Intramolecular N to N acyl migration in conformationally mobile 1′-acyl-1-benzyl-3′,4′-dihydro-1′H-spiro[piperidine-4, 2′-quinoline] systems promoted by debenzylation conditions (HCOONH 4/Pd/C)

Article abstract of DOI:10.2478/s11532-011-0082-y

We report an efficient and useful synthesis of new attractive spiropiperdine scaffolds 4 based on an intramolecular acyl transfer process in 1'-acyl-1-benzyl-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinolines] 3 using simple and mild debenzylation reaction conditions (HCOONH₄/Pd/C). The compounds 3 were prepared by acylating 1-benzyl-4'-methyl-3',4'-dihydro-1'H- spiro[piperidine- 4,2'-quinolines] 2 that are easily available from 1-benzyl-4-piperidone 1. The intramolecular character of this process was proven primarily through a crossover experiment technique. Through an examination of all spectroscopic information (¹H, ¹³C NMR, VT ^-1H NMR, and ²D NMR) it was possible to correctly predict amide configurations and piperidine ring conformations of starting and final spiropiperidine compounds. Versita Sp. z o.o.

Full text of DOI:10.2478/s11532-011-0082-y

Cent. Eur. J. Chem. • 9(5) • 2011 • 877-885
DOI: 10.2478/s11532-011-0082-y
Central European Journal of Chemistry
Intramolecular N to N acyl migration in
conformationally mobile 1´-acyl-1-benzyl-3´,4´-
dihydro-1´H-spiro[piperidine-4,2´-quinoline]
systems promoted by debenzylation
conditions (HCOONH4/Pd/C)
Research Article
Leonor Y. Vargas Méndez1, Vladimir V. Kouznetsov2*
1Environmental Research Group, Environmental Chemistry Faculty,
Santo Tomas University, A.A. 1076, Bucaramamga, Colombia
2Laboratory of Organic & Biomolecular Chemistry , School of Chemistry,
Industrial University of Santander, A.A. 678, Bucaramamga, Colombia
Received 17 March 2011; Accepted 22 May 2011
Abstract:
We report an efficient and useful synthesis of new attractive spiropiperdine scaffolds 4 based on an intramolecular acyl transfer
process in 1´-acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinolines] 3 using simple and mild debenzylation reaction
conditions (HCOONH4/Pd/C). The compounds 3 were prepared by acylating 1-benzyl-4´-methyl-3´,4´-dihydro-1´H-spiro[piperidine-
4,2’-quinolines] 2 that are easily available from 1-benzyl-4-piperidone 1. The intramolecular character of this process was
proven primarily through a crossover experiment technique. Through an examination of all spectroscopic information (1H, 13C NMR,
VT-1H NMR, and 2D NMR) it was possible to correctly predict amide configurations and piperidine ring conformations of starting and
final spiropiperidine compounds.
Keywords: Spiropiperidines • 1´-Acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinolines] • Intramolecular acyl transfer process
• Debenzylation reaction
© Versita Sp. z o.o.
1. Introduction
or isoquinoline and pyridine derivatives [14] and do not
focus on synthetic aspects of these types of the organic
Intra- and intermolecular transfer processes of one
chemical group (acyl, amine, amide etc) as a part of
a molecule (donor) to another one (acceptor) are very
important in organic chemistry and bioorganic chemistry,
where they play a pivotal role in normal cellular function
[1-4]. Among these transfer reactions, the acyl (acetyl)
group transfer of organic molecules, both synthetic and
natural, is studied more often. In the biological processes,
this is usually an intermolecular reaction catalyzed by
acetyltransferases [5,6],which can detoxicate xenobiotics
or drugs by a N-acetylation reaction [7-10]. In the organic
investigations, acyl transfer reactions were, and still are,
objects of discussion of possible mechanisms. Moreover,
the studies on N-N acyl migration limit with simple
substrates, e.g. fenolates and phenyl acetates [11-13]
reactions. In contrast, intramolecular O-N acyl migration
reactions are more used in the synthesis of complex
substrates both in organic and medicinal chemistry
[15-17].
