Ring expansions of 2-alkenylazetidinium salts - A new route to pyrrolidines and azepanes

Article abstract of DOI:10.1002/ejoc.200600362

Series of enantiomerically pure 3-alkenylpyrrolidines, substituted azepanes and stereodefined aminoalkenes were synthesized from 2-alkenylazetidinium trifluoromethanesulfonate salts. The high chemoselectivity of these reactions was found to be strongly de

Full text of DOI:10.1002/ejoc.200600362

FULL PAPER
DOI: 10.1002/ejoc.200600362
Ring Expansions of 2-Alkenylazetidinium Salts – a New Route to Pyrrolidines
and Azepanes
François Couty,*[a] François Durrat,[a] Gwilherm Evano,[a] and Jérome Marrot[a]
Keywords: Azetidines / Azepanes / Pyrrolidines / Sigmatropic shifts
Series of enantiomerically pure 3-alkenylpyrrolidines, substi-
tuted azepanes and stereodefined aminoalkenes were syn-
thesized from 2-alkenylazetidinium trifluoromethanesulfon-
ate salts. The high chemoselectivity of these reactions was
found to be strongly dependent both on the nature of the
base involved in the process (PhLi or KHMDS) and on the
relative cis or trans stereochemistry of the intermediate am-
monium ylide. When the ylide and the adjacent alkene are
trans, a [1,2] sigmatropic shift occurs exclusively, producing
a pyrrolidine with high levels of regioselectivity. On the other
hand, clean conversion into 4,5-dehydroazepanes through a
[2,3] sigmatropic shift is observed when these two groups are
in a cis relationship.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Thanks to the growing number of available methods for
the generation of ammonium ylides, the Stevens rearrange-
ment is clearly emerging as a powerful synthetic tool:[1] re-
cent examples of the application of this rearrangement to
the synthesis of natural products include the synthesis of
complex alkaloids such as desoxycodein-D,[2] epilupinine,[3]
tuniforcidine and platynecine.[4] Despite extensive mechan-
istic investigations,[5] however, there is still a need to under-
stand and predict both the regioselectivity and the dia-
stereoselectivity of this reaction, especially in order to plan
its use in a total synthesis. In this context, four-membered-
ring azetidines (more specifically as their ammonium deriv-
atives) have only been rarely used as substrates for this re-
arrangement,[6] in spite of the important ring strain in this
heterocycle, which could be useful as an efficient driving
force for the ring expansion involved in the process.[7] As
part of our continuing interest in the chemistry of azetid-
ines,[8] we recently reported the ring expansion of enantio-
merically pure 2-alkenylazetidinium salts 1 in Stevens re-
arrangements[9] to give 3-alkenylpyrrolidines 2 with total re-
gioselectivity and modest to good diastereoselectivity. In
this article we offer a full account on this work, which de-
fines the stereochemical requirements needed in 2-alkenyla-
zetidinium salts 1 to drive the reaction selectively either
towards the production of pyrrolidines 2, through Stevens
rearrangements, or towards azepanes 3, through a [2,3] sig-
matropic shift/ring expansion methodology (Figure 1).
Figure 1. Rearrangements of 2-alkenylazetidinium salts.
Results
Synthesis of 2-Alkenylazetidines
The starting materials required for this study, the 2-alk-
enylazetidines 13–19 with different substitution patterns
both on the heterocycle and on the alkene moiety
(Scheme 1), were all prepared in good yields from the corre-
sponding 2-cyanoazetidines 4–5.[10] The key step for the al-
kene formation involves a Wittig olefination performed
either on ketones 8–10 or on aldehydes 11–12 to afford 2-
alkenylazetidines 13–18.
The ketones were prepared by addition of organolithium
reagents to nitrile moieties as described previously,[11]
whereas aldehydes 11 and 12 were produced by Swern oxi-
dation of the corresponding primary alcohols 6 and 7,
respectively.[12] Gratifyingly, these aldehydes were produced
without any detectable epimerization, even though α-amino
aldehydes are known to have low configurational stabilit-
ies;[13] this notable stability is attributed to the presence of
the four-membered ring, which most certainly disfavours
the formation of an intermediate exocyclic enol.[14] Unsatu-
rated (E)-ester 13 was stereoselectively prepared from 7 in
a one-pot, two-step Swern oxidation/Wittig olefination se-
quence, with subsequent reduction of 13 with DIBALH
[a] Institut Lavoisier de Versailles, UMR 8180, Université de Ver-
sailles,
45, avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: couty@chimie.uvsq.fr
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Ring Expansions of 2-Alkenylazetidinium Salts
FULL PAPER
giving allylic alcohol 19. As a note, a hindered ketone (8: R
= tBu) failed to give the corresponding alkene upon trial
Wittig olefination (Scheme 1).
Synthesis of 2-Alkenylazetidinium Salts
Those enantiomerically pure 2-alkenylazetidines with
various representative substitution patterns were next
treated with MeOTf or TfOCH2CO2Et to give the corre-
sponding azetidinium triflates. This allowed for the isola-
tion of compounds 20–30 in excellent yields and with high
diastereoselectivity (de Ͼ95%), except in the case of 23
(de = 12%; Figure 2). The relative stereochemistry in these
salts was determined by a NOESY experiment performed
on 21.
The high stereoselectivity observed during the formation
of the trifluoromethanesulfonate salts, which proved to be
crucial for their further rearrangement, can be explained by
simply considering the four different conformers and in-
vertomers of the azetidine ring (A–D) depicted in Figure 3.
Among these, conformer C (all substituents in pseudoequa-
torial positions) appears to be the most stable and, further-
more, the lone pair of the nitrogen atom is sterically not
hindered by the substituents and so is especially readily
available to react with an electrophile. The observed selec-
tivity can therefore be explained by the favoured alkylation
of this conformer. In the particular case of compound 17,
a similar conformational analysis does not clearly show one
conformer as more stable than the others, which may ac-
count for the low selectivity observed in the synthesis of 23.
Scheme 1. a) Trimethylphosphonium iodide, BuLi, –78 °C, THF,
79% (14), 84% (15), 86% (16), 62% from 6 (17), 62% from 7 (18).
b) Swern oxidation. c) Swern oxidation, then (C6 H5 )3 -
PCH=CHCO2Et, 84%. d) DIBALH, THF, –78 °C, quant.
Figure 2. Prepared azetidinium trifluoromethanesulfonate salts.
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F. Couty, F. Durrat, G. Evano, J. Marrot
FULL PAPER
Figure 3. Conformational analysis for 2,3-trans-azetidines.
With a set of representative azetidinium triflates at hand, [1,3] Shifts of Ylides Derived from 2-Alkenylazetidinium
we next focused on the reactivity of the ylides obtained af- Salts
ter treatment with a strong base.
We next addressed the reactivity of azetidinium ions 27–
30, bearing ethoxycarbonylmethyl and benzyl groups – both
groups susceptible to participation in rearrangement pro-
cesses – on the nitrogen atom. Compounds 27–30 were
Stevens Rearrangements of 2-Alkenylazetidinium Salts
In order to perform the Stevens rearrangements, com- therefore treated with KHMDS at –78 °C as previously, and
pounds 20, 21 and 23–26, all possessing methyl and benzyl in this case we were pleased to observe that a completely
groups on the nitrogen atom, were treated with KHMDS different mechanistic pathway prevailed, since azepanes 35–
in THF at –78 °C. Under these conditions, the 3-alkenylpyr- 38 were now produced in high yields and with variable dia-
rolidines 31–34 were cleanly produced with complete re- stereoselectivity at C-2 (Scheme 2). Interestingly, the crude
gioselectivity and moderate diastereoselectivity at C-2 reaction mixtures were systematically very clean, with no
(Table 1). The azetidinium salts 23 and 25, however, failed products resulting from Stevens rearrangements being de-
to produced the desired pyrrolidines and gave complex mix- tectable. The formation of seven-membered rings can be ex-
tures of inseparable compounds.
plained in terms of a [2,3] shift of the ylide generated after
Table 1. Stevens rearrangement of azetinium ylides.
Substrate
Conditions
Product
Yield [%]
de [%]
20
21
24
26
KHMDS
KHMDS
KHMDS
KHMDS
31 (R = Ph, RЈ = H)
32 (R = Me, RЈ = H)
33 (R = H, RЈ = H)
69
94
83
72
8
72
6
34 (R = Ph, RЈ = CH2OH)
12
Scheme 2. Formation of azepanes from azetidinium trifluoromethanesulfonate salts.
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Ring Expansions of 2-Alkenylazetidinium Salts
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selective deprotonation α to the ester groups. Epimeric mix-
tures were in most cases difficult to separate by flash
chromatography, but a pure sample of the major epimer 35a
could be obtained, allowing for its structure to be secured
by X-ray crystallography[15] (Figure 4), whilst the absolute
configuration of the C-3 stereocenter in compound 37 was
tentatively assigned on the basis of mechanistic considera-
tions (vide infra).
Figure 5. Possible transition states for the [2,3] shift in the ylide
derived from 29.
