Synthesis of 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides from 2-acetylcyclohexanone via palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1007/s00706-015-1535-3

6-(1-Iodovinyl)-1,4-dioxaspiro[4.5]decane, an iodoalkene obtained from 2-acetylcyclohexanone via ethylene ketal formation, hydrazone formation and iodination, was aminocarbonylated in the presence of a palladium-phosphine precatalyst. Systematic investigations revealed that 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides can be obtained in high yields via palladium-catalysed aminocarbonylation. The influence of the amine nucleophiles and of the reaction conditions on the isolated yields was investigated. Graphical abstract: (Chemical Equation Presented).

Full text of DOI:10.1007/s00706-015-1535-3

Monatsh Chem (2015) 146:1665–1671
DOI 10.1007/s00706-015-1535-3
ORIGINAL PAPER
Synthesis of 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides from 2-
acetylcyclohexanone via palladium-catalysed aminocarbonylation
2
Roland Farkas1 Andea Petz1 Laszlo Kollar
•
•
´
´
´
Received: 12 May 2015 / Accepted: 8 July 2015 / Published online: 1 August 2015
Ó Springer-Verlag Wien 2015
Abstract 6-(1-Iodovinyl)-1,4-dioxaspiro[4.5]decane, an
iodoalkene obtained from 2-acetylcyclohexanone via ethy-
lene ketal formation, hydrazone formation and iodination,
was aminocarbonylated in the presence of a palladium-
phosphine precatalyst. Systematic investigations revealed
that 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides can be
obtained in high yields via palladium-catalysed aminocar-
bonylation. The influence of the amine nucleophiles and of
the reaction conditions on the isolated yields was
investigated.
Introduction
Since the early discovery of palladium-catalysed alkoxy-
and aminocarbonylation of aryl halides [1], hundreds of
aryl esters and amides were synthesised. The great variety
of primary and secondary amines used as N-nucleophiles
allowed for the synthesis of a countless variety of car-
boxylic acid derivatives. The synthetic potential of these
carbonylation reactions was illustrated using several aryl
halides and their synthetic surrogates, aryl triflates. Simple
model compounds and substrates of practical importance
were investigated [2–6]. Its industrial importance and
application have been recently reviewed [7, 8]. Moreover,
the intramolecular alkoxy- and aminocarbonylations
resulted in the formation of lactones and lactames,
respectively [9].
Graphical abstract
I
X
O
O
O
O
O
O
NR'R"
I2, TMG
CO, R'R''NH
Pd(OAc)2
PPh3
O
X = O
X = NNH2
As analogues of aryl halides, iodo- and bromo-alkenes
were also synthesised and widely used as substrates [5, 6].
Besides the substrates of direct practical (biological,
pharmacological) importance, simple (basic) structures
were also investigated with the aim of clearing-up the
reaction mechanism and of synthesising new and useful
building blocks [10].
N2H4, Et3N
Keywords Carbonylation Á Carbon monoxide Á
Amine nucleophile Á Palladium catalyst Á Iodoalkene
As a part of our ongoing research interests on the car-
bonylation of iodoalkenes, the synthesis of various building
blocks was carried out [11–13]. Recently, we turned our
attention towards the synthesis of compounds with substi-
tuted cyclohexanone backbone.
´
´
´
& Laszlo Kollar
kollar@ttk.pte.hu
2-Acetylcyclohexanone is one of the key representatives
of b-diketones. Its Schiff base derivatives obtained with
diaminoalkanes [14], 2-benzoyl-3-hydroxy-2H-indazol
obtained with benzohydrazide [15], enolate alkylation [16]
and nitrosation [17] products were published. The elec-
trochemically induced Michael reactions of o-
benzoquinones with 2-acetylcyclohexanone led to the
1
´
Department of Inorganic Chemistry, University of Pecs and
Szentagothai Research Centre, P.O. Box 266, Pecs 7624,
Hungary
´
2
MTA-PTE Research Group for Selective Chemical
´ ´
Syntheses, Ifjusag u. 6., Pecs 7624, Hungary
123

1666
R. Farkas et al.
formation of the corresponding catechols [18]. The double
Mannich reaction of 2-acetylcyclohexanone proved to be
the key step to the synthesis of pyrazole- and oxazol-fused
azatricyclic ring systems [19]. The regioselective reaction
of cyanothioacetamide with 2-acetylcyclohexanone resul-
ted in pyridine-2(1H)-thione derivatives.
