Gold-catalysed synthesis of exocyclic vinylogous amides and β-amino ketones: A detailed study on the 5-exo/6-endo-dig selectivity, methodology and scope

Article abstract of DOI:10.1002/ejoc.201500205

The gold(I)-catalysed reaction of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, which gives synthetically useful vinylogous amides (β-enaminones), has been studied in detail, in order to optimize the reaction conditions, enlarge the scope and gain i

Full text of DOI:10.1002/ejoc.201500205

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FULL PAPER
DOI: 10.1002/ejoc.201500205
Gold-Catalysed Synthesis of Exocyclic Vinylogous Amides and β-Amino
Ketones: A Detailed Study on the 5-exo/6-endo-dig Selectivity, Methodology
and Scope
Dina Scarpi,*[a] Stefano Begliomini,[a] Cristina Prandi,[b] Alberto Oppedisano,[b]
Annamaria Deagostino,[b] Enrique Gómez-Bengoa,[c] Béla Fiser,[c] and
Ernesto G. Occhiato*[a]
Dedicated to Professor Antonio Guarna on the occasion of his retirement
Keywords: Homogeneous catalysis / Gold / Enynes / Nitrogen heterocycles / Amides / Regioselectivity
The gold(I)-catalysed reaction of N-Boc-protected 6-alkynyl-
3,4-dihydro-2H-pyridines, which gives synthetically useful
vinylogous amides (β-enaminones), has been studied in de-
tail, in order to optimize the reaction conditions, enlarge the
scope and gain insight into the mechanism and the structural
features that selectively favour the 6-endo-dig oxyauration of
the triple bond. Experimental studies and DFT calculations
demonstrate that the 6-endo-dig approach is exclusive with
substituted alkynes, whereas with terminal alkynes the 5-
exo-dig cyclization prevails, despite the large angle (120°) at
C-6. The same selectivity was observed with N-Cbz-pro-
tected 2-alkynylpiperidines. With these compounds, β-amino
ketones are obtained as a consequence of the 6-endo-dig at-
tack onto a substituted triple bond. Sedamine alkaloids are
easily obtained by this approach.
Introduction
Vinylogous amides (β-enaminones) constitute an impor-
tant class of valuable intermediates in the synthesis of het-
erocyclic and natural compounds.[1] They also have impor-
tant therapeutic potential against the multidrug resistance
(MDR) of cancer cells,[2] and against epilepsy.[3] For these
reasons, much effort has been put into the search for new
methods for their efficient synthesis.[3,4] Exocyclic vinylog-
ous amides built on a piperidine ring are versatile interme-
diates for the preparation of many N-heterocycles[5] and
natural alkaloids (Figure 1), such as desoxoprosophylline,[6]
cassine,[7] pinidinone,[8] deoxyfebrifugine,[9] norallosed-
amine,[10] and others.[11] The synthesis of other related alka-
loids such as sedamine,[12] 5-hydroxy-sedamine,[13] ha-
losaline,[14] and pelletierine[15] could also be easily envisaged
by exploiting the reactivity of such vinylogous amides.
Figure 1. Naturally occurring alkaloids prepared from vinylogous
amides, and some related compounds.
[a] Dipartimento di Chimica “U. Schiff”, Università degli Studi di
Firenze,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
E-mail: dina.scarpi@unifi.it
We recently reported a new approach to the synthesis of
exocyclic vinylogous amides 1 in which the key step was a
gold(I)-catalysed rearrangement of N-Boc (tert-butoxy-
carbonyl) enynes 2 (Scheme 1).[11] N-Boc enynes 2 were ob-
tained by the Sonogashira coupling of lactam-derived enol
phosphates and triflates 3 with a variety of terminal alk-
ynes.[11]
ernesto.occhiato@unifi.it
www.egocch.it/
[b] Dipartimento di Chimica, Università degli Studi di Torino,
Via P. Giuria 7, 10125 Torino, Italy
[c] Departamento de Química Orgánica I, Universidad del País
Vasco/UPV-EHU,
Manuel de Lardizabal 3, 20018 Donostia-San Sebastián, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500205.
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the gold(I)-catalysed cycloisomerization of 2-alkynylpiper-
idines 4 (Scheme 1) as an alternative synthetic route in
which reduction of the double bond to give the β-amino
ketone 5 is carried out before (as opposed to after) the gold-
catalysed step.
Results and Discussion
In gold(I)-catalysed processes, the catalyst is generally
used at a catalyst loading between 1 and 5 mol-%,[21] al-
though some exceptions to this have been reported.[22] The
active gold(I) catalysts are generally prepared in situ by
anion exchange between LAuX (X = Cl, Br) and a silver
salt (AgY) so that the highly coordinating anion X– can be
eliminated as AgX. Besides the fact that silver does play a
role in some gold(I)-catalysed processes,[23] issues related to
the decay/decomposition of the active gold catalyst have re-
cently been pointed out.[24,25] This is what we actually ob-
served in our previous study of the gold(I)-catalysed re-
arrangement of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-
pyridines, and for this reason we then used 2–3 mol-% of
the catalyst to achieve complete conversion within a reason-
able time.[11] In a study by Bezzenine-Lafollée and Gandon
on anion metathesis,[24] it was found that by slowing down
the rate of the anion exchange, for example by changing the
source of the weakly coordinating anion from silver to cop-
per salts, the decomposition of the catalyst could be pre-
vented. This was a result of slow release of the active LAu+
species in the solution over a longer period of time.[26]
Among the various catalytic systems, Cu(OTf)2 proved to
be the best, and so we decided to evaluate these new condi-
tions, aiming for a lower catalyst loading (Table 1).
Scheme 1. Retrosynthetic analysis.
The gold(I)-catalysed step, which was carried out in the
presence of Ph3PAuOTf (2–3 mol-%) in refluxing toluene,
included a 6-endo-dig attack onto the activated triple bond
by the Boc carbonyl oxygen of the enyne to form a labile
cyclic urethane intermediate (I). Because of its instability,
this intermediate could not be isolated, and thus its hyd-
rolysis was carried out in situ to give the corresponding
vinylogous amide (i.e., 1) in good yields (generally no less
than 70%, irrespective of the R residue), and as the Z
isomer only.
In view of possible applications of this method to large-
scale synthesis, we wanted to further decrease the catalyst
loading. Moreover, the scope of the reaction had only been
explored in terms of the alkyne chain, so we decided to
explore the compatibility of various functional groups on
the piperidine ring with the reaction conditions, as well as
to explore the reactivity of 7-alkynyl-2,3,4,5-tetra-
hydroazepine derivatives. Furthermore, we envisaged that
the method could be extended further by replacing the N-
Boc protection with an N-Cbz (benzyloxycarbonyl) group;
in theory, this would result in C-1Ј-substituted vinylogous
amides deriving from a carbodeauration step.[16]
Table 1. Gold(I)-catalysed reaction of enyne 2 in the presence of
Cu(OTf)2.[a]
A key point of our previous work was that with sub-
strates such as N-Boc enynes 2, the exclusive formation of
products derived from a 6-endo-dig oxyauration step was
observed, whereas for N-Boc propargylamines and 2-alk-
ynyl N-Boc-substituted pyrrolidines and piperidines[17–19]
only a 5-exo-dig cyclization has been reported.[20] Also,
based on other reports from the literature, it seemed reason-
able to us that in our case the alternative 5-exo-dig mecha-
nism was disfavoured by the larger bond angle at C-6 (due
to the presence of the endocyclic double bond), which also
caused substrates 2 to have a much lower reactivity than
the corresponding saturated compounds.[18,19] Therefore,
the strikingly different results obtained with substrates 2
prompted us to carry out further investigations, including
theoretical calculations, to reveal the role of the hybridiza-
tion of C-6, and also other possible structural features, in
the 6-endo/5-exo-dig preference during the gold-catalysed
cyclization of enynes 2. Finally, since all of the natural com-
Entry
Ph3PAuCl Cu(OTf)2
Time
[h]
I [%][b]
1 [%][c]
[mol-%]
[mol-%]
1
2
3
4
5
0.5
0.5
0.2
0.1
0
10
5
5
5
10
0.5
0.5
3.5
6.5
2.5
100
100
76
70
40
70
72
–
–
–
[a] Reactions were run on a 0.5 mmol scale under an inert atmo-
sphere. [b] Conversion was measured by 1H NMR spectroscopy.
[c] Yield after chromatographic purification.
Using compound 2 as a model substrate, we carried out
pounds potentially derived from exocyclic vinylogous the reaction in refluxing toluene, and lowered the amount
amides (Figure 1) are β-amino ketones (or alcohols ob- of gold(I) to 0.5 mol-% and added Cu(OTf)2 in a 20:1 molar
tained from β-amino ketones), we decided to also explore ratio (Table 1, entry 1). We were delighted to find out that
2
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Exocyclic Vinylogous Amides and β-Amino Ketones
after just 30 min, the starting material had been completely
consumed, and the corresponding vinylogous amide (i.e., 1)
was obtained after alkaline hydrolysis of intermediate I in
the usual 70% yield after purification. The same result was
obtained using a 10:1 molar ratio by lowering the quantity
of Cu(OTf)2 to 5 mol-% (Table 1, entry 2). However, with
lower amounts of Ph3PAuCl, the reaction did not go to
completion (Table 1, entries 3 and 4), even when the reac-
tion time was prolonged to 6.5 h (Table 1, entry 4). Not un-
expectedly, Cu(OTf)2 used alone at a catalyst loading of
10 mol-% did have some catalytic properties,[24,27] but the
reaction required 2.5 h to reach a conversion of 40%
(Table 1, entry 5), so the cationic gold(I) species is the true
catalyst. Based on these results, we decided to use
Ph3PAuCl at 0.5 mol-% together with 5 mol-% of Cu-
(OTf)2 as the new catalytic system for the next gold(I)-cata-
lysed experiments.
Scheme 3. Synthesis of compounds 11a–11c.
the gold–copper catalytic system (Scheme 4). Only in the
case of 8f was the reaction best carried out by using the
Ph3PAuCl/AgOTf system[11] to give the corresponding vin-
ylogous amide (i.e., 12f, which contains a masked amino
group on the piperidine ring) in good yield after purifica-
tion. As we reported in our previous work, the cyclic inter-
mediates were unstable, and thus the hydrolysis was carried
out in situ at 80 °C by addition of KOH and tert-butanol.[35]
In all cases, the vinylogous amides were obtained in good
yields over the two steps (57–73%).
The synthesis of substrates bearing functional groups on
the piperidine ring, and also of larger heterocyclic rings,
was carried out in order to expand the scope of the reac-
tion.
Enynes 8a–8f and 11a–11c were all prepared by Sonoga-
shira coupling of lactam-derived enol phosphates 7a–7c and
10,[34] respectively (Schemes 2 and 3).[11] Lactams 6a[28] and
6b[29] were obtained by oxidation of the corresponding race-
mic N-Boc-protected methylpiperidines,[30,31] whereas
lactam 6c (Scheme 2) was prepared from (S)-(+)-γ-hydroxy-
methyl-γ-butyrolactone,[32,33] using standard chemistry for
the final two protection steps of the 5-hydroxy-δ-valero-
lactam.[33] As we have already reported for analogous sub-
strates, enynes 8 and 11 were unstable when neat, and so
they were stored in solution in the presence of Et3N (1%
v/v).[11]
Scheme 4. Synthesis of compounds 12a–12i.
To further expand the scope of the reaction, we then de-
cided to focus our attention on different substrates in which
Scheme 2. Synthesis of compounds 8a–8f; KHMDS = potassium
hexamethyldisilazide; TIPS = triisopropylsilyl.
a
benzyloxycarbonyl group replaces the tert-butoxy-
carbonyl group. According to the reaction mechanism, in
Enynes 8a–8f and 11a–11c were all successfully used for the case of N-Boc-protected substrates, once the carbonyl
the synthesis of the corresponding vinylogous amides with oxygen of the Boc group attacks the gold-activated triple
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bond, the resulting tert-butyl cation decomposes to give iso- source. Compounds 1 and 17 were not separated by
butylene and H+, generating the proton necessary for the chromatography, but the structure of 17 was easily assigned
1
protodeauration step. Since carbodeauration has been dem- by H NMR spectroscopic analysis of the mixture, which
onstrated with substrates that are able to generate a carbo- showed a diagnostic ABX system that was assigned to the
cation (mainly allylic),[16] we decided to verify whether this two benzylic protons (dd at δ = 3.06 ppm, J = 13.5, 4.7 Hz;
process would be possible in our case with a benzylic carbo- and dd at δ = 2.73 ppm, J = 13.5, 10.2 Hz), and 3-H (m at
cation derived from an N-Cbz protecting group. This would δ = 2.64–2.58 ppm).
lead to vinylogous amides 14 bearing a C-1Ј substituent
(Scheme 5).
Scheme 5. Planned synthesis of 14.
The synthesis of N-Cbz enyne 13a (Scheme 6), a model
substrate, was carried out by Sonogashira coupling between
N-Cbz enol phosphate 15[36] and 1-hexyne. As was seen for
the analogous N-Boc compound, 13a also proved to be un-
Scheme 7. AuI-catalysed reaction of 13a.
stable when neat, and was stored in solution in the presence
of Et3N.
