Dramatic base-oriented chemoselective tandem wacker cyclizations: Synthesis of bisbenzannelated spiroketals and 2-substituted chromans

Article abstract of DOI:10.1055/s-0030-1260775

A Pd(II)/Cu(II)-catalyzed chemoselective tandem aerobic cyclization of phenolic olefins leads to [5,6]-bisbenzannelated spiroketals or 2-substituted chromans, wherein it was interestingly found that the presence or absence of base could be responsible for the tunable selectivity. The [5,6]- bisbenzannelated spiroketals were achieved from tandem Wacker cyclization-aroxylation in moderate yields in the absence of base, and 2-substituted chromans were formed through base-mediated Pd(II)/Cu(II)-catalyzed tandem Wacker cyclization-Michael addition in good yields. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260775

LETTER
1579
Dramatic Base-Oriented Chemoselective Tandem Wacker Cyclizations:
Synthesis of Bisbenzannelated Spiroketals and 2-Substituted Chromans
S
ynthesis of Bis
h
benzannelat
i
ed Spir
j
oketals
u
and 2-Subst
n
ituted Chromans Xin, Yuan Zhang, Hua Tao, Jijun Xue,* Ying Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: xuejj@lzu.edu.cn; E-mail: liying@lzu.edu.cn
Received 7 March 2011
their bioactivities.7–12 At present, the synthetic methods13–
Abstract: A Pd(II)/Cu(II)-catalyzed chemoselective tandem aero-
bic cyclization of phenolic olefins leads to [5,6]-bisbenzannelated
spiroketals or 2-substituted chromans, wherein it was interestingly
found that the presence or absence of base could be responsible for
16
reported were mainly based on the acid-catalyzed
spiroketalization of bisphenolic ketones,14 haloetherifica-
tion of a benzofuran,13a or cycloaddition type reaction.15
the tunable selectivity. The [5,6]-bisbenzannelated spiroketals were The most recent work on metal-catalyzed spiroketaliza-
achieved from tandem Wacker cyclization–aroxylation in moderate
tion of bisphenolic alkynes was reported by our group us-
ing gold reagents as catalysts.16 The catalytic and efficient
yields in the absence of base, and 2-substituted chromans were
formed through base-mediated Pd(II)/Cu(II)-catalyzed tandem
construction of such synthetically interesting bisbenzan-
Wacker cyclization–Michael addition in good yields.
nelated spiroketal cores is still of high demand in modern
Key words: palladium, chemoselectivity, spiroketals, chromans,
Wacker cyclization
organic synthesis of the structurally related natural prod-
ucts.17
R2
R1
Palladium-catalyzed Wacker-type oxidative functional-
O
O
O
ization of alkenes is of great interest in the formation of
various carbon–oxygen bonds in modern organic synthe-
sis, and it has been proven to be one of the most versatile
methods for rapid increase in molecular complexity.
Among them, the intramolecular Wacker cyclization has
shown to be extremely effective for the synthesis of
furans,1 pyrans,2 benzofurans,3 chromans,4 and dioxabicy-
clic compounds.5 In these reactions, palladium activates
the double bond for nucleophilic attack. Nevertheless, to
the best of our knowledge, there is no report on the syn-
thesis of bisbenzannelated spiroketals by Pd(II)-catalyzed
intramolecular Wacker cyclization so far. Very few inter-
molecular difunctionalization reactions and spiroketaliza-
tion reactions of olefins have been reported using Pd (II)-
catalyzed oxidations, especially those involving a nu-
cleopalladation process.6
2
+
R1
HO
Pd(II), CuCl2
R2
MeOH, O2, 60 °C
R1
OH
OH
3
minor
R2
1
MeO
R2
HO
R1
O
Pd(II), CuCl2
base, O2, MeOH, r.t.