hydrazine (Scheme 1). The reaction was performed with
ethylene glycol, in chloroform at reflux and in the pres-
ence of p-toluenesulfonic acid (PTSA) as catalyst. The
target monoketal 2 was isolated from the reaction mixture
by column chromatography. However, the formation of 2
(Table 1) was accompanied by the formation of several
side products, such as the regioisomeric ketal 2x, diketal
2y and surprisingly cyclohexanone ketal 2z besides an
open-chain diketal 2w. It has to be added that the target
compound 2 was isolated and fully characterised, 2x–2w
were identified by MS only. Some representative experi-
ments carried out during the optimisation are shown in
Table 1.
Due to its facile tautomerization [20, 21], 2-acetylcy-
clohexanone forms enolate complexes with various metals
such as Fe(II), Co(II), Ni(II), Cu(II), Cu(I), Zn(II), V(III),
V(IV), Cr(III), U(VI) [22–29]. Some of them proved to be
active catalyst in C-N and C-O bond formation [23, 25, 26]
and Ziegler–Natta polymerisation [27].
In the present study, the synthesis of 2-(1,4-dioxaspiro-
[4.5]decan-6-yl)acrylamides from 2-acetylcyclohexanone is
reported. To the best of our knowledge, the selective
functionalisation of 2-acetylcyclohexanone (or that of
compounds with similar structure) in the side chain is
unprecedented. Starting from 2-acetylcyclohexanone a
high-yielding palladium-catalysed aminocarbonylation of
the corresponding iodoalkene was used as a key reaction.
It can be stated that (1) long reaction times (up to 4 days)
are necessary to obtain reasonable conversion; (2) the pro-
duct ratio is sensitive to the molar ratio of 1 to PTSA (entries
3–5); (3) the highest chemoselectivity towards 2 is 77 %
(entries 4, 6); (4) the reaction is scalable to 0.1 mol without
decreasing chemoselectivity (entry 6); and (5) the target
compound monoketal 2 can be isolated in 40–44 % yields.
The 1,4-dioxaspiro[4.5]decane derivative 2 was then
transformed into the corresponding hydrazone 3 in the
presence of hydrazine hydrate and barium oxide in ethanol
at reflux. Crude 3 was then treated with iodine in the
presence of a strong base, TMG (N,N,N0,N0-tetramethyl-
guanidine) (Scheme 1). The iodoalkenyl derivative 4 was
obtained in 62 % yield (based on 2). Although the general
methodology for the preparation of iodoalkenes from
ketones has been known for a long time [30, 31], the
optimised reported procedure shows several marked dif-
ferences with respect to reported ones, such as differences
in reaction temperature (hydrazone formation), in using
BaO (hydrazone formation), in the amount of base (TMG).
Therefore, a complete description of the preparation of 4 is
given in the ‘‘Experimental’’ section.
Results and discussion
Synthesis of the iodoalkene substrate, 6-(1-
iodovinyl)-1,4-dioxaspiro[4.5]decane (4)
2-Acetylcyclohexanone (1) was protected at the ring keto
functionality as ethylene ketal with the aim to reduce
unwanted side reactions in the subsequent reaction with
Scheme 1
O
O
O
NNH2
O
O
O
O
H2NNH2
HOCH2CH2OH
BaO, EtOH
reflux
CHCl3, pTsOH
reflux
Palladium-catalysed aminocarbonylation of 4
1
2
3
I2, TMG
The iodoalkene substrate 4 was aminocarbonylated in the
presence of a palladium catalyst formed in situ by the
reaction of palladium(II) acetate and two molar equivalents
of triphenylphosphine. The reactions were performed in
DMF, in the presence of triethylamine as base, at 50 °C,
under a balloon of carbon monoxide. The N-nucleophiles
5a–5g were used in excess as given in the ‘‘Experimental’’
section (Scheme 1).
