Rhodium(III)-Catalyzed Redox-Neutral C-H Annulation of Arylnitrones and Alkynes for the Synthesis of Indole Derivatives

Article abstract of DOI:10.1002/adsc.201500580

By using a nitrone as the oxidizing directing group, a mild, practical and efficient rhodium(III)-catalyzed C-H functionalization for the synthesis of indole derivatives has been developed. This reaction obviates the need for an external oxidant and shows good functional group tolerance. The employment of a sterically hindered Mes group on the carbon center of the nitrone is crucial to produce indoles in high yield.

Full text of DOI:10.1002/adsc.201500580

UPDATES
DOI: 10.1002/adsc.201500580
À
Rhodium(III)-Catalyzed Redox-Neutral C H Annulation of
Arylnitrones and Alkynes for the Synthesis of Indole Derivatives
Zhi Zhou,a Guixia Liu,a,* Yan Chen,a and Xiyan Lua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax: (+86)-21-6416-6128; e-mail: guixia@sioc.ac.cn or xylu@mail.sioc.ac.cn
Received: June 15, 2015; Revised: July 17, 2015; Published online: September 11, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500580.
Abstract: By using a nitrone as the oxidizing direct-
H functionalization, which will open new aspects of
nitrones by acting as an oxidizing directing group.[7a,b]
It should be noted that during the preparation of this
manuscript, an attractive cyclization of arylnitrones
with alkynes to indolines catalyzed by Rh(III)
under external oxidant-free conditions was reported
independently by Changꢀs and Liꢀs groups
(Scheme 1a).[7c,d] It would be intriguing to explore
other transfromations by the use of nitrones as an oxi-
dizing directing group.
ing group, a mild, practical and efficient rhodi-
À
um(III)-catalyzed C H functionalization for the
synthesis of indole derivatives has been developed.
This reaction obviates the need for an external oxi-
dant and shows good functional group tolerance.
The employment of a sterically hindered Mes group
on the carbon center of the nitrone is crucial to pro-
duce indoles in high yield.
Indole represents a privileged structural framework
widely existing in natural products, biologically active
molecules and pharmaceuticals, which has attracted
broad and continued interest in the development of
synthetic approaches for this motif.[8,9] Of the many
À
Keywords: alkynes; annulation; C H activation; ni-
trones; oxidizing directing group; rhodium
À
Transition metal-catalyzed directed C H functionali-
zation represents an atom- and step-economical ap-
proach for complex molecules from less functional-
ized substrates.[1] Despite the notable advances, stoi-
chiometric amounts of external oxidants are generally
required for catalyst regeneration. To circumvent the
use of external oxidants, an attractive redox-neutral
strategy employing an oxidizing directing group,
which acts as both directing group and internal oxi-
dant, has been applied in this field.[2] In recent years,
diverse oxidizing directing groups have been devel-
[3]
À
À
N
oped, which typically contain an oxidizing N O,
N,[4] or N S bond.[5] Further development of novel ox-
idizing directing groups with desired synthetic fea-
tures is still in demand.
À
In a search for innovative oxidizing directing
groups that enable novel transformations to deliver
valuable structures under mild conditions, we turned
our attention to nitrones. Nitrones are easily accessi-
ble and can be viewed as promising compounds due
to their diversity in chemical properties and synthetic
utility.[6] Being the N-oxide of an imine, we envisioned
that the nitrone moiety may serve as an internal oxi-
À
Scheme 1. C H activation using a nitrone as the oxidizing
directing group.
À
À
dant by the cleavage of the N O bond during the C
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Rhodium(III)-Catalyzed Redox-Neutral C H Annulation of Arylnitrones
Table 1. Optimization of reaction conditions for the synthe-
ed,
and
the
representative
data
using
sis of indoles.[a]
[Cp*Rh(MeCN)3](SbF6)2 as the catalyst are shown in
Table 1. With HOPiv as the additive, the desired
indole product 3ba was produced in 30% NMR yield
(Table 1, entry 3).[12] Subsequently, nitrones bearing
different substituents on the carbon center were
screened. Fortunately, a significantly improved yield
was observed with N-(4-methylphenyl)-C-mesitylni-
trone as the substrate, although other analogous nitro-
nes were found to be less effective (Table 1, entries 4–
7). Simply changing the solvent from dichloroethane
to methanol significantly increased the yield to 78%
(Table 1, entry 8). Lowering the reaction temperature
gave an inferior result (Table 1, entry 9). When the re-
action was performed in the presence of 4Š molecu-
lar sieves or water (5 equiv.), the yield of indole was
decreased (Table 1, entries 10 and 11). The optimized
conditions were ultimately identified as: 5 mol% of
[Cp*Rh(MeCN)3](SbF6)2 and HOPiv (2 equiv.) in
MeOH (0.1M) at 808C (Table 1, entry 12). No reac-
tion occurred in the absence of a rhodium catalyst.
