Tandem 1,6-addition/cyclization/vinylcyclopropane rearrangement at low temperature under metal-free conditions: an approach to spiro[4.5]cyclohexadienones

Article abstract of DOI:10.1039/C7CC00677B

A tandem 1,6-addition/cyclization/vinylcyclopropane rearrangement reaction (VCPR) of vinylogous para-quinone methides at low temperature under metal-free conditions has been disclosed for the first time. This method provides an efficient strategy for the construction of a range of spiro[4.5]cyclohexadienones in good yield, exhibiting good functional group tolerance as well as gram-scale capacity.

Full text of DOI:10.1039/C7CC00677B

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Tandem 1,6-Addition/Cyclization/Vinylcyclopropane
Rearrangement at Low Temperature under Metal-free Conditions:
An Approach to Spiro[4.5]cyclohexadienones
Received 00th January 20xx,
Accepted 00th January 20xx
Zhenbo Yuan†, Kuo Gai†, Youzhi Wu, Jie Wu, Aijun Lin, and Hequan Yao*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Our previous work:
a)
strategy for the synthesis of spiro[2.5]cyclohexadienones
A
tandem
1,6-addition/cyclization/vinylcyclopropane
O
O
R2
R2
rearrangement reaction (VCPR) of vinylogous para-quinone
methides at low temperature under metal-free conditions has
been disclosed for the first time. This method provided an
R2
R2
'C'-LG
1,6-addition/cyclization
R1
R2
R
6
R
efficient strategy for the construction of
a
range of
This work:
b)
strategy for the synthesis of spiro[4.5]cyclohexadienones
spiro[4.5]cyclohexadienones in good yields, exhibiting good
functional group tolerance as well as gram-scale capacity.
O
O
O
R2
R2
t-Bu
t-Bu
t-Bu
t-Bu
'C'-LG
1,6-addition/cyclization
Spiro[4.5]cyclohexadienones as unique bioactive and spatial
structures, are privileged in natural products and
pharmaceutical molecules (Figure 1).1 Additionally, they are
also extensively utilized as key intermediates in natural
products syntheses.2 As such, their preparation is of high
synthetic interest. Many efforts have been devoted to the
construction of the skeletons, and the majority of methods
focused on Pd3, Ir4, Au5-catalyzed intramolecular
VCP Rearrangement
8
Ph
R
8
6
R
R
R
Ph
6
7
7
6
R
8
Scheme 1. Strategy for the synthesis of spiro[4.5]cyclohexadienone.
addition/cyclization
strategy
employing
para-quinone
methides (p-QMs) with bromomalonates and sulfur ylides
(Scheme 1a). In view of our continuous interest in 1,6-
conjugate addition10/annulation11 of p-QMs, we herein
dearomatization
reactions,
Rh-catalyzed
enyne
cycloisomerization reaction6, and Pd-catalyzed [3+2]
annulation7. Though the employment of catalysts based on
heavy metals, expensive ligands, highly reactive reagents,
could limit the synthetic scope and scalability of these
methods to some extent, these initial explorations enlightened
chemists to develop more efficient and simple synthetic
methods to the construction of spiro[4.5]cyclohexadienones.
Recently, our group8 and Fan group9 showed efficient metal-
free intermolecular [2+1] annulation approaches for the
synthesis of spiro[2.5]cyclohexadienones through a 1,6-
reported
addition/cyclization/vinylcyclopropane rearrangement (VCP
rearrangement)12
to the synthesis of the
an
unprecedented
tandem
1,6-conjugate
spiro[4.5]cyclohexadienones from newly designed vinylogous
p-QMs at low temperature under metal-free conditions
(Scheme 1b).
We commenced our research by examining the reaction of
vinylogous p-QM 1a and bromomalonate 2a at room
temperature with CH2Cl2 as solvent in the presence of several
bases (Table 1, entries 1–8). Notably, the 1H NMR of crude
reaction solution showed that 3aa and 3aa’ were detected
when KOH, KOtBu and Cs2CO3 were used. Moreover, the use of
Cs2CO3 showed better result among all the tested bases,
affording 3aa and 3aa’ in 82% total yield with the ratio of
1:0.8. Further optimization of conditions found that better
H3C
OH
MeO
HO
N
O
H2
N
O
N
N
HO
O
Me
O
Br
OH
HN
O
Br
Saldedines A
OCH3
(-)-spirocalcaridine A
(+)-Anhydro-β -rotunol
Spirobacillene A
Figure 1. Natural products containing spiro[4.5]cyclohexadienone.
yield and selectivity were obtained (88% yield, 3aa:3aa’>20:1,
entry 9) when the reaction temperature was raised up to 40
oC. Next, a series of solvents were examined, and EA served as
the best solvent, offering the exclusive product 3aa in 96%
yield (entry 14).