I
O
O
CO, R'R"NH (5a-5g) O
O
NR'R"
Pd(OAc)2 / PPh3
O
6a-6g (37-93%)
4 (40-44%)
R'
H
R''
tBu
a
b
-(CH2)5-
It is worth mentioning that the above Pd(OAc)2/2 PR3-
type ‘precatalyst’ is widely used in various cross-coupling
and carbonylation reactions. It serves as a precursor of
‘in situ’ formed palladium(0)-tertiary phosphine systems. It
has been proved by cyclic voltammetry and NMR mea-
surements that palladium(II) is reduced to palladium(0),
c
d
e
f
-(CH2)O(CH2)2-
CH2COOCH3
H
H
H
CH(CH3)COOCH3
CH(CH(CH3)2)COOCH3
g
-CH(COOCH3)(CH2)3-
123

Synthesis of 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides from 2-acetylcyclohexanone via…
Table 1 Product distribution obtained in the ethylene ketal formation from 1
1667
Entr.
1
PTSA
/mmol
Time
/h
Conv.
/% a
Composition of the product mixture/%
/mmol
(isolated yields)a
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
2
2x
2y
2z
2w
1
21
21
35
35
35
107
0.1
0.5
0.05
0.6
0.8
1.3
96
96
40
90
90
96
82
36 (27)
69 (40)
37 (25)
77 (44)
65 (40)
75 (42)
4
17
16
12
3
9
2
>99
77
5
5
1
3
3
7
7
4
6
5
3
3
28
9
4
>99
95
7
5
15
6
7
6 b
95
8
Reaction conditions: 1/ethylene glycol = 1/1, chloroform (reflux)
a
Determined by GC and GC–MS
b
Described in the ‘‘Experimental’’ section
Table 2 Aminocarbonylation of 4 in the presence of palladium-PPh3 in situ catalysts
Entr.
N
Time/h
Conv.a/ %
Isolated yield of 6
1
2b
a
18
10
2
[98
[98
95
51 (6a)
93 (6a)
80 (6a)
64 (6b)
67 (6b)
56 (6c)
53 (6c)
47 (6d)
43 (6e)
41 (6f)
37 (6g)
a
3
a
4
5b
bc
bc
cc
cc
dd
ed
fd
gd
21
72
72
72
24
25
144
144
[98
85
6
90
7b
8
85
78
9
[98
93
10
11
65
Reaction conditions (unless otherwise stated): 1 mmol of substrate 4; 0.025 mmol of Pd(OAc)2; 0.05 mmol of PPh3; 3 mmol of a; 0.5 cm3 of
triethylamine; solvent: 10 cm3 of DMF, reaction temperature: 50 °C; 1 bar CO, n.d.: not determined
a
Determined by GC and GC–MS (naphthalene as internal standard)
b
3 mmol of 4
c
Substrate 4/amine ratio = 1/1.5
d
Substrate 4/amine ratio = 1/1.1, i.e. 1.1 mmol of d, e, f and g (as a hydrochloride salt) were used
while one of the two equivalents of phosphine ligands is
oxidised [32–34]. In our case, the formation of coordina-
tively highly unsaturated Pd(PPh3)(S)n (S stands for a
coordinating solvent (DMF)) complex is supposed, while
the ‘second’ equivalent of PPh3 is oxidised to tri-
phenylphosphine oxide. Under the aminocarbonylation
conditions used, the action of other compounds (amine,
carbon monoxide) as reducing agents cannot be excluded.
A highly chemoselective reaction was observed in the
presence of all N-nucleophiles 5a–5g resulting in the
formation of the corresponding carboxamide derivative 6a–
6g in moderate to high yields. Although the highest con-
versions were obtained with primary amine 5a (Table 2,
entries 1, 3) and cyclic secondary amines (5b, 5c) (entries 4,
6), all of the amines tested, including amino acid methyl
esters (5d–5g) (entries 8–11), gave satisfactory results. The
aminocarbonylations with sterically more bulky N-nucle-
ophiles (5f, 5g) needed longer reaction times (entries 10, 11).
