Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization

Article abstract of DOI:10.1021/acs.joc.8b01441

The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH₃ group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH₃ group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.

Full text of DOI:10.1021/acs.joc.8b01441

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Article
Azetidine-Borane Complexes: Synthesis,
Reactivity and Stereoselective Functionalization
Michael Andresini, Sonia De Angelis, Antonella Uricchio, Angelica Visaggio, Giuseppe
Romanazzi, Fulvio Ciriaco, Nicola Corriero, Leonardo Degennaro, and Renzo Luisi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01441 • Publication Date (Web): 19 Jul 2018
Downloaded from http://pubs.acs.org on July 19, 2018
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Azetidine-Borane Complexes: Synthesis, Reactivity and
Stereoselective Functionalization
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Michael Andresini,a Sonia De Angelis,a Antonella Uricchio,a Angelica Visaggio,a Giuseppe
Romanazzi,b Fulvio Ciriaco,c Nicola Corriero,d Leonardo Degennaro,a,* Renzo Luisia,*
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aDepartment of Pharmacy ꢀ Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4, Bari
70125, Italy.
bDICATECh, Politecnico di Bari, Via E. Orabona 4, Bari 70125, Italy.
cDepartment of Chemistry, University of Bari “A. Moro” Via E. Orabona 4, Bari 70125, Italy.
dInstitute of Crystallography – CNR Via Amendola 122o, Bari 70125, Italy.
Corresponding authors email: renzo.luisi@uniba.it, leonardo.degennaro@uniba.it
Abstract
The present study reports, for the first time, synthesis and structural features of azetidine borane
complexes, as well as their reactivity in lithiation reactions. A temperatureꢀdependent stereoselectivity
has been disclosed in the reaction of borane with Nꢀalkylꢀ2ꢀarylazetidines, allowing for a
stereoselective preparation of azetidine borane complexes 2 and 3. A regioselective hydrogen/lithium
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permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a
syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was
noticed in complexes lacking such a stereochemical requirement. The configurational stability of the
lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of
the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental
observations, concerning structure and reactivity of these azetidine borane complexes. Data suggest
that the BH3 group could promote the lithiation reaction likely by an electrostatic Complex Induced
Proximity Effect. Interestingly, a new synthetic strategy for the synthesis of Nꢀalkylꢀ2,2ꢀdisubstituted
azetidines has been developed.
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Introduction
The fourꢀmembered heterocycle azetidine represents an interesting scaffold in medicinal
chemistry and agrochemistry,1 due to its peculiar chemical properties (such as robustness and
molecular rigidity), allowing for an efficient tuning of pharmacological properties displayed by
molecules including such unit.2,3 In addition, azetidineꢀbearing molecules have been used as ligands for
transitionꢀmetals, and as chiral auxiliaries.4 Several methodologies are available for the preparation of
azetidines, mostly based on the construction of the cyclic core by intramolecular cyclization reactions.5
However, such strategies suffer the limitations due to multistep synthesis, and a previous installation of
other functionalities before the ringꢀforming step. A more direct approach makes use of an already
formed azetidine ring, which can be functionalized by a metalation/trapping sequence.6 Recent studies
on the lithiation of Nꢀprotected azetidines shed some light on the structural factors playing a key role in
the metalation reaction.7 For example, we disclosed that in the lithiation of 2ꢀarylazetidines, the nature
of the Nꢀgroup is able to affect the regioselectivity of the metalation reaction. In fact, when an electronꢀ
withdrawing group is installed on the azetidine’s nitrogen, exclusive αꢀlithiation is observed.8 In
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striking contrast, the presence of an electronꢀdonating alkyl group converted the azetidine ring into an
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orthoꢀdirecting group promoting exclusive orthoꢀlithiation (Scheme 1, a).9
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According to what previously observed with the lower homologue aziridines, the availability of the
nitrogen lone pair is crucial for deciding the regioselectivity of the metalation (lithiation).10 In
continuation of our research interest in the chemistry of azetidines, we describe herein the preparation
of unprecedented azetidineꢀborane complexes reporting structural features, and their reactivity towards
lithiating agents. The investigation started from the observation that quaternization of the azetidine
nitrogen could promote ring metalation. Recent examples by Couty,11 Tayama12 and Aggarwal13
demonstrated that ring metalation was feasible, and that the corresponding azetidine ylide intermediates
showed a peculiar reactivity undergoing to either Stevens or Sommelet–Hauser rearrangements, as well
as borylation, and ring opening reactions (Scheme 1, b). Holding on previous results on the highly
stereoꢀ and regioꢀselective lithiation of aziridinesꢀborane complexes14 (Scheme 1, c), we were keen to
demonstrate if azetidineꢀborane complexes could be regioselectively lithiated, and trapped without
undergoing ring opening or rearrangement.
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Scheme 1. General aspects on the metalation of azetidines.
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Results and Discussion
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By reacting azetidines 1a-e with a THF solution of BH3, diastereomeric azetidine borane complexes
2a-e and 3a-e were obtained as solids after 5 minutes at 0 °C (Table 1, entries 1ꢀ5). The diastereomeric
complexes resulted by a syn and anti attack of the boron atom with respect to the aromatic ring, leading
to complexes 2 and 3 respectively. Interestingly, we noticed a temperatureꢀdependent change of the
2/3 diastereomeric ratio. In particular, the amount of complex 2 slightly increased at low temperature
(i.e. ꢀ78 °C, Table 1, entries 6,7). By contrast, heating a solution of distereomeric complexes (enriched
in 2) up to 80 °C, a switch in the composition was observed in favor of complexes 3 (Table 1, entries 8ꢀ
11). As exception, complex 2c, was found stable even at high temperature. The relative
stereochemistry of complexes 2 and 3 was ascertained by NMR and NOE experiments (see Supporting
Information), and in the case of 2d demonstrated by single crystal Xꢀray analysis.15
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Table 1. Synthesis of diastereomeric azetidine borane complexes
Time
T
Entry 1a
R
Ar
solvent
dr 2/3c
(min) (°C)b
1
2
3
4
5
6
7
8
Me Ph
THF
THF
THF
THF
THF
THF
THF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
5
5
5
5
5
60
60
60
180
180
180
0
0
0
0
80:20
80:20
95:5d
72:28
78:22
99:1
90:10
69:31
20:80
9:91
1a
1b
1c
1d
1e
1a
1b
1a
1a
1d
1e
Et
Ph
tBu Ph
Me oꢀtolyl
Me mꢀxylyl
Me Ph
0
ꢀ78
ꢀ78
40
80
80
80
Et
Ph
Me Ph
Me Ph
Me oꢀtolyl
Me mꢀxylyl
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10
11
10:90
aRacemic azetidines were used for complexation with BH3. See
b
c
supporting information for reaction conditions. Diastereomeric
ratio established by H NMR on the crude reaction mixture.
1
d
Diasteromeric ratio didn’t change even upon warming the sample
at 70 °C for several hours.