Based on these results, we decided to reduce the double
bond of 13a (to obtain 16a) so that no benzylic addition
could occur, and, by exploiting toluene as a proton source,
products formally derived from double-bond reduction of
vinylogous amides 1 (i.e., β-amino ketones) could be ob-
tained instead (Scheme 8).
Scheme 6. Synthesis of compounds 13a–13c and 16a–16d; TFA =
trifluoroacetic acid; TES = triethylsilyl.
Compound 13a was then tested in the gold(I)-catalysed
process under the usual conditions, but the reaction failed
to go to completion even when the reaction time was pro-
longed to 4.5 h, and it did not provide, after hydrolysis,
compound 14 deriving from carbodeauration. With this N-
Cbz derivative, the reaction was best carried out with 3 mol-
% of Ph3PAuOTf (Scheme 7), but whatever conditions were
used, the reaction took place by a 6-endo-dig oxyauration
mechanism and, together with unreacted starting material,
we obtained only a mixture of vinylogous amides 1 and
Scheme 8. Planned synthesis of β-amino ketones.
As mentioned above, this would represent an alternative
17 (Table S1 in the Supporting Information). Compound 1 synthetic route to β-amino ketones in which reduction of
derives from a protodeauration process, and compound 17 the double bond is carried out before the gold-catalysed
from an electrophilic addition of the benzylic carbocation step. For example, a series of natural products, including
onto the piperidine double bond (before or after the proto- various Sedamine alkaloids, has been obtained from β-
deauration step), with subsequent release of a proton. amino ketone 19b (Scheme 9),[10] which is itself a natural
Moreover, o-benzyltoluene and p-benzyltoluene were de- product (norsedaminone).[37] The selective reduction was
tected in the 1H NMR spectrum of the crude mixture, both carried out at low temperature with NaBH3CN under
deriving from an electrophilic aromatic substitution reac- acidic conditions,[38] and gave compound 16a in good yield
tion on toluene, which thus represents an additional proton (Scheme 6).
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Exocyclic Vinylogous Amides and β-Amino Ketones
should be highlighted that if our hypothesis was correct,
treatment of 16d with the gold catalyst would give the same
product previously obtained by Gagosz and Buzas starting
from the analogous N-Boc substrate.[19] We were delighted
to verify that 16d, under the usual gold catalysis conditions,
gave only compound 21 (Scheme 9), which derives from a
5-exo-dig reaction followed by isomerization of the double
bond to the endocyclic position.[43] Furthermore, an experi-
ment carried out with unsaturated N-Boc compound 22
(Scheme 10) gave known compound 23,[44] derived from the
5-exo-dig intermediate. Taken together, these results show
that the 6-endo/5-exo-dig selectivity we observe with our
substrates depends on whether the triple bond is internal or
terminal.
Scheme 9. Synthesis of compounds 19a, 19b, and 21.
We were glad to observe that the subsequent gold-cata-
lysed step [best catalysed by 3 mol-% of the gold(I) salt to-
gether with 15 mol-% of Cu(OTf)2] gave only compound
18a, which was derived from a 6-endo-dig approach; we
were instead unable to find any signal in the 1H NMR spec-
trum of the crude reaction mixture that could be assigned
to the 5-exo-dig isomer (Scheme 9).[39] To confirm our find-
ings, we decided to synthesize compound 16b through Son-
ogashira coupling of 15 with phenylacetylene followed by
reduction of the double bond of 13b as already described
(Scheme 6). Compound 18b is a known compound,[40] and
since it was synthesized by a [4+2] cycloaddition of N-acyl-
iminium ion with phenylacetylene, its structure was as-
signed unambiguously. Treatment of 16b with Ph3PAuCl
and Cu(OTf)2 under the usual conditions gave only 18b
(Scheme 9), with spectroscopic data identical to those re-
ported in the literature.[41] Further confirmation of the
structures of both 18a and 18b came from hydrolysis under
basic conditions, which gave β-amino ketones 19a and 19b,
which, being quite volatile, were converted into their HCl
salts in good overall yield (89 and 78%, respectively).
These results seemed to be in contrast with data pre-
viously reported in the literature for N-Boc-protected prop-
argylamines, in which only 5-exo-dig products were ob-
tained, even though a 6-endo-dig mechanism was equally
possible. Also, when heterocyclic substrates were used, i.e.,
Scheme 10. Synthesis of compound 23. TMS = trimethylsilyl.
To get further insight into the reason for the different
selectivities for terminal and internal alkynes, and to ascer-
tain whether the large N–Csp2–Csp angle has a role in the
high 6-endo-dig preference with those substrates with an in-
ternal triple bond, DFT calculations were carried out with
the Gaussian 09 suite of programs (see Computational
Methods section). Since the 5-exo/6-endo-dig selectivity
trend does not depend on the alkoxycarbonyl moiety, the
N-Cbz protecting group was chosen, and compounds 13b,
13d, 16b, and 16d (Figure 2) were selected as model sub-
strates for the cyclization reaction, as examples of the four
possible combinations of saturated/unsaturated rings and
substituted/unsubstituted alkynes. Triphenylphosphine–
gold(I) cation was used as the reaction catalyst, and the
N-Boc-2-ethynylpyrrolidine,[18,19]
N-Boc-2-ethynylpiper-
idine,[19] and N-Boc-2-ethynylazepane,[19] 5-exo-dig prod-
ucts were obtained,[20] but all of these compounds had a
terminal alkyne moiety. Since all the substrates we tested
had substituted alkyne groups, we wondered whether a situ-
ation analogous to the gold(I)-catalysed propargylic ester
migration could exist. In this process, the 1,2-rearrangement
is favoured for terminal alkynes, whereas the 1,3-rearrange-
ment becomes a competing, or even the major, pathway for
internal alkynes.[42] The synthesis of a substrate with a ter-
minal alkyne was therefore necessary; this was carried out
by Sonogashira coupling of phosphate 15 with triethylsil-
ylacetylene (to give 13c), followed by reduction of the
double bond (to give 16c), and deprotection with TBAF
(tetrabutylammonium fluoride; to give 16d; Scheme 6). It Figure 2. Model substrates for DFT studies.
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study focussed on the cyclization step, which is the regiose- perimental fact could be confirmed computationally with
lectivity-determining step. substrates 13d and 16d. We found that the 5-exo-dig cycliza-
Given the very different degrees of steric hindrance at the tion occurs with a very low barrier (3.9 kcal/mol for TS13-
two carbons of the triple bond in terminal alkynes (13d and H-5-exo) or, in the case of the corresponding saturated
16d), it would seem reasonable to hypothesize at first sight compound 16b, with essentially no activation barrier (TS16-
that steric effects were important for the observed 5-exo-dig H-5-exo, Figure 4).
regioselectivity in these substrates, since the gold atom
could preferably be placed at the least substituted terminal
position during the attack of the oxygen atom. However,
although this could be an important factor, this effect alone
cannot explain the regioselectivity found in internal alkynes
(13b and 16b), since in those cases the two carbon atoms
are sterically quite similar. Thus, calculations were carried
out for the four alkyne–gold(I) complexes (only the un-
saturated complexes, i.e., V-Ph and V-H are shown in Fig-
ure 3), and unsurprisingly, the complexes showed clear
structural differences in terms of alkyne–gold complex-
ation.
Figure 4. Transition-state structures and energies for terminal alk-
ynes.
In fact, no convergence or a convergence to the starting
material was observed during the search for a transition
state in the latter case, even though we tested different func-
tionals (B3LYP, M06, BHandHLYP) and basis sets. To fur-
ther analyse this issue, a potential scan for the O–C bond
formation was carried out, and this confirmed that it is a
downhill process without appreciable activation energy. On
Figure 3. Structures of complexes V-Ph and V-H.
the other hand, the transition states for the regioisomeric
6-endo cyclizations were located, and were found to have
Specifically, in V-H, gold coordination induces a weaken- low but measurable activation energies (8.2 and 5.6 kcal/
ing of the triple bond [δ(Ca–Cb) = 1.23 Å] and a strong mol, Figure 4), which are ca. 4–5 kcal/mol higher than
asymmetry of the C–Au bonds [δ(Ca–Au) = 2.73 Å, δ(Cb– those of the 5-exo processes. This energy difference can ex-
Au) = 2.16 Å]. The resulting complex can be considered to plain the absolute experimental preference for the five-
some extent as a vinyl cation. The calculated natural pop- membered cyclic products. This is also consistent with the
ulation atomic charges at the two carbon atoms are fact that a 1,2-acyl shift is preferred for propargylic acetates
+0.203 e (Ca) and –0.480 e (Cb), which confirms that the with an unsubstituted alkyne moiety.[42b]
positive charge of the complex is centred at Ca. These values
On the other hand, the transition-state structures for the
are consistent with those calculated for a simple unsubsti- reaction of the internal triple bonds are consistent with the
tuted propargylic acetate,[42b] although in our case the posi- experimental preference for the Cb attack. Thus, the lowest
tive charge on Ca is even higher (+0.203 e vs. +0.063 e), the calculated activation energies were 7.8 kcal/mol for the un-
Ca–Au bond length longer (2.73 vs. 2.514 Å), and the Cb– saturated ring (TS13-Ph-6-endo, Figure 5 and Figure S1 in
Au bond length shorter (2.16 vs. 2.239 Å). On the other Supporting Information), and 8.4 kcal/mol for TS16-Ph-6-
hand, alkyne–gold complex V-Ph has a much more sym- endo. It is interesting to note that the endo/exo selectivity is
metrical structure, with nearly identical Au–C distances predicted to be better for 13 (ΔΔG‡
= 2.5 kcal/mol)
exo–endo
(Figure 3), and NPA (natural population analysis) charges than for 16 (ΔΔG‡
= 1.3 kcal/mol). This effect can
exo–endo
(Ca = –0.056 e, Cb = –0.002 e). In this case, the positive be attributed to the increase in the N–C–Ca angle induced
charge is centred on the gold atom (Au = +0.437 e in V-Ph, by the presence of the double bond, from 113° (16d, N–
vs. +0.365 e in V-H).
As a result of the more positively-charged character of against the formation of the smaller five-membered ring.[45]
the internal Ca carbon atom in V-H, the attack of the oxy- The data shown in Figures 3 and 5 are not informative
gen atom takes place exclusively at that position. This ex- enough about the exact reason for the 6-endo selectivity
Csp3–Ca) to 119° (13d, N–Csp2–Ca), a factor that plays
6
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Exocyclic Vinylogous Amides and β-Amino Ketones
terminal position. It is worth mentioning that a similar
preference, but to a lesser extent (ΔΔG‡ = 2.3 kcal/mol), was
found for computational model compound VII, with satu-
rated rings, which is consistent with the generally lower
selectivity of this type of substrates (vide supra).
Conclusions
In this work, we have studied in detail the gold(I)-cata-
lysed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-
2H-pyridines to give synthetically useful exocyclic vinylog-
ous amides, with three objectives in mind. First, bearing in
mind possible large-scale applications of the method, we
wanted to optimize the reaction conditions to reduce the
amount of the gold catalyst as far as possible. This was
realized by using Cu(OTf)2 as the triflate source, which al-
lowed us to use 0.5 mol-% of AuI without affecting the reac-
tion rate. Secondly, we expanded the scope of the reaction
to substituted piperidines and different nitrogen heterocy-
cles to assess the tolerance to the reaction conditions of
some functional groups often present in natural products
that could easily be prepared from the vinylogous amide
products. Our third goal was to assess the structural
features that selectively favour the 6-endo-dig oxyauration
of the triple bond. We found that a 6-endo-dig mechanism
operates exclusively with substituted alkynes, whereas with
terminal alkynes a 5-exo-dig cyclization prevails, despite the
large angle (120°) at C-6. An analogous selectivity was ob-
served with N-Cbz-protected 2-alkynylpiperidines. These
compounds, after gold-catalysed cyclisation and hydrolysis
of the cyclic intermediates, give β-amino ketones as a result
of a 6-endo-dig attack onto the internal triple bond. DFT
calculations showed that with both types of substrates, the
oxyauration step has a low barrier or almost no barrier at
all when it involves the internal position of a terminal triple
bond, resulting in a 5-exo-dig process. In contrast, the 6-
endo-dig mechanism is always favoured with substituted
alkynes, this preference being purely geometrical and irre-
spective of the type of substitution, thus providing either β-
enaminones or their reduced equivalents, β-amino ketones,
in a robust, reliable, and convenient way.
Figure 5. Transition-state structures and energies for internal alk-
ynes.
with internal alkynes, since Ca and Cb have very similar
electronic properties, and their bonding distances with the
gold atom are virtually equal (Figure 3). Thus, we envi-
sioned an indirect way to analyse the geometrical factors
that determine the reactivity of the internal alkynes, by
using symmetrical computational substrates (Figure 6).
Experimental Section
General Remarks: Chromatographic separations were carried out
under pressure on silica gel using flash-column techniques. Rf val-
Figure 6. Comparison of the activation energies for the 5-exo and
6-endo-dig pathways.
ues refer to TLC carried out on 0.25 mm silica gel plates (F254
)
with the same eluent as indicated for the column chromatography.
