Ring expansion of 2-(α-hydroxyalkyl)azetidines: A synthetic route to functionalized pyrrolidines

Article abstract of DOI:10.1002/ejoc.200800316

A series of 2-(α-hydroxyalkyl)azetidines synthesized from enantiomerically pure β-amino alcohols and presenting various patterns both on the four-membered ring and on the adjacent hydroxy group were treated with either thionyl chloride or methanesulfonyl chloride in the presence of triethylamine. The thus-prepared 2-(α-chloro- or α- methanesulfonyloxyalkyl) azetidines were shown to rearrange stereospecifically into 3-(chloro- or methanesulfonyloxy)pyrrolidines. When this rearrangement is conducted in the presence of an added nucleophile (NaN₃, KCN, KOH, or NaOAc), the produced pyrrolidine incorporates the added nucleophile at C-3 stereospecifically. The relative configuration of the substituents in the formed pyrrolidines is consistent with a mechanism involving the formation of an intermediate bicyclic aziridinium ion, which is opened regioselectively at the bridgehead carbon atom. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800316

FULL PAPER
DOI: 10.1002/ejoc.200800316
Ring Expansion of 2-(α-Hydroxyalkyl)azetidines: A Synthetic Route to
Functionalized Pyrrolidines
François Durrat,[a] Monica Vargas Sanchez,[a] François Couty,*[a] Gwilherm Evano,[a] and
Jérôme Marrot[a]
Keywords: Nitrogen heterocycles / Rearrangement / Ring expansions
A series of 2-(α-hydroxyalkyl)azetidines synthesized from en-
antiomerically pure β-amino alcohols and presenting various
patterns both on the four-membered ring and on the adjacent
hydroxy group were treated with either thionyl chloride or
methanesulfonyl chloride in the presence of triethylamine.
The thus-prepared 2-(α-chloro- or α-methanesulfonyloxy-
alkyl)azetidines were shown to rearrange stereospecifically
into 3-(chloro- or methanesulfonyloxy)pyrrolidines. When
this rearrangement is conducted in the presence of an added
nucleophile (NaN3, KCN, KOH, or NaOAc), the produced
pyrrolidine incorporates the added nucleophile at C-3 stereo-
specifically. The relative configuration of the substituents in
the formed pyrrolidines is consistent with a mechanism in-
volving the formation of an intermediate bicyclic aziridinium
ion, which is opened regioselectively at the bridgehead car-
bon atom.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Nitrogen heterocycles, particularly pyrrolidines and pip- key step in a number of syntheses.[3] In contrast, the similar
eridines, are ubiquitous in nature, and the search for new rearrangement involving azetidine 3 as starting material,
synthetic methodologies towards such heterocycles with the leading to a pyrrolidine 4, has been reported only recently
aim to control the relative and absolute stereochemistry of by Outurquin,[4] us,[5] and later on by De Kimpe.[6] We re-
the stereocenters on the ring represents much efforts from port herein a full study of this rearrangement and its exten-
the synthetic community.[1] Among the numerous ap- sion to the synthesis of pyrrolidines bearing various func-
proaches described so far, the ring expansion of function- tional groups at C-3.
alized pyrrolidines of general structure 1 and presenting a
leaving group on the α-carbon atom of the C-2 side chain
has been known for decades[2] to produce 3-substituted pip-
eridines 2 (Figure 1), and this reaction has been used as a
Results
Synthesis of 2-(α-Hydroxyalkyl)azetidines
The 2-(α-hydroxyalkyl)azetidines required to conduct
this study were prepared from 2-cyanoazetidines[7] as de-
scribed previously.[8] Thus, primary alcohols 5–10 were
prepared by LiAlH4 reduction of the ethyl ester (prepared
by treatment of the nitrile with H2SO4/EtOH), whereas
secondary alcohols 11–13 were prepared by diastereoselec-
tive reduction of the corresponding ketone (NaBH4/ZnBr2).
Finally, tertiary alcohols 14 and 15 were prepared by reac-
Figure 1. Ring expansion of functionalized pyrrolidines and azetid-
tion of the corresponding ester with either methylmagne-
ines.
sium bromide or phenylmagnesium bromide. The structures
of these hydroxylated azetidines are shown in Figure 2.
Having in hand a reasonable scope of hydroxylated azet-
idines with various substituent patterns, we next turned our
attention towards the activation of the hydroxy moiety as a
leaving group.
[a] Universud Paris, Institut Lavoisier de Versailles, UMR 8081,
Université de Versailles,
45, avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: couty@chimie.uvsq.fr
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A Synthetic Route to Functionalized Pyrrolidines
Figure 2. Structures of 2-(α-hydroxyalkyl)azetidines used in this study.
Activation of the Hydroxy Moiety
ple color of the reaction medium was observed, which can
Two activation modes of the hydroxy moiety were envi- be attributed to the formation of a stable diphenylcarben-
sioned in order to promote the ring enlargement mentioned ium ion. Upon hydrolysis, this carbenium ion traps water
in the introduction. First, treatment with thionyl chloride and gives back the starting compound. In case of substrate
of these alcohols occurred with different outcomes, de- 14, the intermediate carbenium ion gives compounds 25
pending on the class of the hydroxy center. Thus, chlorina- and 26 resulting from elimination and 1,2-hydride shift,
tion of primary alcohols 5–8 gave excellent yields of pri- respectively. In the last case, the resulting iminium ion then
mary chlorides 16–19, without any trace of rearranged hydrolyzes into amino ketone 26. Alternatively, 26 could be
product. In the case of secondary alcohols, compound 13 produced by the hydrolysis of an intermediate 2-methyl-
gave single diastereoisomer 24, in which the absolute con- eneazetidine resulting from proton removal at the C-2 car-
figuration of the chlorinated center was not unambiguously bon of the azetidine.[9] Structures of the obtained products
determined (Table 1, Entry 7). However, the stereochemis- are collected in Table 1.
try of this stereocenter is not expected to result from an-
The second mode of activation of the amino alcohols
chimeric assistance of the α-amino moiety as a result of the was mesylation. In this case, different outcomes were also
absence of pyrrolidine formation. We therefore think that observed, depending on the class of the alcohol. Primary
this compound results from clean inversion of the chloro- alcohols 5–7, 9, and 10 were cleanly transformed into the
sulfite intermediate by the chloride anion, and we have corresponding primary mesylate upon treatment with meth-
therefore attributed a syn relative stereochemistry to this anesulfonyl chloride and triethylamine in THF at 0 °C.
compound. In the case of benzylic alcohols 11 and 12, chlo- Workup gave crude mesylates that were contaminated with
rination is not stereospecific, and epimeric chlorides 20–23 small amounts (5–10%) of the corresponding rearranged
were obtained, probably through the intervention of an SN1 pyrrolidines. The rearrangement could be then completed
pathway (Table 1, Entries 5 and 6). The relative configura- by heating the crude mixture overnight at reflux in chloro-
tions in the produced chlorides were determined on the ba- form: 3-methanesulfonyloxypyrrolidines 27–31 were thus
sis of careful analysis of the rearranged pyrrolidines ob- obtained in good yield and in a stereospecific manner
tained from these chlorides (vide supra). Major syn isomers (Table 2, Entries 1–5). Mesylation of secondary benzylic
20 and 22 produced in each case result from inversion of alcohols 11 and 12 directly furnished rearranged chlorides
configuration, without anchimeric assistance of the α- 34 and 35 in good yield if the reaction medium was heated
amino moiety and, therefore, supports also the syn struc- at reflux for 1 h because of the presence of the chloride
ture of 24. Finally, tertiary alcohols behaved differently. anion as an external nucleophile (Table 2, Entries 7, 8).
Upon treatment of 15 with thionyl chloride, an intense pur- However, when the mesylation was rapidly conducted at
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F. Durrat, M. V. Sanchez, F. Couty, G. Evano, J. Marrot
Table 2. Mesylation of hydroxylated azetidines.
FULL PAPER
Table 1. SOCl2 chlorination of hydroxylated azetidines.
[a] Yield of isolated product.
0 °C (0.5 h), a crude mixture of mesylate 32 and 33 (85:15
ratio) was obtained in good yield (Table 2, Entry 6). Finally,
in the case of secondary alcohol 13, corresponding mesylate
36 proved to be stable enough and was isolated in very good
yield without a trace of rearranged product. Table 2 gathers
the structures of the obtained compounds.
[a] Yield of isolated product. [b] Only the first step was conducted.
Crude ratio of 32/33, 85:15. [c] Only the first step was conducted,
but the reaction mixture was heated at reflux for 1 h.
corresponding chlorides proved much more stable and re-
quired heating to promote the ring expansion. Further-
Ring Expansion of 2-(α-Chloroalkyl)azetidines
Although the 2-(α-methanesulfonyloxyalkyl)azetidines more, the ease of this rearrangement was shown to depend
(except compound 36) were not stable and were very prone on the relative configuration (syn or anti) of the starting
to rearrange into 3-methanesulfonyloxypyrrolidines, the chloride and also on the class (primary or secondary) of
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A Synthetic Route to Functionalized Pyrrolidines
the chloride. Thus, primary chlorides required heating in nucleophile. Four types of nucleophiles were selected
refluxing DMF to promote the rearrangement to give 37 (NaOH, KCN, NaOAc, and NaN3). After some experimen-
and 38 in fair-to-modest yields. It should be noted that an tation and guided by the work of De Kimpe,[6] we selected
overnight reflux in chloroform left these products un- DMSO as the reaction solvent in order to solubilize a suf-
changed. The same behavior was observed with syn chlo- ficient amount of added salt (10 equiv. in each case), and
rides 20 and 22: the first one, under protracted heating in the rearrangements were conducted at strictly controlled
refluxing DMF gave only a trace amount of the rearranged temperature in order to limit the amount of formed byprod-
pyrrolidine together with extensive decomposition, whereas ucts. As a matter of fact, preliminary experiments con-
22 gave 40 in fair yield. In contrast, anti secondary chlorides ducted with chloride 18 in the presence of KOH demon-
21 and 23 rearranged smoothly in refluxing chloroform to strated that the rearrangement occurred optimally at 50 °C
afford 34 and 35 in excellent yields. These latter compounds to produce 3-hydroxypyrrolidine 42. At lower temperature,
proved to be identical to those obtained during the mesyl- only rearranged chloride 41 could be isolated, whereas
ation of anti-alcohols 11 and 12 (see Table 2, Entries 6 and higher temperatures promoted the elimination to give dehy-
7). All these experiments are gathered in Table 3.
dropyrrole 43 almost exclusively (Table 4, Entries 1–4).
