Direct Access to Indoles by IrIII-Catalyzed C–H Functionalization of Acetanilides with Diazo Compounds

Article abstract of DOI:10.1002/ejoc.201700095

A one-pot synthesis of indole derivatives from readily available acetanilides and diazo compounds was developed. This Ir^III-catalyzed C–H alkylation and annulation reaction proceeds under mild conditions and generates molecular nitrogen and water as byproducts. Various types of synthetically versatile N-substituted indoles, including N-acetyl, N-pivolyl, and N-benzoyl indoles, were prepared.

Full text of DOI:10.1002/ejoc.201700095

A Journal of
Accepted Article
Title: A Direct Access to Indoles via Ir(III)-Catalyzed C-H
Functionalization of Acetanilides with Diazo Compounds
Authors: Pitambar Patel and Gongutri Borah
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700095
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700095
Supported by

10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
A Direct Access to Indoles via Ir(III)-Catalyzed C–H
Functionalization of Acetanilides with Diazo Compounds
Pitambar Patel,* Gongutri Borah
Abstract: A one pot synthesis of indole derivatives from readily
available acetanilide via Ir(III)-catalyzed C–H alkylation and
annulations with diazo compounds have been developed. The
reaction proceeds under mild conditions and generates molecular
nitrogen and water as by-products. Various types of synthetically
adaptable N-substituted indoles were accessed which includes N-
acetyl, N-Pivolyl and N-Benzoyl groups.
using N-phenylpyrimidin-2-amine and diazo compounds via Rh
(III)-catalyzed C–H bond activation (Scheme 1a). On the other
hand, Li et al. disclosed the reaction of N-phenylpyrimidin-2-
amine with diazo compounds under Ir(III)-catalytic conditions to
afford N-pyrimidinyl indoles which is the only reports so far using
Ir(III).[12d] Furthermore, Li and coworkers also demonstrated the
synthesis of functionalized indoles from N-phenylacetimidamides
via Rh(III) and Ru(III)- catalyzed C–H carbenoid functionalization
Introduction
Indole represents one of the most abundant structural unit found
in a wide range of biologically active compounds and drug
molecules.[1] Because of their tremendous significant role in drug
discovery various synthetic approaches have been established
to access indole skeleton,[2] such as the Fischer indole
synthesis,[3] heteroannulations/cyclization of 2-alkynylanilines[4]
and
metal-catalyzed
coupling/condensation
cascades.[5]
However, general and efficient methods for the synthesis of
functionalized indoles from easily available starting material is
still of great interest. In the past decade the transition metal
catalyzed C–H activations have emerged as one of the powerful
efficient and straightforward tool for the construction of various
heterocyclics from simple substrates.[6,
7]
In this context,
synthesis of indoles from the N-substituted anilines and alkynes
via C–H annulation was reported by using Rhodium, palladium,
ruthenium, nickel and cobalt catalysts.[8] However, most of these
methods suffers in the regioselectivity with unsymmetrical
alkynes to produce indoles.
(Scheme 1a).[12e-f]
Scheme 1. Synthesis of indole via metal catalyzed C–H activation
More recently, metal-catalyzed carbenoid functionalization
and annulations have been scrutinized as efficient and atom
economic approach for the synthesis of various N-heterocyclic
compounds.[9] In this context, Yu and co-worker documented the
pioneering work on Rh(III)-catalyzed carbenoid functionalization
of arenes.[9a] Following this results, the groups of Glorius,[10]
Wang,[11] Li,[12] Kim[13] and others[14] have successfully
demonstrated the synthesis of various heterocycles by same
approach. Very recently, Wang et al. reported the Rh(III)-
Inspite of these advancements, most of the methods are
limited to Rh(III)-catalyst, where as only one literature precedent
is available on indole synthesis via Ir(III)-catalyzed carbenoid
functionalization.[12d, 16] To the best of our knowledge synthesis
of indole from readily available acetanilide via metal catalyzed
C–H carbenoid functionalization has not been realized till
date.[17] In continuation of our ongoing study on Ir(III)-catalyzed
of C–H annulations,[18] we recently reported the synthesis of
oxindole from acetanilide and diazotized Meldrum’s acid.[18c] At
this stage, we envisioned the possible formation of indole
derivatives when the diazotized Meldrum’s acid is replaced with
ethyl 2-diazo-3-oxobutanoate (Scheme 1b). Herein we report the
results of Ir(III)-catalyzed carbenoid functionalization of
acetanilide to obtain poly-substituted indole derivatives. Indole
with various N-substitutions such as acetyl, pivolyl, and benzoyl
can be synthesized easily using this protocol (Scheme 1b).
catalyzed
carbenoid
functionalization
of
2-acetyl-1-
arylhydrazines to afford 1-aminoindole derivatives (Scheme
1a).[11a] While Lin and Yao,[15] Kim[13b] and Wang[11c]
independently documented the efficient synthesis of indoles
Chemical Science and Technology Division
CSIR-North East Institute of Science and Technology, Jorhat
Jorhat, Assam, India, 785006
E-mail:patel.pitambar@gmail.com
Results and Discussion
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
We initiated our optimization study with acetanilide 1a and ethyl
2-diazo-3-oxobutanoate 2a as model substrates. Use of
[IrCp*Cl2]2 (2.0 mol %), AgNTf2 (8.0 mol %) as catalyst in 1,2-
dichloroethane (1,2-DCE, 1 mL) at 60 °C for 10 h, did not
promote the reaction of 1a with 2a (Table 1, entry 1). We then
other carbonyl chelating groups such as ester or ketone (3i, 3j).
Nevertheless, the reactions of ortho-substituted acetanilide gave
relatively low yield of indole derivative (3k), likely due to low
reactivity (steric reasons). Moreover, m-methyl acetanilide gave
inseparable regiomeric products 3l-i and 3l-ii. Similarly, 3,4-
checked various additives and with AcOH (1.0 equiv) as additive, dimethoxy acetanilide produced a mixture of 3m-i and 3m-ii in
the desired ethyl 1-acetyl-2-methyl-1H-indole-3-carboxylate 3a
was obtained in 86% isolated yield (entry 2–5). Screening of
various solvents indicated that 1,2-Dichloroethane was the best
solvent (entries 6−7). Among the various silver salts tested,
AgNTF2 was found to be most effective (entries 9−10).
Decreasing the catalyst loading (1.0 mol %) led to lower yield of
3a (entries 11). Control experiments showed that both [IrCp*Cl2]2
or AgNTf2 were essential for this reaction (entries 12−13). It
should be noted that the present C–H annulations did not
proceed at all when [RhCp*Cl2]2 and [Ru(p-Cymene)Cl2]2
catalyst were employed (entries 14−15).
3:1 ratio. Annulation of substrate containing fused arenes such
as naphthyl (3n) was also smooth under the present conditions.
Next we explored the substituent effect on the diazo compound
by changing the carbonyl substituents. Pleasantly, reaction of
ethyl 2-diazo-3-oxo-3-phenylpropanoate (2b) with 1a under
standard conditions furnished the desired ethyl 1-acetyl-2-
phenyl-1H-indole-3-carboxylate (3o) in good yields. Similarly,
diazo compounds having para-substituted aryl group such as
methyl (3p) and chloro (3q) underwent annulations to furnish the
desired product in high yields.