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The variability of the diastereomeric ratio in complexes 2 and 3, could be explained taking into
consideration two factors, namely: a) the role of the ethereal solvent; b) the azetidine’s nitrogen
inversion. In fact, as reported in Figure 1, it is likely that the solvent could take up the BH3 from the
azetidine nitrogen, and the temperature, as well as the nature of the R group and nitrogen’s
stereochemistry, could affect this equilibrium.16 Additionally, the nitrogen dynamics in free azetidines
1 must be taken into consideration. As depicted in Figure 1, invertomer A is likely the most stable, and
this would explain the prevalent formation of complexes 2 at lower temperature (Table 1, entries 1ꢀ7).17
Nevertheless, higher temperature could affect all the equilibriums in Figure 1, favoring the formation of
the most stable complex 3. It is reasonable to assume that 2 are kinetic complexes and 3 the
thermodynamic ones. With the aim to support these hypotheses other experiments were executed. A
diastereomeric ratio 2a/3a of 85/15 was observed performing the complexation reaction in a non polar
solvent such as dichloromethane, thus confirming that 2a is the kinetic product. In addition, to support
the role of the ethereal solvent in the isomerization 2a ꢀ 3a, toluene was use as the solvent. Refluxing
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a solution of 2a in toluene, and monitoring the progress by H NMR (see supporting information), the
2a ꢀ 3a transition occurred slower than in 2ꢀMeTHF, and after 41 hours a diastereomeric ratio 2a/3a
of 39/61 was obtained jointly with a small amount of free azetidine 1a. It is likely that, upon heating, a
partial loss of BH3 occurs, and that the free azetidine promote the isomerization according to the
mechanism reported in Figure 1. In order to provide more evidences supporting our hypotheses, we run
a NMR and computational investigation on complexes 2a and 3a. Complexes 2a and 3a were firstly
separated by flash chromatography, and separately subjected to 11B and 1H NMR analysis in d8ꢀTHF at
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60 °C. In Figure 1 is reported the change observed in the B NMR spectra for the transition 2a ꢀ 3a.
A similar experiment was executed on pure complex 3a, but without any evident change in
composition after 3 days in d8ꢀTHF at 60 °C (see Supporting Information). DFT calculations at B3LYP
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6ꢀ311ꢀG level of theory also confirmed that complex 3a was 1.4 Kcal/mol more stable than 2a (see SI),
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thus supporting the rationale in Figure 1.
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most stable
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H
Ph
H
Ph
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R
N
R
S-BH3
+
N
+ S-BH3
B
A
S
S
most stable
H
H
BH3
N
R
N
Ph
Ph
3a
R
BH3
2a
Erel = 1.4 Kcal/mol
Erel = 0 Kcal/mol
3
2
S = Solvent
3a
dr: 26:74
2a
8h
dr: 37:63
5h
dr: 71:29
2h
dr: 100:0
t0
-7.5
-8.5
-9.5
-10.5
-11.5
-12.5
-13.5
-14.5
-15.5
11
THF-d8, 11B NMR 160 MHz, 60 °C
THF-d8, B NMR 160 MHz, 60 °C
Figure 1. Rationale for temperature – dependent diastereomeric switch for complexes 2 and 3
Next, we investigated the reactivity of diastereomeric complex 3a in lithiation reactions. Initially, we
tested the conditions used for the lithiation of aziridinesꢀborane complexes.14 Optimal conditions
employed 3 equiv of sꢀBuLi, at ꢀ50 °C in THF for 5 min (Table 2, entry 3). A longer reaction time was
needed reducing the equivalent of base (Table 2, entry 1), while lithiation at higher temperature (ꢀ20 °C
or 0 °C) resulted in lower yield in deuterated products (Table 2, entries 5 and 6). However, all the
lithiation experiments, run in THF, led to a diastereomeric mixture of deuterated products 2a-D and 3a-
D being the latter the most abundant. The use of toluene as the solvent, in the presence of
tetramethylethylenediammine (TMEDA) as the ligand, again produced a mixture of 2a-D and 3a-D but
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with a reversed stereoselectivity with respect to THF (Table 2, entries 7, 8). It is worth mentioning that,
based on an electrostatic Complex Induced Proximity Effect (eꢀCIPE),18,19 lithiation must occur syn to
the BH3, and protons Ha and Hb could be potentially removed (Table 2). In all cases, the lithiation was
found highly regioselective being the proton Ha (syn to the BH3 group) preferentially removed.
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Table 2. Lithiation of azetidine borane complex 3a.
T
(°C)
base
time
dr
yield
(%)a
>99
>99
98
entry
solvent
(equiv.) (min.) 3a-D/2a-D
THF
1
2
3
4
5
6
7
8
9
ꢀ50
ꢀ50
ꢀ50
ꢀ78
ꢀ20
0
1.5
3
120
60
5
76/24
76/24
79/21
75/25
37:63
38:62
38:62
36:64
ꢀ
THF
THF
3
THF
3
5
96
3
5
84b
52c
97
THF
THF
3
5
toluened
toluened
toluenee
ꢀ50
ꢀ50
ꢀ50
3
5
3
60
5
>99
0
3
aYield determined by H NMR analysis. Residual protonated
1
b
complexes 3a and 2a were found respectively in a 61:39
c
diastereomeric ratio. Residual protonated complexes 3a and 2a
were found respectively in a 75:25 diastereomeric ratio.
dTMEDA (3 equiv) was employed as ligand. eReaction run
without TMEDA.
For sake of comparison, we investigated the reactivity of complexes 2a and 2c (Scheme 2). In this case,
according to what observed with aziridines borane complex, regioselective removal of Hc was
expected.14 Nevertheless, 2a was found less reactive than 3a; in fact, when 2a was reacted with sꢀBuLi
under the same optimal reaction conditions adopted for 3a (Table 2, entry 3), no reaction occurred, and
unreacted starting material was recovered (Scheme 2). However, prolonging the lithiation time up to 70
min, 2a underwent, to some extent, to benzylic lithiation (removal of Ha), producing 3a-D and 2a-D in
22% yield, with a dr of 63/37 respectively.20 Interestingly, product 4, deriving from a βꢀelimination
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reaction, was also found in the reaction mixture. This latter result could be explained considering the
thermodynamic acidity of the benzylic position that compete with the propensity of the strained ring to
undergoing βꢀelimination leading to product 4. The sensible reluctance of 2a to undergo full
deprotonation under the optimal conditions adopted for 3a, could likely be ascribed to the assistance of
the BH3 group in 3a possessing the suitable stereochemical requirement. Complex 2c was however
found unreactive under varied reaction conditions. It is likely that this diastereomer does not meet the
stereochemical requirement (i.e. proximity Hc – BH3) needed for lithiation, and in addition there could
be a steric effect brought about by the bulky Nꢀsubstituent.21
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Scheme 2. Reactivity of diastereomeric complexes 2a and 2c.
Next, in order to explain the presence of a diastereomeric mixture in the lithiation/trapping
experiments, the configurational stability of the lithiated intermediate generate from 3a was
investigated (Scheme 3). Upon lithiation/deuteration under optimized conditions (Table 1, entry 3),
chiral complex (1R,2R)ꢀ3a (er: 85:15) furnished a mixture of (1R,2R)ꢀ3a-D (er 85:15) and (1R,2S)ꢀ2a-
D (er 84:16) in 75:25 diastereomeric ratio respectively, as ascertained by chiral HPLC analysis (see SI).
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Scheme 3. Evaluating the configurational stability of lithiated (1R,2R)ꢀ3a.
From the experiment run on (1R,2R)ꢀ3a, it is possible to conclude that the lithiated intermediates are
configurationally unstable, and that exclusive inversion at the lithiated carbon occurs.22 Based on these
results, we investigated the reaction of lithiated complex 3a with representative electrophiles (Scheme
4). As reported in Scheme 3, alkylation, benzylation, borylation furnished complexes 2f-h and 3f-h
with good yields and a variable degree of stereoselectivity (Scheme 4). Interestingly, the main
diasteromer resulted from the introduction of the electrophile syn to the BH3 group. However, the
stereoselectivity seemed to be dependent on the electrophile, as observed in the borylation reaction
furnishing only diastereomer 3h.23 The lithiation/borylation sequence run on (1R,2R)ꢀ3a, led to
enantioenriched (1R,2R)ꢀ3h (er = 80:20) in 70% yield and as single diastereomer (Scheme 4).
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Scheme 4. Scope of the lithiation/trapping sequence of complex 3a.
In the reactions with acetone, NꢀBoc benzylidene imine, and tertꢀbutyldicarbonate the corresponding
BH3ꢀfree azetidines 5a-c were isolated after flash chromatography (see supporting information)
probably as a consequence of the presence of a basic site in the product (i.e. O, N) able to interact with
the BH3 group. These results are, in our opinion, remarkable because open the possibility to
functionalize selectively the benzylic position of Nꢀalkylꢀ2ꢀarylazetidines. It is worth mentioning that
an electronꢀwithdrawing group is required for benzylic lithiation of these systems (Scheme 1, a).