Table 3. Thermal ring expansion of 2-(α-chloroalkyl)azetidines.
Table 4. Ring expansion in the presence of an added nucleophile.
[a] Yield of isolated product. [b] Only a trace amount of impure
product was produced.
Ring Expansion of 2-(α-Chloro- and α-Methanesulfonyl-
oxyalkyl)azetidines in the Presence of an Added Nucleophile
Having established that this ring expansion proceeds well
and in a stereospecific manner, we turned our attention to
broaden its scope by adding an external nucleophile that
would be able to compete with the leaving group as the
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Table 4. (Continued).
It can be concluded from these experiments that it is in-
deed possible to introduce all kinds of nucleophiles at C-3
with various yields, in a stereospecific manner. However,
the yields are sometime modest and byproducts could be
isolated and characterized in some cases. As a matter of
fact, the success of the rearrangement in the presence of an
external nucleophile is to a large extent substrate depend-
ent, but some general trends become apparent. First, the
reaction conditions (particularly the temperature), have to
be strictly controlled for each substrate, as some of them
are very prone to elimination and even aromatization to the
corresponding pyrrole (Table 4, Entries 4, 7, 10). Secondly,
syn chloride 24 again proved its reluctance to rearrange, as
it gave a complex mixture (Table 4, Entry 5). Finally, reac-
tions involving the azide anion as a nucleophile did not pro-
duce any azetidine product (aside from Table 4, Entries 12
and 14). This last point will be commented in the last part
of this article.
Discussion
Determination of the Relative Configurations in the
Produced Pyrrolidines
The relative configuration of the substituents in the pro-
duced pyrrolidines was determined on the basis of nOe ex-
periments conducted with pyrrolidines 27, 33, 40 (resulting
from rearrangement of α-chloro- or α-methanesulfonyloxy-
azetidines), and 45 (resulting from a rearrangement in the
presence of KOH). Key nOe interactions for these com-
pounds are shown in Figure 3. Furthermore, we were able
to grow suitable crystals for X-ray analysis of compound
50, whose ORTEP structure is shown in Figure 3.[10]
[a] Yield of isolated product. [b] Compound 43 was also isolated
in 9% yield.
Figure 3. nOe measurements in pyrrolidines 27, 33, 38, and 45; ORTEP diagram of 50.
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A Synthetic Route to Functionalized Pyrrolidines
Mechanistic Considerations
Finally, the fact that syn chlorides or mesylates are more
difficult to rearrange relative to their anti isomers can be
explained by the examination of the corresponding azetid-
inium intermediates. These two intermediates, resulting
from the SNi reaction involving syn-22 and anti-23 are de-
picted in Figure 4. In the bicyclic ammonium ion produced
from syn-22, the phenyl group is placed in an endo position,
which results in severe steric interaction. Therefore, forma-
tion of this intermediate can be expected to require more
energy than the exo diastereoisomer. As a result, if the pro-
duction of this strained intermediate is the rate-limiting
step, then the reduced reactivity of syn-22 relative to that
of anti-23 is easy to understand.
Considering the relative configuration of the substituents
in the produced pyrrolidines, we can deduce that the stereo-
specificity of the rearrangement results from the production
of intermediate bicyclic aziridinium ion 61, which opens
with high regioselectivity at the bridgehead carbon atom.[11]
Taking into account the structure of the byproducts pro-
duced in some cases during the rearrangement performed
in the presence of external nucleophiles, the detailed mecha-
nism depicted in Scheme 1 can be proposed. The produced
bicyclic intermediate 61 is opened by the leaving group X–
(chloride anion or methanesulfonate anion) at the bridge-
head carbon atom to give 3-chloro- or 3-methanesulfo-
nyloxypyrrolidine 62. This is a reversible process, as this
compound, produced as a byproduct in case of reactions
conducted in the presence of an external nucleophile when
the reaction time is too short or when the temperature is
not high enough (Table 4 Entries 2, 8, 9; compounds 41 and
49) is totally converted into the expected 3-hydroxy- or 3-
cyanopyrrolidine in case of protracted reaction times or
harsher conditions. In contrast, opening of 61 by the added
–
nucleophile (HO–, NC–, AcO–, or N3 ) is expected to be an
irreversible process and drives the equilibrium to 63. The
high regioselectivity observed in this reaction (i.e., opening
of the intermediate at the bridgehead carbon atom under
kinetic control) is reflected by the exclusive obtention of
ring-expanded pyrrolidines by nucleophilic opening with
HO–, NC–, or AcO–. It should be noted that the opening
of the homologous bicyclic intermediate shown in Figure 1
and leading to a piperidine has been reported to be much
less regioselective in some cases under kinetic control.[12] In
Figure 4. syn-Chlorides or mesylates produced highly strained endo
bicyclic ammonium ions.
–
Conclusions
the case of N3 , minor amounts of α-azidoalkylazetidines
53 and 56 were, however, produced (Table 4, Entries 12 and
14). We think that these products arise from direct nucleo-
philic opening in starting azetidines 18 and 36, rather than
a nonregioselective opening of 61. This assumption is
guided by two points. First, the high nucleophilicity of the
azide anion accounts for a possible competition between
the formation of 64 (SN2 reaction) and 61 (SNi reaction).
Second, the absence of any azetidines in the case of other
nucleophiles supports the high regioselectivity of the open-
ing of 61 as a general rule. For these reasons, we have attrib-
uted a syn relative configuration to 56, resulting from an
SN2 reaction.
We showed that the recently disclosed rearrangement of
2-(α-chloro- or α-methanesulfonyloxyalkyl)azetidines into
the corresponding 3-chloro- or 3-methanesulfonyloxypyrro-
lidines could be extended to the incorporation of an ad-
ditional nucleophile to the synthesis of an array of pyrrol-
idines bearing various moieties at C-3. The stereospecificity
of the mechanism was confirmed in all cases, and this re-
arrangement in the presence of an external nucleophile was
studied for the first time with substrates involving primary
and secondary chlorides (or mesylates). A very high re-
gioselectivity of the nucleophilic opening of the azetidinium
intermediate was observed in each case under kinetic con-
trol, which contrasts with the low regioselectivity observed
in some cases for the homologous system leading to piper-
idines. Application of this new synthetic methodology to
the synthesis of natural pyrrolidinic compounds is under
study in our group.
Experimental Section
General Comments: 1H and 13C spectra were recorded with a
Bruker Avance 300 spectrometer; chemical shifts are reported in
ppm from TMS. Optical rotations were determined with a Perkin–
Elmer 141 instrument. All the reactions were carried out under an
atmosphere of argon. Column chromatography was performed on
Scheme 1. Proposed mechanism for the rearrangement.
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silica gel 230–400 mesh by using various mixtures of diethyl ether
(Et2O), ethyl acetate (AcOEt) petroleum ether (PE), and cyclohex-
ane (CyH). TLCs were run on Merck Kieselgel 60F254 plates. Melt-
ing points are uncorrected. THF and ether were distilled from so-
dium/benzophenone ketyl. Dichloromethane was distilled from cal-
cium hydride. The mention of a “usual workup” means: (i) decan-
tation of the organic layer, (ii) extraction of the aqueous layer with
ether, (iii) drying of the combined organic layers over MgSO4, (iv)
solvent evaporation under reduced pressure. Isomeric ratios were
determined by NMR spectroscopic analysis of crude reaction mix-
tures before purification. Mass spectra were recorded with a Hew-
lett–Packard MS Engin HP5989B equipped with an ESI source
Analytica Branford. Elementary analyses were performed by the
Service de Microanalyses de Gif sur Yvette (France). HRMS analy-
ses were performed by the Service d’analyses du CNRS (Vernaison,
France).
4:6). Yield: 184 mg (88%); oil. [α]2D0 = 46.2 (c = 0.8, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.24–7.15 (m, 5 H, Ph), 3.46–3.40
(m, 1 H, CHHCl), 3.26–3.13 (m, 2 H, CHMe, 2-H), 2.87–2.79 (m,
2 H, CHHCl, 4-H), 2.49 (dd, J = 3.6 and 10.6 Hz, 1 H, 4Ј-H),
2.09–1.83 (m, 2 H, 3-H), 1.16 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 143.5 (Cipso Ph), 128.5, 127.8, 127.7
(CH-Ph), 68.2 (C2), 65.5 (CH), 50.2 (CH2), 47.5 (C-4), 21.8 (CH3),
20.3 (CH2) ppm. MS (ESI+): m/z = 210.2 [M + H]+, 192.3, 105.0.
HRMS: calcd. for C12H17NCl [M + H]+ 210.1050; found 210.1055.
