Nucleophilic ring-opening of azetidinium ions: Insights into regioselectivity

Article abstract of DOI:10.1002/ejoc.200600200

Enantiopure azetidinium salts presenting various and representative substitution patterns at C-2, C-3 and C-4 have been prepared by alkylation of the corresponding azetidine with methyl trifluoromethanesulfonate. These compounds were treated with an array

Full text of DOI:10.1002/ejoc.200600200

FULL PAPER
DOI: 10.1002/ejoc.200600200
Nucleophilic Ring-Opening of Azetidinium Ions: Insights into Regioselectivity
François Couty,*[a] Olivier David,[a] François Durrat,[a] Gwilherm Evano,[a] Sami Lakhdar,[a]
Jérome Marrot,[a] and Monica Vargas-Sanchez[a]
Keywords: Azetidines / Azetidinium ions / Nucleophilic ring-opening / Density functional calculations / Regioselectivity
Enantiopure azetidinium salts presenting various and repre-
sentative substitution patterns at C-2, C-3 and C-4 have been
prepared by alkylation of the corresponding azetidine with
methyl trifluoromethanesulfonate. These compounds were
treated with an array of nitrogen (azide anion or benzyl-
amine) and oxygen (acetate anion or alkoxides) nucleophiles
which provided interesting insights into the regioselectivity
of the ring-opening process. Nucleophilic opening occurred
in most cases regioselectively at C-4 with azetidinium ions
possessing no substituent at this position. On the other hand,
highly regioselective opening at C-2 occurred with trisubsti-
tuted azetidinium ions bearing a methyl group at C-4. Exper-
imental selectivities together with DFT calculations have al-
lowed a better understanding of the parameters governing
the regioselectivities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
cycle still has to be addressed. As part of our ongoing inter-
est in the chemistry of azetidines,[10] we wish to present
herein a full and detailed report[11] on the nucleophilic
opening of a range of functionalized azetidinium salts with
nitrogen and oxygenated nucleophiles as well as insights
into the regioselectivity of this efficient ring-opening pro-
cess.
Introduction
Owing to the ease of their ring-opening by various nu-
cleophiles, aziridines have been widely used as electrophilic
building blocks in synthesis.[1] In contrast, the electrophilic
reactivity of their higher homologs, azetidines 1, is still un-
derstudied which is quite amazing since they could act as
versatile precursors to various functionalized amine deriva-
tives in which the nitrogen and all three carbon atoms from
the azetidine would be incorporated into the skeleton. One
explanation for this reactivity having been neglected for
years lies in the lack of efficient and general methods for
the preparation of azetidines, especially in an enantiomer-
ically pure form.[2] Moreover, the ring strain in azetidines is
less important than in aziridines and their nucleophilic ring-
opening therefore requires stronger activation. An efficient
solution to the activation of this heterocycle towards nu-
cleophiles relies on its transformation into the correspond-
ing cyclic ammonium salt 2: the amine is then sufficiently
activated and a wide range of heteronucleophiles (amines,[3]
alkoxides,[4] phenols,[5] carboxylates,[6] sulfur nucleophiles,[7]
phosphorus nucleophiles[8] and halides[9]) have been shown
to smoothly ring-open these salts. However, few reports
have addressed the regioselectivity issue: although it seems
that nucleophiles preferably react at the unsubstituted posi-
tion[3b,5a,6] or at a benzylic site (Figure 1),[5a] there has been
no general and extensive study of this process and the intro-
duction of functional groups at the reacting center as well
as the influence of the relative configuration of the hetero-
Figure 1. Azetidinium ions as functionalized electrophiles.
Results
Synthesis of Functionalized Azetidinium Salts
The azetidinium salts prepared for this study are depicted
in Figure 2. They were all synthesized in good yield by sim-
ply treating the corresponding azetidine with methyl trifluo-
romethanesulfonate (the yields are shown in Figure 2). The
starting azetidines[12] can be divided into three categories:
those derived from (R)-phenylglycinol, which gave azetidin-
ium salts 3–7 bearing a variable substituent at C-2 and a
[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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phenyl substituent at C-3, those derived from (1R,2S)-
ephedrine, which gave azetidinium salts 8–11 bearing an ad-
ditional methyl group at C-4, and those derived from (–)-
phenylethylamine, which gave azetidinium salts 12 and 13
unsubstituted at C-3 and C-4.
Figure 3. The alkylation of N-phenylethyl-substituted azetidines
occurs with high diastereoselectivity.
Nucleophilic Ring-Opening with Nitrogen Nucleophiles
Two representative nitrogen nucleophiles were selected
for this study: sodium azide and benzylamine. The reactions
were conducted overnight in DMF in the case of sodium
azide and in dichloromethane in the case of the amine. In
all cases 5 equiv. of the nucleophile were used and the re-
sults are detailed in Table 1.
Some general trends can be stated after examination of
this first set of experiments. First, the ring-opening reaction
with nitrogen nucleophiles is quite efficient and acyclic
products are obtained in good yields except in the case of
azetidinium 9 (entry 5). Moreover, we were pleased to see
that no competitive elimination or SN1 processes occurred,
as evidenced by the diastereoisomeric purity of the prod-
ucts. One exception was however noted in the case of azeti-
dinium salt 7, which reacts through an exclusive SN2Ј reac-
tion to yield trisubstituted alkene 18 as a Z/E mixture of
isomers. In contrast, related alkenylazetidinium salt 6 gave
a complex mixture upon reaction with sodium azide.
The regioselectivity of the reaction seems to be governed
by the following general parameters: C-2 and C-3 disubsti-
tuted azetidinium ions react regioselectively at the unsubsti-
tuted C-4 carbon atom (entries 1, 2 and 7) while azetidin-
ium salts possessing a methyl group at C-4 are preferably
opened at the C-2 position (entries 5, 6 and 8). Note that
the structure of the minor inseparable compound contami-
nating the product resulting from an attack at C-2 in entry 4
could not be ascertained: from the NMR spectrum of the
mixture, all signals except the singlet due to the N(Me)2
group being overlapped. This suggests that the minor com-
pound is an epimer since 2-H signals in the closely related
regioisomers 14 and 15 show a difference in chemical shifts
of nearly 1 ppm. Finally, the reactivity of azetidinium salts
12 and 13 bearing a single substituent at C-2 (ester or ni-
trile) was deeply influenced by the nature of that substitu-
ent; while 12 was exclusively opened at C-4, the ester 13
induced a reverse of the regioselectivity with opening at C-
2 (entries 9 and 10) slightly preferred.
Figure 2. Azetidinium salts prepared by alkylation with methyl tri-
fluoromethanesulfonate.
This alkylation step was found to be highly diastereo-
selective in the case of N-benzyl- or N-phenylethyl-substi-
tuted azetidines since azetidinium salts 3–7 and 12 and 13
were obtained as unique compounds. This stereochemical
outcome has already been commented on[12c] for 3–7 and
the stereochemistries in 12 and 13 were deduced from the
same behavior, that is, an attack of the axial lone pair on
Structure Determination of the Regioisomers Obtained by
Chemical Transformation
The structures of the compounds produced upon treat-
the nitrogen atom in the conformer having all its substitu- ment with nitrogen nucleophiles had to be ascertained by
ents in an equatorial position (Figure 3). chemical transformation since it was quite hazardous to de-
Having prepared a set of azetidinium salts with various termine the location of the incoming nucleophile on the ba-
substitution patterns and stereochemistries, we next studied sis of chemical shifts only. Thus, compound 14 was sub-
their opening with various heteronucleophiles.
jected to catalytic hydrogenation to give lactam 33 in which
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Table 1. Reaction of azetidinium ions with sodium azide and benzylamine.
[a] DMF was used as solvent with sodium azide and DCM was used with benzylamine. [b] Yield of pure isolated product. [c] An
inseparable minor compound (14%) contaminated compound 20 (C-2 attack), but we could not determine whether it was the regioisomer
19 or an epimer of 20 (see text).
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Scheme 1. Structure determination of the regioisomers obtained.
the large coupling constant observed for the proton adja- as inter- or intramolecular nucleophiles was also evaluated.
cent to the lactam (ca. 9 Hz) is in accordance with a 3,4-cis The results of these experiments are collected in Table 2.
stereochemistry, as depicted in Scheme 1, and, by deduc-
Nucleophilic ring-opening with oxygenated nucleophiles
tion, with an attack by the azide at C-4. In contrast, when shows some discrepancies compared with the results ob-
subjected to the same conditions, compounds 20 and 22, tained with their nitrogen counterparts. First, the nature of
respectively, gave amines 34 and 35, and the latter was fur- the oxygen nucleophile has a dramatic influence: although
ther protected as the N-Boc derivative. Careful analysis of sodium acetate reacts readily in some cases (entries 1 and
1
the H NMR spectra of 35 and 36 unambiguously allowed 2), use of the more nucleophilic caesium acetate is some-
the determination of the location of the carbamate in the times necessary to obtain reasonable-to-good yields (com-
acyclic skeleton (relevant data shown in Scheme 1). Simi- pare entries 4 and 5). Moreover, while benzyl alkoxide led
larly, compounds 29, 31 and 32 were also transformed into to extensive decomposition when used as an external nu-
their N-Boc derivatives 37–39; comparison of their 1H cleophile (entry 3), potassium alkoxides act as intramolecu-
NMR chemical shifts with those of the unprotected amine lar nucleophiles to efficiently give the expected epoxides 48
allowed the location of the secondary amine to be deter- and 49 (entries 10 and 11). Considering the regioselectivity,
mined.
the exclusive C-2 attack previously observed in the case of
the reaction of C-4-substituted azetidinium salts with nitro-
gen nucleophiles is still observed when oxygenated nucleo-
philes are used (entries 5–9). However, and in contrast with
Nucleophilic Ring-Opening with Oxygen Nucleophiles
The acetate anion was chosen as a model oxygenated nu- previous results (Table 1), the regioselectivity observed for
cleophile which was delivered overnight as its sodium or the ring-opening of 3 and 4 is not homogeneous (entries 1
caesium salt in DMF at room temperature; sodium triace- and 2): although azetidinium ion 4 is regioselectively
toxyborohydride was also found to be an efficient source of opened at C-4 as previously observed with the azide anion
acetate anion in refluxing THF. The use of alkoxides acting (compare entries 2 of Table 1 and Table 2), azetidinium ion
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Table 2. Reaction of azetidinium ions with acetates and alkoxides.
