Synthesis of azetidine and pyrrolidine derivatives through selenium-induced cyclization of secondary homoallylamines - A 77Se NMR study

Article abstract of DOI:10.1002/1099-0690(200203)2002:6<995::AID-EJOC995>3.0.CO;2-A

Treatment of α-alkyl and α,α-dialkyl homoallylic amines 1 with PhSeX (X = C1, Br, I), in CH₃CN containing sodium carbonate produced mixtures of azetidines 2 and pyrrolidines 3. The cyclization also occurred in the absence of Na₂CO₃, and the corresponding azetidinium and pyrrolidinium salts 2(HX) and 3(HX) were formed in CDCl₃ or CH₃CN. The crude reaction mixtures were analysed by ⁷⁷Se NMR. Each product - 2, 3, 2(HX), and 3(HX) - was characterized by its ⁷⁷Se chemical shift, and the product ratios were determined for each reaction. The ratios of azetidine 2 to pyrrolidine 3 increased not only according to the steric hindrance around the α-carbon, but also with the nature of the counterion X^- (PhSeCl < PhSeBr < PhSeI). Use of PhSeI and amines 1g to 1k (R¹, R² ≠H), produced only the azetidinium salts 2(HI), allowing the isolation of the corresponding azetidines 2, albeit in poor yield. Some reactions were monitored by ⁷⁷Se NMR at the beginning of the addition-cyclization process. No intermediates were observed when PhSeI was used, but the thermodynamic addition products 5(Br), 5(HBr), and some dibromoselenuranes 8 were detected. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200203)2002:6<995::AID-EJOC995>3.0.CO;2-A

FULL PAPER
Synthesis of Azetidine and Pyrrolidine Derivatives through Selenium-Induced
77
Cyclization of Secondary Homoallylamines ؊ A Se NMR Study
Xavier Pannecoucke,[a] Francis Outurquin,*[a] and Claude Paulmier[a][†]
Keywords: Cyclizations / Nitrogen heterocycles / NMR spectroscopy / Selenium
Treatment of α-alkyl and α,α-dialkyl homoallylic amines 1
with PhSeX (X = Cl, Br, I), in CH3CN containing sodium car-
but also with the nature of the counterion X− (PhSeCl Ͻ
PhSeBr Ͻ PhSeI). Use of PhSeI and amines 1g to 1k (R1, R2
bonate produced mixtures of azetidines 2 and pyrrolidines 3. ϶H), produced only the azetidinium salts 2(HI), allowing the
The cyclization also occurred in the absence of Na2CO3, and
the corresponding azetidinium and pyrrolidinium salts 2(HX)
isolation of the corresponding azetidines 2, albeit in poor
yield. Some reactions were monitored by 77Se NMR at the
and 3(HX) were formed in CDCl3 or CH3CN. The crude reac- beginning of the addition−cyclization process. No intermedi-
tion mixtures were analysed by 77Se NMR. Each product − 2, ates were observed when PhSeI was used, but the thermody-
3, 2(HX), and 3(HX) − was characterized by its 77Se chemical
namic addition products 5(Br), 5(HBr), and some dibromose-
shift, and the product ratios were determined for each reac- lenuranes 8 were detected.
tion. The ratios of azetidine 2 to pyrrolidine 3 increased not
only according to the steric hindrance around the α-carbon,
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
CH2Cl2 or CH3CN at room temperature in the presence of
sodium carbonate[10] (Scheme 1, route A).
The electrophile-induced ring-closure of unsaturated
carboxylic acids, alcohols, and amine derivatives is now an
efficient method for the synthesis of lactones, cyclic ethers,
and N-substituted aza-heterocycles, respectively.[1] Selenium
methodology plays an important role in this field,[2,3] and
various electrophilic selenium reagents such as benzenese-
lenenyl halides,[1,2,3] N-(phenylseleno)phthalimide,[4] and
benzeneselenenyl triflate[5] and sulfate[6] are commonly
used. A seleniranium intermediate is involved and the at-
tack of the internal nucleophile occurs with stereospecific
anti-addition. The exo-trig mode is favoured,[7] especially
with
a
terminal olefinic bond. 1-Alkoxycarbonyl-2-
(phenylselanylmethyl)pyrrolidines[1,2] and piperidines[8]
have been prepared. Under acidic conditions, 1,2-dialkyl-
5-(phenylselanylmethyl)pyrrolidines have been prepared, in
modest yields, from secondary pent-4-en-1-ylamines
through a 5-exo-trig process.[9]
Some years ago, we observed that mixtures of α-
(phenylselanylmethyl)azetidines 2 and β-(phenylselanyl)pyr-
rolidines 3 were formed upon treatment of homoallyl
benzylamines 1 with PhSeX (X ϭ Cl, Br; 1.5 equiv.) in
Scheme 1
The formation of azetidines through a selenium-induced
cyclization of homoallylamines by a 4-exo-trig process has
now been observed for the first time. In the case of amines
1 (R2 ϭ H), the azetidines cis-2 and the pyrrolidines cis-3
and trans-3 were separated, with some difficulties, by silica
gel chromatography. In the course of this study, we found
that the proportion of azetidine cis-2 increased with the size
of R1 and that azetidines 2 were the major products of
amines 1 bearing two α-substituents. It was also observed
that the proportion of azetidines increased when PhSeBr
was used instead of PhSeCl.[10] The geminal α-effect ap-
pears similar to that described for the electrophile-induced
[a]
`
´ ´
Laboratoire de Synthese Thio- et Seleno-organique (LHO)-
´
IRCOF, UFR Sciences, Universite de Rouen,
76821 Mont Saint-Aignan Cedex, France
Fax: (internat.) ϩ 33-2/35522959
E-mail: francis.outurquin@univ-rouen.fr
In memoriam Professor Claude Paulmier who passed away on
November 28, 2001
[†]
Eur. J. Org. Chem. 2002, 995Ϫ1006
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0306Ϫ0995 $ 17.50ϩ.50/0
995

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
formation of small rings.[11,12] CH3CN was a better solvent 1b to 1f (R2 ϭ H). In some cases, the complete separation
than CH2Cl2 for a more efficient 4-exo-trig cyclization pro- of the four isomers was not achieved; the isomerization of
cess, affording azetidines derivatives.[10]
trans-2b- (R1ϭMe) into trans-3b during chromatography
The synthesis of azetidines is at present an important ob- prevented the isolation of trans-2b. Moreover, trans-3c and
jective and is usually carried out by cyclization of 4-haloalk- cis-2c were eluted together. The separation of the pyrrolid-
ylamines or δ-amino alcohols.[13] The azetidine skeleton ap- ines 3 from the azetidines 2 was achieved without difficulty
pears in natural substances,[14] and so routes to optically when R1 and R2 ϶ H.
active species are of great interest.[15]
In the absence of Na2CO3, mixtures of azetidinium and
We now report a complete study of this new reaction in- pyrrolidinium salts 2(HX) and 3(HX) were formed by treat-
volving N-benzyl but-3-en-1-ylamines 1a to 1k and ben- ment of amines 1 with PhSeBr or PhSeI (1.2 equiv.) in
zeneselenenyl halides PhSeX (X ϭ Cl, Br, I) (Scheme 1). In CDCl3 or CH3CN at room temperature (Scheme 1, route
the absence of Na2CO3, the corresponding azetidinium and B). The δSe values of each salt cis-2(HX), trans-2(HX), cis-
pyrrolidinium halides 2(HX) and 3(HX) were formed 3(HX), and trans-3(HX) were assigned for each crude salt
(Scheme 1, route B).
product (Table 2). Basic aqueous treatment produced azeti-
The following paper describes the synthesis of β-halopyr- dines 2 and pyrrolidines 3 in ratios very close to those for
rolidines when an excess of PhSeX (X ϭ Cl, Br) was used. the corresponding salts.
The stereocontrolled synthesis of 4-halo-1,2-dialkypyrrolid-
Cyclization occurred slowly for 1a, 1b, 1c, 1d, 1e, and 1f,
ines from azetidines 2 and pyrrolidines 3 is also re- especially in CDCl3. Compounds 1b, 1c and 1f needed more
ported.[16]
than 48 h of treatment to reach completion of reaction
when PhSeBr was used (Table 2, entries 5, 6, 8, and 17). As
described below, intermediate addition products could be
characterized. The additionϪcyclization process occurred
more rapidly with PhSeI and when α,α-disubstituted amines
Results and Discussion
The addition-cyclization process was first achieved at 1g to 1k were used as substrates. The 2a(HX)/3a(HX) ratios,
room temp. on amines 1, in acetonitrile containing sodium given in Table 2 (entries 1Ϫ4), were modified, according to
carbonate (route A).[10] Either PhSeBr or PhSeI (1.5 equiv., the excess of PhSeX, by a PhSe-induced isomerization of
preformed from diphenyldiselenide and iodine) was then 2a(HX), also discussed below.
added. Amines 1 were consumed more slowly with PhSeBr,
The 77Se chemical shifts of cis-2(HX) and trans-2(HX)
but all reactions went to completion after stirring for 16 h. underwent a slight deshielding effect (∆δSe ഠ 15Ϫ20 ppm)
77Se NMR analysis of the crude reaction mixtures permit- compared to those of the corresponding azetidines cis-2
ted the assignment of the chemical shift for each product: and trans-2.
cis-2, trans-2, cis-3, and trans-3. The value δSeϭ 467.0 for
Examination of Tables 1 and 2 shows that the signals of
PhSeSePh, often present beside the cyclized products, was cis-3(HX) (R2 ϭ H) were shifted upfield (∆δSe ϭ Ϫ35 to
adopted as internal reference. The δSe values and the com- Ϫ10 ppm). On going from trans-3 to trans-3(HX), an op-
positions of the crude mixtures are collected in Table 1. The posite effect took place (∆δSe ϭ ϩ10 to ϩ35 ppm). The δSe
signal attributable to trans-2 appeared very close to that of values for cis-3f and trans-3f (R1 ϭ Ph, R2 ϭ H) could not
cis-2 (∆δ Յ 1.5 ppm) in the δ ϭ 249.2Ϫ257.2 range. We be assigned and compared to those of other α-alkylpyrroli-
were, however, able in most cases to determine the respect- dines, as a consequence of the difficulty in gauging the di-
ive proportions. The peaks attributable to pyrrolidines 3 rection of the phenyl group’s anisotropic effect (Table 1, ent-
were found in the δ ϭ 362Ϫ420 range for cis-3 and ries 12 and 13; Table 2, entry 17). It is interesting to note
338Ϫ394 for trans-3. The stereochemistry of cis-2d, trans- that only one stereoisomer of each azetidinium salt cis-
2d, cis-3d, trans-3d, cis-2e, and cis-2h was secured by NOE 2(HX) and trans-2(HX) was formed for R1 ϭ H, Me, Et,
experiments (Figure 1, Structures A, B for 2d and C, D for Ph (R2 ϭ H) and for the pyrrolidinium salts cis-3(HX) and
3d).
