Synthesis of vinylogous amides by gold(I)-catalyzed cyclization of N-boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines

Article abstract of DOI:10.1021/jo4019914

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro- 2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of n

Full text of DOI:10.1021/jo4019914

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Article
Synthesis of Vinylogous Amides by Gold(I)-catalyzed Cyclization
of N-Boc-protected 6-Alkynyl-3,4-dihydro-2H-pyridines
Alberto Oppedisano, Cristina Prandi, Paolo Venturello, Annamaria
Deagostino, Giulio Goti, Dina Scarpi, and Ernesto Giovanni Occhiato
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4019914 • Publication Date (Web): 01 Oct 2013
Downloaded from http://pubs.acs.org on October 9, 2013
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Synthesis of Vinylogous Amides by Gold(I)-catalyzed Cyclization of N-Boc-
protected 6-Alkynyl-3,4-dihydro-2H-pyridines
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Alberto Oppedisano,a Cristina Prandi,a Paolo Venturello,a Annamaria Deagostino,a Giulio Goti,b
Dina Scarpi,b and Ernesto G. Occhiatob,*
aDipartimento di Chimica, Università di Torino, via P. Giuria 7, 10125 Torino, Italy
bDipartimento di Chimica ”Ugo Schiff”, Università di Firenze, Via della Lastruccia 13, 50019
Sesto Fiorentino (FI), Italy
Corresponding author: Ernesto G. Occhiato
Phone: +39-055 4573480.
E-mail address: ernesto.occhiato@unifi.it
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TOC
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R
R
6
7
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9
R
KOH, tBuOH
2% Ph3PAuOTf
toluene, reflux
85 °C
N
N
N
H
Boc
R'
O
O
R'
O
R'
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16 examples
53-90%
not isolated
Abstract. The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-
pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates,
provides vinylogous amides which are useful intermediates in the synthesis of natural compounds.
The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo
dig cyclization to form a vinylgold species which, after protodeauration, generates a cyclic
carbamate intermediate. This is in most cases not isolated, but the addition to the reaction mixture
of a base rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a
natural compound from Sonneratia hainanensis has been accomplished by this approach.
Introduction
Exocyclic vinylogous amides built on pyrrolidine and piperidine rings (Figure 1), form a valuable
class of intermediates for the synthesis of a variety of N-heterocyclic compounds. Anisomycin,1
apomitomycin,2 mesembrenone,3 desoxoprosophylline,4 cassine,5 pinidinone and related 2,6-
piperidine derivatives,6 deoxyfebrifugine,7 and sedacryptine,8 are just some examples of natural
alkaloids obtained by exploiting the reactivity of these compounds. A number of methods have been
established for the preparation of exocyclic vinylogous amides, especially from enolizable lactams.
Traditionally, the formation of vinylogous amides relies on the sulfide contraction procedure
developed by the Eschenmoser’s group.9 The Knoevenagel-based modification using preformed
(alkylthio)alkylideniminium salts10 or lactam-derived iminium chlorides, lactim ethers and lactim
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thioethers11 provides an alternative to the Eschenmoser procedure. Another general method is the
direct condensation of chiral lactim ethers with β-ketoesters in the presence of catalytic nickel
acetylacetonate followed by decarboxylation.6,12,13 Some useful and generally relevant approaches
in which the heterocyclic system is built at the last stage of the synthesis include the intramolecular
aza-Wittig reaction of ω-azido β-dicarbonyl derivatives,14 and the Horner–Wadsworth–Emmons
[3+2]-1,3-dipolar cycloaddition reaction cascade of 5-azidoaldehyde derivatives.4,5,15 Also,
exocyclic vinylogous amides were obtained by quite a long sequence from pyridine-2-
carboxaldehyde and Grignard reagents.16
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O
R''
Z
( )n
( )n
R''
E
N
R'
N
R'
O
Exocyclic vinylogous amides
OMe
OH
HO
OH
OAc
O
OH
( )10
N
( )10
N
N
H
H
H
Anisomycin
Cassine
Desoxoprosophylline
OH
O
N
O
OH
OH
N
Ph
N
N
H
N
H
H
O
Sedacryptine
Pinidinol
(±)-Deoxyfebrifugine
Figure 1. Vinylogous amides and some natural compounds prepared from them
In continuation of our studies on the chemistry and synthetic applications of lactam-derived enol
phosphates17 and triflates,18 we envisaged that the gold(I)-catalyzed cyclization of N-Boc-protected
6-alkynyl-3,4-dihydro-2H-pyridines 1 (Scheme 1), obtained by Sonogashira coupling of the above
electrophiles with various alkynes, should provide cyclic urethane intermediates 2 which are then
easily converted into the target E or Z vinylogous amides 3.
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R1
6
R1
R1
6
R1
4
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6
O
2
4
or
N
2
N
R2
1'
2'
N
N
H
1'
H
R2
3
Boc
R2
O
O
2'
6
O
R2
7
Z
E
2
3
1
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Scheme 1
As in similar Au(I)-catalyzed cycloisomerization of N-Boc protected propargylamines to 1,3-
oxazolidinones19,20 (eq. 1) as well as in the cyclization of propargyl carbonates,21 (eq. 2) the t-butyl
group should be eliminated after carbonyl addition to the alkyne to produce an intermediate vinyl-
gold species.22 However, whereas in those cases the vinyl-gold moiety is exocyclic following a 5-
exo-dig cyclization (with an exception in which a 2-ethynyl-N-Boc pyrrolidine reacted to give a
small amount of 6-endo-dig product),19c we envisaged that the larger bond angle at C6 (120° instead
of 109.5°) in enyne 1 should instead force a 6-endo pathway, thus providing the six-membered
cyclic urethane 2 after proto-deauration. Related 6-endo-dig gold-catalyzed cyclizations have been
previously observed in the case of 2-alkynylphenyl carbonyl derivatives, as in the formation of
isocoumarines.23
R2
R2
O
R3
R1
Au(I)
Au(I)
R1
(eq. 1)
(eq. 2)
N
N
R3
O
O
t-BuO
R1
R2
R1
R2
O
O
O
O
t-BuO
O
Results and discussion
In order to test our assumption and find the optimal reaction conditions, we first synthesized simple
carbamate 1a (R1 = H, R2 = nPr) as the model substrate. This was realized by converting N-Boc δ-
valerolactam 5 into the corresponding enol triflate 6a by treatment with LiHMDS at -78 °C, and
then trapping the enolate with N-phenyl triflimide (Scheme 2). The enol triflate was not purified but
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used directly in the next Sonogashira coupling with 1-pentyne to give enyne 1a in 71% yield.24 This
compound, as well as most of the other enynes 1 we prepared, proved quite labile when neat, as
they started to decompose soon after the chromatographic purification on silica gel. So, they were
better stored in solution or immediately used after their preparation.25
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alkyne, 10% CuI
5% (Ph3P)2PdCl2,
Et3N, CHCl3
KHMDS,
(PhO)2POCl,
−78 °C or
55 °C, 4-7 h
LiHMDS,
PhNTf2, −78 °C
N
R
O
N
N
OX
Boc
1a-q
R
Boc
4 R = H
6a X = Tf
6b X = P(O)(OPh)2
5 R = Boc (80%)
1a R = nPr (from 6a, 71%)
1b R = nBu (59%)
1i R = CH2CH2OTIPS (from 1h, 82%)
1j R = CH2CH2CH2OH (62%)
1c R = Ph (82%)
1k R = CH2CH2CH2OBn (62%)
1l R = CH2CH2CH2OTHP (64%)
1m R = CH2(CH2)2CH2OH (72%)
1n R = (CH2)3CH2OTIPS (from 1m, 78%)
1d R = C6H4-p-OMe (71%)
1e R = cPr (50%)
1f R = CH2CH2Ph (77%)
1g R = (CH2)2C6H4-pOMe (79%) 1o R = CH2(CH2)3CH2OH (69%)
1h R = CH2CH2OH (83%)
1p R = CH2(CH2)2CH2CO2Me (63%)
O
1q R =
(85%)
O
Scheme 2
The gold-catalyzed cyclization of 1a was initially carried out in the presence of 2 mol % of
Ph3PAuOTf as the catalyst (Table 1) to examine the effect of the solvent and reaction temperature
(entries 1-7). The catalyst was prepared by suspending the gold salt (Ph3PAuCl) in a solvent and
then adding AgOTf either as a solid or in a solution of the same solvent at a known concentration,
causing the immediate precipitation of AgCl. The latter approach was the most reproducible and
used for the evaluation of the scope of the reaction (see infra). We were pleased to find that the
reaction occurred in both dichloromethane (entry 1) and dichloroethane (entry 2), though slowly,
with conversion into 2a of 20 and 30% (by GLC), respectively after 1 h at room temperature (after
which time the reaction was stopped). Acetonitrile, THF, and DME were much poorer solvents as
the reaction did not proceed at all or the conversion was less than 9% (DME) after 1 h at room
temperature. Even when the reactions were carried out in refluxing acetonitrile (81-82 °C, entry 3)
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and THF (65-67 °C, entry 4) the conversion into compound 2a was very low, in DME (85 °C, entry
5) was barely acceptable (58%), whereas in boiling DCE (83 °C, entry 6) the reaction was almost
complete (84%) in 1 h.