On the other hand, the piperidine ring is the
commonest heterocyclic unit of many alkaloids, and
is a key part of numerous drug candidates, this is why
research in piperidine chemistry and synthesis continues
to be prominent [18]. It was reported that during a
decade (1988-1998) there were over 12.000 piperidine
compounds mentioned in clinical and preclinical
studiem, and among them, 1,4-disubstituted piperidines
dominated [19]. Thus, it is not surprising that the chemical
literature reveals an increasing number of publications
on these derivatives with varied biological activities.
* E-mail: kouznet@uis.edu.co
877

Intramolecular N to N acyl migration in conformationally mobile
1´-acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinoline]
systems promoted by debenzylation conditions (HCOONH4/Pd/C)
Among diverse simple piperidine derivatives 1-benzyl-
4-piperidone has been used as starting material en
route to a considerable number of piperidine drugs.
1-benzyl-4-piperidone continues to be very useful and
important starting material because of its availability,
physical stability, chemical reactivity, and low cost, due
to the N-benzyl moiety as latent protector group. The
benzyl moiety is one of the most commonly employed
protecting groups for the heteroatom functionality in
organic synthesis. Deprotection of N-benzyl group by
catalytic transfer hydrogenolysis is a safe and simple
operation between a catalyst and hydrogen gas or
another hydrogen donor [20]. Spiropiperdine derivatives
are also important piperidine scaffolds in the drug
development. For instance, some 1’H-spiro[piperidine-
4,2’-quinolines] A or 4’,4’-dimethyl-3’,4’-dihydro-1’H-
spiro[piperidine-4,2’-quinolines] B were designed as
potential antioxidant agents [21]. The spiro system
2. Experimental procedure
2.1. General
The general route for the synthesis is shown
in Scheme 1.
2.1.1 Formylation
(Compounds 3a, 3d, 3i, 3k). A solution of Ac2O
(2.00 mmol), HCOOH (3.00 mmol) and two drops of
pyridine was added to the respective 1-benzyl-4’-methyl-
3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinolines]
2
(1.00 mmol) at 0ºC. The reaction mixture was stirred
for 0.5-1 h at the same temperature. Then, the reaction
mixture was treated with NH4OH to get a pH 7-8, and
then it was extracted with CH2Cl2 (3×10 mL). Organic
extracts were washed with water and dried over Na2SO4,
concentrated, then purified by column chromatography
on neural alumina, using heptane–ethyl acetate mixture
(15:1, 10:1, 5:1) as an eluent.
of
3´-methyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-
quinoline] C, where the spiranic center is the carbon
adjacent to the phenylamine nitrogen, also shows
interesting features that make it attractive for synthetic
and pharmacological use [22,23] (Fig. 1).
2.1.2 Acetylation
(Compounds 3b and 3e). A mixture of the respective
1-benzyl-4’-methyl-3’,4’-dihydro-1’H-spiro[piperidine-
4,2’-quinolines] 2 (1.00 mmol) and Ac2O (3.00 mmol)
was refluxed for 1-2 h in the presence of NEt3 (two
drops). Then, reaction mixture was treated with NH4OH
to get a pH 7-8, and then it was extracted with CH2Cl2
(3×10 mL). Organic extracts were washed with water
and dried over Na2SO4, concentrated, then purified
by column chromatography on neural alumina, using
heptane–ethyl acetate mixture (15:1, 10:1, 5:1) as an
eluent.
We report herein an efficient and useful synthesis
of new attractive spiropiperdine scaffolds based on an
intramolecular acyl transfer process in 1´-acyl-1-benzyl-
3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinolines]
using simple and mild benzylation reaction conditions
(HCOONH4/Pd/C), we also discuss spatial piperidine
structures deduced from careful spectroscopic data
analysis and our logical steps to propose a plausible
mechanism of the intramolecular N-N acyl transfer
reactions in a conformationally mobile 1´-acyl-1-benzyl-
3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinoline]
system.
