Enantioselective preparation of 2,4-disubstituted azetidines

Article abstract of DOI:10.1002/(sici)1099-0690(200005)2000:9<1815::aid-ejoc1815>3.0.co;2-8

Chiral C₂-symmetric N-benzylazetidines have been conveniently prepared from optically pure anti-1,3-diols without loss of enantiomeric purity. N- Debenzylation led to the corresponding N-unsubstituted azetidines, which were then subjected to palladium-catalysed coupling reactions with aryl bromides to afford chiral N-arylazetidines. (R,R)-N-Benzyl-2,4-dimethylazetidine has been employed in the synthesis of a new cyclopalladated complex, which can be used, for instance, as a chiral recognition agent for phosphorus ligands.

Full text of DOI:10.1002/(sici)1099-0690(200005)2000:9<1815::aid-ejoc1815>3.0.co;2-8

FULL PAPER
Enantioselective Preparation of 2,4-Disubstituted Azetidines
[a]
[a]
[a]
ˆ
Angela Marinetti,* Philippe Hubert, and Jean-Pierre Genet
Keywords: Chiral azetidines / Palladium-catalysed couplings / Palladacycles
Chiral C2-symmetric N-benzylazetidines have been conveni- bromides to afford chiral N-arylazetidines. (R,R)-N-Benzyl-
ently prepared from optically pure anti-1,3-diols without loss
2,4-dimethylazetidine has been employed in the synthesis of
of enantiomeric purity. N-Debenzylation led to the corres- a new cyclopalladated complex, which can be used, for in-
ponding N-unsubstituted azetidines, which were then sub-
stance, as a chiral recognition agent for phosphorus ligands.
jected to palladium-catalysed coupling reactions with aryl
have also been considered.[5b,7] Known enantioselective ap-
proaches to the four-membered ring are: (a) intramolecular
cyclization of 3-amino-1,2-diols (CϪN bond formation),
Introduction
Amongst chiral nitrogen heterocycles, azetidines seem to which are obtained from chiral epoxy alcohols, in turn ob-
be the least well studied to date, in terms of both synthetic tained from Sharpless epoxidation reactions;[8] (b) photo-
approaches and applications. This is also the case for chiral chemical ring closure of α-(N-methylamino) ketones (CϪC
2,4-disubstituted azetidines, as compared to the corres- bond formation), prepared from a commercially available,
ponding aziridines and pyrrolidines. Thus, for instance, C2- optically pure aminodiol,[9] and (c) reduction of enantiom-
symmetric bis(aziridines)[1] and bis(pyrrolidines)[2] have erically pure β-lactams.[10] As far as we are aware, direct
been prepared and used as bidentate ligands in transition cyclization between primary amines and optically pure 1,3-
metal catalysed reactions, while trans-2,5-disubstituted pyr- diol derivatives[11] has hitherto not been developed as a syn-
rolidine moieties find wide application as building blocks thetic route to chiral, symmetrically substituted azetidines.
for chiral ligands,[3] as chiral bases, and as auxiliaries for
We report herein on a general stereoselective synthesis of
asymmetric synthesis.[4] On the other hand, literature re- new symmetrically 2,4-disubstituted N-alkylazetidines from
ports on optically active symmetrically disubstituted azetid- optically pure 1,3-diols. The convenient preparation of N-
ines[5] are largely restricted to azetidine-2,4-dicarboxylic aryl-substituted azetidines through Pd-catalysed coupling
acid derivatives 1a and azetidine-2,4-dimethanol analogues reactions is also described.
1b derived therefrom. These compounds have only been
used as stoichiometric chiral auxiliaries in asymmetric
amide alkylations and in catalytic amounts in additions of
diethylzinc to aldehydes.
Results and Discussion
Synthesis of Chiral Azetidines from 1,3-Diols
The general approach to chiral azetidines described here
(Scheme 1) is based on the ready availability of optically
pure 1,3-diols. Thus, trans-2,4-pentanediol is commercially
available in optically pure form, while many other diols can
conveniently be prepared through catalytic hydrogenation
of the corresponding 1,3-diketones, as promoted by (chiral
phosphane)ruthenium complexes.[12] In this work, (R)- and
(S)-Binap have been used as chiral ligands in hydrogenation
reactions leading to the 1,3-diols 1 shown in Scheme 1.
These highly diastereo- and enantioselective hydrogenations
Ϫ de and ee values in excess of 95% Ϫ have been performed
on a scale of up to 10 g in small stainless steel autoclaves
using standard laboratory equipment. There is still scope
for further scale-up. As a representative example, the syn-
thesis of (S,S)-4,6-nonanediol (1c) is described in the Ex-
perimental Section.
The reason for the lack of progress in the development
of the chemistry of optically active azetidines is unclear, but
it could be related to synthetic difficulties, given that forma-
tion of the four-membered ring from acyclic derivatives is
a priori a disfavoured process compared to the analogous
construction of five- and even three-membered rings.
