Synthesis of novel pipecolic acid derivatives: A multicomponent approach from 3, 4, 5, 6-tetrahydropyridines

Article abstract of DOI:10.1039/a905119h

A simple approach to several derivatives of pipecolic acid is via a multicomponent reaction starting from cyclic imines 2, which are synthesized on a large scale and with different substitution patterns. The protected amino acids 3 are formed in high yields. In cases where chiral imines are used the target compounds are obtained with remarkable diastereoselectivity. Bisamides 3 serve as versatile precursors for the preparation of a wide range of amino acid derivatives. Different methods of hydrolysis of 3 lead to the free pipecolic acids or its derivatives. Employment of methanol or ethanethiol as a nucleophile in the acid-mediated conversion of enamides 3 results in W-acylated amino acid esters 5. Furthermore a method for the resolution of the obtained racemic a-amino acids via diastereomeric salt formation is described. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a905119h

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Synthesis of novel pipecolic acid derivatives: a multicomponent
approach from 3,4,5,6-tetrahydropyridines
Wolfgang Maison, Arne Lützen, Marc Kosten, Imre Schlemminger, Ole Westerhoff and
Jürgen Martens*
Department of Organic Chemistry, University of Oldenburg, 26111 Oldenburg, Germany
Received (in Cambridge, UK) 25th June 1999, Accepted 7th October 1999
A simple approach to several derivatives of pipecolic acid is via a multicomponent reaction starting from cyclic
imines 2, which are synthesized on a large scale and with different substitution patterns. The protected amino acids 3
are formed in high yields. In cases where chiral imines are used the target compounds are obtained with remarkable
diastereoselectivity. Bisamides 3 serve as versatile precursors for the preparation of a wide range of amino acid
derivatives. Different methods of hydrolysis of 3 lead to the free pipecolic acids or its derivatives. Employment of
methanol or ethanethiol as a nucleophile in the acid-mediated conversion of enamides 3 results in N-acylated amino
acid esters 5. Furthermore a method for the resolution of the obtained racemic α-amino acids via diastereomeric salt
formation is described.
Introduction
Results and discussion
Among the methods for the multicomponent synthesis of pep-
tides or amino acids, the Ugi 4CC is one of the most popular.9
This versatile α-amido alkylation leads to the synthesis of
several amino acid derivatives and peptides in a simple, one-
pot procedure. Reaction of an isocyanide, an oxo compound,
a carboxylic acid, and an amine generates bisamides which
contain a totally protected α-amino acid skeleton (4CC,
Scheme 1). In some cases substitution of the oxo and amine
component by the corresponding imine is advantageous,
resulting in a three-component condensation (3CC, Scheme 1).
Growing interest is focussed on the synthesis of unnatural
non-proteinogenic α-amino acids since they became a more-
and-more important factor in peptide chemistry. Their incor-
poration into biologically relevant peptides may influence their
properties dramatically. In some cases increasing binding
affinity to receptors or improvement of metabolic stability is
the consequence of such incorporation.1 In addition, non-
proteinogenic α-amino acids are interesting compounds with
regard to the study of peptide conformations.2 In this context
conformationally restricted amino acid derivatives are of
particular interest. In particular, cyclic amino acids related to
proline exhibit remarkable effects.3 The noncoded α-amino acid
pipecolic acid, also called homoproline, is a proline homologue
with a six-membered hexahydropyridine ring. Pipecolic acid
is abundant in many natural products such as immuno-
suppressants or cyclic peptides with antifungal activity. Many
applications of homoproline as a precursor in organic chem-
istry have been reported, including the synthesis of alkaloids
and a lot of pharmaceutically important compounds such
as antipsychotica, anticonvulsants, local anaesthetics or
analgesics.4 Replacement of proline by its higher homologue
in peptides is reported to produce a significant change in bio-
activity and leads to interesting model compounds for studies
on peptide conformations,5 where derivatives of pipecolic acid
often find a role as β-turn mimics.6 Comparing investigations of
pipecolic acid residues to other cyclic amino acids incorporated
in peptides gives detailed insight into local mechanisms relevant
for peptide-folding processes in relation to ring size.7
Scheme 1
Taking these remarkable properties of pipecolic acid deriv-
atives into account only a few methods for the synthesis of these
compounds were known until now.8 Most of them require
several steps for the preparation and on top of that also restrict
the substitution pattern rigorously. Herein we would like to
report on a versatile, one-pot approach to totally protected
pipecolic acid derivatives with variable substitution patterns
from 3,4,5,6-tetrahydropyridines via Ugi Three-Component
Condensation (Ugi 3CC). Furthermore, an efficient method for
the optical resolution of N-protected homoprolines leading to
enantiomerically pure pipecolic acid derivatives is described.
Recently we demonstrated the use of Ugi 3CC for the
preparation of small peptides including heterocyclic amino
acids from 3-thiazolines and 3-oxazolines.10 However, the
synthesis of amino acids via Ugi reaction suffers from a severe
problem since the generated amides ‘protecting’ the carboxylic
function within the cyclic amino acids are difficult to cleave in
general.11 A few methods12 to circumvent these problems have
been reported but most of them require harsh conditions and
are incompatible with additional functional groups within the
same molecule.13 In this context Ugi and, later, Armstrong,
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This journal is © The Royal Society of Chemistry 1999
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Table 1 Synthesis of tetrahydropyridines
Educt
Imine
Methoda
R1
R2
R3
R4
Yield (%)
21
15
22
15
22
15
1a15
1b15
1c15
1c15
1d15
1e15
1a
2a
A
A
A
A
A
B
B
B
B
B
B
B
C
C
Me
Et
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
2b
2c
-(CH2)5-
2d
Me
Me
Me
Me
Me
Pr
2e
Ph
Me
Ph
Ph
H
2f
Ph
Ph
Ph
Me
Et
Pri
Ph
Me
Ph
cis-2g
trans-2g
2h
36b
53b
1e
1c
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
49
15
1c
2i
2j
1c
40
92
44
73
1c
2k
1a
2l
Me
Me
Me
Me
1a
2m
a A: 1. LiAlH4, Et2O–THF; 2. HCl, H2O; 3. NaOH. B (GP1): 1. R3MgX, Et2O (X = Cl, Br or I); 2. LiAlH4, Et2O–THF; 3. HCl, H2O; 4. NaOH. C
(GP2): 1. CeCl3ؒ7H2O, R3Li, abs. THF; 2. HCl, H2O; 3. NaOH. b cis- and trans-2g were obtained from the diastereomeric mixture of 2g by column
chromatography.
Table 2 Preparation of protected pipecolic acids 3 according to GP3 (see Experimental section)
R1
R2
R3
R4
R5
R6
Yield (%)
dra
b
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
t-Bu
t-Bu
Ph
Ph
H
H
H
H
H
H
H
Ph
89
98
93
100
91
100
83
91
96
42
85
CH2Cl
2-NPhc
2,4-DPhd
Pri
50:50b
50:50b
50:50b
H
Ph
Ph
H
H
Me
Ph
CH3
CH3
Pri
>95:5
>95:5
Et
-(CH2)5-
H
Me
Ph
Pri
3j
3k
Me
Me
Me
Me
Pri
Pri
1
a Diastereomeric ratio (trans:cis) of the crude reaction products, measured by H-NMR spectroscopy. b As expected, chiral isocyanides had no
effect on the diastereomeric course of the reaction. However, the employed chiral isocyanides are easy to handle and therefore useful precursors
1
for the synthesis of bisamides 3. The diastereomeric ratio of 3a could not be unambiguously determined from the H-NMR spectrum. c 2-NPh:
2-nitrophenyl. d 2,4-DPh: 2,4-dimethoxyphenyl.
reported on the use of cyclohexenyl isocyanide as a suitable
isocyanide in the Ugi 4CC.14 The generated bisamides contain
a vinylic amide comprising a carboxy-protecting group which
can be cleaved selectively under mild acidic conditions to yield
N-protected α-amino acids or derivatives thereof. Our aim was
to extend this methodology to the synthesis of cyclic amino
acid derivatives. The preparation of pipecolic acid derivatives
via Ugi 3CC requires the synthesis of corresponding 3,4,5,6-
tetrahydropyridines 2 as imino compounds.
The cyclic imines 2a–k were prepared from cyanodioxolanes
1 on a large scale according to methods A and B (defined
in Table 1), which were recently described by us.15 The new
tetrahydropyridines 2g,h and 2j,k are obtained as colourless
liquids of a characteristic sweetish odour in moderate to good
yields. As an extension of this work we developed a route to
tetrasubstituted achiral imines 2l,m (method C in Table 1).
These were prepared by reaction of cyanodioxolane 1a15 with
cerium organyls. Subsequent hydrolysis of the acetal and
intramolecular imine formation led to the cyclic imines 2l,m
which were obtained in moderate to good yields.
Synthesis of convertible protected derivatives of pipecolic acid
Together with a cyclohexenyl isocyanide derivative and a
carboxylic acid the cyclic imines 2 were applied to Ugi 3CC
to give the totally protected homoproline analogues 3 in high
yields (see Table 2).
Both cyclohexenyl isocyanides and tetrahydropyridines 2
show an extraordinary high reactivity in the Ugi reaction,
resulting in a desirable short reaction time but also in a con-
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Table 3 Hydrolysis of enamides 3
Educt
Product
Methoda
R1
R2
R3
R4
R5
Yield (%)
3e
3h
3i
3g
3e
3f
3d
3a
3b
3a
3c
4a
4b
4c
4d
4e
4f
4g
4h
4i
A
A
A
A
B
B
B
B
B
B
B
Me
Et
Me
Et
H
H
H
Ph
H
Ph
H
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
NH2
NH2
NH2
H
H
H
78
76
67
70
94
87
100
65
100
31
61
-(CH2)5-
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
Me
Me
Me
Me
Me
Me
Me
Ibb
Ac
2,4-DBc
Bz
ClAcd
Bz
4j
4k
2-NBe
a A (GP5): 1. 10% conc. HCl in THF, 2. 4 M HCl, reflux, 3 h; B (GP4): 10% HCl in THF. b Ib: isobutyryl. c 2,4-DB: 2,4-Dimethoxybenzoyl. d ClAc:
2-chloroacetyl. e 2-NB: 2-nitrobenzoyl.
siderable evolution of heat while the isocyanide is being added
to the reaction mixture. TLC usually indicated the absence of
the starting materials after 30 min to 1 h. Bisamides 3 were
obtained in high yields after purification by chromatography or
crystallization. We used different carboxylic acids in the Ugi
reaction to obtain N-acyl-protected bisamides 3. It should be
noted that this methodology may be extended to carbamate-
protected derivatives by using CO2 and alcohols as previously
described in the synthesis of other amino acids via a Five-
Component Condensation.16
Fig. 1 Strong NOEs of hydrogens at C-2 and C-6 observed in the
2D-NOESY experiments of 4e and 4f.
Ugi reactions of tetrahydropyridines 2 with a prochiral
C᎐N double bond led to the formation of a stereogenic centre
᎐
the amino acid carboxy group as confirmed by 2D-NOESY-
NMR investigations for 4e and 4f (Fig. 1).
at the α-carbon atom of the totally protected cyclic amino
acids 3. During the course of our investigations we focussed
our efforts to find a way to control the diastereoselectivity
of the reaction using chiral imines 2f,g as reactants. Recent
studies showed a low diastereomeric excess for Ugi reactions
using chiral reactants in most cases.9b However, in our hands
chiral tetrahydropyridines 2f,g with a stereogenic centre next
to the nitrogen atom led to a high excess of one diastereomer
Unfortunately the cis- or trans-geometry of the N-acyl side
chain could not be determined unambiguously by the 2D-
NOESY experiments because either the spectra were taken
at temperatures above coalescence as in the case of 4f, or
the signals of the cis- and the trans-form for the single hydrogen
in the N-isobutyryl residue happened to be isochronic,
thus leading to NOEs of these signals to both hydrogens at C-2
and C-6. Therefore, these NOEs are omitted in the scheme
above since they do not contribute to the elucidation of the
stereochemical substitution pattern of the piperidine ring.
