Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation-Borylation-Ring-Opening of Azetidinium Ions

Article abstract of DOI:10.1055/s-0035-1562447

In situ generated 2-phenyl-azetidinium ylides react with boronic esters to form acyclic γ-dimethylamino tertiary boronic esters. The transformation is believed to involve the formation of a zwitterionic boronate, which subsequently undergoes ring-opening 1,2-migration, which is promoted by the relief of ring strain. Owing to the configurational instability of the initially formed ylides, which appear to be in equilibrium with the open-chain carbene form, the reaction is not stereospecific. The C-B bond of the γ-dimethylamino tertiary boronic esters can be transformed into a variety of functional groups (C-OH, C-vinyl, C-H, C-BF₃), thus giving a diverse selection of 3-aryl-1-aminopropanes, which represent a privileged motif among drug molecules.

Full text of DOI:10.1055/s-0035-1562447

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–M
paper
A
G. Casoni et al.
Paper
Synthesis
Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation–Boryl-
ation–Ring-Opening of Azetidinium Ions
Giorgia Casoni
R
Bpin (1.2 equiv)
N
Eddie L. Myers
R
Bpin
N
LDA (2.0 equiv)
–78 °C to r.t.
Varinder K. Aggarwal*
B
N
O
R
44–75%
yield
O
School of Chemistry, University of Bristol, Cantock’s Close,
Bristol, BS8 1TS, UK
OTf
v.aggarwal@bristol.ac.uk
Dedicated to the memory of Professor Jean Normant
FG
R
R
aryl, heteroaryl, alkyl, allyl
OH, H, BF3K, vinyl
=
=
N
FG
Received: 14.05.2016
Accepted after revision: 05.06.2016
Published online: 07.07.2016
One of the most privileged structural motifs among
marketed drugs and drug candidates is the 3-aryl-1-amino-
propane unit (Figure 1).6 Bedaquiline, an antituberculosis
agent, is one of the more high-profile and structurally com-
plex members of this class of drug molecule (Figure 1).7
This motif can be introduced through the addition of aryl
metal reagents to β-aminoketones,8 the hydroformyla-
tion/reductive amination of styrenes,9 the Heck–Matsuda
addition of aryl halides/pseudohalides to allyl amines10 and
the electrophilic addition of amine-containing electrophiles
to diarylmethyl anions.11
DOI: 10.1055/s-0035-1562447; Art ID: ss-2016-c0356-op
Abstract In situ generated 2-phenyl-azetidinium ylides react with bo-
ronic esters to form acyclic γ-dimethylamino tertiary boronic esters.
The transformation is believed to involve the formation of a zwitterionic
boronate, which subsequently undergoes ring-opening 1,2-migration,
which is promoted by the relief of ring strain. Owing to the configura-
tional instability of the initially formed ylides, which appear to be in
equilibrium with the open-chain carbene form, the reaction is not ste-
reospecific. The C–B bond of the γ-dimethylamino tertiary boronic es-
ters can be transformed into a variety of functional groups (C–OH, C–
vinyl, C–H, C–BF3), thus giving a diverse selection of 3-aryl-1-aminopro-
panes, which represent a privileged motif among drug molecules.
Key words 3-aryl-1-aminopropanes, azetidinium ion, lithiation, bory-
lation, ring-opening, boronic esters
HO
N
N
N
Boronic esters are arguably the most versatile of organic
functional groups. This group can be transformed to intro-
duce C–O, C–N, C–C, or C–X bonds under mild conditions, a
characteristic that makes boronic esters (and boronic acids)
extremely valuable late-stage intermediates in medicinal
chemistry programs.1 Although this value has mostly been
demonstrated in the context of sp2-hybridised boron-bear-
ing carbon centres (the transformation of aryl and vinyl bo-
ronic esters and acids through Suzuki–Miyaura cross-cou-
pling),2 the diversification of sp3-hybridised boron-bearing
carbon centres is much less common, despite the identified
need to populate compound libraries with such 3D mole-
cules.3 However, the relatively recent development of ro-
bust and generally applicable methods for the enantioselec-
tive preparation of secondary and tertiary alkyl boronic es-
ters,4 together with stereospecific methods for the
subsequent transformation of the C–B bonds,5 is expected
to lead to a step-change in the use of organoboron chemis-
try in the pharmaceutical industry.
Diisoproamine
(spasmolytic/choleretic)
Tolpropamine
(antihistaminic/antipuritic)
Tolterodine
(antimuscarinic)
N
Br
OH
N
N
X
O
X = H; Pheniramine
X = Cl; Chloropheniramine
X = Br; Bromopheniramine
(antihistaminic)
Bedaquiline
(antituberculosis)
Figure 1 Marketed drugs containing the 3-aryl-1-aminopropane motif
We were particularly interested in accessing a diverse
selection of 3-aryl-1-aminopropanes 1 through C–B func-
tionalisation of γ-dimethylamino tertiary boronic esters
(Scheme 1). We envisioned that these boronic ester inter-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

B
G. Casoni et al.
Paper
Synthesis
mediates could be accessed through lithiation–borylation of
azetidinium ions 3. Specifically, we hoped that azetidinium
ions 3 could be deprotonated to give ylide/lithium-stabi-
lised carbenoid 4, which could then be trapped with boron-
ic ester 5 to give zwitterionic boronate 6, which in turn
could undergo ring-opening 1,2-migration to give γ-amino
tertiary boronic ester 2. Ideally, the entire transformation
would be stereospecific, a characteristic that would require
conditions under which enantiomerically enriched azeti-
dinium ion 3 could be deprotonated to give 4 that rests in
the lithium-stabilised carbenoid form (rather than the ylid-
ic form), is configurationally stable, and undergoes ste-
reospecific trapping with a boronic ester 5; the resulting
boronate 6 would then undergo 1,2-migration, processes
that are usually highly stereospecific and involve inversion
at the leaving-group-bearing carbon atom, thus giving en-
antiomerically enriched tertiary boronic ester 2.
figurational stability of less stabilised ylides, such as those
derived from phenyl-substituted azetidinium ions, was un-
clear.
OTES
OTES
1. EtBin, LiTMP
2. TESOTf
NaOH/H2O2
O
OH
Bpin
Et
Et
Et
7
9
Et
Et
8
>98:2 d.r.
99:1 e.r.
NHBoc
OH
1. PhBin, LiTMP
2. NaOH/H2O2
NBoc
iPr
iPr
Ph
>99:1 e.r.
10
Boc
N
1. iPrBNeop, LiTMP
no reaction
Ph
2. NaOH/H2O2
11
OTf
N
CO2Me
LiHMDS
CN
N
N
CO2Me
NC
THF, –78 °C to –30 °C
NC
4a
C–B
functionalization
12 71%
3a
R2
R1
R2
R1
Bpin
FG
Scheme 2 Previous studies from our laboratory and that of Couty and
David
N
N
2
1
N
LiX
R1
To test our reaction, we first prepared the triflate salt of
phenyl-substituted azetidinium ion 3b in four steps from
commercially available 3-chloro-1-propiophenone (13)
(Scheme 3). Ketone 13 was first reduced to the alcohol16
1,2-migration
R2
Bpin
5
N
N
X
RLi
X
N
R1
R2
and then converted into the corresponding dichloride.14b
A
R1
R1
Bpin
H
Li
ring-closing double displacement reaction with methyl-
amine gave azetidine 14, which was subsequently N-al-
kylated in good yield to give azetidinium ion 3b.14b,15b
3
4
6
Scheme 1 Synthesis of 3-aryl-1-aminopropanes through C–B function-
alisation of γ-dimethylamino tertiary boronic esters, which could be
formed through lithiation–borylation
1. NaBH4 (3.0 equiv)
MeOH
2. SOCl2 (3.0 equiv)
CH2Cl2
MeOTf (2.1 equiv)
O
Previous experience within our laboratory gave us
cause to be both optimistic and hesitant. For example, we
have shown that such ring-opening lithiation–borylation
reactions can be carried out with both epoxides 7 and N-
Boc aziridines 9 to give the corresponding products 8 and
10 with high levels of enantiospecificity (Scheme 2).12,13
However, this type of reaction failed with N-Boc azetidines
11, presumably owing to the ring-opening 1,2-migration
step being slow (Scheme 2).14 However, the recent work of
Couty and David suggested that ring-opening of the corre-
sponding azetidinium ions might be more facile.15 Specifi-
cally, they showed that cyano-substituted azetidinium ions
3a can be deprotonated with LiHMDS to give ylides 4a that
can be trapped with electrophiles; when the electrophile is
an aldehyde, ketone, or acrylate, the resulting alkoxide or
enolate undergoes an intramolecular SN2 reaction to open
the azetidinium ion (Scheme 2). The ylides were chemically
unstable, even at cryogenic temperatures, necessitating that
the electrophile be present during their formation. These
studies also showed that these stabilised azetidinium ylides
are configurationally unstable, even within the short life-
time imposed by in situ trapping. However, the level of con-
3. MeNH2, EtOH
N
Et2O
N
OTf
Ph
3b >95%
Ph
Cl
Ph
13
14 49%
Scheme 3 Synthesis of phenyl-substituted azetidinium ion 3b
With azetidinium ion 3b in hand, we subjected it to the
conditions similar to those established by Couty and
David15b—LiHMDS (1.7 equiv), THF, –78 °C, 1 hour, then
warming to room temperature—in the presence of EtBpin.
Under these conditions, γ-dimethylamino tertiary boronic
ester 2b was isolated in 41% yield (Table 1, entry 1). When
the putative ylide was generated in the absence of the bo-
ronic ester, which was subsequently added, the desired
product was not observed, thus highlighting the instability
of the ylide. Increasing the amount of base to 3.0 equiva-
lents, adding the base at –20 °C, or subsequently warming
the reaction mixture to reflux (to promote 1,2-migration)
did not result in improved yields (Table 1, entries 2–4). The
use of KHMDS and LiTMP in place of LiHMDS led to reduced
yields; however, the use of LDA led to a higher yield (57%;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

C
G. Casoni et al.
Paper
Synthesis
Table 1, entry 7). Further investigation informed us that the
addition of 2.0 equivalents of this base was optimum (Table
1, entry 10).