1H NMR spectra were recorded at 200 or 400 MHz, and 13C NMR
spectra were recorded at 50.33 or 100.4 MHz, both in CDCl3 solu-
tion, unless otherwise specified. The solvent reference line was set
at δ = 7.26 (CDCl3) or 4.79 (D2O) ppm. Mass spectra were either
recorded at an ionizing voltage of 70 eV, or measured with an LCQ
FleetTM Ion-Trap LC–MS system with an electrospray ionization
(ESI) interface in positive-ion mode by direct inlet of a 10 ppm
solution in CH3OH. Microanalyses were carried out with an ele-
For example, in the model system VI, the triple bond is
symmetrically substituted, and the two carbons (Ca and Cb)
are absolutely identical, which reduces the factors that af-
fect the formation of one ring or the other to a simple geo-
metrical preference. Interestingly, the activation energy is
lower for the 6-endo cyclization by 4.4 kcal/mol, indicating
that in principle, the preference for the six-membered ring
is purely geometrical, and could be generalized to any type
of internal alkynes, irrespective of the substituent on the mental analyser. Compounds 6a,[28] 6b,[29] 10,[34] 15,[36] and 5-hy-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
D. Scarpi, E. G. Occhiato et al.
FULL PAPER
droxy-δ-valerolactam[32] were prepared as reported. All enynes 2,
8, 11, 13, and 22, as well as intermediates 16 decompose when neat
and must be stored in solution in the presence of Et3N (1% v/v).
1.84 (m, 1 H, 4-HЈ), 1.48 [s, 9 H, C(CH3)3], 1.10–0.95 (m, 21 H,
TIPS) ppm. 13C NMR (100.4 MHz): δ = 170.8 (s, C-2), 152.3 (s,
C=O), 82.7 [s, C(CH3)3], 64.4 (d, C-5), 52.5 (t, C-6), 31.0 (t, C-3),
29.1 (t, C-4), 27.9 (q, 3 C, CH3 Boc), 17.8 (q, 6 C, CH3 TIPS), 12.0
(d, 3 C, CH TIPS) ppm. MS (ESI): m/z (%) = 766 (33), 765 [2M +
Na]+ (100), 394 [M + Na]+ (7). C19H37NO4Si (371.59): calcd. C
61.41, H 10.04, N 3.77; found C 61.25, H 9.98, N 3.91.
Computational Methods: The structures were optimized using den-
sity functional theory (DFT) with BHandHLYP[46] functional and
the 6-31G* (LANL2DZ for Au) basis set as implemented in
Gaussian 09.[47] The B3LYP functional was also evaluated; it gave
similar results to BHandHLYP, but some of the lowest-in-energy tert-Butyl (؎)-6-(Diphenoxyphosphoryloxy)-4-methyl-3,4-dihydro-
transition states (TS13-H-5-exo and TS16-H-5-exo) did not con-
verge properly when using B3LYP. The energy values shown in Fig-
ures 3[48] and 4 also include single-point refinements at the M06-
2X/6-311++G**(SDD) level of theory[49] on the previously opti-
mized structures, to better account for the dispersion forces of such
large systems. The stationary points were characterized by fre-
quency calculations in order to verify that they had the right
number of imaginary frequencies. The intrinsic reaction coordi-
nates (IRC)[50] were followed to verify the energy profiles connect-
ing each TS to the correct associated local minima. Natural bond
orbital (NBO) analysis[51] was carried out to evaluate the NPA
atomic charges.
2H-pyridine-1-carboxylate (7a): KHMDS (0.5 m solution in tolu-
ene; 6.4 mL, 3.2 mmol) was diluted with anhydrous THF (18 mL),
and the solution was cooled to –78 °C. A solution of 6a[28] (455 mg,
2.13 mmol) in anhydrous THF (10 mL) was then added dropwise,
keeping the temperature below –70 °C, and the resulting mixture
was stirred for 1.5 h. Diphenylchlorophosphate (663 μL, 3.2 mmol)
was slowly added. After 1 h, the mixture was warmed to 0 °C, and
the reaction was quenched by the addition of NaOH (10% aq.;
50 mL). The mixture was extracted with Et2O (3ϫ 40 mL), and the
combined organic extracts were washed once with NaOH (10%
aq.; 28 mL), and dried with anhydrous K2CO3. The mixture was
filtered, and the solvent was evaporated. The residue was purified
over a short pad of silica gel (n-hexane/EtOAc, 7:1 + 1% Et3N; Rf
= 0.13) to give pure 7a (800 mg, 85%) as a colourless oil. 1H NMR
(400 MHz): δ = 7.37–7.31 (m, 4 H, Ar), 7.25–7.17 (m, 6 H, Ar),
5.01–4.99 (m, 1 H, 5-H), 3.61–3.50 (m, 2 H, 2-H), 2.45–2.38 (m, 1
H, 4-H), 1.87–1.79 (m, 1 H, 3-H), 1.43 [s, 9 H, C(CH3)3], 1.41–1.33
(m, 1 H, 3-HЈ), 1.01 (d, J = 6.0 Hz, 3 H, CH3) ppm. 13C NMR
(100.4 MHz): δ = 153.1 (s, C=O), 150.6 (s, Ph), 150.5 (s, Ph), 140.0
(s, C-6), 129.7 (d, 4 C, CAr), 125.4 (d, Ph), 125.3 (d, Ph), 120.09 (d,
Ph), 120.08 (d, Ph), 120.04 (d, Ph), 120.03 (d, Ph), 105.3 (d, C-5),
81.7 [s, C(CH3)3], 44.1 (t, C-2), 31.1 (d, C-4), 28.1 [q, 3 C,
C(CH3)3], 27.8 (t, C-3), 21.3 (q, CH3) ppm. MS (ESI): m/z (%) =
913 [2M + Na]+ (100), 468 [M + Na]+ (20), 446 [M + 1]+ (35).
tert-Butyl (5S)-2-Oxo-5-(triisopropylsilanyloxy)piperidine-1-carb-
oxylate (6c): 5-Hydroxy-δ-valerolactam[32] (680 mg, 5.9 mmol) was
dissolved in anhydrous DMF (12 mL). Imidazole (1.21 g,
17.7 mmol) and triisopropylsilyl chloride (1.27 mL, 5.9 mmol) were
added, and then the resulting mixture was warmed to 40 °C. A
second equivalent of triisopropylsilyl chloride (1.27 mL, 5.9 mmol)
was added in portions over 8 h, and the reaction was stirred at
40 °C overnight. The mixture was cooled to room temperature,
then water was added (120 mL), and the mixture was extracted with
Et2O (4ϫ 50 mL). The combined organic phases were dried with
anhydrous Na2SO4 and filtered, and the solvent was evaporated.
The residue was purified by flash chromatography (EtOAc; Rf =
0.27) to give pure 5-(triisopropylsilanyloxy)piperidin-2-one (1.36 g, tert-Butyl (؎)-6-(Diphenoxyphosphoryloxy)-2-methyl-3,4-dihydro-
85%) as a colourless oil. [α]2D1 = –11.3 (c = 1.12, CHCl3). 1H NMR
2H-pyridine-1-carboxylate (7b): Prepared as described for 7a, start-
(400 MHz): δ = 7.05 (br. s, 1 H, NH), 4.17–4.12 (m, 1 H, 5-H), ing from 6b[29] (362 mg, 1.7 mmol), to give, after purification (n-
3.41–3.37 (m, 1 H, 6-H), 3.23–3.19 (m, 1 H, 6-HЈ), 2.56 (dt, J = hexane/EtOAc, 6:1 + 1% Et3N; Rf = 0.12), pure 7b (658 mg, 87%)
1
17.6, 7.6 Hz, 1 H, 3-H), 2.27 (dt, J = 17.6, 6.1 Hz, 1 H, 3-HЈ), 1.90– as a clear yellowish oil. H NMR (400 MHz): δ = 7.38–7.28 (m, 4
1.86 (m, 2 H, 4-H), 1.05–0.98 (m, 21 H, TIPS) ppm. 13C NMR H, Ph), 7.26–7.12 (m, 6 H, Ph), 5.11 (q, J = 3.5 Hz, 1 H, 5-H),
(100.4 MHz): δ = 172.1 (s, C-2), 64.1 (d, C-5), 49.4 (t, C-6), 29.0
4.67–4.53 (m, 1 H, 2-H), 2.21–2.10 (m, 2 H, 4-H), 1.77–1.66 (m, 1
(t, C-3), 27.5 (t, C-4), 17.9 (q, 6 C, CH3 TIPS), 12.1 (d, 3 C, CH H, 3-H), 1.63–1.57 (m, 1 H, 3-HЈ), 1.43 [s, 9 H, C(CH3)3], 1.15 (d,
TIPS) ppm. MS (ESI): m/z (%) = 565 [2M + Na]+ (100), 543 [2M
+ 1]+ (16). C14H29NO2Si (271.47): calcd. C 61.94, H 10.77, N 5.16;
found C 61.72, H 10.50, N 4.91.
J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (100.4 MHz): δ = 153.2 (s,
C=O), 150.5 (s, Ph), 150.4 (s, Ph), 138.3 (s, C-6), 129.7 (d, 4 C, Ph),
125.4 (d, Ph), 125.3 (d, Ph), 120.12 (d, Ph), 120.10 (d, Ph), 119.98
(d, Ph), 119.93 (d, Ph), 99.3 (d, C-5), 81.6 [s, C(CH3)3], 49.2 (d, C-
2), 28.1 [q, 3 C, C(CH3)3], 27.1 (t, C-4), 18.6 (t, C-3), 15.7 (q, CH3)
ppm. MS (ESI): m/z (%) = 913 [2M + Na]+ (100), 468 [M + Na]+
(41), 446 [M + 1]+ (27).
5-(Triisopropylsilanyloxy)piperidin-2-one (1.3 g, 4.79 mmol) was
dissolved in anhydrous CH2Cl2 (30 mL). Et3N (740 μL,
5.27 mmol), di-tert-butyl dicarbonate (1.1 g, 4.79 mmol), and
DMAP (4-dimethylaminopyridine; 59 mg, 0.48 mmol) were added,
and the resulting mixture was heated under reflux. After 2 h, a
second equivalent of di-tert-butyl dicarbonate (1.1 g, 4.79 mmol)
was added. When the reaction was complete (TLC; 5 h), the mix-
ture was cooled to room temperature, water (40 mL) was added,
and the layers were separated. The aqueous phase was extracted
tert-Butyl (3S)-6-(Diphenoxyphosphoryloxy)-3-(triisopropylsilanyl-
oxy)-3,4-dihydro-2H-pyridine-1-carboxylate (7c): Prepared as de-
scribed for 7a, starting from 6c (1.44 g, 3.87 mmol), to give, after
purification (n-hexane/EtOAc, 5:1 + 1% Et3N; Rf = 0.50), pure 7c
1
(2.33 g, 99%) as a pale yellow oil. H NMR (400 MHz): δ = 7.37
with CH2Cl2 (3ϫ 20 mL), and the combined organic extracts were (m, 4 H, Ph), 7.27–7.25 (m, 4 H, Ph), 7.21–7.18 (m, 2 H, Ph), 5.06–
washed with KHSO4 (5% aq.; 40 mL), satd. NaHCO3 (40 mL), 5.04 (m, 1 H, 5-H), 4.11–4.06 (m, 1 H, 3-H), 3.71 (dd, J = 12.9,
water (40 mL), and brine (40 mL), and finally dried with anhydrous
Na2SO4. The mixture was filtered, and the solvent was evaporated.
The residue was purified by flash chromatography (n-hexane/
3.1 Hz, 1 H, 2-H), 3.51 (dd, J = 12.9, 7.4 Hz, 1 H, 2-HЈ), 2.51–2.43
(m, 1 H, 4-H), 2.16–2.08 (m, 1 H, 4-HЈ), 1.44 [s, 9 H, C(CH3)3],
1.13–1.01 (m, 21 H, TIPS) ppm. 13C NMR (100.4 MHz): δ = 153.0
EtOAc, 8:1; Rf = 0.12) to give pure 6c (1.44 g, 81%) as a colourless (s, C=O), 150.5 (s, 2 C, CAr), 140.0 (s, C-6), 129.7 (d, 4 C, CAr),
oil. [α]2D0 = +10.0 (c = 0.92, CHCl3). 1H NMR (400 MHz): δ =
125.4 (d, 2 C, CAr), 120.0 (d, 4 C, CAr), 97.8 (d, C-5), 81.6 [s,
4.26–4.21 (m, 1 H, 5-H), 3.73 (dd, J = 13.1, 4.7 Hz, 1 H, 6-H), 3.62 C(CH3)3], 65.2 (d, C-3), 51.2 (t, C-2), 32.4 (t, C-4), 28.0 (q, 3 C,
(dd, J = 13.1, 3.5 Hz, 1 H, 6-HЈ), 2.75–2.67 (m, 1 H, 3-H), 2.40 CH3 Boc), 17.9 (q, 6 C, CH3 TIPS), 12.1 (d, 3 C, CH TIPS) ppm.
(dt, J = 17.2, 5.9 Hz, 1 H, 3-HЈ), 1.98–1.92 (m, 1 H, 4-H), 1.91– MS (ESI): m/z (%) = 1229 [2M + Na]+ (100), 792 [M + Na]+ (7).
