A facile method for the synthesis of dihydroquinoline-Azide from the Lewis acid-catalyzed reaction of alkylidenecyclopropanes with TMSN3

Article abstract of DOI:10.1039/c9ob02309g

A facile synthetic method for the formation of dihydroquinoline-Azide from alkylidenecyclopropanes and TMSN₃ under the catalysis of a Lewis acid has been developed, and a number of azide-containing compounds can be instantly accessed in moderate to good yields. A click reaction with these azido compounds was also realized along with a mechanistic investigation.

Full text of DOI:10.1039/c9ob02309g

Organic &
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A facile method for the synthesis of
dihydroquinoline-azide from the
Lewis acid-catalyzed reaction of
alkylidenecyclopropanes with TMSN3†
Cite this: Org. Biomol. Chem., 2019,
17, 9990
Received 25th October 2019,
Accepted 11th November 2019
DOI: 10.1039/c9ob02309g
Mintao Chen, Yin Wei * and Min Shi
*
rsc.li/obc
A facile synthetic method for the formation of dihydroquinoline- the applications of ACPs in organic transformations.7
azide from alkylidenecyclopropanes and TMSN3 under the catalysis Considering the importance of azide compounds in click reac-
of a Lewis acid has been developed, and a number of azide-con- tions, we decided to explore the possibility of synthesizing
taining compounds can be instantly accessed in moderate to good valuable azide compounds from ACPs. It is well known that in
yields. A click reaction with these azido compounds was also rea- the presence of a Lewis acid, ACPs together with nucleophiles
lized along with a mechanistic investigation.
could efficiently produce a variety of homoallylic compounds
in good yields under mild conditions (Scheme 2a).8 Moreover,
an iminium species could be in situ generated from nucleophi-
lic enamines upon treatment with Lewis acid (Scheme 2b).9
Thus, we envisaged that it might be possible to afford azide
products through a Lewis acid catalyzed cascade reaction of
enamine-ACPs with stable and safe azide reagents such as
TMSN3 under simple operation (Scheme 2c).
We first investigated the reaction of ACP 1a and TMSN3
under the catalysis of Fe(OTf)3 (20 mol%) in 1,2-dichloro-
ethane (DCE) at 80 °C for about 7 h, and found that the
desired azide product 2a was successfully obtained in a yield
of 51% (Scheme 3). The structure of 2a was confirmed by X-ray
crystal diffraction. Its ORTEP drawing is shown in Fig. 1 and
the CIF data are presented in the ESI.†
Click reactions are well known for their high efficiency in the
synthesis of a vast variety of compounds.1 Copper(I)-catalyzed
azide–alkyne cycloaddition (CuAAC) for triazole synthesis is
one of click reactions and has been widely applied in material
synthesis,2 drug development3 and biochemistry4 (Scheme 1).
Currently, the development of a more feasible and efficient
method to prepare various azide compounds has been an
urgent task for chemists.5
Alkylidenecyclopropanes (ACPs) are important building
blocks in organic synthesis due to their diverse reactivities.6
Our group and others have continuously made efforts to study
Encouraged by this finding, we attempted to investigate the
relevant factors involved which would affect the reaction out-
comes of 1a and TMSN3. To establish the optimal conditions
Scheme 1 Applications of the CuAAC reaction in materials science and
drug chemistry.
State Key Laboratory of Organometallic Chemistry, Center for Excellence in
Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. E-mail: weiyin@sioc.ac.cn, mshi@mail.sioc.ac.cn
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of new compounds. CCDC 1584465. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c9ob02309g
Scheme 2 Our proposal for the Lewis acid catalyzed synthesis of azide
compounds through a cascade reaction of ACPs.
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Table 2 Optimization of the reaction conditions
3 ðx mol%Þ;TMSN3
1a InðOꢀTꢀfÞꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ!
ðy equiv:Þ 2a
DCE;60 °C
In(OTf)3
(x/mol%)
TMSN3
(y/equiv.)
