Synthesis of 2-(3-hydroxy-2-methyl-1-alkenyl)-1-pyrrolines and 2-(3-hydroxybutyl)-1-pyrroline using α-lithiated 2-methyl-1-pyrroline

Article abstract of DOI:10.1016/j.tet.2009.02.050

Condensation of 2-methyl-1-pyrroline with chloroacetone or 3-chloro-2-butanone using LDA in THF afforded novel 2-(3-hydroxy-2-methyl-1-alkenyl)-1-pyrrolines via a peculiar reaction mechanism instead of the anticipated 2-(3-oxobutyl)-1-pyrrolines. The inte

Full text of DOI:10.1016/j.tet.2009.02.050

Tetrahedron 65 (2009) 3753–3756
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Synthesis of 2-(3-hydroxy-2-methyl-1-alkenyl)-1-pyrrolines and
2-(3-hydroxybutyl)-1-pyrroline using
a-lithiated 2-methyl-1-pyrroline
y
*
Matthias D’hooghe, Kourosch Abbaspour Tehrani , Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 January 2009
Received in revised form 5 February 2009
Accepted 16 February 2009
Available online 26 February 2009
Condensation of 2-methyl-1-pyrroline with chloroacetone or 3-chloro-2-butanone using LDA in THF
afforded novel 2-(3-hydroxy-2-methyl-1-alkenyl)-1-pyrrolines via a peculiar reaction mechanism in-
stead of the anticipated 2-(3-oxobutyl)-1-pyrrolines. The intermediacy of 2-(2,3-epoxy-2-methylalkyl)-
1-pyrrolines in the latter transformation was demonstrated by immediate reductive epoxide ring
opening utilizing lithium aluminium hydride in diethyl ether. Furthermore, 2-(3-oxobutyl)-1-pyrroline
was prepared via an alternative approach through alkylation of 2-methyl-1-pyrroline with 3-chloro-2-
(methoxymethyloxy)-1-propene using LDA in THF, followed by acid hydrolysis. Reduction of 2-(3-oxo
butyl)-1-pyrroline by sodium borohydride in methanol afforded the corresponding 2-(3-hydroxybutyl)-
1-pyrroline in good yield.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
azaheterocyclic systems.8,9 If, however, the synthesis of 2-(3-
hydroxyalkyl)-1-pyrrolines is contemplated, other approaches are
For many years, the pyrrolidine scaffold has attracted both
synthetic and medicinal chemists due to its wide applicability,
resulting in the synthesis of a large variety of bioactive pyrrolidine
derivatives.1 On the other hand, the closely related 1-pyrroline
motif has received considerably less attention in the literature.
Whereas, for example, the class of 2-(hydroxyalkyl)pyrrolidines has
been evaluated rather extensively,2 only few reports are available
regarding the synthesis and utility of 2-(hydroxyalkyl)-1-pyrro-
lines. In that respect, 2-(2-carbamoyl-2-hydroxyethyl)-1-pyrrolines
have been reported as potential bactericides,3 2-(3-hydroxyalkyl)-
1-pyrrolines have been applied as synthons for the preparation of
pyrrolizidine derivatives4 and 2-(4-hydroxyalkyl)-1-pyrrolines
have been used as precursors for the synthesis of (ꢀ)-slaframine,5
(ꢀ)-swainsonine6 and (þ)-cylindricine C.7
required such as the condensation of 2-methoxy-1-pyrrolines with
acetylbutyrolactones, followed by acid hydrolysis,4 or addition re-
actions to 1-pyrrolinium salts.10 To date, no examples are known
regarding the synthesis of 2-(3-hydroxyalkyl)-1-pyrrolines starting
from 2-methyl-1-pyrroline.
In the present report, the utility of 2-methyl-1-pyrroline as
a substrate for the synthesis of functionalized pyrrolines and pyr-
rolidines bearing an oxygenated side-chain at the 2-position will be
discussed. For this purpose, a-lithiated 2-methyl-1-pyrroline was
quenched with electrophiles in which both a chloroalkane moiety
and either a carbonyl or a masked carbonyl group is present,
leading to two different classes of compounds via different reaction
mechanisms.