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
Exocyclic Vinylogous Amides and β-Amino Ketones
1
General Procedure for Sonogashira Coupling: Phosphate (7a–7c,
10,[34] 15[36]) was dissolved in an anhydrous mixture of Et3N and
CHCl3 (3:1; 0.13 m), and the alkyne (1 mmol), CuI (0.1 mmol), and
(Ph3P)2PdCl2 (0.05 mmol) were added. The resulting solution was
heated at 55 °C (external) for 2 h, after which time further alkyne
CHCl3). H NMR (400 MHz): δ = 7.45–7.32 (m, 2 H, Ph), 7.33–
7.27 (m, 3 H, Ph), 5.60 (t, J = 4.1 Hz, 1 H, 5-H), 4.13–4.08 (m, 1
H, 3-H), 3.87 (dd, J = 12.5, 2.7 Hz, 1 H, 2-H), 3.36 (dd, J = 12.5,
8.0 Hz, 1 H, 2-HЈ), 2.53 (dt, J = 19.1, 5.3 Hz, 1 H, 4-H), 2.18 (ddd,
J = 19.1, 5.6, 4.1 Hz, 1 H, 4-HЈ), 1.49 [s, 9 H, C(CH3)3], 1.11–1.02
(0.5 mmol), CuI (0.05 mmol), and (Ph3P)2PdCl2 (0.025 mmol) were (m, 21 H, TIPS) ppm. 13C NMR (100.4 MHz): δ = 153.0 (s, C=O),
added, if necessary. The mixture was heated at 55 °C until the reac-
tion was complete (TLC, usually after 4–7 h). The mixture was
cooled to room temperature, then water (12 mL) was added, and
the mixture was extracted with Et2O (3ϫ 12 mL). The combined
organic extracts were dried with anhydrous K2CO3 and filtered,
and the solvent was evaporated. The crude enyne (8a–8d, 11a–11c,
13a–13c) was purified by flash chromatography (eluent containing
1% Et3N), and stored at 4 °C as a 0.1 m solution in the eluent until
use.
131.3 (d, 2 C, Ph), 128.3 (d, 2 C, Ph), 128.0 (d, Ph), 123.3 (s, C-6),
122.1 (s, Ph), 120.5 (d, C-5), 87.8 (s, C-1Ј), 86.3 (s, C-2Ј), 81.1 [s,
C(CH3)3], 65.1 (d, C-3), 50.0 (t, C-2), 34.7 (t, C-4), 28.2 (q, 3 C,
CH3 Boc), 18.0 (q, 6 C, CH3 TIPS), 12.3 (d, 3 C, CH TIPS) ppm.
MS (ESI): m/z (%) = 933 [2M + Na]+ (100), 478 [M + Na]+ (12),
456 [M + 1]+ (11).
tert-Butyl
6-(Trimethylsilanylethynyl)-3,4-dihydro-2H-pyridine-1-
carboxylate (22a): Colourless oil (229 mg, 82%). Rf = 0.63 (petro-
leum ether/EtOAc, 9:1 + 1% Et3N). 1H NMR (200 MHz): δ = 5.63
(t, J = 4.0 Hz, 1 H, 5-H), 3.57–3.52 (m, 2 H, 2-H), 2.16 (td, J = 6.9,
4.1 Hz, 2 H, 4-H), 1.83–1.71 (m, 2 H, 3-H), 1.52 [s, 9 H, C(CH3)3],
0.19 [s, 9 H, Si(CH3)3] ppm. 13C NMR (50.33 MHz): δ = 153.2 (s,
C=O), 124.0 (s, C-6), 122.5 (d, C-5), 101.9 (s, C-2Ј), 91.9 (s, C-1Ј),
81.4 [s, C(CH3)3], 43.2 (t, C-2), 28.3 (q, 3 C, CH3 Boc), 23.7 (t, C-
4), 22.7 (t, C-3), –0.1 [q, 3 C, Si(CH3)3] ppm. MS: m/z (%) = 279
[M]+ (23), 223 (92), 206 (15), 179 (87), 178 (100), 164 (72), 57 (56).
tert-Butyl (؎)-6-(Hex-1-ynyl)-4-methyl-3,4-dihydro-2H-pyridine-1-
carboxylate (8a): Pale yellow oil (205 mg, 74%). Rf = 0.12 (n-hex-
1
ane/EtOAc, 30:1 + 1% Et3N). H NMR (400 MHz): δ = 5.34 (d, J
= 3.5 Hz, 1 H, 5-H), 3.59 (ddd, J = 12.9, 7.0, 3.1 Hz, 1 H, 2-H),
3.46 (ddd, J = 12.9, 8.2, 2.7 Hz, 1 H, 2-HЈ), 2.36–2.30 (m, 1 H, 4-
H), 2.30 (t, J = 7.0 Hz, 2 H, 3Ј-H), 1.88–1.83 (m, 1 H, 3-HЈ), 1.55–
1.46 (m, 2 H, 4Ј-H), 1.49 [s, 9 H, C(CH3)3], 1.44–1.36 (m, 3 H, 5Ј-
H, 3-H), 1.00 (d, J = 7.0 Hz, 3 H, CH3), 0.90 (t, J = 7.4 Hz, 3 H,
6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 153.1 (s, C=O), 126.7 (d,
C-5), 121.4 (s, C-6), 88.3 (s, C-1Ј), 80.7 [s, C(CH3)3], 77.6 (s, C-2Ј),
42.2 (t, C-2), 30.9 (d, C-4), 30.7 (t, C-4Ј), 29.0 (t, C-3), 28.3 (q, 3
C, CH3 Boc), 22.0 (q, CH3), 21.0 (t, C-5Ј), 19.1 (t, C-3Ј), 13.6 (q,
C-6Ј) ppm. MS (ESI): m/z (%) = 577 [2M + Na]+ (100), 300 [M +
Na]+ (30). MS/MS (ESI of [M + Na]+): m/z (%) = 300 (4), 244
(100).
Benzyl 6-(Hex-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylate (13a):
Colourless oil (720 mg, 81%). Rf = 0.11 (n-hexane/EtOAc, 20:1 +
1
1% Et3N). H NMR (400 MHz): δ = 7.42–7.27 (m, 5 H), 5.52 (t,
J = 3.9 Hz, 1 H, 3-H), 5.20 (s, 2 H, CH2Ph), 3.65–3.62 (m, 2 H, 6-
H), 2.21–2.13 (m, 4 H, 4-H, 3Ј-H), 1.82–1.75 (m, 2 H, 5-H), 1.45–
1.31 (m, 4 H, 4Ј-H, 5Ј-H), 0.87 (t, J = 7.0 Hz, 3 H, 6Ј-H) ppm. 13
C
NMR (100.4 MHz): δ = 153.9 (s, C=O), 136.4 (s, Ph), 128.3 (d, 2
C, Ph), 127.9 (d, 2 C, Ph), 127.8 (d, Ph), 122.2 (s, C-6), 121.9 (d,
C-5), 89.1 (s, C-1Ј), 77.1 (s, C-2Ј), 67.5 (t, CH2Ph), 44.0 (t, C-2),
30.6 (t, C-4Ј), 23.5 (t, C-4), 22.6 (t, C-3), 22.0 (t, C-5Ј), 18.9 (t, C-
3Ј), 13.6 (q, C-6Ј) ppm. MS (ESI): m/z (%) = 617 [2M + Na]+ (100),
320 [M + Na]+ (12), 298 [M + 1]+ (31).
tert-Butyl (؎)-6-(Hex-1-ynyl)-2-methyl-3,4-dihydro-2H-pyridine-1-
carboxylate (8b): Yellow oil (160 mg, 58%). Rf = 0.18 (n-hexane/
1
EtOAc, 30:1 + 1% Et3N). H NMR (400 MHz): δ = 5.44 (t, J =
3.7 Hz, 1 H, 5-H), 4.56–4.49 (m, 1 H, 2-H), 2.30 (t, J = 7.0 Hz, 2
H, 3Ј-H), 2.15–2.09 (m, 2 H, 4-H), 1.83–1.73 (m, 1 H, 3-H), 1.62–
1.55 (m, 1 H, 3-HЈ), 1.49 [s, 9 H, C(CH3)3], 1.55–1.38 (m, 4 H, 4Ј-
H, 5Ј-H), 1.11 (d, J = 6.7 Hz, 3 H, CH3), 0.90 (t, J = 7.3 Hz, 3 H,
6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 153.0 (s, C=O), 119.9 (d,
C-5), 119.8 (s, C-6), 87.6 (s, C-1Ј), 80.6 [s, C(CH3)3], 78.3 (s, C-2Ј),
46.8 (d, C-2), 30.7 (t, C-4Ј), 28.3 (q, 3 C, CH3 Boc), 27.0 (t, C-4),
22.1 (t, C-5Ј), 19.8 (t, C-3), 19.1 (t, C-3Ј), 15.9 (q, CH3), 13.6 (q,
C-6Ј) ppm. MS/MS (ESI of [M + Na]+): m/z (%) = 300 (3), 244
(100).
Benzyl
6-(Phenylethynyl)-3,4-dihydro-2H-pyridine-1-carboxylate
(13b): Pale yellow oil (260 mg, 82%). Rf = 0.21 (n-hexane/EtOAc,
20:1 + 1% Et3N). 1H NMR (400 MHz): δ = 7.42–7.39 (m, 2 H,
Ph), 7.29–7.23 (m, 8 H, Ph), 5.73 (t, J = 4.1 Hz, 1 H, 5-H), 5.24 (s,
2 H, CH2Ph), 3.73–3.70 (m, 2 H, 2-H), 2.25 (td, J = 6.8, 4.1 Hz, 2
H, 4-H), 1.88–1.83 (m, 2 H, 3-H) ppm. 13C NMR (100.4 MHz): δ
= 153.9 (s, C=O), 136.2 (s, Ph), 131.4 (d, 2 C, Ph), 128.4 (d, 2 C,
Ph), 128.1 (d, 2 C, Ph), 128.04 (d, 2 C, Ph), 128.02 (d, Ph), 127.9
(d, Ph), 123.4 (d, C-5), 123.1 (s, C-6), 122.0 (s, Ph), 88.1 (s, C-1Ј),
86.1 (s, C-2Ј), 67.8 (t, CH2Ph), 44.0 (t, C-2), 23.7 (t, C-4), 22.5 (t,
C-3) ppm. MS (ESI): m/z (%) = 657 [2M + Na]+ (100), 318 [M +
1]+ (30).
tert-Butyl (3S)-6-(Hex-1-ynyl)-3-(triisopropylsilanyloxy)-3,4-dihy-
dro-2H-pyridine-1-carboxylate (8c): Yellow oil (279 mg, 64%). Rf =
0.36 (n-hexane/EtOAc, 20:1 + 1% Et3N). [α]1D9 = +37.9 (c = 0.77,
1
CHCl3). H NMR (400 MHz): δ = 5.40 (t, J = 4.0 Hz, 1 H, 5-H),
Benzyl 6-(Triethylsilanylethynyl)-3,4-dihydro-2H-pyridine-1-carb-
oxylate (13c): Colourless oil (709 mg, 82%). Rf = 0.25 (n-hexane/
4.05–3.99 (m, 1 H, 3-H), 3.84 (dd, J = 12.4, 3.0 Hz, 1 H, 2-H), 3.21
(dd, J = 12.4, 8.4 Hz, 1 H, 2-HЈ), 2.44 (dt, J = 18.9, 5.2 Hz, 1 H,
4-H), 2.31 (t, J = 7.0 Hz, 2 H, 3Ј-H), 2.08 (ddd, J = 18.9, 6.3,
4.0 Hz, 1 H, 4-HЈ), 1.53–1.46 (m, 2 H, 4Ј-H), 1.48 [s, 9 H,
C(CH3)3], 1.44–1.39 (m, 2 H, 5Ј-H), 1.07–1.04 (m, 21 H, TIPS),
0.90 (t, J = 7.3 Hz, 3 H, 6Ј-H) ppm. 13C NMR (100.4 MHz): δ =
152.9 (s, C=O), 122.2 (s, C-6), 119.2 (d, C-5), 88.7 (s, C-1Ј), 80.7
[s, C(CH3)3], 77.3 (s, C-2Ј), 65.2 (d, C-3), 49.8 (t, C-2), 34.5 (t, C-
4), 30.7 (t, C-4Ј), 28.1 (q, 3 C, CH3 Boc), 22.0 (t, C-5Ј), 19.1 (t, C-
3Ј), 18.0 (q, 6 C, CH3 TIPS), 13.6 (q, C-6Ј), 12.1 (d, 3 C, CH TIPS)
ppm. MS (ESI): m/z (%) = 909 [2M + K]+ (43), 893 [2M + Na]+
(100), 458 [M + Na]+ (26).
