Palladium-catalyzed Oxa-[4+2] Annulation of para-Quinone Methides

Article abstract of DOI:10.1002/adsc.201700978

A palladium-catalyzed oxa-[4+2] annulation of para-quinone methides with allyl carbonates bearing a nucleophilic alcohol side chain has been developed. This method provided an efficient strategy to the construction of 2-oxaspiro-cyclohexadienones via 1,6-conjugated addition-mediated allylation in moderate to good yields. Preliminary results on asymmetric derivatives promised potential in the synthesis of enantioenriched frameworks. (Figure presented.).

Full text of DOI:10.1002/adsc.201700978

Title: Palladium-catalyzed Oxa-[4+2] Annulation of para-Quinone
Methides
Authors: Zhenbo Yuan, Rui Pan, He Zhang, Lina Liu, Aijun Lin, and
Hequan Yao
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700978
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Palladium-catalyzed Oxa-[4+2] Annulation of para-Quinone
Methides
Zhenbo Yuan,‡ Rui Pan,‡ He Zhang, Lina Liu, Aijun Lin* and Hequan Yao*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing, 210009, P. R. China
Fax: (+86)-25-8327-1042; e-mail: ajlin@cpu.edu.cn and hyao@cpu.edu.cn
‡These authors contributed equally to this work.
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: A palladium-catalyzed oxa-[4+2] annulation of
para-quinone methides with allyl carbonates bearing a
nucleophilic alcohol side chain has been developed. This
method provided an efficient strategy to the construction
of 2-oxaspiro-cyclohexadienones via 1,6-conjugated
addition-mediated allylation in moderate to good yields.
Preliminary results on asymmetric derivatives promised
potential in the synthesis of enantioenriched frameworks.
Keywords: palladium-catalyzed; para-quinone methides;
spirocyclic compounds; oxa-[4+2] annulation; allylation
Spiro-cyclohexadienones are privileged structures
existed
in
various natural
products
and
pharmaceutical molecules with remarkable biological
activities.[1] So that many efforts have been
contributed to construct these skeletons. However, 2-
oxaspiro[5.5]undeca-7,10-dien-9-one as a member of
the spiro-cyclohexadienone family and the key
skeleton of gymnothelignans (Figure 1), was rarely
Scheme 1. Strategies to the synthesis of spiro-
cyclohexadienones from p-QMs.
Recently, para-quinone methides (p-QMs)[4] as
mentioned,[2] and only few examples related to their versatile synthons have been employed to construct
synthesis has been reported.[3] Thus, it is highly varieties of spiro-cyclohexadienones. Since 2015, our
desirable to develop an effective synthetic method to group, Fan’s group and Waser’s group successively
synthesize them for chemists to comprehensively achieved spiro[2.5]octa-4,7-dien-6-ones from p-QMs
investigate their bioactivity and medicinal value.
via 1,6-addition-mediated [2+1] annulation with
bromomalonates[5], sulfur ylides[6] and ammonium
ylides[7] (Scheme 1a). In addition, our group and
Zhao’s group revealed that spiro[4.5]deca-6,9-dien-8-
ones could be approached through palladium or
silver-catalyzed 1,6-addition-mediated allylation[8] or
alkenylation[9] of p-QMs (Scheme 1b). In 2017, our
group and Fan’s group simultaneously constructed
spiro[4.5]deca-6,9-dien-8-ones again through cascade
1,6-addition/VCP rearrangement reactions of vinyl p-
quinone methides (p-VQMs) with bromomalonates[10]
or sulfur ylides[11] (Scheme 1c). To further strengthen
our continuous interest in the synthesis of spiro-
cyclohexadienones and characterizing the reactivity
of p-QMs,[12] herein, we will describe our latest work
Figure 1. 2-Oxaspiro[5.5]undeca-7,10-dien-9-one existed
in nature products.
1
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
on palladium-catalyzed oxa-[4+2] annulation of p- monophosphorus or phosphine oxide[15] ligands were
QMs with allyl carbonates bearing a nucleophilic ineffective (Table 2, entries 7–9). Among a variety of
alcohol
side
chain[13]
to
achieve
2- solvents, Et2O emerged as the optimal one (Table 2,
oxaspiro[5.5]undeca-7,10-dien-9-ones. The process entries 10 and 11), which may stabilize both the
underwent tandem oxa-1,6-addition and palladium- reacting partners and intermediates well than other
catalyzed allylation dearomatization reactions nonpolar solvents.[16] Carrying out the reaction at
o
(Scheme 1d).
room temperature or 60 C proved less efficiency
(Table 2, entries 12 and 13). Further decreasing the
catalyst loadings led to low yield (Table 2, entries 14
and 15).