With the optimized conditions in hand, we first ex-
amined the reaction scope of the internal alkynes
(Scheme 2). Symmetric diarylacetylenes bearing vari-
ous substituents at the para or meta positions were
compatible with the reaction conditions, furnishing
the corresponding indoles in high yields (81–94%). A
relatively low yield was obtained for ortho-methyl-
substitued diarylacetylene (3af, 32%). Notably, 1,2-
di(naphthalene-1-yl)ethyne was also tolerated to give
a moderate yield of the desired product (3ai, 60%
yield). Moreover, an unsymmetrical diarylacetylene
also reacted smoothly, affording a mixture of two re-
gioisomers (3ah and 3ah’). The aryl-alkyl disubstituted
alkynes seemed to be less effective (3aj and 3an)
Entry
R
Additive (equiv.) Solvent Yield [%][b]
1[c]
2
3
4
5
Ph
Ph
Ph
2-thienyl
CH=CHPh HOPiv (1)
Mes HOPiv (1)
cyclohexyl HOPiv (1)
Mes
Mes
Mes
Mes
Mes
CsOAc (0.5)
–
HOPiv (1)
HOPiv (1)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
NR
6
30
32
55
56
<5
6
7
8
HOPiv (1)
HOPiv (1)
HOPiv (1)
HOPiv (1)
HOPiv (2)
MeOH 78
MeOH 49
MeOH 69
9[d]
10[e]
11[f]
12[g]
MeOH 65
MeOH 88 (85)[h]
[a]
Reaction conditions:
1
(0.14 mmol), 2a (0.1 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol%) and additives in sol-
vent (0.5 mL) at 808C for 24 h under air. Mes=2,4,6-tri-
methylphenyl.
[b]
[c]
[d]
[e]
[f]
Yield determined by 1H NMR.
2.5 mol% of [Cp*RhCl2]2 were used as the catalyst.
Reaction was run at 508C.
20 mg of 4Š MS were added.
5 equiv. of water were added.
MeOH (1 mL).
[g]
[h]
Isolated yield is shown in parentheses.
approaches developed, the transition metal-catalyzed unless an electron-withdrawing group was present on
À
C H functionalization provides a straightforward and the aryl ring (3ak–3am). It is interesting to note that
efficient way to produce indole derivatives.[10] Though a good yield of desired indole product 3ao was ob-
several directing groups, including oxidizing directing served when phenyl-tert-butylacetylene was em-
groups,[4,11] were designed to construct this structural ployed. Nevertheless, dialkylalkynes and terminal al-
moiety, the nitrone has been rarely exploited in such kynes gave poor results.
transformations. Wanꢀs group[7b] and Liꢀs group[7d]
A variety of readily available nitrones bearing vari-
À
demonstrated that the C H functionalization of C,N- ous N-aryl substituents was next assessed (Scheme 3).
diphenylnitrone with diphenylacetylene could furnish Nitrones containing F, Cl, Br, CH3 and OMe groups
2,3-diphenylindole (Scheme 1b). However, this kind on the N-aryl moiety were well tolerated, giving the
of reaction has not been well studied. Herein, we dis- desired products in moderate to good yields. The
À
close our development of a mild Rh(III)-catalyzed C
para-cyano-substituted and ortho-methyl-substituted
H functionalization of N-aryl-C-mesitylnitrone with N-phenyl-C-mesitylnitrones seemed to be less effec-
internal alkynes for the synthesis of indoles tive, and the desired products 3ga and 3ha were ob-
(Scheme 1c). Compared to Changꢀs and Liꢀs indoline tained in moderate yields with higher catalyst loading
synthesis, the employment of a sterically hindered at 1008C. When meta-methyl-substituted N-phenyl-C-
Mes group on the carbon center of nitrones led to mesitylnitrone was employed, the arene rhodation
a markedly different coupling and mechanistic experi- took place at the less hindered site selectively (3ia).
ments were conducted to verify the different reaction
pathways.