1
EtOAc, 20:1 + 1% Et3N). H NMR (400 MHz): δ = 7.42–7.40 (m,
2 H, Ph), 7.39–7.28 (m, 3 H, Ph), 5.70 (t, J = 4.1 Hz, 1 H, 5-H),
5.21 (s, 2 H, CH2Ph), 3.65–3.62 (m, 2 H, 2-H), 2.18 (td, J = 6.6,
4.1 Hz, 2 H, 4-H), 1.82–1.72 (m, 2 H, 3-H), 0.96 [t, J = 8.0 Hz, 9
H, Si(CH2CH3)3], 0.57 [q, J = 8.0 Hz, 6 H, Si(CH2CH3)3] ppm. 13
C
NMR (100.4 MHz): δ = 153.9 (s, C=O), 136.5 (s, Ph), 128.3 (d, 2
C, Ph), 127.8 (d, 2 C, Ph), 127.7 (d, Ph), 124.5 (s, C-6), 122.0 (d,
C-5), 102.2 (s, C-2Ј), 90.6 (s, C-1Ј), 67.3 (t, CH2Ph), 43.8 (t, C-2),
23.6 (t, C-4), 22.5 (t, C-3), 7.4 [q, 3 C, Si(CH2CH3)3], 4.3 [t, 3 C,
Si(CH2CH3)3] ppm. MS (ESI): m/z (%) = 733 [2M + Na]+ (100),
356 [M + 1]+ (30).
tert-Butyl (3S)-6-(Phenylethynyl)-3-(triisopropylsilanoxy)-3,4-dihy-
dro-2H-pyridine-1-carboxylate (8d): Yellow oil (314 mg, 69%). Rf =
0.13 (n-hexane/EtOAc, 20:1 + 1% Et3N). [α]2D7 = +22.5 (c = 2.03,
tert-Butyl 7-(Hex-1-ynyl)-2,3,4,5-tetrahydroazepine-1-carboxylate
(11a): Colourless oil (194 mg, 70%). Rf = 0.24 (n-hexane/EtOAc,
20:1 + 1% Et3N). H NMR (200 MHz): δ = 5.81 (t, J = 6.6 Hz, 1
1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
D. Scarpi, E. G. Occhiato et al.
FULL PAPER
H, 6-H), 3.42 (t, J = 5.3 Hz, 2 H, 2-H), 2.28 (t, J = 6.8 Hz, 2 H, 207 [M]+ (22), 151 (65), 134 (29), 107 (81), 106 (71), 92 (41), 79
3Ј-H), 2.19–2.10 (m, 2 H, 5-H), 1.78–1.66 (m, 2 H, 4-H), 1.66–1.35 (12), 57 (100), 41 (26).
(m, 6 H, 3-H, 4Ј-H, 5Ј-H), 1.46 [s, 9 H, C(CH3)3], 0.89 (t, J =
tert-Butyl (3R)-3-Azido-6-(hex-1-ynyl)-3,4-dihydro-2H-pyridine-1-
6.9 Hz, 3 H, 6Ј-H) ppm. 13C NMR (50.33 MHz): δ = 153.6 (s,
carboxylate (8f): Compound 8e (280 mg, 1.00 mmol) and triethyl-
C=O), 131.0 (s, C-7), 127.8 (d, C-6), 87.3 (s, C-2Ј), 80.0 [s,
amine (180 μL, 1.3 mmol) were dissolved in anhydrous CH2Cl2
C(CH3)3], 78.5 (s, C-1Ј), 47.2 (t, C-2), 30.7 (t, C-4Ј), 29.6 (t, C-5),
(1.44 mL), and the solution was cooled to –30 °C. MsCl (103 μL,
28.3 [q, 3 C, C(CH3)3], 27.5 (t, C-4), 23.8 (t, C-3), 22.0 (t, C-5Ј),
1.3 mmol) was added dropwise. After 5 min, the cooling bath was
19.0 (t, C-3Ј), 13.5 (q, C-6Ј) ppm. MS: m/z (%) = 277 [M]+ (4), 221
removed, and the reaction mixture was stirred for 2 h at room tem-
(61), 179 (68), 162 (65), 148 (57), 135 (87), 57 (100).
perature. Then KHSO4 (5% aq.; 6 mL) was added dropwise, and
after 10 min, the mixture was extracted with CH2Cl2 (3ϫ 5 mL).
The combined organic layers were washed with water (3ϫ 10 mL),
ate (11b): Yellow oil (205 mg, 69%). Rf = 0.21 (n-hexane/EtOAc,
tert-Butyl 7-(Phenylethynyl)-2,3,4,5-tetrahydroazepine-1-carboxyl-
20:1 + 1% Et3N). 1H NMR (200 MHz): δ = 7.44–7.37 (m, 2 H,
Ph), 7.32–7.28 (m, 3 H, Ph), 6.02 (t, J = 6.6 Hz, 1 H, 6-H), 3.54–
3.49 (m, 2 H, 2-H), 2.29–2.20 (m, 2 H, 5-H), 1.83–1.72 (m, 2 H, 4-
H), 1.58–1.45 (m, 2 H, 3-H), 1.48 [s, 9 H, C(CH3)3] ppm. 13C NMR
(50.33 MHz): δ = 153.3 (s, C=O), 132.4 (d, Ph), 131.1 (d, 2 C, Ph),
128.1 (d, 2 C, Ph), 127.8 (d, C-6), 127.3 (s, Ph), 123.0 (s, C-7), 87.5
(s, C-2Ј), 86.4 (s, C-1Ј), 80.1 [s, C(CH3)3], 47.2 (t, C-2), 29.4 (t, C-
5), 28.2 [q, 3 C, C(CH3)3], 27.6 (t, C-4), 23.6 (t, C-3) ppm. MS: m/z
(%) = 297 [M]+ (3), 241 (100), 197 (67), 196 (99), 182 (47), 169 (54).
dried with Na2SO4, and filtered, and the solvent was evaporated.
The residue was purified by flash chromatography (n-hexane/
EtOAc, 4:1 + 1% Et3N; Rf = 0.20) to give the mesylate (307 mg,
86%) as a pale yellow oil. 1H NMR (400 MHz): δ = 5.36 (t, J =
3.9 Hz, 1 H, 5-H), 5.01–4.98 (m, 1 H, 3-H), 4.06 (dd, J = 13.7,
5.9 Hz, 1 H, 2-H), 3.43 (dd, J = 13.7, 1.9 Hz, 1 H, 2-HЈ), 2.99 (s,
3 H, CH3 Ms), 2.56 (dm, J = 19.9 Hz, 1 H, 4-H), 2.38 (dm, J =
19.9 Hz, 1 H, 4-HЈ), 2.28 (t, J = 7.0 Hz, 2 H, 3Ј-H), 1.52–1.43 (m,
2 H, 4Ј-H), 1.46 [s, 9 H, C(CH3)3], 1.42–1.36 (m, 2 H, 5Ј-H), 0.87
(t, J = 7.0 Hz, 3 H, 6Ј-H) ppm.
tert-Butyl 7-(Cyclopropylethynyl)-2,3,4,5-tetrahydroazepine-1-carb-
oxylate (11c): Colourless oil (196 mg, 75%). Rf = 0.30 (n-hexane/
EtOAc, 20:1 + 1% Et3N). H NMR (200 MHz): δ = 5.81 (t, J =
The intermediate mesylate (301 mg, 0.84 mmol) was dissolved in
anhydrous CH3CN (2 mL), and 15-crown-5 (34 μL, 0.17 mmol)
and NaN3 (82 mg, 1.26 mmol) were added under a nitrogen atmo-
sphere. The mixture was heated at reflux for 6 h, and then stirred
at room temperature for a further 12 h. The mixture was filtered
through a pad of silica/Celite (1:1), and the filtrate was concen-
trated under vacuum. The residue was purified by flash chromatog-
raphy (n-hexane/EtOAc, 30:1 + 1% Et3N; Rf = 0.14) to give pure
8f (120 mg, 47%) as a pale yellow oil. [α]2D1 = –21.0 (c = 1.16,
1
6.5 Hz, 1 H, 6-H), 3.44–3.39 (m, 2 H, 2-H), 2.18–2.09 (m, 2 H, 5-
H), 1.77–1.66 (m, 2 H, 4-H), 1.52–1.40 (m, 2 H, 3-H), 1.47 [s, 9 H,
C(CH3)3], 1.37–1.24 (m, 1 H, 3Ј-H), 0.83–0.64 (m, 4 H, 4Ј-H) ppm.
13C NMR (50.33 MHz): δ = 153.5 (s, C=O), 131.0 (d, C-6), 127.7
(s, C-7), 90.2 (s, C-2Ј), 80.0 [s, C(CH3)3], 73.9 (s, C-1Ј), 47.3 (t, C-
2), 29.6 (t, C-5), 28.4 [q, 3 C, C(CH3)3], 27.5 (t, C-4), 23.8 (t, C-3),
8.2 (t, 2 C, C-4Ј), –0.1 (d, C-3Ј) ppm. MS: m/z (%) = 261 [M]+ (10),
205 (100), 204 (41), 160 (44), 57 (43).
1
CHCl3). H NMR (400 MHz): δ = 5.37 (t, J = 3.9 Hz, 1 H, 5-H),
3.80–3.74 (m, 1 H, 3-H), 3.66–3.57 (m, 2 H, 2-H), 2.47 (ddd, J =
19.5, 6.2, 3.9 Hz, 1 H, 4-H), 2.86 (t, J = 7 Hz, 2 H, 3Ј-H), 2.15 (dt,
J = 19.5, 4.7 Hz, 1 H, 4-HЈ), 1.53–1.44 (m, 2 H, 4Ј-H), 1.48 [s, 9
H, C(CH3)3], 1.43–1.35 (m, 2 H, 5Ј-H), 0.88 (t, J = 7.0 Hz, 3 H,
6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 153.0 (s, C=O), 122.9 (s,
C-6), 117.2 (d, C-5), 89.2 (s, C-1Ј), 81.4 [s, C(CH3)3], 76.7 (s, C-2Ј),
54.4 (d, C-3), 46.3 (t, C-2), 30.5 (t, C-4), 29.4 (t, C-4Ј), 28.1 (q, 3
C, CH3 Boc), 21.9 (t, C-5Ј), 18.9 (t, C-3Ј), 13.5 (q, C-6Ј) ppm. MS
(ESI): m/z (%) = 631 [2M + Na]+ (100), 343 [M + K]+ (8), 327 [M
+ Na]+ (35).
tert-Butyl (3S)-6-(Hex-1-ynyl)-3-hydroxy-3,4-dihydro-2H-pyridine-
1-carboxylate (8e): TBAF (1 m solution in THF; 1.94 mL,
1.94 mmol) was slowly added to a solution of 8c (740 mg,
1.7 mmol) in anhydrous THF (82 mL), under a nitrogen atmo-
sphere. After 30 min, the solvent was evaporated under vacuum,
and the residue was dissolved in Et2O (82 mL). The solvent was
evaporated again, and the residue was purified by flash chromatog-
raphy (n-hexane/EtOAc, 2:1 + 1% Et3N; Rf = 0.24) to give pure 8e
(410 mg, 86%). [α]2D2 = –10.6 (c = 0.97, CHCl3). 1H NMR
(400 MHz): δ = 5.40 (t, J = 3.9 Hz, 1 H, 5-H), 4.07–4.02 (m, 1 H,
3-H), 3.56 (AB system, JAB = 12.8 Hz, 1 H, 2-H), 3.54 (AB system,
JAB = 12.8 Hz, 1 H, 2-HЈ), 2.53 (br. s, 1 H, OH), 2.44 (dt, J = 19.1,
4.3 Hz, 1 H, 4-H), 2.29 (t, J = 7 Hz, 2 H, 3Ј-H), 2.09 (dt, J = 19.1,
4.7 Hz, 1 H, 4-HЈ), 1.54–1.45 (m, 2 H, 4Ј-H), 1.47 [s, 9 H, C(CH3)
3], 1.44–1.36 (m, 2 H, 5Ј-H), 0.89 (t, J = 7.4 Hz, 3 H, 6Ј-H) ppm.
13C NMR (100.4 MHz): δ = 153.8 (s, C=O), 122.4 (s, C-6), 118.6
(d, C-5), 88.8 (s, C-1Ј), 81.2 [s, C(CH3)3], 77.0 (s, C-2Ј), 64.3 (d, C-
3), 49.2 (t, C-2), 32.8 (t, C-4), 30.6 (t, C-4Ј), 28.2 (q, 3 C, CH3 Boc),
22.0 (t, C-5Ј), 19.0 (t, C-3Ј), 13.6 (q, C-6Ј) ppm. MS (ESI): m/z (%)
= 597 [2M + K]+ (24), 581 [2M + Na]+ (100), 302 [M + Na]+ (21).
Gold-Catalysed Rearrangement and Hydrolysis Procedure: A vol-
ume of the enyne solution containing 1 mmol of substrate was con-
centrated and dried under vacuum (no heating) for 30 min, and
then the enyne was dissolved in anhydrous toluene (5 mL).