Nevertheless, NꢀBocꢀ2ꢀphenylazetidines undergo dimerization after lithiation at the benzylic
position.7,8 Thus, this strategy would allow for a facile and effective functionalization at the benzylic
position of Nꢀalkylꢀ2ꢀarylazetidines by a sequence of BH3ꢀcomplexation/lithiation/electrophileꢀ
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trapping/BH3ꢀremoval. With the aim to demonstrate this, we explored the possibility to remove the BH3
group in complexes 3f,g. As reported in Scheme 5, by refluxing complex 3g in aqueous NH3 (28%
w/w), free azetidine 5d was obtained quantitatively. However, under the same conditions, complex 3f
undergoes βꢀelimination furnishing exclusively alkene 6 (Scheme 5).
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Bn
Me
BH3
NH3 (28%)
Ph
N
N
Ph
H2O
90 °C
quant.
Bn
Me
3g
5d
Me
CH2
6
BH3
NH3 (28%)
Me
N
Ph
N
Ph
H2O
90 °C
quant.
H
Me
3f
Scheme 5. Deprotection of azetidine borane complexes 3.
A surprising result was obtained in the lithiation of complex 3d, bearing an orthoꢀmethyl group on the
aromatic ring, and in principle susceptible of lithiation at two benzylic positions (Ha and Hb in Scheme
5). Upon reaction of 3d with sꢀBuLi (3 equiv), exclusive formation of ringꢀopening product 7 was
observed after quenching with CD3OD (Scheme 5). This result could be explained, as reported in
Scheme 5, taking into consideration a regioselective lateral deprotonation (removal of Hb), followed by
dearomatization, and azetidine ring opening, leading to intermediate I. Nucleophilic attack of sꢀBuLi to
I furnished intermediates II that could react with CD3OD. For sake of comparison, the lithiation of
azetidine complexes 2d was also investigated. According to what observed with complex 2a and 2c
(Scheme 2), complex 2d was also found unreactive, under varied reaction conditions, likely for the lack
of the syn stereochemical requirement between the BH3 group and the benzylic protons (see infra).
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Proximity relationship
X-Ray structure
of 2d
2d
unreactive
3d
reactive
Scheme 6. Orthoꢀeffect in the lithiation of complexes 2d and 3d.
Equilibrium geometries, calculated at B3LYP 6ꢀ311+G level of theory, for complexes 2d and 3d
revealed a proximity relationship between the orthoꢀmethyl and BH3 groups in 3d (Scheme 6). In the
case of 2d, optimized structure is very similar to the Xꢀray structure (reported in Scheme 6 for
comparison) in which the orthoꢀmethyl and BH3 groups sit trans each other. Thus, it is likely that the
proximity relationship in 3d would promote an eꢀCIPE favoring lateral lithiation.
Conclusions
In conclusion, this work reported, for the first time, structural features of azetidine borane complexes.
Synthetic studies demonstrated a temperature dependent stereoselectivity in the reaction of borane with
Nꢀalkylꢀ2ꢀarylazetidines in polar solvents such as THF or 2ꢀMeTHF. The lithiation studies disclosed a
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regioselective hydrogen/lithium permutation at the benzylic position of azetidine 3a. The syn
relationship, between the ring proton and the BH3 group, seems to be a needed stereochemical
requirement for the lithiation to occur. In fact, poor or no reactivity was observed in complexes lacking
such a stereochemical requirement (i.e 2a, 2c and 2d). The variable degree of stereoselectivity,
observed in the lithiation/electrophile trapping sequence, has been ascribed to the configurational
instability of the lithiated intermediates. Calculations helped in supporting experimental observations
concerning structure and reactivity towards lithiating agents. This investigation provides useful
information on the role of the BH3 group in promoting the lithiation reaction, likely by an eꢀCIPE, and
introduces a new synthetic strategy for the synthesis of Nꢀalkylꢀ2,2ꢀdisubstituted arylazetidines. Further
investigations are underway in our laboratory in order to further exploit the synthetic potential of these
complexes. Results will be reported in due course.
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Experimental section
General (standard techniques).THF and Et2O was freshly distilled under a nitrogen atmosphere over
Na/benzophenone. N,N,N',N'ꢀtetramethylethylenediamine (TMEDA) was distilled over finely
powdered CaH2, hexyllithium was purchased as hexane solution and was filtered on celite before using
and title established by titration method. The solvent toluene was freshly distilled under nitrogen
atmosphere over CaH2. All the chemicals and solvents used were commercially available (TCI Europe,
Fluorochem, VWR, Aldrich Chemical Company) and used without further purification. Melting points
were incorrected and recorded with Büchi melting point Bꢀ545. Resonance spectra were recorded
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using BRUCKER 300, 600, AGILENT 500 MHz (1H NMR 400, 500, 600 MHz, CꢀNMR 75, 125,
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150 MHz e B NMR 160 MHz), CDCl3, CD3OD, THFꢀd8 or Tolueneꢀd8 were used as solvents. Data
are reported as follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, m = multiplet, coupling constant in Hz, integration]. Chemical shifts are reported in
ppm. Infraꢀred spectra of the compounds were recorded neat, as film, as KBr disc as indicated, by a
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PerkinꢀElmer 283 spectrometer in reciprocal centimetre (cmꢀ1) or by using ATR spectrophotometer.
ESIꢀMS analysis were performed on Agilent 110 LC/MSD mass spectrometer with ionic single
quadrupole trap system and Exalibur data system. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel thick plates (Merck) with fluorescence indicator Fꢀ254; visualization
was performed using a UV lamp (254 nm) or using a KMnO4 0,02M solution. Enantiomeric ratios and
enantiomeric excesses were determined with HPLC AGILENT 1260, chiral column (Lux_1ꢀCellulose),
following the condition reported. For flash chromatography silica gel 70ꢀ230 mesh and 230ꢀ400 mesh
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were used. Optical rotation [a]D values were measured by using a polarimeter with 1 dm cell path
length; the concentration (c) is expressed in g/100 mL. All reactions and reagent sensible to oxygen and
water were carried out using nitrogen dry atmosphere. The title of base (secꢀBuLi) was determined by
titration with Nꢀphenylbenzamide, following the procedure reported in literature.24
General Preparations of 1-alkyl-2-arylazetidines, 1a-c, e.
Procedure A. According to the procedure reported in the literature,9 to a solution of commercially
available 3ꢀchloroꢀ2ꢀarylpropanꢀ1ꢀones (10 mmol, 1 equiv.) in MeOH (10 mL) cooled at 0°C, 756 mg
of NaBH4 (2 equiv.) were added slowly, and the solution was stirred at room temperature for 2 hours.