However, the cis- and trans-geometry can be revealed by anal-
ysis of the chemical shifts of the hydrogens at C-2 and C-6
in cases where the spectra were taken at temperatures beneath
coalescence.
1
in the corresponding bisamides 3f,g according to H-NMR
spectroscopy of the crude products. The bisamides 3f,g exhibit
preferentially a trans geometry of alkyl or aryl substituents at
C-2 and C-6, as confirmed by 2D-NOESY-NMR studies of
compound 4f (see Fig. 1, vide infra).
Conversion of Ugi-adducts
The totally protected derivatives of pipecolic acid 3 serve as
versatile precursors for the synthesis of cyclic amino acids or
further derivatives thereof. Recently, Keating and Armstrong
reported on several acid-mediated conversions of cyclohexenyl-
amides.14b Therefore, we also treated our Ugi adducts 3 with
different nucleophiles under acidic conditions.
Employment of water as a nucleophile under mildly acidic
conditions (method B in Table 3) led to N-acylated amino
acids 4e–h in good yields. Compound 4f was synthesized
from 3f in diastereomerically pure form without changing the
configuration.
A second method for hydrolysis requiring a larger excess of
hydrochloric acid (method A in Table 3) led to novel amino
acids 4a–d in a one-pot process. Several new derivatives of
pipecolic acid were synthesized in this way. Again amino
acid 4d was formed, without changing the configuration of
the starting bisamide 3g, in diastereomerically pure form. All
products 4e–k and 5 seem to prefer an axial arrangement of
The stereogenically unfavourable axial arrangement of the
carboxy group is imposed by the presence of the N-acyl group
attached to the six-membered ring system. Such configurations
are known to cause excessive 1,3-allylic strain in the case of
neighbouring equatorial carboxylic functions.17
Surprisingly, acidic hydrolysis of Ugi adducts 3b,c did not
yield the expected corresponding carboxylic acid derivatives
(pathway I, Scheme 2). Instead the primary amides 4i,k were
observed as main products. A significant amount of primary
amide 4j was also obtained as a second reaction product in
the hydrolysis of 3a to give 4h. Keeping these observations in
mind we believe that properties of bisamides 3 with regard to
hydrolysis may be modulated by the nature of the carboxylic
acid derivatives employed in the Ugi 3CC.
The mechanism of the acidic conversion of cyclohexenamides
to carboxylic acids or esters like 4a–h and 5 is supposed to
involve a reactive münchnone species as an intermediate (path-
way I, Scheme 2).14b Electron-withdrawing groups attached to
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Table 4 Ugi 3CC and in situ conversion of enamides according to GP6 (see Experimental section)
Educts
Producta
drb
Yield (%)
2h, 4-phenylcyclohex-1-enyl isocyanide, isobutyric acid, methanol
78:22
60
2j, 4-tert-butylcyclohex-1-enyl isocyanide, isobutyric acid, methanol
2k, 4-phenylcyclohex-1-enyl isocyanide, isobutyric acid, methanol
>95:5
>95:5
67
44
2i, 4-tert-butylcyclohex-1-enyl isocyanide, isobutyric acid, ethanethiol
>95:5
29
2d, 4-tert-butylcyclohex-1-enyl isocyanide, isobutyric acid, ethanethiol
2e, 4-tert-butylcyclohex-1-enyl isocyanide, isobutyric acid, ethanethiol
50:50
50:50
54
53
a 5a: main diastereomer is shown; one enantiomer of racemic 5a–d is shown; Ib: isobutyryl. b Diastereomeric ratio (trans:cis) of the crude reaction
products, measured by 1H-NMR spectroscopy.
utilization of ethanethiol gave thioesters 5d–f. Given yields
(Table 4) include the two steps of Ugi reaction and hydrolysis of
enamides to carboxylic esters 5.
Derivatives 5b–d were obtained in diastereomerically pure
form from cyclic imines 2i–k. Due to the diastereomeric ratios
of the crude carboxylic esters Ugi reactions proceeded with
high diastereoselectivity even with small substituents R3 (see
Table 1) in cyclic imines 2. Employment of imines 2d,e with a
stereogenic centre in 3-position in the Ugi 3CC resulted in no
diastereoselection in products 5e,f. However, diastereomeric
mixtures of 5e,f were easily separated by chromatography to
yield diastereomerically pure compounds.
Acyl residues R such as the trifluoroacetamide in bisamide 6
could also be selectively removed as illustrated in Scheme 3.
The trifluoroacyl group of 6 was cleaved under mild alkaline
conditions in the presence of the cyclohexenyl amide to give the
N-deprotected amino acid 7, which is now available for further
modifications at the N-terminus. The somewhat lower yield
of the trifluoroacetamide 6 in comparison to other Ugi adducts
3 is due to a TFA-mediated cleavage of the cyclohexenyl amide.
As a consequence reaction conditions have to be controlled
carefully.
Scheme 2
Resolution of pipecolic acids
R (Scheme 2) destabilize the reactive intermediate, resulting in
hydrolysis of bisamides 3b,c to primary amides 4i,k and a
cyclohexanone derivative (pathway II, Scheme 2).
Different esters and thioesters can be prepared if alcohols
or thiols, respectively, are employed as nucleophiles instead of
water, e.g. methyl esters 5a–c resulted from an acid-mediated
in situ conversion of 3CC products using methanol, whereas
As mentioned before, amino acid derivatives 3, 4 and 5 were
obtained as racemates. Since enantiomerically pure com-
pounds are far more attractive as building blocks for peptide
or natural product synthesis we finally concentrated our efforts
on the resolution of these amino acids. Racemic N-acylated
amino acid 4h was chosen as a model compound for the
resolution via diastereomeric salt formation. Resolution of the
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The synthesis of enantiomerically pure amino acid deriv-
atives (Ϫ)-4h and (ϩ)-4h was achieved via an efficient resolution
procedure employing (Ϫ)-norephedrine.
In conclusion we were able to present a highly diastereo-
selective multicomponent approach to novel pipecolic acid
derivatives which were converted to enantiomerically pure com-
pounds via diastereoselective salt formation with norephedrine.
We are currently investigating the incorporation of these new
amino acids into small peptides in order to study their effects
on the structural properties of these compounds. The results of
these investigations will be reported in due course.
Experimental
General remarks
If indicated with ‘abs.’, solvents were purified prior to use
as follows: dichloromethane was distilled from CaCl2; THF
and Et2O were distilled from sodium and benzophenone.
CeCl3ؒ7H2O was dried prior to use at 150 ЊC for 3 h. Thin-layer
chromatography (TLC) analyses were performed on silica gel
Polygram plates and fluorescence indicator from Macherey
Nagel and Co., Düren. For preparative chromatography
Merck silica gel 60, 230–400 mesh, was used. Lewatit MP 62
was a gift from Bayer AG Leverkusen. Mps were determined
in open capillaries in a Dr Lindström instrument and are un-
corrected. Specific optical rotations [α]D were determined with
a Perkin-Elmer polarimeter (241 MC), at 21 ЊC, and are given
in units of 10Ϫ1 deg cm2 gϪ1. IR spectra were recorded on a
Scheme 3 Reagents and conditions: i, dichloromethane, 1 h; ii, K2CO3,
aq. MeOH.
N-benzoylated amino acid ( )-4h was achieved by formation
of its diastereomeric salts18 with (Ϫ)-norephedrine. The nor-
ephedrinium salt of (Ϫ)-4h precipitated from diethyl ether upon
cooling. Acidic treatment of this norephedrine salt gave the
desired enantiomerically pure N-benzoylated amino acid (Ϫ)-
4h (Scheme 4). The corresponding enantiomer (ϩ)-4h was
1
Beckmann spectrophotometer (IR 4220). H-NMR and 13C-
NMR spectra were recorded on a Bruker-Karlsruhe AM 300
or an Avance 300 spectrometer (300.1 MHz/75 MHz). 2D-
NOESY-spectra were recorded on a Bruker-Karlsruhe Avance
500 spectrometer (500.1 MHz). Chemical shifts are reported
on the δ-scale (ppm) relative to residual nondeuterated solvent
or tetramethylsilane (TMS) in [D3]MeOD, D2O, CDCl3, or
[D6]DMSO. Coupling constants, J, are given in Hz. Mass
spectra were taken on a Finnigan-MAT 212 instrument in
CI mode with isobutane or NH3 as reactant gas. Elemental
analyses were performed with a C, H, N-Analyser EA 1108
from Fisons Instrument. Abbreviations: mi: minor isomer;
ma: major isomer.
Scheme 4 Reagents and conditions: i, (Ϫ)-norephedrine, Et2O, ii, aq.
HCl.
obtained from the filtrate by repeating the procedure described
above. Finally, deprotection of compounds (ϩ)-4h and
(Ϫ)-4h should be possible in an analogous manner to the
hydrolysis of compounds 3e,g–i. Unfortunately we have not
yet been able to determine the absolute configuration of the
enantiomerically pure N-benzoylated α-amino acids (ϩ)-4h
and (Ϫ)-4h because we have not been able to obtain suitable
crystals from their norephedrinium salts for X-ray crystal-
structure analysis.
General procedures (GPs)
Preparation of cyclic imines 2f–k (GP1). A solution of 0.1
mol of cyanodioxolane 1 in 100 ml of abs. Et2O was added
dropwise to 0.13 mol of the appropriate Grignard reagent in
200 ml of abs. Et2O. After addition of 50 ml of abs. THF the
solution was heated to reflux for 3 h and 5 g (0.13 mol) of
LiAlH4 were added carefully. The reaction mixture was
heated to reflux for 13 h and subsequently hydrolysed by careful
addition of 5 ml of water, 2 ml of 20% aq. NaOH, and 25 ml
of water. The resulting precipitate was filtered off after 3 h of
stirring at room temperature and the filtrate was dried over
MgSO4. The solvent was removed in vacuo to give a crude
amino dioxolane as a yellow oil, which was dissolved in a
mixture of 50 ml of water and 15 ml of conc. HCl. After 2 h of
stirring at room temperature, 10 g of solid NaOH were added
accompanied by 50 g of ice. The resulting red solution exhibited
the typical sweetish odour of cyclic imines 2 and was stirred
at room temperature for 1 h. After three-fold extraction with
150 ml of CHCl3 each time the organic layer was dried over
MgSO4. Evaporation of the solvent under reduced pressure
gave the crude imine as a red oil, which was further purified by
distillation or chromatography.
Conclusions
The synthesis of new pipecolic acid analogues from cyclic
imines 2 via Ugi multicomponent condensation has been
described. Several previously unknown 3,4,5,6-tetrahydro-
pyridines 2 were prepared and used as imine components in the
Ugi 3CC to yield totally protected derivatives of cyclic amino
acids. Chiral tetrahydropyridines 2f–k led to the diastereo-
selective formation of Ugi products 3f,g, hydrolysis products
4d,f and N-acylated amino acid esters 5a–d. The obtained
bisamides 3 serve as versatile precursors for a wide range of
amino acid derivatives. An acid-mediated nucleophilic con-
version of Ugi adducts yielded carboxylic esters 5a–c, thioesters
5d–f, N-protected amino acids 4e–h, and the free amino acids
4a–d. It was found that electron-rich substituents as in 3d gave
rise to carboxylic acid derivatives such as 4g, whereas electron-
withdrawing substituents present in 3b,c led to primary amides
such as 4i,k when exposed to otherwise identical acidic
hydrolysis conditions.
