Piperidines from acid-catalysed cyclisations: Pitfalls, solutions and a new ring contraction to pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2017.07.058

The success of acid-catalysed cyclisations of alka-4-enylamine derivatives to piperidines depends very much on the nature of the amine protecting group: while carbamates and related amides can usually be readily and cleanly transformed, the corresponding sulfonamides react further by ring contraction leading to pyrrolidines, especially when such substrates are sterically crowded.

Full text of DOI:10.1016/j.tetlet.2017.07.058

Accepted Manuscript
Piperidines from acid-catalysed cyclisations: pitfalls, solutions and a new ring
contraction to pyrrolidines
Abdul H. Aldmairi, Charlotte Griffiths-Jones, Alexis Dupauw, Laura
Henderson, David W. Knight
PII:
S0040-4039(17)30913-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.058
TETL 49140
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 April 2017
7 July 2017
14 July 2017
Please cite this article as: Aldmairi, A.H., Griffiths-Jones, C., Dupauw, A., Henderson, L., Knight, D.W., Piperidines
from acid-catalysed cyclisations: pitfalls, solutions and a new ring contraction to pyrrolidines, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.058
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Piperidines from acid-catalysed cyclisations: pitfalls, solutions and a new
ring contraction to pyrrolidines.
Abdul H. Aldmairi, Charlotte Griffiths-Jones, Alexis Dupauw, Laura Henderson and David W. Knight*
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
___________________________________________________________________________________
Abstract- The success of acid-catalysed cyclisations of alka-4-enylamine derivatives to piperidines depends
very much on the nature of the amine protecting group: while carbamates and related amides can usually be
readily and cleanly transformed, the corresponding sulfonamides react further by ring contraction leading to
pyrrolidines, especially when such substrates are sterically crowded.
Keywords: Piperidines; intramolecular; acid-catalysed; cyclisation; ring contraction.
Phone: (UK)2920876000; Fax: (UK)2920874030; E-mail: knightdw@cardiff.ac.uk

Although arguably counter-intuitive, it has been found possible to realise good to excellent yields of pyrrolidines
by acid-catalysed cyclisations of unsaturated amine derivatives,1 in our case in reactions initially directed
towards the elaboration of the highly substituted proline analogues 2 from the amino-ester derivatives 1 (Scheme
1), along with tetrahydroisoquinolines.2 Overall, such transformations can be viewed as intramolecular
hydroaminations3 and so, not surprisingly, a number of examples of related intermolecular hydroaminations,
induced under such acidic conditions, have also been reported.4
CO2Me
H+
R1
R2
a) R1 = R2 =Me
b) R1 = Ph; R2 = H
c) R1 = Me; R2 = H
R2
R1
CO2Me
N
Ts
NHTs
1
2
Scheme 1. An acid-catalysed approach to highly substituted prolines.
In most examples, be these inter- or intra-molecular, additions of carbamates or sulfonamides to unactivated
alkenes require exposure of the precursor(s) to strongly acidic conditions, typically obtained using 0.1-0.5
equivalents of concentrated sulfuric acid or the super acid trifluoromethanesulfonic (triflic) acid, usually in either
a chloroalkane or toluene. Current views on the mechanism of such hydroaminations form a consensus that the
best descriptor consists of additions of a proton and the nitrogen atom to the alkene in a concerted if
asynchronous fashion. Alternative stepwise processes seem much less likely.5 In our work, the asynchronous
nature of the cyclisations was consistent with an observed direct relationship between the ease of reaction and
carbenium ion stability: thus, the prenyl derivative 1a underwent cyclisation in a few minutes at ice bath
temperatures whereas the cinnamyl derivative 1b required a few hours at ambient temperature and the crotyl
analogue 1c only reacted when heated to ~60 oC.2
An extension to this methodology to the elaboration of piperidines 4 (Scheme 2) seemed viable, especially as the
necessary precursors 3 were readily available using a variety of flexible approaches; some evidence that this
could indeed be the case had already been provided by Hartwig and Schlummer1 (see later).

