Regioselective α-benzylation of 3-iodoazetidine via Suzuki cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2019.04.008

An efficient protocol for the synthesis of α-benzyl azetidines starting from benzylboronic acid pinacol ester derivatives and 3-iodoazetidine was developed. A wide range of α-benzyl azetidine derivatives were obtained in moderate to good yields with high regioselectivity (>99%).

Full text of DOI:10.1016/j.tetlet.2019.04.008

Accepted Manuscript
Regioselective α-benzylation of 3-iodoazetidine via Suzuki Cross-Coupling
Zhenjiang Qiu, Mingxiang Zhu, Lu Zheng, Jingya Li, Dapeng Zou, Yangjie Wu,
Yusheng Wu
PII:
S0040-4039(19)30331-4
https://doi.org/10.1016/j.tetlet.2019.04.008
TETL 50723
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 February 2019
25 March 2019
2 April 2019
Please cite this article as: Qiu, Z., Zhu, M., Zheng, L., Li, J., Zou, D., Wu, Y., Wu, Y., Regioselective α-benzylation
of 3-iodoazetidine via Suzuki Cross-Coupling, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2
019.04.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Regioselective α-benzylation of 3-iodoazetidine via
Suzuki Cross-Coupling
Leave this area blank for abstract info.
Zhenjiang Qiu, Mingxiang Zhu, Lu Zheng, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*

1
Tetrahedron Letters
Regioselective α-benzylation of 3-iodoazetidine via Suzuki Cross-Coupling
a
a
a
b,c
a,b
a
b,d
Zhenjiang Qiu , Mingxiang Zhu , Lu Zheng , Jingya Li , Dapeng Zou , Yangjie Wu , Yusheng Wu 
a
The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China.
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China.
Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, PR China.
Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
b
c
d
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient protocol for the synthesis of α-benzyl azetidines starting from benzylboronic acid
pinacol ester derivatives and 3-iodoazetidine was developed. A wide range of α-benzyl azetidine
derivatives were obtained in moderate to good yields with high regioselectivity (>99%).
2
019 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Regioselective
Azetidines
α-benzylation
1
0
11,12
Introduction
1,3-dielectrophiles. b) The ring contraction and the ring
2
expansion of saturated nitrogen-containing heterocycles
Scheme 1, b). c) Lithiation-electrophilic substitution of N-
thiopivaloylazetidine. Although significant achievements have
been made, it is still highly desirable to explore new, mild and
straightforward methods for the synthesis of azetidines.
Saturated nitrogen-containing azetidines have recently
received increasing attention due to their unique application
values in drug discovery and development. Particularly, 2-
(
13
1
benzylazetidines have attracted much attention for its widespread
2
3
bioactivity and potential pharmaceutical composition. For
Suzuki reaction is a widely used carbon-carbon bond-forming
process, especially in the cross-coupling between alkylboron
agents with alkyl halides. Alkyl boron agents such as 9-
borabicyclo[3.3.1]nonane(9-BBN borane), alkylboronic acid and
potassium trifluoroborate were always utilized in the coupling
example, this sort of compounds has a good affinity to TAAR
4
(trace amine-associated receptor) ligands, which are widely used
for the treatment of Parkinson’s disease and Alzheimer’s disease.
Several 2-benzylazetidine-containing substances have become
5
the hot spot in drug research for its anticancer activety, anti-
3
3
6
7
reaction to construct C(sp )-C(sp ) bonds. 9-BBN borane was
inflammatory activety, and anxiolytic property (Figure 1).
1
4
used to construct carbon-carbon bonds by Fu’s group . In 2002,
they reported the similar cross-coupling reaction using
1
5
alkylboronic acid as nucleophile . In 2012, Molander and
1
6
3
3
coworkers reported the Csp -Csp cross-coupling of potassium
cyclopropyl-trifluoroborate with benzyl chlorides. In those
reactions, the coupling occurred at original position rather than
elsewhere. The Pd-catalyzed 1,2-migration in azetidines was less
reported. The limited example was established by our group in
2017. In that paper, the first ligand-dependent regio- rearranged
and selective Suzuki coupling of 1-Boc-3-iodoazetidine with
pyridineboronic acid pinacol ester was reported. However, in
the same condition, the cross-coupling reaction of benzylboronic
acid pinacol ester with 3-iodoazetidine cannot be achieved. As
part of our particular interest in the development of novel
Figure 1. Some pharmaceutical molecules containing 2-benzyl-
azetidine scaffolds
1
7
Over the past few decades, a variety of protocols for the
8
preparation of azetidines have been reported. In general,
azetidines have been obtained by the following methods: a)
9
Intramolecular cyclization of open-chain structures and
—inte—rm—olecular cyclization (Scheme 1, a) of primary amines with

Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, zdp@zzu.edu.cn,
wyj@zzu.edu.cn.