Methanol was distilled off under reduced pressure and 25 mL of Et2O and H2O were added, the
aqueous phase was extracted with Et2O (3 x 20 mL) and the combined organic phases were dried over
Na2SO4, filtered and the solvent evaporated under reduced pressure. 3ꢀChloroꢀ1ꢀarylpropanꢀ1ꢀols were
obtained without further purification. To a solution of 3ꢀchloroꢀ1ꢀarylpropanꢀ1ꢀol (10 mmol, 1 equiv.)
in CH2Cl2 (10 mL) at 25 °C, a solution of SOCl2 (30 mmol, 3 equiv.) in CH2Cl2 (3 mL) was added
dropwise. After 2 hours at 25 °C the reaction mixture was poured into water and aqueous NaOH (15%
p/v) was slowly added to neutralize the excess of HCl. The aqueous phase was extracted with CH2Cl2
(3 x 15 mL) and the combined organic phases were dried over Na2SO4, filtered and evaporated under
reduced pressure to give 1ꢀarylꢀ1,3ꢀdichloropropane that was employed without further purification. To
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a solution of 1ꢀarylꢀ1,3ꢀdichloropropane in EtOH (12.5 mL) and Et3N (20 mmol, 2 equiv) at 25 °C, a
solution of RꢀNH2 in EtOH (9,7 equiv.) was added. The reaction mixture was refluxed for 24 hours and
then allowed to cool to room temperature. The solvent was removed in vacuo and aqueous NaCO3 (15
% p/v) was added. The aqueous phase was extracted with CH2Cl2 (3 x 20 mL), dried over Na2SO4,
filtered and evaporated under reduced pressure. The crude mixture was purified to give the desired
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azetidine. This procedure was used for the synthesis of chiral azetidine (R)ꢀ1a, [α]D = −16° (c = 1 ,
CHCl3). Enantiomeric excess = 70%. Chiral (R)ꢀ3ꢀchloroꢀ1ꢀphenylpropanꢀ1ꢀol (er = 91:9) was
prepared by reduction of the corresponding ketone by using the (R)ꢀCBS catalyst as reported.9
Procedure B. According to the reported procedure,9 to a solution of 1ꢀmethylꢀ2ꢀphenylazetidine 1a
(210 mg, 1.43 mmol) in dry Et2O (7.42 mL), TMEDA (3.65 mmol, 2.5 equiv.) was added.
Subsequently, a solution of hexyllithium (2.3M in hexane, 2.86 mmol, 2 equiv.) was added dropwise
and the solution was stirred at room temperature for 1 hour under dry nitrogen atmosphere. After, MeI
(3.56 mmol, 2.5 equiv) was added and after 20 minutes the reaction was quenched with an aqueous
solution of NH4Cl. The aqueous phase was extracted with Et2O (3 x 15 mL) and the combined organic
phases were dried over Na2SO4, filtered and evaporated under reduced pressure.
1-Methyl-2-phenylazetidine (1a). Prepared according to General Procedure A and purified by flash
column chromatography (SiO2, dry loaded, 100% Et2O) to afford the title azetidine as a colourless oil,
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Rf = 0.45 (100% Et2O); 65%, 957 mg. H NMR (400 MHz, CDCl3): δ 7.40−7.32 (m, 4H), 7.27−7.23
(m, 1H), 3.88 (t, J = 8.2 Hz, 1H), 3.49−3.44 (m, 1H), 2.86 (dt, J = 9.7, 7.0 Hz, 1H), 2.34 (s, 3H),
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2.31−2.25 (m, 1H), 2.15 (quint, J = 9.2, 1H); C NMR (150 MHz, tolueneꢀd8) δ 144.0, 128.5, 127.3,
126.9, 71.4 (Cq), 53.0, 44.2, 28.0. HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C10H13NNa 170.0940;
found 170.0938. IR (film, cmꢀ1) υ: 2959, 1452, 1190, 964, 745.
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(R)-1-Methyl-2-phenylazetidine (R)-1a. Prepared accordingly to reported procedure.9 [α]D = +113
(c = 1, CHCl3), enantiomeric ratio (er) = 85:15.
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1-Ethyl-2-phenylazetidine (1b). Prepared according to General Procedure A and purified by flash
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column chromatography (SiO2, dry loaded, 100% Et2O) to afford the title azetidine as a colourless oil.
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Rf = 0.40 (100% Et2O); 61%, 982 mg. H NMR (600 MHz, CDCl3) δ 7.41−7.42 (m, 2H), 7.34−7.31
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(m, 2H), 7.25−7.22 (m, 1H), 3.94 (t, J = 8.2 Hz, 2H), 3.47−3.44 (m, 1H), 2.8 (dt, J = 7.5, 9.5 Hz, 1H),
2.66−2.61 (m, 1H), 2.46−2.41 (m, 1H), 2.31−2.32 (m, 1H), 2.11 (quint, J = 9.1 Hz, 1H), 0.92 (t, J =
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7.1 Hz, 3H); C NMR (150 MHz, CDCl3) δ 143.9, 128.4, 127.2, 126.7, 69.7(Cq), 53.1, 50.9, 27.1,
12.8. HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C11H15NNa 184.1097; found 184.1095. IR (film, cmꢀ1)
υ: 2961, 1450, 1191, 964, 752.
1-terz-Butyl-2-phenylazetidine (1c). Prepared according to General Procedure A and purified by flash
column chromatography (SiO2, dry loaded, 100% Et2O) to afford the title azetidine as a colourless oil.
Rf = 0.45 (100% Et2O); 78%, 1.477g.1H NMR (600 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.32−7.29 (m,
2H), 7.23−7.20 (m, 1H), 4.30 (t, J = 8.0, 1H), 3.18−3.13 (m, 2H), 2.19−2.14 (m, 1H), 1.94 (quint like, J
= 8.5 Hz, 1H), 0.89 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 146.3, 128.2, 127.1, 127.0, 62.4, 53.0, 43.2,
27.0, 25.3. IR (film, cmꢀ1) υ: 2966, 1454, 1236, 1065, 758, 699. HRMS (ESIꢀTOF) m/z [M+H]+ calcd
for C13H20N 190.1596; found 190.1590.
1-Methyl-2-o-tolylazetidine (1d). Prepared according to General Procedure B by using azetidine 1a
and purified by flash column chromatography (SiO2, dry loaded, CH2Cl2/MeOH 90:10) to afford the
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title azetidine as a colourless oil. Rf = 0.60; 65%, 150 mg. H NMR (400 MHz, CDCl3) δ 7.62 (d, J =
7.6 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 7.14 (dt, J = 11.4, 7.1 Hz, 2H), 4.09 (t, J = 7.9 Hz, 1H), 3.50−3.46
(m, 1H), 2.98−2.92 (m, 1H), 2.44−2.37 (m overlapping s at 2.39 ppm, 4H), 2.24 (s, 3H), 1.97 (quint
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like, J = 9.2 Hz, 1H). C NMR (100 MHz, CDCl3) δ 141.4, 134.5, 129.9, 126.6, 125.4, 68.5, 53.2,
44.8, 26.7, 18.8. IR (film, cmꢀ1) υ: 2958, 1458, 1351, 1192, 967, 748. HRMS (ESIꢀTOF) m/z [M+Na]+
calcd for C11H15NNa 184.1097; found 184.1090.
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1-Methyl-2-(2’,4’-dimethylphenyl)azetidine (1e). Prepared according to General Procedure A and
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azetidine as a colourless oil. Rf = 0.60; 67%, 1.174 g. H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.7
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Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 6.96 (s, 1H), 4.04 (t, J = 8.1 Hz, 1H), 3.47 (t, J = 7.6Hz, 1H),
2.94−2.90 (m, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 1.95 (quint like, J = 9.7 Hz, 1H), 13C NMR
(125 MHz, CDCl3) δ 138.5, 136.1, 134.4, 130.8, 126.8, 125.5, 68.4 (Cq), 53.2, 44.9, 27.0, 21.2, 18.8.
HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C12H18N 176.1439; found 176.1434. FTꢀIR (film, cmꢀ1) υ
2958, 2770, 1446, 1350, 1193, 967, 809.
General preparations of 1-borane-1-alkyl-2-arylazetidines 2a-e/3a-e.
Procedure A. To a solution of 1ꢀalkylꢀ2ꢀarylazetidines 1a-e (10,6 mmol) in 8 mL of THF a solution of
BH3·THF (1M in THF) was added dropwise (13.73 mmol, 1.3 equiv.) at 0°C. The solution was stirred
at 0°C for 5 minutes, then at room temperature for 10 minutes. The solvent was distilled off under
reduced pressure to give a diastereomeric mixture of 1ꢀboraneꢀ1ꢀalkylꢀ2ꢀarylazetidines 2a-e/3a-e.