In the ylide derived from alkenylazetidine 29, the alkene
can adopt either an extended conformation (29-A) or a
folded conformation (29-B). In the latter case, in which
there is efficient overlap of the reacting centres, the Si face
of the alkene can be attacked by the ylide without any steric
congestion, which results in the formation of 37-B, while in
29-A overlapping of the reacting centres clearly brings
about a severe steric interaction that probably disfavours
the formation of 37-A (Figure 5). The C-2 epimeric mix-
tures obtained in all these reactions are probably the results
of unselective removal of the diastereotopic protons in the
starting ammonium salts, resulting in (Z) and (E) mixtures
of intermediate ylides. Finally, the complex mixtures ob-
Figure 4. ORTEP view of azepane 35 (major 2,6-cis diastereoiso-
mer).
Discussion
The dramatically different behaviour of the different az- tained from 23 (epimeric mixture of ammonium salts) can
etidinium ylides, giving rise to the formation either of pyr- be easily explained since both [1,2] or [2,3] shifts can occur,
rolidines or of azepanes, clearly depends on the relative con- depending on the configuration of the starting ammonium.
figuration of the starting ylide (i.e., the relative stereochem- Moreover, the ammonium salt 25, which also gives a com-
istry between the ylide and the alkene group). On the one plex mixture when treated with a base, might be deproton-
hand, the anions are generated at the benzylic positions of ated in a competitive manner at C-2 of the azetidinium ring,
the quaternary amines when starting from azetidinium salts due to the presence of the vinylogous ester moiety: this
20–21 and 24–26, which means that these anions are in would allow an epimerization at this stereocenter[18] that
trans relationships with the adjacent alkenes: the two re- would ultimately result in the two possible rearrangements.
acting centres for [2,3] shifts to produce azepanes are too
In order to analyse the parameters governing the re-
far away from each other and so [1,2] shifts (Stevens re- arrangement processes further, we finally briefly studied the
arrangements) occur exclusively, resulting in the selective influence of the base used to promote the reactions, and
formation of pyrrolidines. When, on the other hand, the eventually found that its nature was of great importance.
anions are generated from azetidinium salts 27–30, selective On switching from KHMDS to phenyllithium, a base com-
deprotonation occurs α to the ester moieties and the ylides monly used in similar reactions,[7] different results were ob-
now have cis relationships with the adjacent alkenes, so the tained depending on the starting azetidinium salt: while a
two reacting centres involved in the [2,3] shift can efficiently Stevens rearrangement still occurred in the case of 26 (69%
overlap and this pathway now occurs exclusively.[16] With yield, 8% de), extensive degradation was observed in the
regard to the configurations of the C-3 stereocenters in the case of substrates 20 and 24 and a surprising outcome was
pyrrolidines, these were deduced from the well-established obtained with 21, with SN2Ј addition of the organolithium
fact[17] that the migration during the Stevens rearrangement reagent occurring on the alkene, resulting in an opening of
process occurs with retention of configuration. In the case the azetidine to give alkene 39 with high (E) selectivity
of azepane 37 the absolute configuration at C-3 in the (Table 2, Entry 1): clearly, the SN2Ј process is more rapid
azepane is only tentatively assigned since we were not able than the ylide formation in this isolated case. Similar behav-
to grow suitable crystals of one epimer and NOE experi- iour was also noted with n-butyl or tert-butyllithium
ments were inconclusive, so the assignment of the configu- (Table 2, Entries 2 and 3), but in the latter case the stereose-
ration is the result only of an examination of the possible lectivity dropped. Azetidinium salt 22, bearing a similar al-
transition states for the production of 37 (depicted in Fig- kenyl side chain, behaved similarly with organolithium rea-
ure 5).
gents (Table 2, Entries 4 and 5).
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F. Couty, F. Durrat, G. Evano, J. Marrot
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Table 2. SN2Ј opening of azetidinium salts by organolithium rea- into the underrated chemistry of functionalized azetidines,
for which efficient asymmetric syntheses have emerged.[22]
gents.
Experimental Section
1
General Comments: H and 13C NMR spectra were recorded with
a Bruker Avance 300 spectrometer at 300 and 75 MHz, respectively;
chemical shifts are reported in ppm from TMS. Optical rotations
were determined with a Perkin–Elmer 141 instrument. All the reac-
tions were carried out under argon. Column chromatography was
performed on silica gel (230–400 mesh) with various mixtures of
diethyl ether (Et2O), ethyl acetate (AcOEt), petroleum ether (PE)
and cyclohexane (CyH). TLC was performed on Merck Kieselgel
This reaction was quite unexpected, since ammonium
salts and amines have only seldom been reported to act as
leaving groups in SN2Ј reactions with organometallic rea-
gents. As a matter of fact, such reactions are restricted to
particular cases in which the functioning of the nitrogen
atom as a leaving group is favoured by strain release, such
as in 2-vinyl-[19a] or 2-ethynyl-N-tosylaziridines.[19b] This is
indeed also the case with our strained, cyclic substrates and
to the best of our knowledge represents the first example of
ammonium ions acting as leaving groups in SN2Ј processes
involving organometallic nucleophiles.[20] Interestingly, al-
kenes 39–43 are produced stereoselectively, and the exclus-
ive (or major) isomer was in each case shown to have an
(E) configuration by NOE experiments performed on 39
and 41. This stereochemistry involves the reactive confor-
mation of the double bond in the starting azetidinium ions
being a folded one (Figure 6), as in the case of the forma-
tion of azepanes (Figure 5). We were not able to determine
whether this reaction occurs through a syn or an anti
mechanism, however, since it was restricted to this particu-
lar alkene substituted by a phenyl group. This last point,
though, does give some insights into the mechanism of this
60 F254 plates. Melting points are uncorrected. THF and diethyl
ether were distilled from sodium/benzophenone ketyl, and dichlo-
romethane was distilled from calcium hydride. The mention of “us-
ual workup” means: (i) decantation of the organic layer, (ii) extrac-
tion of the aqueous layer with diethyl ether, (iii) drying of the com-
bined organic phases with MgSO4, and (iv) solvent evaporation un-
der reduced pressure. The compositions of the stereoisomeric mix-
tures were determined by NMR analysis on the crude products
before any purification.
General Procedure for the Preparation of 2-Alkenylazetidines 14–18
Through Wittig Olefination of 2-Oxoazetidines: A solution of n-
butyllithium (1.6  in hexanes, 0.87 mL, 1.4 mmol) was added
dropwise at 0 °C to a suspension of methyltriphenylphosphonium
iodide (606 mg, 1.5 mmol) in dry THF (5 mL). After the mixture
had been kept at 0 °C for 10 min, a solution of the required 2-
oxoazetidine (1 mmol) in THF (2 mL) was added dropwise. After
stirring at room temp. for 1 h, the reaction mixture was hydrolysed
by addition of water. Usual workup (water/diethyl ether) provided
a residue that was purified by flash chromatography.
(2R,3R)-1-Benzyl-3-phenyl-2-(1-phenylvinyl)azetidine (14): This
compound was purified by flash chromatography (Et2O/PE, 2:98,
5:95, 10:90, 20:80), yield: 79%, oil. [α]2D0 = +59 (c = 1, CH2Cl2). 1H
NMR (CDCl3): δ = 7.41–7.12 (m, 15 H, Ph), 5.66–5.65 (m, 1 H,
reaction, which probably involves the creation of a transient HHC=), 5.42 (d, J = 2.0 Hz, 1 H, HHC=), 4.11 (d, J = 7.9 Hz, 1
H, 2-H), 4.00 (A part of AB system, J = 13.1 Hz, 1 H, NCHHPh),
3.70 (t, J = 7.2 Hz, 1 H, 3-H), 3.53–3.43 (m, 2 H, 4-H, NCHHPh),
3.07 (dd, J = 6.8 and 8.9 Hz, 1 H, 4Ј-H) ppm. 13C NMR: δ = 148.9
(C-q), 141.2, 139.9, 138.4 (C-ipso Ph), 128.9–126.6 (CHPh), 114.1
(CH2), 76.0 (C-2), 62.1 (C-5), 57.6 (C-4), 45.2 (C-3) ppm. MS (ESI,
pos.): m/z = 348.1 [M+Na]+, 326.1 [M+H]+.
partial negative charge – which would be stabilized by the
aromatic ring – on the alkenyl carbon atom.
(2R,3R)-1-Benzyl-2-isopropenyl-3-phenylazetidine (15): This com-
pound was purified by flash chromatography (Et2O/PE, 2:8), yield:
1
84%, oil. [α]2D0 = –27 (c = 0.15, CH2Cl2). H NMR (CDCl3): δ =
Figure 6. Organolithium reagents preferably react on the folded
conformation of the alkene.
7.40–7.20 (m, 10 H, Ph), 5.06 (s, 1 H, HHC=C), 4.85 (s, 1 H,
HHC=), 3.91 (A part of AB system, J = 13.1 Hz, 1 H, NCHHPh),
3.70–3.63 (m, 2 H, 2-H, 4-H), 3.56–3.43 (m, 2 H, 3-H, NCHHPh),
2.97 (dd, J = 6.8 and 8.8 Hz, 1 H, 4Ј-H), 1.76 (s, 3 H, Me) ppm.
