synthesized by an addition of 1-(tri-
phenyl-k5-phosphanylidene)-propan-2-one on the for-
myl-ester (8a or 8b) (Scheme 4).
The selectivity is more pronounced for the piperidine
system (4a cis/4a trans = 3.5/1 for the N-hydroxypyr-
rolidine and 4b cis/4b trans > 95/5 for the N-hydroxy-
piperidine). In the cis 4b both substituents are
equatorial, while in trans 4b one, is equatorial and the
other is axial. Under the conditions used, the double
Michael addition is reversible and leads to the thermo-
dynamic mixture. The cis isomer is clearly favoured over
the trans isomer (Fig. 2). The double 1,4-addition also
works efficiently for spiro systems.
When 9a or 9b are stirred overnight with 3 equiv of
hydroxylamine the expected N-hydroxypyrrolidine and
N-hydroxypiperidine (10a cis,trans or 10b cis,trans) are
obtained in reasonable yields (for the five as for the six
member ring).5 The ketone, however is also converted
into the corresponding oxime. Diaz’s group observed
similar results when they synthesized cis-1-hydroxy-
2,6-diphenyl-piperidinone oxime by condensation of
hydroxylamine on dibenzalacetone4a (Scheme 5).
CO2Et
CO2Et
NHOH
NHOH
CO2Et
CO2Et
NH2OH
CO2Et
CO2Et
CO2Et
CO2Et
NOH
CO2Et
NOH
CO2Et
Two different routes can be considered for this transfor-
mation. Either the hydroxylamine reacts first with
ketone to generate the oxime and then the double 1,4-
addition occurs or the 1,4 addition occurs first followed
by oxime formation (Fig. 3). To determine the order of
reaction, the keto-ester was treated with 0.5 equiv of
hydroxylamine. In addition to the starting material (9a
or 9b) three different compounds could be expected in
the mixture. The N-hydroxyimino-pyrrolidine and N-
hydroxyimino-piperidine (10a or 10b), the N-hydroxy-
keto-pyrrolidine and N-hydroxyketo-piperidine (11a or
11b) and the a,b-unsaturated oximes (12a or 12b).
Among these three products, 11a or b turns out to be
the major product in the mixture. The transformation
Figure 2.
CO2Et
CO2Et
OH
CO2H
CO2H
a-c
d
N
CO2Et
CO2Et
6
5
7
Scheme 3. Reagents and conditions: (a) LiAlH4, 8 equiv, THF 0 °C to
rt, 90%; (b) (ClCO)2, DMSO, Et3N, CH2Cl2 ꢀ78 °C; (c) Pu3CMe-
CO2Et 1 equiv, CH2Cl2 rt 52% (two steps); (d) NH2OHÆH2O EtOH/
H2O 9/1 rt 73%.
O
O
O
OEt
Me
OEt
O
O
OEt
OEt
H
H
b
n=1 9a 75%
n=2 9b 72%
a
+
n
n
n
n
O
n=1 2a
n=2 2b
O
O
n=1 8a 32% (2 steps)
n=2 8b 48%
n=1 3a 12% (2 steps)
n=2 3b 20%
Scheme 4. Reagents and conditions: (a) P(Ph)3CHCO2Et 0.5 equiv, CH2Cl2 rt. For n = 1: %(E/Z > 9/1) and for n = 2: %(E/Z > 9/1); (b)
P(Ph)3CMeCO2Et 1 equiv, CH2Cl2 rt. For n = 1: %(E/Z > 9/1) and for n = 2: %(E/Z > 9/1).

F. C. Bargiggia, W. V. Murray / Tetrahedron Letters 47 (2006) 3191–3193
3193
O
for either the keto or the oximino N-hydroxypiperidine.
The same is true for the oximino or keto N-hydroxy-
pyrrolidine.
CO2Et
CO2Et
OEt
Me
NH2OH
N
OH
N
+
N
OH
N
EtOH/H2O 9/1
n
n
In conclusion, a versatile and efficient method to
produce a,a0 disubstituted N-hydroxypiperidine and
N-hydroxypyrrolidine is reported.
n
OH
OH
Me
Me
O
n=1 10a cis (58%)
n=2 10b cis (69%)
n=1 10a trans (12%)
n=2 10b trans (<5%)
n=1 9a
n=2 9b
References and notes
Scheme 5.
1. Marradi, M.; Cicchi, S.; Ignacio, D. J.; Rosi, L.; Tejero, T.;
Merino, P.; Goti, A. Tetrahedron Lett. 2005, 46, 1287–1290;
Laventine, D. M.; Davies, M.; Evinson, E. L.; Jenkins, P.
R.; Cullis, P. M.; Fawcett, J. Tetrahedron Lett. 2005, 46,
307–310; Bakunov, S. A.; Denisov, A. Y.; Tkachev, A. V.
CO2Et
`
Tetrahedron 1995, 8565–8572; Pichon, M.; Figadere, B.
N
OH
O
Tetrahedron: Asymmetry 1996, 7, 927–964, and references
cited therein; Parker, W.; Raphael, R. A.; Wilkinson, D. I.
J. Chem. Soc. 1959, 2433–2437.
n
O
n=1 11a
n=2 11b
Me
CO2Et
2. Baldwin, J. E.; Harwood, L. M.; Lombard, M. J. Tetra-
hedron 1984, 40, 4363–4370; Burns, E. G.; McGarry, L. W.;
Proehl, G. S.; Latimer, L. H. Patent EP0761647A2,
1997.
3. Becke, F.; Muz, G. Chem. Ber. 1965, 98, 1322–1324.
4. (a) Aguilera, J. L.; Sosa, G.; Reynolds, W. F.; Diaz, E.;
Barrios, H. Magn. Reson. Chem. 1989, 27, 823–829; (b)
Yamamura, H.; Otto, H. H. Arch. Pharm. 1985, 318, 193–
198.
OEt
NH2OH
N
OH
N
EtOH/H2O 9/1
O
n
n
OH
Me
n=1 10a
n=2 10b
Me
n=1 9a
n=2 9b
OEt
O
n
5. Typical procedure for double 1,4-addition: To a solution of
the bis a,b-unsaturated system in ethanol/water 9/1 (0.1 M)
was added the hydroxylamine (3 equiv). The resulting
mixture was stirred until TLC showed complete disappear-
ance of starting material (typically overnight). The solvents
were, then, evaporated under vacuum. Water and dichloro-
methane were poured in the system and the water layer
was extract twice with the dichloromethane. The organic
layers were then combined, washed with brine, dried over
MgSO4 and the solvent evaporated under vacuum. The
crude was purified by flash chromatography (typical eluant
EtOAc/hexane 30/70).
Me
n=1 12a
n=2 12b
N
HO
Figure 3.
of the ketone into oxime happens at a much slower rate
than the double 1,4-addition. Consequently, by adjust-
ing the amount of hydroxylamine it is possible to select