Diastereoselective aldol reaction of zincated 3-Chloro-3-methyl-1- azaallylic anions as key step in the synthesis of 1,2,3,4-tetrasubstituted 3-chloroazetidines

Article abstract of DOI:10.1021/jo300203t

Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-β-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-β-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.

Full text of DOI:10.1021/jo300203t

Article
pubs.acs.org/joc
Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-
azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-
Tetrasubstituted 3-Chloroazetidines
Sven Mangelinckx,†,§ Bart De Sterck,‡,# Filip Colpaert,†,§ Saron Catak,‡ Jan Jacobs,†,§ Stijn Rooryck,†
Michel Waroquier,‡ Veronique Van Speybroeck,‡ and Norbert De Kimpe*,†
†Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
‡Center for Molecular Modeling, Ghent University, Technologiepark 903, B-9052 Zwijnaarde, Belgium, Member of QCMM Alliance
Ghent-Brussels
S
* Supporting Information
ABSTRACT: Zincated 3-chloro-3-methyl-1-azaallylic anions
undergo a stereoselective aldol addition across aromatic aldehydes
and subsequent mesylation to produce syn α-chloro-β-mesylox-
yketimines, which were isolated in 80−84% yield and high
diastereomeric excess (dr > 97/3) after purification via flash
chromatography. The syn α-chloro-β-mesyloxyketimines were
further stereoselectively reduced to give stereochemically defined
3-aminopropyl mesylates, which were cyclized to 1,2,3,4-
tetrasubstituted 3-chloroazetidines containing three contiguous
stereogenic centers. DFT calculations on the key aldol addition
revealed the presence of a highly ordered bimetallic six-membered
twist-boat-like transition state structure with a tetra-coordinated
metal cyclic structure. DFT calculations revealed that chelation of
both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of
aldol reactions.
Scheme 1. Synthesis of Highly Substituted 3-Haloazetidines
3
INTRODUCTION
■
The stereoselective synthesis of azetidines, particularly of highly
substituted derivatives, represents an underdeveloped research
area, despite their importance as a class of strained
azaheterocyclic compounds, which occur in a wide range of
natural products and with application in medicinal chemistry
for the synthesis of bioactive compound libraries.1 3-
Haloazetidines, in particular, form an important subclass of
functionalized four-membered azaheterocycles due to their
potential physiological activities and their use as synthons in the
synthesis of 3-substituted azetidine derivatives.2 Only very
recently, our group reported the first asymmetric synthesis of
trans-2-aryl-3-chloroazetidines via cyclization of optically pure
β-chloro-γ-sulfonylamino alcohols under Mitsunobu condi-
tions.3 The latter result, together with a variety of other
examples,1h,4 demonstrated that the cyclization of a preformed
aminopropyl chain via nucleophilic substitution of a leaving
group, such as a chloride, bromide, or an activated hydroxyl
group, in the γ-position, forms a general method to prepare
azetidines. The applicability of this method for the stereo-
selective synthesis of highly substituted 3-haloazetidines 3
depends, naturally, on the efficient synthetic accessibility of the
corresponding stereochemically defined aminopropyl precur-
sors 2 (Scheme 1). Metalated 3-chloro-1-azaallylic anions 15
have proven to be suitable building blocks in organic synthesis
by reaction with electrophiles and elaboration of the resulting
functionalized α-chloroketimines.6 More specifically, the aldol
reaction of 3,3-dichloro-1-azaallylic anions 1 (R3 = Cl) with
aromatic aldehydes, followed by mesylation to the correspond-
ing β-mesyloxyketimines,7 and reduction afforded amines 2 (R3
= Cl) as precursors of stereochemically defined 2,4-diaryl-3,3-
dichloroazetidines 3 (R3 = Cl).8 In previous computational
research, the 3-chloro-3-methyl-1-azaallylic anion 1 (R3 = Me)
was chosen as a model compound to obtain deeper insight into
the structural features of 3-halo-1-azaallylic anions and a better
Received: January 27, 2012
Published: March 5, 2012
© 2012 American Chemical Society
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Table 1. Aldol Reaction of Anions 1a and 1b Derived from Imine 4a with Benzaldehyde 5a
a
entry
LDA (equiv)
M
reaction conditions
1.05 equiv 5a, 0 °C, 1 h
1.05 equiv 5a, −78 °C, 1 h
0.5 equiv 5a, −78 °C, 10 min
1.05 equiv 5a, −40 °C, 1 h
1.05 equiv 5a, −40 °C, 1 h
1.05 equiv 5a, −78 °C, 10 min
0.5 equiv 5a, −78 °C, 5 min
0.5 equiv 5a, −78 °C, 5 min then 0 °C, 1 h
1.05 equiv 5a, −78 °C, 5 min then 0 °C, 1 h
1.05 equiv 5a, −78 °C, 5 min then rt, 1 h
0.5 equiv 5a, −78 °C, 5 min then rt, 1 h
0.75 equiv 5a, −78 °C, 5 min then rt, 1 h
0.25 equiv 5a, −78 °C, 5 min then rt, 1 h
0.5 equiv 5a, rt, 1 h
syn 6a/anti 6a/cis 7a/trans 7a
b
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.3
1.3
1.3
1.3
1.3
1.3
1.3
Li
47/0/6/47
2
Li
57/33/0/10
58/39/0/3
52/14/7/27
66/32/0/2
80/20/0/0
89/11/0/0
85/12/0/3
75/17/0/8
3
Li
4
Li
5
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
6
7
8
9
c
10
11
12
13
14
15
72/4/0/24
d
87/2/0/11
77/0/0/23
80/0/0/20
e
85/0/0/15
f
Li
0.5 equiv 5a, −78 °C, 5 min then rt, 1 h
63/0/0/37
a
b
Determined via 1H NMR analysis (300 MHz, CDCl3) of the crude reaction mixture. syn 6a (dr >99/1) was isolated in 39% yield via crystallization
from the reaction mixture in MeOH and an impure sample of trans 7a was obtained via a second crystallization from the mother liquor. syn 8a (dr
c
>95/5) was isolated via column chromatography in 68% yield after mesylation of the reaction mixture with 1.5 equiv MsCl in pyridine at room
d
temperature for 22 h. syn 8a (dr >97/3) was isolated via column chromatography in 80% yield after mesylation of the reaction mixture with 1.5
e
equiv MsCl in pyridine at room temperature for 22 h. syn 8a (dr >99/1) was isolated via column chromatography in 63% yield after mesylation of
f
the reaction mixture with 1.5 equiv MsCl in pyridine at room temperature for 22 h. LiCl was added instead of ZnCl2.