ꢁꢂꢃꢄꢅ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢄꢅꢂꢃꢁ
Table 1. Optimization of reaction parameters
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢆ
ꢆ
ꢆ
ꢀꢃ
ꢎ
ꢀ
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
ꢀꢐ
ꢡꢢ
ꢂ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢝꢕ ꢋ
ꢂ
ꢆꢌ
R
3
1
2
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢉ
ꢆꢌ
entry
1
[Ag] salt
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgSbF6
AgOAc
AgNTf2
AgNTf2
none
additive
-
solvent
yield (%)b
ꢀ
ꢀ
ꢀ
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
MeOH
0
0
ꢂ
ꢂ
ꢂ
2
NaOAc
AcOH
PivOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
ꢆ ꢏ ꢁꢐꢑꢒ 3b ꢓꢔꢕꢖꢗ
ꢆ ꢏ ꢀꢘꢊꢙꢒ 3c ꢓꢚꢚꢖꢗ
ꢆ ꢏ ꢂꢇꢈꢒ 3d ꢓꢚꢛꢖꢗ
ꢆ ꢏ ꢜꢙꢒ 3e ꢓꢚꢝꢖꢗ
ꢆ ꢏ ꢁꢍꢒ 3f ꢓꢛꢛꢖꢗ
ꢆ ꢏ ꢞꢒ 3g ꢓꢛꢑꢖꢗ
ꢆꢌ ꢏ ꢁꢞꢑꢒ 3h ꢓꢟꢔꢖꢗ
ꢆꢌ ꢏ ꢁꢂꢃꢇꢈꢒ 3i ꢓꢛꢠꢖꢗ
ꢆꢌ ꢏ ꢡꢢꢒ 3j ꢓꢚꢝꢖꢗ
3
88 (86)
70
60
<10
15
10
72
10
58
0
4
5c
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
6
7
MeCN
ꢎ
8
toluene
ꢀ
ꢀ
ꢂ
ꢀ
9
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
ꢂ
ꢂ
ꢂꢇꢈ
3k
3l-i + 3l-ii
10
11d
12e
13
14f
15g
ꢓꢟꢕꢖꢗ
ꢓꢢꢣꢤꢥꢦꢧꢈ ꢨꢦꢈꢍꢩ ꢛꢟꢖꢗ
ꢂꢇꢈ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
12
0
ꢇꢈꢂ
ꢇꢈꢂ
ꢇꢈꢂ
AgNTf2
AgNTf2
ꢎ
0
ꢀ
ꢀ
ꢀ
ꢂ
ꢂ
ꢂ
aReaction conditions: 1a (0.15 mmol, 1.0 equiv), 2a (0.18 mmol, 1.2 equiv),
catalyst and additive in solvent (1 mL) at 60 °C for 10 h. b1H NMR yield
3m-i ꢓꢪꢠꢖꢗ
3m-ii ꢓꢃꢟꢖꢗ
3n ꢓꢪꢃꢖꢗ
c
(CH2Br2 as internal standard); isolated yield in parentheses. 0.5 equiv of
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
d
e
AcOH was used. 1.0 mol % of [IrCp*Cl2]2 was used. Reaction without
[IrCp*Cl2]2. f [RhCp*Cl2]2 was used as catalyst. g [Ru(p-Cymene)Cl2]2 was used
as catalyst.
ꢊꢋ
ꢀ
ꢁꢍ
ꢀ
ꢀ
ꢂ
ꢂ
ꢂ
3o ꢓꢛꢃꢖꢗ
3p ꢓꢛꢕꢖꢗ
3q ꢓꢟꢔꢖꢗ
With the optimized reaction conditions, we then explored
the scope of indole formation with differentially substituted
acetanilides (Scheme 2). Acetanilides bearing electron-donating
(3b-3d) and -withdrawing (3e-3j) substituents at para-position
underwent the annulations reaction smoothly and furnished the
desired indole derivative in good yields. It’s worth noting that
these alkylations are highly selective occurring at the ortho-
position relative to the N-acetyl moiety even in the presence of
Scheme 2. Substrate scope for indole synthesis. Reaction conditions: 1 (0.15
mmol), 2 (1.2 equiv), in 1,2-DCE (1 mL); yields of isolated products are given.
Next, the scope of various types of N-substitutions was
investigated (Scheme 3). We found that a range of synthetically
useful N-substituents could readily be employed to furnish the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
desired N-protected indole derivatives. Reaction of anilines
having N-substitution such as propenoyl, pivolyl, phenyl acetyl
group smoothly furnished the corresponding indole derivatives
3r-3t in good to high yields. Similarly, N-phenylbenzamide gave
exclusively the desired product 3u in 62% yield. Further 1,1-
dimethyl-3-phenylurea also gave the desired ethyl 1-
(dimethylcarbamoyl)-2-methyl-1H-indole-3-carboxylate 3v in
excellent yield. Thus, various easily removable N-protected 2,3-
disubstituted indole derivative could be synthesized through the
present procedure, which offers synthetic flexibility in the
utilization of the obtained products.
note that, only alkylated product was observed with 2e under
Rh(III)-catalytic conditions.[15] Next we checked the scope of
various N-arylamides for 3-phosphorylated indole synthesis.
Overall it was observed that substrates having electron donating
group gave higher yield as compared to substrates with
electron-withdrawing group (4b-4e). Substrate with different N-
substitutions such as N-phenylpropionamide and 1,1-dimethyl-3-
phenylurea were compatible to present annulations reaction and
furnished the desired indole derivatives 4f and 4g in good yield.
Surprisingly, reaction with other diazo compound such as 3-
diazopentane-2,4-dione and diethyl 2-diazomalonate were found
to be sluggish.
ꢁꢂꢃꢄꢅ
ꢐ
ꢀ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢻꢗ ꢷꢈꢵꢅꢈꢙꢦꢵꢤ ꢺꢢꢙꢻꢤꢥꢍꢦꢧꢱ ꢦꢧ ꢻꢥꢺꢈꢧꢢꢈ ꢣꢳ ꢩꢦꢻꢼꢣ ꢢꢣꢤꢭꢣꢵꢧꢩ
ꢐꢹꢷ
ꢐ
ꢂ
2a
ꢎ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢀ
ꢐ
ꢐ
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢝꢕ ꢋ
ꢀ
ꢀ
R
ꢂ
1
3
R
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
D2O (100 L)
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢟ ꢋ
ꢂ
ꢂ
ꢐꢹꢷ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
ꢁꢂꢃꢄꢅ
1a-dn ꢓꢚꢃꢖ ꢷꢗ
ꢥꢗ ꢷꢈꢵꢅꢈꢙꢦꢵꢤ ꢺꢢꢙꢻꢤꢥꢍꢦꢧꢱ ꢦꢧ ꢭꢙꢈꢺꢈꢧꢢꢈ ꢣꢳ ꢩꢦꢻꢼꢣ ꢢꢣꢤꢭꢣꢵꢧꢩ
ꢀ
ꢀ
ꢀ
ꢀ
ꢁꢂꢃꢄꢅ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢂ
ꢂ
ꢂ
ꢂ
ꢐꢹꢷ
ꢐ
ꢆ
ꢜꢧ
3t ꢓꢟꢑꢖꢗ
ꢊꢋ
ꢇꢈꢃꢀ
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢎ
ꢀꢐ
ꢎ
2a
ꢀ
ꢆ ꢏ ꢄꢅꢒ 3r ꢓꢔꢃꢖꢗ
ꢆ ꢏ ꢁꢘꢜꢵꢒ 3s ꢓꢚꢔꢖꢗ
3u ꢓꢟꢝꢖꢗ
3v ꢓꢔꢛꢖꢗ
ꢡꢢ
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
D2O (100 L)
ꢀ
ꢡꢢ
ꢡꢢ
ꢐꢹꢷ
ꢐꢹꢷ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢑ ꢋ
3a-dn ꢓꢽꢪꢖ ꢷꢗ 1a-dn ꢓꢠꢕꢖ ꢷꢗ
Scheme 3. Scope of various N-substitutions. Reaction conditions: 1 (0.15
mmol), 2a (1.2 equiv), in 1,2-DCE (1 mL); yields of isolated products are given.