trans-3(HX). The spectrum of the 2d(HBr)/3d(HBr) (R1 ϭ
The parent amine 1a afforded a 18:82 mixture of azetid- iPr, R2 ϭ H) mixture deserves particular attention (Table 2,
ine 2a and pyrrolidine 3a whether PhSeBr or PhSeI was entries 11Ϫ13). The azetidinium salt area displays four
used (Table 1, entries 1, 2). In the other cases, the propor- peaks (Figure 2, spectra a). Surprisingly, trifluoroacetic acid
tion of azetidines 2 was always greater when PhSeI was treatment of a crude 2d ϩ 3d mixture (spectrum b) resulted
used. This reached 86% for 2e (R1 ϭ tBu, R2 ϭ H, entry in the formation of the corresponding trifluoroacetic salts
11) and 95% for 2i (R1 ϭ R2 ϭ Et, entry 19). Proportions (spectrum c) with the same composition as observed for the
of 44, 48, and 57% of azetidines 2c (R1 ϭ Et, R2 ϭ H) were HBr salts. Moreover, a pure sample of cis-2d, also treated
found in the reaction mixtures obtained from 1c treated with CF3COOH, gave only the two major signals with very
with PhSeCl, PhSeBr, and PhSeI, respectively (entries 5, 6, close δSe values (∆δSe ϭ 0.2 ppm). The two external peaks
7).
(∆δSe ϭ 13.5 ppm) must be attributable to the trans-
Silica gel chromatography of the crude mixtures permit- 2d(HBr) stereoisomers.
ted the isolation of pure samples of cis-3, trans-3, cis-2, and
This observation allowed us to assign the structures E
trans-2 (except for trans-2b and trans-2c) in that order of and F for trans-2d(HBr), and G and H for trans-2d(HBr)
elution (heptane/CH2Cl2) for the mixtures obtained from (Figure 3). The difference of anisotropic effect of the benzyl
996
Eur. J. Org. Chem. 2002, 995Ϫ1006

Selenium-Induced Cyclization of Secondary Homoallylamines
FULL PAPER
Table 1. Crude product composition of the selenium-induced cyclization of N-benzyl homoallylamines 1 (PhSeX, 1.5 equiv., Na2CO3,
MeCN, room temp., 16 h)
Entry
X
Substrate
R1
77Se NMR (δ ppm)[a]
Azetidine 2
Composition (%)
Pyrrolidine 3
2
3
No.
R2
cis
trans
cis
trans
cis
trans
cis
trans
1
2
3
4
5
6
7
8
Br
I
Br
I
Cl
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
1a
1a
1b
1b
1c
1c
1c
1d
1d
1e
1e
1f
H
H
Me
Me
Et
Et
Et
iPr
iPr
tBu
tBu
Ph
H
H
H
H
H
H
H
H
H
H
H
H
256.8
256.8
257.1
257.1
255.2
255.2
255.2
252.0
252.0
250.6[c]
250.6[c]
253.4
253.4
250.9
250.9
252.0
252.0
252.2
252.2
251.1
251.1
249.8
249.8
396.1
18
82
82
24[b]
24
29
22
22
19[b]
12
5
396.1
419.8
419.8
416.6
416.6
416.6
407.3
407.3
362.1
362.1
425.3
425.3
403.5
403.5
417.6
417.6
392.7
392.7
411.3
411.3
401.2
401.2
18
256.0
256.0
254.3
254.3
254.3
251.2
251.2
249.2[c]
249.2[c]
254.4
254.4
386.2
386.2
380.1
380.1
380.1
372.7
372.7
338.7
338.7
388.2
388.2
29[b]
38
13
17
34[b]
21
27
30
21
13[b]
8
12
9
30
20
44
35[b]
57
13
46[b]
80
22[b]
31
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
52[b]
86
5
34
45
83
12
13
24
22
17
16
12
6
12
5
10
7
1f
Ph
H
1g
1g
1h
1h
1i
Me
Me
Ph
Ph
Et
Et
Et
Et
-(CH2)5-
-(CH2)5-
Me
Me
Me
Me
Et
Et
Me
Me
84
250.4
250.4
394.6
394.6
70[b]
66
14
25
4
3
Br
I
Br
I
Br
I
88
95
58
88
88
93
1i
1j
250.4
250.4
391.1
391.1
24
8
5
1j
1k
1k
12
7
[a]
[b]
[c]
PhSeSePh as internal reference. δSe ϭ 467.0 ppm. Stereochemistry assigned by NOE experiments. Doublet (∆δSe ϭ 0.2 ppm).
jor stereoisomer could be represented by structure G
(R1 ϭ iPr).
It may also be observed that the spectra of azetidines
cis-2e and trans-2e exhibit two doublets (∆δSe ϭ 0.2 ppm)
(Table 1, entries 10 and 11). As a consequence of severe
steric hindrance, the high barrier of inversion around the
nitrogen atom is probably responsible for the existence of
the two conformers for each azetidine cis-2e and trans-2e.
From these observations, we deduced that the formation
of the azetidinium and pyrrolidinium salts 2(HX) and
3(HX) is the result of protonation of 2 and 3 by the conjug-
ated acids 1(HX), 4(HX), and 5(HX), affording the more
stable isomeric salt.
The mechanistic aspects of this new multistep reaction
were then investigated. It is generally accepted that selenir-
anium halide intermediates such as 6 (Scheme 2) are in-
Figure 1. NOE correlations from NOESY spectra of A: cis-2d, B:
trans-2d, C: cis-3d, and D: 3d
volved in competitive exo- and endo-trigonal ring-closure
reactions of γ- or δ-unsaturated alcohols, phenols, carb-
oxylic acids, amides and carbamates.[2,3]
group is negligible for the cis isomers but has some import-
ance for the trans isomers. We cannot assign the stereo-
To gain further insight into this reaction, we monitored
chemistry of G and H, however. The pyrrolidinium salts cis- the reactions between 1a-c and PhSeBr, in both CDCl3 and
3d(HBr) and trans-3d(HBr) appeared only as one unattrib- CD3CN, by 77Se NMR. As indicated in Scheme 2, the ther-
utable stereoisomer (Figure 3, structures I and J). As shown modynamic addition products 5a, 5b, and 5c, their ammo-
in Table 2 (entries 14, 15), a change of an isopropyl group nium salts 5a(HBr), 5b(HBr), and 5c(HBr) and the β-
for a tert-butyl substituent, resulted in two close signals bromo dibromoselenuranes 8b and 8c were characterized by
(∆δSe ϭ 0.2) observed for cis-2e(HBr), with structures E their 77Se chemical shifts. The adducts 5d, 5g, 5i, and 5k
and F. Compound trans-2e(HBr) appeared as an unique ste- were also detected at the beginning of the reaction when
reoisomer (δSe ϭ 260.5) analogous to the major one (δSe
ϭ
PhSeBr (1 equiv.) was added to the corresponding amine 1
262.7) observed for trans-2d(HBr). We believe that this ma- (Figure 4). No iodo intermediates were observed when
Eur. J. Org. Chem. 2002, 995Ϫ1006
997

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
Table 2. 2(HX)/3(HX) salt composition of the selenium-induced cyclization of N-benzyl homoallylamines 1 in the absence of Na2CO3
(PhSeX, 1.2 equiv., CDCl3 or MeCN, room temp., 24 h)
Entry
X
Substrate
Solvent
77Se NMR (δ ppm)[a][b]
Composition (%)
2(HX)
3(HX)
2(HX)
3(HX)
No.
R1
R2
cis
trans
cis
trans
cis
trans
cis
trans
1
2
3
4
5
6
7
8
Br
Br
I
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
H
H
H
H
Me
Me
Me
Et
Et
Et
iPr
H
H
H
H
H
H
H
H
H
H
H
CDCl3
CH3CN
CDCl3
CH3CN
270.7
270.7
271.8
271.8
274.6
274.6
275.5
273.3
273.3
275.2
270.1
270.3
270.1
270.3
273.7
273.9
273.1
273.3
273.1
273.3
273.5
277.5
385.3
385.3
386.0
386.0
384.9
384.9
386.2
378.4
378.4
380.2
359.7
12
16
24
16
24
25
45
40
42
58
38
88
84
76
84
19
16
17
13
17
24
16
I
[c][d]
Br
Br
I
Br
Br
I
CDCl3
271.1
271.1
274.0
271.3
271.3
273.8
262.7
275.8
262.7
275.8
265.4
279.9
260.5
396.7
396.7
395.9
394.7
394.7
390.3
382.6
6
8
17
51
51
21
47
41
18
31
CH3CN[c][d]
CH3CN
[c][e]
CDCl3
9
10
11
CH3CN
CH3CN
CDCl3
Br
15
20
18
22
30
29
12
13
14
15
Br
I
1d
1d
1e
1e
iPr
H
H
H
H
CH3CN
CH3CN
CDCl3
359.7
362.3
352.5
352.5
382.6
380.0
373.5
373.5
46
56
44
50
13
14
14
9
21
12
20
11
iPr
Br
Br
tBu
tBu
CH3CN
260.5
16
17
18
19
20
21
22
23
24
25
26
27
28
I
Br
I
Br
Br
I
Br
Br
Br
I
1e
1f
1f
1g
1g
1g
1h
1i
tBu
Ph
Ph
Me
Me
Me
Ph
Et
H
H
H
Me
Me
Me
Me
Et
Et
Et
CH3CN
265.6
276.2
354.1
396.1
372.9
416.9
55
45
5
17
11
48
[c]
CDCl3
CH3CN
CDCl3
Complex mixture of products
274.0
274.0
274.1
411.7; 417.9
411.7; 417.9
/
77
80
100
100
85
6; 17
6; 14
0
0
15
7
0
0
10
0
CH3CN
CH3CN
CH3CN
265.3; 265.3[f]
269.3; 263.5
269.3; 263.5
271.0; 271.2
270.9; 271.5
271.5; 271.7
270.9
/
[c]
CDCl3
401.9
401.9
/
/
408.7; 411.2
/
1i
Et
Et
Et
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
93
1i
100
100
90
I
Br
I
1j
Me
1k
1k
Ϫ(CH2)5Ϫ
ЈЈ
100
[a]
[b]
[c]
[d]
PhSeSePh as internal reference. δSe ϭ 467.0.
