Facile Synthesis of 2-Arylindoles through Plancher-Type Rearrangement of 3-Alkyl-3-Arylindolenines

Article abstract of DOI:10.1055/s-0036-1588448

3-Alkylindoles on reaction with a cyclohexa-2,4-dien-1-one catalyzed by BF ₃ ·OEt ₂ gave the corresponding 3-alkyl-3-arylindolenines in high yields through a tandem Michael addition/aromatization sequence. In the presence of HCl, these indolenine derivatives underwent a facile Plancher-type C-3 to C-2 aryl rearrangement to deliver the corresponding 2-arylindoles.

Full text of DOI:10.1055/s-0036-1588448

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
S. K. Chittimalla et al.
Letter
Synlett
Facile Synthesis of 2-Arylindoles through Plancher-Type Rear-
rangement of 3-Alkyl-3-Arylindolenines
R1
O
R1
HCl, r.t.
OH
OH
Santhosh Kumar Chittimalla*
Chennakesavulu Bandi
Vinod Kumar Gadi
OCH3
OCH3
when
R2 = H
OCH3
OCH3
BF3•OEt2
0 °C
N
N
R3
R1
H
R3
12 examples
up to 90% yield
R3
OH
14 examples
up to 94% yield
+
Siva Ramakrishna Gunturu
HO
then
sat. NH4Cl
OCH3
R3
H3CO
R3
when
R1 = H
R2
Medicinal Chemistry Department, AMRI Singapore
Research Centre, 61 Science Park Road, #05-01, The
Galen, Science Park II, Singapore 117525, Singapore
santhosh.chittimalla@amriglobal.com
N
when R1
CH2CH2OH
=
H
R2
N
chemcsk@gmail.com
7 examples
up to 93% yield
2 examples
up to 94% yield
H
O
N
includes R3 = OCH3; Br; CO2CH3; Cl; CH3
H
includes R2 = H; R1 = CH3; Et; CH2CH2Br; CH2CH2CH2CO2CH3
includes R1 = H; R2 = CH3; Et; CH2CO2Et
Received: 10.04.2017
Accepted after revision: 09.05.2017
Published online: 05.07.2017
ed indole to a cyclohexa-2,4-dien-1-one (an electrophilic
aryl equivalent) to furnish a 3-arylindole.15d However, un-
der the optimized conditions (HClO4·SiO2 as catalyst) no re-
action occurred between the C-3-substituted indole skatole
(2a; 3-methyl-1H-indole) and 5,6,6-trimethoxycyclohexa-
2,4-dien-1-one (1a). We wondered whether a Lewis acid as
a catalyst16 instead of a Brønsted acid might facilitate a pos-
sible reaction between such 3-alkylindoles and a cyclo-
hexa-2,4-dien-1-ones. Consequently, we explored this
speculation, and our preliminary results are presented here.
We began our investigation by selecting skatole (2a) as
representative substrate in Lewis-acid-mediated reaction
with 5,6,6-trimethoxycyclohexa-2,4-dien-1-one (1a) as an
electrophilic aryl equivalent. At the outset, when a solution
of skatole (2a) and dienone 1a at –78 °C was treated with
BF3·OEt2, three products, namely 3aa (27%), 3aa′ (13%) and
3aa′′ (24%), were obtained (Table 1, entry 1). Obviously, un-
der these reaction conditions skatole (2a) and dienone 1a
could be coupled, but various products from competing re-
action pathways were isolated. Remarkably, however, the
BF3·OEt2-catalyzed reaction at 0 °C, after silica-gel column
chromatography, provided the 2-arylindole 3aa as the only
product in 82% yield (entry 2). As expected, the reaction
time had to be prolonged when a catalytic amount of
BF3·OEt2 was used; nevertheless, the yield of 2-arylindole
3aa (entry 3) was unaffected. A possible reaction pathway
for the formation of all the observed isomeric products is
rationalized in Scheme 3 (see below).17 Subsequently, we
explored various Lewis acids as catalysts for this reaction
and we found that the Sc(OTf)3- and Bi(OTf)3-catalyzed re-
actions were complete in 16 hours and gave the 2-arylin-
dole 3aa and the N-arylindole 3aa′′ in ~70% total yield and a
DOI: 10.1055/s-0036-1588448; Art ID: st-2017-b0247-l
Abstract 3-Alkylindoles on reaction with a cyclohexa-2,4-dien-1-one
catalyzed by BF3·OEt2 gave the corresponding 3-alkyl-3-arylindolenines
in high yields through a tandem Michael addition/aromatization se-
quence. In the presence of HCl, these indolenine derivatives underwent
a facile Plancher-type C-3 to C-2 aryl rearrangement to deliver the cor-
responding 2-arylindoles.
Key words arylindoles, indolenines, Plancher rearrangement, cyclo-
hexadienone, tandem reaction
The indole nucleus is a renowned pharmacophore in
medicinal chemistry.1 Because of the indisputable impor-
tance of the indole core, the synthetic community contin-
ues to explore novel methods either to construct indole
rings2 or to functionalize them selectively at various posi-
tions.3 Arylindole structures appear in several natural prod-
ucts as well as in pharmacologically active compounds. For
this reason, protocols for installing an aryl group directly
onto an indole ring are likewise a focus of current research.