Interestingly, the isolated yields increased when practi-
cally full conversion was achieved but the reaction time
123

1668
R. Farkas et al.
2-substituted cyclohexanones, chiral propionic amides with
cyclohexyl moieties, can be synthesised.
Scheme 2
O
ox.
R
R
The aminocarbonylation of 4 can be rationalised as
follows. Compound 4 undergoes facile oxidative addition
to palladium(0) resulting in the palladium(II)-alkenyl
intermediate (A) (Scheme 3). It has to be noted that the
iodo-carbon bond has higher polarizability than the corre-
sponding C(sp2)-X bonds in its structural analogues such as
chloro- and bromo-alkenes. In general, in line with the
decreasing carbon-halide bond energy, the rate of the
oxidative addition to palladium(0) and consequently the
efficiency of carbonylations decrease in the order
C-I [ C(OTf) C C–Br [ C–Cl [ C-F [2, 9]. The forma-
tion of the complex containing terminal carbonyl ligand
(B) is followed by carbon monoxide insertion into palla-
dium(II)-alkenyl bond. The highly reactive acyl
intermediate (C) gives the target carboxamide (5) in the
product forming (reductive elimination) step, while the
coordinatively unsaturated Pd(0) intermediate is re-formed.
2 RNH2 + CO
N
H
N
H
Pd(OAc)2 / PPh3
Scheme 3
I
O
O
O
O
NR'R"
PdLn
6
4
O
+ 2L
PdLn-2
- 2L
Et3NHI
Et3N
HNR'R''
O
O
O
O
PdLn-2I
PdLn-2
I
A
C
O
Conclusions
CO
B
The aminocarbonylation of 6-(1-iodovinyl)-1,4-dioxa-
spiro[4.5]decane 4 provides an easy access to synthetically
useful building blocks possessing a,b-unsaturated carbox-
amide moieties. The target compounds were synthesised
via mono(ethyleneketal)-hydrazone-iodoalkene-carboxam-
O
O
PdLn-2(CO)I
ide
sequence
and
2-(1,4-dioxaspiro[4.5]decan-6-
yl)acrylamides 6a–6g were isolated in yields of practical
interest.
was limited to 2 h (entries 1 and 3). Similarly, scaling-up
the reaction resulted in higher isolated yields (entries 1, 2).
Thus, when the amount of the substrate 4 to be converted
was increased (from the generally used 1 to 3 mmol),
higher isolated yields were obtained even if isolation was
done at lower conversion (entries 4, 5). These results can
be explained taking into account the competitive
aminocarbonylation reactions of the reacting nucleophiles
giving rise to N,N0-disubstituted ureas [35, 36] as undesired
side products (Scheme 2). Since the nucleophiles are pre-
sent in excess, prolonged reaction times resulted in the
formation of large amount of by-products which made the
chromatographic purification of the crude reaction products
more difficult.
Experimental
1H and 13C NMR spectra were recorded in CDCl3 on a
Varian Inova 400 spectrometer at 400.13 MHz and
100.62 MHz, respectively. Chemical shifts are reported in
1
ppm relative to CHCl3 (7.26 and 77.00 ppm for H and
13C, respectively). Elemental analyses were measured on a
1108 Carlo Erba apparatus. Samples of the catalytic reac-
tions were analysed with an Agilent Technologies 6890 N
gas chromatograph fitted with an HP-1MS capillary col-
umn [injector temp. 250 °C; oven: starting temp. 50 °C
(hold-time 1 min), heating rate 15 °C min-1, final temp.