From a synthetic point of view, 2-(2-hydroxyalkyl)-1-pyrrolines
2. Results and discussion
can be easily obtained via the addition of a-lithiated 2-methyl-1-
pyrroline onto carbonyl compounds, which has been demonstrated
by the synthesis of a range of representatives.8 Indeed, function-
alization of 2-methyl-1-pyrroline via nucleophilic substitution or
addition reactions of the corresponding 1-azaallylic anion consti-
tutes a useful methodology for the preparation of a variety of
1-Azaallylic anions comprise an extremely useful class of re-
active synthons for further elaboration due to their ability to form
new carbon–carbon bonds with minimal side reactions.11 Although
little information can be found regarding the reactivity of 1-
azaallylic anions towards
synthesis of pyrroles has been described in this way utilizing N-
(ethylidene)amines and
-haloketones.12 The underlying mecha-
nism has been explained as an SN2 reaction of the -metalated
a-halogenated carbonyl compounds, the
a
a
* Corresponding author. Tel.: þ32 92645951; fax: þ32 92646243.
E-mail address: norbert.dekimpe@UGent.be (N. De Kimpe).
imine with the halomethyl derivative, followed by cyclization of the
enamine form and elimination of water. The reaction of the aza-
enolate derived from N-(isopropylidene)cyclohexylamine with
chloroacetone also resulted in a pyrrole derivative, although in this
y
Present address: Vrije Universiteit Brussel, Faculty of Sciences, Department of
Applied Biological Sciences and Engineering, Laboratory for Organic Chemistry,
Pleinlaan 2 (WE-ORGC), B-1050 Brussel, Belgium.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.050

3754
M. D’hooghe et al. / Tetrahedron 65 (2009) 3753–3756
O
R
1) 1.2 equiv LDA
1) LDA
X
N
N
N
THF, -78 °C, 2 h
OH
O
2)
O
2) 1.1 equiv
R
R
Cl
R
Cl
3
1
2a (R = H, 62%, E/Z : 9/1)
2b (R = Me, 92%, E/Z : 9/1)
THF, -78 °C to r.t.
11-14 h
Scheme 1.
case an initial nucleophilic addition across the carbonyl was ob-
served.12 As this methodology has not been applied before on cyclic
imines, 2-methyl-1-pyrroline 1 was evaluated as a synthon for the
preparation of bicyclic systems such as pyrrolizine derivatives upon
The ring opening of epoxides 5 can be explained considering
their imine (5)denamine (6) tautomerism, furnishing 2-(3-hy-
droxy-2-methyl-1-alkenyl)-1-pyrrolines 2 as the final products.
The E-isomer E-2a could be obtained in pure form via re-
crystallization from diethyl ether, allowing the performance of
NOE-experiments in order to establish its relative stereochemistry
(Scheme 2). Spontaneous isomerization of E-2a to a 1/1 mixture of
E/Z-isomers was observed upon standing at room temperature.
The intermediacy of the reactive epoxides 5 in this peculiar
transformation was further substantiated by adding 2 equiv of
lithium aluminium hydride to the reaction mixture obtained after
treatment of 2-methyl-1-pyrroline (1) with LDA and chloroacetone,
resulting in 2-(2-hydroxy-2-methylpropyl)pyrrolidine (7) via re-
duction of the imino moiety and hydride-induced ring opening at
the unsubstituted epoxide carbon atom in oxirane 5a (Scheme 3). It
is worth mentioning that the 2-(2-hydroxyalkyl)pyrrolidine motif
is present in several naturally occurring compounds such as the
alkaloids (pseudo-)hygroline13 and dihydrocuscohygrine.14 Re-
cently, 1-aryl-2-(2-hydroxyethyl)pyrrolidines have also been de-
scribed as oxidative hair dyes.15
consecutive treatment with a strong base and a a-haloketone. Thus,
the 1-azaallylic anion derived from 2-methyl-1-pyrroline (1) by the
treatment with 1.2 equiv of lithium diisopropylamide (LDA) in THF
was quenched with 1.1 equiv of chloroacetone or 3-chloro-2-
butanone, affordingdquite surprisinglyd2-(3-hydroxy-2-methyl-
1-alkenyl)-1-pyrrolines 2a,b as 9/1 mixtures of E/Z-isomers after
11–14 h reaction at room temperature (Scheme 1). 1H NMR analysis
of the reaction mixture obtained immediately after workup (for
R¼H) suggested the formation of an epoxide, which easily rear-
ranged into 1-pyrroline 2a upon standing at room temperature for
11–14 h.