Scheme 2. Aldol Reaction of Imines 4 and Further Transformation to 3-Chloroazetidines 3
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Table 2. Stability Study of syn-Chlorohydrin 6a
a
entry
temp (°C)/time (min)
syn 6a/trans 7a
1
2
3
−78/5
0/5
97/3
96/4
96/4
0/5 + rt/60
a
1
Determined via H NMR analysis (300 MHz, CDCl3) of the crude reaction mixture.
understanding of the factors that control the stereochemical
be accomplished upon lowering the reaction temperature to
−40 or −78 °C, which resulted in even more tedious
inseparable reaction mixtures due to the additional presence
of significant amounts of the anti-aldol adduct 6a (14−39%)
besides the epoxides 7a (entries 2−4). At 0 °C, the initially
formed lithiated anti-adduct spontaneously cyclized to form the
trans-imidoylepoxide 7a, while the lithiated syn-adduct cyclized
only to a minor extent due to sterical hindrance of the
benzimidoyl and phenyl substituents during cyclization16 and
formed the syn α-chloro-β-hydroxyketimine 6a after aqueous
workup. Similar results were obtained for aldol reactions at 0
°C using imine 4b and 4-chlorobenzaldehyde 5b, resulting in
the isolation of syn α-chloro-β-hydroxyketimines 6b,c in low
yields (Scheme 2).
Use of the zincated 3-chloro-3-methyl-1-azaallylic anion 1b,
obtained via transmetalation of the lithiated anion 1a with
ZnCl2 at 0 °C, proved to be beneficial as it slightly improved
the diastereoselectivity of the aldol reaction with benzaldehyde
5a at −40 °C and afforded smaller amounts of the epoxides 7a
(Table 1, entry 5). The syn-diastereoselectivity of the aldol
reaction with the zincated anion 1b was, however, greatly
improved (up to dr syn/anti 89/11) by further lowering the
reaction temperature to −78 °C, shortening the reaction time,
and increasing the amount of 1-azaallylic anion (Table 1,
entries 6 and 7). Nevertheless, it was not possible to separate
the syn α-chloro-β-hydroxyketimine 6a from the anti-adduct 6a
via crystallization in good yield and good diastereomeric excess
due to the occurrence of concomitant retro-aldol reactions.
Therefore, to reduce the undesired amount of anti α-chloro-β-
hydroxyketimine 6a present in the reaction mixture, the initial
temperature of the aldol reaction at −78 °C was increased
again, resulting in some decrease of syn-diastereoselectivity and
partial or full cyclization of the zincated anti-adduct to trans-
epoxide 7a (entries 8−13).
Eventually, it was found that at room temperature almost all
of the zincated anti-adduct cyclized, conveniently providing the
syn α-chloro-β-hydroxyketimine 6a as the major compound (syn
6a/anti 6a = 98/2) in the reaction mixture after workup (entry
11). The latter adduct was chromatographically isolated as the
corresponding syn-mesylate 8a (to avoid retro-aldol reaction) in
80% yield (dr > 97/3) after treatment of the crude reaction
mixture with mesyl chloride in pyridine for 22 h (Scheme 2).
Changing the amount of benzaldehyde 5a to 0.25 and 0.75
equiv, added under the latter optimized conditions, did not
afford improved diastereoselectivities (entries 12 and 13).
Furthermore, when benzaldehyde 5a was added directly at
room temperature to the zincated 1-azaallylic anion 1b, only a
small decrease of diastereoselectivity was observed, but after
mesylation the corresponding syn-mesylate 8a was isolated in a
outcome of the reactions involving these anions.9,10
Herein, the use of 3-chloro-3-methyl-1-azaallylic anions 1 (R3
= Me) in aldol reactions with aromatic aldehydes is
reported,11,12 en route to the stereoselective synthesis of new
azetidines 3 (R3 = Me) with a chlorinated quaternary
stereocenter at the 3-position and tertiary stereocenters at the
2- and 4-positions. To the best of our knowledge, the only
report on the synthesis of such type of 3-haloazetidines with
carbon-centered substituents at the 1-, 2-, 3-, and 4-positions
involves the reaction of 1,2,2,3-tetrasubstituted aziridines or
substituted 4-oxazolines, via the corresponding intermediate
azomethine ylides, with sulfur ylides.13 The aldol step has been
investigated by means of theoretical calculations in order to
better understand the effect of metal-coordination in the
transition state structures and its effect on the diastereoselective
outcome.
RESULT AND DISCUSSION
■
Experimental Results. Previous reported theoretical
calculations demonstrated that the lithiated 3-chloro-3-meth-
yl-1-azaallylic anion 1a (M = Li, R1 = iPr, R2 = C6H5, R3 = Me)
is present in a monosolvated monomeric Z-isomer form and
should readily undergo transmetalation to the zincated Z-
isomer 1b (M = ZnCl, R1 = iPr, R2 = C6H5, R3 = Me).9,10 In
order the verify these calculations and to use these new
fundamental insights in stereoselective organic synthesis, anions
1a and 1b, derived from the N-isopropylimine 4a of α-
chloropropiophenone, were reacted with aromatic aldehydes 5
(Table 1, Scheme 2). N-Isopropyl-α-chloro imine 4a was
prepared by condensation of α-chloropropiophenone with
isopropylamine in the presence of titanium(IV) chloride.14
Treatment of N-isopropyl-α-chloro imine 4a with lithium
diisopropylamide in tetrahydrofuran at 0 °C provided the
lithiated 3-chloro-3-methyl-1-azaallylic anion 1a,9 which was
further reacted with benzaldehyde 5a at 0 °C for 1 h. After
aqueous workup, a mixture of syn α-chloro-β-hydroxyketimine
6a (major compound) together with the corresponding ring-
closed cis- and trans-imidoylepoxides 7a was obtained (Table 1,
entry 1). The former syn-adduct 6a was isolated in 39% yield
from the reaction mixture via rapid crystallization in methanol,
while all attempts to isolate other reaction products in pure
form by a second crystallization from the mother liquor or
through column chromatography on silica gel failed. Only an
impure sample of trans epoxide 7a was obtained after a second
crystallization from the mother liquor and the trans stereo-
3
chemistry was confirmed by the fact that a JCH of ∼0 Hz was
observed for the trans-CH3 and -H oxirane ring substituents.15
No improvement on the stereoselectivity of the reaction could
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Scheme 3. Attempted Cyclization of syn-Chlorohydrin 6a to cis-Imidoylepoxide 7a
lower yield of 63% (dr > 99/1) (entry 14). When LiCl was
used instead of ZnCl2, a large decrease of diastereoselectivity
was observed (entry 15).
Scheme 4. Model for the Stereoselective Reduction of Imine
8
Noteworthy, only a negligible decrease of syn-diastereose-
lectivity was observed when the initial temperature of the aldol
reaction at −78 °C was increased for 1 h to room temperature
(entry 7, syn/anti 89/11 versus entry 11, syn/anti 87/13).
Probably, this can be explained by the fact that the aldol
reaction of zincated anion 1b with benzaldehyde 5a is not an
equilibrated reaction, in which retro-aldol reaction of the
formed zincated syn-adduct at room temperature is prevented
or only occurs to a minor extent. This was confirmed by
treating isolated syn α-chloro-β-hydroxyketimine 6a under
similar reaction conditions (Table 2). ZnCl2 was added to
LDA in THF at 0 °C for 15 min, after which syn α-chloro-β-
hydroxyketimine 6a was added and the reaction was stirred at
−78 °C for 5 min (entry 1), at 0 °C for 5 min (entry 2) or at 0
°C, followed by 1 h at room temperature (entry 3). In all cases,
the retro-aldol-mediated isomerization of adduct syn 6a to
epoxide trans 7a was very limited (<5%) (Table 2).