ꢢꢗ ꢾꢦꢧꢈꢅꢦꢢ ꢦꢺꢣꢅꢣꢭꢈ ꢈꢳꢳꢈꢢꢅ ꢺꢅꢵꢩꢨ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢁꢂꢃꢄꢅ
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢂ
ꢷꢪꢹꢐꢪ
2a
ꢂꢇꢈ
ꢷꢪꢹꢐꢪ
ꢎ
ꢐ
ꢂꢇꢈ
ꢂꢇꢈ
ꢇꢈꢂ
ꢀꢃ
ꢊ
ꢀ
ꢡꢢ
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢑꢕ ꢤꢦꢧ
ꢊ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢀꢐ
ꢡꢢ
ꢆ
ꢂ
ꢀꢐ
ꢆ
ꢎ
ꢂꢃꢄꢃꢅꢅꢆꢅ ꢆꢇꢂꢆꢄꢀꢈꢆꢉꢁꢊ ꢋꢌꢍ ꢎ ꢏꢐꢑ
ꢒꢓꢈꢂꢆꢁꢀꢁꢀꢔꢆ ꢆꢇꢂꢆꢄꢀꢈꢆꢉꢁꢊ ꢋꢌꢍ ꢎ ꢕꢐꢖ
ꢡꢢꢂꢐ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢟꢕ ꢸꢁꢒ ꢝꢕ ꢋ
ꢀ
ꢂ
2e
ꢆꢌ
ꢂ
ꢂ
ꢂ
1
4
ꢆꢌ
ꢩꢗ ꢁꢣꢤꢭꢈꢅꢦꢅꢦꢶꢈ ꢈꢿꢭꢈꢙꢦꢤꢈꢧꢅꢺ
ꢡꢢ
ꢂ
ꢂ
ꢁꢂꢃꢄꢅ
ꢂꢇꢈ
ꢂꢇꢈ
ꢂꢇꢈ
ꢊ
ꢂꢇꢈ
ꢂꢇꢈ
ꢂꢇꢈ
ꢁꢂꢃꢄꢅ
ꢎ
ꢊ
ꢊ
ꢀꢐ
2a ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
standard conditions
ꢆ
ꢎ
ꢡꢢ
ꢀ
ꢡꢢ
ꢀ
ꢀꢐ
ꢀ
ꢀ
ꢂ
ꢀ
ꢃ ꢋ
ꢡꢢ
ꢂ
ꢂ
3aꣀ3b ꢏ ꢝꣀꢝꢰꢔ ꢓꢆ ꢏ ꢁꢐꢑꢗ
3aꣀ3f ꢏ ꢝꢰꢛꣀꢝ ꢓꢆ ꢏ ꢁꢍꢗ
ꢆ
4a ꢓꢟꢔꢖꢗ
4b ꢓꢛꢪꢖꢗ
4c ꢓꢛꢝꢖꢗ
ꢂ
ꢊ
ꢂ
ꢂ
ꢂꢇꢈ
ꢂꢇꢈ
ꢂꢇꢈ
ꢂꢇꢈ
ꢊ
ꢂꢇꢈ
ꢊ
ꢩꢗ ꢬꢺꢣꢍꢻꢅꢦꢣꢧ ꢣꢳ ꢻꢍꣁꢨꢍꢻꢅꢈꢩ ꢭꢙꢣꢩꢵꢢꢅ
ꢂꢇꢈ
ꢇꢈꢂ
ꢇꢈꢂꢃꢁ
ꢂꢇꢈ
ꢇꢈꢂ
ꢊ ꢂ
ꢀ
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ ꢓꢃꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢂꢇꢈ ꢡꢱꢀꢲꢳꢃ ꢓꢚꢰꢕ ꢤꢣꢍ ꢖꢗ
ꢀ
ꢀ
ꢂ
ꢂ
ꢊ
ꢂ
ꢂ
ꢂ
1a ꢎ
ꢆꢌ
ꢀꢻꢂꢡꢢ ꢓꢝꢰꢕ ꢈꢴꢵꢦꢶꢗ
ꢂꢇꢈ
ꢂ
4d ꢓꢟꢟꢖꢗ
4e ꢓꢪꢔꢖꢗ
ꢆꢌ ꢏ ꢄꢅꢒ 4f ꢓꢛꢝꢖꢗ
ꢆꢌ ꢏ ꢀꢇꢈꢃꢒ 4g ꢓꢪꢔꢖꢗ
ꢀꢐ
ꢝꢒꢃꢘꢷꢁꢄꢒ ꢛꢕ ꢸꢁꢒ ꢝꢃ ꢋ
ꢀꢃ
ꢂ
5a ꢓꢛꢃꢖꢗ
2e
Scheme 4. Scope of diazo compounds. Reaction conditions: 1 (0.15 mmol),
2e (1.2 equiv), in 1,2-DCE (1 mL); yields of isolated products are given.
ꢈꢗ ꢡꢧꢧꢵꢍꢻꢅꢦꢣꢧ ꢣꢳ ꢻꢍꣁꢨꢍꢻꢅꢈꢩ ꢭꢙꢣꢩꢵꢢꢅ
ꢂꢇꢈ
ꢇꢈꢂ
ꢊ
ꢂ
ꢺꢅꢻꢧꢩꢻꢙꢩ ꢢꢣꢧꢩꢦꢅꢦꢣꢧꢺ
With the successful exploration of substrate scope for N-
aryl amides, we then investigate the feasibility of other diazo
compounds. Gratifyingly, reaction of dimethyl (1-diazo-2-
oxopropyl)phosphonate (2e) with 1a under standard condition
furnished the desired dimethyl (1-acetyl-2-methyl-1H-indol-3-
yl)phosphonate (4a) in good yields (Scheme 4). It is important to
ꢝꢒꢃꢘꢷꢁꢄ
ꢟꢕ ꢸꢁꢒ ꢚ ꢋ
5a
5a
4a ꢎ
ꢚ ꢋ
ꢀ
ꢓꢝ ꣀ ꢃꢰꢚꢗ
ꢔꢔꢖ ꢢꢣꢧꢶꢈꢙꢺꢦꢣꢧ
4a
ꢂ
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10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
Scheme 5 Preliminary mechanistic studies.
assumed to take place before the subsequent migratory
insertion of carbene to the C−Ir bond, leading to IV. Alternatively,
intramolecular 1,2-migratory insertion of the aryl group would led
to IV. Next, Protodemetalation of IV delivers the alkylated
product V, and regenerates the active catalytic species. The
enol intermediate VI, formed through keto–enol tautomerization
of V, which undergo a dehydrative cyclization to furnish the
indole product 3a.