13C NMR: δ = 139.2 (C-q), 134.9, 134.0 (C-ipso Ph), 133.2, 131.4,
130.1, 129.5, 128.8, 127.6, 127.1 (CHPh), 124.2 (CH2), 80.3 (C-2),
67.5 (CH2), 63.8 (C-4), 44.7 (C-3), 36.7 (CH3) ppm. MS (ESI, pos.):
m/z = 286.1 [M+Na]+, 264.1 [M+H]+.
In conclusion, we have shown that efficient ring expan-
sions, selectively leading either to pyrrolidines or to
azepanes through [1,2] or [2,3] sigmatropic shifts, respec-
tively, can be performed from 2-alkenylazetidinium salts.
The sizes of the cyclic products obtained after rearrange-
ment were shown to be dependent on the relative stereo-
chemistry of the intermediate ylides. Furthermore, we have
for the first time discovered an SN2Ј reaction involving an
organolithium reagent and an ammonium ion acting as a
leaving group. This work reports an original route to
azepane alkaloids, which are of high interest in view of their
(2S,3S,4S)-1,6-Dimethyl-3-phenyl-2-(1-phenylvinyl)azetidine
(16):
This compound was purified by flash chromatography (Et2O/PE,
10:90, 20:80, 50:50), Rf = 0.80 (Et2O/PE, 1:1), yield: 86%, oil.
[α]2D0 = +13 (c = 1, CH2Cl2). H NMR (CDCl3): δ = 7.30–7.13 (m,
1
10 H, Ph), 5.54 (s, 1 H, HHC=), 5.40 (d, J = 0.3 Hz, 1 H, HHC=),
3.75 (dd, J = 0.9 and 7.7 Hz, 1 H, 2-H), 3.12–2.92 (m, 2 H, 4-H,
diverse biological activities,[21] and gives further insights 3-H), 2.41 (s, 3 H, NMe), 1.28 (d, J = 5.7 Hz, 3 H, Me) ppm.
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13C NMR: δ = 149.3 (C-q), 140.7, 140.2 (C-ipso Ph), 128.4–126.6
(CDCl3): δ = 7.18–7.02 (m, 10 H, Ph), 6.86 (dd, J = 5.8 and
(CHPh), 113.8 (CH2), 74.7 (C-2), 67.0 (C-4), 53.6 (C-3), 42.8 15.6 Hz, 1 H, CH=CHCO2Et), 5.87 (dd, J = 1.35 and 15.6 Hz, 1
(CH3), 20.3 (CH3) ppm. MS (ESI, pos.): m/z = 286.1 [M+Na]+,
264.1 [M+H]+. C24H23N (325.45): calcd. C 88.57, H 7.12, N 4.30;
found C 88.43, H 6.98, N 4.44.
H, CH=CHCO2Et), 4.03 (q, J = 7.1 Hz, 2 H, CH2O), 3.69 (A part
of AB system, J = 12.7 Hz, 1 H, NCHHPh), 3.63 (dd, J = 0.96
and 6.0 Hz, 1 H, 2-H), 3.55 (td, J = 0.6 and 7.5 Hz, 1 H, 4-H),
3.41–3.28 (m, 2 H, 3-H, NCHHPh), 2.91 (dd, J = 6.5 and 9.1 Hz,
1 H, 4Ј-H), 1.27 (t, J = 7.0 Hz, 3 H, Me) ppm. 13C NMR: δ =
166.6 (CO), 147.7 (CH), 140.4, 137.7 (C-ipso Ph), 129.0, 128.6,
128.5, 127.4, 127.2, 127.0 (CHPh), 121.6 (CH), 72.9 (C-2), 62.2
(CH2), 60.5 (CH2), 57.9 (C-4), 43.8 (C-3), 14.4 (Me) ppm. MS (ESI,
pos.): m/z = 344.1 [M+Na]+, 322.1 [M+H]+. HRMS: m/z calcd.
for C21H24NO2 [M+H]+ 322.1800; found 322.1802.
Through Wittig Olefination of 2-Formylazetidines. First Step –
Swern Oxidation: Oxalyl chloride (0.13 mL, 1.5 mmol) was added
dropwise at –78 °C to a solution of dry DMSO (0.12 mL,
1.7 mmol) in dichloromethane (6 mL). After the mixture had been
stirred at –78 °C for 20 min, a solution of the required 2-hydroxy-
methylazetidine (1 mmol) in dichloromethane (2 mL) was added
dropwise, and after the mixture had additionally been stirred at –
60 °C for 0.5 h, triethylamine (0.52 mL, 3.7 mmol) was added drop-
wise. The temperature was slowly (1 h) raised to ca. –15 °C and
water was added. Usual workup (water/dichloromethane) gave the
aldehyde, which was used crude in the olefination step. Second
Step – Wittig Olefination: The following compounds were obtained
by the described general procedure, starting either with the 2-
oxoazetidine or with the crude 2-formylazetidine.
(2E)-3-[(2S,3R)1-Benzyl-3-phenylazetidin-2-yl]prop-2-en-1-ol (19):
A solution of DIBALH in toluene (1.2 , 1 mL, 1.22 mmol) was
added at –78 °C to a solution of the above ester 13 (157 mg,
0.49 mmol) in THF (8 mL). The reaction mixture was gradually
(1.5 h) warmed to –20 °C with stirring and was hydrolyzed at this
temperature by addition of an aqueous saturated solution of
NH4Cl (3 mL). Usual workup (water/diethyl ether) gave an oil that
was used as such for the next step (137 mg, quant.). Rf = 0.46
(CH2Cl2/MeOH, 9:1). [α]2D0 = +19 (c = 1.1, CH2Cl2). 1H NMR
(CDCl3): δ = 7.26–7.09 (m, 10 H, Ph), 5.79–5.61 (m, 2 H,
CH=CH), 3.98 (d, J = 5.0 Hz, 2 H, CH2O), 3.72 (A part of AB
system, J = 12.7 Hz, 1 H, NCHHPh), 3.65–3.55 (m, 2 H, 2-H, 4-
H), 3.50–3.36 (m, 2 H, 3-H, NCHHPh), 2.94 (dd, J = 6.6 and
9.1 Hz, 1 H, 4Ј-H), 1.89 (br. s, 1 H, OH) ppm. 13C NMR: δ =
141.1, 137.9 (C-ipso Ph), 132.5, 131.6, 129.3, 128.5, 128.4, 128.3,
127.2, 127.1, 126.7, 125.4 (CHPh), 74.4 (C-2), 63.1 (CH2O), 62.3
(NCH2), 58.0 (C-4), 43.5 (C-3) ppm. MS (ESI, pos.): m/z = 302.1
[M+Na]+, 280.1 [M+H]+. HRMS: m/z calcd. for C19H21NO2
[M+H]+ 280.1696; found 280.1683.
(2R,3R)-1-Benzyl-3-phenyl-2-vinylazetidine (17): This compound
was purified by flash chromatography (Et2O/PE, 2:98, 5:95), Rf =
0.77 (Et2O/PE, 3:7), yield: 62%, oil. [α]2D0 = –10 (c = 0.7, CH2Cl2).
1H NMR (CDCl3): δ = 7.63–7.59 (m, 2 H, Ph), 7.55–7.33 (m, 8 H,
Ph), 5.69–5.57 (m, 1 H, CH=CH2), 5.32 (ddd, J = 1.2, 2.3 and
17.3 Hz, 1 H, CH=CHH), 5.07 (ddd, J = 0.77, 2.3 and 10.2 Hz, 1
H, CH=CHH), 4.13 (t, J = 7.3 Hz, 1 H, 2-H), 4.05 (A part of AB
system, J = 13.5 Hz, 1 H, NCHHPh), 3.73 (td, J = 2.5 and 7.9 Hz,
1 H, 3-H), 3.62–3.57 (m, 2 H, 4-H, NCHHPh), 3.42 (t, J = 7.5 Hz,
1 H, 4Ј-H) ppm. 13C NMR: δ = 140.6, 138.6 (C-ipso Ph), 136.7
(CH), 128.9, 128.6, 128.3, 128.2, 126.9, 126.4 (CHPh), 117.1 (CH2),
71.3 (C-2), 61.3 (CH2), 57.4 (C-4), 41.6 (C-3) ppm. MS (IC, NH3):
m/z = 250 [M+H]+.
General Procedure for the Preparation of 2-Alkenylazetidinium Tri-
fluoromethanesulfonates 20–30: Methyl trifluoromethanesulfonate
(0.225 mL, 2 mmol) or ethyl trifluoromethylsulfonyloxyacetate
(472 mg, 2.0 mmol) was added dropwise at 0 °C to a solution of
the azetidine (1 mmol) in dichloromethane (5 mL). The mixture
was stirred at room temp. for 1 h and the solvent was then evapo-
rated under reduced pressure. The residue was washed with small
quantities of dry diethyl ether and then dried under vacuum.
