Rhodium(iii)-catalyzed indole synthesis at room temperature using the transient oxidizing directing group strategy

Article abstract of DOI:10.1039/c9cc04529e

Rh-catalyzed reactions of N-alkyl anilines with internal alkynes at room temperature have been developed using an in situ generated N-nitroso group as a transient oxidizing directing group. Due to mild reaction conditions, this method enabled synthesis of a broad range of N-alkyl indoles, including even two indole-based medicinal compounds. Our work disclosed the feasibility of the transient oxidizing directing group strategy in C-H functionalization reactions, which possesses the potential to enhance overall step-economy and impart new reactivity patterns to substrates.

Full text of DOI:10.1039/c9cc04529e

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DOI: 10.1039/C9CC04529E
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Rhodium(III)-Catalyzed Indole Synthesis at Room Temperature
Using the Transient Oxidizing Directing Group Strategy
Yaping Shang, Krishna Jonnada,Subhash Laxman Yedage, Hua Tu, Xiaofeng Zhang, Xin Lou, Shijun
Huang, and Weiping Su*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The Rh-catalyzed reaction of N-alkyl anilines with internal alkynes conversion of directing groups require additional chemical
at room temperature has been developed using in-situ generated manipulations, especially when the directing groups are not
N-nitroso group as a transient oxidizing directing group. Due to mild expected in the targeted molecules. Thus far, the examples for
reaction conditions, this method enabled syntheses of a broad the synthesis of indole from commercially available N-
range of N-alkyl indoles,including even two indole-based medicinal unprotected or N-alkyl anilines via C-H bond activation have
compounds. Our work disclosed the feasibility of the transient been very scarce.9
oxidizing directing group strategy in C-H functionalization
The concept of transient directing group has recently
reactions, which possesses a potential to enhance overall step- emerged as an effective strategy for fascinating regio-selective
economy and impart new reactivity pattern to substrates.
C-H functionalization method.10-12 In this context, the regio-
selective C-H bond functionalization of aldehydes, ketones and
amines have been achieved, in which imine was generated in-
situ as a traceless directing group via reversible aldehyde-amine
or ketone-amine condensation (Scheme 1a).11 And the in-situ
installation of carboxyl group enabled interesting meta-C-H
functionalization of substituted arenes12 (Scheme 1b),
demonstrating that carboxyl group is a versatile traceless
directing group for C-H activation.10d, 13 In spite of these elegant
studies, to date, the transient directing groups have been
limited to non-oxidizing functionalities. Inspired by the success
in the development of the traceless oxidizing directing group
strategy,6,8 we envisioned whether an appropriate oxidant
could in-situ install a transient oxidizing directing group which
Due to the prevalence of indole structural motifs in natural
products, pharmaceuticals and agrochemicals,1 the efficient
method for indole synthesis has always been a target sought
after by chemists.2,3 Among the established metal-catalyzed
methods, both the intermolecular annulation of ortho-halo-
substituted anilines with internal alkynes3 and the cross-
coupling of ortho-alkynylanilines with electrophiles4 represent
powerful tools for the construction of 2,3-disubstituted indole
scaffolds. To bypass the pre-functionalization of substrates, a
variety of direct C-H functionalization approaches towards
indole synthesis have been developed during the past decade.2
These methods mainly focus on the directing group-assisted
ortho-C-H functionalization reactions of N-substituted aniline
derivatives with alkyne partners,5,6 the intramolecular
dehydrogenative annulation reactions of N-aryl enamines,
azides, imines and ortho-alkenylanilines.7 Notably, the traceless
oxidizing directing group strategy for C-H activation has been
developed8 and successfully applied to syntheses of N-
unprotected indoles without the need for external oxidants.6
Despite undisputed advance, these C-H functionalization
reactions largely relied on the preinstalled specific directing
groups on the nitrogen atoms of anilines, and occurred at the
elevated temperatures. Both installation and removal or
Previous work:
Transient non-oxidizing directing group strategy
a) In-situ installation of amino acid for -C-H functionalization of carbonyls
R1
O
Ar
O
H
R2
R3
O
Pd(OAc)2
OH
n
ArI
N
R1
R3
R1
R3
O
Pd
R2
R2
H2N
n
O
b) In-situ installation of carboxyl for meta C-H functionalization
OH
OH
OH
OH
CO2H
Ar
CO2
CO2H
-CO2
Pd cat.
