Interaction of push-pull tert-enamines with phenylglyoxal

Article abstract of DOI:10.1007/s00706-009-0110-1

The reaction of push-pull enamines with 1,2-biselectrophilic phenylglyoxal was investigated. Phenylglyoxal was found to react depending on the structure of the push-pull enamine, affording either a hydroxyalkylation product at the methyl group or the cycl

Full text of DOI:10.1007/s00706-009-0110-1

Monatsh Chem (2009) 140:639–643
DOI 10.1007/s00706-009-0110-1
ORIGINAL PAPER
Interaction of push–pull tert-enamines with phenylglyoxal
Dmitry A. Sibgatulin Æ Dmitry M. Volochnyuk Æ
Aleksander N. Kostyuk Æ Sergey P. Ivonin Æ
Andriy V. Lapandin
Received: 11 July 2008 / Accepted: 25 November 2008 / Published online: 24 February 2009
Ó Springer-Verlag 2009
Abstract The reaction of push–pull enamines with 1,2-
biselectrophilic phenylglyoxal was investigated. Phenyl-
glyoxal was found to react depending on the structure of
the push–pull enamine, affording either a hydroxyalkyla-
tion product at the methyl group or the cyclic product via
participation of the methyl group and the b-carbon of the
enamine.
benzene derivatives [4–6]. One can assume that tertiary
push–pull enamines in reactions with 1,2-biselectrophilic
reagents can also behave analogously, affording cyclo-
pentenone derivatives. Thus, 1,3-bis(silyl)enol ethers and
1,3-dicarbonyl dianions have been shown to react with 1,2-
diketones affording functionalized 4-hydroxycycloprop–2-
en-1-ones. Although reaction with phenylglyoxal itself
proved unsuccessful, its ketal, 2,2-dimethoxy-2-phenyl-
acetaldehyde, afforded cyclopentenone derivatives in
moderate yields [7]. It is worth noting that primary and
secondary push–pull enamines have been shown to react
with 1,2-biselectrophilic reagents as CCN binucleophiles,
affording five-membered heterocyclic derivatives [8–10].
The main object of our study was the reaction of tertiary
push–pull enamines with 1,2-biselectrophilic reagents with
the objective of synthesizing cyclopentane derivatives.
Keywords Cyclizations ꢀ Electrophilic additions ꢀ
Ene reactions ꢀ Alcohols ꢀ Ketones
Introduction
Until now the main object of our study has been the
reaction with electrophilic reagents of tertiary push–pull
enamines bearing a methyl group at the a-position. We
have shown that these enamines, depending on their
structure, react readily with monoelectrophilic reagents
either at the methyl group or at the b-carbon of the
enamines [1–3]. The enamines thus functionalized at the
methyl group have a b-carbon capable of further acting as a
C-nucleophile. Indeed, it has been found that the tertiary
push–pull enamines react both at the methyl group and at
the b-carbon with 1,3-biselectrophilic reagents affording
six-membered cyclic products, thus providing a convenient
synthetic approach to polyfunctionalized cyclohexanes and
Results and discussion
For this study a set of tertiary push–pull enamines with
dialkylamino substituents of different basicity—pyrrolidine
and morpholine—and electron-withdrawing groups (EWG)
were chosen as model compounds (Fig. 1). Phenylglyoxal
(1) was used as the 1,2-biselectrophilic reagent.
We found that enamines 3a and 3b, derivatives of
b-aminocrotonic acid, depending on the structure of the
dialkylamino group, gave different products. Enamine 3a
in the reaction with phenylglyoxal gave the product
resulting from hydroxyalkylation at the methyl group, 6a.