Application of the optimized reaction conditions of the aldol
reaction (Table 1, entry 11) allowed the isolation of syn α-
chloro-β-mesyloxyketimines 8b−d (dr > 97/3) in 80−84%
yield after purification via flash chromatography (Scheme 2). It
is noteworthy that in all cases α-chloro-α-methanesulfonylke-
timines 9 (formed by reaction of the excess of imines 4 with
mesyl chloride) were also isolated as byproduct in 12−19%
yield.
In order to confirm the syn-stereochemistry of chlorohydrin
6a, attempts for a stereospecific cyclization to cis-imidoylep-
oxide 7a via treatment with potassium hydroxide (1.5 equiv) in
water/tetrahydrofuran (1:1) were made.6c However, all
attempts (0 °C, 3 h; room temperature, 6 h; 40 °C, 4 h)
failed due to the competitive retro-aldol reaction, resulting in
inseparable mixtures of benzaldehyde 5a, syn-chlorohydrin 6a
(0−9%), α-chloropropiophenone imine 4a (16−25%), cis-
epoxide 7a (36−61%), and trans-epoxide 7a (21−30%)
(Scheme 3).
On the other hand, the syn β-hydroxyketimines 6 could be
stereospecifically and stereoselectively converted into the
targeted azetidines 3. This transformation involved mesylation,
followed by stereoselective reduction of the β-mesyloxyketi-
mines 8 with NaCNBH3 and base-induced cyclization of the
stereochemically defined β-chloro-γ-mesyloxypropylamines 2
upon heating in DMSO (Scheme 2).8 The observed stereo-
selectivity for the reduction of syn α-chloro-β-mesyloxyketi-
mines 8 to amines 2 can be best rationalized by means of
merging Evans’ steric model for 1,3-induction8a,17 and Cram’s
chelation model for 1,2-induction,18 as shown in Scheme 4.19
Noteworthy, after reduction of β-mesyloxyketimine 8d (R1 =
Me, R2 = H), a mixture of β-chloro-γ-mesyloxypropylamine 2d
and 2,4-diaryl-3-chloro-3-methylazetidine 3d was obtained in a
ratio of 71:29. After flash chromatography, γ-mesyloxypropyl-
amine 2d and 2,4-diaryl-3-chloro-3-methylazetidine 3d were
isolated in 58% and 23% yield, respectively.
The cis-relationship of the methine C2- and C4-protons of
azetidines 3 was ascertained by the chemical equivalence of
these protons in 1H NMR for symmetrical azetidine 3a.
Furthermore, the cis-relationship of the C3-methyl substituent
and the C2- and C4-aromatic groups was concluded from the
typical upfield chemical shift (0.71−0.72 ppm) of the methyl
protons in 1H NMR due to the shielding caused by the
1
aromatic rings. Moreover, comparison with H NMR chemical
shift data of 3-methyl substituents of similar cis- and trans-3-
methyl-2(,4-di)phenylazetidines and -oxetanes from literature
confirmed this cis-relationship.4a−d,h,20 The stereochemistry of
azetidines 3 confirmed the previously assigned stereochemistry
of the syn-chlorohydrins 6.
From the experimental results mentioned above, it is clear
that syn-chlorohydrins 6 are the kinetically favored products of
the aldol reaction between lithiated and especially zincated
azaallylic anions 1 and aromatic aldehydes 5. On the other
hand, a thermodynamic equilibration of the aldol products 6 via
retro-aldol reaction under basic conditions (Scheme 3) results
in the increased formation of the trans-imidoylepoxides 7.
Earlier theoretical literature showed that the bidentate
monomeric Z/anti azaallylic anions 1a and 1b are the most
favored configurations due to a strong internal halogen-metal
interaction. Therefore, the formation of the kinetic syn-
chlorohydrins 6 upon protonation of the metal-chelated syn
adducts 10,21 the expected diastereomers from an enolate with
Z-geometry,22 is reasonably explained via the postulated boat-
like transition state model in which the halogen-metal
coordination is expected to be crucial (Scheme 5).23
In the six-membered chelated transition structure (syn-TS,
Scheme 5), the phenyl group of benzaldehyde occupies the
less-hindered pseudoequatorial position. The following section
focuses on the theoretical elucidation of the stereochemical
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Scheme 5. Postulated Boat-Like Transition State Model for the Aldol Reaction of Azaallylic Anions 1
Figure 1. Syn and anti transition state structures for the aldol reaction of 3-chloro-3-methyl-1-azaallylic anions 1 and benzaldehyde 5a in the presence
of a Li+ cation (with one solvating THF molecule). B3LYP/6-31+G(d,p) optimized geometries.
outcome of this aldol reaction, paying particular attention to
metal coordination of the 1-azaallylic anion and its influence on
the conformation of transition states involved. We will thus be
able to further validate the proposed transition state in Scheme
5.
Theoretical Results. In order to explain the experimentally
observed syn stereoselectivity, transition states leading to both
the syn and anti adducts 10 were modeled in the presence of
lithium and zinc counterions. Due to the strong coordination
with these counterions, a very well-defined and low barrier
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Figure 2. Syn and anti transition state structures for the aldol reaction of 3-chloro-3-methyl-1-azaallylic anions 1 and benzaldehyde 5a in the presence
of a ZnCl+ and Li+ cation (with one solvating THF molecule). B3LYP/6-31+G(d,p) optimized geometries.
transition state could be located for both the anti and syn
addition of the 3-chloro-3-methyl-1-azaallylic anions 1 across
benzaldehyde 5a. These transition states are characterized by a
“boat-like” geometry that is stabilized by the strong interaction
between the metal cation, the halogen, and the benzaldehyde
oxygen (Scheme 5 and Figure 1). Other possible transition
state structures resulting from a rotation around the forming
C−C bond were located; however, these structures all lack the
beneficial metal−oxygen interaction and are less stable by 31.3
kJ/mol (for Li+) and 70−88 kJ/mol (for ZnCl+). In the
literature, several crystallographic studies of aldol reactions are
known in which the aldolate six-membered ring adopts boat-
like and/or half-chair chelate conformations.24
All computations were performed using the Gaussian09
program package.25 Geometry optimizations for the transition
states were carried out using the B3LYP26−28 hybrid functional
and a 6-31+G(d,p) basis set. The nature of the transition states
was confirmed by normal modes analysis. From these
optimized structures, energy refinements were performed
using recently developed density functionals B97D29 and
M06-2X30 and a 6-311+G(d,p) basis set. Both electronic
structure methods are able to account for dispersion
interactions. In the case of B97D, this is realized by explicit
inclusion of damped atom-pairwise dispersion corrections,
whereas the M06-2X functional is a high-nonlocal functional
shown to perform well in organic systems with dispersion
effects.31 The effect of solvation is taken into account as the
sum of two contributions: one resulting from the coordination
of solvent molecules to the solute by adding explicit THF
molecules and the other originating from the bulk solvent effect
by embedding the system in a polarizable continuum model.
This approach, known as the explicit/implicit solvation model,
has been used extensively to model organic reactions in
solution.32 The parameter set used for the description of the
cavity and the solvent is crucial for obtaining reliable energies,
and therefore the recently developed SMD model is used.33
Syn and anti transition state structures (TS1-syn and TS1-
anti, respectively) for the aldol reaction of azaallylic anions 1
and benzaldehyde 5a in the presence of a Li+ cation (with one
solvating THF molecule) are shown in Figure 1. In our
previous work,9,10 it was shown that transmetalation of lithiated
azaallylic anions 1a to zincated anions 1b takes place with ease.