ArI, Ag+
H
Ar
This work
: Transient oxidizing directing group strategy
c) In-situ installation of nitroso for ortho C-H fuctionalization of anilines
R2
H
H
Rh cat.
R1
NO-OR
room temp.
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academyof Sciences, Fuzhou 350002, China.
R
R1
R1
R
NO
R2
N
NH
R'
N
R'
R'
E-mail: wpsu@fjirsm.ac.cn
†Electronic Supplementary Information (ESI) available: Experimental procedures,
experimental data and spectra data. See DOI: 10.1039/x0xx00000x
Scheme 1 Transient directing group strategy for C-H functionalization.
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Journal Name
Table 1 Optimization of the Reaction Conditions.a
could trigger the targeted C-H bond activation/functionalization
while generate the product via reductive cleavage of its
oxidizing bond. This transient oxidizing directing group strategy
would enhance the overall step economy and impart new
reactivity pattern to substrate. Herein, we report a Rh-catalyzed
room temperature reaction of readily available N-alkyl anilines
with internal alkynes, which produces indoles via in-situ
installation of N-nitroso group on N-alkyl anilines (Scheme 1c).
Our work exemplifies that the transient oxidizing directing
group strategy is viable for the regioselective C-H
functionalization.
View Article Online
[Cp*RhCl2]2 (2.5 mol%)
DOI: 10.1039/C9CC04529E
AgSbF6 (10 mol%), additive
Ph
Ph
N
+
N
Isoamyl nitrite (1.5 equiv), solvent
room temperature, 24 h
H
H
Ph
Ph
1a
2a
3a
Entry
Solvent
Additive
Yield
(%)b
40
0
0
1
2
3
DCM
CH3CN
tert-amyl
alcohol
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
-
-
-
4c
5
6
-
24
7
To implement the transient oxidizing directing group
strategy for this Rh-catalyzed indole synthesis reaction, we
NaOAc (1.0 equiv)
PivOH (1.0 equiv)
PivOH (0.5 equiv)
benzoic acid
need to prevent overoxidation of N-alkyl anilines in the N-
70
68
57
40
83
38
31
40
14a-b
7
nitrosylation with nitrite ester.
Recently, the reaction of
8d
nitrite ester with aniline and internal alkyne has been reported
9d
2,4,6-trimenthylbenzoic acid
p-tBuPhCO2H
14c
to produce 2,5-dihydrooxazole very fast,
which did not
10d
11d
12d
13e
involve N-nitrosoaniline intermediate. In addition, the reaction
of aniline with nitrite ester tends to produce overoxidized
product, namely N-nitroso N-alkyl nitroaniline, even at room
temperature.14a Our strategy to suppress competitive
overoxidizing side reactions is the identification of the active
Rh-catalyst system that enables fast C-H functionalization
reaction under mild conditions.
With these considerations in mind, we initiated our
investigations by examining Rh(III)-catalyzed coupling of
1,2,3,4-tetrahydroquinoline (1a) with diphenylacetylene (2a)
using isoamyl nitrite as an oxidant (Table 1). Previously reported
Rh-catalyzed C-H functionalization reactions involving internal
alkynes in which substrates bearing oxidizing directing groups6
(e.g. N-nitrosoanilines)6b, 6d generally occurred at the elevated
temperatures. However, we sought after room temperature
conditions to avoid over-oxidization of anilines by isoamyl
nitrite. Gratifyingly, the desired indole product 3a could be
obtained in 40% yield from the reaction of 1a with 2a conducted
m-NO2-PhCO2H
p-OMe-PhCO2H
p-tBuPhCO2H
DCM
aReaction Conditions: 1a (0.2 mmol),
2a (0.3 mmol), [Cp*RhCl2]2 (0.005 mmol, 2.5
mol%), AgSbF6 (0.02 mmol, 10 mol%), additive (0.5-1.0 equiv.),isoamyl nitrite (0.3
mmol), N2 and solvent (1.0 mL) at room temperature for 24 h. bYield of isolated
product. cCp*Rh(CH3CN)3[SbF6]2 (0.01mmol, 5 mol%) was used.daryl carboxylic
acids(0.5 equive) was used. et-butyl nitrite (0.3 mmol) was used as oxidant.