2.1.3 Benzoylation
(Compounds 3c and 3f). A solution of PhCOCl
(2.00 mmol) in dry toluene (10 mL) was dropped slowly
to the solution of the respective 1-benzyl-4’-methyl-
Me
H
N
H
N
H
NH
N
R1
R
N
R1
R
N
3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinolines]
2
R
Me Me
C
(1.00 mmol) and NEt3 (1.00 mmol) in dry toluene
(20 mL) at 0ºC. The reaction mixture was stirred for
2-3 h at the room temperature. Then, the reaction
mixture was treated with NH4OH to get a pH 7-8, and
B
A
Me
Figure 1. Compounds with spiro[piperidine-4,2‘-quinoline] skeleton
as possible pharmaceuticals.
O
R4
H
N
N
Ph
N
Ph
Ph
R3
R2
R3
R2
N
ArNH2
N
Acylating
methods
Ref. 30
O
R1 Me
R1 Me
1
2
3a-l
Acylating methods: a. HCOOH/Ac2O/Py/0ºC; b. Ac2O/NEt3/∆;
c. PhCOCl/NEt3/PhMe/r.t.; d. MeCOCl/NEt3/CH2Cl2/0ºC;
e. p-NO2C6H4COCl/NEt3/PhMe/5ºC.
Scheme 1. Preparation of starting acyl derivatives 3.
878

L. Y. Vargas Méndez, V. V. Kouznetsov
then it was extracted with CH2Cl2 (3×10 mL). Organic
All data for the synthetized compounds 3,4
extracts were washed with water and dried over Na2SO4, are presented in Supplementary Information.
concentrated, then purified by column chromatography
on neural alumina, using heptane–ethyl acetate mixture
(15:1, 10:1, 5:1) as an eluent.
3. Results and discussion
2.1.4 Chloroacetylation
The main materials, - 1-benzyl-4‘-methyl-3‘,4‘-dihydro-
1‘H-spiro[piperidine-4,2‘-quinolines] are easily
(Compounds 3g and 3l). A solution of ClCH2COCl
(2.00 mmol) in dry CH2Cl2 (10 mL) was dropped slowly
to the solution of the respective 1-benzyl-4’-methyl-
2
available from commercial and cheap 1-benzyl-4-
piperidone 1. Simple acylation reactions of these
piperidine compounds give the corresponding the 1´-
acyl-1-benzyl-3´,4´-dihydro-1’H-spiro[piperidine-4,2´-
quinolines] 3a-l in excellent yields. All N-amides 3 are
solid or oil substances. Their structure was confirmed
by IR and GC-MS data. Mass spectra of the compounds
3a-l showed molecular ion with very poor intensity (0.5-
8.0%) (Table 1 and Supplementary Table 1).
3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinolines]
2
(1.00 mmol) and NEt3 (1.00 mmol) in dry CH2Cl2
(20 mL) at 0ºC. The reaction mixture was stirred for
1-2 h at the same temperature. Then, the reaction
mixture was treated with NH4OH to get a pH 7-8, and
then it was extracted with CH2Cl2 (3×10 mL). Organic
extracts were washed with water and dried over Na2SO4,
concentrated, then purified by column chromatography
on neural alumina, using heptane–ethyl acetate mixture
(15:1, 10:1, 5:1) as an eluent.
Since acyl spiranes are complex conformationally
mobile systems their facile preparation and MS analysis
differs significantly from the structural characterization
by the NMR. Their 1H NMR spectra have confused
aliphatic zones that become considerably cleaner when
the chemical nature of the amide group is changing
(from formyl to benzoyl). For example, spectra of
formamides 3a,d,i,k (R4 = H) showed signals as a broad
singlet without any resolution, one of acetamides 3b,e
(R4 = CH3) and chloroacetamide 3g,l (R4 = CH2Cl)
indicated a better resolution and spectra of benzoyl
derivatives 3c,f (R4 = C6H5) and p-nitrobenzoyl derivative
3h (R4 = 4-NO2-C6H4) presented clear and separate
signals of each aliphatic piperidine protons. For example,
2.1.5 Nitrobenzoylation
(Compound 3h). A p-NO2PhCOCl (1.73 g, 9.30 mmol)
was added in small portions to the solution of 1-benzyl-4’-
methyl-3’,4’-dihydro-1’H-spiro[piperidine-4,2’-quinoline]
2a (1.49 g, 4.65 mmol) y NEt3 (0.46 g, 1 mmol) in dry
toluene (20 mL) at 0ºC. After 5 min, reaction mixture
was treated with NH4OH to get a pH 7-8, and then it
was extracted with CH2Cl2 (3×10 mL). Organic extracts
were washed with water and dried over Na2SO4,
concentrated, then purified by column chromatography
on neural alumina, using heptane–ethyl acetate mixture
(15:1, 10:1, 5:1) as an eluent.