Several preliminary experiments were performed to shed
light in to the reaction mechanism (Scheme 5). A notable
deuterium scrambling of 1a was observed when the reaction
was performed using D2O in the absence of diazo compound,
indicating the reversibility of the C−H activation step (Scheme
5a). However, when the same step was performed in presence
of 2a no deuterium scrambling was observed in product 3a,
confirming that the C−C bond formation was faster than the back
reaction (Scheme 5b). Next, a significant kinetic isotope effect
(KIE) was observed both in parallel (2.8) and competitive
experiments (3.4), which indicate the C H activation to be the
rate-determining step (Scheme 5c).[19] One pot intermolecular
competitive experiment of 1a with electron rich acetanilide 1b or
electron deficient acetanilide 1f revealed that electron rich
substrates were more efficient for the reaction (Scheme 5d).
This also indicates the putative involvement of aromatic
electrophilic mechanism. After a careful screening of the
reaction parameters, the alkylated product 5a was successfully
isolated (Scheme 5e). When compound 5a was stirred in 1,2-
DCE at 60 °C for 8 hours, formation of desired annulated
product 4a was observed along with reamining 5a (Scheme 5f).
However, under standard conditions compound 5a was
completely converted to indole derivative 4a. These results
confirmed that the reaction proceeds via C–H alkylation followed
by annulations to give the final product.
Conclusions
In summary, we developed
a
one step synthesis of
functionalized indole from readily available acetanilides and α-
diazocarbonyl compounds. The reaction proceeds under mild
condition with high functional group tolerance and generate
molecular nitrogen and water as side products. Using the
present protocol, 3-phosphorylated indole derivative can be
easily synthesized from aniline. The easily removable N-
protecting group can also be used as directing group for further
selective C7 functionalization.20 Further studies on extension of
present methods for sp3 C–H functionalization as well as
extension of this methodology for synthesis of biologically active
indole derivatives are on progress.
Experimental Section
ꢫꢬꢙꢁꢭꢮꢁꢍꢃꢯꢃ
ꢡꢱꢀꢲꢳꢃ
ꢡꢱꢁꢍ
ꢫꢬꢙꢁꢭꢮꢉꢃꢯ
ꢂ
General remarks
ꢐ
ꢂ
ꢀ
ꢂꢡꢢ
Unless otherwise stated, all commercial reagents and solvents were
used without additional purification. Analytical thin layer chromatography
(TLC) was performed on pre-coated silica gel 60 F254 plates. Column
chromatography was carried out by using spectrochem silica gel (100–
ꢄꢅꢂꢃꢁ V
ꢂ
ꢉ ꢏ ꢂꢡꢢ ꢣꢙ ꢀꢲꢳꢃ
1
200, 230–400 mesh). H NMR spectra were recorded on Bruker AV 500
ꢐ
1a
ꢀ
MHz spectrometers. TMS was used as an internal standard and the
chemical shifts were reported in parts per million (δ) relative to internal
standard TMS (0.0 ppm) or CDCl3 (7.27 ppm). In case of the peak
patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of
doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J is
reported in Hertz (Hz). 13C NMR spectra were obtained by Bruker AV
(125 MHz) spectrometers and referenced to the internal solvent signals
(central peak is 77.0 ppm in CDCl3). For carbon appearing as doublet, its
indicated as ‘d’. High-resolution mass spectra (HRMS) were recorded on
a Thermo Scientific Q-Exactive, Accela 1250 pump and WATER’s XEVO
G2 XS9T. All the N-aryl amides[8a] and diazo compounds[18] were
prepared by following literature procedure.
ꢀꢐ
ꢂꢐ
ꢉ
ꢂ
ꢐ
ꢬꢙ
ꢀ
I
ꢂ
ꢁꢭꢮ
VI
ꢄꢅꢂꢃꢁ
ꢘꢐꢃꢂ
ꢉ
ꢁꢭꢮ
ꢁꢂꢃꢄꢅ
ꢀꢃ
ꢂ
IV
ꢂ
ꢬꢙ
ꢐꢀ
ꢉ
ꢁꢭꢮ
ꢀ
3a
ꢉ
ꢀ
ꢐꢀ
ꢁꢂꢃꢄꢅ
ꢂ
ꢬꢙ
ꢂ
ꢁꢭꢮ
II
ꢁꢂꢃꢄꢅ
ꢂ
ꢀꢃ
Experimental Details
III
General procedure for Ir-catalyzed C–H annulations of acetanilides:
To a 3 mL screw capped vial with a spinvane triangular-shaped Teflon
stirbar were added acetanilide (0.15 mmol, 1.0 equiv), diazocompounds
(0.18 mmol, 1.2 equiv), [IrCp*Cl2]2 (2.0 mol %), AgNTf2 (8.0 mol %),
AcOH (9.0 mg, 1.0 equiv) and 1,2-dichloroethane (1.0 mL) under air. The
reaction mixture was stirred at 60 °C for 10 h. After the completion of
reaction, the reaction mixture was filtered through a pad of celite followed
by washing of the pad with CH2Cl2 (10 mL x 2). The combined solvents
were removed under reduced pressure and the residue was purified by
column chromatography (EtOAc/hexane) to obtain the pure product.
Scheme 6 Plausible catalytic cycle.
Based on the above results and literature precedents, a
plausible mechanistic pathway is proposed in Scheme 6. The
first step is the generation of a cationic Ir(III) species from the
[IrCp*Cl2]2 with AgNTf2 and AcOH, which facilitates the key C−H
bond activation to afford a six-membered iridacyclic intermediate
I. Coordination of diazocompound to I, gave the diazonium
intermediate II. Generation of the carbene intermediate III is
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10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
Ethyl-1-acetyl-2-methyl-1H-indole-3-carboxylate (3a): White solid
1
CDCl3) δ 1.48 (t, J = 7.2 Hz,, 3H), 2.80 (s, 3H), 3.00 (s, 3H), 4.46 (q, J =
7.2 Hz, 2H), 7.55 (dd, J = 8.8, 1.6 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 8.42 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 14.3, 15.2, 27.9, 60.6, 111.2, 114.6,
119.2 (q, J = 3.6 Hz), 121.2 (q, J = 3.6 Hz), 124.6 (q, J = 272.5 Hz),
126.2 (q, J = 32.7 Hz), 127.2, 136.8, 146.0, 164.7, 170.7 ppm. HRMS
(ESI+): calcd. for C15H15F3NO3 [M+H]+: 314.1004, found: 314.1001.
(31.8 mg, 86%); mp: 58-60 °C; H NMR (500 MHz, CDCl3) δ 1.47 (t, J =
7.1 Hz, 3H), 2.79 (s, 3H), 2.98 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H), 7.28–
7.40 (m, 2H), 7.82–7.94 (m, 1H), 8.12 (dd, J = 6.7, 2.6 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.4, 15.2, 27.9, 60.3, 111.2, 114.2, 121.7, 123.9,
124.4, 127.4, 135.2, 144.8, 165.4, 171.0 ppm. HRMS (ESI+): calcd. for
C14H16O3N [M+H]+: 246.1125, found: 246.1124.