(2S,3R)-1-Benzyl-3-phenyl-2-vinylazetidine (18): This compound
was purified by flash chromatography (Et2O/PE, 15:85), Rf = 0.38
1
(Et2O/PE, 3:7), yield: 62%, oil. [α]2D0 = +60 (c = 0.6, CH2Cl2). H
NMR (CDCl3): δ = 7.39–7.23 (m, 10 H, Ph), 6.09–5.98 (m, 1 H,
CH=CH2), 5.26 (ddd, J = 0.96, 1.74 and 17.2 Hz, 1 H, CH=CHH),
5.13 (ddd, J = 0.77, 1.93 and 10.2 Hz, 1 H, CH=CHH), 3.89 (A
part of AB system, J = 12.7 Hz, 1 H, NCHHPh), 3.73 (q, J =
6.8 Hz, 1 H, 4-H), 3.66 (d, J = 7.5 Hz, 1 H, 2-H), 3.58 (t, J =
8.5 Hz, 1 H, 3-H), 3.55 (B part of AB system, J = 12.7 Hz, 1 H,
(2R,3R)-1-Benzyl-2-(1-methylvinyl)-3-phenylazetidinium Trifluoro-
methanesulfonate (20): Yield: 96%, white solid; m.p. 142 °C. [α]2D0
=
NCHHPh), 3.07 (dd, J = 8.9 and 9.1 Hz, 1 H, 4Ј-H) ppm. 13C +43 (c = 0.3, CH2Cl2). H NMR ([D6]acetone): δ = 7.72–7.68 (m,
1
NMR: δ = 141.2 (C-ipso Ph), 139.2 (CH), 138.1 (C-ipso Ph), 129.1,
128.5, 128.4, 127.2, 127.1, 126.6 (CHPh), 116.4 (CH2), 75.5 (C-2),
62.2 (C-5), 57.9 (C-4), 43.4 (C-3) ppm. MS (IC, NH3): m/z = 250
[M+H]+. HRMS: m/z calcd. for C18H20N [M+H]+ 250.1590;
found 250.1585.
2 H, Ph), 7.46–7.39 (m, 3 H, Ph), 7.28–7.16 (m, 5 H, Ph), 5.59 (s,
1 H, C=CHH), 5.52 (d, J = 1.6 Hz, 1 H, C=CHH), 5.40–5.32 (m,
1 H, 4-H), 5.04 (A part of AB system, J = 12.9 Hz, 1 H,
NCHHPh), 4.72 (B part of AB system, J = 12.9 Hz, 1 H,
NCHHPh), 4.71–4.59 (m, 2 H, 2-H, 4Ј-H), 4.12–4.0 (m, 1 H, 3-H),
3.07 (s, 3 H, NMe), 1.95 (s, 3 H, Me) ppm. 13C NMR: δ = 141.2
(C-ipso Ph), 139.2 (CH), 138.1 (C-ipso Ph), 129.1, 128.5, 128.4,
127.2, 127.1, 126.6 (CHPh), 116.4 (CH2), 75.5 (C-2), 62.2 (CH3),
57.9 (C-4), 43.4 (C-3) ppm. MS (ESI, pos.): m/z = 278.1 [M –
OTf]+.
Ethyl 3-[(2S,3R)-1-Benzyl-3-phenylazetidin-2-yl]acrylate (13): Oxa-
lyl chloride (0.15 mL, 1.7 mmol) was added dropwise at –78 °C to
a solution of dry DMSO (0.14 mL, 1.9 mmol) in dichloromethane
(8 mL). After the mixture had been stirred at –78 °C for 20 min, a
solution of the 2-(hydroxymethyl)azetidine 7 (289 mg, 1.14 mmol)
in dichloromethane (3 mL) was added dropwise. After the mixture
had additionally been stirred at –60 °C for 0.5 h, triethylamine
(0.60 mL, 4.2 mmol) was added dropwise, followed after 10 min by
a solution of Ph3P=CHCO2Et (760 mg, 2.2 mmol) in dichloro-
methane (3 mL). The reaction mixture was allowed to slowly (1 h)
reach room temp. and stirred for an additional hour and water was
added. Usual workup (water/dichloromethane) gave an oil that was
purified by flash chromatography (AcOEt/CyH, 10:90, 25:75). The
title compound was obtained as an oil (239 mg, 84%), Rf = 0.63
(AcOEt/CyH, 1:1). [α]2D0 = –14 (c = 1.3, CH2Cl2). 1H NMR
(2R,3R)-1-Benzyl-3-phenyl-2-(1-phenylvinyl)azetidinium Trifluoro-
methanesulfonate (21): Yield: quant; oil. [α]2D0 = +90 (c = 1, ace-
1
tone). H NMR ([D6]acetone): δ = 7.50–7.21 (m, 15 H, Ph), 5.96–
5.83 (m, 3 H, 2-H, C=CH2), 4.75–4.51 (m, 3 H, 3-H, 4-H,
CHHPh), 3.89–3.82 (m, 2 H, 4Ј-H, CHHPh), 2.94 (s, 3 H, Me)
ppm. 13C NMR: δ = 139.2, 137.7, 134.6, 132.2 (C-ipso Ph, C-7),
130.9, 129.6, 129.4, 128.7, 127.7, 127.4, 125.6 (CHPh), 80.6 (C-2),
67.9 (CH2), 64.5 (C-4), 43.6 (Me), 37.6 (C-3) ppm. MS (ESI, pos.):
340.2 [M – OTf]+. C26H26F3NO3S (489.55): calcd. C 63.79, H 5.35,
N 2.86; found C 63.62, H 5.54, N 2.72.
Eur. J. Org. Chem. 2006, 4214–4223
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4219

F. Couty, F. Durrat, G. Evano, J. Marrot
FULL PAPER
(2S,3S,4S)-1,1,4-Trimethyl-3-phenyl-2-(1-phenylvinyl)azetidinium
165.1 (CO), 138.7, 137.5, 135.1, 132.7, 131.4, 129.9, 129.7, 129.6,
Trifluoromethanesulfonate (22): Yield: 94 %, white solid; m.p. 129.4, 129.1 (C-ipso Ph, CHPh, C=CH2), 128.6 (C=CH2), 127.4,
182 °C. [α]2D0 = +54 (c = 0.4, CH2Cl2). 1H NMR ([D6]acetone): δ =
127.3 (CHPh), 81.0 (C-2), 65.0 (CH2), 63.2, 62.8 (C-4, CH2), 54.8
7.76–7.64 (m, 4 H, Ph), 7.54–7.33 (m, 6 H, Ph), 6.17 (d, J = (CH2O), 36.6 (C-3), 13.9 (Me) ppm. MS (IC, NH3, pos.): m/z =
10.5 Hz, 1 H, 2-H), 5.93 (s, 2 H, C=CH2), 4.95–4.80 (m, 1 H, 4- 412 [M – OTf]+.
H), 4.58 (t, J = 10.5 Hz, 1 H, 3-H), 3.24 (s, 3 H, NMe), 2.96 (s, 3
(2S,3R)-1-Benzyl-1-[(ethoxycarbonyl)methyl]-3-phenyl-2-vinylazeti-
H, NMe), 1.67 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR: δ = 140.0,
dinium Trifluoromethanesulfonate (28): Yield: 91%; oil. [α]2D0 = –30
138.7 (C-ipso Ph), 135.6 (C-q), 130.1–128.0 (CHPh), 124.4 (CH2),
1
(c = 1.7, acetone). H NMR ([D6]acetone): δ = 7.59–7.46 (m, 5 H,
79.9, 76.9 (C-5, C-6), 53.0 (C-2), 45.9 (C-4), 40.0 (C-3), 12.8 (CH3)
Ph), 7.28–7.22 (m, 3 H, Ph), 7.10–7.07 (m, 2 H, Ph), 6.02–5.91 (m,
1 H, CH=CH2), 5.70 (d, J = 17.1 Hz, 1 H, CH=CHH), 5.60 (d, J
= 10.4 Hz, 1 H, CH=CHH), 5.38 (dd, J = 6.8 and 9.8 Hz, 1 H, 2-
H), 4.98 (A part of AB system, J = 13.3 Hz, 1 H, NCHHPh), 4.87–
ppm. MS (ESI, pos.): m/z = 277.1 [M – OTf]+. C21H24F3NO3S
(427.48): calcd. C 59.00, H 5.66, N 3.28; found C 59.29, H 5.72, N
3.36.
4.76 (m, 3 H, 4-H, NCHHPh, CHHCO), 4.65 (q, J = 9.4 Hz, 1 H,
3-H), 4.44 (t, J = 10.0 Hz, 1 H, 4Ј-H), 4.25–4.35 (m, 2 H, CH2O),
3.88 (BЈ part of AЈBЈ system, J = 17.3 Hz, 1 H, CHHCO), 1.32 (t,
J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 165.3 (CO), 135.1,
132.5 (C-ipso Ph), 131.3 (CH=CH2), 129.9, 129.3 (CHPh), 129.1
(CH=CH2), 128.5, 127.7, 127.3, 126.4 (CHPh), 81.7 (C-2), 65.4,
65.2 (C-4, C-5), 63.1 (NCH2), 53.7 (OCH2), 37.2 (C-3), 13.9 (Me)
ppm. MS (ESI, pos.): m/z = 336.1 [M – OTf]+. C23H26F3NO5S
(485.52): calcd. C 56.90, H 5.40, N 2.88; found C 57.02, H 5.42, N
2.92.
(2R,3R)-1-Benzyl-1-methyl-3-phenyl-2-vinylazetidinium Trifluoro-
methanesulfonate (23): Yield: quant; oil; mixture of stereoisomers.