A literature survey reveals that optically pure azetidines
are generally obtained from racemic mixtures, using stoichi-
ometric amounts of chiral auxiliaries to form diastereom-
eric pairs.[5a,6] Enzymatic resolutions, such as lipase-cata-
lysed acylation of racemic 2,4-bis(hydroxymethyl)azetidines,
[a]
`
´
Laboratoire de Synthese Selective Organique et Produits
Naturels, CNRS, UMR 7573, ENSCP,
11, rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax: (internat.) ϩ 33-1/44071062
E-mail: marinet@ext.jussieu.fr
Eur. J. Org. Chem. 2000, 1815Ϫ1820
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0509Ϫ1815 $ 17.50ϩ.50/0
1815

ˆ
A. Marinetti, P. Hubert, J.-P. Genet
FULL PAPER
N-phenylazetidines, e.g. from aniline and (R,R)-2,4-pen-
tanediyl bis(methanesulfonate). In this reaction, the use of
nBuLi as a strong base is required and the desired N-
phenyl-2,4-dimethylazetidine is obtained in low yield along
with several side-products. It has already been shown that
harsh conditions (130 °C in HMPA) are required for ana-
logous azetidine syntheses from aniline, even when the
starting materials are primary 1,3-diol derivatives.[19] An al-
ternative, convenient approach to arylazetidines can be de-
vised, based on palladium-catalysed coupling of secondary
amines with aryl halides, as independently described by
Hartwig and by Buchwald.[20] N-Unsubstituted chiral azeti-
dines can be expected to be suitable substrates for this coup-
ling reaction, provided that their optical purities are not
affected during the catalytic reaction. The reaction se-
quence is shown in Scheme 2.
Scheme 1. Synthesis of chiral N-benzylazetidines (R ϭ Me, Et, Pr,
CH2Ph, iPr): (i) H2, 40Ϫ70 bar, r.t. to 80 °C, MeOH, 70 h, catalyst:
0.5% (R)- or (S)-Binap, (COD)Ru(2-methylallyl)2, HBr (see ref.[13]);
(ii) MeSO2Cl, Et3N; (iii) excess PhCH2NH2, 45 °C, 60 h
The 1,3-diols were treated with methanesulfonyl chloride
in the presence of triethylamine to afford the corresponding
bis(methanesulfonates). The crude mesylates were then
treated with an excess of benzylamine, according to a pro-
cedure previously used for the synthesis of pyrrolidines.[14]
The cyclization reactions were found to proceed in moder-
ate to high yields for R ϭ Me, Et, Pr, CH2Ph. However, the
sterically more hindered 2,6-dimethyl-3,5-heptanediyl bis-
(methanesulfonate) failed to react under analogous condi-
Scheme 2. Synthesis of chiral N-arylazetidines (R ϭ Me, Et): (i) 7
bar H2, Pd(OH)2 cat., MeOH; (ii) HOAc; (iii) ArBr, catalyst:
Pd2(dba)3/rac-Binap, NaOtBu, toluene, 70Ϫ100 °C, 3Ϫ6 h
1
tions. In the synthesis of 2, H-NMR analysis of the crude
reaction mixture revealed exclusive formation of the anti
isomer through a stereospecific substitution reaction,[15]
thus we presume that the optical purities of the final azetid-
ines are the same as those of the starting diols.[16] Total
inversion at the chiral carbon centres would, of course, be
expected on the basis of an SN2 reaction mechanism. Con-
sequently, the absolute configurations of 2a؊c and 2d have
been assigned as (R,R) and (S,S), respectively.
(S,S)-2,4-Pentanediyl bis(methanesulfonate) was also
treated with 0.5 equivalents of ethylenediamine in the
presence of triethylamine to afford 1,2-bis(2,4-dimethyl-
azetidino)ethane (3), albeit in low yield (25%).
The N-unsubstituted azetidines required for the arylation
reaction were conveniently prepared by hydrogenation of
the corresponding benzylazetidines 2a؊c under standard
reaction conditions using 20% Pd(OH)2 as a catalyst. In
small-scale experiments, the N-unsubstituted azetidines are
difficult to recover from the reaction mixtures owing to
their low boiling points.[21] They are more easily isolated
and characterized as their acetic acid salts, 4, obtained by
addition of acetic acid to the crude reaction mixtures. At-
tempted debenzylation of azetidine 2d (R ϭ CH2Ph) led
mainly to the ring-opened product, 1,5-diphenyl-2-pen-
tylamine.
The azetidinium acetates are themselves suitable starting
materials for the synthesis of N-arylazetidines through pal-
ladium-catalysed coupling reactions with aryl bromides.
These reactions require the presence of a base, usually
tBuOK, which also serves to generate the free azetidine
from its acetic acid adduct. The results of these coupling
reactions are summarized in Table 1. The reaction condi-
tions used in this work were those recommended by Buch-
wald for the coupling of optically active amines.[22] Most
notably, the use of rac-Binap and moderate reaction tem-
peratures seem to be crucial features for suppressing racem-
ization of the starting amines. According to the proposed
mechanism, racemization results from a reversible β-elim-
ination process; when azetidines 4 are involved, this should
lead to the corresponding cis-azetidine derivatives. The
formation of cis-azetidines was never observed in this work,
even in reactions performed at high temperature (100 °C).