1
the H NMR spectrum of benzamide 3c showed a nice
picture with 8 signals for piperidine ring and 4 signals
for dihydroquinoline moiety (see, Supplementary Fig. 1).
The piperidine signals had the following characteristics:
axial and equatorial 3-H hydrogens appeared at
1.36 and 3.29 ppm as doublet doublets with vicinal
coupling constants J = 12.5, 2.3 Hz and J = 12.7,
4.5 Hz, respectively; axial and equatorial 5-H hydrogens
were located at 1.57 ppm (doublet doublets, J = 12.8,
2.3 Hz) and at 3.34 ppm (triplet doublets, J = 12.2,
4.1 Hz), respectively; axial and equatorial 4-H hydrogens
resonated at 2.06 ppm (triplet doublets, J = 12.0,
2.3Hz)andat2.81ppm(tripletdoublets, J=11.7, 2.0Hz),
respectively. Finally, axial and equatorial 6-H hydrogens
appeared at 2.38 and 2.94 ppm as triplet doublets with
the corresponding vicinal constants J = 12.0, 2.9 Hz
and J = 11.8, 2.3 Hz. The dihydroquinoline protons gave
the following characteristics: triplet doublets (J = 12.8,
1.2 Hz) at 1.07 ppm belonging to the axial 3´-H hydrogen,
doublet doublets (J = 12.9, 3.0 Hz) at 2.54 ppm for the
equatorial 3´-H hydrogen and a sextet (J = 6.7 Hz) at
2.89 ppm was generated by a 4´-H proton. It should be
2.2 Typical experimental procedure for
synthesis of 1-acyl -3´,4´-dihydro-1´H-
spiro[piperidine-4,2´-quinolines] 4a-k
A mixture of compound 3 (1.00 mmol), HCOONH4
(315.3 mg, 5.00 mmol) and 2.5% molar amounts of 10%
Pd/C was refluxed in methanol (20 mL) for 7-15 min.
The reaction mixture was filtered and the solvent was
taken off. Crude products 4 were purified by alumina
column chromatography using ethyl acetate or ethyl
acetate-methanol mixture (10:1, 5:1, 2:1 or 1:1) as
eluents (Scheme 2).
O
O
R4
H
N
N
N
R4
Ph
R3
R2
N
R3
R2
+
HCOO-NH4
Pd/C, MeOH/∆
5-10 min
R1 Me
R1 Me
3a-l
4a-k
Scheme 2. Preparation of new 1-acyl-3´,4´-dihydro-1´H-
spiro[piperidine-4,2´-quinolines] 4.
879

Intramolecular N to N acyl migration in conformationally mobile
1´-acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinoline]
systems promoted by debenzylation conditions (HCOONH4/Pd/C)
Table 1. Physicochemical characteristics of 3.
Condensed Weight
GC: tR
IR νN-C=O
Comp.
R1
R2
R3
R4
M+.