3-Ethyl-5-methyl-1-acetyl-2-methyl-1H-indole-3,5-dicarboxylate (3i):
White solid (33.7 mg, 74%); mp: 113-115 °C; 1H NMR (500 MHz, CDCl3)
δ 1.50 (t, J = 7.2 Hz, 3H), 2.81 (s, 3H), 2.99 (s, 3H), 3.96 (s, 3H), 4.47 (q,
J = 7.2 Hz, 2H), 7.92–7.95 (m, 1H), 8.01 (dd, J = 8.9, 1.7 Hz, 1H), 8.82 (d,
J = 0.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.4, 15.2, 27.9, 52.1,
60.6, 111.5, 114.0, 123.9, 125.7, 125.8, 127.2, 137.7, 145.7, 164.9,
167.3, 170.8 ppm. HRMS (ESI+): calcd. for C16H18O5N [M+H]+: 304.1179,
found: 304.1178.
Ethyl 1-acetyl-2,5-dimethyl-1H-indole-3-carboxylate (3b): White solid
1
(35.0 mg, 90%); mp: 85-88 °C; H NMR (500 MHz, CDCl3) δ 1.47 (t, J =
7.1 Hz, 3H), 2.48 (s, 3H), 2.77 (s, 3H), 2.95 (s, 3H), 4.42 (q, J = 7.1 Hz,
2H), 7.15 (dd, J = 8.2, 0.7 Hz, 1H), 7.72 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 14.4, 15.2, 22.0, 28.0, 60.3, 111.0, 114.5,
121.2, 124.9, 125.3, 134.4, 135.4, 144.0, 165.5, 171.1 ppm. HRMS
(ESI+): calcd. for C15H18O3N [M+H]+: 260.1281, found: 260.1280.
Ethyl-1-acetyl-5-isopropyl-2-methyl-1H-indole-3-carboxylate
(3c):
Ethyl-1,5-diacetyl-2-methyl-1H-indole-3-carboxylate (3j): White solid
(35.0 mg, 81%); mp: 106-109 °C; 1H NMR (500 MHz, CDCl3) δ 1.50 (t, J
= 7.1 Hz, 3H), 2.69 (s, 3H), 2.81 (s, 3H), 2.99 (s, 3H), 4.47 (q, J = 7.1 Hz,
2H), 7.93–7.99 (m, 2H), 8.77 (d, J = 0.9 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.4, 15.3, 26.7, 27.9, 60.6, 111.5, 114.2, 123.1, 124.4, 127.3,
133.1, 137.7, 145.9, 164.9, 170.7, 198.0 ppm. HRMS (ESI+): calcd. for
C16H18NO4 [M+H]+: 288.1236, found: 288.1241.
1
White solid; mp (38.0 mg, 88%): 93-94 °C; H NMR (500 MHz, CDCl3) δ
1.31 (d, J = 6.9 Hz, 6H), 1.48 (t, J = 7.2 Hz, 3H), 2.77 (s, 3H), 2.96 (s,
3H), 3.03 (sep, J = 6.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 7.20 (dd, J = 8.7,
1.8 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.4, 15.3, 24.3, 27.9, 34.1, 60.2, 111.2, 114.0,
119.0, 123.2, 127.6, 133.6, 144.7, 144.9, 165.5, 170.9 ppm. HRMS
(ESI+): calcd. for C17H20O3N [M+H]+: 286.1438, found: 286.1440.
Ethyl-1-acetyl-7-methoxy-2-methyl-1H-indole-3-carboxylate
(3k):
Ethyl-1-acetyl-5-methoxy-2-methyl-1H-indole-3-carboxylate
(3d):
White solid (25.0 mg, 60%); mp: 117-119 °C; 1H NMR (500 MHz, CDCl3)
δ 1.45 (t, J = 7.1 Hz, 3H), 2.56 (s, 3H), 2.76 (s, 3H), 3.94 (s, 3H), 4.41 (q,
J = 7.2 Hz, 2H), 6.77 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.75 (d,
J = 8.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.7, 14.5, 28.6, 55.7,
60.0, 104.9, 107.9, 114.5, 124.0, 124.3, 129.5, 144.2, 146.1, 165.6,
174.3 ppm. HRMS (ESI+): calcd. for C15H18O4N [M+H]+: 276.1236, found:
276.1236.
White solid (36.0 mg, 87%); mp: 92-95 °C; NMR (500 MHz, CDCl3) δ
1.47 (t, J = 7.2 Hz, 3H), 2.75 (s, 3H), 2.96 (s, 3H), 3.88 (s, 3H), 4.43 (q, J
= 7.2 Hz, 2H), 6.91 (dd, J = 9.1, 2.7 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H),
7.81 (d, J = 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.4, 15.4, 27.8,
55.5, 60.3, 104.2, 111.0, 112.9, 115.2, 128.6, 129.9, 145.1, 156.5, 165.4,
170.7 ppm. HRMS (ESI+): calcd. for C15H18O4N [M+H]+: 276.1230, found:
276.1229.
Ethyl-1-acetyl-2,6-dimethyl-1H-indole-3-carboxylate and ethyl-1-
acetyl-2,7-dimethyl-1H-indole-3-carboxylate (3l-i+3l-ii): Colorless
sticky liquid (29.5 mg, 76%); 1H NMR (500 MHz, CDCl3) δ 1.47 (t, J = 7.2
Hz, 0.9H), 1.48 (t, J = 7.2 Hz, 3H), 2.47 (s, 3H), 2.49 (s, 0.9H), 2.78 (s,
3.9 H), 2.96 (s, 0.9H), 2.96 (s. 3H), 4.4.–4.46 (m, 2.6H), 7.13–7.16 (m,
1.3H), 7.73 (s, 0.3 H), 7.77 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.98 (d, J =
8.1 Hz, 0.3H); 13C NMR (125 MHz, CDCl3) δ 14.9, 14.9, 15.3, 15.4, 21.5,
22.0, 27.9, 28.0, 60.3, 60.3, 110.9, 111.0, 113.9, 114.5, 121.2, 121.5,
124.9, 125.3, 125.6, 127.5, 133.3, 133.5, 134.4, 135.4, 144.1, 144.8,
165.5, 171.0, 171.2 ppm. HRMS (ESI+): calcd. for C15H18O3N [M+H]+:
260.1281, found: 260.1281.
Ethyl 1-acetyl-5-bromo-2-methyl-1H-indole-3-carboxylate (3e): White
solid (32.0 mg, 81%); mp: 82-85 °C; 1H NMR (500 MHz, CDCl3) δ 1.47 (t,
J = 7.2 Hz, 3H), 2.76 (s, 3H), 2.97 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.40
(dd, J = 8.9, 2.0 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 8.25 (d, J = 2.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 14.4, 15.3, 27.9, 60.5, 110.6, 115.8,
117.5, 124.4, 127.3, 129.0, 134.0, 145.4, 164.8, 170.6 ppm. HRMS
(ESI+): calcd. for C14H15O3NBr [M+H]+: 324.0230 and 326.0209 (81Br),
found: 324.0229 and 326.0209 (81Br).