Spectra recorded in CDCl3.
Incomplete reaction after 48 h.
Presence of the
[e]
[f]
addition products 5b and 5b(HBr). Presence of the addition products 5c and 5c(HBr). Stereochemistry not assigned.
PhSeI was added. The assignments were corroborated by a and 12 (Scheme 3, entry 2). Bromine treatment of the 15/16
preliminary study of the addition of PhSeX (X ϭ Cl, Br) mixture resulted in the dibromoselenurane 18 derived from
to 1-hexene.
the thermodynamic adduct 16, with only traces of the re-
PhSeBr addition to terminal olefins in CH3CN[17] or gioisomer 17 (entry 4). We were then surprised to find that
[18]
CHCl3 produced mixtures of the two regioisomers. The introduction of a second equivalent of PhSeBr resulted par-
thermodynamic adduct, bearing the PhSe group at the ter- tially in the dibromoselenurane 18. No trace of the isomeric
minal CH2 group, is the major component in equilibrium Se-dibromo complex 17 was detected (entry 5). β-Chloro
with the minor kinetic adduct at room temperature. The dichloroselenuranes, analogous to 14, were obtained by
isomerization of the kinetic addition product of 1-butene treatment of terminal olefins with a large excess of PhSeCl
with PhSeBr occurred in less than 5 min in CH3CN but in CH3CN[20] or CH2Cl2.[21]
required 24 h for the corresponding PhSeCl adduct.[17]
It has also been shown that dihaloselenuranes are easily
Acid catalysis is efficient for the isomerization of the reac- dehalogenated in the presence of PhSeSePh[20,22] and that
tion products of terminal olefins with sulfenyl chlorides.[19] PhSeX3 (X ϭ Cl, Br) adds irreversibly to terminal olefins
We characterized the two addition products derived from to afford the anti-Markovnikov (kinetic) adducts, such as
1-hexene [11 and 12 (PhSeCl)/15 and 16 (PhSeBr)] by their 14 (X ϭ Cl) and 18 (X ϭ Br), as the major products in
77Se chemical shifts (Scheme 3, entries 1 and 3). It should ether at 0 °C.[23]
be noted that the dichloroselenurane 14, derived from the
The reaction between PhSeBr and amine 1c (R1 ϭ Et,
thermodynamic adduct 12, was also formed (7.5%). The 11/ R2 ϭ H) in CD3CN containing Na2CO3 was then mon-
12 and 15/16 ratios were similar to those previously ob- itored by 77Se NMR. Formation of PhSeSePh was immedi-
served.[17,18] The two β-chloro dichloroselenuranes 13 and ately observed with 0.5 molar equiv. of selenium reagent.
14 were also characterized after addition of SO2Cl2 to 11 The pyrrolidine trans-3c and trace amounts of cis-3c ap-
998
Eur. J. Org. Chem. 2002, 995Ϫ1006

Selenium-Induced Cyclization of Secondary Homoallylamines
FULL PAPER
creased, relative to that of pyrrolidine trans-3c, at the ex-
pense of PhSeSePh. The appearance of PhSeSePh in the
early stage of the process is a result of the following equilib-
ria:[2]
3 PhSeBr o PhSeSePh ϩ PhSeBr3
2 PhSeBr o PhSeSePh ϩ Br2
(1)
(2)
The presence of Na2CO3 probably favours the decom-
position of PhSeBr.[24] Under these conditions, PhSeBr3
adds to the olefinic double bond to produce the kinetic di-
bromoselenurane 7, allowing the formation of the pyrrolid-
ines 3(HBr) at the beginning of the reaction through SN2
substitution either before or after the PhSeSePh reduction
of 7 (Scheme 2). The release of bromine explains the pres-
ence of 8, derived from the thermal addition product 5, eas-
ily reduced by PhSeSePh. In absence of Na2CO3, the am-
monium bromides 5(HBr) were detected for R1 ϭ H, Me,
Et (R2 ϭ H). The formation of these salts probably results
from a greater basicity of 5 than of 1, and similarly that of
the products 2 and 3.
Figure 2. 77Se NMR spectra in CDCl3 of: a) 2d (HBr), cis/trans-
3d(HBr) mixture (route B); b) 2d, cis/trans-3d mixture (route A);
c) CF3COOH treatment of mixture b)
At this point, the question was: what is the nature of
the nucleophilic centre involved in the cyclization? It is well
known that PhSeX (X ϭ Cl, Br) reacts instantaneously
with dialkylamines to form unstable selenamides
(PhSeNR1R2),[25,26] after capture of HX by a molar equiva-
lent of amine or in the presence of another base. The 77Se
chemical shifts of some selenenamides were measured some
years ago.[27] The signals of N-(phenylselanyl)morpholine
19[27] and its stable SeϪdichloro adduct 20[28] appeared at
δ ϭ 931 for 19 and δ ϭ 987 for 20 (Figure 5). In this range
of 77Se NMR chemical shifts, we never observed a charac-
teristic signal attributable to a selenenamide 21 derived
from 21(HX).[29]
The acid-catalysed addition of sulfenamides or selenena-
mides to olefins has been described.[30,31] In the reaction
between PhSeX and amines 1, the very reactive interme-
diate 21(HX) must be an efficient PhSeϩ donor to the ol-
efinic double bond. The difference in bond strengths be-
tween the NϪS and NϪSe bonds must explain the lower
reactivity of protonated sulfenamides.[30,31] Actually, to our
surprise, only the PhSCl-induced cyclizations of N-(but-3-
en-1-yl)aniline (Scheme 4) and of 2-allyl-3-benzylpyrrolid-
ine have been studied.[32]
In this work, addition of PhSCl to the double bond was
carried out after protonation of the amino group, to avoid
the formation of the corresponding sulfenamide. The intro-
duction of K2CO3, favouring the appearance of a thiiran-
ium intermediate, allowed cyclization into 1-phenyl-3-
(phenylsulfanyl)pyrrolidine without any trace of 1-phenyl-2-
(phenylsulfanyl)methylazetidine. Under these experimental
Figure 3. 77Se NMR structure determination of salts cis/trans-
2d(HBr); cis/trans-3d(HBr), and cis/trans-2e(HBr)
peared progressively. The azetidines cis-2c and trans-2c were conditions, the amino group was the nucleophile in this
then slowly formed after the introduction of 1.0 molar case.
equiv. of PhSeBr. Azetidines cis-2c, trans-2c and pyrrolidine
Coming back to the reaction between amines 1 and
cis-3c were present, in similar ratios, after a 2 h reaction PhSeX (X ϭ Cl, Br, I), we observed that a slight excess of
time at room temperature. Their proportions then in- selenium reagent was needed to obtain total disappearance
Eur. J. Org. Chem. 2002, 995Ϫ1006
999

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
Scheme 2
Figure 5. 77Se NMR characterization of selenenamide derivatives
of the amine. From experiments described below, we sup-
posed that the selenenamide-seleniranium intermediate 9
(Scheme 2) could be also involved in the cyclization process.
Addition of PhSeBr (2 equiv.) to the crude 2a(HBr)/
3a(HBr) salt mixture in CD3CN was monitored by 77Se
NMR. The azetidinium salt 2a(HBr) was completely iso-
merized into a pyrrolidinium salt 3a(HBr), characterized by
a chemical shift (δSe ϭ 379.8) different from that of the
initial signal of 3a(HBr) (δSe ϭ 386.3). We also observed a
Figure 4. 77Se NMR characterization of the bromo intermediates
5, 5 (HBr), and 8 (CDCl3)
Scheme 3
1000
Eur. J. Org. Chem. 2002, 995Ϫ1006

Selenium-Induced Cyclization of Secondary Homoallylamines
FULL PAPER
the stereoisomers K and L of 10a must afford 3a(HBr) with
the structures M and N, respectively.
This unexpected isomerization of 2a(HBr) and 3a(HBr)
was also (in part) observed in CDCl3 (∆δSe ϭ 0.9 ppm) and
upon treatment of 2a(HI)/3a(HI) with PhSeI (∆δSe
ϭ
0.7 ppm). In another experiment, a 70:30 mixture of the
two M and N isomers of 3a (CF3COOH) (δSe ϭ 388.6 and
385.6) was formed by addition of trifluoroacetic acid (1.0
equiv.) to a pure sample of 3a. In all cases, 3a was regener-
ated after aqueous sodium carbonate treatment.
In the selenium-induced isomerization of 2a(HBr) and
3a(HBr), we observed that the 4-exo-trigonal cyclization of
9a to afford 2a(HBr) was not efficient, unlike the direct
Scheme 4
slower decrease of this signal to the benefit of the new peak.
This fact must be interpreted as a partial isomerization of
the initially formed pyrrolidinium salt. At the end of the
process, a 45:55 mixture of isomers was obtained.
formation of 2(HX)/3(HX) mixtures from amines
1
(Table 2). From 1, only one stereoisomer was formed for
each pyrrolidinium salt cis-3(HBr) and trans-3(HBr), while
the isomerization of the 2a(HBr)/3a(HBr) mixture provided
the two stereoisomers of 3a(HBr). These results, coupled
with observations from 77Se NMR analysis of the salt mix-
tures 2d(HBr)/3d(HBr) and 2e(HBr)/3e(HBr) (Figure 3),
prompted us to view the amino group of the seleniranium
halide 6 (Br, I) as probably the nucleophile in the competit-
ive 4-exo-trig and 5-endo-trig cyclization processes
(Scheme 2). The selenenamide-seleniranium halide, such as
9, could only be operative in the formation of the (phenylse-
lanyl)pyrrolidiniuum halides 10. The efficiency of the reac-
tion in the absence of Na2CO3 must be the consequence of
greater basicity in the cyclized products 2 and 3, allowing
the deprotonation of 1(HX).