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Table 1. Gold(I)-catalyzed Cyclization of 6-Alkynyl-3,4-dihydro-2H-pyridine 1aa
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N
N
Boc
O
O
1a
2a
Entry Solvent
Catalyst/Additive
T (°C) T (min) Conv.b
(%)
1
2
DCM
DCE
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuOTf
2% Ph3PAuBF4
2% Ph3PAuSbF6
2% Ph3PAuPF6
-
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25
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6
3
CH3CN
THF
82
4
67
15
58
84
>99
9
5
DME
85
6
DCE
83
7
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
111
111
111
111
111
111
111
111
111
8
9
69
59
0
10
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15
5% Ph3PAuCl
5% AgOTf
0
15
57
>99
1% Ph3PAuOTf
1%
Ph3PAuOTf/AcOHc
16
toluene
0.5%
Ph3PAuOTf/AcOHc
111
60
90
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toluene
AcOHc
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aTypical reaction conditions: a solution of 1a (1 mmol) in the solvent (5 mL) is added to a solution
of the catalyst in the solvent (5 mL), then heating as reported. Conversion measured by GLC. 2
equiv.
b
c
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Eventually, when performing the reaction in boiling toluene (110-111 °C, entry 7) we observed the
complete conversion of 1a into 2a after just 20 min. In this case we tried to isolate 2a by
chromatography but this cyclic carbamate was in our hand very prone to decomposition. In fact, we
were never able to keep neat 2a for a long time as a quick degradation occurred within minutes.
Besides the Ph3PAuOTf catalyst, we tried also the corresponding tetrafluoroborate (entry 8),
hexafluoroantimonate (entry 9), and hexafluorophosphate (entry 10) gold complexes (2 mol %) in
refluxing toluene, but they were all less competent than Ph3PAuOTf, with Ph3PAuSbF6 being the
best one (69% conversion into 2a after 1 h). Control experiments were carried out without catalyst
(entry 11), triflate source (entry 12) and gold source (entry 13) and in no case we observed
formation of 2a after 1 h in refluxing toluene with the exception of the latter case in which a
minimal amount (15%) of product was formed in the presence of only a high loading (5%) of
AgOTf, arguably because of the catalysis exerted by Ag(I).26
When we reduced the catalyst loading to 1 mol % of Ph3PAuOTf (Table 1, entry 14) the conversion
was 57% after 1 h. However, the addition of 2 equiv. of acetic acid as a proton source increased the
reaction rate and the conversion into 2a was complete in just 15 min with 1 mol % of catalyst (entry
15) and almost complete (90%) in 60 min with 0.5 mol % of Ph3PAuOTf (entry 16).27 No reaction
at all occurred without catalyst in the presence of acetic acid (entry 17). Despite the lower catalyst
amount required in the presence of AcOH, we envisaged that the presence of the latter could not be
tolerated by a range of substrates under the reaction conditions and so we opted for a general
procedure which uses 2 mol % of catalyst without acetic acid in boiling toluene.
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Despite its quick decomposition when neat, we were able to assign the structure of 2a - and thus
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1
confirm our initial hypothesis about the reaction outcome - as in the H NMR spectrum of 2a the
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signal assigned to vinylic proton H4 resonates at 5.37 ppm as a singlet (in the 5-exo dig product it
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should be a triplet because of the J coupling with the methylene hydrogens of the side chain). In
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one case, intermediate 2r, prepared by Sonogashira coupling of enol phosphate 9 with 1-hexyne, as
reported in Scheme 3, proved instead more stable and could be purified by flash chromatography on
silica gel.28
KHMDS,
(PhO)2POCl,
−78 °C
O
O
O
1-Hexyne,
5% (Ph3P)2PdCl2
O
O
O
10% CuI, Et3N,
CHCl3,55 °C
N
O
N
N
OX
Boc
nBu
R
Boc
9 X = P(O)(OPh)2
1r (65%, two steps)
7 R = H
8 R = Boc (81%)
O
2% Ph3PAuOTf
O
5
toluene, reflux
+ 1r (33%)
4
20 min
N
3
O
O
2r (37%)
Scheme 3
1
Again, in its H NMR spectrum, the vinylic H4 proton diagnostically resonates as a singlet at 5.43
ppm, whereas the other olefinic proton (H5) resonates as a doublet at about 4.65 ppm. In both 2a
and 2r, the 13C resonances for C4 as doublets at 99.2 and 99.3 ppm, respectively, are in accordance
with the proposed structure of the intermediate.
A mechanism for the formation of cyclic urethane 2a is depicted in Scheme 4. This is similar to that
previously reported for the formation of 5-methylene-1,3-oxazolidinones from N-Boc protected
propargylamines,19 with the main difference being the oxy-auration step of the triple bond which
occurs in an 6-endo fashion to furnish a neutral endo vinyl-gold species with concurrent or
subsequent t-butyl fragmentation to isobutene. Protodeauration would then provide cyclic urethane
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2a with the concomitant regeneration of the gold(I)-catalyst. Compared with the 5-exo-dig
processes leading to oxazolidinones,19 the conversion of enyne 1a into cyclic urethane 2a requires
higher temperatures and longer reaction times if acetic acid is not added. With 1 mol % of catalyst
(Ph3PAuNTf2 or Ph3PAuSbF6), the cyclization of a N-Boc 2-alkynylpiperidine in which the side
chain is on a sp3 C atom quantitatively generates the corresponding 1,3-oxazolidinones after 1 h at
room temperature,19a whereas in our case enyne 1a requires boiling toluene to be completely
converted in 20 min in the presence of 2 mol % of catalyst. This could be due to a greater difficulty
in the nucleophilic attack by the carbonyl group to the activated alkyne due to the larger bond angle
at C6.
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H
AuPPh3
N
1a
O
O
2a
AuPPh3
N
O
O
H+
AuPPh3
N
O
O
+
H+
Scheme 4
Because of the intrinsic instability of compound 2a, we decided to hydrolyze this carbamate to the
corresponding vinylogous amide 3a (Scheme 5) in the same reaction vessel after the gold-catalyzed
reaction was complete (monitoring by TLC). Amongst the tested methods, those in which a base
(KOH) and a co-solvent (tBuOH or MeOH) were added proved optimal. With tBuOH as a co-
solvent and KOH as a base (6 equiv), the reaction was complete after 30 min at 85 °C, whereas with
MeOH as a co-solvent and heating at 65 °C the reaction was, as expected, much slower and it was
complete in 2 h. Of the two possible isomers, only one was produced during the hydrolysis step. A
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NOESY experiment on compound 3a (and then on all of the other vinylogous amides 3) showed a
correlation between olefinic 1-H’ and the proton(s) on C3 of the ring, consistent with a Z geometry
of the double bond. This could arise from thermodynamic factors, as the formation of the
intramolecular H-bonding N-H···O should be favored, as already reported in other cases.5,6
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Having assessed the general methodology for the conversion of lactams into vinylogous amides, to
explore the scope of the reaction we coupled lactam-derived enol phosphate 6b (Scheme 2) to
alkynes bearing differently substituted alkyl and aryl groups. Functional groups such as hydroxyl,
carbonyl and carboxyl were chosen as these are generally present in the side chains of natural
piperidines synthesized from vinylogous amides.
For the synthesis of compound 1g, 1k-l, and 1p-q, the corresponding alkynes were prepared as
reported or according to standard procedures. Lactam-derived enol phosphates are generally more
stable than the corresponding triflates and are prepared by trapping the corresponding enolates with
diphenylchlorophosphate. Whereas the Sonogashira coupling of lactam-derived enol triflates has
been reported,24 the same reaction with the corresponding enol phosphates like 6b has never been
carried out. We found that the conditions we had reported for imide-derived enol phosphates [5%
(Ph3P)2PdCl2, 10% CuI, in Et3N-CHCl3, at 55 °C)]17c were suitable to successfully convert 6b into
enynes 1. In all cases, these enynes were unstable when neat and were either used immediately after
a chromatographic purification or stored in the eluent. In some cases (1e, 1l, and 1q) it was not
possible to obtain the enynes in pure form by chromatography, however this did not affect the
reaction outcome and rate when they were subjected to the next Au(I)-catalyzed reaction.
The gold(I)-catalyzed cyclization of enynes 1b-q (Scheme 5) was carried out in the presence of 2
mol % of catalyst in boiling toluene according to the general procedure, and the subsequent
hydrolysis carried out in situ by addition of KOH (6 equiv) and t-BuOH (1:1 ratio with toluene) and
then heating at 85 °C. With enynes 1b-f, bearing no particular functionality on the side chain, the
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reaction occurred smoothly providing vinylogous amides 3b-f with Z geometry (as demonstrated by
nOe studies) in generally good yield (58-86% over two steps) after chromatography.29 Of these,
vinylogous amide 3c is of particular interest because it has recently been used to prepare a series of
Sedamine alkaloids.9b Instead with enyne 1h, bearing a β-hydroxy group, whereas the gold-
catalyzed cyclization occurred without any problem (as seen by TLC monitoring), the next
hydrolysis step caused either the partial or complete elimination of water providing the α,β-
unsaturated vinylogous amide 3i.30 This occurred also with substrate 1i, prepared by protecting the
OH group of 1h as TIPS ether.
