Synthesis of 1,2,3-trisubstituted pyrrolidines and 2,3-disubstituted tetrahydrofurans via diastereoselective reductive cyclization of γ-chloroimines and γ-chloroketones

Article abstract of DOI:10.1055/s-0031-1289544

A new diastereoselective synthetic approach towards 1,2,3-trisubstituted pyrrolidines and 2,3-disubstituted tetrahydrofurans is described. The synthesis of the pyrrolidines involves reductive cyclization of -chloroketimines, which were generated in situ from the reaction of 3-substituted 5-chloro-2-pentanones and a primary amine. Various reduction conditions were explored to induce a diastereoselective reductive cyclization. 2,3-Disubstituted tetrahydrofurans were obtained by the direct reduction of 3-substituted 5-chloro-2-pentanones with sodium borohydride. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289544

2852
LETTER
Synthesis of 1,2,3-Trisubstituted Pyrrolidines and 2,3-Disubstituted
Tetrahydrofurans via Diastereoselective Reductive Cyclization of
g-Chloroimines and g-Chloroketones
1, 2,3-Trisubstituted
Py
u
rrolidine
s
an
d
d
2,3-Disubs
i
tituted
g
T
etrahydrof
a
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646221; E-mail: norbert.dekimpe@ugent.be
Received 16 August 2011
cyclizations of g-amino- and g-hydroxyketones, olefin
metathesis reactions, and intramolecular cyclizations by
SN2 nucleophilic substitution.15,16 The latter method main-
ly involves the stereospecific intramolecular SN2 cycliza-
Abstract: A new diastereoselective synthetic approach towards
1,2,3-trisubstituted pyrrolidines and 2,3-disubstituted tetrahydro-
furans is described. The synthesis of the pyrrolidines involves re-
ductive cyclization of g-chloroketimines, which were generated in
situ from the reaction of 3-substituted 5-chloro-2-pentanones and a tion of an acyclic substrate in which all stereocenters are
already in place.15,16 In the present paper, an alternative,
primary amine. Various reduction conditions were explored to in-
duce a diastereoselective reductive cyclization. 2,3-Disubstituted
unexplored synthetic route to 1,2,3-trisubstituted pyrro-
tetrahydrofurans were obtained by the direct reduction of 3-substi-
lidines via diastereoselective reductive SN2 cyclization of
tuted 5-chloro-2-pentanones with sodium borohydride.
g-chloroketimines and a similar approach for the synthe-
Key words: pyrrolidines, tetrahydrofurans, cyclization, halo-
sis of 2,3-disubstituted tetrahydrofurans using g-chloroke-
imines, haloketones
tones is disclosed,17,18 in extension of our research on the
application of w-functionalized imines, and more specifi-
cally w-chloroimines,19 for the synthesis of heterocyclic
compounds.20 Whereas a-, b-, and d-haloimines have
Substituted pyrrolidines and tetrahydrofurans are com-
mon structural subunits found in a broad array of natural
been used successfully in the reductive cyclization to the
corresponding aziridines,19d–19f azetidines19a and pipe-
ridines,19c,d respectively, a similar approach towards the
five-membered azaheterocycles via reduction of g-halo-
genated imines has proven elusive up to now.19h,20 This
important gap in the application of haloimines towards the
synthesis of azaheterocycles is partly filled by the results
presented herein.
