Iridium(I)-catalyzed direct C-H bond alkylation of the C-7 position of indolines with alkenes

Article abstract of DOI:10.1002/adsc.201300917

A cationic iridium-catalyzed C-7 alkylation of N-substituted indoline derivatives with various alkenes has been developed. A variety of 7-alkylindolines were obtained in moderate to high yields. This protocol relies on the use of the carbonyl group on the nitrogen atom of indoline as a directing group and it is potentially applicable to the large-scale synthesis of 7-alkylindoles.

Full text of DOI:10.1002/adsc.201300917

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DOI: 10.1002/adsc.201300917
À
Iridium(I)-Catalyzed Direct C H Bond Alkylation of the C-7
Position of Indolines with Alkenes
Shiguang Pan,a Naoto Ryu,a and Takanori Shibataa,b,*
a
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku,
Tokyo 169-8555, Japan
Fax : (+81)-3-5286-8098; e-mail: tshibata@waseda.jp
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
b
Received: October 14, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300917.
Abstract: A cationic iridium-catalyzed C-7 alkyla-
tion of N-substituted indoline derivatives with vari-
ous alkenes has been developed. A variety of 7-
a new and direct approach for the C-7 position-selec-
tive C H alkylation of indolines with alkenes. Nota-
bly, various indoline derivatives are commercially
available and the obtained C-7 alkylated indolines
can be readily transformed into C-7 alkylated indoles
by dehydrogenation (Method C).
[9]
À
alkylACHTUNGTRENNUNGindolines were obtained in moderate to high
yields. This protocol relies on the use of the carbon-
yl group on the nitrogen atom of indoline as a di-
recting group and it is potentially applicable to the
large-scale synthesis of 7-alkylindoles.
Over the past several years, we have focused on the
development of cationic iridium-catalyzed reactions
[10]
À
initiated by C H bond activation, and have recent-
À
Keywords: alkenes; alkylation; C H functionaliza-
ly developed a C-2 position-selective alkylation of in-
doles with alkenes (Scheme 2).[5c] This protocol relies
on the use of a carbonyl group on the nitrogen atom
of indole as a directing group. Thus, we assumed that
C-7 position-selective C-H alkylation could also be
possible with the use of N-acylindolines in place of N-
tion; iridium catalysts; N-substituted indolines
Nitrogen-containing heterocycles are widely found as acylindoles.
a core skeleton in many biologically active com-
We initiated our study of C-7 position-selective al-
pounds. Among them, indole is one of the most im- kylation with the reaction of N-acetylindoline (1a)
portant structural units and the development of an ef- with ethyl acrylate (2a) (Table 1). When cationic Ir-
ficient method for the synthesis of substituted indoles BINAP catalyst with BF4 as a counteranion was used
has been strongly desired.[1] The installation of desired
substituent(s) along with construction of the indole
skeleton has been a conventional protocol for regiose-
lective synthesis.[2] However, a more straightforward
À
approach is the C H functionalization of indole de-
rivatives.[3] Regarding alkylation, a C-3 position-selec-
tive alkylation is most well-established, and was real-
ized by Friedel–Crafts reaction, allylation, conjugate
addition, and so on.[4] In contrast, C-2 alkylation is
a newcomer, and the Pd-catalyzed reaction with alkyl
halides and the Ir-catalyzed reaction with alkenes
have recently been reported.[5] However, to the best
of our knowledge, there has been no previous report
[6]
À
on C H alkylation at the C-7 position of indole.
7-Alkylindoles can be conventionally prepared by
the Wittig or Horner–Wadsworth–Emmons reaction
of 7-formylindoles with alkyl halides,[7] and the Heck
Scheme 1. Preparation of 7-alkylindoles. Method A: Alkeny-
reaction of 7-haloindoles with alkenes,[8] both of
lation along with hydrogenation. B: Heck reaction along
with hydrogenation. C: Direct C H bond alkylation along
Scheme 1). In this communication, we described with dehydrogenation (this work).
which follow hydrogenation (Methods A and B in
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Table 2. Screening of the directing group.[a]
Entry
Substrate 1
R group
Yield of 3 (%)
1
2
3
4
5
6
1b
1c
1d
1e
1f
1g
Boc
Cbz
COEt
CO-t-Bu
COPh
CONMe2
n.d.
n.r.