(entry 10). However, other aryl carboxylic acids failed to
enhance the reaction to a comparable degree. Finally, the use
of t-butyl nitrite as an alternative to isoamyl nitrite was less
effective (entry 13).
With the optimized reaction conditions in hand, we
evaluated the substrate scope with respect to N-substituted
anilines (Table 2). As illustrated, anilines with various groups at
the nitrogen atom participated in this transformation smoothly
(3b-3i). Notably, both allylic substituent and an alkyl nitrile
group could be tolerated to give 3h and 3i in 72% and 55% yields,
respectively. Interestingly, diphenyl amine (3f) show a similar
reactivity to N-alkyl anilines. Once again, cyclic anilines proved
to be suitable substrates for easy construction of important
fused tricyclic indoles (3a, 3j-3n). Furthermore, a variety of
electronically diverse functionalities (3m-3y) including halogen
substituents on the phenyl rings of anilines were well tolerated
to give desired indole products in excellent yields regardless of
the substituted positions. It is worth mentioning that an
excellent regioselectivity was observed when meta-substituted
anilineswere employed. In most cases, these anilines (3z, 3aa,
3ac-3ah) underwent reaction exclusively at positions para to
the substituents, probably due to the effects of steric hindrance.
One exception is the meta-fluorine substituented product (3ab),
which furnished the product at the position ortho to fluorine
atom (confirmed by single crystal X-ray diffraction).15 This
difference in selectivity might originate from the small atomic
radius of fluorine, which renders the electronic effect overriding
steric effect in C-H functionalization steps.
at room temperature for 24
h using [Cp*RhCl2]2 (2.5
mol%)/AgSbF6 (10 mol%) as a precatalyst and dichloromethane
as solvent (entry 1). Screenings of reaction parameters revealed
that switch of solvent to CH3CN or t-AmylOH completely shut
down this transformation (entries 2-3). In the case of CH3CN,
the solvent molecules might coordinate to Rh center, thus
leaving no spare coordination site for substrate molecules.
Similarly, cationic Cp*Rh(CH3CN)3[SbF6]2 was observed to have
a negative effect (entry 4). Although previous report revealed
that acetate salts had a beneficial effect on the Rh-catalyzed
reaction of N-nitrosoanilines with internal alkynes,6d the use of
NaOAc as additive proved to be futile (entry 5). Delightfully,
further screenings revealed that decent yields were accessible
by identifying suitable carboxylic acid as an additive. For
instance, we found that adding pivalic acid remarkably
improved the yield (entry 6) and reducing the amount of acid
from 1.0 equiv. to 0.5 equiv. led to a slight decrease in reaction
yield (entry 7). Next, we turned our attention to aryl carboxylic
acids bearing various substituents (entries 8-12) and found out
that the addition of 4-tert-butylbenzoic acid delivered the best
result, furnishing the desired product 3a in 83% isolated yield
We then turned our attention to the substrate scope of
internal alkynes (Table 3). To our delight, the reaction proved to
be general for a variety of symmetric diarylacetylenes (4a-4j).
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of N-substituted anilines.a,b
Additionally, the reaction with dialkylacetylene (4q) also
proceeded smoothly. Notably, the internal alkynes bearing
View Article Online
DOI: 10.1039/C9CC04529E
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
Isoamyl nitrite (1.5 equiv)
R1
Ph
NH
electron-deficient groups were effective in this transformation
(4r, 4s), which generated C-2 arylated indoles exclusively.15 The
high regioselectivity displayed in this protocol is seldom
observed in previously reported annulation reactions, thus
providing a complement to indole synthesis.
Our protocol also enables facile syntheses of two indole-
based medicinal compounds, namely, bazedoxifene16,and
zindoxifene17. As shown in scheme 2, both the immediate
precursor to marketed bazedoxifene and zindoxifene could be
prepared in good yields from readily available starting materials,
demonstrating the merit of our protocol in organic synthesis.
Compared with previous procedures, our protocol offers a more
concise pathway to syntheses of these molecules.