(2S,3S,4S,7S)-2-(Chlorophenylmethyl)-1,4-dimethyl-3-phenylazetid-
ine (20): Purified by flash chromatography (Et2O/PE, 10:90 then
20:80). Rf = 0.46 (Et2O/PE, 1:1). Yield: 162 mg (57%); oil. [α]2D5
=
+66 (c = 1.1, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.23–7.22
(m, 2 H, Ph), 7.17–7.14 (m, 3 H, Ph), 7.13–7.05 (m, 3 H, Ph), 6.77–
6.75 (m, 2 H, Ph), 4.97 (d, J = 8.9 Hz, 1 H, CHCl), 3.40 (t, J =
8.5 Hz, 1 H, 3-H), 2.96 (m, 1 H, 4-H), 2.73 (t, J = 8.2 Hz, 1 H, 2-
H), 2.65 (s, 3 H, 5-H), 1.27 (d, J = 5.7 Hz, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 139.1, 137.7 (Cipso Ph), 128.6, 128.4,
128.1, 127.9, 127.5, 126.4 (CH Ph), 77.1 (CHCl), 68.4 (C-2), 66.7
(C-4), 50.6 (C-3), 44.1 (NMe), 20.5 (C-6) ppm. MS (ESI+): m/z =
308.4 [M + Na]+, 286.3 [M + H]+. C18H20ClN (285.81): calcd. C
75.64, H 7.05, N 4.90; found C 75.58, H 6.98, N 4.95.
General Procedure for the Preparation of 2-(α-Chloroalkyl)azetid-
ines 16–24: To a solution of 2-hydroxyalkylazetidine (1 mmol) in
DCM (5 mL) was added thionyl chloride (0.145 mL, 2 mmol) drop-
wise at room temperature. The reaction mixture was heated at re-
flux for 1.5 h and then hydrolyzed at 0 °C by dropwise addition of
an aqueous saturated solution of NaHCO3 until neutrality of the
aqueous layer. After addition of water, usual workup gave crude
chlorinated azetidines that were further purified by flash
chromatography (see Table 1).
(2S,3S,4S,7R)-2-(Chlorophenylmethyl)-1,4-dimethyl-3-phenylazetid-
ine (21): Purified by flash chromatography (Et2O/PE, 10:90 then
20:80). Rf = 0.60 (Et2O/PE, 1:1). Yield: 40 mg (14%); oil. [α]2D5
=
(2S,3R)-1-Benzyl-2-chloromethyl-3-phenylazetidine (16): Purified by
flash chromatography (Et2O/CyH, 10:90 then 15:85). Rf = 0.57
(Et2O/PE, 7:3). Yield: 265 mg (98%); oil. [α]2D5 = +96 (c = 1,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.39–7.23 (m, 10 H,
Ph), 3.96 (d, J = 12.5 Hz, 1 H, CHHCl), 3.79 (t, J = 6.9 Hz, 1 H,
3-H), 3.74 (d, J = 12.5 Hz, 1 H, CHHCl), 3.63–3.48 (m, 4 H, 2-H,
4-H, NCH2Ph), 3.08 (dd, J = 6.9 and 8.5 Hz, 4Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.8, 137.8 (Cipso Ph), 129.1–126.9 (CH
Ph), 72.9 (C-2), 62.8 (C-5), 58.0 (C-4), 47.5 (CH2Cl), 41.4 (C-3)
ppm. MS (ESI+): m/z = 294.1 [M + Na]+, 272.3 [M + H]+.
–69 (c = 0.6, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.49–7.42
(m, 3 H, Ph), 7.40–7.33 (m, 4 H, Ph), 7.30–7.23 (m, 3 H, Ph), 4.87
(d, J = 8.5 Hz, 1 H, CHCl), 3.42 (t, J = 7.9 Hz, 1 H, 3-H), 3.02 (t,
J = 7.9 Hz, 1 H, 2-H), 2.90–2.81 (m, 1 H, 4-H), 1.94 (s, 3 H, NMe),
1.22 (d, J = 6.2 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3):
δ = 140.5, 139.1 (Cipso Ph), 128.7, 128.6, 128.5, 128.3, 128.2, 128.1,
127.8, 127.2, 126.8 (CH Ph), 76.2 (CHCl), 67.5 (C-2), 66.7 (C-4),
51.8 (C-3), 42.9 (NCH3), 20.5 (Me) ppm. MS (ESI+): m/z = 308.5
[M + Na]+, 286.4 [M + H]+.
(2R,3R)-1-Benzyl-2-chloromethyl-3-phenylazetidine (17): Purified
by flash chromatography (Et2O/CyH, 15:85). Rf = 0.81 (Et2O/PE,
7:3). Yield: 214 mg (79%); oil. [α]2D5 = +16 (c = 1, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.60–7.31 (m, 10 H, Ph), 4.04 (A part of
AB syst., J = 13.1 Hz, 1 H, CHHPh), 3.81 (td, J = 5.9 and 7.9 Hz,
1 H, 3-H), 3.70 (td, J = 2.3 and 7.5 Hz, 1 H, 2-H), 3.69 (B part of
AB syst., J = 13.1 Hz, 1 H, CHHPh), 3.58 (dd, J = 2.3 and 7.6 Hz,
1 H, CHHCl), 3.36 (t, J = 7.6 Hz, 1 H, CHHCl), 3.18–3.06 (m, 2
H, 4-H, 4Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.9, 138.3
(Cipso Ph), 129.1–127.0 (CH Ph), 69.3 (C-2), 62.5 (C-5), 57.0 (C-
4), 43.7 (CH2Cl), 39.1 (C-3) ppm. MS (ESI+): m/z = 294.1 [M +
Na]+, 272.1 [M + H]+. C17H18ClN (282.79): calcd. C 75.13, H 6.68,
N 5.15; found C 74.97, H 6.77, N 5.07.
(2R,3R,6R)-1-Benzyl-2-(chlorophenylmethyl)-3-phenylazetidine (22):
Purified by flash chromatography (Et2O/PE, 10:90 then 20:80). Rf
= 0.62 (Et2O/PE, 1:1). Yield: 229 mg (66%); oil. [α]2D5 = +60 (c =
1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.45–7.27 (m, 7 H,
Ph), 7.23–7.19 (m, 3 H, Ph), 7.09–7.06 (m, 3 H, Ph), 6.74–6.71 (m,
2 H, Ph), 5.11 (d, J = 8.4 Hz, 1 H, CHCl), 4.43 (A part of AB
syst., J = 12.9 Hz, 1 H, NCHHPh), 3.83 (t, J = 8.5 Hz, 1 H, 2-H),
3.70–3.62 (m, 2 H, 4-H, NCHHPh), 3.30 (q, J = 8.1 Hz, 1 H, 3-
H), 3.01 (dd, J = 7.0 and 8.8 Hz, 1 H, 4Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.1, 138.0, 137.7 (Cipso Ph), 129.0, 128.5,
128.4, 128.3, 128.0, 127.9, 127.3, 127.1, 126.3 (CH Ph), 77.6
(CHCl), 68.0 (C-2), 62.7 (NCH2Ph), 57.0 (C-4), 41.5 (C-3) ppm.
MS (ESI+): m/z = 370.1 [M + Na]+, 312.2 [M – HCl]+. C23H22ClN
(347.88): calcd. C 79.41, H 6.37, N 4.03; found C 79.21, H 6.30, N
4.00.
(2R)-2-(Chloromethyl)-1-[(1S)-1-phenylethyl]azetidine (18): Purified
by flash chromatography (Et2O/PE, 20:80). Rf = 0.30 (Et2O/PE,
2:8). Yield: 203 mg (97%); white solid. M.p. 42 °C. [α]2D5 = +91.3 (c
= 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.61–7.25 (m, 5 H,
Ph), 3.75 (dd, J = 3.9 and 10.4 Hz, 1 H, CHHCl), 3.65–3.45 (m, 3
H, CHHCl, CHMe, 2-H), 3.12 (td, J = 2.5 and 8.2 Hz, 1 H, 4-H),
2.75 (q, J = 8.6 Hz, 1 H, 4Ј-H), 2.26–2.16 (m, 1 H, 3-H), 2.01–1.89
(m, 1 H, 3Ј-H), 1.29 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.4 (Cipso Ph), 128.4, 127.3, 127.2 (CH-
Ph), 67.1 (C2), 64.8 (CH), 49.2 (CH2), 48.8 (C-4), 22.1 (CH3), 21.9
(CH2) ppm. MS (ESI+): m/z = 232.2, 210.2 [M + H]+, 174.2, 105.0.
HRMS: calcd. for C12H17NCl [M + H]+ 210.1050; found 210.1045.
(2R,3R,6S)-1-Benzyl-2-(chlorophenylmethyl)-3-phenylazetidine (23):
Purified by flash chromatography (Et2O/PE, 10:90 then 20:80). Rf
= 0.59 (Et2O/PE, 1:1). Yield: 59 mg (17%); oil. [α]2D5 = +26 (c =
0.9, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.62–7.61 (m, 2 H,
Ph), 7.51–7.20 (m, 12 H, Ph), 7.12–7.07 (m, 1 H, Ph), 5.99 (d, J =
7.9 Hz, 1 H, CHCl), 3.92 (A part of AB syst., J = 10.5 Hz, 1 H,
NCHHPh), 3.80–3.57 (m, 3 H, 2-H, 4-H, NCHHPh), 3.50–3.40
(m, 1 H, 3-H), 2.97 (t, J = 9.9 Hz, 1 H, 4Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.4, 138.9, 138.5 (Cipso Ph), 128.9, 128.7,
128.5, 128.4, 128.3, 128.2, 127.9, 127.4, 127.2, 127.0, 126.9 (CH
(2S)-2-(Chloromethyl)-1-[(1S)-1-phenylethyl]azetidine (19): Purified Ph), 72.0 (CHCl), 58.9 (C-2), 57.9 (NCH2Ph), 52.2 (C-4), 42.7 (C-
by flash chromatography (Et2O/PE, 40:60). Rf = 0.60 (Et2O/PE,
3) ppm. MS (ESI+): m/z = 348.1 [M + H]+, 312.1 [M – HCl]+.