R-Bpin 5a–i (1.2 equiv)
N
R
Bpin
LDA (2 equiv)
Ph
Ph
N
TfO
THF
2ba–bg
3b
–78 °C, 1 h, r.t., 1 h
Table 1 Optimisation of the Lithiation–Borylation Reaction of Azeti-
dinium Ion 3ba
Ph
Bpin
Bpin
Bpin
EtBpin (1.2 equiv)
N
Bpin
base (n equiv)
Ph
N
Ph
N
Ph
N
Ph
Ph
N
TfO
T to r.t., THF
2ba
69%
2bb
2bc
3b
2b
50%
46%
Entry
Base
Equiv of base T (°C)
Yield of 2b (%)
1
2
LiHMDS
LiHMDS
LiHMDS
LiHMDS
KHMDS
LiTMP
LDA
1.7
1.7
1.7
3.0
1.7
1.7
1.7
1.2
1.5
2.0
3.0
–78
–20
–78
–78
–78
–78
–78
–78
–78
–78
–78
41b
<5b
23d
33d
26d
26d
57b
16d
43d
69b
58d
Bpin
Bpin
Bpin
Ph
N
Ph
N
Ph
N
3c
4
2bd
44%
2be
2bf
66%
45%
5
MeO
6
S
Ph OH
OH
7
Bpin
Ph
N
Ph
N
Ph
N
8
LDA
9
LDA
2bg
75%
15bha,b
15bia,c
10
11
LDA
70%
49%
LDA
Scheme 4 Scope of the boronic ester for the lithiation–borylation of 3b.
a Isolation of the tertiary boronic ester was not possible owing to pro-
todeboronation; in situ oxidation using aqueous H2O2/NaOH allowed
the isolation of the corresponding tertiary alcohols. b The in situ oxida-
tion was carried out at 0 °C. c The in situ oxidation was carried out at
–40 °C.
a Reactions were carried out using 0.2 mmol of 3b.
b Yield of isolated material.
c After stirring the reaction mixture at –78 °C (1 h), the mixture was
warmed to reflux.
d Yield determined by 1H NMR analysis of the crude mixture in the presence
of an internal standard.
Having established optimum conditions for this trans-
formation, we explored the scope of the methodology by
testing a range of boronic esters (5a–i) (Scheme 4). The use
of primary (5a–c) and secondary boronic esters (5d and 5e)
gave moderate to good yields of the corresponding γ-di-
methylamino tertiary boronic esters 2ba–be. Additionally,
the use of allylic boronic ester 5f gave the corresponding
product in 45% yield. Aryl boronic esters proved to be more
challenging. When electron-rich boronic esters, such as 5g,
was employed the expected product 2bg could be isolated
in good yield. However, when more electron-poor aryl bo-
ronic esters were used, such as phenyl- and 2-thienyl-bo-
ronic ester, the corresponding boronic ester products could
not be isolated owing to facile protodeboronation. Pleasing-
ly, the unstable boronic ester products could be function-
alised in situ, prior to work-up, to give more stable deriva-
tives; the addition of aqueous H2O2/NaOH to the reaction
mixture led to the corresponding tertiary alcohols 15bh
and 15bi being isolated in good yields. Interestingly, in our
experience, similar tertiary boronic esters, not containing a
dimethylamino group, do not undergo protodeboronation
so readily,4n,17 suggesting that complexation of the boronic
ester with the proximal amino group promotes fragmenta-
tion. Because protodeboronation can be desirable—γ-amino
diarylmethines are prominent members of this family of
therapeutics (Figure 1)—we sought conditions to effect this
transformation more efficiently. Considering our previously
reported conditions for the protodeboronation of diarylal-
kyl boronic esters,5c upon lithiation–borylation of 3b and 5j,
the reaction mixture was warmed to room temperature
and CsF (1.5 equiv) and H2O (1.1 equiv) were added sequen-
tially; within 1 hour of stirring the resulting mixture at
room temperature, the tertiary boronic ester was complete-
ly consumed and, subsequently, diarylmethine 16bj could
be isolated in 71% yield (Scheme 5).
Cl
1. R-Bpin 5j (1.2 equiv)
LDA (2 equiv), THF,
N
–78 °C, 1 h; r.t., 1 h
Ph
Ph
N
TfO
2. CsF (1.5 equiv)
H2O (1.1 equiv), THF
r.t., 1 h
3b
16bj
71%
Scheme 5 Lithiation–borylation with in situ protodeboronation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

D
G. Casoni et al.
Paper
Synthesis
To further demonstrate the versatility of these tertiary
boronic esters, we subjected 2ba to a variety of conditions
to effect functionalisation of the C–B bond (Scheme 6). In
situ oxidation of 2ba using H2O2/NaOH gave the corre-
sponding tertiary alcohol 15ba in 58% yield. Other oxidizing
conditions (NaBO3·4H2O, NaBO3·4H2O/CH3COOH,18 Ox-
one/acetone,19 TMANO·2H2O20) were less effective and led
to partial oxidation of the tertiary amine group. Olefination
of isolated 2ba under modified Zweifel conditions21 with
vinyl lithium gave alkene 17ba in 52% yield. Protodeborona-
tion of isolated 2ba using TBAF·3H2O gave the desired γ-di-
methylamino aryl-dialkyl methine 16ba in 73% yield.5c We
also attempted to transform 2ba into the corresponding tri-
fluoroborate salt using standard conditions (KHF2, MeOH).22
However, the trifluoroborate moiety underwent partial li-
gand exchange with the pendant amine to give a mixture of
the desired trifluoroborate salt and intramolecularly com-
plexed difluoroborane 18ba (2:1, 82% overall yield), as de-
available 2-phenylpyrrolidine. Upon treatment of a THF
solution of 19a and EtBpin at –78 °C with LDA (2 equiv)
with subsequent warming to room temperature,
1,2,3,4,7,8-hexahydroazocine 20a (48%) was initially isolat-
ed, a species that in solution isomerised over a short period
of time into the corresponding benzo-fused 1,2,3,4,5,8-
hexahydroazocine 21a; the desired tertiary boronic ester
was not observed (Scheme 7). Hexahydroazocine 20a pre-
sumably arises from a Sommelet–Hauser rearrangement:
proton transfer of the initially formed benzylic ylide to the
methylenic ylide followed by a 2,3-sigmatropic rearrange-
ment.24 The transformation suggests that either the
Sommelet–Hauser rearrangement is faster than the trap-
ping of the benzylic ylide with EtBpin, or that trapping is in-
deed efficient but that the subsequent 1,2-migration of the
boronate is slow, thus allowing fragmentation back to the
ylide. Operation of the latter scenario would suggest that
the relief of ring-strain in the 1,2-migration of the azetidin-
ium boronates is an important contributor to the success of
the transformation.
1
termined by H and 19F NMR analysis.23 Pleasingly, when
the crude mixture was heated at reflux in MeCN, complete
conversion into 18ba was effected (67% yield).
EtBpin (1.2 equiv)
N
TfO
N
LDA (2 equiv)
N
Ph
N
THF
17ba
52%
–78 °C, 1 h; r.t., 1 h
F
19a
20a 48%
21a
F
N
B
Ph
Li
THF
then I2, MeOH;
NaOMe, MeOH
A
18ba
55% (two steps)
N
N
B
1. KHF2, MeOH,
2. MeCN, reflux
D
Bpin
OH
aq H2O2/NaOH
Ph
N
Ph
N
Scheme 7 Competing Sommelet–Hauser rearrangement of pyrrolidini-
THF
2ba
um ylides
15ba
58%
TBAF·3H2O
THF
C
The configurational stability of azetidinium ylide 4b
was then investigated. Enantiomerically enriched azetidini-
um ion (R)-3b was prepared from (S)-3-chloro-1-phenyl-
propan-1-ol, which was obtained through asymmetric re-
duction of ketone 13.25 When a solution of (R)-3b and
EtBpin in THF at –78 °C was treated with LiHMDS followed
by an oxidative work-up (aq H2O2/NaOH), the resulting ter-
tiary alcohol 15ba was found to be racemic, thus revealing
that 4b (like 4a) is configurationally unstable (Table 2, entry
1).
Presumably, lithium-stabilised ylide 4b-Li, should it be
an intermediate, would undergo solvent-mediated dissoci-
ation into the ylide 4b (deprotonation might lead to 4b di-
rectly), which if pyramidalised, undergoes rapid inversion,
a process that could occur via the ring-open carbene form
of 4b (Scheme 8).14c,26 We surmised that in a less-coordinat-
ing solvent, such as TBME, 4b-Li might be more stable.
However, when the lithiation–borylation–oxidation reac-
H
Ph
N
16ba
73%
Scheme 6 C–B Functionalisation of γ-tertiary boronic ester 2ba. Reac-
tion conditions: (A) (i) vinyl lithium (5 equiv), THF, –78 °C, 30 min,
–40 °C, 20 min; (ii) I2 (5 equiv), MeOH, –78 °C, 15 min; (iii) NaOMe (10
equiv), MeOH, r.t., 1 h. (B) Lithiation–borylation; then aq H2O2/NaOH,
THF, 1 h. (C) TBAF·3H2O (1.5 equiv), THF, reflux, 90 min. (D) (i) KHF2
(4.5 equiv), MeOH, 30 min, r.t.; (ii) MeCN, 5 h, reflux.
We then set out to understand the mechanism of the
transformation. First, we prepared pyrrolidinium ion 19a
and subjected it to the lithiation–borylation conditions to
investigate the contribution of relief of ring strain in the pu-
tative 1,2-migration step. The substrate, 19a, was prepared
through reductive alkylation/alkylation of commercially
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

E
G. Casoni et al.
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Synthesis
Table 2 Investigation of the Enantiospecificity of the Lithiation–
Borylation–Oxidation Reaction of (R)-3ba
In conclusion, when 2-phenyl-azetidinium ions are con-
verted into azetidinium ylides, through deprotonation with
LDA in the presence of boronic esters, they undergo ring-
opening carboboration to give γ-dimethylamino tertiary
boronic esters. The transformation presumably involves the
complexation of the boronic ester with the carbanion of the
ylide to form a boronate, which then undergoes ring-open-
ing 1,2-migration, a process that is promoted by the relief of
ring-strain of the azetidinium ion. This strain also contrib-
utes to the configurational instability of the in situ formed
ylides, which appear to be in equilibrium with the ring-
opened carbene form. The C–B bond of the products can be
transformed into a range of functional groups to give a se-
lection of highly functionalised 3-aryl-aminopropanes,
which are attractive targets for the pharmaceutical indus-
try.