Preparation of cyclic imines 2l,m (GP2). 15 g (40.2 mmol)
of CeCl3ؒ7H2O were suspended in 80 ml of abs. THF and the
mixture was stirred for 2 h at room temperature. After the
suspension was cooled to Ϫ50 ЊC the appropriate organic
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Li-compound was added and the resulting solution was stirred
for 30 min under argon. 2.20 g (13 mmol) of cyanodioxolane
1a14 were added at Ϫ65 ЊC and the reaction mixture was stirred
for 2 h. After warming to Ϫ40 ЊC, 25 ml of saturated aq. NH4Cl
were added carefully and the suspension was filtered through
Celite. After evaporation of the solvent in vacuo the residue
was dissolved in 30 ml of toluene, treated with 30 ml of H3PO4
(3%, aq.), and the solution stirred for 15 min. The organic
phase was extracted three times with 10 ml of water each
and the combined aqueous extracts were treated with 2 M
NaOH until they were slightly alkaline. Three-fold extraction
with 30 ml of dichloromethane each, drying of the organics
over MgSO4, and evaporation of the solvent gave a yellow oil,
which was treated with 15 ml of water and 2 ml of conc.
HCl. After the solution was stirred for 2 h it was treated with
1.5 g of solid NaOH and extracted three times with 30 ml
of CHCl3 each. Drying over MgSO4 and evaporation of the
solvent in vacuo led to the cyclic imine, which was further
purified by column chromatography on silica gel (dichloro-
methane–methanol, 9:1).
methane. After filtration the solvent was removed in vacuo. The
resulting crude ester was purified by column chromato-
graphy on silica gel with a 0–2% methanol in dichloromethane
gradient.
3-Methyl-3,6-diphenyl-3,4,5,6-tetrahydropyridine† cis/trans-
2g.—The title compound was prepared according to GP1 using
23.1 g (0.1 mol) cyanodioxolane 1e15 as starting material.
The cyclic imine 2g (22.70 g, 92%) was obtained as a yellow oil
without any purification. The crude diastereomeric mixture
(60:40) was separated into the cis and trans racemates by
column chromatography on silica gel with a Et2O–CH2Cl2–
n-hexane (10:5:5) gradient with cis-2g eluting as the first
fraction.
(3SR,6RS)-3-Methyl-3,6-diphenyl-3,4,5,6-tetrahydro-
pyridine† cis-2g.—Yield: 9.01 g (36%); Rf 0.82 (Et2O–CH2Cl2–
n-hexane, 10:5:5) [Found: C, 87.02; H, 7.70; N, 5.62. C18H19N
(249.4) requires C, 86.70; H, 7.68; N, 5.62%]; δH (CDCl3) 1.45
(3H, s, CH3), 1.5–2.0 (4H, m, CH2CH2), 4.59 (1H, m, NCH),
7.2–7.4 (10H, m, ArH), 7.88 (1H, s, N᎐CH); δ (CDCl ) 24.26,
᎐
C
3
28.17, 34.77, 41.71, 61.52, 126.22, 126.65, 127.11, 128.33,
128.52, 128.68, 144.32, 145.91, 168.47; m/z (CI-isobutane) 250
(100%) [MHϩ].
(3SR,6SR)-3-Methyl-3,6-diphenyl-3,4,5,6-tetrahydro-
pyridine† trans-2g.—Yield: 13.16 g (53%); Rf 0.71 (Et2O–CH2-
Cl2–n-hexane, 10:5:5) (Found: C, 86.65; H, 7.59; N, 5.51%);
δH (CDCl3) 1.4–2.1 (4H, m, CH2CH2), 1.45 (3H, s, CH3), 4.49
General procedure for the preparation of totally protected
pipecolic acids 3 (GP3). The appropriate imine 2 (2 mmol) and
the carboxylic acid (2 mmol) were dissolved in 7 ml of abs.
MeOH. The isocyanide (2.0 mmol) was added and the solu-
tion was stirred for 1 h at room temperature. The solvent
was removed in vacuo and the resulting crude enamide 3 was
purified by column chromatography or crystallized from a
suitable solvent.
(1H, m, NCH), 7.1–7.3 (10H, m, ArH), 7.92 (1H, s, N᎐CH);
᎐
δC (CDCl3) 26.91, 27.38, 35.19, 41.30, 62.27, 126.17, 126.37,
126.47, 127.94, 128.32, 128.50, 144.40, 145.47, 168.10; m/z
(CI-isobutane) 250 (100%) [MHϩ].
rac-3-Methyl-2-azaspiro[5.5]undec-1-ene 2h.—The title com-
pound was prepared according to GP1 starting from 21.0 g
(0.1 mol) of cyanodioxolane 1c.15 The cyclic imine was purified
by distillation in vacuo at 75 ЊC (0.05 mbar‡) to give 2h (8.10 g,
49%) as a colourless liquid, Rf 0.54 (dichloromethane–methanol,
95:5) [Found: C, 80.26; H, 11.62; N, 8.51. C11H19N (165.3)
requires C, 79.94; H, 11.59; N, 8.47%]; νmax(film)/cmϪ1 1630;
General procedure for hydrolysis of enamides 3 to carboxylic
acids 4e–h and primary amides 4i–k (GP4). The appropriate
enamide 3 (1–2 mmol) was dissolved in a stock solution of
1 ml of conc. HCl and 9 ml of THF. The solution was stirred
for 12 h at room temperature. Solid Na2CO3 was added for
neutralization and the solution was filtered. The filtrate was
evaporated to dryness in vacuo and the residue dissolved in
10 ml of dichloromethane. The solution was extracted three
times with 10 ml of pH 10 water each. The combined aqueous
phases were acidified with 4 M HCl (pH 1) and extracted
three times with 20 ml of dichloromethane each. After drying
of the organics over MgSO4 and evaporation of the solvent
under reduced pressure the desired carboxylic acids 4e–h were
obtained. In some cases the obtained products were further
purified by column chromatography on silica gel.
3
δH (CDCl3) 1.0–1.8 (14H, m, CH2), 1.18 (3H, d, CH3, J 7.2),
3.32 (1H, m, CH), 7.34 (1H, s, N᎐CH); δ (CDCl ) 20.62, 20.78,
᎐
C
3
22.96, 25.70, 26.61, 28.25, 32.84, 35.62, 54.21, 169.81; m/z
(CI-isobutane) 166 (100%) [MHϩ].
rac-3-Isopropyl-2-azaspiro[5.5]undec-1-ene 2j.—The title
compound was prepared from 21.0 g (0.1 mol) of cyanodi-
oxolane 1c15 according to GP1. The cyclic imine was purified
by distillation in vacuo at 125 ЊC (0.05 mbar) to give 2j (7.72 g,
40%) as a colourless liquid, Rf 0.72 (dichloromethane–methanol,
95:5) [Found: C, 80.49; H, 11.87; N, 7.23. C13H23N (193.3)
requires C, 80.76; H, 11.99; N, 7.24%]; νmax(film)/cmϪ1 1635;
General procedure for hydrolysis of enamides 3 to amino
acids 4a–d (GP5). The appropriate enamide 3 (1–2 mmol) was
dissolved in a stock solution of 1 ml of conc. HCl and 9 ml of
THF. The solution was stirred for 12 h at room temperature.
After removal of the solvent under reduced pressure 20 ml of
4 M aq. HCl was added and the solution was heated to reflux
for 3 h. Water was evaporated in vacuo and the residue was
dissolved in MeOH. The solution was treated with Lewatit MP
62 until it was slightly alkaline. Subsequent filtration and
evaporation of the solvent in vacuo gave the crude amino acids,
which were crystallized from acetone to give the pure cyclic
amino acids.
3
δH (CDCl3) 0.90 and 0.95 [6H, 2d, CH(CH3)2, J 6.6], 1.0–1.7
[15 H, m, CH2 ϩ CH(CH3)2], 3.03 (1H, m, NCH), 7.47 (1H, s,
N᎐CH); δ (CDCl3) 18.48, 18.90, 20.72, 20.91, 25.81, 29.03,
᎐
C
32.16, 33.44, 36.47, 64.26, 170.21; m/z (CI-isobutane) 194
(100%) [MHϩ].
rac-3-Phenyl-2-azaspiro[5.5]undec-1-ene 2k.—The title com-
pound was prepared according to GP1 using 21.0 g (0.1 mol)
of cyanodioxolane 1c15 as starting material. The cyclic imine
2k (20.91 g, 92%) was obtained without any purification, Rf
0.84 (dichloromethane–methanol, 95:5) [Found: C, 85.16;
H, 9.30; N, 6.32. C16H21N (227.3) requires C, 84.53; H, 9.31;
N, 6.16%]; νmax(film)/cmϪ1 1635; δH (CDCl3) 1.2–2.1 (14H, m,
CH2), 4.44 (1H, m, CH), 7.1–7.3 (5H, m, ArH), 7.59 (1H, s,
General procedure for in situ conversions of Ugi adducts to
carboxylic esters 5a–c and thioesters 5d–f (GP6). The appro-
priate imine 2 (2 mmol) and the carboxylic acid (2 mmol) were
dissolved in 7 ml of abs. MeOH. The isocyanide (2.0 mmol)
was added and the solution was stirred for 1 h at room tem-
perature. The solvent was removed in vacuo and the residue
was dissolved in 20 ml of MeOH or ethanethiol. 10 mol equiv.
of acetyl chloride were added and the solution was heated
to reflux for 3 h. The solvent was removed under reduced
pressure and the residue was taken up in 20 ml of dichloro-
N᎐CH); δ (CDCl3) 20.64, 20.84, 25.74, 27.90, 28.15, 32.96,
᎐
C
35.41, 36.48, 62.46, 126.39, 126.59, 127.06, 128.18, 144.56,
171.48; m/z (CI-isobutane) 228 (100%) [MHϩ].
3,3,6,6-Tetramethyl-3,4,5,6-tetrahydropyridine† 2l.—The title
compound was prepared according to GP2 using 40 mmol
of MeLi. The cyclic imine 2l (0.80 g, 44%) was obtained as a
† Non-systematic name.
‡ 1 bar = 105 Pa.
3520
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525

View Article Online
colourless oil, Rf 0.57 (dichloromethane–methanol, 9:1)
[Found: C, 77.91; H, 12.34; N, 10.13. C9H17N (139.2) requires
C, 77.63; H, 12.31; N, 10.06%]; δH (CDCl3) 1.02 (6H, s, CH3),
1.18 (6H, s, CH3), 1.53 (4H, m, CH2), 7.34 (1H, s, NCH);
δC (CDCl3) 26.68, 29.89, 30.67, 31.58, 32.84, 53.99, 167.66;
m/z (CI-isobutane) 140 (100%) [MHϩ].
3,3-Dimethyl-6,6-diphenyl-3,4,5,6-tetrahydropyridine† 2m.—
The title compound was prepared according to GP2 using 40
mmol of PhLi. The cyclic imine 2m (2.50 g, 73%) was obtained
as a colourless solid without purification, mp 84 ЊC [Found:
C, 86.79; H, 8.06; N, 5.41. C19H21N (263.4) requires C, 86.65;
H, 8.04; N, 5.32%]; δH (CDCl3) 1.01 (6H, s, CH3), 1.42 (2H, m,
CH2), 2.31 (2H, m, CH2), 7.1–7.4 (10H, m, ArH), 7.78 (1H, s,
NCH); δC (CDCl3) 26.29, 30.27, 31.14, 33.63, 65.87, 126.12,
126.53, 126.94, 127.97, 147.75, 169.92; m/z (CI-isobutane) 264
(100%) [MHϩ].
126.42, 126.54, 126.68, 127.29, 127.91, 128.23, 128.44, 129.63,
129.94, 132.40, 133.97, 134.45, 145.10, 146.33, 146.52, 166.52,
167.31, 168.33, 168.81; m/z (CI-NH3) 290 (100%) [MHϩ Ϫ
4-phenylcyclohexylideneamine].