[a] Yield of pure isolated product. [b] Yields were difficult to reproduce. [c] The absolute stereochemistry at C-2 was not rigorously
ascertained (see the Discussion section). [d] These epoxides were not purified since they were unstable on silica gel; exclusive formation
of the epoxide was observed in the crude reaction mixture.
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3, bearing an ester moiety in place of the nitrile, is prefera- equilibrium should strongly favor the conformer 9a with
bly opened at C-2, although with a low selectivity, a result all its substituents in a pseudoequatorial orientation. This
which was completely unexpected in view of the reactivity conformer however appears to be less reactive towards nu-
of the azide anion (compare entries 1 of Table 1 and cleophilic ring-opening owing to an unfavorable steric inter-
Table 2). This highlights again the determining effects of action between the phenyl group and the incoming nucleo-
both the nature of the functional group at C-2 (ester or phile. The less stable conformer 9b, with severe 1,3-diaxial
nitrile) and the incoming nucleophile on the regioselectivity interactions between the substituents, would therefore be
of the reaction.
the more reactive one. Starting from 10, its conformer 10b
Interestingly, substrates 9 and 10, for which C-2 attack is would also, for the same reasons, be the more reactive one.
exclusive, afforded two isomers at this C-2 position in the This conformer is however more stable than 9b since the
same ratio, regardless of the absolute configuration of the cyano group is now in an equatorial position. In this case,
reacting center in the starting material. Diastereoisomers 46 the kinetics of the nucleophilic attack should be less ham-
and 47 were separated by flash chromatography and the pered by an unfavorable preconformational equilibrium.
relative stereochemistry of the major isomer 46 was deter-
mined by X-ray crystallography.[13]
Discussion
The surprising and unprecedented low diastereoselectiv-
ity observed in this case suggests that an equilibration of
substrates 9 and 10 through a deprotonation/reprotonation
sequence involving an intermediate ylide 50 occurs prior
to ring-opening (Scheme 2). The identical diastereoisomeric
ratio obtained starting from 9 or 10 might therefore reflect
the ease of opening of these diastereoisomers by the acetate
anion. Since the major isomer 46 results from a SN2 reac-
tion involving the 2,3-cis isomer 10, it can be deduced that
this isomer reacts faster than the 2,3-trans-9. This is in ac-
cordance with entries 5 and 6 of Table 1 involving the open-
ing of 9 and 10 by the azide anion; comparison of the yields
obtained for each of these substrates (27% for the 2,3-trans
Figure 4. Conformational equilibrium in 9 and 10.
In order to gain a better understanding of the intimate
isomer and quantitative for the 2,3-cis isomer) fits well with reaction profile, DFT[14] calculations were performed on
this assumption.
model azetidinium ions 51–53 and 12 and their reaction at
This epimerization process was easily evidenced by inde- C-2 or C-4 with ammonia or the azide anion (for 12) (Fig-
pendently treating 9 and 10 overnight with triethylamine in ure 5). After complete optimization of the substrates, the
[D6]acetone. A thermodynamic distribution of 9 (ca. 80%) energies and the optimized structures for each transition
and 10 (ca. 20%) was obtained in each case with the disap- state were determined. Two of them, involving C-4 attack
pearance of the 2-H proton from the 1H NMR spectra. The on 51 and 52 are depicted in Figure 6. These calculations
occurrence of this possible competitive epimerization and show that attack at C-4 is favored by 0.66 kcalmol–1 in 51,
the low yield obtained for product 45 in entry 5 of Table 2 which is in accordance (although this value is low) with the
led us to be cautious in determining the absolute configura- preferred experimental regioselectivity observed with ben-
tion at C-2 in 45. Although the observed coupling constant zylamine (entry 7, Table 1). This value corresponds to a cal-
3J for 2-H/3-H fits well with a 2,3-syn stereochemistry (J = culated 76:24 ratio of C-4 versus C-2 attack at 293 K, which
4.2 Hz in 45 and 3.7 Hz in 42), we cannot rule out epimeri- is lower than the 2:98 distribution observed experimentally.
zation prior to the nucleophilic opening.
However, the calculation did not take into account the
The higher reactivity of the 2,3-cis compound 10 relative bulkiness of the nucleophile (benzylamine) and of the N-
to its 2,3-trans isomer 9 can be explained by conformational benzyl substituent present in 4. In contrast, calculations
analysis: Figure 4 illustrates the conformational equilibria show that C-2 attack on azetidinium ion 52 is favored by a
in the diastereoisomeric salts 9 and 10. In compound 9, the much larger amount (3.4 kcalmol–1) and this fits perfectly
Scheme 2. Epimerization of 9 and 10.
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Nucleophilic Ring-Opening of Azetidinium Ions
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well with the constantly high regioselectivity observed with light the important influence of the moiety (ester or nitrile)
C-4 methyl-substituted azetidinium ions. Finally, C-2 attack linked to C-2 and are in agreement with the experimental
is preferred by 1.17 kcalmol–1 in 53, while 12 is opened at regioselectivities (entries 9 and 10, Table 1). More interest-
C-4 (∆∆E# = 3.51 kcalmol–1). These last results again high- ingly, the optimized transition state for the disfavored C-4
attack in 52 merits some comments: the long distance be-
tween N(NH3) and C-4 (2.249 Å) relative to the value of
2.097 Å in the transition state involving 51 reflects the diffi-
cult approach of the nucleophile due to the shielding of the
methyl group. Moreover, the N(NH3)−C-4−N-1 angle, with
a value of 167°, shows an important deviation from the
ideal value of 180°. This explains the high energy of this
transition state[15] and the excellent regioselectivities ob-
served with related substrates.
In conclusion, this work has disclosed several features of
azetidine chemistry. First, we have demonstrated that polys-
ubstituted azetidinium ions can react in a highly regioselec-
tive way depending on different parameters such as the de-
gree of substitution, the nature of the linked moiety at C-2
(nitrile, ester, alkene) and the nature of the incoming nu-
cleophile. We have also shown that the relative configura-
tion of the substituents on the azetidinium ring is an impor-
tant parameter for the success of the ring-opening and that
a side-reaction involving an epimerization process can take
place in some cases. Finally, we have shown that DFT cal-
culations are a good way of predicting the regioselectivity of
this nucleophilic ring-opening reaction. Since this reaction
produces stereodefined highly functionalized building
Figure 5. Calculated ∆∆E# values for C-2 or C-4 attack of ammo-
blocks and considering the new methodologies available for
nia on azetidinium ions 51–53 and 12.
the preparation of enantiopure azetidines,[2] this study
should find applications in organic synthesis.
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 relative to TMS. Optical rota-
tions were determined with a Perkin–Elmer 141 instrument. All the
reactions were carried out under argon. Column chromatography
was performed on silica gel (230–400 mesh) using various mixtures
of diethyl ether (Et2O), ethyl acetate (AcOEt), petroleum ether (PE)
and cyclohexane (CyH). TLC was performed on Merck Kieselgel
60F254 plates. Melting points were recorded with a Mettler FP61
apparatus and are uncorrected. Infrared spectra were recorded with
a Nicolet apparatus. Mass spectra were recorded with a Hewlett-
Packard MS Engine HP 5989 B equiped with an Analytica Brand-
ford ESI source. THF and diethyl ether were distilled from sodium/
benzophenone ketyl. Dichloromethane was distilled from calcium
hydride. The mention of a “usual work up” means: (i) decanting
the organic layer, (ii) extraction of the aqueous layer with diethyl
ether, (iii) drying of the combined organic layers with MgSO4 and
(iv) solvent evaporation under reduced pressure. Stereoisomeric ra-
tios were determined by NMR analysis of crude reaction mixtures
before purification.
General Procedure for the Preparation of Azetidinium Salts: Methyl
trifluoromethanesulfonate (0.225 mL, 2 mmol) was added dropwise
to a solution of azetidine (1 mmol) in DCM (5 mL) at 0 °C. The
reaction mixture was stirred at room temp. for 1 h before evaporat-
ing the solvent under reduced pressure. The residue was washed
with small quantities of dry diethyl ether and dried under vacuum.
Figure 6. Optimized transition states for the nucleophilic opening
by C-4 attack on 51 and 52.