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(a) 2% Ph3PAuOTf,
toluene, reflux
20-60 min
(b) KOH,
tBuOH-toluene, 1:1
85 °C, 1 h
N
N
H
Boc
R
O
R
3a-q
1a-q
N
H
N
N
N
H
H
H
O
Ph
O
O
O
3d (82%)
3a (90%)
3b (67%)
3c (82%)
OMe
OH
N
N
H
N
H
N
H
H
O
O
O
O
Ph
OMe
3e (86%)
3g (53%)
3h
3f (58%)
N
N
H
N
N
H
H
H
( )3
( )2
O
OTIPS
( )2
O
OTHP
O
OBn
O
3k (74%)
3n (72%)
3i (36%)
3l (72%)
N
N
H
N
H
H
O
O
( )2
O
( )3
( )4
O
CO2H
O
OH
3o (72%)
3q (78%)
3p (65%)
Scheme 5
When instead the reaction was carried out with substrate 1j (from 4-pentyn-1-ol) the gold-catalyzed
cyclization did not occur at all. Even with 5% mol of catalyst, or in the presence of AcOH, we
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recovered, after 1 h in boiling toluene, the unaltered substrate. The same occurred with enyne 1m
deriving from 5-hexyn-1-ol. The reason for the unsuitability of a γ- or δ-hydroxy group as in
substrate 1j and 1m is unclear, but it is possible that an Au(I)-promoted cyclization onto C2’
involving the side chain OH group takes place to form a vinyl-gold species in which proto-
deauration is prevented by coordination of gold to the Boc carbonyl group.31 In fact, when the OH
group was protected both as benzyl ether (1k) and THP ether (1l) the whole process took place
smoothly and vinylogous amides 3k and 3l were obtained in 74% and 72% yield, respectively after
chromatography. Similarly, when carrying out the reaction on O-TIPS protected enyne 1n (in this
case obtained directly from 1m), vinylogous amide 3n was obtained in 72% yield after
chromatography. Interestingly, and reasonably because of the less favored formation of a seven-
membered ring in the competing pathway, the Au(I)-catalyzed reaction of enyne 1o, obtained from
6-heptyn-1-ol, did occur although it was much slower than usual, requiring 2.5 hours to reach a
complete conversion into 3o with 6 mol % of catalyst. In any case, the above results suggest that a
protection of the OH group in the side chain is either necessary or preferable.
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The ester group of enyne 1p was compatible with the conditions for the Au(I)-catalyzed reaction,
but as expected it was converted into carboxylate under the next basic step. However, carboxylic
acid 3p was obtained in good yield (65%) after an acidic work-up and subsequent chromatography.
Because aldehydes do not generally tolerate strong basic conditions, the carbonyl group has to be
protected, for example as in enyne 1q prepared from 5,5-dimethyl-2-pent-4-ynyl-[1,3]dioxane. The
cyclic acetal moiety of 1q, like the tetrahydropyranyl ether in 1l, proved compatible with the
reaction conditions and the sequence provided the corresponding vinylogous amide 3q in 78%
yield.
Having assessed the scope of the reaction, a specific substrate (1g) was prepared and subjected to
the usual sequence providing the corresponding vinylogous amide 3g (Scheme 5) in 53% yield. We
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used this as an intermediate for the first synthesis of a natural product (compound 11, Scheme 6)
isolated as a racemate from the leaves of the Chinese coast mangrove Sonneratia hainanensis.32
Thus, reduction of the double bond was carried out by catalytic hydrogenation9b providing
9
1
compound 11 in 73% yield and with H and 13C NMR spectra identical to those reports for the
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natural compound.32 Its unsubstituted analogue 10 was also prepared according to the same route.
H2(g), PtO2,
HClO4, MeOH
25 °C
N
H
N
H
O
O
R
R
3f R = H
3g R = OMe
(±)-10 R = H (100%)
(±)-11 R = OMe (73%)
Scheme 6
Conclusion
In conclusion we have demonstrated that the gold(I)-catalyzed cyclization of N-Boc-protected 6-
alkynyl-3,4-dihydro-2H-pyridines allows for a facile synthesis of vinylogous amides which are
useful intermediates in the synthesis of natural compounds. The substrates are prepared by the
Sonogashira coupling of lactam-derived enol triflates and phosphates, which provides the
corresponding enynes in good yields. The next Au(I)-catalyzed reaction is carried out with
Ph3PAuOTf as a catalyst and proceeds via a 6-endo dig cyclization to form a vinylgold species
which after protodeauration generates a cyclic carbamate intermediate. This is in most cases not
isolated, but the addition to the reaction mixture of KOH and t-BuOH at 85 °C rapidly and
quantitatively delivers the target vinylogous amide. Albeit in one particular case the strong basic
conditions caused elimination of water from the side chain, the preparation of a series of products
with different substituents and protecting groups on the side chain shows that this methodology has
a wide scope and is well suited for the preparation of natural products embedding a 2-substituted
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piperidine moiety. Accordingly, the first synthesis of a natural compound from Sonneratia
hainanensis has been accomplished by this approach.
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Experimental Section
General. Chromatographic separations were performed under pressure on silica gel by flash-column
techniques; Rf values refer to TLC carried out on 0.25-mm silica gel plates, with the same eluent as indicated
for the column chromatography. H NMR spectra were recorded at 200 or 400 MHz and 13C NMR spectra
1
were recorded at 50.33 or 100.4 MHz, both in CDCl3 solution. Solvent reference line was set at 7.26 ppm.
Mass spectra were either recorded at an ionizing voltage of 70 eV or carried out by direct inlet of a 10 ppm
solution in CH3OH on an Ion Trap LC/MS system with an electrospray ionization (ESI) interface in the
positive mode. Pent-4-ynyloxymethylbenzene,33 1-but-3-ynyl-4-methoxybenzene34 and 6-heptyn-1-ol35 were
prepared as reported. Compounds 6a18g and 6b36 are known.
6-(Pent-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1a).
Triflate 6a (1 mmol) was dissolved in anhydrous THF (0.1 M), under nitrogen atmosphere; LiCl (1 mmol),
diisopropylamine (4 mmol), Pd(OAc)2 (0.05 mmol), Ph3P (0.1 mmol), CuI (0.1 mmol) and the alkyne (1.5
mmol) were then added and the resulting mixture left under stirring at room temperature overnight. Satd
aqueous NH4Cl (10 mL) was added and the product extracted with Et2O (3 x 10 mL); the combined organic
extracts were washed once with brine (15 mL) and dried over anhydrous K2CO3. After filtration and
evaporation of the solvent, crude enyne 1a was purified by flash chromatography (eluent: petroleum ether-
EtOAc, 9:1 containing 1% Et3N; Rf = 0.25) and stored at 4 °C as 0.1 M solution in the eluent until use.
1
Colourless oil (177 mg, 71%). H NMR (200 MHz) δ (ppm): 5.41 (t, J = 4.1 Hz, 1 H), 3.53-3.39 (m, 2 H),
2.23 (t, J = 7.0 Hz, 2 H), 2.12-2.04 (m, 2 H), 1.76-1.74 (m, 2 H), 1.56-1.44 (m, 2 H), 1.43 (s, 9 H), 0.93 (t, J
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= 7.5 Hz, 3 H). 13C NMR (50.33 MHz) δ (ppm): 153.0 (s), 122.5 (s), 120.9 (d), 87.8 (s), 80.5 (s), 77.7 (s),
43.4 (t), 28.2 (q, 3 C), 23.5 (t), 22.6 (t), 21.9 (t), 21.2 (t), 13.5 (q). MS (EI) m/z %: 249 ([M]+, 55), 193 (45),
148 (90), 121 (85), 57 (100).
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Sonogashira coupling (general procedure from phosphate 6b). Phosphate 6b (1 mmol) was dissolved in
anhydrous 3:1 Et3N-CHCl3 mixture (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 a
second portion of alkyne (0.5 mmol) and (Ph3P)2PdCl2 (0.025 mmol) were added, if necessary. The mixture
was heated at 55 °C until completion (TLC, usually in 4-7 h). After cooling at r.t., water (12 mL) was added
and the product extracted with Et2O (3 x 12 mL); the combined organic extracts were dried over anhydrous
K2CO3. After filtration and evaporation of the solvent, crude enyne 1 was purified by flash chromatography
(eluent containing 1% Et3N) and stored at 4 °C as 0.1 M solution in the eluent until use.
6-(Hex-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1b).
Colourless oil (155 mg, 59%). Rf = 0.68 (n-hexane-EtOAc, 3:1). FCC eluent: n-hexane-EtOAc, 20:1 + 1%
Et3N. 1H NMR (400 MHz) δ (ppm): 5.45 (t, J = 4.1 Hz, 1 H), 3.55-3.52 (m, 2 H), 2.30 (t, J = 6.8 Hz, 2 H),
2.15-2.10 (m, 2 H), 1.78-1.72 (m, 2 H), 1.54-1.38 (m, 4 H), 1.48 (s, 9 H), 0.90 (t, J = 7.2 Hz, 3 H). 13C NMR
(100.4 MHz) δ (ppm): 153.2 (s), 122.6 (s), 121.1 (d), 88.1 (s), 80.7 (s), 77.6 (s), 43.5 (t), 30.7 (t), 28.3 (q, 3
C), 23.6 (t), 22.7 (t), 22.0 (t), 19.1 (t), 13.6 (q). MS (ESI) m/z %: 549 ([2M+Na]+, 25), 286 ([M+Na]+, 19).
6-Phenylethynyl-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1c).