1-(2,4-Dimethoxybenzoyl)-3,3-dimethylpiperidine-2-carb-
oxylic acid (4-phenylcyclohex-1-enyl)amide 3d.—The title
compound was prepared according to GP3 using 0.22 g
(2 mmol) of 2a, 0.37 g (2 mmol) of 4-phenylcyclohex-1-enyl
isocyanide,19 and 0.36 g (2 mmol) of 2,4-dimethoxybenzoic acid
as starting materials. The enamide 3d (0.95 g, 100%) was
obtained as a 50:50 mixture of racemic diastereomers. Rf 0.48
(dichloromethane–methanol, 99:1) [Found: C, 73.12; H,
8.02; N, 5.94. C29H36N2O4 (476.6) requires C, 73.08; H, 7.61;
N, 5.88%]; δH (CDCl3) 1.07 (mi), 1.12 (ma) [3H, s, C(CH3)2],
1.16 (ma), 1.21 (mi) [3H, s, C(CH3)2], 1.2–2.9 (11H, m), 3.4–3.7
(2H, m, NCH2), 3.81 (6H, s, OMe), 4.69 (ma), 4.91 (mi) (1H,
1-Benzoyl-3,3-dimethylpiperidine-2-carboxylic acid (4-tert-
butylcyclohex-1-enyl)amide 3a.—The title compound was pre-
pared according to GP3 starting from 3.93 g (35 mmol) of 2a,
5.72 g (35 mmol) of 4-tert-butylcyclohex-1-enyl isocyanide,19
and 4.27 g (35 mmol) of benzoic acid. The enamide 3a (12.38 g,
89%) was obtained as a mixture of racemic diastereomers.
However, the diastereomeric ratio could not unambiguously
be determined from the 1H-NMR spectrum. Rf 0.45 (dichloro-
methane) [Found: C, 75.91; H, 9.16; N, 7.19. C25H36N2O2
(396.6) requires C, 75.72; H, 9.15; N, 7.06%]; δH (CDCl3)
0.84 [9H, s, C(CH3)3], 1.06, 1.10 [6H, 2s, C(CH3)2], 1.2–2.4
(11H, m), 3.54 (2H, m, NCH2), 4.77 (1H, s, CHN), 6.12 (1H,
m, CH=C), 7.39 (5H, m, ArH), 7.90 (1H, s, NH); δC (CDCl3,
two diastereomers) 21.46, 23.57, 23.62, 25.34, 26.36, 27.10,
27.49, 29.17, 29.33, 32.00, 32.33, 32.54, 43.49, 44.68, 61.28,
112.55, 112.79, 126.90, 128.33, 129.78, 132.46, 132.54, 135.77,
168.10, 168.21, 172.02; m/z (CI-NH3) 244 (100%) [MHϩ Ϫ
4-tert-butylcyclohexylideneamine].
1-Chloroacetyl-3,3-dimethylpiperidine-2-carboxylic acid (4-
tert-butylcyclohex-1-enyl)amide 3b.—The title compound was
prepared according to GP3 using 0.22 g (2 mmol) of 2a, 0.33 g
(2 mmol) of 4-tert-butylcyclohex-1-enyl isocyanide,19 and 0.19 g
(2 mmol) of chloroacetic acid as starting materials. The enam-
ide 3b (0.72 g, 98%) was obtained as a 50:50 mixture of racemic
diastereomers. Rf 0.56 (dichloromethane–methanol, 99:1)
[Found: C, 65.63; H, 9.15; N, 7.63. C20H33ClN2O2 (368.9)
requires C, 65.11; H, 9.02; N, 7.59%]; δH (CDCl3) 0.84 (mi), 0.92
(ma) [9H, s, C(CH3)3], 0.99 (mi), 1.03 (ma) [3H, s, C(CH3)2],
1.14 (mi), 1.19 (ma) [3H, s, C(CH3)2], 1.2–2.4 (11H, m),
3.55–3.72 (2H, m, NCH2), 4.17 (1H, d, ClCH2, 2J 16.0),
4.20 (1H, d, ClCH2, 2J 16.0), 4.50 (mi), 4.59 (ma) (1H,
s, NCH), 6.23 (1H, m, C᎐CH), 6.4–6.5 (2H, m), 7.1–7.4 (6H,
᎐
m), 7.68 (mi), 7.96 (ma) (1H, br, NH); δC (CDCl3, two diastereo-
mers) 21.19, 26.13, 27.08, 28.48, 29.26, 32.25, 32.34, 39.57,
43.44, 44.44, 55.12, 55.29, 60.42, 61.16, 97.99, 98.42, 104.70,
111.72, 111.92, 118.28, 125.94, 126.65, 127.87, 128.21, 130.02,
132.42, 132.56, 135.25, 146.37, 156.24, 156.97, 161.61, 161.75,
167.79, 168.35, 168.44, 169.25; m/z (CI-NH3) 305 (100%)
[MHϩ Ϫ 4-phenylcyclohexylideneamine], 322 (80) [MHϩ ϩ
NH3 Ϫ 4-phenylcyclohexylideneamine].
rac-1-Isobutyryl-3,3-dimethylpiperidine-2-carboxylic
acid
cyclohex-1-enylamide 3e.—According to GP3 the title
compound was prepared starting from 0.22 g (2 mmol) of
2a, 0.21 g (2 mmol) of cyclohex-1-enyl isocyanide,19 and 0.18 g
(2 mmol) of isobutyric acid. The enamide 3e (0.56 g, 91%)
was obtained as a colourless solid, mp 149–150 ЊC; Rf 0.61
(dichloromethane–methanol, 99:1) [Found: C, 70.72; H, 10.02;
N, 9.19. C18H30N2O2 (306.4) requires C, 70.55; H, 9.87; N,
9.14%]; δH (CDCl3) 0.92 [3H, s, C(CH3)2], 1.08 [3H, d, CH-
3
(CH3)2, J 6.6], 1.10 [3H, s, C(CH3)2], 1.17 [3H, d, CH(CH3)2,
3J 6.6], 1.26–1.69 (7H, m, CH2), 2.1 (4H, m, CH2), 2.34
2
3
[1H, m, CH2C(CH3)2, J 13.2, J 4.4], 2.86 [1H, m, CH(CH3)2,
3J 6.6], 3.42 [1H, m, NCH2, 2J 13.2, 3J 3.9], 3.77 [1H, d, NCH2,
2J 13.2], 4.60 (1H, s, NCH), 6.04 (1H, m, C᎐CH), 7.24 (1H, br,
᎐
NH); δC (CDCl3, two diastereomers) 18.85, 19.80, 21.69, 26.27,
27.23, 28.53, 28.68, 29.37, 30.58, 32.15, 32.30, 39.68, 42.23,
60.77, 112.26, 132.43, 168.75, 177.55; m/z (CI-NH3) 210
(100%) [MHϩ Ϫ cyclohexylideneamine].
(2RS,6RS)-1-Acetyl-3,3-dimethyl-6-phenylpiperidine-2-carb-
oxylic acid cyclohex-1-enylamide 3f.—The title compound
was prepared from 1.87 g (10 mmol) of 2f, 1.07 g (10 mmol)
cyclohex-1-enyl isocyanide,19 and 0.60 g (10 mmol) of acetic
acid according to GP3. The enamide 3f (3.54 g, 100%)
was obtained as a colourless solid, mp 149–150 ЊC [Found: C,
74.19; H, 8.51; N, 8.03. C22H30N2O2 (354.5) requires C, 74.54;
H, 8.53; N, 7.90%]; δH (CDCl3) 1.14 [3H, s, C(CH3)2], 1.19
[3H, s, C (CH3)2], 1.2–2.3 (12H, m, CH2), 1.65 (3H, s, COCH3),
s, NCH), 5.81 (mi), 6.17 (ma) (1H, m, C᎐CH); δ (CDCl3,
᎐
C
two diastereomers) 21.19, 23.37, 25.85, 25.94, 27.32, 27.47,
32.17, 32.34, 35.67, 41.44, 42.98, 43.15, 46.58, 46.96, 59.86,
60.23, 113.15, 113.35, 132.35, 166.91, 167.11, 169.21, 171.61;
m/z (CI-NH3) 216 (100%) [MHϩ Ϫ 4-tert-butylcyclohexylidene-
amine].
4.69 (1H, s, NCH), 5.08 (1H, m, NCHPh), 6.09 (1H, m, C᎐CH),
᎐
3,3-Dimethyl-1-(2-nitrobenzoyl)piperidine-2-carboxylic acid
(4-phenylcyclohex-1-enyl)amide 3c.—The title compound was
prepared from 0.22 g (2 mmol) of 2a, 0.37 g (2 mmol) of
4-phenylcyclohex-1-enyl isocyanide,19 and 0.33 g (2 mmol)
of 2-nitrobenzoic acid according to GP3. The enamide 3c
(0.86 g, 93%) was obtained as a 50:50 mixture of racemic
7.2–7.4 (5H, m, ArH), 7.61 (1H, br, NH); δC (CDCl3)
21.92, 22.44, 23.91, 25.25, 27.67, 27.78, 28.77, 30.93, 31.20,
32.30, 58.44, 65.76, 112.43, 126.03, 126.83, 128.79, 132.60,
145.38, 170.23, 175.93; m/z (CI-NH3) 258 (100%) [MHϩ Ϫ
cyclohexylideneamine].
(2RS,3SR,6RS)-1-Acetyl-3-methyl-3,6-diphenylpiperidine-2-
carboxylic acid cyclohex-1-enylamide 3g.—According to GP3
the title compound was obtained from 1.25 g (5 mmol) of
cis-2g, 0.54 g (5 mmol) of cyclohex-1-enyl isocyanide,19 and
0.30 g (5 mmol) of acetic acid. The enamide 3g (1.72 g, 83%)
was obtained as a colourless solid, mp 203–204 ЊC [Found: C,
77.92; H, 7.76; N, 6.81. C27H32N2O2 (416.6) requires C, 77.85;
H, 7.74; N, 6.72%]; δH (CDCl3) 1.44 (3H, s, CCH3), 1.4–1.7 (5H,
m, CH2), 1.54 (3H, s, COCH3), 2.03 (6H, m, CH2), 2.40 (1H, m,
CH2), 5.06 (1H, m, NCHPh), 5.83 (1H, s, NCH), 6.20 (1H, m,
1
diastereomers. Several signals in the H-NMR spectrum were
extremely broadened. Rf 0.66 (dichloromethane–methanol,
99:1) [Found: C, 70.41; H, 6.87; N, 9.29. C27H31N3O4 (461.6)
requires C, 70.26; H, 6.77; N, 9.10%]; δH (CDCl3) 1.08 (mi), 1.13
(ma) [3H, s, C(CH3)2], 1.24 (ma), 1.30 (mi) [3H, s, C(CH3)2],
1.3–2.9 (11H, m), 3.25 (1H, m, NCH2), 3.46 (mi), 3.91 (ma)
(1H, m, NCH2), 4.78 (ma), 5.14 (mi) (1H, br, NCH), 6.23 (ma),
6.27 (mi) (1H, m, C᎐CH), 7.1–8.3 (10H, m, 9 ArH ϩ NH);
᎐
δC (CDCl3, two diastereomers) 20.93, 21.31, 26.01, 26.43, 26.88,
27.59, 28.10, 28.36, 29.16, 31.99, 32.31, 32.47, 32.60, 33.80,
39.51, 41.22, 43.69, 45.04, 60.76, 111.96, 112.65, 124.63, 135.94,
C᎐CH), 6.9–7.5 (10H, m, ArH), 7.85 (1H, br, NH); δ (CDCl )
᎐
C
3
21.93, 22.47, 23.99, 26.12, 27.70, 29.29, 30.41, 32.84, 39.93,
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525 3521

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58.83, 62.78, 112.25, 126.03, 126.07, 126.26, 126.64, 128.65,
128.72, 132.59, 146.38, 146.49, 170.35, 176.38; m/z (CI-NH3)
320 (100%) [MHϩ Ϫ cyclohexylideneamine].
rac-3,3-Dimethylpiperidine-2-carboxylic acid 4a.—Following
GP5 the title compound was prepared from 0.28 g (0.90 mmol)
of 3e. The amino acid 4a (0.11 g, 78%) was obtained as a colour-
less solid after crystallization from acetone, mp >260 ЊC
[Found: C, 61.02; H, 9.67; N, 8.95. C8H15NO2 (157.2) requires
C, 61.12; H, 9.62; N, 8.91%]; δH (D2O) 0.81 [3H, s, C(CH3)2],
0.99 [3H, s, C(CH3)2], 1.3–1.7 (4H, m, CH2), 2.73 (1H,
m, NCH2), 3.19 (1H, s, NCH2), 3.21 (1H, s, NCH); δC (D2O)
18.34, 19.52, 28.73, 31.64, 36.98, 43.52, 67.28, 173.12; m/z
(CI-isobutane) 158 (100%) [MHϩ].