3292
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3286–3297

A Synthetic Route to Functionalized Pyrrolidines
(1R,2S,3S,4S)-2-(1-Chloropentyl)-1,4-dimethyl-3-phenylazetidine (10 mL) was heated at reflux overnight. The solvent was evaporated
(24): Purified by flash chromatography (Et2O/PE, 40:60). Rf =0.50
under reduced pressure, and the crude residue was purified by flash
chromatography (Et2O/CyH, 7:3). Compound 28 was obtained as
(Et2O/PE, 4:6). Yield: 265 mg (quant.); oil. [α]2D0 = –41.1 (c = 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.66–7.13 (m, 5 H, Ph), a colorless solid. Rf = 0.19 (Et2O/CyH, 7:3). Yield: 262 mg (79%).
M.p. 131 °C. [α]2D5 = +378 (c = 0.5, CH2Cl2). H NMR (300 MHz,
CDCl3): δ = 7.39–7.23 (m, 10 H, Ph), 5.28 (m, 1 H, 3-H), 3.81 (m,
2 H, NCH2Ph), 3.62 (m, 1 H, 4-H), 3.44 (dd, J = 5.6 and 11.8 Hz,
1 H, 2-H), 3.13 (dd, J = 7 and 9.5 Hz, 1 H, 5-H), 3.03 (d, J =
9.5 Hz, 1 H, 5Ј-H), 2.96 (dd, J = 2.3 and 11.8 Hz, 1 H, 2Ј-H), 2.28
(s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.6, 136.8
(Cipso Ph), 129.5–127.3 (CHPh), 82.7 (C-3), 61.1–60.4 (C-2, C-5),
57.2 (C-6), 48.7 (C-4), 37.6 (CH3) ppm. MS (ESI+): m/z = 354.1
[M + Na]+, 332.1 [M + H]+, 236.2 [M – MsOH]+. C18H21NO3S
(331.43): calcd. C 65.23, H 6.39, N 4.23; found C 66.16, H 6.33, N
3.95.
1
3.90 (td, J = 2.5 and 8.5 Hz, 1 H, CHCl), 3.05 (t, J = 7.0 Hz, 1 H
2-H), 2.80–2.72 (m, 2 H, 3-H, 4-H), 2.50 (s, 3 H, NMe), 1.51–1.01
[m, 6 H, (CH2)3], 1.16 (d, J = 5.4 Hz, 3 H, Me), 0.70 (t, J = 7.2 Hz,
3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 139.8 (Cipso Ph),
128.6, 127.9, 126.3 (CH-Ph), 75.6 (C2), 68.7, 67.4, 50.6 (CH), 44.2
(CH3), 33.2, 27.9, 21.9 (CH2), 20.2, 13.1 (CH3) ppm. MS (ESI+):
m/z = 266.3 [M + H+], 230.3. HRMS: calcd. for C16H25NCl [M +
H]+ 266.1676; found 266.1675.
(2S,3R)-1-Benzyl-2-isopropenyl-3-phenylazetidine (25) and (2R)-1-
Benzylamino-4-methyl-2-phenylpentan-3-one (26): Starting with ter-
tiary alcohol 14 and following the general procedure used for chlo-
rination with thionyl chloride, a crude residue was obtained that
was purified by flash chromatography (Et2O/PE, gradient from
2:98 to 100:0). Title compounds were obtained by order of elution.
Compound 25: Rf = 0.81 (Et2O/PE, 5:95). Yield: 79 mg (30%); oil.
(3S)-3-Methanesulfonyloxy-1-[(1S)-1-phenylethyl]pyrrolidine (29): A
solution of 2-mesyloxyazetidine (269 mg, 1 mmol) in chloroform
(10 mL) was heated at reflux overnight. The solvent was evaporated
under reduced pressure, and the crude residue was purified by flash
chromatography (Et2O/PE, 9:1). Rf = 0.32 (Et2O/PE, 9:1). Yield:
226 mg (84%); colorless oil. [α]2D0 = +20 (c = 1.3, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.61–7.25 (m, 5 H, Ph), 5.22–5.16 (m, 1 H,
3-H), 3.21 (q, J = 6.3 Hz, 1 H, CHMe), 2.91 (s, 3 H, Me), 2.79–
2.68 (m, 2 H, 2-H), 2.59–2.44 (m, 2 H, 5-H), 2.27–2.15 (m, 1 H, 4-
H), 2.02–1.92 (m, 1 H, 4Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 144.6 (Cipso Ph), 128.5, 127.2, 127.1 (CH Ph), 80.4 (C-3), 58.8
(C-2), 50.5 (C-5), 38.5 (Me), 32.4 (C-4), 22.9 (Me) ppm. MS
(ESI+): m/z = 270.3 [M + H]+, 192.3, 174.3, 105.0.
1
[α]2D5 = +13 (c = 0.9, CH2Cl2). H NMR (300 MHz, CDCl3): δ =
7.49–7.27 (m, 10 H, Ph), 5.22 (s, 1 H, C=CHH), 4.77 (s, 1 H,
C=CHH), 4.07 (A part of AB syst., J = 13.6 Hz, 1 H, NCHHPh),
3.99 (d, J = 8.1 Hz, 1 H, 2-H), 3.68 (td, J = 2.2 and 8.1 Hz, 1 H,
3-H), 3.39 (B part of AB syst., J = 13.6 Hz, 1 H, NCHHPh), 3.29–
3.40 (m, 1 H, 4-H), 3.27 (t, J = 6.2 Hz, 1 H, 4Ј-H), 1.34 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.8, 140.7, 139.0
(Cipso Ph, C=CH2), 129.1, 128.5, 128.4, 127.7, 126.9, 126.3 (CH
Ph), 111.3 (C=CH2), 73.0 (C-2), 61.8 (C-5), 57.4 (C-4), 41.2 (C-3),
19.2 (Me) ppm. MS (ESI+): m/z = 264.5 [M + H]+. Compound 26:
Rf = 0.35 (Et2O). Yield: 84 mg (30%); oil. 1H NMR (300 MHz,
CDCl3): δ = 7.43–7.21 (m, 10 H, Ph), 4.10 (dd, J = 6.2 and 7.7 Hz,
1 H, 2-H), 3.78 (s, 2 H, NCH2Ph), 3.26 (dd, J = 8.1 and 11.9 Hz,
1 H, NCHH), 2.82 (dd, J = 6.6 and 12.1 Hz, 1 H, NCHH), 2.69–
2.60 [m, 1 H, CH(Me)2], 1.11 (d, J = 7.0 Hz, 3 H, Me), 0.92 (d, J
= 7.0 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 214.0
(C=O), 140.2, 137.4 (Cipso Ph), 129.0, 128.6, 128.5, 128.1, 127.6,
127.0 (CH Ph), 57.6 (CH2), 54.1 (CH), 52.0 (CH2), 40.1 (CH), 19.1,
18.2 (CH3) ppm.
(3S,4S,5S)-3-Methanesulfonyloxy-1,5-dimethyl-4-phenylpyrrolidine
(30): A solution of 2-mesyloxyazetidine (269 mg, 1 mmol) in chlo-
roform (10 mL) was heated at reflux overnight. The solvent was
evaporated under reduced pressure, and the crude residue was puri-
fied by flash chromatography (Et2O/CyH, 8:2; then Et2O/MeOH,
9:1). Rf = 0.30 (CH2Cl2/MeOH, 95:5). Yield: 204 mg (76%); clear
oil. [α]2D5 = +67 (c = 0.5, CH2Cl2). H NMR (300 MHz, CDCl3): δ
1
= 7.39–7.26 (m, 5 H, Ph), 5.15 (td, J = 3.7 and 6.6 Hz, 1 H, 3-H),
3.82 (dd, J = 6.6 and 11.8 Hz, 1 H, 2-H), 3.01 (dd, J = 6.6 and
11 Hz, 1 H, 4-H), 2.82 (qd, J = 3.3 and 5.9 Hz, 1 H, 6-H), 2.72
(dd, J = 3.7 and 11.8 Hz, 1 H, 2Ј-H), 2.44 (s, 3 H, Me), 2.20 (s, 3
H, Me), 1.07 (d, J = 5.9 Hz, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 135.7 (Cipso Ph), 130.1, 128.4, 127.5 (CH Ph), 81.4
(C-3), 63.6 (C-5), 63.2 (C-2), 57.0 (C-4), 39.9, 37.3, 16.7 (Me) ppm.
MS (ESI+): m/z = 270.1 [M + H]+, 174.1 [M – MsOH]+.
General Procedure for the Preparation of 2-(α-Methanesulfonyloxy-
alkyl)azetidines and Their Rearrangement Into Pyrrolidines: To a
solution of 2-(α-hydroxyalkyl)azetidine (1 mmol) in THF (5 mL)
was added dropwise at room temperature methanesulfonyl chloride
(84 µL, 1.5 mmol) and triethylamine (0.41 mL, 4 mmol). The reac-
tion mixture was stirred at 0 °C for 1 h and then hydrolyzed by
addition of an aqueous solution of NaOH (1 ). Usual workup
gave crude mesylate (contaminated with 5–10% of the rearranged
pyrrolidine) that was used as such for the ensuing rearrangement.
