Palladium(II) Acetate-Catalyzed Dual C–H Functionalization and C–C Bond Formation: A Domino Reaction for the Synthesis of Functionalized (E)-Bisindole-2-ones from Diarylbut-2-ynediamides

Article abstract of DOI:10.1002/adsc.201600767

A domino reaction of palladium(II)-catalyzed dual C–H functionalization with subsequent intramolecular annulation is presented. This method provides a convenient synthesis of a range of symmetrical and unsymmetrical biologically important (E)-bisindole-2-ones under extremely mild reaction conditions – room temperature, green oxidant and no additive. The reaction mechanism is elucidated in light of the yield values as well as additional control experiment results. (Figure presented.).

Full text of DOI:10.1002/adsc.201600767

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DOI: 10.1002/adsc.201600767
Palladium(II) Acetate-Catalyzed Dual C–H Functionalization
and C–C Bond Formation: A Domino Reaction for the Synthesis
of Functionalized (E)-Bisindole-2-ones from Diarylbut-2-yne-
diamides
Guangchen Li,a Guangshuai Zhou,a Daisy Zhang-Negrerie,a Yunfei Du,a,b,*
Jianhui Huang,a,b,* and Kang Zhaoa
a
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, Peopleꢀs Republic of China
Fax : (+86)-22–2740–4031; phone: (+86)-22–2740-403; e-mail: duyunfeier@tju.edu.cn or jhuang@tju.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, Peopleꢀs Republic of
b
China
Received: July 17, 2016; Revised: August 30, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600767.
Abstract: A domino reaction of palladium(II)-cata-
lyzed dual C–H functionalization with subsequent
intramolecular annulation is presented. This
method provides a convenient synthesis of a range
of symmetrical and unsymmetrical biologically im-
portant (E)-bisindole-2-ones under extremely mild
reaction conditions – room temperature, green oxi-
dant and no additive. The reaction mechanism is
elucidated in light of the yield values as well as ad-
ditional control experiment results.
tories have developed novel strategies for forming
heterocycles under conditions both with[6] and with-
out[7] transition metals. As starting substrates, alkyne
amides have been recognized as a class of useful
building blocks for the assemblage of the oxindole
skeleton via palladium-catalyzed C–H functionaliza-
tion followed by intramolecular annulation reac-
tions.[8–11] In 2006, Zhu reported a domino reaction[12]
for the synthesis of 3-(diarylmethylenyl)oxindoles
from alkyne amides and aryl iodides, which involves
a palladium-catalyzed carbopalladation, C–H activa-
tion and two C–C bond formations [Scheme 1, Eq.
(1)].[9] Lately, Tang realized the construction of
a framework that simultaneously contains an oxindole
and a dibenzoazepine moiety starting from arylpro-
piolamide compounds [Scheme 1, Eq. (2)].[10] This
process involves a sequential intramolecular arylation
of the alkynyl moiety and an annulation reaction be-
Keywords: domino reaction; intramolecular annula-
tion; mild reaction conditions; palladium(II)-cata-
lyzed process
The bisindole-2-one skeleton is an important structur- tween the vinyl carbon and an aryl ring carbon. In
al framework found not only in natural products but 2012, Li reported a synthetic route to selectively build
also in a number of synthetic bioactive compounds[1] two heterocyclic rings from various arylpropiolamides
including Meisoindigo and Natura, which have been by palladium-catalyzed C–O bond formation with
demonstrated as successful drugs for treating leuke-
mia (Figure 1).[2] Additionally, bisindol-2-ones have
recently emerged as promising scaffolds for the prep-
aration of conjugated polymers,[3,4] many of which
have found applications in organic photovoltaics as
key components in the active layers of organic solar
cells.[3] For example, isoindigo has been used in the
design of low-band gap semiconductor materials.[4]
The transition metal-catalyzed C–H functionaliza-
tion and C–C bond formation process is undoubtedly
a powerful tool for the construction of N-containing
Figure 1. Representative compounds containing a bisindole-
heterocycles.[5] During the past few years, our labora- 2-one moiety.