Procedure B: isomerization of 1ꢀboraneꢀ1ꢀmethylꢀ2ꢀarylazetidines 2a, 2d, 2e. A solution of 1ꢀboraneꢀ1ꢀ
methylꢀ2ꢀarylazetidine (10.6 mmol) in 8 mL of 2ꢀMeTHF was stirred at 80°C under reflux for 6 hours,
then cooled at room temperature. The solvent was distilled off under reduced pressure to give a mixture
of 1ꢀboraneꢀ1ꢀalkylꢀ2ꢀarylazetidine 2a,d-e/3a,d-e (dr 3/2 see table 1).
(1S*, 2R*)-1-Borane-1-methyl-2-phenylazetidine (2a). Waxy solid. Column chromatography on
silica gel (Hexane/AcOEt 8:2), 70% yield, 1.195g (procedure A), 14% yield, 239 mg (procedure B).
1HꢀNMR (500 MHz, CDCl3, ppm) δ 7.44−7.39 (m, 5H), 4.75 (dd, J = 10.9, 8.0 Hz, 1H), 3.61 (td, J =
8.8, 2.5 Hz, 1H), 3.55 (quart like, J = 8.7, 1H), 3.17 (quint like, J = 10.1, 1H), 2.82 (s, 3H), 2.29 (dtd, J
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= 10.6, 7.9, 2.6 Hz, 1H). CꢀNMR (125 MHz, CDCl3, ppm) δ 133.8 (Cq), 129.6, 129.5, 128.2, 74.2,
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59.8, 53.8, 20.5. BꢀNMR (160 MHz, CDCl3, ppm) δ −14.6 (q, JBꢀH = 100.7 Hz). HRMS (ESIꢀTOF)
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m/z [M+H]+ calcd for C10H17BN 162.1454; found 162.1433. FTꢀIR (ATR, cmꢀ1) υ 2969, 2265, 1451,
1150, 750.
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(1R*, 2R*)-1-Borane-1-methyl-2-phenylazetidine (3a). Waxy solid. Column chromatography on
silica gel (Hexane/AcOEt 8:2), 17% yield, 290 mg (procedure A), 70% yield, 1.195 g (procedure B).
1HꢀNMR (500 MHz, CDCl3, ppm) δ 7.45−7.39 (m, 5H), 5.25 (t, J = 8.6 Hz, 1H), 3.99 (q, J = 8.6 Hz,
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1H), 3.375 (td, J = 9.8, 5.6 Hz, 1H), 2.84–2.77 (m, 1H), 2.15 (s, 3H). CꢀNMR (125 MHz, CDCl3,
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ppm) δ 133.7 (Cq), 129.5, 129.0, 128.8, 73.0, 59.5, 45.6, 19.0. BꢀNMR (160 MHz, THFꢀd8, ppm) δ –
8.7 (q, JBꢀH = 96.8 Hz). HRMS (ESIꢀTOF) m/z [M+H]+ calcd for C10H17BN 162.1454; found 162.1439.
FTꢀIR (film, cmꢀ1) υ 2967, 2260, 1453, 1360, 883. (1R, 2R)-1-borane-1-methyl-2-phenylazetidine,
(1R, 2R)-3a. The enantiomeric ratio (er = 85/15) of optically active diastereoisomer was determined by
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HPLC analysis (see page S3), [α]D = −106 (c = 1, CHCl3).
(1R*, 2S*)- and (1R*, 2R*)-1-borane-1-ethyl-2-phenylazetidine (2b/3b). Waxy solid, prepared
following procedure A, 98% yield, 1.819 g, inseparable mixture of stereoisomers (2b major : 3b minor
= 90:10). 1H NMR (600 MHz, CDCl3) δ 7.50−7.37 (m, 5H major + 5H minor), 5.34 (t like, J = 8.1 Hz,
1H minor), 4.75 (t like, J = 9.2 Hz, 1H major), 3.82−3.72 (m, 1H minor), 3.67−3.60 (m, 2H minor),
3.54−3.49 (m, 1H major), 3.47−3.43 (m, 1H major), 3.20−3.08 (m, 2H major), 3.00−2.95 (m, 1H
major), 2.83−2.76 (m, 1H minor), 2.68−2.62 (m, 1H minor), 2.46−2.36 (m, 1H minor), 2.27 (dt, J =
13.2, 5.1 Hz, 1H major), 1.24 (t, J = 7.3 Hz, 3H major), 0.99 (t, J = 7.2 Hz, 3H minor); 13C NMR major
(150 MHz, CDCl3) δ 134.4, 130.0, 129.2, 128.0, 73.8, 60.7, 56.8, 20.7, 9.9; 11BꢀNMR (160 MHz,
CDCl3) δ major −16.31 (q, JBꢀH = 96.3 Hz), minor −11.27 (q, JBꢀH = 94.9 Hz). FTꢀIR (ATR, cmꢀ1) υ
2970, 2258, 1449, 1160, 961. HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C11H18BNNa 198.1430; found
198.1425. IR (film, cmꢀ1) υ: 2970, 2258, 1449, 1160, 961.
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°C (dec), prepared following procedure A, 98% yield, 2.110 g, inseparable mixture of diastereoisomers
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(2c major : 3c minor = 95:5). Selected signals of the major 2c: H NMR (400 MHz, CDCl3) δ 7.62–
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7.56 (m, 2H), 7.42–7.29 (m, 3H), 5.25 (t like, J = 9.5 Hz, 1H), 3.73 (q like, J = 8.5 Hz, 1H), 3.22 (t
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like, J = 9.0 Hz, 1H), 3.10 (quint like, J = 10.0 Hz, 1H), 2.15–2.07 (m, 1), 1.34 (s, 9H); C NMR (150
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MHz, CDCl3) δ 135.5, 131.5, 129.0, 127.7, 66.4, 62.2, 52.0, 25.7, 20.5; BꢀNMR (160 MHz, CDCl3) δ
−17.49 (q, JB = 95.1Hz). FTꢀIR (ATR, cmꢀ1) υ 2980, 2292, 1392, 1286, 909. HRMS (ESIꢀTOF) m/z
[M+Na]+ calcd for C13H22BNNa 226.1743; found 226.1735. IR (film, cmꢀ1) υ: 2980, 2292, 1392, 1286,
909.
(1R*, 2S*)-1-borane-1-methyl-2-(ortho-tolyl)azetidine (2d). Waxy solid. Column chromatography
on silica gel (Hexane/AcOEt 8:2), 5% yield, 93 mg (procedure B). 1HꢀNMR (500 MHz, CDCl3, ppm) δ
7.76–7.74 (m, 1H), 7.32–7.27 (m, 2H), 7.20–7.18 (m, 1H), 5.085 (dd, J = 10.5, 8.2Hz, 1H), 3.60 (td, J =
9.0, 3.0 Hz, 1H), 3.55 (dd, J = 17.7, 8.7, 1H), 3.18 (quint like, J = 10.1 Hz, 1H), 2.88 (s, 3H), 2.41 (s,
3H), 2.27 (dtd J = 11.2, 8.1, 3.1 Hz, 1H); 13CꢀNMR (125 MHz, CDCl3, ppm) δ 137.4 (Cq), 132.1 (Cq),
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130.9, 130.5, 129.3, 125.8, 70.5, 59.3, 54.9, 20.7, 20.5; BꢀNMR (160 MHz, CDCl3, ppm) δ –14.4 (q,
JBꢀH = 98.5 Hz). FTꢀIR (ATR, cmꢀ1) υ 2968, 2249, 1448, 1165, 760. HRMS (ESIꢀTOF) m/z [M+Na]+
calcd for C11H18BNNa 198.1430; found 198.1428. IR (film, cmꢀ1) υ: 2969, 2270, 1449, 1175, 770.