4
syn/anti between 9.6:1 and 4.3:1
Scheme 1 PdCl2/CuCl2-catalyzed chemoselective tandem aerobic
Importantly, the bisbenzannelated spiroketal cores exist
widely in natural products, such as rubromycins and heli-
quinomycins (Figure 1) and play very important roles in
cyclization
As a preliminary investigation on Pd(II)-catalyzed in-
tramolecular oxidative difunctionalization of olefins as
well as the continuing research on the synthesis of rubro-
mycins, we wanted to integrate intramolecular Wacker
oxidation and spontaneous ketalization in the synthetic
realm of bisbenzannelated spiroketal chemistry, which is
crucial for the synthesis of the corresponding natural
products. Interestingly during such exploration, an unex-
pected reaction chemoselectivity was revealed for the pal-
ladium-catalyzed oxidative functionalization of alkenes.
As shown in Scheme 1, the biscyclized spiroketal and 5-
endo-trig cyclization products 2 and 3 or 6-exo-trig cy-
clization product 46 could be individually afforded from
the phenolic olefin 1 in the presence of oxygen under the
catalysis of Pd(II)/Cu(II), wherein the selectivity is main-
ly dependent on the absence or presence of base. Notably,
O
HO
O
O
OH
CO2Me
MeO
O
O
R3
R1
R2
O
OH
γ-rubromycin R1 = R2 = R3 = H
purpuromycin R1 = R2 = H, R3 = OH
heliquinomycin R1 = O-cymarose, R2 = OH, R3 = H
Figure 1 The natural bioactive rubromycin compounds
SYNLETT 2011, No. 11, pp 1579–1584
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260775; Art ID: W06711ST
© Georg Thieme Verlag Stuttgart · New York

1580
Z. Xin et al.
LETTER
this palladium-catalyzed Wacker-type oxidative cycliza- also examined in this reaction, but no positive improve-
tion provided a novel divergent route from phenolic ole- ment was observed in this case (Table 1, entry 5). To fur-
fins 1 to bisbenzannelated spiroketals 2 or functionalized ther investigate the solvent effect, the aprotic CH2Cl2,
chromans 4.6 Herein we wish to report our preliminary re- DME, DMF, or toluene as reaction media were also used
sults on this topic.
in this model cyclization. However, no reaction happened
or the reaction gave messy products. Interestingly, when a
base was used as an additive to improve the recycling ef-
ficiency of catalyst, the chroman 4a instead of 2a and 3a
was unexpectedly formed via 6-exo-trig cyclization in
high yield and in short reaction time. For example, using
Cs2CO3 as a base, the reaction gave 4a in 7.1:1 dr and 89%
yield (Table 1, entry 6), in which the syn configuration of
major product was determined by NMR spectral analysis
as well as comparison with the literature data.6c Further in-
vestigations disclosed that other inorganic and organic
bases, such as KHCO3 and DABCO, were also effective
for this cyclization (Table 1, entries 7 and 8). For this in-
teresting 6-exo-trig cyclization, the catalyst PdCl2 showed
good result (Table 1, entry 9). Other palladium catalysts
such as Pd(MeCN)2Cl2 (Table 1, entry 9) and Pd(OAc)2
(Table 1, entry 10) proved to be less effective for this
transformation. The co-catalyst CuCl2 was also an indis-
pensable reagent for this case (Table 1, entry 11), and de-
Initially, the phenolic olefin 1a, which was readily pre-
pared from Julia olefination,18 was treated with oxygen
under the catalysis of PdCl2/CuCl2 in MeOH. The desired
spiroketal 2a was formed in 65% yield, along with 5-
endo-trig cyclization product 3a in 28% yield (Table 1,
entry 1). In order to improve the efficiency, different pal-
ladium reagents, copper reagents, as well as solvents were
screened in detail. In MeOH as solvent and without base,
it was found that PdCl2/CuCl2 as catalyst gave the best re-
sult. While using catalytic Pd(MeCN)2Cl2/CuCl2, the re-
action provided 2a in a slightly lower yield and took
longer reaction time (Table 1, entry 2). Analogously,
Pd(OAc)2 as a co-catalyst also showed obviously lower