The unexpected molecular structure of pyrrolines 2 was con-
firmed by detailed spectroscopic analysis, pointing to a peculiar
reaction mechanism. According to the previously reported re-
activity of acyclic lithiated imines and
of 2-methyl-1-pyrroline with -chloroketones was expected to
a
-haloketones,12 alkylation
a
afford 2-(3-oxobutyl)-1-pyrrolines 3 (Scheme 1). Instead, nucleo-
philic addition of the 1-azaallylic anion derived from 2-methyl-1-
Based on the above-described findings, the straightforward
synthesis of 2-(3-oxobutyl)-1-pyrroline (3a) (Scheme 1, R¼H)
pyrroline across the carbonyl moiety in
a
-chloroketones results in
through
a-alkylation of 2-methyl-1-pyrroline with chloro-
adducts 4, followed by epoxide formation through nucleophilic
displacement of chloride by the in situ formed alkoxide anion
(Scheme 2). Direct nucleophilic substitution of lithiated 2-methyl-
1-pyrroline at the chlorinated carbon atom of chloroacetone,
followed by enolization and migration of the double bond into
conjugation with the imine would lead to 2-(3-hydroxy-1-
butenyl)-1-pyrroline, which was never observed under the reaction
conditions. This fact, in combination with the intermediacy of
epoxides 5, excludes this alternative mechanism.
propanone cannot be realized, meaning that other approaches
should be devised. Due to the peculiar reactivity of the azaallylic
anion derived from 2-methyl-1-pyrroline towards
2-methyl-1-pyrroline (1) was treated with 3-chloro-2-(methoxy-
methyloxy)-1-propene as a masked -chloroketone under similar
a-chloroketones,
a
reaction conditions. The latter electrophile was easily prepared
from 1,3-dichloro-2-(methoxymethyloxy)propane through a de-
hydrochlorination process.16
Thus, treatment of 2-methyl-1-pyrroline (1) with 1.1 equiv of
LDA and 1.2 equiv of 3-chloro-2-(methoxymethyloxy)-1-propene
in THF afforded the corresponding alkylated pyrroline 8 in 82%
yield after 15 h at room temperature. Subsequent hydrolysis of the
acetal moiety in the latter pyrroline 8 by means of 7 equiv of an
aqueous solution of hydrochloric acid (0.5 M) yielded the desired
Cl
R
N
N
N
LDA
O
R
O
O
g-iminoketone 3a after reflux for 4 h in a dichloromethane/water
R
1
4
5
solvent system (Scheme 4). Consequently, the use of 3-chloro-2-
(methoxymethoxy)-1-propene provides a convenient alternative
for the hypothetical alkylation of 2-methyl-1-pyrroline by means of
chloroacetone.
Finally, ketone 3a was reduced towards the corresponding al-
cohol upon careful treatment with 0.375 molar equivalents of so-
dium borohydride (i.e., 1.5 equiv of hydride) in methanol, affording
2-(3-hydroxybutyl)-1-pyrroline 94b after 4.5 h at 45–50 ꢁC (Scheme
4). It should be noted that the scale had to be limited to 0.5 mmol
and the reaction temperature had to be controlled carefully
Cl
3.8 %nOe
R
R
H
N
N
N
OH
0.4 %nOe
OH
O
E-2a
2
6
Scheme 2.
