Palladium-catalyzed [2+2+1] oxidative annulation of 4-hydroxycoumarins with unactivated internal alkynes: Access to spiro cyclopentadiene-chroman-2,4-dione complexes

Article abstract of DOI:10.1002/adsc.201300893

Herein, we report our new results regarding a palladium-catalyzed [2+2+1] oxidative annulation of 4-hydroxycoumarins with unactivated internal alkynes, which affords a new class of compounds: the spiro cyclopentadiene-chroman-2,4- diones.

Full text of DOI:10.1002/adsc.201300893

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DOI: 10.1002/adsc.201300893
Palladium-Catalyzed [2+2+1] Oxidative Annulation of
4-Hydroxycoumarins with Unactivated Internal Alkynes: Access
to Spiro Cyclopentadiene-Chroman-2,4-dione Complexes
Shiyong Peng,a,b Tao Gao,a Shaofa Sun,a Yanhong Peng,a Minghu Wu,a
Haibing Guo,a and Jian Wanga,b,*
a
Hubei Collaborative Innovation Centre for Non-power Nuclear Technology, College of Chemistry and Biological
Sciences, Hubei University of Science and Technology, Hubei Province 437100, Peopleꢀs Republic China
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
b
E-mail: chmwangj@nus.edu.sg
Received: October 5, 2013; Revised: November 24, 2013; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300893.
[5]
À
Abstract: Herein, we report our new results regard-
ing a palladium-catalyzed [2+2+1] oxidative annu-
lation of 4-hydroxycoumarins with unactivated in-
ternal alkynes, which affords a new class of com-
pounds: the spiro cyclopentadiene-chroman-2,4-
diones.
via a C H functionalization to construct indoles.
The group of Wu used a similar strategy to successful-
ly access substituted naphthalenes using internal alk-
AHCTUNGTRENNUNG
ynes as building blocks.[6] Most recently, Sahoo et al.
disclosed an example of benzofuran synthesis through
a palladium-catalyzed oxidative annulation of phenols
and internal alkynes.[7] Our group recently disclosed
the palladium-catalyzed oxidative annulations of
4-hydroxycoumarins and internal alkynes to access
highly substituted cyclopentadiene-fused chromones
(Scheme 1a).[8b] As part of our continued interest in
transition metal-catalyzed oxidative coupling process-
es,[8] herein, we report our new discovery regarding
a palladium-catalyzed [2+2+1] oxidative annulation
À
Keywords: C H activation; palladium-catalyzed ox-
idative annulations;
plexes
ACHTUNGTNER[NUNG 2+2+1] reactions; spiro com-
The realm of transition metal-catalyzed cross-coupling of 4-hydroxycoumarins with unactivated internal
reactions has traditionally depended on prefunctional- alkynes, which affords a new class of compounds:
ized substrates for both reactivity and selectivity.[1] the
spiro
The quest for improved atom economy and efficiency (Scheme 1b).
has brought forward revolutionary changes and im- Initially, we investigated the influence of various
cyclopentadiene-chroman-2,4-diones
portant advances especially in the palladium-cata- catalyst parameters on the catalytic activity for annu-
À
lyzed direct C H functionalization, which efficiently lation of 4-hydroxycoumarin 1a with diphenyl acety-
leads to the diversity-oriented synthesis of various
functional molecules.[2] Although these strategies
offer numerous advantages (e.g., mild conditions,
readily accessible starting materials and environmen-
tally benign procedures), the development of general
and flexible routes to a vast number of heterocycles
still remains an important goal.
Internal alkynes are important building blocks ex-
À
tensively used in the palladium-catalyzed direct C H
functionalization for the preparation of a wide range
of pharmaceuticals, agrochemicals, and heterocycles.[3]
In recent reports, the Ellman group described a syn-
thesis of dihydropyridine and pyridine from imines
and internal alkynes through a palladium-catalyzed
[4]
À
direct C H functionalization. Jiao and co-workers
Scheme 1. Palladium-catalyzed cascade reactions of 4-hy-
reported an elegant Pd-catalyzed oxidative annulation droxycoumarins with internal alkynes.
Adv. Synth. Catal. 2014, 356, 319 – 324
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Shiyong Peng et al.
Table 1. Optimization of the reaction conditions.[a]
further lowering (608C) or increasing the temperature
(1008C) led to a slow reaction progress (entries 10
and 11, 66% and 57%, respectively). Moreover, the
lowering of the catalyst loading decreased the chemi-
cal yields dramatically (entries 18 and 19).
With these optimized conditions in hand, we sur-
veyed the scope of 4-hydroxycoumarins 1. Table 2 il-
lustrates the substitution pattern on our validated 4-
hydroxycoumarins 1a–l. Electron-withdrawing, neu-
tral and electron-donating substituents on the C-4 po-
sition were tolerated and gave high yields (3aa–da,
3fa). Substrates with electron-withdrawing or elec-
tron-donating substituents at the C-3, C-5 or C-6 posi-
tion also showed moderate to high reactivity and af-
forded the corresponding spiro cyclopentadiene-chro-
man-2,4-dione products (Table 2, 3ea, 3ga–ja). In ad-
dition, naphthalene ring-based 4-hydroxycoumarins
were also tolerated and gave the corresponding spiro
products in good yields (Table 2, 3ka and 3la, 80%
and 63%, respectively).
