Synthesis of aryloxyazetidine derivatives by CuI/l-proline catalyzed coupling reaction of arylboronic acid with 1-Boc-3-iodoazetidine

Article abstract of DOI:10.1016/j.tetlet.2014.02.098

A novel CuI/l-proline catalyzed coupling reaction of 1-Boc-3-iodoazetidine with various arylboronic acids which produced aryloxyazetidine derivatives in moderate to good yields was investigated.

Full text of DOI:10.1016/j.tetlet.2014.02.098

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of aryloxyazetidine derivatives by CuI/L-proline catalyzed
coupling reaction of arylboronic acid with 1-Boc-3-iodoazetidine
b,c,
Juanjuan Song a, Xinjian Li a, Apeng Liang a, Jingya Li b, Dapeng Zou a,b, Yangjie Wu a, , Yusheng Wu
⇑
⇑
a College of Chemistry and Molecular Engineering, Key Laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou,
Henan 450052, PR China
b Tetranov Biopharm, LLC. 75 Daxue Road, Zhengzhou, Henan 450052, PR China
c Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel CuI/
which produced aryloxyazetidine derivatives in moderate to good yields was investigated.
Ó 2014 Published by Elsevier Ltd.
L-proline catalyzed coupling reaction of 1-Boc-3-iodoazetidine with various arylboronic acids
Received 6 January 2014
Revised 24 February 2014
Accepted 25 February 2014
Available online xxxx
Keywords:
Aryloxyazetidines
CuI/L-proline
1-Boc-3-iodoazetidine
Arylboronic acid
Introduction
cently there have been a lot of reports about the synthesis of phe-
nols by oxidative hydroxylation of arylboronic acids. These
methods have broad functional group compatibility for both elec-
tron-rich and -deficient substituents.8 On the other hand, the cop-
per catalyzed carbon-oxygen coupling reaction has been
successfully achieved in the last decades.9
We were interested in the synthesis of functional organoboron
derivatives and their application in the coupling reaction.10 Herein,
we report an efficient two-step one pot synthesis of aryloxyazeti-
dines by the coupling of organoboronic acid with 1-Boc-3-iodoaz-
In the past decades, aryloxyazetidines have been discovered as
privileged motifs in some pharmacological molecules, such as
drugs for the treatment of obesity and metabolic syndrome.1 Thus
the development of an efficient method for the synthesis of
aryloxyazetidine derivatives is necessary, and this research has at-
tracted great interest among chemists.
In general, the synthesis of aryloxyazetidines has been accom-
plished by the following three methods: (1) nucleophilic substitu-
tion of 3-hydroxyazetidines with aryl halides.2 (2) nucleophilic
substitution of 3-iodoazetidines with phenolic compounds3 and
(3) Mitsunobu reaction of 3-hydroxyazetidines with phenolic com-
pounds.4 However, the above mentioned methods have limitations
in some aspects such as: the nucleophilic substitution reactions
usually need a strong base, aryl halides with electron-withdrawing
groups are necessary, and the Mitsunobu condition will produce
equiv of PPh3O which causes pollution to the environment.5 The
preparation of phenols usually requires harsh conditions for non-
activated substrates.6 So the establishment of a mild and efficient
access to aryloxyazetidines is of great significance.
etidine using CuI/L-proline as catalyst system, K3PO4 as base and
DMA as solvent.
Results and discussion
The reaction of phenylboronic acid with 1-Boc-3-iodoazetidine
was chosen as a model reaction to explore the optimized reaction
condition.
Initially, the influence of different protective gases on this reac-
tion was studied by employing CuI/TMEDA(N1,N1,N2,N2-tetra-
methylethane-1,2-diamine) as catalyst system (Table 1). When
the reaction was protected by argon, the yield of target product
was 18% (entry 1). If the reaction proceeded in open air (without
bubbling air), its yield was 30% (entry 2). So the influence of base
and solvent on this reaction was also studied in open air (Table 1).
Among the bases K3PO4, K2CO3, NaOH, Cs2CO3, CsF and KF that
Arylboronic acids are readily available and have found broad
applications in synthetic chemistry.7 It is worth noting that re-
⇑
Corresponding authors. Tel.: +1 732 253 7326; fax: +1 732 253 7327.
E-mail addresses: wyj@zzu.edu.cn (Y. Wu), yusheng.wu@tetranovglobal.com,
yushengwusp@yahoo.com (Y. Wu).
http://dx.doi.org/10.1016/j.tetlet.2014.02.098
0040-4039/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Song, J.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.02.098