Mp, oC
Yields,%
Formula
(g mol-1) (min)
(cm-1)
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
CH3
C22H26N2O
C23H28N2O
C28H30N2O
C23H28N2O
C24H30N2O
C29H32N2O
C24H29ClN2O
C29H31N3O3
C22H25FN2O
C24H30N2O
C25H31ClN2O
334.46
348.48
410.55
348.48
362.51
424.58
396.95
469.58
352.45
362.61
410.98
49.13
44.09
42.67
53.99
47.45
45.89
36.24
30.74
30.25
33.49
36.81
334 (1)
1676
1657
1648
1677
1663
1641
1669
1648
1666
1660
1668
oil
oil
95
89
82
85
86
81
89
70
90
100
79
348 (5)
H
H
H
C6H5
H
-
348 (1)
362 (8)
-
124-125
90-91
26-27
oil
H
CH3
CH3
CH3
CH3
CH3
F
H
H
H
CH3
H
H
C6H5
CH2Cl
C6H4NO2-p
H
3g
3h
3i
H
H
396 (1)
-
119-120
147-148
oil
H
H
H
H
352 (0.5)
362 (1)
-
3k
3l
CH3
CH3
H
CH3
CH3
H
oil
H
CH2Cl
158-159
mentioned that despite of many studies on simple acyclic
amide conformational aspects [24-26], conformational
analysis of N-acyl bond rotation in the N-heterocyclic
systems is very complex, and still poorly investigated
[26]. In our case of N-acyl spiro derivatives 3 obtained,
the situation is also complex and confusing. This is
due to two different phenomena of amide rotation and
piperidine ring inversion. From 13C NMR data analysis
for the formamides 3a,d,i,k (R4 = H) one could see a
duplication of each of the carbon atoms. Moreover, the
1H NMR spectra of the formamides 3a,k showed two
signals of N-C(O)H proton; in the case of compound 3k
these signals resonated separately enough to calculate
its 2.5:1 ratio (Fig. 2).
Me
Me
H
O
O
Me
Me
N
Me
Me
N
H
N
N
Z
E
3k
Ph
Ph
Figure 2. Z- and E-isomers of formamide 3k.
1
From early H NMR studies simple N-methyl- and
N-ethylformamides strong preference for the Z-isomer
(N-bulkier group anti to carbonyl oxygen) is known
to exist [25]. Thus, this information and our findings
permit us to believe that the major isomer of amides
3 has a Z-favored form. Additional information on
conformational aspects of these new N-acyl derivatives
was obtained from correlation spectroscopy (COSY)
experiments. In the spectra of the compounds 3c and 3f
a cross-peak between a 3´-Ha dihydroquinoline proton
and a 5-He piperidine proton was observed, those long-
range coupling constants 4J were 1.2 Hz. Molecular
modeling studies on the benzamide 3c performed by
the Gaussian program [27] were in agreement with the
reported NMR observations, and a W-configuration in
forced rigid molecular architecture of these derivatives
was suggested. Both the experiment and calculation
results allowed us to propose a possible geometry of
more stable Z-conformer of the benzamide 3c, where its
dihydroquinoline ring adopts a semi-chair form and the
piperidine has a twisted boat (Fig. 3).
Figure 3. Capped-stick model of lowest energy of compound 3c.
indicating that these signals can coalesce at room
temperature. It is important to note that during 1H NMR
and 13C NMR spectra analysis of these compounds we
could not observe the process of N-benzylpiperidine
ring inversion.
After the characterization of amide series 3, N-N
acyl migration process was studied under debenzylation
conditions. All these amides were treated with an
excess of ammonium formate in refluxing methanol in
the presence of 10% Pd/C for 5-20 min. With these mild
reaction conditions and the classical work-up exclusive
rearranged products 4 were obtained in excellent yield
as white (or yellow) crystalline high-melting solids
(Table 2). Structural elucidation of all the N-acylpiperidine
derivatives 4a-k was realized in the same order using
set of the spectroscopic and spectrometric techniques. It
should be mentioned that during the N-N acyl migration
reaction of 3a-l, all functionalities were intact except for
the amides 3g,l (R4 = CH2Cl) and 3h (R4 = C6H5NO2-p),
1H NMR and 13C NMR spectra analysis of the
acylated spiro products 3 showed no observation of
conformers signals for the acetamides and benzamides
880

L. Y. Vargas Méndez, V. V. Kouznetsov
Table 2. Physicochemical properties of 4.
M+.
Mp, oC Yields,%
Condensed
Formula
Weight
GC: tR
(min)
IRνN-H/νN-C=O
Comp.