1. boronic ester (1.2 equiv)
base (1.7 equiv), solvent,
N
OH
Et
–78 °C, 1 h; r.t., 1 h
N
X
2. H2O2/NaOH, THF,
0 °C to r.t., 1 h
(R)-3b
15ba
Entry Boronic
ester
X–
Base
Solvent
Yield
(%)
ee
(%)
–
1
2
3
4
EtBpin
EtBpin
EtBNeo
EtBpin
F3CSO3
LiHMDS
THF
27
0
0
0
0
–
–
–
F9C4SO3
F9C4SO3
F9C4SO3
LiHMDS
LiHMDS
LDA
TBME
TBME
TBME
37
26
n.d.
a Reactions conducted using 0.3 mmol of (R)-3b. n.d. = not determined.
Reaction mixtures were stirred magnetically. Air- and moisture-sen-
sitive reactions were carried out in flame-dried glassware under a ni-
trogen atmosphere using standard Schlenk manifold techniques. Fine
chemicals were purchased from Acros Organics, Alfa Aesar, Inochem-
Frontier Scientific, Sigma-Aldrich, TCI Europe or Santa Cruz Biotech-
nology and used as received unless otherwise stated. The following
pinacol boronic esters were purchased from commercial suppliers: 5e
(Frontier Scientific), 5f (Sigma-Aldrich), 5h (Sigma-Aldrich). n-BuLi
was received from Acros Organics as a 1.6 M solution in hexane. Lithi-
um diisopropylamide (LDA) was freshly prepared from n-BuLi and
distilled diisopropylamine immediately before use. Et3N and diisopro-
pylamine were distilled over CaH2 before use. Anhydrous MeCN,
CH2Cl2, Et2O, THF and toluene were obtained from a purification col-
umn composed of activated alumina and stored subsequently over 3 Å
molecular sieves. Analytical TLC was carried out on aluminium-
backed silica plates (Merck, Silica Gel 60 F254, 0.25). Flash column
chromatography was carried out on silica gel (Aldrich, Silica Gel 60,
40–63 μm). Microwave reactions were performed using a Biotage Ini-
tiator EXP EU microwave synthesiser. Infrared (IR) spectra were re-
corded on neat compounds using a PerkinElmer Spectrum One FT-IR
tion was performed in TBME [the nonaflate salt of (R)-3b
was used owing to the poor solubility of the corresponding
triflate salt in TBME], the tertiary alcohol was again isolated
as the racemate. The insolubility of the azetidinium sub-
strate frustrated attempts to use even less-coordinating sol-
vents (e.g., hexanes). The use of LDA in place of LiHMDS or
the use of the less-sterically hindered neopentylglycol bo-
ronic ester, EtBNeo, did not lead to enantiomerically en-
riched product. The intermediacy of a carbene was sup-
ported by the isolation of cyclopropane 22 when using vi-
nyl boronic ester 5k (Scheme 8). Presumably, the desired
boronate does not form or undergo 1,2-migration owing to
steric hindrance and instead the carbene reacts with the
alkene moiety.27
spectrophotometer, irradiating between 4000 cm–1 and 600 cm–1
.
N
Li
N
Li
TfO
TfO
Only strong and selected absorbance values (νmax) are reported. 1H
NMR spectra were acquired using a Joel ECS 300, Joel ECS 400 or Vari-
an 400-MR Fourier transform spectrometer for samples in CDCl3 or
CD3OD at 301 or 400 MHz as indicated. Chemical shifts (δH) are ex-
pressed in parts per million (ppm) and are referred to the residual
protio solvent signals of CHCl3 (7.26 ppm) or MeOH (3.31 ppm). 1H
NMR coupling constants are expressed in hertz (Hz) and are quoted
as apparent multiplicities (s = singlet, br s = broad singlet, d = doublet,
t = triplet, q = quartet, quin = quintet, sept = septet, m = multiplet,
dd = doublet of doublets, ps = pseudo). 13C NMR spectra were record-
ed at 101 MHz; chemical shifts (δC) and are expressed in ppm. Carbon
atoms attached to boron or to bromine are usually not observed due
to quadrupolar relaxation. See the Supporting Information for proton
and carbon assignments and molecule numbering. 11B NMR spectra
were measured using Norell S-200-QTZ quartz tubes at 128 MHz with
complete proton decoupling. Some γ-dimethylamino tertiary boronic
esters show two or even three signals, the upfield signals indicative of
amine-assisted complexation of CD3OD (the solvent) and/or H2O. 19F
NMR spectra were recorded at 376 MHz. HRMS ESI was performed on
either a Bruker Daltonics Apex IV, 7-Tesla FT-ICR or micrOTOF II. MS
samples were submitted in EtOAc or CH2Cl2. Optical rotations were
Ph
Ph
4b-Li
ent-4b-Li
inversion
TfO
Ph
N
LiHMDS
LiOTf
(R)-3b
LiOTf
Ph
4b (carbene)
LiOTf
N
N
N
Ph
Ph
ent-4b
4b
Ph
5k
(1.2 equiv)
B
pin
Bpin
Ph
Ph
22
N
LDA (2 equiv)
N
Ph
TfO
–78 °C to r.t., THF
3b
24% yield
Scheme 8 Possible mechanism of racemisation of 4b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

F
G. Casoni et al.
Paper
Synthesis
observed using a Bellingham + Stanley Ltd. ADP220 polarimeter at
589 nm (Na D-line) in a cell with path length of 1 dm. GC–MS experi-
ments were carried out using an Agilent 6890 apparatus (column: Su-
pelco SLBTM-5ms capillary column 15 m × 0.25 mm × 0.25 μm).
times). The combined organic layers were washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (EtOAc/
Et3N = 100:0.5) to afford the pure tertiary alcohol.
Synthesis of Pinacol Boronic Esters from Boronic Acids; General
Procedure (GP1)
Lithiation–Borylation of 1,1-Dimethyl-2-phenylazetidin-1-ium
Trifluoromethanesulfonate (3b) with in situ Protodeboronation;
General Procedure (GP4)
A mixture of boronic acid (1.0 equiv), pinacol (1.0 equiv) and anhy-
drous MgSO4 (4.0 equiv) in Et2O (0.5 M) was stirred at r.t. for 16 h. The
reaction mixture was filtered and the solvent removed in vacuo. The
crude material was purified by distillation or flash column chroma-
tography to give the pure boronic ester.
To a solution of diisopropylamine (2.0 equiv) in anhydrous THF (2.0
M) was added n-BuLi (2.0 equiv) at –78 °C. After stirring for 30 min,
the solution was added dropwise to a mixture of azetidinium salt 3b
(1.0 equiv) and the boronic ester (1.2 equiv) in dry THF (0.03 M) at
–78 °C. The reaction mixture was stirred at –78 °C for 1 h and then
allowed to warm to r.t. CsF (1.5 equiv) was added at r.t., followed by
H2O (1.1 equiv) and the reaction mixture was stirred at r.t. for 1 h. The
solvent was removed in vacuo and the residue was partitioned be-
tween H2O and CH2Cl2. The phases were separated and the aq layer
was re-extracted with CH2Cl2 (2 times). The combined organic layers
were washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel (EtOAc/Et3N = 100:0.5) to afford the pure pro-
todeboronated product.
Lithiation–Borylation of 1,1-Dimethyl-2-phenylazetidin-1-ium
Trifluoromethanesulfonate (3b) To Give the Tertiary 3-Dimethyl-
amino-Boronic Ester; General Procedure (GP2)
To a solution of diisopropylamine (2.0 equiv) in anhydrous THF (2.0
M) was added n-BuLi (2.0 equiv) at –78 °C. After stirring for 30 min,
the solution was added dropwise to a mixture of azetidinium salt 3b
(1.0 equiv) and the boronic ester (1.2 equiv) in dry THF (0.03 M) at
–78 °C. The reaction mixture was stirred at –78 °C for 1 h and then
allowed to warm to r.t. The solvent was removed in vacuo and the
crude residue was taken up with H2O and extracted with CH2Cl2 (3
times). The combined organic layers were dried over MgSO4 and con-
centrated under reduced pressure to afford the crude tertiary boronic
ester, which was purified by chromatography on silica gel (EtOAc/
Et3N = 100:0.5) to afford the γ-dimethylamino tertiary boronic ester.
2-Ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5a)
Following general procedure GP1, ethylboronic acid (5.0 g, 67.4
mmol) and pinacol (8.0 g, 64.7 mmol) afforded, after distillation (40–
50 °C, ambient pressure), boronic ester 5a (10.1 g, 96%) as a colourless
liquid. All analytical data matched that previously reported.28
1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 12 H, 4 × C-CH3), 0.95 (t, J = 7.7
Hz, 3 H, CH2-CH3), 0.76 (q, J = 7.8 Hz, 2 H, CH2).
Lithiation–Borylation of 1,1-Dimethyl-2-phenylazetidin-1-ium
Trifluoromethanesulfonate (3b) with in situ Oxidation; General
Procedure (GP3a)
To a solution of diisopropylamine (2.0 equiv) in anhydrous THF (2.0
M) was added n-BuLi (2.0 equiv) at –78 °C. After stirring for 30 min,
the solution was added dropwise to a mixture of azetidinium salt 3b
(1.0 equiv) and the boronic ester (1.2 equiv) in dry THF (0.03 M) at
–78 °C. The reaction mixture was stirred at –78 °C for 1 h and then
allowed to warm to r.t. The reaction mixture was cooled to 0 °C and a
2:1 mixture of aq NaOH (2.0 M) and 30% H2O2 was added under vigor-
ous stirring. The cooling bath was removed and the reaction mixture
was stirred at r.t. for 1 h. The solvent was removed in vacuo and the
residue was partitioned between H2O and CH2Cl2. The phases were
separated and the aq layer was re-extracted with CH2Cl2 (2 times).
The combined organic layers were washed with brine, dried over Mg-
SO4, filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (EtOAc/Et3N =
100:0.5) to afford the pure tertiary alcohol.