Subsequently, azaallylic anions 1b are present as monomers and
bear a ZnCl+ cation; however, free lithium cations are also
expected to interact with the benzaldehyde oxygen to which the
negative charge will be transferred after the addition reaction.
This interaction was modeled by including both lithium and
zinc in the transition states, resulting in the bicoordinated
structures shown in Figure 2 (TS2-syn and TS2-anti). In both
syn transition states (TS1-syn and TS2-syn), the six-membered
ring aldolate adopts a more energetically favored “twist-boat-
like” conformation, whereas in the anti counterparts (TS1-anti
and TS2-anti) a less energetically favored “boat-like”
conformation is observed. Furthermore, in the syn transition
states, the phenyl group of benzaldehyde occupies the less-
hindered pseudoequatorial position, whereas in the anti, the
phenyl group of benzaldehyde occupies the more hindered
pseudoaxial position leading to a more pronounced steric
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hindrance. In all four transition states, the benzaldehyde
carbonyl moiety still has a double bond character; bond lengths
in the 1-azaallylic anion show partial double bond character,
which are indicative of early transition states. Figures 1 and 2
also indicate differences in metal coordination between the
transition states. Noteworthy, TS2-syn and TS2-anti appear as
four/six-membered bicyclic aldolates, in which the lithium is
part of a four-membered metal cycle, coordinating with the
benzaldehyde oxygen and with the chlorine atom attached to
the zinc−metal.
Noteworthy, in Table 1 entries 10−13, it was shown in the
aldol reaction that the best syn-diastereoselectivity was obtained
using 0.5 equiv benzaldehyde 5a (i.e., 2.0 equiv of the zincated
anion 1b) (entry 11) instead of 0.25, 0.75, or 1.05 equiv 5a
(entries 10, 12, 13). This may be explained by the possibility of
the interference of a second azaallylic anion in the transition
state structure TS2, in which lithium is replaced by this second
azaallylic anion, leading to a more energetically favored
conformation.
CONCLUSIONS
■
This combined experimental-theoretical study shows that the
aldol reaction of lithiated and zincated 3-chloro-3-methyl-1-
azaallylic anions 1 across aromatic aldehydes 5 mainly yields the
kinetic syn-adducts. The proposed “twisted-boat-like” transition
states associated with this diastereoselective reaction benefit
from coordination of the carbonyl oxygen with a second metal
cation, resulting in extra stabilization of the transition states
leading to the syn adducts. This explains the increased syn
selectivity in the reaction when lithium and zinc are both
present in the reaction mixture. Furthermore, the stereochemi-
cally defined syn-chlorohydrins can be used in a stereoselective
synthesis of new tetrasubstituted 3-chloroazetidines.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of syn α-Chloro-β-
hydroxyketimines 6. Under a nitrogen atmosphere, n-butyl lithium
(15.7 mmol, 2.5 N in hexanes, 6.3 mL) was added dropwise to a
solution of diisopropylamine (15.7 mmol, 2.03 g) in THF (50 mL) at
0 °C. After 30 min of stirring at 0 °C, α-chloroketimine 4 (14.3
mmol), which was dissolved in 10 mL of THF, was added dropwise,
and the reaction mixture was stirred for 30 min at 0 °C. Then
benzaldehyde 5 (15.0 mmol), dissolved in 2 mL of THF, was added
dropwise to the reaction mixture, after which stirring was continued
for 1 h at 0 °C. After the addition of three drops of saturated aqueous
ammonium chloride, 20 mL of an ice-cold solution of 0.5 N aqueous
sodium hydroxide was added to the reaction mixture. The mixture was
poured in a separatory funnel containing 30 mL of diethyl ether and
60 mL of 0.5 N aqueous sodium hydroxide. The aqueous layer was
extracted three times with diethyl ether, and the combined organic
extracts were washed with 30 mL of 0.5 N aqueous sodium hydroxide.
After drying (MgSO4), the solvent was evaporated in vacuo, and pure
syn α-chloro-β-hydroxyketimines 6a−c were isolated after recrystalliza-
tion from methanol in 26−39%.
Table 3 shows the free energy difference ΔΔGsyn‑anti between
the transition state structures leading to the syn and anti
Table 3. Free Energy Difference ΔΔG⧧
(in kJ/mol) of
syn‑anti
the Transition State Structures Leading to the syn and anti
a c
−
Adducts 10 for the Studied Cases
ΔΔG⧧
syn‑anti
M06-2X (SMD)
B97-D (SMD)
TS1 (Li-THF)
−3.6
−11.3
−1.7
−9.3
TS2 (ZnCl-Li-THF)
a
b
B3LYP/6-31+G(d,p) optimized geometries. SMD calculations in
c
THF (ε = 7.4257). ΔΔG⧧
= ΔG⧧ − ΔG⧧
.
anti
syn‑anti
syn
adducts 10, where two different levels of theory, accounting for
dispersive interactions, have been employed. M06-2X is known
to perform very well in organic systems with long-range
interactions,31 as is the case in this study. The supermolecule
comprising the metal ions and an explicit THF molecule is also
embedded in a bulk continuum via the SMD solvation model,
which is a universal solvent model based on solute electron
density and is applicable to both charged and uncharged solutes
in any solvent.
As indicated earlier, both syn transition states adopt a more
energetically favored “twist-boat-like” conformation, whereas
the anti counterparts are in a less energetically favored “boat-
like” conformation. Energetics show that there is only a slight
preference for the formation of the syn adduct in the case of
coordination with a single metal cation (Li+), which is in
accordance with the experimental results from entries 1−4 in
Table 1 (syn 6a+cis 7a/anti 6a+trans 7a 53:47 to 59:41).
Meanwhile, syn selectivity is enhanced in the presence of a
second coordinating metal cation, consistent with the
experimental results from entries 6−14 in Table 1 (syn 6a+cis
7a/anti 6a+trans 7a 72:28 to 89:11). Compared to its anti
counterpart (TS2-anti), the syn transition state (TS2-syn) is
clearly more stabilized in the presence of two metal ions. This is
due to the extra ordering caused by two coordinating metal
ions, which favors the syn transition state structure more than
the anti.
2-Chloro-3-isopropylimino-2-methyl-1,3-diphenylpropan-1-
ol 6a. White crystals, 39% yield. Mp 103.9−104.5 °C. 1H NMR
(CDCl3): δ 1.11 and 1.13 (2 × 3H, d, J = 6.2 Hz, (CH3)2-CH), 1.32
(3H, s, CCl-CH3); 3.26 (1H, septet, J = 6.2 Hz, (CH3)2-CH), 5.28
(1H, d, J = 2.8 Hz, CH-OH), 6.63 (1H, d, J = 2.8 Hz, CH-OH), 7.29−
7.43 (8H, m, 8 × CHar), 7.52−7.56 (2H, m, 2 × CHar). 13C NMR
(CDCl3): δ 23.2, 23.5, 26.8, 52.9, 73.9, 79.0, 127.5 (3 × CHar), 128.0
(2 × CHar), 128.2, 128.5 (2 × CHar), 129.2 (2 × CHar), 134.3, 138.8,
171.9. IR (cm−1): νmax 3256, 1637. MS (ES) m/z (%): 316/318 (M +
H+, 100). Anal. Calcd for C19H22ClNO: C 72.25, H 7.02, N 4.43.