320 °C; detector temp. 150 °C; carrier gas: helium (rate:
1.5 cm3 min-1)]. The FT-IR spectra were taken in KBr
pellets using an IMPACT 400 spectrometer (Nicolet)
For comparison, the reactivity of substrates bearing
1-iodovinyl functionalities such as a-iodo-styrene [37, 38]
and a-iodoethenyl-naphthalene isomers [39] was related to
that of 4 in carbonylation reactions. It can be stated that the
reactivity of the above aryl-iodoalkenes, synthesised and
used as substrates in our laboratory [35–39], proved to be
definitely higher than that of 4. However, the tolerance
towards dioxolane ring makes this reaction valuable since
otherwise unobtainable building blocks such as
applying a DTGS detector in the region of 400–4000 cm-1
,
the resolution was 4 cm-1. The amount of the samples was
ca. 0.5 mg.
The iodoalkene substrate (4) was synthesised by the
modified Barton procedure [30, 31]. The amine
123

Synthesis of 2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamides from 2-acetylcyclohexanone via…
1669
Yield: 10.2 g brownish yellow, viscous oil (62 % based
on 2); Rf = 0.72 (15 % acetone/hexane, this mixture was
used also for chromatography); 1H NMR (CDCl3):
d = 6.25 (1H, s, =CH), 5.97 (1H, s, =CH), 3.79–4.07
(4H, m, OCH2), 2.29–2.44 (1H, m, CH), 1.22–1.80 (8H, m,
CH2) ppm; 13C NMR (CDCl3): d = 129.3, 110.0, 109.4,
65.1, 65.0, 56.7, 36.8, 32.3, 24.8, 23.6 ppm; IR (KBr):
vꢀ = 1609 (C=C) cm-1; MS: m/z (%) = 294 (M?), 167
(100), 125 (8), 99 (11), 95 (15), 67 (16).
nucleophiles were purchased from Sigma-Aldrich and were
used without further purification.
1-(1,4-Dioxaspiro[4.5]decan-6-yl)ethanone (2)
In a typical experiment, a mixture of 15.0 g 2-acetylcy-
clohexanone (107 mmol), 6.64 g, ethylene glycol
(107 mmol) and 0.22 g p-toluenesulfonic acid (1.3 mmol)
in 200 cm3 chloroform was heated under reflux for 68 h in
a Dean-Stark apparatus. The reaction mixture was cooled
and then neutralised and washed with 0.3 M aqueous
sodium hydroxide (3 9 60 cm3). The combined organic
solution was dried on sodium sulfate and evaporated to
dryness. The crude compound was subjected to column
chromatography [silicagel 60 (Fluka), 0.035–0.070 mm],
acetone/hexane (15/85). Yield: 8.72 g (44 %). The spectral
data of 2 are in good agreement with those published
previously [40].
Aminocarbonylation of 6-(1-iodovinyl)-1,4-dioxaspiro[4.5]-
decane (4) in the presence of N-nucleophiles under atmo-
spheric carbon monoxide pressure
In a typical experiment, 5.6 mg Pd(OAc)2 (0.025 mmol),
13.2 mg triphenylphosphine (0.05 mmol), 294 mg 6-(1-
iodovinyl)-1,4-dioxaspiro[4.5]decane (4, 1 mmol), amine
nucleophile (3 mmol of 5a/1.5 mmol of 5b or 5c/1.1 mmol
of 5d–5g) and 0.5 cm3 triethylamine were dissolved in
10 cm3 DMF under argon in a 100 cm3 three-necked flask
equipped with a gas inlet, reflux condenser with a balloon
(filled with argon) at the top. The atmosphere was changed
to carbon monoxide. The reaction was conducted for the
given reaction time upon stirring at 50 °C and analysed by
GC–MS. The mixture was then concentrated and evapo-
rated to dryness. The residue was dissolved in 20 cm3
chloroform and washed with water (3 9 20 cm3). The
organic phase was dried over sodium sulfate, filtered, and
evaporated to give a crystalline material or a waxy residue.
All compounds were subjected to column chromatography
(silicagel 60 (Merck), 0.063–0.200 mm), EtOAc/CHCl3
(solvent ratios are specified, vide infra).