2
J. Song et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
lead to slightly lower yields. Next, several copper salts such as
CuCl, CuCl2, CuO, and Cu were investigated for this coupling reac-
Effects of bases and solvents on the cross-coupling of 1-Boc-3-iodoazetidine with
phenylboronic acida
tion under the condition of
L-proline as ligand. As shown in the re-
I
OH
OH
CuI/TMEDA
O
sults given in Table 2, none of these catalysts surpassed CuI (entries
+
B
N
12–15). Thus CuI was chosen as the catalyst and
sen as the ligand.
L-proline was cho-
N
1
Boc
base solvent
120°C 24h
Boc
Finally, the effects of reaction temperature, the equivalent of
phenylboronic acid, and reaction time on the cross-coupling of
1-Boc-3-iodoazetidine with phenylboronic acid were further studied.
Decreasing the reaction temperature from 80 °C to 70 °C or
increasing temperature to 90 °C, the yields were decreased (Table 3,
entry 1–3). Similar results were obtained when 1.5 equiv and
2.0 equiv of phenylboronic acid were used in the reaction (entry
1 vs 4), while the yield of tert-butyl 3-phenoxyazetidine-1-carbox-
ylate was decreased to 45% when 1.2 equiv of phenylboronic acid
was used (entry 5). When the reaction time was shortened to
22 h, the yield was the same as that for 24 h. However, when the
reaction time was shortened to 20 h, the starting material could
not be transformed completely and the yield decreased to 46% (en-
2a
3a
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
K3PO4
K3PO4
K2CO3
NaOH
Cs2CO3
CsF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
18c
30
18
17
22
10
13
34
29
20
27
KF
K3PO4
K3PO4
K3PO4
K3PO4
DMF/H2O (10:1)
DMSO
NMP
10
11
a
Reaction conditions: 1-Boc-3-iodoazetidine (0.5 mmol), PhB(OH)2 (1.0 mmol),
CuI (10 mol %), TMEDA (10 mol %), base (1 mmol), solvent (2 mL), 120 °C, 24 h.
try 7). So, the combination of CuI/L-proline in DMA in the presence
of K3PO4 at 80 °C for 22 h was the optimum condition for this cou-
pling reaction.
b
Isolated yield based on 1.
Ar protected.
c
Under the optimized reaction conditions the scope of phenylbo-
ronic acid derivatives was then explored, and the results were
summarized in Table 4. It could be noted that most reactions pro-
ceeded smoothly to provide the corresponding products in moder-
ate to good yields. Moreover, a wide variety of functional groups
including halide, nitrile, nitro, ester, and ketone were found to tol-
erate this condition. Generally, phenylboronic acids with
electron-withdrawing groups gave better yields than those with
electron-donating groups. Both 4-fluorophenylboronic acid and
3-fluorophenylboronic acid showed good reactivity, providing the
corresponding products in moderate yields. While the reactivity
of 2-fluorophenylboronic acid only provided the corresponding
product in 9% yield. When 2-o-tolylboronic acid was used as the
substrate, tert-butyl 3-(o-tolyloxy)azetidine-1-carboxylate was
isolated in 47% yield. 4-Methylphenylboronic acid showed lower
reactivity and provided tert-butyl 3-(p-tolyloxy)azetidine-1-car-
boxylate in 29% yield.
were used in the reaction, K3PO4 was provided to be the most effi-
cient candidate (entry 2–7). After screening of solvents, it was
found that DMA resulted in a slightly better yield (entry 2, 8–11).
Therefore, K3PO4 was chosen as base and DMA was chosen as sol-
vent in the subsequent studies.
Then, the different ligands were tested by using CuI as a catalyst
(Table 2). It is a pity that all the reactions offered lower yields at
120 °C even though the catalyst was changed to other Cu-sources
such as CuCl2, Cu2O, and CuO. To our delight, when the reaction
temperature reduced to 80 °C, the CuI/L-proline catalyst system
gave 52% isolated yield (entry 5). Similar results were observed
when the ligand was changed to D-proline (entry 6). Other ligands
Table 2
Effects of catalysts and ligands on the cross-coupling of 1-Boc-3-iodoazetidine with
The encouraging results from phenylboronic acid prompted us
to check if the coupling of pyridinyl boronic acids with 1-Boc-3-
iodoazetidine could work at the same catalyst system. As shown