It would therefore appear that the carbon stereochemistry
is fully retained during the catalytic process. This is also
The C2-symmetric diamine 3 can be expected to find ap-
plication as a chiral ligand in several transition metal cata-
lysed reactions, as already shown for the aziridine and pyr-
rolidine analogues.[1,2]
The aforementioned direct cyclization route to azetidines
is somewhat less efficient than the analogous synthesis of
pyrrolidines,[14] probably due to ring strain[17] and unfa-
vourable entropy factors in the ring-closing step.[18] How-
ever, this synthetic approach remains highly convenient
from a preparative point of view, given the ready availability
of the chiral starting materials.
Synthesis of N-Arylazetidines through Palladium-Promoted
Coupling Reactions
The synthetic approach to N-alkylazetidines shown in demonstrated by the optical purity of the azetidine 5a ob-
Scheme 1 is much less efficient for the preparation of chiral tained in this way, which was found to be the same as that
1816
Eur. J. Org. Chem. 2000, 1815Ϫ1820

Enantioselective Preparation of 2,4-Disubstituted Azetidines
FULL PAPER
Table 1. Palladium-catalysed coupling of azetidines with aryl brom- be expected to represent alternative sources of chiral pallad-
ides
acycles, as we show in the following.
Reaction of (R,R)-1-benzyl-2,4-dimethylazetidine (2a)
with Na2PdCl4 in methanol at room temperature led to a
yellow precipitate, the spectral data of which were consist-
ent with the expected dimeric complex 8. A single isomer
possessing two non-equivalent azetidine moieties was
formed, which corresponds to a cis arrangement of these
ligands across the dimer, as shown in Scheme 3.
Entry Aryl halide
Amine Product Yield
1
2
3
4
5
6
7
8
bromobenzene
4a
5a
5b
5c
5d
5e
5f
75%
85%
83%
95%
80%
96%
32%
58%
o-tolyl bromide
2-bromoanisole
1,2-dibromobenzene
1-bromonaphthalene
1-bromo-4-(trifluoromethyl)benzene
3-bromobenzyl bromide
2-bromotoluene
5g
5h
4b
Scheme 3. Synthesis of a cyclopalladated N-benzylazetidine
of the product derived from aniline by the direct cycliza-
tion route.
An analogous cis arrangement has been established for 7
on the basis of X-ray crystal studies,[27] while 6 has been
shown to adopt mainly a trans geometry. Compared to 6
and 7, complex 8 displays peculiar structural features, in
as much as its chiral centres are located on the nitrogen
substituents, outside the palladacycle. The effect of this un-
precedented arrangement on the efficiency of chiral dis-
crimination by 8 is difficult to predict and thus merits ex-
amination.
Complex 8 was thus tested as a chiral recognition reagent
for optically active phosphanes by means of 31P-NMR
measurements[23b,23d,23h,23j] using (±)-Binap as a model sub-
strate. A mixture of (±)-Binap and 8 (2:1 ratio) was stirred
at room temperature in CDCl3. The 31P-NMR spectrum of
the crude mixture showed rather broad signals, which were,
however, converted into two well-defined AB signals follow-
ing the addition of one equivalent of AgPF6: δ ϭ 13.68 and
36.53, JPP ϭ 42.4 Hz for (Ϫ)-Binap; δ ϭ 13.15 and 39.95,
JPP ϭ 48.8 Hz for (ϩ)-Binap.[28] The low-field signals in
particular give an excellent diastereomeric peak separation
(∆δ ϭ 3.4) and would allow the evaluation of enantiomeric
As shown in Table 1, a variety of aryl bromides were
found to be effective coupling partners. Azetidines were
successfully arylated with ortho-substituted halides, al-
though in some cases a high reaction temperature was re-
quired (e.g. 100 °C in Entries 4 and 8). Use of 3-bromoben-
zyl bromide furnished the unsymmetrical bis(azetidine) 5g
in moderate yield (Entry 7), while reaction with 1,2-dibro-
mobenzene gave exclusively the mono(azetidine) 5d, even
after prolonged heating with excess azetidine (Entry 4).
Generally speaking, the flexible synthetic method shown
in Schemes 1 and 2 allows access to a number of C2-sym-
metric azetidines, which constitute a new class of readily
available chiral amines. Their efficiencies as chiral auxiliar-
ies in catalytic and stoichiometric reactions will be explored
in due course. Nevertheless, a first application involving the
use of a palladium complex of the N-benzylazetidine 2a as
a
31P-NMR probe in determining enantiomeric excesses is
presented in the following section.
Synthesis and Use of a Cyclopalladated Azetidine Complex
Optically active cyclopalladated compounds derived from excesses within the limits of NMR detection. The use of 8
N-donor ligands are well known as valuable reagents in en- as a resolving agent for chiral phosphanes can also be envis-
antioselective synthesis, in the resolution of chiral sub- aged.
strates, as well as in the determination of enantiomeric ex-
In summary, we have developed a short, stereoselective
cesses of chiral phosphanes by NMR.[23] Moreover, recent preparation of C2-symmetric azetidines, starting from read-
work has shown that they also display interesting catalytic ily available 1,3-diols. Moreover, the efficient coupling of
properties in enantioselective transformations.[24] Chiral N-unsubstituted azetidines with aryl bromides considerably
benzylamines and ferrocenylmethylamines afford the most widens the scope of this synthetic approach. These azetid-
commonly used cyclopalladated complexes, such as 6[25] ines represent a new series of potentially useful chiral auxili-
and 7[26,24] (X ϭ Cl, MeCO2). The N-benzylazetidines 2 can aries and synthons.