These endeavors have paved the way to plethora of metal-
catalyzed or nonmetal-mediated procedures for the selec-
tive arylation of indoles at the C-3,4 C-2,5 or N-1 posi-
tion.3a,4a,b,6 Towards this objective, a variety of aryl precur-
sors, including diaryliodonium salts,7 aryl halides,8 arylbo-
ronic
acids,9
potassium
aryltrifluoroarylborates,10
arylphosphines,11 arylsiloxanes,12 arylsulfonyl hydrazides,13
arylsulfinic acids,14 and cyclohexadienones15 have been
successfully employed.
In general, the indole molecule is well known to be sus-
ceptible to electrophilic attack at the C-3, C-2, and N-1 posi-
tions as a result of the electronic nature of the ring. Recent-
ly, we reported a Brønsted-acid-catalyzed tandem protocol
involving a Michael addition reaction of a C-3 unsubstitut-
~1:1 ratio (entries
4 and 5). Interestingly, Yb(OTf)3,
Gd(OTf)3, and In(OTf)3 were not efficient catalysts for this
reaction (entries 6–8); under these conditions, selectivity
was poor and three products, the 2-arylindoles 3aa and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
S. K. Chittimalla et al.
Letter
Synlett
3aa′′′, and the N-arylindole 3aa′′, were obtained in 25–30%
total yield. It should be noted that the reaction of skatole
(2a) with dienone 1a catalyzed by metal triflates at elevated
temperature became complex. In a nutshell, of the Lewis
acids that we examined (Table 1), BF3·OEt2 was the best cat-
alyst in terms of selectivity and product yield.
indolenine 3aa′ (polar spot) underwent a facile C-3 to C-2
aryl migration (Plancher-type rearrangement)18 during
workup and silica-gel chromatography to give the 2-arylin-
dole 3aa (nonpolar spot). On a separate note, after the
BF3·OEt2-catalyzed reaction of skatole (2a) with dienone 1a
at 0 °C for 30 min, when 2 N HCl was added and the mixture
was stirred for 30 minutes at room temperature, the 2-
arylindole 3aa, was formed directly (see Scheme 3, Path a,
Table 1 Reaction of Skatole (2a) with Dienone 1a in the Presence of
Various Lewis Acidsa
a
O
δ 2.46
CH3
b
c
OCH3
OH
a: R2 = CH3, R3 = H;
H3CO
HO
R2
a
c
b: R2 = Et, R3 = H;
OCH3
OCH3
R3
O
c: R2 = CH2CH2CH2CO2CH3, R3 = H;
OCH3
OCH3
δ 1.68
CH3
N
OCH3
OCH3
OCH3
N
d: R2 = CH2CH2Br, R3 = H;
e: R2 = CH2CO2CH3, R3 = OBn;
g: R2 = CH2CH2OH, R3 = H
H
δ 7.98
H
1a
2
Ja,c = 2.0 Hz
+
R1
+
N
1
Ph
3aa'
3aa
a: R1 = OCH3
b: R1 = Br
conditions
CH3
δ 8.10 (1H)
δ 2.38
CH3
BF3•OEt2 (1.0 equiv)
CH2Cl2, 0 °C, 30 min
then aq NH4Cl (sat.)
δ 178.1 (13C)
c: R1 = Cl
CH3
δ 2.41
N
δ 7.09
d: R1 = CO2CH3
e: R1 = CH3
H
2f
N
CH3 Ja,b = 8.8 Hz
H
N
a
b
2a
OH
OH
OH
a
H3CO
H3CO
H3CO
CO2CH3
OH
c
N
J
a,c = 2.4 Hz
OH
OCH3
R1
H3CO
H3CO
CH3
H3CO
OCH3
H
H3CO
CH3
3aa''
3aa'''
2D NOESY
N
N
N
3ab' / 80%g
3ba': R1 = Br / 79%a,b
3ca': R1 = Cl / 34%c
3da': R1 = CO2CH3 / 70%d
3ea': R1 = CH3 / 81%e,f
3ac' / 90%
Entry Conditions
Product(s) Yieldb (%)
1b
BF3·OEt2 (1.0 equiv), CH2Cl2, –78 °C, 3 h
27
13
24
OH
3aa
3aa′
3aa′′
H3CO
R1
BnO
H3CO
OH
CO2CH3
OH
H3CO
2
3
4
BF3·OEt2 (1.0 equiv), CH2Cl2, 0 °C, 20 min
3aa
82
84
Br
H3CO
Ph
BF3·OEt2 (0.1 equiv), CH2Cl2, 0 °C to rt, 16 h 3aa
H3CO
N
3ae': R1 = OCH3 / 95%
3be': R1 = Br / 91%a
3ce': R1 = Cl / 79%
Bi(OTf)3 (0.1 equiv), MeCN, rt, 16 h
Sc(OTf)3 (0.1 equiv), MeCN, rt, 16 h
Yb(OTf)3 (0.1 equiv), MeCN, rt, 20 h
3aa
3aa′′
35
31
CH3
N
N
5
3aa
3aa′′
36
35
3ad' / 83%
3af' / 84%
3de': R1 = CO2CH3 / 75%
OH
OH
6c,d
3aa
3aa′′
3aa′′′
1:1:1e
H3CO
H3CO
H3CO
OH
H3CO
R
H3CO2C
7c,d
8c
Gd(OTf)3 (0.1 equiv), MeCN, rt, 20 h
In(OTf)3 (0.1 equiv), MeCN, rt, 20 h
As above
As above
O
O
OH
N
H
N
N
H
a Reaction conditions: dienone 1a (1.0 mmol), skatole (2a; 1.0 mmol). Diag-
nostic 1H & 13C NMR chemical shifts (in ppm), J-couplings, and 2D-NOESY
cross-peaks are indicated for the respective structures.
