Bronsted acid or lewis acid catalyzed [3+3] cycloaddition of azomethine imines with N-benzyl azomethine ylide: A facile access to bicyclic N-heterocycles

Article abstract of DOI:10.1055/s-0035-1560506

1,3-Dipolar cycloaddition reactions are one of the most important methods to obtain diverse heterocycles with novel skeletons. We herein report the Bronsted acid or Lewis acid catalyzed [3+3] cycloaddition of azomethine imines with nonstabilized azomethine ylide generated in situ from an N-benzyl precursor, providing a clean and facile access to diverse bicyclic N-heterocycles in moderate to good yields for further biological testing. Also, the protocol developed achieved the formation of C-C and C-N bonds simultaneously in a single step.

Full text of DOI:10.1055/s-0035-1560506

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 282–286
letter
282
S.-n. Li et al.
Letter
Synlett
Brønsted Acid or Lewis Acid Catalyzed [3+3] Cycloaddition of
Azomethine Imines with N-Benzyl Azomethine Ylide: A Facile
Access to Bicyclic N-Heterocycles
Shuo-ning Lia
Bin Yuc
Jia Liu*a,b
Hong-lian Lia
Risong Na*a,b
O
O
Bn
N
Bn
–
N
N
N
TFA or Zn(OTf)2
R
10 °C, CH2Cl2
N
19 examples
53–82% yield
MeO
TMS
N
R
R = aryl
a Collaborative Innovation Center of Henan Grain Crops, National
Key Laboratory of Wheat and Maize Crop Science, College of
Plant Protection, Henan Agricultural University, Wenhua Road
NO.95, Zhengzhou 450002, P. R. of China
b Modern Experimental Technology Center (Management), Henan
Agricultural University, Wenhua Road NO.95, Zhengzhou
450002, P. R. of China
risongna@163.com
c School of Pharmaceutical Sciences, Zhengzhou University,
Zhengzhou 450001, P. R. of China
Received: 08.08.2015
Accepted after revison: 20.09.2015
Published online: 30.10.2015
ing effective methods to prepare the analogues of these an-
tibiotics. Among them, the intermolecular 1,3-dipolar cyc-
loadditions of azomethine imines have been found to be
highly efficient in constructing structurally novel bicyclic
N-heterocycles.2j Recently, the [3+2],3a–t [3+3],4a–j [4+3],4a,5a,b
[3+2+1],6 and [3+2+3]5a cycloaddition reactions of azome-
thine imines have witnessed rapid development and have
shown their powerfulness in accessing structurally novel N-
heterocycles. N-Benzyl-substituted compound 1 has been
proved to be a useful precursor for generating the azome-
thine ylide 2 in situ and therefore has been widely used for
preparing bioactive pyrrolidine and oxazolidine derivatives
through the [3+2] cycloaddition reactions (Scheme 1).7a–x
However, the efficient constructions of biologically import-
ant bicyclic N-heterocycles through the [3+3] cycloaddition
reactions are relatively rare and have long been highly pur-
sued. Our group and Wang’s group previously reported the
transition-metal-catalyzed [3+3] cycloaddition reactions of
imines and azomethine ylides for the synthesis of new bicy-
clic N-heterocycles with the pyrazolo-triazine framework
(Scheme 1).4e,g In this work, we herein report a new clean
and rapid route for these bicyclic N-heterocycles without
the use of transition metals. It is the first example of Brøn-
sted acid catalyzed [3+3] cycloaddition of azomethine
imines with N-benzyl azomethine ylide. It also provides a
method of transition-metal-catalyzed [3+3] cycloaddition
without the use of P ligand.
DOI: 10.1055/s-0035-1560506; Art ID: st-2015-w0624-l
Abstract 1,3-Dipolar cycloaddition reactions are one of the most im-
portant methods to obtain diverse heterocycles with novel skeletons.