2
Tetrahedron Letters
Scheme 1. Typical methods for the synthesis of 2-substituted
azetidines.
found to give a better result with 40% yield. Increasing the
amount of substrate 1a led to an improvement in the yield (see
supporting information). Using 2.0 equiv of 1a gave a good yield
of the desired product. Then a series of bases such as K PO ,
3
4
Na CO , Cs CO , CsF, and NaOH were studied, and Cs CO was
2
3
2
3
2
3
proved to be the optimal one to afford the α-substituted product
in moderate yield with good regioselectivity (Table 1, entries 6-
1
1
0). Then, the mixed solvents were screened (solvent: water =
:1, v/v) (Table 1, entries 11-15). The results indicated that polar
aprotic solvents, such as DMSO, DMF and NMP were less
effective for the reaction (Table 1, entries 11-13), and 1,4-
dioxane was the best one compared with DME and THF (Table 1,
entries 10 vs 14, 15). Furthermore, a variety of ligands such as
PPh , dppf, dppp, Xant-Phos, DavePhos, CyJhonPhos, Ru-Phos
3
and S-Phos were also examined. The electron-rich
monophosphine ligands were found to provide the desired
product in higher yields. Whereas, electron-deficient one resulted
in lower yield (Table 1, entries 16-19 vs 20). Diphosphine
ligands were not good for the reaction (Table 1, entries 21-23).
RuPhos afforded a better yield for the α-substituted product (67%)
than XPhos (62%) (Table 1, entries 19 vs 10). When sterically
hindered monophosphine ligand was used, the reaction yield
improved significantly and the target product was obtained in
high regioselectivity. Finally, additives such as LiCl, TBAB,
1
8
methods for Pd-catalyzed cross-coupling reactions , we herein
report an efficient Pd-catalyzed Suzuki coupling of
benzylboronic acid pinacol ester derivatives with 3-iodoazetidine
to construct α-benzyl azetidines.
CuBr were further screened, and TBAB was found to be the
2
optimal one (Table 1, entries 24-26). Thus, the optimum reaction
conditions were obtained: benzylboronic acid pinacol ester 1a
(1.0 mmol), 1-Boc-3-iodoazetidine 4a (0.5mmol), Pd(COD)Cl2
Results and Discussion
(0.05 mmol), RuPhos (0.10 mmol), TBAB (0.05 mmol) and
Cs CO (1.5 mmol) in 3 mL 1,4-dioxane/H O (1:1) at 80 °C
2
3
2
In order to optimize the reaction conditions, the Suzuki-
coupling of 3-iodoazetidine with benzylboronic acid pinacol ester
was chosen as model reaction (Table 1). Initially, the conditions
of arylation of azetidines reported earlier were used in this
reaction, but no desired product was obtained. Then Pd(PPh3)4
which usually used in Suzuki reactions was tested, and the
desired α-substituted product 2a was obtained in 31% yield along
with 14% of 3a (see supporting information (SI)). Then, other
palladium sources were screened and the results were
summarized in Table 1. All catalysts generated from XPhos
provided the α-substituted product (2a) rather than the -
substituted one with good regioselectivity (>99%) indicated that
the choice of ligand might influence the regioselectivity of
products (Table 1, entries 1-5). Various palladium precursors
under argon atmosphere for 24 h. The structure of product 2a was
1
9
confirmed by X-ray crystallographic analysis (Figure 2) .
(
Pd (dba) , Pd(acac) , PdCl (NBD), Pd(COD)Cl and Pd(OAc) )
2 3 2 2 2 2
Figure 2. X-ray structure of 2a
were investigated (Table 1, entries 1-5), and Pd(COD)Cl was
Table 1. Reaction Conditions Optimization
2
a
b
entry
catalyst
Pd (dba)
Pd(acac)
PdCl
Pd(COD)Cl
Pd(OAc)
base
solvent(ratio=1:1)
ligand
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
additive
yield of 2a(%)
c
1
2
3
4
5
6
7
8
9
2
3
2
Na
2
2
2
2
2
CO
3
3
3
3
3
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
-
-
-
-
-
-
-
-
-
-
-
-
-
-
17
c
Na
Na
Na
Na
CO
CO
CO
CO
6
c
2
(NBD)
37
c
2
40
c
2
10
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
2
2
2
2
2
2
2
2
2
CsF
PO
CO
NaOH
0
K
3
4
46
50
39
62
14
6
Na
2
3
1
1
1
1
1
0
1
2
3
4
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
3
3
3
3
3
2
DMSO/H O
2
DMF/H O
2
NMP/H O
10
24
2
THF/H O