H
1) 1.2 equiv LDA
THF, -78 °C, 2 h
N
N
N
2 equiv LiAlH4
Et2O, r.t., 14 h
O
O
OH
2) 1.1 equiv
Cl
1
5a
7 (74%)
THF, -78 °C to r.t.
11-14 h
Scheme 3.

M. D’hooghe et al. / Tetrahedron 65 (2009) 3753–3756
3755
1) 1.1 equiv LDA
THF, -78 °C, 2 h
butanone, no intermediate epoxide 5b could be isolated). The
resulting crude compound was left at room temperature for 11–
14 h, affording 2-(3-hydroxy-2-methyl-1-alkenyl)-1-pyrroline 2 as
a mixture of the E- and Z-isomer (E/Z:9/1).
N
N
O
OMe
2) 1.2 equiv
Cl
THF
O
OMe
1
8 (82%)
-78 °C to r.t., 15 h
7 equiv HCl (0.5 M)
CH2Cl2, Δ, 4 h
3.2.1. E-2-(3-Hydroxy-2-methyl-1-propenyl)-1-pyrroline E-2a
Recrystallized from diethyl ether. White crystals. Yield after
OH
O
recrystallization: 40%. Mp 97 ꢁC. 1H NMR (270 MHz, CDCl3):
d 1.90
N
N
0.375 equiv NaBH4
(3H, s), 1.90 (2H, quint, J¼7.8 Hz), 2.71 (2H, t, J¼8.1 Hz), 3.83 (2H, t,
MeOH, 45-50 °C, 4.5 h
J¼7.3 Hz), 4.03 (2H, s), 6.06 (1H, br s), 6.40 (1H, s). 13C NMR
9 (56%)
3a (67%)
(68 MHz, CDCl3):
d 15.9 (CH3), 22.8 (CH2), 38.1 (CH2), 59.6 (CH2),
66.8 (CH2), 118.5 (CH), 148.0 (C), 174.2 (C). IR (NaCl, cmꢀ1):
nC]N¼1659, nOH¼3400–2400. MS (70 eV): m/z (%): 139 (Mþ, 91),
138 (13), 122 (10), 120 (20), 111 (12), 110 (26), 109 (11), 108 (100), 83
(11), 82 (19), 80 (38), 68 (10), 53 (13). Anal. Calcd for C8H13NO: C,
69.03; H, 9.41; N, 10.06. Found: C, 69.19; H, 9.62; N, 9.93.
Scheme 4.
(45–50 ꢁC) in order to achieve a selective reduction of
tone 3a into -hydroxyimine 9.
g-iminoke-
g
In conclusion, the synthesis of 2-(3-hydroxy-2-methyl-1-
alkenyl)-1-pyrrolines through condensation of 2-methyl-1-pyrro-
line with chloroacetone or 3-chloro-2-butanone using LDA in THF
via a new and peculiar reaction mechanism has been described. The
intermediacy of 2-(2,3-epoxy-2-methylalkyl)-1-pyrrolines in the
latter transformation was demonstrated by immediate reductive
epoxide ring opening utilizing lithium aluminium hydride in
diethyl ether. As a convenient alternative for the preparation of the
anticipated 2-(3-oxobutyl)-1-pyrrolines, the alkylation of 2-
methyl-1-pyrroline with 3-chloro-2-(methoxymethyloxy)-1-pro-
pene using LDA in THF, followed by acid hydrolysis, has been shown
to afford 2-(3-oxobutyl)-1-pyrroline, which was subsequently re-
duced by sodium borohydride in methanol towards the corre-
sponding 2-(3-hydroxybutyl)-1-pyrroline.
In the NMR spectra of the reaction mixture the following signals
for the Z-isomer Z-2a could be distinguished. 1H NMR (270 MHz,
CDCl3):
d
2.59 (2H, t, J¼7.9 Hz), 3.96 (2H, t, J¼6.9 Hz), 5.98 (1H, s).
22.3 (CH3), 24.7 (CH2), 38.6 (CH2), 60.7
13C NMR (68 MHz, CDCl3):
d
(CH2), 63.2 (CH2), 120.7 (CH), 151.6 (C), 173.2 (C).