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Table 1. Optimization of the reaction conditions.[a]
Entry [Pd]
Base (3 equiv.) Time [h] Yield [%][b]
1[c]
2[c]
3
Pd(OAc)2
–
Pd(OAc)2
Pd(OAc)2
PdCl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
4
12
6
6
6
6
6
6
6
6
5
5
5
5
5
18
58
0[d]
68
69
66
50
5
61
40
64
78
43
23
17
21
67
4[e]
5
6
7
8
9
10
11
12[f]
13[g]
14[h]
15[i]
16
PdCl2(PPh3)2 Cs2CO3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2[j]
Pd(OAc)2
Cs2CO3
Na2CO3
Et3N
K3PO4
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
[a]
Reactions conditions: 1a (0.5 mmol), [Pd] (10 mol%), air
as the oxidant and base (2 equiv.) in DMF (c=0.05M) at
room temperature unless otherwise stated.
Isolated yield.
Cu(OAc)2 (3 equiv.) as the oxidant.
No reaction occurred.
[b]
[c]
[d]
[e]
[f]
O2 (in balloon) as the oxidant.
The reaction was run in DMSO.
The reaction was run in CH3CN.
The reaction was run in DCM.
The reaction was run in toluene.
Pd(OAc)2 (5 mol%).
[g]
[h]
[i]
[j]
Scheme 1. Formation of oxindoles via intramolecular annu-
lation of alkyne amides.
for the conversion, as no reaction occurred in the ab-
sence of Pd(OAc)2 (Table 1, entry 2). To our surprise,
subsequent oxidative intramolecular C–C bond for- the reaction with no added Cu(OAc)2 afforded the
mation [Scheme 1, Eq. (3)].[11] Here, we report the product 2a in a slightly improved yield (Table 1,
first intramolecular annulation of diarylbut-2-ynedi- entry 3). This observation indicated that oxygen in the
ACHTUNGTRENNUNGamides via a palladium-catalyzed double annulation air could adequately serve as the oxidant for this pro-
processes leading to a convenient synthesis of versa- cess. Counterintuitively, the yield did not improve
tile biologically intersting bisindole-2-one compounds when pure oxygen gas was supplied (Table 1, entry 4).
[Scheme 1, Eq. (4)].
Under these initial conditions, several palladium
N1,N4-Dimethyl-N1,N4-diphenylbut-2-ynediamide 1a catalysts including PdCl2, PdCl2(PPh3)2 and Pd(PPh3)4
was selected as a model substrate in the search for were examined. Results showed that none of them
the ideal reaction conditions. Results are summarized gave better yields than Pd(OAc)2 (Table 1, entries 5–
in Table 1. Our investigation began with having 1a re- 7). Our next study for identifying an effective base
acting with 0.1 equivalent of Pd(OAc)2, 3 equivalents showed that NaOAc was the best to promote the re-
of Cu(OAc)2, and 2 equivalents of Cs2CO3 in DMF at action as with it the desired product was obtained in
room temperature[8–11] (Table 1, entry 1). To our de- the highest yield (78%) (Table 1, entries 8–11). The
light, the target product 2a was obtained in 58% yield solvent screening study suggested that DMF was by
(Table 1, entry 1). Further control experiments indi- far the most appropriate solvent among all the sol-
cated that the palladium reagent was indispensable vents put to test, including DMSO, CH3CN, toluene
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and DCM (Table 1, entries 12–15). Reducing the load- were concluded to be: 10 mol% of Pd(OAc)2, 2 equiv-
ing of Pd(OAc)2 to 5 mol% resulted in a sluggish re- alents of NaOAc in DMF and air as the oxidant at
action and a decreased yield of 67% (Table 1, room temperature (Table 1, entry 11).
entry 16). Based on these results, the best conditions
Table 2. Synthesis of functionalized bisindole-2-ones.[a]
[a]
Conditions: 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), NaOAc (1.0 mmol) in dry DMF (c=0.05M) at room temperature.