and unnatural products with interesting and diverse bio-
logical activities.2 The 1,2,3-trifunctionalized pyrrolidine
moiety is present in numerous natural products such as
naturally occurring proline analogues.3 Besides this,
1,2,3-trisubstituted pyrrolidines are useful building blocks
for the synthesis of various natural products, as exempli-
fied by the successful synthesis of the natural 1-amido-
pyrrolizidine alkaloid, ( )-laburnamine, starting from a
1,2,3-trisubstituted pyrrolidine precursor.4 Furthermore,
several 1,2,3-trisubstituted pyrrolidine derivatives exhibit
bioactivities such as antitumor, antiosteoarthritis,5 and an-
tipsychotic activities.6 On the other hand, the substituted
tetrahydrofuran motif is a common core structure of a
large family of natural products, namely the annonaceous
acetogenins, which possess a range of biological proper-
ties such as anthelmintic, antimalarial, antimicrobial, an-
tiprotozoal, cytotoxic, and antitumor activities.7 In
addition, substituted tetrahydrofurans are also found in
many other classes of natural products including lignans,8
polyether ionophores,9 and macrodiolides.10 The signifi-
cant biological interests associated with these compounds
has stimulated the scientific community to develop a num-
ber of methods for the synthesis of substituted pyrro-
lidines and tetrahydrofurans. Common ring-formation
methods involve radical, electrophilic,11 and, more recent-
ly, palladium-catalyzed cyclizations2,12 of amino- and
hydroxyalkenes,13 1,3-dipolar cycloadditions,14 reductive
The required starting compounds, that is, 3-alkyl-5-chlo-
ro-2-pentanones 1, were prepared in analogy with alkyla-
tion procedures on 2-acetyl-g-butyrolactone reported in
the literature.21 The imination of g-chloroketone 1a with
isopropylamine (4 equiv, r.t.) or benzylamine (3.4 equiv,
reflux), in the presence of 0.6 equivalents titanium(IV)
chloride,22 resulted in reaction mixtures which were diffi-
cult to characterize (Scheme 1). The obtained intermedi-
ate imines 2 were not stable enough for characterization
by 1H NMR or 13C NMR spectroscopy, and all attempts to
isolate them in pure form by distillation failed. The imines
2 tend to cyclize and decompose upon storage even at low
temperature. Some analytical and chemical proof for the
formation and reactivity of ketimine 2a was obtained as
follows. GC-MS analysis (HP5-MS capillary column) of
the reaction mixture containing imine 2a resulted in ther-
molysis during analysis with formation of one large peak,
together with two minor peaks in a ratio of 98.3:0.8:0.9.
The large peak was assigned to pyrroline 3a (MW = 153),
resulting from intramolecular N-alkylation with elimina-
tion of HCl. The first eluting minor peak corresponded
with the g-chloroketone 1a (m/z = 148/150). The mass
spectrum of the second minor peak showed a signal at
m/z = 151 and corresponded with the molecular weight of
SYNLETT 2011, No. 19, pp 2852–2856
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.10.2011
DOI: 10.1055/s-0031-1289544; Art ID: D26411ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,2,3-Trisubstituted Pyrrolidines and 2,3-Disubstituted Tetrahydrofurans
2853
R2
N
R2
N
R2
R2NH2 (3.4–4 equiv)
TiCl4 (0.6 equiv)
O
N
GC
Cl
Cl
1a
+
+
for 2a
Et2O–pentane
r.t. or heat, 2– 2.5 h
R1
1a (R1 = Et)
2a (R2 = i-Pr)
2b (R2 = Bn)
3a (R2 = i-Pr)
4a (R2 = i-Pr)
3a/4a/1a = 98.3:0.8:0.9
0.5 N HCl (aq)
R2
N
R2
N
0 °C, 1 h
(85% from 2a)
[H]
(see Table 1)
+
cis-5a
cis-5b
trans-5a
trans-5b
Scheme 1
pyrrole 4a. All attempts to repeat the thermolysis of imine determined by GC. Analogously, reduction of N-benzyl
2a under more standard conditions by heating in EtOH or imine 2b with sodium borohydride resulted in the isola-
DMF under reflux or by microwave heating in DMF or tion of pyrrolidines cis-5b and trans-5b as a 1:1 mixture
neat resulted in complex reaction mixtures.
in 78% overall yield (Table 1, entry 2). The pyrrole 4b
was present as a small impurity in the reaction mixture
(ca. 6% determined by GC) and the distillation fraction,
and was identified by NMR spectroscopy of an analytical
sample obtained via column chromatography on silica gel
(Figure 1).
The hydrolysis of imine 2a under mild reaction conditions
upon treatment with aqueous 0.5 N HCl at 0 °C for one
hour resulted in the regeneration of g-chloroketone 1a in
85% yield.