3.2.2. E-2-(3-Hydroxy-2-methyl-1-butenyl)-1-pyrroline E-2b
Crude yield: 92%. 1H NMR (270 MHz, CDCl3):
d 1.30 (3H, d,
J¼6.3 Hz), 1.89 (2H, quint, J¼7.8 Hz), 1.97 (3H, s), 2.68 (2H, t,
J¼8.2 Hz), 3.87 (2H, t, J¼7.3 Hz), 4.26 (1H, q, J¼6.5 Hz), 6.29 (1H, s).
13C NMR (68 MHz, CDCl3):
d 14.7 (CH3), 21.8 (CH3), 22.8 (CH2), 38.4
(CH2), 60.0 (CH2), 72.5 (CH), 119.1 (CH), 151.3 (C), 173.9 (C). IR (NaCl,
cmꢀ1): nC]N¼1670, nOH¼3350–2480. MS (70 eV): m/z (%): 153 (Mþ,
75), 152 (12), 134 (23), 125 (11), 108 (100), 68 (12), 53 (15).
3. Experimental part
3.1. General
3.2.3. 2-(2,3-Epoxy-2-methylpropyl)-1-pyrroline 5a
1H NMR (270 MHz, CDCl3):
d 1.35 (3H, s), 1.89 (2H, quint,
J¼7.1 Hz), 2.47–2.71 (6H, m), 3.81–3.86 (2H, m). 13C NMR (68 MHz,
CDCl3):
d 21.2 (CH3), 22.6 (CH2), 38.2 (CH2), 41.4 (CH2), 53.6 (CH2),
1H NMR spectra were recorded at 270 MHz (JEOL JNM-EX 270)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 68 MHz (JEOL JNM-EX 270) with
CDCl3 as solvent. Mass spectra were obtained with a mass spectro
meter (VARIAN MAT 112, 70 eV) using a GC–MS coupling (RSL 200,
20 m glass capillary column, i.d. 0.53 mm, He carrier gas). IR spectra
were measured with a Perkin Elmer 1310 spectrophotometer or
a Spectrum One FT-IR. Elemental analyses were performed with
a PerkinElmer Series II CHNS/O Analyzer 2400. Dichloromethane
was dried over calcium hydride, while diethyl ether and THF were
dried by distillation over sodium benzophenone ketyl. Other sol-
vents were used as received from the supplier.
55.3 (C), 60.9 (CH2), 174.2 (C). IR (NaCl, cmꢀ1): nC]N¼1637.
3.2.4. 2-(2-Hydroxy-2-methylpropyl)pyrrolidine 7
The crude 2-(2,3-epoxy-2-methylpropyl)-1-pyrroline (5a)
(7.2 mmol) was dissolved in dry diethyl ether (15 mL), followed by
the addition of lithium aluminium hydride (14.4 mmol) at room
temperature. The resulting suspension was stirred for 14 h at room
temperature. Afterwards, water (2 mL) was added at 0 ꢁC in order
to neutralize the excess of LiAlH4. The mixture was stirred for
10 min, after which the grey suspension was filtered over K2CO3
and Celite. The filter cake was then washed thoroughly with dry
diethyl ether (3ꢂ20 mL). Removal of the solvent in vacuo afforded
2-(2-hydroxy-2-methylpropyl)pyrrolidine (7), which was purified
by distillation (bp 106–110 ꢁC/13 mmHg).