Pale yellow solid (232 mg, 82%). Rf = 0.35 (petroleum ether-EtOAc, 95:5). 1H NMR (200 MHz) δ (ppm):
7.38-7.35 (m, 2 H), 7.25-7.20 (m, 3 H), 5.60 (t, J = 4.0 Hz, 1 H), 3.59-3.54 (m, 2 H), 2.13-2.04 (m, 2 H),
1.75-1.63 (m, 2 H), 1.43 (s, 9 H). 13C NMR (50.33 MHz) δ (ppm): 153.0 (s), 131.1 (d, 2 C), 128.1 (d, 2 C),
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127.8 (d), 123.2 (s), 122.5 (s), 122.2 (d), 87.2 (s), 86.8 (s), 80.9 (s), 43.2 (t), 28.1 (q, 3 C), 23.6 (t), 22.5 (t).
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MS (EI) m/z %: 283, ([M]+, 5), 227 (75), 182 (85), 127 (25), 57 (100).
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6-(4-Methoxyphenylethynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1d).
White solid (223 mg, 71%). Rf = 0.32 (petroleum ether-EtOAc, 95:5). 1H NMR (200 MHz) δ (ppm): 7.30 (d,
J = 9.0 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 2 H), 5.56 (t, J = 4.0 Hz, 1 H), 3.71 (s, 3 H), 3.57-3.52 (m, 2 H), 2.19-
2.10 (m, 2 H), 1.81-1.68 (m, 2 H), 1.42 (s, 9 H). 13C NMR (50.33 MHz) δ (ppm): 159.2 (s), 153.1 (s), 132.5
(d, 2 C), 122.3 (s), 121.9 (d), 115.3 (s), 113.8 (d, 2 C), 87.1 (s), 85.2 (s), 80.1 (s), 55.0 (q), 43.2 (t), 28.1 (q, 3
C), 23.6 (t), 22.5 (t). MS (EI) m/z %: 313 ([M]+, 15), 257 (100), 212 (80), 198 (55), 57 (35).
6-Cyclopropylethynyl-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1e).
1
1
Pale yellow oil (124 mg, 50%, 81% purity by H NMR). Rf = 0.45 (petroleum ether-EtOAc, 9:1). H NMR
(200 MHz) δ (ppm): 5.39 (t, J = 4.0 Hz, 1 H), 3.49-3.44 (m, 2 H), 2.11-2.02 (m, 2 H), 1.75-1.63 (m, 2 H),
1.44 (s, 9 H), 1.43-1.42 (m, 1 H), 0.76-0.63 (m, 4 H). 13C NMR (50.33 MHz) δ (ppm): 153.0 (s), 122.3 (s),
121.3 (d), 90.8 (s), 80.7 (s), 72.8 (s), 43.2 (t), 28.1 (q, 3 C), 23.4 (t), 22.5 (t), 8.0 (t, 2 C), 0.8 (d). MS (EI) m/z
%: 247 ([M]+, 5), 191 (100), 146 (75), 132 (20), 57(45).
6-(4-Phenylbut-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1f).
Pale yellow oil (240 mg, 77%). Rf = 0.28 (n-hexane-EtOAc, 25:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
7.31-7.18 (m, 5 H), 5.46 (t, J = 4.1 Hz, 1 H), 3.57-3.54 (m, 2 H), 2.87 (t, J = 7.8 Hz, 2 H), 2.60 (t, J = 7.8 Hz,
2 H), 2.17-2.12 (m, 2 H), 1.80-1.74 (m, 2 H), 1.49 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 153.1 (s), 140.7
(s), 128.4 (d, 2 C), 128.3 (d, 2 C), 126.2 (d), 122.5 (s), 121.4 (d), 87.3 (s), 80.7 (s), 78.3 (s), 43.5 (t), 35.1 (t),
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28.3 (q, 3 C), 23.6 (t), 22.7 (t), 21.6 (t). MS (ESI) m/z %: 645 ([2M+Na]+, 22), 324 ([M+Na]+, 100), 312
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([M+1]+, 9).
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6-[4-(4-Methoxyphenyl)but-1-ynyl]-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1g).
1
Pale yellow oil (270 mg, 79%, 96% purity by H NMR). Rf = 0.27 (n-hexane-EtOAc, 14:1 + 1% Et3N). 1H
NMR (400 MHz) δ (ppm): 7.14 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 5.46 (t, J = 3.9 Hz, 1 H), 3.79
(s, 3 H), 3.57-3.53 (m, 2 H), 2.81 (t, J = 7.4 Hz, 2 H), 2.56 (t, J = 7.4 Hz, 2 H), 2.16-2.12 (m, 2 H), 1.79-1.73
(m, 2 H), 1.49 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 158.1 (s), 153.1 (s), 132.9 (s), 129.4 (d, 2 C), 122.5
(s), 121.4 (d), 113.8 (d, 2 C), 87.4 (s), 80.7 (s), 78.3 (s), 55.2 (q), 43.5 (t), 34.2 (t), 28.3 (q, 3 C), 23.6 (t), 22.7
(t), 21.9 (t). MS (ESI) m/z %: 705 ([2M+Na]+, 37), 364 ([M+Na]+, 100), 342 ([M+1]+, 7).
6-(4-Hydroxybut-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1h).
Pale yellow oil (208 mg, 83%). Rf = 0.24 (n-hexane-EtOAc, 3:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
5.48 (t, J = 4.1 Hz, 1 H), 3.73 (t, J = 5.7 Hz, 2 H), 3.56-3.53 (m, 2 H), 2.53 (t, J = 5.7 Hz, 2 H), 2.15-2.10 (m,
2 H), 1.79-1.75 (m, 2 H), 1.47 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 152.7 (s), 121.8 (s), 120.7 (d), 86.1
(s), 81.0 (s), 79.8 (s), 60.9 (t), 44.0 (t), 28.3 (q, 3 C), 23.9 (t), 23.3 (t), 22.6 (t). MS (EI) m/z %: 251 ([M]+, 7),
194 (23), 150 (32), 125 (15), 57 (45).
6-(4-Triisopropylsilanoxybut-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1i).
Imidazole (35 mg, 0.52 mmol) and triisopropylsilyl chloride (40 ꢀL, 0.19 mmol) were added under nitrogen
atmosphere to a solution of alcohol 1h (44 mg, 0.17 mmol) in anhydrous DMF (525 ꢀL). The resulting
mixture was heated at 40 °C for 1 h. After cooling at room temperature, water was added (6 mL) and the
product extracted with Et2O (5 x 6 mL). The combined organic extracts were dried over anhydrous K2CO3.
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After filtration and evaporation of the solvent crude 1i was obtained and purified by flash chromatography
(eluent: n-hexane-EtOAc, 25:1 + 1% Et3N; Rf = 0.25), affording pure 1i (58 mg, 82%) as a colourless oil.
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1H NMR (400 MHz) δ (ppm): 5.47 (t, J = 4.1 Hz, 1 H), 3.82 (t, J = 7.4 Hz, 2 H), 3.55-3.52 (m, 2 H), 2.56 (t,
J = 7.4 Hz, 2 H), 2.15-2.10 (m, 2 H), 1.79-1.73 (m, 2 H), 1.49 (s, 9 H), 1.05 (m, 21 H). 13C NMR (100.4
MHz) δ (ppm): 153.2 (s), 122.4 (s), 121.6 (d), 84.6 (s), 80.8 (s), 78.8 (s), 62.1 (t), 43.4 (t), 28.3 (q, 3 C), 23.8
(t), 23.6 (t), 22.7 (t), 17.9 (q, 6 C), 11.9 (d, 3 C). MS (ESI) m/z %: 430 ([M+Na]+, 100).
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6-(5-Hydroxypent-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1j).
Pale yellow oil (165 mg, 62%). Rf = 0.24 (n-hexane-EtOAc, 2:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
5.47 (t, J = 4.1 Hz, 1 H), 3.76 (t, J = 6.1 Hz, 2 H), 3.55-3.52 (m, 2 H), 2.45 (t, J = 6.8 Hz, 2 H), 2.15-2.10 (m,
2 H), 1.81-1.72 (m, 4 H), 1.48 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 152.9 (s), 122.3 (s), 121.4 (d), 87.5
(s), 80.8 (s), 78.2 (s), 61.7 (t), 43.7 (t), 31.0 (t), 28.3 (q, 3 C), 23.5 (t), 22.7 (t), 16.2 (t). MS (ESI) m/z %: 553
([2M+Na]+, 62), 288 ([M+Na]+, 100).
6-(5-Benzyloxypent-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1k).
1
1
Colourless oil (220 mg, 62%, 75% purity by H NMR). Rf = 0.82 (petroleum ether-EtOAc, 9:1). H NMR
(200 MHz) δ (ppm): 7.41-7.26 (m, 5 H), 5.44 (t, J = 4.1 Hz, 1 H), 4.52 (s, 2 H), 3.59 (t, J = 6.1 Hz, 2 H),
3.58-3.52 (m, 2 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.20-2.08 (m, 2 H), 1.93-1.72 (m, 4 H), 1.50 (s, 9 H). 13C NMR
(50.33 MHz) δ (ppm): 152.9 (s), 138.3 (s), 128.2 (d, 2 C), 127.4 (d, 2 C), 127. 1 (d), 122.3 (s), 121.4 (d),
87.4 (s), 80.7 (s), 77.9 (s), 72.8 (t), 68.8 (t), 43.6 (t), 28.8 (t), 28.3 (q, 3 C), 23.6 (t), 22.7 (t), 16.2 (t). MS (EI)
m/z %: 355 ([M]+, 5), 298 (30), 254 (40), 121 (100), 91 (50), 57 (45).