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(1R,2R,3R)-1-Benzyl-2-ethoxycarbonyl-1-methyl-3-phenylazetidin- (2S,3S,4S)-2-Ethoxycarbonyl-1,1,4-trimethyl-3-phenylazetidinium
20
ium Trifluoromethanesulfonate (3): Yield: 90%; m.p. 135 °C. [α]
Trifluoromethanesulfonate (8): Yield: 90%; oil. [α]2D5 = +16 (c = 0.4,
acetone). 1H NMR ([D6]acetone): δ = 7.56–7.54 (m, 2 H, Ph), 7.45–
365
1
= –5 (c = 0.5, acetone). H NMR ([D6]acetone): δ = 7.84–7.82 (m,
2 H, Ph), 7.81–7.55 (m, 3 H, Ph), 7.38–7.33 (m, 5 H, Ph), 5.75 (d, 7.34 (m, 3 H, Ph), 5.60 (d, J = 10.8 Hz, 1 H, 2-H), 5.08–4.98 (m,
J = 10.0 Hz, 1 H, 2-H), 5.06 (A part of AB syst., J = 13.1 Hz, 1
H, CHHPh), 5.01 (B part of. AB syst., J = 13.1 Hz, 1 H, CHHPh),
1 H, 4-H), 4.47 (t, J = 10.8 Hz, 1 H, 3-H), 4.36 (q, J = 7.1 Hz, 2
H, CH2O), 3.61 (s, 3 H, Me), 3.39 (s, 3 H, Me), 1.75 (d, J = 6.8 Hz,
4.95–4.80 (m, 2 H, 3-H, 4-H), 4.58–4.52 (m, 1 H, 4Ј-H), 4.32 (q, J 3 H, Me), 1.29 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 164.8
= 7.1 Hz, 2 H, CH2CH3), 3.55 (s, 3 H, Me), 1.27 (d, J = 7.1 Hz, 3
H, Me) ppm. 13C NMR: δ = 164.7 (CO), 135.9 (ipso-C, Ph), 133.3, 75.8 (C-2), 63.7 (CH2O), 53.5, 42.0 (C-5, C-6), 44.9 (C-3), 14.1
131.4, 130.0, 129.4, 128.8, 128.7, 128.1 (CH Ph), 75.1 (C-2), 68.7
(C-10), 13.3 (C-7) ppm. MS (ESI Pos): m/z = 248.2 [M – OTf]+.
(CO), 135.0 (ipso-C, Ph), 129.7, 129.1, 128.4 (CHPh), 77.9 (C-4),
(CH2Ph), 66.7 (C-4), 63.5 (CH2O), 46.4 (Me), 37.2 (C-3), 13.8 C16H22F3NO5S (397.1): C 48.36, H 5.58, N 3.52; found C 48.29, H
(Me) ppm. MS (ESI Pos): m/z = 310.4 [M – OTf]+. C21H24F3NO5S 5.64, N 3.49.
(459.48): C 54.89, H 5.26, N 3.05; found C 54.66, H 5.32, N 2.94.
methanesulfonate (9): Yield: 90%; oil. [α]2D5 = +17 (c = 0.8, acetone).
(1R,2R,3R)-1-Benzyl-2-cyano-1-methyl-3-phenylazetidinium Tri-
(2S,3S,4S)-2-Cyano-1,1,4-trimethyl-3-phenylazetidinium Trifluoro-
1H NMR ([D6]acetone): δ = 7.60–7.45 (m, 2 H, Ph), 7.44–7.43 (m,
3 H, Ph), 6.09 (d, J = 10.6 Hz, 1 H, 2-H), 5.32–5.22 (m, 1 H, 4-
H), 4.81 (t, J = 10.6 Hz, 1 H, 3-H), 3.72 (s, 3 H, NMe), 3.66 (s, 3
H, NMe), 1.11 (d, J = 6.8 Hz, 3 H, Me) ppm. 13C NMR: δ = 133.0
(ipso-C, Ph), 130.0, 128.5 (CH Ph), 112.1 (CN), 79.8 (C-4), 65.3
(C-2), 53.4, 43.6 (Me), 46.9 (C-3), 13.6 (Me) ppm. MS (ESI Pos):
m/z = 201.2 [M – OTf]+. C14H17F3N2O3S (350.4): C 47.99, H 4.89,
N 8.00; found C 48.12, H 4.89, N 8.00.
fluoromethanesulfonate (4): Yield: 99%; m.p. 116 °C. [α]2D0 = –34 (c
= 0.5, acetone). 1H NMR ([D6]acetone): δ = 7.89–7.82 (m, 2 H,
Ph), 7.67–7.42 (m, 8 H, Ph), 6.34 (d, J = 9.3 Hz, 1 H, 2-H), 5.31–
5.14 (m, 4 H, 3-H, 4-H, CH2Ph), 4.91–4.81 (m, 1 H, 4Ј-H), 3.70 (s,
3 H, Me) ppm. 13C NMR: δ = 133.9 (ipso-C, Ph), 133.1, 131.9,
130.5, 129.9, 129.8, 128.4 (CHPh), 128.3 (ipso-C, Ph), 112.3 (CN),
69.3, 69.2 (C-4, CH2Ph), 65.3 (C-2), 46.9 (Me), 39.6 (C-3) ppm.
MS (ESI Pos): m/z = 263.2 [M – OTf]+. C19H19F3N2O3S (412.4):
C 55.33, H 5.26, N 6.79; found C 55.23, H 4.66, N 6.74.
(2R,3S,4S)-2-Cyano-1,1,4-trimethyl-3-phenylazetidinium Trifluoro-
methanesulfonate (10): Yield: 89%; m.p. 122 °C. [α]2D5 = –2 (c = 0.5,
acetone). 1H NMR ([D6]acetone): δ = 7.58–7.42 (m, 5 H, Ph), 6.06
(d, J = 9.4 Hz, 1 H, 2-H), 5.74–5.59 (m, 1 H, 4-H), 4.97 (t, J =
9.6 Hz, 1 H, 3-H), 3.66 (s, 6 H, 2×Me), 1.81 (d, J = 6.6 Hz, 3 H,
Me) ppm. 13C NMR: δ = 132.7 (ipso-C, Ph), 129.9, 129.8, 129.1
(CH Ph), 112.1 (CN), 78.2 (C-4), 69.8 (C-2), 51.1, 43.6 (Me), 46.6
(C-3), 13.9 (Me) ppm. MS (ESI Pos): m/z = 201.2 [M – OTf]+.
C14H17F3N2O3S (350.4): C 47.99, H 4.89, N 8.00; found C 47.86,
H 4.90, N 7.88.
(1R,1ЈR,2R,3R)-1-Benzyl-2-(1Ј-hydroxyphenylmethyl)-1-methyl-3-
phenylazetidinium Trifluoromethanesulfonate (5): Yield: 94%; m.p.
135 °C. [α]2D5 = –2 (c = 0.5, acetone). H NMR ([D6]acetone): δ =
1
7.84–7.80 (m, 2 H, Ph), 7.63–7.60 (m, 3 H, Ph), 7.35–7.32 (m, 2 H,
Ph), 7.21–7.09 (m, 8 H, Ph), 5.66 (br. s, 1 H, OH), 5.36 (br. s, 1 H,
CHOHPh), 5.17 (d, J = 10.0 Hz, 1 H, 2-H), 5.01 (s, 2 H, CH2Ph),
4.92 (q, J = 9.8 Hz, 1 H, 3-H), 4.69 (t, J = 10.0 Hz, 1 H, 4-H), 4.52
(t, J = 8.5 Hz, 1 H, 4Ј-H), 3.60 (s, 3 H, Me) ppm. 13C NMR: δ =
140.5, 137.5 (ipso-C, Ph), 133.4, 131.5, 130.3, 129.5, 129.3, 129.2,
128.9, 128.5, 128.3, 127.3 (CHPh), 83.1 (C-1Ј), 69.5 (C-2), 68.8
(CH2Ph), 68.3 (C-4), 45.3 (Me), 34.4 (C-3) ppm. MS (ESI Pos): m/z
= 344.3 [M – OTf]+. C25H26F3NO4S (493.5): C 60.84, H 5.31, N
2.84; found C 60.91, H 5.40, N 2.99.
(2S,3S,4S)-2-Hydroxymethyl-1,1,4-trimethyl-3-phenylazetidinium
Trifluoromethanesulfonate (11): Yield: quant.; oil. [α]2D5 = +10 (c =
1
0.4, CH2Cl2). H NMR ([D6]acetone): δ = 7.49–7.32 (m, 5 H, Ph),
5.26 (br. s, 1 H, OH), 4.91–4.76 (m, 2 H, 2-H, 4-H), 4.21 (dd, J =
8.9, 13.9 Hz, 1 H, CHHOH), 4.06–3.99 (m, 2 H, 3-H, CHHOH),
3.47 (s, 3 H, Me), 3.33 (s, 3 H, Me), 1.66 (d, J = 6.8 Hz, 3 H,
Me) ppm. 13C NMR: δ = 136.0 (ipso-C, Ph), 129.8, 128.9, 128.3
(CH Ph), 80.8, 77.3 (C-2, C-4), 58.5 (CH2OH), 54.3, 39.6 (Me),
43.7 (C-3), 13.2 (Me) ppm. MS (ESI Pos): m/z = 206.2 [M –
OTf]+.
(1R,2S,3R,2ЈE)-1-Benzyl-2-(2Ј-ethoxycarbonylvinyl)-1-methyl-3-
phenylazetidinium Trifluoromethanesulfonate (6): Yield: 96%; m.p.