R1
R2
R3
R4
(g mol-1)
(cm-1)
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C15H20N2O
C16H22N2O
C21H24N2O
C16H22N2O
C17H24N2O
C22H26N2O
244.33
258.36
320.43
258.36
272.39
334.46
32.89
33.71
31.79
34.28
35.34
33.75
244 (98)
258 (61)
320 (47)
258 (100)
272 (67)
334 (48)
3388/1676
3348/1623
3437/1645
3394/1679
3354/1635
3420/1641
153-154
136-137
106-107
168-169
114-115
155-156
93
96
90
91
88
75
CH3
C6H5
H
H
CH3
CH3
CH3
CH3
C6H5
3471, 3338,
3212/1622
4g
H
CH3
H
C6H4NH2-p
C22H27N3O
349.47
36.78
349 (8)
147-148
92
4h
4i
H
F
H
H
H
H
H
C15H19FN2O
C17H24N2O
C18H26N2O
262.32
272.38
286.41
23.21
24.81
25.45
262 (100)
272 (82)
286 (40)
3343/1665
3343/1669
3405/1657
160-161
104-105
169-170
97
98
CH3
CH3
CH3
CH3
4k
CH3
100
Table 3. Conformer ratio of obtained N-formyl(acetyl) piperidine derivatives 4.
Compound
Signals
A
B
A
B
δ, ppm
H-C=O
H-C=O
CH3-C=O
CH3-C=O
4a
4b
4d
4e
8.05/8.04
2.12/2.10
8.05/8.03
2.11/2.10
1
1
0.88
0.88
1
1
0.84
0.84
4h
4i
8.05/8.04
8.04/8.03
1
0.88
1
0.96
both of which were converted into rearranged products 3.79 ppm) of the piperidine 2-He proton converted
4b,k (R4 = CH3) and 4g (R4 = C6H5NH2-p), respectively. It into two independent signals, when the temperature
was easily proven by IR and GC-MS data (Table 2).
is higher than -25ºC a broad signal at -65ºC appeared
Analyzing 1H and 13C NMR data for formamides (Table 5). This phenomenon is very different from the
4a,d,h,i and acetamides 4b,e we clearly observed two one discussed above: at this temperature, the amide
isomers generated by amide C-N bond rotation. We C-N bond rotation process stops being significant and
were also able to analyze the ratio of presented amide the coalescence strongly indicates at a piperidine ring
rotation isomers A (syn) and B (anti) for these types of inversion.
amides that were found using formyl and acetyl protons
in room temperature solution (Table 3).
Analyses of the information obtained from dynamic
1H NMR experiments suggest two dynamic processes:
To study this phenomenon at greater length, we amide C-N bond rotation and piperidine ring inversionin
carried out diverse dynamic (variable temperature) the N-acetyl(formyl) piperidine series. Assignments of all
VT-NMR experiments [28,29] in two solvents, - CDCl3 piperidine protons were based on COSY cross coupling.
and C3D3O ([D6]acetone) of the acetamide 4e. CDCl3 These processes are shown in Scheme 3.
solution VT 1H NMR experiments were conducted
Generally, C-4 substituted N-acetylpiperidines adopt
at five degree intervals between -40 and +40oC syn conformation and its syn rotamer can be easily
(see Supplementary Fig. 6), and the results showed that identified by deshielded piperidine 2(6)-He protons
as the temperature grows, the σv values between two [26,30-32]. In our case, the similar N-acetylpiperidine
singlets of the Me amide group considerably decrease derivative 4e presented two rotamers, syn and anti,
(Table 4). Since coalescence could not be observed, it from 1H NMR study syn rotamer was found to be major.
1
would suggest that these signals and conformers will Moreover, using a H-decoupled 13C MNR experiment
coalesce at the temperature higher than 40ºC.
(T = 25ºC, time between scans: 20 sec., total scans -
C3D3O solution VT 1H NMR experiments were 1024) (see Supplementary Fig. 8), it was possible to find
conducted at five or ten degree intervals between a rotamer ratio for this acetamide (1:0.81), which is very
1
-65 and +20oC (see, Supplementary Fig. 7). With the similar to ratio found from H NMR spectrum (1:0.84,
temperature decrease, very complex signals (δ 3.89- Table 3).