efficiency (Table 1, entry 3). In addition to palladium cat-
alyst, the employment of copper salt as a co-catalyst was
vital to this oxidative transformation, and only trace
amount of 2a could be observed in the absence of CuCl2
(Table 1, entry 4). Besides, CuCl instead of CuCl2 was
Table 1 Optimization of the Palladium-Catalyzed Cyclization of 1aa
OH OMe
OH
O
HO
O
O
Pd(II), CuCl2
OH
base
MeOH, O2
O
1a
2a
3a
4a
Entry
1
Catalyst
PdCl2
Base
none
Time (h)
Yield of 2a (%)b
Yield of 3a (%)b Yield of 2a (%)b
syn/antic
10
12
16
10
10
5
65
60
33
4
28
25
31
trace
30
0
trace
trace
0
2
Pd(MeCN)2Cl2
Pd(OAc)2
PdCl2
none
3
none
4d
5e
6
none
0
PdCl2
none
35
0
trace
89
PdCl2
Cs2CO3
KHCO3
DABCO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7.1:1
7:1
7
PdCl2
7
0
0
72
8
PdCl2
10
5
0
0
60
6.3:1
7:1
9
Pd(MeCN)2Cl2
Pd(OAc)2
PdCl2
0
0
87
10
11d
12e
10
8
0
0
56
7:1
0
0
7
7:1
PdCl2
12
0
0
60
6.5:1
a Reactions were carried out using 1a (0.2 mmol, 1.0 equiv), Pd(II) (0.02 mmol, 0.1 equiv), CuCl2 (0.04 mmol, 0.2 equiv), and base (0.04 mmol,
0.2 equiv) in solvent (2.0 mL) under an ambient atmosphere of O2.
b Isolated yields.
c The dr of 4a was measured by 1H NMR and the relative configurations were determined by comparison with the data of literature.6c See Sup-
porting Information for details.
d Without CuCl2 in the reactions.
e CuCl was used in place of CuCl2.
Synlett 2011, No. 11, 1579–1584 © Thieme Stuttgart · New York

LETTER
Synthesis of Bisbenzannelated Spiroketals and 2-Substituted Chromans
1581
creased yield was observed when using CuCl instead of Wacker cyclization is a dynamic kinetic reaction, and the
CuCl2 (Table 1, entry 12). In terms of the investigations two OH groups have similar nucleophility. Generally, the
mentioned above, PdCl2/CuCl2 as catalyst and MeOH as preferential formation of five-membered ring resulted
solvent in the presence or absence of Cs2CO3 was finally from the left phenolic OH group which was more close to
identified as optimal reaction conditions for this chemo- the activated double bond. As the second stage, the further
selective divergent oxidative cyclization.
conversion of 3a to 2a could happen in the second cycle
of palladium catalysis involving aroxylation cyclization.
In order to understand more about this spiroketalization,
benzofuran 3a was isolated and treated with PdCl2 in However, when a base was involved in this catalytic reac-
MeOH at 60 °C. As shown in Equation 1, the desired tion, an intramolecular phenolic anion exchange hap-
spiroketal 2a was formed after 18 hours in 62% yield, fol- pened, leading to the formation of 9 from 5. A similar
lowed by the recovery of 3a in 30% yield. This control ex- mechanism has been depicted by Sigman and co-work-
periment clearly demonstrated that 5-endo-trig ers.6 Following the intramolecular nucleophilic attack of
cyclization product 3a was the precursor of biscyclized right phenolic OH group in 9, the benzopyran intermedi-
spiroketal 2a, to some extent giving a mechanistic insight ate 10 was formed. After the elimination of HCl under
into this Pd(II)/Cu(II)-catalyzed Wacker-type oxidative base, a Pd(0) complex with methide quinine, 11, was gen-
cyclization.
erated in situ. Then further intermolecular attack of
MeOH resulted in the formation of the chroman 4a. Dur-
ing the addition of MeOH to the methide quinone com-
plex, notably, the nucleophilic attack of the hydroxyl
group of MeOH mainly took place from the less hindered
Re face, giving the major product with syn stereochemis-
try.6 In the above-mentioned two catalytic cycles, the se-
lectivity between 5-endo-trig cyclization and 6-exo-trig
cyclization in 5 was mainly controlled by phenolic anion
exchange at Pd(II) center in the presence of base or a di-
rect nucleophilic addition of phenol hydroxy group to
Pd(II)-activated double bond in the absence of base.