3,3-Diethyl rac-1-isobutyrylpiperidine-2-carboxylic acid cyclo-
hex-1-enylamide 3h.—The title compound was prepared accor-
ding to GP3 using 0.70 g (5 mmol) of 2b, 0.53 g (5 mmol) of
cyclohex-1-enyl isocyanide,19 and 0.44 g (5 mmol) of isobutyric
acid as starting materials. The enamide 3h (1.53 g, 91%)
was obtained as a colourless solid, mp 115–116 ЊC; Rf 0.48
(dichloromethane–methanol, 99:1) [Found: C, 71.69; H, 10.21;
N, 8.39. C20H34N2O2 (334.5) requires C, 71.81; H, 10.25; N,
8.37%]; δH (CDCl3) 0.66 and 0.75 (6H, 2t, CH3CH2, 3J 7.7), 1.01
rac-3,3-Diethylpiperidine-2-carboxylic acid 4b.—Standard
hydrolysis, following GP5, of 0.88 g (2.64 mmol) of 3h gave the
title compound. The amino acid 4b (0.37 g, 76%) was obtained
as a colourless solid after crystallization from acetone,
mp >260 ЊC [Found: C, 65.19; H, 10.26; N, 7.58. C10H19NO2
(185.3) requires C, 64.83; H, 10.34; N, 7.56%]; δH (D2O) 0.76
3
and 1.09 [6H, 2d, CH(CH3)2, J 6.6], 1.2–1.7 (11H, m, CH2),
2.02 (5H, m, CH2), 2.78 [1H, m, CH(CH3)2, 3J 6.6], 3.40 [1H, dt,
2
3
2
NCH2, J 12.7, J 3.9], 3.68 [1H, d, NCH2, J 12.7], 4.68 (1H,
s, CHN), 5.96 (1H, s, CH=C), 7.39 (1H, s, NH); δC (CDCl3)
6.99, 7.10, 18.79, 19.64, 20.99, 21.91, 22.41, 23.53, 23.91,
26.74, 27.77, 27.95, 30.56, 37.22, 42.31, 58.14, 113.25, 132.66,
168.15, 177.37; m/z (CI-NH3) 238 (100%) [MHϩ Ϫ cyclo-
hexylideneamine].
3
3
(3H, t, CH2CH3, J 7.2), 0.88 (3H, t, CH2CH3, J 7.2), 1.1–1.7
(8H, m, CH2), 2.80 (1H, m, NCH2), 3.24 (1H, s, NCH2), 3.43
(1H, s, NCH); δC (D2O) 8.31, 8.68, 19.05, 25.35, 29.74, 29.83,
38.27, 44.62, 65.80, 173.73; m/z (CI-isobutane) 186 (100%)
[MHϩ].
rac-2-Isobutyryl-2-azaspiro[5.5]undecane-1-carboxylic acid
cyclohex-1-enylamide 3i.—The title compound was prepared
using 0.91 g (6 mmol) of 2c, 63 g (6 mmol) of cyclohex-1-enyl
isocyanide,19 and 0.54 g (6 mmol) of isobutyric acid as starting
materials according to GP3. The enamide 3i (2.00 g, 96%)
was obtained as a colourless solid, mp 135–136 ЊC; Rf 0.69
(dichloromethane–methanol, 99:1) [Found: C, 72.71; H, 9.86;
N, 8.12. C21H34N2O2 (346.5) requires C, 72.79; H, 9.89; N,
rac-2-Azaspiro[5.5]undecane-1-carboxylic acid 4c.—The title
compound was prepared according to GP5 using 1.02 g (2.93
mmol) of 3i as starting material. The amino acid 4c (0.39 g,
67%) was obtained as a colourless solid after crystallization
from acetone, mp >260 ЊC [Found: C, 66.81; H, 9.70; N, 7.10.
C11H19NO2 (197.3) requires C, 66.97; H, 9.71; N, 7.10%];
δH (D2O) 1.1–1.9 (13H, m, CH2), 2.34 (1H, m), 2.85 (1H, m,
NCH2), 3.22 (1H, s, NCH), 3.28 (1H, m, NCH2); δC (D2O)
18.68, 21.58, 26.99, 27.75, 29.86, 35.89, 36.61, 44.67, 69.75,
172.69; m/z (CI-isobutane) 198 (100%) [MHϩ].
(2RS,3SR,6RS)-3-Methyl-3,6-diphenylpiperidine-2-carb-
oxylic acid 4d.—According to GP5 the title compound was
obtained from 0.36 g (0.86 mmol) of 3g. The racemic amino
acid 4d (0.18 g, 70%) was obtained as a colourless solid after
crystallization from acetone, mp 193–194 ЊC [Found: C, 77.09;
H, 7.12; N, 4.81. C19H21NO2 (295.4) requires C, 77.26; H, 7.17;
N, 4.74%]; δH ([D3]MeOD) 1.43 (3H, s, CCH3), 2.1–2.5 (4H,
m, NCHPhCH2CH2), 4.46 (1H, s, NCHCOOH), 5.54 (1H, s,
NCHPh), 7.3–7.6 (10H, m, ArH); δC ([D3]MeOD) 26.79, 30.96,
31.51, 39.70, 56.24, 65.94, 127.62, 127.86, 128.75, 130.10,
130.19, 138.00, 145.68, 172.64; m/z (CI-isobutane) 296 (100%)
[MHϩ].
3
8.08%]; δH (CDCl3) 1.02 [3H, d, CH(CH3)2, J 6.6], 1.10 [3H,
d, CH(CH3)2, 3J 6.6], 1.2–2.2 (22H, m, CH2), 2.80 [1H,
m, CH(CH3)2, 3J 6.6], 3.55 [1H, dt, NCH2, 2J 13.6, 3J 2.2], 3.70
2
3
[1H, dd, NCH2, J 13.6, J 6.4], 4.91 (1H, s, NCH), 6.00 (1H,
s, cyclohexenyl-C᎐CH), 7.58 (1H, br, NH); δ (CDCl ) 18.77,
᎐
C
3
19.67, 20.53, 20.71, 21.21, 21.86, 22.35, 23.85, 26.20, 27.85,
28.37, 30.49, 32.72, 34.65, 35.28, 42.37, 59.06, 113.03, 132.66,
168.22, 177.15; m/z (CI-Isobutane) 250 (100%) [MHϩ Ϫ
cyclohexylideneamine].
rac-1-Isobutyryl-3,3,6,6-tetramethylpiperidine-2-carboxylic
acid cyclohex-1-enylamide 3j.—The title compound was pre-
pared according to GP3 starting from 0.28 g (2 mmol) of
2l, 0.21 g (2 mmol) of cyclohex-1-enyl isocyanide,19 and 0.18 g
(1.7 mmol) of isobutyric acid. The enamide 3j (0.28 g, 42%)
was obtained as a colourless solid, mp 110–113 ЊC; Rf 0.47
(dichloromethane–methanol, 99:1) [Found: C, 71.93; H, 10.26;
N, 8.51. C20H34N2O2 (334.5) requires C, 71.81; H, 10.25; N,
8.37%]; δH (CDCl3) 1.09 [3H, s, C(CH3)2], 1.18 [6H, d,
CH(CH3)2, 3J 7.2], 1.24 [3H, s, C(CH3)2], 1.3–2.5 (12H, m,
rac-1-Isobutyryl-3,3-dimethylpiperidine-2-carboxylic
acid
4e.—The title compound was prepared according to GP4
starting from 0.56 g (1.83 mmol) of 3e. The carboxylic acid 4e
(0.39 g, 94%) was obtained as a colourless solid after crystal-
lization from dichloromethane (two rotamers in a 79:21 ratio
CH2), 1.46 [3H, s, C(CH3)2], 1.53 [3H, s, C(CH3)2], 3.09 [1H, m,
3
1
CH(CH ) , J 7.2], 4.68 (1H, s, NCH), 6.03 (1H, m, C᎐CH),
were observed in the H-NMR spectrum in CDCl3 at room
᎐
3
2
7.75 (1H, br, NH); δC (CDCl3) 20.01, 20.46, 21.98, 22.48, 23.93,
27.79, 28.04, 28.88, 30.14, 31.37, 32.34, 32.46, 33.51, 38.08,
54.85, 63.45, 112.71, 132.62, 170.24, 181.77; m/z (CI-NH3) 335
(100%) [MHϩ Ϫ cyclohexylideneamine].
temperature), mp 122–123 ЊC; Rf 0.38 (dichloromethane–
methanol, 98:2) [Found: C, 62.92; H, 9.26; N, 6.38. C12H21NO3
(227.3) requires C, 63.41; H, 9.31; N, 6.16%]; δH (CDCl3) 1.00
[2.4H, s, C(CH3)2], 1.10 [2.4H, d, CH(CH3)2, 3J 6.6], 1.12 [2.4H,
s, C(CH3)2], 1.60 [2.4H, d, CH(CH3)2, 3J 6.6], 1.1–1.9 (6.4H, m),
2.88 [0.79H, m, CH(CH3)2, 3J 6.6], 2.90 [0.21H, m, CH(CH3)2,
3J 6.6], 3.12 (0.21H, m, NCH2), 3.61 (0.79H, dt, NCH2, 2J 12.5,
rac-1-Isobutyryl-3,3-dimethyl-6,6-diphenylpiperidine-2-
carboxylic acid cyclohex-1-enylamide 3k.—According to GP3
the title compound was obtained from 0.45 g (1.7 mmol) of
2l, 0.18 g (1.7 mmol) of cyclohex-1-enyl isocyanide,19 and 0.15 g
(1.7 mmol) of isobutyric acid. The enamide 3k (0.66 g,
85%) was obtained as a colourless solid, mp 52 ЊC; Rf 0.41
(dichloromethane–methanol, 99:1) [Found: C, 78.91; H, 8.37;
N, 6.24. C30H38N2O2 (458.7) requires C, 78.56; H, 8.35; N,
6.11%]; δH (CDCl3) 0.91 [3H, s, C(CH3)2], 1.04 [3H, s, C(CH3)2],
1.12 [3H, d, CH(CH3)2, 3J 7.2], 1.23 [3H, d, CH(CH3)2, 3J 7.2],
2
3J 4.4), 3.81 (0.79H, d, NCH2, J 12.5), 4.20 (0.21H, s, NCH),
4.61 (0.21H, m, NCH2), 4.98 (0.79H, s, NCH), 8.81 (1H, br,
COOH); δC (CDCl3) 18.51 (ma), 19.21 (mi), 19.38 (ma), 19.75
(mi), 20.21 (mi), 21.15 (ma), 25.78 (ma), 26.05 (mi), 27.56
(mi), 27.76 (ma), 29.84 (mi), 30.56 (ma), 32.12 (ma), 32.26 (mi),
32.35 (mi), 32.75 (ma), 37.76 (mi), 41.76 (ma), 59.85 (ma), 64.35
(mi), 172.76 (mi), 174.41 (ma), 177.90 (ma), 178.01 (mi); m/z
(CI-isobutane) 328 (100%) [MHϩ].
3
1.3–2.7 (12H, m, CH2), 3.09 [1H, m, CH(CH3)2, J 7.2], 3.92
(1H, s, NCH), 5.68 (1H, m, C᎐CH), 7.1–7.6 (11H, m,
(2RS,6RS)-1-Acetyl-3,3-dimethyl-6-phenylpiperidine-2-carb-
oxylic acid 4f.—The title compound was prepared according
to GP4 starting from 3.50 g (9.87 mmol) of 3f. The carb-
oxylic acid 4f (2.37 g, 87%) was obtained as a colourless
solid after crystallization from dichloromethane, mp 125 ЊC
[Found: C, 69.91; H, 7.71; N, 5.04. C16H21NO3 (275.2) requires
᎐
ArH ϩ NH); δC (CDCl3) 19.99, 20.81, 21.38, 21.63, 23.00,
25.37, 29.00, 29.61, 31.47, 32.92, 36.00, 38.00, 60.97, 63.12,
125.52, 126.60, 126.72, 127.44, 128.69, 128.89, 129.05, 136.96,
144.48, 150.02, 176.78, 181.97; m/z (CI-NH3) 459 (100%)
[MHϩ Ϫ cyclohexylideneamine].