The following reductive cyclizations, with the aim to in-
duce diastereoselectivity during the reduction, were per-
formed on the crude reaction mixtures of imines 2
(Scheme 1, Table 1 and Table S1 in the Supporting Infor-
mation). Reduction of imine 2a with two equivalents of
sodium borohydride in methanol under reflux resulted in
a clean conversion into pyrrolidines cis-5a and trans-5a,
which were isolated by vacuum distillation as an insepa-
rable 1:1 mixture in 67% overall yield for the two-step
process from ketone 1a (Table 1, entry 1). The cis/trans
ratios and degree of conversion into pyrrolidines 5 were
4.2% NOE
δ = 6.57 (d, J = 2.8 Hz)
N
H
3.2% NOE
2.2% NOE
H
δ = 6.03 (d, J = 2.8 Hz)
4b
1
Figure 1 Structural identification of pyrrole 4b via H NMR and
DIFNOE experiments
Table 1 Reductive Cyclization of g-Chloroketimine 2a and 2b
Entry
Substrate
2a
Reduction conditions
dr cis/transa
50:50
Conv. to 5 (%)a,b
1
2
3
4
5
6
7
8
9
NaBH4 (2 equiv), MeOH, heat, 2 h
NaBH4 (2 equiv), MeOH, heat, 2 h
NaBH4 (1.2 equiv), MeOH, 0 °C, 2 h
NaBH4 (1.3 equiv), MeOH, –40 °C to –20 °C, 2 h
NaBH4 (1.3 equiv), MeOH, –78 °C to –40 °C, 2 h
H2 (5 atm)/Pd(0) (10 mol%), MeOH, r.t., 3 h
DIBAL (1.3 equiv), THF, –78 °C, 3 h
9-BBN (1.3 equiv), THF, 0 °C, 3 h
9-BBN (1.3 equiv), THF, 0 °C, 4 h
98 (67)
96 (78)c
98
2b
50:50
2a
60:40
2a
52:48
92
2a
55:45
86
2a
89:11
90 (52)
64
2a
77:23
2a
76:24
76
2b
87:13
90 (48)
a Determined via GC.
b Parentheses indicate overall isolated yields for the two-step process from ketone 1a.
c Contained pyrrole 4b (< 4% as determined by GC).
Synlett 2011, No. 19, 2852–2856 © Thieme Stuttgart · New York

2854
M. N. V. Sastry et al.
LETTER
All attempts to improve the diastereoselectivity of the re- synthesis of 3-benzylated pyrrolidines. Imination of 3-
duction of imine 2a by lowering the reaction temperature benzyl-5-chloro-2-pentanone (1b) with isopropylamine
during the reaction with sodium borohydride (Table 1, en- directly afforded, somewhat surprisingly, the correspond-
tries 3–5) or by using alternative reducing reagents, that ing 2-pyrroline 6 in 92% crude yield in >90% purity as de-
is, NaBH4·CeCl3·7H2O, NaCNBH3, Zn(BH4)2, Li(Et)3BH, termined by GC (Scheme 2). Reduction of the reaction
LiBH4, LiAlH4, L-Selectride, and BH3·SMe2, failed, lead- mixture with sodium borohydride or sodium cyanoboro-
ing to poor diastereomeric ratios (see Supporting Informa- hydride in methanol afforded the expected pyrrolidines
tion: Table S1, entries 1–3, 5, 6, 8–10) and/or resulting in cis- and trans-7 with poor diastereoselectivity (Table 2,
lower degrees of conversion into pyrrolidines 5a (see Sup- entries 1 and 2). The diastereoselectivity could be im-
porting Information: Table S1, entries 1, 2, 4, 7, 9–11). proved again by palladium-catalyzed hydrogenation lead-
However, palladium-catalyzed hydrogenation of g-chlo- ing to the isolation of pyrrolidines 7 as a 78:22 cis/trans
roketimine 2a resulted in an improved diastereoselectivity mixture in 42% yield after vacuum distillation (Table 2,
with good conversion affording pyrrolidines cis-5a and entry 3).