Ph3PAuCl (0.005 mmol) was dissolved in anhydrous toluene (5 mL)
in
a two-necked round-bottomed flask, and then Cu(OTf)2
(0.05 mmol) was added to this solution under a nitrogen atmo-
sphere. After 15 min, the solution of the enyne was added, and the
resulting mixture was heated at reflux until the starting material
had disappeared (TLC, usually 30 min.). The mixture was cooled
to 85 °C (external), and tert-butyl alcohol (10 mL) was added, fol-
lowed by powdered KOH (6 mmol). The mixture was heated at
85 °C until the reaction was complete (TLC, usually 15 min.). The
mixture was then cooled to room temp., water (15 mL) was added,
and the mixture was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic extracts were washed once with brine (15 mL), dried
with anhydrous Na2SO4, and filtered, and the solvent was evapo-
rated. The crude vinylogous amide (12a–12e, 12g–12i) was purified
by flash chromatography to give the pure compound.
tert-Butyl 6-Ethynyl-3,4-dihydro-2H-pyridine-1-carboxylate (22b):
Prepared as described for 8e, starting from 22a (279 mg, 1.0 mmol),
to give, after purification by flash chromatography (petroleum
ether/EtOAc, 9:1; Rf = 0.50), pure 22b (205 mg, 99%) as a colour-
1
less oil. H NMR (200 MHz): δ = 5.65 (t, J = 4.0 Hz, 1 H, 5-H),
3.59–3.54 (m, 2 H, 2-H), 2.93 (s, 1 H, 2Ј-H), 2.21–2.12 (m, 2 H, 4-
H), 1.84–1.72 (m, 2 H, 3-H), 1.50 [s, 9 H, C(CH3)3] ppm. 13C NMR
(50.33 MHz): δ = 152.9 (s, C=O), 123.8 (s, C-6), 121.5 (d, C-5),
81.5 (s, C-1Ј), 80.6 [s, C(CH3)3], 75.9 (d, C-2Ј), 43.4 (t, C-2), 28.3 (؎)-1-(4-Methylpiperidin-2-ylidene)hexan-2-one (12a): Pale yellow
(q, 3 C, CH3 Boc), 23.6 (t, C-4), 22.5 (t, C-3) ppm. MS: m/z (%) = solid (133 mg, 68%). Rf = = 0.23 (n-hexane/EtOAc, 7:1). Mp 52.6–
10
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Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
Exocyclic Vinylogous Amides and β-Amino Ketones
1
1
54.1 °C. H NMR (400 MHz): δ = 11.09 (br. s, 1 H, NH), 4.81 (s,
= 1.34, CHCl3). H NMR (400 MHz): δ = 10.95 (br. s, 1 H, NH),
1 H, 1Ј-H), 3.39–3.34 (m, 1 H, 6-H), 3.28–3.21 (m, 1 H, 6Ј-H), 4.89 (s, 1 H, 1Ј-H), 4.29 (br. s, 1 H, OH), 4.08–4.02 (m, 1 H, 5-H),
2.33–2.79 (m, 1 H, 3-HЈ), 2.15 (t, J = 7.4 Hz, 2 H, 3Ј-H), 1.98 (dd, 3.44 (br. d, J = 13.3 Hz, 1 H, 6-H), 3.17 (dd, J = 13.3, 5.5 Hz, 1
J = 17.1, 10.5 Hz, 1 H, 3-HЈ), 1.82–1.73 (m, 2 H, 4-H, 5-HЈ), 1.55– H, 6-HЈ), 2.57 (ddd, J = 17.5, 7.4, 5.8 Hz, 1 H, 3-H), 2.30 (dt, J =
1.48 (m, 2 H, 4Ј-H), 1.40–1.24 (m, 3 H, 5-H, 5Ј-H), 0.96 (d, J =
17.5, 6.6 Hz, 1 H, 3-HЈ), 2.13 (t, J = 7.8 Hz, 2 H, 3Ј-H), 1.89–1.83
6.3 Hz, 3 H, CH3), 0.85 (t, J = 7.0 Hz, 3 H, 6Ј-H) ppm. 13C NMR (m, 1 H, 4-H), 1.76–1.69 (m, 1 H, 4-HЈ), 1.53–1.45 (m, 2 H, 4Ј-H),
(100.4 MHz): δ = 197.4 (s, C-2Ј), 163.6 (s, C-2), 92.8 (d, C-1Ј), 41.5 1.32–1.22 (m, 2 H, 5Ј-H), 0.85 (t, J = 7.4 Hz, 3 H, 6Ј-H) ppm. 13C
(t, C-6), 40.7 (t, C-3Ј), 36.7 (d, C-4), 30.1 (t, C-5), 28.5 (t, C-3),
25.8 (t, C-4Ј), 22.6 (t, C-5Ј), 21.2 (q, CH3), 13.8 (q, C-6Ј) ppm. IR
NMR (100.4 MHz): δ = 197.5 (s, C-2Ј), 163.8 (s, C-2), 92.8 (d, C-
1Ј), 63.3 (d, C-5), 47.6 (t, C-6), 41.5 (t, C-3Ј), 28.6 (t, C-3), 27.2 (t,
(KBr): ν = 1611 (CO), 1572 (C=C) cm–1. MS (ESI): m/z (%) = 413 C-4Ј), 25.4 (t, C-4), 22.5 (t, C-5Ј), 13.8 (q, C-6Ј) ppm. IR (neat): ν
˜
˜
= 3346 (br., OH), 1607 (CO), 1548 (C=C) cm–1. MS (ESI): m/z (%)
= 417 [2M + Na]+ (100), 220 [M + Na]+ (14), 198 [M + 1]+ (17).
MS/MS (ESI of [M + 1]+): m/z (%) = 198 (22), 180 (100), 162 (34),
113 (58), 95 (21). C11H19NO2 (197.27): calcd. C 66.97, H 9.71, N
7.10; found C 67.37, H 10.00, N 7.03.
[2M + Na]+ (100), 196 [M + 1]+ (44). MS/MS (ESI of [M + 1]+):
m/z (%) = 178 (5), 112 (100). C12H21NO (195.30): calcd. C 73.80,
H 10.84, N 7.17; found C 73.75, H 10.97, N 7.30.
(؎)-1-(6-Methylpiperidin-2-ylidene)hexan-2-one (12b): Orange oil
(111 mg, 57%). Rf = 0.13 (n-hexane/EtOAc, 7:1). 1H NMR
(400 MHz): δ = 11.06 (br. s, 1 H, NH), 4.81 (s, 1 H, 1Ј-H), 3.45–
3.37 (m, 1 H, 6-H), 2.31–2.26 (m, 2 H, 3-H), 2.17 (t, J = 7.5 Hz, 2
H, 3Ј-H), 1.91–1.84 (m, 1 H, 5-H), 1.80–1.72 (m, 1 H, 4-H), 1.63–
1.49 (m, 3 H, 4-HЈ, 4Ј-H), 1.36–1.24 (m, 3 H, 5-HЈ, 5Ј-H), 1.20 (d,
J = 6.5 Hz, 3 H, CH3), 0.86 (t, J = 7.4 Hz, 3 H, 6Ј-H) ppm. 13C
NMR (100.4 MHz): δ = 197.3 (s, C-2Ј), 163.6 (s, C-2), 92.5 (d, C-
1Ј), 47.3 (d, C-6), 41.5 (t, C-3Ј), 30.6 (t, C-5), 28.3 (t, C-3), 28.1 (t,
C-4Ј), 22.6 (t, C-5Ј), 22.5 (t, C-4), 18.9 (q, CH3), 13.9 (q, C-6Ј)
ppm. MS (ESI): m/z (%) = 413 [2M + Na]+ (100), 218 [M + Na]+
(17), 196 [M + 1]+ (65). MS/MS (ESI of [M + 1]+): m/z (%) = 111
(100), 94 (3). C12H21NO (195.30): calcd. C 73.80, H 10.84, N 7.17;
found C 73.61, H 10.93, N 7.14.
1-Azepan-2-ylidenehexan-2-one (12g): Colourless oil (142 mg,
1
73%). Rf = 0.25 (n-hexane/EtOAc, 3:1). H NMR (200 MHz): δ =
11.0 (br. s, 1 H, NH), 4.96 (s, 1 H, 1Ј-H), 3.36–3.28 (m, 2 H, 7-H),
2.32–2.19 (m, 4 H, 3-H, 3Ј-H), 1.68–1.28 (m, 10 H, 4-H, 5-H, 6-
H, 4Ј-H, 5Ј-H), 0.90 (t, J = 7.2 Hz, 3 H, 6Ј-H) ppm. 13C NMR
(50.33 MHz): δ = 198.7 (s, C-2Ј), 169.6 (s, C-2), 93.6 (d, C-1Ј), 44.2
(t, C-7), 41.9 (t, C-3Ј), 34.9 (t, C-3), 30.6 (t, C-6), 29.5 (t, C-5), 28.5
(t, C-4Ј), 26.0 (t, C-4), 22.7 (t, C-5Ј), 14.0 (q, C-6Ј) ppm. MS: m/z
(%) = 195 [M]+ (23), 138 (100), 111 (35). C12H21NO (195.30): calcd.
C 73.80, H 10.84, N 7.17; found C 74.01, H 10.90, N 7.03.
2-Azepan-2-ylidene-1-phenylethanone (12h): Yellow oil (140 mg,
1
65%). Rf = 0.22 (n-hexane/EtOAc, 3:1). H NMR (200 MHz): δ =
(5S)-1-(5-Triisopropylsilanyloxypiperidin-2-ylidene)hexan-2-one
(12c): Yellow oil (219 mg, 62%). Rf = 0.24 (n-hexane/EtOAc, 10:1).
[α]2D0 = –25.4 (c = 0.98, CHCl3). 1H NMR (400 MHz): δ = 11.02
(br. s, 1 H, NH), 4.99 (br. s, 1 H, 1Ј-H), 4.17–4.12 (m, 1 H, 5-H),
3.48 (dd, J = 13.2, 4.0 Hz, 1 H, 6-H), 3.21 (dd, J = 13.2, 5.8 Hz, 1
H, 6-HЈ), 2.64 (ddd, J = 17.5, 7.8, 5.9 Hz, 1 H, 3-H), 2.31 (ddd, J
= 17.5, 7.1, 5.9 Hz, 1 H, 3-HЈ), 2.21–2.18 (m, 2 H, 3Ј-H), 1.91–1.84
(m, 1 H, 4-H), 1.80–1.71 (m, 1 H, 4-HЈ), 1.57–1.55 (m, 2 H, 4Ј-H),
1.37–1.25 (m, 2 H, 5Ј-H), 1.10–0.96 (m, 21 H, TIPS), 0.88 (t, J =
7.4 Hz, 3 H, 6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 197.9 (s, C-
2Ј), 163.0 (s, C-2), 93.1 (d, C-1Ј), 64.7 (d, C-5), 48.3 (t, C-6), 41.6
(t, C-3Ј), 28.4 (t, C-4Ј), 28.3 (t, C-3), 25.4 (t, C-4), 22.6 (t, C-5Ј),
17.9 (q, 6 C, CH3 TIPS), 13.9 (q, C-6Ј), 12.1 (d, 3 C, CH TIPS)
11.54 (br. s, 1 H, NH), 7.90–7.82 (m, 2 H, Ph), 7.42–7.35 (m, 3 H,
Ph), 5.67 (s, 1 H, 1Ј-H), 3.45–3.37 (m, 2 H, 7-H), 2.47–2.42 (m,
2 H, 3-H), 1.80–1.60 (m, 6 H, 4-H, 5-H, 6-H) ppm. 13C NMR
(50.33 MHz): δ = 188.1 (s, C-2Ј), 171.3 (s, C-2), 140.6 (s, Ph), 130.3
(d, Ph), 128.0 (d, 2 C, Ph), 126.8 (d, 2 C, Ph), 91.0 (d, C-1Ј), 44.4
(t, C-7), 35.3 (t, C-3), 30.5 (t, C-6), 29.3 (t, C-5), 25.8 (t, C-4) ppm.
MS: m/z (%) = 215 [M]+ (81), 214 (100), 186 (22), 105 (24).
C14H17NO (215.29): calcd. C 78.10, H 7.96, N 6.51; found C 77.92,
H 7.90, N 6.24.
2-Azepan-2-ylidene-1-cyclopropylethanone (12i): Colourless oil
(108 mg, 60%). Rf = 0.31 (n-hexane/EtOAc, 3:1). 1H NMR
(200 MHz): δ = 10.89 (br. s, 1 H, NH), 5.12 (s, 1 H, 1Ј-H), 3.34–
3.26 (m, 2 H, 7-H), 2.34–2.29 (m, 2 H, 3-H), 1.78–1.54 (m, 7 H, 4-
H, 5-H, 6-H, 3Ј-H), 0.99–0.90 (m, 2 H, 4Ј-H), 0.82–0.66 (m, 2 H,
4Ј-HЈ) ppm. 13C NMR (50.33 MHz): δ = 197.1 (s, C-2Ј), 168.7 (s,
C-2), 93.6 (d, C-1Ј), 44.2 (t, C-7), 35.0 (t, C-3), 30.6 (t, C-6), 29.5
(t, C-5), 26.0 (t, C-4), 19.8 (d, C-3Ј), 8.61 (t, 2 C, C-4Ј) ppm. MS:
m/z (%) = 179 [M]+ (80), 138 (100). C11H17NO (179.26): calcd. C
73.70, H 9.56, N 7.81; found C 73.44, H 9.82, N 8.05.
ppm. IR (neat): ν = 1610 (CO), 1574 (C=C) cm–1. MS (ESI): m/z
˜
(%) = 729 [2M + Na]+ (69), 707 [2M + 1]+ (14), 706 [2M]+ (33),
354 [M + 1]+ (100). MS/MS (ESI of [M+ + 1]): m/z (%) = 354 (4),
270 (5), 180 (100), 162 (9). C20H39NO2Si (353.61): calcd. C 67.93,
H 11.12, N 3.96; found C 67.63, H 11.21, N 3.77.
(5S)-1-Phenyl-2-(5-triisopropylsilanoxypiperidin-2-ylidene)ethanone
(12d): Yellow oil (119 mg, 63%). Rf = 0.10 (n-hexane/EtOAc, 10:1).