The mechanism suggested for the PhSeBr-induced iso-
merization of 2a(HBr) and 3a (HBr) is depicted in
Scheme 5. A second molar equivalent of PhSeBr must assist
the opening of 2a(HBr) and of 3a(HBr) with formation of
the (phenylselanyl)ammonium-seleniranium salt 9a(HBr).
The selenenamide group of 9a is suggested as the nucleo-
philic centre, affording the (phenylselanyl)pyrrolidinium
bromide 10a (mixture of the two stereoisomers K and L,
Scheme 6). Under acidic conditions, the formation of the
pyrrolidinium salt must occur stereoselectively, and the two
isomers of 3a(HBr) are obtained. As shown in Scheme 6,
The efficiency of the 4-exo-trig process, affording cis and
trans azetidines 2, increases progressively according to the
size of R1 (R2 ϭ H). This fact also agrees with the geminal
α-effect governing the formation of small rings[11,12] when
two α-substituents are present (Tables 1 and 2). The ste-
reoisomer ratios of azetidines 2(HX) were found to be
slightly greater (Route B) than those of the corresponding
azetidines 2 (Route A).
We were surprised to obtain only the azetidinium salts
2(HI) when amines 1g to 1k (R1, R2 ϶ H) were treated with
PhSeI (Table 2, entries 21, 22, 25, 26, 28). Regarding the
cis/trans azetidine ratios, we observed that cis-2 and cis-
2(HX) were always the major isomers. This result could be
explained by a greater stability of the cis isomers and a
greater reactivity of the corresponding diastereoisomeric se-
leniranium intermediates 6.
Scheme 5
Conclusions
77Se NMR analysis of the crude mixtures of products
formed by PhSeX-induced cyclization of N-benzyl homoal-
lylamines 1 in CH3CN containing Na2CO3, has permitted
the characterization of cis and trans azetidines 2 and cis
and trans pyrrolidines 3 through their 77Se chemical shifts.
The relative proportions of each isomer were measured, as
well as those of the corresponding HX salts (X ϭ Br, I)
when the reaction was carried out in the absence of
Na2CO3. The structures of cis-2d(HBr), trans-2d(HBr), cis-
Scheme 6
Eur. J. Org. Chem. 2002, 995Ϫ1006
1001

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
bromide, THF).[35] The α,α-disubstituted amines 1gϪ1k were ob-
tained by reductive allylation of the corresponding ketimines (allyl-
magnesium chloride in ether, THF, Ϫ20 °C). All amines were puri-
fied by distillation under reduced pressure or silica gel chromato-
graphy (CH2Cl2/hexane, 40:60). Some are known compounds:
1b,[36,37] 1c,[38] 1d,[38] 1f,[39] 1h,[40] 1i,[41] and 1k.[40]
3d(HBr), and trans-3d(HBr) were studied and some reac-
tions between PhSeBr and amines 1a, 1b, 1c and 1d were
monitored by 77Se NMR. The thermal addition products 5,
5(HBr), and dibromoselenuranes 8 were characterized after
a preliminary study involving the addition of PhSeX (X ϭ
Cl, Br) to 1-hexene. Compounds 2(HI) and 3(HI) were
formed, without any traces of iodo intermediates, when
PhSeI was used.
N-Benzyl-2,2-dimethylhex-5-en-3-ylamine (1e): Oil, b.p.0.02 80 °C.
1
77% yield. H NMR: δ ϭ 0.97 (s, 9 H, tBu), 1.20 (br, 1 H, NH),
1.88Ϫ2.08 (m, 1 H, 4-H), 2.20Ϫ2.30 (m, 1 H, 4-H), 2.40Ϫ2.55 (m,
The proportions of 2 and 2(HX) increased with the size
of R1 (R2 ϭ H) and when two substituents were present
on the carbon linked to the nucleophilic centre. The same
proportions also increased with the nature of the selenium
reagent, in the order PhSeCl Ͻ PhSeBr Ͻ PhSeI. Azetidines
2 and their salts 2(HX) resulted from a 4-exo-trigonal ring-
closure involving the seleniranium intermediates 6(X), kin-
etically favoured by a geminal α-effect (R1, R2 ϶ H).[11,12]
PhSeI treatment of amines 1g to 1k allowed the isolation
of 1-benzyl-2,2-dialkyl-4-(phenylselanylmethyl)azetidines
2g to 2k after neutralisation, without any traces of the cor-
responding pyrrolidines 3. This fact is not very useful for
synthetic purposes, the amine not being completely con-
sumed.
1 H, 3-H), 3.72 (d, JAB ϭ 13.7 Hz, 1 H, Bn), 3.87 (d, JAB
ϭ
13.7 Hz, 1 H, Bn), 5.02Ϫ5.16 (m, 2 H, 6-H), 5.92 (m, 1 H, 5-H),
7.22Ϫ7.45 (m, 5 H, Ph). 13C NMR: δ ϭ 27.1(Me), 35.8 (C-2), 36.4
(C-4), 55.3 (CH2Ph), 66.4 (C-3), 116.3 (C-6), 126.8, 128.2, 128.3,
137.9 (C-5), 141.3. C15H23N: calcd. C 82.95, H 10.60, N 6.45; found
C 82.84, H 10.54, N 6.53.
N-Benzyl-2-methylpent-4-en-2-ylamine (1g): Oil, b.p.0.02 65 °C. 66%
1
yield. H NMR: δ ϭ 1.07 (s, 6 H, Me), 1.33 (br, 1 H, NH), 2.17
(d, J ϭ 7.4 Hz, 2 H, 3-H), 3.59 (s, 2 H, Bn), 4.98Ϫ5.08 (m, 2 H,
5-H), 5.80 (m, 1 H, 4-H), 7.18Ϫ7.30 (m, 5 H, Ph). 13C NMR: δ ϭ
27.0 (Me), 45.2 (C-3), 46.6 (CH2Ph), 52.6 (C-2), 117.7 (C-5), 126.7,
128.2, 128.3, 134.8 (C-4), 141.2. C13H19N: calcd. C 82.54, H 10.05,
N 7.41; found C 82.45, H 10.11, N 7.37.
As described in the following paper,[16] treatment of 1b
to 1f (R2 ϭ H) with an excess of PhSeX (X ϭ Cl, Br) af-
forded β-halopyrrolidines. Amines 1g to 1k (R2 ϶ H), how-
ever, treated with an excess of PhSeBr in the presence of
Na2CO3, afforded the corresponding azetidines 2, in very
good yields, after chromatographic elimination of the minor
pyrrolidines 3.
N-Benzyl-3-methylhex-5-en-3-ylamine (1j): Oil, b.p.0.02 79 °C. 63%
1
yield. H NMR: δ ϭ 0.91 (t, J ϭ 7.4 Hz, 3 H, Me), 1.07 (s, 3 H,
Me), 1.30 (br, 1 H, NH), 1.46 (m, 2 H, MeCH2), 2.22 (dd, J ϭ 4.7,
5.9 Hz, 2 H, 4-H), 3.66 (s, 2 H, Bn), 5.05Ϫ5.15 (m, 2 H, 6-H), 5.85
(m, 1 H, 5-H), 7.22Ϫ7.38 (m, 5 H, Ph). 13C NMR: δ ϭ 7.9 (C-1),
24.3 (Me), 31.0 (C-2), 42.9 (C-4), 46.2 (CH2Ph), 54.8 (C-3), 117.5
(C-6), 126.8, 128.3, 128.4, 134.9 (C-5), 141.5. C14H21N: calcd. C
82.76, H 10.34, N 6.89; found C 82.51, H 10.29, N 6.93.
This work is now being extended to the PhSeX-induced
cyclization of β-, γ-, or δ- substituted secondary homoal-
lylamines. An asymmetric version of this reaction, using
chiral substrates, is also being studied. For comparison, the
PhSCl-induced cyclization of amines 1 is under investi-
gation.
PhSeBr-Induced Cyclization of Amines 1 in the Presence of Na2CO3.
General Procedure: A solution of amine 1 (10 mmol) in freshly dis-
tilled acetonitrile (30 mL) containing anhydrous sodium carbonate
(2 g) was treated dropwise at room temp., under inert atmosphere,
with a solution of PhSeBr (15 mmol) in the same solvent (50 mL).
The mixture was stirred for 16 h at room temp. and then treated
with a saturated aq. NaCl solution. After separation, the aqueous
phase was extracted with CH2Cl2 (3 ϫ 20 mL) and the organic
layers were dried and the solvents evaporated under reduced pres-
sure. The residual oil was chromatographed on silica gel. Diphenyl-
diselenide was first eliminated by cyclohexane elution. The pyrroli-
dine cis-3 (R2 ϭ H) was next eluted with a cyclohexane/CH2Cl2
mixture (90:10) followed by the pyrrolidine trans-3 (R2 ϭ H) (80:20
mixture of the same solvents). The azetidine cis-2 (R2 ϭ H) was
then isolated (cyclohexane/CH2Cl2, 70:30). Azetidines trans-2b and
trans-2c slowly isomerized during the chromatographic separation
into trans-3b and trans-3c, respectively. Samples of trans-2d, trans-
2e and trans-2f were obtained (cyclohexane/CH2Cl2, 60:40).
Experimental Section
General: Solvents were purified by conventional methods prior to
use. TLC was performed on Merck 60F-250 silica gel plates and
column chromatography over SI 60 silica gel (230Ϫ240 mesh). Mps
were taken on a Kofler apparatus and were uncorrected. Elemental
analyses were carried out on a CarloϪErba EA 1100 analyser.