(3R,4S,5S)-3-Methanesulfonyloxy-1,5-dimethyl-4-phenylpyrrolidine
(31): A solution of 2-mesyloxyazetidine (269 mg, 1 mmol) in chlo-
roform (10 mL) was heated at reflux overnight. The solvent was
evaporated under reduced pressure, and the crude residue was puri-
fied by flash chromatography (CH2Cl2/MeOH, 98:2). Rf = 0.59
(CH2Cl2/MeOH, 9:1). Yield: 204 mg (76%); clear oil. [α]2D5 = +14
(c = 1.2, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.19 (m,
5 H, Ph), 5.11 (m, 1 H, 3-H), 3.48 (d, J = 11.8 Hz, 1 H, 2-H), 3.00
(dd, J = 4.4 and 9.9 Hz, 1 H, 4-H), 2.86 (s, 3 H, 6-H), 2.74 (dd, J
= 6.3 and 11.8 Hz, 1 H, 2Ј-H), 2.35 (s, 3 H, Me), 2.20 (m, 1 H, 5-H),
1.12 (d, J = 6.2 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 139.4 (Cipso Ph), 129.0, 128.1, 127.5 (CH Ph), 85.5 (C-3), 69.0
(C-5), 63.1 (C-2), 60.7 (C-4), 39.7 (C-6), 38.5 (C-8), 16.5 (C-7) ppm.
MS (ESI+): m/z = 292.1 [M + Na]+, 270.1 [M + H]+, 174.1 [M –
MsOH]+. C13H19NO3S (269.36): calcd. C 57.97, H 7.11, N 5.20;
found C 57.93, H 7.23, N 5.02.
(3S,4R)-1-Benzyl-3-methanesulfonyloxy-4-phenylpyrrolidine (27): A
solution of 2-mesyloxyazetidine (332 mg, 1 mmol) in chloroform
(10 mL) was heated at reflux overnight. The solvent was evaporated
under reduced pressure, and the crude residue was purified by flash
chromatography (Et2O/CyH, 3:7 then 1:1). Rf = 0.44 (CH2Cl2/
MeOH, 99:1). Yield: 265 mg (80%); colorless oil. [α]2D5 = –14 (c =
1
2.5, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 7.40–7.25 (m, 10
H, Ph), 5.09–5.15 (m, 1 H, 3-H), 3.72 (m, 2 H, NCH2Ph), 3.59–
3.47 (m, 1 H, 4-H), 3.25 (dd, J = 8.2 and 9.5 Hz, 1 H, 2-H), 3.14–
3.03 (m, 2 H, 5-H, 5Ј-H), 2.84 (s, 3 H, Me), 2.61 (dd, J = 7.5 and
9.5 Hz, 1 H, 2Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.7,
138.1 (Cipso Ph), 128.9–127.5 (CHPh), 86.8 (C-3), 60.1–59.9 (C-2,
C-5, C-6), 51.1 (C-4), 38.2 (Me) ppm. MS (ESI+): m/z = 354.1 [M
+ Na]+, 332.1 [M + H]+, 236.1 [M – MsOH]+.
(2S,3R,4S,5S)-3-Chloro-1,5-dimethyl-2,4-diphenylpyrrolidine (34): A
(3R,4R)-1-Benzyl-3-methanesulfonyloxy-4-phenylpyrrolidine (28): A solution of 2-chloromethylazetidine (286 mg, 1 mmol) in chloro-
solution of 2-mesyloxyazetidine (332 mg, 1 mmol) in chloroform form (10 mL) was heated at reflux overnight. The solvent was evap-
Eur. J. Org. Chem. 2008, 3286–3297
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3293

F. Durrat, M. V. Sanchez, F. Couty, G. Evano, J. Marrot
FULL PAPER
orated under reduced pressure, and the crude residue was purified
by flash chromatography (Et2O/PE, 5:95 then 2:8). Rf = 0.80 (Et2O/
PE, 4:6). Yield: 268 mg (94%); orange oil. [α]2D5 = +91 (c = 0.4,
1 H, 2-H), 3.17 (t, J = 8.6 Hz, 1 H, 5-H), 2.95 (dd, J = 5.7 and
10.1 Hz, 1 H, 5Ј-H), 2.78 (dd, J = 6.8 and 9.4 Hz, 1 H, 2Ј-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 141.9, 138.5 (Cipso Ph), 128.8–
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.34–7.17 (m, 10 H, 127.5 (CH Ph), 63.4 (CH2Ph), 63.3 (C-3), 60.6 and 60.1 (C-5, C-
Ph), 3.96–3.82 (m, 2 H, 2-H, 3-H), 3.56–3.48 (m, 1 H, 5-H), 3.00– 2), 54.8 (C-4) ppm. MS (ESI+): m/z = 272.1 [M + H]+. C17H18ClN
2.94 (m, 1 H, 4-H), 2.11 (s, 3 H, Me), 1.16 (d, J = 7.5 Hz, 3 H, (271.78): calcd. C 75.13, H 6.68, N 5.15; found C 74.96, H 6.51, N
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 142.1, 139.5 (Cipso
Ph), 128.9, 128.7, 128.2, 127.8, 127.2 (CH Ph), 75.4 (C-2), 71.2 (C-
3), 65.1 (C-5), 62.2 (C-4), 34.7, 15.8 (Me) ppm. MS (ESI+): 286.1
[M + H]+. The same compound was obtained by the following
procedure: To a solution of hydroxymethylazetidine 11 (1 mmol) in
THF (5 mL) was added methanesulfonyl chloride (0.084 mL,
1.5 mmol) and triethylamine (0.41 mL, 4 mmol). The reaction mix-
ture was heated at reflux for 2 h and then hydrolyzed by addition
of NaOH (1 , 10 mL). Addition of ether was followed by usual
workup and purification as above to give the title compound
(77%).
5.12.
(3R,4R)-1-Benzyl-3-chloro-4-phenylpyrrolidine (38): A solution of
17 in DMF (10 mL for 1 mmol) was heated at reflux for 12 h. Evap-
oration of the solvent under reduced pressure, followed by purifica-
tion by flash chromatography (Et2O/CyH, 1:9 then 2:8) gave the
title compound. Rf = 0.46 (Et2O/CyH, 3:7). Yield: 106 mg (39%);
1
oil. [α]2D5 = –340 (c = 0.5, CHCl3). H NMR (300 MHz, CDCl3): δ
= 7.26–7.42 (m, 10 H, Ph), 4.70–4.65 (td, J = 3.0 and 5.9 Hz, 1 H,
3-H), 3.89 (m, 2 H, NCH2Ph), 3.76 (td, J = 6.6 and 10.2 Hz, 1 H,
4-H), 3.63 (dd, J = 5.6 and 11.5 Hz, 1 H, 2-H), 3.26 (dd, J = 6.9
and 9.2 Hz, 1 H, 5-H), 3.16 (t, J = 9.2 Hz, 1 H, 5Ј-H), 3.06 (dd, J
= 3.0 and 11.5 Hz, 1 H, 2Ј-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 138.9, 138.2 (Cipso Ph), 128.9–127.1 (CH Ph), 63.6 (CH2Ph),
62.1 (C-3), 61.0 (C-2), 56.3 (C-5), 49.5 (C-4) ppm. MS (ESI+): m/z
= 272.1 [M + H]+, 236.1 [M – HCl]+. C17H18ClN (271.78): calcd.
C 75.13, H 6.68, N 5.15; found C 75.43, H 6.89, N 5.12.
(2R,3S,4R)-1-Benzyl-3-chloro-2,4-diphenylpyrrolidine (35): A solu-
tion of 2-chloromethylazetidine (348 mg, 1 mmol) in chloroform
(10 mL) was heated at reflux overnight. The solvent was evaporated
under reduced pressure, and the crude residue was purified by flash
chromatography (Et2O/PE, 5:95 then 2:8). Rf = 0.82 (Et2O/PE, 4:6).
Yield: 328 mg (95%); orange oil. [α]2D5 = –42 (c = 1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 6.9 Hz, 2 H, Ph), 7.48–
7.27 (m, 13 H, Ph), 4.01 (dd, J = 6.9 and 8.5 Hz, 1 H, 3-H), 3.94
(A part of AB syst., J = 13.1 Hz, 1 H, NCHHPh), 3.71 (d, J =
8.2 Hz, 1 H, 2-H), 3.51–3.44 (m, 1 H, 4-H), 3.24 (dd, J = 3.6 and
9.8 Hz, 1 H, 5-H), 3.17 (B part of AB syst., J = 13.1 Hz, 1 H,
NCHHPh), 3.00 (t, J = 9.8 Hz, 1 H, 5Ј-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.4, 138.9, 138.5 (Cipso Ph), 128.9, 128.8,
128.7, 128.4, 128.2, 127.4, 127.2, 127.0 (CH Ph), 78.0 (C-2), 72.0
(C-5), 58.8 (CH2), 57.9 (C-4), 52.1 (C-3) ppm. MS (ESI+): m/z =
348.1 [M + H]+. C23H22ClN (331.43): calcd. C 79.41, H 6.37, N
4.03; found C 79.11, H 6.51, N 4.02. The same compound was
obtained by the following procedure: To a solution of hydroxy-
methylazetidine 12 (1 mmol) in THF (5 mL) was added meth-
anesulfonyl chloride (0.084 mL, 1.5 mmol) and triethylamine
(0.41 mL, 4 mmol). The reaction mixture was heated at reflux for
2 h and then hydrolyzed by addition of NaOH (1 , 10 mL). Ad-
dition of ether was followed by usual workup and purification as
above to give title compound (65%).
