Regioselective synthesis of azetidines or pyrrolidines by selenium-induced cyclization of secondary homoallylic amines

Article abstract of DOI:10.1016/j.tetlet.2010.06.087

Azetidines or pyrrolidines can be regioselectively obtained by selenocyclization of homoallylic amines, according to the double bond substitution.

Full text of DOI:10.1016/j.tetlet.2010.06.087

Tetrahedron Letters 51 (2010) 4437–4440
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of azetidines or pyrrolidines by selenium-induced
cyclization of secondary homoallylic amines
*
*
Xavier Franck , Stéphane Leleu, Francis Outurquin
UMR-CNRS6014 & FR3038 COBRA, Université de Rouen, INSA de Rouen, IRCOF, 1 rue Tesnière, 76130 Mont Saint Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Azetidines or pyrrolidines can be regioselectively obtained by selenocyclization of homoallylic amines,
according to the double bond substitution.
Received 28 May 2010
Revised 14 June 2010
Accepted 16 June 2010
Available online 20 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Azetidines
Pyrrolidines
Selenocyclization
77Se NMR
Cyclofunctionalizations are cyclizations mediated by an electro-
philic reagent and are called selenocyclizations, in the case of sel-
enenylated reagents. The reaction of selenium electrophiles with
olefins is a stereospecific anti addition and internal nucleophiles
lead to cyclic products. Selenocyclizations of unsaturated alcohols
and amines (Scheme 1) are efficient methods for the synthesis of
oxygenated or nitrogenated heterocycles.1 Numerous studies con-
cerning the influence of the nature of the electrophilic selenium
species have been reported. These include [benzeneselenyl halides,
N-(phenylseleno)phthalimides, and benzeneselenyl triflates or sul-
fates], including their counter-ion.2 Asymmetric use of selenium
reagents has also been developed recently.3 The synthetic interest
of the presence of an organoselenium function is obvious as it is
one of the easiest functional groups to be transformed, either to
double bond (syn-elimination of selenoxide) or to generate a stabi-
lized carbanion or radical.
ble bond and mainly focus on the synthesis of azetidines. Few
reports describe that the regioselective obtention of azetidines5 oc-
curs by the cyclization of 4-haloamines, d-aminoalcohols, or diols.6
The development of new methods is therefore of high importance,
due to the biological relevance of such moiety.7
Homoallylic amines 1 bearing different substituents in the c- or
d-position of the double bond and with various R1, R2 substituents
(Scheme 3) were prepared. The application of Barbier conditions
R1
R2 Nu
n
SePh
exo-trig
R3
SeR
R3
R1
R2
R1
R2
RSeX
R3
n
NuH
n
NuH
SePh
R3
n
R1
Nu=O,NR
n=1,2,...
endo-trig
R2
Nu
Some years ago, we showed for the first time that azetidines
could be formed as a mixture with pyrrolidines from simple homo-
allylic secondary amines by selenium-induced ring closure, accord-
Scheme 1. Selenocyclizations of alcohols and amines.
ing to
a 4-exo-trig process, when treated with 1.5 equiv of
SePh
benzeneselenyl halide, whereas, the use of 2.5 equiv yielded only
the halo-pyrrolidine ring when R2 = H (Scheme 2).4 We also
showed that the regioselectivity was dependent on the R1, R2 sub-
stitutions. Until now, no regioselective 4-exo-trig selenocyclization
has been reported. We now report on the control of the regioselec-
tivity of this cyclization, according to the substitution on the dou-
R1
R2
R1
PhSeX (1.5 eq.)
Na2CO3, CH3CN
+
R1
R2
SePh
R2
N
Bn
NH
Bn
N
Bn
amine
pyrrolidine
azetidine
PhSeX (2.5 eq.)
R2=H
R1=R2=H
R1=R2=Me
X
18
83
82
17
R1
R2
N
Bn
* Corresponding authors.
E-mail addresses: xavier.franck@insa-rouen.fr (X. Franck), francis.outurquin@u-
niv-rouen.fr (F. Outurquin).