Eur. J. Org. Chem. 2000, 1815Ϫ1820
1817

ˆ
A. Marinetti, P. Hubert, J.-P. Genet
FULL PAPER
In small-scale experiments, the final azetidine could be purified by
TLC on silica gel plates eluting with cyclohexane/ethyl acetate
(90:10). Where necessary, the azetidines were distilled under re-
duced pressure in a kugelrohr apparatus.
Experimental Section
(S,S)-4,6-Nonanediol (1c, R ؍ Pr): The synthesis of the catalyst
was carried out under argon. (S)-Binap (72 mg, 0.12 mmol) and
(COD)(2-methylallyl)2Ru (32 mg, 0.10 mmol) were first suspended
in anhydrous acetone (5 mL). A methanolic HBr solution (1.5 mL,
0.16 ) was then added and the resulting mixture was stirred at
room temperature for 30 min. The solvent was subsequently re-
moved in vacuo and the residual yellow solid was used directly as
the catalyst for the hydrogenation reaction. Methanol (15 mL) and
4,6-nonanedione (20 mmol) were added to the reaction vessel,
which was then placed in a stainless steel autoclave under argon.
The argon was replaced by hydrogen and the autoclave was pressur-
ized to 50 bar. The reaction was allowed to proceed at 50 °C for
70 h. Complete conversion into the anti-diol 1c was confirmed by
NMR spectroscopy. The final product was crystallized from a
cyclohexane/diethyl ether mixture as a colourless solid. Yield 2.8 g
(86%). Ϫ 1H NMR (CDCl3): δ ϭ 0.92 (t, J ϭ 6.6 Hz, Me), 1.2Ϫ1.4
(m, 8 H, CH2), 1.58 (t, J ϭ 5.4 Hz, CHCH2CH), 3.96 (m, 2 H,
CHO). Ϫ [α]D ϭ ϩ6 (c ϭ 1, CHCl3). Ϫ The enantiomeric excess
of 1c was shown to be higher than 95% by 1H NMR (OMe signal:
δ ϭ 3.60) and GC analysis of the corresponding Mosher ester (DB
1701 column, J. W. Scientific, 200Ϫ250 °C, retention time ϭ
33.5 min). For comparison, the (R,R) enantiomer of 1c was pre-
pared by hydrogenation of 4,6-nonanedione using (R)-Binap as the
1
(R,R)-N-Benzyl-2,4-dimethylazetidine (2a): H NMR (CDCl3): δ ϭ
1.12 (d, J ϭ 5.8 Hz, Me), 1.89 (t, J ϭ 6.4 Hz, CHCH2CH), 3.59
(AB, J ϭ 13.5 Hz, 1 H, NCH2), 3.65 (m, NCH), 3.76 (AB, 1 H,
NCH2), 7.2Ϫ7.4 (m, Ph). Ϫ 13C NMR (CDCl3): δ ϭ 18.2 (Me),
33.3 (CH2), 54.0 (NCH2Ph), 56.8 (NCH), 126.4, 128.0, 128.4 (CH),
139.7 (C). Ϫ MS: m/z (%) ϭ 175 [Mϩ] (25), 91 (100). Ϫ [α]2D5
Ϫ45 (c ϭ 1, CHCl3).
ϭ
(R,R)-N-Benzyl-2,4-diethylazetidine (2b): 1H NMR (CDCl3): δ ϭ
0.80 (t, J ϭ 7.4 Hz, 6 H, Me), 1.47Ϫ1.61 (m, 4 H, CH2), 1.88 (t,
J ϭ 6.5 Hz, 2 H, CHCH2CH), 3.33Ϫ3.47 (m, 2 H, NCH), 3.61
(AB, J ϭ 13.8 Hz, 1 H, NCH2), 3.85 (AB, 1 H, NCH2), 7.2Ϫ7.4
(m, Ph). Ϫ 13C NMR (CDCl3): δ 9.6 (Me), 25.3 (CH2), 29.0 (CH2),
54.4 (NCH2Ph), 63.1 (NCH), 126.5, 128.2, 128.3 (CH), 140.5 (C).
Ϫ MS: m/z (%) ϭ 203 [Mϩ] (8), 174 [Mϩ Ϫ C2H5] (54), 91 (100).
Ϫ [α]2D5 ϭ Ϫ88 (c ϭ 1, CHCl3).