T
(°C)
Time
(h)
Entrya
Solvent
Yieldb/%
1
2
3
4
5
6
10
30
20
20
20
20
2.0
2.0
1.0
2.0
3.0
4.0
DCE
DCE
DCE
DCE
DCE
DCE
60
60
60
60
60
60
7
2
2
2
0.5
0.25
40
65
55
79
85
84
Scheme 3 A first examination on the reaction of 1a with TMSN3.
a Reaction conditions: 1a (0.2 mmol), TMSN3 (y mmol), and In(OTf)3
(x mol%) were placed in a flask and 2 mL DCE was added. Then the
mixture was stirred at 60 °C. b Isolated yields.
entries 8, 10 and 11), while THF would suppress the reaction
completely without the formation of product 2a (Table 1, entry
9). On the basis of these examinations, DCE was the most suit-
able solvent in this reaction. We also adjusted the reaction
temperature using In(OTf)3 as the catalyst in DCE and deter-
mined that carrying out the reaction at 60 °C afforded 2a in an
isolated yield of 79% within 2 h (Table 1, entries 12–14).
To further optimize the reaction conditions, we screened
the loading amounts of In(OTf)3 and TMSN3 in this reaction
(Table 2). On using 10 mol% of Lewis acid the yield of 2a
decreased to 40% (Table 2, entry 1), but on increasing the con-
centration of Lewis acid to 30 mol% the yield of 2a also
decreased presumably due to the decomposition of 1a in the
presence of excess amounts of Lewis acid (Table 2, entry 2). We
also screened the amount of TMSN3 in this reaction, and it
was revealed that when the dosage of TMSN3 was reduced to
1.0 equiv., the yield of 2a decreased to 55% (Table 2, entry 3)
and when the dosage was increased to 3.0 equiv., the yield of
2a could be increased to 85% along with the reaction time
being reduced to 0.5 h (Table 2, entry 5). Further increasing
the dosage of TMSN3 to 4.0 equiv. did not improve the yield of
2a after the reaction was performed for 0.25 h (Table 2, entry
6). Thus, we have found the optimal conditions under which
the corresponding azide compound 2a could be obtained in
the highest yield (Table 2, entry 5).
Fig. 1 The X-ray crystal structure of 2a.
Table 1 Optimization of the reaction conditions
1a catalyst ð20 mol%Þ;TMSN
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ!
ð2:0 equiv:Þ 2a
3
Solvent;T;time
Entrya
Catalyst
Solvent
T (°C)
Time (h)
Yieldb/%
1
2
3
4
5
6
7
8
Eu(OTf)3
La(OTf)3
Ce(OTf)3
In(OTf)3
Sc(OTf)3
AgSbF6
Yb(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
THF
Toluene
CH3CN
DCE
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
60
40
20
5
5
5
1
5
7
5
7
7
7
7
2
7
NR
NR
NR
76 (68)c
50
60
23
39
ND
50
9
10
11
12
13
14
43
89 (79)c
45
24
30
a Reaction conditions: 1a (0.2 mmol), TMSN3 (0.4 mmol), and catalyst
(20 mol%) were placed in a flask and 2 mL solvent was added. Then
the mixture was stirred at different temperatures. b Determined by 1H
NMR spectroscopy, with 1,3,5-trimethoxybenzene as an internal stan-
dard. c Isolated yields.
With the optimal conditions in hand, we next examined the
substrate scope and the results are shown in Scheme 4. For
for the reaction, different Lewis acids, solvents, temperatures halogen atom substituted substrates 1b–1f, the reactions were
and reaction times were tested, and the results are shown in compatible, affording the desired products 2b–2f in moderate
Table 1.