4ag'-Cyc / 94%
4dg'-Cyc / 82%
LA
b An inseparable mixture of other products (~15% ) was also formed.
c The reaction did not proceed to completion [~50% conversion based on
recovery of skatole (2a)].
CH3
R1
OCH3
5ba-Di: R1 = Br; R2 = CH3 / 5%
5da-Di: R1 = CO2CH3; R2 = CH3 / 15%
5ea-Di: R1 = CH3; R2 = CH3 / 8%
5ab-Di: R1 = OCH3; R2 = Et / 5%
OH
OH
d The reaction performed at 70 °C produced a complex mixture.
e Ratio determined from diagnostic peak integration in the 1H NMR of the
crude reaction mixture. 9–11% each of 3aa, 3aa′′ and 3aa′′′ were isolated.
N
R2
OCH3
OH
H3CO
N
Intriguingly, TLC analyses of the BF3·OEt2-catalyzed re-
action of skatole (2a) and dienone 1a before and after silica-
gel column chromatographic purification produced differ-
ent results. Whereas TLC analysis of the reaction mixture
showed a polar spot (Rf = 0.2; 30% EtOAc–hexanes) as the
major reaction product, to our surprise, upon silica-gel col-
umn chromatography of the reaction mixture, a new non-
polar spot (Rf = 0.3) appeared exclusively. After close inspec-
tion, it became clear that the initially formed C-3 arylated
R1
OCH3
3ab'' / 5%
Scheme 1 BF3·OEt2-catalyzed reaction of 3-alkylindoles 2a–g with cy-
clohexadienones 1a–e. a 0.1 equivalents of BF3·OEt2 and a reaction time
of 16 h were required for the reactions of dienone 1b. b ~5% of indole-
nine 5ba-Di was formed (isolated as a 1:1 inseparable mixture of 3ba′
and 5ba-Di). c 38% of 3ca was also isolated. d 15% of indolenine 5da-Di
was isolated. e the C-3-ortho-isomer was present in minor inseparable
quantities. f 8% of indolenine 5ea-Di was isolated. g Products 3ab′′ (5%)
and 5ab-Di (5%) were also isolated.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
S. K. Chittimalla et al.
Letter
Synlett
below). This result implied that C-3 arylated indolenine
structures are prone to undergo acid-mediated Plancher-
type rearrangement.
scope of the reaction, we examined the reactions of dien-
ones 1b–e with indoles 2a and 2e. The reaction of skatole
(2a) with dienones 1b–e at 0 °C for 30 min in the presence
of BF3·OEt2 as catalyst followed by workup with saturated
aqueous NH4Cl, provided the corresponding indolenine de-
rivative 3ba′–ea′ in up to 81% isolated yield. In these reac-
tions, the corresponding 2,3-diarylindolenine 5ba-Di, 5da-
Di, and 5ea-Di were also isolated as minor reaction prod-
ucts (5–15%). 3-Alkyl-3-arylindolenine 3ca′ appeared to be
sensitive to silica gel and gave 2-arylindole 3ca (38%)
during purification. The reaction of indole 2e with dienones
1b–d under the general reaction conditions gave the corre-
sponding products 3be′–3de′ in good yields (up to 91%). In-
terestingly, the reactions of 2-(1H-indol-3-yl)ethanol (2g)
with dienones 1a and 1d gave the cyclized products 4ag′-
To extend the scope of the reaction we examined the re-
actions of indoles 2b–f with cyclohexadienone 1a under the
general reaction conditions.19 Intriguingly, the correspond-
ing 3-alkyl-3-arylindolenines 3ab′–af′ formed from the re-
action of indoles 2b–f and dienone 1a were stable to silica-
gel purification and could be isolated in 80–95% yield
(Scheme 1). Small quantities of N-arylindole 3ab′′ (5%) and
2,3-diarylindolenine 5ab-Di (5%) were also isolated from
the reaction of 3-ethylindole (2b) and dienone 1a. The for-