HO
O
O
O
PdCl2 (10mol%)
MeOH, 60 °C
18 h
3a
2a
62% isolated yields
Equation 1 The conversion of 3a into 2a
Hosokawa and co-workers have reported an analogous
catalytic cycle, which proceeded through an intermolecu-
lar Wacker reaction and led to the formation of acetals.19
Based on the above results, the mechanism for the forma-
tion of 2a was proposed in Scheme 2. The catalytic pro-
cess mainly included two stages. In the first stage, Pd(II)
combined with the double bond and activated it. Then the
phenolic hydroxyl group attacked the double bond, lead-
ing to the formation of five-membered ring 6. Through b-
hydride elimination, intermediate 3a was formed. This
To extend the generality of this Wacker-type oxidative cy-
clization reaction, various substrates were treated with the
above optimized conditions, and the results are summa-
rized in Table 2. All cases showed significant base-orient-
ed chemoselectivity. And the substituents on the phenol
ring had obvious effects on this Wacker cyclization.
When the substituents at para position of phenolic hy-
droxyl in the left phenyl ring A were the electron-donating
HO
H
O
4a
MeO
HO
HCl
O
O
PdL
H
O
6-exo-trig
PdCl2
PdCl2
H
7
11
MeOH
HO
O
PdCl
O
O
O
O
3a
PdCl
HCl
8
Pd0
10
CuCl2
HPdCl
syn-
elimination
O2
Pd(0)
2a
HO
CuCl
PdCl2
O
PdCl2
O
PdCl
6
1a
OH
PdCl
OH
1a
5-endo-trig
OH
OH
9
OH
HCl
PdCl2
PdCl2
5
HCl
base
5
Scheme 2 Proposed mechanism of Pd-catalyzed Wacker cyclization and conjugated addition of phenolic olefins
Synlett 2011, No. 11, 1579–1584 © Thieme Stuttgart · New York

1582
Z. Xin et al.
LETTER
groups, such as methyl or tert-butyl group, the reactions position of phenolic hydroxyl group of phenyl ring A gave
gave the corresponding bisbenzannelated spiroketals 2b,c better yields (entries 2, 3, and 7) than that with electron-
in moderate yields along with low yields of the benzofu- withdrawing groups (Table 3, entries 4–6). The reaction
ran side products 3b,c (Table 2, entries 2 and 3). In con- using the substrate with methoxyl group at ortho position
trast, electron-withdrawing groups on the same position, of the phenol ring A (R2 = OMe) or at ortho position of the
such as phenyl, chlorine, or ester group, caused longer re- phenol ring B (R3 = OMe) was also investigated, and the
action time, lower yields of the bisbenzannelated spiroket- desired chromans 4g (Table 3, entry 7) was obtained in
als 2d–f, and higher yields of the benzofuran side product 95%. Compared with the aforementioned spiroketaliza-
3d–f (Table 2, entries 4–6). When using substrate 1g with tion (Table 2), this chroman-forming difunctionalization
a methoxyl group ortho to the phenol ring A, the Wacker- reaction mostly took shorter time and gave higher yields
type oxidative cyclization smoothly proceeded, and 2g (Table 3).
was formed in higher yield (Table 2, entry 7). From these
In summary, an efficient and highly chemoselective syn-
results, it may conclude that the electron-rich phenyl ring
thesis of [5,6]-bisbenzannelated spiroketals and 2-sub-
A might benefit the formation of spiroketal product 2, as
stitued chromans has been developed by using Pd(II)/
the electron-donating group on ring A will increase the
Cu(II)-catalyzed heteroatom difunctionalization of phe-
Pd(II)-involved nucleophilic activation of the double
nolic olefins. This base-oriented selective Wacker-type
oxidative cyclization was unprecedented, and the high
chemoselectivity was drastically controlled by the pres-
bonds in benzofuran 3, which will make acceleration for
the further aroxylation of the second phenolic OH group.