1
(R,R)-N-Benzyl-2,4-dipropylazetidine (2c): H NMR (CDCl3): δ ϭ
0.87 (t, J ϭ 7.1 Hz, 6 H, Me), 1.1Ϫ1.3 (m, 4 H, CH2), 1.49 (m, 4
H, CH2), 1.88 (t, J ϭ 6.5 Hz, 2 H, CHCH2CH), 3.33Ϫ3.47 (m, J ϭ
6.5 Hz, 2 H, NCH), 3.58 (AB, J ϭ 13.9 Hz, 1 H, NCH2), 3.82 (AB,
1 H, NCH2), 7.2Ϫ7.3 (m, Ph). Ϫ 13C NMR (CDCl3): δ ϭ 14.3
(Me), 18.8 (CH2), 30.1 (CH2), 34.7 (CH2), 54.2 (NCH2Ph), 61.6
(NCH), 126.4, 128.1, 128.2 (CH), 140.0 (C). Ϫ MS: m/z (%) ϭ 231
[Mϩ] (5), 188 [Mϩ Ϫ C3H7] (66), 91 (100). Ϫ [α]2D5 ϭ Ϫ92 (c ϭ
1, CHCl3).
1
chiral ligand. The corresponding Mosher ester showed a H-NMR
signal at δ ϭ 3.54 due to the OMe group and a GC retention time
of 33.0 min. The absolute configuration of 1c was assumed to be
(S,S) by analogy with ref.[11]
Diols (S,S)-1a and (S,S)-1b[29] were prepared according to the same
procedure as above, using (S)-Binap as the chiral ligand. Diol
(R,R)-1d was obtained by [(R)-Binap]ruthenium-promoted hydro-
genation.
1
(S,S)-N-Benzyl-2,4-dibenzylazetidine (2d): H NMR (CDCl3): δ ϭ
1.93 (t, J ϭ 6.4 Hz, 2 H, CHCH2CH), 2.76 (AB, JAB ϭ 12.8 Hz,
3
3JHH ϭ 9.4 Hz, 2 H, CH2Ph), 2.85 (AB, JHH ϭ 5.2 Hz, 2 H,
CH2Ph), 3.64 (AB, J ϭ 13.8 Hz, 1 H, NCH2), 3.8 (m, 2 H, NCH),
3.89 (AB, 1 H, NCH2), 7.1Ϫ7.4 (m, Ph). Ϫ 13C NMR (CDCl3):
δ ϭ 29.2 (CH2), 38.9 (PhCH2), 54.2 (NCH2Ph), 62.5 (NCH). Ϫ
MS: m/z (%) ϭ 327 [Mϩ] (Ͻ5), 236 [Mϩ Ϫ CH2Ph] (57), 91 (100).
Ϫ [α]2D5 ϭ ϩ112 (c ϭ 1, CHCl3).
(S,S)-4,6-Nonanediyl Bis(methanesulfonate): To a solution of (S,S)-
4,6-nonanediol (1c) (2.5 g, 16 mmol) in CH2Cl2 (60 mL) was added
triethylamine (50 mL, 36 mmol). The resulting mixture was cooled
to 0 °C, whereupon methanesulfonyl chloride (2.7 mL, 35 mmol)
was added dropwise over a period of 10 min. After completion of
the addition, the mixture was stirred at 0 °C for 1 h and then
poured into 40 mL of cold 1  HCl. The aqueous layer was ex-
tracted with CH2Cl2 (2 ϫ 30 mL) and the combined organic phases
were washed with saturated NaHCO3 solution, dried with MgSO4,
filtered, and concentrated. The bis(methanesulfonate) was obtained
in quantitative yield (5.0 g) as a colourless oil and was used without
further purification. Ϫ 1H NMR (CDCl3): δ ϭ 0.95 (t, J ϭ 7.2 Hz,
Me), 1.3Ϫ1.5 (m, 4 H, CH2), 1.6Ϫ1.9 (m, 4 H, CH2), 1.97 (dd, J ϭ
5.5 and 6.7 Hz, CHCH2CH), 2.98 (MeSO2), 4.06 (m, 2 H, CHO).
(2R,2ЈR,4R,4ЈR)-1,1Ј-(1,2-Ethanediyl)-2,2Ј,4,4Ј-tetramethylbis-
(azetidine) (3): A mixture of the bis(methanesulfonate) of 1a (1.0 g,
4 mmol), triethylamine (1.7 mL, 12 mmol), and freshly distilled
ethylenediamine (0.14 mL, 2 mmol) was heated at 45 °C for 60 h.
A diethyl ether/MeOH (1:1) mixture was then added to the cooled
reaction mixture. The resulting precipitate was filtered off and the
filtrate was concentrated to dryness. The residual azetidine was
chromatographed on a basic alumina column using an ethyl acet-
ate/methanol (95:5) mixture as eluent (Rf ϭ 0.3) to afford 0.10 g
1
(25%) of a colourless oil. Ϫ H NMR (CDCl3): δ ϭ 1.18 (d, J ϭ
The same procedure was employed for the syntheses of the bis(mes-
ylates) of diols 1a, 1b, and 1d.
6.3 Hz, Me), 1.84 (t, J ϭ 6.4 Hz, CHCH2CH), 2.4Ϫ2.6 (m, 4 H,
NCH2), 3.53 (m, J ϭ 6.4 Hz, NCH). Ϫ 13C NMR (CDCl3): δ ϭ
18.4 (Me), 33.2 (CH2), 49.0 (NCH2), 56.7 (NCH). Ϫ MS: m/z ϭ
196 [Mϩ] (5), 98 (100).