mation of 2,3-diarylindolenine 5ab-Di can be attributed to
the reaction of the 2-arylindole 3ab, generated in situ, with
dienone 1a (see Scheme 3, Path f, below). To broaden the
R1
Ar
O
R2
1) BF3•OEt2, CH2Cl2
0 °C, 30 min
R3
2) 2 N HCl (aq), r.t., 16 h
OCH3
OCH3
a: R1 = OCH3
b: R1 = Br
+
N
R4
N
R1
c: R1 = Cl
R4
1
2
d: R1 = CO2CH3
e: R1 = CH3
f: R1 = t-Bu
2h: R2 = R3 = CH3, R4 = H
2i: R2 = CH3, R3 = H, R4 = Bn,
2a: R2 = CH3, R3 = R4 = H;
2b: R2 = Et, R3 = R4 = H;
2j: R2 = CH3, R3 = H, R4 = CH2CO2Et
2k: R2 = R4 = CH3, R3 = H
2l: R2 = CH2CO2CH3, R3 = R4 = H
2c: R2 = CH2CH2CH2CO2CH3, R3 = R4 = H;
2e: R2 = CH2CO2CH3, R3 = OBn; R4 = H
H
2D NOESY
CH3
CH3
CH3
OH
OH
CO2CH3
OH
CH3
CH3
OCH3
N
OCH3
OH
H
N
H
N
N
H
3ea''''
N
H
H
R1
HO
OCH3
CH3
3ba R1 = Br: 70%
3ea
OCH3
3ea + 3ea'''' (76% total yield)b
OCH3
H3CO
3ca R1 = Cl: 73%
3da R1 = CO2CH3: 63%a
3ab / 42%
OCH3
3ac / 68%
H3CO2C
CH3
CH3
H3CO2C
OH
OH
H3C
OH
R1
OH
Br
BnO
OCH3
OCH3
OCH3
N
OCH3
OCH3
N
H
N
N
OCH3
R4
H
H
3bl 72%e
3ae R1 = OCH3: 60%c; 3be R1 = Br: 26%c
3ce R1 = Cl: 65%; 3de R1 = CO2CH3: 27%c,d
3ai R4 = Bn, 81%; 3aj R4 = CH2CO2Et, 75%
3ak R4 = CH3, 84%
3ah 82%
H3CO2C
BnO
H3CO2C
H3CO2C
CO2CH3
CH3
CH3
CH3
OH
OCH3
CH3
OCH3
N
tBu
OCH3
N
H
H
N
N
H
H
HO
HO
OCH3
3fe'''' 44%
H3C
HO
3fl'''' 30%
3el''' 30%
3el'''' 55%
Other products/isomers formed from the reaction between cyclohexa-2,4-dienones and 3-alkylindoles:
tBu
H3CO
OCH3
OH
H3CO2C
tBu
H3CO2C
BnO
BnO
Ha; δ 4.88 (d, J = 3.2 Hz, 1H)
OCH3 Hb; δ 6.63 (d, J = 3.2 Hz, 1H)
OCH3
O
deuterium exchange
OH
N
H
CH3
N
H
Hb; δ 6.63 (s, 1H)
b
7 21%
6
LA
a
N
H
8ap 38%
Scheme 2 A two-pot protocol for the synthesis of 2-arylindoles through a Plancher-type rearrangement of 3-alkyl-3-arylindolenine derivatives. a Reac-
tion conditions for Step 2: 4 N HCl in 1,4-dioxane (25 equiv), r.t., 16 h. b An inseparable mixture of 3ea + 3ea′′′′ in a 1:0.3 ratio (by 1 H NMR integration)
was obtained. c Reaction conditions for Step 2: 4 N HCl in 1,4-dioxane (25 equiv), 50 °C, 8 h. d 3de′ was also isolated in 30% yield. e 10% of a mixture of
other isomers was formed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
S. K. Chittimalla et al.
Letter
Synlett
Cyc and 4dg′-Cyc exclusively in 94% and 82% yield, respec-
tively. A possible reaction pathway leading to these prod-
ucts is shown in Scheme 1.
From the above results, it was apparent that 3-alkyl-3-
arylindolenines undergo an acid-mediated Plancher-type
rearrangement to the corresponding 3-alkyl-2-arylindoles.
Consequently, with the aim of simplifying the reaction pro-
cedure to obtain 3-alkyl-2-arylindoles, we decided to skip
the purification at the 3-alkyl-3-arylindolenine stage. To
this end, as shown in Scheme 2, after the initial BF3·OEt2-
mediated reaction of dienone 1a and 3-alkylindole 2b, 2c,
2e, or 2h–k for 30 minutes, the solvent was removed to give
a residue.19,20 This residue was treated with 2 N aqueous
HCl, and the mixture was stirred at room temperature to
give the corresponding 2-arylindoles 3ab (42%), 3ac (68%),
3ae (60%), 3ah (82%), 3ai (81%), 3aj (75%), and 3ak (84%),
respectively. Among these 3-alkylindole substrates, a com-
peting ethyl-versus-aryl migration from the C-3 position to
the C-2 position was observed only in the case of 3-ethylin-
dole (2b), which gave product 8ap in 38% isolated yield.