(2S,3S,4R)-1-Benzyl-3-chloro-2,4-diphenylpyrrolidine (40): A solu-
tion of 22 (348 mg, 1 mmol) in DMF (10 mL) was heated at reflux
overnight. The solvent was evaporated under reduced pressure, and
the crude residue was purified by flash chromatography (Et2O/PE,
2:98 then 1:9). Rf = 0.88 (Et2O/PE:4:6). Yield: 215 mg (65%); pink
oil. [α]2D5 = +60 (c = 1, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
7.58 (d, J = 6.9 Hz, 2 H, Ph), 7.48–7.27 (m, 13 H, Ph), 4.01 (dd, J
= 6.9 and 8.5 Hz, 1 H, 3-H), 3.94 (A part of AB syst., J = 13.1 Hz,
1 H, NCHHPh), 3.71 (d, J = 8.2 Hz, 1 H, 2-H), 3.51–3.44 (m, 1
H, 4-H), 3.24 (dd, J = 3.6 and 9.8 Hz, 1 H, 5-H), 3.17 (B part of
AB syst., J = 13.1 Hz, 1 H, NCHHPh), 3.00 (t, J = 9.8 Hz, 1 H,
5Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.4, 138.9, 138.5
(Cipso Ph), 128.9, 128.8, 128.7, 128.4, 128.2, 127.4, 127.2, 127.0
(CH Ph), 78.0 (C-2), 72.0 (C-5), 58.8 (C-6), 57.9 (C-4), 52.1 (C-3)
ppm. MS (ESI+): m/z = 348.1 [M + H]+. C23H22ClN (331.43):
calcd. C 79.41, H 6.37, N 4.03; found C 79.23, H 6.47, N 4.07.
General Procedure for the Rearrangement of Activated 2-(α-Hy-
droxyalkyl)azetidines in the Presence of an External Nucleophile: To
a solution of 2-(α-chloro- or α-methanesulfonyloxyalkyl)azetidine
(1 mmol) in DMSO (8 mL) was added the required nucleophile
(KOH, NaN3, KCN, or AcONa, 10 equiv.). When the added nu-
cleophile was KOH, water (60 µL) was added as a cosolvent. The
mixture was heated whilst stirring at 50 °C until complete con-
sumption of the starting material (see Table 4). Usual workup (Ac-
OEt) followed by flash chromatography gave the following com-
pounds.
(1S,2S,3S,4S)-2-(1-Methanesulfonyloxypentyl)-1,4-dimethyl-3-phen-
ylazetidine (36): Following the general procedure used for the syn-
thesis of the mesylates, crude compound 36 was obtained and used
as such for the ensuing rearrangement. Rf = 0.50 (Et2O/PE, 4:6).
1
Yield: 96%; clear oil. H NMR (300 MHz, CDCl3): δ = 7.46–7.17
(m, 5 H, Ph), 4.72–4.78 (m, 1 H, CHOMs), 3.14 (s, 3 H, Me), 3.15–
3.05 (m, 2 H, 2-H, 3-H), 2.92 (quint., J = 6.5 Hz, 1 H, 4-H), 2.39
(s, 3 H, NMe), 1.51–1.01 [m, 6 H, (CH2)3], 1.14 (d, J = 6.4 Hz, 3
H, Me), 0.79 (br. t, J = 7.2 Hz, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 140.1 (Cipso Ph), 128.6, 127.8, 126.9 (CH-Ph), 83.6
(CHO), 72.8 (C2), 68.2 (CH), 50.6 (CH), 46.7, 42.2, 39.3, 31.0, 27.4,
23.0 (CH2), 19.8, 13.8 (CH3) ppm.
(3S)-3-Chloro-1-[(1S)-1-Phenylethyl]pyrrolidine (41): Following the
above procedure, but with heating at 40 °C for 48 h and starting
from 18, compound 41 was obtained as a clear oil after purification
by flash chromatography (Et2O/PE, 7:3). Rf = 0.5 (Et2O/PE:7:3).
Yield: 81 mg (39%). [α]2D5 = –81 (c = 0.9, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H, Ph), 4.28–4.20 (m, 1 H,
3-H), 3.27 (q, J = 6.4 Hz, 1 H, CHMe), 2.90 (dd, J = 6.4 and
10.7 Hz, 1 H, 2-H), 2.70 (td, J = 4.1 and 8.4 Hz, 1 H, 5-H), 2.60–
2.50 (m, 2 H, 5-H and 2-H), 2.38–2.26 (m, 1 H, 4-H), 2.01–1.91
(m, 1 H, 4Ј-H), 1.29 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 145.0 (Cipso Ph), 128.4, 127.2, 127.1 (CH
Ph), 65.3 (CH), 62.3 (C-2), 56.4 (C-3), 51.1 (C-5), 35.9 (C-4), 22.9
(Me) ppm. MS (ESI+): m/z = 210.2 [M + H]+. HRMS: calcd. for
C12H17NCl [M + H]+ 210.1046; found 210.1050.
Thermal Ring Expansion of 2-(α-Chloroalkyl)azetidines (Table 3)
(3S,4R)-1-Benzyl-3-chloro-4-phenylpyrrolidine (37): A solution of
16 in DMF (10 mL for 1 mmol) was heated at reflux for 12 h. Evap-
oration of the solvent and purification by flash chromatography
(Et2O/CyH, 1:9 then 3:7) afforded the title compound. Rf = 0.75
(Et2O/CyH, 3:7). Yield: 203 mg (75%); oil. [α]2D5 = –41 (c = 1,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.23 (m, 10 H,
Ph), 4.33–4.21 (m, 1 H, 3-H), 3.73 (m, 2 H, NCH2Ph), 3.51 (ddd,
J = 1.8, 6.6, and 13.0 Hz, 1 H, 4-H), 3.25 (dd, J = 6.8 and 10.3 Hz,
3294
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3286–3297

A Synthetic Route to Functionalized Pyrrolidines
(3S)-3-Hydroxy-1-[(1S)-1-Phenylethyl]pyrrolidine (42): Following
the above procedure, but with heating at 50 °C for 48 h and starting
from 18, compound 42 was obtained as a clear oil after purification
by flash chromatography (DCM/EtOH, 9:1). Rf = 0.12 (DCM/
EtOH, 9:1). Yield: 134 mg (70%). [α]2D5 = +14 (c = 0.4, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.65–7.26 (m, 5 H, Ph), 4.40–4.35
(m, 1 H, 3-H), 3.38–3.31 (q, J = 6.6 Hz, 1 H, CHMe), 2.93–2.89
(3S)-3-Cyano-1-[(1S)-1-phenylethyl]pyrrolidine (47): Following the
above procedure, and starting from 18, compound 47 was obtained
as a clear oil after purification by flash chromatography (PE/Et2O,
6:4). Rf = 0.4 (PE/Et2O, 6:4). Yield: 152 mg (76%). [α]2D0 = –57 (c
= 1.2, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.62–7.03 (m, 5
H, Ph), 3.35–3.32 (m, 1 H, CHMe), 3.02–2.93 (m, 2 H, 3-H and 5-
H), 2.85–2.65 (m, 2 H, 2-H), 2.57–2.51 (m, 1 H, 5Ј-H), 2.27–2.09
1
(m, 1 H, 2-H), 2.77–2.71 (m, 1 H, 5-H), 2.56 (q, J = 5.2 Hz, 1 H, (m, 2 H, 4-H), 1.45 (d, J = 6.4 Hz, 3 H, Me) ppm. 13C NMR
2Ј-H), 2.40–2.32 (m, 1 H, 5Ј-H), 2.23–2.16 (m, 1 H, 4-H), 1.78– (75 MHz, CDCl3): δ = 144.6 (Cipso Ph), 128.5, 127.3, 127.1 (CH
1.74 (m, 1 H, 4Ј-H), 1.45 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 144.4 (Cipso Ph), 128.5, 127.3, 127.2 (CH
Ph), 122.5 (CN), 64.6 (CH), 56.1, 51.4 (CH2), 29.1 (C-4), 26.3 (C-
3), 23.0 (Me) ppm. MS (ESI+): m/z = 201.1 [M + H]+, 185.0.
Ph), 71.3 (CHOH), 65.4 (CH), 61.5 (C-2), 51.2 (C-5), 34.7 (C-4), HRMS: calcd. for C13H17N2 [M + H]+ 201.1392; found 201.1387.
22.7 (Me) ppm. MS (ESI+): m/z = 192.3 [M + H]+, 105.1. HRMS:
(3R)-3-Cyano-1-[(1S)-1-phenylethyl]pyrrolidine (48): Following the
calcd. for C12H18NO [M + H]+ 192.1388; found 192.1396.
above procedure, and starting from 19, compound 48 was obtained
(1S)-1-Phenylethyl-2,5-dihydro-1H-pyrrole (43): Following the
above procedure, but with heating at 60 °C for 24 h and starting
from 18, compound 43 was obtained as a clear oil after purification
by flash chromatography (Et2O/PE, 7:3). Rf = 0.2 (Et2O/PE, 7:3).
as a clear oil after purification by flash chromatography (PE/Et2O,
1:1). Rf = 0.4 (PE/Et2O, 1:1). Yield: 88 mg (44%). [α]2D0 = –3 (c =
0.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.62–7.09 (m, 5 H,
Ph), 3.33 (q, J = 6.5 Hz, 1 H, CHMe), 3.05–2.95 (m, 2 H, 3-H and
2-H), 2.85–2.65 (m, 2 H, 2Ј-H and 5-H), 2.56–2.50 (m, 1 H, 5Ј-H),
2.25–2.07 (m, 2 H, 4-H), 1.43 (d, J = 6.4 Hz, 3 H, Me) ppm. 13C
1
Yield: 168 mg (97%). H NMR (300 MHz, CDCl3): δ = 7.31–7.14
(m, 5 H, Ph), 5.71 (s, 2 H, 3,4-H), 3.50–3.24 (m, 5 H, 2,5-H and
CHMe), 1.32 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, NMR (75 MHz, CDCl3): δ = 144.5 (Cipso Ph), 128.6, 127.3, 127.0
CDCl3): δ = 145.6 (Cipso Ph), 128.4, 127.8, 127.3 (CH Ph), 126.9
(C-3,4), 65.2 (CH), 58.6 (C-2,5), 23.6 (Me) ppm. MS (ESI+): m/z
= 174.3 [M + H]+.