[α]2D4 = –12.3 (c = 1.49, CHCl3). 1H NMR (400 MHz): δ = 11.61
(br. s, 1 H, NH), 7.85–7.83 (m, 2 H, Ph), 7.40–7.35 (m, 3 H, Ph),
5.62 (s, 1 H, 1Ј-H), 4.23–4.20 (m, 1 H, 5-H), 3.56 (dt, J = 13.3,
2.9 Hz, 1 H, 6-H), 3.30 (ddd, J = 13.3, 5.3, 2.0 Hz, 1 H, 6-HЈ), 2.80
(ddd, J = 17.4, 8.0, 6.1 Hz, 1 H, 4-H), 2.45 (dt, J = 17.4, 6.2 Hz, 1
H, 4-HЈ), 1.95–1.89 (m, 1 H, 3-H), 1.88–1.81 (m, 1 H, 3-HЈ), 1.12–
1.04 (m, 21 H, TIPS) ppm. 13C NMR (100.4 MHz): δ = 187.2 (s,
C-2Ј), 165.0 (s, C-2), 140.5 (s, Ph), 130.2 (d, Ph), 128.1 (d, 2 C, Ph),
126.8 (d, 2 C, Ph), 90.1 (d, C-1Ј), 64.6 (d, C-5), 48.6 (t, C-6), 28.3
(t, C-3), 25.9 (t, C-4), 18.0 (q, 6 C, CH3 TIPS), 12.2 (d, 3 C, CH
1-(1,4,5,6-Tetrahydropyridin-2yl)ethanone (23):[44] Pale yellow oil
1
(22 mg, 35%). H NMR (200 MHz; 2:1 mixture of isomers A and
B): δ = 5.61 (t, J = 4.4 Hz, 1 H, 2-H, A), 4.19 (br. s, 1 H, NH, A),
3.84–3.79 (m, 2 H, 5-H, B), 3.14 (t, J = 5.3 Hz, 2 H, 5-H, A), 2.38–
2.31 (m, 2 H, 2-H, B), 2.33 (s, 3 H, CH3, B), 2.31–2.20 (m, 2 H, 3-
H, A), 2.26 (s, 3 H, CH3, A), 1.85–1.73 (m, 2 H, 4-H, A), 1.73–
1.54 (m, 4 H, 3-H, 4-H, B) ppm.
(5R)-1-(5-Azidopiperidin-2-ylidene)hexan-2-one (12f): A volume of
the enyne solution containing 1 mmol of substrate was concen-
trated and dried under vacuum (no heating) for 30 min, and then
the enyne was dissolved in anhydrous toluene (5 mL). Separate
solutions in anhydrous toluene of AgOTf (0.2 m) and of Ph3PAuCl
(4 mm) were prepared. The AgOTf solution (100 μL, 0.02 mmol)
was added at room temp. to the Ph3PAuCl solution (5 mL,
0.02 mmol) while stirring under a nitrogen atmosphere, and a white
precipitate immediately formed. The solution of enyne 8f
TIPS) ppm. IR (CHCl ): ν = 1604 (CO), 1538 (C=C) cm–1. MS
˜
3
(ESI): m/z (%) = 769 [2M + Na]+ (100), 746 [2M]+ (72), 374 [M +
1]+ (66). C22H35NO2Si (373.60): calcd. C 70.73, H 9.44, N 3.75;
found C 70.59, H 9.72, N 3.91.
(5S)-1-(5-Hydroxypiperidin-2-ylidene)hexan-2-one (12e): Yellow oil
(128 mg, 65%). Rf = 0.19 (n-hexane/EtOAc, 3:1). [α]2D3 = –16.5 (c
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
D. Scarpi, E. G. Occhiato et al.
FULL PAPER
(1.0 mmol) in anhydrous toluene (5 mL) was then added, and the
(100.4 MHz): δ = 155.0 (s, C=O), 136.7 (s, Cbz), 131.7 (d, 2 C, Ph),
resulting mixture was heated at reflux until the starting material 128.5 (d, Ph), 128.2 (d, 2 C, Ph), 128.1 (d, 2 C, Cbz), 127.9 (d, 2
had disappeared (TLC, 30 min). The mixture was cooled to 85 °C
(external), and tert-butyl alcohol (10 mL) was added, followed by
powdered KOH (6 mmol). The mixture heated at 85 °C until the
reaction was complete (TLC, 10 min.). The mixture was cooled to
room temperature, then water (15 mL) was added, and the mixture
was extracted with EtOAc (3ϫ 10 mL). The combined organic ex-
tracts were washed once with brine (15 mL), dried with anhydrous
Na2SO4, and filtered, and the solvent was evaporated. The residue
was purified by flash chromatography (n-hexane/EtOAc, 3:1; Rf =
0.24) to give pure vinylogous amide 12f (142 mg, 64%) as a colour-
C, Cbz), 127.7 (d, Cbz), 122.9 (s, Ph), 84.4 (s, C-1Ј), 77.2 (s, C-2Ј),
67.2 (t, CH2Ph), 45.0 (t, C-6), 40.7 (d, C-2), 30.8 (t, C-3), 25.3 (t,
C-5), 20.0 (t, C-4) ppm. MS (ESI): m/z (%) = 661 [2M + Na]+
(100), 342 [M + Na]+ (10), 320 [M + 1]+ (3). C21H21NO2 (319.40):
calcd. C 78.97, H 6.63, N 4.39; found C 78.79, H 6.41, N 4.84.
Benzyl 2-(Triethylsilanylethynyl)piperidine-1-carboxylate (16c): Pre-
pared as described for 16a, starting from 13c (702 mg, 1.97 mmol),
to give, after purification by flash chromatography (n-hexane/
EtOAc, 20:1; Rf = 0.31), pure 16c (383 mg, 54%) as a colourless
oil. 1H NMR (400 MHz): δ = 7.36–7.28 (m, 5 H, Ph), 5.25–5.09
(m, 1 H, 2-H), 5.14 (s, 2 H, CH2Ph), 4.01 (br. d, J = 11.3 Hz, 1 H,
6-H), 3.20–3.05 (br. m, 1 H, 6-HЈ), 1.90–1.74 (m, 2 H, 3-H), 1.70–
1.60 (m, 3 H, 5-H, 4-H), 1.48–1.33 (m, 1 H, 5-HЈ), 0.97 [t, J =
7.8 Hz, 9 H, Si(CH2CH3)3], 0.59 [q, J = 7.8 Hz, 6 H, Si-
(CH2CH3)3] ppm. 13C NMR (100.4 MHz): δ = 155.0 (s, C=O),
136.8 (s, Ph), 128.4 (d, 2 C, Ph), 127.9 (d, 2 C, Ph), 127.6 (d, Ph),
104.8 (s, C-2Ј), 86.3 (s, C-1Ј), 67.1 (t, CH2Ph), 45.2 (t, C-6), 40.5
(d, C-2), 30.7 (t, C-3), 25.3 (t, C-5), 19.8 (t, C-4), 7.4 [q, 3 C,
Si(CH2CH3)3], 4.4 [t, 3 C, Si(CH2CH3)3] ppm. MS (ESI): m/z (%)
= 737 [2M + Na]+ (100), 380 [M + Na]+ (10), 358 [M + 1]+ (3).
C21H31NO2Si (357.56): calcd. C 70.54, H 8.74, N 3.92; found C
70.24, H 8.46, N 4.24.
1
less oil. [α]2D3 = –11.5 (c = 0.92, CHCl3). H NMR (400 MHz): δ =
10.99 (br. s, 1 H, NH), 4.93 (s, 1 H, 1Ј-H), 3.89–3.83 (m, 1 H, 5-
H), 3.49 (ddd, J = 13.3, 4.7, 2.3 Hz, 1 H, 6-H), 3.23 (ddd, J = 13.3,
6.2, 1.9 Hz, 1 H, 6-HЈ), 2.55 (ddd, J = 17.6, 7.8, 5.9 Hz, 1 H, 3-H),
2.36 (ddd, J = 17.6, 7.4, 6.3 Hz, 1 H, 3-HЈ), 2.22–2.18 (m, 2 H, 3Ј-
H), 2.03–1.95 (m, 1 H, 4-H), 1.85–1.76 (m, 1 H, 4-HЈ), 1.57–1.50
(m, 2 H, 4Ј-H), 1.35–1.28 (m, 2 H, 5Ј-H), 0.88 (t, J = 7.4 Hz, 3 H,
6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 198.5 (s, C-2Ј), 161.4 (s,
C-2), 93.5 (d, C-1Ј), 54.4 (d, C-5), 44.5 (t, C-6), 41.7 (t, C-3Ј), 28.3
(t, C-3), 25.4 (t, C-4), 24.6 (t, C-4Ј), 22.6 (t, C-5Ј), 13.9 (q, C-6Ј)
ppm. IR (neat): ν = 2106 (N ), 1614 (CO), 1574 (C=C) cm–1. MS
˜
3
(ESI): m/z (%) = 467 [2M + Na]+ (100), 245 [M + Na]+ (38), 223
[M + 1]+ (18). MS/MS (ESI of [M + 1]+): m/z (%) = 166 (94), 110
(32), 93 (100), 81 (93). C11H18N4O (222.29): calcd. C 59.44, H 8.16,
N 25.20; found C 59.83, H 7.82, N 24.98.
Benzyl 2-Ethynylpiperidine-1-carboxylate (16d): Prepared as de-
scribed for 8e, starting from 16c (341 mg, 0.95 mg), to give, after
purification by flash chromatography (n-hexane/EtOAc, 20:1; Rf =
0.18), pure 16d (207 mg, 89%) as a colourless oil. 1H NMR
(400 MHz): δ = 7.39–7.29 (m, 5 H, Ph), 5.18–5.12 (m, 1 H, 2-H),
5.15 (s, 2 H, CH2Ph), 4.03 (br. d, J = 11.7 Hz, 1 H, 6-H), 3.12 (br.
t, J = 12.3 Hz, 1 H, 6-HЈ), 2.30 (d, J = 2.3 Hz, 1 H, 2Ј-H), 1.83–
1.74 (m, 2 H, 3-H), 1.71–1.65 (m, 3 H, 5-H, 4-H), 1.46–1.35 (m, 1
H, 5-HЈ) ppm. 13C NMR (100.4 MHz): δ = 155.0 (s, C=O), 136.6
(s, Ph), 128.4 (d, 2 C, Ph), 127.9 (d, 2 C, Ph), 127.8 (d, Ph), 81.6
(s, C-1Ј), 72.3 (d, C-2Ј), 67.2 (t, CH2Ph), 44.2 (t, C-6), 40.5 (d, C-
2), 30.3 (t, C-3), 25.1 (t, C-5), 19.7 (t, C-4) ppm. MS (ESI): m/z
(%) = 509 [2M + Na]+ (100), 266 [M + Na]+ (37), 244 [M + 1]+
(7). C15H17NO2 (243.30): calcd. C 74.05, H 7.04, N 5.76; found C
73.79, H 7.41, N 5.84.
Benzyl 2-(Hex-1-ynyl)piperidine-1-carboxylate (16a): Enyne 13a
(217 mg, 0.73 mmol) was dissolved in anhydrous CH2Cl2 (36 mL),
and NaBH3CN (275 mg, 4.37 mmol) was added. The mixture was
vigorously stirred at r.t. for 20 min, and then it was cooled to
–50 °C. A solution of TFA (561 μL, 7.28 mmol) in anhydrous
CH2Cl2 (4.9 mL) was added dropwise, keeping the temperature
constant during the addition. The mixture was then warmed to
–20 °C, and then stirred at that temperature until the reaction was
complete (TLC; 2–3 h). The reaction was then quenched by ad-
dition of satd. aq. NaHCO3 (40 mL). The phases were separated,
and the aqueous phase was extracted with CH2Cl2 (2ϫ 20 mL).
The combined organic extracts were washed once with satd. aq.
NaHCO3 (40 mL), dried with anhydrous Na2SO4, and filtered, and
the solvent was evaporated. The residue was purified by flash
chromatography (n-hexane/EtOAc, 20:1; Rf = 0.11) to give pure
16a (129 mg, 59%) as a colourless oil. 1H NMR (400 MHz): δ =
7.36–7.28 (m, 5 H, Ph), 5.18–5.08 (m, 1 H, 2-H), 5.14 (s, 2 H,
CH2Ph), 3.98 (br. d, J = 12.5 Hz, 1 H, 6-H), 3.11 (br. t, J = 12.3 Hz,
1 H, 6-HЈ), 2.19 (td, J = 6.8, 2.0 Hz, 2 H, 3Ј-H), 1.81–1.56 (m, 5
H, 3-H, 4-H, 5-H), 1.51–1.36 (m, 5 H, 4Ј-H, 5Ј-H, 5-HЈ), 0.91 (t, J
= 7.2 Hz, 3 H, 6Ј-H) ppm. 13C NMR (100.4 MHz): δ = 155.1 (s,
C=O), 136.9 (s, Ph), 128.4 (d, 2 C, Ph), 127.9 (d, 2 C, Ph), 127.7
(d, Ph), 84.8 (s, C-1Ј), 77.7 (s, C-2Ј), 67.1 (t, CH2Ph), 44.6 (t, C-6),
40.5 (d, C-2), 31.0 (t, C-3), 30.9 (t, C-4Ј), 25.4 (t, C-5), 21.9 (t, C-
5Ј), 19.9 (t, C-4), 18.3 (t, C-3Ј), 13.6 (q, C-6Ј) ppm. MS (ESI): m/z
(%) = 621 [2M + Na]+ (100), 322 [M + Na]+ (17), 300 [M + 1]+
(4). C19H25NO2 (299.41): calcd. C 76.22, H 8.42, N 4.68; found C
76.33, H 8.82, N 4.40.