3522
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525

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C, 69.79; H, 7.69; N, 5.09%]; δH (CDCl3) 1.11 [3H, s, C(CH3)2],
1.14 [3H, s, C(CH3)2], 1.3–1.5 (2H, m, CH2), 1.98 (3H, s, Ac),
2.0–2.3 (2H, m, CH2), 3.83 (1H, s, 2-H), 5.06 (1H, m, 6-H),
7.2–7.4 (5H, m, ArH), 10.10 (1H, br, COOH); δC (CDCl3)
22.52, 26.97, 28.43, 32.38, 33.15, 34.19, 57.98, 63.26, 125.86,
127.15, 129.00, 141.39, 173.43, 173.73; m/z (CI-isobutane) 276
(100%) [MHϩ].
N-acylated α-amino acid (ϩ)-4h (2.01 g, 73%) as a colourless
solid. [α]D ϩ44.2 (c 1, CHCl3).
(Ϫ)-1-Benzoyl-3,3-dimethylpiperidine-2-carboxylic acid (Ϫ)-
4h.—The filtrate of the (Ϫ)-norephedrinium-(ϩ)-4h salt form-
ation described above was heated to reflux and an additional
1.59 g (10.5 mmol) of (Ϫ)-norephedrine were added to the hot
solution. The mixture was heated for 15 min at reflux. Colour-
less crystals separated from the solution upon slow cooling
to room temperature. The solid was filtered off and further
purified by recrystallization from dichloromethane to yield the
(Ϫ)-norephedrinium salt of (Ϫ)-4h (3.65 g, 84%) as a colourless
solid, mp 146–147 ЊC (Found: C, 70.24; H, 7.90; N, 6.86%);
δH ([D6]DMSO, two rotamers in a 64:36 ratio) 0.80 [3H,
rac-1-(2,4-Dimethoxybenzoyl)-3,3-dimethylpiperidine-2-carb-
oxylic acid 4g.—The title compound was prepared according
to GP4 starting from 0.83 g (1.74 mmol) of 3d. The carb-
oxylic acid 4g (0.58 g, 100%) was obtained as a colourless
oil. Due to hindered rotation around the amidic N–C-bond
1
two rotamers in a 65:35 ratio were observed in the H-NMR
3
spectrum. Rf 0.24 (dichloromethane–methanol, 95:5) [Found:
C, 63.19; H, 7.38; N, 4.41. C17H23NO5 (321.4) requires C, 63.54;
H, 7.21; N, 4.36%]; δH (CDCl3) 0.87 (ma), 0.90 (mi) [3H, s,
C(CH3)2], 1.12 (ma), 1.16 (mi) [3H, s, C(CH3)2], 1.2–1.8 (4H, m,
NCH2CH2CH2), 3.49 (1H, m, NCH2), 3.7–3.8 (6H, 4s, OMe),
4.69 (1H, m, NCH2), 4.99 (ma), 5.10 (mi) (1H, s, NCH), 6.3–6.5
(2H, m, ArH), 7.1–7.2 (1H, m, ArH); δC (CDCl3) 20.17 (mi),
20.95 (ma), 25.24 (mi), 25.76 (ma), 27.76 (ma), 32.27 (mi), 32.53
(mi), 32.85 (ma), 33.18 (ma), 37.82 (mi), 44.21 (ma ϩ mi), 54.46
(mi), 55.06 (mi), 55.25 (ma), 55.31 (ma), 60.52 (mi), 65.48 (ma),
97.63 (mi), 98.06 (ma), 104.76 (ma), 104.89 (mi), 117.35 (mi),
117.87 (ma), 129.20 (ma), 129.80 (mi), 156.19 (mi), 156.29
(ma), 161.77 (ma ϩ mi), 169.79 (ma), 170.06 (mi), 173.99 (ma),
174.20 (mi); m/z (CI-isobutane) 322 (100%) [MHϩ].
s, C(CH3)2], 0.86 (3H, d, CH3CH, J 6.7), 1.00, 1.07 [3H, 2s,
C(CH3)2], 1.0–2.0 (4H, m, CH2), 3.2–3.6 (3H, m), 3.94
(mi), 4.38 (mi) (1H, m, NCH2), 4.61 (mi), 4.96 (1H, s, NCH-
COO), 7.1–7.5 (10H, m, ArH); δC ([D6]DMSO, mixture of
rotamers) 12.09, 20.58, 21.31, 26.16, 26.42, 28.45, 28.85, 32.03,
32.65, 33.03, 33.22, 37.48, 43.54, 51.75, 62.79, 69.11, 71.60,
125.91, 126.31, 126.73, 126.96, 128.02, 128.39, 128.68, 128.89,
137.51, 141.96, 169.83, 170.23, 173.84, 174.20.
The (Ϫ)-norephedrinium salt of (Ϫ)-4h was dissolved in 50
ml of water and treated with 1 ml of conc. HCl. The mixture
was extracted with 30 ml of dichloromethane three times. After
drying of the combined organics over MgSO4 the solvent was
removed in vacuo to give the enantiomerically pure N-acylated
α-amino acid (Ϫ)-4h (1.72 g, 63%) as a colourless solid,
[α]D Ϫ43.8 (c 1, CHCl3).
rac-1-Benzoyl-3,3-dimethylpiperidine-2-carboxylic
acid
4h.—According to GP4, hydrolysis of 13.00 g (33 mmol) of
3a gave the title compound. The carboxylic acid 4h (5.60 g,
65%) was obtained as a colourless solid, mp 47–49 ЊC. Due to
hindered rotation around the amidic NC-bond two rotamers in
a 68:32 ratio were observed in the 1H-NMR spectrum. Rf 0.60
(dichloromethane–methanol, 9:1) [Found: C, 68.82; H, 7.46; N,
5.72. C15H19NO3 (261.3) requires C, 68.94; H, 7.33; N, 5.36%];
δH (CDCl3) 0.92 (ma), 0.94 (mi) [3H, s, C(CH3)2], 1.14 (mi), 1.16
(ma) [3H, s, C(CH3)2], 1.2–2.0 (4H, m, NCH2CH2CH2), 3.36
(mi), 3.58 (ma), 3.80 (mi) (2H, m, NCH2), 4.66 (mi), 5.04 (ma)
(1H, s, NCH), 7.41 (5H, m, ArH), 10.17 (1H, br, COOH);
δC (CDCl3) 20.20 (mi), 21.05 (ma), 25.65 (mi), 26.16 (ma), 27.49
(mi), 27.87 (ma), 32.56 (mi), 33.06 (ma), 38.33 (ma), 39.65 (mi),
44.57 (ma ϩ mi), 60.57 (ma), 66.39 (mi), 126.60 (mi), 126.86
(ma), 128.40 (ma ϩ mi), 129.83 (mi), 130.02 (ma), 133.53 (ma),
135.53 (mi), 171.25 (mi), 172.72 (ma), 174.50 (ma ϩ mi); m/z
(CI-isobutane) 262 (100%) [MHϩ].
(ϩ)-1-Benzoyl-3,3-dimethylpiperidine-2-carboxylic acid (ϩ)-
4h.—5.50 g (21 mmol) of N-acylated α-amino acid ( )-4h
were dissolved in diethyl ether and heated to reflux. 1.59 g
(10.5 mmol) of (Ϫ)-norephedrine were added to the hot solu-
tion and the mixture was heated to reflux for 15 min. Colourless
crystals separated from the solution upon slow cooling to room
temperature. The solid was filtered off, and crystallized from
diethyl ether–dichloromethane to yield the (Ϫ)-norephedrinium
salt of (ϩ)-4h (3.90 g, 89%) as a colourless solid, mp 158–
159 ЊC [Found: C, 69.59; H, 7.57; N, 6.92. C24H32N2O4 (412.6)
requires C, 69.87; H, 7.82; N, 6.79%]; δH ([D6]DMSO–CDCl3,
two rotamers in a 68:32 ratio) 0.84, 0.91 [3H, 2s, C(CH3)2],
0.96 (3H, d, CH3CH, 3J 6.7), 1.03, 1.09 [3H, 2s, C(CH3)2], 1.0–
2.0 (4H, m, CH2), 3.2–3.9 (3H, m), 4.48 (mi) (1H, m, NCH2),
4.69 (mi), 5.06 (1H, s, NCHCOO), 7.1–7.4 (10H, m, ArH);
δC ([D6]DMSO–CDCl3, mixture of rotamers) 10.74, 19.41,
20.24, 24.87, 25.24, 27.16, 27.39, 30.86, 31.61, 31.96, 33.12,
36.66, 42.78, 51.22, 61.99, 67.95, 70.49, 124.66, 125.20, 125.43,
125.74, 126.73, 126.98, 127.47, 127.77, 136.06, 140.11, 169.70,
169.95, 173.91.
rac-1-Chloroacetyl-3,3-dimethylpiperidine-2-carboxamide
4i.—The title compound was prepared according to GP4
using 0.25 g (0.68 mmol) of 3b as starting material. The
carboxamide 4i (0.17 g, 100%) was isolated from the dichloro-
methane extracts which resulted from extraction of the alkaline
aqueous phase as a colourless solid; Rf 0.30 (dichloromethane–
methanol, 95:5) [Found: C, 51.92; H, 7.42; N, 12.09.
C10H17ClN2O2 (232.7) requires C, 51.61; H, 7.36; N, 12.04%];
δH (CDCl3) 0.97 [3H, s, C(CH3)2], 1.10 [3H, s, C(CH3)2], 1.2–2.4
(4H, m, NCH2CH2CH2), 3.68 (2H, m, NCH2), 4.09 (1H, d,
ClCH2, 2J 15.9), 4.18 (1H, d, ClCH2, 2J 15.9), 4.64 (1H, s,
NCH), 6.03 (1H, s, NH2), 6.52 (1H, s, NH2); δC (CDCl3) 21.21,
25.98, 27.18, 31.68, 32.12, 41.45, 43.04, 59.94, 167.11, 171.93;
m/z (CI-isobutane) 234 (100%) [MHϩ].
rac-1-Benzoyl-3,3-dimethylpiperidine-2-carboxamide
4j.—
The title compound was prepared according to GP4 using
13.00 g (33 mmol) of 3a as starting material. The carboxamide
4f was isolated from the dichloromethane extracts from the
extraction of the alkaline aqueous phase. It was crystallized
from diethyl ether to give 4j (2.7 g, 31%) as a colourless solid,
mp 154–155 ЊC [Found: C, 69.39; H, 7.58; N, 10.81. C15H20-
N2O2 (260.3) requires C, 69.20; H, 7.74; N, 10.76%]; δH (CDCl3)
1.06, 1.10 [6H, 2s, C(CH3)2], 1.2–2.2 (4H, m, NCH2CH2CH2),
3.53 (2H, m, NCH2), 4.77 (1H, s, NCH), 6.08 (1H, s, NH2),
6.87 (1H, s, NH2), 7.38 (5H, m, ArH); δC (CDCl3) 21.40,
26.22, 27.20, 32.15, 44.43, 59.86, 126.72, 128.36, 129.72,
135.75, 171.85, 174.50; m/z (CI-isobutane) 261 (100%) [MHϩ].
rac-3,3-Dimethyl-1-(2-nitrobenzoyl)piperidine-2-carboxamide
4k.—The title compound was prepared from 0.69 g (1.49
mmol) of 3c according to GP4. The carboxamide 4k (0.28 g,
61%) was isolated from the dichloromethane extracts from the
extraction of the alkaline aqueous phase as a colourless solid,
mp 163–164 ЊC. Due to hindered rotation around the amidic
NC-bond two rotamers in a 58:42 ratio were observed in the
1H-NMR spectrum [Found: C, 59.28; H, 6.34; N, 13.80.