(CH Ph), 122.1 (CN), 64.6 (CH), 55.9, 51.4 (CH2), 29.1 (C-4), 26.4
(C-3), 22.3 (Me) ppm. MS (ESI+): m/z = 201.1 [M + H]+, 185.0,
123.0, 105, 0. HRMS: calcd. for C13H17N2 [M + H]+ 201.1392;
found 201.1386.
(2S,3S,4S,5S)-2-Butyl-3-hydroxy-1,5-dimethyl-4-phenylpyrrolidine
(44): Following the above procedure, and starting from 36, com-
pound 44 was obtained as a clear oil after purification by flash
chromatography on basic alumina (DCM/MeOH, 95:5). Rf = 0.3
(DCM/MeOH, 95:5). Yield: 116 mg (47%). [α]2D0 = +34 (c = 0.5,
(3R)-3-Chloro-1-[(1S)-1-phenylethyl]pyrrolidine (49): Following the
above procedure, but with heating at 50 °C for 24 h and starting
from 19, compound 49 was obtained as a clear oil after purification
by flash chromatography (Et2O/PE, 7:3). Rf =0.5 (Et2O/PE, 7:3).
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.42–7.06 (m, 5 H, Ph), Yield: 44 mg (21%). 1H NMR (300 MHz, CDCl3): δ = 7.39–7.28
3.91 (dd, J = 4.0 and 6.3 Hz, 1 H, 3-H), 3.11–3.00 (m, 2 H, 5-H
(m, 5 H, Ph), 4.25–4.18 (m, 1 H, 3-H), 3.19 (q, J = 6.4 Hz, 1 H,
and 2-H), 2.86–2.76 (m, 1 H, 4-H), 2.37 (s, 3 H, Me), 1.77–1.66 CHMe), 2.85–2.68 (m, 3 H, 2-H, 3-H, 5-H), 2.62–2.52 (m, 2 H, 5-
(m, 1 H, Bu), 1.45–1.14 (m, 5 H, Bu), 1.08 (d, J = 6.2 Hz, 3 H, Me), H and 2-H), 2.35–2.24 (m, 1 H, 4-H), 1.98–1.91 (m, 1 H, 4Ј-H),
0.85 (t, J = 6.9 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ 1.28 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3):
= 140.4 (Cipso Ph), 128.8, 127.8, 127.1 (CH Ph), 82.6 (C-3), 70.7
δ = 144.9 (Cipso Ph), 128.4, 127.2, 126.9 (CH Ph), 65.2 (CH), 61.9
(C-2), 64.5 (C-5), 61.7 (C-4), 34.5 (Me) 27.9, 27.4, 23.0 (CH2), 14.0
(C-2), 56.2 (C-3), 49.8 (C-5), 35.7 (C-4), 22.8 (Me) ppm. MS
(Me) ppm. MS (ESI+): m/z = 248.3 [M + H]+, 230.3. HRMS: (ESI+): m/z = 210.2 [M + H]+.
calcd. for C16H26NO [M + H]+ 248.2014; found 248.2019.
(2S,3S,4S,5S)-3-Cyano-1,5-dimethyl-2,4-diphenylpyrrolidine
(50):
(2S,3S,4S,5S)-3-Hydroxy-1,5-Dimethyl-2,4-diphenylpyrrolidine (45): Following the above procedure, and starting from 32 + 33, com-
Following the above procedure, and starting from 32 + 33, com-
pound 45 was obtained as a white solid after purification by flash
chromatography (PE/Et2O, 6:4). Rf = 0.25 (PE/Et2O, 6:4). Yield:
pound 50 was obtained as a white solid after purification by flash
chromatography (PE/Et2O, 8:2). Rf = 0.5 (PE/Et2O, 8:2). Yield:
1
63 mg (23%). [α]2D0 = +55 (c = 0.6, CHCl3). H NMR (300 MHz,
1
150 mg (56%). [α]2D0 = +41 (c = 0.6, CHCl3). H NMR (300 MHz,
CDCl3): δ = 7.52–7.30 (m, 10 H, Ph), 4.02 (d, J = 8.9 Hz, 1 H, 2-
H), 3.60 (br. s, 1 H, 5-H), 3.10 (dd, J = 4.6 and 8.6 Hz, 1 H, 4-H),
CDCl3): δ = 7.53–7.16 (m, 10 H, Ph), 4.02 (t, J = 7.2 Hz, 1 H, 3-
H), 3.66 (d, J = 7.2 Hz, 1 H, 2-H), 3.46 (q, J = 6.3 Hz, 1 H, 5-H), 2.88 (br. s, 1 H, 3-H), 2.14 (s, 3 H, Me), 1.16 (d, J = 6.7 Hz, 3 H,
2.75–2.71 (m, 1 H, 4-H), 2.09 (s, 3 H, Me), 1.92 (br. s, 1 H, OH), Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 142.5, 140.3 (Cipso
1.14 (d, J = 6.4 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3):
Ph), 129.1, 129.0, 128.7, 127.7, 127.4 (CH Ph), 120.2 (CN), 71.0
δ = 142.8, 140.8 (Cipso Ph), 128.7, 128.6, 128.1, 127.8, 127.7, 126.7 (C-2), 65.5 (C-5), 56.6 (C-4), 47.3 (C-3), 34.3, 15.1 (Me) ppm. MS
(CH Ph), 86.5 (C-3), 74.3 (C-2), 64.5 (C-5), 60.9 (C-4), 34.5, 16.7
(Me) ppm. MS (ESI+): m/z = 268.2 [M + H]+, 250.3, 148.1.
HRMS: calcd. for C18H22NO [M + H]+ 268.1701; found 268.1708.
(ESI+): m/z = 299.3, 277.3 [M + H]+. HRMS: calcd. for C19H21N2
[M + H]+ 277.1705; found 277.1699.
(2S,3S,4S,5S)-2-Butyl-3-cyano-1,5-dimethyl-4-phenylpyrrolidine
1,5-Dimethyl-2,4-diphenylpyrrole (46): Following the above pro- (51): Following the above procedure, and starting from 36, com-
cedure, and starting from 32 + 33, compound 46 was obtained as
pound 51 was obtained as a clear oil after purification by flash
a white solid after purification by flash chromatography (PE/Et2O,
chromatography (PE/Et2O, 6:4). Rf = 0.3 (PE/Et2O, 6:4). Yield:
1
6:4). Rf = 0.7 (PE/Et2O, 6:4). Yield: 72 mg (29%). M.p. 155 °C. 1H 210 mg (82%). [α]2D0 = +66 (c = 1.1, CHCl3). H NMR (300 MHz,
NMR (300 MHz, CDCl3): δ = 7.37–7.14 (m, 10 H, Ph), 6.26 (s, 1 CDCl3): δ = 7.46–7.16 (m, 5 H, Ph), 3.20–3.06 (m, 2 H, 5-H and
H, 3-H), 3.50 (s, 3 H, Me), 2.35 (s, 3 H, Me) ppm. 13C NMR 2-H), 2.96 (dd, J = 3.3 and 6.4 Hz, 1 H, 3-H), 2.58 (t, J = 7.6 Hz,
(75 MHz, CDCl3): δ = 137.3 (C-2), 133.9, 133.6 (Cipso Ph), 128.9,
1 H, 4-H), 2.29 (s, 3 H, Me), 1.77–1.66 (m, 1 H, Bu), 1.43–1.23 (m,
128.5, 128.4, 128.2, 128.1, 126.9 (CHPh), 126.7 (C-4), 125.3 (C-5), 5 H, Bu), 1.01 (d, J = 6.3 Hz, 3 H, Me), 0.85 (t, J = 6.9 Hz, 3 H,
108.1 (C-3), 32.1, 11.5 (Me) ppm. MS (ESI+): m/z = 248.3
[M + H]+. HRMS: calcd. for C18H17N [M + H]+ 248.1439; found
248.1438.
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.0 (Cipso Ph),
129.0, 127.5, 127.4 (CH Ph), 121.8 (CN), 66.7 (C-2), 64.9 (C-5),
56.8 (C-3), 42.0 (C-4), 34.7 (Me) 31.2, 27.6, 23.0 (CH2), 15.2, 14.1
Eur. J. Org. Chem. 2008, 3286–3297
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3295

F. Durrat, M. V. Sanchez, F. Couty, G. Evano, J. Marrot
FULL PAPER
(Me) ppm. MS (ESI+): m/z = 279.3, 257.3 [M + H]+. HRMS: NMR (75 MHz, CDCl3): δ = 139.9 (Cipso Ph), 128.6, 127.8, 127.0
calcd. for C18H24N2 [M + H]+ 257.2018; found 257.2013.