6-(1-Iodovinyl)-1,4-dioxaspiro[4.5]decane (4)
Step 1 8.72 g compound 2 (47.4 mmol), 3.41 g freshly
distilled hydrazine hydrate (98 %, 68.2 mmol) and 2.4 g
barium oxide (15.6 mmol) were heated in 80 cm3 refluxing
ethanol for 21 h. After completion of the reaction, the
mixture was poured onto water and extracted with
dichloromethane (3 9 50 cm3). Then the combined
organic phase was washed with water (3 9 100 cm3) and
50 cm3 brine, and dried over sodium sulfate. After the
evaporation of the solvent, the crude hydrazone derivative
3 was obtained and used in the next step without further
purification.
Step 2 to a stirred solution of 20.5 g iodine (80.8 mmol)
in 70 cm3 ether 12.97 g N,N,N0,N0-tetramethylguanidine
(112.6 mmol) was added at ice bath cooling. To this
solution, the etheral solution (50 cm3) of 7.59 g 3
(38.3 mmol) was added drop-wise at room temperature.
The reaction mixture was stirred for 1 h and the precip-
itated salt was filtered. The solvent was evaporated and the
residue was heated at 90 °C under argon atmosphere for
2 h. The mixture was poured onto 240 cm3 iced water and
extracted with dichloromethane (3 9 50 cm3). The com-
bined organic layer was washed with 1 N aqueous
hydrochloric acid (3 9 50 cm3), 50 cm3 water, 5 % aque-
ous sodium hydrogen carbonate (2 9 50 cm3), then with
50 cm3 water, 10 cm3 saturated aqueous sodium thio-
sulphate, and water (3 9 50 cm3) again. The dichloro-
methane solution was dried on sodium sulfate and
evaporated. The highly pure product 4 was used as
obtained. In order to avoid its oxidative and photochemical
decomposition, 4 has to be kept under argon in refrigerator.
Using it in carbonylation reactions, reproducible results can
be obtained even after 2 months. No changes in its colour
and analytical characteristics were observed within this
time interval.
N-(tert-Butyl)-2-(1,4-dioxaspiro[4.5]decan-6-yl)-
acrylamide (6a, C15H25NO3)
Yield: 307 mg (93 %); white solid; m.p.: 123–124 °C;
Rf = 0.44 (6 % EtOAc/CHCl3, this mixture was used also
for chromatography); 1H NMR (CDCl3): d = 6.68 (1H, bs,
NH), 5.84 (1H, s, =CH), 5.33 (1H, s, =CH), 3.83–3.97 (4H,
m, OCH2), 2.65–2.73 (1H, m, CH), 1.64–1.83 (6H, m,
CH2), 1.43–1.53 (2H, m, CCH2), 1.32 (9H, s, CH3) ppm;
13C NMR (CDCl3): d = 169.5, 146.6, 121.4, 110.3, 65.1,
64.4, 50.7, 50.3, 46.9, 36.2, 30.3, 29.4, 28.7, 25.4,
23.7 ppm; IR (KBr): vꢀ = 3334 (NH), 1648 (CON), 1620
(C=C) cm-1; MS: m/z (%) = 267 (5, M?), 252 (2), 195
(24), 167 (54), 153 (27), 99 (100), 86 (52).
1-(Piperidin-1-yl)-2-(1,4-dioxaspiro[4.5]decan-6-yl)-
prop-2-en-1-one (6b, C16H25NO3)
Yield: 560 mg (67 %); yellow viscous oil; Rf = 0.49
(50 % EtOAc/CHCl3, this mixture was used also for
chromatography); 1H NMR (CDCl3): d = 5.29 (1H, s,
=CH), 5.16 (1H, s, =CH), 3.87 (4H, s, OCH2), 3.18–3.72
(4H, m, NCH2), 2.80 (1H, dd, J = 11.2, 3.9 Hz, CH),
1.38–1.85 (12H, m, CH2), 1.26–1.37 (2H, m, CCH2) ppm;
123

1670
R. Farkas et al.
13C NMR (CDCl3): d = 171.6, 144.6, 116.3, 110.2, 64.2,
63.8, 48.1, 46.5, 42.5, 34.4, 29.5, 26.2, 25.5, 24.9, 24.7,
Methyl 2-[2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamido]-
3-methylbutanoate (6f, C17H27NO5, 1/1 mixture of two
diastereomers)
23.5 ppm; IR (KBr): vꢀ = 1636 (CON), 1616 (C=C) cm-1
;
MS: m/z (%) = 279 (22, M?), 234 (67), 167 (40), 138 (22),
Yield: 180 mg (41 %); yellowish brown viscous oil;
112 (39), 99 (100), 86 (75), 84 (63).