We herein report the Brønsted acid or Lewis acid catalyzed [3+3] cyc-
loaddition of azomethine imines with nonstabilized azomethine ylide
generated in situ from an N-benzyl precursor, providing a clean and fac-
ile access to diverse bicyclic N-heterocycles in moderate to good yields
for further biological testing. Also, the protocol developed achieved the
formation of C–C and C–N bonds simultaneously in a single step.
Key words cycloaddition, bicyclic N-heterocycles, azomethine imines,
N-benzyl azomethine ylide, TFA, Zn(OTf)2
Bicyclic N-heterocycles (highlighted in red in Figure 1)
are valuable building blocks that are utilized in drug discov-
ery and agrochemistry.1 For example, pinoxaden2a is a high-
ly selective systemic herbicide used to control monocotyle-
donous grass weeds in crops. Tetrahydropyrazolo-pyrazolo-
nes2b have been used for the treatment of infections and
Alzheimer’s disease. Pyrazolo-indazolones2c have shown
the anti-inflammatory activity. Cyclic amidoxime deriva-
tives2d are anticoagulants for inhibiting clotting factor Xa
and used for the treatment of thromboembolism. Spiro-
pyrazolidinediones2e were discovered by structure-based
drug design and characterized as potent acetyl-CoA carbox-
ylase (ACC) inhibitors. Cinnopentazone2f has exhibited the
anti-inflammatory and antipyretic activities. Bimane2g–i de-
rivatives are flexible fluorescent molecules and widely used
in fluorescent probes and dyes. Since the discovery of a
class of non-β-lactam antibacterials2j,k such as LY186826,
considerable attention has been directed toward develop-
N-Benzyl-substituted 1 with azomethine imine 3a were
chosen as model substrates to optimize the reaction condi-
tions as shown in Table 1. Initially, the reaction was carried
out in CH2Cl2 at different temperatures in the presence of
catalytic TFA (10%, Table 1, entries 1–4). Evidently, the high-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 282–286

283
S.-n. Li et al.
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Synlett
O
O
O
Et
O
O
O
H
N
R
R
N
N
N
N
R1
R4
N
N
Me
O
N
H
R2
R3
Et
OPiv
R1, R2 = H, alkyl, aryl
pyrazolo-indazolone
pinoxaden
tetrahydropyrazolo-pyrazolone
MeO
O
N
N
N
O
O
N
S
N
O
N
O
N
N
N
HN
O
Et
H
O
N
O
H
cyclic amidoxime
spiro-pyrazolidinedione
Ar
O
OMe
R2
N
O
R1
O
O
N
N
N
N
N
N
HN
EWG
N
R1
R4
n-pentyl
H2N
S
O
EWG
R2
R3
O
R1, R2 = alkyl
antibacterials (LY186826)
R1, R2 = H, alkyl, aryl
bimane
cinnopentazone
Figure 1 Biologically active bicyclic N-heterocycles.
est yield was obtained when the reaction was performed at
10 °C (37%, Table 1, entry 2). Decrease of the temperature to
0 °C gave 21% yield (Table 1, entry 1), which was probably
due to the poor solubility of azomethine imine 3a in CH2Cl2
at 0 °C as observed. When the reaction was performed at
room temperature, the yield was slightly decreased to 33%
(Table 1, entry 3). A relatively messy reaction was observed,
giving product 4a in 29% yield when the reaction was kept
at 40 °C (Table 1, entry 4). It is supposed that the azome-
thine ylide generated in situ was unstable at high tempera-
ture and resulted in unexpected side reactions. Subse-
quently, different reaction solvents were screened, showing
that the reaction can be carried out in CHCl3 and DCE with
comparable yields (Table 1, entries 5 and 6) as that in
CH2Cl2, while the reactions in MeOH and THF did not work
well with very low yields (Table 1, entries 7 and 8). Several