1
134 °C. [α]2D5: –45 (c = 0.8, acetone). H NMR ([D6]acetone): δ =
7.86–7.82 (m, 2 H, Ph), 7.63–7.53 (m, 3 H, Ph), 7.48–7.32 (m, 5 H,
Ph), 7.08 (dd, J = 7.1, 15.6 Hz, 1 H, CH=CH), 6.45 (dd, J = 1.2,
15.6 Hz, 1 H, CH=CH), 5.86 (dd, J = 7.1, 9.4 Hz, 1 H, 2-H), 5.09
(A part of AB syst., J = 13.1 Hz, 1 H, CHHPh), 5.04 (B part of
AB syst., J = 13.1 Hz, 1 H, CHHPh), 4.96 (t, J = 10 Hz, 1 H, 4-
H), 4.83 (qd, J = 1.5, 8.3 Hz, 1 H, 3-H), 4.56 (t, J = 8.7 Hz, 1 H,
4Ј-H), 4.18 (q, J = 7.1 Hz, 2 H, CH2O), 3.37 (s, 3 H, Me), 1.24 (t,
J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ = 164.8 (CO), 136.2, 135.2
(ipso-C, Ph), 133.2 (C=C), 132.1, 131.5 (CHPh), 130.2 (C=C),
129.8, 129.2, 129.1, 128.3 (CHPh), 78.9 (C-2), 68.5 (CH2Ph), 67.7
(C-4), 61.6 (CH2O), 44.2 (Me), 39.1 (C-3), 14.3 (Me) ppm. MS (ESI
Pos): m/z = 336.4 [M – OTf]+. C23H26F3N2O5S (485.5): C 56.90, H
5.40, N 2.88; found C 57.12, H 5.54, N 2.72.
(1ЈS,2S)-2-Cyano-1-methyl-1-(1-phenylethyl)azetidinium Trifluoro-
methanesulfonate (12): Yield: 90%; Rf = 0.1 (DCM/MeOH, 9:1);
m.p. 85 °C, white solid. [α]2D0 = –42 (c = 0.7, CHCl3). 1H NMR
([D6]acetone): δ = 7.79–7.76 (m, 2 H, CHAr), 7.60–7.51 (m, 3 H,
CHAr), 6.24 (t, J = 9.9 Hz, 1 H, CNCH), 5.38 (q, J = 6.8 Hz, 1
H, CH3CH), 5.09 (q, J = 9.8 Hz, 1 H, NCHH), 3.88 (td, J = 9.8,
3.2 Hz, 1 H, NCHH), 3.45 (s, 3 H, NCH3), 3.44–3.32 (m, 1 H,
CNCHCHH), 3.08–2.97 (m, 1 H, CNCHCHH), 1.88 (d, J =
6.9 Hz, 3 H, CH3) ppm. 13C NMR: δ = 132, 131.9, 130.6, 130.3
(CAr), 113.7 (CN), 74.0 (CH), 63.6 (CH2), 60.3 (CH), 41.9 (CH3),
20.6 (CH2), 13.4 (CH3). CIMS (NH3 gas): m/z = 351 [MH+], 335,
324.
(1R,2R,3R)-1-Benzyl-1-methyl-3-phenyl-2-(1Ј-phenylvinyl)azetidin-
ium Trifluoromethanesulfonate (7): Yield: quant.; oil. [α]2D5 = +90 (c
= 1, acetone). 1H NMR ([D6]acetone): δ = 7.50–7.21 (m, 15 H,
Ph), 5.96–5.83 (m, 3 H, 2-H, =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 (ipso-C, Ph,
CCH2Ph), 130.9, 129.6, 129.4, 128.7, 127.7, 127.4, 125.6 (CHPh),
(1ЈS,2S)-2-tert-Butoxycarbonyl-1-methyl-1-(1-phenylethyl)azetidin-
ium Trifluoromethanesulfonate (13): Yield: 90%; Rf = 0.2 (DCM/
1
MeOH, 9:1). [α]2D0 = +18 (c = 1, CHCl3). H NMR ([D6]acetone):
δ = 7.51–7.49 (m, 2 H, CHAr), 7.34–7.39 (m, 3 H, CHAr), 5.50 (t,
J = 9.6 Hz, 1 H, 2-H), 4.76 (dd, J = 9.7, 19.6 Hz,1 H, 4-H), 3.96
80.6 (C-2), 67.9 (CH2Ph), 64.5 (C-4), 43.6 (Me), 37.6 (C-3) ppm. (td, J = 3.5, 9.5 Hz, 1 H, 4Ј-H), 3.07 (s, 3 H, NMe), 2.68–2.88 (m,
MS (ESI Pos): m/z = 340.2 [M – OTf]+. C26H26F3NO3S (489.5): C
63.79, H 5.35, N 2.86; found C 63.62, H 5.54, N 2.72.
2 H, 3-H), 1.60 (d, J = 7.0 Hz, 3 H, CH3), 1.10 (s, 9 H, tBu) ppm.
13C NMR: δ = 163.2 (CO), 131.6 (ipso-C, Ph), 130.8, 130.1, 129.4
3486
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3479–3490

Nucleophilic Ring-Opening of Azetidinium Ions
FULL PAPER
(CHAr), 85.0 (Cq), 73.0, 70.1 (CH), 62.6 (CH2), 39.4, 27.5 (CH3),
18.1 (CH2), 13.5 (CH3) ppm. CIMS (NH3 gas): m/z = 276.3 [M –
OTf]+, 220.2, 116.0, 105.0.
fied by flash chromatography (Et2O/CyH, 2:8); Rf = 0.52 (Et2O/
PE, 3:7); yield: 88%; oil. The following signals are characteristic of
1
each isomer. Major isomer: H NMR (CDCl3): δ = 7.40–7.12 (m,
15 H, Ph), 6.26 (d, J = 9.4 Hz, 1 H, 3-H), 4.32 (s, 2 H, CH2Ph),
3.70–3.50 (m, 3 H, 1-H, 1Ј-H, 2-H), 2.37 (s, 2 H, CH2N3) ppm.
Minor isomer: 1H NMR (CDCl3): δ = 7.40–7.12 (m, 15 H, Ph),
6.00 (d, J = 10.2 Hz, 1 H, 3-H), 4.09 (s, 2 H, CH2Ph), 3.73–3.64
(m, 1 H, 2-H), 3.54–3.40 (m, 2 H, 1-H, 1Ј-H), 2.14 (s, 2 H,
CH2N3) ppm.
General Procedure for the Nucleophilic Ring-Opening of Azetidinium
Salts with Sodium Azide: Sodium azide (162 mg, 5 mmol) was
added to a solution of azetidinium trifluoromethanesulfonate
(1 mmol) in DMF (5 mL). The suspension was stirred at room
temp. for 15 h and diluted with water and diethyl ether. The usual
work up was then followed by purification by flash chromatog-
raphy.
Ethyl (2R,3S,4S)-2-Azido-4-dimethylamino-3-phenylpentanoate
(20): Major regioisomer obtained from azetidinium 8. Purified by
flash chromatography (Et2O/CyH, 5:95 then 1:9 then 15:85); Rf =
0.44 (Et2O/CyH, 3:7); yield: 86%; oil. [α]2D5 = +13 (c = 0.5, CH2Cl2).
1H NMR (CDCl3): δ = 7.26–7.13 (m, 5 H, Ph), 4.60 (d, J = 5.2 Hz,
1 H, 2-H), 4.01 (q, J = 7.1 Hz, 2 H, OCH2), 3.11 (dd, J = 5.6,
11.2 Hz, 1 H, 3-H), 3.02–2.92 (m, 1 H, 4-H), 2.19 (s, 6 H, NMe2),
1.10 (t, J = 7.1 Hz, 3 H, Me), 0.58 (d, J = 6.4 Hz, 3 H, Me) ppm.
13C NMR: δ = 170.1 (C=O), 138.1 (ipso-C, Ph), 129.3, 128.5, 127.5
(CH Ph), 64.9 (C-2), 61.3 (CH2O), 59.9 (C-4), 52.0 (C-3), 40.1
(2×NMe), 14.3 (Me), 8.7 (Me) ppm. MS (ESI Pos): m/z = 291 [M
Ethyl (2R,3R)-4-Azido-2-[benzyl(methyl)amino]-3-phenylbutyrate
(14): Major regioisomer obtained from azetidinium 3. Purified by
flash chromatography (Et2O/CyH, 1:9 then 2:8 then 4:6); Rf = 0.61
(Et2O/PE, 3:7); yield: 93%; oil. [α]2D5 = –90 (c = 1, CH2Cl2). 1H
NMR (CDCl3): δ = 7.38–7.19 (m, 10 H, Ph), 4.67 (d, J = 4.2 Hz,
1 H, 2-H), 4.17 (q, J = 7.1 Hz, 2 H, OCH2), 3.66 (d, J = 13.1 Hz,
1 H, CHHPh), 3.54–3.47 (m, 2 H, 3-H, CHHPh), 3.01 (t, J =
11.9 Hz, 1 H, 4-H), 2.47 (dd, J = 4.2, 12.3 Hz, 1 H, 4Ј-H), 2.28 (s,
3 H, NMe), 1.22 (t, J = 7.1 Hz, 3 H, Me) ppm. 13C NMR: δ =
170.2 (C-1), 138.9, 138.1 (ipso-C, Ph), 129.2, 128.9, 128.5, 128.4,
127.6, 127.3 (CH Ph), 64.3 (C-2), 62.9 (CH2Ph), 61.7 (CH2O), 59.3
(C-4), 45.2 (C-3), 42.5 (NMe), 14.2 (Me) ppm. MS (ESI Pos): m/z
= 353 [M + H]+. C20H24N4O (352.4): C 68.16, H 6.86, N 15.90;
found C 68.03, H 6.91, N 15.80.