Rf = 0.70 (49 % EtOAc/CHCl3, this mixture was used
1
also for chromatography); H NMR (CDCl3): d = 7.71/
1-Morpholino-2-(1,4-dioxaspiro[4.5]decan-6-yl)prop-2-
en-1-one (6c, C15H23NO4)
7.32 (1H, d, J = 8.4 Hz, NH), 6.01/5.94 (1H, s, =CH),
5.46/5.42 (1H, s, =CH), 4.49-4.64 (1H, m, NHCH), 3.81-
4.00 (4H, m, OCH2), 3.71/3.70 (3H, s, OCH3), 2.79/2.67
(1H, dd, J = 12.4, 3.8 Hz, CCH), 2.12–2.26 (1H, m,
CH(CH3)2), 1.41–1.87 (8H, m, CH2), 0.90 (3H, d,
J = 6.8 Hz, CHCH3), 0.84 (3H, d, J = 6.8 Hz, CHCH3)
ppm; 13C NMR (CDCl3): d = 173.8, 169.8, 145.0/144.9,
123.7/123.1, 110.1, 65.4/65.0, 64.6/64.5, 57.2/57.1, 51.9,
47.2/47.0, 36.5/36.0, 31.2/31.0, 30.5/30.0, 25.5/25.4, 23.7,
18.9, 17.7 ppm; IR (KBr): vꢀ = 3359 (NH), 1744 (COO),
1653 (CON), 1620 (C=C) cm-1; MS: m/z (%) = 325 (4,
M?), 310 (4), 294 (2), 266 (22), 195 (25), 167 (45), 130 (6),
99 (100), 86 (43).
Yield: 280 mg (53 %); jonquil/yellowish white solid; m.p.:
88–89 °C; Rf = 0.33 (50 % EtOAc/CHCl3, this mixture
was used also for chromatography); 1H NMR (CDCl3):
d = 5.40 (1H, s, =CH), 5.21 (1H, s, =CH), 3.81–3.99 (4H,
m, OCH2), 3.38–3.72 (8H, m, N(CH2)2O), 2.86 (1H, dd,
J = 11.0, 4.1 Hz, CH), 1.42–1.89 (6H, m, CH2), 1.35 (2H,
td, J = 12.5, 4.0 Hz, CCH2) ppm; 13C NMR (CDCl3):
d = 171.9, 143.9, 117.5, 110.2, 66.8, 64.2, 63.9, 47.8, 46.4,
42.0, 34.2, 29.4, 24.9, 23.6 ppm; IR (KBr): vꢀ = 1644
(CON), 1620 (C=C) cm-1; MS: m/z (%) = 281 (12, M?),
236 (16), 209 (22), 195 (10), 167 (36), 139 (22), 99 (100),
86 (60).
Methyl 1-[2-(1,4-dioxaspiro[4.5]decan-6-yl)acryloyl]-
pyrrolidine-2-carboxylate (6g, C17H25NO5, 1/1 mixture
of two diastereomers)
Methyl 2-[2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamido]-
acetate (6d, C14H21NO5)
Yield: 160 mg (47 %); yellowish brown oil; Rf = 0.17
(10 % EtOAc/CHCl3, this mixture was used also for
chromatography); 1H NMR (CDCl3): d = 7.47 (1H, bs,
NH), 5.98 (1H, s, =CH), 5.45 (1H, s, =CH), 3.94–4.19 (2H,
m, NHCH2), 3.75–3.94 (4H, m, OCH2), 3.72 (3H, s,
OCH3), 2.73–2.78 (1H, m, CH), 1.53–1.89 (6H, m, CH2),
1.31–1.53 (2H, m, CCH2) ppm; 13C NMR (CDCl3):
d = 170.7, 170.3, 144.6, 123.4, 110.1, 65.2, 64.6, 52.1,
46.8, 41.3, 36.2, 30.2, 25.4, 23.7 ppm; IR (KBr): vꢀ = 3339
(NH), 1755 (COO), 1659 (CON), 1622 (C=C) cm-1; MS:
m/z (%) = 283 (3, M?), 268 (1), 252 (2), 224 (1), 167 (28),
99 (100), 86 (43).