NMR spectra were recorded on a Bruker DPX 300 spectrometer
operating at 300 MHz for hydrogen and 75.4 MHz for carbon. This
probe was equipped with pulsed-field (z) gradients. 77Se NMR
spectra were recorded at 21 °C on a Bruker DPX 400 spectrometer
operating at 76.29 MHz for 77Se, with a 19 µs pulse length (90°
pulse ϭ 19 µs) and an optimized relaxation delay of 2 s, which is
rather low compared to T1 observed for dialkylated selenide.[33] An
average of 1500 scans for 77Se NMR was necessary to provide reli-
The azetidines 2gϪ2k were synthesized, in better yield,[5] after sep-
aration from the minor pyrrolidine 3 (cyclohexane/CH2Cl2, 90:10)
when an excess of PhSeBr (2.5 equiv.) was used in the same experi-
mental conditions.
able information. Chemical shifts (δ) are expressed in ppm relative Cyclization of Amine 1a (85% overall yield):
to TMS for H and 13C nuclei and to Me2Se for 77Se nuclei; coup-
ling constants (J) are given in Hertz; coupling multiplicities are
reported using conventional abbreviations.
1
1-Benzyl-3-(phenylselanyl)pyrrolidine (3a): Flash chromatography
(cyclohexane/CH2Cl2, 85:15). Oil. 2.050 g, 65% yield. 1H NMR:
δ ϭ 1.93 (m, 1 H, 4-H), 2.38 (m, 1 H, 4-H), 2.51Ϫ2.74 (m, 3 H, 2-
N-benzyl-but-3-en-1-ylamine 1a was prepared by
a known H and 5-H), 3.10 (dd, J ϭ 7.2, 10.1 Hz, 1 H, 2-H), 3.59 (d, 1 H,
method.[34] The homoallylic amines 1b؊1f were synthesised by a JAB ϭ 12.9 Hz, Bn), 3.68 (d, 1 H, JAB ϭ 12.9 Hz, Bn), 3.77 (m, 1
Barbier-like reaction from the corresponding aldimines (Mg, allyl
1002
H, 3-H), 7.20Ϫ7.35 (m, 8 H), 7.46Ϫ7.54 (m, 2 H). 13C NMR: δ ϭ
Eur. J. Org. Chem. 2002, 995Ϫ1006

Selenium-Induced Cyclization of Secondary Homoallylamines
32.5 (C-4), 37.6 (C-3), 53.1 (C-5), 59.7 (CH2Ph), 61.0 (C-2), 126.7, (d, 1 H, JAB ϭ 13.0 Hz, Bn), 7.20Ϫ7.30 (m, 8 H), 7.45Ϫ7.47 (m, 2
FULL PAPER
128.0, 128.4, 128.7, 130.4, 132.9, 138.5. C17H19NSe: calcd. C 64.55,
H 6.05, N 4.42; found C 64.42, H 6.18, N 4.75.
H). 13C NMR: δ ϭ 10.1 (Me), 26.1 (CH2Me), 36.1 (C-4), 38.6 (C-
3), 58.0 (C-5), 61.3 (CH2Ph), 64.6 (C-2),126.8, 128.1, 128.7, 129.3,
132.2, 133.1, 139.0. C19H23NSe: calcd. C 66.27, H 6.73, N 4.07;
found C 65.91, H 6.63, N 3.72.
1-Benzyl-2-(phenylselanylmethyl)azetidine (2a): Flash chromato-
graphy (cyclohexane/CH2Cl2, 1:1). Oil. 0.140 g, Ͻ 5% yield. 1H
NMR: δ ϭ 1.89 (m, 1 H, 3-H), 2.10 (m, 1 H, 3-H), 2.79 (dd, J ϭ
1.5, 7.4 Hz, 1 H, 2-H), 2.86 (m, 2 H, CH2SePh), 3.32 (m, 2 H, 4-
H), 3.56 (d, 1 H, JAB ϭ 12.5 Hz, Bn), 3.73 (d, 1 H, JAB ϭ 12.5 Hz,
Bn), 7.18Ϫ7.50 (m, 10 H, Ph). 13C NMR: δ ϭ 24.5 (C-3), 33.0
(CH2SePh), 50.6 (C-4), 62.5 (CH2Ph), 65.5 (C-2), 126.6, 127.1,
128.6, 128.9, 132.3, 137.6.
cis-1-Benzyl-2-ethyl-4-(phenylselanylmethyl)azetidine (2c): Flash
chromatography (cyclohexane/CH2Cl2, 75:25). Oil. 0.512 g, 15%
1
yield. H NMR: δ ϭ 0.75 (t, J ϭ 7.4 Hz, 3 H, Me), 1.30Ϫ1.44 (m,
3 H, CH2Me and 3-H), 2.23 (m, 1 H, 3-H), 2.73 (d, J ϭ 6.4 Hz, 2
H, CH2SePh), 2.81 (m, 1 H, 2-H), 3.10 (m, 1 H, 4-H), 3.57 (d, 1
H, JAB ϭ 12.5 Hz, Bn), 3.69 (d, 1 H, JAB ϭ 12.5 Hz, Bn),
7.15Ϫ7.40 (m, 10 H). 13C NMR: δ ϭ 9.4 (Me), 29.1 (CH2Me), 30.2
(C-3), 33.6 (CH2SePh), 61.6 (C-4), 62.0 (CH2Ph), 63.2(C-2), 126.4,
126.9, 128.0, 128.8, 129.3, 132.1, 133.1, 138.5. C19H23NSe: calcd.
C 66.27, H 6.73, N 4.07; found C 66.01, H 6.93, N 3.98.
Cyclization of Amine 1b (82% overall yield):
cis-1-Benzyl-2-methyl-4-(phenylselanyl)pyrrolidine (3b): Flash chro-
matography (cyclohexane/CH2Cl2, 85:15). Oil. 0.230 g, 7% yield.
1H NMR: δ ϭ 1.27 (d, J ϭ 5.7 Hz, 3 H, Me), 1.73 (m, 1 H, 3-H),
2.58 (m, 2 H, 2-H and 3-H), 2.73 (dd, J ϭ 7.6, 10.7 Hz, 1 H, 5-H),
3.15 (dd, J ϭ 3.1, 10.7 Hz, 1 H, 5-H), 3.31 (d, 1 H, JAB ϭ 13.5 Hz,
Bn), 3.71 (m, 1 H, 4-H), 4.12 (d, 1 H, JAB ϭ 13.5 Hz, Bn),
7.20Ϫ7.38 (m, 8 H), 7.45Ϫ7.50 (m, 2 H). 13C NMR: δ ϭ 18.9 (Me),
36.6 (C-4), 41.8 (C-3), 57.0 (C-5), 57.1 (C-2), 61.0 (CH2Ph), 126.9,
128.2, 128.8, 130.9, 133.2.
Cyclization of Amine 1d (88% overall yield):
cis-1-Benzyl-2-isopropyl-4-(phenylselanyl)pyrrolidine (3d): Flash
chromatography (cyclohexane/CH2Cl2, 90:10). m.p. 41 °C. 0.320 g,
1
9% yield. H NMR: δ ϭ 0.92 (d, J ϭ 6.9 Hz, 3 H, Me), 0.96 (d,
J ϭ 6.9 Hz, 3 H, Me), 1.77 (m, 1 H, 3-H), 2.00 (m, 1 H, CHMe2),
2.28 (m, 1 H, 3-H), 2.48 (m, 1 H, 2-H), 2.68 (dd, J ϭ 7.4, 10.5 Hz,
1 H, 5-H), 3.07 (dd, J ϭ 3.7, 10.5 Hz, 1 H, 5-H), 3.22 (d, 1 H,
trans-1-Benzyl-2-methyl-4-(phenylselanyl)pyrrolidine (3b): Flash
chromatography (cyclohexane/CH2Cl2, 80:20). Oil. 0.525 g, 16%
JAB ϭ 13.2 Hz, Bn), 3.62 (m, 1 H, 4-H), 4.05 (d, 1 H, JAB
ϭ
1
yield. H NMR: δ ϭ 1.15 (d, J ϭ 6.0 Hz, 3 H, Me), 2.06 (m, 2 H,
13.2 Hz, Bn), 7.20Ϫ7.35 (m, 8 H), 7.43Ϫ7.50 (m, 2 H). 13C NMR:
δ ϭ 15.5 (Me), 20.1 (Me), 28.3 (CHMe2), 33.7 (C-3), 37.2 (C-4),
57.7 (C-5), 61.2 (CH2Ph), 69.3 (C-2), 126.8, 128.1, 128.2, 128.8,
133.3. C20H25NSe: calcd. C 67.03, H 7.03, N 3.91; found C 66.98,
H 7.24, N 3.97.
3-H), 2.28 (dd, J ϭ 8.4, 9.9 Hz, 1 H, 5-H), 2.64 (m, 1 H, 2-H), 3.17
(d, 1 H, JAB ϭ 12.9 Hz, Bn), 3.31 (dd, J ϭ 7.3, 9.9 Hz, 1 H, 5-H),
3.68 (m, 1 H, 4-H), 4.00 (d, 1 H, JAB ϭ 12.9 Hz, Bn), 7.20Ϫ7.30
(m, 8 H), 7.42Ϫ7.48 (m, 2 H). 13C NMR: δ ϭ 18.7 (Me), 35.7 (C-
4), 41.5 (C-3), 57.7 (C-5), 58.5 (C-2), 61.1 (CH2Ph), 126.8, 128.1,
128.7, 133.0, 139.0. C18H21NSe: calcd. C 65.45, H 6.41, N 4.24;
found C 65.15, H 6.34, N 4.54.
trans-1-Benzyl-2-isopropyl-4-(phenylselanyl)pyrrolidine (3d): Flash
chromatography (cyclohexane/CH2Cl2, 85:15). Oil. 0.135 g, Ͻ 5%
1
yield. H NMR: δ ϭ 0.89 (d, J ϭ 6.7 Hz, 3 H, Me), 0.91 (d, J ϭ
cis-1-Benzyl-2-methyl-4-(phenylselanylmethyl)azetidine (2b): Flash
6.7 Hz, 3 H, Me), 1.82 (m, 1 H, 3-H), 1.96 (m, 1 H, CHMe2), 2.14
(m, 1 H, 3-H), 2.28 (dd, J ϭ 6.7, 9.5 Hz, 1 H, 5-H), 2.58 (m, 1 H,
2-H), 3.17 (d, 1 H, JAB ϭ 13.1 Hz, Bn), 3.28 (dd, J ϭ 9.2, 9.6 Hz,
1 H, 5-H), 3.57 (m, 1 H, 4-H), 4.02 (d, 1 H, JAB ϭ 13.1 Hz, Bn),
7.18Ϫ7.30 (m, 8 H), 7.43Ϫ7.50 (m, 2 H). 13C NMR: δ ϭ 15.3 (Me),
20.0 (Me), 28.4 (CHMe2), 33.3 (C-3), 36.8 (C-4), 58.3 (C-5), 61.4
(CH2Ph), 68.2 (C-2), 126.7, 126.9, 128.1, 128.5, 128.9, 133.3.