Given the great value of alkynes, we then examined
various internal alkynes 2 that could potentially react
with 1a to construct a diversity of spiro cyclopenta-
diene-chroman-2,4-dione complexes. As the results in-
dicated in Table 3 demonstrate, the reaction presented
a broad substrate tolerance among internal alkynes.
Electron-rich internal alkynes reacted to give good re-
action yields (Table 3, 3ab–ad, 3af–ag) while electron-
deficient systems were less facile (Table 3, 3ae). A
heteroaryl-containing alkyne was also tolerated (3aj).
When asymmetrical internal alkynes were employed,
a mixture of regioisomers was usually observed (3ah,
3ai, and 3aj).
Entry Catalyst
Oxidant
Solvent
3aa [%][b]
[c]
1
PdCl2
Cu(OAc)2 DMSO
T
–
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
U
N
58
[c]
N
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
O2
U
–
69
23
R
N
R
27
8
A
9[d]
10[e]
11[f]
12
13
14
15
16
17
18[i]
19[j]
Pd
G
79
66
57
24
64
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
R
E
R
R
E
N
R
E
DMSO
DMSO
AgOAc
[c]
PhI
G
–
–
–
–
BQ[g]
DMSO
DMSO
DMSO
[c]
[c]
Oxones
DDQ[h]
[c]
R
A
Cu
Cu
U
52
33
[a]
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a
(0.5 mmol, 2.5 equiv.), catalyst (10 mol%), oxidant
(2.0 equiv.), solvent (2 mL), 808C, 48 h unless otherwise
indicated.
[b]
[c]
[d]
[e]
[f]
Isolated yield of 3aa.
No desired product detected.
Using 2a (0.8 mmol, 4.0 equiv.).
At 608C.
At 1008C.
1,4-Benzoquinone.
2,3-Dichloro-5,6-dicyanobenzoquinone.
Using 5 mol% of catalyst for 48 h.
Using 1 mol% of catalyst for 96 h.
In the survey of oxidants, an exception was ob-
served using oxidant K2S2O8. As shown in Table 4, 4-
hydroxycoumarins reacted with various alkynes in the
presence of K2S2O8 oxidant to directly generate a vari-
[g]
[h]
[i]
[j]
ety of valuable furoACTHUNGTRENNG[U 3,2-c]coumarins 4 in moderate
yields (33–53%).[10] We predicted that the reaction
could involve a Pd(II) to Pd(IV) mechanism to afford
lene 2a in DMSO at 808C with 10 mol% of catalysts 4aa.[11] As indicated in Scheme 2, a plausible key in-
[e.g., PdCl2, Pd
G
N
ACHTUNGRTEN(NNUG OAc)2] and termediate 7 could be generated in the presence of
2.0 equivalents of oxidant CuAHCNUTGTRENNUNG
(Table 1, entries 1–4). It was found that the reaction prove the reaction efficiency are under way in our
occurred and yielded the desired product 3aa[9] only laboratory.
in the presence of Pd
G
G
Due to the various bioactivities of heterocycles, we
lysts (entries 2 and 4, 58% and 69%, respectively). turned our attention to the late-stage diversification
Next, we examined a series of solvents (entries 4–8). of functional molecules. It was found that cyclic
As a result, DMSO supported a high chemical yield ketone 1m efficiently reacted with diphenylacetylene
(entry 4). To further improve the efficacy of the reac- 2a to form the corresponding spiro structure 3ma in
tion, we tested the ratio of 1a/2a. Notably, changing 85% yield under the standard conditions [Eq. (1)].
the ratio of 2a from 2.5 to 4.0 equivalents increased Upon treatment of product 4aa with KOH and MeI
the chemical yield to 79% (entry 9). Variation of the in DMSO at 808C for 2 h, the tetrasubstituted furan 5
oxidants [e.g., O2, AgOAc, PhIACHTNURTGENUNG(OAc)2, BQ, Oxones, was obtained in 80% yield [Eq. (2)]. The photolysis
DDQ] led to no reaction (entries 14–17) or a decrease of 4aa was accomplished in the presence of iodoben-
in chemical yield (entries 12 and 13). The effects of zene diacetate and UV light, smoothly affording the
temperature are summarized in Table 1. However, C-2 functionalized coumarin 6.
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Palladium-Catalyzed [2+2+1] Oxidative Annulation
Table 2. Substrate scope of coumarins.[a]
[a]
Reaction conditions: DMSO (2 mL), 1a–l (0.2 mmol, 1.0 equiv.), 2a (0.8 mmol, 4.0 equiv.),
PdACHTUNGTRENNUNG(OAc)2 (10 mol%), CuCAHTUNGTRNEN(UGN OAc)2 (2.0 equiv.), 808C, 48 h.