881

Intramolecular N to N acyl migration in conformationally mobile
1´-acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinoline]
systems promoted by debenzylation conditions (HCOONH4/Pd/C)
Table 4. Observation of amide rotamers 4e by dynamic 1H NMR
GC-MS technique to find possible products 3A, 3B and
4 that could be formed during this process (Scheme 4).
Detailed GC-MS analysis followed by 1H NMR
experiments of all series of each purified amide showed
the following results: 1. reaction of formamide and
acetamide spiro derivatives 3 did perform fully toward
N-acylpiperidine products 4 without observation of any
other products: nor 3A, neither 3B; 2. crude reaction
mixtureofdebenzylationreactionforthebenzamideseries
contained a small amount (<10% by GC-MS) of products
3A. Many attempts to improve the benzoyl migration
process have failed. (Major loading of reactants or long
time reaction did not improve situation). These findings
gave us a basis to believe in a possible intramolecular
acyl transfer reaction during the debenzylation process
induced by HCOONH4. To prove this fact we resorted
to a crossover experiment technique that is particularly
relevant for many molecular rearrangements [33].Three
types of similar experiments were carried out: a) with
mixture of two different acetamides 3a and 3e (Exp.1); b)
with mixture of acetamide 3b and formamide 3k (Exp.2),
and c) with mixture of acetamide 3b and formamide 3i
(Exp.3) (Scheme 5).
(CDCl3).
O
CH3
O
N
A
N
H
N
N
CH3
C
C
O
CH3
B
4e
CH3
T, ºC
δ ppm, CH3
δ ppm, CH3
δv, ppm
40
35
30
25
20
15
10
5
2.110
2.113
2.115
2.116
2.119
2.121
2.124
2.126
2.096
2.096
2.097
2.098
2.099
2.101
2.104
2.106
0.014
0.017
0.018
0.018
0.020
0.020
0.020
0.020
0
2.129
2.136
2.142
2.178
2.155
2.108
2.114
2.120
2.155
2.132
0.021
0.022
0.022
0.023
0.023
-10
-20
-30
-40
Table 5. Observation of piperidine conformers 4e by dynamic
1H NMR (J, Hz, C3D3O).
These amides mixtures were subjected to the
same reaction conditions, in which each rearranged
N-acylpiperidine products were obtained. GC-MS
analysis of the final product’s crude reaction revealed
that each mixture produced only the corresponding
O
CH3
N
H
N
N
CH3
- 65 ºC
C
He
C
He
O
CH3
O
N
H3C
4e
CH3
T, ºC
2-He, δ, ppm
2-He, δ, ppm
δv, ppm
N-acylpiperidine derivatives
4 that were obtained
during the independent experiments. Although these
experiments were a good evidence for intramolecular
acyl transfer reactions, it was decided to find another
proof for a workable hypothesis, the trapping technique.
Piperidine and morpholine molecules were chosen,
because they are more suitable nitrogen reactants
with similar nucleophilic characteristics. Thus, an
equimolar mixture of acetyl derivative 3e and piperidine
(morpholine) was subjected to a debenzylation reaction
keeping the same reaction conditions. The GC-MS data
of final product’s crude reaction indicated the formation
of compound 4e and did not show any formation of
N-acetylpiperidine or N-acetylmorpholine (Scheme 6).
With this information, it was concluded that studied
acyl transfer reactions in spiropiperidine series are
intramolecular. Based on the findings, we could propose
a plausible mechanism given in Scheme 7 that explains
a remarkable reactivity of compound 3.