In a few hours the reaction comes to completion in dry
ether at room temperature in high yield. By increasing the
reaction time and temperature c-functionalized enamine 6a
gave cyclic product 7. In contrast, the enamine derived
from the less basic morpholine 6b does not cyclize, but is
D. A. Sibgatulin ꢀ D. M. Volochnyuk ꢀ A. N. Kostyuk (&)
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Murmanska 5, 02094 Kiev-94, Ukraine
e-mail: a.kostyuk@enamine.net
S. P. Ivonin ꢀ A. V. Lapandin
PBMR Inc., Murmanska 1, 02094 Kiev-94, Ukraine
123

640
D. A. Sibgatulin et al.
Me
behaviour of enaminones bearing an acyl group in reac-
tions with strongly electrophilic reagents [1]. In going to
enaminones 5a and 5b (EWG = COPh), the reaction with
phenylglyoxal runs analogously to those with enamines 3.
Thus, in ether at room temperature phenylglyoxal readily
reacts with enamines 5a and 5b giving hydroxyalkylation
products 9a and 9b which, in acidic media, cyclize into the
corresponding cyclopentenones 10a and 10b. It should be
noted that heating the reactants in benzene results in
complex mixtures of unidentifiable products. Unfortu-
nately, our attempts to prepare cyclopentanediones by
hydrolysis of compounds 10 failed. Thus, under mild
conditions (two-phase CH2Cl2–5% aqueous HCl or in
MeOH–5% aqueous HCl mixture) the starting material was
recovered intact. In contrast with that, under more drastic
conditions (dissolution in 5% aqueous HCl) compounds
10 decompose. Numerous attempts at hydrolysis of
compounds 9 also failed. Thus, under mild conditions
(two-phase CH2Cl2–5% aqueous HCl) the acidic cleav-
age product of 9—benzoyl acetone 12—was separated
(Scheme 2).
EWG
Alk2N
2-5
Alk2N = a: N(CH2)4, b: N(CH2CH2)2O
EWG = 2: CN; 3: CO2Et; 4: COMe; 5: COPh
Fig. 1 The structures of the starting ‘push–pull’ enamines
easily hydrolysed to its ketone derivative 8 instead.
Recently [7], it was demonstrated that such compounds are
key intermediates in the synthesis of functionalized 4-
hydroxy-2-penten-1-ones, which are present in a number of
natural products, for example prostaglandins [11, 12]
(Scheme 1).
The structures of products 6a, 6b, and 7 were confirmed
1
by use of physicochemical methods. H NMR spectra of
compounds 6a and 6b are unequivocally indicative of an
acyclic structure. The signal of the methylene group is
indicative of an ABX-system, and the signal of the a-car-
bonyl proton is indicative of an AB-system. Furthermore,
the doublet of ortho-phenyl protons is shifted downfield to
*8.2 ppm because of conjugation with the carbonyl group.
With other 1,2-biselectrophilic reagents we failed to
achieve reaction. Thus, in the reaction of enamines 2–5
with 1,2-biselectrophilic butan-2,3-dione (13) at room
temperature the starting materials were recovered. Our
attempts at running the reaction at 80 °C resulted in a
complex mixture of unidentifiable products. To promote
the reaction we used lithiated enamine 3a. It was found that
the reaction leads to formation of bicyclic product 17
(Scheme 3).
1
At the same time the H NMR spectrum of compound 7
shows the methylene group as an AB-system, whereas the
signal of the a-carbonyl proton is absent. Furthermore,
ortho-phenyl protons shifted upfield compared with acyclic
products confirm the absence of conjugation between the
phenyl ring and the carbonyl group. Unlike enamines 3,
enaminonitriles 2 and enaminones 4 react with phenyl-
glyoxal at room temperature in ether with low selectivity
affording a mixture of hardly separable products. An
attempt to run the reaction at -20 °C gave the same result.
