Diastereoselective cyclisation of N-alkenylideneamines into 3,4-dihydro-2H-pyrrol-1-ium halides

Article abstract of DOI:10.1002/ejoc.200601081

A number of new chiral 2-(α-bromoalkyl)pyrrolinium salts and 2-(α-selenoalkyl)pyrrolidines were synthesized by the halocyclisation and selenocyclisation, respectively, of N-(alkenylidene)alkylamines and subsequent reduction. These cyclisations were implem

Full text of DOI:10.1002/ejoc.200601081

FULL PAPER
DOI: 10.1002/ejoc.200601081
Diastereoselective Cyclisation of N-Alkenylideneamines into 3,4-Dihydro-2H-
pyrrol-1-ium Halides
Daniela Schley[a] and Jürgen Liebscher*[a]
Dedicated to Prof. Dr. Manfred Christl on the occasion of his 65th birthday
Keywords: Diastereoselective cyclisation / Pyrrolin-1-ium salts / Pyrrolidines / Heterocycles / Synthetic methods
A number of new chiral 2-(α-bromoalkyl)pyrrolinium salts
and 2-(α-selenoalkyl)pyrrolidines were synthesized by the
halocyclisation and selenocyclisation, respectively, of N-(alk-
enylidene)alkylamines and subsequent reduction. These cy-
clisations were implemented in a diastereomeric fashion for
the first time. Substrate control (starting imines possessing
chirality in the N-alkyl or the N-alkenyl substituent) and re-
agent control (chiral organoselenenyl bromides) were
applied. Asymmetric induction by stereocentres of the alken-
ylidene or double asymmetric induction by chiral selenenyl
bromides on unsaturated imines with a chiral N-alkyl group
resulted in diatereoselectivities up to 84:16.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
The asymmetric functionalisation of olefins is an impor-
tant goal in synthetic organic chemistry. Thus, highly
stereoselective epoxidations, dihydroxylations and hydro-
borations were developed. The addition of electrophiles to
C=C bonds can also be combined with an intramolecular
nucleophilic attack by ring formation, when alkenes with
additional nucleophilic sites (O, S or N) are used as sub-
strates. This electrophile-induced cyclisation is a versatile
strategy for the construction of heterocycles. The halolac-
tonisation, where unsaturated carboxylic acids are cyclised
by a reaction with halogens to form lactones, is a well-
known example of this type of reaction. Other common
starting materials are unsaturated carboxylic acid deriva-
tives, imines (Scheme 1), alcohols and amines. Halogens, N-
halogenated succinimides, mercury(II) acetate, tert-butyl
hydroperoxide[1] (Sharpless conditions) and organose-
lenenyl halides[2–5] commonly serve as electrophiles.[6]
The general mechanism of the electrophile-induced
cyclisation of unsaturated imines is shown in Scheme 1.
Chemo-, regio- and diastereoselectivity are important as-
pects of such ring formations. Thus, the reaction of the elec-
trophile can give just an addition to the double bond (e.g.
to adduct 5) rather than undergoing a cyclisation to prod-
ucts 6 or 7. On the other hand, in accordance with the Bal-
dwin rules[7] the cyclisation can follow either the exo-trig or
Scheme 1. General mechanism of the electrophile-induced cyclis-
ation of unsaturated imines.
the endo-trig mode, leading to ring 3 or 4, respectively. Fi-
nally, cis-trans isomers can be formed when nucleophiles are
added to the primary cyclisation products affording cyclic
amine 6 or 7. A number of studies were devoted to the
influence of different electrophiles and reaction conditions
on the mode of the cyclisation of alcohols,[2–4,6] thio-
[a] Institut für Chemie, Humboldt-Universität Berlin,
Brook-Taylor-Straße 2, 12489 Berlin, Germany
E-mail: liebscher@chemie.hu-berlin.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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D. Schley, J. Liebscher
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ethers,[8–12] protected amines[6,13–22] and hydrazines,[23] car-
bonyl derivatives such as unsaturated oximes,[24–31] hydra-
zones,[30,32] imines,[33–39] acetals,[40–42] hemiaminals[43,44] and
aminals[45] and carboxyl derivatives, such as amides,[46,47]
thioamides[48,49] and carboxylic acids.[2–4,6] A comprehen-
sive overview of the whole spectrum of this type of reaction
is given in the reviews by Cardillo et al.,[6] Wessjohann et
al.,[2] Wirth[3] and Petragnani et al.[4]
Remarkably, there have been no systematic, stereochemi-
cal studies on the ring-closing reaction of chiral N-(alkenyl-
idene)alkylamines (unsaturated imines) 1, even though the
resulting product 3 or 4 is a suitable candidate for further
functionalisation by reaction with nucleophiles at the imin-
ium moiety, giving rise to the formation of interesting het-
erocycle (pyrrolidine or piperidine) 6 or 7.
De Kimpe et al.[33,34,36] investigated the reaction of achi-
ral N-(alkenylidene)alkylamines with different electrophiles,
focusing on its regio- and stereochemistry and the further
derivatization of the resulting iminium salts 3 with nucleo-
philes, such as LiAlH4,[34] alkoxides[36,50] and cyanides.[51]
The formation of five-membered, cyclic, iminium salts (pyr-
rolinium salts) 3 was observed in most cases. However, these
Scheme 2. Cyclisation of optically active N-(alkenylidene)alk-
pyrrolinium salts 3 can ring expand to six-membered ring ylamines (chiral R1) with achiral electrophiles.
products 7 in a subsequent reaction of nucleophiles with
the C=N bond. An example of the cyclisation of racemic
N-(alkenylidene)alkylamines[33] was published, resulting in
The electrophile-induced cyclisation of chiral and achiral
a diastereomeric ratio (dr) of 1:1. The cyclisation of unsatu-
rated optically active oximes[24,28,30,31] leads to cyclic nitro-
nes with dr values from 50:50 to 86:14. A 5:1 diastereomeric
mixture was obtained by the iodocyclisation of a racemic
oxime.[29] Optically active N-anilino-2-pyrrolidones were
formed by the iodocyclisation of pentose-derived phenylhy-
drazones in a dr of 70:30.[30]
imines 9 by bromine was carried out in dichloromethane at
0 °C (Table 1, entries 1, 3–7). In all cases, 2-bromomethyl-
3,4-dihydro-2H-pyrrol-1-ium salts 10 were obtained in a 5-
exo-trig mode. These compounds were isolated in high
yields and fully characterized by NMR spectroscopy, show-
1
ing typical H and 13C chemical shifts for the characteristic
functional groups in the products: 8.7–10.5 ppm/186–
191 ppm (CH=N+), 3.3–4.4 ppm/32–34 ppm (CH2Br) and
5.3–6.0 ppm/67–74 ppm (BrCH2–CH–N+). Furthermore,
the X-ray analysis of the tribromide of the 5S stereoisomer
of 10e (Figure 1) confirmed the proposed structure. The
corresponding six-membered 6-endo-trig product was not
observed.
So far, optically active products have not been obtained
by the electrophile-induced cyclisation of N-(alkenylidene)-
alkylamines. Herein, we report three possible approaches to
the stereoselective halo- or selenocyclisation of unsaturated
imines. Following a substrate control, imines were used with
chiral centres in the amine part of the unsaturated imine or
in the alkene moiety. Reagent control was attempted by chi-
ral selenyl bromides.
Results
Cyclisation of Chiral N-(Alkenylidene)alkylamines with
Achiral Reagents
N-(Alkenylidene)alkylamines of the general type 1 are
easily accessible by the reaction of an appropriate amine
and an aldehyde. 2,2-Dimethylpent-4-enal 8 was chosen as
a suitable aldehyde because unwanted enamine tautomer-
ism is excluded, which probably would affect the stereoin-
duction in the cyclisation of the corresponding imines.
Compound 8 was converted into the N-(alkenylidene)alk-
ylamines 9 (Scheme 2, Table 1) with various chiral amines
as well as achiral or racemic amines at room temperature
in dichloromethane in the presence of magnesium sulfate
(see the Supporting Information).
Figure 1. X-ray crystal analysis of the tribromide of the 5S stereo-
isomer of 10e.
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Diastereoselective Cyclisation of N-Alkenylideneamines
FULL PAPER
The determination of dr values by 1H NMR spec-
Using less reactive iodine in dichloromethane at 0 °C for
troscopy of the crude products revealed an unsatisfactory the cyclisation of the imine 9f and the achiral tert-butyl-
stereoselectivity (dr = 50:50–42:58) under these conditions. substituted 9k led to mixtures of constitutionally isomeric
In order to overcome this problem, the reaction tempera- pyrrolinium salts 11 and tetrahydropyridinium salts 13 as
ture was lowered in the cyclisation of compound 9f from a result of competition between 5-exo-trig and 6-endo-trig
0 °C to –60 °C or –78 °C (Table 1, entry 7). A modest in- cyclisation. The latter might occur as a result of thermo-
crease in diastereoselectivity from 45:55 (0 °C) to 35:65 dynamic control, achieved by iodine, which is less reactive
(–75 °C) was observed. Attempts to improve the dia- than bromine. Imine 9f gave rise to a constitutional isomer
stereomeric ratio by the addition of Lewis acids to the reac- ratio of 86:14 (dr = 63:37 and 69:31, respectively) in favour
tion mixture were not successful. The addition of ZnBr2 or of the five-membered ring 11a (Table 1, entry 9), whereas
LiBr did not cause a significant improvement, whereas in the case of the N-tert-butyl substrate 9k, the pyridinium
strong Lewis acids such as BF3·Et2O or Et2AlCl prevented iodide 13b was formed as the major isomer of a 19:81 mix-
the cyclisation (Table 1, entry 6).
ture (Table 1, entry 15). Obviously, the bulkiness of the N-
Table 1. Synthesis of iminium salts 10–13 and pyrrolidines 14.
1
[a] Determined by H NMR spectroscopy (Ϯ 5%). [b] Racemate. [c] Lewis acids were added, and the corresponding values obtained are
given in parentheses: ZnBr2 (dr = 42:58), LiBr (dr = 42:58), BF3·Et2O (no reaction), Et2AlCl (no reaction). [d] dr = 40:60 at –60 °C, dr
= 35:65 at –78 °C, dr = 36:64 at –90 °C. [e] Separation of diastereomers by column chromatography. [f] A mixture of constitutional
isomers was obtained: pyrrolidinium iodide 11a, 86%, dr = 63:37; pyridinium iodide 13a, 14%, dr = 69:31. [g] dr = 40:60 at –50 °C in
CHCl3. [h] A mixture of constitutional isomers was obtained: pyrrolidinium iodide 11b/pyridinium iodide 13b = 19:81.
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D. Schley, J. Liebscher
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alkyl substituent governs the regioselectivity in these cases.
Sterically hindered organoselenenyl halides were success-
The products of these iodocyclisations could not be sepa- fully used by Lipshutz et al.[52] to improve the diastereo-
rated but were unambiguously assigned by 13C NMR spec- selectivity of the electrophile-induced cyclisation of
troscopy (e.g. CH2I (9.7 ppm) and CH–I (12.7 ppm) for 11b alcohols. Interestingly, the application of 2,4,6-(triisopro-
and 13b, respectively).
pylphenyl)selenenyl bromide in the cyclisation of the imine
Cyclisations of optically active, racemic (9g) and achiral 9j caused the opposite effect; in other words, the diastereo-
(9a, 9k) imines 9 with arylselenyl bromide as the electro- selectivity was slightly lower than that observed with phen-
phile were carried out at –78 °C in dichloromethane ylselenyl bromide (Table 1, entries 13 and 14).