3.83 ddd
(13.7, 10.7, 5.1 Hz)
3.76 ddd
(13.3, 10.5, 5.5 Hz)
25
0.070
0.071
0.071
0.072
0.072
0.071
0.065
0.071
0.067
3.83 ddd
(13.5, 10.6, 3.8 Hz)
3.76 ddd
(13.5, 10.3, 3.7 Hz)
15
3.84 ddd
(13.5, 10.5, 5.2 Hz)
3.77 ddd
(13.3, 10.2, 5.0 Hz)
5
3.85 ddd
(13.5, 10.5, 5.2 Hz)
3.78 ddd
(13.3, 10.3, 4.9 Hz)
-5
3.85 ddd
(13.6, 10.4, 4.9 Hz)
3.78 ddd
(13.3, 10.1, 4.9 Hz)
-15
-25
-35
-45
-55
3.86 ddd
(13.7, 10.1, 4.8 Hz)
3.79 ddd
(13.4, 10.0, 5.0 Hz)
3.81 ddd
(13.7, 9.7, 4.8 Hz)
3.87 ddd
(13.7, 9.3, 4.4 Hz)
3.81 bd
(13.2 Hz)
3.88 bd
(13.4 Hz)
3.89 bd
(12.2 Hz)
3.83 bd
(12.0 Hz)
-65
-75
3.87 bs
3.88 bs
-
-
Aftercarefulexaminationofthesyntheticresultsithas
been concluded that according to the migration capacity,
acyl groups are arranged in the following order: acetyl >
formyl > phenyl, based on the tetrahedral mechanism
[34]. This mechanism suggests an initial attack of a
In order to elucidate this type of acyl migration
process, which could be inter- or intramolecularly
processed, a number of diverse experiments were
conducted. Crude reaction mixture of the debenzylation
process for all starting compounds was analyzed by
882

L. Y. Vargas Méndez, V. V. Kouznetsov
O
CH3
O
Amide rotation
40 - 60 ºC
N
N
C
He
C
He
CH3
O
Ha
anti
syn
Ha
H
N
N
CH3
Piperidine ring inversion
- 65 ºC
H3C
4e
CH3
Ha
Ha
He
He
C
CH3
O
O
N
N
syn
C
anti
CH3
Scheme 3. Conformational equilibrium for acetamide 4e.
O
R4
R1
O
R4
R1
O
R1
R1
H
N
NH
N
Ph
HCOO-NH4
NH
H
N
N
R4
R2
R3
N
+
R2
R3
N
R2
R2
+
+
Pd/C, MeOH/∆
R3
R3
3
3A
Me
Me
Me
3B
Me
4
Scheme 4. Possible products of debenzylation process.
Scheme 5. Crossover experiments of two different amides.
O
H3C
O
X
H
N
Ph
+
N
CH3
+
X
N
N
i
N
N
H
X = CH2, O
Me
Me
H3C
O
3e
3e
4e
Me
Me
-
+
i:
(1 mmol), piperidine or morpholine (1 mmol), HCOO NH4 (5 mmol),
Pd/C (2.5% mmol), MeOH (10 mL), T = 64 ºC, t = 10 min.
Scheme 6. Acetyl trapping experiments with piperidine (morpholine) molecules.
883

Intramolecular N to N acyl migration in conformationally mobile
1´-acyl-1-benzyl-3´,4´-dihydro-1´H-spiro[piperidine-4,2´-quinoline]
systems promoted by debenzylation conditions (HCOONH4/Pd/C)
Scheme 7. Intramolecular acyl transfer reaction in spiropiperidine system 4.
nucleophile on a carbonyl group that could result in these acyl transfer reactions, acetyl migration was
joining to the carbonyl group followed by elimination chosen to be the best; it is easy to perform, clean, fast,
of the leaving group. Thus, the migratory aptitudes of efficient, economic and possible under green reaction
these acyl groups would depend on a combination of the conditions. Detailed spectroscopic data analysis would
inductive effect of the radical on the reactivity of the C=O certainly be very useful in piperidine alkaloid chemistry
group and on the ease of expelling the leaving group by and in drug design and development. Biological assays
the tetrahedral intermediate.
of spiropiperidine products obtained in this investigation
and further applications of this methodology to similar
piperidine systems will be disclosed in due course.
4. Conclusions
In summary, we described an efficient and useful Acknowledgements
synthesis of new and attractive spiropiperdine scaffolds
based on an intramolecular acyl transfer process using This work was supported by the grant of Instituto
simple and mild debenzylation reaction conditions. Colombiano para el Desarrollo de la Ciencia y la
Through rigorous examination of all spectroscopic Tecnologia
(COLCIENCIAS-CENIVAM, grant 432-
information it was possible to correctly assign amide 2004). LYVM thanks COLCIENCIAS for the doctoral
configurations and piperidine ring conformations that are fellowship.
closely involved in the acyl migration reaction. Among
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