General Procedure for the Synthesis of N-Benzylazetidines 2: The
synthesis of 2a is described here as a representative case. The bis-
(methanesulfonate) of (R,R)-1a (50 mmol) was dissolved in benzyl-
amine (32 mL, 0.30 mol) and the resulting solution was heated at
45 °C for 60 h. A cyclohexane/diethyl ether (1:1) mixture was then
added to the cooled reaction mixture so as to cause precipitation
of benzylammonium methanesulfonate. After filtration and con-
centration of the filtrate to dryness, the residual azetidine was chro-
matographed on a basic alumina column using cyclohexane/ethyl
acetate (95:5) as eluent (Rf ϭ 0.2) in order to separate the excess
benzylamine. Azetidine 2a was obtained in 60% yield (5.3 g) as a
colourless oil.
Synthesis of N-Unsubstituted Azetidines: The procedure for the syn-
thesis of 4a is described here as a representative example.
(R,R)-2,4-Dimethylazetidinium Acetate (4a): N-Benzylazetidine 2a
(2.0 g, 11 mmol) was dissolved in methanol (20 mL) and then 20%
Pd(OH)2 on carbon (0.5 g) was added. The reaction vessel was
placed in a stainless steel autoclave, pressurized to 7 bar with H2,
and heated to 50 °C for 20 h. After cooling to room temperature,
the mixture was filtered and acetic acid (0.75 mL) was added to the
filtrate. The solvent was then evaporated, the residue was taken up
1818
Eur. J. Org. Chem. 2000, 1815Ϫ1820

Enantioselective Preparation of 2,4-Disubstituted Azetidines
in ethyl acetate, and this solution was filtered through Celite to
FULL PAPER
[ArNCHMe] (93), 184 [ArNCH] (100). Ϫ [α]D ϭ Ϫ166 (c ϭ 1,
afford pure 4a. Ϫ 1H NMR (CDCl3): δ ϭ 1.50 (d, J ϭ 6.8 Hz, CHCl3).
Me), 1.99 (s, Me), 2.24 (t, J ϭ 7.6 Hz, CHCH2CH), 4.32 (m, NCH).
(R,R)-2,4-Dimethyl-N-(1-naphthyl)azetidine (5e):
1H NMR
Ϫ
13C NMR (CDCl3): δ ϭ 19.2 (Me), 23.4 (MeCO), 33.1 (CH2),
(CDCl3): δ ϭ 1.21 (d, J ϭ 6.2 Hz, Me), 2.19 (t, J ϭ 6.5 Hz,
CHCH2CH), 4.64 (m, NCH), 6.65 (m, 1 H), 7.3Ϫ7.5 (m, 4 H), 7.8
(m, 1 H), 7.9 (m, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 19.1 (Me), 32.8
(CH2), 57.9 (NCH), 109.7, 119.9, 123.7, 124.4, 125.6, 126.0 (CH),
126.7 (C), 128.3 (CH), 134.6 (C), 145.0 (NC). Ϫ MS: m/z (%) ϭ
51.7 (NCH), 177.5 (CO2). Ϫ MS (DCI/NH3): m/z (%) ϭ 103
[C5H12N ϩ NH3] (10), 86 [C5H12N] (100). Ϫ [α]2D5 ϭ Ϫ8 (c ϭ 1,
CHCl3).
1
(R,R)-2,4-Diethylazetidinium Acetate (4b): H NMR (CDCl3): δ ϭ
0.97 (t, J ϭ 7.4 Hz, Me), 1.9 (m, 4 H, CH2), 2.06 (s, Me), 2.26 (t, 211 [Mϩ] (90), 196 [Mϩ Ϫ Me] (43), 169 [ArNCHMe] (100), 154
J ϭ 7.8 Hz, CHCH2CH), 4.25 (m, NCH). Ϫ 13C NMR (CDCl3): [ArNCH] (100). Ϫ [α]D ϭ Ϫ222 (c ϭ 1, CHCl3).
δ ϭ 9.3 (Me), 21.0 (MeCO), 26.8 (CH2), 29.2 (CH2), 58.4 (NCH),
(R,R)-2,4-Dimethyl-N-[p-(trifluoromethyl)phenyl]azetidine (5f): 1H
176.0 (CO2). Ϫ MS (DCI/NH3): m/z (%) ϭ 156 [C7H16N ϩ NH3]
NMR (CDCl3): δ ϭ 1.35 (d, J ϭ 6.2 Hz, Me), 2.11 (t, J ϭ 6.4 Hz,
(10), 114 [C7H16N] (100). Ϫ [α]2D5 ϭ Ϫ23 (c ϭ 1, CHCl3).