(Table 1). In all cases, the 5-membered-ring iminium salts
We further investigated the effect of introducing substitu-
12 (X = SePh) formed by the cyclisation were subsequently ents into the alkylidene moiety of chiral imines 9 or of chain
reduced by sodium borohydride. The resulting pyrrolidines homologation. Thus, N(alkenylidene)alkylamines 15 were
14 were stable enough for isolation and purification by col- cyclised with phenylselenyl bromide, and in the case of 15c,
umn chromatography, but the yields were generally lower also with bromine (Scheme 3). Again, the selenocyclisation
than those obtained in halocyclisations. This might be an products 16 (X = SePh) were reduced to the corresponding
indication that the reduction step from 12 (X = RSe) to pyrrolidines 17 by sodium borohydride. The cyclisation of
pyrrolidines 14 is a low-yielding reaction. NMR spectro- the N(hexenylidene)amine 15a (Table 2, entry 2), which rep-
scopic studies [2.8–3.2 ppm /33–36 ppm (CH2–Se), 2.9– resents a homolog of the imine 9j, afforded a six-membered
3.2 ppm /59–63 ppm (SeCH2–CH), 1.4–1.9 ppm/46–47 ppm ring product by the exo-trig mode. The dr determined for
(CH–CH2–Cq) and 2.0–2.8 ppm/60–68 ppm (d, N–CH2– the corresponding piperidine 17a was lower than that deter-
Cq)] and X-ray analysis of the 5S stereoisomer (S)-14f of mined in the case of 9j cyclisation. Thus, this homologation
the pyrrolidine 14 (Figure 2) verified the assigned structure. had a disadvantageous effect on the diastereoselectivity
We determined the dr values of these products as ranging (Table 2, entries 1 and 2).
from 48:52 to 33:67, which were slightly higher than those
obtained in the bromocyclisation. It turned out that N-(alk-
enylidene)alkylamines with an additional heteroatom in the
N-alkyl substituent gave a somewhat higher induction in
selenocyclisations than pure hydrocarbon substituents
(Table 1).
Scheme 3. Cyclisation of optically active N-(alkenylidene)alk-
ylamines 15.
It can be expected that an R1 methyl substituent shields
the C=C bond to a certain extent, and thus, could give rise
to an increase in stereoselectivity in electrophile-induced
cyclisation. However, the opposite effect was observed
(Table 2, compare entry 1 with entry 3 and entry 1 with
entry 5). The application of bromine instead of phenylse-
lenyl bromide gave the same unsatisfactory diastereoselec-
tivity (Table 2, entries 1 and 4). Finally, we investigated the
effect of a phenyl group at position 1 of the alkylidene moi-
ety of imines 15 (Table 2, entry 6). Selenocyclisation fol-
lowed by reduction gave rise to a mixture of four dia-
stereomeric products 17d (dr = 13:21:38:28). The cyclisation
Figure 2. X-ray crystal analysis of the 5S stereoisomer of the pyr-
rolidine 14f (major isomer).
Table 2. Syntheses of 14 and 17 and comparison of diastereomeric ratios.
Iminium
salt
Saturated
heterocycle
Entry
Imine
R1
R2
R3
R4
n
X
dr
Yield [%]
1
2
3
4
5
6
9j
12f
16a
16b
16c
12b
16d
14f
17a
17b
–
14b
17d
H
H
Me
Me
H
H
H
H
H
H
Ph
COOCH3
COOCH3
COOCH3
COOCH3
Ph
Ph
Ph
Ph
Ph
Me
Me
1
2
1
1
1
1
PhSe
PhSe
PhSe
Br
PhSe
PhSe
35:65
46:54
46:54
46:54
47:53
58
64
36
quant.
62
57
15a
15b
15c
9f
15d
H
Ph
13:21:38:28
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Diastereoselective Cyclisation of N-Alkenylideneamines
FULL PAPER
to 16d as well as the subsequent reduction to 17d, where a Table 3. Synthesis of pyrrolidines 20.
second stereogenic centre was formed, occurred with unsat-
isfactory diastereoselectivity. In summary, homologation as
well as the introduction of substituents into the alkylidene
moiety of chiral imines did not lead to higher stereoselecti-
vities.
We further approached diastereoselective seleno- or halo-
cyclisation by introducing chirality into the alkenylidene
moiety of unsaturated imines. Imines 18 were obtained from
a ribose-derived aldehyde (see electronic Supporting Infor-
mation).[53–55] In the N(alkenylidene)alkylamine 18a, chiral-
ity is only found in the alkylidene part, while the other im-
ines 18 are chiral in both the alkylidene and the amine moi-
ety (Scheme 4, Table 3). In all the imines 18, a chiral centre
is near the C=C bond, and thus, a better facial selectivity
of the primary electrophilic attack can be expected, which
is probably crucial for the overall diastereoselective forma-
tion of products 19. Indeed, an increase in diastereoselectiv-
ity to dr = 20:80 was observed in the selenocyclisation of
[a] 38%, dr = 75:25 at –50 °C in CHCl3. [b] cis/trans assignments
18a with phenylselenyl bromide. But similar to the other
selenocyclisations (vide supra), the product 20a was formed
in low yield. Working at low temperature in CHCl3 had no
advantageous effect (Table 3, entry 1, footnote a). Remark-
ably, the application of the bulkier 2,4,6-(triisopropyl-
phenyl)selenyl bromide gave lower stereoselectivity (38:62)
as it did for 9j (Table 3, entry 3 and Table 2, entry 14). The
same stereochemical result was obtained with bromine
(Table 3, entry 2), and bromopyrrolinium salt 19b was ob-
tained in high yield.
for the isomers were not possible by NMR spectroscopy.
8). The selenocyclisation of the phenylglycine derivative 18d
gave a marked diastereoselectivity of dr = 19:81, but the
yields were even lower. NOE investigations of the products
20 and an X-ray crystal analysis of the pyrrolidine 20d (see
Figure 3) revealed that in all cases the all-cis-isomer (R)-20
was the major isomer.
Scheme 4. Cyclisation of optically active N-(alkenylidene)alk-
ylamines 18 with chiral alkylidene groups with achiral electro-
philes.
Figure 3. X-ray crystal analysis of the 5S stereoisomer of 20d.
Epimers 18b and 18c appeared as a matched/mismatched
pair in the selenocyclisation. We observed dr values of 16:84
and 40:60, respectively. Obviously, the chirality in the alk-
ylidene moiety of the unsaturated imine exerts the predomi-
nating asymmetric induction. This fact also matches with
Cyclisation of N-(Alkenylidene)alkylamines with Chiral
Electrophiles
Inspired by the fact that chiral organoselenenyl halides
the very poor stereoselectivities in the cyclisation of imines can stereoselectively react with alkenes on one hand[56,57]
9 lacking chirality in the alkylidene part (see Table 1, entry and that this methodology has not yet been applied to the
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D. Schley, J. Liebscher
FULL PAPER
inter- or intramolecular additions of imines to alkenes on temperature and the presence of Lewis acids were investi-
the other hand, we tried to apply such chiral selenyl bro- gated. As a result, marked diastereoselectivities (up to dr
mides to the selenocyclisation of unsaturated imines. The = 84:16) were only obtained with a pentose-derived chiral
chiral selenyl bromides 22[58–67] and 23,[68–77] generated in alkylidene substituent and in the case of double asymmetric
situ from the corresponding diselenides and bromine, were induction when the imine (S)-9j, with a chiral N-alkyl group
applied to the achiral imine 9a at –78 °C (Scheme 5).
(phenylalanine derivative), was cyclised with a camphor-de-
rived selenyl bromide. These are the first cases reported for
stereoselective electrophile-induced cyclisations of unsatu-
rated N-alkylidene-N-alkylamines.
Experimental Section
1
General Remarks: H NMR and 13C NMR spectra were recorded
at 300 MHz and 75.5 MHz, respectively, with a Bruker AC 300
spectrometer in CDCl3 with TMS as an internal standard. Dia-
stereomeric ratios were determined by 1H NMR spectroscopy of
the crude products. Cyclisation products were obtained as dia-
stereomeric mixtures, and their spectra were recorded from the mix-
tures, if not otherwise mentioned. Silica gel (0.04–0.063 mm,
Merck) was used for preparative column chromatography. Starting
materials were purchased from commercial suppliers. All
N(alkenylidene)alkylamines and 3,4-dihydro-2H-pyrrolium bro-
mides decompose easily but can be stored in a freezer (–20 °C) for
a few days.
Scheme 5. Cyclisation of N-(alkenylidene)alkylamines 9 with chiral
selenenyl bromides.
General Procedure for the Synthesis of 3,4-Dihydro-2H-pyrrolium
Bromides 10: The appropriate N(alkenylidene)alkylamine
9
The camphor-derived selenyl bromide 22 gave a slightly
higher diastereoselectivity than did 23, but it was still unsat-
isfactory (dr = 41:59 and 48:52, Table 4, entries 1 and 2,
respectively). In a double asymmetric induction[78] ap-
proach, selenyl bromide 22 was reacted with the chiral
amines 9j and (S)-9j. Compound (S)-9j appeared as a
matched case (38:62 and 24:76, Table 4, entries 3 and 4,
respectively). Each of the diastereomeric products 21c exists
in two rotameric forms, as proven by temperature-depend-
(0.50 mmol) was dissolved in dry CH2Cl2 (10 mL) at 0 °C under
argon in a flame-dried flask. A solution of bromine in dry CH2Cl2
(0.04 , 0.50 mmol) was added over 30 min, and the temperature
was maintained for 2 h at 0 °C. The mixture was warmed slowly to
room temperature. The solution was concentrated under vacuum
below room temperature, and the remaining product was stored
under argon at –20 °C.
rac-1-Benzyl-2-bromomethyl-4,4-dimethyl-3,4-dihydro-2H-pyrrolium
Bromide (10a): Starting material 9a (300 mg, 1.49 mmol). Yield:
518 mg (96%), colourless solid, m.p. 60 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.04 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 2.04 [dd, J
= 7.5 Hz, J = 13.6 Hz,1 H, CHH–C(CH3)2], 2.42 [dd, J = 8.7 Hz,
J = 13.6 Hz, 1 H, CHH–C(CH3)2], 3.74 (dd, J = 1.9 Hz, J =
12.4 Hz, 1 H, CHH–Br), 4.12 (dd, J = 4.3 Hz, J = 12.2 Hz, 1 H,
CHH–Br), 5.32 (d, J = 6.4 Hz 2 H, CHH–Ph), 5.44–5.55 (m, 1 H,
CH–N), 7.37–7.39 (m, 3 H, CHar), 7.56–7.59 (m, 2 H, CHar), 8.99
(s, 1 H, CH=N+) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 24.8
(CH3), 25.7 (CH3), 32.2 (CH2–Br), 39.1 [CH2–C(CH3)2], 47.5
[C(CH3)2], 55.5 (CH2–Ph), 70.5 (CH–N), 129.2 (Car), 129.8 (2
CHar), 130.2 (3 CHar), 186.2 (CH=N+) ppm. C14H19Br2N
(361.115): calcd. C 46.56, H 5.30, Br 44.25, N 3.88; found C 46.60,
H 5.32, Br 43.78, N 3.87.
1
ent dynamic H NMR investigations.
Table 4. Synthesis of pyrrolidines 21[a]
.
Pyrroli-
dines
Entry R1
Imine R2–SeBr
Yield [%] dr
1
2
3
4
H
H
CO2Me
CO2Me
9a
9a
9j
22
23[b]
22
21a
21b
21c
21d
33
72
46
40
41:59
48:52
38:62[c,d]
24:76
(S)-9j
22
[a] Reactions were performed at 0 °C. [b] AgPF6 was added. [c]
Separation of diastereomers by column chromatography. [d] Dia-
stereomers were isolated as a mixture of rotamers.