But the electron-withdrawing groups on ring A will re- ence or absence of base. This divergent synthetic protocol
duce the reactivity of the double bond as donor for Pd(II)- could serve as a good complement to the existing method-
mediated olefin activation, giving the decreased ratios of ologies, and will be potentially useful in the synthesis of
2/3. Otherwise, 1h gave mainly 3h along with messy nature products with such spiro and chroman skeletons.
product, which may be responsible to the steric hindrance
of the methoxyl group.
According to the preliminary investigation of base-orient-
ed chemoselectivity, the phenolic olefins 1a–g, in the
presence of Cs2CO3 (20 mol%) together with PdCl2 (10
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
mol%) and CuCl2 (20 mol%) in MeOH, underwent the ex-
pected 6-exo-trig cyclization to give the corresponding 2-
substituted chromans 4 in good yields (Table 3). Similar
to the spiroketalization, these difunctionalization reac-
tions of olefins with election-donating groups at the para
Acknowledgment
We are grateful for the financial support of the National Natural Sci-
ence Foundation of China (Grant No. 20802028).
Table 2 Wacker Cyclization of Phenolic Olefinsa
R2
R3
R2
R2
OH
OH
HO
R3
O
PdCl2 (10 mol%)
CuCl2 (20 mol%)
A
O
O
R3
+
R1
R1
MeOH
O2, 60 °C
B
R1
2
3
1
Entry
Substrate
Time (h)
Yield of 2 (%)b
2a 65
Yield 3 (%)b
3a 28
1
2
3
4
5
6
7
8
1a R1 = R2 = R3 = H
10
10
11
14
16
22
8
1b R1 = Me, R2 = R3 = H
1c R1 = t-Bu, R2 = R3 = H
1d R1 = Ph, R2 = R3 = H
1e R1 = Cl, R2 = R3 = H
1f R1 = EtOOC, R2 = R3 = H
1g R1 = R3 = H, R2 = MeO
1h R1 = R2 = H, R3 = MeO
2b 63
3b 27
2c 60
3c 25
2d 50
3d 32
2e 45
3e 42
2f 36
3f 28
2g 71
3g 22
13
2h messy
3h 47
a All reactions were performed on a 0.2 mmol scale.
b Isolated yields.
Synlett 2011, No. 11, 1579–1584 © Thieme Stuttgart · New York

LETTER
Synthesis of Bisbenzannelated Spiroketals and 2-Substituted Chromans
1583
Table 3 Palladium-Catalyzed Cyclization and Conjugated Addition of Phenolic Olefinsa
R2
A
OH OMe
PdCl2 (10 mol%)
CuCl2 (20 mol%)
OH
R2
OH
B
R3
O
R3
Cs2CO3 (20 mol%)
MeOH, O2, r.t.
R1
R1
1
4
Entry
Substrate
Time (h)
Yield of 4 (%)b
4a 89
syn/antic
1
2
3
4
5
6
7
8
1a R1 = R2 = R3 = H
5
4
7.1:1
7.7:1
4.3:1
9.1:1
6.2:1
6:1
1b R1 = Me, R2 = R3 = H
1c R1 = t-Bu, R2 = R3 = H
1d R1 = Ph, R2 = R3 = H
1e R1 = Cl, R2 = R3 = H
1f R1 = EtOOC, R2 = R3 = H
1g R1 = R3 = H, R2 = MeO
1h R1 = R2 = H, R3 = MeO
4b 90
5
4c 89
6
4d 85
8
4e 88
10
3
4f 56
4g 95
9.6:1
4
4h messy
a All reactions were performed on a 0.2 mmol scale.
b Average isolated yield of two reactions.
c Measured by 1H NMR.
(10) Brasholz, M.; Sörgel, S.; Azap, C.; Reißig, H. U. Eur. J. Org.
Chem. 2007, 3801.
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LETTER
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