This can be explained by assuming that the EWG function
is reactive toward phenylglyoxal. This is probably typical
Most probably its formation proceeds in a stepwise
manner as presented in Scheme 4. An excess of lithiated
enamine in the reaction mixture is the main cause of the
Benzene, reflux, 2h
NAlk2
NAlk2
CO2Et
N
NAlk2
ii or v
i
COPh
+
1
3a,b
CO2Et
for 6a
O
COPh
ii
i
HO
1 + 5a,b
O
HO
Ph
O
Ph
7, 84%
O
Ph
Ph
9a, 63%
9b, 52%
6a, 75%
6b, 62%
10a, 55%
10b, 41%
iv
iv
O
OH
O
O
O
O
O
Ph
Ph
8, 86%
12
39%
(i) diethyl ether, rt, 6–8 h; (ii) diethyl ether, rt, 48 h; (v) diethyl ether,
reflux, 5 h; (iv) CH2Cl2, 5% aq HCl, rt, 48 h
(i) diethyl ether, rt, 6–8 h; (ii) benzene, aq. HCl, rt, 12 h; (iv) CH2Cl2,
5% aq HCl, rt, 48 h
Scheme 1
Scheme 2
123

Interaction of push–pull tert-enamines
641
O
N
O
N
O
N
O
Me
i
+
3a
O
Me
i
O
+
3a
O
Me
O
Me
O
O
13
R O
O
Me
Me
R
18a: R = Me
18b: R = H
O
17
>95%
ii
19a: R = Me, 78%
19b: R = H, 85%
(i) diisopropylamine, n-BuLi, THF, -78 °C, 30 min
N
Scheme 5
Me
O
O
O
19b (Scheme 5). Hydroxyalkylation products of type 6 were
never observed. Thus, we have shown that phenylglyoxal
reacts with push–pull enamines affording c-functionalized
enamines which could then be cyclized into cyclopentenone
derivatives. The enamines bearing a nitrile or acyl group
react with phenylglyoxal non-selectively affording a com-
plex mixture. Cyclic enamines 7 and 10 were shown to be
stable to hydrolysis.
Me
16
>98%
(i) diisopropylamine, n-BuLi, THF, -78 °C, 10–20 min; (ii)
diisopropylamine, n-BuLi, THF, -78 °C, 30 min (reverse addition of
reagents)
Scheme 3
Thus, it was demonstrated that phenylglyoxal in the
presence of triethylamine in the reaction with push–pull
enamines uniquely behaves as 1,2-biselectrophilic reagent
affording cyclopentanone derivatives.
formation of compound 17. Indeed, changing the order of
addition of the reagents enables isolation of monocyclic
compound 16 in good preparative yield.
Monoelectrophilic derivatives of methylglyoxal dimeth-
ylacetal 18a and butan-2,3-dione 18b behave analogously
with lithiated enamine 14 yielding cyclic products 19a and
Experimental
All solvents were purified and dried by standard methods.
1H NMR spectra were recorded on a Varian VXR-300
spectrometer and 13C NMR spectra were recorded on a
Varian Mercury-400 spectrometer. 1H and 13C NMR
spectra were measured at 300 and 100 MHz, respectively,
with TMS as internal standard. IR spectra of samples as
KBr discs were recorded on a Nexus-470 spectrometer.
Mass spectra were obtained on a MX-1321 instrument (EI
70 eV) by direct inlet or on VG 70-70EQ, VG Analytical
(FAB). Microanalyses were performed in the Microana-
lytical Laboratory of the Institute of Organic Chemistry,
National Academy of Sciences of Ukraine, and their results
agreed favourably with calculated values. Starting enam-
ines were prepared in accordance with Refs. [13] and [14].
O
N
O
O
Me
-
O
N
Me
OEt
Me
O
O
OEt
-
14
15
Me
N
N
O
N
O
+ 14
General procedure for reaction of enamines
with phenylglyoxal
Me
O
O
Me
16
O
O
O
Me
Me
17
To a solution of 0.5 g phenylglyoxal (3.73 mmol) in 5 cm3
dry diethyl ether was added a solution of 3.73 mmol
enamine in 10 cm3 dry diethyl ether. The resulting mixture
Scheme 4
123