(1R*,2R*)-1-borane-1-methyl-2-(ortho-tolyl)azetidine (3d). Waxy solid. Column chromatography on
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silica gel (Hexan/AcOEt 8:2), 81% yield, 1.503 g (procedure B). HꢀNMR (500 MHz, CDCl3, ppm) δ
7.53–7.51 (m, 1H), 7.34–7.26 (m, 3H), 5.44 (dd, J = 9.0, 6.1 Hz, 1H), 3.89 (td, J = 9.2, 5.6 Hz, 1H),
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3.49 (q like, J = 9.4 Hz, 1H), 2.97–2.89 (m, 1H), 2.66–2.59 (m, 1H), 2.47 (s, 3H), 2.13 (s, 3H); Cꢀ
NMR (125 MHz, CDCl3, ppm) δ 140.0 (Cq), 132.3 (Cq), 131.4, 129.6, 127.9, 126.3, 70.1, 60.1, 46.4,
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20.5, 19.5; BꢀNMR (160 MHz, CDCl3, ppm) δ –8.86. HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for
C11H18BNNa 198.1430; found 198.1432.FTꢀIR (ATR, cmꢀ1) υ 2967, 2258, 1448, 1165, 770.
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(1R*,2S*)-1-borane-1-methyl-2-(2,4-dimethylphenyl)azetidine (2e). White solid, m.p.= 114,5−117,5
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°C. Column chromatography on silica gel (Hexane/AcOEt 8:2), 6% yield, 120 mg (procedure B). H
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NMR (500 MHz, CDCl3, ppm) δ: 7.625 (d, J = 8.02 Hz, 1H), 7.115 (d, J = 8.05 Hz, 1H), 7.01 (s, 1H),
5.045 (dd, J = 7.45, 9.7 Hz, 1H), 3.58 (td, J = 8.9, 3.0 Hz, 1H), 3.52 (dd, J = 17.7, 8.7 Hz, 1H), 3.15
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(quint like, J = 10.1, 1H), 2.86 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H), 2.29ꢀ2.23 (m, 1H). C NMR (125
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MHz, CDCl3, ppm) δ: 139.2, 137.2, 131.3, 130.8, 129.2, 126.6, 70.4, 59.2, 54.8, 21.3, 20.8, 20.4. B
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NMR {1H} (160 MHz, CDCl3, ppm) δ: −14.5 (s). B NMR (160 MHz, CDCl3, ppm) δ: −14.5 (q, J =
93.7 Hz). HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C12H20BNNa 212.1583; found 212.1591. IR
(NaCl, cmꢀ1) υ: 2970, 2262, 1614, 1448, 1169, 800.
(1R*, 2R*) -1-borane-1-methyl-2-(2,4-dimethylphenyl)azetidine (3e). White solid, m.p. = 40,7−41,9
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°C. Column chromatography on silica gel (Hexane/AcOEt 8:2), 79% yield, 1.583 g (procedure B). H
NMR (500 MHZ, CDCl3, ppm) δ: 7.39 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.39
(d, J = 7.9 Hz, 1H), 5.40 (dd, J = 9.0, 6.2 Hz, 1H), 3.87 (td, J = 9.3, 5.6 Hz, 1H), 3.46 (dd, J = 18.0, 9.4
Hz, 1H), 2.95–2.85 (m, 1H), 2.63−2.55 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H). 13C NMR (150
MHZ, CDCl3, ppm13C NMR (125 MHz, CDCl3) δ 139.7, 139.4, 132.1, 129.2, 127.7, 126.8, 69.8, 59.8,
46.2, 21.1, 20.3, 19.4. 11B NMR (160 MHz, CDCl3, ppm) δ: −9.0 (q, J = 100.4 Hz). IR (NaCl, cmꢀ1) υ:
2967, 2263, 1615, 1450, 1167, 809. HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C12H20BNNa 212.1583;
found 212.1592.
General Procedure of Metalation/electrophile trapping sequence for the synthesis of 1-borane-1-
methyl-2,2 disubstituted azetidines. To a solution of (1R*,2R*)ꢀ1ꢀboraneꢀ1ꢀmethylꢀ2ꢀphenylazetidine
3a (70 mg, 0,43 mmol) in dry THF (8 mL), under inert atmosphere, stirred at −50°C a solution of secꢀ
BuLi (1,4M hexane solution, 1,29 mmol, 3 equiv.) was added dropwise. The solution was stirred at
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−50°C for 5 minutes, then the electrophile was added and the reaction stirred at the same temperature
for a variable time (5ꢀ120 min) depending of used electrophile. The reaction was stopped with an
aqueous solution of NH4Cl, the aqueous phase was extracted with Et2O (3 x 15 mL) and the combined
organic phases were dried over Na2SO4, filtered and the solvent removed under reduced pressure. The
same procedure has been applied for metalation/deuteration of (1R*,2S*)ꢀ1ꢀboraneꢀ1ꢀmethylꢀ2ꢀ
phenylazetidine 2a.
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(1R*, 2R*)- and (1R*, 2S*)-1-Borane-1-methyl-2-deuterium-2-phenylazetidine (3a-D/2a-D).
Mixture of diastereoisomers. Prepared following general procedure [Electrophile = CD3OD (100 µL,
excess), stirring with electrophile = 5 minutes], white solid, 99% yield, 69 mg. Selected data for Major
3a-D: 1HꢀNMR (500 MHz, CDCl3, ppm) δ 7.47−7.38 (m, 5H), 4.00 (q like, J = 8.9 Hz, 1H), 3.37 (td, J
= 10.0, 5.6 Hz, 1H), 2.81−2.79 (m, 1H), 2.72−2.64 (m, 1H), 2.16 (s, 3H); 13CꢀNMR (125 MHz, CDCl3,
ppm) δ 133.6, 129.6, 129.0, 128.8, 72.6 (t, J = 23.2 Hz), 59.5, 45.6, 18.9. 11B NMR (160 MHz, CDCl3,
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ppm) δ: −12.0 (q, J = 93.3 Hz). Selected data for Minor 2a-D: HꢀNMR (500 MHz, CDCl3, ppm) δ
7.43−7.37 (m, 5H), 3.62−3.51 (m, 2H), 3.14 (q like, J = 9.9 Hz, 1H), 2.81 (s, 3H), 2.31−2.25 (m, 1H);
13CꢀNMR (125 MHz, CDCl3, ppm) δ 133.7, 129.5, 129.4, 128.1, 73.6 (t, J = 20.8 Hz) 59.7, 53.6, 20.4.
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11B NMR (160 MHz, CDCl3, ppm) δ: −17.1 (s). B NMR (160 MHz, CDCl3, ppm) δ: −17.1 (q, J =
103.4 Hz). HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C10H15BDNNa 185.1333; found 185.1341. FTꢀIR
(ATR, cmꢀ1) υ 2968, 2270, 1450, 1150, 750.
(1R, 2R)- and (1R, 2S)-1-borane-1-methyl-2-deuterium-2-phenylazetidine, (1R,2R)-3a-D/(1R,2S)-
2a-D). The enantiomeric ratio of both optically active diastereoisomers was determined by HPLC
analysis (see page S3ꢀ4).
(1R*,2R*)-1-borane-1,2-dimethyl-2-phenylazetidine (3f). Prepared following general procedure
[Electrophile = CH3I (3 equivalents, 1.29 mmol, 132 mg), stirring with electrophile = 5 minutes], waxy
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solid. Column chromatography on silica gel (Hexane/AcOEt 8:2), 68% yield, 51 mg.1HꢀNMR (500
MHz, CDCl3, ppm) δ 7.45−7.30 (m, 5H), 4.02−3.96 (m, 1H), 3.23ꢀ3.16 (m, 2H), 2.32 (s, 3H),
2.30−2.24 (m, 1H), 1.94 (s, 3H); 13CꢀNMR (125 MHz, CDCl3, ppm) δ 141.2 (Cq), 128.7, 128.4, 125.8,
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74.8 (Cq), 57.6, 49.9, 28.7, 27.9; 11B NMR (160 MHz, CDCl3, ppm) δ −13.9 (q, JBꢀH = 95.3 Hz). HRMS
(ESIꢀTOF) m/z [M+Na]+ calcd for C11H18BNNa 198.1425; found 198.1424.