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Table 1. Optimization of reaction conditionsa
Table 2. Substrate scope of p-QMs and malonatesa,b
O
R1
R1
O
R1
R2
R1
X
Cs2CO3
EA, 40 o
+
GWE
EWG
C
EWG
EWG
R2
2
3
1
Entry
Base
T(oC)
Solvent
Yieldb,c
3aa:3aa’ c
1
2
Et3N
25
25
25
25
25
25
25
25
40
40
40
40
40
40
DCM
DCM
NR
3
-
-
K2CO3
Li2CO3
KOH
3
DCM
NR
75
66
NR
8
-
4
DCM
1:0.8
1:0.8
-
5
KOtBu
DCM
6
NaOAc
K3PO4
DCM
7
DCM
-
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DCM
82
88
76
85
45
42
96d
1:0.8
>20:1
10:1
9:1
11:1
4:1
>20:1
9
DCM
10
11
12
13
14
Acetone
CH3CN
Toluene
Dioxane
EA
a Conducted with 1a (0.1 mmol), 2a (0.11 mmol), base (0.2 mmol) in solvent (1.0
mL) at the corresponding temperature. b Total yield of 3aa and 3aa’. c The yields
and the ratios were determined by 1H NMR of crude reaction mixtures using
d
CH2Br2 as internal standard. DCM = dichloromethane, EA = ethyl acetate.
Isolated yield.
With the optimized conditions in hand, we next examined
the substrate scope of the reaction (Table 2). Firstly, a series of
1
bearing electron-neutral, electron-rich and electron-deficient
aromatic groups were tested, affording the desired products
3aa 3ja in excellent yields. Moreover, it was found that ortho-,
meta-, or para-substituents at the phenyl rings had little
effects on the yield (3ga 3ia, 87–94% yields). The structure of
–
–
3ga was confirmed by X-ray crystallographic analysis.13
Besides, polycyclic and heterocyclic-substituted substrates (2k
and 2l) tolerated well under optimized conditions, which
delivered the products 3ka and 3la in 99% and 97% yield,
respectively. The reaction also proceeded well when the bulky
t-butyl group was replaced by methyl and i-propyl groups,
producing 3ma and 3na in 84% and 91% yields. With regard to
a
Reaction Conditions: X = Br, 1 (0.1 mmol), 2 (0.11 mmol), Cs2CO3 (0.2 mmol) in
EA (1.0 mL) at 40 oC for 12 hours. b All yields refer to the isolated yields. c X = Cl. d
bromomalonates 2, products 3ab–3af were achieved in 87–
2 (0.2 mmol) was used.
94% yields. Furthermore, 2g with the carbonyl group could
deliver the corresponding product 3ag in 45% yield.
could be transformed to the phenol derivative 4aa in 88% yield
with Pd/C under ambient pressure of hydrogen. And glycol
derivative 5aa could be obtained in 62% yield with LiAlH4.
To gain insight into the reaction pathway, isolation of 3aa’
or monitoring the rearrangement process would offer the
direct evidence to support the mechanism14. When the
Next, we turned our attention to the exploration of chain-
extended vinylogous p-QMs. When 2,6-di-tert-butyl-4-((2E,4E)-
5-phenylpenta-2,4-dien-1-ylidene)cyclohexa-2,5-dien-1-one 1o
was tested as the model substrate under standard conditions
(Table 3), spiro[4.5]cyclohexadienones 3oa–3of with exocyclic
double bonds were obtained in 79–93% yields. The structure
of 3oa was also confirmed by X-ray crystallographic analysis.13
To probe the synthetic utility in preparative area, a gram-
scale synthesis of 3aa was performed. The reaction of 1a (3
mmol, 963 mg) with 2a (3.3 mmol, 789 mg) under the optimal
condition afforded 3aa in 1.3 g (90% yield) (Scheme 3). Further
transformations of 3aa were also carried out (Scheme 4). 3aa
o
1
reaction was performed at -10 C for 12 h, H NMR analysis of
the crude reaction mixture showed that only 3aa’ was formed
(Figure 2, a). A parallel experiment showed that the mixture of
3aa and 3aa’ was formed when the reaction was conducted at
-10 oC for 12 h and then at 40 oC for 1 h (Figure 2, b).