C20H25NSe: calcd. C 67.03, H 7.03, N 3.91; found C 66.75, H 6.68,
N 4.26.
chromatography (cyclohexane/CH2Cl2, 75:25). Oil. 0.395 g, 12%
yield. H NMR: δ ϭ 1.03 (d,3 H, J ϭ 6.0 Hz, Me), 1.42 (m,1 H,
1
3-H), 2.27 (m,1 H, 3-H), 2.82 (m,2 H, CH2SePh), 2.99 (m,1 H, 2-
H), 3.15 (m,1 H, 4-H), 3.65 (s,2 H, Bn), 7.18Ϫ7.30 (m, 8 H),
7.35Ϫ7.45 (m, 2 H). 13C NMR: δ ϭ 21.8 (Me), 32.6 (C-3), 33.5
(CH2SePh), 58.0 (C-2), 61.6 (CH2Ph), 62.0 (C-4), 126.5, 127.0,
128.1, 128.8, 129.4, 133.1, 138.1. C18H21NSe: calcd. C 65.45, H
6.41, N 4.24; found C 65.56, H 6.62, N 4.39.
Cyclization of Amine 1c (84% overall yield):
cis-1-Benzyl-2-isopropyl-4-(phenylselanylmethyl)azetidine
(2d):
cis-1-Benzyl-2-ethyl-4-(phenylselanyl)pyrrolidine (3c): Flash chro-
matography (cyclohexane/CH2Cl2, 85:15). Oil. 0.308 g, 9% yield.
1H NMR: δ ϭ 0.90 (t, 3 H, J ϭ 7.45 Hz, Me), 1.42 (m, 1 H,
CH2Me), 1.70 (dd, J ϭ 5.0, 6.4 Hz, 1 H, 3-H), 1.76 (m, 1 H,
CH2Me), 2.42Ϫ2.51 (m, 2 H, 2-H and 3-H), 2.67 (dd, J ϭ 7.4,
10.6 Hz, 1 H, 5-H), 3.07 (dd, J ϭ 3.3, 10.6 Hz, 1 H, 5-H), 3.25 (d,
Flash chromatography (cyclohexane/CH2Cl2, 75:25). Oil. 0.935 g,
1
26% yield. H NMR: δ ϭ 0.82 (d, J ϭ 6.7 Hz, 3 H, Me), 0.89 (d,
J ϭ 6.7 Hz, 3 H, Me), 1.45 (m, 1 H, 3-H), 1.64 (m, 1 H, CHMe2),
2.22 (m, 1 H, 3-H), 2.58Ϫ2.70 (m, 3 H, 2-H and CH2SePh), 3.09
(m, 1 H, 4-H), 3.47 (d, 1 H, JAB ϭ 12.6 Hz, Bn), 3.89 (d, 1 H,
JAB ϭ 12.6 Hz, Bn), 7.22Ϫ7.33 (m, 10 H). 13C NMR: δ ϭ 17.5
(Me), 18.9 (Me), 27.8 (C-3), 33.7 (CH2SePh), 34.0 (CHMe2), 61.1
(C-4), 62.9 (CH2Ph), 68.0 (C-2), 126.3, 127.0, 128.0, 128.7, 129.3,
132.0. C20H25NSe: calcd. C 67.03, H 7.03, N 3.91; found C 67.13.
H, 7.39, N 4.14.
1 H, JAB ϭ 13.6 Hz, Bn), 3.63 (m, 1 H, 4-H), 4.03 (d, 1 H, JAB
ϭ
13.6 Hz, Bn), 7.20Ϫ7.32 (m, 8 H), 7.45Ϫ7.47 (m, 2 H). 13C NMR:
δ ϭ 10.2 (Me), 26.0 (CH2Me), 36.9 (C-4), 38.7 (C-3), 57.3(C-5),
61.0 (CH2Ph), 65.4 (C-2), 126.8, 128.1, 128.9, 131.0, 133.2.
C19H23NSe: calcd. C 66.27, H 6.73, N 4.07; found C 66.56, H 6.52,
N 4.21.
trans-1-Benzyl-2-isopropyl-4-(phenylselanylmethyl)azetidine
(2d):
trans-1-Benzyl-2-ethyl-4-(phenylselanyl)pyrrolidine (3c): Flash chro-
Flash chromatography (cyclohexane/CH2Cl2, 60:40). Oil. 0.165 g,
1
matography (cyclohexane/CH2Cl2, 80:20). Oil. 0.345 g, 10% yield. Ͻ 5% yield. H NMR: δ ϭ 0.77 (dd, 6 H, J ϭ 2.6, 6.7 Hz, Me),
1H NMR: δ ϭ 0.89 (t, J ϭ 7.4 Hz, 3 H, Me), 1.37 (m, 1 H, 1.64 (m, 1 H, CHMe2), 1.72 (m, 1 H, 3-H), 2.00 (m, 1 H, 3-H),
CH2Me), 1.73 (m,1 H, CH2Me), 2.06 (m, 2 H, 3-H), 2.30 (t,1 H, J 2.92Ϫ3.08 (m, 2 H, CH2SePh), 3.19 (m, 1 H, 2-H), 3.57 (m, 1 H,
ϭ 9.4 Hz, 5-H), 2.54 (m, 1 H, 2-H), 3.20 (d, 1 H, JAB ϭ 13 Hz, 4-H), 3.69 (d, 1 H, JAB ϭ 14.2 Hz, Bn), 3.81 (d, 1 H, JAB ϭ 14.2 Hz,
Bn), 3.31 (dd, J ϭ 7.1, 9.8 Hz, 1 H, 5-H), 3.65 (m, 1 H, 4-H), 4.01
Bn), 7.05Ϫ7.26 (m, 10 H).
Eur. J. Org. Chem. 2002, 995Ϫ1006
1003

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
Cyclization of Amine 1e (87% overall yield):
trans-1-Benzyl-2-phenyl-4-(phenylselanylmethyl)azetidine (2f): Flash
chromatography (cyclohexane/CH2Cl2, 60:40). Oil. 0.161 g, Ͻ 5%
yield. H NMR: δ ϭ 2.30 (m, 2 H, 3-H), 3.10 (m, 2 H, CH2SePh),
3.53 (d, 1 H, JAB ϭ 13.8 Hz, Bn), 3.64 (d, 1 H, JAB ϭ 13.8 Hz,
Bn), 3.84 (m, 1 H, 4-H), 4.58 (dd, J ϭ 6.0, 7.7 Hz, 1 H, 2-H),
7.10Ϫ7.40 (m, 15 H). 13C NMR: δ ϭ 30.0 (C-3), 33.0 (CH2SePh),
54.0 (CH2Ph), 60.2 (C-4), 64.6 (C-2), 126.5, 126.7, 127.3, 127.5,
128.1, 128.3, 128.9, 129.9, 131.7, 138.9, 141.6.
trans-1-Benzyl-2-tert-butyl-4-(phenylselanyl)pyrrolidine (3e): Flash
chromatography (cyclohexane/CH2Cl2, 90:10). Oil. 0.180 g, Ͻ 5%
1
1
yield. H NMR: δ ϭ 0.92 (s, 9 H, tBu), 1.98 (m, 1 H, 3-H), 2.15
(m, 1 H, 3-H), 2.45 (dd, J ϭ 8.6, 10.1 Hz, 1 H, 5-H), 2.73 (dd, J ϭ
4.0, 9.4 Hz, 1 H, 2-H), 3.27 (dd, J ϭ 5.8, 10.1 Hz, 1 H, 5-H), 3.62
(m, 1 H, 4-H), 3.62 (d, 1 H, JAB ϭ 13.9 Hz, Bn), 4.15 (d, 1 H,
JAB ϭ 13.9 Hz, Bn), 7.15Ϫ7.37 (m, 8 H), 7.45Ϫ7.50 (m, 2 H). 13C
NMR: δ ϭ 26.8 (Me), 35.6 (C-3), 39.5 (C-4), 62.0 (C-5), 63.2
(CH2Ph), 72.7 (C-2), 126.5, 127.0, 127.8, 128.1, 128.9, 133.6.
Cyclization of Amine 1g (90% overall yield):
1-Benzyl-2,2-dimethyl-4-(phenylselanyl)pyrrolidine (3g): Flash chro-
matography (cyclohexane/CH2Cl2, 75:25). Oil; 0.150 g, Ͻ 5% yield.
1H NMR: δ ϭ 1.10 (s, 3 H, Me), 1.16 (s, 3 H, Me), 1.89 (dd, J ϭ
6.7, 13.2 Hz, 1 H, 3-H), 2.26 (dd, J ϭ 9.3, 13.2 Hz, 1 H, 3-H), 2.81
(dd, J ϭ 6.5, 10.2 Hz, 1 H, 5-H), 3.07 (dd, J ϭ 8.0, 10.2 Hz, 1 H,
cis-1-Benzyl-2-tert-butyl-4-(phenylselanylmethyl)azetidine
(2e):
Flash chromatography (cyclohexane/CH2Cl2, 85:15). m.p. 32 °C.