(1R*,2R*)-1-borane-1-methyl-2-benzyl-2-phenylazetidine (3g). Prepared following general
procedure [Electrophile = benzyl bromide (3 equivalents, 1.29 mmol, 240 mg), stirring with
electrophile = 5 minutes], white solid, m.p. 132−133 °C. Column chromatography on silica gel
(Hexane/AcOEt 8:2), 54% yield, 58 mg. 1H NMR (500 MHz, CDCl3, ppm) δ: 7.45−7.01 (m, 8H), 6.565
(d, J = 7.7 Hz, 2H), 4.18−4.11 (m, 1H), 3.965 (d, J = 13.3 Hz, 1H), 3.665 (d, J = 13.3 Hz, 1H), 3.265 (dt,
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J = 9.4, 9.3 Hz, 1H), 2.91 (q like, J = 11.8 Hz, 1H), 2.58−2.54 (m, 1H), 2.43 (s, 3H). C NMR (75
MHz, CDCl3, ppm) δ: 139.2 (Cq), 136.1 (Cq), 130.7, 128.7, 128.4, 127.8, 127.3, 126.6, 78.3 (Cq),
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57.8, 50.4, 45.0, 24.9. B NMR (160 MHz, CDCl3, ppm) δ: −13.9 (s). B NMR (160 MHz, CDCl3,
ppm) δ: −13.9 (q, J = 97.76 Hz). HRMS (ESIꢀTOF) m/z [M+Na]+ calcd for C17H22BNNa 274.1741;
found 274.1749. IR (NaCl, cmꢀ1) υ: 2324, 1449, 1150, 700.
(1R*,2S*)-1-borane-1-methyl-2-benzyl-2-phenylazetidine (2g). Prepared following general
procedure [Electrophile = benzyl bromide (3 equivalents, 1.29 mmol, 240 mg), quenching time= 5
minutes], waxy solid. Column chromatography on silica gel (Hexane/AcOEt 8:2), 30% yield, 32 mg.
1H NMR (500 MHz, CDCl3, ppm) δ: 7.45−6.94 (m, 8H), 6.52 (d, J = 8.5 Hz, 2H), 3.82−3.68 (m, 2H),
3.50 (d, J = 12.0 Hz, 1H), 3.37 (d, J = 12.0 Hz, 1H), 3.11 (q, J = 10.7 Hz, 1H), 2.97 (s, 3H), 2.36−2.28
(m, 1H). 13C NMR (75 MHz, CDCl3, ppm) δ: 140.0 (Cq), 134.9 (Cq), 130.7 (2C), 128.0, 127.8, 127.4,
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127.1, 126.9, 78.0 (Cq), 58.6, 46.3, 42.9, 24.8. B NMR (160 MHz, CDCl3, ppm) δ: −11.1 (s). HRMS
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(ESIꢀTOF) m/z [M+Na]+ calcd for C17H22BNNa 274.1741; found 274.1747. IR (NaCl, cmꢀ1) υ: 2324,
1448, 1147, 700.
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(1R*,2R*)-1-borane-1-methyl-2-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)azetidine
(3h). Prepared following general procedure [Electrophile = 2ꢀisopropoxyꢀ4,4,5,5ꢀtetramethylꢀ1,3,2ꢀ
dioxaborolane (3 equivalents, 1.29 mmol, 240 mg), quenching time = 120 minutes], pale yellow waxy
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solid. Column chromatography on silica gel (Hexane/AcOEt 8:2), 67% yield, 82 mg. HꢀNMR (500
MHz, CDCl3, ppm) δ 7.50−7.48 (m, 2H), 7.39−7.36 (m, 2H), 7.33−7.29 (m, 1H), 4.09 (dd, J = 17.7, 8.9
Hz, 1H), 3.26 (td, J = 9.4, 4.6 Hz, 1H), 2.95−2.89 (m, 1H), 2.85−2.79 (m, 1H), 2.24 (s, 3H), 1.26 (s,
6H), 1.22 (s, 6H); 13CꢀNMR (125 MHz, CDCl3, ppm) δ 137.6 (Cq), 128.2, 128.2, 128.1, 84.8 (Cq), 60.2,
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47.6, 24.9, 23.3; BꢀNMR (160 MHz, CDCl3, ppm) δ 30.5 (s), −10.2 (q, 90.9 Hz). HRMS (ESIꢀTOF)
m/z [M+Na]+ calcd for C16H27B2NNaO2 310.2126; found 310.2130. (1R,2R)-1-Borane-1-methyl-2-
phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)azetidine (1R,2R)-3h. [α]D ˗2 (c 0.5, CHCl3).
The enantiomeric ratio of optically active diastereoisomer was determined by HPLC analysis (see page
S5).
2-(1-Methyl-2-phenylazetidin-2-yl)-propan-2-ol (5a). Prepared following procedure [Electrophile =
dry acetone (5 equivalents, 2.05 mmol, 118 mg), stirring with electrophile = 30 minutes], pale yellow
solid, m.p. 65−68°C. Column chromatography on silica gel (CH2Cl2/MeOH 85:15), 70% yield, 62 mg.
1H NMR (500 MHZ, CD3OD, ppm) δ: 7.49−7.41 (m, 5H), 4.02 (s, 1H), 3.42−3.38 (m, 1H), 3.33−3.31
(m, 1H), 3.07−3.02 (m, 1H), 2.96−2.90 (m, 1H), 2.85 (s, 3H), 1.26 (s, 3H), 1.05 (s, 3H). 13C NMR (150
MHz, CD3OD, ppm): δ 129.8 (3C), 129.1, 85.5 (Cq), 74.5, 52.6, 41.4, 26.4, 25.3, 25.1. HRMS (ESIꢀ
TOF) m/z [M+H]+ calcd for C13H20NO 206.1539; found 206.1542. IR (NaCl, cmꢀ1) υ: 3326, 2915,
1446, 1263, 1099.
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tert-Butyl(1-methyl-2-phenylazetidin-2-yl)phenylmethylcarbammate (5b). Isolated diastereomer
whose dr and stereochemistry are not assigned. Prepared following general procedure [Electrophile =
tertꢀbutylbenzylidenecarbamate (2.5 equivalents, 1.25 mmol, 210 mg), stirring with electrophile = 60
minutes], pale yellow oil. Column chromatography on silica gel (Hexane/AcOEt 8:2), 65% yield, 98
mg. 1H NMR (300 MHz, CDCl3, ppm) δ 7.39−7.30 (m, 3H), 7.26−7.22 (m, 2H) 7.07−7.02 (m, 2H),
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6.85−6.82 (m, 2H),3.31−3.26 ( m, 1H), 2.75−2.47 (m, 1H), 2.14−1.97 (m, overlapping 2.01 (s, 3H)
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1H), 1.45−1.33 (m, 9H). C NMR (75 MHz, CDCl3, ppm) δ: 156.2 (Cq), 139.1 (Cq), 136.5, 128.6,
127.9, 127.4, 127.1, 126.5, 79.2, 74.4, 59.9 (Cq), 49.6, 38.9, 28.3, 23.2. HRMS (ESIꢀTOF) m/z [M+H]+
calcd for C22H29N2O2 353.2224; found 353.2224. IR (NaCl, cmꢀ1) υ: 2922, 1720, 1454, 1366, 246,
1168, 1099, 700.
tert-Butyl(1-methyl-2-phenylazetidin-2-yl)carboxylate (5c).