(2S)-2-Bromomethyl-1-[(1S,2S)-1-methoxycarbonyl-2-methylbutyl]-
4,4-dimethyl-3,4-dihydro-2H-pyrrolium Bromide and (2R)-2-Bro-
momethyl-1-[(1S,2S)-1-methoxycarbonyl-2-methylbutyl]-4,4-dimeth-
yl-3,4-dihydro-2H-pyrrolium Bromide (10b): Starting material 9b
(60 mg, 0.25 mmol). Diastereomers were not separated. Yield:
100 mg (0.25 mmol, quant.), dr = 44:56, yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 0.78–0.95 (m, 4 H, CH–CH3, CH2–CH3),
0.98 (s, 3 H, CH3), 1.01 (s, 3 H, CH3), 1.51, 1.54 (d, J = 6.1 Hz, J
= 7.9 Hz, 3 H, CH–CH3), 1.30–1.55 (m, 2 H, CH2–CH3), 1.94–2.56
[m, 2 H, CH2–C(CH3)2], 3.82–4.41 (m, 2 H, CH2–Br), 3.79, 3.84
(s, 3 H, COOCH3), 4.88, 4.95 (d, J = 9.1 Hz, J = 5.6 Hz 1 H, CH–
COO), 5.59–5.68, 5.89–5.98 (m, 1 H, CH–N), 9.38, 9.64 (s, 1 H,
Conclusions
In summary, a series of new chiral 2-(α-bromoalkyl)pyr-
rolinium salts 10, 16c and 19b and 2-(α-selenoalkyl)pyrrol-
idines 14, 17, 20 and 21 were obtained by the halo- or sele-
nocyclisations, respectively, of unsaturated imines (N-alk-
ylidene-N-alkylamines) and subsequent reduction. Several
effects on the stereoselectivity, such as chirality in the amine
or the alkylidene substituent, the size of substituents in the
alkylidene moiety, the type of electrophile (bromine, iodine,
arylselenyl bromides, or chiral organoselenenyl bromides), CH=N+) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 11.3, 11.4
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Diastereoselective Cyclisation of N-Alkenylideneamines
FULL PAPER
(CH2–CH3), 14.8, 15.2 (CH–CH3), 24.7, 24.9 (Cq–CH3), 25.8, 26.8
[C(CH3)2], 62.5, 63.0 (CH–CH3), 69.1, 72.0 (CH–N), 126.6, 127.7
(Cq–CH3), 25.2, 27.1 (CH2–CH3), 33.0, 34.2 (CH2–Br), 36.6, 40.2 (2 CHar), 128.1, 128.8 (CHar), 130.1, 130.2 (2 CHar), 134.2, 134.4
(CH–CH3), 37.8, 38.4 [CH2–C(CH3)2], 48.9, 49.0 [C(CH3)2], 53.9,
(CH–Car), 185.1, 185.2 (CH=N+) ppm. Minor isomer 13a: 1H
54.2 (COOCH3), 66.7, 67.4 (CH–N), 73.3, 74.6 (CH–COO), 166.8, NMR (300 MHz, CDCl3): δ = 0.99, 1.10 (s, 3 H, CH3), 1.53, 1.58
167.9 (COO), 189.2, 190.3 (CH=N+) ppm. HRMS (EI): calcd. for
C14H25BrNO2 318.1069/320.1048; found 318.1069/320.1049.
(s, 3 H, CH3), 2.03–2.00 (m, 4 H, CH–CH3, CHH–Cq), 2.07–2.30
(m, 1 H, CHH–Cq), 4.61–4.70, 4.92–5.03 (m, 3 H, CH–CH3, CH2–
N), 4.65–4.74 (m, 1 H, CH–I), 7.32–7.48 (m, 5 H, CHar), 9.22, 9.56
(s, 1 H, CH=N+) ppm.
(2S)-2-Bromomethyl-1-[(1S)-1-methoxymethyl-2-methylpropyl]-4,4-
dimethyl-3,4-dihydro-2H-pyrrolium Bromide and (2R)-2-Bro-
momethyl-1-[(1S)-1-methoxymethyl-2-methylpropyl]-4,4-dimethyl-
3,4-dihydro-2H-pyrrolium Bromide (10e): Starting material 9e
(379 mg, 1.79 mmol). Diastereomers were not separated. Yield:
1-tert-Butyl-2-iodomethyl-4,4-dimethyl-3,4-dihydro-2H-pyrrolium
Iodide (11b) and 1-tert-Butyl-3-iodo-5,5-dimethyl-2,3,4,5-tetra-
hydropyridinium Iodide (13b): 9k (100 mg, 0.598 mmol) was dis-
616 mg (1.66 mmol, 93 %), dr = 42:58, yellow oil. 1H NMR solved in dry CH2Cl2 (10 mL) at 0 °C under argon in a flame-dried
(300 MHz, CDCl3): δ = 1.09 (d, J = 6.4 Hz, 3 H, CH–CH3), 1.17
(d, J = 6.8 Hz, 3 H, CH–CH3), 1.52 (s, 3 H, CH3), 1.61 (s, 3 H,
CH3), 2.16–2.62 [m, 4 H, CH–CH3, CH–CH2O, CH2–C(CH3)2],
3.43, 3.45 (s, 3 H, OCH3), 3.70–4.14 (m, 4 H, CH2–Br, CH2O),
5.30–5.41 (m, 1 H, CH–N), 8.72, 8.86 (s, 1 H, CH=N+) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 18.8, 19.3 (CH–CH3), 19.5, 20.4
(CH–CH3), 24.8, 25.0 (Cq–CH3), 26.0, 26.6 (Cq–CH3), 27.7, 31.0
flask. A solution of iodine (152 mg, 0.598 mmol) in dry CH2Cl2
(10 mL) was added over 30 min, and the temperature was main-
tained at 0 °C for 2 h. The mixture was warmed slowly to room
temperature and was concentrated under vacuum. The crude prod-
uct was recrystallized from CH2Cl2/Et2O to give a white solid
(170 mg, 0.404 mmol, 67% yield). Isomers (19:81) were not sepa-
rated, m.p. 214 °C (CH2Cl2/Et2O). HRMS (ESI+): calcd. for
(CH–CH3), 32.2, 33.0 (CH2–Br), 38.4, 38.5 [CH2–C(CH3)2], 48.3, C11H21IN 294.0713; found 294.0710. C11H21I2N (421.100): calcd.
48.5 [C(CH3)2], 59.5, 59.6 (OCH3), 67.8, 68.5 (CH–CH2O), 68.6, C 31.37, H 5.03, N 3.33; found C 31.52, H 5.30, N 3.40. Major
68.7 (CH2–O), 71.9, 74.0 (CH–N), 187.3, 187.8 (CH=N+) ppm. isomer 13b: 1H NMR (300 MHz, [D6]DMSO): δ = 1.04 (s, 3 H,
HRMS (EI): calcd. for C13H25BrNO 290.1120; found 290.1118. CH3), 1.10 (s, 3 H, CH3), 1.25 [s, 9 H, C(CH3)3], 1.93 (m, 1 H,
Tribromide (S)-10e was obtained from a CHCl3 solution with ex-
cess Br2 as an orange solid with m.p. 114 °C (CH2Cl2/Et2O).
CHH–Cq), 2.07 (m, 1 H, CHH–Cq), 3.75 (m, 1 H, CHH–N), 4.11
(m, 1 H, CHH–N), 4.23–4.36 (m, 1 H, CH–I), 8.54 (s, 1 H,
CH=N+) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ = 12.7 (CH–
I), 25.0 (CH3), 25.5 (CH3), 26.9 [3 C, C(CH3)3], 46.8 [C(CH3)2],
42.0 (CH2), 53.6 (CH2–N), 69.2 [C(CH3)3], 178.9 (CH=N+) ppm.
X-ray Crystal Analysis of the Corresponding Tribromide (S)-10e:[79]
Empirical formula: C13H25Br4NO, formula weight: 530.98 g/mol,
temperature: 180(2) K, wavelength: 0.71073 Å, crystal system: or-
thorhombic, space group: P21 21 21, unit cell dimensions: a =
9.341(3) Å, b = 13.381(4) Å, c = 13.381(4) Å, V = 1928.1(12) Å3,
Z = 4, density (calculated): 1.829 Mg/m3, absorption coefficient:
8.343 mm–1, F(000) = 1032, crystal size: 0.80ϫ 0.32 ϫ0.28 mm,
theta range for data collection: 2.01 to 25.90°, limiting indices: –8
Յ h Յ 11, 0 Յ k Յ 16, 0 Յ l Յ 18; reflections collected: 4078,
unique: 3586 [R(int.) = 0.0515], completeness to θ = 25.90 is 99.9%,
absorption correction: empirical (psi-scan), max./min. trans-
mission: 0.2035/0.0573, refinement method: full-matrix least-
squares on F2, data/restraints/parameters: 3586–0–189, goodness-
1
Minor isomer 11b: H NMR (300 MHz, [D6]DMSO): δ = 1.17 (s,
3 H, CH3), 1.25 (s, 3 H, CH3), 1.32 [s, 9 H, C(CH3)3], 1.84–1.93
(m, 1 H, CHH–Cq), 2.32–2.43 (m, 1 H, CHH–Cq), 3.59–3.68 (m, 1
H, CHH–I), 3.91–4.02 (m, 1 H, CHH–I), 4.98–5.09 (m, 1 H, CH),
9.25 (s, 1 H, CH=N+) ppm. 13C NMR (75.5 MHz, [D6]DMSO): δ
= 9.7 (CH2–I), 19.0 (CH3), 25.6 (CH3), 28.8 [3 C, C(CH3)3], 46.7
[C(CH3)2], 41.8 (CH2), 65.2 [C(CH3)3], 72.6 (CH–N), 187.9
(CH=N+) ppm.
General Procedure for the Selenocyclisation and Reduction to Pyr-
rolidines 14: The appropriate N(alkenylidene)alkylamine 9
of-fit on F2: 1.112, final R indices [I Ͼ 2σ(I)]: R1 = 0.0631, wR2 = (0.50 mmol) was dissolved in dry CH2Cl2 (10 mL) at –78 °C under
0.1328, R indices (all data): R1 = 0.1124, wR2 = 0.1650, absolute
argon in a flame-dried flask. A solution of phenylselenyl bromide
structure parameter: 0.03(4), extinction coefficient: 0.0010(4), (0.60 mmol, 1.2 equiv.) in dry CH2Cl2 was added over 30 min. Af-
largest diff. peak and hole: 0.889 and –1.144 e/Å3.
ter 2 h at –78 °C, MeOH (10 mL) and NaBH4 (0.74 mmol) were
added. The mixture was warmed slowly to room temperature. The
organic layer was separated and washed with water (10 mL). After
separating the layers, the aqueous layer was washed with CH2Cl2
(2ϫ5 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. The remaining yellow oil was
purified by column chromatography (40 g silica gel, 2.3 cm column
diameter, cyclohexane/EtOAc mixture).