0.860 g, 23% yield. 1H NMR: δ ϭ 0.88 (s, 9 H, tBu), 1.47 (m, 1 H,
3-H), 2.09 (m, 1 H, 3-H), 2.54 (m, 2 H, CH2SePh), 2.72 (m, 1 H,
2-H), 3.01 (m, 1 H, 4-H), 3.38 (d, 1 H, JAB ϭ 12.8 Hz, Bn), 3.94
(d, 1 H, JAB ϭ 12.8 Hz, Bn), 7.15Ϫ7.35 (m, 10 H). 13C NMR: δ ϭ
25.1 (C-3), 25.8 (Me), 33.4 (CH2SePh), 48.0 (CMe3), 60.9 (C-4),
63.5 (CH2Ph), 70.8 (C-2), 126.2, 126.4, 127.9, 128.7, 129.1, 131.7.
C21H27NSe: calcd. C 67.73, H 7.31, N 3.76; found C 67.64, H 7.37,
N 4.02.
5-H), 3.49 (d, 1 H, JAB ϭ 13.4 Hz, Bn), 3.58 (d, 1 H, JAB
ϭ
13.4 Hz, Bn), 3.70 (m, 1 H, 4-H), 7.18Ϫ7.50 (m, 10 H). 13C NMR:
δ ϭ 23.2 (Me), 23.7 (Me), 35.1 (C-4), 48.0 (C-3), 52;0 (C-5), 58.4
(CH2Ph), 60.5 (C-2), 126.5, 126.7, 128.0, 128.1, 129.8, 131.7, 132.9.
C19H23NSe: calcd. C 66.26, H 6.73, N 4.06; found C 65.92, H 6.58,
N 4.18.
trans-1-Benzyl-2-tert-butyl-4-(phenylselanylmethyl)azetidine
(2e):
1-Benzyl-2,2-dimethyl-4-(phenylselanylmethyl)azetidine (2g): Flash
chromatography (cyclohexane/CH2Cl2, 65:35). Oil. 2.465 g, 72%
yield. 1H NMR: δ ϭ 1.08 (s, 3 H, Me), 1.19 (s, 3 H, Me), 1.65 (dd,
J ϭ 7.9, 10.3 Hz, 1 H, 3-H), 1.92 (dd, J ϭ 7.4, 10.3 Hz, 1 H, 3-H),
2.66Ϫ2.86 (m, 2 H, CH2SePh), 3.34 (m, 1 H, 4-H), 3.51 (d, 1 H,
JAB ϭ 13.1 Hz, Bn), 3.69 (d, 1 H, JAB ϭ 13.1 Hz, Bn), 7.10Ϫ7.30
(m, 10 H). 13C NMR: δ ϭ 20.7 (Me), 30.5 (Me), 34.2 (CH2SePh),
38.8 (C-3), 54.0 (CH2Ph), 59.2 (C-2), 60.2 (C-4), 126.2, 126.6,
127.8, 128.6, 128.9, 131.9, 139.9. C19H23NSe: calcd. C 66.26, H
6.73, N 4.06; found C 66.58, H 6.78, N 3.98.
Flash chromatography (cyclohexane/CH2Cl2, 70:30). m.p. 46 °C.
1
0.253 g, 7% yield. H NMR: δ ϭ 0.90 (s, 9 H, tBu), 1.66 (m, 1 H,
3-H), 2.14 (m, 1 H, 3-H), 3.06 (q, J ϭ 11.6 Hz, 1 H, 5-H), 3.16 (m,
1 H, 5-H), 3.27 (t, J ϭ 8.0 Hz, 1 H, 2-H), 3.57 (m, 1 H, 4-H), 3.78
(d, 1 H, JAB ϭ 14.5 Hz, Bn), 3.91 (d, 1 H, JAB ϭ 14.5 Hz, Bn),
7.05Ϫ7.15 (m, 4 H), 7.22Ϫ7.35 (m, 6 H). 13C NMR: δ ϭ 26.0 (C-
3), 26.4 (Me), 28.7 (CH2SePh), 34.2 (CMe3), 55.5 (CH2Ph), 56.7
(C-4), 72.2 (C-2), 126.6, 127.0, 127.9, 128.2, 128.8, 129.4, 131.4,
140.4. C21H27NSe: calcd. C 67.73, H 7.31, N 3.76; found C 67.34,
H 7.35, N 4.10.
Cyclization of Amine 1h (92% overall yield):
Cyclization of Amine 1f (82% overall yield):
cis-1-Benzyl-2-methyl-2-phenyl-4-(phenylselanyl)pyrrolidine
(3h):
cis-1-Benzyl-2-phenyl-4-(phenylselanyl)pyrrolidine(3f): Flash chro-
matography (cyclohexane/CH2Cl2, 90:10). m.p. 35 °C. 0.387 g, 10%
yield. H NMR: δ ϭ 1.97 (m, 1 H, 3-H), 2.70 (m, 1 H, 3-H), 2.75
Flash chromatography (cyclohexane/CH2Cl2, 85:15). Oil. 0.180 g,
1
1
Ͻ 5% yield. H NMR: δ ϭ 1.44 (s, 3 H, Me), 2.19 (dd, J ϭ 8.0,
13.3 Hz, 1 H, 3-H), 2.38 (dd, J ϭ 10.4, 13.3 Hz, 1 H, 3-H), 3.04
(dd, J ϭ 8.3, 10.7 Hz, 1 H, 5-H), 3.17 (d, 1 H, JAB ϭ 13.5 Hz, Bn),
3.27 (dd, J ϭ 3.6, 10.7 Hz, 1 H, 5-H), 3.59 (d, 1 H, JAB ϭ 13.5 Hz,
Bn), 3.83 (m, 1 H, 4-H), 7.15Ϫ7.66 (m, 15 H). 13C NMR: δ ϭ 16.9
(Me), 37.1 (C-4), 52.0 (C-3), 53.0 (C-5), 58.0 (CH2Ph), 62.6 (C-2),
126.8, 128.1, 128.7, 129.3, 132.2, 133.1, 139.0.
(dd, J ϭ 2.7, 10.5 Hz, 1 H, 5-H), 3.09 (d, 1 H, JAB ϭ 13.6 Hz, Bn),
3.28 (dd, J ϭ 2.6, 10.5 Hz, 1 H, 5-H), 3.48 (dd, J ϭ 7.1, 9.1 Hz, 1
H, 2-H), 3.75 (m, 1 H, 4-H), 3.86 (d, 1 H, JAB ϭ 13.6 Hz, Bn),
7.15Ϫ7.40 (m, 11 H), 7.45Ϫ7.55 (m, 4 H). 13C NMR: δ ϭ 37.1 (C-
4), 43.8 (C-3), 56.9 (CH2Ph), 60.3 (C-5), 69.4 (C-2), 126.6, 127.0,
127.6, 128.0, 128.2, 128.4, 128.9, 133.7, 139.1. C23H23NSe: calcd.
C 70.40, H 5.91, N 3.57; found C 70.25, H 5.85, N 3.81.
cis-1-Benzyl-2-methyl-2-phenyl-4-(phenylselanylmethyl)azetidine
(2h): Flash chromatography (cyclohexane/CH2Cl2, 70:30). Oil.
2.280 g, 56% yield. 1H NMR: δ ϭ 1.62 (s, 3 H, Me), 1.89 (dd, J ϭ
7.9, 10.3 Hz, 1 H, 3-H), 2.33 (dd, J ϭ 7.4, 10.3 Hz, 1 H, 3-H), 2.57
trans-1-Benzyl-2-phenyl-4-(phenylselanyl)pyrrolidine (3f): Flash
chromatography (cyclohexane/CH2Cl2, 85:15). Oil. 0.308 g, 8%
1
yield. H NMR: δ ϭ 2.37 (m, 1 H, 5-H), 2.40 (m, 2 H, 3-H), 3.13
(d, 1 H, JAB ϭ 13.6 Hz, Bn), 3.60 (m, 1 H, 5-H), 3.65 (m, 1 H, 2-
H), 3.87 (m, 1 H, 4-H), 3.87 (d, 1 H, JAB ϭ 13.6 Hz, Bn), 7.15Ϫ7.55
(m, 15 H). 13C NMR: δ ϭ 36.4 (C-4), 43.9 (C-3), 57.6 (C-5), 60.4
(CH2Ph), 68.1 (C-2), 126.8, 127.1, 127.2, 127.4, 128.1, 128.5, 129.0,
129.5, 132.2, 133.3. C23H23NSe: calcd. C 70.40, H 5.91, N 3.57;
found C 70.19, H 5.76, N 3.68.
(m, 2 H, CH2SePh), 3.49 (m, 1 H, 4-H), 3.58 (d, 1 H, JAB
ϭ
12.7 Hz, Bn), 3.93 (d, 1 H, JAB ϭ 12.7 Hz, Bn), 7.15Ϫ7.50 (m, 10
H). 13C NMR: δ ϭ 21.8 (Me), 34.2 (CH2SePh), 41.0 (C-3), 55.2
(CH2Ph), 61.2 (C-4), 63.6 (C-2), 126.2, 126.4, 127.9, 128.7, 129.1,
131.7, 138.8, 141.7. C24H25NSe: calcd. C 70.92, H 6.20, N 3.45;
found C 70.64, H 6.08, N 3.58.
cis-1-Benzyl-2-phenyl-4-(phenylselanylmethyl)azetidine (2f): Flash
Cyclization of Amine 1i (87% overall yield):
chromatography (cyclohexane/CH2Cl2, 75:25). Oil. 0.475 g, 12%
1
yield. H NMR: δ ϭ 1.72 (m, 1 H, 3-H), 2.52 (m, 1 H, 3-H), 2.76 1-Benzyl-2,2-diethyl-4-(phenylselanyl)pyrrolidine (3i): Flash chro-
(m, 2 H, CH2SePh), 3. 28 (m, 1 H, 4-H), 3.90 (m, 1 H, 2-H), 3.52 matography (cyclohexane/CH2Cl2, 85:15). Oil. 0.164 g, Ͻ 5% yield.