Found: C 72.37, H 7.10, N 4.38.
2-Chloro-1-(4-chlorophenyl)-3-isopropylimino-2-methyl-3-
phenylpropan-1-ol 6b. Yellow crystals, 34% yield. Mp 77.6−78.2
1
°C. H NMR (CDCl3): δ 1.10 and 1,12 (2 × 3H, d, J = 6.2 Hz,
(CH3)2-CH), 1.30 (3H, s, CCl-CH3), 3.26 (1H, septet, J = 6.2 Hz,
(CH3)2-CH), 5.25 (1H, s, CH−OH), 6.74 (1H, br. s, CH-OH), 7.33
(2H, d, J = 8.5 Hz, 2 × CHar), 7.40−7.42 (5H, m, 5 × CHar), 7.48
(2H, d, J = 8.5 Hz, 2 × CHar). 13C NMR (CDCl3): δ 23.2, 23.5, 26.7,
52.9, 73.5, 78.4, 127.6, 127.7 (2 × CHar), 128.2, 128.6, 129.5, 130.6 (2
× CHar), 130.9, 133.9, 134.1, 137.3, 171.8. IR (cm−1): νmax 3401, 1634.
MS (ES) m/z (%): 350/352 (M + H+, 100). Anal. Calcd for
C19H21Cl2NO: C 65.15, H 6.04, N 4.00. Found: C 65.02, H 6.17, N
4.06.
2-Chloro-1-(4-chlorophenyl)-3-isopropylimino-2-methyl-3-
p-tolylpropan-1-ol 6c. White crystals, 26% yield. Mp 79.9−80.6 °C.
1H NMR (CDCl3): δ 1,10 and 1,11 (2 × 3H, d, J = 6.2 Hz, (CH3)2-
CH), 1.29 (3H, s, CCl-CH3), 2.38 (3H, s, CH3-C6H4), 3.28 (1H,
septet, J = 6.2 Hz, (CH3)2-CH), 5.24 (1H, s, CH−OH), 6.80 (1H, br.
s, CH-OH), 7.04 (2H, d, J = 7.7 Hz, 2 × CHar), 7.21 (2H, d, J = 7.7
Hz, 2 × CHar), 7.33 (2H, d, J = 8.5 Hz, 2 × CHar), 7.48 (2H, d, J = 8.5
Hz, 2 × CHar). 13C NMR (CDCl3): δ 21.3, 23.1, 23.5, 26.7, 52.8, 73.7,
78.4, 127.7 (4 × CHar), 128.9 (2 × CHar), 130.6 (2 × CHar), 131.0,
133.8, 137.4, 138.5, 172.0. IR (cm−1): νmax 3140, 1637. MS (ES) m/z
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Article
(%): 364/366/368 (M + H+, 100). Anal. Calcd for C20H23Cl2NO: C
65.94, H 6.36, N 3.84. Found: C 66.03, H 6.44, N 3.89.
C20H23Cl2NO3S: C 56.08, H 5.41, N 3.27. Found: C 56.23, H 5.57, N
3.34.
Synthesis of syn α-Chloro-β-mesyloxyketimines 8. Proce-
dure A: Starting from Pure Isolated syn α-Chloro-β-hydroxyketi-
mines 6a−c. Methanesulfonyl chloride (8.26 mmol, 0.95 g) was
added dropwise to a solution of α-chloro-β-hydroxyketimines 6
(5.5 mmol) in 15 mL of pyridine at room temperature. The
reaction mixture was stirred at ambient temperature for 22 h,
after which it was poured in 20 mL of ice-cold 0.5 N aqueous
sodium hydroxide. The aqueous phase was extracted three
times with dichloromethane, and the combined organic phases
were dried (MgSO4). After solvent evaporation in vacuo, the
reaction crudes were recrystallized from hexane/diethyl ether
(4:1) to yield syn α-chloro-β-mesyloxyketimines 8a−c in a yield
of 60−76%.
2-Chloro-1-(4-chlorophenyl)-3-isopropylimino-2-methyl-3-
p-tolyl-propyl Methanesulfonate 8c. Yellow crystals, yield 60%
(A), 84% (B). Mp 112.7−113.5 °C. Rf = 0.23, petroleum ether/Et2O
1
(80:20). H NMR (CDCl3): δ 1.08 and 1.10 (2 × 3H, d, J = 6.5 Hz,
(CH3)2-CH), 1.49 (3H, s, CCl-CH3), 2.35 (3H, s, CH3-C6H4), 2.86
(3H, s, CH3SO2), 3.29 (1H, septet, J = 6.5 Hz, (CH3)2-CH), 6.59 (1H,
s, CH-OMs), 7.11−7.22 (4H, m, 4 × CHar), 7.36 (2H, d, J = 8.7 Hz, 2
× CHar), 7.56 (2H, d, J = 8.7 Hz, 2 × CHar). 13C NMR (CDCl3): δ
21.5, 23.4, 23.6, 26.7, 39.7, 54.0, 74.8, 86.1, 127.0 (2 × CHar), 128.5 (2
× CHar), 129.1 (2 × CHar), 131.1 (2 × CHar), 132.6, 133.8, 135.5,
138.4, 167.9. IR (cm−1): νmax 1640, 1177. MS (ES) m/z (%): 442/
444/446 (M + H+, 100), 328/330 (20). Anal. Calcd for
C21H25Cl2NO3S: C 57.01, H 5.70, N 3.17. Found: C 57.14, H 5.81,
N 3.08.
Procedure B: Aldol Reaction of 3-Chloro-3-methyl-1-azaallylic
Anions 1 Derived from Imines 4 with Aromatic Aldehydes 5,
Immediately Followed by Mesylation. Under a nitrogen atmosphere,
n-butyl lithium (15.7 mmol, 2.5 N in hexanes, 6.3 mL) was added
dropwise to a solution of diisopropylamine (15.7 mmol, 2.03 g) in
THF (50 mL) at 0 °C. After 30 min of stirring at 0 °C, α-
chloroketimine 4 (12.1 mmol), which was dissolved in 10 mL of THF,
was added dropwise, and the reaction mixture was stirred for 45 min at
0 °C. After deprotonation, a solution of zinc chloride (12.7 mmol) in
10 mL of THF was added, and the reaction mixture was stirred for 15
min at 0 °C. The reaction mixture was cooled to −78 °C, and then
benzaldehyde 5 (6.05 mmol), which was dissolved in 2 mL of THF,
was added dropwise to the reaction mixture, after which stirring was
continued for 5 min at −78 °C, followed by 1 h at room temperature.