642
D. A. Sibgatulin et al.
3
3JHH = 8.1 Hz, CH2), 3.03 (1H, dd, JHH = 16.8 Hz,
was maintained at rt for 6–8 h. The ether was decanted
3JHH = 3.3 Hz, CH2), 3.54 (2H, s, CH3), 4.17 (2H, q,
3JHH = 7.2 Hz, OCH2), 5.48 (1H, dd, JHH = 8.1 Hz,
3JHH = 3.3 Hz, CH), 7.48–7.66 (3H, m, CH), 7.93 (2H, d,
3JHH = 7.2 Hz, CH) ppm; 13C NMR (125 MHz, CDCl3):
d = 14.1, 47.7, 50.1, 61.6, 69.8, 128.7, 129.0, 133.2, 134.2,
166.8, 199.9, 200.3 ppm.
from the precipitate, which was crystallized from n-hexane.
3
Ethyl 5-hydroxy-3-pyrrolidin-1-yl-6-oxo-6-phenylhex-2-
enoate (6a, C18H23NO4)
1
Yellow solid; mp = 85 °C; H NMR (300 MHz, CDCl3):
d = 1.28 (3H, t, 3JHH = 7.2, CH3), 1.88 (4H, br s, CH2), 2.97
(1H, dd, JHH = 11.7 Hz, CH2), 3.26 (4H, m, NCH2), 3.52
2
(1H, m, CH2),4.14(2H, q,3JHH = 7.2 Hz, OCH2),4.6(2H, br
s, CH and OH), 5.39(1H, dd, 3JHH = 11.7 Hz, CH), 7.52(3H,
5-Hydroxy-1,6-diphenyl-3-(pyrrolidin-1-yl)-hex-2-en-1,6-
dione (9a, C22H23NO3)
Colourless solid; mp = 132 °C; 1H NMR (300 MHz,
DMSO-d6): d = 1.88 (4H, br s, CH2), 3.09 (1H, m, CH2),
3.48 and 3.54 (4H, m, NCH2), 3.79 (1H, m, CH2), 5.39 (1H,
m, CH), 5.67 (1H, s, CH), 6.05 (1H, d, 3JHH = 6.9 Hz, OH),
3
m, CH), 8.26 (2H, d, JHH = 7.1 Hz, CH) ppm; 13C NMR
(125 MHz,C6D6):d = 14.8,24.7, 36.1, 48.1,58.5,73.4, 84.9,
128.6, 129.9, 133.6, 134.3, 159.0, 169.7, 201.7 ppm.
Ethyl 5-hydroxy-3-morpholin-4-yl-6-oxo-6-phenylhex-2-
enoate (6b, C18H23NO5)
3
7.44–7.65 (6H, m, CH), 7.86 (2H, d, JHH = 7.1 Hz, CH),
8.14 (2H, d, 3JHH = 7.1 Hz, CH) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 26.7, 51.1, 69.4, 87.1, 126.4, 127.5, 128.4,
129.1, 138.6, 163.4, 197.5, 199.6 ppm; MS (EI 70 eV): m/z
(%) = 349 (11) [M?], 331 (17) [M? - H2O], 244 (16)
[M? - PhCO], 226 (100) [M? - PhCO - H2O], 105 (92)
[PhCO?], 77 (61) [Ph?], 70 (50).
Yellow solid; mp = 95–97 °C; 1H NMR (300 MHz,
3
CDCl3): d = 1.27 (3H, t, JHH = 7.2 Hz, CH3), 2.95
2
3
(1H, dd, JHH = 14.1 Hz, JHH = 9.9 Hz, CH2), 3.24
(4H, m, NCH2), 3.66 (5H, m), 4.14 (2H, q, 3JHH = 7.2 Hz,
3
OCH2), 4.89 (1H, s, CH), 5.35 (1H, dd, JHH = 9.9 Hz,
3JHH = 4.5 Hz, CH), 7.55 (3H, m, CH), 8.21 (2H, d,
3JHH = 7.2 Hz, CH) ppm; 13C NMR (125 MHz, C6D6):
d = 14.6, 37.5, 49.6, 58.7, 66.3, 74.1, 82.1, 128.5, 130.1,
132.5, 133.7, 160.1, 168.6, 200.8 ppm; MS (EI 70 eV): m/z
(%) = 333 (6) [M?], 315 (38), 242 (100), 172 (11), 128
(15), 77 (10).