Scheme 2. Plausible mechanism.
clodiene 11, which subsequently undergoes reductive
A plausible mechanism for the synthesis of spiro elimination to yield the spiro cyclopentadiene-chro-
cyclopentadiene-chroman-2,4-diones is illustrated in man-2,4-dione 3aa.
Scheme 2. The catalytic cycle starts from the pallada-
In summary, we have developed an efficient synthe-
tion of 4-hydroxycoumarin 1a to yield the palladium sis of spiro cyclopentadiene-chroman-2,4-dione het-
intermediate 8 (Scheme 3). Then the syn-addition of erocycles. The method employs a direct Pd(II)-cata-
intermediate 8 to diphenylacetylene 2a generates the lyzed oxidative [2+2+1] cycloaddition of readily
vinylpalladium intermediate 9. The following inser- available 4-hydroxycoumarins and unactivated inter-
tion of the 2a entity affords the butadienylpalladium nal alkynes. Various substituents are well tolerated in
intermediate 10. Finally, the intramolecular pallada- the reaction, which leads to a number of unique mo-
tion of 10 leads to the formation of palladabenzocy- lecular structures. Further extension of this synthetic
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Shiyong Peng et al.
Table 3. Substrate scope of alkynes.[a]
[a]
Reaction conditions: DMSO (2 mL), 1a (0.2 mmol, 1.0 equiv.), 2b–j (0.8 mmol, 4.0 equiv.),
Pd(OAc)2 (10 mol%), Cu(OAc)2 (2.0 equiv.), 808C, 48 h.
Ratio of regioisomers (r.r.), determined by NMR.
Mixture of regioisomers.
G
ACHTUNGTRENNUNG
[b]
[c]
134.24, 133.52, 130.09, 129.36, 128.35, 127.93, 127.80, 127.55,
127.37, 125.02, 119.91, 117.62, 80.24, 77.42, 77.16, 76.91; HR-
MS (EI): m/z=516.1727, calcd. for [C37H24O3]+: 516.1725.
4-Hydroxycoumarin 1a (0.2 mmol), diphenylacetylene 2a
strategy to other types of substrates is under way in
our laboratory and will be presented in due course.
(0.4 mmol), PdACHTUNGTRENGN(U OAc)2 (0.02 mmol), and K2S2O8 (0.4 mmol)
Experimental Section
were added into DMSO (2 mL). The mixture was stirred at
808C under an N2 atmosphere for 2 d. For work-up the
crude mixture was cooled down to room temperature and
then poured into ethyl acetate (20 mL), which was washed
with brine (10 mLꢂ4), dried with MgSO4 and filtered. The
solvent was removed to obtain crude product, which was pu-
rified by column chromatography on silica gel eluted by
ethyl acetate/hexane=1:30 to afford the desired product 4aa
Typical Procedure
4-Aminocoumarin 1a (0.2 mmol), diphenylacetylene 2a
(0.8 mmol), PdACHTUNGTRENNUNG(OAc)2 (0.02 mmol) and CuACHTUNGTREN(NUGN OAc)2
(0.4 mmol) were added into DMSO (2 mL). The mixture
was stirred at 808C under an N2 atmosphere for 48 h. The
crude product was purified by column chromatography on
silica gel eluted by EtOAc/hexane=1:30 to afford the de-
sired product 3aa as a yellow solid; yield: 79%. 1H NMR
(500 MHz, CDCl3): d=7.84 (d, J=7.6 Hz, 1H), 7.50 (t, J=
7.7 Hz 1H), 7.16–6.98 (m, 22H); 13C NMR (125 MHz,
CDCl3): d=188.27, 164.89, 154.83, 149.09, 142.68, 137.40,
1
as a yellow solid; yield: 35.9 mg (53%). H NMR (500 MHz,
CDCl3): d=7.99 (d, J=7.7 Hz, 1H), 7.59–7.49 (m, 5H),
7.48–7.42 (m, 4H), 7.38 (t, J=7.5 Hz, 1H), 7.35–7.29 (m,
3H); 13C NMR (125 MHz, CDCl3): d=157.59, 156.56,
152.82, 151.50, 130.84, 130.36, 130.30, 129.43, 128.94, 128.72,
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Palladium-Catalyzed [2+2+1] Oxidative Annulation
Table 4. Synthesis of furan-fused chromen-2-one complexes.[a]
[a]
Reaction conditions: DMSO (2 mL), 1 (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 4.0 equiv.), Pd
(10 mol%), K2S2O8 (2.0 equiv.), 808C, 48 h, N2 balloon.
ACHTUNGERTN(NUNG OAc)2
Scheme 3. Plausible mechanism.
128.70, 128.53, 126.82, 124.55, 121.02, 120.99, 117.35, 112.87, References
111.43, 77.41, 77.16, 76.91; HR-MS (EI): m/z=338.0954,
calcd. for [C23H14O3]+: 338.0943.
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