other Brønsted acids were also tested (Table 1, entries 9–
12). Triflic acid can also catalyze the reaction as TFA, gener-
ating the product in 35% yield (Table 1, entry 9), the reac-
tion catalyzed by acetic acid gave the product in 25% yield
(Table 1, entry 10). Reactions catalyzed by HCl and HSbF6
did not give any product (Table 1, entries 11 and 12). The
[3+2] reaction can also be catalyzed by LiF in MeCN, afford-
ing the product in 17% yield (Table 1, entry 13), while KF
failed to catalyze this reaction in DMF even when one
equivalent of catalyst was used (Table 1, entry 14). Addi-
tionally, we found that Lewis acids such as TMSOTf and
metal salts can also catalyze the [3+3] cycloaddition reac-
tions with similar yields (Table 1, entries 16–22). This is a
rare example for N-benzyl azomethine ylide. Very few Lew-
is acids such as ZnCl27a and TiCl47d have previously been re-
ported to be able to catalyze the [3+2] cycloaddition reac-
tions of N-benzyl azomethine ylides. Interestingly, we
found that Zn(OTf)2 gave a relatively higher yield (36%) than
other Lewis acids (Table 1, entry 19). Finally, TFA and
Zn(OTf)2 were used as catalysts for the [3+3] cycloaddition
reactions. The product was finally obtained in 69% and 71%
yields catalyzed by TFA and Zn(OTf)2, respectively when
four equivalents of ylide 1 were used (Table 1, entries 24
and 25). The significant improvement in terms of yields by
improving the amount of ylide was also observed in other
groups.7a,x
previous work of N-benzyl azomethine ylide
Bn
N
Bn
Bn
H+, F–, LA
N
[3+2]
X
MeO
N
TMS
X
2
X = CH2 or O
1
previous work in our group and wang group
O
O
N
N
Ph
P
M
N
N
Ph
Cu+ or Ag+
P
N
O
O
NH
Ph
N
COOMe
[3+3]
P-ligand Ph
OMe
R
COOMe
this work
MeO
O
N
N
N
Bn
N
Ph
Bn
N
H+, F–, Zn2+
N
TMS
N
Bn
[3+3]
R
1
2
clean route without metal salt
diverse catalyst choice: H+, F–, Zn2+
without phosphorus ligand such as PPh3, chiral P-ligand
one-pot reaction
Scheme 1 N-Benzyl azomethine ylide 2 as three-atom synthon in
[3+2] cycloaddition and [3+3] cycloaddition
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Table 1 Optimization for the [3+3] Cycloaddition of N-Benzyl-Substi-
tuted Reagent 1 with Azomethine Imines 3aa
O
O
Bn
N
–
N
TFA or Zn(OTf)2
CH2Cl2, 10 °C
N
N
N
MeO
TMS
O
R
O
N
R
Bn
O
1
3
4
N
Bn
N
N
N
N
MeO
TMS
N
O
O
Bn
Ph
Ph
1
3a
4a
N
N
N
N
N
Me
N
N
N
N
Me
Bn
Bn
Entry
Catalyst
Solvent
Temp (°C) Yield (%)e
Bn
Bn
Bn
O
4a: 71%a
4b: 69%a
4c: 67%a
1
2
TFA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
0
10
25
40
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
21
37
33
29
34
35
0
70%b
66%b
65%b
TFA
O
O
3
TFA
N
N
N
N
N
N
4
TFA
N
N
N
Me
Me
5
TFA
Bn
Bn
4d: 68%a
4e: 64%a
4f: 65%a
6
TFA
Me
t-Bu
67%b
65%b
64%b
7
TFA
MeOH
THF
O
O
O
8
TFA
<5
35
25
0
N
N
9
TfOH
AcOH
HCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
DMF
N
N
N
N
N
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
N
N
MeO
Bn
Bn
4g: 55%a
4i: 60%a
4h: 53%a
MeO
57%b
61%b
55%b
HSbF6
LiFb
0
17
0
O
N
O
N
O
KFb
N
N
N
N
Cl
TBAF
TMSOTf
Zn(OAc)2
AgOAc
Zn(OTf)2
AgOTf
ZnCl2
TiCl4
TFAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
N
N
N
Cl
Bn
Bn
28
27
23
36
27
<5
0
Bn
4j: 74%a
78%b
4k: 72%a
4l: 76%a
Cl
78%b
80%b
O
O
O
N
N
N
N
N
N
F
N
N
N
F
Bn
Bn
Bn
4m: 73%a
4n: 73%a
4o: 75%a
80%b
O
F
82%b
79%b
59
69
71
O
O
TFAd
N
N
N
N
N
N
F
N
d
Zn(OTf)2
N
N
Bn
Bn
Bn
a Unless otherwise indicated, reactions were carried out with 3a (0.2
mmol), 1 (0.3 mmol, 1.5 equiv), catalyst (0.02 mmol, 0.1 equiv) in solvent
(2 mL) for 72 h.