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6-[5-(Tetrahydropyran-2-yloxy)pent-1-ynyl]-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl
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Ester (1l).
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Colourless oil (223 mg, 64%, 71% purity by H NMR). Rf = 0.75 (petroleum ether-EtOAc, 4:1). H NMR
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(200 MHz) δ (ppm): 5.47 (t, J = 4.1 Hz, 1 H), 4.55-4.30 (m, 1 H), 3.72-3.65 (m, 2 H), 3.55-3.52 (m, 4 H, 2-
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H), 2.42 (t, J = 6.8 Hz, 2 H), 2.35-2.30 (m, 2 H), 1.80-1.40 (m, 10 H), 1.48 (s, 9 H). 13C NMR (50.33 MHz) δ
(ppm): 154.0 (s), 123.3 (s), 121.2 (d), 99.6 (d), 87.5 (s), 81.4 (s), 80.5 (s), 65.8 (t), 62.0 (d), 43.5 (t), 30.5 (t),
28.6 (t), 28.1 (q, 3 C), 25.3 (t), 23.4 (t), 22.5 (t), 19.6 (t), 19.3 (t). MS (EI) m/z %: 349 ([M]+, 1), 165 (100),
121 (73), 57 (85).
6-(6-Hydroxyhex-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1m).
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Colourless oil (201 mg, 72%). Rf = 0.38 (n-hexane-EtOAc, 1:1 + 1% Et3N). H NMR (400 MHz) δ (ppm):
5.46 (t, J = 4.1 Hz, 1 H), 3.67 (t, J = 6.1 Hz, 2 H), 3.55-3.51 (m, 2 H), 2.36 (t, J = 6.8 Hz, 2 H), 2.15-2.10 (m,
2 H), 1.78-1.73 (m, 2 H), 1.72-1.60 (m, 4 H), 1.48 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 153.0 (s), 122.4
(s), 121.3 (d), 87.9 (s), 80.7 (s), 78.0 (s), 62.2 (t), 43.6 (t), 31.8 (t), 28.3 (q, 3 C), 24.7 (t), 23.5 (t), 22.7 (t),
19.1 (t). MS (ESI) m/z %: 581 ([2M+Na]+, 47), 302 ([M+Na]+, 100).
6-(6-Triisopropylsilanoxyhex-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1n).
Prepared as reported for 1i, starting from 1m (75 mg, 0.27 mmol).
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Colourless oil (90 mg, 78%). Rf = 0.27 (n-hexane-EtOAc, 20:1 + 1% Et3N). H NMR (400 MHz) δ (ppm):
5.46 (t, J = 4.1 Hz, 1 H), 3.70 (t, J = 5.9 Hz, 2 H), 3.56-3.53 (m, 2 H), 2.34 (t, J = 6.6 Hz, 2 H), 2.16-2.11 (m,
2 H), 1.79-1.73 (m, 2 H), 1.66-1.61 (m, 4 H), 1.49 (s, 9 H), 1.06-1.03 (m, 21 H). 13C NMR (100.4 MHz) δ
(ppm): 153.2 (s), 122.6 (s), 121.2 (d), 88.0 (s), 80.7 (s), 77.8 (s), 62.8 (t), 43.5 (t), 32.3 (t), 28.3 (q, 3 C), 25.2
(t), 23.6 (t), 22.8 (t), 19.3 (t), 18.0 (q, 6 C), 12.0 (d, 3 C). MS (ESI) m/z %: 893 ([2M+Na]+, 10), 458
([M+Na]+, 100).
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6-(7-Hydroxyhept-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1o).
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Pale yellow oil (202 mg, 69%). Rf = 0.29 (n-hexane-EtOAc, 2:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
5.44 (t, J = 3.9 Hz, 1 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.53-3.49 (m, 2 H), 2.30 (t, J = 6.6 Hz, 2 H), 2.14-2.08 (m,
2 H), 1.90 (br s, 1 H), 1.76-1.70 (m, 2 H), 1.59-1.50 (m, 4 H), 1.49-1.42 (m, 2 H), 1.46 (s, 9 H). 13C NMR
(100.4 MHz) δ (ppm): 153.1 (s), 122.4 (s), 121.3 (d), 87.9 (s), 80.7 (s), 77.7 (s), 62.5 (t), 43.5 (t), 32.1 (t),
28.2 (q, 3 C), 24.9 (t, 2 C), 23.4 (t), 22.7 (t), 19.3 (t). MS (ESI) m/z %: 609 ([2M+Na]+, 52), 316 ([M+Na]+,
100).
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6-(6-Methoxycarbonylhex-1-ynyl)-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl Ester (1p).
Pale yellow oil (202 mg, 63%). Rf = 0.30 (n-hexane-EtOAc, 10:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
5.46 (t, J = 3.9 Hz, 1 H), 3.66 (s, 3 H), 3.55-3.52 (m, 2 H), 2.35-2.25 (m, 4 H), 2.15-2.10 (m, 2 H), 1.79-1.70
(m, 4 H), 1.61-1.53 (m, 2 H), 1.48 (s, 9 H). 13C NMR (100.4 MHz) δ (ppm): 173.8 (s), 153.1 (s), 122.5 (s),
121.4 (d), 87.4 (s), 80.7 (s), 78.1 (s), 51.5 (q), 43.5 (t), 33.6 (t), 28.3 (q, 3 C), 28.0 (t), 24.2 (t), 23.6 (t), 22.7
(t), 19.1 (t). MS (ESI) m/z %: 344 ([M+Na]+, 100).
6-[6-(5,5-Dimethyl-[1,3]dioxan-2-yl)hex-1-ynyl]-3,4-dihydro-2H-pyridine-1-carboxylic Acid tert-Butyl
Ester (1q).
Pale yellow oil (309 mg, 85%, 93% purity by 1H NMR). Rf = 0.64 (petroleum ether-EtOAc, 4:1 + 1% Et3N).
1H NMR (200 MHz) δ (ppm): 5.44 (t, J = 4.0 Hz, 1 H), 4.45-4.39 (m, 1 H), 3.60-3.48 (m, 4 H), 3.44-3.35 (m,
2 H), 2.33 (t, J = 6.8 Hz, 2 H), 2.18-2.07 (m, 2 H), 1.83-1.63 (m, 6 H), 1.48 (s, 9 H), 1.16 (s, 3 H), 0.69 (s, 3
H). 13C NMR (50.33 MHz) δ (ppm): 153.1 (s), 122.5 (s), 121.3 (d), 101.7 (d), 87.6 (s), 80.7 (s), 78.0 (s), 77.2
(t, 2 C), 43.4 (t), 33.9 (s), 30.1 (t), 28.3 (q, 3 C), 23.6 (t), 23.0 (t), 22.7 (t), 21.8 (q, 2 C), 19.2 (t). MS (EI) m/z
%: 363 ([M]+, 2), 307 (5), 178 (100), 141 (60), 121 (55), 57 (41).
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The Journal of Organic Chemistry
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(±)-4,5-O-Isopropylidene-4,5-dihydroxy-5,6-dihydro-2-(hex-1-ynyl)-4H-pyridine-1-carboxylic
tert-Butyl Ester (1r).
Acid
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Pale yellow oil (218 mg, 65%). Rf = 0.06 (n-hexane-EtOAc, 20:1 + 1% Et3N). 1H NMR (400 MHz) δ (ppm):
5.61 (d, J = 3.9 Hz, 1 H), 4.46 (dd, J = 6.2, 2.3 Hz, 1 H), 4.21-4.16 (m, 1 H), 3.89 (dd, J = 12.9, 4.1 Hz, 1 H),
3.15 (dd, J = 12.9, 8.4 Hz, 1 H), 2.31 (t, J = 7.0 Hz, 2 H), 1.54-1.46 (m, 2 H), 1.47 (s, 9 H), 1.45-1.38 (m, 2
H), 1.42 (s, 3 H), 1.34 (s, 3 H), 0.89 (t, J = 7.2 Hz, 3 H). 13C NMR (100.4 MHz) δ (ppm): 152.7 (s), 126.2
(s), 118.1 (d), 108.9 (s), 91.1 (s), 81.3 (s), 76.3 (s), 72.5 (d), 69.9 (d), 46.0 (t), 30.4 (t), 28.1 (q, 3 C), 27.8 (q),
25.6 (q), 21.9 (t), 19.0 (t), 13.5 (t). MS (ESI) m/z %: 693 ([2M+Na]+, 19), 358 ([M+Na]+, 100).
Gold-catalyzed rearrangement and hydrolysis procedure. A volume of the enyne solution containing 1 mmol
of substrate was concentrated and dried under vacuum (no heating) for 30 minutes before dissolving in
anhydrous toluene. A 0.2 M AgOTf and a 4 mM Ph3PAuCl solutions, both in anhydrous toluene, were
prepared. The AgOTf solution (100 ꢀL, 0.02 mmol) was added at r.t. to the 4 mM Ph3PAuCl solution (5 mL,
0.02 mmol), under stirring and nitrogen atmosphere, and a white precipitate immediately formed. A solution
of the enyne 1 (1.0 mmol) in anhydrous toluene (5 mL) was then added and the resulting mixture heated
under reflux until disappearance of the starting material (TLC, usually 30 minutes). After cooling at 85 °C
(external), the mixture was diluted with tert-butanol (10 mL) and powdered KOH (6 mmol) was added. The
mixture was the heated at 85 °C until completion (TLC, usually 1 h). After cooling at r.t., water (15 mL) was
added and the product extracted with EtOAc (3 x 10 mL); the combined organic extracts were washed once
with brine (15 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, crude
vinylogous amide 3 was purified by flash chromatography to obtain the pure compound.