3
1
1
1
1
1
2
2
2
2
2
2
2
5
6
7
8
9
0
1
2
3
4
5
6
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
Pd(COD)Cl
2
2
2
2
2
2
2
2
2
2
2
2
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
DME/H
2
O
X-Phos
DavePhos
CyJohnPhos
S-Phos
-
-
-
34
35
26
30
67
4
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
dioxane/H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
Ru-Phos
-
PPh
3
-
Dppf
Dppp
-
10
0
-
-
Xant-Phos
Ru-Phos
Ru-Phos
Ru-Phos
0
LiCl
TBAB
77
d
84(79% )
CuBr
2
78
a
Reactions conditions: 1a (1.0 mmol), 4a (0.5 mmol), Pd(COD)Cl
solvent (3 mL, organic solvent : H O = 1 : 1) at 80 °C for 24 h unless otherwise noted. Determined by GC-MS using n-dodecane as an internal
standard. Ratio of 1a
2
(0.05 mmol), ligand (0.10 mmol), base (1.5 mmol), additive (0.05 mmol), in
b
2
c
d
:
4a = 1.2 : 1, 1a (0.6 mmol). Isolated yield. TBAB = tetra-n-butylammoniumbromide, NBD = 2,5-norbornadiene, COD = 1,5-
cyclooctadiene.
a
Scheme 2. Synthesis of α-benzyl azetidine derivatives
(3-chloro-2-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane gave the dechlorination product 2i in the same
conditions. Notably, when the phenyl ring of benzylboronic
acid pinacol ester was replaced by naphthyl or biphenyl
group, the target product was obtained in 43%, 42% yields,
respectively
(2o, 2p). Unfortunately, the substrates
containing electron-withdrawing groups were not suitable
for this system (2q, 2r and 2s).
Different protecting groups on the nitrogen-atoms of 3-
idoazetidines were also examined (Scheme 3). Substrate
bearing -Cbz protecting group could afford the desired
product in good yields (entry 2). Whereas, the one with -Ts
group didn’t compatible in this reaction.
Scheme 3. Synthesis of α-benzyl azetidine derivatives with
a
other protecting groups
entry
R
product
2a
yield
84%
86%
trace
1
2
3
Boc (4a)
Cbz (4t)
Ts (4u)
2t
2u
a
a
Reactions conditions: 1a (1.0 mmol), 3-iodoazetidine (0.5 mmol),
Pd(COD)Cl (0.05 mmol), Ru-Phos (0.1 mmol), TBAB (0.05 mmol) and
Cs CO (3.0 mmol) in solvent (3 mL, organic solvent : H O = 1 : 1 ) at 80 °C
Reactions conditions: benzylboronic acid pinacol ester (1.0 mmol), N-
Boc-3-iodoazetidine
cyclooctadiene)palladium(II) (0.05 mmol), Ru-Phos (0.1 mmol), TBAB
0.05 mmol) and Cs CO (3.0 mmol) in solvent (3 mL, organic solvent :
O = 1 : 1 ) at 80 °C for 24 h unless otherwise noted. Isolated yields.
(0.5mmol),
dichloro(1,5-
2
2
3
2
for 24 h unless otherwise noted. Isolated yields. The possible α/β isomers
were estimated to be >99% compared with the desired products (See
Supporting Information for details).
(
H
2
3
2
The possible α/β isomers were estimated to be >99% compared with the
desired products. Product 2i was obtained from the substrate2-(3-
chloro-2-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1i
b
Conclusions
.
Under the optimal reaction conditions, various
benzylboronic acid pinacol esters 1a-1s were reacted with 3-
iodoazetidine (4a) to give desired α-benzyl azetidine
derivatives 2a-2s in moderate to good yields with excellent
regioselectivities (>99%). The benzylboronic acid pinacol
esters possessing electron donating group (MeO (1b), i-Pr
In conclusion, a convenient, efficient and practical
3
palladium-catalyzed regioselective protocol for the C(sp )-
3
C(sp ) bond formation through the reaction of benzylboronic
acid pinacol esters and 3-iodoazetidine was developed. The
method shows good functional group tolerance and affords a
variety of α-benzyl azetidine derivatives in moderate to good
yields with high regioselectivity (>99%). In addition, this
method provides an operationally simple and mild strategy
for the preparation of α-benzyl azetidines which will be
valuable building blocks in material science and drug
discovery.
(
1c), t-Bu (1d) and Me (1f) on the para-position worked
efficiently. The substrate with methyl group on the meta-
position gave the similar performance to that on para-
position (2f, 2g). When benzylboronic acid pinacol esters 1h
bearing a methyl group on ortho-position was used, the
desired 2h was obtained in low yield which might due to the
steric hindrance. The trifluoromethoxy bearing substrate
gave the desired product in 72% yield (2e). When 2-, 3-, and
Acknowledgments
4
-fluorobenzylboronic acid pinacol ester were used in the
We are grateful to the Natural Science Foundation of China
(21172200, 21702191) for financial support.
reaction, the desired products were obtained in 60%, 75%,
and 72%, respectively. In case of meta-, and para-
chlorobenzylboronic acid pinacol ester, the moderate yields
of the desired products were obtained (2m, 2n). However, 2-