Further experiments were then carried out to gain
more insights into the reaction mechanism. When the
Initially, the reaction of N-(4-methylphenyl)-C-phe- reaction of 1b was conducted in CD3OD in the ab-
nylnitrone and diphenylacetylene (2a) was investigat- sence of alkyne, 1b was partially decomposed, and
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Zhi Zhou et al.
Scheme 2. Scope of alkyne substrates.
Scheme 3. Scope of nitrone substrates.
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Rhodium(III)-Catalyzed Redox-Neutral C H Annulation of Arylnitrones
27% deuterium incorporation was observed at the lene derivatives 2c and 2d revealed that the product
ortho-positions of recovered 1b [Eq. (1)]. If the same formation favors indole 3ac derived from the more
reaction was performed in the presence of 2a, 3ba electron-rich alkyne [Eq. (5)], which is consistent
was obtained smoothly. No deuterium incorporation with the reported Rh-catalyzed annulation of arenes
was found in 3ba while 32% deuterium incorporation with alkynes.[13]
was detected in unreacted 1b [Eq. (2)]. These results
Under the standard conditions, indole 3aa could
À
imply that the C H activation might be reversible also be efficiently accessed by using in situ formed ni-
under the reaction conditions. Furthermore, a primary trone from commercially available N-phenylhydroxyl-
KIE value of 4.3 was observed in the intermolecular amine 4 and mesitaldehyde [Eq. (6)]. Since the reac-
À
isotopic study [Eq. (3)], indicating that the C H bond tion of nitrone 1a with 2a produced a good yield of
cleavage process was most likely involved in the rate- mesitaldehyde besides the desired indole product,[14]
determining step. Competition experiments showed we wondered whether a catalytic amount of mesital-
that electron-rich arenes are preferentially functional- dehyde could promote the reaction of 4 and 2a. How-
ized [Eq. (4)], hence rendering an electrophilic activa- ever, lowering the amount of mesitaldehyde signifi-
tion manifold more likely to be operative. Additional- cantly decreased the yield of indole due to the insta-
ly, a competition experiment between diphenylacety- bility of 4 under the reaction conditions.
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Zhi Zhou et al.
According to Changꢀs work, the rhodium(III)-cata-
lyzed cyclization of C-phenyl-substituted nitrones and
alkynes in dry 1,4-dioxane containing molecular
sieves leads to the construction of indolines
(Scheme 1a).[7c] In contrast, our work revealed that
with a similar catalytic system the reaction of C-mes-
tiyl-substituted nitrones with alkynes in methanol
under air delivered indoles exclusively (Scheme 1c).
The different results observed between these two
works prompted us to investigate the factors that in-
fluence the reaction outcome. When C,N-diphenylni-
trone was subjected to our reaction conditions, only
a trace of indole was obtained and no detectable in-
doline was observed. When C-mestiyl-substituted ni-
trone 1b was subjected to Changꢀs reaction conditions,
no trace of indole or indoline product was detected.
These experiments indicate that the appropriate
choice of substituents and reaction conditions is criti-
cal for high chemoselectivity.
For the reaction of 1b with alkyne under Changꢀs
conditions, the main products were impossible to be
isolated because they decomposed on neutral alumina
or silica gel column affording indole and mesitalde-
hyde. When the crude products obtained from this re-
action were treated with HOPiv in methanol, a 54%
yield of indole could be produced (Scheme 4a). In
contrast, indoline could not be transformed to indole
under the same conditions (Scheme 4b). From these
Scheme 4. Investigation of the factors that influence the re-
action outcome.