Intermediate 2a was isolated by filtration over a Celite pad of the mixture resulting from the gold-catalyzed
rearrangement. The solvent was removed under vacuum and the residue analyzed without any purification.
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Intermediate 2r, isolated as reported for 2a, was enough stable to be purified by flash chromatography
(eluent: n-hexane-EtOAc, 10:1 + 1% Et3N; Rf = 0.09) and pure 2r could be characterized.
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3-Propyl-7,8-dihydro-6H-pyrido[1,2-c][1,3]oxazin-1-one (2a).
Yellow oil (191 mg, 99%). 1H NMR (200 MHz) δ (ppm): 5.37 (s, 1 H), 4.63 (t, J = 4.2 Hz, 1 H), 3.80-3.74
(m, 2 H), 2.27-2.08 (m, 2 H), 1.93-1.84 (m, 2 H), 1.71-1.52 (m, 4 H), 0.99 (t, J = 7.4 Hz, 3 H). 13C NMR
(50.33 MHz) δ (ppm): 151.1 (s), 148.6 (s), 132.0 (s), 100.4 (d), 99.2 (d), 42.4 (t), 33.8 (t), 21.2 (t), 20.5 (t),
19.1 (t), 13.2 (q).
(±)-6,7-O-Isopropylidene-6,7-dihydroxy-3-butyl-7,8-dihydro-6H-pyrido[1,2-c][1,3]oxazin-1-one (2r).
Colourless oil (103 mg, 37%). 1H NMR (400 MHz) δ (ppm): 5.43 (s, 1 H), 4.66 (d, J = 4.1 Hz, 1 H), 4.55 (t,
J = 4.9 Hz, 1 H), 4.27-4.23 (m, 1 H), 3.98 (dd, J = 13.5, 9.2 Hz, 1 H), 3.59 (dd, J = 13.5, 7.4 Hz, 1 H), 2.21
(t, J = 7.2 Hz, 2 H), 1.57-1.52 (m, 2 H), 1.45 (s, 3 H), 1.38 (s, 3 H), 1.38-1.30 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3
H). 13C NMR (100.4 MHz) δ (ppm): 154.6 (s), 148.4 (s), 134.1 (s), 109.2 (s), 99.3 (d), 96.3 (d), 70.1 (d), 69.0
(d), 42.6 (t), 31.8 (t), 28.6 (t), 27.9 (q), 26.3 (q), 22.0 (t), 13.7 (q). MS (ESI) m/z %: 581 ([2M+Na]+, 32), 302
([M+Na]+, 100).
(Z)-1-Piperidin-2-ylidene-pentan-2-one (3a).12c
Pale yellow oil (151 mg, 90%). Rf = 0.15 (Petroleum ether-EtOAc, 4:1). 1H NMR (400 MHz) δ (ppm): 11.1
(br s, 1 H), 4.86 (s, 1 H), 3.31 (td, J = 5.9, 1.8 Hz, 2 H), 2.35 (t, J = 6.4 Hz, 2 H), 2.19 (t, J = 7.4 Hz, 2 H),
1.81-1.75 (m, 2 H), 1.73-1.65 (m, 2 H), 1.64-1.55 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H). 13C NMR (50.33 MHz)
δ (ppm): 197.1 (s), 163.9 (s), 92.8 (d), 43.7 (t), 40.7 (t), 28.3 (t), 22.1 (t), 19.6 (t), 19.2 (t), 13.9 (q). MS (ESI)
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m/z %: 357 ([2M+Na]+, 100), 190 ([M+Na]+, 18), 168 ([M+1]+, 17). C10H17NO (167.25): calcd C, 71.81; H,
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10.25; N, 8.37. Found: C, 71.45, H, 10.32, N 8.17.
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(Z)-1-Piperidin-2-ylidene-hexan-2-one (3b).
Pale yellow oil (121 mg, 67%). Rf = 0.16 (n-Hexane-EtOAc, 3:1). 1H NMR (400 MHz) δ (ppm): 11.1 (br s, 1
H), 4.86 (s, 1 H), 3.31 (td, J = 6.1, 2.3 Hz, 2 H), 2.35 (t, J = 6.4 Hz, 2 H), 2.21-2.17 (m, 2 H), 1.81-1.75 (m, 2
H), 1.73-1.66 (m, 2 H), 1.59-1.51 (m, 2 H), 1.37-1.27 (m, 2 H), 0.89 (t, J = 7.4 Hz, 3 H). 13C NMR (100.4
MHz) δ (ppm): 197.5 (s), 164.0 (s), 92.9 (d), 41.7 (t), 40.9 (t), 28.6 (t), 28.4 (t), 22.7 (t), 22.3 (t), 19.3 (t),
13.9 (q). MS (ESI) m/z %: 182 ([M+1]+, 100). C11H19NO·1/10 H2O (183.07): calcd C, 72.17; H, 10.57; N,
7.65. Found: C, 72.09; H, 10.90; N, 7.58.
(Z)-2-Phenyl-1-piperidin-2-ylidene-ethanone (3c).9b,12c,13
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Yellow solid (165 mg, 82%). Rf = 0.18 (n-Hexane-EtOAc, 3:1). M. p. 57.6-58.2 °C. H NMR (400 MHz) δ
(ppm): 11.7 (br s, 1 H), 7.86-7.82 (m, 2 H), 7.41-7.35 (m, 3 H), 5.57 (s, 1 H), 3.41 (td, J = 5.9, 2.3 Hz, 2 H),
2.51 (t, J = 6.4 Hz, 2 H), 1.87-1.81 (m, 2 H), 1.80-1.73 (m, 2 H). 13C NMR (100.4 MHz) δ (ppm): 187.0 (s),
165.8 (s), 140.7 (s), 130.1 (d), 128.1 (d, 2 C), 126.7 (d, 2 C), 90.4 (d), 41.1 (t), 28.9 (t), 22.2 (t), 19.3 (t). MS
(ESI) m/z %: 425 ([2M+Na]+, 100), 224 ([M+Na]+, 10), 202 ([M+1]+, 12). C13H15NO (201.26): calcd C,
77.58; H, 7.51; N, 6.96. Found: C, 77.40, H, 7.54, N 6.58.
(Z)-2-(4-Methoxyphenyl)-1-piperidin-2-ylidene-ethanone (3d).
Yellow solid (190 mg, 82%). Rf = 0.20 (n-Hexane-EtOAc, 2:1). M. p. 230 °C (dec.). 1H NMR (400 MHz) δ
(ppm): 11.6 (br s, 1 H), 7.82 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.53 (s, 1 H), 3.84 (s, 3 H), 3.40
(t, J = 5.7 Hz, 2 H), 2.50 (t, J = 6.4 Hz, 2 H), 1.86-1.80 (m, 2 H), 1.79-1.73 (m, 2 H). 13C NMR (100.4 MHz)
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δ (ppm): 189.3 (s), 165.2 (s), 161.3 (s), 133.3 (s), 128.5 (d, 2 C), 113.3 (d, 2 C), 89.7 (d), 55.3 (q), 41.1 (t),
28.9 (t), 22.3 (t), 19.4 (t). MS (ESI) m/z %: 485 ([2M+Na]+, 100), 254 ([M+Na]+, 14), 232 ([M+1]+, 41).
C14H17NO2 (231.29): calcd C, 72.70; H, 7.41; N, 6.06. Found: C, 72.44; H, 7.71; N, 6.33.
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(Z)-2-Cyclopropyl-1-piperidin-2-ylidene-ethanone (3e).
Yellow oil (142 mg, 86%). Rf = 0.21 (n-Hexane-EtOAc, 3:1). 1H NMR (400 MHz) δ (ppm): 11.0 (br s, 1 H),
5.03 (s, 1 H), 3.30 (td, J = 5.9, 2.3 Hz, 2 H), 2.37 (t, J = 6.2 Hz, 2 H), 1.80-1.74 (m, 2 H), 1.73-1.66 (m, 2 H),
1.63-1.56 (m, 1 H), 0.93-0.89 (m, 2 H), 0.69-0.65 (m, 2 H). 13C NMR (100.4 MHz) δ (ppm): 195.9 (s), 163.2
(s), 92.9 (d), 40.9 (t), 28.4 (t), 22.3 (t), 19.5 (d), 19.4 (t), 8.3 (t, 2 C). MS (ESI) m/z %: 353 ([2M+Na]+, 100),
188 ([M+Na]+, 26), 166 ([M+1]+, 32). C10H15NO (165.23): calcd C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33,
H, 9.07, N 8.78.
(Z)-4-Phenyl-1-piperidin-2-ylidene-butan-2-one (3f).
Pale yellow foam (133 mg, 58%). Rf = 0.31 (n-Hexane-EtOAc, 3:1). 1H NMR (400 MHz) δ (ppm): 11.2 (br
s, 1 H), 7.29-7.14 (m, 5 H), 4.88 (s, 1 H), 3.33 (td, J = 5.6, 2.3 Hz, 2 H), 2.94-2.89 (m, 2 H), 2.55-2.51 (m, 2
H), 2.35 (t, J = 6.4 Hz, 2 H), 1.82-1.76 (m, 2 H), 1.75-1.67 (m, 2 H). 13C NMR (100.4 MHz) δ (ppm): 195.6
(s), 164.3 (s), 142.2 (s), 128.3 (d, 2 C), 128.2 (d, 2 C), 125.6 (d), 92.9 (d), 43.4 (t), 41.0 (t), 32.3 (t), 28.5 (t),
22.3 (t), 19.4 (t). MS (ESI) m/z %: 230 ([M+1]+, 100). C15H19NO (229.32): calcd C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.91; H, 8.29; N, 5.89.