C15H19N3O4 (305.3) requires C, 59.01; H, 6.27; N, 13.76%];
δH (CDCl3) 1.09 [3H, s, C(CH3)2], 1.21 (ma), 1.26 (mi) [3H,
s, C(CH3)2], 1.2–2.4 (4H, m, NCH2CH2CH2), 3.16 (1H, m,
NCH2), 3.41 (mi), 3.69 (ma) (1H, m, NCH2), 4.74 (ma), 4.99
(mi) (1H, s, NCH), 5.85 (mi), 5.97 (ma) (1H, s, NH2), 6.44 (mi),
6.82 (ma) (1H, s, NH2), 7.3–8.2 (4H, m, ArH); δC (CDCl3) 20.91
(ma), 21.26 (mi), 26.05 (mi), 26.31 (ma), 26.92 (ma), 27.57 (mi),
The (Ϫ)-norephedrinium salt of (ϩ)-4h was dissolved in 50
ml of water and treated with 1 ml of conc. HCl. The mixture
was extracted with 30 ml of dichloromethane three times.
After drying of the combined organics over MgSO4 the solvent
was removed in vacuo to give the enantiomerically pure
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525
3523

View Article Online
32.00 (mi), 32.09 (ma ϩ mi), 32.30 (ma), 43.54 (ma), 44.69 (mi),
59.45 (ma ϩ mi), 124.63 (mi), 124.74 (ma), 127.37 (mi), 128.01
(ma), 129.68 (mi), 129.92 (ma), 132.73 (ma), 132.97 (mi), 134.32
(mi), 134.54 (ma), 144.81 (ma ϩ mi), 167.42 (mi), 168.12 (ma),
170.52 (ma), 172.14 (mi); m/z (CI-isobutane) 306 (100%)
[MHϩ].
46.37, 54.16, 61.57, 177.52, 198.88; m/z (CI-isobutane) 358
(100) [MHϩ].
1-Isobutyryl-3-methyl-3-propylpiperidine-2-thiocarboxylic
acid S-ethyl ester 5e.—The title compound was prepared accor-
ding to GP6 starting from 0.28 g (2 mmol) of 2d, 0.33 g
(2 mmol) of 4-tert-butylcyclohex-1-enyl isocyanide,19 and 0.18 g
(2 mmol) of isobutyric acid. The S-ethyl ester 5e (0.32 g, 54%)
was obtained as a 50:50 (trans:cis) mixture of two racemic
diastereomers as a colourless oil. The diastereomers were
separated by column chromatography (n-hexane–ethyl acetate
9:1).
2-Isobutyryl-3-methyl-2-azaspiro[5,5]undecane-1-carboxylic
acid methyl ester 5a.—The title compound was prepared
according to GP6 using 0.33 g (2 mmol) of 2h, 0.37 g (2 mmol)
of 4-phenylcyclohex-1-enyl isocyanide,19 and 0.18 g (2 mmol)
of isobutyric acid as starting materials. The methyl ester 5a
(0.35 g, 60%) was obtained as a 78:22 (trans :cis) mixture
of two racemic diastereomers as a colourless oil. Rf 0.80
(dichloromethane–methanol, 98:2) [Found: C, 68.91; H, 10.01;
N, 4.82. C17H29NO3 (295.3) requires C, 69.12; H, 9.89; N,
4.74%]; δH (CDCl3) 1.11 [3H, d, CH(CH3)2, 3J 6.6], 1.17
[3H, d, CH(CH3)2, 3J 6.6], 1.31 [3H, d, CHCH3, 3J 7.2], 1.3–2.0
(14H, m, CH2), 2.84 (ma), 3.00 (mi) [1H, m, CH(CH3)2, 3J 6.6],
3.64 (ma), 3.66 (mi) (3H, s, OCH3), 4.18 (ma), 4.77 (mi) (1H, m,
CH3CHN), 5.21 (ma), 5.35 (mi) (1H, s, NCH); δC (CDCl3, two
diastereomers) 19.23, 19.56, 20.44, 21.14, 21.33, 23.59, 24.04,
24.49, 24.91, 26.07, 27.44, 29.87, 30.60, 33.31, 33.59, 34.48,
35.45, 44.17, 47.34, 51.12, 51.38, 57.08, 62.08, 170.60, 172.41,
177.86, 178.31; m/z (CI-isobutane) 296 (100%) [MHϩ].
First fraction: 0.16 g (27%) yield; Rf 0.33 (n-hexane–ethyl
acetate 9:1) [Found: C, 64.52; H, 9.81; N, 4.70. C16H29NO2S
(299.5) requires C, 64.17; H, 9.76; N, 4.68%]; δH (C–N rotamers
in a 87:13 ratio, CDCl3) 0.92 (3H, m, CH3CH2CH2), 1.00 (3H,
3
3
s, CH3C), 1.11 [3H, d, J 6.6, CH(CH3)2], 1.16 [3H, d, J 6.6,
CH(CH3)2], 1.23 (3H, t, 3J 7.4, CH3CH2S), 1.39–1.73 (6H,
m, CH2), 1.90 (1H, dt, 3J 4.9, 2J 12.9, 4-H), 2.38 (1H, m, 2J 13.2,
3
3
4-H), 2.91 [3H, m, J 6.6, J 7.4, CH3CH2S, CH(CH3)2], 3.42
3
2
(1H, dt, J 4.4, J 12.9, NCH2), 3.80 (ma), 4.63 (mi) (1H, d,
2J 13.2, NCH2), 4.22 (mi), 5.14 (ma) (1H, s, NCH); δC (CDCl3,
two rotamers) 14.27, 14.69, 16.29, 18.75, 19.47, 19.76, 20.18,
21.28, 23.25, 23.90, 27.49, 29.91, 30.21, 30.55, 32.34, 39.36,
41.21, 42.01, 46.16, 63.97, 176.20, 197.68; m/z (CI-isobutane)
335 (100%) [MHϩ].
(1RS,3RS)-2-Isobutyryl-3-isopropyl-2-azaspiro[5,5]undec-
ane-1-carboxylic acid methyl ester 5b.—According to GP6
the title compound was obtained from 0.39 g (2 mmol) of 2j,
0.33 g (2 mmol) of 4-tert-butylcyclohex-1-enyl isocyanide,19
and 0.18 g (2 mmol) of isobutyric acid. The methyl ester 5b
(0.43 g, 67%) was obtained as a colourless oil, Rf 0.82
(dichloromethane–methanol, 98:2) [Found: C, 70.82; H, 10.19;
N, 4.35. C19H33NO3 (323.5) requires C, 70.55; H, 10.28; N,
Second fraction: 0.16 g (27%) yield; Rf 0.25 (n-hexane–ethyl
acetate 9:1) (Found: C, 64.40; H, 9.69; N, 4.74%); δH (C–N
rotamers in a 89:11 ratio, CDCl3) 0.88 (3H, m, CH3CH2CH2),
0.91 (3H, s, CH3C), 1.12 [3H, d, 3J 6.6, CH(CH3)2], 1.17 [3H, d,
3
3J 6.6, CH(CH3)2], 1.23 (3H, t, J 7.7, CH3CH2S), 1.31–1.80
3
2
(6H, m, CH2), 1.96 (1H, dt, J 4.9, J 13.2, 4-H), 2.86 [3H, m,
3J 6.6, 3J 7.7, CH3CH2S, CH(CH3)2], 3.42 (1H, dt, 3J 3.9,
3
3
4.33%]; δH (CDCl3) 0.99 [3H, d, CHCH(CH3)2, J 6.6], 1.02
2J 13.2, NCH2), 3.81 (ma), 4.62 (mi) (1H, d, J 13.2, NCH2),
3
3
[3H, d, CHCH(CH ) , J 6.6], 1.09 [3H, d, O᎐CCH(CH ) , J
4.24 (mi), 5.18 (ma) (1H, s, NCH); δC (CDCl3, two rotamers)
14.38, 14.75, 16.34, 18.83, 19.46, 19.70, 20.25, 21.55, 21.98,
22.67, 23.17, 23.65, 27.52, 29.63, 30.52, 31.29, 31.66, 38.41,
41.24, 42.20, 42.45, 63.97, 69.58, 176.04, 197.21; m/z (CI-
isobutane) 301 (100%) [MHϩ].
1-Isobutyryl-3-methyl-3-phenyl-piperidine-2-thiocarboxylic
acid 5f. According to GP6 the title compound was prepared
using 0.35 g (2 mmol) of 2e, 0.33 g (2 mmol) of 4-tert-butyl-
cyclohex-1-enyl isocyanide,19 and 0.18 g (2 mmol) of isobutyric
acid as starting materials. The S-ethyl ester 5f (0.35 g, 53%)
was obtained as a 50:50 (trans :cis) mixture of two racemic
diastereomers as a colourless oil. The diastereomers were
separated by column chromatography (n-hexane–ethyl acetate
9:1).
᎐
3
2
3 2
6.6], 1.13 [3H, d, O=CCH(CH3)2, 3J 6.6], 1.2–1.9 (15H, m,
NCHCH ϩ 7 × CH ), 2.82 [1H, m, O᎐CCH(CH ) , 3J 6.6],
᎐
2
3 2
3.52 (1H, m, NCHCH), 3.65 (3H, s, OCH3), 5.38 (1H, s, CHN);
δC (CDCl3) 18.89, 19.12, 19.28, 19.37, 21.26, 23.18, 25.85, 26.76,
27.09, 28.08, 28.36, 30.27, 33.12, 37.65, 50.91, 60.34, 60.74,
169.00, 176.30; m/z (CI-isobutane) 324 (100%) [MHϩ].
(1RS,3RS)-2-Isobutyryl-3-phenyl-2-azaspiro[5,5]undecane-
1-carboxylic acid methyl ester 5c. The title compound was pre-
pared according to GP6 using 0.45 g (2 mmol) of 2k, 0.37 g
(2 mmol) of 4-phenylcyclohex-1-enyl isocyanide,19 and 0.18 g
(2 mmol) of isobutyric acid as starting materials. The methyl
ester 5c (0.31 g, 44%) was obtained as a colourless oil, Rf 0.66
(dichloromethane–methanol, 98:2) [Found: C, 74.02; H, 8.69;
N, 3.90. C22H31NO3 (357.5) requires C, 73.92; H, 8.74; N,
First fraction: 0.12 g (18%) yield; Rf 0.26 (n-hexane–ethyl
acetate 9:1) [Found: C, 68.54; H, 8.23; N, 4.02. C19H27NO2S
(333.5) requires C, 68.43; H, 8.16; N, 4.20%]; δH (CDCl3) 0.96
[3H, d, 3J 6.7, CH(CH3)2], 1.09 [3H, d, 3J 6.7, CH(CH3)2], 1.27
3
3.92%]; δH (CDCl ) 0.86 [3H, d, O᎐CCH(CH ) , J 6.6], 1.05
᎐
3
3 2
[3H, d, O᎐CCH(CH ) , 3J 6.6], 1.2–2.4 (14H, m, 7 × CH ), 2.56
᎐
3
2
2
[1H, m, O᎐CCH(CH ) , 3J 6.6], 3.66 (3H, s, OCH ), 4.18 (1H, s,
᎐
3
2
3
3
3
CHN), 5.05 [1H, dd, NCHPh, J 6.1 and 6.6], 7.1–7.4 (5H, m,
ArH); δC (CDCl3) 18.71, 19.84, 21.34, 21.48, 25.81, 26.74,
27.56, 31.39, 32.41, 35.41, 36.05, 51.34, 57.05, 63.74, 125.36,
126.71, 128.42, 143.84, 171.48, 179.03; m/z (CI-isobutane) 358
(100%) [MHϩ].