Scheme 2. Azetidine/pyrrolidine formation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.087

4438
X. Franck et al. / Tetrahedron Letters 51 (2010) 4437–4440
γ
β
Me
CH
H
R1
R2
α
Me
Br
THF, Mg
Me
Me
Me
R1
R2
δ
H
H
H
CH
NBn
Me
NH
Bn
N
Barbier conditions
Bn
NBn
H2C
H
amine 1a-1i
H
SePh
H2C
cis
SePh
trans
Ph
γ
β
Br
1 α
R2
R1
R2
R1
R2
R
THF, Mg
Figure 1. NOe correlations on 2d.
Ph
+
N
δ
Ph
NH
Bn
NH
Bn
Barbier conditions
Bn
1/1
amine 1j-1n
chromatography
silica-gel
R1
R2
R1
R2
(separation of regioisomers on silicagel chromatography)
R1
R2
PhSeBr (1.5 eq.)
Na2CO3, CH3CN
SePh
SePh
N
Bn
N
Bn
NH
Bn
Scheme 3. Preparation of amines 1.
H
2
acid-catalysed isomerisation
amine 1
R2
R1
R2
R1
PhSeBr (1.5 eq.)
Na2CO3, CH3CN
R2
R1
+
SePh
SePh
NHBn
SePh
SePh
N
Bn
R1
R2
NH
Bn
R1
R2
N
Bn
N
Bn
3
(trans)-2
amine 1
(cis)-2
Scheme 5. Acid-catalyzed isomerization of azetidine 2 into pyrrolidine 3.
Scheme 4. Regioselective synthesis of azetidines 2.
H4b
N
(in situ generation and addition of Grignard reagent on preformed
imines)4b allowed us to obtain amines 1a–1i with methallyl bro-
mide (in 50–70% average yield); amines 1j–n were obtained (in
10–30% average yield) from cinnamyl bromide after separation
from their regioisomer.
H4b
N
SePh
Ph
SePh
Ph
4aH
R1
4aH
R1
R1
R2
PhSeBr (1.5 eq.)
Na2CO3, CH3CN
Ph
+
R2
R2
NH
Bn
Bn
Bn
(trans)-3
Δδ (H4a,H4b)=0
amine 1j-n
(cis)-3
Δδ (H4a,H4b)=0.6-0.8 ppm
Having in hand homoallylic amines substituted at position
c or
d, we studied the regioselectivity of the selenium-induced cycliza-
tion. The reaction of homoallylic amines 1a–j with 1.5 equiv of
phenylselenium bromide afforded azetidines 2 as the only regio-
isomer (Scheme 4, Table 1).
Scheme 6. Regioselective synthesis of pyrrolidines 3.
Table 2
Regioselective synthesis of pyrrolidines 3
Azetidines 2 were obtained as mixtures of cis (between R1 and
CH2SePh) and trans isomers, with a large preference for the cis one
(cis/trans > 80:20) regardless of the substituents R1 and R2. Yields
of 2 increased when the size of R1, R2 substituents increased. From
1b R1 = Me to 1f R1 = tBu, keeping R2 = H, the yields increased from
45% to 68% (entries 2–5). Also, when R1 = R2 = H, a moderate 35%
yield was obtained (entry 1). The Thorpe Ingold effect is therefore
very important in order to achieve this transformation in good
yields, but has no effect on the stereoselectivity.
Entry amine 1 R1, R2
Yield% of 3 (cis + trans)
Pyrrolidines 3
2,4-cis
2,4-trans
1
2
1j14
1k
H, H
Et, H
55
73
(373.5)
80
20
(367.2)
15
(359.7)
16
(376.6)
(392.6)
85
(403.4)
84
3
4
5
1l
iPr, H
80
72
1m
1n
Ph, H
(397.5)
(375.2)
We have determined the relative stereochemistry of cis/trans
azetidines by the use of nOe correlations on compound 2d
(Fig. 1). According to the literature, we have represented the trans
isomer like a nearly planar ring and the cis isomer like a puckered
ring.10 We could also generalize and attribute the relative abun-
dance of each cis/trans diastereomer by using 77Se NMR which is
a very powerful tool we have already used for the determination
of diastereomeric ratios of cyclopropanes and dienes.11 In the
azetidine series, homogeneous values for cis and trans azetidines
2 were observed with 77Se d 242–244 ppm and 77Se d 249–
252 ppm, respectively.