Next, to broaden the scope of the reaction, we examined
the reactions of dienones 1b–d with indoles 2a and 2e. By
the general reaction procedure,19 dienones 1b–d reacted
with indoles 2a and 2e to give the requisite 3-alkyl-2-
arylindoles 3ba (70%), 3ca (73%), 3da (63%), and 3ce (65%),
in acceptable yields, however, products 3be (26%) and 3de
(27%) were produced in low yields. Attempts to improve the
yields by increasing the reaction time led to complex reac-
tion mixtures.
The reaction between 5-alkyl-substituted dienones 1e
and 1f with 3-alkylindoles 2a, 2e, and 2l were not regiose-
lective. Thus, in these reactions regioisomers 3ea′′′′, 3fe′′′′
(44%), 3el′′′ (30%), 3el′′′′ (55%), and 3fl′′′′ (30%) were isolat-
ed. The reason for this reversal in regioselectivity is not
presently clear, but recently a reversal of regioselectivity
was noticed when cyclohexa-2,4-dien-1-ones participated
in a Friedel–Crafts-type reaction.16 The production of prod-
uct 7 can be rationalized in terms of its formation from the
initially generated 3-arylindolenine 6, which eventually un-
dergoes cyclization by attack of the phenolic hydroxy group
on the imine moiety in the molecule.
R
OH
OCH3
OCH3
H3C
OCH3
N
H3C
Path b
N
OCH3
O
R = OCH3
3aa''
LA
OCH3
H3CO
O
OCH3
HO
O
OCH3
OCH3
R
R
Path a
H3C
R
Path a
H3C
H3C
N
N
Path b
NH
R = OCH3(3aa')
HCl
Plancher-type rearrangement
OCH3
OCH3
HO
HO
OCH3
R
HO
R
R
H3C
H3C
H3C
H3C
H3C
N
N
N
H
H
H
CH3
OH
OCH3
OCH3
OCH3
OCH3
OH
HO
OCH3
H3C
H3C
NH
NH
NH
3ea''''
3aa'''
3aa
Path e
Path c
Path d
R = OCH3
R = OCH3
R = CH3
OCH3
O
LA
O
O
OCH3
O
LA
Plausible reactions pathways leading to the observed
products are shown in Scheme 3.
OCH3
OCH3
CH3
H3C
O
CH3
CH
R
3
In the present work, we identified BF3·OEt2 as the cata-
lyst of choice for the reaction between cyclohexa-2,4-dien-
1-ones and 3-substituted indoles. We therefore extended
the use of BF3·OEt2 as catalyst to the reaction of cyclohexa-
2,4-dien-1-ones and 3-unsubstituted indoles (Scheme 4).15d
The reaction of dienones 1a, 1b, 1d, and 1e with 3-unsub-
stituted indoles 2m–q gave the corresponding 3-arylindoles
8am–aq, 8bm, 8dm, and 8em in high isolated yields
through a tandem Michael addition/aromatization se-
quence. Consequently, comparison of the analytical data for
these products with those of the 3-alkyl-2-arylindole deriv-
atives (Scheme 2), proved further proof that migration of
the aryl group, and not the methyl group, occurred during
the Plancher-type rearrangement of 3-alkyl-3-arylindole-
nines.
R
R
LA
NH
NH
NH
R2
OH
H3CO
H3CO
Path f
OH
HO
OCH3
OCH3
N
H
OCH3
OCH3
+
Et
O
OCH3
OCH3
N
OCH3
5ab-Di
Scheme 3 Possible reaction pathways leading to the observed prod-
ucts from the Lewis-acid-mediated reactions of cyclohexa-2-4-dien-2-
ones and 3-alkylindoles
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
S. K. Chittimalla et al.
Letter
Synlett
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R5
m: R4 = H, R5 = CH3 o: R4 = Bn, R5 = CH3
a
b
O
n: R4 = R5 = CH3
p: R4 = H, R5 = Et
N
R4
q: R4 = H, R5 = CH2CO2Et
2
OCH3
OCH3
c
BF3•OEt2, CH2Cl2
0 °C, 30 min
R1
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Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. For metal free
N-arylations see: (e) Xu, H.; Fan, L.-L. Z. Naturforsch., B 2008, 63,
298. (f) Smith, W. J. III.; Sawyer, J. S. Heterocycles 1999, 51, 157.
(g) Maiorana, S.; Baldoli, C.; Del Buttero, P.; Di Ciolo, M.;
Papagni, A. Synthesis 1998, 735.
(7) For C3-arylation, see: (a) Vásquez-Céspedes, S.; Chepiga, K. M.;
Möller, N.; Schäfer, A. H.; Glorius, F. ACS Catal. 2016, 6, 5954.
(b) Pitts, A. K.; O’Hara, F.; Snell, R. H.; Gaunt, M. J. Angew. Chem.