+ H]+. IR (film): ν = 3175, 2115, 1685, 1623 cm–1. A yield of 14%
˜
of a minor product (based on the integration of a signal due to
NMe2 at δ = 2.26 ppm) contaminated this product. We could not
determine however whether it was a regioisomer or an epimer.
(2R,3S,4S)-2-Azido-4-dimethylamino-3-phenylpentanenitrile (22):
Unique regioisomer obtained from azetidinium 9. Purified by flash
chromatography (Et2O/CyH, 5:95 then 1:9 then 15:85); Rf = 0.7
Ethyl (2S,3R)-2-Azido-4-[benzyl(methyl)amino]-3-phenylbutyrate
(15): Minor regioisomer obtained from azetidinium 3. Purified by
flash chromatography (Et2O/CyH, 1:9 then 2:8 then 4:6); Rf = 0.63
(Et2O/PE, 3:7); yield: 7%; oil. 1H NMR (CDCl3): δ = 7.30–7.11
(m, 10 H, Ph), 3.93–3.82 (m, 2 H, CH2O), 3.77–3.71 (m, 2 H, 4-H,
CHHPh), 3.63–3.54 (m, 3 H, 2-H, 4Ј-H, CHHPh), 3.34–3.27 (m, 1
H, 3-H), 2.27 (s, 3 H, NMe), 0.94 (d, J = 7.1 Hz, 3 H, Me) ppm.
13C NMR: δ = 169.2 (C-1), 139.0, 137.6 (ipso-C, Ph), 128.9, 128.8,
128.6, 128.5, 127.6 (CHPh), 67.9 (C-2), 60.0 (CH2O), 59.4
(CH2Ph), 54.0 (C-4), 44.7 (C-3), 37.8 (NMe), 14.4 (Me) ppm.
1
(Et2O/PE, 1:1); yield: 27%; oil. [α]2D5 = +6 (c = 0.55, CH2Cl2). H
NMR (CDCl3): δ = 7.32–7.18 (m, 5 H, Ph), 5.14 (d, J = 3.1 Hz, 1
H, 2-H), 3.11–3.01 (m, 1 H, 4-H), 2.81 (dd, J = 3.1, 11.2 Hz, 1 H,
3-H), 2.30 (s, 6 H, NMe2), 0.74 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C
NMR: δ = 136.2 (ipso-C, Ph), 129.5, 128.8, 128.3 (CH Ph), 116.7
(CN), 58.6 (C-4), 53.3 (C-2), 52.9 (C-3), 40.1 (2 × NMe), 8.52
(Me) ppm. MS (ESI Pos): m/z = 266.2 [M + Na]+ , 244.2
[M + H]+.
(2R,3R)-4-Azido-2-[benzyl(methyl)amino]-3-phenylbutyronitrile
(16): Major regioisomer obtained from azetidinium 4. Purified by
flash chromatography (Et2O/PE, 5:95 then 1:9); Rf = 0.6 (Et2O/PE,
1:1); yield: 82%; m.p. 66 °C. [α]2D5 = +94 (c = 1, CH2Cl2). 1H NMR
(CDCl3): δ = 7.48–7.24 (m, 10 H, Ph), 3.95 (d, J = 11.6 Hz, 1 H,
2-H), 3.88 (A part of a AB syst., J = 13.1 Hz, 1 H, CHHPh), 3.80
(dd, J = 3.9, 12.3 Hz, 1 H, 4-H), 3.70 (dd, J = 7.3, 12.3 Hz, 1 H,
4Ј-H), 3.62 (B part of syst. AB, J = 13.1 Hz, 1 H, CHHPh), 3.30–
3.22 (m, 1 H, 3-H), 2.46 (s, 3 H, NMe) ppm. 13C NMR: δ = 137.2,
137.0 (ipso-C, Ph), 129.2, 129.1, 128.8, 128.6, 128.4, 128.0 (CH Ph),
115.2 (C-1), 60.3 (NCH2), 59.4 (C-2), 52.9 (C-4), 46.1 (C-3), 38.3
(NMe) ppm. MS (ESI Pos): m/z = 328.3 [M + Na]+, 279.3 [M –
CN]+.
(2S,3S,4S)-2-Azido-4-dimethylamino-3-phenylpentanenitrile (24):
Unique regioisomer obtained from azetidinium 10. Purified by
flash chromatography (Et2O/CyH, 1:9); Rf = 0.8 (Et2O/PE, 1:1);
yield: quant.; m.p. 74 °C. [α]2D5 = –52 (c = 0.6, CH2Cl2). H NMR
1
(CDCl3): δ = 7.38 (br. s, 5 H, Ph), 4.96 (d, J = 4.8 Hz, 1 H, 2-H),
3.24 (qd, J = 6.4, 13.0 Hz, 1 H, 4-H), 2.99 (dd, J = 4.8, 11.4 Hz, 1
H, 3-H), 2.30 (s, 6 H, NMe2), 0.74 (d, J = 6.4 Hz, 3 H, Me) ppm.
13C NMR: δ = 136.3 (ipso-C, Ph), 129.2, 129.1, 128.6 (CHPh),
115.8 (CN), 59.9 (C-4), 54.1 (C-2), 52.7 (C-3), 40.1 (2×NMe), 8.4
(Me) ppm. MS (ESI Pos): m/z = 266.2 [M + Na]+ , 244.2
[M + H]+. C13H17N5 (243.3): C 64.17, H 7.04, N 28.78; found C
64.01, H 7.14, N 28.71.
General Procedure for the Nucleophilic Ring-Opening of Azetidinium
Salts with Benzylamine: Benzylamine (0.54 mL, 5 mmol) was added
to a solution of azetidinium trifluoromethanesulfonate (1 mmol) in
CH2Cl2 (5 mL). The solution was stirred at room temp. for 5 h.
Addition of water and DCM, followed by the usual work up gave
a residue which was purified by flash chromatography.
(2S,3R)-2-Azido-4-[benzyl(methyl)amino]-3-phenylbutyronitrile (17):
Minor regioisomer obtained from azetidinium 4. Purified by flash
chromatography (Et2O/PE, 5:95 then 1:9); Rf = 0.58 (Et2O/PE, 1:1);
yield: 18%; oil. [α]2D5 = –88 (c = 1, CH2Cl2). H NMR (CDCl3): δ
1
= 7.26–7.15 (m, 10 H, Ph), 4.88 (d, J = 2.9 Hz, 1 H, 2-H), 3.55 (A
part of AB syst., J = 13.1 Hz, 1 H, CHHPh), 3.44 (B part of AB
syst., J = 13.1 Hz, 1 H, CHHPh), 3.09–3.06 (m, 1 H, 3-H), 2.96 (t,
J = 11.2 Hz, 1 H, 4-H), 2.45 (dd, J = 4.1, 12.3 Hz, 1 H, 4Ј-H), 2.21
(s, 3 H, NMe) ppm. 13C NMR: δ = 138.5, 136.0 (ipso-C, Ph), 129.1,
129.0, 128.8, 128.6, 128.4, 127.5 (CH Ph), 116.2 (C-1), 63.0
(CH2Ph), 57.3 (C-4), 53.1 (C-2), 46.4 (C-3), 42.8 (Me) ppm. MS
(ESI Pos): m/z = 328.3 [M + Na]+, 279.3 [M – CN]+.
(2R,3R)-4-Benzylamino-2-[benzyl(methyl)amino]-3-phenylbutyro-
nitrile (25): Unique regioisomer obtained from azetidinium 4. Puri-
fied by flash chromatography (CH2Cl2/MeOH, 99:1 then 97:3); Rf
= 0.44 (CH2Cl2/MeOH, 97:3); yield: 89%; m.p. 128 °C. [α]2D5 = +87
(c = 0.35, CH2Cl2). 1H NMR (CDCl3): δ = 7.37–7.19 (m, 15 H,
Ph), 3.84 (d, J = 3.3 Hz, 1 H, 2-H), 3.82–3.73 (m, 3 H, NHCH2Ph,
CHHPh), 3.50 (d, J = 13.1 Hz, 1 H, CHHPh), 3.34–3.26 (m, 1 H,
3-H), 3.19 (dd, J = 4.8, 12.1 Hz, 1 H, 4-H), 2.85 (dd, J = 8.3,
12.1 Hz, 1 H, 4Ј-H), 2.39 (s, 3 H, NMe), 1.56 (br. s, 1 H, NH) ppm.
(Z)- and (E)-(2R)-(5-Azido-2,4-dipenylpent-3-enyl)(benzyl)methyl-
amine (18): Mixture of isomers obtained from azetidinium 7. Puri-
Eur. J. Org. Chem. 2006, 3479–3490
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3487

F. Couty et al.
FULL PAPER
13C NMR: δ = 140.0, 138.6, 137.4 (ipso-C, Ph), 129.2–127.1 (CH
Ph), 115.7 (CN), 61.1 (C-2), 60.1 (CH2Ph), 54.0 (CH2Ph), 51.1 (C-
4), 46.7 (C-3), 38.5 (NMe) ppm. MS (ESI Pos): m/z = 370.3 [M +
H), 3.10 (q, J = 9.3 Hz, 1 H, 4-H), 2.85 (s, 3 H, NMe), 1.83 (br. s,
2 H, NH, NHMe) ppm. 13C NMR: δ = 174.3 (C-2), 139.3 (ipso-C,
Ph), 128.9, 127.4 (CH Ph), 59.5 (C-3), 52.8 (C-5), 48.7 (C-4), 30.0
(NMe) ppm. MS (ESI Pos): m/z = 213.1 [M + Na]+, 191.1 [M +
H]+.