to good yields ranging from 54%–70%. In the case of fluorine
Firstly, we screened several Lewis acids in this reaction and atom including substrate 1d, the corresponding product 2d
revealed that Eu(OTf)3, La(OTf)3 and Ce(OTf)3 (20 mol%) was formed in a moderate yield (54%). Introduction of an alkyl
could not catalyze the reaction under identical conditions group such as the methyl, isopropyl or tert-butyl group into the
(Table 1, entries 1–3), but In(OTf)3 enhanced the yield of 2a to benzene ring of substrates 1 could afford the desired products
76% within 1 h (Table 1, entry 4). Furthermore, Sc(OTf)3, 2g–2j in good yields ranging from 70%–80%. In addition,
AgSbF6 and Yb(OTf)3 could also catalyze the reaction, giving methoxyl group and phenyl group substituted substrates 1k, 1l
2a in moderate yields ranging from 20%–60% (Table 1, entries and 1m were also tolerated, giving the azide products 2k–2m
5–7). Therefore, In(OTf)3 was identified as the most efficient in 63%–68% yields. All these results suggested that the substi-
Lewis acid in this transformation. Then, we examined different tuent on the benzene ring of 1 did not have a significant influ-
solvents other than DCE and found that CHCl3, toluene and ence on the transformation. Furthermore, when R1 was a
acetonitrile could all afford 2a in moderate yields (Table 1, methyl, a thienyl or a naphthyl group, the corresponding pro-
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Scheme 6 Application of 2a in the CuAAC reaction.
Scheme 7 Deuteration labeling experiment.
a
Scheme 4 Screening of the substrate scope. Reaction conditions: 1a
(0.2 mmol), TMSN3 (0.6 mmol), and In(OTf)3 (20 mmol%) were placed in
a flask and 2 mL DCE was added. Then the mixture was stirred at 60 °C
within 30 min. b Isolated yields.
Scheme 8 The plausible mechanism for the cascade azidation
reaction.
the reaction system was conducted to identify the source of the
hydrogen atom (Scheme 7). We found that 2a was afforded in
60% yield along with 30% deuterium incorporation ([D]-2a),
suggesting that the extra hydrogen atom was derived from the
ambient proton source (see the ESI† for more details). On the
Scheme 5 Conformational analysis of substrate 1.
basis of these experimental results and previous reports,10
a
ducts 2n (75%), 2o (60%) and 2p (55%) could also be obtained
successfully, demonstrating a broad substrate scope for this
reaction. However, for substrate 1q, in which R1 was a hydro-
gen atom, a decomposed product 2q was formed in 50% yield.
To explain this observation, the conformation of substrate 1
was analyzed. As shown in Scheme 5, when R1 was not a hydro-
gen atom, the sterically large R1 substituent forced the methyl-
enecyclopropane moiety in substrate 1 to approach the in situ
formed electrophilic center (Scheme 2c), triggering the
cascade reaction. However, when R1 was a hydrogen atom, the
conformation did not facilitate electrophilic cyclization,
leading to its decomposition.
plausible mechanism is outlined in Scheme 8. Firstly, In(OTf)3
activated the enamine moiety of 1 to give a highly electrophilic
iminium intermediate A, which gave intermediate B through
aza-Prins cyclization. Then intermediate B underwent a cyclo-
propane ring-opening process via the nucleophilic attack of
TMSN3 to afford the desired product 2.
In summary, we have developed a facile and highly efficient
method for the rapid synthesis of azide products through a
In(OTf)3-catalyzed cascade reaction of ACPs with TMSN3 under
mild conditions. A preliminary investigation on the mecha-
nism revealed a plausible reaction pathway for this cascade
azidation process. Further application of this new azidation
method is under investigation in our lab.
The CuAAC reaction of 2a with phenylacetylene under the
catalysis of CuTc (copper(I)thiophene-2-carboxylate) was then
performed, delivering the corresponding triazole compound
3a in a yield of 90% (Scheme 6).
Conflicts of interest
To gain more insights into this cascade azidation reaction
mechanism, an isotopic labeling experiment by adding D2O to There are no conflicts of interest to declare.
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Acknowledgements
We are grateful for the financial support from the National
Basic Research Program of China [(973)-2015CB856603], the
Strategic Priority Research Program of the Chinese Academy
of Sciences (Grant No. XDB20000000) and sioczz201808, and
the National Natural Science Foundation of China (21372241,
21572052, 21421091, 21372250, 21121062, 21302203, 21772037,
21772226 and 21861132014).
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