Int. Ed. 2015, 54, 5451. (c) Phipps, R. J.; Grimster, N. P.; Guant,
M. J. J. Am. Chem. Soc. 2008, 130, 8172. For C2-arylation, see
(d) Duan, L.; Fu, R.; Zhang, B.; Shi, W.; Chen, S.; Wan, Y. ACS
Catal. 2016, 6, 1062. (e) Malmgren, J.; Nagendiran, A.; Tai, C.-W.;
Bäckvall, J.-E.; Olofsson, B. Chem. Eur. J. 2014, 20, 13531.
(f) Ibañez, S.; Oresmaa, L.; Estevan, F.; Hirva, P.; Sanaú, M.;
Úbeda, M. A. Organometallics 2014, 33, 5378. (g) Tang, D.-T. D.;
Collin, K. D.; Ernst, J. B.; Glorius, F. Angew. Chem. Int. Ed. 2014,
53, 1809. (h) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972.
(8) For C3-arylation, see: (a) Joucla, L.; Batail, N.; Djakovitch, L. Adv.
Synth. Catal. 2010, 352, 2929. (b) Bellina, F.; Benelli, F.; Rossi, R.
J. Org. Chem. 2008, 73, 5529. (c) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.;
Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48, 2415. For C2-
arylation, see Ref. 8 (a) and: (d) Lane, B. S.; Brown, M. A.; Sames,
D. J. Am. Chem. Soc. 2005, 127, 8050. (e) Wang, X.; Lane, B. S.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (f) Xu, Z.; Xu, Y.; Lu,
H.; Yang, T.; Lin, X.; Shao, L.; Ren, F. Tetrahedron 2015, 71, 2616.
(g) Islam, S.; Larrosa, I. Chem. Eur. J. 2013, 19, 15093.
(9) For C3-arylation, see: (a) Yamaguchi, K.; Kondo, H.; Yamaguchi,
J.; Itami, K. Chem. Sci. 2013, 4, 3753. For C2-arylation, see:
(b) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem. Int. Ed. 2008, 47, 1473. (c) Zhang, L.; Li, P.; Liu, C.;
Yang, J.; Wang, M.; Wang, L. Catal. Sci. Technol. 2014, 4, 1979.
(10) For C2-arylation, see: Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem.
2008, 73, 7428.
1
OCH3
OCH3
OH
OCH3
OH
H3CO
H3CO
R1
OH
CH3
CH3
N
CH3
N
N
H
CH3
8an 93%a
Bn
8ao 89%b
8am R1 = OCH3: 82%
8bm R1 = Br: 85%
8dm R1 = CO2CH3: 84%
OCH3
R1
OCH3
H3CO
8em R1 = CH3: 84%
OH
OH
CO2Et
CH3
N
H
N
H
8ap 81%
8aq R1 = OCH3: 92%
8bq R1 = Br: 93%
Scheme 4 BF3·OEt2-catalyzed tandem Michael addition reaction and
aromatization sequence for the synthesis of 3-arylindoles. a 6% of an in-
separable mixture of an ortho-isomer was formed. b 8% of an insepara-
ble mixture of an ortho-isomer was formed.
To conclude, we have shown that dearomatized C-3 ary-
lated indole obtained through a BF3·OEt2-catalyzed reaction
of a cyclohexa-2,4-dien-1-one with a 3-alkylindole effort-
lessly undergoes acid-mediated rearrangement to yield the
corresponding 2-arylindole. The reaction provides access to
2-arylindole derivatives straightforwardly from readily
available starting materials. We also found that BF3·OEt2 can
also be successfully used in the synthesis of 3-arylindoles.
Work towards improving the reaction protocol is being pur-
sued, including expanding the substrate scope and improv-
ing the yields of 2-arylindoles. At the same time, studies on
the application of these findings are underway.
(11) For C2-arylation, see: Li, Z.; Zhou, H.; Xu, J.; Wu, X.; Yao, H. Tet-
rahedron 2013, 69, 3281.
(12) For C2-arylation, see: Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010,
12, 3185.
Supporting Information
(13) For C2-arylation, see: Liu, C.; Ding, L.; Guo, G.; Liu, W.; Yang, F.-
L. Org. Biomol. Chem. 2016, 14, 2824.
(14) For C2-arylation, see: Miao, T.; Li, P.; Wang, G.-W.; Wang, L.
Chem. Asian J. 2013, 8, 3185.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588448.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(15) (a) Ye, Y.; Wang, H.; Fan, R. Synlett 2011, 923. (b) Yadav, J. S.;
Reddy, B. V. S.; Shankar, K. S.; Swamy, T.; Premalatha, K. Bull.
Korean Chem. Soc. 2008, 29, 1418. (c) Hsieh, M. F.; Rao, P. D.;
Liao, C.-C. Chem. Commun. 1999, 1441. For the synthesis of 3-
arylindoles by ClO4/SiO2 catalyzed reaction of cyclohexa-2,4-
dien-1-ones and 3-unsubstituted indoles, see: (d) Chittimalla, S.
