A simple method for the direct arylation of indoles

Article abstract of DOI:10.1016/j.tet.2008.09.028

The scope and limitations are described for a powerful new method to access indoles bearing a quaternary center at C-3 using easily accessible bisaryl λ³-iodanes and a cheap organic base.

Full text of DOI:10.1016/j.tet.2008.09.028

Tetrahedron 65 (2009) 3149–3154
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple method for the direct arylation of indoles
*
Kyle Eastman, Phil S. Baran
The Scripps Research Institute, Department of Chemistry, 10650 N. Torrey Pines Road, La Jolla, CA 92037, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2008
Received in revised form 3 September 2008
Accepted 4 September 2008
Available online 20 September 2008
The scope and limitations are described for a powerful new method to access indoles bearing a quater-
nary center at C-3 using easily accessible bisaryl l
3-iodanes and a cheap organic base.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Justin DuBois on the
occasion of his receipt of the Tetrahedron
Young Investigator Award
1. Introduction
Fig. 2). Tri- and tetra-aryl bismuth-V reagents have been shown to
be versatile arylating agents for heteroatoms and arenes,7,10 simi-
Challenging chemical architectures of natural origin often point
to gaps in synthetic methodology. For instance, there is a shortage
of methods for C-3 quaternization of indoles with an aryl ap-
pendage. A number of natural products including haplophytine,1
bipleiophylline,2 hodgkinsine,3 and leptosin D4 (Fig. 1) contain
a quaternary indole C-3 with an aryl appendage or a structure
theoretically derived from such a motif as with haplophytine.1h
Recent efforts by Nicolaou and co-workers,5 and Fukuyama and co-
workers6 in the context of haplophytine have demonstrated the
feasibility of the synthetic union of a substituted indole C-3 with an
aryl nucleophile,6 or a pseudo-aryl electrophile,5 however, both
approaches were highly substrate specific and proceed in less than
25% yield. In a much simpler context, Barton and co-workers have
shown that treatment of skatole with tert-butyl tetramethylgua-
nidine (BTMG) in the presence of 1.5 equiv of Ph4BiOTs results in
95% conversion to the C-3 disubstituted indolenine 1 (Fig. 2).7 This
approach suffers from the required use of 4 equiv of aryl donor for
each aryl group transfer. Additionally, extensive studies in these
laboratories have shown that this bismuth mediated protocol does
not have broad substrate scope and requires a tedious five-step
reagent preparation.8 In this article, we report the scope and limi-
tations of a powerful method to access such structures using easily
larly, bisaryl l a-arylation of
3-iodanes have been employed in the
ketones, esters, silyl enol ethers, 1,3-dicarbonyl compounds, and
heteroatoms as well as alkylative dearomatization.11 In a different
context, Sanford and co-workers have utilized bisaryl l
3-iodanes as
both an oxidant and aryl transfer agent in the palladium mediated
C-2 arylation of indole.12
H
H
N
MeO2C
Me
Me
N
O
N
O
H
H
N
N
HO
O
O
O
O
N
H
Me
MeO
bipleiophylline
OH
OMe
O
haplophytine
N
N
Me
N
H
N
H
H
Me
MeO2C
HN
H
H
accessible bisaryl
l
3-iodanes and a cheap organic base.9
3-iodanes as an alternative to
A priori, utilization of bisaryl
l
N
H
N
Me
bismuth-V reagents for the arylation of indole was a logical choice
based on their similar hypervalent nature and reactivity profile (see
presumed intermediates [2 and 3] and mechanistic rationale in
OH
O
N
N
Me
N
H
N
H
S
H
O
H
S
N
Me
i-Pr
hodgkinsine
leptosin D
* Corresponding author. Tel.: þ1 858 784 7373; fax: þ1 858 784 7375.
E-mail address: pbaran@scripps.edu (P.S. Baran).
Figure 1. Natural products embodying the C-3 aryl indole motif.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.028