Yield: 160 mg (37 %); yellowish brown viscous oil;
Rf = 0.44 (49 % EtOAc/CHCl3, this mixture was used also
for chromatography); 1H NMR (CDCl3): d = 5.47/5.45
(1H, s, =CH), 5.41/5.37 (1H, s, =CH), 4.37–4.59 (1H, m,
NCH), 3.82–4.03 (4H, m, OCH2), 3.71 (3H, s, OCH3), 3.44–
3.82 (2H, m, NCH2), 2.94–3.04/2.77–2.91 (1H, m, CCH),
1.26–2.38 (10H, m, CH2) ppm; 13C NMR (CDCl3):
d = 173.0/172.8, 171.3/170.9, 145.5/144.9, 118.2/116.8,
110.3/110.0, 64.5, 64.1/63.9, 58.5, 52.0, 49.3/48.8, 46.7/
45.4, 34.7/34.1, 29.6/29.2, 29.3, 25.7/25.2, 24.9, 23.6 ppm;
IR (KBr): vꢀ = 1747 (COO), 1643 (CON), 1616 (C=C)
cm-1; MS: m/z (%) = 323 (11, M?), 308 (2), 292 (3), 264
(15), 195 (55), 167 (44), 128 (31), 99 (100), 86 (46), 70 (45).
Methyl 2-[2-(1,4-dioxaspiro[4.5]decan-6-yl)acrylamido]-
propanoate (6e, C15H23NO5, 1/1 mixture of two
diastereomers)
Acknowledgments The authors thank the Hungarian Scientific
Research Fund (K113177) and Developing Competitiveness of
Universities in the South Transdanubian Region (SROP-4.2.2.A-11/1/
KONV-2012-0065) for the financial support and Johnson Matthey for
the generous gift of palladium(II) acetate. The present scientific
contribution is dedicated to the 650th anniversary of the foundation of
Yield: 150 mg (43 %); white solid; m.p.: 57–58 °C;
Rf = 0.40 (20 % EtOAc/CHCl3, this mixture was used
1
also for chromatography); H NMR (CDCl3): d = 7.64–
7.71/7.43–7.50 (1H, m, NH), 6.03/5.95 (1H, d, J = 1.2 Hz,
=CH), 5.48/5.45 (1H, s, =CH), 4.66 (1H, q, J = 7.2 Hz,
CHCH3), 3.86–3.97 (4H, m, OCH2), 3.72/3.77 (3H, s,
OCH3), 2.82 (1H, dd, J = 11.9, 4.5 Hz, CCH)/2.72 (1H,
dd, J = 12.3, 4.0 Hz, CCH), 1.86–1.48 (8H, m, CH2), 1.44/
1.38 (3H, d, J = 7.2, CHCH3) ppm; 13C NMR (CDCl3):
d = 173.8, 169.8/169.3, 144.9/144.7, 123.5/122.9, 110.2,
65.3/65.1, 64.6/64.5, 52.3, 48.1/48.0, 46.9/46.7, 36.3/36.1,
30.4/29.9, 25.5/25.4, 23.7, 18.5/18.4 ppm; IR (KBr):
vꢀ = 3273 (NH), 1751 (COO), 1652 (CON), 1619 (C=C)
cm-1; MS: m/z (%) = 297 (3, M?), 282 (1), 266 (2), 238
(3), 195 (16), 167 (34), 99 (100), 86 (48).
´
the University of Pecs, Hungary.
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