H
?
TsHN
R
N
Ts
R
3
4
Scheme 2. An extension to piperidine synthesis?
Our initial studies focussed on the cyclisation behaviour of precursors 5 and 6, obtained by alkylation of the
carbanion 76 using the corresponding homoallylic halides followed by protecting group exchange (Scheme 3).
The logic behind our choice was that, whatever the mechanistic subtleties, the intermediacy of even a partly
formed, tertiary carbenium ion should be favoured in such substrates.
N
CO2Me
TsHN
CO2Me
TsHN
CO2Me
Ph
5
6
7
Scheme 3. Model precursors 5 and 6 prepared using carbanion 7.
However, molecular life is often not so simple: upon exposure to triflic acid (0.6 equiv.) in dichloromethane at
ambient temperature, both precursors 5 and 6 were unexpectedly converted into the corresponding pyrrolidines 8
and 9 (Scheme 4).
5
6
N
Ts
N
Ts
CO2Me
CO2Me
9
8 (cis:trans 3:2)
Scheme 4. Unexpected formation of pyrrolidines 8 and 9 from
precursors 5 and 6. Reagents and conditions: triflic acid (0.6 eq.),
CH2Cl2, 20 oC, 1 h; yields > 90%.

To make certain of our structural assignments, an authentic sample of pyrrolidine 8 was synthesised from the
known precursor 10 by sequential iodocyclisation7 to give the iodo-pyrrolidine 11 and hydrogenolytic removal
of the iodine atom, which provided pyrrolidine 8, albeit in a different ratio of isomers to that obtained from the
acid-catalysed cyclisation (Scheme 5). Despite this, the forgoing structural assignments 8 and 9 were clearly
correct based on comparative 1H and 13C NMR data.
I
I2 (3 eq.)
CO2Me
K2CO3, MeCN
N
Ts
TsHN
10
CO2Me
0.5 h, 20 oC.
83%
11
Et3N, MeOH
H2, 5% Pd-C
3 h, 20 oC.
95%
CO2Me
N
Ts
8 (cis:trans 1:4)
Scheme 5. Structural proof using a known iodocyclisation.7
Wondering if the ester group was playing some unanticipated role, we examined similar acid-catalysed
cyclisations of the less functionalised sulfonamide 13, which was readily and efficiently synthesised from the
commercial ketone 12 by sequential oximation, reduction and tosylation reactions (Scheme 6).
i) NH2OH, EtOH, 2 h, 20 oC (90%)
ii) LiAlH4, Et2O, 1 h, 0-20 oC (85%)
O
iii) TsCl, py, 18 h, 20 oC (89%).
TsHN
12
13
Scheme 6. Synthesis of a simpler piperidine precursor 13.
All attempts at cyclisation of the precursor 13 resulted in the formation of mixtures of the desired piperidine 14
together with the starting amino-alkene and/or the pyrrolidine 15 (Table 1). The results shown are a
representative summation of many experiments in which variations to the acid (c. H2SO4 or TfOH), its quantity,