5-Hydroxy-1,6-diphenyl-3-(4-morpholinyl)hex-2-en-1,6-
dione (9b, C22H23NO4)
1
Colourless solid; mp = 121–123 °C; H NMR (300 MHz,
DMSO-d6): d = 2.81 (1H, m, CH2), 3.26 (5H, m, NCH2
and CH2), 3.71 (4H, m, OCH2), 5.22 (1H, m, CH), 5.53
(1H, s, CH), 7.31–7.52 (6H, m, CH), 7.91 (2H, d,
3JHH = 7.2 Hz, CH), 8.15 (2H, d, JHH = 7.2 Hz, CH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 37.5, 48.6,
66.8, 73.4, 89.5, 127.3, 128.0, 128.5, 130.2, 130.6, 167.4,
197.3, 200.1 ppm.
Ethyl 4-oxo-5-phenyl-2-(pyrrolidin-1-yl)cyclopent-1-
enoate (7, C18H21NO3)
3
The general procedure was applied. The resulting reaction
mixture was maintained at rt for 48 h (or heated under reflux
for 5 h). The ether was decanted from the precipitate, which
was crystallized from n-pentane. Colourless solid;
1
General procedure for synthesis of cyclic compounds 10
mp = 112 °C; H NMR (300 MHz, DMSO-d6): d = 1.33
(3H, t, JHH = 7.5 Hz, CH3), 2.03 (4H, t, JHH = 5.4 Hz,
3
3
To a solution of 2.5 mmol acyclic compound in 10 cm3
benzene was added 0.1 cm3 concentrated HCl and the
mixture was maintained at rt for 12 h. The benzene was
decanted from the precipitated oil, and the oil was dis-
solved in EtOH and maintained at 0 °C for 2 h. The
precipitate formed was collected by filtration.
3
CH2), 3.45 (4H, t, JHH = 5.4 Hz, NCH2), 3.63 and 4.04
2
(1H, 2H, AB-syst., JHH = 3.4 Hz), 4.31 (2 h, q,
3JHH = 7.5 Hz, CH2), 5.05 (1H, s, CH), 7.3 (2H, d,
3
3JHH = 8.9 Hz, CH), 7.38 (1H, d, JHH = 8.9 Hz, CH),
7.45 (2H, t, 3JHH = 8.9 Hz, CH) ppm; 13C NMR (125 MHz,
C6D6): d = 14.2, 25.2, 46.3, 52.3, 54.7, 59.4, 92.3, 126.5,
129.3, 131.5, 167.4, 209.4 ppm; MS (EI 70 eV): m/z
(%) = 299 (37) [M?], 226 (100), 128 (10), 70 (21).
3-Benzoyl-2-phenyl-4-(pyrrolidin-1-yl)cyclopent-3-enone
(10a, C22H21NO2)
Colourless solid; mp = 191 °C; 1H NMR (300 MHz,
Ethyl 5-hydroxy-4,6-dioxo-6-phenylhexanoate
(8, C14H16O5)
3
DMSO-d6): d = 1.82 (4H, t, JHH = 6.6 Hz, CH2), 3.45
3
2
(4H, t, JHH = 6.6 Hz), 3.69 (1H, d, JHH = 3.4 Hz), 4.02
(1H, d, 2JHH = 3.4 Hz), 5.2 (1H, s, CH), 7.18 (2H, m, CH),
7.31–7.45 (5H, m, CH), 7.7–7.81 (3H, m, CH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 25.8, 48.6, 53.1, 57.3,
92.7, 126.7, 127.3, 127.9, 129.8, 137.3, 154.1, 191.4,
208.4 ppm; MS (EI 70 eV): m/z (%) = 331 (46) [M?], 226
(100), 105 (75), 77 (43).
