Copper-Catalyzed Tandem Cross-Coupling/[2 + 2] Cycloaddition of 1,6-Allenynes with Diazo Compounds to 3-Azabicyclo[5.2.0] Ring Systems

Article abstract of DOI:10.1021/acs.orglett.9b03727

An unprecedented copper-catalyzed tandem cross-coupling/[2 + 2] cycloaddition of 1,6-allenynes with diazo compounds was reported, chemo- and regioselectively providing 3-azabicyclo[5.2.0] frameworks in moderate to excellent yields under mild reaction conditions. Moreover, the products readily convert to highly functionalized quinolines via oxidative radical rearrangement.

Full text of DOI:10.1021/acs.orglett.9b03727

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Tandem Cross-Coupling/[2 + 2] Cycloaddition of
1,6-Allenynes with Diazo Compounds to 3‑Azabicyclo[5.2.0] Ring
Systems
Min He,†,§ Nuan Chen,†,§ Ting Zhou,† Qing Li,† Hongguang Li,† Ming Lang,† Jian Wang,†,‡
and Shiyong Peng*,†
†School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, P. R. China
‡School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of
Education), Tsinghua University, Beijing, 100084, P. R. China
S
* Supporting Information
ABSTRACT: An unprecedented copper-catalyzed tandem cross-coupling/[2 + 2] cycloaddition of 1,6-allenynes with diazo
compounds was reported, chemo- and regioselectively providing 3-azabicyclo[5.2.0] frameworks in moderate to excellent yields
under mild reaction conditions. Moreover, the products readily convert to highly functionalized quinolines via oxidative radical
rearrangement.
ransition-metal-catalyzed intermolecular reactions of
different diazo compounds (or their precursor N-
Scheme 1. Previous Reports and Our Proposal
T
tosylhydrazones) with functionalized substrates are powerful
tools for the creation of chemical diversity and new chemical
entities in organic synthesis.1 Particularly, the copper-catalyzed
reaction of diazo compounds generates a copper-carbene
intermediate that undergoes diverse transformations, and the
breakthrough has been made in allene synthesis by copper-
catalyzed carbene cross-coupling with terminal alkynes.2−4
Moreover, the copper-catalyzed cross-coupling reaction of
diazo compounds with terminal alkynes generates allene
intermediates and offers opportunities for further intra-
molecular cyclization to afford cyclic scaffolds.5−7 In 2011,
Wang and co-workers reported a copper-catalyzed tandem
reaction of N-tosylhydrazones with terminal alkynes to prepare
2-alkylated indoles and benzofurans, in which the formation of
the allene intermediate was considered to be the key step
(Scheme 1a).5 In 2015, Sun and co-workers employed this
strategy to synthesize five-membered N-heterocycles via a
tandem reaction of copper-catalyzed allenoate formation
followed by an intramolecular Michael addition (Scheme
1b).6a Following this seminal work, Sun and co-workers
reported a series of copper-catalyzed tandem annulations of
diazo compounds with terminal alkynes to prepare different
four- to seven-membered ring systems.6b−g
Since Malacria’s seminal work on the cobalt-catalyzed
cycloisomerization of allenynes,8 a variety of metals have
been reported to catalyze the cyclization of allenynes.9
Allenynes were found to possess diverse reactivities and have
been utilized in various transition-metal-catalyzed cyclization
reactions for the rapid assembly of complex polycyclic
skeletons from simple linear substrates with atom economy.
Received: October 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03727
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Organic Letters
Letter
a
However, the use of copper in catalytic reaction of allenynes is
quite rare.10 On the other hand, the development of bisallene
chemistry is far behind compared to the advances of allenyne
chemistry, presumably because of their high instability and
difficulty of synthesis.11 Thus, we propose that the copper-
catalyzed reaction of allenynes bearing a terminal triple bond
with diazo compounds could possibly form an in situ bisallene
intermediate and then undergo an intramolecular [2 + 2]
cycloaddition to form cyclobutane skeletons through the
common metallacyclic or radical pathway (Scheme 1c).11a,12 In
this proposal, the control of chemo- and regioselectivity (head-
to-head, tail-to-tail, head-to-tail) would be a formidable
challenge (Scheme 1d).