2-Iodomethyl-4,4-dimethyl-1-[(R)-1-phenylethyl]-3,4-dihydro-2H-pyr-
rolium Iodide (11a) and 3-Iodo-5,5-dimethyl-1-[(R)-1-phenylethyl]-
2,3,4,5-tetrahydropyridinium Iodide (13a): 9f (69 mg, 0.32 mmol)
was dissolved in dry CH2Cl2 (10 mL) at 0 °C under argon in a
flame-dried flask. A solution of iodine (81 mg, 0.32 mmol) in dry
CH2Cl2 (10 mL) was added over 30 min, and the temperature was
maintained for 2 h at 0 °C. The mixture was warmed slowly to
room temperature and was concentrated under vacuum below
room temperature to give 0.15 g (0.32 mmol, quant. yield) of a yel-
low oil. Isomers were not separated. 11a/13a = 86:14; dr (11a) =
37:63; dr (13a) = 31:69). HRMS (EI): calcd. for C15H21IN
rac-1-Benzyl-4,4-dimethyl-2-[(phenylselenyl)methyl]pyrrolidine
(14a): Starting material 9a (244 mg, 1.21 mmol). Yield: 258 mg
(0.719 mmol, 59%), colourless oil, Rf = 0.14 (hexane/EtOAc, 20:1).
1H NMR (300 MHz, CDCl3): δ = 0.98 (s, 3 H, Cq–CH3), 1.10 (s,
342.0713; found 342.0713. Major isomer 11a: 1H NMR (300 MHz, 3 H, Cq–CH3), 1.65 (dd, J = 7.9 Hz, J = 12.8 Hz, 1 H, CH–CHЈH–
CDCl3): δ = 1.46, 1.49 (s, 3 H, CH3), 1.58, 1.65 (s, 3 H, CH3), 1.82– Cq), 1.83 (dd, J = 8.1 Hz, J = 12.6 Hz, 1 H, CH–CHЈH–Cq), 2.01
1.96 (m, 1 H, CH2–Cq), 2.03, 2.00 (d, J = 10.0 Hz, 3 H, CH–CH3),
2.40, 2.57 (dd, J = 8.0 Hz, J = 13.5 Hz, 1 H, CHH–Cq), 3.54–3.62 CHЈH–Cq), 2.88 (m, 1 H, CH–CH2Se), 3.11 (dd, J = 3.1 Hz, J =
(m, 1 H, CHH–I), 3.74–3.80 (m, 1 H, CHH–I), 5.07–5.16, 5.33– 11.4 Hz, 1 H, CHЈH–Se), 3.15 (dd, J = 4.1 Hz, J = 11.5 Hz, 1 H,
(d, J = 9.0 Hz, 1 H, N–CHЈH–Cq), 2.65 (d, J = 9.0 Hz, 1 H, N–
5.42 (m, 1 H, CH–CH3), 4.13–4.25, 5.40–5.49 (m, 1 H, CH), 7.32– CHЈH–Se), 3.17 (d, J = 13.2 Hz, 1 H, Ph–CHЈH), 4.04 (d, J =
7.48 (m, 5 H, CHar), 9.92, 10.10 (s, 1 H, CH=N+) ppm. 13C NMR 13.2 Hz, 1 H, Ph–CHЈH), 7.19–7.48 (m, 10 H, CHar) ppm. 13C
(75.5 MHz, CDCl3): δ = 5.9, 7.8 (CH2–I), 20.9, 21.6 (CH–CH3),
NMR (75.5 MHz, CDCl3): δ = 28.9 (CH3), 30.1 (CH3), 33.2
24.6, 25.3 (CH3), 26.1, 26.4 (CH3), 41.6, 42.0 (CH2), 47.6 (CH2Se), 35.9 [C(CH3)2], 46.5 (CH–CH2–Cq), 58.3 (CH2–Ph), 63.6
Eur. J. Org. Chem. 2007, 2945–2957
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2951

D. Schley, J. Liebscher
FULL PAPER
(CH), 68.2 (N–CH2–Cq), 126.5 (CHar), 126.9 (CHar), 128.2 (2 11.5 Hz, 1 H, SeCHЈH), 2.98 (dd, J = 7.9 Hz, J = 11.7 Hz 1 H,
CHar), 128.7 (2 CHar), 129.1 (2 CHar), 131.4 (CarSe), 132.3 (2 SeCHЈH), 3.21 (dq, J = 3.1 Hz, J = 7.7 Hz 1 H, CH–CH2Se), 3.61
CHar), 139.8 (CH–Car) ppm. C20H25NSe (358.379): calcd. C 67.03, (s, 3 H, COOCH3), 4.65 (s, 1 H, CH–COOCH3), 7.13–7.35 (m, 10
H 7.03, N 3.91; found C 67.26, H 7.07, N 3.82.
H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.5 (Cq–CH3),
29.2 (Cq–CH3), 33.0 (CH2Se), 35.8 [C(CH3)2], 46.3 (CH–CH2), 51.3
(COOCH3), 60.3 (CH), 62.6 (N–CH2), 66.1 (CH), 126.5 (CHar),
127.8 (CHar), 128.3 (2 CHar), 128.5 (2 CHar), 128.9 (2 CHar), 130.8
(CarSe), 132.2 (2 CHa r), 137.1 (Car ), 172.0 (COO) ppm.
C22H27NO2Se (416.415): calcd. C 63.45, H 6.54, N 3.36; found C
63.40, H 6.39, N 3.34.
(2R)-4,4-Dimethyl-1-[(1R)-1-phenylethyl]-2-[(phenylselenyl)methyl]-
pyrrolidine and (2S)-4,4-Dimethyl-1-[(1R)-1-phenylethyl]-2-[(phen-
ylselenyl)methyl]pyrrolidine (14b): Starting material 9f (82 mg,
0.38 mmol). Diastereomers were separated, dr = 47:53. Minor iso-
mer: yield 42 mg (0.11 mmol, 29%), colourless oil, Rf = 0.57 (hex-
ane/EtOAc, 9:1). [α]2D5 = –45.9 (c = 1.4, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.92 (s, 3 H, Cq–CH3), 1.06 (s, 3 H, Cq– X-ray Crystal Analysis of (S)-14f:[79] Empirical formula:
CH3), 1.21 (d, J = 6.7 Hz, 3 H, CH–CH3), 1.54 (dd, J = 6.3 Hz, J 22H27NO2Se, formula weight: 416.41 g/mol, temperature:
C
= 12.6 Hz, 1 H, CH–CHЈH–Cq), 1.74 (dd, J = 8.3 Hz, J = 12.6 Hz, 180(2) K, wavelength: 0.71073 Å, crystal system: monoclinic, space
1 H, CH–CHЈH–Cq), 2.24 (d, J = 8.9 Hz, 1 H, N–CHЈH), 2.44 (d, group: P21, unit cell dimensions: a = 6.006(2) Å, b = 14.311(3) Å,
J = 8.9 Hz, 1 H, N–CHЈH), 2.79–2.82 (m, 2 H, CH2Se), 3.06–3.10
(m, 1 H, CH–CH2Se), 3.78 (q, J = 6.6 Hz, 1 H, CH–CH3), 7.10–
β = 95.82(4)°, c = 11.812(3) Å, V = 1009.9(5) Å3, Z = 2, density
(calculated): 1.369 Mg/m3, absorption coefficient: 1.874 mm–1
,
7.34 (m, 10 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = F(000): 432, crystal size: 0.60ϫ0.48ϫ0.32 mm, theta range for
15.1 (CH–CH3), 28.3 (Cq–CH3), 29.0 (Cq–CH3), 33.3 (CH2Se), 35.4 data collection: 2.24 to 25.24°, limiting indices: –7 Յ h Յ 7, –17 Յ
[C(CH3)2], 45.8 (CH–CH2), 57.8 (CH), 60.7 (CH), 62.1 (N–CH2), k Յ 17, –14 Յ l Յ 14; reflections collected: 6613, unique: 3487
126.0 (CHar), 126.3 (CHar), 127.2 (2 CHar), 127.7 (2 CHar), 128.5 [R(int.) = 0.1335], completeness to θ = 25.24 is 96.8%, absorption
(2 CHar), 130.6 (CarSe), 131.8 (2 CHar), 144.9 (CH–Car) ppm. correction: empirical (psi-scan), max./min. transmission: 0.5854/
HRMS (EI): calcd. for C21H27NSe 373.13087; found 373.13084.
Major isomer: yield of 47 mg (0.13 mmol, 33%), colourless oil, Rf
= 0.46 (hexane/EtOAc, 9:1). [α]2D5 = 142.7 (c = 1.1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.74 (s, 3 H, Cq–CH3), 1.03 (s, 3 H,
Cq–CH3), 1.30 (d, J = 6.9 Hz, 3 H, CH–CH3), 1.52 (dd, J = 6.5 Hz,
J = 12.6 Hz, 1 H, CH–CHЈH–Cq), 1.64 (dd, J = 8.0 Hz, J =
12.6 Hz, 1 H, CH–CHЈH–Cq), 2.15 (d, J = 8.9 Hz, 1 H, N–CHЈH),
2.59 (d, J = 8.9 Hz, 1 H, N–CHЈH), 2.90–2.94 (m, 1 H, CH–
CH2Se), 3.00–3.13 (m, 2 H, CH2Se), 3.75 (q, J = 6.8 Hz, 1 H,
CH–CH3), 7.06–7.41 (m, 10 H, CHar) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 21.6 (CH–CH3), 28.3 (Cq–CH3), 29.1 (Cq–CH3), 34.3
[C(CH3)2], 35.9 (CH2Se), 46.2 (CH–CH2), 59.3 (CH), 59.4 (CH),
62.9 (N–CH2), 126.6 (CHar), 126.8 (CHar), 127.9 (2 CHar), 128.0
(2 CHar), 129.0 (2 CHar), 131.0 (CarSe), 132.7 (2 CHar), 142.1 (CH–
Car) ppm. C21H27NSe (372.406): calcd. C 67.73, H 7.31, N 3.76;
found C 67.69, H 7.07, N 3.74.
0.3993, refinement method: full-matrix least-squares on F2, data/
restraints/parameters: 3487/1/239, goodness-of-fit on F2: 0.960, fi-
nal R indices [I Ͼ 2σ(I)]: R1 = 0.0867, wR2 = 0.2052, R indices (all
data): R1 = 0.1140, wR2 = 0.2235, absolute structure parameter:
–0.06(3), extinction coefficient: 0.026(6), largest diff. peak and hole:
1.560 and –1.293 e/Å3.
(R)-Methyl 2-{(2R)-4,4-Dimethyl-2-[(2,4,6-triisopropylphenylselen-
yl)methyl]pyrrolidin-1-yl}-2-phenylacetate and (R)-Methyl 2-{(2S)-
4,4-Dimethyl-2-[(2,4,6-triisopropylphenylselenyl)methyl]pyrrolidin-1-
yl}-2-phenylacetate (14g): Methyl (R)-2-(2,2-dimethylpent-4-enyl-
ideneamino)-2-phenylacetate (9j) (807 mg, 3.11 mmol) was dis-
solved in dry CH2Cl2 (40 mL) at –78 °C under argon in a flame-
dried flask. A solution of (2,4,6triisopropylphenyl)selenyl bromide
(5.10 mmol, 1.6 equiv.), generated in situ from bis(2,4,6-triisopro-
pylphenyl) diselenide (1.44 g, 2.55 mmol) and bromine (407 mg,
2.55 mmol) at –78 °C in dry CH2Cl2 (30 mL), was added over
30 min. After 2 h at –78 °C, MeOH (10 mL) and NaBH4 (241 mg,
6.37 mmol) were added. The mixture was warmed slowly to room
temperature. The organic layer was separated and washed with
water (10 mL). The aqueous layer was extracted with CH2Cl2
(2ϫ5 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. The remaining oil was purified
by column chromatography (400 mL silica gel, 4.5 cm column dia-
(R)-Methyl 2-[(2R)-4,4-Dimethyl-2-(phenylselenylmethyl)pyrrolidin-
1-yl]-2-phenylacetate [(R)-14f] and (R)-Methyl 2-[(2S)-4,4-Dimethyl-
2-(phenylselenylmethyl)pyrrolidin-1-yl]-2-phenylacetate [(S)-14f]:
Starting material 9j (98 mg, 0.38 mmol). Diastereomers were sepa-
rated. dr = 35:65. (R)-14f: yield of 57 mg (0.14 mmol, 37%), colour-
less crystals, Rf = 0.26 (hexane/EtOAc, 9:1), m.p. 46–48 °C
(CHCl3). [α]2D0 = –7.9 (c = 1.00, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.72 (s, 3 H, Cq–CH3), 1.03 (s, 3 H, Cq–CH3), 1.48 meter, cyclohexane/EtOAc, 9:1). Diastereomers were not separated.