K.; Bandi, C.; Putturu, S.; Kuppusamy, R.; Boellaard, K. C.; Tan, D.
C. A.; Lum, D. M. J. Eur. J. Org. Chem. 2014, 2565.
References and Notes
(1) (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620. (b) Sharma,
V.; Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47, 491.
(2) (a) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469. (b) Taber, D. F.;
Tirunahari, P. K. Tetrahedron 2011, 67, 7195. (c) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (d) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(3) (a) Djakovitch, L.; Batail, N.; Genelot, M. Molecules 2011, 16,
5241. (b) Simonetti, M.; Cannas, D. M.; Panigrahi, A.; Kujawa, S.;
Kryjewski, M.; Xie, P.; Larrosa, I. Chem. Eur. J. 2017, 23, 549.
(16) Parumala, S. K. R.; Peddinti, R. K. Org. Lett. 2013, 15, 3546.
(17) See Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
S. K. Chittimalla et al.
Letter
Synlett
(18) For indole C-3 to C-2 alkyl migration furnishing 2-alkylated
indoles see: (a) Wu, Q.-F.; Zhen, C.; Zhuo, C.-X.; You, S.-L. Chem.
Sci. 2016, 7, 4453. (b) Mari, M.; Lucarini, S.; Bartoccini, F.;
Piersanti, G.; Spadoni, G. Beilstein J. Org. Chem. 2014, 10, 1991.
(c) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc.
2007, 129, 9631. For indole C-3 to C-2 aryl migration furnishing
2-arylindole derivatives see: (d) Chai, Z.; Chen, J.-N.; Liu, Z.; Li,
X.-F.; Yang, P.-J.; Hu, J.-P.; Yang, G. Org. Biomol. Chem. 2016, 14,
1024. (e) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012,
134, 10815. For indole C-3 arylation with masked; p-benzoqui-
nones see: (f) Shu, C.; Liao, L.-H.; Liao, Y.-J.; Hu, X.-Y.; Zhang, Y.-
H.; Yuan, W.-C.; Zhang, X.-M. Eur. J. Org. Chem. 2014, 4467.
(19) BF3·OEt2-Catalyzed Reaction of a Cyclohexadienone and an
Alkylindole; Typical Procedure
Methyl 4-[3-(3-Hydroxy-4,5-dimethoxyphenyl)-3H-indol-3-
yl]butanoate (3ac′); Typical Procedure
A freshly prepared stock solution of BF3·Et2O (0.3 mL, 0.54
mmol, 1 mL) in CH2Cl2 (4 mL) was added to stirred solution of
cyclohexadienone 1a (100 mg, 0.54 mmol) and methyl 4-(1H-
indol-3-yl)butanoate (2c; 120 mg, 0.54 mmol) in CH2Cl2 (2.5
mL) at 0 °C, and the mixture was stirred for 30 min. The mixture
was then diluted with sat. aq NH4Cl (10 mL) and extracted with
CH2Cl2 (3 × 20 mL). The extracts were concentrated by rotary
evaporation and the crude product was purified by column
chromatography (silica gel, 0–70% EtOAc–hexane) to give a
brown solid; yield: 180 mg (90%). 1H NMR (400 MHz, CDCl3):
δ = 8.14 (s, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.40–7.27 (m, 3 H), 6.58
(d, J = 2.0 Hz, 1 H), 6.22 (d, J = 2.0 Hz, 1 H), 5.82 (br s, 1 H), 3.85
(s, 3 H), 3.75 (s, 3 H), 3.62 (s, 3 H), 2.26–2.17 (m, 4 H), 1.53–1.47
(m, 1 H), 1.32–1.26 (m, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 177.0 (CH), 173.3 (C), 154.9 (C), 152.6 (C), 149.7 (C), 142.0
(C), 135.0 (C), 133.2 (C), 128.2 (CH), 126.6 (CH), 123.2 (CH),
121.5 (CH), 106.8 (CH), 102.5 (CH), 65.2 (C), 60.8 (CH3), 55.9
(CH3), 51.5 (CH3), 34.3 (CH2), 33.8 (CH2), 19.9 (CH2). ESI-MS: m/z
= 370 [C21H23NO5 + H]+.
BF3·OEt2 (0.067 mL, 0.54 mmol) was added to a stirred solution
of cyclohexadienone 1a (100 mg, 0.54 mmol) and skatole (2a;
71 mg, 0.54 mmol) in CH2Cl2 (2.0 mL) at –78 °C, and the mixture
was stirred at –78 °C for 3 h. MeOH (2 mL) was added and the
mixture was stirred for 30 min. The solvent was removed by
rotary evaporation, and the crude residue was purified by flash
column chromatography (silica gel, 0–30% EtOAc–hexanes) to
give 3aa (62 mg, 27%), 3aa′′ (55 mg, 24%) and 3aa′ (30 mg, 13%),
along with inseparable mixture of other uncharacterized prod-
ucts.