and to the reaction temperature and time all resulted in the formation of mixtures. The products, 14 and 15, could
be separated by column chromatography and were fully characterized.8,9
Table 1. Acid-catalysed cyclisation and contraction of precursor 13
N
Ts
TsHN
N
Ts
13
14
15
Temp.
oC
Acid
(equiv.)
Precursor
Time
min.
Ratio of 13:14:15
13
13
13
13
13
13
13
14
14
14
14
20
TfOH (0.3)
48:7:45
0:0:100
5:85:10
25:73:2
53:35:12
75:18:7
100:0:0
10:85:5
0:25:75
0:7:93
6
60
15
60
90
120
180
5
20
0
TfOH (0.3)
c.H2SO4 (0.4)
c.H2SO4 (0.4)
TfOH (0.4)
0
-10
-30
-60
20
20
20
20
TfOH (0.4)
TfOH (0.4)
c.H2SO4 (0.4)
c.H2SO4 (0.4)
c.H2SO4 (0.5)
c.H2SO4 (0.5)
15
45
75
0:0:100
All reactions were carried out in dry dichloromethane and worked up by adding a slight
excess of aq. 3M K2CO3, separation and evaporation.
All product mixtures were isolated in ~95% yields, according to weight and NMR data.
There was clearly only a very narrow window of opportunity available for the formation of piperidine 14 and
then only as a major product. Significantly, when a separated sample of the latter was re-exposed to the acidic
conditions, it was rapidly converted into the pyrrolidine 15, indicating that it was a genuine intermediate between
the precursor 13 and pyrrolidine 15. This led us to propose the mechanism shown in Scheme 7 as an explanation
for the results given in Table 1. An initial cyclisation of the precursor 13 does indeed lead to the piperidine 14,
by formation of an electron-deficient species, here represented by the ‘carbenium form 16, but that this is an
equilibration, brought about by N-protonation. An alternative, less favoured pathway leads, by way of the

secondary carbenium ion 17, to the pyrrolidine 15 which, crucially, is not in equilibrium with its precursor
carbenium ion, and hence is the thermodynamically favoured product.
H
H
H
TsHN
TsHN
TsHN
16
13
17
N
Ts
N
Ts
14
15
Scheme 7. An explanation for the results shown in Table 1.
This led us to wonder if this chemistry could constitute a new type of ring contraction for the conversion of
piperidines into pyrrolidines; the results thus far obtained are presented in Table 2. As shown above (Table 1),
the essentially quantitative yield of pyrrolidine 15 suggested that the 2,2-dimethyl analogue (Entry 1) should also
undergo such a contraction. It did, but more slowly and less efficiently. That the considerable steric crowding
present in piperidine 14 is a key factor was exemplified by the very slow conversions of the 2-substituted
piperidines into the corresponding pyrrolidines (Entries 2, and 3). A 2,6-disubstituted piperidine (Entry 4)
underwent more rapid contraction, leading to a useful synthetic yield of the corresponding pyrrolidine, while
piperidines unsubstituted adjacent to nitrogen were essentially inert (Entries 5, and 6). Finally, the bulkier 2-
cyclohexylpiperidine (Entry 7) reacted slowly but cleanly while the 2-phenyl derivative (Entry 8) underwent
slow decomposition, possibly involving transfer of the sulfonyl group to the phenyl ring, a tentative conclusion
based only on 1H NMR data obtained for crude samples.10

Table 2: Acid-catalysed ring contraction of N-tosylpiperidines
Conditionsa
Yield of
pyrrolidineb
Pyrrolidine
Piperidine
Entry
1
80%
0.5 eq. TfOH, 25 h
N
Ts
N
Ts
9%
21%
5%
0.2 eq. c.H2SO4, 72 h
0.6 eq. c.H2SO4, 24 h
2
N
Ts
N
Ts
0.5 eq. TfOH, 72 h
0.5 eq. TfOH, 24 h
2.0 eq. TfOH, 24 h
30%
57%
44%
27%
3
N
Ts
N
Ts
0.5 eq. TfOH, 72 h
Ph
Ph
0.4 eq. c.H2SO4, 24 h
54% (28:26)c
72% (50:22)
57% (43:14)
38% (15:23)
0.4 eq. c.H2SO4, 3 h
0.4 eq. c.H2SO4, 24 h
0.3 eq. c.H2SO4, 72 h
0.5 eq. TfOH, 72 h
4
N
Ts
N
Ts
5
6
0%
0.5 eq. TfOH, 72 h
N
Ts
N
Ts
0%
0.5 eq. TfOH, 72 h
N
Ts
N
Ts
32%
48%
23%
0.4 eq. TfOH, 24 h
0.4 eq. TfOH, 48 h
0.4 eq. c.H2SO4, 23 h
N
Ts
N
Ts
7
8
0.5 eq. TfOH, 72 h
[slow decomn]
N
H
Ph
N
Ts
Ts
a All reactions were carried out in toluene heated at reflux;
b Remainder unreacted piperidine; total yield >95%;
c cis/trans ratios.