4
Tetrahedron
References and notes
12 N. Kern, A. S. Felten, J. M. Weibel, P. Pale and A. Blanc, Org. Lett.
014, 16, 6104.
D. M. Hodgson and J. Kloesges, Angew. Chem. Int. Ed. 2010, 49,
900.
14 (a) T. Ishiyama, S. Abe, N. Miyaura and A. Suzuki, Chem. Lett.
992, 21, 691.(b) M. R. Netherton, C. Dai, K. Neuschütz and G. C.
2
1
(a) C. T. Vo and J. W. Bode, J. Org. Chem. 2014, 79, 2809; (b) E. A.
Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel and B. U. W. Maes,
Chem. Eur. J. 2012, 18, 10092.
A. Brandi, S. Cicchi and F. M. Cordero, Chem. Rev. 2008, 108, 3988.
G. Gerona-Navarro, M. J. P. de Vega, M. T. García-López, G.
Andrei, R. Snoeck, E. De Clercq, J. Balzarini and R. J. González-
Muñiz, J. Med. Chem. 2005, 48, 2612.
1
3
2
2
3
1
Fu, J. Am. Chem. Soc. 2001, 123, 10099. (c) J. H. Kirchhoff, C. Dai
and G. C. Fu, Angew. Chem. Int. Ed. 2002, 41, 1945.
J. H. Kirchhoff, M. R. Netherton, I. D. Hills and G. C. Fu, J. Am.
Chem. Soc, 2002, 124, 13662.
1
5
4
5
G. Cecere, G. Galley, R. Norcross, P. Pflieger and E. Rauber, WO
2
016030310, 2016
.
16 V. Colombel, F. Rombouts, D. Oehlrich and G. A. Molander, J. Org.
Chem. 2012, 77, 2966.
P. Pérez-Faginas, M. T. Aranda, M. T. García-López, A. Francesch,
C. Cuevas and R. González-Muñiz, Eur. J. Med. Chem. 2011, 46,
1
7
Y. D. Zhang, Z. Y. Geng, J. Y. Li, D. P. Zou, Y. J. Wu and Y. S. Wu,
Adv. Synth. Catal.2017, 359, 390.
5
108.
6
L. R. M. Saniere, M. R. Pizzonero, N. Triballeau, N. E. R.
Vandeghinste, S. I. J.de Vos, R. C. X. Brys, C. D. Pourbaix-l'ebraly,
1
8
(a) S. J. Han, X. X. Ren, Q. S. Wu, A. P. Liang, J. Y. Li, D. P. Zou,
Y. J. Wu and Y. S. Wu, Adv. Synth. Catal. 2018, 360, 2308. (b) Q. S.
Wu, S. J. Han, X. X. Ren, H. T. Lu, J. Y. Li, D. P. Zou, Y. J. Wu and
Y. S. Wu, Org. Lett. 2018, 20, 6345. (c) X. Y. Gao, Y. Geng, S. J.
Han, A. P. Liang, J. Y. Li, D. P. Zou, Y. L. Wu and Y. S. Wu, Org.
Lett. 2018, 20, 3732.
Crystallographic data for the structure has been deposited with the
Cambridge Crystallographic Data Centre (CCDC 1876328).
WO 2012098033, 2012
D. A. Burnett, M. A. Caplen, M. F. Czarniecki, M. S. Domalski, G.
D. Ho, D. Tulshian, and W. L. Wu, WO 2003043980, 2003
D. Antermite, L. Degennaro and R. Luisi, Org. Biomol. Chem. 2017
5, 34.
.
7
8
9
.
,
1
1
9
F. Couty, G. Evano, Synlett. 2009, 3053.
1
0
A. Marinetti, P.Hubert and J. P. Genet, Eur. J. Org. Chem. 2000
,
1
815.
(a) D. Enders, J. Gries and Z. S. Kim, Eur. J. Org. Chem. 2004, 4471;
b) M. Tiecco, L. Testaferri, A. Temperini, R. Terlizzi, L. Bagnoli, F.
Marini and C. Santi, Org. Biomol. Chem. 2007, 5, 3510.
1
1
(

5
Highlights
A new approach to construct C(sp3)-C(sp3) bond
was developed.
α-benzyl azetidine derivatives were obtained with
high regioselectivity (>99%).
This catalytic system features mild conditions and
good substrate tolerance.