H]+. IR (film): ν = 2289, 1621 cm–1.
˜
(2R,3R,4S)-2-Benzylamino-4-dimethylamino-3-phenylpentanoic
Acid Benzylamide (28): Unique regioisomer obtained from azetidi-
nium 8. Purified by flash chromatography (CH2Cl2/MeOH, 99:1
then 97:3); Rf = 0.47 (CH2Cl2/MeOH, 97:3); yield: 68 %; m.p.
101 °C. [α]2D5 = –10 (c = 0.3, CH2Cl2). 1H NMR (CDCl3): δ = 7.30–
7.07 (m, 15 H, Ph), 6.84 (br. s, 2 H, NH), 4.13 (d, J = 5.2 Hz, 2 H,
CONHCH2), 3.93 (d, J = 3.1 Hz, 1 H, 2-H), 3.70 (s, 2 H,
NHCH2Ph), 3.39 (d, J = 10.4 Hz, 1 H, 3-H), 3.05 (br. s, 1 H, 4-
H), 2.25 (br. s, 6 H, NMe2), 0.67 (d, J = 6.2 Hz, 3 H, Me) ppm.
13C NMR: δ = 173.9 (CO), 140.1, 138.9, 138.5 (ipso-C, Ph), 129.4–
127.0 (CH Ph), 62.9 (C-2), 58.6 (CH2Ph), 53.7 (C-3), 52.4 (C-4),
42.9 (CH2Ph), 40.2 (2×NMe), 8.9 (Me) ppm. MS (ESI Pos): m/z
= 416.3 [M + H]+.
2-Ethyl (2R,3R,4S)-2-Amino-4-dimethylamino-3-phenylpentanoate
(34): Following the procedure described for the preparation of 32
and starting with 20 (160 mg, 0.551 mmol), the title compound was
obtained crude in quantitative yield (145 mg). Rf = 0.41 (CH2Cl2/
1
MeOH, 9:1). [α]2D5 = +12 (c = 0.75, CH2Cl2). H NMR (CDCl3): δ
= 7.23–7.10 (m, 5 H, Ph), 4.03–3.94 (m, 3 H, 2-H, CH2O), 3.09–
2.94 (m, 2 H, 3-H, 4-H), 2.19 (s, 6 H, NMe2), 1.41 (br. s, 2 H,
NH2), 1.14 (t, J = 7.1 Hz, 3 H, Me), 0.57 (d, J = 6.0 Hz, 3 H,
Me) ppm. 13C NMR: δ = 175.4 (C-1), 139.2 (ipso-C, Ph), 129.2,
128.4, 127.1 (CH Ph), 60.5 (OCH2), 59.2 (C-4), 56.2 (C-2), 53.8 (C-
3), 40.2 (2×NMe), 14.3 (Me), 8.7 (Me) ppm. MS (ESI Pos): m/z =
265 [M + H]+.
(2R,3R,4S)-2-Amino-4-dimethylamino-3-phenylpentanenitrile (35):
Following the procedure described for the preparation of 33 and
starting with 22 (122 mg, 0.5 mmol), the title compound was ob-
tained crude in quantitative yield (122 mg). Rf = 0.34 (CH2Cl2/
(2S)-4-Benzylamino-2-[methyl(1-phenylethyl)amino]butyronitrile
(29): Yield: 50%; Rf = 0.2 (Et2O/EP: 6:4). [α]2D0 = –83 (c = 1.2,
CHCl3). 1H NMR (CDCl3): δ = 7.25–7.09 (m, 10 H, CHAr), 3.67–
3.56 (m, 3 H, 2-H, NCH2Ph), 3.45 (q, J = 6.6 Hz, 1 H, CH3CH),
2.63–2.48 (m, 2 H, NHCH2), 2.31 (s, 3 H, NCH3), 1.88–1.66 (m, 2
H, 3-H), 1.30 (d, J = 6.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 143.9, 140.2 (CqAr), 128.8, 128.4, 128.0, 127.7, 127.2,
127.0 (CHAr), 117.5 (CN), 63.8 (CH), 53.8 (CH2), 52.6 (CH), 45.3
(CH2), 33.7 (CH3), 31.8 (CH2), 21.6 (CH3) ppm. CIMS (NH3 gas):
m/z = 308, 281, 202, 162, 120, 105, 91.
MeOH, 95:5). [α]2D5 = –26 (c = 1, CH2Cl2). H NMR (CDCl3): δ =
1
7.41–7.30 (m, 5 H, Ph), 4.18 (d, J = 2.3 Hz, 1 H, 2-H), 3.42–3.31
(m, 1 H, 4-H), 2.91 (dd, J = 2.1, 11.4 Hz, 1 H, 3-H), 2.36 (s, 6 H,
NMe2), 0.73 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR: δ = 139.0
(ipso-C, Ph), 129.0, 128.6, 127.7 (CH Ph), 122.4 (CN), 59.8 (C-2),
53.4 (C-4), 47.7 (C-3), 40.4 (NMe2), 9.1 (Me) ppm. MS (ESI Pos):
m/z = 230.3 [M + Na]+, 218.3 [M + H]+.
tert-Butyl (2S)-4-Benzylamino-2-[methyl(1-phenylethyl)amino]buty-
rate (31): Yield: 23%; Rf = 0.4 (Et2O/30% aqueous ammonia: 99:1);
(2R,3R,4S)-2-tert-Butoxycarbonylamino-4-dimethylamino-3-phenyl-
pentanenitrile (36): A solution of the above crude 34 (110 mg,
0.452 mmol) and Boc2O (109 mg, 0.5 mmol) in AcOEt (3 mL) was
heated at 60 °C overnight. Evaporation of the solvent under re-
duced pressure followed by purification of the residue by flash
chromatography (Et2O/PE, 5:95 then 10:90 then 20:80) gave 88 mg
(61%) of the title compound. Rf = 0.49 (Et2O/PE, 3:7). [α]2D5 = +12
oil. [α]2D0 = +22 (c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
7.26–7.13 (m, 10 H, CHAr), 3.73–3.68 (m, 3 H, CH3CH,
NHCH2Ph), 3.60 (t, J = 7.5 Hz, 1 H, 2-H), 2.68 (t, J = 6.8 Hz, 2
H, 4-H), 2.05 (s, 3 H, NMe), 1.83 (q, J = 6.8, 2 H, 3-H), 1.70 (br.
s, 1 H, NH), 1.39 (s, 9 H, CH3), 1.27 (d, J = 6.6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 172.5 (CO), 146.5, 140.4 (CqAr),
128.4, 128.1, 127.7, 127.1, 126.9, 126.7 (CHAr), 80.7 (Cq), 62.9
(CH), 59.6 (CH), 54.2 (CH2), 46.7 (CH2), 34.6 (CH3), 29.5 (CH2),
28.4 (CH3), 21.2 (CH3) ppm. FAB MS: m/z = 421.3 [M + K]+,
405.4 [M + Na+], 389.4, 383.4 [M + H+].
1
(c = 1, CH2Cl2). H NMR (CDCl3): δ = 7.39–7.30 (m, 5 H, Ph),
7.02 (br. s, 1 H, NH), 5.05 (d, J = 7.3 Hz, 1 H, 2-H), 3.49–3.39 (m,
1 H, 3-H), 2.90 (d, J = 10.8 Hz, 1 H, 2-H), 2.38 (s, 6 H, NMe2),
1.50 (s, 9 H, tBu), 0.75 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR:
δ = 163.2 (CO), 138.4 (ipso-C, Ph), 129.2, 128.3, 128.0 (CH Ph),
118.9 (CN), 80.6 [C(Me)3], 60.6 (C-3), 51.9 (C-2), 48.6 (C-1), 40.2
(NMe2), 28.4 (tBu), 9.4 (Me) ppm. MS (ESI Pos): m/z = 340.2 [M
+ Na]+, 318.2 [M + H]+.
tert-Butyl (2R)-2-Benzylamino-4-[methyl(1-phenylethyl)amino]buty-
rate (32): Yield: 29%; Rf = 0.6 (Et2O/30% aqueous ammonia, 99:1);
oil. [α]2D0 = –33 (c = 0.8, CHCl3). H NMR (CDCl3): δ = 7.22–7.12
1
(m, 10 H, CHAr), 3.70 (d, J = 12.8 Hz, 1 H, PhCHH), 3.53–3.44
(m, 2 H, CH3CH, PhCHH), 3.09 (t, J = 6.2 Hz, 1 H, 2-H), 2.52–
2.43 (m, 1 H, 4-H), 2.37–2.28 (m, 1 H, 4Ј-H), 2.08 (s, 3 H, NCH3),
1.86–1.56 (m, 2 H, 3-H), 1.75 (br. s, 1 H, NH), 1.37 (s, 9 H, tBu),
1.26 (d, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 174.7 (CO), 140.2, 143.8 (CqAr), 128.4, 128.3, 128.1, 127.7,
126.9, 126.8 (CHAr), 80.9 (Cq), 63.6 (CH), 60.0 (CH), 52.1 (CH2),
51.1 (CH2), 38.4 (CH3), 31.0 (CH2), 28.2 (CH3), 18.6 (CH3) ppm.