R2
Ph
H
Ph
Ph
+
R2
4-tert-butylbenzoic acid (50 mol%)
N
R1
DCM (1.0 mL), room temperature, 24 h
1
2a
3
Me
Ph
Ph
Ph
3b
3c
3d
3e
3f
, R = Ph, 73%
, R = Me, 65%
Ph
3g
3h
, R = Et, 84%
, R = Bn, 83%
Ph
i
N
, R = Pr, 88%
, R = Allyl, 72%
N
Ph
N
Me
Cl
3i
, R = Cy, 70%
, R = (CH2)2CN, 55%
R
Me
3a
, 83%
Ph
3j
, 71%
Me
Ar
Me
Me
Ph
Ph
N
Ph
Ph
Ph
N
Ar
Ph
Ph
N
N
N
Me
Ar = 4-iPr-Ph
3o
Br
3n
F
c
3l
3m
, 76%
, 70%
, 71%
, 76%
3k
, 75%
To check whether this Rh-catalyzed reaction involves in-
situ installation of nitroso directing groups, the reaction of
1,2,3,4-tetrahydroquinoline (1a) with isoamyl nitrite was
carried out in the presence of 4-tert-butylbenzoic acid in CH2Cl2
at room temperature for 6 hours (eq.1 Scheme 3), in which
proceeded N-nitroso 1,2,3,4-tetrahydroquinoline 5a was
obtained in quantitative yield. Moreover, 5a was observed to
react with diphenylacetylene at room temperature for 6 hours
with [Cp*RhCl2]2/AgSbF6 as a precatalyst, dichloromethane as
solvent and 4-tert-butylbenzoic acid as an additive to form 2,3-
diphenyl indole (3a) in 43% yield. In the absence of 4-tert-
butylbenzoic acid, however, the same reaction run for even 24
hours gave 3a in only 15% yield (eq.2 Scheme 3), which might
shed light on the key role of benzoic acid in enhancement of
catalyst activity.
e
3ab
3ac
3ad
3ae
3p
3q
3v
, R = 4-F, 96%
, R = 5-Me, 78%
, R = 7-Cl, 76%
R = 7-OMe, 66%
,
R = 5-NO2, 71%d
Ph
d
, R = 6-Cl, 80%
, R = 6-Br, 75%
3w
, R = 7-NO2, 76%
R
Ph
R = 5-CN, 77%d
3r
3x
,
,
e
N
, R = 6-I, 65%
3s
,
3y
3z
, R = 5-OMe 72%
,
R = 5-CF3, 78%
Me
3af
,
R = 6-CF3, 76%
3ag, R = 6-NO2, 61%e
,
R = 7-CO2Me, 71%d
, R = 6-Me, 75%
3t
f
3ah
, R = 6-COMe, 68%
3u
3aa
, R = 5-CO2Me, 85%
,
R = 6-CH2OMe, 73%
aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (0.005 mmol, 2.5
mol%), AgSbF6 (0.02 mmol, 10 mol%), 4-tert-butylbenzoic acid (50 mol%), isoamyl
nitrite (0.3 mmol), N2 and DCM (1.0 mL) at room temperature for 24 h. bYield of
isolated product. cThe reaction was carried out at 80 oC in DCE (1.0 mL). dThe
reaction was carried out at 50 oC in DCE (1.0 mL). ePivOH (1.0 equiv) was used as
additive. The reaction was carried out at 80 oC in DCM (1.0 mL) with PivOH (1.0
f
equiv) as an additive instead of 4-tert-butylbenzoic acid.