Based on the hypothesis and in continuation with our
interest in diazo carbene chemistry for developing novel
methodologies on polycyclic skeleton synthesis,13 we initially
tested the copper-catalyzed reactions of different readily
available allenynes 1a−5a with donor−acceptor diazo
compound 6a. To our delight, a bicyclo[5.2.0] structure 7aa
was chemo- and regioselectively obtained as the single product
when 1,6-allenyne 5a was used in the presence of a catalytic
amount of CuCl (Scheme 2). The structure of 7aa was
unambiguously confirmed by X-ray diffraction analysis (CCDC
1956559; Figure 1). Herein, we report our preliminary
results.14
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
−
CuI
CuOTf
CuCl
CuBr
Cu(PPh3)3Br
FeCl3
CoCl2
NiCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
−
−
−
50
71
88
−
−
−
−
−
−
65
−
−
−
cd
,
Ph3PAuCl
Rh2(esp)2
PtCl2
c
c
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
Cu(PPh3)3Br
MeCN
toluene
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
e
<10
63
70
−
f
cg
,
Scheme 2. Initial Try
19
20
h
a
Reaction conditions: 5a (0.2 mmol), 6a (0.4 mmol), catalyst (10
mol %), CH2Cl2 (3.0 mL), 12 h, rt. Isolated yields. Catalyst (5 mol
%). NaBArF (5 mol %). At 0 °C. At 60 °C. 24 h. Cs2CO3 (1.0
b
c
d
e
f
g
h
equiv).
reaction (entries 7−12). Next, different solvents were
screened. CH2Cl2 was the best choice, and the alternative
1,2-dichloroethane (DCE) gave a moderate yield, whereas
other solvents such as acetonitrile (MeCN), toluene, and 1,4-
dioxane were not suitable for the reaction (entries 13−16).
Moreover, the reaction was sluggish under low temperature
(entry 17), while high temperature led to a lower yield due to
product decomposition (entry 18). A decrease of the catalyst
loading for the reaction gave product 7aa in 70% yield with a
longer reaction time (entry 19). Notably, base was detrimental
to the reaction. When 1 equiv of Cs2CO3 was added, no
product was obtained (entry 20).
With the optimal reaction conditions in hand, we next set
out to investigate the scope of diazo compounds (Scheme 3).
Varying the ester group of diazo compounds did not decrease
the yield of the reaction (7aa−ac). Moreover, even the bulky
tert-butyl or active allyl group did not inhibit the reaction
(7ad−ae). Then, the reaction of 1,6-allenyne 5a with different
substituted aryl diazoacetates bearing electron-donating or
electron-withdrawing substituents at the aryl moiety all
proceeded smoothly to afford the desired products in
moderate to excellent yields (7af−as). Additionally, different
disubstituted phenyl diazoacetates, bulky naphthyl diazoace-
tate, and benzofuran-derived diazoacetate were also well
tolerated for the reaction (7at−ax). However, the target
product 7ay was not obtained from the reaction with
thiophene-derived diazoacetate under standard reaction
conditions. Gram-scale synthesis was examined under standard
reaction conditions and gave product 7aa in 79% yield. The
Figure 1. X-ray structure of 7aa.
We first utilized 1,6-allenyne 5a and phenyl diazoacetate 6a
as model substrates to screen the reaction conditions (Table
1). The reaction was highly dependent upon the catalyst, the
reaction medium, and the reaction temperature. When the
reaction was performed in methylene dichloride (CH2Cl2) at
room temperature without catalyst, the reaction did not occur
(entry 1). Then various copper catalysts were examined. The
reaction did not work with CuI or CuOTf as catalyst (entries
2−3). Gratifyingly, CuCl and CuBr gave product 7aa in 50%
and 71% yields respectively (entries 4−5). The yield was
further increased to 88% when Cu(PPh3)3Br was employed as
catalyst (entry 6). Other metals were totally inert for the
B
DOI: 10.1021/acs.orglett.9b03727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
a b
,
Scheme 3. Scope of Diazo Substrates
Scheme 4. Scope of 1,6-Allenyne Substrates
a
Reaction conditions: 5 (0.2 mmol), 6a (0.4 mmol), Cu(PPh3)3Br
b
(10 mol %), CH2Cl2 (3.0 mL), 12 h, rt. Isolated yields.