1H NMR ([D6]acetone): δ = 7.86–7.82 (m, 2 H, Ph), 7.77–7.74 (m,
3 H, Ph), 7.63–7.51 (m, 5 H, Ph), 7.48–7.32 (m, 10 H, Ph), 6.37
(td, J = 10.2 and 17.0 Hz, 1 H, CH=CH2), 5.97–5.79 (m, 3 H), 5.71
(dd, J = 1.4 Hz, 1 H), 5.65 (d, J = 1.4 Hz, 1 H), 5.61–5.50 (m, 4
H), 5.22–5.15 (m, 1 H), 5.07 (s, 2 H), 5.0–4.90 (m, 2 H), 4.84 (A
part of AB system, J = 12.9 Hz, 1 H, CHHPh), 4.47–4.39 (m, 1
H), 4.36 (B part of AB system, J = 12.9 Hz, 1 H, CHHPh), 3.49
(s, 3 H, Me for major isomer), 3.07 (s, 3 H, Me for minor isomer)
ppm.
(2S,3R)-1-Benzyl-1-[(ethoxycarbonyl)methyl]-2-[2-(ethoxycarbonyl)-
vinyl]-3-phenylazetidinium Trifluoromethanesulfonate (29): Yield:
(2S,3R)-1-Benzyl-1-methyl-3-phenyl-2-vinylazetidinium Trifluoro-
methanesulfonate (24): Yield: quant; oil. [α]2D0 = –13 (c = 0.4, ace-
1
95%; oil. [α]2D0 = –74 (c = 0.3, acetone). H NMR ([D6]acetone): δ
1
= 7.78–7.74 (m, 2 H, Ph), 7.64–7.56 (m, 3 H, Ph), 7.43–7.30 (m, 5
H, Ph), 7.03 (dd, J = 7.1 and 15.8 Hz, 1 H, CH=CH), 6.47 (dd, J
= 1.2 and 15.6 Hz, 1 H, CH=CH), 6.03 (td, J = 1.2 and 8.1 Hz, 1
H, 2-H), 5.34 (A part of AB system, J = 13.3 Hz, 1 H, NCHHPh),
5.19 (B part of AB system, J = 13.3 Hz, 1 H, NCHHPh), 5.09–
4.82 (m, 4 H, 3-H, 4-H, CH2CO), 4.43–4.26 (m, 3 H, 4Ј-H, OCH2),
4.16 (q, J = 7.1 Hz, 2 H, OCH2), 1.34 (t, J = 7.1 Hz, 3 H, Me),
1.23 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 165.9, 164.7
(CO), 135.9 (CH), 134.5, 133.3 (C-ipso Ph), 132.4–128.2 (CHPh,
CH), 80.5 (C-2), 66.9, 66.7 (CH2), 63.5, 61.6 (OCH2), 54.2 (C-4),
38.5 (C-3), 14.3, 14.1 (Me) ppm. MS (ESI, pos.): m/z = 408.3 [M –
OTf]+.
tone). H NMR ([D6]acetone): δ = 7.55–7.41 (m, 5 H, Ph), 7.31–
7.23 (m, 3 H, Ph), 7.12–7.09 (m, 2 H, Ph), 5.98–5.86 (m, 1 H,
CH=CH2), 5.62 (d, J = 3.7 Hz, 1 H, CH=CHH), 5.57 (d, J =
3.5 Hz, 1 H, CH=CHH), 5.16 (t, J = 7.1 Hz, 1 H, 2-H), 4.70 (A
part of AB system, J = 13.1 Hz, 1 H, NCHHPh), 4.62 (B part of
AB system, J = 13.1 Hz, 1 H, NCHHPh), 4.47 (t, J = 8.7 Hz, 1 H,
4-H), 4.37–4.31 (m, 1 H, 3-H), 4.28–4.22 (m, 1 H, 4Ј-H), 3.12 (s, 3
H, NMe) ppm. 13C NMR: δ = 135.0 (C-ipso Ph), 132.5, 130.9,
129.7, 129.3, 128.5 (CHPh), 128.3 (CH), 127.7 (CH2), 127.3, 126.9
(CHPh), 79.4 (C-2), 67.4 (CH2), 65.9 (C-4), 44.0 (C-5), 38.2 (C-3)
ppm. MS (ESI, pos.): m/z = 264.1 [M – OTf]+.
(2S,3R)-1-Benzyl-2-(3-hydroxy-1-propenyl)-1-methyl-3-phenylazeti-
dinium Trifluoromethanesulfonate (26): Yield: quant; oil. [α]2D0
=
(2S,3S,4S)-1-Benzyl-1-[(ethoxycarbonyl)methyl]-4-methyl-3-phenyl-
2-(1-phenylvinyl)azetidinium Trifluoromethanesulfonate (30): Yield:
81%; white solid. [α]2D0 = –19 (c = 0.7, acetone). 1H NMR ([D6]-
acetone): δ = 7.68–7.34 (m, 15 H, Ph), 6.45 (s, 1 H, C=CHH), 6.26
(s, 1 H, C=CHH), 6.24 (d, J = 11.2 Hz, 1 H, 2-H), 5.62 (A part of
AB system, J = 12.7 Hz, 1 H, NCHHPh), 5.39 (B part of AB sys-
tem, J = 12.7 Hz, 1 H, NCHHPh), 4.89–4.69 (m, 3 H, 3-H, 4-H,
CHHCO), 4.25–4.21 (m, 2 H, OCH2), 4.16 (BЈ part of AЈBЈ system,
J = 17.3 Hz, 1 H, CHHCO), 1.39 (d, J = 6.6 Hz, 3 H, Me), 1.30
(t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 166.1 (CO), 142.4
(C-q), 139.1, 138.7, 136.1 (C-ipso Ph), 134.8–127.3 (CHPh), 120.4
(CH2), 81.1 (C-2), 66.0, 65.7 (CH2), 63.3 (CH2O), 58.4 (C-4), 46.1
(C-3), 14.5 (Me), 14.2 (Me) ppm. MS (ESI, pos.): m/z = 426.3 [M –
OTf]+.
1
–18 (c = 0.8, acetone). H NMR ([D6]acetone): δ = 7.68–7.64 (m,
2 H, Ph), 7.45–7.38 (m, 3 H, Ph), 7.29–7.17 (m, 5 H, Ph), 6.35 (tdd,
J = 0.8, 3.7 and 15.5 Hz, 1 H, CH=CH), 5.96 (tdd, J = 1.9, 7.9
and 15.5 Hz, 1 H, CH=CH), 5.45 (t, J = 9.8 Hz, 1 H, 2-H), 4.83
(A part of AB system, J = 13.1 Hz, 1 H, NCHHPh), 4.75 (B part
of AB system, J = 13.1 Hz, 1 H, NCHHPh), 4.69 (t, J = 10.2 Hz,
1 H, 4-H), 4.51 (qd, J = 10.2 and 1.7 Hz, 1 H, 3-H), 4.29 (dd, J =
8.5 and 9.4 Hz, 1 H, 4Ј-H), 4.03–4.01 (m, 2 H, CH2O), 3.09 (s, 3
H, NMe) ppm. 13C NMR: δ = 146.7 (CH), 136.9 (C-ipso Ph), 133.1
(CHPh), 131.3 (C-ipso Ph), 130.1, 129.7, 129.4, 128.9, 128.2
(CHPh), 118.4 (CH), 81.6 (C-2), 68.1 (CH2), 66.6 (C-4), 61.7
(CH2), 43.6 (Me), 39.7 (C-3) ppm. MS (ESI, pos.): m/z = 294.1
[M – OTf]+.
General Procedure for the Ring Expansions Starting from 2-Alkenyl-
azetidinium Trifluoromethanesulfonates: A solution of KHMDS
(0.5  in toluene, 2.4 mL, 1.2 mmol) was added dropwise at –78 °C
to a solution of 2-alkenylazetidinium salt (1 mmol) in THF (6 mL).
The temperature was slowly (1.5 h) raised to –30 °C and the mix-
ture was hydrolyzed at this temperature by addition of a saturated
aqueous solution of NH4Cl (5 mL). Usual workup gave an oil that
was purified by flash chromatography.