After the addition of three drops of saturated aqueous ammonium
chloride, 20 mL of an ice-cold solution of 0.5 N aqueous sodium
hydroxide was added to the reaction mixture. The mixture was poured
in a separatory funnel containing 30 mL of diethyl ether and 60 mL of
0.5 N aqueous sodium hydroxide. The aqueous layer was extracted
three times with diethyl ether, and the combined organic extracts were
washed with 30 mL of 0.5 N aqueous sodium hydroxide. After drying
(MgSO4), the solvent was evaporated in vacuo, and the crude mixture
was dissolved in 16 mL of pyridine. Methanesulfonyl chloride (9.08
mmol, 1.04 g) was added dropwise, and the reaction mixture was
stirred at room temperature for 22 h, after which it was poured in 22
mL of ice-cold 0.5 N aqueous sodium hydroxide. The aqueous phase
was extracted three times with dichloromethane, and the combined
organic phases were dried (MgSO4). After solvent evaporation in
vacuo, the reaction crudes were purified via flash chromatography to
obtain pure syn α-chloro-β-mesyloxyketimines 8a−d in a yield of 80−
84% (dr >97/3). Noteworthy, in all cases α-chloro-α-methanesulfo-
nylketimines 9 were also isolated as byproduct in 12−19% yield.
2-Chloro-3-isopropylimino-2-methyl-1,3-diphenylpropyl
Methanesulfonate 8a. Yellow crystals, yield 76% (A), 80% (B). Mp
2-Chloro-3-isopropylimino-2-methyl-1-phenyl-3-p-tolyl-
propyl Methanesulfonate 8d. Yellow crystals, yield 81% (B). Mp
1
123.7−124.0 °C. Rf = 0.22, petroleum ether/Et2O (80:20). H NMR
(CDCl3): δ 1.09 and 1.10 (2 × 3H, d, J = 6.2 Hz, (CH3)2-CH), 1.51
(3H, s, CCl-CH3), 2.35 (3H, s, CH3-C6H4), 2.80 (3H, s, CH3SO2),
3.28 (1H, septet, J = 6.2 Hz, (CH3)2-CH), 6.57 (1H, s, CH-OMs),
7.02−7.28 (3H, m, 3 × CHar), 7.31−7.41 (4H, m, 4 × CHar), 7.56−
7.63 (2H, m, 2 × CHar). 13C NMR (CDCl3): δ 21.3, 23.2, 23.4, 26.8,
39.5, 53.7, 74.8, 87.1, 128.0 (3 × CHar), 128.8 (2 × CHar), 129.2 (2 ×
CHar), 129.6 (2 × CHar), 132.7, 134.8, 138.0, 167.8. IR (cm−1): νmax
1641, 1174. MS (ES) m/z (%): 408/410 (M + H+, 100). Anal. Calcd
for C21H26ClNO3S: C 61.83, H 6.42, N 3.43. Found: C 61.64, H 6.61,
N 3.28.
(2-Chloro-2-methanesulfonyl-1-phenylpropylidene)-
isopropylamine 9a. Yellow oil, yield 19%. Rf = 0.35, petroleum
1
ether/Et2O (80:20). H NMR (CDCl3): δ 1.09 (6H, d, J = 6.1 Hz,
(CH3)2-CH), 1.89 (3H, s, CCl-CH3), 3.31 (1H, septet, J = 6.1 Hz,
(CH3)2-CH), 3.34 (3H, s, CH3SO2), 7.18−7.25 (2H, m, 2 × CHar),
7.38−7.46 (3H, m, 3 × CHar). 13C NMR (CDCl3): δ 22.8, 22.9, 23.0,
37.9, 53.9, 83.9, 127.3 (2 × CHar), 128.5 (2 × CHar), 129.0, 134.1,
163.9. IR (cm−1): νmax 2967, 1638, 1311, 1144. MS (ES) m/z (%):
288/290 (M + H+, 100). HRMS: calcd for C13H18ClNO2S 288.0819
[M + H+], found 288.0819 [M + H+].
(2-Chloro-2-methanesulfonyl-1-p-tolylpropylidene)-
isopropylamine 9b. Yellow oil, yield 15%. Rf = 0.31, petroleum
1
ether/Et2O (80:20). H NMR (CDCl3): δ 1.08 (6H, d, J = 6.1 Hz,
(CH3)2-CH), 1.89 (3H, s, CCl-CH3), 2.38 (3H, s, CH3-C6H4), 3.32
(3H, s, CH3SO2), 3.33 (1H, septet, J = 6.1 Hz, (CH3)2-CH), 7.09 (2H,
d, J = 8.3 Hz, 2 × CHar), 7.22 (2H, d, J = 7.7 Hz, 2 × CHar). 13C NMR
(CDCl3): δ 21.3, 22.7, 22.9, 23.0, 37.9, 53.8, 84.1, 127.2 (2 × CHar),
129.1 (2 × CHar), 131.0, 138.9, 164.1. IR (cm−1): νmax 2968, 1638,
1310, 1146. MS (ES) m/z (%): 302/304 (M + H+, 100). HRMS: calcd
for C14H20ClNO2S 302.0976 [M + H+], found 302.0972 [M + H+].
General Procedure for the Synthesis of β-Chloro-γ-
mesyloxyamines 2. Sodium cyanoborohydride (10.5 mmol) and
acetic acid (5.03 mmol) were subsequently added to a solution of α-
chloro-β-mesyloxyketimines 8 (4.20 mmol) in 20 mL of methanol, and
the reaction mixture was stirred for 24 h at room temperature. The
reaction mixture was poured in 20 mL of 0.5 N aqueous sodium
hydroxide, and the aqueous phase was extracted three times with
dichloromethane. The combined organic extracts were dried
(MgSO4), and the solvent was evaporated in vacuo. The reaction
crudes were purified by a recrystallization from hexane/diethyl ether
(9:1) to give β-chloro-γ-mesyloxyamines 2a−c in 63−78% yield.
Reduction of β-mesyloxyketimine 8d (R1 = Me, R2 = H) afforded a
mixture of β-chloro-γ-mesyloxypropylamine 2d and 2,4-diaryl-3-
chloro-3-methylazetidine 3d in a ratio of 71:29. After purification via
flash chromatography, β-chloro-γ-mesyloxypropylamine 2d and 2,4-
diaryl-3-chloro-3-methylazetidine 3d were isolated in 23% and 58%
yield, respectively.
1
122.3−123.0 °C. Rf = 0.20, petroleum ether/Et2O (80:20). H NMR
(CDCl3): δ 1.10 and 1,11 (2 × 3H, d, J = 6.2 Hz, (CH3)2-CH), 1.52
(3H, s, CCl-CH3), 2.80 (3H, s, CH3SO2), 3.27 (1H, septet, J = 6.2 Hz,
(CH3)2-CH), 6.59 (1H, s, CH-OMs), 7.27−7.43 (8H, m, 8 × CHar),
7.57−7.64 (2H, m, 2 × CHar). 13C NMR (CDCl3): δ 23.2, 23.3, 26.9,
39.5, 53.9, 74.7, 87.1, 128.1 (3 × CHar), 128.2 (2 × CHar), 129.3 (2 ×
CHar), 129.6 (3 × CHar), 134.7, 135.7, 167.7. IR (cm−1): νmax 1640,
1177. MS (ES) m/z (%): 394/396 (M + H+, 100). Anal. Calcd for
C20H24ClNO3S: C 60.98, H 6.14, N 3.56. Found: C 61.11, H 6.26, N
3.54.