5-(3,5-Dimethyl-1H-indol-2-yl)-2,3-dimethoxyphenol (3ah);
Typical Procedure
A freshly prepared stock solution of BF3·Et2O (0.3 mL, 0.54
mmol, 1 mL) in CH2Cl2 (4 mL) was added to stirred solution of
cyclohexadienone 1a (100 mg, 0.54 mmol) and 3,5-dimethyl-
1H-indole (2h, 79 mg, 0.54 mmol) in CH2Cl2 (2.5 mL) at 0 °C, and
the mixture was stirred for 30 min, the solvent was removed to
give a residue. The residue was then diluted with 2 N aq HCl (10
mL) and stirred for 2–6 h (16 h for reactions of indole 2e). The
mixture was extracted with EtOAc (3 × 20 mL), and the extracts
were dried (Na2SO4), filtered, and concentrated in vacuo. The
crude product was purified by column chromatography (silica
gel, 0–70% EtOAc–hexane) to give a reddish solid; yield: 131 mg
(82%). 1H NMR (400 MHz, CDCl3): δ = 7.87 (br s, 1 H), 7.37 (br s,
1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.03 (dd, J = 8.0, 1.2 Hz, 1 H), 6.81
(d, J = 1.6 Hz, 1 H), 6.67 (d, J = 1.6 Hz, 1 H), 5.89 (br s, 1 H), 3.96
(s, 3 H), 3.93 (s, 3 H), 2.48 (s, 3 H), 2.44 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 152.5 (C), 149.5 (C), 134.9 (C), 134.0 (C), 133.9
(C), 130.0 (C), 129.6 (C), 128.8 (C), 123.9 (CH), 118.6 (CH), 110.3
(CH), 108.1 (C), 107.5 (CH), 104.0 (CH), 61.1 (CH3), 56.0 (CH3),
21.5 (CH3), 9.6 (CH3). ESI-MS: m/z 298 [C18H19NO3 + H]+.
(20) Even with N-substituted indoles 2i–k as substrates, it appeared
that C-3-arylation occurred first, and only after HCl treatment
did these reaction mixtures become cleaner for isolation. We
found that a prolonging reaction time under BF3·OEt2-catalyzed
condition for the Plancher-type rearrangement was not suitable
for delivering 2-arylindole derivatives. Under these conditions,
2-arylindoles were obtained in low yields together with unchar-
acterized product mixtures.
2,3-Dimethoxy-5-(3-methyl-1H-indol-2-yl)phenol (3aa)
1H NMR (400 MHz, CDCl3): δ = 7.98 (br s, 1 H), 7.60–7.57 (m, 1
H), 7.37–7.34 (m, 1 H), 7.24–7.18 (m, 1 H), 7.17–7.12 (m, 1 H),
6.82 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 2.0 Hz, 1 H), 5.89 (br, s 1 H),
3.97 (s, 3 H), 3.93 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 152.5 (C), 149.5 (C), 135.7 (C), 135.0 (C), 133.8 (C),
130.0 (C), 129.4 (C), 122.3 (CH), 119.5 (CH), 118.9 (CH), 110.6
(CH), 108.5 (C), 107.6 (CH), 104.0 (CH), 61.1 (CH3), 56.0 (CH3),
9.7 (CH3). ESI-MS: m/z = 284 [C17H17NO3 + H]+.
2,3-Dimethoxy-5-(3-methyl-3H-indol-3-yl)phenol (3aa′)
1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.66 (app d, J = 8.0
Hz, 1 H), 7.40–7.34 (m, 1 H), 7.28–7.27 (m, 2 H), 6.56 (d, J = 2.0
Hz, 1 H), 5.79, (s, 1 H), 6.12 (d, J = 2.0 Hz, 1 H), 3.86 (s, 3 H), 3.73
(s, 3 H), 1.68 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 178.1 (CH),
154.3 (C), 152.5 (C), 149.6 (C), 144.5 (C), 135.0 (C), 134.0 (C),
128.1 (CH), 126.7 (CH), 122.5 (CH), 121.4 (CH), 106.4 (CH),
102.1 (CH), 61.1 (CH3), 60.8 (C), 55.8 (CH3), 20.2 (CH3). ESI-MS:
m/z = 284 [C17H17NO3 + H]+.
2,3-Dimethoxy-5-(3-methyl-1H-indol-1-yl)phenol (3aa′′)
1H NMR (400 MHz, CDCl3): δ = 7.63–7.56 (m, 2 H), 7.25–7.14
(m, 2 H), 7.09 (app q, J = 1.2 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H),
6.60 (d, J = 2.4 Hz, 1 H), 5.93 (s, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H),
2.38 (d, J =1.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 152.8 (C),
149.8 (C), 136.2 (C), 136.0 (C), 133.7 (C), 129.7 (C), 125.5 (CH),
122.3 (CH), 119.7 (CH), 119.2 (CH), 112.6 (C), 110.5 (CH), 104.1
(CH), 100.7 (CH), 61.1 (CH3), 56.1 (CH3), 9.5 (CH3). ESI-MS m/z
284 [C17H17NO3 + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F