Me, Me 88
R3
R4
R3
α
R4
R3
SePh
R5
R4
R5
γ
β
PhSeBr (1.5 eq.)
Na2CO3, CH3CN
i-Pr
SePh
+
i-Pr
R5
i-Pr
N
Bn
δ
N
NH
Bn
Bn
pyrrolidine 3
amine 1
azetidine 2
Scheme 7. Influence of the position of a methyl on the regioselectivity of the
cyclization.
Table 1
Regioselective synthesis of azetidines
Entry
Amine 1
R1, R2
Yield% of 2 (cis + trans)
Azetidines 2%, (77Se NMR d ppm)
cis
trans
1
2
3
4
5
6
7
8
1a8
1b
1c
H, H
Me, H
Et, H
iPr, H
tBu, H
Ph, H
Me, Me
(CH2)5
35
45
58
65
68
67
72
69
(244.2)
82 (244.3)
82 (243.1)
82 (242.5)
81 (243.2)
82 (244.3)
(245.4)
18 (252.1)
18 (251.1)
18 (250.6)
19 (248.8)
18 (252.6)
1d
1f
1g9
1h
1i9
(244.4)

X. Franck et al. / Tetrahedron Letters 51 (2010) 4437–4440
4439
Table 3
Variation of the regioselectivity
Entry
Amine 1
R3, R4, R5
Azetidine 2% (77Se NMR d ppm)
Pyrrolidine 3% (77Se NMR d ppm)
cis
trans
cis
trans
1
2
3
4
1o15
1p16
1d
H, H, H
46 (252.0)
51 (247.2)
82 (242.4)
56 (356.7)
22 (251.2)
25 (249.7)
18 (250.2)
22 (367.1)
19 (407.3)
24 (393.7)
—
13 (372.7)
Me, H, H
H, Me, H
H, H, Me
—
—
—
1q
22 (414.4)
shown in Scheme 4 and Table 1. With amine 1q having a methyl
in the d-position, only 22% of pyrrolidine 3 was obtained after sele-
nocyclization (entry 4). This relatively low yield in pyrrolidine
compared to that in entry 1 (d-carbocation should be stabilized
by d-methyl, thus expected to increase pyrrolidine formation)
can be explained by steric interaction between nucleophilic nitro-
gen and d-methyl, increasing the azetidine formation.
R
Boc
N
1) Boc2O
Boc
N
R
H
N
PPh3
OH
2) Swern
O
R'
R'
92%
H
4
6a R=R'=H, 66%
5
6b R=H, R'=Ph, 79%
TFA
H
N
R
(
E/Z 67/33)
7 a, 41%
7 b, 90%
6c R=R'=Me, 60%
R'
To further increase molecular diversity, we tried to prepare
bicyclic azetidines or pyrrolidines by selenocyclization of 2-allylpi-
peridines 7, which are constrained analogues of homoallylic
amines 1 (where R1 and N-substituents are joined in a six-mem-
bered ring). 2-allylpiperidines 7a–b17,18 were prepared from 2-
hydroxyethyl piperidine 419 by N-Boc protection, Swern oxida-
PhSeBr
Na2CO3
PhSeBr
Na2CO3
R'
R
SePh
R'
R
SePh
R'
R
O
O
SePh
10 a, 66%
10 b, 44%
10 c, 38%
tion20
, Wittig reaction, and TFA removal of the Boc group
N
N
N
(Scheme 8). Unfortunately, addition of PhSeBr in the presence of
Na2CO3 to allylpiperidines 7a–b did not afford any bicyclic amines
8 or 9. This unreactivity may be explained by the cyclic strain
allowing less freedom for the nitrogen to add onto seleniranium
ion. On the other hand, the reaction of N-Boc allylpiperidines 6a–
c21,22 with PhSeBr resulted in an oxyselenenylation of the double
bond giving rise to bicyclic carbamates 10a–c, precursors of sedum
alkaloids. In the case of 10a (R = R0 = H) and 10c (R = R0 = Me), a
mixture of inseparable cis and trans isomers was obtained.23 In
the case of 10b, a mixture of 4 isomers was obtained, as the start-
ing alkene 6b20 was a cis/trans mixture.