2-Chloro-1-(4-chlorophenyl)-3-isopropylimino-2-methyl-3-
phenylpropyl Methanesulfonate 8b. Yellow crystals, yield 70%
(A), 83% (B). Mp 109.3−110.3 °C. Rf = 0.23, petroleum ether/Et2O
1
(80:20). H NMR (CDCl3): δ 1.08 and 1.11 (2 × 3H, d, J = 6.3 Hz,
(CH3)2-CH), 1.48 (3H, s, CCl-CH3), 2.88 (3H, s, CH3SO2), 3.26
(1H, septet, J = 6.3 Hz, (CH3)2-CH), 6.59 (1H, s, CH-OMs), 7.37
(2H, d, J = 8.4 Hz, 2 × CHar), 7.30−7.42 (5H, m, 5 × CHar), 7.55
(2H, d, J = 8.4 Hz, 2 × CHar). 13C NMR (CDCl3): δ 23.2, 23.4, 26.6,
39.5, 53.8, 74.4, 86.0, 128.2 (2 × CHar), 128.3 (5 × CHar), 130.9 (2 ×
CHar), 133.5, 135.3, 135.4, 167.4. IR (cm−1): νmax 1645, 1176. MS
(ES) m/z (%): 428/430/432 (M + H+, 100). Anal. Calcd for
2-Chloro-3-isopropylamino-2-methyl-1,3-diphenylpropyl
methanesulfonate 2a. Yellow crystals, yield 78%. Mp 138.0−139.4
°C. 1H NMR (CDCl3): δ 0.95 en 1.07 (2 × 3H, d, J = 6.2 Hz, (CH3)2-
CH), 1.22 (3H, s, CCl-CH3), 1.51 (1H, br s, NH), 2.59 (3H, s,
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CH3SO2), 2.66 (1H, septet, J = 6.2 Hz, (CH3)2-CH), 4.32 (1H, s,
CHNH), 6.27 (1H, s, CH-OMs), 7.32−7.40 (8H, m, 8 × CHar),
7.56−7.58 (2H, m, 2 × CHar). 13C NMR (CDCl3): δ 22.0 (2 × CH3),
24.6, 39.9, 47.1, 65.0, 74.8, 85.0, 127.5, 127.7 (2 × CHar), 128.2 (2 ×
CHar), 129.5, 129.7 (2 × CHar), 129.8 (2 × CHar), 134.6, 139.1. IR
(cm−1): νmax 3335, 1172. MS (ES) m/z (%): 396/398 (M + H+, 100).
Anal. Calcd for C20H26ClNO3S: C 60.67, H 6.62, N 3.54. Found: C
60.39, H 6.71, N 3.62.
2-Chloro-1-(4-chlorophenyl)-3-isopropylamino-2-methyl-3-
phenylpropyl Methanesulfonate 2b. Yellow crystals, yield 67%.
Mp 111.1−111.3 °C. 1H NMR (CDCl3): δ 0.94 en 1.06 (2 × 3H, d, J
= 6.3 Hz, (CH3)2-CH), 1.20 (3H, s, CCl-CH3), 1.55 (1H, br s, NH),
2.66 (1H, septet, J = 6.3 Hz, (CH3)2-CH), 2.68 (3H, s, CH3SO2), 4.28
(1H, s, CHNH), 6.27 (1H, s, CH-OMs), 7.30−7.40 (7H, m, 7 ×
CHar), 7.52 (2H, d, J = 8.3 Hz, 2 × CHar). 13C NMR (CDCl3): δ 22.0
(2 × CH3), 24.6, 40.0, 47.1, 65.0, 74.6, 84.0, 127.6, 127.7 (2 × CHar),
128.5 (2 × CHar), 129.7 (2 × CHar), 130.9 (2 × CHar), 133.3, 135.6,
138.9. IR (cm−1): νmax 3359, 1176. MS (ES) m/z (%): 430/432/434
(M + H+, 100). Anal. Calcd for C20H25Cl2NO3S: C 55.81, H 5.85, N
3.25. Found: C 55.73, H 5.97, N 3.33.
(CH3)2-CH), 4.46 and 4.50 (2H, s, 2 × CH), 7.29−7.40 (5H, m, 5 ×
CHar), 7.47−7.55 (4H, m, 4 × CHar). 13C NMR (CDCl3): δ 21.6,
21.7, 22.5, 60.0, 66.5, 77.7 (2 × CH), 127.3 (2 × CHar), 127.7, 128.1
(2 × CHar), 128.3 (2 × CHar), 128.6 (2 × CHar), 133.3, 137.5, 138.6.
IR (cm−1): νmax 2970, 1489, 1332, 1070. MS (ES) m/z (%): 334/336/
338 (M + H+, 70), 286 (100), 268 (35). Anal. Calcd for C19H21Cl2N:
C 68.27, H 6.33, N 4.19. Found: C 68.16, H 6.43, N 4.15.
3-Chloro-2-(4-chlorophenyl)-1-isopropyl-3-methyl-4-p-toly-
lazetidine 3c. Colorless oil, yield 73%. Rf = 0.32, petroleum ether/
EtOAc (95:5). 1H NMR (CDCl3): δ 0.71 (3H, s, CCl-CH3), 0.84 and
0.85 (2 × 3H, d, J = 6.3 Hz, (CH3)2-CH), 2.36 (3H, s, CH3-C6H4),
2.80 (1H, septet, J = 6.3 Hz, (CH3)2-CH), 4.44 and 4.46 (2H, s, 2 ×
CH), 7.17 (2H, d, J = 8.0 Hz, 2 × CHar), 7.33 (2H, d, J = 8.4 Hz, 2 ×
CHar), 7.40 (2H, d, J = 8.0 Hz, 2 × CHar), 7.49 (2H, d, J = 8.4 Hz, 2 ×
CHar). 13C NMR (CDCl3): δ 21.2, 21,7 (2 × CH3), 22.4, 60.0, 66.6,
77.6 (2 × CH), 127.2 (2 × CHar), 128.3 (2 × CHar), 128.7 (2 ×
CHar), 128.8 (2 × CHar), 133.3, 135.7, 137.3, 137.6. IR (cm−1): νmax
2977, 1489, 1371, 1328, 1070. MS (ES) m/z (%): 348/350/352 (M +
H+, 100), 349 (30), 312 (45). Anal. Calcd for C20H23Cl2N: C 68.97, H
6.66, N 4.02. Found: C 69.10, H 6.82, N 4.09.
3-Chloro-1-isopropyl-3-methyl-2-phenyl-4-p-tolylazetidine
3d. Colorless oil, yield 64%. Rf = 0.36, petroleum ether/EtOAc (95:5).
1H NMR (CDCl3): δ 0.72 (3H, s, CCl-CH3), 0.86 (6H, d, J = 6.2 Hz,
2-Chloro-1-(4-chlorophenyl)-3-isopropylamino-2-methyl-3-
p-tolylpropyl Methanesulfonate 2c. Yellow crystals, yield 63%.
Mp 123.0−123.6 °C. 1H NMR (CDCl3): δ 0.94 and 1.05 (2 × 3H, d, J
= 6.3 Hz, (CH3)2-CH), 1.20 (3H, s, CCl-CH3), 1.47 (1H, br s, NH),
2.36 (3H, s, CH3-C6H4), 2.65 (1H, septet, J = 6.3 Hz, (CH3)2-CH),
2.68 (3H, s, CH3SO2), 4.23 (1H, s, CHNH), 6.26 (1H, s, CH-OMs),
7.16 (2H, d, = 8.1 Hz, 2 × CHar), 7.23 (2H, d, J = 8.1 Hz, 2 × CHar),
7.37 (2H, d, J = 8.5 Hz, 2 × CHar), 7.51 (2H, d, J = 8.5 Hz, 2 × CHar).