Ethyl 1-acetyl-5-chloro-2-methyl-1H-indole-3-carboxylate (3f): White
solid (32.5 mg, 77%); mp: 81-83 °C; 1H NMR (500 MHz, CDCl3) δ 1.48 (t,
J = 7.2 Hz, 3H), 2.78 (s, 3H), 2.98 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 7.22–
7.32 (m, 1H), 7.84–7.93 (m, 1H), 8.07 (d, J = 2.1 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 14.4, 15.4, 28.0, 60.6, 110.5, 115.5, 121.2, 124.6, 128.4,
129.6, 133.5, 145.6, 164.9, 170.7 ppm. HRMS (ESI+): calcd. for
C14H15O3NCl [M+H]+: 280.0735, found: 280.0736.
Ethyl-1-acetyl-5,6-dimethoxy-2-methyl-1H-indole-3-carboxylate (3m-
i): White solid (25.0 mg, 54%); mp: 124-129 °C; 1H NMR (500 MHz,
CDCl3) δ 1.47 (t, J = 7.1 Hz, 3H), 2.73 (s, 3H), 2.94 (s, 3H), 3.94 (s, 3H),
3.96 (s, 3H), 4.43 (q, J = 7.1 Hz, 2H), 7.60 (s, 1H), 7.68 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 14.4, 15.5, 27.8, 55.9, 56.2, 60.2, 98.9, 102.9, 111.3,
120.3, 129.7, 141.7, 147.0, 147.5, 165.4, 170.9 ppm. HRMS (ESI+):
calcd. for C16H20O5N [M+H]+: 306.1336, found: 306.1337.
Ethyl 1-acetyl-5-fluoro-2-methyl-1H-indole-3-carboxylate (3g): White
solid (35.6 mg, 73%); mp: 75-79 °C; 1H NMR (500 MHz, CDCl3) δ 1.48 (t,
J = 6.9 Hz, 3H), 2.78 (s, 3H), 2.99 (s, 3H), 4.43 (q, J = 7.0 Hz, 2H), 7.05
(td, J = 9.0, 2.2 Hz, 1H), 7.77 (dd, J = 9.5, 2.4 Hz, 1H), 7.94 (dd, J = 9.2,
4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 14.4, 15.4, 28.0, 60.5, 107.5
(d, J = 25.4 Hz), 110.9 (d, J = 4.5 Hz), 112.3 (d, J = 25.4 Hz), 115.6 (d, J
= 9.1 Hz), 128.4 (d, J=10.9 Hz), 131.6, 145.9, 159.8 (d, J = 239.8 Hz),
165.0, 170.7 ppm. HRMS (ESI+): calcd. for C14H15O3NF [M+H]+:
264.1030, found: 264.1028.
Ethyl-1-acetyl-6,7-dimethoxy-2-methyl-1H-indole-3-carboxylate (3m-
1
ii): Sticky solid (8.0 mg, 26%); H NMR (500 MHz, CDCl3) δ 1.42 (t, J =
7.0 Hz, 3H), 2.67 (s, 3H), 2.71 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.43 (q,
J = 7.1 Hz, 2H), 6.94 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 14.3, 15.5, 27.5, 56.9, 60.9, 61.3, 110.5, 111.2,
113.8, 121.8, 131.4, 138.4, 140.8, 148.7, 166.4, 170.2 ppm. HRMS
(ESI+): calcd. for C16H20O5N [M+H]+: 306.1336, found: 306.1337.
Ethyl-1-acetyl-2-methyl-5-(trifluoromethyl)-1H-indole-3-carboxylate
(3h): White solid (32.3 mg, 69%); mp: 67-69 °C; 1H NMR (500 MHz,
Ethyl-1-acetyl-2-methyl-1H-benzo[g]indole-3-carboxylate (3n): White
solid (23.0 mg, 52%); mp: 82-84 °C; 1H NMR (500 MHz, CDCl3) δ 1.49 (t,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
J = 7.2 Hz, 3H), 2.63 (s, 3H), 2.85 (s, 3H), 4.46 (q, J = 7.2 Hz, 2H), 7.45–
7.50 (m, 1H), 7.53–7.58 (m, 1H), 7.75 (t, J = 7.4 Hz, 2H), 7.98 (d, J = 8.1
Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.8,
14.5, 28.8, 60.2, 109.0, 120.8, 121.3, 121.5, 124.4, 124.7, 125.3, 126.2,
128.9, 129.4, 131.5, 142.3, 165.5, 175.4 ppm. HRMS (ESI+): calcd. for
C18H18O3N [M+H]+: 296.1281, found: 296.1277.
CDCl3) δ 14.5, 14.5, 60.2, 110.0, 113.3, 121.5, 123.4, 123.5, 127.0,
129.0, 130.3, 134.1, 134.2, 136.0, 145.3, 165.5, 169.7 ppm. HRMS
(ESI+): calcd. for C19H18O3N [M+H]+: 308.1281, found: 308.1281.
Ethyl-1-(dimethylcarbamoyl)-2-methyl-1H-indole-3-carboxylate (3v):
Sticky liquid (40.0 mg, 97%); 1H NMR (500 MHz, CDCl3) δ 1.46 (t, J = 7.2
Hz, 3H), 2.76 (s, 3H), 2.79 (br s., 3H), 3.27 (br s., 3H), 4.42 (q, J = 7.1 Hz,
2H), 7.21–7.23 (m, 1H), 7.24–7.27 (m, 2H), 8.12–8.14 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 12.6, 14.5, 36.7, 38.2, 59.8, 106.8, 110.4, 121.7,
122.6, 123.3, 126.5, 134.1, 143.4, 152.6, 165.6 ppm. HRMS (ESI+):
calcd. for C15H19O3N2 [M+H]+: 275.1396, found: 275.1398.
Ethyl-1-acetyl-2-phenyl-1H-indole-3-carboxylate (3o): White solid
(33.0 mg, 72%); mp: 102-105 °C; 1H NMR (500 MHz, CDCl3) δ 1.16 (t, J
= 7.2 Hz, 3H), 1.91 (s, 3H), 4.20 (q, J = 7.2 Hz, 2H), 7.37–7.44 (m, 2H),
7.45–7.53 (m, 5H), 8.20–8.24 (m, 1H), 8.30–8.34 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 13.9, 27.8, 60.1, 112.4, 115.6, 121.6, 124.5, 125.7, 126.8,
128.3, 129.5, 130.3, 132.6, 136.2, 143.6, 164.2, 171.8 ppm. HRMS
(ESI+): calcd. for C19H18O3N [M+H]+: 308.1287, found: 308.1285.
Dimethyl (1-acetyl-2-methyl-1H-indol-3-yl)phosphonate (4a): Sticky
liquid (29.0 mg, 69%); 1H NMR (500 MHz, CDCl3) δ 2.81 (s, 3H), 2.97 (d,
J = 2.3 Hz, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 7.25–7.42 (m, 2H), 7.83–7.85
(m, 1H), 7.90–7.92 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 15.6, 27.9,
52.3, 52.34, 104.2 (d, J = 212.5 Hz), 114.5, 120.8, 123.9, 124.6, 129.0, J
= 10.9 Hz), 135.7 (d, J = 12.7 Hz), 147.1 (d, J = 26.3 Hz), 170.7 ppm.