4,4,5,5-Tetramethyl-2-phenethyl-1,3,2-dioxaborolane (5b)
Following general procedure GP1, 2-phenethylboronic acid (10.0 g,
66.7 mmol) and pinacol (7.9 g, 66.7 mmol) afforded pure 5b as a
white crystalline solid (15.4 g, >99%), which was used in the next step
without further purification. All analytical data matched that previ-
ously reported.29
1H NMR (400 MHz, CDCl3): δ = 7.26–7.19 (m, 4 H, Ar-H), 7.14 (m, 1 H,
Ar-H), 2.74 (t, J = 8.3 Hz, 2 H, CH2-Ph), 1.21 (s, 12 H, 4 × C-CH3), 1.13 (t,
J = 8.2 Hz, 2 H, CH2-B).
2-Isobutyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5c)
Following general procedure GP1, isobutylboronic acid (3.5 g, 34.5
mmol) and pinacol (4.1 g, 34.5 mmol) afforded, after chromatograph-
ic purification (SiO2, PE/Et2O = 20:1), boronic ester 5c as a colourless
liquid (5.4 g, 85%). All analytical data matched that previously report-
ed.30
1H NMR (400 MHz, CDCl3): δ = 1.86 (sept, J = 6.7 Hz, 1 H, CH), 1.25 (s,
12 H, 4 × C-CH3), 0.92 (d, J = 6.7 Hz, 6 H, 2 × CH3), 0.73 (d, J = 7.2 Hz, 2
H, CH2).
Lithiation–Borylation of 1,1-Dimethyl-2-phenylazetidin-1-ium
Trifluoromethanesulfonate (3b) with in situ Oxidation at Low
Temperature; General Procedure (GP3b)
To a solution of diisopropylamine (2.0 equiv) in anhydrous THF (2.0
M) was added n-BuLi (2.0 equiv) at –78 °C. After stirring for 30 min,
the solution was added dropwise to a mixture of azetidinium salt 3b
(1.0 equiv) and the boronic ester (1.2 equiv) in dry THF (0.03 M) at
–78 °C. The reaction mixture was stirred at –78 °C for 1 h and then
allowed to warm to r.t. The reaction mixture was cooled to –40 °C and
a 2:1 mixture of aq NaOH (2.0 M) and 30% H2O2 was added under vig-
orous stirring. The cooling bath was removed and the reaction mix-
ture was stirred at r.t. for 1 h. The solvent was removed in vacuo and
the residue was partitioned between H2O and CH2Cl2. The phases
were separated and the aq layer was re-extracted with CH2Cl2 (2
2-Cyclohexyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5d)
Following general procedure GP1, cyclohexylboronic acid (1.5 g, 11.7
mmol) and pinacol (1.4 g, 11.7 mmol) afforded, after chromatograph-
ic purification (SiO2, 3% Et2O/pentane), boronic ester 5d as a colour-
less liquid (2.2 g, 90%). All analytical data matched that previously re-
ported.29
1H NMR (400 MHz, CDCl3): δ = 1.68–1.54 (m, 5 H, cHex-H), 1.38–1.26
(m, 5 H, cHex-H), 1.23 (s, 12 H, 4 × C-CH3), 0.97 (m, 1 H, CH).
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G. Casoni et al.
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Synthesis
2-(4-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(5g)
reaction mixture was stirred at r.t. for 20 min, then a solution of phe-
nylsilane (3 mL, 24 mmol) in toluene (32 mL) was added. The mixture
was cooled to –20 °C and a solution of 3-chloro-1-propiophenone
(13) (3.4 g, 20 mmol) in toluene (32 mL) was added under vigorous
stirring. The flask was stoppered and the reaction mixture was stirred
for 24 h at the above temperature. Upon completion, the mixture was
treated with 10% HCl (130 mL) and the organic product was extracted
with Et2O (3 × 150 mL). The combined organic layers were washed
with H2O, dried over MgSO4, filtered and concentrated in vacuo. Puri-
fication by column chromatography on silica gel (hexane/EtOAc, 10:1)
afforded alcohol (S)-23 (2.5 g, 73%) as a white solid.
Following general procedure GP1, (4-methoxyphenyl)boronic acid
(3.0 g, 20 mmol) and pinacol (2.4 g, 20 mmol) afforded boronic ester
5g as a white solid (3.0 g, 85%), which was used in the next step with-
out further purification. All analytical data matched that previously
reported.17b
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.6 Hz, 2 H, Ar-H), 6.90 (d,
J = 8.6 Hz, 2 H, Ar-H), 3.83 (s, 3 H, O-CH3), 1.33 (s, 12 H, 4 × C-CH3).
4,4,5,5-Tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (5i)
The ee value was determined by chiral HPLC analysis with a Chiralcel
IB column (eluent: hexane/2-propanol = 98:2; flow rate: 1 mL/min;
detection: 254 nm), tR (R) = 16.2 min (area% 97), tR (S) = 18.1 min (ar-
ea% 3). Spectral data matched those previously reported for 23. The
optical rotation matched literature data.32
Following a modified literature procedure,30 n-BuLi (13.5 mL, 21.6
mmol) was added dropwise to a solution of thiophene (2.0 g, 1.90 mL,
23.8 mmol) in dry THF (50 mL) at –78 °C. The solution was stirred at
r.t. for 1 h, then it was cooled again to –78 °C and 2-isopropoxy-
4,4,5,5-tetramethydioxoborolane (5.2 g, 5.7 mL, 28.1 mmol) was add-
ed. The reaction mixture was stirred at r.t. for 16 h, then the solvent
was removed under reduced pressure. The residue was taken up with
H2O (30 mL) and the aq phase was extracted with Et2O (3 × 30 mL).
The combined organic layers were dried over MgSO4 and concentrat-
ed in vacuo. The crude product was purified by chromatography on
silica gel (PE/EtOAc = 95:5) to give boronic ester 5i as a white solid
(3.99 g, 88%). All analytical data matched that previously reported.31
[α]D27.4 –23 (c 1.0, CHCl3).
1-Methyl-2-phenylazetidine (14)
Following a procedure by Luisi,14b to a solution of 3-chloro-1-phenyl-
propan-1-ol (23) (3.1 g, 18.2 mmol) in dry CH2Cl2 (18 mL), a solution
of SOCl2 (4.0 mL, 54.6 mmol) in dry CH2Cl2 (5.5 mL) was added drop-
wise at r.t. After stirring for 1 h, the reaction mixture was poured into
H2O (20 mL) and aq NaOH (15% w/v) was added slowly to neutralise
the excess of HCl until the pH of the solution was 7. The aq phase was
extracted with CH2Cl2 (3 × 30 mL) and the combined organic layers
were dried over MgSO4, filtered and evaporated under vacuum to af-
ford 1-phenyl-1,3-dichloropropane that was employed in the next
step without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.65 (m, 2 H, thio-H), 7.20 (t, J = 4.4 Hz,
1 H, thio-H), 1.35 (s, 12 H, 4 × C-CH3).
2-(4-Chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5j)
Following general procedure GP1, (4-chlorophenyl)boronic acid (3.9
g, 16.4 mmol) and pinacol (1.9 g, 16.4 mmol) afforded, after Kugelrohr
distillation (80→110 °C/0.1 mbar), pure boronic ester 5j as a white
solid (5.5 g, 92%). All analytical data matched that previously report-
ed.17b
1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 8.1 Hz, 2 H, Ar-H), 7.34 (d,
J = 8.0 Hz, 2 H, Ar-H), 1.34 (s, 12 H, 4 × C-CH3).
To a solution of 1-phenyl-1,3-dichloropropane in EtOH (23 mL) and
Et3N (5.1 mL, 36.4 mmol) in a sealed flask, a solution of MeNH2 (33%
w/v in EtOH, 23 mL) was added at r.t. The reaction mixture was heat-
ed at 70 °C for 16 h and then allowed to cool to ambient temperature.
The solvent was removed in vacuo and HCl (30 mL, 2.0 M) was added.
The aq phase was extracted with CH2Cl2 (3 × 40 mL) and subsequently
basified by addition of aq NaOH (15% w/v) until the pH of the solution
was >12. The basic aq phase was extracted with CH2Cl2 (3 × 50 mL),
and the combined organic layers were dried over MgSO4, filtered and
concentrated in vacuo. The crude mixture was purified by flash silica
gel column chromatography (EtOAc/Et3N = 100:0.5) to afford azeti-
dine 14 (1.34 g, 50%, over two steps) as a colourless oil. The analytical
data matched that previously reported.14b
1H NMR (400 MHz, CDCl3): δ = 7.38–7.30 (m, 4 H, Ar-H), 7.26–7.22
(m, 1 H, Ar-H), 3.87 (t, J = 8.4 Hz, 1 H, 1-H), 3.45 (m, 1 H, 3-H), 2.85 (dt,
J1 = 9.6 Hz, J2 = 7.1 Hz, 1 H, 3-H), 2.33 (s, 3 H, CH3), 2.26 (m, 1 H, 2-H),
2.14 (quin, J = 8.9 Hz, 1 H, 2-H).
13C NMR (101 MHz, CDCl3): δ = 142.99 (Ar-C), 128.46 (2 C, Ar-C),
127.39 (Ar-C), 126.71 (2 C, Ar-C), 71.30 (1-C), 53.06 (3-C), 44.61 (CH3),
27.01 (2-C).
3-Chloro-1-phenylpropan-1-ol (23)
Following a literature reported procedure,16 NaBH4 (5.7 g, 150 mmol)
was added in small portions at 0 °C to a stirred solution of 3-chloro-
1-propiophenone (13) (8.4 g, 50 mmol) in MeOH (104 mL). The mix-
ture was stirred at r.t. for 18 h and was then quenched with H2O (90
mL). The solvent was removed in vacuo and the residue was extracted
with Et2O (3 × 50 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo to give the title compound as a co-
lourless oil (8.4 g, 98% yield). The product was used in the next step
without further purification. All analytical data matched that previ-
ously reported.16
1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H, Ar-H), 4.93 (dd, J1 =
11.3 Hz, J2 = 6.4 Hz, 1 H, CH-OH), 3.73 (ddd, J1 = 14.5 Hz, J2 = 10.8 Hz,
J3 = 7.6 Hz, 1 H, CH2-Cl), 3.55 (m, 1 H, CH2-Cl), 2.23 (m, 1 H, CH2-CH),
2.10 (m, 1 H, CH2-CH), 2.03 (br s, 1 H, OH).