(CH Ph), 73.7 (C-3), 68.2 (C-2), 67.6 (C-5), 49.0 (C-4), 43.8 (Me)
30.1, 28.1, 22.4 (CH2), 20.1 (CH), 13.9 (Me) ppm. MS (ESI+): m/z
= 295.3, 273.3 [M + H]+. HRMS: calcd. for C16H24N4 [M + H]+
273.2079; found 273.2083.
(3S)-3-Azido-[(1S)-1-phenylethyl]pyrrolidine (52): Following the
above procedure, and starting from 18, compound 52 was obtained
as a clear oil after purification by flash chromatography (PE/Et2O,
2:1). Rf = 0.2 (PE/Et2O, 2:1). Yield: 184 mg (85%). [α]2D0 = –43 (c
(2S,3S,4S,5S)-3-Azido-1,5-dimethyl-2,4-diphenylpyrrolidine
(57):
1
Following the above procedure, and starting from 32 + 33, com-
pound 57 was obtained as an oil after purification by flash
chromatography (PE/Et2O, 6:4). Rf = 0.6 (PE/Et2O, 6:4). Yield:
= 0.7, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.74–7.25 (m, 5
H, Ph), 3.96 (m, 1 H, 3-H), 3.31 (q, J = 6.5 Hz, 1 H, CHMe), 2.73–
2.58 (m, 4 H, 2-H and 5-H), 2.93–2.17 (m, 1 H, 4-H), 1.94–1.84
(m, 1 H, 4Ј-H), 1.43 (d, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 145.1 (Cipso Ph), 128.6, 128.4, 127.1 (CH
Ph), 65.2 (CH), 59.8 (C-3), 58.4, 51.4, 31.4 (CH2), 22.3 (Me) ppm.
MS (ESI+): m/z = 217 [M + H]+, 160, 105. HRMS: calcd. for
C12H17N4 [M + H]+ 217.1453; found 217.1442.
1
55 mg (19%). [α]2D0 = +44 (c = 0.3, CHCl3). H NMR (300 MHz,
CDCl3): δ = 7.50–7.30 (m, 10 H, Ph), 3.98–3.78 (m, 2 H, 2-H and
3-H), 3.67–3.59 (m, 1 H, 5-H), 2.90 (dd, J = 4.2 and 6.5 Hz, 1 H,
4-H), 2.22 (s, 3 H, Me), 1.25 (d, J = 6.7 Hz, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 142.7, 140.2 (Cipso Ph), 129.9, 128.8,
128.1, 127.9, 127.6, 127.1 (CH Ph), 76.1 (C-3), 72.4 (C-2), 64.8 (C-
5), 58.6 (C-4), 34.4, 15.4 (Me) ppm. MS (ESI+): m/z = 293.3 [M +
H]+.
(2R)-2-(Azidomethyl)-1-[(1S)-1-phenylethyl]azetidine (53): Follow-
ing the above procedure, and starting from 18, compound 53 was
obtained as a clear oil after purification by flash chromatography
(PE/Et2O, 2:1). Rf = 0.3 (PE/Et2O, 2:1). Yield: 17 mg (8%). [α]2D0
=
(3S)-3-Acetoxy-1-[(1S)-1-phenylethyl]pyrrolidine (58): Following the
above procedure, and starting from 18, compound 58 was obtained
as a clear oil after purification by flash chromatography (PE/Et2O,
3:7). Rf = 0.2 (PE/Et2O, 3:7). Yield: 158 mg (68%). [α]2D0 = –8 (c =
0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.43–7.24 (m, 5 H,
Ph), 5.21–5.14 (m, 1 H, 3-H), 3.28 (q, J = 6.0 Hz, 1 H, CHMe),
2.82–2.70 (m, 2 H, 2-H), 2.67–2.59 (m, 1 H, 5-H), 2.54–2.45 (m, 1
H, 5Ј-H), 2.32–2.20 (m, 1 H, 4-H), 2.08 (s, 3 H, Me), 1.89–1.79 (m,
1 H, 4Ј-H), 1.42 (d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.8 (C=O), 144.8 (Cipso Ph), 128.4, 127.2, 127.1
(CH Ph), 74.1 (C-3), 65.6 (CH), 59.2, 51.5, 31.8 (CH2), 22.9, 21.3
(Me) ppm. MS (ESI+): m/z = 256.3 [M + Na]+. HRMS: calcd. for
C14H20NO2 [M + H]+ 234.1494; found 234.1480.
1
–10 (c = 1.2, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.61–7.09
(m, 5 H, Ph), 3.96–3.48 (m, 3 H, CHMe, CHHN3 and 2-H), 3.30–
3.27 (d, J = 9.3 Hz, 1 H, CHHN3), 3.16–3.11 (m, 1 H, 4-H), 2.74
(q, J = 9.0 Hz, 1 H, 4Ј-H), 2.11–2.04 (m, 2 H, 3-H), 1.18 (d, J =
6.0 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.5
(Cipso Ph), 128.4, 127.3, 127.1 (CH Ph), 67.5 (C-2), 63.9 (CH), 56.1
(C-2), 49.8 (CH2), 22.2 (Me), 20.1 (C-3) ppm. MS (ESI+): m/z =
217 [M + H]+, 160, 105.
(3R)-3-Azido-1-[(1S)-1-phenylethyl]pyrrolidine: Following the above
procedure, and starting from 19, compound 54 was obtained as a
clear oil after purification by flash chromatography (PE/Et2O, 6:4).
Rf = 0.3 (PE/Et2O, 6:4). Yield: 189 mg (87%). [α]2D0 = +15 (c = 1.3,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.27–7.14 (m, 5 H, Ph),
3.85–3.74 (m, 1 H, 3-H), 3.15 (q, J = 6.5 Hz, 1 H, CHMe), 2.80
(td, J = 5.4 and 8.7 Hz, 1 H, 5-H), 2.63–2.57 (m, 1 H, 2-H), 2.45
(dd, J = 3.3 and 10.3 Hz, 1 H, 2Ј-H), 2.25 (td, J = 6.3 and 8.6 Hz,
1 H, 5Ј-H), 2.16–2.04 (m, 1 H, 4-H), 1.86–1.76 (m, 1 H, 4Ј-H), 1.31
(d, J = 6.5 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
145.0 (Cipso Ph), 128.5, 128.4, 127.1 (CH Ph), 65.2 (CH), 59.8 (C-
3), 58.6, 51.5, 31.1 (CH2), 23.1 (Me) ppm. MS (ESI+): m/z = 217
[M + H]+. HRMS: calcd. for C12H17N4 [M + H]+ 217.1453; found
217.1446.
(2S,3S,4S,5S)-3-Acetoxy-2-butyl-1,5-dimethyl-4-phenylpyrrolidine
(59): Following the above procedure, and starting from 36, com-
pound 59 was obtained as a clear oil after purification by flash
chromatography (PE/Et2O, 6:4). Rf = 0.2 (PE/Et2O, 6:4). Yield:
185 mg (64%). [α]2D0 = +26 (c = 1.1, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 7.27–7.16 (m, 5 H, Ph), 4.98 (dd, J = 4.8 and 2.2 Hz,
1 H, 3-H), 3.02–2.98 (m, 1 H, 2-H), 2.85–2.72 (m, 2 H, 4-H and 5-
H), 2.31 (s, 3 H, Me), 1.96 (s, 3 H, Me), 1.74–1.61 (m, 1 H, Bu),
1.50–1.13 (m, 5 H, Bu), 1.03 (d, J = 5.7 Hz, 3 H, Me), 0.85 (t, J =
6.6 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.6
(C=O), 141.2 (Cipso Ph), 128.6, 127.9, 126.7 (CH Ph), 84.1 (C-3),
69.3 (C-2), 64.7 (C-5), 59.9 (C-4), 34.8 (Me) 28.4, 26.0, 23.1 (CH2),
16.4, 14.1 (Me) ppm. MS (ESI+): m/z = 312.3, 290.3 [M + H]+.
HRMS: calcd. for C18H28NO2 [M + H]+ 290.2120; found 290.2131.
(2S,3S,4S,5S)-3-Azido-2-butyl-1,5-dimethyl-4-phenylpyrrolidine
(55): Following the above procedure, and starting from 36, com-
pound 55 was obtained as a clear oil after purification by flash
chromatography (PE/Et2O, 6:4). Rf = 0.3 (PE/Et2O, 6:4). Yield:
71 mg (26%). [α]2D0 = +7 (c = 1.1, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.40–7.27 (m, 5 H, Ph), 3.65 (dd, J = 6.5 and 5.2 Hz,
1 H, 3-H), 3.10 (quint., J = 6.2 Hz, 1 H, 5-H), 3.02–2.96 (m, 1 H,
2-H) 2.81 (t, J = 7.6 Hz, 1 H, 4-H), 2.40 (s, 3 H, Me), 1.80–1.78
(m, 1 H, Bu), 1.49–1.27 (m, 5 H, Bu), 1.11 (d, J = 6.3 Hz, 3 H, Me),
0.98 (t, J = 6.6 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 141.4 (Cipso Ph), 128.8, 127.8, 127.1 (CH Ph), 72.3 (C-3), 68.0
(C-2), 64.3 (C-5), 59.1 (C-4), 34.7 (Me) 28.6, 27.7, 23.1 (CH2), 15.8,
14.1 (Me) ppm. MS (ESI+): m/z = 273.3 [M + H]+. HRMS: calcd.
for C16H25N4 [M + H]+ 273.2079; found 273.2078.
Acknowledgments
F. D. thanks the Ministère de la Recherche et de l’Enseignement
Supérieur, and M. V.-S. thanks the Consenjo Nacional de Cienca y
Tecnología for fellowships.
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Received: March 26, 2008
Published Online: May 19, 2008
Eur. J. Org. Chem. 2008, 3286–3297
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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