Functionalized enamine 6b (1 g, 3 mmol) was dissolved in
15 cm3 dichloromethane and 15 cm3 5% aq. HCl were
added. The resulting two-phase system was stirred at rt for
48 h. The organic layer was dried over sodium sulfate,
filtered, and evaporated. Light yellow solid; mp = 73 °C;
1H NMR (300 MHz, CDCl3): d = 1.26 (3H, t,
3
3JHH = 7.2 Hz, CH3), 2.86 (1H, dd, JHH = 16.8 Hz,
123

Interaction of push–pull tert-enamines
643
3-Benzoyl-2-phenyl-4-(4-morpholinyl)cyclopent-3-enone
(10b, C22H21NO3)
25.2, 33.7, 47.7, 47.9, 82.0, 83.1, 157.9, 166.9, 211.0 ppm;
MS (EI 70 eV): m/z (%) = 223 (11) [M?], 181 (14), 180
(100), 138 (22), 70 (13), 43 (22).
Colourless solid; mp = 193 °C; 1H NMR (300 MHz,
DMSO-d6): d = 3.21 (4H, m, NCH2), 3.25 and 3.43 (2H,
AB-system, JHH = 13.1 Hz, CH2), 3.63 (4H, m, OCH2),
6-(1,1-Dimethoxyethyl)-5,6-dihydro-6-methyl-4-
2
(1-pyrrolidinyl)-2H-pyran-2-one (19a, C14H23NO4)
The procedure for compound 17 was applied. Colourless
solid (1.3 g, 78%); mp = 93 °C; 1H NMR (300 MHz,
CDCl3): d = 1.41 (3H, s, CH3), 1.43 (3H, s, CH3), 1.98
(4H, br s, CH2), 2.32 and 2.86 (2H, AB-syst.,
2JHH = 16.8 Hz), 3.41 (4H, br s, NCH2), 3.57 (6H, s,
CH3), 4.62 (1H, s, CH) ppm; 13C NMR (125 MHz,
CDCl3): d = 20.7, 21.3, 24.4, 30.4, 46.8, 57.3, 57.9,
81.1, 82.3, 106.7, 159.1, 165.7 ppm.
4.51 (1H, s, CH), 7.18 (5H, m, CH), 7.36 (2H, m, CH), 7.74
(3H, m, CH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 49.1, 50.3, 57.8, 68.2, 93.0, 124.4, 125.1, 125.9, 126.7,
128.7, 135.1, 155.4, 193.4, 208.8 ppm.
2,20-Dimethyl-4,40-dipyrrolidin-1-yl-2,20,3,30-tetrahydro-
6H,60H-2,20-bipyran-6,60-dione (17, C20H28N2O4)
To a solution of 0.55 g diisopropylamine (5.46 mmol) in
15 cm3 THF 2.2 cm3 2.5 M n-BuLi was added at -78 °C.
The reaction mixture was allowed to warm to 0 °C and at
that temperature 1 g 3a (5.46 mmol) was added. The
reaction mixture was stirred for 10 min at -78 °C and then
0.47 g 13 (5.46 mmol) in 5 cm3 THF was added. The
reaction mixture was allowed to reach room temperature
and was poured into 50 cm3 water and extracted with
3 9 20 cm3 EtOAc. The organic layer was dried and
evaporated in vacuo. The residue was crystallized from
ether to give 17 as a colourless solid (1.86 g, 95%).
