Synthesis of Difluoromethylated and Phosphorated Spiro[5.5]trienones via Dearomative Spirocyclization of Biaryl Ynones

Article abstract of DOI:10.1021/acs.orglett.8b01027

Copper- or silver-catalyzed cascade radical addition/dearomative spirocyclization of biaryl ynones with fluoroalkyl bromides or diethylphosphite has been realized for the first time. This method provides a novel and step-economical protocol for the divergent synthesis of a wide range of difluoromethylated or monofluoromethylated and phosphorated spiro[5.5]trienones in moderate to high yields.

Full text of DOI:10.1021/acs.orglett.8b01027

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Difluoromethylated and Phosphorated
Spiro[5.5]trienones via Dearomative Spirocyclization of Biaryl
Ynones
Yan Zhang,* Junhua Zhang, Boyue Hu, Mingming Ji, Shangyi Ye, and Gangguo Zhu*
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, 688 Yingbin Road, Jinhua
321004, China
S
* Supporting Information
ABSTRACT: Copper- or silver-catalyzed cascade radical addition/dearomative spirocyclization of biaryl ynones with fluoroalkyl
bromides or diethylphosphite has been realized for the first time. This method provides a novel and step-economical protocol for
the divergent synthesis of a wide range of difluoromethylated or monofluoromethylated and phosphorated spiro[5.5]trienones in
moderate to high yields.
Scheme 1. Dearomatizing Reactions for Access to
Spirocycles
piro compounds exist in a large number of natural
Sproducts, biologically active molecules, and functional
materials.1,2 In particular, spiro[5.5]trienones have been widely
utilized as valuable intermediates for organic synthesis and drug
discovery. Typical examples include platencin (Figure 1, I), a
FabH and FabF dual inhibitor with potent broad-spectrum
antibiotic activity, the natural product laurencenone B (Figure
1, II), and compound III, which is a spirane amine inhibitor
against WT A/M2.2e As such, the exploration of novel and
efficient strategies for the synthesis of spirocarbocycles
continues to be an important task in organic synthesis.
In this aspect, spirocyclization via dearomatization has
emerged as a very attractive strategy for the rapid synthesis
of structurally diverse spiro molecules. Traditional methods for
the synthesis of spiro compounds include oxidative dearoma-
tization,3 nucleophilic or electrophilic dearomatization,4 and
transition-metal-mediated dearomatization.5 For example, the
Pd-catalyzed intramolecular and intermolecular dearomatizing
annulations of biaryl compounds were developed by the groups
of Buchwald, Hamada, Luan and others (see Scheme 1A).5b,d,i,j
Pioneered by Curran and co-workers, radical spirocyclization
has become a highly efficient and alternative approach for
constructing spiro carbo- or heterocycles, which permits the
rapid construction of various spiro compounds from readily
available starting materials. However, many methods have
focused on the 5-exo-trig cyclization, thus leading to
spiro[4.5]trienones or their analogues (Scheme 1B).6 As
compared to the 5-exo-trig cyclization, the 6-exo-trig cyclization
Received: March 31, 2018
Figure 1. Significance of spiro[5.5]trienones.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions for Cu-
Catalyzed Fluoroalkylation-Initiated Dearomative
Spirocyclization
Scheme 2. Scope of Fluoromethylated Spiro[5.5]trienones
a
b
entry
[Cu]
ligand
base
solvent
yield (%)
1
2
CuCl
CuOAc
CuTc
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
L1
L1
L1
L1
L2
L3
L4
L4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
37
10
trace
56
50
66
74
37
trace
71
63
20
0
3
4
5
6
7
8
9
K2CO3
KHCO3
Na2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14
L4
L4
L4
L4
L4
DCE
PhCF3
0
a
Reaction conditions: 1aa (0.2 mmol), 2a (0.4 mmol), [M] (10 mol
%), L (20 mol %), base (0.2 mmol), solvent (2 mL), under N2, 90 °C,
b
10 h. Yields of isolated products. DCE = 1,2-dichloroethane.
is more challenging,7 and such a radical spirocyclization
permitting the formation of spiro[5.5]trienones is highly
desirable.8
On the other hand, biaryls are challenging substrates for the
radical dearomatization, because of the challenge of controlling
the site selectivity of radical cyclization. As part of our interest
in radical reactions and fluorine chemistry,9 we explored the
possibility of radical addition/dearomatization of biaryl ynones
to form the spiro[5.5]structural motif, which was reported to
have special biological properties.10 Here, we report a novel
copper/silver-catalyzed cascade radical addition/dearomative
spirocyclization of biaryl ynones with fluoroalkyl bromides or
diethylphosphite as the radical source, producing difluorome-
thylated or monofluoromethylated and phosphorated
spiro[5.5]trienones in good yields. The reaction constitutes a
new advance in the uncommon 6-exo-trig radical dearomative
spirocyclization process (see Scheme 1C).