This method was also used for the synthesis of enantiopure azetidine,
(R)-14, employing (S)-3-chloro-1-phenylpropanol-1-ol [(S)-23] as
starting material.14b The absolute configuration of enantioenriched
azetidine (R)-14 was assigned assuming retention of configuration in
the reaction with SOCl2 and inversion of configuration in the cyclisa-
tion step with MeNH2. The ee value for (R)-14 was determined by chi-
ral GC (Cycloβdex, iso: 90 °C, length: 30 m, i.d.: 0.25). For enantioen-
riched material, the result was tR (S) = 35.21 (area% 13), tR (R) = 35.57
(area% 87).
13C NMR (101 MHz, CDCl3): δ = 143.83 (Ar-C), 128.81 (2 C, Ar-C),
128.06 (Ar-C), 125.91 (2 C, Ar-C), 71.49 (CH), 41.84 (CH2), 41.59 (CH2).
(S)-3-Chloro-1-phenylpropan-1-ol [(S)-23]
Following
a
procedure recently reported by Wu and Li,25
Cu(OAc)2·H2O (119.8 mg, 0.6 mmol) and (S)-P-Phos (151.4 mg, 0.2
mmol) were weighed under air and dissolved in toluene (66 mL). The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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G. Casoni et al.
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Synthesis
1,1-Dimethyl-2-phenylazetidin-1-ium Trifluoromethanesulfon-
ate (3b)
1H NMR (400 MHz, CD3OD): δ = 7.39 (d, J = 7.6 Hz, 2 H, Ar-H), 7.31 (t,
J = 7.5 Hz, 2 H, Ar-H), 7.23 (t, J = 7.5 Hz, 2 H, Ar-H), 7.18–7.09 (m, 4 H,
Ar-H), 2.42–2.37 (m, 2 H, 5-H), 2.30–2.26 (m, 2 H, 1-H), 2.23 [s, 6 H,
N-(CH3)2], 2.13–2.02 (m, 4 H, 2-H + 4-H), 1.26 (s, 6 H, 2 × C-CH3), 1.25
(s, 6 H, 2 × C-CH3).
13C NMR (101 MHz, CD3OD): δ = 146.14 (Ar-C), 144.35 (Ar-C), 129.36
(2 C, Ar-C), 129.23 (2 C, Ar-C), 129.20 (2 C, Ar-C), 128.52 (2 C, Ar-C),
126.67 (Ar-C), 126.48 (Ar-C), 84.72 (2 C, 2 × B-O-C), 57.34 (1-C), 45.77
[2 C, N-(CH3)2], 39.42 (2-C), 33.10 (5-C), 32.81 (4-C), 25.34 (4 C, 4 × C-
CH3); C attached to boron not observed.
Following a modified procedure by Couty,15b azetidine 14 (515.3 mg,
3.5 mmol) was dissolved in dry Et2O (30 mL). After cooling to 0 °C,
methyl trifluoromethanesulfonate (830 μL, 7.3 mmol) was added. The
mixture was stirred for 1 h, then all the volatiles were removed under
vacuum to afford azetidinium triflate 3b (1.075 g, >95%) as an orange
oil.
IR (neat): 1465, 1254, 1223, 1152, 1028, 975, 830, 770, 756, 706 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.47 (m, 5 H, Ar-H), 5.84 (dd, J1 =
10.5 Hz, J2 = 8.6 Hz, 1 H, 1-H), 4.59 (ps q, J = 9.3, 1 H, 3-H), 4.07 (ps td,
J1 = 10 Hz, J2 = 3.5 Hz, 1 H, 3-H), 3.29 (s, 3 H, CH3), 3.24 (m, 1 H, 2-H),
2.78 (m, 1 H, 2-H), 2.59 (s, 3 H, CH3).
11B NMR (128 MHz, CD3OD): δ = 31.62, 13.02.
HRMS (ESI): m/z [M + H]+ calcd for C25H37BNO2: 394.2916; found:
394.2933.
13C NMR (101 MHz, CDCl3): δ = 131.85 (Ar-C), 129.86 (2 C, Ar-C),
129.71 (2 C, Ar-C), 128.80 (Ar-C), 122.40 (CF3), 79.05 (1-C), 62.62 (3-
C), 52.50 (CH3), 45.67 (CH3), 18.96 (2-C).
N,N,5-Trimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)hexan-1-amine (2bc)
19F NMR (376 MHz, CDCl3): δ = –78.31.
HRMS (ESI): m/z [M – SO3CF3]+ calcd for C11H16N: 162.1277; found:
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155.7 mg, 0.5 mmol) and 2-
isobutyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5c) (110.5 mg, 0.6
mmol) in anhydrous THF (12 mL) afforded, after purification on silica
gel (EtOAc/Et3N = 100:0.5), γ-dimethylamino boronic ester 2bc (79.5
mg, 46%) as a colourless oil.
162.1283.
N,N-Dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)pentan-1-amine (2ba)
According to general procedure GP2, diisopropylamine (561 μL, 4
mmol), n-BuLi (2.5 mL, 4 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (622.6 mg, 2 mmol) and 2-ethyl-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5a) (374.5 mg, 2.4 mmol) in
anhydrous THF (35 mL) afforded, after purification on silica gel
(EtOAc/Et3N = 100:0.5), γ-dimethylamino boronic ester 2ba (437.5
mg, 69%) as a colourless oil.
IR (neat): 2952, 1447, 1371, 1143, 701 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.39 (d, J = 8.0 Hz, 2 H, Ar-H), 7.26 (t,
J = 7.6 Hz, 2 H, Ar-H), 7.12 (t, J = 7.3 Hz, 1 H, Ar-H), 2.19 [s, 6 H, N-
(CH3)2], 2.17–1.99 (m, 4 H, 1-H + 2-H), 1.77 (m, 2 H, 4-H), 1.56 (sept,
J = 6.7 Hz, 1 H, CH), 1.21 (s, 6 H, 2 × C-CH3), 1.19 (s, 6 H, 2 × C-CH3),
0.82 (d, J = 6.7 Hz, 3 H, CH-CH3), 0.78 (d, J = 6.7 Hz, 3 H, CH-CH3).
13C NMR (101 MHz, CD3OD): δ = 146.53 (Ar-C), 129.05 (2 C, Ar-C),
128.56 (2 C, Ar-C), 126.30 (Ar-C), 84.66 (2 C, 2 × B-O-C), 57.09 (1-C),
45.64 [2 C, N-(CH3)2], 45.45 (4-C), 33.00 (2-C), 26.78 (CH), 25.30 (2 C,
2 × C-CH3), 25.20 (2 C, 2 × C-CH3), 24.85 (CH-CH3), 24.61 (CH-CH3); C
attached to boron not observed.
11B NMR (128 MHz, CD3OD): δ = 32.36, 19.17, 16.11.
HRMS (ESI): m/z [M + H]+ calcd for C21H37BNO2: 346.2916; found:
IR (neat): 2973, 2936, 1460, 1370, 1350, 1308, 1260, 1143, 1031, 967,
851, 759 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.29 (m, 2 H, Ar-H), 7.27–7.23
(m, 2 H, Ar-H), 7.11 (tt, J1 = 6.8 Hz, J2 = 1.3 Hz, 1 H, Ar-H), 2.20 [s, 6 H,
N-(CH3)2], 2.19–2.13 (m, 2 H, 1-H), 2.04–1.91 (m, 2 H, 2-H), 1.91–1.75
(m, 2 H, CH2-CH3), 1.20 (s, 6 H, 2 × C-CH3), 1.17 (s, 6 H, 2 × C-CH3),
0.70 (t, J = 7.4 Hz, 3 H, CH2-CH3).
13C NMR (101 MHz, CDCl3): δ = 145.53 (Ar-C), 128.07 (2 C, Ar-C),
127.68 (2 C, Ar-C), 125.10 (Ar-C), 83.22 (2 C, 2 × B-O-C), 56.46 (1-C),
45.96 [2 C, N-(CH3)2], 31.93 (2-C), 29.85 (3-C), 28.10 (CH2-CH3), 24.98
(2 C, 2 × C-CH3), 24.96 (2 C, 2 × C-CH3), 9.27 (CH2-CH3).
346.2911.
3-Cyclohexyl-N,N-dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)propan-1-amine (2bd)
11B NMR (128 MHz, CDCl3): δ = 31.77.
HRMS (ESI): m/z [M + H]+ calcd for C19H33BNO2: 318.2602; found:
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (159 mg, 0.51 mmol) and 2-cy-
clohexyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5d) (126.1 mg, 0.6
mmol) in anhydrous THF (12 mL) afforded, after purification on silica
gel (EtOAc/Et3N = 100:0.5), γ-dimethylamino boronic ester 2bd (84.2
mg, 44%) as a colourless oil.
318.2608.
N,N-Dimethyl-3,5-diphenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)pentan-1-amine (2bb)
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155 mg, 0.5 mmol) and 4,4,5,5-
tetramethyl-2-phenethyl-1,3,2-dioxaborolane (5b) (139 mg, 0.6
mmol) in anhydrous THF (12 mL) afforded, after purification on silica
gel (EtOAc/Et3N = 100:0.5), γ-dimethylamino boronic ester 2bb (97
mg, 50%) as an orange solid.
IR (neat): 2926, 2852, 1450, 1371, 1350, 1300, 1269, 1141, 1036, 852
cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.35 (d, J = 7.5 Hz, 2 H, Ar-H), 7.24 (t,
J = 7.5 Hz, 2 H, Ar-H), 7.13 (t, J = 7.3 Hz, 1 H, Ar-H), 2.24–2.10 (m, 2 H,
3-H + cHex-H), 2.17 [s, 6 H, N-(CH3)2], 2.02–1.93 (m, 2 H, 1-H + cHex-
H), 1.89 (m, 1 H, cHex-H), 1.76–1.48 (m, 5 H, 3 × cHex-H + 2 × 2-H),
1.33 (s, 6 H, 2 × C-CH3), 1.32 (s, 6 H, 2 × C-CH3), 1.29–0.91 (m, 5 H,
5 × cHex-H).