Mp [ 250 °C; 1H NMR (500 MHz, CDCl3): d = 1.53 and
1.54 (6H, br s, CH3), 1.98 (8H, br s, CH2), 2.47 and 2.88
6-(Dimethoxymethyl)-6-methyl-4-pyrrolidin-1-yl-5,6-
dihydro-2H-pyran-2-one (19b, C13H21NO4)
The procedure for compound 17 was applied. Colourless
solid (1.17 g, 85%); mp = 84–86 °C; 1H NMR (300 MHz,
CDCl3): d = 1.41 (3H, s, CH3), 1.98 (4H, br s, CH2), 2.30
2
and 2.88 (2H, AB-syst., JHH = 16.8 Hz), 3.22 and 3.41
(4H, br s, NCH2), 3.54 (3H, s, CH3), 3.57 (3H, s, CH3),
4.25 (1H, s, CH), 4.59 (1H, s, CH) ppm; 13C NMR
(125 MHz, CDCl3): d = 20.9, 24.8, 30.1, 47.7, 57.8, 58.3,
80.7, 82.0, 108.7, 157.1, 166.7 ppm; MS (EI 70 eV): m/z
(%) = 255 (4) [M?], 194 (7), 181 (13), 180 (100), 138
(12), 75 (42), 70 (7).
2
(2H, AB-syst., JHH = 17 Hz), 2.59 and 2.89 (2H, AB-
syst., 2JHH = 17 Hz), 3.17 and 3.25 (4H, br s, NCH2), 3.42
(4H, br s, NCH2), 4.59 (2H, s, CH) ppm; 13C NMR
(125 MHz, CDCl3): d = 20.0 and 20.3, 24.7 and 25.3, 31.5
and 31.7, 47.9 and 48.2, 81.2 and 81.3, 81.5 and 81.6, 157.3
and 157.6, 166.5 ppm; MS (EI 70 eV): m/z (%) = 360 (12)
[M?], 181 (17), 180 (100), 136 (14), 110 (7), 70 (14), 44
(174), 43 (14).
References
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(2004) Synthesis 15:2545
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Kuklya AS, Vovk MV (2004) Synthesis 13:2196
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(2005) Tetrahedron 61:2839
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6-Acetyl-6-methyl-4-pyrrolidin-1-yl-5,6-dihydro-2H-
pyran-2-one (16, C12H17NO3)
To a solution of 0.55 g diisopropylamine (5.46 mmol) in
15 cm3 THF 2.2 cm3 2.5 M n-BuLi was added at -78 °C.
The reaction mixture was allowed to warm to 0 °C and at
that temperature 1 g 3a (5.46 mmol) was added. The
reaction mixture was cooled to -78 °C and added drop-
wise to a solution of 0.47 g 13 (5.46 mmol) via Chem-Flex
needle (system for safe transfer of air- and moisture-
sensitive liquids). The reaction mixture was stirred for
10 min, and then poured into 50 cm3 water and extracted
with 3 9 20 cm3 EtOAc. The organic layer was dried and
evaporated in vacuo. The residue was crystallized from
ether to give 16 as a colourless solid (1.19 g, 98%);
10. Agami C, Beauseigneur A, Comesse S, Dechoux L (2003) Tet-
rahedron Lett 44:7667
11. Nicolaou KC, Sorensen EJ (1996) Classics in Total Synthesis,
edn. Wiley, Weinheim, p 137
¨
12. Steglich W, Fugmann B, Fugmann SL (2001) Rompp Encyclo-
1
mp = 87–89 °C; H NMR (300 MHz, CDCl3): d = 1.47
(3H, s, CH3), 1.97 (4H, br s, CH2), 2.29 (3H, s, CH3), 2.46
pedia of Natural Products, edn. Thieme, Stuttgart, p 237
13. Hickmott PW, Sheppard GJ (1971) Chem Soc C 1358
14. Dedina J, Kuthan J, Palecek J, Schraml J (1975) Collect Czech
Chem Commun 40:3476
2
and 3.19 (2H, AB-syst., JHH = 15.9 Hz), 3.12 (2H, br s,
NCH–), 3.41–3.52 (2H, br m, NCH2), 4.52 (1H, s, CH)
ppm; 13C NMR (125 MHz, CDCl3): d = 24.0, 24.7, 25.1,
123