89 (3b)
<5
n.d.
À
Scheme 2. Ir-catalyzed C H bond alkylation.
n.d.
Table 1. Optimization of the reaction conditions.[a]
[a]
The reaction conditions were as follows: N-substituted
indoline 1 (0.1 mmol), ethyl acrylate (2a) (0.4 mmol), [Ir-
AHCTUNTGREN(NGUN cod)2]BF4 (0.01 mmol), rac-BINAP (0.01 mmol), diox-
ane (0.2 mL), 1358C, 24 h.
9). We used the conditions in entry 1 for further in-
vestigation.
A variety of carbonyl functionalities on the nitro-
gen atom of indoline were examined as potential di-
recting groups (Table 2). Boc- and Cbz-protected in-
dolines 1b and 1c did not give the desired products at
all (entries 1 and 2). A propanoyl group achieved
almost the same yield as an acetyl group (entry 3),
but a bulky pivaloyl group significantly hindered the
reaction (entry 4). Thus, the efficient coordination of
an oxygen atom to the metal center is important. In
contrast to the C-2 alkylation of indole,[5c] a benzoyl
group was an inappropriate directing group in the C-7
alkylation of indoline: while N-benzoylindole (1f) was
completely consumed, however, the desired alkylated
product was not obtained at all (entry 5). A carbamo-
yl group was also ineffective (entry 6),[11] and we de-
termined that an acetyl group was the directing group
of choice.
Entry
X
Ligand
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
BF4
rac-BINAP
rac-BINAP
rac-BINAP
2PPh3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DME
91
84
OTf
BARF[b]
BF4
BF4
BF4
BF4
BF4
BF4
80
n.d.[c]
80
BIPHEP[d]
DPPF[e]
68
40
74
31
rac-BINAP
rac-BINAP
rac-BINAP
PhCl
toluene
[a]
The reaction conditions were as follows: N-acetylindoline
(1a) (0.1 mmol), ethyl acrylate (2a) (0.4 mmol), [Ir-
ACHTUNGTRENNUNG
[b]
[c]
[d]
[e]
BARF=tetrakisACHTUNGTRENNUNG[3,5-bis(trifluoromethyl)phenyl]borate.
n.d.=not detected.
2,2’-Bis(diphenylphosphino)-1,1’-biphenyl.
1,1’-Bis(diphenylphosphino)ferrocene.
The scope of substituted N-acetylindolines and al-
kenes was examined using Ir-rac-BINAP catalyst
(Table 3). We first introduced substituents to N-acety-
in heated 1,4-dioxane, the expected C-7 alkylated lindoline. As a result, the corresponding 7-alkylindo-
product 3a was exclusively obtained in 91% yield lines 3c–3h were obtained, and the highest yield of
(entry 1). We further screened other counteranions of 98% was achieved with a phenyl group at the C-2 po-
the iridium complex, but the results did not exceed sition of N-acetylindoline. Significant electronic ef-
those with BF4 (entries 2 and 3). We next tuned the fects on the reactivities were not observed: a bromo
phosphine ligands: the monodentate ligand PPh3 was or methoxy substituent at the C-5 position of N-
ineffective and product 3a was not detected at all acetylACTHNUTRGNEiNUG ndoline did not impair the reaction, and the
(entry 4). The bidentate ligands BIPHEP and DPPF corresponding products 3f and 3g were obtained in
facilitated the reactions to give 3a in good yields, but good yields. The reaction of 3,3-disubstituted N-
the results were not better than those with BINAP acetylACHTUNTRGNEUNGindoline 1n with ethyl acrylate also gave the
(entries 5 and 6). We next investigated the solvent corresponding product 3i in high yield. The scope of
effect. After the reaction was examined in 1,2-dime- alkene was investigated by the reaction of N-acetylin-
thoxyethane, chlorobenzene, and toluene, 1,4-dioxane doline (1a). Other alkyl acrylates, such as benzyl acry-
was determined to be the solvent of choice (entries 7– late and cyclohexyl acrylate also underwent smooth
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Iridium(I)-Catalyzed Direct C H Bond Alkylation
Table 3. Synthesis of 7-substituted indolines.[a]
Scheme 3. Synthetic transformations of 3a.