Prepared following general procedure [Electrophile = diꢀtertꢀbutyl dicarbonate (2.5 equivalents, 1.25
mmol, 273 mg), stirring with electrophile = 30 minutes], waxy solid. Column chromatography on silica
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gel (Hexane/AcOEt 7:3), 77% yield, 82 mg. H NMR (500 MHz, CDCl3, ppm) δ 7.47−7.23 (m, 5H),
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3.36−3.26 (m, 2H), 2.87−2.82 (m, 1H), 2.37 (s, 3H), 2.38−2.34 (m, 1H), 1.43 (s, 9H). C NMR (125
MHz, CDCl3) δ 171.8 (Cq), 142.1 (Cq), 128.1, 127.0, 125.3, 81.5 (Cq), 75.0 (Cq), 51.5, 39.81, 29.3,
28.1. IR (NaCl, cmꢀ1) υ: 2928, 1719, 1447, 1367, 1255, 1162, 1121, 698. HRMS (ESIꢀTOF) m/z
[M+H]+ calcd for C15H22NO2 248.1651; found 248.1644.
(Cinnamyl(methyl)ammonio)trihydroborate (4).
Waxy solid. Column chromatography on silica gel (Hexan/AcOEt 8:2), 10% yield, 7 mg.1HꢀNMR (500
MHz, CDCl3, ppm) δ 7.47−7.28 (m, 5H), 6.63 (d, J = 15.9 Hz, 1H), 6.31 (ddd, J = 15.8, 8.1, 6.4 Hz,
1H), 3.75−3.70 (m, 1H), 3.32 (dtd, J = 13.5, 7.9, 0.7 Hz, 1H), 2.57 (d, J = 5.9 Hz, 3H); 13CꢀNMR (125
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CDCl3, ppm) δ −9.4 (q, JBꢀH = 98.4 Hz). IR (ATR, cmꢀ1) υ: 3187, 2945, 2262, 1158, 969. HRMS (ESIꢀ
TOF) m/z [M+Na]+ calcd for C10H16BNNa 184.1273; found 184.1265. IR (film, cmꢀ1) υ: 2959, 1452,
1190, 964, 745.
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Metalation/Deuteration Procedure of (1R*, 2R*)-1-borane-1-methyl-2-(ortho-tolyl)azetidine (3d)
To a solution of (1R*,2R*)ꢀ1ꢀboraneꢀ1ꢀmethylꢀ2ꢀ(orthoꢀtolyl)azetidine 3d (0,29 mmol, 51 mg) in 5 mL
of dry THF stirred at −50°C, a solution of secꢀBuLi (1,4M hexane solution, 0,87 mmol, 3 equiv.) was
added dropwise and the solution was stirred at low temperature for 5 minutes. Then, 100 µL of CD3OD
(excess) were added and after 5 minutes the reaction was quenched with an aqueous solution of NH4Cl.
The aqueous phase was extracted with Et2O (3 x 15 mL) and the combined organic phases were dried
over Na2SO4, filtered and solvent removed under reduced pressure. Crude of reaction was purified by
flash chromatography (Hexane/ AcOEt = 7:3).
1-borane-3-deuterio-3-(2-(2-methylbutyl)phenyl)propyl)methylammonium (7)
Diastereomeric mixture, stereochemistry and dr not assigned. Waxy solid. Column chromatography on
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silica gel (Hexane/AcOEt 8:2), 75% yield, 51 mg. Selected data for the major isomer: HꢀNMR (500
MHz, CDCl3, ppm) δ 7.16−7.11 (m, 4H), 2.97−2.89 (m, 1H), 2.71−2.60 (m, 3H), 2.52 (s, 3H), 2.36
(ddd, J = 13.7, 8.4, 2.3 Hz, 1H), 1.96 (q, J = 7.7 Hz, 2H), 1.63−1.55 (m, 1H), 1.46−1.38 (m, 1H),
1.24−1.17 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H), 0.865 (d, J = 6.3 Hz, 3H); 13CꢀNMR (125 MHz, CDCl3,
ppm) δ 139.3 (Cq), 138.4, 130.5, 128.9, 126.2, 126.1, 56.9, 42.1, 39.9, 36.4, 29.5, 29.5 (t, J = 19.3 Hz),
27.8, 19.0, 11.6; 11BꢀNMR (160 MHz, CDCl3, ppm) δ −14.75 (q, J = 91.4 Hz). HRMS (ESIꢀTOF) m/z
[M+Na]+ calcd for C15H27BDNNa 257.2272; found 257.2285. IR (ATR, cmꢀ1) υ: 3022, 2964, 2289,
1735, 1371.
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General Procedure for N-Deborylation of 1-borane-1-methyl-2-phenylazetidines (3f-g).
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In a reaction flask 0.167 mmol of αꢀfunctionalized 1ꢀboraneꢀ1ꢀmethylꢀ2ꢀphenylazetidine were
dissolved in AcOEt (3 mL). An aqueous solution of NH3 28% (1 mL) was added and the solution was
stirred at 90°C under reflux for 3 hours. Crude of reaction was dried over Na2SO4, filtered, evaporated
under reduced pressure.
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54
55
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59
60
1-Methyl-2-benzyl-2-phenylazetidine (5d)
Prepared following general procedure, colourless oil. Column chromatography on silica gel (Et2O),
1
91% yield, 36 mg. H NMR (500 MHz, CDCl3, ppm) δ: 7.25−7.06 (m, 6H), 6.98−6.90 (m, 2H),
6.76−6.68 (m, 2H) 3.49−3.42 (m, 1H), 3.37 (d, J = 12.57 Hz, 1H), 3.27 (td, J = 8.2, 6.8 Hz, 1H), 3.05
13
(d, J = 12.57 Hz, 1H), 2.57 (s, 3H), 2.44−2.36 (m, 2H). C NMR (75 MHz, CDCl3, ppm) δ: 146.8
(Cq), 137.5 (Cq), 130.7, 127.8, 127.7, 126.4, 126.1, 125.8, 71.5 (Cq), 51.2, 40.8, 38.7, 28.3. HRMS
(ESIꢀTOF) m/z [M+H]+ calcd for C17H20N 238.1590; found 238.1596.
N-methyl-3-phenylbut-3-en-1-amine (6)
Prepared following general procedure, brown oil. Column chromatography on silica gel (Hexan/AcOEt
1
8:2), isolated yield 90%, 24 mg. H NMR (500 MHz, CDCl3) δ 7.44−7.28 (m, 5H), 5.40 (s, 1H), 5.21
(s, 1H), 3.12−3.08 (m, 2H), 3.02−2.99 (m, 2H), 2.76 (s, 3H), 2.01 (s, 1H). 13C NMR (126 MHz, CDCl3)
δ 143.2, 138.9, 128.8, 128.2, 126.0, 115.6, 56.9, 43.1, 30.6. HRMS (ESIꢀTOF) m/z [M+H]+ calcd for
C11H16N 162.1283; found 162.1277.
Acknowledgments
This research was supported by the project Laboratorio Sistema code PONa300369 financed by MIUR,
the University of Bari. We are grateful to Marina Zenzola, for the precious contribution in the
preparation of some compounds studied in this work.
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Supporting Information
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Supporting Information is available free of charge on the ACS Publications website. Characterization
of new compounds (1H and 13C NMR, 11B, COSY, HSQC, NOESY spectra), HPLC analysis of
enantioenriched compounds, computational data for compounds 2a, 2d, 3a, 3d, and Xꢀray analysis of
2d.
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15 CCDC depository number for 2d: 1845835.
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20 It is worth noting that for both 2a and 3a, lithiation occurs at the benzylic position. Nevertheless, lithiation of 3a resulted
straightforward likely because of the syn relationship of Ha with the BH3 group. In addition, product 4 was never observed
in the lithiation of 3a.
21 Attempts to optimize lithiation of 2a were unsuccessful.
22 The possibility of inversion at the nitrogen was ruled out as consequence of the observed stability of complex 3a in THF
(see SI).
23
For literature concerning the stereoselectivity of reactions involving organolithium compounds see: a) Wolf, C. in
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24 Degennaro, L.; Musio, B.; Luisi, R. In Lithium Compounds in Organic Synthesis: From Fundamentals to Applications;
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