(dd, J = 6.4 Hz, J = 12.8 Hz, 1 H, CH–CHЈH–Cq), 1.72 (dd, J =
8.1 Hz, J = 12.6 Hz, 1 H, CH–CHЈH–Cq), 2.20 (d, J = 9.0 Hz, 1
dr = 61:39. Major isomer: yield of 0.63 g (37%), colourless oil, Rf
= 0.70 (hexane/EtOAc, 9:1). 1H NMR (300 MHz, CDCl3): δ = 0.96
H, N–CHЈH), 2.81 (d, J = 9.4 Hz, 1 H, N–CHЈH), 2.85 (d, J = (s, 3 H, Cq–CH3), 1.00 (s, 3 H, Cq–CH3), 1.14 [d, J = 6.5 Hz, 6 H,
9.8 Hz, 1 H, SeCHЈH), 2.98 (dd, J = 2.6 Hz, J = 11.7 Hz 1 H, CH(CH3)2], 1.15 [d, J = 5.3 Hz, 6 H, CH(CH3)2], 1.18 [d, J =
SeCHЈH), 3.02–3.09 (m, 1 H, CH–CH2Se), 3.56 (s, 3 H, COOCH3), 6.8 Hz, 6 H, CH(CH3)2], 1.62 (dd, J = 7.2 Hz, J = 12.4 Hz, 1 H,
4.43 (s, 1 H, CH–COOCH3), 7.08–7.37 (m, 10 H, CHar) ppm. 13C CH–CHЈH–Cq), 1.81 (dd, J = 7.7 Hz, J = 12.6 Hz, 1 H, CH–
NMR (75.5 MHz, CDCl3): δ = 28.1 (Cq–CH3), 28.9 (Cq–CH3), 32.9 CHЈH–Cq), 2.40 (d, J = 8.7 Hz, 1 H, N–CHЈH), 2.57 (dd, J =
(CH2Se), 36.0 [C(CH3)2], 46.0 (CH–CH2), 51.8 (COOCH3), 60.5
2.6 Hz, J = 10.9 Hz, 1 H, SeCHЈH), 2.70 (d, J = 8.7 Hz, 1 H, N–
(CH), 63.6 (N–CH2), 67.4 (CH), 126.7 (CHar), 128.0 (CHar), 128.3 CHЈH), 2.73–2.82 [m, 2 H, SeCHЈH, CH(CH3)2], 3.17 (dq, J =
(2 CHar), 129.0 (2 CHar), 129.2 (2 CHar), 130.5 (CarSe), 132.8 (2
CHar), 134.9 (Car), 172.5 (COO) ppm. HRMS (ESI+): calcd. for
2.7 Hz, J = 7.6 Hz, 1 H, CH–CH2Se), 3.54 (s, 3 H, COOCH3), 3.83
[q, J = 6.9 Hz, 2 H, CH(CH3)2], 4.62 (s, 1 H, CH–COOCH3), 6.92
C22H27NO2Se 417.1207; found 417.1207. (S)-14f: yield of 35 mg (s, 2 H, CHar), 7.17–7.28 (m, 5 H, CHar) ppm. 13C NMR
(0.084 mmol, 22%), colourless oil, Rf = 0.35 (hexane/EtOAc, 9:1).
[α]2D0 = 1.2 (c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
0.95 (s, 3 H, Cq–CH3), 1.00 (s, 3 H, Cq–CH3), 1.60 (dd, J = 7.3 Hz,
J = 12.6 Hz, 1 H, CH–CHЈH–Cq), 1.79 (dd, J = 7.9 Hz, J =
(75.5 MHz, CDCl3): δ = 24.1 [2 C, CH(CH3)2], 27.0 [4 C, 2
CH(CH3)2], 28.8 (Cq–CH3), 29.5 (Cq–CH3), 34.3 [CH(CH3)2], 34.4
[2 C, CH(CH3)2], 35.0 (CH2Se), 35.9 [C(CH3)2], 46.6 (CH–CH2),
51.3 (COOCH3), 60.9 (CH), 62.1 (N–CH2), 65.5 (CH), 121.7 (2
12.8 Hz, 1 H, CH–CHЈH–Cq), 2.46 (d, J = 9.0 Hz, 1 H, N–CHЈH), CHar), 127.8 (CHar), 128.4 (2 CHar), 128.5 (2 CHar), 129.3 (CarSe),
2.68 (d, J = 9.0 Hz, 1 H, N–CHЈH), 2.91 (dd, J = 3.2 Hz, J = 137.3 (CarCH), 149.4 [CarCH(CH3)2], 153.2 [2 C, CarCH(CH3)2],
2952
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2945–2957

Diastereoselective Cyclisation of N-Alkenylideneamines
FULL PAPER
172.1 (COO) ppm. Minor isomer: yield of 0.40 g (24%). Rf = 0.60
(hexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ = 0.67 (s, 3
CHar), 137.1 (Car), 171.8 (COO) ppm. Minor isomer: 1H NMR
(300 MHz, CDCl3): δ = 0.78 (s, 3 H, CH3), 0.84 (s, 3 H, CH3),
1.23–1.39 (m, 2 H, CH2), 1.63–1.72 (m, 2 H, CH2), 2.15–2.20 (m,
1 H, CHЈH), 2.25 (d, J = 12.1 Hz, 1 H, CHЈH), 2.98–3.02 (m, 1
H, CH–CH2Se), 3.20 (t, J = 12.1 Hz, 1 H, CHЈHx), 3.46 (dd, J =
6.7 Hz, J = 11.7 Hz, 1 H, CHЈH), 3.69 (s, 3 H, CH3), 5.06 (s, 1
H, CH–COOCH3), 7.15–7.52 (m, 10 H, CHar) ppm. 13C NMR
1
H, Cq–CH3), 1.04 (s, 3 H, Cq–CH3), 1.14 [d, J = 7.2 Hz, 6 H,
CH(CH3)2], 1.16 [d, J = 6.8 Hz, 6 H, CH(CH3)2], 1.20 [d, J =
6.8 Hz, 6 H, CH(CH3)2], 1.47 (dd, J = 6.8 Hz, J = 12.4 Hz, 1 H,
CH–CHЈH–Cq), 1.74 (dd, J = 7.9 Hz, J = 12.8 Hz, 1 H, CH–
CHЈH–Cq), 2.17 (d, J = 9.0 Hz, 1 H, N–CHЈH), 2.63 (d, J =
6.4 Hz, 2 H, SeCH2), 2.80–2.98 [m, 3 H, N–CHЈH, CH(CH3)2, (75.5 MHz, CDCl3): δ = 24.8 (CH3), 27.0 (CH2Se), 28.6 (CH3),
CH–CH2Se], 3.48 (s, 3 H, COOCH3), 3.83 [q, J = 7.0 Hz, 2 H, 30.8 [C(CH3)2], 31.7 (CH–CH2), 36.4 (Cq–CH2), 52.0 (COOCH3),
CH(CH3)2], 4.32 (s, 1 H, CH–COOCH3), 6.89–6.92 (m, 2 H, CHar),
56.9 (N–CH2), 57.3 (SeCH2–CH), 66.1 (CH–COO), 126.8 (CHar),
6.96 (s, 2 H, CHar), 7.14–7.18 (m, 3 H, CHar) ppm. 13C NMR 128.2 (CHar), 128.3 (2 CHar), 128.6 (2 CHar), 129.1 (2 CHar), 130.6
(75.5 MHz, CDCl3): δ = 24.9 [2 C, CH(CH3)2], 27.0 [4 C, 2 (CarSe), 132.6 (2 CHar), 135.8 (Car), 173.2 (COO) ppm.
CH(CH3)2], 28.2 (Cq–CH3), 29.1 (Cq–CH3), 34.3 [CH(CH3)2], 34.4
(R)-Methyl 2-Phenyl-2-[(2R)-2,4,4-trimethyl-2-(phenylselenylmeth-
[2 C, CH(CH3)2], 35.3 (CH2Se), 36.2 [C(CH3)2], 46.3 (CH–CH2),
yl)pyrrolidin-1-yl]acetate and (R)-Methyl 2-Phenyl-2-[(2S)-2,4,4-tri-
51.8 (COOCH3), 60.8 (CH), 63.1 (N–CH2), 66.9 (CH), 121.8 (2
methyl-2-(phenylselenylmethyl)pyrrolidin-1-yl]acetate (17b): Starting
CHar), 127.6 (CarSe), 128.0 (CHar), 128.3 (2 CHar), 129.3 (2 CHar),
material 15b (376 mg, 1.38 mmol). Yield: 216 mg (0.502 mmol,
134.4 (CarCH), 149.6 [CarCH(CH3)2], 153.2 [2 C, CarCH(CH3)2],
36%). Isomers were not separated, dr = 46:54, colourless oil, Rf =
172.6 (COO) ppm. HRMS (ESI+): calcd. for C31H46NO2Se
0.36 (hexane/EtOAc, 20:1). C23H29NO2Se (430.442): calcd. C 64.18,
544.2688; found 544.2683.
1
H 6.79, N 3.25; found C 64.03, H 6.54, N 3.09. Minor isomer: H
(2R)-2-Bromomethyl-1-[(R)-(methoxycarbonyl)(phenyl)methyl]-
2,4,4-trimethyl-3,4-dihydro-2H-pyrrolium Bromide and (2S)-2-Bro-
momethyl-1-[(R)-(methoxycarbonyl)(phenyl)methyl]-2,4,4-trimethyl-
3,4-dihydro-2H-pyrrolium Bromide (16c): Starting material 15c
(240 mg, 0.88 mmol). Yield: 381 mg (0.88 mmol, quant.). Isomers
were not separated, dr = 46:54, yellow foam. HRMS (ESI+ in
MeCN): calcd. for C17H23BrO2N 352.0907; found 352.0907. Major
NMR (300 MHz, CDCl3): δ = 0.98 (s, 3 H, CH3), 0.99 (s, 3 H,
CH3), 1.13 (s, 3 H, N–Cq–CH3), 1.41 (d, J = 12.7 Hz, 1 H, Cq–
CHЈH–Cq), 1.90 (d, J = 13.1 Hz, 1 H, Cq–CHЈH– Cq), 2.33 (d, J
= 9.1 Hz, 1 H, N–CHЈH), 2.95 (d, J = 11.4 Hz, 1 H, Se–CHЈH),
3.02 (d, J = 9.2 Hz, 1 H, N–CHЈH), 3.27 (d, J = 11.3 Hz, 1 H, Se–
CHЈH), 3.65 (s, 3 H, CH3), 4.68 (s, 1 H, CH–COOCH3), 7.14–7.43
(m, 10 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 23.4 (N–
Cq–CH3), 29.2 (CH3), 29.9 (CH3), 35.3 [C(CH3)2], 40.4 (CH2Se),
51.7 (COOCH3), 53.0 (CH2), 59.6 (CH2), 61.7 (CH), 64.3 (Cq),
126.6 (CHar), 128.6 (CHar), 127.7 (2 CHar), 128.4 (2 CHar), 129.2
(2 CHar), 137.9 (CarSe), 132.2 (2 CHar), 138.1 (Car), 174.1 (COO)
ppm. Major isomer: 1H NMR (300 MHz, CDCl3): δ = 0.90 (s, 3
H, CH3), 0.96 (s, 3 H, CH3), 1.21 (s, 3 H, N–Cq–CH3), 1.45 (d, J
= 12.6 Hz, 1 H, Cq–CHЈH–Cq), 2.02 (d, J = 13.0 Hz, 1 H, Cq–
CHЈH– Cq), 2.44 (d, J = 9.1 Hz, 1 H, N–CHЈH), 2.94 (d, J =
11.1 Hz, 1 H, Se–CHЈH), 2.91 (d, J = 9.2 Hz, 1 H, N–CHЈH), 3.15
(d, J = 11.1 Hz, 1 H, Se–CHЈH), 3.63 (s, 3 H, CH3), 4.64 (s, 1
H, CH–COOCH3), 7.14–7.43 (m, 10 H, CHar) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 25.1 (N–Cq–CH3), 28.8 (CH3), 29.4 (CH3),
34.7 [C(CH3)2], 39.8 (CH2Se), 51.8 (COOCH3), 53.4 (CH2), 60.4
(CH2), 62.3 (CH), 64.7 (Cq), 126.7 (CHar), 128.5 (CHar), 128.2 (2
CHar), 128.4 (2 CHar), 129.1 (2 CHar), 137.9 (CarSe), 132.3 (2
CHar), 138.4 (Car), 174.5 (COO) ppm.