Table 1. Investigation of the leaving groups.
Table 2. Effect of the reaction parameters.
Entrya)
2
Leaving group
Yieldb)
1
2
3
4
5
6
OCO2Me
OCO2Et
OCO2iPr
OCO2tBu
OCO2Bn
OAc
64
70
2a
2b
2c
2d
2e
2f
92
94c)
88
NR
NR
7
OPO(OPh)2
2g
a)
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol),
Pd(OAc)2 (10 mol%), BINAP (20 mol%) in Et2O (1.0 mL)
at 40 oC. BINAP = 2,2'-Bis(diphenylphosphino)-1,1'-
binaphthalene.
Entrya) Variation from the standard conditions
Yieldb)
94c)
1
none
2
3
4
5
Pd2(dba)3·CHCl3 instead of Pd(OAc)2
Pd2(dba)3 instead of Pd(OAc)2
Pd(PPh3)4 instead of Pd(OAc)2
PdCl2 instead of Pd(OAc)2
L1 instead of BINAP
44
32
43
NR
72
b)
The yields were determined by 1H NMR of crude
reaction mixtures using CH2Br2 as internal standard. NR =
No reaction.
6
c) Isolated yield.
7
8
9
10
11
12
13
14
L2 instead of BINAP
L3 instead of BINAP
NR
NR
NR
47
NR
NR
87
BINAPO instead of BINAP
PhMe instead of Et2O
CH2Cl2 instead of Et2O
room temperature instead of 40 oC
60 oC instead of 40 oC
5 mol % Pd(OAc)2 and 10 mol %
BINAP were used
66
15
2.5 mol % Pd(OAc)2 and 5 mol %
BINAP were used
56
a)
Reaction conditions: 1a (0.1 mmol), 2f (0.2 mmol), [Pd]
o
(10 mol%), ligand (20 mol%) in solvent (1.0 mL) at 40 C.
Figure 2. Single-crystal X-ray diffraction analysis of 3a.
BINAP = 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene.
BINAPO
=
1,1'-[1,1'-Binaphthalene]-2,2'-diylbis[1,1-
After evaluation of various leaving groups (Table
1), we found that the -OCO2tBu group played as the
most efficient one, giving the desired 2-oxaspiro-
cyclohexadienone 3a in 94% yield (Table 1, entry 4).
diphenylphosphine oxide].
b)
The yields were determined by 1H NMR of crude
reaction mixtures using CH2Br2 as internal standard. NR =
1
No reaction.
The structure of 3a was confirmed by H and 13C
c) Isolated yield.
NMR spectra, mass spectrometry, and single-crystal
X-ray diffraction analysis (Figure 2).[14] It is
noteworthy that the carbonate ester is crucial for this
reaction because no desired product was detected
when other leaving groups were installed (Table 1,
entries 6 and 7). No better result was obtained when
employing other palladium salts to replace Pd(OAc)2
as catalysts (Table 2, entries 2–5). The choice of
bisphosphorus ligands is critical for a productive
With the optimized conditions in hand, we then
examined the versatility of this palladium-catalyzed
oxa-[4+2] annulation, and the results are summarized
in Table 3. Halogen groups (-F, -Cl, -Br) and
electron-withdrawing groups (-CO2Me, -CN, -CF3, -
NO2) at the para-position of phenyl ring of p-QMs
led to the corresponding products 3b–3h in moderate
to good yields. When p-QMs containing para-
methoxyl group was tested, 3i was obtained in 35%
reaction
for
that
other
phosphoramidite,
2
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
mL)
at
40
oC.
DPPF
=
1,1'-
yield under the standard conditions. It is gratifying
that changing the catalyst to Pd2(dba)3·CHCl3 and
employing DPPF as the ligand in THF (Condition B),
3i could be formed in 79% yield and 3j was achieved
in 68% yield.[17] For functionalized p-QMs with
phenyl or alkenyl groups, the reactions proceeded
smoothly to give 4k and 4l in 66% and 51% yields
under the standard conditions. p-QMs with bromine
group at the meta-position of phenyl ring gave 3m in
71% yield. Condition B showed better performance
when substrates with ortho-substituents at the phenyl
ring were employed, delivering 3n–3p in 42%–74%
yields. Product 3q with di-chlorine groups was
obtained in 78% yield. In addition, naphthyl and
heterocyclic-substituted substrates (2q and 2r) were
both tolerated well under condition B, which offered
3q and 3r in 55% and 69% yield, respectively.
Moreover, product 3t could be obtained in 78% yield
from the substrate 2t containing a tertiary alcohol
with the reaction temperature increased to 60 °C.
