Visible-Light-Induced Intermolecular Dearomative Cyclization of 2-Bromo-1,3-dicarbonyl Compounds and Alkynes: Synthesis of Spiro[4.5]deca-1,6,9-trien-8-ones

Article abstract of DOI:10.1021/acs.orglett.8b02463

A visible-light-induced photocatalytic intermolecular dearomative cyclization of 2-bromo-1,3-dicarbonyl compounds and alkynes afforded biologically important spirocarbocycle structures in moderate to good yields via a 5-exo-dig radical cyclization under mild reaction conditions. A 5.0 mmol scale dearomatization reaction proceeded smoothly with 95% yield even when the catalyst loading was reduced to 0.1 mol %, suggesting that this method was suitable for large-scale synthesis.

Full text of DOI:10.1021/acs.orglett.8b02463

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced Intermolecular Dearomative Cyclization of
2‑Bromo-1,3-dicarbonyl Compounds and Alkynes: Synthesis of
Spiro[4.5]deca-1,6,9-trien-8-ones
Wuheng Dong,† Yao Yuan,† Xiaoshuang Gao,† Miladili Keranmu,† Wanfang Li,† Xiaomin Xie,†
and Zhaoguo Zhang*,†,‡
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai
Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A visible-light-induced photocatalytic intermolecular
dearomative cyclization of 2-bromo-1,3-dicarbonyl compounds and
alkynes afforded biologically important spirocarbocycle structures in
moderate to good yields via a 5-exo-dig radical cyclization under
mild reaction conditions. A 5.0 mmol scale dearomatization
reaction proceeded smoothly with 95% yield even when the
catalyst loading was reduced to 0.1 mol %, suggesting that this
method was suitable for large-scale synthesis.
Scheme 1. Visible Light-Induced Radical Cyclization of
Alkynes and 2-Bromo-1,3-dicarbonyl Compounds
piro[4,5]decane systems are biologically significant struc-
Stures, which occur in many biologically active molecules and
natural products, such as cDHAs (4′,5-dihydroxy-6′-methoxy-2-
methylspiro[cyclohexane-1,1′-indene]-2,5-diene-3′,4(2’′H)-
dione), DHAs (4′,5-dihydroxy-6′-methoxy-2-methyl-3′H-spiro-
[cyclohexane-1,1′-isobenzofuran]-2,5-diene-3′,4-dione), schi-
zandrinone, cannabispiradienone, isocannabispiradienone, and
carijodienone (Figure 1).1 For example, schizandrinone is a
potential anticancer agent, which has been used for the
treatment of cervical, lung, and breast cancer.1a Carijodienone,
isolated from the Pacific octocoral Carijoa multiflora, shows
remarkable antibacterial activity.1b Owing to their versatile
biological properties and the synthetic challenges with these
sterically hindered spiro[4,5]decane substructures, simple and
efficient building-up of these scaffolds is of great importance to
chemists. Dearomatization reactions rank among the most
powerful and promising organic transformations, which render a
rapid construction of spiro[4,5]decane systems from readily
available phenols and their derivatives.2 In recent decades, acid3-
and transition-metal-catalyzed dearomative cyclization has been
explored intensively and gained outstanding achievements,
especially for transition-metal-catalyzed asymmetric dearomati-
zation reactions.4 In addition, radical cyclization approaches to
Figure 1. Bioactive or natural compounds bearing spiro[4,5]decane
systems.
Received: August 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope of 2-Bromo-carbonyl Compounds
b
entry
photocatalyst
fac-Ir(ppy)3
Ru(bpy)3Cl2.6H2O
EosinY
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
base
solvent
yield (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
MeOH
DMF
DMA
DMA
DMA
34
0
0
Na2CO3
K2CO3
Li2CO3
iPr2NEt
DBU
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
66
58
52
51
trace
53
63
71
9
10
11
12
c
99 (98 )
d
13
e
0
0
14
fac-Ir(ppy)3
a
Conditions: 1a (30.6 mg, 0.3 mmol), 2a (215.5 mg, 0.6 mmol),
photocatalyst (1 mol %), base (0.36 mmol), solvent (3 mL),
b
irradiation with a 7 W blue LED at rt for 12 h. 1H NMR yield was
c
reported using benzyl ether as an internal standard. Isolated yield.
d
e
Without photocatalyst. Reaction was carried out in the dark.
a
Scheme 2. Substrate Scope of Alkynes
a
Conditions: 1a (0.3 mmol), 2 (215.5 mg, 0.6 mmol), fac-Ir(ppy)3
(4.2 mg, 1 mol %), Na2CO3 (38.2 mg, 0.36 mmol), DMA (3 mL),
irradiation with 7 W blue LED at rt for 12 h; isolated yields were
given.