13C NMR (CDCl3): δ 21.1, 22.0 (2 × CH3), 24.6, 40.0, 47.1, 64.7,
74.9, 84.0, 128.5 (4 × CHar), 129.5 (2 × CHar), 130.9 (2 × CHar),
133.3, 135.5, 135.8, 137.3. IR (cm−1): νmax 3326, 1176. MS (ES) m/z
(%): 444/446/448 (M + H+, 100). Anal. Calcd for C21H27Cl2NO3S: C
56.75, H 6.12, N 3.15. Found: C 56.62, H 6.05, N 3.17.
(CH3)2-CH), 2.35 (3H, s, CH3-C6H4), 2.81 (1H, septet, J = 6.2 Hz,
(CH3)2-CH), 4.47 and 4.46 (2H, s, 2 × CH), 7.16 (2H, d, J = 8.3 Hz,
2 × CHar), 7.22−7.38 (3H, m, 3 × CHar), 7.43 (2H, d, J = 8.3 Hz, 2 ×
CHar), 7.52−7.58 (2H, m, 2 × CHar). 13C NMR (CDCl3): δ 21.2, 21.7
(2 × CH3), 22.4, 59.9, 67.0, 77.6, 77.7, 127.2 (2 × CHar), 127.3 (2 ×
CHar), 127.5, 128.0 (2 × CHar), 128.7 (2 × CHar), 135.9, 137.1, 139.0.
IR (cm−1): νmax 2969, 1439, 1374, 1331, 1199, 1069. MS (ES) m/z
(%): 314/316 (M + H+, 100), 276 (48). Anal. Calcd for C20H24ClN: C
76.53, H 7.71, N 4.46. Found: C 76.18, H 7.49, N 4.31.
ASSOCIATED CONTENT
* Supporting Information
General experimental conditions and copies of H NMR and
2-Chloro-3-isopropylamino-2-methyl-1-phenyl-3-p-tolyl-
■
propyl Methanesulfonate 2d. White crystals, yield 58%. Mp
S
1
131.4−131.8 °C. Rf = 0.09, petroleum ether/EtOAc (95:5). H NMR
1
(CDCl3): δ 0.95 and 1.06 (2 × 3H, d, J = 6.2 Hz, (CH3)2-CH), 1.22
(3H, s, CCl-CH3), 1.47 (1H, br s, NH), 2.36 (3H, s, CH3-C6H4), 2.59
(3H, s, CH3SO2), 2.65 (1H, septet, J = 6.2 Hz, (CH3)2-CH), 4.27 (1H,
s, CHNH), 6.26 (1H, s, CH-OMs), 7.16 (2H, d, = 8.3 Hz, 2 × CHar),
7.25 (2H, d, J = 7.2 Hz, 2 × CHar), 7.34−7.46 (3H, m, 3 × CHar),
7.52−7.64 (2H, m, 2 × CHar). 13C NMR (CDCl3): δ 21.2, 22.0, 22.1,
24.6, 39.9, 47.1, 64.8, 75.0, 85.1, 128.2 (2 × CHar), 128.5 (2 × CHar),
129.5, 129.6 (2 × CHar), 129.7 (2 × CHar), 134.7, 136.0, 137.2. IR
(cm−1): νmax 3347, 1352, 1174. MS (ES) m/z (%): 410/412 (M + H+,
100). Anal. Calcd for C21H28ClNO3S: C 61.52, H 6.88, N 3.42. Found:
C 61.88, H 6.53, N 3.14.
13C NMR spectra for syn α-chloro-β-hydroxyketimines 6, syn α-
chloro-β-mesyloxyketimines 8, α-chloro-α-methanesulfonylke-
timines 9, β-chloro-γ-mesyloxyamines 2, and 2,4-diaryl-3-
chloro-3-methylazetidines 3. Cartesian coordinates of B3LYP/
6-31++G(d,p) optimized transition state structures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +32 (0)9 264 59 51. Fax: +32 (0)9 264 62 43. E-mail:
norbert.dekimpe@ugent.be.
■
General Procedure for the Synthesis of 2,4-Diaryl-3-chloro-
3-methylazetidines 3. Potassium carbonate (4.56 mmol) was added
to a solution of β-chloro-γ-mesyloxyamines 2 (1.52 mmol) in DMSO
(10 mL), and the reaction mixture was stirred for 48 h at 85−90 °C.
The reaction mixture was poured in water, and the aqueous phase was
extracted three times with dichloromethane. The combined organic
extracts were dried (MgSO4), and the solvent was evaporated in vacuo.
The reaction crudes were purified via flash chromatography, which
gave 2,4-diaryl-3-chloro-3-methylazetidines 3 in 53−73% yield.
3-Chloro-1-isopropyl-3-methyl-2,4-diphenylazetidine 3a.
Colorless oil, yield 53%. Rf = 0.34, petroleum ether/EtOAc (95:5).
1H NMR (CDCl3): δ 0.72 (3H, s, CCl-CH3), 0.87 (6H, d, J = 6.3 Hz,
(CH3)2-CH), 2.83 (1H, septet, J = 6.3 Hz, (CH3)2-CH), 4.51 (2H, s, 2
× CH), 7.27−7.40 (6H, m, 6 × CHar), 7.52−7.58 (4H, m, 4 × CHar).
13C NMR (CDCl3): δ 21.7 (2 × CH3), 22.5, 60.0, 66.8, 77.7 (2 ×
CH), 127.3 (4 × CHar), 127.5 (2 × CHar), 128.0 (4 × CHar), 138.9 (2
× Cquat). IR (cm−1): νmax 2970, 1454, 1334, 1069. MS (ES) m/z (%):
300/302 (M + H+, 57), 150/152 (100). Anal. Calcd for C19H22ClN: C
76.11, H 7.40, N 4.67. Found: C 76.22, H 7.53, N 4.70.
Present Address
#LANXESS Rubber N.V., BTR - Competence Center
Technology Process Technologist, Haven 1009 - Canadastraat
21, 2070 Zwijndrecht, Belgium.
Notes
The authors declare no competing financial interest.
§Postdoctoral Fellow of the Research Foundation-Flanders
(FWO).
ACKNOWLEDGMENTS
■
This work was supported by the Fund for Scientific Research
Flanders (FWO-Vlaanderen) and the Research Board of the
Ghent University (BOF-GOA). The computational resources
(Stevin Supercomputer Infrastructure) and services used in this
work were provided by Ghent University. This work is
supported by the IAP-BELSPO program in the frame of IAP
6/27.
3-Chloro-2-(4-chlorophenyl)-1-isopropyl-3-methyl-4-phe-
nylazetidine 3b. Colorless oil, yield 60%. Rf = 0.30, petroleum ether/
EtOAc (95:5). 1H NMR (CDCl3): δ 0.71 (3H, s, CCl-CH3), 0.85 and
0.86 (2 × 3H, d, J = 6.3 Hz, (CH3)2-CH), 2.82 (1H, septet, J = 6.3 Hz,
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Article
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