The stability of sulfonamide groups and of piperidines in general combine to suggest that N-tosylpiperidines are
similarly stable - these results clearly show that they are not, at least under these quite extreme acidic conditions.
We do not claim that this is a synthetically useful ring contraction, except in examples of piperidines which are
highly substituted in the 2- and 6-positions, but we do highlight it as a potential source of material loss in
synthetic steps involving heating such piperidines under acidic conditions. Results reported by Hartwig and
Schlummer1 confirm that the use of a sulfonamide protecting group was not optimal and is consistent with our
observations shown in Table 2, although the stability of 2-phenyl-1-tosylpiperidine is at variance (Scheme 8).
a) TfOH,100 oC, 2 h (83%) or
b) c.H2SO4, 100 oC, 24 h (80%)
Ph HN
Ts
Ph
N
Ts
a) TfOH,100 oC, 2 h (51%) or
b) c.H2SO4, 100 oC, 24 h (0%)
HN
Ts
N
Ts
Ph
Ph
Scheme 8. Hartwig and Schlummer's results, using 20 mol%
of each acid in toluene (ref. 1).
A number of methods for achieving ring contractions of piperidines have been reported over the years. Most
commonly, these rely on the formation of an intermediate aziridinium ion and attack of a nucleophile.11 Such
reactions closely resemble a Favorskii rearrangement12 and can also be carried out photochemically13 and
enzymatically.14 The present method, while limited, appears to be novel.
In a bid to alter the electronics of the sulfonyl group, we tested the 4-nosyl (4-nitrophenylsulfonyl, 4-Ns) group
highlighted by Fukuyama and co-workers, which has the useful property of being removed by exposure to
thiolate ions.15 In the event, the change had little effect: a selection of results is presented in Table 3. There were
few differences to those obtained from the N-tosyl derivatives (Table 1), despite the electronic differences of Ts
and Ns groups; the combined chemical yields were again very high. In contrast, methanesulfonyl (Ms)
derivatives were unstable to the acidic conditions.

Table 3. Using 4-nosyl in place of tosyl.
N
Ns
NsHN
N
Ns
18
19
20
Temp.
oC
Time
min.
Ratio of 18:19:20
0
48:46:6
15:66:19
13:9:78
0:0:100
60
180
20
0
20
20
60
Reagents and conditions: c.H2SO4 (0.5 eq.), CH2Cl2.
All overall yields were >95%.
We therefore turned to using carbonyl-based N-protecting groups.16 Initial attempts using trifluoroacetyl
derivatives also failed due to their instability to the acidic conditions. Similarly, while both N-acetyl1 and N-
phenacyl derivatives underwent some decomposition, we were pleased to note that cyclisations of such
derivatives led only to piperidines uncontaminated by pyrrolidines. We were delighted to then discover that the
o
methyl carbamate 21 underwent rapid cyclisation at 0 C upon exposure to 0.4 equivalents of either sulfuric or
triflic acid in dichloromethane to provide excellent yields of the piperidine 22 (Scheme 9). Notably, if the
isolated piperidine 28 was returned to the acidic conditions for a prolonged period (24 h) at ambient temperature,
there was no sign of either decomposition or contraction to the corresponding pyrrolidine.
a) c.H2SO4 (0.4 eq.)
0 oC, 1 h, 87%
b) TfOH (0.4 eq.),
0 oC, 0.5 h, 96%
or
HN
N
CO2Me
CO2Me
21
22
Scheme 9. Optimized cyclisations of methyl carbamate 21.

