Polyheterocycles by palladium(II)-catalyzed oxidative domino reactions involving direct C-H functionalization

Article abstract of DOI:10.1002/adsc.201000670

A novel palladium(II)-catalyzed oxidative domino reaction sequence of diyne-enones and substituted indoles to afford polyheterocycles involving direct C-H functionalization using air as oxidant has been developed.

Full text of DOI:10.1002/adsc.201000670

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DOI: 10.1002/adsc.201000670
Polyheterocycles by Palladium(II)-Catalyzed Oxidative Domino
À
Reactions Involving Direct C H Functionalization
Renrong Liua and Junliang Zhanga,b,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-021-6223-5039; e-mail: jlzhang@chem.ecnu.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: August 28, 2010; Revised: November 3, 2010; Published online: December 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000670.
Abstract: A novel palladium(II)-catalyzed oxidative
domino reaction sequence of diyne-enones and sub-
stituted indoles to afford polyheterocycles involving
direct C H functionalization using air as oxidant
has been developed.
Recently, we and others have described a number
of catalytic reactions leading to highly substituted
furans that involve cationic furanyl-metals IA as key
reactive intermediates, which were generated from 2-
(1-alkynyl)-2-alken-1-ones (yne-enones) in the pres-
ence of metal catalysts [Scheme 1, Eq. (a)].[7] As a
kind of 1, 3-dipole synthon, IA can readily react with
nucleophiles and electrophiles[7a–g] or undergo cyclo-
additions with nitrones[7h] or heterodienes.[7i] Very re-
cently, we reported a Rh(I)-catalyzed tandem reaction
of diyne-enones and alcohols leading to 2,3-fused bi-
cyclic furans via the corresponding 1,5-dipolar inter-
mediate IB [Scheme 1, Eq. (b)].[8] During these stud-
À
À
Keywords: air; C H functionalization; domino re-
actions; palladium; polyheterocycles; substituted in-
doles
Highly substituted indoles[1] and furans[2] are two ies, we envisaged that indoles may react with IB via
classes of key structural units in many bioactive natu- direct C H functionalization in the presence of palla-
ral products and building blocks in organic synthesis. dium(II) species leading to polyheterocycles
Thus, the development of new methods for accessing [Scheme 1, Eq. (c)].
À
unique indole and furan derivatives for new leads in
We initiated the palladium-catalyzed domino reac-
drug and material discovery is still highly desirable. tion of diyne-enone 2a with N-methylindole 1a under
The direct C H functionalization of indoles presents different reaction conditions.[9] Gratifyingly, after
À
the advantage of convenience and atom economy, many attempts, the desired polycyclic product 3aa
which has been applied successfully in the synthesis of was obtained in 85% isolated yield after running the
indole derivatives.[3] For example, Stoltz,[3a] Shi,[3h] reaction for 18 h at 408C in CH3CN with 6.0 equiva-
Jiao[3i] and their co-workers have accomplished the lents of N-methylindole and 2.0 equivalents of
À
direct C H functionalization of indoles by using envi- LiBr·H2O. There is no difference between air and O2
ronment friendly O2 or air as oxidant. In contrast to as oxidant. Other commonly used oxidants such as
À
indoles, most C H functionalizations of furans are CuX2 (X=Br, Cl), FeCl3, benzoquinone (BQ), and
known to occur at the 2- or 5-position, the functional- additives such as LiCl and CuX (X=Br, Cl) did not
izations at the 3- or 4-position are very difficult,[4a–d] improve the yield. When AgOAc is used as the oxi-
and thus synthesis of highly substituted furans from dant, the reaction cannot afford the expected product
acyclic precursors has become the predominant way.[4] 3aa. To our delight, further screening showed that
We report herein a novel palladium(II)-catalyzed oxi- 2.0 equivalents of 1a and 0.5 equivalent of LiBr·H2O
dative domino reaction[5] by combination of direct led to a satisfactory yield (standard conditions) [Eq.
À
C H functionalization of indoles with cascade cycliza- (1)].
tions of diyne-enones using air as the clean oxidant,
Under these optimized reaction conditions, we next
which provides a rapid access to novel indole-furan examined the scope and limitations of this transfor-
polyheterocycles.[6]
mation via variation of indoles (Table 1). The sub-
stituent (R’) at the 4-, 5- or 6-position of indole has a
Adv. Synth. Catal. 2011, 353, 36 – 40
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
36