trans-5a in an 89:11 diastereomeric ratio in an overall
yield of 52% (Table 1, entry 6). Alternatively, the use of
DIBAL-H or 9-BBN in tetrahydrofuran also afforded
O
N
N
i-PrNH2 (4 equiv)
TiCl4 (0.6 equiv)
Cl
good cis selectivity with moderate conversion into pyrro-
lidines 5a (Table 1, entries 7 and 8). Following the latter
method, N-benzyl pyrrolidine 5b as an 87:13 cis/trans
mixture was isolated in 48% yield (Table 1, entry 9). The
identification of the cis- and trans-diastereomers 5a,b was
made by NMR analysis of diastereomerically pure sam-
ples of cis-5a and trans-5a obtained via preparative GC
and samples of cis-5b and trans-5b obtained via column
chromatography on silica gel. In the literature, the cis/
trans configuration of a related 1,2,3-trisubstituted pyrro-
lidine was assigned based on the 13C NMR data of the 2-
methyl group.23 Based on the g-gauche effect, the cis con-
figuration was assigned to the diastereomer with the reso-
nance of the 2-methyl group shifted upfield by 4 ppm
(CDCl3) relative to the other diastereomer, that is, the
trans-pyrrolidine. In analogy, for 3-ethyl-1-isopropyl-2-
methylpyrrolidine (5a), as well as for 1-benzyl-3-ethyl-2-
methylpyrrolidine (5b), the resonance of the 2-methyl
group of the cis diastereomer was shifted upfield relative
to the trans diastereomer and allowed the assignment of
cis- and trans-5a,b. The assignment of the cis stereochem-
istry of the N-benzylpyrrolidine cis-5b was further sup-
ported by the fact that in this diastereomer C-2 and C-3
were shielded in the 13C NMR spectrum when compared
with the corresponding resonances of the trans-isomer
5b.24
[H]
pentane–Et2O
2–3 h, r.t.
(see Table 2)
1b
6 (92%)
cis/trans-7
Scheme 2
With the positive results on the synthesis of 1,2,3-trisub-
stituted pyrrolidines in hand, the synthesis of valuable 2,3-
disubstituted tetrahydrofurans via direct reductive cy-
clization of g-chloroketones 1 was investigated. Attempt-
ed palladium-catalyzed hydrogenation of g-chloroketone
1a failed to give reasonable conversion into the corre-
sponding tetrahydrofurans. When g-chloroketone 1a was
reduced with sodium borohydride in methanol at 0 °C for
three hours no cyclization occurred and the d-chloroalco-
hol 8 (dr 67:33) was obtained in 82% yield.
However, when the reduction of ketone 1a with NaBH4
was performed under reflux conditions in MeOH, the cor-
responding cyclized 2,3-disubstituted tetrahydrofurans 9
were obtained in 63% yield as a 70:30 cis/trans mixture in
>90% purity (Scheme 3). In analogy with the latter reduc-
tion conditions, the 3-benzyl-, 3-methyl-, and 3-allyl-5-
chloro-2-pentanones 1b–d were reductively cyclized to
diastereomeric mixtures of cis- and trans-tetrahydro-
furans 10–12 in good to excellent yields and purity. The
synthesized tetrahydrofurans could be further purified via
fractionated distillation. 2,3-Dimethyltetrahydrofuran
(11) has been identified as a significant volatile compo-
Having found the most stereoselective reduction condi-
tions, that is, palladium-catalyzed hydrogenation at room
temperature and the most efficient reaction conditions,
that is, reduction with NaBH4 in methanol, the generality
of these reductive cyclizations was extended towards the
Table 2 Reduction of 2-Pyrroline 6
Entry
Reduction conditions
dr cis/transa
Conv.
to 7 (%)a,b
1
2
NaBH4 (2 equiv), MeOH, heat, 2 h
55:45
40:60
96 (66)
94
NaCNBH3 (2 equiv), MeOH
AcOH (1 equiv), heat, 2 h
3
H2 (5 atm)/Pd(0) (10 mol%), MeOH, r.t., 3 h
78:22
93 (42)
a Determined via GC.
b Parentheses indicate overall isolated yields for the two-step process from ketone 1b.