CHCH2CH), 4.36 (m, NCH), 6.43 (d, J ϭ 8.4 Hz, 2 H), 7.40 (d,
(R,R)-2,4-Dipropylazetidinium Acetate (4c): 1H NMR (CDCl3): δ ϭ
J ϭ 8.4 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 19.6 (Me), 33.0 (CH2),
0.93 (t, J ϭ 7.1 Hz, Me), 1.3 (m, 4 H, CH2), 1.8 (m, 4 H, CH2), 55.6 (NCH), 111.6 (CH), 126.2 (CH), 150.3 (NC). Ϫ MS: m/z
2.01 (s, Me), 2.24 (t, J ϭ 7.7 Hz, CHCH2CH), 4.22 (m, J ϭ 7.7 Hz, (%) ϭ 229 [Mϩ] (27), 214 [Mϩ Ϫ Me] (47), 172 [ArNCH] (100). Ϫ
NCH). Ϫ 13C NMR (CDCl3): δ ϭ 13.5 (Me), 18.3 (CH2), 30.1
(CH2), 35.5 (CH2), 56.4 (NCH). Ϫ MS (DCI/NH3): m/z (%) ϭ 142
(C9H20N). Ϫ [α]2D5 ϭ Ϫ24 (c ϭ 1, CHCl3).
[α]D ϭ Ϫ115 (c ϭ 1, CHCl3).
(R,R)-N-{3-[(R,R)-2,4-Dimethyl-1-azetidinylmethyl]phenyl}-2,4-
dimethylazetidine (5g): 1H NMR (CDCl3): δ ϭ 1.12 (d, J ϭ 6.4 Hz,
Me), 1.31 (d, J ϭ 6.4 Hz, Me), 1.85 (t, J ϭ 6.4 Hz, CHCH2CH),
2.05 (t, J ϭ 6.4 Hz, CHCH2CH), 3.47 (AB, JAB ϭ 13.3 Hz, 1 H,
General Procedure for the Palladium-Catalysed Coupling Reactions:
A mixture of the aryl bromide (1 mmol), azetidinium acetate 4
(1.2 mmol), Pd2(dba)3 (9 mg, 2 mol-% Pd), and NaOtBu (0.35 g, NCH2Ph), 3.59 (m, 2 H, NCH), 3.66 (AB, 1 H, NCH2Ph), 4.28
3.6 mmol) in toluene (5 mL) was heated at 70 °C for 6Ϫ9 h. After (m, 2 H, NCH), 6.33 (dd, J ϭ 8.0 Hz, 1 H), 6.45 (s, 1 H), 6.67 (d,
cooling to room temperature, the mixture was diluted with diethyl J ϭ 7.5 Hz, 1 H), 7.10 (t, J ϭ 7.8 Hz, 1 H). Ϫ 13C NMR (CDCl3):
ether and filtered through Celite. After evaporation of the solvent
from the filtrate, the residue was purified by chromatography on
alumina eluting with cyclohexane or cyclohexane/AcOEt mixtures.
The azetidines 5 were recovered as colourless oils in the yields listed
in Table 1. In the syntheses of 5d and 5h, the reaction mixtures
were heated at 100 °C for 18 h.
δ ϭ 18.4 (Me), 19.6 (Me), 33.0 (CH2), 33.3 (CH2), 54.5 (NCH2Ph),
55.5 (NCH), 56.9 (NCH), 111.4, 113.4, 117.4, 128.6 (CH), 140.4
(C), 148.1 (NC). Ϫ MS: m/z (%) ϭ 258 [Mϩ] (18), 175 (100).
(R,R)-2,4-Diethyl-N-(o-tolyl)azetidine (5h): 1H NMR (CDCl3): δ ϭ
0.83 (t, J ϭ 7.4 Hz, Me), 1.3Ϫ1.5 (m, CH2), 2.02 (t, J ϭ 6.1 Hz,
CHCH2CH), 2.12 (Me), 4.07 (m, NCH), 6.61 (d, J ϭ 8.1 Hz, 1 H),
6.76 (t, J ϭ 7.3 Hz, 1 H), 7.02Ϫ7.11 (m, 2 H). Ϫ 13C NMR
(R,R)-2,4-Dimethyl-N-phenylazetidine (5a): 1H NMR (CDCl3): δ ϭ
1.33 (d, J ϭ 6.1 Hz, Me), 2.08 (t, J ϭ 6.4 Hz, CHCH2CH), 4.30 (CDCl3): δ ϭ 9.0 (Me), 19.2 (Me), 26.0 (CH2), 27.8 (CH2), 61.8
(m, J ϭ 6.2 Hz, NCH), 6.48 (d, J ϭ 8.4 Hz, CH-ortho), 6.70 (t,
J ϭ 7.3 Hz, CH-para), 7.20 (m, CH-meta). Ϫ 13C NMR (CDCl3):
δ ϭ 19.5 (Me), 33.0 (CH2), 55.5 (NCH), 113.1, 116.8, 128.8 (CH),
148.2 (NC). Ϫ MS: m/z (%) ϭ 161 [Mϩ] (67), 146 [Mϩ Ϫ Me] (57),
104 [PhNCH] (100). Ϫ [α]D ϭ Ϫ186 (c ϭ 1, CHCl3).
(NCH), 114.1, 119.4, 126.1 (CH), 130.8 (CH). Ϫ MS: m/z (%) ϭ
203 [Mϩ] (33), 174 [Mϩ Ϫ Et] (100), 118 [ArNCH] (77).