Scheme 3. Synthesis of 3aa on Gram-Scale
these spiro-scaffolds have also been reported by several groups.5
For example, Santi and co-workers disclosed an oxidative
cyclization between substituted diethyl benzyl malonates and
alkynes for the synthesis of spiro[4,5]decatriene derivatives by
using stoichiometric amounts of Mn(OAc)3.5c Thus, far, there
still an ongoing research interest in developing simple, mild, and
efficient methodology for the construction of these biologically
relevant spirocarbocycles.
a
Conditions: 1 (0.3 mmol), 2a (215.5 mg, 0.6 mmol), fac-Ir(ppy)3
(4.2 mg, 1 mol %), Na2CO3 (38.2 mg, 0.36 mmol), DMA (3 mL),
irradiation with 7 W blue LED at rt for 12 h; isolated yields were
given. 1/2a = 5:1.
b
The development of C−C bond formation via visible-light-
promoted photoredox catalysis has recently received much
attention owing to its inherent green and sustainable features.6
B
DOI: 10.1021/acs.orglett.8b02463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the benzene ring showed that the electronic nature of the
substituents has hardly any effect on chemical yields, affording
the corresponding spiro[4.5]deca-1,6,9-trien-8-ones in gener-
ally high yields (Scheme 2, 3aa−3ja). As expected, the
substituents at meta- or ortho-position for the phenyl ring also
worked well; 3ka−3ma were obtained in approximately
quantitative yields. In addition, linear and functionalized
aliphatic alkynes were also compatible with the reaction and
moderate yields of the corresponding products were obtained
(Scheme 2, 3na−3pa). It is noteworthy that methyl
propargylate and propiolophenone witnessed a reversed
regioselectivity (3oa and 3pa) wherein the carbonyl groups
end up in the β-position of the newly formed spirocarbon
centers. Gratifyingly, sterically hindered TMS-acetylene was also
amenable to this reaction albeit in lower yield (3qa, 46%).
Internal alkynes were also applicable in this dearomative
cyclization. For example, 1-phenylpropyne (1r) and methyl
phenylpropiolate (1s) participated in this transformation to give
the desired product 3ra and 3sa in 44% and 42% yield,
respectively. Unfortunately, diphenyl acetylene and dimethyl
acetylenedicarboxylate showed no reactivity in this reaction, and
the starting materials were fully recovered. Finally, a variety of
heteroaryl acetylenes containing the thiophene and pyridine
rings were all compatible with the transformation (3ta−3va).
To further diversify the protocol, different 2-bromo-1,3-
dicarbonyl compounds 2 were screened in the annulation with
phenyl acetylene (1a) (Table 2). As expected, when the phenol
hydroxyl was protected with benzyl or TBDMS (tert-
butyldimethylsilanoxy) group, the dearomatization reaction
still proceeded, and good yields were also obtained (Table 2,
entries 1 and 2). Under the optimal conditions, 2d proved to be
a viable substrate to give product 3ad in moderate yield. It is
noteworthy that secondary bromide 2e could also successfully
afford the desired product in 58% yield (3ae). In the case of 3,4-
dimethoxy substituted α-bromomalonate (2f), the target
product 3af was obtained in a good yield of 85%. Notably, a
bromo substituent on the phenyl ring was sustained under the
reaction conditions, and the desired product 3ag was isolated in
60% yield. Moreover, the substrate with a naphthalene ring
yielded the corresponding product in 83% yield (Table 2, entry
7).
Scheme 4. Proposed Mechanism for the Catalysis
Numerous efforts have been devoted to the synthesis of complex
compounds through this powerful tool. Specifically, the
reactions between α-carbonyl alkyl radicals and double or triple
C−C bonds, including inter- and intramolecular additions, have
been widely explored by many groups.7 Recently, Yu developed
an efficient coupling of alkynes and 2-bromo-1,3-dicarbonyl
compounds for the synthesis of functionalized naphthols and
furans by using photoredox catalyst (Scheme 1a).8 A similar
Ir(III)-catalyzed formal [4 + 2] cycloaddition of indole-derived
bromides and alkynes to synthesize carbazoles was reported by
Xiao and co-workers (Scheme 1b).9 Our group has recently
developed a photocatalytic dearomative cyclization of α-bromo-
N-benzyl-alkylamide for the efficient preparation of 2-
azaspiro[4.5]decanes.10 Herein, we describe an efficient and
regioselective formation of interesting spirocarbocycle via visible
light-induced intermolecular dearomative reaction between 2-
bromo-1,3-dicarbonyl compounds and alkynes (Scheme 1c).