Additionally, only 3aa could be monitored when the reaction
was conducted at 40 oC for 12 h (Figure 2, c). What is more,
2 | J. Name., 2012, 00, 1-3
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O
O
O
Table 3. Substrate Scope of extended vinylogous p-QMs a,b
t-Bu
t-Bu
t-Bu
Ha
t-Bu
t-Bu
t-Bu
conditions
Br
+
Ph
COOEt
COOEt
COOEt
COOEt
Hb
EtOOC
COOEt
2a
Ph
Ph
3aa
1a
3aa'
Ha
(a)
(b)
Hb
Hb
Ha
(c)
Figure 2. Monitoring reaction pathway by 1H NMR. (a) Performed at -10 oC for 12h. (b)
Performed at -10 oC for 12 h, then at 40 oC for 1 h. (c) Performed at 40 oC for 12 h.
a Reaction Conditions: X = Br, 1 (0.1 mmol), 2 (0.11 mmol), Cs2CO3 (0.2 mmol) in
EA (1.0 mL) at 40 oC for 12 hours. b All yields refer to the isolated yields. c X = Cl.
O
O
t-Bu
t-Bu
t-Bu
t-Bu
Br
Cs2CO3
+
Ph
COOEt
COOEt
EA, 40 oC, 12 h
EtOOC
COOEt
Scheme 5. Control experiment of transformation from 3aa’ to 3aa.
Ph
3aa
1.3 g, 90% yied
2a
1a
3.3 mmol 789 mg
3 mmol 963 mg
Scheme 3. Gram-scale synthesis of 3aa.
Scheme 4. Transformations of 3aa.
3aa could be obtained from 3aa’ under standard conditions in
96% yield (Scheme 5). These experiments indicated that the
1,6-addition/cyclization step could proceed at -10 oC, while
o
VCP rearrangement occured at 40 C, which is a relatively low
Scheme 6. Plausible mechanism of tandem 1,6-addition/cyclization/VCP rearrangement
temperature compared to previous examples under metal-free
conditions or heating conditions. In order to further
investigate the reaction inherent peculiarity, kinetic
experiments for the rearrangement of 3aa’ to 3aa were
performed. The experimental activation energy was calculated
to be 27.99 ± 2.33 kcal/mol15, which is much lower than the
activation energy of prototypical VCPR independently reported
by Wellington16a (50.0 ± 0.3 kcal/mol) and Baldwin16b (51.7 ±
0.5) kcal/mol). These results well explained why the VCP
rearrangement could occur at such a low temperature (40
oC).17
reaction.
intramolecular ring closure reaction, affording the key three-
membered spiro-intermediate II. When the temperature was
raised to 40 oC, the C-C bond of spirocyclopropane was rapidly
cleaved, and VCP rearrangement occurred smoothly to furnish
the product 3aa
.
Conclusions
Finally, according to previous mechanistic studies on p-QMs
and VCP rearrangement, as well as the results of our control
experiments, a reasonable mechanism was proposed (Scheme
6). Treatment of 2-bromomalonate (2a) with Cs2CO3 formed a
carbanion, which was followed by 1,6-addition of vinylogous p-
In conclusion, we have described an unprecedented tandem
1,6-addition/cyclization/VCP rearrangement reaction of newly
designed vinylogous p-QMs. This powerful but simple method
offered various spiro[4.5]cyclohexadienones in good to
excellent yields under metal-free conditions. Further
explorations on the specific mechanism, the methodology
QMs (1a). Then the aromatization intermediate I underwent
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Acknowledgements
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232), the
Natural Science Foundation of Jiangsu Province (BK20140655)
and the Foundation of State Key Laboratory of Natural
Medicines (ZZJQ201306) is gratefully acknowledged.
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13 Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as Deposition
Numbers CCDC 1433691 (3ga) and 1439295 (3oa). Detailed
information can be found in the Supporting Information.
14 See Supporting Information for details of full spectrum of
control experiments.
15 See Supporting Information for details of kinetic
experiments.
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