HRMS (ESI+): calcd. for C13H17O4NP [M+H]+: 282.0895, found: 282.0898.
Methyl-1-acetyl-2-(p-tolyl)-1H-indole-3-carboxylate (3p): White solid
(34.0 mg, 70%); mp: 113-117 °C; 1H NMR (500 MHz, CDCl3) δ 1.21 (t, J
= 7.2 Hz, 3H), 1.58 (s, 3H), 1.93 (s, 3H), 2.45 (s, 3H), 4.23 (q, J = 7.2 Hz,
2H), 7.28–7.32 (m, 2H), 7.34–7.37 (m, 2H), 7.38–7.41 (m, 2H), 8.17–8.21
(m, 1H), 8.29–8.33 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1, 21.5,
27.9, 60.2, 112.2, 115.6, 121.7, 124.5, 125.6, 126.8, 129.0, 129.5, 130.2,
136.2, 139.7, 144.1, 164.3, 172.0 ppm. HRMS (ESI+): calcd. for
C20H20O3N [M+H]+: 322.1443, found: 322.1441.
Dimethyl (1-acetyl-2,5-dimethyl-1H-indol-3-yl)phosphonate (4b):
White solid (33.2 mg, 75%); mp: 99-103 °C; 1H NMR (500 MHz, CDCl3) δ
2.45 (s, 3H), 2.78 (s, 3H), 2.93 (d, J = 2.3 Hz, 3H), 3.76 (s, 3H), 3.78 (s,
3H), 7.14 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.76 (dd, J = 8.6, 1.9 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 15.6, 21.3, 27.8, 52.2, 52.2, 104.2 (d, J =
212.6 Hz), 114.2, 120.8, 125.8, 129.4 (d, J = 11.8 Hz), 133.6, 134.0 (d, J
= 12.7 Hz), 147.1 (d, J = 26.3 Hz), 170.6 ppm. HRMS (ESI+): calcd. for
C14H19O4NP [M+H]+: 296.1046, found: 296.1045.
Ethyl-1-acetyl-2-(4-chlorophenyl)-1H-indole-3-carboxylate
(3q);
White solid (35.7 mg, 69%); mp: 124-129 °C; 1H NMR (500 MHz, CDCl3)
δ 1.22 (t, J = 7.1 Hz, 3H), 1.98 (s, 3H), 4.23 (q, J = 7.1 Hz, 2H), 7.39–
7.45 (m, 4H), 7.46–7.51 (m, 2H), 8.19–8.22 (m, 1H), 8.28–8.31 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 14.0, 28.1, 60.3, 112.8, 115.6, 121.8,
124.7, 126.0, 126.7, 128.6, 131.0, 131.7, 135.8, 136.2, 142.2, 164.1,
171.3 ppm. HRMS (ESI+): calcd. for C19H17O3NCl [M+H]+: 342.0897,
found: 342.0896.
Dimethyl (1-acetyl-5-isopropyl-2-methyl-1H-indol-3-yl)phosphonate
1
(4c): Sticky liquid (34.4 mg, 71%); H NMR (500 MHz, CDCl3) δ 1.30 (d,
J = 6.9 Hz, 6H), 2.78 (s, 3H), 2.93 (d, J = 2.3 Hz, 3H), 3.03 (hept, J = 6.9
Hz, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 7.21 (dd, J = 8.7, 1.8 Hz, 1H), 7.69 (d,
J = 1.7 Hz, 1H), 7.80 (dd, J = 8.7, 2.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 15.6, 24.3, 27.7, 34.0, 52.2, 52.3, 105.1 (d, J = 211.6 Hz), 114.3,
118.3, 123.1, 129.3 (d, J = 11.8 Hz), 134.2 (d, J = 12.7 Hz), 144.8, 147.1
(d, J = 27.2 Hz), 170.6 ppm. HRMS (ESI+): calcd. for C16H22O4NP
[M+H]+: 324.1359, found: 324.1356.
Ethyl-2-methyl-1-propionyl-1H-indole-3-carboxylate (3r): White solid
1
(35.7 mg, 92%); mp: 92-94 °C; H NMR (500 MHz, CDCl3) δ 1.37 (t, J =
7.2 Hz, 3H), 1.47 (t, J = 7.2 Hz, 3H), 2.97 (s, 3H), 3.06 (q, J = 7.3 Hz, 2H),
4.43 (q, J = 7.3 Hz, 2H), 7.29–7.32 (m, 2H), 7.81–7.85 (m, 1H), 8.11–
8.14 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 9.4, 14.4, 15.2, 33.2, 60.3,
110.8, 113.9, 121.7, 123.7, 124.2, 127.4, 135.0, 144.8, 165.5, 175.3 ppm.
HRMS (ESI+): calcd. for C15H18O3N [M+H]+: 260.1281, found: 260.1282.
Dimethyl (1-acetyl-5-methoxy-2-methyl-1H-indol-3-yl)phosphonate
1
(4d): Sticky liquid (31.0 mg, 66%); H NMR (500 MHz, CDCl3) δ 2.77 (s,
Ethyl-2-methyl-1-pivaloyl-1H-indole-3-carboxylate (3s): Sticky liquid
(38.4 mg, 89%); 1H NMR (500 MHz, CDCl3) δ 1.37 (s, 9H), 1.46 (t, J =
7.2 Hz, 3H), 2.70 (s, 3H), 4.42 (q, J = 7.1 Hz, 2H), 7.17–7.21 (m, 1H),
7.22–7.26 (m, 2H), 8.06–8.16 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
13.6, 14.5, 28.0, 44.9, 59.8, 106.4, 111.1, 121.7, 122.4, 122.9, 126.4,
134.7, 142.8, 165.7, 186.5 ppm. HRMS (ESI+): calcd. for C17H22O3N
[M+H]+: 288.1594, found: 288.1595.
3H), 2.93 (d, J = 1.5 Hz, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 6.92
(dd, J = 9.1, 2.7 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.83 (dd, J = 9.2, 1.4
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 15.7, 27.7, 52.2, 52.3, 55.6, 103.4,
104.2 (d, J = 210.7 Hz), 112.9, 115.5, 130.2 (d, J = 11.8 Hz), 130.4 (d, J
= 12.7 Hz), 147.3 (d, J = 26.3 Hz), 156.5, 170.3 ppm. HRMS (ESI+):
calcd. for C14H19O5NP [M+H]+: 312.0995, found: 312.0992.