1
experiments together with MS, IR and H NMR data,
we suspected that the imine compound X might be
one of the products formed in the reaction of 1b with
2a under Changꢀs conditions, and X might be the in-
On the basis of the results obtained above and the
termediate for the formation of the indole. The origin precedent literature,[7,15] a proposed reaction mecha-
of the different reactivity of 1b and 1l could be as- nism is put forward in Scheme 5. Coordination of ni-
cribed to the different substituents on the carbon trone to the cationic rhodium followed by a reversible
À
center of the nitrones. Guided by the assumption that C H cleavage generates rhodacycle A. Subsequent
a bulky substituent on the carbon center of nitrones insertion of alkyne yields a seven-membered inter-
may favour the formation of indoles, substrates 1m– mediate B, which is believed to undergo reductive
1o were exposed to our reaction conditions elimination to form intermediate C together with
(Scheme 4c). As expected, while phenyl- and o-tolyl- Rh(I).[15] The resulting Rh(I) could be oxidized by the
subsitiuted nitrones (1m and 1n) gave low yields of N O bond in intermediate C via oxidative addition
indole, 2,6-dimethylphenyl-subsitiuted nitrone 1o affording Rh(III) enolate D, which upon protonolysis
could be converted to the indole in good yield (85%). provides enolate intermediate E and regenerates
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Rhodium(III)-Catalyzed Redox-Neutral C H Annulation of Arylnitrones
Finally, a relatively large-scale reaction was con-
ducted. Under the standard conditions, the desired
indole product could be produced conveniently on
a gram scale without any obvious decrease in yield
[Eq. (7)].
In summary, by using the nitrone as the oxidizing
directing group,
a mild, practical and efficient
À
Rh(III)-catalyzed C H functionalization for the syn-
thesis of indole derivatives was developed. This redox
neutral strategy circumvents the use of external oxi-
dants. Moreover, a step-economic process using com-
mercially available N-phenylhydroxylamine as the
precursor of the nitrone was demonstrated. More de-
tailed investigations to explore new transformation
À
properties of nitrones for C H bond activation are in
progress.
Scheme 5. Proposed reaction mechanism.
Experimental Section
Rh(III) to complete the catalytic cycle. Enolate inter- Representative Procedure
mediate E is in equilibrium with keto intermediate F,
Without any particular precautions to exclude oxygen or
which can be transformed to indole facilely after
imine hydrolysis and intramolecular cyclization.[16]
According to Changꢀs and Liꢀs indoline synthesis,[7c,d]
an alternative pathway from Rh(III) enolate D is also
shown in Scheme 4 (pathway b). Tautomerization of
the O-bond enolate D produces the C-bond enolate
moisture, the N-aryl-C-mesitylnitrone 1 (1.4 equiv.), the
alkyne 2 (1 equiv.), [Cp*Rh(MeCN)3](SbF6)2 (5 mol%) and
HOPiv (2 equiv.) were weighed into a 10-mL tube with
a stir bar. MeOH (0.1M) was then added. The reaction mix-
ture was stirred at 808C and monitored by TLC. Afterwards,
it was diluted with EtOAc and transferred to a round-
bottom flask. Silica gel was added to the flask and volatiles
were evaporated under reduced pressure. The purification
was performed by flash column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate) to give the de-
sired indole product 3.
À
D’, which undergoes nucleophilic addition of the C
Rh bond to give an intramolecular imine affording
the indoline product. No indoline was detected when
the mesityl-substituted nitrone 1a was used as the
substrate, probably due to the bulky substitution on
the imine in intermediate D’ sterically inhibited the
cyclization. Although substitution on the carbon
center of the nitrones is believed to be crucial for che-
moselectivity, the reaction conditions could influence
the reaction outcome. The fact that a trace of water
was beneficial for the indole synthesis (Table 1, en-
tries 9 and 10) is consistent with the proposed me-
chamism (from F to G to indole). In Changꢀs indoline
synthesis, the addition of molecular sieves may pre-
vent the imine intermediate (the analogue of D or
D’) from hydrolysis, thus lead to a high yield of indo-
line product. The mechanism proposed here for the
synthesis of indole is similar to the one in Liꢀs paper
except that Lewis acid was added in Liꢀs work to fa-
cilitate the hydrolysis of imine F thus favouring the
formation of indole.
Acknowledgements
We thank the National Basic Research Program of China
(2015CB856600), the National Natural Science Foundation of
China (21202184, 21232006), and the Chinese Academy of
Sciences for financial support.
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