in Table 5, under the optimized reaction conditions, several substi-
tuted pyridinyl boronic acids were successfully transformed to the
desired products. Using (6-ethoxypyridin-3-yl)boronic acid as the
phenylboronic acida
catalyst
ligand(4a-h)
O
I
OH
+
B
N
Boc
N
OH
K3PO4 DMA
air 24h
Boc
1
2a
3a
Entry
Catalyst
Ligandb
Yieldc (%) (120 °C)
Yieldc (%) (80 °C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl2
Cu2O
CuO
CuCl
CuCl2
CuO
Cu
4a
4b
4c
4d
4e
4f
4g
4h
4a
4a
4a
4e
4e
4e
4e
34
35
22
9
36
—
30
—
34
30
26
—
34
43
46
51
52
52
45
47
—
—
—
52
44
8
Table 3
Effects of temperature, the amount of phenylboronic acid, and reaction time on the
cross-coupling of 1-Boc-3-iodoazetidine with phenylboronic acida
CuI/L-proline
I
O
K3PO4
OH
+
B
N
N
1
Boc
OH
DMA temp.
time air
Boc
2a
3a
Entry Temperature
Phenylboronic acid
(equiv)
Time
(h)
Yieldb
(%)
(°C)
—
—
—
1
2
3
4
5
6
7
80
70
90
80
80
80
80
2.0
2.0
2.0
1.5
1.2
1.5
1.5
24
24
24
24
24
22
20
52
45
45
52
45
52
46
32
a
Reaction conditions: 1-Boc-3-iodoazetidine (0.5 mmol), PhB(OH)2 (1.0 mmol),
catalyst (10 mol %), ligand (10 mol %), K3PO4 (1.0 mmol), DMA (2 mL), 120 °C or
80 °C, 24 h.
4a: TMEDA,4b: N1,N1,N2-trimethylethane-1,2-diamine, 4c: N1,N1-dimethyle-
thane-1,2-diamine, 4d: ethane-1,2-diamine, 4e: L-proline, 4f: D-proline, 4g: (1R,2R)-
b
a
Reaction conditions: 1-Boc-3-iodoazetidine (0.5 mmol), PhB(OH)2, catalyst
2-aminocyclohexanol, 4h: cyclohexane-1,2-diamine.
(10 mol %), ligand (10 mol %), K3PO4 (1.0 mmol), and DMA (2 mL).
c
b
Isolated yield based on 1.
Isolated yield based on 1.
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J. Song et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 4
I
O
CuI/L-proline, K3PO4
OH
OH
Synthesis of aryloxyazetidines via coupling of 1-Boc-3-iodoazetidine with phenylbo-
(a)
(b)
+
B
N
N
ronic acidsa,b
N
N
Boc
Boc
°
DMA 80 C air 22h
Boc
Boc
CuI/L-proline
I
52%
O
B(OH)2
K3PO4
R
R
+
N
N
Boc
I
DMA 80°C
22h air
Boc
O
OH
CuI/L-proline, K3PO4
+
1
2a-n
3a-n
O
°
DMA 80 C air 22h
60%
O
O
F
N
N
N
Boc
Boc
Boc
Boc
Boc
F
O
CuI/L-proline, K3PO4
OH
OH
(c)
B
3a, 52%
O
3b, 57%
O
3c, 58%
O
+
N
Boc
N
OH
°
DMA 80 C air 22h
Boc
Br
N
not detected
N
N
Boc
N
Cl
F
3d, 9%
3e, 51%
O
3f, 51%
O
Scheme 1. Exploring the mechanism.
O
NC
O2N
phenol, the yield of target product was 60% (b). While the reaction
of 1-N-Boc-3-hydroxyazetidine with phenylboronic acid lead to a
no target product (c). The pathway of the model reaction may be
N
N
N
Boc
Boc
Boc
Boc
NC
3g, 72%
O
3h, 51%
O
3i, 59%
O
that CuI/L-proline first catalyzed the transformation of phenylbo-
ronic acid to phenol, then catalyzed the C–O coupling of phenol
with 1-N-Boc-3-iodoazetidine.
N
O
Boc
N
Boc
O
O
3j, 70%
O
3k, 67%
O
3l, 29%
Conclusion
N
N
Boc
Boc
O
In conclusion, a novel method for the synthesis of aryloxyazeti-
dine derivatives in moderate to good yields has been developed by
using 1-Boc-3-iodoazetidine and arylboronic acids as substrates,
3m, 47%
3n, trace
a
Reaction conditions: 1-Boc-3-iodoazetidine (0.5 mmol), PhB(OH)2 (1.0 mmol),
catalyst (10 mol %), ligand (10 mol %), K3PO4 (1.0 mmol), DMA (2 mL), 80 °C, 24 h.
very cheap CuI/L-proline as catalyst system, K3PO4 as base, DMA
b
Isolated yield based on 1.
as solvent, at relatively low temperature. And a variety of func-
tional groups (halide, nitrile, nitro, ester, and ketone) are tolerated,
pyridinyl boronic acids are also tolerated in this methodology.
Thereby our method provides a useful tool for the synthesis of aryl-
oxyazetidine derivatives.
Table 5
Synthesis of aryloxyazetidines via coupling of 1-Boc-3-iodoazetidine with pyridinyl
boronic acidsa,b
Acknowledgments
CuI/L-proline
I
K3PO4
R
O
R
B(OH)2
+
N
We are grateful to the Natural Science Foundation of China
(20772114, 21172200), the Innovation Fund for Outstanding Scho-
lar of Henan Province (0621001100) and the Research Program of
Fundamental and Advanced Technology of the Henan Province
(122300413203) for financial support.
N
N
DMA 80°C
22h air
Boc
N
Boc
1
2o-u
3o-u
N
O
O
O
N
N
Boc
N
N
Boc
Boc
References and notes
N
3o, 47%
O
3p, 50%
O
3q, 46%
O
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