1
isomer: H NMR (300 MHz, CDCl3): δ = 1.48 (s, 3 H, CH3), 1.66
(s, 3 H, CH3), 1.94 (s, 3 H, N–Cq–CH3), 2.23 (d, J = 7.0 Hz, 1 H,
Cq–CHЈH–Cqx), 2.53 (d, J = 13.9 Hz, 1 H, Cq–CHЈH–Cq), 3.82 (d,
J = 12.0 Hz, 1 H, Br–CHЈH), 3.86 (s, 3 H, CH3), 4.67 (d, J =
12.8 Hz, 1 H, Br–CHЈH), 6.63 (s, 1 H, CH–COOCH3), 7.37–7.78
(m, 5 H, CHar), 9.41 (s, 1 H, CH=N) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 24.7 (N–Cq–CH3), 26.6 (CH3), 27.8 (CH3), 37.5
(CH2Br), 48.1 [C(CH3)2], 45.9 (CH2), 54.9 (COOCH3), 63.3 (CH),
83.8 (Cq), 128.4 (2 CHar), 130.5 (2 CHar), 131.5 (CHar), 131.0 (Car),
166.7 (COO), 189.7 (CH=N) ppm. Minor isomer: 1H NMR
(300 MHz, CDCl3): δ = 1.49 (s, 3 H, CH3), 1.67 (s, 3 H, CH3), 1.96
(s, 3 H, N–Cq–CH3), 2.26 (d, J = 13.9 Hz, 1 H, Cq–CHЈH–Cq),
2.50 (d, J = 13.8 Hz, 1 H, Cq–CHЈH–Cq), 3.84 (d, J = 12.7 Hz, 1
H, Br–CHЈH), 3.90 (s, 3 H, CH3), 4.93 (d, J = 12.8 Hz, 1 H, Br–
CHЈH), 6.79 (s, 1 H, CH–COOCH3), 7.37–7.78 (m, 5 H, CHar),
8.87 (s, 1 H, CH=N) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 25.2
(N–Cq–CH3), 25.3 (CH3), 27.0 (CH3), 38.3 (CH2Br), 48.2
[C(CH3)2], 45.8 (CH2), 55.2 (COOCH3), 64.3 (CH), 83.1 (Cq), 129.9
(2 CHar), 130.2 (2 CHar), 131.2 (CHar), 130.0 (Car), 167.6 (COO),
189.7 (CH=N) ppm.
3,3-Dimethyl-2-phenyl-1-[(R)-1-phenylethyl]-5-(phenylselenylmeth-
yl)pyrrolidine (17d): Starting material 15d (0.25 g, 0.86 mmol).
Yield: 0.22 g (0.49 mmol, 57%). Isomers were not separated, dr =
13:21:38:28. After being column chromatographed twice, three of
these isomers could be isolated as a mixture, colourless oil, Rf =
0.22 (hexane/EtOAc, 20:1). 13C NMR (75.5 MHz, CDCl3): δ =
14.6, 18.2, 24.2 (CH3), 24.9, 25.7, 26.3 (CH3), 28.5, 28.9, 31.0
(CH3), 34.6, 34.9, 37.1 (CH2Se), 40.3, 40.6, 40.9 [C(CH3)2], 44.7,
45.7, 46.6 (CH–CH2), 54.8, 55.7, 56.7 (CH–CH3), 58.4, 59.4, 60.5
(CH–CH2Se), 74.6, 75.2, 78.0 (CH–Ph), 125.9–133.0 (15CHar),
129.6, 129.8, 130.7 (SeCar), 140.7, 142.1, 142.3 (Car), 143.8, 144.6,
146.7 (Car) ppm. HRMS (EI): calcd. for C27H31NSe 449.1616;
found 449.1612.
(R)-Methyl 2-[(2R)-5,5-Dimethyl-2-(phenylselenylmethyl)piperidin-
1-yl]-2-phenylacetate and (R)-Methyl 2-[(2S)-5,5-Dimethyl-2-(phen-
ylselenylmethyl)piperidin-1-yl]-2-phenylacetate (17a): Starting mate-
rial 15a (0.15 g, 0.55 mmol). Yield: 0.15 g (0.35 mmol, 64%). Iso-
mers were not separated, dr = 54:46, colourless oil, Rf = 0.34 and
0.29 (hexane/EtOAc, 8:2). C23H29NO2Se (430.442): calcd. C 64.18,
1
H 6.79, N 3.25; found C 64.04, H 6.91, N 3.25. Major isomer: H
NMR (300 MHz, CDCl3): δ = 0.91 (s, 3 H, CH3), 1.00 (s, 3 H,
CH3), 1.10–1.27 (m, 2 H, CH2), 1.76–1.82 (m, 2 H, CH2), 1.99 (d,
J = 11.6 Hz, 1 H, CHЈH), 2.56 (d, J = 11.1 Hz, 1 H, CHЈH), 2.85–
2.90 (m, 1 H, CH–CH2Se), 2.91–2.96 (m, 1 H, CHЈH), 3.16–3.24 (3aR,4R,6aS)-5-Benzyl-4-bromonium-2,2-dimethyl-4,6a-dihydro-
(m, 1 H, CHЈH), 3.65 (s, 3 H, CH3), 4.49 (s, 1 H, CH–COOCH3),
3aH-[1,3]dioxolo[4,5c]pyrrol-5-ium Bromide and (3aR,4S,6aS)-5-
Benzyl-4-bromonium-2,2-dimethyl-4,6a-dihydro-3aH-[1,3]dioxolo-
7.15–7.52 (m, 10 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 25.2 (CH2Se), 25.5 (CH3), 28.1 (CH–CH2), 28.4 (CH3), 30.7 [4,5-c]pyrrol-5-ium Bromide (19b): N-Benzyl[(4S,5R)-(2,2-dimethyl-
[C(CH3)2], 33.3 (Cq–CH2), 51.4 (COOCH3), 54.5 (SeCH2–CH), 5-vinyl[1,3]dioxolane-4-yl)methylene]amine (18a) (0.56 g,
56.7 (N–CH2), 69.8 (CH–COO), 126.8 (CHar), 127.8 (CHar), 128.6 2.3 mmol) was dissolved in dry CH2Cl2 (20 mL) at –78 °C under
(2 CHar), 129.0 (2 CHar), 129.2 (2 CHar), 131.1 (CarSe), 132.6 (2
argon in a flame-dried flask. A 1.0  solution of bromine (2.3 mL,
Eur. J. Org. Chem. 2007, 2945–2957
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2953

D. Schley, J. Liebscher
FULL PAPER
1.0 equiv.) in CH2Cl2, which was diluted with dry CH2Cl2 (20 mL)
was added over 2 h. After 1 h at –78 °C, the mixture was concen-
trated under vacuum (T Ͻ 30 °C). Yield: 0.93 g (2.3 mmol, quant.),
dr = 38:62 (HPLC/MS in MeOH of the crude product), brown
foam. HRMS (ESI+): calcd. for C15H19BrNO2 324.0599/326.0579;
found 324.0601/326.0581.
12.0 Hz, 1 H, CHHSe), 3.99 (q, J = 7.2 Hz, 1 H, CH–Ph), 4.44
(dd, J = 4.5 Hz, J = 6.4 Hz, 1 H, CH2CH–O), 4.62 (dd, J = 4.9 Hz,
J = 6.4 Hz, 1 H, CH–CH–O), 6.89–7.59 (m, 10 H, CHar) ppm. 13
C
NMR (75.5 MHz, CDCl3): δ = 19.0 (CH–CH3), 25.9 (Cq–CH3),
26.1 (CH2Se), 26.5 (Cq–CH3), 52.4 (CH2N), 55.3 (CH–Ph), 63.5
(CHN), 77.1 (CHCH2), 81.0 (CHCH), 111.5 [C(CH3)2], 127.1
(CHar), 127.3 (CHar), 128.0 (2 CHar), 128.5 (2 CHar), 129.1 (2
CHar), 130.9 (CarSe), 134.0 (2 CHar), 137.9 (Car) ppm. Minor iso-
mer (S)-20d: 1H NMR (300 MHz, CDCl3): δ = 1.24 (d, J = 6.4 Hz,
3 H, CH–CH3), 1.31 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 2.84 (dd, J
= 9.4 Hz, J = 12.0 Hz, 1 H, CHHSe), 3.04–3.08 (m, 3 H, CHHSe,
CH2), 3.41 (dd, J = 2.3 Hz, J = 8.7 Hz, 1 H, CHN), 3.88 (q, J =
6.5 Hz, 1 H, CH–Ph), 4.54–4.63 (m, 1 H, CH2CH–O), 4.66 (dd, J
= 1.9 Hz, J = 6.4 Hz, 1 H, CH–CH–O), 6.89–7.59 (m, 10 H, CHar)
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 18.5 (CH–CH3), 25.4 (Cq–
CH3), 27.1 (Cq–CH3), 27.2 (CH2Se), 53.8 (CH2N), 57.8 (CH–Ph),
65.0 (CHN), 78.9 (CHCH2), 84.4 (CHCH), 112.1 [C(CH3)2], 127.1
(3 CHar), 127.4 (3 CHar), 128.4 (2 CHar), 129.2 (2 CHar), 133.1
(CarSe), 144.8 (Car) ppm.
X-ray Crystal Analysis of 20d:[79] Empirical formula: C22H27NO2Se,
formula weight: 416.41 g/mol, temperature: 150(2) K, wavelength:
0.71073 Å, crystal system: orthorhombic, space group: P 21 21 21,
unit cell dimensions: a = 9.568(4) Å, b = 9.999(3) Å, c =
20.383(3) Å, V = 1950.1(12) Å3, Z = 4, density (calculated):
1.418 Mg/m3, absorption coefficient: 1.941 mm–1, F(000): 864, crys-
tal size: 0.80 ϫ0.80ϫ0.60 mm, Theta range for data collection:
2.00 to 27.48 deg, limiting indices: –12 Յ h Յ 12, –12 Յ k Յ 12,
–26 Յ l Յ 26; reflections collected: 12622, unique: 4461 [R(int.) =
0.0234], completeness to θ = 27.48 is 99.9%, absorption correction:
empirical (psi-scan), max./min. transmission: 0.3888/0.3057, refine-
ment method: full-matrix least-squares on F2 data/restraints/pa-
rameters: 4461/0/344, goodness-of-fit on F2: 1.067, final R indices
[I Ͼ 2σ(I)]: R1 = 0.0217, wR2 = 0.0440, R indices (all data): R1
= 0.0283, wR2 = 0.0467, absolute structure parameter: –0.011(6),
extinction coefficient: 0.0020(3), largest diff. peak and hole: 0.240
and –0.319 e/Å3.