Our initial study focused on the reaction of biaryl ynone 1aa
using BrCF2CO2Et (2a) as the radical source. Selected results
are shown in Table 1. The reaction proceeded in the presence
of CuCl (10 mol %), L1 (20 mol %) and K2CO3 (1.0 equiv) in
MeCN at 90 °C, affording the spirocyclic product 3aa in 37%
yield (Table 1, entry 1). Encouraged by this preliminary
observation, we attempted to improve the reaction efficiency by
screening various copper salts and ligands (Table 1, entries 2−
7).
It was found that Cu2O was the best catalyst. Among the
ligands screened, L4 afforded the best yield (Table 1, entry 7).
Low conversions were observed in the absence of the K2CO3
and ligand (Table 1, entries 8 and 9). The reaction was
examined by using other bases such as KHCO3 and Na2CO3
a
Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2 (0.4
mmol), Cu2O (10 mol %), L4 (0.04 mmol), base (0.2 mmol), solvent
(2 mL), under N2, 90 °C, 10 h.
(Table 1, entries 10 and 11), but none of them could give
comparable results. Finally, the effect of solvents was
B
DOI: 10.1021/acs.orglett.8b01027
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Organic Letters
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Table 2. Optimization of Reaction Conditions for
Phosphorylation-Initiated Dearomative Spirocyclization
Scheme 3. Reaction Scope for the Synthesis of PO(OEt)2-
Containing Spiroconjugated Compounds
a
a
b
yield
entry
1
catalyst
additive
solvent
(%)
Mn(OAc)3·2H2O
AcOH
AcOH
34
46
52
28
44
50
62
30
70
50
65
47
c
2
AgNO3
AgNO3
AgOAc
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
c
3
MeCN
c
4
MeCN
d
5
Mg(NO3)2
Zn(NO3)2
K2S2O8
MeCN
d
6
MeCN
d
7
MeCN
d
8
Na2S2O8
K2S2O8
MeCN
d
9
MeCN/H2O = 1:1
MeCN/H2O = 1:2
MeCN/H2O = 2:1
acetone/H2O = 2:1
d
10
K2S2O8
d
11
K2S2O8
d
12
K2S2O8
a
Reaction conditions: 1aa (0.2 mmol), 2c (0.4 mmol), additives,
b
c
solvent (2 mL) under N2, 90 °C, 10 h. Isolated yields. AgX (2.0
equiv) was used. AgNO3 (20 mol %) was used.
d
investigated. Employing common solvents such as DMF, DCE,
and PhCF3 dramatically reduced the yield (Table 1, entries 12−
14) in the reaction.
To ascertain the scope and limitations of the reaction, many
biaryl ynones 1 were investigated and the results are shown in
Scheme 2. Generally, the electronic effect of substituents on Ar′
does not influence the reaction efficiency, and moderate to
good yields of spiro[5.5]trienones were obtained (3aa−3ea). It
is noteworthy that functional groups such as ether, ester,
chloro, and bromo are compatible with the reaction (3fa−3ja),
which offers an opportunity for further derivatization. The
scope of Ar′ was also extended to polysubstituted substrates
and biaryl ynones 1ka−1na afforded the corresponding
products in satisfactory yields (3ka−3na), indicating that the
steric hindrance of Ar′ has little impact on the reaction.
After examining the effect of various substitutions on the Ar′
group, substitution on the Ar group in the reaction outline was
investigated. Substrates bearing either electron-withdrawing or
electron-donating groups affected the reactivity of 1. In
particular, substitution at the ortho-position of the benzoyl
group had a positive effect on this transformation (3wa−3xa).
Heteroaryl and naphthyl substituents were also compatible, and
the expected products were found in relatively low yields (3ya
and 3za). The substrate with a Me group at the ortho-position
of OMe (1ab) also formed the expected compound 3ab. In
addition, BrCFHCO2Et was attempted as the radical precursor,
and the desired monofluoromethylated products were isolated
in moderate yields (3ac−3ad). The structure of 3fa was
confirmed by X-ray crystallographic analysis.
a
Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2c (0.4
mmol), AgNO3 (20 mol %), K2S2O8 (0.5 mmol), MeCN (1 mL), H2O
(1 mL), under N2, 90 °C, 10 h.