Remarkably, given its sensitivity to acidic conditions, a Z-carbamate group also survived the acidic conditions
required for cyclisation: the benzyl derivative 23 was converted into piperidine 24 following very brief exposure
to sulfuric acid (0.4 equiv.) in excellent yield (Scheme 10).
0.4 eq. c.H2SO4
N
HN
20 oC, 7 min., CH2Cl2
92%
CO2Bn
CO2Bn
23
24
Scheme 10. With care, even a ‘Z’ carbamate survives.
In contrast, the cinnamyl derivative 25 required prolonged exposure to acid at ambient temperature to provide an
excellent yield of the piperidine 26, again unaccompanied by any pyrrolidines (Scheme 11).
c.H2SO4, (0.4 eq.),
20 oC, 24 h, 87%
Ph
Ph
N
HN
CO2Me
CO2Me
25
26
Scheme 11. Optimized conditions for cyclisation of the
cinnamyl derivative 25 to give the cis-piperidine 26.
1
The cis-diastereoisomer 26 was formed exclusively; both substituents occupied axial positions, according to H
NMR data, which indicated that neither proton adjacent to nitrogen could be in an axial position.17,18 However, if
there was competition between the products, as usual, the overall 5-exo pathway was favoured: thus, the
unsaturated carbamate 33 was converted exclusively into pyrrolidine 34 (Scheme 12).
0.5 eq. TfOH
N
CH2Cl2, 40 oC, 3.5 h
NHCO2Me
CO2Me
98%; cis:trans ~1:1
27
28
Scheme 12. Overall 5-exo cyclisation is favoured over 6-endo.

In a final illustration, we have shown that spiro-piperidines can also be made in this way. Wittig homologation
of cyclohexanone 29 gave the cyclohexylidenecarboxylic acid 30,19 Curtius rearrangement of which20 then led to
o
the required cyclisation precursor 31. Brief exposure to triflic acid (0.5 equiv.) at 0 C led to a 95% yield of the
spiro-piperidine 32 (Scheme 13).
Br
O
CO2H
Ph3P(CH2)4CO2H
NaH, THF
29
30
i) Ph2P(O)N3, Et3N ii) CuCl (cat.),
MeOH, reflux, 1 h.
toluene, reflux, 1 h
NHCO2Me
0.5 eq. TfOH
N
CH2Cl2,
0 oC, 0.5 h
95%
CO2Me
32
31
Scheme 13. An application to spiro-piperidine synthesis.
Despite the strongly acidic conditions required, both for the ring contractions and the piperidine syntheses, these
examples show that this simple methodology can be highly effective for the elaboration of many types of
pyrrolidine and piperidine derivatives, especially sterically crowded examples. Further work is in progress to
expand the utility of this methodology, especially with a view to allowing the incorporation of more functional
groups.21
Acknowledgements.
We are grateful to Professor W. R. Jackson (Monash) for an exchange of results and for helpful discussions and
to Damascus University (AHA), the Lilly Research Centre Ltd., Windlesham (LH) and the Erasmus Scheme
(AD) for financial support.
References and notes
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Mueller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795-3892.
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9.
Jones, A. D.; Knight, D. W.; Redfern, A. L.; Morgan, I. R.; Williams, A. C. Tetrahedron, 2006, 62, 9247-9257.
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[Graphic abstract]
Piperidines from acid-catalysed cyclisations: pitfalls,
solutions and a new ring contraction to pyrrolidines
Abdul H. Aldmairi, Charlotte Griffiths-Jones,
Alexis Dupauw, Laura Henderson and David W. Knight
H+
N
Ts
N
Ts
Keywords: Piperidines; intramolecular; acid-catalysed; cyclisation; ring contraction.

HIGHLIGHTS
A new approach to piperidines by acid-catalysed cyclisation of amine derivatives.
Determination of suitable N-protecting groups which lead to acid-stable piperidines.
A novel ring contraction of N-sulfonyl piperidines to give pyrrolidines.
Derivation of the likely mechanism of the ring contraction.