4p: 81%a
85%b
4q: 70%a
4r: 65%a
F
F
O2N
69%b
69%b
b 0.2 mmol (1 equiv) catalyst was used.
c 1 (0.6 mmol, 3 equiv).
O
O
d 1 (0.8 mmol, 4 equiv).
e Isolated yields.
N
N
N
N
N
N
With the optimized conditions in hand, we then ex-
plored the scope of the TFA- and Zn(OTf)2-catalyzed [3+3]
cycloaddition reactions of N-benzyl-substituted 1 by vary-
ing the azomethine imines 3. As shown in Scheme 2,TFA
and Zn(OTf)2 gave moderate and comparable yields for the
cycloaddition reaction regardless of the positions and elec-
tronic properties of substituents on the phenyl ring (4a–s).
However, when the substituent was the hexyl group, no
product was obtained possibly because of the poor stability
Bn
Bn
4s: 69%a
4t: no yieldb
no yieldc
67%b
Scheme 2 Substrate scope of acid-catalyzed [3+3] cycloaddition of N-
benzyl-substituted 1 with azomethine imines 3. Unless otherwise indi-
cated, reactions were carried out with 3 (0.2 mmol), 1 (0.8 mmol, 4
equiv), catalyst (0.02 mmol, 0.1 equiv) in CH2Cl2 (2 mL) for 72 h. a Iso-
lated yields, catalyzed by TFA. b Isolated yields, catalyzed by Zn(OTf)2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 282–286

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of azomethine imine under the acidic conditions (4t). Spe-
cifically, when the groups attached to the phenyl ring were
alkyl groups, the yields of the corresponding products were
slightly lower than that of compound 4a (4b–f).8,9 However,
when the substituents were changed to the strong electron-
rich groups such as the methoxy group (4g–i), The yields
were decreased significantly for both TFA- and Zn(OTf)2-
catalyzed reactions. It is worth noting that when R substit-
uents of aromatic azomethine imines were the electron-de-
ficient groups such as fluorine, chlorine, and nitro groups
(4j–q), the higher yields (70–81% and 69–82%, respectively)
were observed for both catalysts. The cycloaddition reac-
tion can also be extended to substrates with the naphthyl
group in good yields (4r,s).
studies will be focused on exploring new [3+3] cycloaddi-
tion reactions of N-benzyl azomethine ylide with diverse
1,3-dipoles and the asymmetric version.
Acknowledgment
We thank the Special Fund for Agroscientific Research in the Public
Interest (No. 201503112), Science and Technology Planning Project of
Henan Province of China (No. 142102110050), the Educational Com-
mission of Henan Province of China (No. 14A210027), Henan Key Lab-
oratory of the Innovation and Application of Novel Pesticide,
Collaborative Innovation Center of Henan Grain Crops, National Key
Laboratory of Wheat and Maize Crop Science for the financial support
of this study.
To illustrate the protocol developed clearly, we present
here a plausible mechanism for the Brønsted acid or Lewis
acid catalyzed [3+3] cycloaddition of azomethine imines
with nonstabilized azomethine ylide 2 generated in situ
from tert-amine 1 (Scheme 3). Firstly, an iminium ion 6 was
formed from the ylide precursor 1 in the presence of Brøn-
sted acids or Lewis acids by releasing a molecule of MeOH.