(Z)-4-(4-Methoxyphenyl)-1-piperidin-2-ylidene-butan-2-one (3g).
Pale yellow solid (137 mg, 53%). Rf = 0.28 (n-Hexane-EtOAc, 1:1). M.p. 59.1-60.2 °C. 1H NMR (400 MHz)
δ (ppm): 11.2 (br s, 1 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 4.87 (s, 1 H), 3.77 (s, 3 H), 3.32
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(td, J = 5.9, 2.3 Hz, 2 H), 2.87-2.83 (m, 2 H), 2.51-2.46 (m, 2 H), 2.34 (t, J = 6.4 Hz, 2 H), 1.81-1.75 (m, 2
H), 1.73-1.66 (m, 2 H). 13C NMR (100.4 MHz) δ (ppm): 195.8 (s), 164.3 (s), 157.6 (s), 134.3 (s), 129.1 (d, 2
C), 113.6 (d, 2 C), 92.9 (d), 55.2 (q), 43.7 (t), 40.9 (t), 31.4 (t), 28.4 (t), 22.2 (t), 19.3 (t). MS (ESI) m/z %:
541 ([2M+Na]+, 100), 282 ([M+Na]+, 42), 260 ([M+1]+, 23). C16H21NO2 (259.34): calcd C, 74.10; H, 8.16;
N, 5.40. C, 73.84; H, 7.97; N, 5.45.
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(Z)-1-Piperidin-2-ylidene-3-buten-2-one (3i).
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Starting from 1i. Pale yellow oil (54 mg, 36%). Rf = 0.22 (n-Hexane-EtOAc, 1:1). H NMR (400 MHz) δ
(ppm): 11.7 (br s, 1 H), 6.27 (dd, J = 17.2, 10.2 Hz, 1 H), 6.09 (dd, J = 17.2, 2.1 Hz, 1 H), 5.41 (dd, J = 10.2,
2.1 Hz, 1 H), 4.97 (s, 1 H), 3.37 (td, J = 6.1, 2.1 Hz, 2 H), 2.42 (t, J = 6.4 Hz, 2 H), 1.84-1.78 (m, 2 H), 1.75-
1.69 (m, 2 H). 13C NMR (100.4 MHz) δ (ppm): 184.8 (s), 166.2 (s), 138.0 (d), 121.8 (t), 93.9 (d), 41.1 (t),
28.5 (t), 22.1 (t), 19.2 (t). MS (ESI) m/z %: 325 ([2M+Na]+, 100), 152 ([M+1]+, 93). C9H13NO (151.21):
calcd C, 71.49; H, 8.67; N, 9.26. Found: C, 71.72; H, 8.59; N, 8.87.
(Z)-5-Benzyloxy-1-piperidin-2-ylidene-pentan-2-one (3k).
Pale yellow oil (202 mg, 74%). Rf = 0.23 (Petroleum ether-EtOAc, 8:1). 1H NMR (400 MHz) δ (ppm): 11.1
(br s, 1 H), 7.34-7.29 (m, 5 H), 4.87 (s, 1 H), 4.50 (s, 2 H), 3.51 (t, J = 6.6 Hz, 2 H), 3.32 (td, J = 6.0, 2.0 Hz,
2 H), 2.36-2.28 (m, 4 H), 1.97-1.88 (m, 2 H), 1.82-1.76 (m, 2 H), 1.73-1.67 (m, 2 H). 13C NMR (100.4 MHz)
δ (ppm): 196.4 (s), 164.2 (s), 138.7 (s), 128.3 (d, 2 C), 127.6 (d, 2 C), 127.4 (d), 93.0 (d), 72.7 (t), 70.1 (t),
40.9 (t), 38.2 (t), 28.4 (t), 26.3 (t), 22.3 (t), 19.3 (t). MS (ESI) m/z %: 569 ([2M+Na]+, 100), 296 ([M+Na]+,
66), 274 ([M+1]+, 86). C17H23NO2 (273.37): calcd C, 74.69; H, 8.48; N, 5.12. Found: C, 74.81; H, 8.83; N,
4.83.
(Z)-1-Piperidin-2-ylidene-5-(tetrahydropyran-2-yloxy)pentan-2-one (3l).
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Pale yellow oil (192 mg, 72%). Rf = 0.23 (n-Hexane-EtOAc, 3:1). 1H NMR (400 MHz) δ (ppm): 11.1 (br s, 1
H), 4.82 (s, 1-H), 4.52 (m, 1 H), 3.82-3.78 (m, 1 H), 3.71-3.65 (m, 1 H), 3.44-3.40 (m, 1 H), 3.39-3.33 (m, 1
H), 3.27-3.24 (m, 2 H), 2.31-2.21 (m, 4 H), 1.86-1.79 (m, 2 H), 1.78-1.70 (m, 2 H), 1.69-1.60 (m, 2 H), 1.57-
1.38 (m, 4 H). 13C NMR (100.4 MHz) δ (ppm): 196.3 (s), 163.9 (s), 98.5 (d), 92.8 (d), 67.1 (t), 62.0 (t), 40.8
(t), 38.2 (t), 30.6 (t), 28.3 (t), 26.2 (t), 25.4 (t), 22.2 (t), 19.4 (t), 19.2 (t). MS (ESI) m/z %: 557 ([2M+Na]+,
14), 535 ([2M+1]+, 16). C15H25NO3 (267.36): calcd C, 67.38; H, 9.42; N, 5.24. Found: C, 67.12; H, 9.34; N,
5.18.
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(Z)-1-Piperidin-2-ylidene-6-triisopropylsilanyloxy-hexan-2-one (3n).
Pale yellow oil (54 mg, 72%). Rf = 0.23 (n-Hexane-EtOAc, 6:1). 1H NMR (400 MHz) δ (ppm): 11.1 (br s, 1
H), 4.87 (s, 1 H), 3.68 (t, J = 6.6 Hz, 1 H), 3.34-3.30 (m, 2 H), 2.35 (t, J = 6.4 Hz, 2 H), 2.22 (t, J = 7.2 Hz, 2
H), 1.81-1.76 (m, 2 H), 1.73-1.52 (m, 6 H, 4-H), 1.07-1.04 (m, 21 H). 13C NMR (100.4 MHz) δ (ppm): 197.1
(s), 163.9 (s), 92.9 (d), 63.2 (t), 41.6 (t), 40.8 (t), 32.8 (t), 28.4 (t), 22.7 (t), 22.2 (t), 19.3 (t), 17.9 (q, 6 C),
11.9 (d, 3 C). MS (ESI) m/z %: 729 ([2M+Na]+, 40), 376 ([M+Na]+, 10), 354 ([M+1]+, 100). C20H39NO2Si
(353.61): calcd C, 67.93; H, 11.12; N, 3.96. Found: C, 67.79; H, 11.34; N, 4.18.
(Z)-7-Hydroxy-1-piperidin-2-ylidene-heptan-2-one (3o).
Pale yellow oil (152 mg, 72%). Rf = 0.22 (EtOAc). 1H NMR (400 MHz) δ (ppm): 11.1 (br s, 1 H), 4.84 (s, 1
H), 3.62 (t, J = 6.4 Hz, 2 H), 3.30 (td, J = 5.9, 2.1 Hz, 2 H), 2.34 (t, J = 6.4 Hz, 2 H), 2.20 (t, J = 7.2 Hz, 2
H), 2.00 (br s, 1 H), 1.80-1.74 (m, 2 H), 1.71-1.65 (m, 2 H), 1.63-1.52 (m, 4 H), 1.40-1.32 (m, 2 H). 13C
NMR (100.4 MHz) δ (ppm): 197.0 (s), 164.2 (s), 93.0 (d), 62.6 (t), 41.6 (t), 40.9 (t), 32.5 (t), 28.4 (t), 25.9
(t), 25.5 (t), 22.2 (t), 19.3 (t). MS (ESI) m/z %: 445 ([2M+Na]+, 100), 234 ([M+Na]+, 9), 212 ([M+1]+, 30).
C12H21NO2 (211.30): calcd C, 68.21; H, 10.02; N, 6.63. Found: C, 68.35; H, 10.17; N, 6.88.
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(Z)-6-Oxo-1-piperidin-2-ylidene-heptanoic Acid (3p).