(2R,3R)-1-Benzyl-1-[(ethoxycarbonyl)methyl]-3-phenyl-2-(1-phenyl-
vinyl)azetidinium Trifluoromethanesulfonate (27): Yield: 93%; white
solid; m.p. 57 °C. [α]2D0 = +7 (c = 0.5, acetone). 1H NMR ([D6]-
acetone): δ = 7.69–7.22 (m, 13 H, Ph), 6.90–6.86 (m, 2 H, Ph), 6.40
(s, 1 H, C=CHH), 5.99 (s, 1 H, C=CHH), 5.65 (d, J = 10.8 Hz, 1
H, 2-H), 5.34 (A part of AB system, J = 17.1 Hz, 1 H, CHHCO),
5.05 (q, J = 10.2 Hz, 1 H, 3-H), 4.83 (t, J = 10.5 Hz, 1 H, 4-H),
4.70 (AЈ part of AЈBЈ system, J = 12.9 Hz, 1 H, NCHHPh), 4.43–
4.28 (m, 3 H, 4Ј-H, CH2O), 3.86 (BЈ part of AЈBЈ system, J = (2R,3S,4R)- and (2S,3S,4R)-1-Methyl-2,4-diphenyl-3-(1-phenyl-
13.2 Hz, 1 H, NCHHPh), 3.73 (B part of AB system, J = 17.1 Hz,
vinyl)pyrrolidine (31): This compound was purified by preparative
TLC (Et2O/PE, 6:4), inseparable mixture of two isomers at C-2 in
1 H, CHHCO), 1.39 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ =
4220
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4214–4223

Ring Expansions of 2-Alkenylazetidinium Salts
FULL PAPER
a 54:46 ratio; yield: 68%, oil. The following data are characteristic
of the major isomer. Rf = 0.67 (Et2O/PE, 4:6). H NMR (CDCl3):
58:42 ratio; overall yield: 72%, oil. Isolated major isomer: Rf = 0.65
1
1
(Et2O/PE, 9:1). [α]2D0 = –53 (c = 0.3, CH2Cl2). H NMR (CDCl3):
δ = 7.55–6.82 (m, 15 H, Ph), 5.19 (s, 1 H, C=CHH), 5.14 (s, 1 H, δ = 7.33–7.07 (m, 10 H, Ph), 5.55 (tdd, J = 1.6, 8.1 and 15.4 Hz, 1
C=CHH), 3.92 (d, J = 8.1 Hz, 1 H, 2-H), 3.70–3.39 (m, 3 H, 4-H, H, CH=CH), 5.14 (tdd, J = 0.96, 5.6 and 15.4 Hz, 1 H, CH=CH),
5-H, 5Ј-H), 3.06 (t, J = 9.4 Hz, 1 H, 3-H), 2.58 (s, 3 H, NMe) ppm.
3.84 (dd, J = 0.96 and 5.6 Hz, 2 H, CH2O), 3.27 (dd, J = 3.3 and
13C NMR: δ = 147.3 (C-q), 143.0, 142.2, 141.6 (C-ipso Ph), 129.5– 9.6 Hz, 1 H, 5-H), 3.07–3.00 (m, 1 H, 4-H), 2.95 (d, J = 9.5 Hz, 1
126.3 (CHPh), 115.6 (CH2), 74.3 (C-2), 63.7 (C-5), 55.1 (C-3), 49.9
H, 2-H), 2.79 (t, J = 9.6 Hz, 1 H, 5Ј-H), 2.62 (q, J = 8.1 Hz, 1 H,
3-H), 2.09 (s, 3 H, NMe) ppm. 13C NMR: δ = 145.9 (CH), 140.8
(CH), 131.4, 131.0 (C-ipso Ph), 128.6, 128.4, 128.2, 128.1, 127.6,
127.5, 126.3 (CHPh), 78.2 (C-2), 63.7 (C-5), 63.3 (CH2O), 61.6 (C-
3), 49.1 (C-4), 40.7 (C-6) ppm. MS (ESI, pos.): m/z = 294.1 [M+H]
+. C20H23NO (293.4): calcd. C 81.87, H 7.90, N 4.77; found C
81.74, H 7.83, N 4.89. Isolated minor isomer: Rf = 0.55 (Et2O/PE,
(C-4), 40.7 (Me) ppm. MS (ESI, pos.): m/z = 340.1 [M+H]+.
(2R,3S,4R)- and (2S,3S,4R)-3-Isopropenyl-1-methyl-2,4-diphenyl-
pyrrolidine (32): This compound was purified by flash chromatog-
raphy (Et2O/PE, 2:98, 5:95, 10:90), mixture of two isomers at C-2
in a 86:14 ratio; overall yield: 94%, oil. Isolated major isomer: Rf
= 0.71 (Et2O/PE, 3:7). [α]2D0 = –16 (c = 0.6, CH2Cl2). 1H NMR
(CDCl3): δ = 7.35–7.09 (m, 10 H, Ph), 4.64–4.56 (m, 1 H,
C=CHH), 4.55–4.53 (m, 1 H, C=CHH), 3.65 (d, J = 10.2 Hz, 1 H,
2-H), 3.56–3.42 (m, 2 H, 4-H, 5-H), 3.11 (t, J = 9.2 Hz, 1 H, 3-H),
2.49 (td, J = 0.96 and 8.5 Hz, 1 H, 5Ј-H), 2.24 (s, 3 H, NMe), 1.13
(s, 3 H, Me) ppm. 13C NMR: δ = 144.3, 142.6 (C-ipso Ph), 140.6
(C-q), 129.0, 128.6, 128.5, 128.4, 127.9, 127.7, 127.6, 127.5, 127.4,
126.8 (CHPh), 113.9 (CH2), 74.4 (C-2), 64.0 (C-5), 59.3 (C-3), 47.0
(C-4), 41.2 (Me), 22.4 (Me) ppm. MS (ESI, pos.):m/z = 300.1
[M+Na]+, 278.1 [M +H]+. C20H23N (277.4): calcd. C 86.59, H
8.36, N 5.05; found C 86.47, H 8.25, N 4.92. Isolated minor isomer:
9:1). [α]2D0 = –34 (c = 0.6, CH2Cl2). H NMR (CDCl3): δ = 7.26–
1
7.08 (m, 10 H, Ph), 5.19–5.04 (m, 2 H, CH=CH), 3.62–3.57 (m, 32
H, CH2O, 2-H), 3.44 (dd, J = 6.7 and 9.1 Hz, 1 H, 5-H), 3.17 (td,
J = 7.5 and 10.5 Hz, 1 H, 4-H), 2.95 (q, J = 8.5 Hz, 1 H, 3-H),
2.50 (dd, J = 9.1 and 10.4 Hz, 1 H, 5Ј-H), 2.22 (s, 3 H, NMe) ppm.
13C NMR: δ = 142.3 (CH), 140.2 (CH), 134.5, 130.1 (C-ipso Ph),
128.7, 128.5, 128.1, 127.8, 127.0, 126.6 (CHPh), 75.3 (C-2), 64.3
(C-5), 63.2 (CH2O), 55.2 (C-3), 50.3 (C-4), 40.9 (NMe) ppm. MS
(ESI, pos.): m/z = 294.1 [M+H]+.
Ethyl (2R,6R)- and (2S,6R)-1-Benzyl-4,6-diphenyl-2,3,6,7-tetra-
hydro-1H-azepane-2-carboxylate (35): This compound was purified
1
Rf = 0.57 (Et2O/PE, 3:7). [α]2D0 = –22 (c = 0.3, CH2Cl2). H NMR
(CDCl3): δ = 7.46–7.23 (m, 10 H, Ph), 4.74 (s, 1 H, C=CHH), 4.65 by flash chromatography (Et2O/PE, 5:95, 10:90, 15:85), mixture of
(s, 1 H, C=CHH), 3.76 (d, J = 10.1 Hz, 1 H, 2-H), 3.66–3.52 (m, two isomers at C-2 in a 60:40 ratio; overall yield: 93%, oil. Isolated
2 H, 4-H, 5-H), 3.21 (t, J = 9.6 Hz, 1 H, 3-H), 2.69–2.56 (m, 1 H,
major isomer: Rf = 0.56 (Et2O/PE, 3:7). [α]2D0 = +6 (c = 0.4,
5Ј-H), 2.34 (s, 3 H, NMe), 1.23 (s, 3 H, Me) ppm. 13C NMR: δ = CH2Cl2). 1H NMR (CDCl3): δ = 7.41–7.20 (m, 15 H, Ph), 6.04 (d,
144.3, 142.6 (C-ipso Ph), 140.7 (C-q), 129.0, 128.6, 128.5, 128.4,
127.9, 127.7, 127.6, 127.5, 127.4, 126.5 (CHPh), 113.1 (CH), 76.2
J = 4.1 Hz, 1 H, 5-H), 4.19 (q, J = 7.1 Hz, 2 H, CH2O), 4.09 (t, J
= 4.0 Hz, 1 H, 2-H), 3.95–3.82 (m, 3 H, 6-H, NCH2Ph), 3.26–3.08
(C-2), 64.1 (C-5), 59.3 (C-3), 47.6 (C-4), 40.8 (NMe), 20.5 (Me) (m, 4 H, 3-H, 3Ј-H, 7-H, 7Ј-H), 1.22 (t, J = 7.1 Hz, 3 H, Me) ppm.
ppm. MS (ESI, pos.): m/z = 300.1 [M+Na]+, 278.1 [M+H]+.