(d, 1 H, JAB ϭ 12.8 Hz, Bn), 3.86 (d, 1 H, JAB ϭ 12.8 Hz, Bn),
1H NMR: δ ϭ 0.90 (m, 6 H, Me), 1.25Ϫ1.50 (m, 4 H, CH2Me),
1.85 (dd, J ϭ 6.6, 13.1 Hz, 1 H, 3-H), 2.21 (dd, J ϭ 9.1, 13.1 Hz,
7.15Ϫ7.45 (m, 15 H). 13C NMR: δ ϭ 34.2 (CH2SePh), 34.9 (C-3),
61.4 (CH2Ph), 62.0 (C-4), 64.8 (C-2), 126.2, 126.4, 127.9, 128.7, 1 H, 3-H), 2.81 (dd, J ϭ 6.5, 10.2 Hz, 1 H, 5-H), 3.09 (dd, J ϭ 8.0,
129.1, 131.7, 138.8, 141.7. C23H23NSe: calcd. C 70.40, H 5.91, N 10.2 Hz, 1 H, 5-H), 3.60 (m, 3 H, 4-H and Bn), 7.15Ϫ7.40 (m,
3.57; found C 70.53, H 5.88, N 3.90.
10 H).
1004
Eur. J. Org. Chem. 2002, 995Ϫ1006

Selenium-Induced Cyclization of Secondary Homoallylamines
FULL PAPER
1-Benzyl-2,2-diethyl-4-(phenylselanylmethyl)azetidine (2i): Flash
chromatography (cyclohexane/CH2Cl2, 70:30). Oil. 2.60 g, 70%
yield. H NMR: δ ϭ 0.77 (t, J ϭ 7.4 Hz, 3 H, Me), 0.80 (t, J ϭ
[1]
[2]
G. Cardillo, M. Orena, Tetrahedron 1990, 46, 3321.
1
C. Paulmier, Selenium Reagents and Intermediates in Organic
Synthesis, Pergamon: Oxford, 1986, Chapter VII.
M. Tiecco, Top. Curr. Chem. 2000, 208, 7.
K. C. Nicolaou, N. A. Petasis, D. A. Claremon, Tetrahedron
1985, 41, 4835.
S. Murata, T. Suzuki, Chem. Lett. 1987, 849; S. Murata, T.
Suzuki, Tetrahedron Lett. 1987, 28, 4297; S. Murata, T. Suzuki,
Tetrahedron Lett. 1987, 28, 4415.
M. Tiecco, L. Testaferri, M. Tingoli, D. Bartoli, R. Balducci,
J. Org. Chem. 1990, 55, 429.
7.4 Hz, 3 H, Me), 1.23Ϫ1.72 (m, 5 H, 3-H and CH2Me), 1.88 (dd,
J ϭ 7.8, 10.7 Hz, 1 H, 3-H), 2.50Ϫ2.61 (m, 2 H, CH2SePh), 3.23
(m, 1 H, 4-H), 3.41 (d, 1 H, JAB ϭ 13.05 Hz, Bn), 3.74 (d, 1 H,
JAB ϭ 13.05 Hz, Bn), 7.08Ϫ7.30 (m, 10 H). 13C NMR: δ ϭ 8.4
(Me), 9.1 (Me), 24.8 (CH2Me), 31.6 (CH2Me), 33.7 (C-3), 34.8
(CH2SePh), 54.9 (CH2Ph), 61.0 (C-4), 65.5 (C-2), 126.7, 127.2,
128.5, 129.3, 129.5, 131.0, 132.3, 141.2. C21H27NSe: calcd. C 67.73,
H 7.31, N 3.76; found C 67.93, H 7.13, N 3.98.
[3]
[4]
[5]
[6]
[7]
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734 and
736.
Cyclization of Amine 1j (91% overall yield):
[8]
[9]
A. M. Morella, A. D. Ward, Aust. J. Chem. 1995, 48, 445.
M. Wada, H. Aiura, K. Akiba, Heterocycles 1987, 26, 929.
B. Berthe, F. Outurquin, C. Paulmier, Tetrahedron Lett. 1997,
38, 1393.
R. D. Evans, J. W. Magee, J. H. Schauble, Synthesis 1988, 862.
M. E. Jung, Synlett 1999, S1, 843 and references cited therein.
N. De Kimpe, In Comprehensive Heterocyclic Chemistry II
(Ed.: A. Padwa); Elsevier: Oxford, 1996; Vol 1B, Chapter 1.18,
pp 507Ϫ589; N. H. Cromwell, B. Phillips, Chem. Rev. 1979,
79, 331.
cis-1-Benzyl-2-ethyl-2-methyl-4-(phenylselanylmethyl)azetidine (2j):
Flash chromatography (cyclohexane/CH2Cl2, 70:30). Oil. 1.246 g,
35% yield. 1H NMR: δ ϭ 0.80 (t, J ϭ 7.5 Hz, 3 H, CH3CH2), 1.17
(s, 3 H, Me), 1.33 (m, 2 H, CH3CH2), 1.64 (dd, J ϭ 7.8, 10.4 Hz,
1 H, 3-H), 1.81 (dd, J ϭ 7.6, 10.4 Hz, 1 H, 3-H), 2.62Ϫ2.79 (m, 2
H, CH2SePh), 3.31 (m,1 H, 4-H), 3.48 (d, 1 H, JAB ϭ 13.0 Hz, Bn),
3.70 (d, 1 H, JAB ϭ 13.0 Hz, Bn), 7.15Ϫ7.37 (m, 10 H). 13C NMR:
δ ϭ 8.1 (CH3CH2), 18.6 (Me), 34.1 (C-3), 35.5 (CH2Me), 36.0
(CH2SePh), 54.6 (CH2Ph), 60.3 (C-4), 126.3, 126.7, 128.0, 128.8,
129.0, 132.9. C20H25NSe: calcd. C 67.03, H 7.03, N 3.91; found C
66.88, H 6.93, N 3.87.
[10]
[11]
[12]
[13]
[14]
[15]
A. Yazima, H. Takikawa, K. Mori, Liebigs Ann. 1996, 1083; R.
M. Rodebaugh, N. H. Cromwell, J. Heterocyclic Chem. 1969, 6,
435 and 993.
trans-1-Benzyl-2-ethyl-2-methyl-4-(phenylselanylmethyl)azetidine
(2j): Flash chromatography (cyclohexane/CH2Cl2, 60:40). Oil.
0.155 g, Ͻ 5% yield. 1H NMR: δ ϭ 0.83 (t, J ϭ 7.5 Hz, 3 H,
CH3CH2), 1.07 (s, 3 H, Me), 1.50 (m, 2 H, CH3CH2), 1.77 (dd,
J ϭ 7.5, 10.5 Hz, 1 H, 3-H), 2.05 (dd, J ϭ 7.8, 10.5 Hz, 1 H, 3-H),
2.65Ϫ2.83 (m, 2 H, CH2SePh), 3.36 (m,1 H, 4-H), 3.52 (d, 1 H,
JAB ϭ 13.0 Hz, Bn), 3.78 (d, 1 H, JAB ϭ 13.0 Hz, Bn), 7.15Ϫ7.38
(m, 10 H). 13C NMR: δ ϭ 8.8 (CH3CH2), 13.4 (Me), 29.8
(CH2Me), 34.5 (C-3), 35.7 (CH2SePh), 53.1 (CH2Ph), 60.1 (C-4),
126.3, 126.8, 127.3, 127.9, 128.7, 128.9, 131.9.
A. Marinetti, P. Hubert, J-P. Genet, Eur. J. Org. Chem. 2000,
1815; M. Shi, J-K. Jiang, Tetrahedron Asym. 1999, 10, 1673; S.
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[16]
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[20]
Cyclization of Amine 1k (88% overall yield):
Spiro Compound 3k: Flash chromatography (cyclohexane/CH2Cl2,
1
70:30). Oil. 0.160 g, Ͻ 5% yield. H NMR: δ ϭ 1.35Ϫ1.76 (m, 10
[21]
[22]
[23]
[24]
[25]
[26]
[27]
H, (CH2)5], 1.94 (dd, J ϭ 6.5, 13.4 Hz, 1 H, 3-H), 2.35 (dd, J ϭ
10.0, 13.4 Hz, 1 H, 3-H), 2.85 (dd, J ϭ 6.4, 10.0 Hz, 1 H, 5-H),
3.12 (dd, J ϭ 6.5, 10.0 Hz, 1 H, 5-H), 3.62 (d, 1 H, JAB ϭ 13.7 Hz,
Bn), 3.67 (d, 1 H, JAB ϭ 13.7 Hz, Bn), 3.65 (m, 1 H, 4-H),
7.16Ϫ7.34 (m, 8 H), 7.46Ϫ7.49 (m, 2 H). 13C NMR: δ ϭ 23.0,
23.3, 25.0, 29.7, 33.4 (CH2)5, 34.6 (C-4), 50.6 (C-3), 52.3 (C-5),
56.9 (CH2Ph), 60.2 (C-2), 126.6, 127.1, 127.8, 127.9, 128.1, 129.0,
130.4, 132.3.
[28]
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Spiro Compound 2k: Flash chromatography (cyclohexane/CH2Cl2,
60:40). Oil. 2.650 g, 69% yield. 1H NMR: δ ϭ 1.17Ϫ1.66 (m, 10 H,
(CH2)5], 1.92 (dd, J ϭ 2.5, 10.4 Hz, 1 H, 3-H), 2.06 (dd, J ϭ 7.7,
10.4 Hz, 1 H, 3-H), 2.68Ϫ2.78 (m, 2 H, CH2SePh), 3.37 (m, 1 H,
4-H), 3.46 (d, 1 H, JAB ϭ 13.1 Hz, Bn), 3.80 (d, 1 H, JAB ϭ 13.1 Hz,
Bn), 7.10Ϫ7.35 (m, 10 H). 13C NMR: δ ϭ 22.9, 23.1, 25.7, 30.3,
34.5 (CH2)5, 35.8 (C-3), 40.4 (CH2SePh), 53.2 (CH2Ph), 60.0 (C-
4), 62.8 (C-2), 126.0, 126.5, 128.1, 128.4, 129.0, 132.1, 133.1.
C22H27NSe: calcd. C 68.73, H 7.08, N 3.64; found C 68.95, H 7.41,
N 3.78.
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Acknowledgments
We thank C. Martin for the preparation of homoallylic amines.
Eur. J. Org. Chem. 2002, 995Ϫ1006
1005

X. Pannecoucke, F. Outurquin, C. Paulmier
FULL PAPER
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[O01420]
1006
Eur. J. Org. Chem. 2002, 995Ϫ1006