3-Butyl-5,6,7,8-tetrahydro-4aH-pyrido[1,2-c][1,3]oxazin-1-one (18a):
Ph3PAuCl (5.4 mg, 0.011 mmol) was dissolved in toluene (1.8 mL)
in a two-necked round-bottomed flask, and Cu(OTf)2 (20 mg,
0.055 mmol) was added under a nitrogen atmosphere. A solution
of alkyne 16a (108 mg, 0.36 mmol) in toluene (1.8 mL) was added,
and the resulting mixture was heated at reflux until the starting
material had disappeared (TLC, 1.5–2 h). The mixture was cooled,
then water (5 mL) was added, and the mixture was extracted with
EtOAc (3ϫ 5 mL). The combined organic extracts were washed
once with brine (5 mL), dried with anhydrous Na2SO4, and filtered,
and the solvent was evaporated. The residue was purified by flash
chromatography (n-hexane/EtOAc, 5:1; Rf = 0.23) to give pure 18a
(63 mg, 83%) as a colourless oil. 1H NMR (400 MHz): δ = 4.64 (d,
J = 2.8 Hz, 1 H, 4-H), 4.43 (dd, J = 13.2, 1.6 Hz, 1 H, 8-H), 3.78
(d, J = 11.2 Hz, 1 H, 4a-H), 2.67 (td, J = 12.8, 2.8 Hz, 1 H, 8-HЈ),
2.07 (t, J = 7.6 Hz, 2 H, 1Ј-H), 1.89–1.85 (m, 1 H, 7-H), 1.75–1.72
Benzyl 2-(Phenylethynyl)piperidine-1-carboxylate (16b): Prepared as (m, 2 H, 6-H, 7-HЈ), 1.58–1.41 (m, 4 H, 5-H, 6-HЈ, 2Ј-H), 1.39–
described for 16a, starting from 13b (151 mg, 0.47 mmol), to give, 1.27 (m, 3 H, 5-HЈ, 3Ј-H), 0.89 (t, J = 7.2 Hz, 3 H, 4Ј-H) ppm. 13
C
after purification by flash chromatography (n-hexane/EtOAc, 20:1;
Rf = 0.21), pure 16b (93 mg, 62%) as a pale yellow oil. H NMR
NMR (100.4 MHz): δ = 150.2 (s, C-1), 150.0 (s, C-3), 98.6 (d, C-
1
4), 55.0 (d, C-4a), 45.1 (t, C-8), 34.2 (t, C-5), 32.0 (t, C-1Ј), 28.0 (t,
C-2Ј), 25.0 (t, C-7), 24.2 (t, C-6), 22.0 (t, C-3Ј), 13.7 (q, C-4Ј) ppm.
MS (ESI): m/z (%) = 441 [2M + Na]+ (100), 419 [2M + 1]+ (25),
210 [M + 1]+ (9). C12H19NO2 (209.28): calcd. C 68.87, H 9.15, N
(400 MHz): δ = 7.43–7.29 (m, 10 H, Ph), 5.38 (br. s, 1 H, 2-H),
5.17 (s, 2 H, CH2Ph), 4.05 (br. d, J = 12.3 Hz, 1 H, 6-H), 3.21 (br.
t, J = 11.9 Hz, 1 H, 6-HЈ), 1.90–1.83 (m, 2 H, 3-H), 1.77–1.67
(m, 3 H, 5-H, 4-H), 1.51–1.42 (m, 1 H, 5-HЈ) ppm. 13C NMR 6.69; found C 69.05, H 9.13, N 6.54.
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
Exocyclic Vinylogous Amides and β-Amino Ketones
3-Phenyl-5,6,7,8-tetrahydro-4aH-pyrido[1,2-c][1,3]oxazin-1-one
(18b):[40] Prepared as described for 18a, starting from 16b (90 mg,
0.28 mmol), to give, after purification by flash chromatography (n-
hexane/EtOAc, 5:1; Rf = 0.19), pure 18b (48 mg, 75%) as a colour-
less oil. 1H NMR (400 MHz): δ = 7.63–7.61 (m, 2 H, Ph), 7.39–
7.32 (m, 3 H, Ph), 5.42 (d, J = 3.2 Hz, 1 H, 4-H), 4.50 (d, J =
13.6 Hz, 1 H, 8-H), 3.99 (d, J = 10.4 Hz, 1 H, 4a-H), 2.76 (td, J =
12.5, 2.9 Hz, 1 H, 8-HЈ), 1.95–1.92 (m, 1 H, 6-H), 1.83–1.80 (m, 1
H, 5-H), 1.75–1.72 (m, 1 H, 7-H), 1.64–1.46 (m, 3 H, 5-HЈ, 6-HЈ,
7-HЈ) ppm. 13C NMR (100.4 MHz): δ = 149.6 (s, C-1), 147.3 (s, C-
3), 131.8 (s, Ph), 129.2 (d, Ph), 128.4 (d, 2 C, Ph), 124.5 (d, 2 C,
Ph), 98.7 (d, C-4), 55.3 (d, C-4a), 45.2 (t, C-8), 33.9 (t, C-5), 25.0
(t, C-7), 24.2 (t, C-6) ppm. MS (ESI): m/z (%) = 481 [2M + Na]+
(100), 459 [2M + 1]+ (36), 230 [M + 1]+ (32).
(t, C-6), 44.7 (d, C-2), 31.9 (t, C-3), 25.2 (t, C-5), 24.3 (t, C-4) ppm.
MS (ESI): m/z (%) = 204 [M + 1]+ (100).
Data for 19b·HCl:[37] 1H NMR (400 MHz, D2O): δ = 7.98–7.92 (m,
2 H, Ph), 7.70–7.63 (m, 1 H, Ph), 7.55–7.48 (m, 2 H, Ph), 3.73–
3.63 (m, 1 H, 2-H), 3.57–3.48 (m, 1 H, 1Ј-H), 3.44–3.33 (m, 2 H,
6-H, 1Ј-HЈ), 3.05 (td, J = 12.4, 2.8 Hz, 1 H, 6-HЈ), 1.99–1.91 (m, 1
H, 5-H), 1.91–1.80 (m, 2 H, 3-H), 1.70–1.49 (m, 3 H, 4-H, 5-HЈ)
ppm.
1-Methyl-5,6,7,8-tetrahydro-oxazolo[3,4-a]pyridin-3-one (21): Pre-
pared as described for 18a, starting from 16d (100 mg, 0.41 mmol),
to give, after purification by flash chromatography (n-hexane/
EtOAc, 3:1; Rf = 0.07), pure 21 (38 mg, 60%) as a white waxy
solid, m.p. 45.6–46.4 °C. 1H NMR (400 MHz): δ = 3.51 (t, J =
6.0 Hz, 2 H, 5-H), 2.43 (t, J = 6.4 Hz, 2 H, 8-H), 1.98 (s, 3 H,
CH3), 1.83–1.76 (m, 2 H, 6-H), 1.71–1.64 (m, 2 H, 7-H) ppm. 13C
NMR (100.4 MHz): δ = 155.6 (s, C=O), 130.4 (s, C-1), 117.2 (s, C-
9), 40.5 (t, C-5), 22.4 (t, C-8), 20.0 (t, C-6), 19.3 (t, C-7), 9.8 (q,
CH3) ppm. MS (ESI): m/z (%) = 329 [2M + Na]+ (100), 176 [M +
Na]+ (37). C8H11NO2 (153.18): calcd. C 62.73, H 7.24, N 9.14;
found C 63.05, H 6.98, N 8.91.
1-(Piperidin-2-yl)hexan-2-one (19a): Compound 18a (60 mg,
0.29 mmol) was dissolved in toluene (2.9 mL). tert-Butanol
(2.9 mL) was added, followed by powdered KOH (65 mg,
1.16 mmol). The mixture was heated at 85 °C (external) for 45 min.
The mixture was then cooled to r.t., and water (6 mL) was added.
The mixture was extracted with EtOAc (3ϫ 6 mL). The combined
organic extracts were dried with anhydrous Na2SO4 and filtered,
and the solvent was evaporated under vacuum (caution! The prod-
uct is volatile!). The residue was purified by flash chromatography
(EtOAc/MeOH, 1:1; Rf = 0.13). The fractions were concentrated
to a small volume under vacuum. Due to the volatility of the prod-
uct, only a small portion was dried under vacuum for characteriza-
tion as the free amine. Colourless oil. Rf = 0.13 (EtOAc/MeOH,
1:1). 1H NMR (400 MHz): δ = 3.01 (d, J = 11.7 Hz, 1 H, 6-H),
2.98–2.91 (m, 1 H, 2-H), 2.66 (td, J = 11.7, 2.7 Hz, 1 H, 6-HЈ),
2.48 (d, J = 5.9 Hz, 2 H, 1Ј-H), 2.38 (t, J = 7.4 Hz, 2 H, 3Ј-H),
2.33 (br. s, 1 H, NH), 1.78–1.72 (m, 1 H, 5-H), 1.63–1.49 (m, 3 H,
3-H, 4Ј-H), 1.47–1.24 (m, 5 H, 4-H, 5-HЈ, 5Ј-H), 1.21–1.12 (m, 1
H, 3-HЈ), 0.89 (t, J = 7.4 Hz, 3 H, 6Ј-H) ppm. 13C NMR
(100.4 MHz): δ = 210.9 (s, C=O), 52.4 (t, C-1Ј), 49.5 (t, C-3Ј), 46.7
(t, C-6), 43.2 (d, C-2), 32.4 (t, C-3), 25.9 (t, C-4Ј), 25.8 (t, C-5),
24.6 (t, C-4), 22.3 (t, C-5Ј), 13.8 (q, C-6Ј) ppm. MS (ESI): m/z (%)
= 184 [M + 1]+ (100).
Acknowledgments
Financial support from the University of Florence is acknowl-
edged. B. F. thanks the European Commission for a Marie Curie
fellowship (FP7-PEOPLE-2012-ITN, Project: ECHONET “Ex-
panding capability in Heterocyclic Organic Synthesis”, No.
316379). Ente Cassa di Risparmio di Firenze is acknowledged for
granting a 400 MHz NMR instrument. SGI/IZO-SGIker (UPV-
EHU) is acknowledged for allocation of computational resources.
The authors would like to thank Dr. Gabriele Prina Cerai for carry-
ing out some experiments, and Dr. Milán Szõri for useful dis-
cussions. Dr. Maurizio Passaponti and Dr. Cristina Faggi are ac-
knowledged for technical assistance.
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The larger portion was cooled in an ice-bath, and HCl (1.25 m in
MeOH; 500 μL) was added while stirring. After 30 min, the solvent
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under vacuum to give pure 19a hydrochloride (57 mg, 89%) as a
1
white solid, m.p. 115.2–116.6 °C. H NMR (400 MHz, D2O): δ =
3.52–3.43 (m, 1 H, 2-H), 3.34 (dm, J = 13.2 Hz, 1 H, 6-H), 3.01–
2.91 (m, 2 H, 6-HЈ, 1Ј-H), 2.87–2.80 (m, 1 H, 1Ј-HЈ), 2.50 (t, J =
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after purification by flash chromatography (EtOAc/MeOH, 1:1; Rf
= 0.07), a small sample of free amine 19b and pure 19b·HCl (36 mg,
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13C NMR (100.4 MHz): δ = 199.3 (s, C=O), 136.9 (s, Ph), 133.3
(d, Ph), 128.6 (d, 2 C, Ph), 128.1 (d, 2 C, Ph), 52.9 (t, C-1Ј), 46.3
Eur. J. Org. Chem. 0000, 0–0
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D. Scarpi, E. G. Occhiato et al.
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14
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Job/Unit: O50205
/KAP1
Date: 07-04-15 11:36:43
Pages: 16
Exocyclic Vinylogous Amides and β-Amino Ketones
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Received: February 11, 2015
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
15

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/KAP1
Date: 07-04-15 11:36:43
Pages: 16
D. Scarpi, E. G. Occhiato et al.
FULL PAPER
Gold(I) Catalysis
The gold(I)-catalysed reaction of N-alkoxy-
carbonyl-protected 6-alkynyl-3,4-dihydro-
2H-pyridines gives synthetically useful
vinylogous amides (β-enaminones). The 6-
endo-dig approach is exclusive with sub-
stituted alkynes, whereas with terminal
alkynes the 5-exo-dig cyclization prevails.
The extension of the approach to β-amino
ketones is also described.
D. Scarpi,* S. Begliomini, C. Prandi,
A. Oppedisano, A. Deagostino,
E. Gómez-Bengoa, B. Fiser,
E. G. Occhiato* .............................. 1–16
Gold-Catalysed Synthesis of Exocyclic
Vinylogous Amides and β-Amino Ketones:
A Detailed Study on the 5-exo/6-endo-dig
Selectivity, Methodology and Scope
Keywords: Homogeneous catalysis / Gold /
Enynes / Nitrogen heterocycles / Amides /
Regioselectivity
16
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