3.2. Synthesis of 2-(3-hydroxy-2-methyl-1-alkenyl)-1-
pyrrolines 2
Colourlessliquid. Crudeyield: 74%. Yield afterdistillation: 39%.1H
NMR (270 MHz, CDCl3):
d 1.18 (3H, s), 1.26 (3H, s), 1.28–1.96 (4H, m),
General procedure: to a solution of diisopropylamine (24 mmol)
in dry THF (20 mL) at 0 ꢁC was added slowly via a septum
n-butyllithium (24 mmol, 2.5 M in hexane) under nitrogen atmo-
sphere. After 5 min, the solution was cooled to ꢀ78 ꢁC and
2-methyl-1-pyrroline 1 (20 mmol), dissolved in dry THF (20 mL),
was added dropwise. The reaction mixture was then stirred for 2 h
2.78–2.99 (2H, m), 3.49–3.60 (1H, m). 13C NMR (68 MHz, CDCl3):
d
25.8 (CH2), 28.2 (CH3), 31.7 (CH3), 32.9 (CH2), 45.8 (2ꢂCH2), 55.9
(CH), 70.3 (C). IR (NaCl, cmꢀ1): nOH,NH¼3560–3020. MS (70 eV): m/z
(%): 143 (Mþ, 2), 71 (13), 70 (100), 56 (11). HRMS: calcd for C8H18NO
[MþH]þ 144.13883, found 144.13894.
at ꢀ78 ꢁC. Finally, a solution of
a-chloroketone (22 mmol) in dry
3.2.5. 2-(3-Oxobutyl)-1-pyrroline 3a
THF (20 mL) was added slowly, after which the reaction mixture
was stirred for 14 h at room temperature. Workup was carried out
by pouring the reaction mixture in an aqueous sodium hydroxide
solution (75 mL, 0.5 M), followed by extraction with diethyl ether
(2ꢂ75 mL, 1ꢂ50 mL). Drying of the organic phase with K2CO3, fil-
tration of the drying agent and removal of the solvent in vacuo
afforded intermediate 2-(2,3-epoxy-2-methylalkyl)-1-pyrroline 5
(after alkylation of 2-methyl-1-pyrroline with 3-chloro-2-
To a solution of diisopropylamine (22 mmol) in dry THF (20 mL) at
0 ꢁC was added slowly via a septum n-butyllithium (22 mmol, 2.5 M in
hexane) under nitrogen atmosphere. After 5 min, the solution was
cooled to ꢀ78 ꢁC and 2-methyl-1-pyrroline 1 (20 mmol), dissolved in
dry THF (20 mL), was added dropwise. The reaction mixture was then
stirred for 2 h at ꢀ78 ꢁC. Finally, a solution of 3-chloro-2-(methoxy-
methyloxy)-1-propene16 (24 mmol) in dry THF (20 mL) was added
slowly, after which the reaction mixture was stirred for 15 h at room

3756
M. D’hooghe et al. / Tetrahedron 65 (2009) 3753–3756
temperature. Workup was carried out by pouring the reaction mixture
in an aqueous sodium hydroxide solution (75 mL, 0.5 M), followed by
extraction with diethyl ether (2ꢂ75 mL, 1ꢂ50 mL). Drying of the or-
ganic phase with K2CO3, filtration of the drying agent and removal of
the solvent in vacuo afforded 2-[3-(methoxymethyloxy)-3-butenyl]-1-
pyrroline (8). The latter pyrroline 8 (1.4 mmol) was dissolved in
dichloromethane (10 mL), followed by the addition of an aqueous so-
lution of hydrogen chloride (10 mmol, 0.5 M). After reflux for 4 h under
vigorous stirring, the reaction mixture was extracted with dichloro-
methane (3ꢂ20 mL). Drying (K2CO3), filtration of the drying agent and
removal of the solvent in vacuo afforded 2-(3-oxobutyl)-1-pyrroline
(3a), which was purified by distillation (bp 26 ꢁC/0.04 mmHg). The
neat compound appeared to be unstable upon prolonged preservation.
Colourless liquid. Yield after distillation: 67%. 1H NMR (270 MHz,
References and notes
1. For recent reviews, see: (a) Huang, P. Q. Synlett 2006, 1133; (b) Bellina, F.;
Rossi, R. Tetrahedron 2006, 62, 7213; (c) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. Rev. 2006, 106, 4484; (d) Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36,
1142; (e) Cheng, X. C.; Wang, Q.; Fang, H.; Xu, W. F. Curr. Med. Chem. 2008, 15,
374.