13C NMR: δ = 173.9 (CO), 144.7, 144.3, 138.9 (C-ipso Ph, C-4),
133.4 (C-5), 128.9–126.2 (CHPh), 64.3 (C-2), 60.8 (CH2O), 59.4
(NCH2), 57.2 (C-3), 46.3 (C-6), 32.1 (C-7), 14.3 (Me) ppm. MS
(IC, NH3): m/z = 412 [M+H]+. Minor isomer (not isolated pure):
(2R,3S,4R)- and (2S,3S,4R)-1-Methyl-2,4-diphenyl-3-vinylpyrroli-
dine (33): This compound was purified by flash chromatography
(Et2O/PE, 5:95, 10:90, 15:85), mixture of two isomers at C-2 in a
53:47 ratio; overall yield: 83%, oil. Isolated major isomer: Rf = 0.78
1
Rf = 0.55 (Et2O/PE, 3:7). H NMR (CDCl3): δ = 7.33–7.11 (m, 15
H, Ph), 6.04 (d, J = 4.1 Hz, 1 H, 5-H), 5.56–3.88 (m, 5 H, 2-H,
NCH2, CH2O), 3.73 (dd, J = 2.7 and 8.7 Hz, 1 H, 6-H), 3.57 (dd,
J = 10.8 and 11 Hz, 1 H, 3-H), 3.26 (ddd, J = 1.35, 8.7, 15.6 Hz,
1 H, 7-H), 2.99 (dd, J = 2.5 and 15.6 Hz, 1 H, 7Ј-H), 2.74 (dd, J
= 2.7 and 13.7 Hz, 1 H, 3Ј-H), 0.99 (t, J = 7.1 Hz, 3 H, Me) ppm.
13C NMR: δ = 173.2 (CO), 144.9, 144.0, 139.4, 139.0 (C-ipso Ph,
C-4), 134.5 (C-5), 128.8–126.1 (CHPh), 63.0 (C-2), 60.4 (CH2O and
CH2N), 55.1 (C-3), 46.1 (C-6), 34.6 (C-7), 14.1 (Me) ppm. HRMS:
m/z calcd. for C28H30NO2 [M+H]+ 412.2271; found 412.2270.
(Et2O/PE, 3:7). [α]2D0 = +27 (c = 0.1, CH2Cl2). H NMR (CDCl3):
1
δ = 7.44–7.21 (m, 10 H, Ph), 5.37 (td, J = 9.8 and 16.8 Hz, 1 H,
CH=CH2), 4.66–4.58 (m, 2 H, CH=CH2), 3.71 (d, J = 9.6 Hz, 1
H, 2-H), 3.55 (dd, J = 6.7 and 8.9 Hz, 1 H, 5-H), 3.28 (td, J = 6.8
and 10.6 Hz, 1 H, 4-H), 3.05 (q, J = 9.1 Hz, 1 H, 3-H), 2.63 (dd,
J = 9.1 and 10.4 Hz, 1 H, 5Ј-H), 2.34 (s, 3 H, NMe) ppm. 13C
NMR: δ = 142.2 (C-ipso Ph), 139.3 (CH), 128.6, 128.4, 128.0,
127.8, 127.4, 126.8, 126.4 (CHPh), 114.9 (CH2), 74.9 (C-2), 64.1
(C-5), 56.8 (C-3), 50.1 (C-4), 40.9 (C-6) ppm. MS (ESI, pos.): m/z
= 286.1 [M+Na]+, 264.1 [M+H]+. HRMS: m/z calcd. for C19H22N
[M+H]+ 264.1747; found 264.1758. Isolated minor isomer: Rf =
0.77 (Et2O/PE, 3:7). [α]2D0 = –63 (c = 0.3, CH2Cl2). 1H NMR
Ethyl (2R,6R)- and (2S,6R)-1-Benzyl-6-phenyl-2,3,6,7-tetrahydro-
1H-azepane-2-carboxylate (36): This compound was purified by
flash chromatography (Et2O/PE, 5:95, 10:90, 15:85), mixture of two
(CDCl3): δ = 7.46–7.19 (m, 10 H, Ph), 5.89–5.71 (m, 1 H, isomers at C-2 in a 90:10 ratio; overall yield: 99%, oil. Major iso-
CH=CH2), 4.90 (dd, J = 1.4 and 10.2 Hz, 1 H, CH=CHH), 4.67 mer (not isolated pure): Rf = 0.55 (Et2O/PE, 3:7). 1H NMR
(dd, J = 0.66 and 17 Hz, 1 H, CH=CHH), 3.41 (dd, J = 3.3 and
9.8 Hz, 1 H, 5-H), 3.22–3.12 (m, 1 H, 4-H), 3.07 (d, J = 9.4 Hz, 1
H, 2-H), 2.91 (t, J = 9.6 Hz, 1 H, 5Ј-H), 2.70 (q, J = 8.3 Hz, 1 H,
3-H), 2.22 (s, 3 H, NMe) ppm. 13C NMR: δ = 146.2, 141.0 (C-
(CDCl3): δ = 7.40–7.15 (m, 10 H, Ph), 5.81–5.74 (m, 2 H, 4-H, 5-
H), 4.21 (q, J = 7.1 Hz, 2 H, CH2O), 3.98–3.94 (m, 1 H, 6-H),
3.84–3.81 (m, 2 H, NCH2Ph), 3.13–2.97 (m, 2 H, 7-H, 7Ј-H), 2.85–
2.73 (m, 2 H, 3-H, 3Ј-H), 1.31 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C
ipso Ph), 138.0 (C-q), 128.6, 128.4, 128.3, 128.1, 127.6, 127.4, 126.2 NMR: δ = 173.7 (CO), 144.1, 139.0 (C-ipso Ph), 135.0, 128.8,
(CHPh), 116.3 (CH2), 78.1 (C-2), 63.7 (C-5), 63.5 (C-3), 48.9 (C-
4), 40.8 (C-6) ppm. MS (ESI, pos.): m/z = 286.1 [M+Na]+, 264.1
[M+H]+.
128.6, 128.4, 128.2, 127.9, 127.6, 127.0, 126.9, 126.3 (CHPh,
CH=CH), 65.3 (C-2), 60.7 (CH2O), 57.7 (C-7), 56.4 (CH2N), 46.4
(C-6), 28.9 (C-3), 14.3 (Me) ppm. MS (IC, NH3): m/z = 336
[M+H]+. HRMS: m/z calcd. for C22H26NO2 [M+H]+ 336.1958;
found 336.1941.
3-[(2R,3S,4R)- and (2S,3S,4R)-1-Methyl-2,4-diphenylpyrrolidin-3-
yl]prop-2-en-1-ol (34): For this compound, 2.2 equiv. of KHMDS
was used. This compound was purified by flash chromatography
(Et2O/PE, 5:95, 10:90, 15:85), mixture of two isomers at C-2 in a
Diethyl (2R,3R,6R)- and (2S,3R,6R)-1-Benzyl-6-phenyl-2,3,6,7-
tetrahydro-1H-azepane-2,3-dicarboxylate (37): This compound was
Eur. J. Org. Chem. 2006, 4214–4223
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4221

F. Couty, F. Durrat, G. Evano, J. Marrot
purified by flash chromatography (Et2O/PE, 5:95, 10:90, 15:85), (Benzyl)[(2R,3E)- and (2R,3Z)-6,6-dimethyl-2,4-diphenylhept-3-en-
FULL PAPER
mixture of two isomers at C-2 in a 80:20 ratio; overall yield: 75%,
oil. Major isomer (not isolated pure): Rf = 0.80 (Et2O/PE, 4:6). H
NMR (CDCl3): δ = 7.33–6.99 (m, 10 H, Ph), 5.80–5.64 (m, 2 H,
4-H, 5-H), 4.20–4.06 (m, 6 H, 2-H, 3-H, 2×CH2O), 4.05–3.97 (m,
yl](methyl)amine (41): This compound was purified by flash
chromatography (Et2O/PE, 10:90), yield: quant.; oil; 35:65 mixture
of (Z) and (E) isomers; Rf = 0.71 (Et2O/PE, 3:7). Major isolated
isomer: [α]2D0 = –17 (c = 0.3, CH2Cl2). 1H NMR (CDCl3): δ = 7.34–
1
1 H, NCHHPh), 3.84–3.83 (m, 2 H, 6-H, NCHHPh), 2.97 (dd, J 7.16 (m, 15 H, Ph), 5.78 (d, J = 9.7 Hz, 1 H, 3-H), 3.95 (q, J =
= 5 and 14 Hz, 1 H, 7-H), 2.83 (dd, J = 10.4 and 14 Hz, 1 H, 7Ј-
H), 1.24–1.16 (m, 6 H, 2×Me) ppm. 13C NMR: δ = 173.0, 172.6
(CO), 143.6, 138.9 (C-ipso Ph), 135.5, 128.8, 128.6, 128.5, 128.4,
128.1, 127.9, 127.4, 127.2, 127.1, 126.6, 125.2 (CHPh, C-4, C-5),
66.7 (C-2), 61.3, 61.2 (2×CH2O), 57.8 (C-7), 55.3 (NCH2Ph), 47.4
(C-3), 45.6 (C-6), 14.3, 14.2 (2×Me) ppm. MS (ESI, pos.): m/z
7.7 Hz, 1 H, 2-H), 3.57 (A part of AB system, J = 13.1 Hz, 1 H,
NCHHPh), 3.47 (B part of AB system, J = 13.1 Hz, 1 H,
NCHHPh), 2.81–2.58 (m, 2 H, 1-H, 1Ј-H), 2.54 (s, 2 H, 5-H, 5Ј-
H), 2.26 (s, 3 H, NMe), 0.76 (s, 9 H, tBu) ppm. 13C NMR: δ =
146.1, 146.0, 139.9, 136.2 (C-ipso Ph, C-4), 134.6 (C-3), 129.0–126.2
(CHPh), 64.4 (C-1), 62.7 (C-8), 43.8 (C-2), 42.9 (NMe), 32.8 (C-5),
= 430.3 [M+Na]+. HRMS: m/z calcd. for C25H30NO4 [M+H]+ 31.2 (C-q), 30.8 (tBu) ppm. MS (ESI, pos.): m/z = 420.2 [M+Na]+,
408.2169; found 408.2200.