Yield of gram scale reaction in parentheses (see the Supporting Information for details).
The reaction was carried out using 0.2 equiv. of Pd(OAc)2.
Some unidentified by-products were formed.
[b]
[c]
[d]
[e]
The yield was 10% when the reaction was carried out at À108C for 24 h.
[f]
The structure of 2q was assigned by X-ray single crystal diffraction analysis.[13]
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Our next step was to investigate the generality of
this newly established protocol. A variety of diaryl-
ACHTUNGTRENNUNGbut-2-ynediamides 1a–q were investigated under the
optimized conditions (Table 2). The method worked
well with symmetrical substrates bearing an ethyl, n-
butyl and benzyl groups as R3 and R4 (Table 2, 2b–d).
The method showed to be equally applicable to un-
symmetrical substrates, as 1e was successfully convert-
ed into the corresponding unsymmetrical bisindole
product 2e in very good yield. For symmetrical sub-
strates bearing the same R1 and R2 groups, similar
yields were obtained for those bearing a methyl or di-
methyl R1/R2 groups (Table 2, 2f–h), with the o-sub-
stituted substrate 2g giving a relatively lower yield.
On the contrary, drastically different yields (68% vs.
23%) were observed between substrates with R1/R2
being p-OMe and m-OMe (Table 2, 2i vs. 2j[14]). With
regard to substrate 1j, the low yield was probably
caused by the formation of some unidentified by-
products during the reaction. We tried to further im-
prove the yield by restricting the side reactions at
a lower temperature, however, the yield was reduced
to 10% when the reaction was carried out at À108C
after 24 h. Those substrates bearing electron-with-
drawing halogen groups – F, Cl, and Br – all gave the
desired products 2k–m in nearly identical, satisfactory
yields of 65–70%. For the unsymmetrical, mono-sub-
stituted substrates (R1 =H, R2 =Me, OMe, and F), re-
action yield was the highest when the substrate was
F-substituted (83%) while the lowest for the MeO-
substituted (60%) (Table 2, 2n–p). The highest yield
of all (91%) was obtained from 1q, which bears an
electron-donating (OMe) and an electron-withdraw-
ing (Cl) group at the R1/R2 positions (Table 2, 2q).
During the process of the reaction, the substrates
(1a–q) were completely consumed in each case, ac-
companied by the occurrence of different degrees of
side reactions.
Scheme 2. Synthesis of Isoindigo 3r.
Scheme 3. Synthesis of Meisoindigo 3s.
Isoindigo and Meisoindigo, two important pharma-
ceutical agents found to offer effective treatment for termediate A then undergoes cis- or trans-addition to
chronic myeloid leukemia (CML),[2] could be synthe- the triple bond realizing the first annulation via an
sized by using our method in a fairly straightforward electrophilic aromatic substitution (EAS) mechanism.
manner. As illustrated in Scheme 2, the coupling of In path a, the EAS product (E)-B or (Z)-B undergoes
the acetylenedicarboxylic acid with aniline afforded a second intramolecular EAS reaction to form inter-
substrate 1r, and palladium-catalyzed intramolecular mediate C. By losing the leaving group as Pd(0) and
cyclization followed by the removal of the para-me- the acetate ion, intermediate C is converted to inter-
thoxybenzyl ether (PMB) protective group afforded mediate D, which further gives rise to the final prod-
isoindigo 3r in an overall yield of 41%. Likewise, as uct (E)-2a after deprotonation. However, the pathway
depicted in Scheme 3, Meisoindigo 3s could be syn- is inconsistent with the result of the competitive ex-
thesized from readily available 4-methoxy-4-oxobut-2- periment (Scheme 5) involving 1i and 1q, in which 2q
ynoic acid in 6 steps (30% overall yield) (see the Sup- was formed in much higher yield (with ratio of
porting Information for details).