To initiate our study, ethynylbenzene (1a) and 2-bromo-2-(4-
methoxybenzyl)malonate (2a) were chosen as model substrates
to examine the dearomatization reaction. Fortunately, a 34%
yield of the desired spiro[4,5]decane compound (3aa) was
obtained when using 1 mol % of fac-Ir(ppy)3 as the
photocatalyst in CH3CN at room temperature (Table 1, entry
1). Other types of photocatalyst like Ru(bpy)3Cl2·6H2O or
EosinY proved to be futile because no desired products were
detected (Table 1, entries 2 and 3). To drive the dearomative
cyclization to complete, external base is required to neutralize
the hydrobromic acid generated thereof. When Na2CO3 was
added, the yield was significantly increased to 66% (Table 1,
entry 4). Encouraged by this result, various bases were examined
(Table 1, entries 5−8). Inorganic bases, such as K2CO3 and
Li2CO3, resulted in moderate conversions. Organic bases such as
iPr2NEt and DBU led to even much lower yields. Considering
the different solubility of inorganic bases in varies organic
solvent, we next examined different solvents (Table 1, entries 9−
12). To our delight, the isolated yield was remarkably increased
to 98% when DMA was used as solvent (Table 1, entry 12).
Finally, control experiments showed that both photocatalyst and
irradiation were essential, and no reaction occurred if photo-
catalyst or visible light irradiation was omitted (Table 1, entries
13 and 14).
To further demonstrate the synthetic potential of this
synthetic method, a gram-scale reaction with 1a and 2a was
carried out. The intermolecular dearomatization reaction of 1a
on a 5.0 mmol scale gave the desired product 3aa in 95% yield
with a catalyst loading of 0.1 mol % (Scheme3).
On the basis of the control experiments and related reports,10
a possible mechanism was proposed for the reaction as shown in
Scheme 4. First, excitation of the metal catalyst under visible
light generated the excited IrIII* species, which underwent a SET
oxidation by 2-bromo-2-(4-methoxybenzyl)malonate (2a) to
give IrIV, whereby radical A was formed. Subsequently, A
underwent a rapid addition with ethynylbenzene (1a) to provide
the radical intermediate B. The following key C−C bond
formation was finalized through an intramolecular 5-exo-trig
radical cyclization. The resultant radical C could be oxidized by
IrIV metal complex to oxynium cation D. Finally, the desired
product 3aa was released from intermediate D in the presence of
a base.7h,10
With the optimal conditions in hand, we next investigated the
generality of this visible-light-induced intermolecular dearoma-
tive cyclization by exploring the scope of alkynes. First, a variety
of substituted aryl acetylenes smoothly coupled with 2-bromo-2-
(4-methoxybenzyl)malonate (2a) under standard reaction
conditions to produce the target product 3 in excellent yields.
Except for the nitro group, various aryl acetylenes with electron-
donating or electron-withdrawing group on the para-position of
In conclusion, we have developed an efficient visible light-
induced intermolecular dearomative 5-exo-trig radical cycliza-
tion between 2-bromo-1,3-dicarbonyl compounds and alkynes
under mild reaction conditions, affording the biologically
C
DOI: 10.1021/acs.orglett.8b02463
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02463.
Preparation of substrates, general procedure, character-
ization data, and 1H and 13C NMR spectra (PDF)
(5) (a) Boivin, J.; Yousfi, M.; Zard, S. Z. Tetrahedron Lett. 1997, 38,
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*Fax: (+86)-21-5474-8925. Phone: (+86)-21-5474-8925. E-
mail: zhaoguo@sjtu.edu.cn.
ORCID
Xiaomin Xie: 0000-0002-5798-291X
Zhaoguo Zhang: 0000-0003-3270-6617
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
The authors acknowledge the financial support provided by the
National Natural Science Foundation of China (No. 21232003).
■
DEDICATION
■
Dedicated to Professor Xiyan Lu on the occasion of his 90th
birthday.
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