2. For a few recent examples, see: (a) Torres-Sanchez, M. I.; Borrachero, P.;
Cabrera-Escribano, F.; Gomez-Guillen, M.; Angulo-Alvarez, M.; Alvarez,
E.; Favre, S.; Vogel, P. Tetrahedron: Asymmetry 2007, 18, 1809; (b) Peng, J.;
Clive, D. L. J. Org. Lett. 2007, 9, 2939; (c) Behr, J.-B.; Gainvors-Claisse, A.;
Belarbi, A. Nat. Prod. Res., Part A 2007, 21, 76; (d) Behr, J.-B.; Gainvors-
Claisse, A.; Belarbi, A. Nat. Prod. Res., Part B 2006, 20, 1308.
3. Du¨rckheimer, W.; Martin, W.; Schrinner, E. Ger. Offen., 1974, DE 2319019; Chem.
Abstr. 1975, 82, 43170.
4. (a) Provot, O.; Celerier, J.-P.; Petit, H.; Lhommet, G. J. Org. Chem. 1992, 57, 2163;
(b) Provot, O.; Celerier, J.-P.; Lhommet, G. J. Heterocycl. Chem. 1998, 35, 371.
5. Choi, J. R.; Han, S.; Cha, J. K. Tetrahedron Lett. 1991, 32, 6469.
6. Cha, J. K.; Bennett, R. B., III. U.S. Patent 5,187,279 A; Chem. Abstr. 1993, 118,
255177.
7. Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2004, 45, 5921.
8. (a) Dannhardt, G.; Obergrusberger, R. Arch. Pharm. 1979, 312, 498; (b) Dann-
hardt, G.; Obergrusberger, R. Arch. Pharm. 1979, 312, 896; (c) Bo¨hme, R.; Rot-
scheidt, K.; Breitmaier, E. Synthesis 1989, 109; (d) Schuster, E.; Hesse, C.;
Schumann, D. Synlett 1991, 916.
9. (a) Dannhardt, G.; Lehr, M.; Steindl, L. Chem. Ztg. 1986, 110, 267; (b) Dannhardt,
G.; Meindl, W.; Gussmann, S.; Ajili, S.; Kappe, T. Eur. J. Med. Chem. 1987, 22, 505;
(c) Tirel, P. J.; Vaultier, M.; Carrie, R. Tetrahedron Lett. 1989, 30, 1947; (d) Hua, D.
H.; Bharathi, S. N.; Robinson, P. D.; Tsujimoto, A. J. Org. Chem. 1990, 55, 2128; (e)
Barluenga, J.; Tomas, M.; Kouznetsov, V.; Rubio, E. J. Chem. Soc., Chem. Commun.
1992, 1419; (f) Bartoli, G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. Tetrahedron
1995, 51, 8613; (g) Dannhardt, G.; Bauer, A.; Nowe, U. J. Prakt. Chem. 1998, 340,
256; (h) Fustero, S.; de la Torre, M. G.; Jofre, V.; Carlon, R. P.; Navarro, A.;
Fuentes, A. S.; Carrio, J. S. J. Org. Chem. 1998, 63, 8825; (i) Fustero, S.; de la Torre,
M. G.; Pina, B.; Fuentes, A. S. J. Org. Chem. 1999, 64, 5551; (j) Abbaspour Tehrani,
K.; D’hooghe, M.; De Kimpe, N. Tetrahedron 2003, 59, 3099; (k) Park, K.-H.;
Marshall, W. J. J. Org. Chem. 2005, 70, 2075; (l) Fustero, S.; Piera, J.; Sanz-Cer-
vera, J. F.; Roman, R.; Brodsky, B. H.; Sanchez-Rosello, M.; Acena, J. L.; Ramirez
de Arellano, C. Tetrahedron 2006, 62, 1444; (m) Movassaghi, M.; Chen, B. Angew.
Chem., Int. Ed. 2007, 46, 565.