Synthesis of the Cyclopalladated Complex 8: According to the pro-
cedure described by Cope and Friedrich,[30] a mixture of Na2PdCl4
(0.29 g, 1 mmol) and (R,R)-N-benzyl-2,4-dimethylazetidine (2a)
(R,R)-2,4-Dimethyl-N-(o-tolyl)azetidine (5b): 1H NMR (CDCl3): (0.21 g, 1.2 mmol) in methanol (10 mL) was stirred at room tem-
δ ϭ 1.19 (d, J ϭ 6.2 Hz, Me), 2.05 (t, J ϭ 6.4 Hz, CHCH2CH),
2.15 (Me), 4.32 (m, J ϭ 6.3 Hz, NCH), 6.61 (d, J ϭ 8.2 Hz, CH- ate. The product was filtered off, washed with MeOH, and dried
ortho), 6.80 (t, CH-para), 7.10 (m, CH-meta). Ϫ 13C NMR
in vacuo. It was redissolved in chloroform and the resulting solu-
perature for 16 h, which led to the deposition of a yellow precipit-
(CDCl3): δ ϭ 19.1 (Me), 19.3 (Me), 32.6 (CH2), 56.1 (NCH), 114.3, tion was filtered through Celite to afford pure 8 as a pale-yellow
119.5, 126.2 (CH), 127.1 (C), 131.0 (CH), 146.7 (NC). Ϫ MS: m/z powder. Yield: 0.29 g (93%). Ϫ 1H NMR (400.13 MHz, CDCl3):
(%) ϭ 175 [Mϩ] (50), 160 [Mϩ Ϫ Me] (40), 118 [ArNCH] (100). Ϫ δ ϭ 1.43 (d, J ϭ 7.0 Hz, Me), 1.45 (d, J ϭ 7.1 Hz, Me), 1.78 (d,
[α]D ϭ Ϫ101 (c ϭ 1, CHCl3).
J ϭ 6.6 Hz, Me), 1.81 (d, J ϭ 6.6 Hz, Me), 2.0Ϫ2.1 (m, 2 H, CH2),
2.35 (dt, J ϭ 10.6 Hz, J ϭ 7.5 Hz, 1 H, CH2), 2.45 (dt, J ϭ 10.9 Hz,
J ϭ 8.2 Hz, 1 H, CH2), 3.58 (m, 2 H, CH), 3.73 (AB, J ϭ 13.3 Hz,
1 H, NCH2Ph), 3.74 (AB, J ϭ 13.3 Hz, 1 H, NCH2Ph), 4.58 (AB,
1 H, NCH2Ph), 4.60 (AB, 1 H, NCH2Ph), 4.73 (m, 2 H, NCH),
6.8Ϫ6.9 (m, 6 H, Ph), 7.13 (d, J ϭ 7.7 Hz, 2 H, Ph). Ϫ 13C NMR
(100.62 MHz, CDCl3): δ ϭ 15.8 (Me), 15.9 (Me), 25.9 (Me), 26.0
(Me), 32.4 (CH2), 32.5 (CH2), 60.9 (NCH), 62.0 (NCH), 65.7
(NCH2Ph), 65.8 (NCH2Ph), 69.0 (NCH), 69.3 (NCH), 121.2,
124.3, 125.0, 125.1, 132.7, 133.1 (CH), 142.8, 143.0, 145.9, 146.1
(C). Ϫ [α]2D5 ϭ Ϫ115 (c ϭ 0.5, CHCl3).
(R,R)-N-(o-Anisyl)-2,4-dimethylazetidine (5c): 1H NMR (CDCl3):
δ ϭ 1.20 (d, J ϭ 6.2 Hz, Me), 2.05 (t, J ϭ 6.5 Hz, CHCH2CH),
3.81 (OMe), 4.33 (m, NCH), 6.6 (m, 1 H), 6.8Ϫ6.9 (m, 3 H). Ϫ
13C NMR (CDCl3): δ ϭ 19.4 (Me), 33.2 (CH2), 55.0 (NCH), 56.7
(OMe), 110.3, 114.2, 119.4, 120.9 (CH), 137.7 (C), 149.8 (NC). Ϫ
MS: m/z (%) ϭ 191 [Mϩ] (63), 176 [Mϩ Ϫ Me] (57), 134 [ArNCH]
(100). Ϫ [α]D ϭ Ϫ139 (c ϭ 1, CHCl3).
(R,R)-N-(o-Bromophenyl)-2,4-dimethylazetidine (5d): 1H NMR
(CDCl3): δ ϭ 1.21 (d, J ϭ 6.2 Hz, Me), 2.06 (t, J ϭ 6.5 Hz,
CHCH2CH), 4.55 (m, NCH), 6.64 (dd, J ϭ 8.1 Hz, 1 H), 6.71 (td,
J ϭ 7.7 Hz, 1 H), 7.18 (td, J ϭ 8.1 Hz, 1 H), 7.43 (dd, J ϭ 7.8 Hz,
1 H). Ϫ 13C NMR (CDCl3): δ ϭ 19.3 (Me), 32.0 (CH2), 56.7
(NCH), 111.8 (C), 116.3, 120.5, 127.6, 133.7 (CH), 146.3 (NC).
Ϫ MS: m/z (%) (81Br) ϭ 241 [Mϩ] (50), 226 [M Ϫ Me] (43), 199
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