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Prepared as reported according to the general procedure. Work-up: after cooling to r.t., water (15 mL)
was added followed by 1 N HCl to reach pH 3; the product was then extracted with EtOAc (3 x 10
mL) and the combined organic extracts were washed once with brine (15 mL) and dried over
anhydrous Na2SO4. After filtration and evaporation of the solvent, crude vinylogous amide 3p was
purified by flash chromatography to obtain the pure compound as a pale yellow oil (146 mg, 65%). Rf
= 0.21 (n-Hexane-EtOAc, 1:3 + 1% AcOH). 1H NMR (400 MHz) δ (ppm): 11.1 (br s, 1 H), 9.7 (br s, 1 H),
4.85 (s, 1 H), 3.33 (t, J = 5.9 Hz, 2 H), 2.37-2.31 (m, 4 H), 2.25-2.21 (m, 2 H), 1.81-1.75 (m, 2 H), 1.73-1.68
(m, 2 H), 1.68-1.63 (m, 4 H). 13C NMR (100.4 MHz) δ (ppm): 196.3 (s), 178.2 (s), 165.0 (s), 93.1 (d), 41.0
(t), 40.9 (t), 34.1 (t), 28.4 (t), 25.8 (t), 24.8 (t), 22.1 (t), 19.2 (t). MS (ESI) m/z %: 473 ([2M+Na]+, 100), 248
([M+Na]+, 6), 226 ([M+1]+, 9). C12H19NO3 (225.28): calcd C, 63.98; H, 8.50; N, 6.22. Found: C, 64.21; H,
8.21; N, 6.17.
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(Z)-6-(5,5-Dimethyl-[1,3]dioxan-2-yl)-1-piperidin-2-ylidene-hexan-2-one (3q).
Pale yellow solid (219 mg, 78%). Rf = 0.24 (n-Hexane-EtOAc, 1:1). M.p. 68.6-70.4 °C. 1H NMR (400 MHz)
δ (ppm): 11.1 (br s, 1 H), 4.84 (s, 1 H), 4.41 (t, J = 4.9 Hz, 1 H), 3.57 (d, J = 11.1 Hz, 2 H), 3.39 (d, J = 10.9
Hz, 2 H), 3.30 (t, J = 5.7 Hz, 2 H), 2.33 (t, J = 6.4 Hz, 2 H), 2.21 (t, J = 7.0 Hz, 2 H), 1.81-1.74 (m, 2 H),
1.72-1.60 (m, 6 H, 4-H), 1.17 (s, 3 H), 0.69 (s, 3 H). 13C NMR (100.4 MHz) δ (ppm): 196.6 (s), 164.1 (s),
102.2 (d), 93.0 (d), 77.2 (t, 2 C), 41.5 (t), 40.9 (t), 34.6 (t), 30.1 (s), 28.5 (t), 23.0 (q), 22.3 (t), 21.9 (q), 20.9
(t), 19.4 (t). MS (ESI) m/z %: 585 ([2M+Na]+, 100), 304 ([M+Na]+, 7), 282 ([M+1]+, 5). C16H27NO3
(281.39): calcd C, 68.29; H, 9.67; N, 4.98. Found: C, 68.35; H, 9.78; N, 5.03.
(±)-4,5-O-Isopropylidene-4,5-dihydroxy-2-oxopiperidine-1-carboxylic acid tert-butyl ester (8).
Et3N (320 ꢀL, 2.29 mmol), di-tert-butyl dicarbonate (460 mg, 1 eq) and DMAP (25 mg, 0.21 mmol) were
added to a solution of 7 (356 mg, 2.08 mmol) in anhydrous DCM (12.5 mL), under stirring and nitrogen
atmosphere. The resulting solution was heated under reflux for 6 h and every 1.5 h a further amount of di-
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tert-butyl dicarbonate (230 mg, 0.5 eq) was added (in all 2.5 eq of di-tert-butyl dicarbonate were used). After
cooling at room temperature, water (15 mL) was added and the product extracted with DCM (6 mL). The
combined organics extracts were washed with aqueous 5% KHSO4 (15 mL), satd NaHCO3 (15 mL), H2O (15
mL), brine (15 mL) and finally dried over anhydrous Na2SO4. After filtration and evaporation of the solvent,
crude 8 was purified by FCC (eluent: n-hexane-EtOAc, 1:1; Rf = 0.20) and pure 8 (455 mg, 81%) was
obtained as a white solid.
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M.p. 79.4-80.4 °C. 1H NMR (400 MHz) δ (ppm): 4.59 (dt, J = 7.8, 2.9 Hz, 1 H), 4.45 (dt, J = 7.8, 2.3 Hz, 1
H), 4.36 (dd, J = 14.6, 2.3 Hz, 1 H), 3.20 (dd, J = 14.6, 2.1 Hz, 1 H), 2.75 (dd, J = 16.0, 2.9 Hz, 1 H), 2.43
(dd, J = 16.0, 3.3 Hz, 1 H), 1.47 (s, 9 H), 1.34 (s, 3 H), 1.28 (s, 3 H). 13C NMR (100.4 MHz) δ (ppm): 168.5
(s), 151.6 (s), 108.9 (s), 82.9 (s), 72.4 (d), 71.5 (d), 46.3 (t), 39.2 (t), 27.8 (q, 3 C), 26.0 (q), 24.1 (q). MS
(ESI) m/z %: 565 ([2M+Na]+, 100), 294 ([M+Na]+, 15), 272 ([M+1]+, 4). C13H21NO5 (271.31): calcd C,
57.57; H, 7.80; N, 5.16. Found: C, 57.57; H, 7.98; N, 5.21.
(±)-3,4-O-Isopropylidene-6-(diphenoxyphosphoryloxy)-3,4-dihydroxy-3,4-dihydro-2H-pyridine-1-
carboxylic Acid tert-Butyl Ester (9).
A solution of 0.5 M KHMDS in toluene (2.4 mL, 1.20 mmol) was diluted in anhydrous THF (6.3 mL) and
cooled at -78°C. A solution of 8 (218 mg, 0.80 mmol) in anhydrous THF (3.7 mL) was then added dropwise,
keeping the temperature below -70 °C, and the resulting mixture was stirred for 1.5 h.
Diphenylchlorophosphate (250 ꢀL, 1.20 mmol) was slowly added and, after 1 h, the mixture was allowed to
warm at 0°C. Aqueous 10% NaOH (19 mL) was slowly added and the product extracted with Et2O (3 x 15
mL). The combined organic extracts were washed with 10% NaOH (10 mL) and dried over K2CO3 for 30
min. After filtration and evaporation of the solvent, the crude was purified over a short pad of silica gel,
eluting with n-hexane-EtOAc, 2:1 containing 1% Et3N (Rf 0.21), affording pure 9 as a colourless oil (399 mg,
99%). This was stored as ~1.0 M solution in the same eluent and concentrated under vacuum immediately
before use for the next step.
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1H NMR (400 MHz) δ (ppm): 7.36-7.32 (m, 4 H), 7.28-7.17 (m, 6 H), 5.31-5.29 (m, 1 H), 4.71-4.68 (m, 1
H), 4.31-4.27 (m, 1 H), 3.91 (dd, J = 13.7, 4.9 Hz, 1 H), 3.55 (dd, J = 13.7, 1.9 Hz, 1 H), 1.45 (s, 3 H), 1.43
(s, 9 H), 1.35 (s, 3 H). 13C NMR (100.4 MHz) δ (ppm): 153.1 (s), 150.3 (s), 144.2 (s), 144.1 (s), 129.8 (d, 4
C), 125.6 (d, 2 C), 120.1 (d, 2 C), 120.0 (d, 2 C), 110.0 (s), 99.6 (d), 73.6 (d), 71.0 (d), 48.7 (t), 28.0 (q, 3 C),
27.7 (q), 25.7 (q).
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(±)-4-Phenyl-1-piperidin-2-ylbutan-2-one (10).
Vinylogous amide 3f (20.9 mg, 0.09 mmol) was dissolved in CH3OH (4 mL); PtO2 (1% mol) and 70%
HClO4 (7 ꢀL) were added and the mixture was flushed with H2 and vigorously stirred under H2 atmosphere
for 19 h. The mixture was neutralized by K2CO3 (s) and left under stirring for 30 min. After filtration over a
short Celite pad, the solvent was removed under vacuum and the residue taken up into DCM (5 mL). The
organic phase was washed once with water (5 mL) and dried over anhydrous Na2SO4. After filtration and
evaporation of the solvent pure amine 10 (21 mg, quantitative) was obtained as a pale yellow oil.
Rf = 0.30 (EtOAc-MeOH, 2:1). 1H NMR (400 MHz) δ (ppm): 7.28-7.24 (m, 2 H), 7.19-7.14 (m, 3 H), 2.99-
2.95 (m, 1 H), 2.95-2.70 (m, 1 H), 2.88 (t, J = 7.4 Hz, 2 H), 2.74-2.70 (m, 2 H), 2.69-2.62 (m, 1 H), 2.44 (d, J
= 6.2 Hz, 2 H), 2.05-1.95 (s br, 1 H), 1.75-1.72 (m, 1 H), 1.60-1.50 (m, 2 H), 1.42-1.27 (m, 2 H), 1.16-1.06
(m, 1 H). 13C NMR (100.4 MHz) δ (ppm): 209.5 (s), 140.9 (s), 128.4 (d, 2 C), 128.2 (d, 2 C), 126.1 (d), 52.4
(d), 50.0 (t), 46.8 (t), 44.8 (t), 32.6 (t), 29.6 (t), 26.0 (t), 24.6 (t). MS (ESI) m/z %: 232 ([M+1]+, 100).
C15H21NO (231.33): calcd C, 77.88; H, 9.15; N, 6.05. Found: C, 77.99; H, 9.08; N, 6.13.
(±)-4-(4-Methoxyphenyl)-1-piperidin-2-ylbutan-2-one (11).32
Prepared as reported for 10, starting from 3g (51 mg, 0.19 mmol) and obtaining, after chromatographic
purification, pure 11 (36 mg, 73%) as a pale yellow oil.
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