13C NMR (101 MHz, CD3OD): δ = 144.80 (Ar-C), 130.16 (2 C, Ar-C),
128.65 (2 C, Ar-C), 126.47 (Ar-C), 84.80 (2 C, 2 × B-O-C), 58.26 (1-C),
48.01 (2-C), 45.45 [2 C, N-(CH3)2], 33.92 (cHex-C), 31.54 (cHex-C),
IR (neat): 2936, 1459, 1138, 1111, 1096, 1079, 1069, 1052, 1022, 988,
839, 757 cm–1
.
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30.20 (cHex-C), 28.42 (cHex-C), 28.23 (cHex-C), 27.96 (cHex-C), 25.68
(2 C, 2 × C-CH3), 25.37 (2 C, 2 × C-CH3); C attached to boron not ob-
served.
11B NMR (128 MHz, CD3OD): δ = 33.25.
HRMS (ESI): m/z [M + H]+ calcd for C23H39BNO2: 372.307254; found:
372.309094.
3-(4-Methoxyphenyl)-N,N-dimethyl-3-phenyl-3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)propan-1-amine (2bg)
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (153 mg, 0.5 mmol) and 2-(4-
methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5g) (140.5
mg, 0.6 mmol) in anhydrous THF (12 mL) afforded, after purification
on silica gel (EtOAc/Et3N = 100:0.5), dimethylamino boronic ester 2bg
(145 mg, 75%) as a yellow oil.
3-Cyclopropyl-N,N-dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)propan-1-amine (2be)
IR (neat): 2969, 1509, 1461, 1341, 1297, 1245, 1181, 1141, 1035, 852,
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155.7 mg, 0.5 mmol) and 2-cy-
clopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5e) (100.8 mg,
0.6 mmol) in anhydrous THF (12 mL) afforded, after purification on
silica gel (EtOAc/Et3N = 100:0.5), γ-dimethylamino boronic ester 2be
(108.2 mg, 66%) as a colourless oil.
827 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.26–7.10 (m, 7 H, Ar-H), 6.80 (d, J =
8.7 Hz, 2 H, Ar-H), 3.76 (s, 3 H, O-CH3), 2.36–2.28 (m, 2 H, 1-H), 2.20
[s, 6 H, N-(CH3)2], 2.10 (ps t, J = 7.8 Hz, 2 H, 2-H), 1.15 (s, 6 H, 2 × C-
CH3), 1.14 (s, 6 H, 2 × C-CH3).
13C NMR (101 MHz, CD3OD): δ = 159.08 (Ar-C), 147.75 (Ar-C), 139.18
(Ar-C), 131.32 (2 C, Ar-C), 130.28 (2 C, Ar-C), 128.82 (2 C, Ar-C),
126.54 (Ar-C), 114.25 (2 C, Ar-C), 84.80 (2 C, 2 × B-O-C), 58.82 (1-C),
55.60 (O-CH3), 45.44 [2 C, N-(CH3)2], 35.85 (2-C), 24.89 (2 C, 2 × C-
CH3), 24.88 (2 C, 2 × C-CH3); C attached to boron not observed.
IR (neat): 2976, 1371, 1306, 1142, 853, 700 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.42 (dd, J1 = 7.9 Hz, J2 = 1.2 Hz, 2 H,
Ar-H), 7.26 (t, J = 7.5 Hz, 2 H, Ar-H), 7.13 (t, J = 7.3 Hz, 1 H, Ar-H), 2.35
(t, J = 8.2 Hz, 2 H, 1-H), 2.20 [s, 6 H, N-(CH3)2], 2.01 (m, 2 H, 2-H), 1.22
(s, 6 H, 2 × C-CH3), 1.20 (s, 6 H, 2 × C-CH3), 1.03 (m, 1 H, 4-H), 0.59–
0.48 (m, 3 H, 5-H/6-H), 0.32 (m, 1 H, 5-H/6-H).
11B NMR (128 MHz, CD3OD): δ = 32.02, 18.66, 15.54.
HRMS (ESI): m/z [M + H]+ calcd for C24H35BNO3: 396.2709; found:
13C NMR (101 MHz, CD3OD): δ = 146.86 (Ar-C), 128.98 (2 C, Ar-C),
128.90 (2 C, Ar-C), 126.39 (Ar-C), 84.65 (2 C, 2 × B-O-C), 57.54 (1-C),
45.52 [2 C, N-(CH3)2], 36.08 (2-C), 25.20 (2 C, 2 × C-CH3), 25.08 (2 C,
2 × C-CH3), 18.09 (4-C), 4.10 (5-C/6-C), 3.43 (5-C/6-C); C attached to
boron not observed.
11B NMR (128 MHz, CD3OD): δ = 31.68.
HRMS (ESI): m/z [M + H]+ calcd for C20H33BNO2: 330.2603; found:
396.2718.
3-(Dimethylamino)-1,1-diphenylpropan-1-ol (15bh)
According to general procedure GP3a, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (153 mg, 0.49 mmol) and 4,4,5,5-
tetramethyl-2-phenyl-1,3,2-dioxaborolane (5h) (122.5 mg, 0.6 mmol)
in anhydrous THF (12 mL) afforded, after purification by flash chro-
matography on silica gel (EtOAc/Et3N = 100:0.5), tertiary alcohol 15bh
(88 mg, 70%) as a white solid.
330.2607.
N,N-Dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)hex-5-en-1-amine (2bf)
IR (neat): 2830, 2783, 1446, 1204, 1064, 1019, 963, 891, 841, 777,
751, 716 cm–1
.
According to general procedure GP2, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155 mg, 0.5 mmol) and 2-allyl-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5f) (101 mg, 0.6 mmol) in
anhydrous THF (12 mL) afforded, after purification on silica gel
(EtOAc/Et3N = 100:0.5), dimethylamino boronic ester 2bf (67 mg,
45%) as a colourless oil.
1H NMR (400 MHz, CDCl3): δ = 7.50 (ps d, J = 8.0 Hz, 4 H, Ar-H), 7.32
(ps t, J = 7.4 Hz, 4 H, Ar-H), 7.20 (ps t, J = 7.2 Hz, 2 H, Ar-H), 2.42 (s, 4 H,
2-H + 1-H), 2.23 [s, 6 H, N-(CH3)2].
13C NMR (101 MHz, CDCl3): δ = 148.07 (2 C, Ar-C), 128.01 (4 C, Ar-C),
126.31 (2 C, Ar-C), 125.84 (4 C, Ar-C), 79.17 (3-C), 56.32 (1-C), 45.10
[2 C, N-(CH3)2], 35.99 (2-C).
IR (neat): 2975, 1457, 1371, 1143, 1057, 700 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C17H22NO: 256.1696; found:
1H NMR (400 MHz, CD3OD): δ = 7.32–7.24 (m, 4 H, Ar-H), 7.11 (ps t,
J = 7.2 Hz, 1 H, Ar-H), 5.62 (tdd, J1 = 17.3 Hz, J2 = 10.2 Hz, J3 = 7.2 Hz, 1
H, 5-H), 5.03 (dd, J1 = 17.1 Hz, J2 = 2.2 Hz, 1 H, 6-Htrans), 4.95 (dd, J1 =
10.2 Hz, J2 = 2.2 Hz, 1 H, 6-Hcis), 2.57 (d, J = 7.2 Hz, 2 H, 4-H), 2.26–2.17
(m, 2 H, 1-H), 2.19 [s, 6 H, N-(CH3)2], 2.02–1.97 (m, 2 H, 2-H), 1.20 (s, 6
H, 2 × C-CH3), 1.19 (s, 6 H, 2 × C-CH3).
256.1697.
3-(Dimethylamino)-1-phenyl-1-(thiophen-2-yl)propan-1-ol (15bi)
According to general procedure GP3b, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155.7 mg, 0.5 mmol) and
13C NMR (101 MHz, CD3OD): δ = 146.00 (Ar-C), 136.91 (5-C), 129.10
(2 C, Ar-C), 128.35 (2 C, Ar-C), 126.34 (6-C), 117.34 (Ar-C), 84.58 (2 C,
2 × B-O-C), 56.82 (1-C), 45.79 [2 C, N-(CH3)2], 40.46 (4-C), 32.26 (2-C),
25.36 (2 C, 2 × C-CH3), 25.32 (2 C, 2 × C-CH3); C attached to boron not
observed.
11B NMR (128 MHz, CD3OD): δ = 30.73.
HRMS (ESI): m/z [M + H]+ calcd for C20H33BNO2: 330.2603; found:
4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane
(5i)
(126.1 mg, 0.6 mmol) in anhydrous THF (12 mL) afforded, after purifi-
cation by flash chromatography on silica gel (EtOAc/Et3N = 100:0.5),
tertiary alcohol 15bi (63.5 mg, 49%) as a white solid.
IR (neat): 2779, 1178, 1068, 847, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 7.4 Hz, 2 H, Ar-H), 7.33 (t,
J = 7.6 Hz, 2 H, Ar-H), 7.22 (t, J = 7.1 Hz, 1 H, Ar-H), 7.18 (d, J = 5.0 Hz, 1
H, 5-H), 6.92 (t, J = 3.6 Hz, 1 H, 6-H), 6.89 (d, J = 3.5 Hz, 1 H, 7-H), 2.52
(m, 1 H, 1-H), 2.47–2.30 (m, 3 H, 1-H + 2-H), 2.24 [s, 6 H, N-(CH3)2].
330.2604.
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13C NMR (101 MHz, CDCl3): δ = 154.41 (4-C), 147.37 (Ar-C), 128.22 (2
C, Ar-C), 126.84 (Ar-C), 126.62 (6-C), 125.54 (2 C, Ar-C), 124.30 (5-C),
122.75 (7-C), 78.53 (3-C), 56.55 (1-C), 45.19 [2 C, N-(CH3)2], 38.10 (2-
C).
HRMS (ESI): m/z [M + H]+ calcd for C15H20NOS: 262.1260; found:
262.1267.
IR (neat): 2929, 1453, 1042, 755, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 2 H, Ar-H), 7.22–7.15 (m, 3 H,
Ar-H), 2.47 (sept, J = 5.0 Hz, 1 H, 3-H), 2.23 (m, 1 H, 1-H), 2.21 [s, 6 H,
N-(CH3)2], 2.09 (td, J1 = 10.3 Hz, J2 = 5.1 Hz, 1 H, 1-H), 1.87 (m, 1 H, 2-
H), 1.80–1.65 (m, 2 H, 2-H + 4-H), 1.59 (m, 1 H, 4-H), 0.78 (t, J = 7.4 Hz,
3 H, 5-H).
13C NMR (101 MHz, CDCl3): δ = 145.41 (Ar-C), 128.42 (2 C, Ar-C),
127.80 (2 C, Ar-C), 126.13 (Ar-C), 58.10 (1-C), 45.97 (3-C), 45.48 [2 C,
N-(CH3)2], 34.25 (2-C), 30.03 (4-C), 12.21 (5-C).