2q:2i=1.4). As is known, the EAS mechanism prefers
On the basis of previous reports,[8–11,15] we tentative- electron-rich aryls, so the second EAS steps proposed
ly postulated two mechanistic pathways for this in path a would then predict a preference for sub-
domino reaction. As illustrated in Scheme 4, the first strates with electron-donating (R1 =OMe) substitu-
step is the carbopalladation between the triple bond ents; yet in contrast, the lower yields were observed
moiety and Pd(OAc)2. The resulted complexation in- in 2i (Scheme 5) with R1 being a methoxy group.
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Scheme 4. Plausible mechanistic pathways.
Scheme 5. Kinetic experiment for electronic effect study.
In the second pathway (path b), after the first EAS
step, intermediate (E)-B undergoes a Pd(II)-catalyzed
C–H functionalization with an aryl hydrogen, passing
through a concerted metalation/deprotonation[16,17]
step to form the Pd(II) complex E. Reductive elimi-
Scheme 6. Kinetic isotope effect experiments.
nation of Pd(0) eventually leads to the final product It is worth noting that the generated Pd(0) species
(E)-2a. As an electron-withdrawing substituent would could be reoxidized by the oxygen in the air back to
increase the acidity of the aryl-H and consequently Pd(II) and enter a new catalytic cycle.
decrease the energy of the transition state for the con-
In summary, we have disclosed an unprecedented
certed metalation/deprotonation,[18] the pathway is approach for the construction of a series of (E)-bisin-
consistent with the competitive experiment results dole-2-ones from the diarylbut-2-ynediamides via
(Scheme 5) which indicated that the higher yield from a palladium(II)-catalyzed intramolecular C–H func-
2q was probably due to the electron-withdrawing tionalization and C–C bond formation protocol. The
R1 =Cl group (which would favor the second annula- method is practically useful and operationally conven-
tion step). Competitive experiments of 1a vs. its deu- ient to perform. The reaction proceeds under mild re-
terated analog (1a-D10) provided the kH/kD value action conditions and can be run on a gram-scale, and
close to 1.4 (Scheme 6), suggesting that the C–H func- the products have important applications as pharma-
tionalization might not be the rate-determining step. ceuticals, dyes and electronic devices.
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Experimental Section
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General Procedure
In a 50-mL round-bottom flask, diarylbut-2-ynediamide
(0.5 mmol) was dissolved in N,N-dimethylformamide (DMF,
10 mL). Pd(OAc)2 (0.05 mmol, 0.1 equiv.) and NaOAc
(1 mmol) were added to the solution. The mixture was then
stirred in the open air at room temperature. The progress of
the reaction was monitored by TLC. Upon completion, the
reaction was quenched with water (40 mL) and then extract-
ed with EA (40 mLꢂ5). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and the solvent was
removed under reduced pressure to provide the crude prod-
uct. The purification was performed by flash column chro-
matography on silica gel.
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Acknowledgements
We acknowledge the National Natural Science Foundation of
China (21472136, 21302136) and the National Basic Research
Project (2014CB932201, 2015CB856500), Tianjin Research
Program of Application Foundation and Advanced Technol-
ogy (15JCZDJC32900) and Tianjin Natural Science Founda-
tion (13JCQNJC04800) for financial support.
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COMMUNICATIONS
8 Palladium(II) Acetate-Catalyzed Dual C–H
Functionalization and C–C Bond Formation: A Domino
Reaction for the Synthesis of Functionalized (E)-Bisindole-
2-ones from Diarylbut-2-yneACTHNUTRGNEUdGN iamides
Adv. Synth. Catal. 2016, 358, 1 – 8
Guangchen Li, Guangshuai Zhou, Daisy Zhang-Negrerie,
Yunfei Du,* Jianhui Huang,* Kang Zhao
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!