Limitations include incompatibility of non-terminal
allylic carbonates, which were unreactive in this
methodology. [18]
bis(diphenylphosphino)ferrocene.
d) 60 oC.
To achieve optically active 2-oxaspiro[5.5]undeca-
7,10-dien-9-ones, an expansion of the present system
to an asymmetric oxa-[4+2] annulation reaction was
also examined, and the preliminary results for the
ligand screening with 1a are shown in Scheme 2.
After screening considerable reaction conditions,[19]
3a could be achieved in 94% yield with 87:13 er
value employing chiral (S)-BINAP (L*1) as ligand.
The chiral ferrocene ligand L*2, chiral spiroketal-
based diphosphine (SKP) ligand L*3, and chiral Trost
ligand L*4 were also tested. However, the
optimization of ligands did not improve the er value
of this transformation. Nevertheless, the result given
by L*1 showed promising reactivity and
enantioselectivity of this palladium-catalyzed oxa-
[4+2] annulation reaction of p-QMs.
Table 3. Substrate scope. a) b)
Scheme 2. Preliminary results on asymmetric experiment.
Scheme 3. Plausible mechanism of palladium-catalyzed
oxa-[4+2] annulation of p-QMs.
a)
Standard conditions: 1a (0.1 mmol), 2 (0.2 mmol),
Finally, according to the previous mechanistic
studies on allylic carbonates[20] and our previous work
on p-QMs, a proposed mechanism of this oxa-[4+2]
annulation is shown in Scheme 3. The reaction is
initiated by the well-established palladium-mediated
oxidative addition of allylic carbonate to Pd(0)
Pd(OAc)2 (10 mol%), BINAP (20 mol%) in Et2O (1.0 mL)
at 40 oC. BINAP = 2,2'-bis(diphenylphosphino)-1,1'-
binaphthalene.
b) All yields refer to the isolated yields.
c)
Condition B: 1a (0.1 mmol),
2
(0.2 mmol),
Pd2(dba)3·CHCl3 (10 mol%), DPPF (20 mol%) in THF (1.0
3
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
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leads to π-allyl-palladium intermediate I, tert-butoxy
anion, as well as carbon dioxide. Next, the hydrogen
atom of the hydroxyl group is deprotonated by the
liberated tert-butoxy anion, forming an oxygen anion
intermediate II. Then, 1,6-conjugated addition of the
oxygen anion to p-QM 1a provides intermediate III,
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by
palladium-catalyzed
allylation
dearomatization ring closure to provide the product
3a and regenerates the active palladium catalyst for
the next catalytic cycle.
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In conclusion, we have developed an
unprecedented
palladium-catalyzed
oxa-[4+2]
annulation of p-QMs with allyl carbonates bearing a
nucleophilic alcohol side chain. This method offered
various 2-oxaspiro[5.5]undeca-7,10-dien-9-ones in
moderate to good yields with good functional group
tolerance under mild conditions. Initial exploration on
the synthesis of chiral products offered moderate
enantioselectivity.
Further
investigations
on
synthesizing 2-oxaspiro-cyclohexadienones with
higher enantioselectivity are currently underway in
our laboratory.
Experimental Section
General procedure for the synthesis of 2-
oxaspiro[5.5]undeca-7,10-dien-9-ones: A sealed tube was
charged with para-quinone methides 1 (0.10 mmol, 1.0
equiv), allyl carbonate 2f (0.20 mmol, 2.0 equiv),
palladium catalyst (0.01 mmol, 10 mol%), and ligand (0.02
mmol, 20 mol%). The vial is thoroughly flushed with argon
and solvent (1.0 mL) was added under argon. Then the
o
reaction mixture was stirred at 40 C for 48 h. After the
reaction vessel was cooled to room temperature, the
solution was concentrated in vacuo and purified by careful
chromatography on silica gel (EtOAc/petroleum ether =
1/200) to afford the desired products 3.
[5] K. Gai, X. Fang, X. Li, J. Xu, X. Wu, A. Lin, H. Yao,
Acknowledgements
Chem. Commun. 2015, 51, 15831.
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC 21572272), the
Natural Science Foundation of Jiangsu Province (BK20140655),
and the Foundation of State Key Laboratory of Natural Medicines
(ZZYQ201605) is gratefully acknowledged.
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201700978
Advanced Synthesis & Catalysis
UPDATE
Palladium-catalyzed Oxa-[4+2] Annulation of
para-Quinone Methides
Adv. Synth. Catal. Year, Volume, Page – Page
Zhenbo Yuan,‡ Rui Pan,‡ He Zhang, Lina Liu,
Aijun Lin* and Hequan Yao*
6
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