3150
K. Eastman, P.S. Baran / Tetrahedron 65 (2009) 3149–3154
(such as DBU or Et3N) is used with skatole and Ph2IBF4 in DCM, the
Ph
Bi
Ph
Ph
OTs
Me
Me
reaction proceeds at a greatly reduced rate producing negligible
amounts of product after 24 h. All experiments that do not proceed
to completion with 1.5 equiv of bisaryl iodide can be pushed to
complete conversion by the addition of excess reagent (1.5–2.0
additional equivalents). Finally, the efficiency of this conversion is
not diminished on gram scale, as demonstrated by the conversion
of 1.0 g of skatole to the desired indolenine in 65% yield with
1.5 equiv of Ph2IBF4.
Ph
Ph
Ph Bi
Ph
[5-step synthesis]
Ph
N
2
N
BF4
I
[Barton
arylation]7
[1-2 step(s)
synthesis]
[–Ph3Bi]
Ph
Ph
In summary, a powerful new method for the direct arylation of
indole has been developed. The strategy has been generalized and
performs well with a wide variety of substrate and reagent com-
binations. While this strategy is somewhat limited with respect to
efficiency in appending very electron rich arene rings to C-3 of
indole substrates, other than highly substrate dependent cases of
Nicolaou5 and Fukuyama,6 there are no comparable methods in the
literature that allow for the direct C-3 quaternization of indoles
with an arene ring. It is anticipated that this work may aid in the
rapid construction of the many known and yet to be discovered C-3
arylated indole alkaloids and medicinally relevant entities.
Ph
Me
Me
[–PhI]
[this work]
I
Ph
N
1
N
3
Figure 2. Speculative mechanism for the arylation of skatole with Ph4BiOTs and
Ph2IBF4.
Investigation probing the feasibility of the hypervalent iodine
mediated arylation began with the simple one-step preparation of
2. Experimental section
2.1. General information
a host of differentially substituted bisaryl
the requisite bisacetoxy iodoarene and commercially available
arylboronic acid.13 With the bisaryl 3-iodanes in hand, the scope of
l
3-iodane reagents from
l
reactivity with skatole as a model indole was explored. Arylation
experiments with skatole were effected via treatment of a mixture
All reactions were carried out under an in inert nitrogen at-
mosphere with dry solvents under anhydrous conditions unless
otherwise stated. Dry tetrahydrofuran (THF), toluene, and
dichloromethane (CH2Cl2) were obtained by passing these pre-
viously degassed solvents through activated alumina columns.
Reagents were purchased at the highest commercial quality and
used without further purification, unless stated otherwise. Percent
conversion is determined from the ratio of desired product to
unreacted starting material. Due to the relatively unstable nature of
the 3,3-disubstituted indolenines, products of the C-3 arylation
were reduced to the indolines for purification and characterization.
Reactions were monitored by thin layer chromatography (TLC)
carried out on 0.25 mm E. Merk silica gel plates (60F254) using UV
light as the visualizing agent and an acidic mixture of phophomo-
lybdic acid and ceric ammonium molybdate and heat as the de-
veloping agent. E. Merk silica gel (60, particle size 0.043–0.063 mm)
was used for flash column chromatography. Preparative thin layer
chromatography (PTLC) separations were carried out on 0.25 or
0.5 mm E. Merk silica gel plates (60F254). NMR spectra were
recorded on Bruker DRX-600 or DRX-500 spectrometer and were
calibrated using tetramethylsilane (TMS) as internal reference. The
following abbreviations were used to explain the multiplicities:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad. IR spectra were recorded on a Perkin–Elmer Spetrum BX
spectrometer. High resolution mass spectra (HRMS) were recorded
on an Agilent Mass spectrometer using ESI-TOF (electrospray ion-
ization-time of flight). Low resolution mass spectra (LRMS) were
recorded on an Agilent LCMS. Azeotroping refers to dissolving or
suspending the compound to be dried in toluene and removing the
solvent by rotary evaporation.
of skatole and the bisaryl l
3-iodane with 1.5 equiv of tert-butyl
tetramethylguanidine (BTMG) to give a relatively unstable indole-
nine, which was quantified in percent conversion based on crude
1H NMR data. For purposes of characterization, all indolenines were
reduced to the more stable indolines, and quantified in percent
isolated yield from skatole. The results for these experiments are
summarized in Table 1. The efficiency of the arylation of skatole14
with a phenyl aryl substituent (entry 1) or more electron poor arene
substituents (entries 2–5) is very good to excellent. The efficiency of
the arylation, when electron rich arene substituents are employed,
appears to be somewhat limited (entries 6–8). Gratifyingly, there
appears to be little disadvantageous steric influence imparted by an
ortho substituent (entries 5 and 8).
In an effort to demonstrate the scope of the indole partner, some
of the more reactive arylating reagents were reacted with a several
variably substituted indole substrates, these results are summa-
rized in Table 2. N-Boc-b-carboline (12) undergoes excellent
conversion to the C-3 arylation product with phenyl (entry 1),
p-chlorophenyl (entry 2), and 1-naphthyl (entry 3) substituents,
demonstrating a lack of sensitivity to having substitution at both C-
2 and C-3 of the indole partner. Extension of this method to
tryptamine was carried out with N-phthalimidyl tryptamine (13) as
the indole model. Both phenyl (entry 4) and naphthyl (entry 6)
were transferred with good efficiency, while p-chlorophenyl (entry
5) was transferred quantitatively to the desired C-3 arylated indo-
lenine. It should be noted that tryptamine required double pro-
tection of the amine functionality. The presence of a secondary
amine N–H or a carbamate N–H nearly shuts down the reaction
sequence under the described conditions. Additionally, extension of
these conditions to the fully protected tryptophan (14) with the
2.2. General procedure
bisphenyl l
3-iodane (entry 7) gave 66% conversion to the desired
C-3 arylated indolenine, while arylation with both chlorophenyl
(entry 8) and naphthyl (entry 9) lead to quantitative and near
quantitative conversion to the arylated indolines, respectively.15
Some preliminary optimization experiments employing skatole,
BTMG, and Ph2IBF4, point to DCM or DCE as the solvent of choice,
both of which can be used interchangeably. Experiments carried
out in THF and toluene resulted in negligible transformation to the
desired product. When a tertiary amine base other than BTMG
A mixture of the indole substrate (0.076 mmol, 1 equiv) and the
bisaryl
l
3-iodane (0.114 mmol, 1.5 equiv) were combined and
azeotroped with toluene 3ꢀ. The dry mixture was then dissolved in
DCM (1.0 mL) under an atmosphere of N2. Next, tert-butyl tetra-
methylguanidine (BTMG) (0.152 mmol, 2 equiv) was added with
stirring, resulting in an immediate darkening of the reaction mix-
ture from a colorless/pale yellow solution (or mixture) to a deep
red/burgundy color. The dark mixture was stirred under N2 until