CIMS (NH3 gas): m/z = 383, 148, 105.
tert-Butyl (2S)-N-Benzyl-N-{3-cyano-3-[methyl(1-phenylethyl)-
amino]propyl}carbamate (37): Following the procedure described
for the preparation of 36, the title compound was prepared. Yield:
78%; Rf = 0.15 (Et2O/pentane, 2:8); oil. [α]2D0 = –75 (c = 1.0,
1
CHCl3). H NMR (CDCl3, broadened signals due to carbamate):
δ = 7.27–7.08 (m, 10 H, CHAr), 4.37–4.12 (m, 2 H, PhCH2NBoc),
3.50–3.29 (m, 3 H, 2-H, 4-H, CH3CH), 2.86 (br. m, 1 H,
BocNCH2Ph), 2.24 (s, 3 H, NMe), 1.75 (br. m, 2 H, 3-H), 1.35 (s, 9
H, CH3), 1.29 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.5 (CO), 143.7, 138.1 (CqAr), 128.9, 128.7, 128.5,
127.7, 127.4, 127.1 (CHAr), 117.4 (CN), 80.3 (Cq), 63.9 (CH), 52.3
(CH), 51.4 (CH2), 43.8 (CH2), 33.4 (CH3), 30.6 (CH2), 28.4 (CH3),
21.6 (CH3) ppm. FAB MS: m/z = 446.3 [M + K]+, 430.3 [M +
Na]+, 414.3, 403.4, 387.4, 381.4, 174.2.
Chemical Transformation for Characterization of Regioisomers
(3R,4R)-3-Methylamino-4-phenylpyrrolidin-2-one (33): A suspen-
sion of 14 (153 mg, 0.434 mmol) and palladium on charcoal (10
wt.-%, 15 mg) in ethanol (3 mL) was stirred vigorously under hy-
drogen for 15 h. Filtration through Celite and evaporation of the
solvent under reduced pressure gave a residue that was purified by
preparative TLC (CH2Cl2/MeOH, 8:2) to give the title compound
tert-Butyl (2S)-4-[Benzyl(tert-butoxycarbonyl)amino]-2-[methyl(1-
phenylethyl)amino]butyrate (38): Yield: 71%; Rf = 0.3 (PE/Et2O,
1
as a clear oil (65 mg, 79%). Rf = 0.41 (CH2Cl2/MeOH, 9:1). [α]2D5
9:1); oil. [α]2D0 = +24 (c = 1, CHCl3). H NMR (CDCl3, broadened
1
= –92 (c = 0.6, CH2Cl2). H NMR (CDCl3): δ = 7.31–7.17 (m, 5 signals due to the carbamate moiety): δ = 7.35–7.20 (m, 10 H,
H, Ph), 3.57–3.47 (m, 2 H, 3-H, 5-H), 3.32 (t, J = 9.6 Hz, 1 H, 5Ј- CHAr), 4.54–4.42 (m, 2 H, PhCH2N), 3.76 (q, J = 6.3 Hz, 1 H,
3488
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3479–3490

Nucleophilic Ring-Opening of Azetidinium Ions
FULL PAPER
CH3CH), 3.52–3.08 (m, 3 H, 2-H, 4-H), 2.10 (s, 3 H, NMe), 2.02–
1.88 (m, 2 H, 3-H), 1.47 (s, 18 H, Boc and tBu), 1.31 (d, J = 6.5 Hz,
(2R,3S)-4-Acetoxy-2-[benzyl(methyl)amino]-3-phenylbutyronitrile
(42): Unique regioisomer obtained from azetidinium 4. Purified by
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0 (CO), flash chromatography (Et2O/CyH, 2:8 then 3:7). Yield: quant.; Rf
146.5, 138.6 (CqAr), 128.5, 128.3, 127.7, 127.1, 126.1, 126.7 = 0.72 (Et2O/PE, 1:1); oil. [α]2D5 = +78 (c = 1.6, CH2Cl2). 1H NMR
(CHAr), 80.9 (Cq), 79.7 (Cq), 62.9 (CH), 59.3 (CH), 50.2 (CH2), (CDCl3): δ = 7.32–7.08 (m, 10 H, Ph), 4.38 (dd, J = 4.1, 11.2 Hz,
44.4 (CH2), 34.3 (CH3), 29.7 (CH2), 28.3 (CH3), 21.4 (CH3) ppm. 1 H, 1-H), 4.25 (dd, J = 6.9, 11.2 Hz, 1 H, 1Ј-H), 3.82 (d, J =
FAB MS: m/z = 505.4.
11.6 Hz, 1 H, 3-H), 3.76 (A part of AB syst., J = 13.1 Hz, 1 H,
CHHPh), 3.45 (B part of AB syst., J = 13.1 Hz, 1 H, CHHPh),
3.31–3.23 (m, 1 H, 2-H), 2.35 (s, 3 H, Me), 1.79 (s, 3 H, Me) ppm.
13C NMR: δ = 170.7 (CO), 137.2 (ipso-C, Ph), 137.1, 129.2, 129.1,
129.0, 128.8, 128.5, 128.3, 127.9 (CH Ph), 115.3 (CN), 64.3 (C-1),
60.4 (CH2), 58.9 (C-3), 45.3 (C-2), 38.4 (NMe), 20.9 (Me) ppm. MS
(ESI Pos): m/z = 323 [M + H]+. C20H22N2O2 (322.4): C 74.51, H
6.88, N 8.69; found C 74.39, H 6.78, N 8.55.
tert-Butyl (2R)-2-[Benzyl(tert-butoxycarbonyl)amino]-4-[methyl(1-
phenylethyl)amino]butyrate ester (39): Yield: 70%; Rf = 0.5 (Et2O);
1
oil. H NMR (CDCl3, broadened signals due to the carbamate
moiety): δ = 7.35–7.23 (m, 10 H, CHAr), 4.63–4.52 (m, 1 H,
NCHHPh), 4.34–4.15 (m, 2 H, 2-H, NCHHPh), 3.72–3.45 (m, 2
H, CHCH3, 4-H), 2.21–2.01 (m, 4 H, NMe, 4Ј-H), 1.82–1.78 (m, 2
H, 3-H), 1.47, 1.41, 1.37 (three s, 18 H, tBu, ester and carbamate),
1.28 (d, J = 6.8 Hz, 3 H, CH3) ppm. FAB MS: m/z = 521.4 [M +
K]+, 505.4 [M + Na]+, 483.4 [M + H]+, 449.3, 427.3, 371.3, 349.3.
Ethyl (2R or 2S,3S,4S)-2-Acetoxy-4-dimethylamino-3-phenylpentan-
oate (45): Unique regioisomer obtained from the reaction of azeti-
dinium 8 with caesium acetate. Purified by flash chromatography
(Et2O/PE, 1:9 then 2:8 then 4:6). Yield: 21–67%; Rf = 0.56 (Et2O/
General Procedure for the Nucleophilic Ring-Opening of Azetidinium
Salts with Acetate Anion: Sodium (or caesium) acetate (5 mmol)
was added to a solution of azetidinium trifluoromethanesulfonate
(1 mmol) in DMF (5 mL). The solution was stirred at room temp.
for 15 h. Addition of water and diethyl ether followed by the usual
work up gave a residue that was examined by NMR and purified
by flash chromatography.
1
PE, 7:3); oil. [α]2D5 = +4 (c = 1, CH2Cl2). H NMR (CDCl3): δ =
7.27–6.91 (m, 5 H, Ph), 5.66 (d, J = 4.2 Hz, 1 H, 2-H), 3.90 (q, J
= 7.1 Hz, 2 H, CH2O), 3.12–3.07 (m, 1 H, 3-H), 3.02–2.96 (m, 1
H, 4-H), 2.17 (s, 6 H, NMe2), 2.06 (s, 3 H, Me), 0.99 (t, J = 6.8 Hz,
3 H, Me), 0.58 (d, J = 6.3 Hz, 3 H, Me) ppm. 13C NMR: δ = 170.3,
170.0 (C=O), 138.3 (ipso-C, Ph), 129.5, 128.6, 127.3 (CH Ph), 73.0
(C-2), 60.9 (CH3CO), 58.9 (CH2O), 51.4 (C-3), 40.1 (2×NMe),
14.1 (Me), 8.8 (Me) ppm. CIMS (NH3 Pos): m/z = 308 [M + H]+.
General Procedure for the Nucleophilic Ring-Opening of Azetidinium
Salts with Sodium Triacetoxyborohydride: A solution of the azetidi-
nium trifluoromethanesulfonate (1 mmol) and sodium triacetoxy-
borohydride (5 mmol) in THF (5 mL) was refluxed overnight. The
mixture was then poured into water (100 mL), basified with sodium
carbonate and extracted five times with DCM. The combined or-
ganic layers were dried with MgSO4 and concentrated under vac-
uum. The residue was analyzed by proton NMR and purified by
flash chromatography (EtO/PE, 3:7).
(2S,3S,4S)-2-Acetoxy-4-dimethylamino-3-phenylpentanenitrile (46):
Major isomer obtained from nucleophilic ring-opening of 9 and 10
with CsOAc or NaBH(OAc)3. Purified by flash chromatography
(Et2O/PE, 3:7). Yield: see Table 2; Rf = 0.25 (Et2O/PE, 7:3); m.p.