HRMS (ESI): m/z [M + H]+ calcd for C13H22N: 192.1747; found:
192.1755.
3-(4-Chlorophenyl)-N,N-dimethyl-3-phenylpropan-1-amine (16bj)
According to general procedure GP4, diisopropylamine (120 μL, 0.88
mmol), n-BuLi (550 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (137 mg, 0.44 mmol), 2-(4-chlo-
rophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5j) (138.3 mg,
0.58 mmol), CsF (99.8 mg, 0.66 mmol) and H2O (9 μL, 0.48 mmol) in
anhydrous THF (8 mL) afforded, after purification by flash chromatog-
raphy on silica gel (EtOAc/Et3N = 100:0.5), protodeboronated com-
pound 16bj (85.2 mg, 71%) as a colourless oil.
3-Ethyl-N,N-dimethyl-3-phenylpent-4-en-1-amine (17ba)
Following a modified literature procedure,5d n-BuLi (1.5 mmol, 940
μL) was added dropwise at r.t. to neat tetravinyltin (0.75 mmol, 140
μL) under an N2 atm. The reaction mixture was stirred for 30 min; the
white solid formed was allowed to settle and the colourless solution
was removed by syringe under N2. The solid (vinyl lithium) was
washed with dry pentane (3 × 1 mL), every time adding and removing
the solvent by syringe under N2, and then dissolved in dry THF (1 mL).
N,N-Dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pentan-1-amine (2ba) (0.3 mmol, 95.2 mg) was dissolved in dry
THF (3 mL) and the vinyl lithium solution was added dropwise at
–78 °C. The reaction mixture was stirred for 30 min at –78 °C,
warmed to –42 °C and then stirred at that temperature for an addi-
tional 20 min. After that time, 11B NMR analysis of the crude reaction
mixture showed complete boronate complex formation. The solution
was cooled to –78 °C and a solution of I2 (1.5 mmol, 380.7 mg) in dry
MeOH (2.4 mL) was added dropwise. After stirring for 15 min at
–78 °C, a suspension of NaOMe (3 mmol, 126.1 mg) in dry MeOH (1.2
mL) was added. The reaction mixture was allowed to warm to r.t. and
stirred for 1 h; then an aq solution of Na2S2O3 (10 mL) was added. The
layers were separated, the organic layer was washed with brine (2 × 5
mL) and the combined aq layers were extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over MgSO4 and concen-
trated under reduced pressure. The crude residue was purified by col-
umn chromatography on silica gel (EtOAc/Et3N = 100:0.5) to afford
alkene 17ba (33.7 mg, 52%) as a colourless oil.
IR (neat): 2942, 2765, 1489, 1092, 1014, 821, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.24 (m, 8 H, Ar-H), 7.15 (m, 1 H,
Ar-H), 3.93 (t, J = 6.0 Hz, 1 H, 3-H), 2.27–2.20 (m, 4 H, 1-H + 2-H), 2.19
[s, 6 H, N-(CH3)2].
13C NMR (101 MHz, CDCl3): δ = 145.52 (Ar-C), 144.96 (Ar-C), 132.94
(Ar-C), 130.36 (2 C, Ar-C), 129.63 (2 C, Ar-C), 129.51 (2 C, Ar-C),
128.73 (2 C, Ar-C), 127.47 (Ar-C), 59.06 (1-C), 49.87 (3-C), 45.43 [2 C,
N-(CH3)2], 33.96 (2-C).
HRMS (ESI): m/z [M + H]+ calcd for C17H21ClN: 274.1357; found:
274.1363.
1-(Dimethylamino)-3-phenylpentan-3-ol (15ba)
According to general procedure GP3a, diisopropylamine (140 μL, 1
mmol), n-BuLi (625 μL, 1 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155.7 mg, 0.5 mmol) and 2-eth-
yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5a) (93.6 mg, 0.6 mmol)
in anhydrous THF (6 mL) afforded, after purification by flash chroma-
tography on silica gel (CH2Cl2/MeOH/Et3N = 100:0.5:0.5), tertiary al-
cohol 15ba (60.4 mg, 58%) as a white solid.
IR (neat): 2936, 2823, 2781, 1464, 1445, 1174, 1042, 1024, 773 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.39 (m, 2 H, Ar-H), 7.34–7.30
(m, 2 H, Ar-H), 7.20 (ps tt, J1 = 8.4 Hz, J2 = 0.9 Hz, 1 H, Ar-H), 2.28 (td,
J1 = 12.5 Hz, J2 = 2.6 Hz, 1 H, 1-H), 2.19 (m, 1 H, 1-H), 2.18 [s, 6 H, N-
(CH3)2], 2.08 (ddd, J1 = 14.7 Hz, J2 = 12.0 Hz, J3 = 3.12 Hz, 1 H, 2-H),
1.84–1.74 (m, 3 H, CH2-CH3 + 2-H), 0.72 (t, J = 7.3 Hz, 3 H, CH2-CH3).
IR (neat): 2937, 2815, 2763, 1462, 1041, 912, 759, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.28 (m, 4 H, Ar-H), 7.18 (m, 1 H,
Ar-H), 5.91 (dd, J1 = 17.7 Hz, J2 = 11.0 Hz, 1 H, 4′-H), 5.20 (dd, J1 = 10.9
Hz, J2 = 1.0 Hz, 1 H, 5′-Hcis), 5.11 (dd, J1 = 17.7 Hz, J2 = 1.0 Hz, 1 H, 5′-
H
trans), 2.19 [s, 6 H, N-(CH3)2], 2.10 (m, 2 H, 1-H), 1.97 (m, 2 H, 2-H),
13C NMR (101 MHz, CDCl3): δ = 147.04 (Ar-C), 128.01 (2 C, Ar-C),
126.06 (Ar-C), 125.86 (2 C, Ar-C), 78.21 (3-C), 56.23 (1-C), 45.15 [2 C,
N-(CH3)2], 37.15 (2-C), 36.69 (CH2-CH3), 7.73 (CH2-CH3).
HRMS (ESI): m/z [M + H]+ calcd for C13H22NO: 208.1696; found:
208.1702.
1.80 (m, 2 H, 4-H), 0.72 (t, J = 7.4 Hz, 3 H, CH2-CH3).
13C NMR (101 MHz, CDCl3): δ = 145.67 (Ar-C), 145.19 (4′-C), 128.15 (2
C, Ar-C), 127.37 (2 C, Ar-C), 125.98 (Ar-C), 113.15 (5′-C), 55.23 (1-C),
47.03 (3-C), 45.67 [2 C, N-(CH3)2], 34.48 (2-C), 30.25 (4-C), 8.56 (5-C).
HRMS (ESI): m/z [M + H]+ calcd for C15H24N: 218.1903; found:
2218.1910.
N,N-Dimethyl-3-phenylpentan-1-amine (16ba)
N,N-Dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)pentan-1-amine (2ba) (63.5 mg, 0.2 mmol) was dissolved in dry
THF (2 mL) and TBAF·3H2O (95 mg, 0.3 mmol) was added at r.t. The
reaction mixture was allowed to stir at reflux for 2 h, then H2O (5 mL)
was added. The mixture was partitioned between H2O and CH2Cl2
and the aq phase was extracted with CH2Cl2 (2 × 5 mL). The combined
organic layers were dried over MgSO4 and the solvent was removed
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel (EtOAc/Et3N = 100:0.5) to afford 16ba
(28 mg, 73%) as a colourless oil.
3-Ethyl-2,2-difluoro-1,1-dimethyl-3-phenyl-1λ4,2λ4-azaboroli-
dine (18ba)
Following a literature reported procedure,33 to a rapidly stirred solu-
tion of N,N-dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)pentan-1-amine (2ba) (95.2 mg, 0.3 mmol) in MeOH (3
mL) was added dropwise a solution of KHF2 (105.4 mg, 1.35 mmol) in
H2O (700 μL) at r.t. The resulting mixture was stirred for 30 min and
then concentrated under reduced pressure. The residue was redis-
solved in a mixture of MeOH/H2O (1:1 v/v, 6 mL) and evaporated to
dryness. This concentration–dissolution cycle was repeated 6 times,
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G. Casoni et al.
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after which 1H NMR analysis of an aliquot of the reaction mixture
showed no presence of pinacol (δ = 1.14) in acetonitrile-d3. The solid
residue was then triturated with dry acetone (5 mL); the liquid phase
was carefully decanted and the residual inorganic salts were addi-
tionally washed with acetone (3 × 1 mL). The combined washings
were collected and concentrated in vacuo to give a 2:1 mixture of the
desired tetrafluoroborate salt and azaborolidine 18ba (82% overall
yield). A portion of the mixture (45 mg) was dissolved in dry MeCN (3
mL) and the solution was heated at reflux for 5 h. The reaction mix-
ture was then filtered through a pad of SiO2 and washed with CH2Cl2
to give azaborolidine 18ba (26.4 mg, 68%) as a white solid.
IR (neat): 2972, 1475, 1256, 1152, 754, 706, 635 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 6.6 Hz, 2 H, Ar-H), 7.45 (t,
J = 8.6 Hz, 3 H, Ar-H), 4.87 (dd, J1 = 11.5 Hz, J2 = 7.8 Hz, 1 H, 1-H), 3.82
(t, J = 7.7 Hz, 2 H, 4-H), 3.07 (s, 3 H, CH3), 2.69 (s, 3 H, CH3), 2.60 (m, 1
H, 2-H), 2.49 (m, 1 H, 2-H), 2.31 (m, 2 H, 3-H).
13C NMR (101 MHz, CDCl3): δ = 131.36 (Ar-C), 130.85 (2 C, Ar-C),
129.47 (2 C, Ar-C), 128.41 (Ar-C), 120.72 (q, J = 322.2 Hz, CF3), 78.69
(1-C), 65.84 (4-C), 50.59 (CH3), 45.18 (CH3), 26.13 (2-C), 19.25 (3-C).