Polyheterocycles by Palladium(II)-Catalyzed Oxidative Domino Reactions
Scheme 1. Previous works and this work.
little effect on the reaction. Introduction of an elec-
Table 1. Variation of indole components.[a]
tron-donating methoxy group improves the yield a
little bit, while the weak electron-withdrawing group
(Br) leads to a slightly lower yield (Table 1, entries 3
and 4), indicating that the high nucleophilicity of the
indole will help the reaction. The N-benzylindole 1h
À
and the unprotected indole 1f with an active N H are
also compatible to give the corresponding products in
high yields, but the former reaction needs higher cata-
lyst loading to accomplish the reaction (Table 1, en-
tries 6–8).
Entry
R’/R (1)
Time
[h]
Product (Isolated
yield [%])
In general, R3 at the terminal alkyne moiety of
diyne-enones has a significant effect on the yield
(Scheme 2). When R3 is an aryl group, the transfor-
mations proceed smoothly to give the corresponding
1
2
3
4
5
6
H/Me (1a)
18
20
18
22
30
18
18
26
3aa (82)
3ba (80)
3ca (85)
3da (70)
3ea (83)
3fa (69)
3ga (70)
3ha (72)
5-Me/Me (1b)
5-OMe/Me (1c)
5-Br/Me (1d)
6-Me/Me (1e)
H/H (1f)
4-Me/H (1g)
H/Bn (1h)
products 3aACTHNUGTRNEUNG(b–e) in high yields, the structure of 3ab
was confirmed by the single-crystal X-ray diffraction
analysis.[10] In contrast, when R3 is an alkyl group, 3af
can be produced in 53% yield under the catalysis of
7
8[b]
20 mol% of [PdCl2ACHTNUTGRNEUNG(CH3CN)2], a higher yield can be
[a]
achieved with more N-methylindole (1a, 10 equiv.).
However, only a 46% yield of 3ag is obtained for the
diyne-enone with a terminal alkyne (R3 =H), which
All reactions were carried out under the optimal condi-
tions reported in the text, unless otherwisw indicated.
20 mol% of PdCl2ACHTNUGTRNEUNG(CH3CN)2 were used
[b]
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asc.wiley-vch.de
37

Renrong Liu and Junliang Zhang
COMMUNICATIONS
out.[9,11] The absorption bands of these products
appear in the region of 250 to 350 nm: depending on
the electron-donating or electron-withdrawing ability
of substituent groups. In CH2Cl2 solution, these com-
pounds exhibit fluorescence ranging from 420 to
450 nm. It is observed that there is a small red shift
with substrates containing electron-donating group at
the indole.
A plausible mechanism that accounts for this
Pd(II)-catalyzed oxidative domino reaction is depict-
ed in Scheme 3. In the presence of LiBr·H2O, the
diyne-enones
(CH3CN)2 [X=Br or Cl, generated from PdCl2
(CH3CN)2 and LiBr.H2O] to give intermediate IC. The
2 interacted with PdX2 or PdX2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
heterocyclization would produce furanyl-palladium ID
and subsequent syn-addition would generate a bicylic
vinyl-palladium species IE with a carbocation. The nu-
cleophilic addition of 1a to the carbocation of IE at
the 3-position of indole would release one proton and
give vinyl-palladium species IF which would undergo
À
direct C H activation at the 2-position of indoles to
generate a palladacycle IG and release the HX. Subse-
quent reductive elimination would yield the final
product and generate a Pd(0) species. An alternative,
less possible Heck-like process is insertion of double
À
C C bond of indole into the vinyl-Pd of IF, followed
by b-H elimination to give the desired product. Pd(0)
can be oxidized by the air to regenerate the PdX2 spe-
cies in the presence of two molecules of HX.
In summary, we have developed a novel palladi-
AHCTUNGTREGuNNUN m(II)-catalyzed oxidative domino reaction of diyne-
enones with indoles or N, N-dimethylaniline involving
À
direct C H functionalization, leading to a series of
polyheterocyclic compounds with three newly formed
Scheme 2. Variation of diyne-enone components.
may be caused by the easy oxidative homocoupling of
the terminal alkyne under the reaction conditions,
LiBr·H2O was left out in this case in order to acceler-
ate the reaction. R1 has a little effect on the reaction
and an alkyl group can be introduced.
The generality of this transformation was further
investigated by employing 2k with TsN as the tether
group and 4 containing a 1, 7-diyne moiety with 1a,
respectively. To our delight, the desired product 3ak
can be obtained in moderate yield [Eq. (2)]. Polycy-
ACHTUNGTRENNUNGclic compound 5 with a newly-formed 5,7,7-tricyclic
core can be produced in 60% yield under the optimal
conditions [Eq. (3)]. Gratifyingly, N,N-dimethylaniline
6 can be applied as the nuclophile, leading to a 37%
yield of compound 7 [Eq. (4)].
With the polyheterocycle products in hand, a pre-
liminary survey of their optical properties was carried Scheme 3. Plausible mechanism
38
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 36 – 40

Polyheterocycles by Palladium(II)-Catalyzed Oxidative Domino Reactions
Supporting Information
Experimental details and copies of H/13C NMR spectra of
fused rings using air as oxidant. Further studies en-
compassing the mechanism, scope and the new reac-
tion design based on diyne-enones are underway in
this laboratory and will be reported in due course.
1
all new compounds are available as supporting information.
Experimental Section
Acknowledgements
We are grateful to National Science Foundation of China
(20972054), Ministry of Education of PRC, and 973 program
(2009CB825300).
Typical Procedure for the Synthesis of 3aa (Table 1,
entry 1)
PdCl2ACHTUNGTRENNUNG(CH3CN)2 (3.9 mg, 0.015 mmol) was added to a mix-
ture of 1a (73.5 mg, 0.15 mmol), 2a (39.3 mg, 0.3 mmol) in
CH3CN (1.5 mL) at 408C. After stirring for 18 h, 1a was
consumed completely according to TLC analysis, and then
the reaction mixture was concentrated under vacuum. The
residue was purified by column chromatography on silica
gel (hexanes:CH2Cl2:Et2O=4:2:0.1) to give the desired
product 3aa as a white solid; yield: 76 mg (82%); mp 142–
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Adv. Synth. Catal. 2011, 353, 36 – 40