73–75 °C (dec.). [α]2D5 = –1.0 (c = 2.4, CHCl3). H NMR (CDCl3):
1
δ = 7.31–7.18 (m, 5 H, Ph), 6.00 (dd, J = 5.4, 0.6 Hz, 1 H, 1-H),
3.22–3.14 (m, 1 H, 3-H), 3.09–3.04 (m, 1 H, 2-H), 2.23 (s, 6 H,
2×NMe), 1.88 (d, J = 0.6 Hz, 3 H, COCH3), 0.63 (d, J = 6.4 Hz,
3 H, Me) ppm. 13C NMR: δ = 169.2 (C=O), 136.6 (ipso-C, Ph),
128.9, 128.7, 127.9 (CH Ph), 116.5 (CN), 64.5 (C-1), 60.0 (C-3),
50.7 (C-2), 39.9 (NMe2), 20.5 (COCH3), 8.2 (C-4) ppm. CIMS
Ethyl (2R,3S)-4-Acetoxy-2-[benzyl(methyl)amino]-3-phenylbutyrate
(40): Minor regioisomer obtained from the reaction of azetidinium
3 with sodium acetate. Purified by preparative TLC (Et2O/CyH,
4:6). Yield: 30%; Rf = 0.51 (Et2O/PE, 4:6); oil. [α]2D5 = +89 (c = 1,
CH2Cl2). 1H NMR (CDCl3): δ = 7.40–7.21 (m, 10 H, Ph), 4.61 (dd,
J = 3.7, 10.9 Hz, 1 H, 4-H), 4.57 (dd, J = 7.3, 10.9 Hz, 1 H, 4Ј-H),
4.05–3.94 (m, 2 H, CH2O), 3.88 (A part of AB syst., J = 13.6 Hz,
1 H, CHHPh), 3.76 (d, J = 11.8 Hz, 1 H, 2-H), 3.67 (B part of AB
syst., J = 13.6 Hz, 1 H, CHHPh), 3.59–3.51 (m, 1 H, 3-H), 2.41 (s,
3 H, NMe), 1.92 (s, 3 H, Me), 1.06 (t, J = 7.1 Hz, 3 H, Me) ppm.
13C NMR: δ = 171.1, 169.3 (C=O), 139.1 (ipso-C, Ph), 128.9, 128.8,
128.5, 128.4, 127.2 (CH Ph), 67.4 (C-2), 65.7 (C-4), 59.9 (CH2O),
59.5 (CH2Ph), 43.8 (C-3), 37.9 (NMe), 21.0 (CH3CO), 14.4
(Me) ppm. MS (ESI Pos): m/z = 392.1 [M + Na]+ , 370.1
[M + H]+.
(NH Pos): m/z = 261 [M + H]+. IR (film): ν = 3180, 2950, 2291,
˜
3
1751, 1695 cm–1.
(2R,3S,4S)-2-Acetoxy-4-dimethylamino-3-phenylpentanenitrile (47):
Minor isomer obtained from nucleophilic opening of 9 and 10 with
CsOAc or NaBH(OAc)3. Purified by flash chromatography (Et2O/
PE, 3:7). Yield: see Table 2; Rf = 0.42 (Et2O/PE, 7:3); oil. [α]2D5
=
+9.1 (c = 4.47, CHCl3). 1H NMR (CDCl3): δ = 7.31–7.19 (m, 5 H,
Ph), 5.92 (d, J = 3.6 Hz, 1 H, 1-H), 2.99–2.86 (m, 2 H, 3-H, 2-H),
2.16 (s, 6 H, NMe2), 2.01 (s, 3 H, COCH3), 0.62 (d, J = 5.9 Hz, 3
H, Me) ppm. 13C NMR: δ = 169.0 (C=O), 136.7 (ipso-C, Ph),
129.4, 128.6, 127.9 (CH Ph), 117.2 (CN), 62.2 (C-1), 58.9 (C-3),
52.3 (C-2), 40.1 (NMe2), 20.3 (COCH3), 8.7 (Me) ppm. CIMS
(NH3 Pos): m/z = 261 [M + H]+.
Ethyl (2S,3R)-2-Acetoxy-4-[benzyl(methyl)amino]-3-phenylbutyrate
(41): Major regioisomer obtained from the reaction of azetidinium
3 with sodium acetate. Purified by preparative TLC (Et2O/CyH,
4:6). Yield: 50%; Rf = 0.43 (Et2O/PE, 4:6); oil. [α]2D5 = –69 (c = 1,
CH2Cl2). 1H NMR (CDCl3): δ = 7.26–7.10 (m, 10 H, Ph), 5.52 (d,
J = 3.7 Hz, 1 H, 2-H), 3.95 (q, J = 7.1 Hz, 2 H, CH2O), 3.58 (A
part of AB syst., J = 13.1 Hz, 1 H, CHHPh), 3.43–3.36 (m, 1 H,
3-H), 3.32 (B part of AB syst., J = 13.1 Hz, 1 H, CHHPh), 2.88 (t,
J = 11.8 Hz, 1 H, 4-H), 2.31 (dd, J = 4.8, 12.3 Hz, 1 H, 4Ј-H), 2.22
(s, 3 H, NMe), 1.92 (s, 3 H, Me), 1.01 (t, J = 7.1 Hz, 3 H, Me) ppm.
13C NMR: δ = 170.4, 169.7 (C=O), 138.3 (ipso-C, Ph), 129.2, 129.0,
128.4, 128.3, 127.4, 127.2 (CH Ph), 72.6 (C-2), 63.1 (CH2Ph), 61.2
General Procedure for Intramolecular Opening with Alkoxides: A
solution of KHMDS (0.5  solution in toluene, 2.4 mL, 1.2 mmol)
was added dropwise to a solution of the azetidinium salt (1 mmol)
in THF (10 mL) cooled to –78 °C. The temperature was allowed to
reach –40 °C and the reaction mixture was treated with water at
this temperature. The usual work up (diethyl ether) gave crude ep-
oxides. These products were unstable upon attempted purification
by flash chromatography on silica gel.
(2S,1ЈS,3ЈR)-Benzyl(methyl)[2-phenyl-2-(3Ј-phenyloxiran-2Ј-yl)ethyl]-
(CH2), 58.3 (CH2), 44.9 (C-3), 42.8 (NMe), 20.8 (MeCO), 14.2 amine (48): Crude yield: 98%; oil. 1H NMR (CDCl3): δ = 7.38–
(Me) ppm. MS (ESI Pos): m/z = 392.1 [M + Na]+ , 370.1
7.05 (m, 15 H, Ph), 3.57 (d, J = 1.9 Hz, 1 H, 3Ј-H), 3.42 (AB syst.,
J = 13.1 Hz, 2 H, CHHPh), 3.08 (dd, J = 2.1, 6.7 Hz, 1 H, 1Ј-H),
[M + H]+.
Eur. J. Org. Chem. 2006, 3479–3490
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3489

F. Couty et al.
FULL PAPER
uty, G. Evano, D. Prim, J. Marrot, Eur. J. Org. Chem. 2004,
3893–3897; f) H. Braüner-Osborne, L. Bunch, N. Chopin, F.
Couty, A. A. Evano, G. Jensen, M. Kusk, B. Nielsen, N. Rab-
asso, Org. Biomol. Chem. 2005, 3, 3926–3936; g) F. Vargas-
Sanchez, M. Couty, G. Evano, D. Prim, J. Marrot, Org. Lett.
2005, 7, 5861–5864.
2.93–2.88 (m, 1 H, 2-H), 2.78 (dd, J = 9.1, 12.3 Hz, 1 H, 1-H), 2.56
(dd, J = 5.9, 12.3 Hz, 1 H, 1Ј-H), 2.19 (s, 3 H, NMe) ppm. 13C
NMR: δ = 140.1, 139.2, 137.8 (ipso-C, Ph), 128.9–125.7 (CH Ph),
65.7 (C-1Ј), 63.0 (CH2Ph), 60.3 (C-1), 58.7 (C-3Ј), 46.4 (C-2), 42.8
(NMe) ppm. MS (ESI Pos): m/z = 344.2 [M + H]+.
(1S,2S,1ЈR)-Dimethyl(1-methyl-2-oxiran-2Ј-yl-2-phenylethyl)amine
[11]
[12]
For a preliminary communication on this work, see:F. Couty,
G. Durrat, F. Evano, Synlett 2005, 1666–1670.
1
(49): Crude yield: 99%; oil. H NMR (CDCl3): δ = 7.38–7.36 (m,
a) F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2003, 44,
5209–5212; b) C. Agami, F. Couty, G. Evano, Tetrahedron:
Asymmetry 2002, 13, 297–302; c) F. Couty, F. Durrat, G. Ev-
ano, D. Prim, Tetrahedron Lett. 2004, 45, 7525–7528; d) F. Co-
uty, M. Vargas-Sanchez, G. Evano, G. Bouzas, J. Org. Chem.
2005, 70, 9028–9031; e) The synthesis of the azetidine required
for the preparation of 13 follows the procedures described in
ref.[12d]
2 H, Ph), 7.31–7.16 (m, 3 H, Ph), 4.57 (br. s, 1 H, 1Ј-H), 4.22–4.17
(m, 2 H, 3Ј-H), 3.97–3.84 (m, 2 H, 2-H, 3Ј-H), 3.32 (s, 3 H, NMe),
3.26 (s, 3 H, NMe), 1.29 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR:
δ = 139.1 (ipso-C, Ph), 129.7, 129.1, 128.5 (CH Ph), 77.2 (C-1),
75.1 (C-1Ј), 74.3 (C-3Ј), 51.8 (NMe), 46.8 (NMe), 11.3 (Me) ppm.
MS (ESI Pos): m/z = 206.3 [M + H]+.
[13]
[1] E. X. Hu, Tetrahedron 2004, 60, 2701–2743.
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CCDC-600371 contains the supplementary crystallographic
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Received: March 7, 2006
Published Online: June 1, 2006
3490
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Eur. J. Org. Chem. 2006, 3479–3490