CDCl3):
d
1.86 (2H, quint, J¼7.8 Hz), 2.19 (3H, s), 2.43–2.59 (4H, m),
2.85 (2H, t, J¼6.9 Hz), 3.72–3.82 (2H, m). 13C NMR (68 MHz, CDCl3):
d
22.5 (CH2), 26.9 (CH2), 30.1 (CH3), 38.0 (CH2), 39.5 (CH2), 60.7 (CH2),
176.8 (C), 208.0 (C). IR (NaCl, cmꢀ1): nC]N¼1642, nC]O¼1715. MS
(70 eV): m/z (%): 139 (Mþ, 8), 124 (69), 121 (15), 120 (21), 97 (34), 96
(100), 84 (12), 82 (21), 80 (13), 69 (14), 68 (34). Anal. Calcd for
C8H13NO: C, 69.03; H, 9.41; N,10.06. Found: C, 69.26; H, 9.68; N, 9.95.
3.2.6. 2-(3-Hydroxybutyl)-1-pyrroline 9
To a solution of 2-(3-oxobutyl)-1-pyrroline (3a) (0.5 mmol) in
dry methanol (1 mL) was added sodium borohydride (0.19 mmol).
The resulting suspension was stirred for 4.5 h at 45–50 ꢁC. After-
wards, the reaction mixture was poured into an aqueous solution of
sodium hydroxide (10 mL, 0.5 M) and extracted with dichloro-
methane (3ꢂ10 mL). Drying (K2CO3), filtration of the drying agent
and removal of the solvent in vacuo afforded 2-(3-hydroxybutyl)-1-
pyrroline (9) (purity >95% by GC).
Light-yellow oil. Yield: 56%.1H NMR (270 MHz, CDCl3):
d 1.19 (3H,
10. (a) Stavinoha, J.; Bay, E.; Leone, A.; Mariano, P. S. Tetrahedron Lett. 1980,
21, 3455; (b) Mariano, P. S.; Stavinoha, J.; Bay, E. Tetrahedron 1981, 37,
3385.
11. Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004, 104, 2353.
12. Wittig, G.; Ro¨derer, R.; Fischer, S. Tetrahedron Lett. 1973, 14, 3517.
d, J¼5.9 Hz), 1.78 (2H, wq, J¼6.3 Hz), 1.82–1.96 (2H, m), 2.41–2.55
(4H, m), 3.73–3.87 (3H, m), 5.30 (1H, s). 13C NMR (68 MHz, CDCl3):
d
22.5 (CH2), 23.7 (CH3), 30.8 (CH2), 34.9 (CH2), 38.0 (CH2), 60.3 (CH2),
ˇ
13. (a) Munoz, O.; Piovano, M.; Garbarino, J.; Hellwing, V.; Breitmaier, E. Phyto-
67.4 (CH), 179.6 (C). IR (NaCl, cmꢀ1): nC]N¼1644, nOH¼3275. MS
(70 eV): m/z (%): no Mþ; 140 (Mþꢀ1, 3), 126 (25), 124 (10), 108 (12),
98 (11), 97 (33), 96 (65), 83 (100), 82 (33), 71 (10), 55 (17).
chemistry 1996, 43, 709; (b) Kim, J. H.; t’Hart, H.; Stevens, J. F. Phytochemistry
1996, 41, 1319; (c) Schneider, M. J.; Brendze, S.; Montali, J. A. Phytochemistry
1995, 39, 1387; (d) Gambaro, V.; Labbr, C.; Castillo, M. Phytochemistry 1983, 22,
1838; (e) San Martin, A.; Rovirosa, J.; Gambaro, V.; Castillo, M. Phytochemistry
1980, 19, 2007.
Acknowledgements
14. Christen, P.; Roberts, M. F.; Phillipson, J. D.; Evans, W. C. Phytochemistry 1995,
38, 1053.
15. Chassot, L.; Braun, H.-J. Eur. Pat. Appl., 2007, EP 1752192 A1; Chem. Abstr. 2007,
146, 235426.
16. Gu, X. P.; Nishida, N.; Ikeda, I.; Okahara, M. J. Org. Chem. 1987, 52,
3192.
The authors are indebted to the ‘Fund for Scientific
ResearchdFlanders (Belgium)’ (FWO-Vlaanderen) and to Ghent
University (GOA) for financial support.