Subsequent desilylation gave azomethine ylide 2, which
then reacted with azomethine imine 3a through the 1,3-cy-
cloaddition reaction, affording the corresponding product
4a. Besides, we found that the ylide precursor 1 was com-
pletely consumed and side product 87a was generated. Due
to the high activity of ylide 2, part of ylide 2 was competi-
tively captured by iminium ion 6. In some cases, this com-
petitive side reaction has posed challenges for developing
N-benzyl azomethine ylide based new reactions. Increasing
the amount of N-benzyl-substituted compound 1 has been
proved to be an efficient solution.7x However, better solu-
tions to solve this type of side reactions for these new reac-
tions are still needed.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035- 1560506.
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References and Notes
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O
–
Bn
N
N
N
3a
Ph
Bn
N
Bn
N
H+ or LA
–
OMe TMS
TMS
2
6
1
O
6
Bn
N
Bn
Bn
N
N
N
H2O
TMS
N
Bn
TMS
N
N
H
Bn
8
7
Ph
4a
Scheme 3 Possible reaction pathways and side reaction for the 1,3-di-
polar cycloaddition of N-benzyl azomethine ylide 2 with azomethine
imines 3a
In conclusion, we have documented the first Brønsted
acid or Lewis acid catalyzed [3+3] cycloaddition reactions
between N-benzyl azomethine ylide and azomethine
imines, offering a clean and efficient access to bicyclic
N-heterocycles from readily available starting materials.
This protocol developed may provide a facile access to di-
verse bicyclic N-heterocycles for drug screening. Further
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(4) For some selected examples of [3+3] cycloaddtion, see:
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(8) General Procedure for the [3+3] Annulation Reaction of N-
Benzyl-Substituted Compound 1 and Azomethine Imines 3
To a solution of azomethine imines 3 (0.02 mmol) and N-
benzyl-substituted compound 1 (0.03 mmol, 1.5 equiv) at 0 °C
in CH2Cl2 (2 mL) was added acid catalyst (0.002 mmol, 0.1
equiv), the reaction mixture was stirred in refrigerated preci-
sion water baths at 10 °C for 72 h (depending on TLC monitor),
N-benzyl-substituted compound 1 (0.05 mmol, 2.5 equiv) was
added during this period. After the completion of the reaction,
the reaction mixture was cooled to 0 °C, and was diluted with
sat. NaHCO3 solution. The filtrate was concentrated under
vacuum and purified by flash column (hexane–EtOAc, 1:9) to
give the product 4.
(5) For some selected examples of [4+3] cycloaddtion, see: (a) Na,
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Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Guo, H.; Kwon, O.
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J.; Chi, Y. R. J. Am. Chem. Soc. 2014, 136, 1214.
(6) For selected examples of [3+2+1] cycloaddition, see: Xu, X.; Xu,
X.; Zavalij, P. Y.; Doyle, M. P. Chem. Commun. 2013, 49, 2762.
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(9) Selected Spectral Data for Compound 4a
Yield 71% for TFA-catalyzed reaction [70% yield for Zn(OTf)2-cat-
alyzed reaction]; white solid. 1H NMR (400 MHz, CDCl3): δ =
7.36–7.27 (m, 10 H), 4.91 (d, J = 11.3 Hz, 1 H), 3.78–3.68 (m, 4
H), 3.36–3.25 (m, 1 H), 2.96–2.89 (m, 1 H), 2.84–2.75 (m, 1 H),
2.69–2.60 (m, 2 H), 2.50–2.39 (m, 1 H). 13C NMR (101 MHz,
CDCl3): δ = 170.35, 138.03, 137.03, 129.04, 128.75, 128.52,
128.33, 127.74, 127.52, 66.99, 61.58, 58.68, 57.61, 47.96, 30.09.
IR (film): νmax = 3029, 2924, 2844, 1695, 1602, 1494, 1453,
1410, 1328, 1280, 1129, 1065, 1027, 929, 979, 758, 100, 633,
569, 529, 498, 466 cm–1
19H22N3O+ [M + H]+: 308.1757; found: 308.1763.
. HRMS (MALDI): m/z calcd for
C
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 282–286