General Procedure for the Selenocyclisation and Reduction to Tetra-
hydro[1,3]dioxolo-[4,5-c]pyrroles 20: The appropriate N(alkenyl-
idene)alkylamine 18 (2.1 mmol) was dissolved in dry CH2Cl2
(20 mL) at –78 °C under argon in a flame-dried flask. A solution
of the appropriate arylselenyl bromide (1.3 equiv.) in dry CH2Cl2
(15 mL) was added over 20 min. After 2.5 h at –78 °C, MeOH
(10 mL) and NaBH4 (4.2 mmol) were added. The mixture was
warmed slowly to room temperature. The organic layer was sepa-
rated and washed with water (20 mL). After separating the layers,
the aqueous layer was washed with CH2Cl2 (2ϫ5 mL). The com-
bined organic layers were dried with MgSO4 and concentrated un-
der vacuum. The remaining yellow oil was purified by column
chromatography (40 g silica gel, 2.3 cm column diameter, cyclohex-
ane/EtOAc mixture).
(3aR,4R,6aS)-5-Benzyl-tetrahydro-2,2-dimethyl-4-(phenylselenyl-
methyl)-3aH-[1,3]dioxolo[4,5-c]pyrrole [(R)-20a] and (3aR,4S,6aS)-
5-Benzyl-tetrahydro-2,2-dimethyl-4-(phenylselenylmethyl)-3aH-
[1,3]dioxolo[4,5-c]pyrrole [(S)-20a]: Starting material 18a (0.52 g,
2.1 mmol). Diastereomers were not separated. Yield: 0.36 g
(0.89 mmol, 42%), dr = 20:80, colourless oil, Rf = 0.26 and 0.31
(hexane/EtOAc, 8:2). C21H25NO2Se (402.389): calcd. C 62.68, H
6.26, N 3.48; found C 62.69, H 6.43, N 3.43. Major isomer (R)-
1
20a: H NMR (300 MHz, CDCl3): δ = 1.33 (s, 3 H, CH3), 1.55 (s,
3 H, CH3), 2.06 (dd, J = 4.7 Hz, J = 11.1 Hz, 1 H, CHH), 2.44–
2.48 (m, 1 H, CHN), 3.06 (d, J = 10.9 Hz, 1 H, CHH), 3.16 (d, J
= 14.0 Hz, 1 H, CHH–Ph), 3.17 (d, J = 9.4 Hz, 2 H, CH2Se), 3.97
(d, J = 13.6 Hz, 1 H, CHH–Ph), 4.55 (dd, J = 4.5 Hz, J = 6.4 Hz,
1 H, CH–CH–O), 4.74 (dd, J = 4.9 Hz, J = 6.4 Hz, 1 H, CH2CH–
O), 7.23–7.27 (m, 8 H, CHar), 7.52–7.55 (m, 2 H, CHar) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 25.3 (CH2Se), 25.7 (CH3), 26.5
(CH3), 57.0 (CH2Ph), 59.7 (CH2N), 67.9 (CHN), 77.6 (CHCH2),
81.1 (CHCH), 111.5 [C(CH3)2], 127.0 (CHar), 127.1 (CHar), 128.4
(2 CHar), 128.7 (2 CHar), 129.2 (2 CHar), 130.9 (CarSe), 132.8 (2
CHar), 138.2 (Car) ppm. Minor isomer (S)-20a: 1H NMR
(300 MHz, CDCl3): δ = 1.31 (s, 3 H, CH3), 1.52 (s, 3 H, CH3), 2.51
(dd, J = 4.1 Hz, J = 10.5 Hz, 1 H, CHH), 3.05–3.16 (m, 4 H), 3.42
(d, J = 12.9 Hz, 1 H, CHH–Ph), 4.01 (d, J = 12.8 Hz, 1 H, CHH–
Ph), 4.59–4.70 (m, 2 H, CH–O), 7.23–7.27 (m, 8 H, CHar), 7.44–
7.48 (m, 2 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 25.3
(CH3), 27.4 (CH3), 29.2 (CH2Se), 57.1 (CH2Ph), 58.2 (CH2N), 67.7
(CHN), 78.0 (CHCH2), 84.3 (CHCH), 113.0 [C(CH3)2], 126.8
(CHar), 127.3 (CHar), 128.4 (2 CHar), 128.8 (2 CHar), 129.2 (2
CHar), 130.9 (CarSe), 132.4 (2 CHar), 138.4 (Car) ppm.
Methyl (1S)-2-Phenyl-2-{(3aR,4R,6aS)-tetrahydro-2,2-dimethyl-4-
(phenylselenylmethyl)[1,3]dioxolo[4,5-c]pyrrol-5-yl}acetate [(R)-20f]
and Methyl (1S)-2-Phenyl-2-{(3aR,4S,6aS)-tetrahydro-2,2-dimethyl-
4-(phenylselenylmethyl)[1,3]dioxolo[4,5-c]pyrrol-5-yl}acetate [(S)-
20f]: Starting material 18d (0.50 g, 1.6 mmol) and phenylselenyl
bromide (0.65 g, 2.7 mmol). Diastereomers were separated, dr =
19:81. Major isomer (R)-20f: yield 0.14 g (0.30 mmol, 18 %),
colourless oil, Rf = 0.12 (cyclohexane/EtOAc, 9:1). [α]2D3 = 201.8 (c
= 0.82, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H,
CH3), 1.58 (s, 3 H, CH3), 2.17 (dd, J = 4.9 Hz, J = 10.9 Hz, 1 H,
N–CHH), 2.57 (ddd, J = 4.1 Hz, J = 4.4 Hz, J = 10.9 Hz, 1 H,
CHN), 3.03 (dd, J = 3.8 Hz, J = 11.9 Hz, 1 H, CHHSe), 3.12 (dd,
J = 10.8 Hz, J = 11.9 Hz, 1 H, CHHSe), 3.35 (d, J = 10.9 Hz, 1
H, N–CHH), 3.66 (s, 3 H, COOCH3), 4.48 (dd, J = 4.9 Hz, J =
(3aR,4R,6aS)-Tetrahydro-2,2-dimethyl-5-[(R)-1-phenylethyl]-4-(phen- 6.4 Hz, 1 H, CH2CH–O), 4.50 (s, 1 H, CH–Ph), 4.70 (dd, J =
ylselenylmethyl)-3aH-[1,3]dioxolo[4,5-c]pyrrole [(R)-20d] and 4.9 Hz, J = 6.4 Hz, 1 H, CH–CH–O), 6.98–7.02 (m, 2 H, CHar),
(3aR,4S,6aS)-Tetrahydro-2,2-dimethyl-5-[(R)-1-phenylethyl]-4-(phen- 7.18–7.32 (m, 6 H, CHar), 7.55–7.58 (m, 2 H, CHar) ppm. 13C
ylselenylmethyl)-3aH-[1,3]dioxolo[4,5-c]pyrrole [(S)-20d]: Starting
material 18b (0.52 g, 2.0 mmol) and phenylselenyl bromide (0.65 g,
2.7 mmol). Diastereomers were not separated. Yield: 0.42 g
(1.01 mmol, 50%), dr = 16:84, white solid, m.p. 117–120 °C, Rf =
0.27 (cyclohexane/EtOAc, 9:1). C22H27NO2Se (416.415): calcd. C
63.45, H 6.54, N 3.36; found C 63.28, H 6.43, N 3.37. Major isomer
NMR (75.5 MHz, CDCl3): δ = 25.8 (CH2Se), 26.1 (Cq–CH3), 26.5
(Cq–CH3), 52.0 (COOCH3), 55.4 (CH2N), 64.9 (CHN), 65.7 (CH–
Ph), 77.1 (CHCH2), 80.5 (CHCH), 111.8 [(C(CH3)2], 127.4 (CHar),
128.2 (CHar), 128.4 (2 CHar), 129.2 (2 CHar), 129.4 (2 CHar), 130.6
(CarSe), 133.0 (Car), 133.7 (2 CHar), 171.9 (COO) ppm. HRMS
(EI): calcd. for C23H27O4NSe 461.11053; found 461.11055. Minor
(R)-20d: 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.43 isomer (S)-20f: yield of 33 mg (0.072 mmol, 4%), colourless oil, Rf
(d, J = 7.2 Hz, 3 H, CH–CH3), 1.54 (s, 3 H, CH3), 2.16 (dd, J = = 0.08 (cyclohexane/EtOAc, 9:1). [α]2D3 = –31.7 (c = 1.16, CHCl3).
4.7 Hz, J = 10.3 Hz, 1 H, CHH), 2.32–2.38 (m, 1 H, CHN), 3.12
(d, J = 10.9 Hz, 2 H, CHH, CHHSe), 3.25 (dd, J = 3.4 Hz, J =
1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.59 (s, 3 H,
CH3), 2.98–3.04 (m, 3 H, CH2Se, CHH), 3.09 (dd, J = 2.9 Hz, J =
2954
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2945–2957

Diastereoselective Cyclisation of N-Alkenylideneamines
11.5 Hz, 1 H, N–CHH), 3.38 (ddd, J = 2.3 Hz, J = 3.6 Hz, J = (CH2–Car), 142.5 (CH2–Car) ppm. Minor isomer: 1H NMR
FULL PAPER
8.2 Hz, 1 H, CHN), 3.64 (s, 3 H, COOCH3), 4.62 (ddd, J = 3.0 Hz,
J = 5.1 Hz, J = 6.4 Hz, 1 H, CH2CH–O), 4.68 (dd, J = 2.3 Hz, J
= 6.4 Hz, 1 H, CH–CH–O), 4.80 (s, 1 H, CH–Ph), 7.19–7.42 (m,
10 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 25.2 (Cq–
(300 MHz, CDCl3): δ = 0.93 (s, 3 H, CH3), 1.08, (s, 3 H, CH3),
1.66 (dd, J = 8.1 Hz, J = 10.0 Hz, 1 H, Cq–CHH–CH), 1.84 (dd,
J = 3.7 Hz, J = 7.9 Hz, 1 H, Cq–CHH–CH), 1.99 (d, J = 8.8 Hz,
1 H, Cq–CHH–N), 2.64 (d, J = 9.0 Hz, 1 H, Cq–CHH–N), 2.84–
CH3), 27.3 (Cq–CH3), 28.7 (CH2Se), 52.0 (COOCH3), 54.6 2.92 (m, 1 H, CH–CH2–Se), 3.05–3.18 (m, 3 H, Se–CH2, CH), 3.53
(CH2N), 65.3 (CH–Ph), 67.0 (CHN), 79.2 (CHCH2), 84.7 (CHCH), (s, 2 H, CH2–Ar), 3.90–4.17 (m, 6 H, 2 CH2–O, 2 CH), 4.40 (s, 2
112.5 [C(CH3)2], 126.9 (CHar), 128.4 (CHar), 128.7 (4 CHar), 129.2 H, CH2–Ph), 4.77 (d, J = 16.2 Hz, 1 H, CH), 5.50 (s, 2 H, 2O–
(2 CHar), 132.5 (2 CHar), 133.8 (CarSe), 136.7 (Car), 171.8 (COO) CH–O), 7.11–7.15 (m, 1 H, CHar), 7.19–7.54 (m, 17 H, CHar), 7.69
ppm. HRMS (EI): calcd. for C23H27O4NSe 461.11053; found
461.11055.