Synlett 2011, No. 19, 2852–2856 © Thieme Stuttgart · New York

LETTER
1,2,3-Trisubstituted Pyrrolidines and 2,3-Disubstituted Tetrahydrofurans
2855
Table 3 Reduction of g-Chloroketone 1c
Entry
Reaction conditions
Result
1
2
NaBH4 (2 equiv), MeOH, 2 h, heat
11 (77%, purity >90%, cis/trans = 55:45)
11 (66%, purity >90%, cis/trans = 40:60)
NaCNBH3 (2 equiv)
AcOH (1 equiv), MeOH, 2 h, heat
3
LiAlH4 (2 equiv), Et2O, 2 h, heat
11 (55%, purity >80%, cis/trans = 70:30)
nent of the odor spectrum produced by streptomycetes, diastereoselectivity, palladium-catalyzed hydrogenation
which are cultivated for the production of important bio- or, alternatively, reduction with 9-BBN proved to be the
logically active compounds, for example, antibiotics.25 best choice. Similarly, 2,3-disubstituted tetrahydrofurans
The use of alternative reducing reagents had only a mod- were obtained by the direct reduction of g-chloroketones.
erate influence on the diastereoselectivity of the reductive
cyclization of g-chloroketone 1c (Table 3), with
Supporting Information for this article is available online at
NaCNBH3 affording a 40:60 cis/trans mixture of tetrahy-
http://www.thieme-connect.com/ejournals/toc/synlett.
drofurans 11 (Table 3, entry 2) and LiAlH4 (Table 3, entry
3) providing a better diastereoselectivity (70:30 cis/trans)
but lower yield and purity.
Acknowledgment
The authors are indebted to Ghent University (GOA) and the Re-
search Foundation-Flanders (FWO) for financial support.
OH
O
NaBH4 (1.5 equiv)
Cl
Cl
MeOH
0 °C to r.t., 3 h
R1
References and Notes
1a (R1 = Et)
1b (R1 = Bn)
1c (R1 = Me)
1d (R1 = Allyl)
8 (82%, dr 67:33)
(1) Postdoctoral Fellow of the Research Foundation-Flanders
(FWO).
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O
O
+
R1
R1
NaBH4 (2 equiv)
MeOH, 2 h, heat
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10 (R1 = Bn, 88%, purity >99%, cis/trans 50:50)
11 (R1 = Me, 77%, purity >90%, cis/trans 55:45)
12 (R1 = Allyl, 89%, purity >90%, cis/trans 60:40)
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Scheme 3
The assignment of the cis and trans configuration of the
2,3-disubstituted tetrahydrofurans 9–12 was based on
comparison of spectroscopic data with literature data for
the known 2,3-dimethyltetrahydrofurans (cis- and trans-
11),26 1H NMR NOE experiments, and analysis of 13C
NMR data of the cis and trans diastereomers 9–12, which
could be separated via preparative GC.
It is stated in the literature that the carbon atoms of the
ring and the a-carbon atoms of the substituents on C-2 and
C-3 in cis-tetrahydrofurans are shielded in the C NMR
13
spectrum when compared with the corresponding reso-
nances of the trans isomers.27
In summary, a novel unexplored diastereoselective syn-
thetic approach towards the synthesis of 1,2,3-trisubstitu-
ted pyrrolidines and 2,3-disubstituted tetrahydrofurans is
described. The synthesis of the pyrrolidines involves re-
ductive cyclization of in situ prepared g-chloroketimines
or reduction of the 2-pyrroline formed directly by imina-
tion of 3-benzyl-5-chloro-2-pentanone. An extensive
study was performed to obtain good diastereoselectivity
during the synthetic protocol. In terms of yields, sodium
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Synlett 2011, No. 19, 2852–2856 © Thieme Stuttgart · New York

2856
M. N. V. Sastry et al.
LETTER
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Synlett 2011, No. 19, 2852–2856 © Thieme Stuttgart · New York

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