MeCN and H2O (v/v = 1:1) at 90 °C for 10 h with AgNO3 (20
mol %) as the catalyst and K2S2O8 (2.5 equiv) as the oxidant,
70% yield of 4a was isolated (see Table 2, entry 9).
We briefly examined the scope of this silver-catalyzed
phosphorylation initiated dearomatization of biaryl ynones.
The diversity of this transformation turned out to be
satisfactory (see Scheme 3). Generally, the electronic properties
of Ar and Ar′ in substrates 1 did not have distinct influence on
the efficiency of the phosphorylation, and moderate to good
yields of the spiro[5.5]trienones 4 were obtained. However,
decreased yields were observed when the Ar′ is a heteroaryl,
such as the thiophenyl group (4r). The structure of 4a was
To further expand this methodology, we next examined other
radical precursors. Radical phosphorylation has become a highly
efficient approach to synthesize phosphonates, which are widely
utilized in organic synthesis.11 Thus, phosphorylation-initiated
dearomative spirocyclization of biaryl ynones was conducted
using 1aa and diethylphosphite (2c) as the model substrate
(Table 2). When the reaction was run in a mixed solvent of
C
DOI: 10.1021/acs.orglett.8b01027
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Organic Letters
Letter
affords a vinyl radical A, which undergoes 6-exo-trig cyclization
to form the radical B. Intermediate B is then oxidized by Mn+1
to form oxocarbenium ion D. Finally, the corresponding
products 3 or 4 are formed after demethylation. The
observation of a TEMPO-adduct 7 by HRMS suggests the
formation of intermediate A, thus supporting the proposed
mechanism.
Scheme 4. Proposed Mechanism
The scalability of this method was also investigated, and a 3
mmol scale reaction yielded 0.97 g of product 4c (70% yield)
from 1ca. With 4c in hand, further functionalization was
performed (see Scheme 5). The biologically relevant
epoxyquinone structure 8 could be obtained in excellent yield
via oxidation, while reduction of the ketone or the olefin
furnished alcohol or ketone (9 and 10, respectively) in good
yield. Interestingly, we found that the phosphoyl group could
be removed under the Wittig reaction conditions, and
compound 11 could be prepared.
In summary, we have successfully developed a novel copper/
silver-catalyzed cascade radical addition/dearomative spirocyc-
lization of biaryl ynones with fluoroalkyl bromides or
diethylphosphite as the radical source. The reaction provides
a divergent and efficient access to difluoromethylated,
monofluoromethylated and phosphorated spiro[5.5]trienones
under mild reaction conditions. It represents one of the 6-exo-
trig radical dearomative spirocyclization process and should be
useful for the construction of spiro compounds. Further
application of the protocol in the preparation of a variety of
novel and potentially useful polycyclic compounds, as well as
natural products, is underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01027.
■
Scheme 5. Gram-Scale Preparation of 4c and Its
Derivatization
S
Detailed experimental procedures, characterization data
for all new compounds 3 and 4 (PDF)
Accession Codes
CCDC 1542882−1542883 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangyan001@zjnu.edu.cn (Y. Zhang).
*E-mail: gangguo@zjnu.cn (G. Zhu).
ORCID
determined by X-ray crystallographic analysis. It is worth
mentioning that the sterically demanding substrate 1af
produced the desired product 4t in 56% yield.
Yan Zhang: 0000-0002-0694-5131
Gangguo Zhu: 0000-0003-4384-824X
Notes
In order to probe the mechanism, the reaction between 1aa
and 2a or 2c was conducted in the presence of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO). The reactions were
completely or partially inhibited and the TEMPO-adducts were
detected by 19F and 31P NMR analysis, respectively (Scheme 4,
eqs 1 and 2).12,13 Based on these results and previous
reports,6a,14 a proposed pathway for the formation of
spiro[5.5]trienones is depicted in Scheme 4. Initially, radicals
Y• are generated in situ from 2 in the presence of copper or
silver catalyst. Radical addition of Y• to C−C triple bonds of 1
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (Nos.
21672191 and 21702188) and Natural Science Foundation of
Zhejiang Province (No. LQ17B020001).
D
DOI: 10.1021/acs.orglett.8b01027
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Organic Letters
Letter
(11) For selected reports, see: (a) Queffel
́
ec, C.; Petit, M.; Janvier, P.;
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