To conclude, in this Letter, we have described an efficient meth-
od to obtain regioselectively selenofunctionalized azetidine with a
good diastereoselectivity in favor toward the cis diastereomer.24 It
was demonstrated that Thorpe Ingold effect plays an important
role for the yield of the selenocyclization reaction. And when a
phenyl group is located in the d-position, the regioselectivity of
selenocyclization was completely reversed to furnish pyrrolidine
products with a preference for cis diastereomer. Further studies
in order to broaden the scope of this reaction, including the influ-
ence of the nitrogen-protecting group, will be reported in due
course.
8 a-b
9 a-b
Scheme 8. Synthesis of bicyclic carbamates 10.
It should be noted that partial rearrangement of azetidine 2 into
pyrrolidine 3 occurred during silica gel chromatography of the
crude material (Scheme 5). Couty has reported in the literature
the similar ring expansion under thermal condition.12 This acid-
catalyzed rearrangement could be totally suppressed by adding
1% Et3N to the eluent but the separation became harder. On the
other hand, the use of alumina column chromatography proved
to be efficient with neither Et3N nor rearrangement.13
We then modified the substitution of the double bond and
introduced a phenyl group in the d-position in order to drive the
selenocyclization of homoallylic amines 1j–n in favor of the 5-
endo-trig mode (Scheme 6, Table 2).
In this case, only pyrrolidines 3 were obtained in yields ranging
from 55% to 88% and, as with azetidines, better yields were ob-
tained in the case of bulky R1 substituents (entries 2–4). 2,4-Cis iso-
mers (between R1 and SePh) were also obtained in higher amount
than the trans one (usually >80/20 ratio). The cis/trans relative con-
figuration of pyrrolidines 3 was determined by 1H NMR. Indeed,
the chemical shifts of geminal H-4 protons are similar in the trans
configuration (between R1 and SePh) whereas they are very differ-
Acknowledgment
We gratefully acknowledge the Région Haute Normandie for
funding.
ent (0.6 <
Dd < 0.8 ppm) in the case of the cis configuration. The
same observation has already been reported in the case of N-tosy-
lated pyrrolidine.1a Again, 77Se NMR also proved very useful for the
determination of cis/trans ratio as d 77Se for cis isomer is comprised
between 393–403 ppm whereas trans isomers show 77Se NMR
chemical shifts ranging from 360 to 377 ppm. Phenyl group in
the d-position directs the cyclization reaction toward the 5-endo
mode exclusively.
We have also studied the influence of only one methyl substitu-
ent migrating from position b to position d of the side chain
(Scheme 7, Table 3). Without any substituent, selenocyclization
of amine 1o gave a mixture of azetidine 2 (68%) and pyrrolidine
3 (32%, entry 1). Introducing a methyl in the b-position, amine
1p increased proportions of azetidine 2 (77%, entry 2). In the case
of amine 1d, no pyrrolidine was obtained (entry 3) as already
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acetonitrile (30 ml) containing anhydrous sodium carbonate (2 g) was added,
dropwise at rt and under inert atmosphere, a solution of PhSeBr (15 mmol) in
acetonitrile (50 ml). The mixture was stirred for16 h at rt and then treated with
a saturated aq NaCl solution. After separation, the aqueous layer was extracted
with CH2Cl2 (3 ꢀ 20 ml) and the organic phases were collected, dried with
anhydrous MgSO4, and concentrated in vacuo. Purification of the residue was
carried out by flash chromatography on alumina gel (199:1–99:1 of
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