Table 3 Scope of internal alkynes.a, b
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
Isoamyl nitrite (1.5 equiv)
R4
R1
NH
R2
R3
R3
R4
H
+
R2
4-tert-butylbenzoic acid (50 mol%)
N
Me
R1
BnO
DCM (1.0 mL), room temperature, 24 h
O
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
Isoamyl nitrite (1.5 equiv)
OBn
OBn
1
2
4
N
HN
+
PivOH (50 mol%)
DCM (1.0 mL), 80 oC, 24 h
Me
Cl
Ar
R1
Ar
Ar
O
O
Cl
3ai,
47% yield
OH
2t
1ai
Ar
Ar
Ar
N
N
N
Me
Me
N
Me
Et
BnO
HO
t
OBn
4h
, Ar = 4- Bu-Ph, 85%
Ar = 3-OMe-Ph, 75%
Ar = 3-Ac-Ph, 70%
4d
4e
4f
4g
, Ar = 3-F-Ph, 68%
, Ar = 3-Me-Ph, 75%
4a
4b
4c
, Ar = 4-Me-Ph, 79%
N
R2
N
NH
4i
4j
,
,
, Ar = 4-Et-Ph, 86%
H2, Pd/C
ref. (16)
i
,
Ar = 4-OMe-Ph, 84%
4k
,
R1 = Et, R2 = Me, 73% (1:1)
4l, R1 = Br, R2 =H , 77% (1:1)
, Ar = 4- Pr-Ph, 80%
, Ar = 3-OCF3-Ph, 78%
CH3CN,reflux
SiMe3
O
O
N
N
R1
3ai-2,
Bazedoxifene
92% yield
, R1 = Me, R2 = Ph, 52%c
4o
MeO2C
R = Me, 70% (1.2 :1)
, R1 = Et, R2 = Ph 70%
c
4p
,
R2
Me
R1 = R2 = (CH2)3CH3 73%
c
4q
4r
,
,
4m,
4n
AcO
N
[Cp*RhCl2
AgSbF6 (10 mol%)
Isoamyl nitrite (1.5 equiv)
]
2 (2.5 mol%)
, R1 = COMe, R2 = Ph, 43%d
Et
N
, R = iPr, 74% (1.5 :1)
OAc
Me
R1 = CO2Me, R2 = Ph,58%d
NH
4s,
R
N
AcO
Me
+
4-tert-butylbenzoic acid (50 mol%)
DCM (1.0 mL), 40 oC, 24 h
Et
H
AcO
Zindoxifene
2u
1aj
3aj,
67 %
aReaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (0.005 mmol, 2.5
mol%), AgSbF6 (0.02 mmol, 10 mol%), 4-tert-butylbenzoic acid (50 mol%), isoamyl
nitrite (0.3 mmol), N2 and DCM (1.0 mL) at room temperature for 24 h. bYield of
isolated product.cThe reaction was carried out at 80 oC with PivOH (1.0 equiv)
instead of 4-tert-butylbenzoic acid. dThe reaction was carried out at 60 oC for 48 h
with PivOH (1.0 equiv) instead of 4-tert-butylbenzoic acid.
Scheme 2 Synthesis of Bazedoxifene and Zindoxifene.
4-tBuPhCO2H (1.0 eq)
O
NO
(1)
+
CH2Cl2 (1 mL)
N2, rt, 24 h
N
N
H
NO
5a
, 100%
1a
1.5 eq
, 0.2 mmol
For unsymmetrical diarylacetylenes (4k-4n), the reaction
delivered approximate 1:1 ratio isomers due to the unbiased
characters of the two phenyl groups. On the contrary,
unsymmetrical alkyl aryl acetylenes (4o, 4p) exhibited excellent
regioselectivity for the indole products with aryl group at C-2
positions (confirmed by X-ray crystallography analysis).15
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
N
(2)
+
Ph
Ph
CH2Cl2 (1 mL), N2, rt
N
Ph
Ph
NO
3a
5a,
0.2 mmol
1.5 eq
with 4-tBuPhCO2H (1 eq): 6 h, 43%
without 4-tBuPhCO2H: 24 h, 15%
Shecme 3 Mechanistic Investigations.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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7
(a) Y. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676;
In conclusion, the Rh(III)-catalyzed reactions of diverse N-
alkyl anilines with internal alkynes have been developed for
facile synthesis of indoles at room temperature. The mild
reaction conditions were ascribed to the reasonable
combination of catalyst, acid additive and solvent. Our work
demonstrated that the transient oxidizing directing group
strategy is promising for the development of C-H
functionalizations with unfunctionalized substrates. Application
of this intriguing strategy to other useful C-H transformation is
currently underway in our laboratory.
This work was supported by the National Key Research and
Development Program of China (2017YFA0206801), National
Natural Science Foundation of China Grants (21431008,
u1505242), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB20000000 and
XDB10040304) and the Key Research Program of the Chinese
Academy of Sciences (ZDRW-CN-2016-1).
View Article Online
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Conflicts of interest
The authors declare no competing financial interest.
Notes and references
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DOI: 10.1039/C9CC04529E
R2
H
H
Rh cat.
R1
NO-OR
room temp.
R1
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R1
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R'
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Transient oxidizing directing group
ortho-C-H accessible to reaction
Room temperature reaction
55 examples, up to 96% yield