Methyl
1-acetyl-3-(dimethoxyphosphoryl)-2-methyl-1H-indole-5-
Ethyl-2-methyl-1-(2-phenylacetyl)-1H-indole-3-carboxylate (3t): Low
melting solid (30.3 mg, 63%); 1H NMR (500 MHz, CDCl3) δ 1.46 (t, J =
7.1 Hz, 3H), 2.92 (s, 3H), 4.38 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 7.25–
7.28 (m, 2H), 7.30–7.33 (m, 3H), 7.34–7.38 (m, 2H), 7.77–7.89 (m, 1H),
8.10–8.17 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 14.4, 14.9, 45.8, 60.3,
110.9, 113.7, 121.9, 123.9, 124.3, 127.5, 127.6, 128.9, 129.2, 132.9,
135.0, 144.8, 165.3, 172.5 ppm. HRMS (ESI+): calcd. for C20H20O3N
[M+H]+: 322.1443, found: 322.1444.
carboxylate (4e): White solid (30.0 mg, 59%); mp: 117-120 °C; 1H NMR
(500 MHz, CDCl3) δ 2.82 (s, 3H), 2.97 (d, J = 2.1 Hz, 3H), 3.79 (s, 3H),
3.81 (s, 3H), 3.95 (s, 3H), 7.96 (dd, J = 8.8, 1.8 Hz, 1H), 8.01 - 8.04 (m,
1H), 8.51 (d, J = 1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 15.5, 27.8,
52.2, 52.4, 52.5, 105.1 (d, J = 212.5 Hz), 114.3, 122.8, 125.8, 126.0,
128.8 (d, J = 10.9 Hz), 138.5 (d, J = 12.7 Hz), 148.1 (d, J = 27.2 Hz),
167.1, 170.5 ppm. HRMS (ESI+): calcd. for C15H19O6NP [M+H]+:
340.0945, found: 340.0943.
Ethyl-1-benzoyl-2-methyl-1H-indole-3-carboxylate (3u): Sticky liquid
(28.0 mg, 61%); 1H NMR (500 MHz, CDCl3) δ 1.48 (t, J = 7.2 Hz, 3H),
2.72 (s, 3H), 4.45 (q, J = 7.1 Hz, 2H), 7.03–7.07 (m, 1H), 7.11 (t, J = 7.7
Hz, 1H), 7.24–7.30 (m, 1H), 7.49–7.54 (m, 2H), 7.68 (t, J = 7.5 Hz, 1H),
7.74 (d, J = 7.3 Hz, 2H), 8.14 (d, J = 7.9 Hz, 1H); 13C NMR (125 MHz,
Dimethyl
(2-methyl-1-propionyl-1H-indol-3-yl)phosphonate
(4f):
Sticky liquid (31.6 mg, 71%); 1H NMR (500 MHz, CDCl3) δ 1.38 (t, J = 7.2
Hz, 3H), 2.95 (d, J = 2.3 Hz, 3H), 3.08 (q, J = 7.3 Hz, 2H), 3.76 (s, 3H),
3.78 (s, 3H), 7.25–7.40 (m, 2H), 7.78–7.91 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 9.3, 15.5, 33.0, 52.2, 52.3, 104.4 (d, J = 212.5 Hz), 114.3, 120.9,
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10.1002/ejoc.201700095
European Journal of Organic Chemistry
FULL PAPER
123.7, 124.4, 129.1 (d, J = 10.9 Hz), 135.6 (d, J = 12.7 Hz), 147.1 (d, J =
26.3 Hz), 175.0 ppm. HRMS (ESI+): calcd. for C14H19O4NP [M+H]+:
296.1046, found: 296.1043.
[4]
For recent examples of the synthesis of indoles from 2-alkynylanilines,
see: a) J. Barluenga, M. Trincado, E. Rubio, J. González, Angew.
Chem. 2003, 115, 2508–2511; Angew. Chem., Int. Ed. 2003, 42, 2406–
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2287.
Dimethyl
(1-(dimethylcarbamoyl)-2-methyl-1H-indol-3-
yl)phosphonate (4g): White solid (27.5 mg, 59%); mp: 110-102 °C; 1H
NMR (500 MHz, CDCl3) δ 2.72 (s, 3H), 2.81 (br s, 3H), 3.27 (br s, 3H),
3.75 (br s, 3H), 3.77 (br s, 3H), 7.18–7.32 (m, 3H), 7.74–7.86 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 12.3, 36.8, 38.3, 52.2, 52.3, 98.9 (d, J =
216.2 Hz), 110.6, 120.8, 122.5, 123.5, 128.3 (d, J = 11.8 Hz), 135.0 (d, J
= 13.6 Hz), 145.2 (d, J = 27.3 Hz), 152.6 ppm. HRMS (ESI+): calcd. for
C14H19O4N2P [M+H]+: 310.1082, found: 310.1080.
[5]
For selected references on the metal-catalyzed cascade synthesis of
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Dimethyl (1-(2-acetamidophenyl)-2-oxopropyl)phosphonate (5a): To
a 3 mL screw capped vial with a spinvane triangular-shaped Teflon
stirbar were added acetanilide (30.0 mg, 1.0 equiv), diazocompounds 2e
(51.2 mg, 1.2 equiv), [IrCp*Cl2]2 (3.5 mg, 2.0 mol %), AgNTf2 (6.9 mg, 8.0
mol %), KOAc (18.2 mg, 1.0 equiv) and 1,2-dichloroethane (1.5 mL)
under air. The reaction mixture was stirred at 70 °C for 12 h. Next, the
reaction mixture was filtered through a pad of celite followed by washing
of the pad with CH2Cl2 (10 mL x 2). The combined solvents were
removed under reduced pressure and the residue was purified by column
chromatography (EtOAc/hexane) to obtain the alkylated product 6a as
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For selected reviews on transition-metal-catalyzed C–H bond activation,
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1
sticky liquid (48.0 mg, 72% yield); H NMR (500 MHz, CDCl3): δ 2.02 (d,
J = 1.5 Hz, 3H), 2.15 (s, 3H), 3.50 (d, J = 10.8 Hz, 3H), 3.94 (d, J = 11.1
Hz, 3H), 4.19 (d, J = 24.6 Hz, 1H), 7.22–7.26 (m, 1H), 7.27–7.30 (m, 1H),
7.39–7.49 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 9.55 (br s, 1H); 13C NMR
(125 MHz, CDCl3): δ 23.7, 28.9 (d, J = 8.2 Hz), 53.0 (d, J = 7.3 Hz), 54.7
(d, J = 7.3 Hz), 58.4 (d, J = 140.3 Hz), 124.3 (d, J = 7.3 Hz), 126.3, 127.4
(d, J = 2.7 Hz), 129.5 (d, J = 3.6 Hz), 132.0 (d, J = 7.3 Hz), 136.6 (d, J =
4.5 Hz), 169.6, 202.9 (d, J = 5.4 Hz) ppm; HRMS (ESI+): calcd. for
C13H19O5NP [M+H]+: 300.0995, found: 300.0995.
Acknowledgements
PP thank DST-INSPIRE Faculty program for fellowship and
funding (GAP-0738). We also thank Dr. D. Ramaiah, Director,
CSIR-NEIST, Jorhat, for his active support, valuable inputs and
for providing all the facilities.
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Keywords: C-H annulation • indole • iridium catalysis • diazo
compounds • acetanilide
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European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201700095
European Journal of Organic Chemistry
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Entry for the Table of Contents
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C–H Annulations
Pitambar Patel,* Gangutri Borah
Page No. – Page No.
A Direct Access to Indoles via Ir(III)-
Catalyzed C-H Functionalization of
Acetanilides with Diazo Compounds
Here in we reported a one pot synthetic approach to poly-substituted indoles from
readily available acetanilide via Ir(III)-catalyzed intermolecular C–H annulations with
diazo compounds.
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