Scheme 5. Radical Inhibition Experiments
a
Reaction conditions: 5a (0.2 mmol), 6 (0.4 mmol), Cu(PPh3)3Br
b
c
(10 mol %), CH2Cl2 (3.0 mL), 12 h, rt. Isolated yields. Gram-scale
(5 mmol).
structure of 7ao was confirmed by X-ray diffraction analysis
(CCDC 1960368).
Next, various substituted 1,6-allenynes were subjected to this
reaction (Scheme 4). First, changing the R1 substitution of 1,6-
allenynes from the p-toluenesulfonyl group (Ts) to other
sulfonyl groups had little influence on the reaction and all
proceeded well to give the corresponding products in
moderate to excellent yields (7ba−ea). Then, the reaction of
phenyl diazoacetate 6a with different substituted 1,6-allenynes
bearing electron-donating or electron-withdrawing substituents
at the 4- or 5-position of the aryl moiety all proceeded
smoothly to provide the desired products in good to excellent
yields (7fa−pa). However, substitution on the 3- or 6-position
of the aryl moiety largely reduced the reaction efficiency (7qa−
ra). Furthermore, different disubstituted 1,6-allenynes on the
aromatic ring linker of 1,6-allenynes were well tolerated for the
reaction (7sa−ua). Gratifyingly, 1,6-allenyne 5v (R2 = Me)
furnished the desired product 7va in 68% yield. Unfortunately,
pyridine-derived 1,6-allenyne was not suitable for the reaction
(7wa).
Although it is premature to discuss the mechanistic details, a
tentative mechanistic proposal is depicted in Scheme 6. The
reaction of 1,6-allenyne 5a with phenyl diazoacetate 6a in the
presence of a copper catalyst generates the copper-carbene
intermediate A. Migratory insertion of the carbenic carbon to
the alkynyl group affords alkyne intermediate B, which was
followed by protonation and demetalation to afford bisallene
intermediate C. The reaction of bisallene C with a copper
species would regioselectively produce the cupracyclopentane
intermediate D by the regioselective coordination of bisallene
C followed by C−C bond formation,15 and cupracycle
intermediate D would undergo quick reductive elimination
to give cyclobutane product 7aa. The observed high
regioselectivity of the reaction could be explained in terms of
the regioselective formation of metallacycle D, which would be
controlled by the electronic and steric effects of the
substitution patterns of bisallene C. Diradical intermediates E
and F were excluded by radical inhibition experiments
(Scheme 5).
To further understand the cycloaddition process, radical
inhibition experiments were conducted (Scheme 5). When a
radical inhibitor (BHT or TEMPO) was present, the reaction
went smoothly to give the desired product 7aa in good yield
(Scheme 5). This result indicated that the reaction did not
proceed via a radical mechanism.
The versatility of this copper-catalyzed cross-couping/[2 +
2] cycloaddition reaction can be further exploited in
chemoselective transformations to access various quinoline
C
DOI: 10.1021/acs.orglett.9b03727
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Organic Letters
Letter
structures attractive for medicinal chemistry. Further studies
will be reported in due course.
Scheme 6. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03727.
Experimental procedures along with characterizing data
and copies of NMR spectra (PDF)
Accession Codes
CCDC 1956559, 1956565, and 1960368 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
derivatives with high degrees of molecular complexity. As
outlined in Scheme 7, the products 7 smoothly transformed to
*E-mail: psy880124@mail.nankai.edu.cn; a0068248@u.nus.
edu.
a b
,
ORCID
Scheme 7. Transformation of Products
Hongguang Li: 0000-0002-6579-7300
Jian Wang: 0000-0002-3298-6367
Shiyong Peng: 0000-0002-2387-5868
Author Contributions
§M.H. and N.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of Guangdong
Province (No. 2018A030310680), the Research Foundation of
Department of Education of Guangdong Province (No.
2017KQNCX204, 2018KTSCX236), and the Science Founda-
tion for Young Teachers of Wuyi University (No. 2019td09)
for their financial support.
a
Reaction conditions: 7 (0.1 mmol), toluene (2.0 mL), 12 h, 80 °C,
b
c
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■
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