19F NMR (376 MHz, CDCl3): δ = –78.37.
HRMS (ESI): m/z [M – SO3CF3]+ calcd for C12H18N: 176.1434; found:
IR (neat): 2959, 2927, 1467, 1053, 950, 755, 724, 701, 658 cm–1
.
176.1440.
1H NMR (400 MHz, CDCl3): δ = 7.29 (m, 4 H, Ar-H), 7.12 (m, 1 H, Ar-
H), 3.00 (m, 1 H, 1-H), 2.90 (m, 1 H, 1-H), 2.61 (s, 3 H, N-CH3), 2.39 (s,
3 H, N-CH3), 2.30 (quin, J = 7.6 Hz, 1 H, 2-H), 1.89 (m, 2 H, 4-H), 1.59
(quin, J = 6.9 Hz, 1 H, 2-H), 0.57 (t, J = 7.2 Hz, 3 H, 5-H).
13C NMR (101 MHz, CDCl3): δ = 147.68 (Ar-C), 137.72 (4 C, Ar-C),
124.39 (Ar-C), 60.41 (1-C), 46.76 (d, J = 9.1 Hz, N-CH3), 46.55 (d, J =
10.1 Hz, N-CH3), 30.94 (4-C), 29.56 (2-C), 9.05 (5-C); C attached to bo-
ron not observed.
11B NMR (96 MHz, CDCl3): δ = 7.36 (t, J = 67.4 Hz).
19F NMR (282 MHz, CDCl3): δ = –152.44, –157.32.
HRMS (ESI): m/z [M + Na]+ calcd for C13H20BF2NNa: 262.1551; found:
(Z)-2-Methyl-1,2,3,4,5,10a-hexahydrobenzo[c]azocine (20a)
To a solution of diisopropylamine (140 μL, 1 mmol) in anhydrous THF
(500 μL) was added n-BuLi (625 μL, 1 mmol) at –78 °C. After stirring
for 20 min at –78 °C and 10 min at r.t., the solution was added drop-
wise to a mixture of pyrrolidinium salt 19a (162.7 mg, 0.5 mmol) and
2-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5a) (93.6 mg, 0.6
mmol) in dry THF (12 mL) at –78 °C. The reaction mixture was stirred
at –78 °C for 1 h and then allowed to warm to r.t. The solvent was re-
moved in vacuo and the crude residue was taken up with H2O (5 mL)
and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo to afford the crude
product, which was purified by chromatography on silica gel
(EtOAc/Et3N = 100:0.5) to afford the pure azocine 20a (42.2 mg, 48%)
as a colourless oil.
1H NMR (400 MHz, CDCl3): δ = 6.05 (d, J = 9.5 Hz, 1 H, 6-H), 5.94 (dd,
J1 = 9.4 Hz, J2 = 5.3 Hz, 1 H, 8-H), 5.77–5.68 (m, 3 H, 4-H, 7-H, 9-H),
3.51 (br s, 1 H, 10-H), 2.70–2.46 (m, 4 H, 2 × 1-H, 3-H, 11-H), 2.42 (s, 3
H, CH3), 2.21 (m, 1 H, 3-H), 2.04 (m, 1 H, 11-H), 1.87 (m, 1 H, 2-H),
1.47 (m, 1 H, 2-H).
262.1551.
1-Methyl-2-phenylpyrrolidine (24)
Following a procedure reported by Turner,34 commercially available
2-phenylpyrrolidine (3.4 mmol, 500 mg) was suspended in H2O (4
mL) in a microwave test tube and formic acid (3.7 mmol, 141 μL) and
formaldehyde (35% solution in H2O, 3.7 mmol, 320 μL) were added at
r.t. The tube was sealed and was heated using microwave irradiation
at 150 °C for 5 min. The reaction mixture was allowed to cool to r.t.,
then it was basified to pH 14 using an aq solution of NaOH (2.0 M)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude material
was purified by Kugelrohr distillation to afford the pure tertiary
amine (396 mg, 72%) as a colourless liquid.
(Z)-2-Methyl-1,2,3,4,5,10a-hexahydrobenzo[c]azocine (20a) was
found to rapidly rearrange at r.t. to give 2-methyl-1,2,3,4,5,6-hexahy-
drobenzo[c]azocine (21a), which could be fully characterised.
2-Methyl-1,2,3,4,5,6-hexahydrobenzo[c]azocine (21a)
IR (neat): 2922, 1448, 1044, 753, 613 cm–1
.
IR (neat): 2968, 2775, 1454, 1044, 754, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.18 (m, 4 H, Ar-H), 3.78 (s, 2 H, 1-H),
2.85 (t, J = 5.8 Hz, 2 H, 5-H), 2.46 (t, J = 4.8 Hz, 2 H, 2-H), 2.39 (s, 3 H,
CH3), 1.71 (quin, J = 5.8 Hz, 2 H, 4-H), 1.61 (quin, J = 5.6 Hz, 2 H, 3-H).
13C NMR (101 MHz, CDCl3): δ = 142.14 (Ar-C), 134.45 (Ar-C), 131.00
(Ar-C), 129.57 (Ar-C), 127.84 (Ar-C), 125.95 (Ar-C), 55.93 (1-C), 54.08
(2-C), 43.61 (CH3), 33.11 (5-C), 30.97 (4-C), 23.70 (3-C).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 4 H, Ar-H), 7.23 (m, 1 H,
Ar-H), 3.24 (td, J1 = 9.4 Hz, J2 = 1.8 Hz, 1 H, 4-H), 3.03 (t, J = 8.8 Hz, 1 H,
1-H), 2.28 (m, 1 H, 4-H), 2.17 (m, 1 H, 2-H), 2.17 (s, 3 H, CH3), 1.95 (m,
1 H, 3-H), 1.78 (m, 2 H, 2-H + 3-H).
13C NMR (101 MHz, CDCl3): δ = 143.40 (Ar-C), 128.47 (2 C, Ar-C),
127.62 (2 C, Ar-C), 127.12 (Ar-C), 71.79 (1-C), 57.22 (4-C), 40.62
(CH3), 35.29 (2-C), 22.63 (3-C).
HRMS (ESI): m/z [M + H]+ calcd for C12H18N: 176.143376; found:
176.143020.
HRMS (ESI): m/z [M + H]+ calcd for C11H16N: 162.127726; found:
162.127190.
2-[1,2-Diphenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)cyclopropyl]-N,N-dimethylethan-1-amine (22)
1,1-Dimethyl-2-phenylpyrrolidin-1-ium Trifluoromethanesulfon-
ate (19a)
According to general procedure GP2, diisopropylamine (140 μL, 1.0
mmol), n-BuLi (625 μL, 1.0 mmol), 1,1-dimethyl-2-phenylazetidin-1-
ium trifluoromethanesulfonate (3b) (155 mg, 0.5 mmol) and 4,4,5,5-
tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (5k) (138 mg, 0.6
mmol) in anhydrous THF (12 mL) afforded, after purification on silica
gel (EtOAc/Et3N = 100:0.5), cyclopropane 22 (47 mg, 24%) as a colour-
less oil.
Following a modified version of a procedure by Couty,15b pyrrolidine
24 (358 mg, 2.22 mmol) was dissolved in dry Et2O (19 mL). After cool-
ing to 0 °C, methyl trifluoromethanesulfonate (500 μL, 4.45 mmol)
was added. The mixture was stirred for 1 h at r.t.; then the volatiles
were removed under vacuum to afford pyrrolidinium triflate 19a (721
g, >99%) as a purple oil.
IR (neat): 2976, 1599, 1448, 1372, 1144, 849, 766, 697 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

L
G. Casoni et al.
Paper
Synthesis
1H NMR (400 MHz, CD3OD): δ = 7.06–6.78 (m, 10 H, Ar-H), 2.54 (ps td,
J1 = 12.4 Hz, J2 = 4.4 Hz, 1 H, 1-H), 2.32 (ps td, J1 = 11.5 Hz, J2 = 4.4 Hz, 1
H, 1-H), 2.17 [s, 6 H, N-(CH3)2], 2.15 (m, 1 H, 2-H), 1.99 (br s, 1 H, 5-H),
1.87 (ps td, J1 = 12.3 Hz, J2 = 4.3 Hz, 1 H, 2-H), 1.36 (d, J = 4.8 Hz, 1 H, 5-
H), 1.26 (s, 6 H, 2 × C-CH3), 1.22 (s, 6 H, 2 × C-CH3).
13C NMR (101 MHz, CD3OD): δ = 141.43 (Ar-C), 141.31 (Ar-C), 131.42
(2 C, Ar-C), 130.56 (2 C, Ar-C), 128.60 (2 C, Ar-C), 128.05 (2 C, Ar-C),
126.83 (Ar-C), 125.81 (Ar-C), 84.96 (2 C, 2 × B-O-C), 58.67 (1-C), 45.27
[2 C, N-(CH3)2], 37.60 (3-C), 36.77 (2-C), 25.34 (2 C, 2 × C-CH3), 25.20
(2 C, 2 × C-CH3), 20.41 (5-C); C attached to boron not observed.
S.; Hesse, M. J.; Zabaleta, N.; Myers, E. L.; Aggarwal, V. K. Chem.
Commun. 2016, 52, 5289. For miscellaneous methods for pre-
paring enantiomerically enriched organoborons, see: (q) Basch,
C. H.; Cobb, K. H.; Watson, M. P. Org. Lett. 2016, 18, 136.
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Am. Chem. Soc. 2014, 136, 17918. (s) Zhang, L.; Lovinger, G. J.;
Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P.
Science 2016, 351, 70.
(5) For
a review on transition-metal-mediated enantiospecific
transformations of organoboron compounds, see: (a) Cherney,
A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587.
For selected recently developed C–B functionalisation reactions,
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Essafi, S.; Aggarwal, V. K. Nat. Chem. 2014, 6, 584. (i) Matthew, S.
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Aggarwal, V. K. J. Am. Chem. Soc. 2015, 137, 10100. (k) Wang, Y.;
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11B NMR (96 MHz, CDCl3): δ = 30.66, 21.12.
HRMS (ESI): m/z [M + H]+ calcd for C25H35BNO2: 392.2760; found:
392.2768.
Acknowledgment
We would like to thank the EPSRC and the University of Bristol for fi-
nancial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562447.
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