398.2 [M+H]+. HRMS: m/z calcd. for C29H36N [M+H]+ 398.2842;
found 398.2855.
Ethyl (2R,6S,7S)- and (2S,6S,7S)-1-Benzyl-4,6-diphenyl-2,3,6,7-
tetrahydro-1H-azepane-2-carboxylate (38): This compound was
purified by flash chromatography (Et2O/PE, 5:95, 10:90, 15:85),
mixture of two isomers at C-2 in a 75:25 ratio; overall yield: 81%,
Dimethyl[(1S,2S,3E)-1-methyl-2,4,5-triphenylpent-3-enyl]amine
(42): This compound was purified by flash chromatography (Et2O/
PE, 30:70, 100:0), yield: 58%, oil; Rf = 0.61 (Et2O). [α]2D0 = –167 (c
1
oil. Major isomer (not isolated pure): Rf = 0.77 (Et2O/PE, 4:6). H
1
= 0.5, CH2Cl2). H NMR (CDCl3): δ = 7.41–7.03 (m, 15 H, Ph),
NMR (CDCl3): δ = 7.34–7.01 (m, 15 H, Ph), 5.86 (d, J = 5.2 Hz,
1 H, 5-H), 4.23 (A part of AB system, J = 14.8 Hz, 1 H,
NCHHPh), 4.00–3.70 (m, 6 H, 2-H, 3-H, 6-H, NCHHPh, CH2O),
3.54–3.41 (m, 1 H, 7-H), 2.79 (dd, J = 4.8 and 15.2 Hz, 1 H, 3Ј-
H), 1.11–1.03 (m, 6 H, 2×Me) ppm. 13C NMR: δ = 174.5 (CO),
144.6, 143.2, 141.1, 135.8, 132.4, 128.7, 128.5, 128.4, 128.2, 126.9,
126.8, 126.7, 126.3 (C-ipso Ph, CHPh, C-4, C-5), 62.3 (C-2), 60.4
(CH2O), 56.7 (C-7), 54.5 (NCH2Ph), 53.4 (C-3), 33.1 (C-6), 19.8
(Me), 14.3 (Me) ppm. MS (ESI, pos.): m/z = 448.1 [M + Na]+.
HRMS: m/z calcd. for C21H32NO2 [M + H]+ 426.2428; found
426.2242.
6.51 (d, J = 9.0 Hz, 1 H, 3-H), 3.88 (s, 2 H, 5-H), 3.54 (t, J =
9.4 Hz, 1 H, 2-H), 3.08–2.93 (m, 1 H, 1-H), 2.26 (s, 6 H, NMe2),
0.72 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR: δ = 144.4, 143.2,
139.9, 136.3 (C-ipso Ph, C-4), 135.1 (C-3), 128.6–125.7 (CHPh),
64.9 (C-1), 50.0 (C-2), 40.7 (2×NMe), 35.9 (C-5), 9.3 (Me) ppm.
MS (ESI, pos.): m/z = 356.1 [M+H]+. C26H29N (355.5): calcd. C
87.84, H 8.22, N 3.94; found C 87.75, H 8.16, N 3.91.
Dimethyl[(1S,2S,3E)- and (1S,2S,3Z)-1-methyl-2,4-diphenylnon-3-
enyl]amine (43): This compound was purified by flash chromatog-
raphy (Et2O/PE, 3:7), yield: 62%, oil; 35:65 mixture of (Z) and (E)
isomers; Rf = 0.75 (Et2O). Major isolated isomer: [α]2D0 = +51 (c =
General Procedure for the Opening of 2-Alkenylazetidinium Trifluor-
omethanesulfonates with Organolithium Reagents. Synthesis of Al-
kenes 39–43: A solution of the required organolithium reagent was
added dropwise at –78 °C to a solution of the trifluoromethanesul-
fonate azetidinium salt (1 mmol) in dry THF (6 mL). The tempera-
ture was gradually (1.5 h) raised to –30 °C and the mixture was
hydrolysed at this temperature by addition of a saturated aqueous
solution of NH4Cl (5 mL). Usual workup gave an oil that was puri-
fied by flash chromatography.
1
1, CH2Cl2). H NMR (CDCl3): δ = 7.38–7.00 (m, 10 H, Ph), 6.12
(d, J = 9.0 Hz, 1 H, 3-H), 3.57 (t, J = 9.4 Hz, 1 H, 2-H), 3.03–2.88
(m, 1 H, 1-H), 2.47–2.43 (m, 2 H, 5-H), 2.29 (s, 6 H, NMe2), 1.28–
1.16 (m, 6 H, 6-H, 7-H, 8-H), 0.79–0.73 (m, 6 H, 2×Me) ppm. 13
C
NMR: δ = 146.0, 143.5, 139.5 (C-ipso Ph, C-4), 132.2 (C-3), 128.5,
128.4, 128.1, 126.7, 126.5, 126.1 (CHPh), 64.7 (C-1), 49.8 (C-2),
40.6 (2×NMe), 32.2 (C-5), 30.2, 28.0, 22.6 (C-6, C-7, C-8), 14.1
(Me), 9.6 (Me) ppm. MS (ESI, pos.): m/z = 335.2 [M+H]+.
(Benzyl)(methyl)[(2R,3E)-2,4,5-triphenylpent-3-enyl]amine (39):
[1] For a very recent review, see: J. A. Vanecko, H. Wan, F. G.
West, Tetrahedron 2006, 62, 1043–1062.
This compound was purified by flash chromatography (Et2O/PE,
2:98, 5:95, 10:90), yield: 80%, Rf = 0.63 (Et2O/PE, 3:7). [α]2D0
=
[2] K. Fukumoto, T. Kametami, S. P. Huang, C. Koseki, M. Ihara,
J. Org. Chem. 1977, 42, 3040–3046.
–97 (c = 0.7, CH2Cl2). 1H NMR (CDCl3): δ = 7.49–7.13 (m, 20 H,
Ph), 6.20 (d, J = 9.4 Hz, 1 H, 3-H), 4.04–3.91 (m, 3 H, 2-H, 5-H),
3.55 (s, 2 H, NCH2Ph), 2.76 (d, J = 7.7 Hz, 2 H, 1-H), 2.25 (s, 3
H, NMe) ppm. 13C NMR: δ = 143.9, 143.1, 140.0, 137.9, 136.2 (C-
ipso Ph, C-4), 133.7 (C-3), 129.1–125.9 (CHPh), 64.3 (C-1), 62.7
(NCH2Ph), 43.7 (C-2), 42.9 (NMe), 36.2 (C-5) ppm. MS (ESI,
pos.): m/z = 418.2 [M+H]+. C31H31N (417.6): calcd. C 89.16, H
7.48, N 3.35; found C 90.22, H 7.39, N 3.48.
[3] F. G. West, B. N. Naidu, J. Am. Chem. Soc. 1994, 116, 8420–
8421.
[4] F. G. West, J. A. Vanecko, Org. Lett. 2005, 7, 2949–2952.
[5] I. E. Markó, in: Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, vol. 3, p. 913–973.
[6] G. Evano. F. Couty, F. Durrat, Targets in Heterocyclic Systems
(Eds.: O. A. Attanasi, D. Spinelli), Italian Society of Chemsitry,
2005, vol. 9.
(Benzyl)[(2R,3E)-2,4-diphenylnon-3-enyl](methyl)amine (40): This
compound was purified by preparative TLC (Et2O/PE, 4:6), yield:
62%, oil: Rf = 0.76 (Et2O/PE, 4:6). [α]2D0 = +22 (c = 1.5, CH2Cl2).
1H NMR (CDCl3): δ = 7.42–7.24 (m, 15 H, Ph), 5.88 (d, J =
9.0 Hz, 1 H, 3-H), 4.04 (q, J = 7.7 Hz, 1 H, 2-H), 3.62 (s, 2 H,
NCH2Ph), 2.78 (dd, J = 2.9 and 7.0 Hz, 2 H, 1-H, 1Ј-H), 2.57–2.53
(m, 2 H, 5-H), 2.34 (s, 3 H, NMe), 1.33–1.26 (m, 6 H, 6-H, 7-H,
8-H), 0.85 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 144.2,
143.1, 140.9, 138.4 (C-ipso Ph, C-4), 139.0 (C-3), 131.0–126.1
(CHPh), 64.1 (C-1), 62.4 (NCH2Ph), 43.1 (C-2), 42.6 (NMe), 30.2
(C-5), 31.0, 29.7, 28.2 (C-6, C-7, C-8), 13.0 (Me) ppm. MS (ESI,
pos.): m/z = 398.2 [M + H]+.
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4222
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4214–4223

Ring Expansions of 2-Alkenylazetidinium Salts
FULL PAPER
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Received: April 26, 2006
Published Online: July 13, 2006
Eur. J. Org. Chem. 2006, 4214–4223
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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