Product structure, number and yield
3c, 92%
3f, 86%
3d, 98%
3g, 86%
3e, 96%
3h, 97%
Scheme 4. Reaction of deuterated substrate 1a-d1 in the
presence of H2O.
coupling to give C-7 alkylated products 3j and 3k in
the respective yields of 92% and 95%. This coupling
reaction turned out to be a versatile reaction, and the
reaction of 1a with aryl acrylates, such as phenyl acry-
late and 2-naphthyl acrylate, gave the corresponding
products 3l and 3m in good yields. Phenyl vinyl sul-
fone was a good coupling partner, and the desired
product 3n was obtained in 97% yield. The reaction
of 1a with terminal alkenes possessing other function-
al groups, such as nitrile and boronic ester, also pro-
ceeded, however, the desired products 3o and 3p
were obtained in moderate yields. Unfortunately,
non-1-ene and n-butyl vinyl ether were inappropriate,
and the corresponding alkylated products could not
be detected. In one case a styrene derivative was used
as a coupling partner: the reaction of para-trifluoro-
methyl-substituted styrene gave the desired product
3q, albeit in low yield. In the reaction with styrene
itself, the substitutions at the C-3 position of N-acety-
lindoline were required, and the corresponding prod-
uct 3r was obtained in high yield. To demonstrate the
further use of the obtained 7-substituted indolines,
the transformations of product 3a was investigated
(Scheme 3). 7-Alkylindole 4 was obtained in high
yield by the oxidation of 3a with the use of DDQ as
an oxidant, and tricyclic compound 5 was obtained in
one step by hydrolysis of the ester moiety.
3i, 94%[b]
3l, 85%
3o, 46%
3j, 92%
3k, 95%
3n, 97%
3q, 39%[d]
3m, 83%[c]
3p, 51%
3r, 92%[e]
[a]
Unless otherwise noted, reaction conditions were as fol-
For a preliminary mechanistic study, we used deu-
terated N-acetylindoline 1a-d1: the reaction was exam-
ined in the presence of H2O (30 equiv.) and the ab-
sence of alkenes under the same reaction conditions
(Scheme 4). As a result, the recovered substrate had
a D content of 57%, and H/D exchange was ascer-
lows: N-substituted indoline 1 (0.1 mmol), alkene 2
(0.4 mmol), [IrACTHNUTRGNEUNG(cod)2]BF4 (0.01 mmol), rac-BINAP
(0.01 mmol), dioxane (0.2 mL), 1358C, 24 h.
Reaction time was 7 d.
Reaction time was 48 h.
The linear/branched ratio was 6.3:1.
Reaction time was 48 h, and the linear/branched ratio
was 7.7:1.
[b]
[c]
[d]
[e]
À
tained. This result implies that the C H bond at the
C-7 position was cleaved under the present condi-
tions.
À
We assume that cleavage of the C H bond at the
C-7 position is an initial step that generates inter-
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Acknowledgements
This work was supported by Grant-in-Aid for Scientific Re-
search on Innovative Areas, “Molecular Activation Directed
toward Straightforward Synthesis,” MEXT, JST, ACT-C, and
Grants for Excellent Graduate School (Practical Chemical
Wisdom), Waseda University, MEXT, Japan.
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which yields a branched alkylated product.
In conclusion, we have developed a cationic Ir(I)-
catalyzed direct C-7 alkyaltion of N-substituted indo-
À
lines with alkenes via C H bond functionalization.
The corresponding 7-alkylindolines were obtained in
moderate to high yields with the use of an acetyl
group as a directing group. The present results dem-
onstrate a new example to the synthesis of C-7 alky-
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Experimental Section
Typical Experimental Procedure for Products 3
[Ir
(cod)2]BF4 (0.01 mmol), rac-BINAP (0.01 mmol) and N-
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À
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6 Iridium(I)-Catalyzed Direct C H Bond Alkylation of the C-
7 Position of Indolines with Alkenes
Adv. Synth. Catal. 2014, 356, 1 – 6
Shiguang Pan, Naoto Ryu, Takanori Shibata*
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