K. Eastman, P.S. Baran / Tetrahedron 65 (2009) 3149–3154
3151
Table 1
Arylation experiments with skatole
Me
Me
Me
Ar
Ar
NaCNBH3
BTMG
+
(Ar)2IBF4
N
N
H
N
H
(2-11)
Entry
Indole
Reagent
Indolenine
(% conversion)
Indoline
(% yield)
Me
Me
Me
1a
I+BF4
-
N
H
N
(100)
N
2
H
4
(65)
F
F
Me
Me
Me
F
2
3
4
5
I+BF4
-
N
H
N
N
H
2
5
(66)
(35)
Cl
Br
Cl
Br
Me
Me
Me
Cl
I+BF4
-
N
H
N
N
H
2
6
(100)
(43)
Me
Me
Me
Br
-
I+BF4
N
H
N
N
H
2
7
(75)
(41)
Me
Me
Me
I+BF4
-
N
H
N
2
N
H
8
(100)
(71)
Me
Me
Me
Me
Me
Me
6
7
I+BF4
-
N
H
N
H
N
2
9
(50)
(36)
OMe
OMe
Me
MeO
Me
Me
I+BF4
-
N
H
N
H
2
N
(25)
10
(17)
Me
Me
Me
-
I+BF4
8
OMe
(33)
OMe
(50)
N
H
N
N
H
2
MeO
11
a
Gram scale reaction.
the starting material was consumed or the reaction appeared not to
be progressing any further (1–4 h). Completion of the reaction was,
in nearly all cases, accompanied by lightening of the reaction
mixture from dark red to a pale yellow/orange mixture. Upon
completion of the reaction, the mixture was poured onto a plug of
silica and rinsed with Et2O. Concentration gave a crude residue
containing only the desired unstable indolenine product, unreacted
starting material, and aryl iodide by-product. The percent conver-
sion of all reactions was determined by 1H NMR as a measure of the
ratio of desired product to unreacted starting material. After de-
termination of the percent conversion, the mixture was reduced to
obtain the more stable indoline product. Thus, the mixture from
above was dissolved (or suspended) in 2 mL of DCM. Next, a solu-
tion of 10 equiv of NaCNBH3 in MeOH (0.5 mL) was added to the
stirring mixture in an open flask. After 30 min of stirring, 0.5 g of
silica gel was added and stirring continued for an additional 30 min
to ensure complete reduction.16 The mixture was then concen-
trated and poured onto a silica gel column and eluted with the
stated eluent to give the desired indoline.
Table 1 entry 1: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 9.0 mg,
57%. Gram scale yield: 1.0 g, 65%. Physical state: colorless oil. Rf:
0.55 (silica gel, 1:1 hexane/Et2O). IR (film) nmax: 3386 cmꢁ1. 1H NMR
(600 MHz, CDCl3):
d
7.30 (m, 4H), 7.20 (t, J¼7.0 Hz, 1H), 7.09 (t, J¼
7.6 Hz, 1H), 6.97 (d, J¼7.4 Hz, 1H), 6.76 (t, J¼7.4 Hz, 1H), 6.72 (d,
J¼7.8 Hz, 1H), 3.78 (br s, 1H), 3.72 (d, J¼8.9 Hz, 1H), 3.57 (d,
J¼8.9 Hz, 1H), 1.72 (s, 3H). 13C NMR (150 MHz, CDCl3):
d 150.7, 147.7,
137.0, 128.2, 127.7, 126.6, 126.2, 124.1, 119.0, 110.0, 63.7, 49.7, 26.2.
HRMS (ESI-TOF): calcd for C15H15
210.1281.
N
[MþHþ] 210.1277, found