(3H, t, J 7.3, CH3CH2S), 1.32 (3H, s, CH3C), 1.56 (1H, dd,
2
3J 2.4, J 13.4, 4-H), 2.08–2.26 (2H, m, 2 × 5-H), 2.35 (1H, dt,
3J 3.7, 2J 13.4, 4-H), 2.72 [1H, m, 3J 6.7, CH(CH3)2], 2.79–3.02
(2H, m, 3J 7.3, CH2S), 3.53 (1H, dt, 3J 3.7, 2J 13.0, NCH2), 3.71
3
2
(1H, dd, J 4.3, J 13.0, NCH2), 5.96 (1H, s, NCH), 7.15–7.35
(5H, m, ArH); δC (CDCl3) 14.24, 18.49, 19.26, 21.59, 23.63,
29.73, 30.58, 31.87, 41.17, 42.34, 62.21, 125.60, 126.01, 128.40,
145.58, 175.99, 197.86; m/z (CI-isobutane) 335 (100%) [MHϩ].
Second fraction: 0.17 g (26%) yield; Rf 0.17 (n-hexane–ethyl
acetate 9:1) (Found: C, 68.31; H, 8.10; N, 4.23%); δH (C–N
rotamers in a 88:12 ratio, CDCl3) 0.95 (3H, t, 3J 7.3,
CH3CH2S), 1.18 [3H, d, 3J 6.7, CH(CH3)2], 1.24 [3H, d, 3J 6.7,
CH(CH3)2], 1.27 (3H, s, CH3C), 1.79–2.02 (3H, m, CH2), 2.47–
2.73 (3H, m, 3J 7.3, CH2S, 4-H), 2.93 [1H, m, 3J 6.7, CH(CH3)2],
3.25 (1H, t, NCH2), 3.90 (ma), 4.72 (mi) (1H, d, 2J 14.0, NCH2),
4.88 (mi), 5.90 (ma) (1H, s, NCH), 7.15–7.50 (5H, m, ArH);
δC (CDCl3, two rotamers) 14.24, 18.81, 19.41, 19.76, 20.18,
21.54, 22.74, 23.26, 26.54, 26.85, 29.21, 29.65, 30.46, 30.78,
39.27, 41.86, 64.54, 70.08, 125.21, 125.44, 126.05, 126.41,
(1RS,3SR)-3-Ethyl-2-isobutyryl-2-azaspiro[5.5]undecane-1-
thiocarboxylic acid S-ethyl ester 5d. Starting from 0.36 g
(2 mmol) of 2i, 0.33 g (2 mmol) of 4-tert-butylcyclohex-1-enyl
isocyanide,19 and 0.18 g (2 mmol) of isobutyric acid the title
compound was prepared according to GP6. The S-ethyl ester
5d (0.20 g, 29%) was obtained as an orange oil, Rf 0.25
(n-hexane–MeOBut, 9:1) [Found: C, 67.44; H, 9.83; N, 4.19.
C19H33NO2S (339.5) requires C, 67.21; H, 9.80; N, 4.13%];
3
3
δH (CDCl3) 0.84 (3H, t, J 7.7, CH3CH2C), 1.14 [3H, d, J 6.6,
3
3
CH(CH3)2], 1.18 [3H, d, J 6.6, CH(CH3)2], 1.21 (3H, t, J 7.7,
3
3
CH3CH2S), 1.33–2.47 (16H, m), 2.82 [3H, m, J 6.6, J 7.7,
CH(CH3)2, CH3CH2S], 3.84 (1H, dd, 3J 6.6, 2J 13.2, NCHCH2),
5.50 (1H, s, NCH); δC (CDCl3) 11.59, 14.24, 19.23, 20.35, 21.35,
22.60, 23.25, 25.36, 26.20, 27.56, 30.87, 33.04, 35.21, 41.25,
3524
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525

View Article Online
M. Keller, D. E. Ryan, B. Rohwedder, T. Wöhr and M. Mutter,
J. Am. Chem. Soc., 1997, 119, 918.
4 M. C. Ng-Youn-Chen, A. N. Serreqi, Q. Huang and R. J.
Kazlauskas, J. Org. Chem., 1994, 59, 2075, and references cited
therein.
5 W. J. Wu and D. R. Raleigh, J. Org. Chem., 1998, 63, 6689, and
references cited therein.
6 M. J. Genin, W. B. Gleason and R. L. Johnson, J. Org. Chem., 1993,
58, 860.
7 D. Kern, M. Schutkowski and T. Drakenberg, J. Am. Chem. Soc.,
1997, 119, 8403.
128.40, 145.58, 176.19, 196.37; m/z (CI-isobutane) 335 (100%)
[MHϩ].
rac-3,3-Dimethyl-1-(trifluoroacetyl)piperidine-2-carboxylic
acid (2-methylcyclohex-1-enyl)amide 6. Reaction of 0.55 g
(5 mmol) of 2a, 0.61 g (5 mmol) of 2-methylcyclohex-1-enyl
isocyanide,20 and 0.70 g (5 mmol) of trifluoroacetic acid accor-
ding to GP3 gave the title compound. Dichloromethane was
substituted for methanol as a solvent. The enamide 6 (0.61 g,
35%) was obtained as a colourless solid after crystallization
from diethyl ether, mp 154–156 ЊC; Rf 0.88 (dichloromethane–
MeOH, 99:1) [Found: C, 59.06; H, 7.23; N, 8.15. C17H25F3N2O2
(346.4) requires C, 58.95; H, 7.27; N, 8.09%]; δH (CDCl3) 0.94,
1.08 [6H, 2s, C(CH3)2], 1.2–2.6 (12H, m, cyclohexenyl-
CH2 ϩ NCH2CH2CH2), 3.80 (2H, m, NCH2), 4.55 (1H, s,
CHN), 7.24 (1H, br, NH); δC (CDCl3) 18.18, 21.18, 22.40,
22.83, 25.86, 27.08, 28.27, 31.68, 32.55, 45.29, 61.85,
116.50 (q, CF3, 1JCF 287.7), 126.10, 127.44, 157.31 (q, CF3C=O,
2JCF 37.1), 166.64; m/z (CI-NH3) 347 (80%) [MHϩ], 236 (100)
[MHϩ Ϫ 2-methylcyclohexylideneamine].
rac-3,3-Dimethylpiperidine-2-carboxylic acid (2-methylcyclo-
hex-1-enyl)amide 7. Trifluoroacetamide 6 (0.39 g, 1.10 mmol)
was dissolved in 5 ml of MeOH and 5 ml of saturated aq.
K2CO3. The solution was stirred for 24 h at room temperature
and extracted three times with 10 ml of dichloromethane each.
After drying of the organics over MgSO4 and evaporation of
the solvent in vacuo the crude product was crystallized from
dichloromethane–diethyl ether to give the N-deprotected amino
acid 7 (0.26 g, 94%) as a colourless solid [Found: C, 71.72; H,
10.51; N, 11.23. C15H26N2O (250.4) requires C, 71.96; H, 10.47;
N, 11.19%]; δH (CDCl3) 0.93, 1.06 [6H, 2s, C(CH3)2], 1.2–2.6
(13H, m, CH2 ϩ NH), 1.59 (3H, s, CH3), 3.67 (2H, m, NCH2),
4.26 (1H, s, CHN), 7.01 (1H, br, NH); δC (CDCl3) 18.22, 21.22,
22.44, 22.87, 25.98, 27.09, 28.34, 30.70, 31.67, 32.55, 42.55,
61.92, 126.81, 127.25, 166.39; m/z (CI-NH3) 251 (70%) [MHϩ],
140 (100) [MHϩ Ϫ 2-methylcyclohexylideneamine].
8 (a) R. T. Shuman, P. L. Ornstein, J. W. Paschal and P. D. Gesellchen,
J. Org. Chem., 1990, 55, 738, and references cited herein; (b) L. F.
Tietze and M. Bratz, Synthesis, 1989, 439; (c) C. Agami, D. Bihan,
L. Hamon, C. Kadouri-Puchot and M. Lusinchi, Eur. J. Org. Chem.,
1998, 2461; (d) R. Pauly, N. A. Sasaki and P. Potier, Tetrahedron
Lett., 1994, 35, 237; (e) P. J. Murray and I. D. Starkey, Tetrahedron
Lett., 1996, 37, 1875; ( f ) P. E. Esch, I. M. Boska, H. Hiemstra,
R. F. de Boer and W. N. Speckamp, Tetrahedron, 1991, 47, 4039.
9 (a) I. Ugi and G. Kaufhold, Justus Liebigs Ann. Chem., 1967, 709,
11; (b) R. O. Duthaler, Tetrahedron, 1994, 50, 1539; (c) A. Dömling,
Combinatorial Chemistry and High Throughput Screening, 1998, 1, 1.
10 M. Hatam, D. Tehranfar and J. Martens, Synthesis, 1994, 619.
11 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 2nd edn., Wiley-Interscience, New York, 1991, p. 349.
12 T. Lindhorst, H. Bock and I. Ugi, Tetrahedron, 1999, 55, 7411.
13 I. Ugi, J. Prakt. Chem., 1997, 339, 499.
14 (a) I. Ugi and F. K. Rosendahl, Justus Liebigs Ann. Chem., 1963, 666,
65; (b) T. A. Keating and W. Armstrong, J. Am. Chem. Soc., 1996,
118, 2574.
15 W. Maison, M. Kosten, A. Charpy, J. Kintscher-Langenhagen,
I. Schlemminger, A. Lützen, O. Westerhoff and J. Martens, Eur. J.
Org. Chem., 1999, 2433.
16 (a) I. Ugi and C. Steinbrückner, Chem. Ber., 1961, 94, 2802; (b) T. A.
Keating and R. W. Armstrong, J. Org. Chem., 1998, 63, 867.
17 For a review see: R. W. Hoffmann, Chem. Rev., 1989, 89, 1841;
D. Seebach, B. Lamatsch, R. Amstutz, A. K. Beck, M. Dobler,
M. Egli, R. Fitzi, M. Gautschi, B. Herradon, P. C. Hidber,
J. J. Irwin, R. Locher, M. Maestro, T. Maetzke, A. Mourino, E.
Pfammatter, D. A. Plattner, C. Schickli, W. B. Schweizer, P. Seiler
and G. Stucky, Helv. Chim. Acta, 1992, 75, 913.
18 E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994.
19 W. Maison, I. Schlemminger, O. Westerhoff and J. Martens, Bioorg.
Med. Chem., submitted for publication.
20 This compound was prepared analogously to other cyclohexenyl
isocyanides by a method recently described by us.19 It was
contaminated with 10% of rac-6-methylcyclohex-1-enyl isocyanide
and was used without further purification.
References and notes
1 (a) M. Williams, E. A. Kowaluk and S. P. Arneric, J. Med. Chem.,
1999, 42, 1481; (b) G. Benz, R. Henning and J.-P. Stasch, Angew.
Chem., Int. Ed. Engl., 1991, 30, 1702; (c) A. S. Dutta, Drugs Future,
1988, 13, 43; (d) 761; (e) M. A. Patane, R. M. DiPardo, R. A. P.
Price, R. S. L. Chang, R. W. Ransom, S. S. O’Malley, J. Di Salvo and
M. G. Block, Bioorg. Med. Chem. Lett., 1998, 8, 2495.
2 (a) I. L. Karle, R. Kaul, R. B. Rao, S. Raghothama and P. Balaram,
J. Am. Chem. Soc., 1997, 119, 12048; (b) M. Kahn, Tetrahedron,
1993, 49, 3433; (c) M. Tanaka, N. Imawaka, M. Kurihara and
H. Suemune, Helv. Chim. Acta, 1999, 82, 494.
21 H. Zondler and W. Pfleiderer, Justus Liebigs Ann. Chem., 1972, 759,
84.
22 J. R. Smolanoff (Rohm and Haas Co.), U.S. Pat. 2 756 360, 1978
(Chem. Abstr., 1978, 89, 124589f).
3 (a) S. Hanessian, G. McNaughton-Smith, H.-G. Lombart and
W. D. Lubell, Tetrahedron, 1997, 53, 12789; (b) M. W. MacArthur
and J. M. Thornton, J. Mol. Biol., 1991, 218, 397; (c) P. Dumy,
Paper 9/05119H
J. Chem. Soc., Perkin Trans. 1, 1999, 3515–3525
3525