(d, J = 7.5 Hz, 1 H, SeCar–CHar) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 28.8 (CH3), 30.2 (CH3), 32.5 (CH2Se), 35.9 [C(CH3)2],
46.6 (CH–CH2–Cq), 53.1 (CH2–Ph), 53.8 (CH2–Ar), 58.6 (2 NCH–
CH2O), 63.7 (CH–CH2Se), 67.0 (2 CH2–O), 68.3 [N–CH2–C-
(CH3)2], 79.7 (2 CH–O), 99.9 (2 Ph–CH–O), 126.5 (4 CHar), 126.6
(CHar), 126.8 (CHar), 127.3 (CHar), 128.2 (4 CHar), 128.5 (4 CHar),
128.7 (CHar), 129.2 (2 CHar), 131.6 (SeCar), 131.8 (CHar), 138.5 (2
CH–Car), 139.9 (CH2–Car), 142.6 (CH2–Car) ppm.
General Procedure for the Selenocyclisation and Reduction to Pyr-
rolidines 21a, 21c and 21d: The appropriate N(alkenylidene)alk-
ylamine 9 (1.64 mmol) was dissolved in dry CH2Cl2 (15 mL) at
–78 °C under argon in a flame-dried flask. A solution of cam-
phorselenyl bromide 22 (0.96 mmol), generated in situ, in dry
CH2Cl2 (30 mL) was added over 30 min. After 2 h at –78 °C,
MeOH (5 mL) and NaBH4 (73 mg, 1.93 mmol) were added. The
mixture was warmed slowly to room temperature. The organic layer
was separated and washed with water (10 mL). After separating the
layers, the aqueous layer was washed with CH2Cl2 (2ϫ5 mL). The
combined organic layers were dried with MgSO4 and concentrated
under vacuum. The remaining yellow oil was purified by column
chromatography (40 g of silica gel, 2.3 cm column diameter, cyclo-
hexane/EtOAc mixture).
Methyl (R)-2-{(2R)-4,4-Dimethyl-2-[(1R,2S,4R)-4,7,7-trimethyl-3-
oxobicyclo[2.2.1]hept-2-yl-selenylmethyl]pyrrolidin-1-yl}-2-phenyl-
acetate and Methyl (R)-2-{(2S)-4,4-Dimethyl-2-[(1R,2S,4R)-4,7,7-
trimethyl-3-oxobicyclo[2.2.1]hept-2-yl-selenylmethyl]pyrrolidin-1-
yl}-2-phenylacetate (21c): Starting material 9j (270 mg, 1.04 mmol).
Diastereomers were isolated as a mixture of rotamers. dr = 38:62.
Major isomer: yield of 122 mg (0.25 mmol, 29%), colourless oil, Rf
= 0.21 (hexane/EtOAc, 9:1). [α]2D2 = –7.4 (c = 1.00, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.75, 0.77 (s, 3 H, CH3), 0.82 (s, 3
H, CH3), 0.84, 085 (s, 3 H, CH3), 0.94 (s, 3 H, CH3), 1.03, 1.04 (s,
3 H, CH3), 1.32–1.63 (m, 4 H, 2 CH2), 1.67–1.74 (m, 3 H, CHH–
N, CH2), 1.99–2.04 (m, 1 H, SeCH2–CH–N), 2.19, 2.21 (d, J =
8.6 Hz, 1 H, CHH–N), 2.72–2.83 (m, 2 H, CHH–Se, CH–CHSe),
2.86–2.92 (m, 1 H, CHH–Se), 2.94–3.15 (m, 1 H, CH–Se), 3.60,
3.61 (s, 3 H, COOCH3), 4.51, 4.52 (s, 1 H, CH–COO), 7.24–7.29
(m, 5 H, CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 9.9 (CH3),
19.8 (2 CH3), 23.4, 23.5 (CH2), 28.4, 28.5 (CH3), 29.1, 29.2 (CH3),
29.5, 29.6 (CH2Se), 30.5, 30.6 (CH2), 36.1, 36.2 [C(CH3)2], 46.0,
46.2 (CH–CH2–Cq), 46.6, 46.7 (CH–Se), 46.9, 47.0 (Cq–CO), 48.4,
48.5 (CH–CHSe), 52.0, 52.1 (COOCH3), 58.1, 58.2 (Cq–CO), 60.6,
60.9 (CH–Ph), 63.7, 63.8 (N–CH2–Cq), 67.6, 67.8 (CH–N), 128.2
(CHar), 128.4, 128.5 (2 CHar), 129.3, 129.4 (2 CHar), 135.2, 135.3
(CH–Car), 172.7, 172.8 (COO), 218.2, 218.3 (C=O) ppm. HRMS
(ESI+) calcd. for C26H37O3NSeNa 514.1831; found 514.1831.
Minor isomer: yield of 74 mg (0.15 mmol, 17%). Rf = 0.26 (hexane/
(4aR,4bR,8aS,9aS)-9-{2-[(2R)-N-Benzyl-4,4-dimethylpyrrolidin-2-
ylselenylmethyl]benzyl}-3,6-diphenyl-hexahydro-2,4,5,7-tetraoxa-9-
azafluoren and (4aR,4bR,8aS,9aS)-9-{2-[(2S)-N-Benzyl-4,4-dimeth-
ylpyrrolidin-2-ylselenylmethyl]benzyl}-3,6-diphenyl-hexahydro-
2,4,5,7-tetraoxa-9-azafluoren (21b): The diselenide (0.32 g,
0.32 mmol) was dissolved in dry CH2Cl2 (10 mL) at –78 °C under
argon in a flame-dried flask. A 0.1  solution of bromine
(0.32 mmol) in dry CH2Cl2 was added over 5 min to generate 23.
After 20 min at –78 °C, AgPF6 (0.19 g, 0.75 mmol) was added. The
mixture was stirred for 20 min and cooled to –100 °C. N-Ben-
zyl(2,2-dimethylpent-4-enylidene)amine (9a) (0.36 g, 1.79 mmol) in
dry CH2Cl2 (5 mL) was added. The mixture was warmed slowly to
room temperature. MeOH (5 mL) and sodium borohydride (73 mg,
1.93 mmol) were added, and the mixture was stirred for 1 h. The
organic layer was separated and washed with water (10 mL). After
separating the layers, the aqueous layer was washed with CH2Cl2
(2ϫ5 mL). The combined organic layers were dried with MgSO4
and concentrated under vacuum. The remaining oil was purified by
column chromatography (40 g silica gel, 2.3 cm column diameter,
cyclohexane/EtOAc, 9:1), yielding 0.33 g (0.46 mmol, 72% yield) of
a colourless oil. Diastereomers were not separated, dr = 48:52, Rf =
0.53 (hexane/EtOAc, 9:1). HRMS (ESI): calcd. for C41H47O2N2Se
711.27010; found 711.27013. Major isomer: 1H NMR (300 MHz,
CDCl3): δ = 0.97 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 1.70 (dd, J =
8.3 Hz, J = 9.7 Hz, 1 H, Cq–CHH–CH), 1.80 (dd, J = 3.9 Hz, J =
8.3 Hz, 1 H, Cq–CHH–CH), 1.99 (d, J = 8.8 Hz, 1 H, Cq–CHH–
N), 2.64 (d, J = 9.0 Hz, 1 H, Cq–CHH–N), 2.84–2.92 (m, 1 H, CH–
CH2–Se), 3.05–3.18 (m, 3 H, Se–CH2, CH), 3.53 (s, 2 H, CH2–Ar),
3.90–4.17 (m, 6 H, 2 CH2–O, 2 CH), 4.40 (s, 2 H, CH2–Ph), 4.75
(d, J = 15.8 Hz, 1 H, CH), 5.49 (s, 2 H, 2O–CH–O), 7.11–7.15 (m,
1 H, CHar), 7.19–7.54 (m, 17 H, CHar), 7.64 (d, J = 7.2 Hz, 1 H,
SeCar–CHar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 28.9 (CH3),
30.2 (CH3), 32.6 (CH2Se), 35.9 [C(CH3)2], 46.7 (CH–CH2–Cq), 53.1
(CH2–Ph), 53.8 (CH2–Ar), 58.3 (2 NCH–CH2O), 63.6 (CH–
CH2Se), 67.1 (2 CH2–O), 68.3 [N–CH2–C(CH3)2], 79.7 (2 CH–O),
1
EtOAc, 9:1). [α]2D2 = 19.8 (c = 1.25, CHCl3). H NMR (300 MHz,
CDCl3): δ = 0.80, 0.82 (s, 3 H, CH3), 0.84 (s, 3 H, CH3), 0.94, 0.95
(s, 3 H, CH3), 0.96 (s, 3 H, CH3), 0.97, 0.98 (s, 3 H, CH3), 1.32–
1.41 (m, 1 H, CHH), 1.52–1.64 (m, 3 H, 3 CHH), 1.71–1.80 (m, 3
H, 2 CHH, CHH–N), 2.01–2.11 (m, 1 H, CHH–N), 2.41–2.49 (m,
1 H, SeCH2–CH–N), 2.64–2.70 (m, 1 H, CH–CHSe), 2.78–2.81 (m,
1 H, CHH–Se), 3.17–3.29 (m, 1 H, CHH–Se), 3.45, 3.51 (d, J =
4.9 Hz, 1 H, CH–Se), 3.65, 3.66 (s, 3 H, COOCH3), 4.65, 4.70 (s,
1 H, CH–COO), 7.19–7.36 (m, 5 H, CHar) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 9.8 (CH3), 19.8 (2 CH3), 23.4, 23.5 (CH2),
28.7, 28.8 (CH3), 29.4 (CH3), 30.0 (CH2Se), 30.5, 30.6 (CH2), 36.0
[C(CH3)2], 46.3, 46.4 (CH–CH2–Cq), 46.6, 47.7 (CH–Se), 46.9 (Cq–
CO), 48.4, 48.5 (CH–CHSe), 51.5, 51.6 (COOCH3), 58.1, 58.2 (Cq–
CO), 60.6, 60.9 (CH–Ph), 62.3, 62.8 (N–CH2–Cq), 65.7, 66.4 (CH–
N), 127.8, 127.9 (CHar), 128.4 (2 CHar), 128.6, 128.7 (2 CHar),
137.4 (CH–Car), 172.2 (COO), 218.3, 218.4 (C=O) ppm. HRMS
(ESI+): calcd. for C26H38O3NSe 492.2011; found 492.2011.
99.9 (2 Ph–CH–O), 126.5 (4 CHar), 126.7 (CHar), 126.8 (CHar), Supporting Information (see also the footnote on the first page of
127.4 (CHar), 128.2 (4 CHar), 128.5 (4 CHar), 128.8 (CHar), 129.2 this article): Experimental and spectroscopic data of imines 9, 10c,
(2 CHar), 131.3 (SeCar), 131.8 (CHar), 138.5 (2 CH–Car), 139.9 10d,10c, 14c, 14d, 14e, 15, 18, 20c, 20e, 21a, and 21d.
Eur. J. Org. Chem. 2007, 2945–2957
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2955

D. Schley, J. Liebscher
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2945–2957

Diastereoselective Cyclisation of N-Alkenylideneamines
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Received: December 13, 2006
Published Online: April 25, 2007
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