3152
K. Eastman, P.S. Baran / Tetrahedron 65 (2009) 3149–3154
Table 2
Arylation experiments with complex indole substrates
R
Ar
Ar
R
R
NaCNBH3
BTMG
(Ar)2IBF4
R'
R'
R'
N
H
N
(4,6 or 8)
N
H
Entry
1
Indole
Reagent
Indolenine (% conversion)
Indoline (% yield)
NBoc
NBoc
NBoc
4
N
H
N
H
N
12
(100)
(98)
Cl
Cl
2
12
6
NBoc
NBoc
N
N
H
(100)
(96)
NBoc
3
4
12
8
4
NBoc
N
H
N
(60)
(90)
N
Phth
Phth
N
Phth
Phth
N
N
H
N
N
H
13
(66)
(40)
Cl
Cl
Phth
Phth
5
13
6
N
N
N
N
H
(100)
(46)
N
6
13
8
4
Phth
N
N
H
N
(47)
(65)
CO2Me
Phth
CO2Me
CO2Me
Phth
N
Phth
N
N
7a
N
H
N
H
N
(66)
(34)
14
Cl
Cl
CO2Me
Phth
CO2Me
Phth
8a
14
6
N
N
N
N
H
(100)
(40)
CO2Me
CO2Me
Phth
9a
14
8
Phth
N
N
N
N
H
(95)
(47)
a
Bisaryl l
3-iodane (2 equiv) was used.

K. Eastman, P.S. Baran / Tetrahedron 65 (2009) 3149–3154
3153
Table 1 entry 2: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 6.0 mg,
35%. Physical state: colorless oil. Rf: 0.53 (silica gel, 1:1 hexane/
Table 1 entry 8: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 6.0 mg,
32%. Physical state: colorless powder. Rf: 0.48 (silica gel,1:1 hexane/
Et2O). IR (film) nmax: 3374 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d
7.27
Et2O). IR (film) nmax: 3380 cmꢁ1.1H NMR (600 MHz, CDCl3):
d 7.72 (br
(d, J¼8.9 Hz, 2H), 7.11 (t, J¼7.6 Hz, 1H), 6.97 (d, J¼8.7 Hz, 2H), 6.95
(d, J¼7.8 Hz, 1H), 6.78 (t, J¼7.4 Hz, 1H), 6.73 (d, J¼7.7 Hz, 1H), 3.8 (br
s, 1H), 3.67 (d, J¼8.9 Hz, 1H), 3.57 (d, J¼8.9 Hz, 1H), 1.7 (s, 3H). 13C
s, 0.5H), 7.53 (br s, 0.5H), 7.20 (t, J¼7.6 Hz, 1H), 7.09 (t, J¼7.5 Hz, 1H),
7.08 (d, J¼7.6 Hz, 1H), 6.99 (d, J¼7.6 Hz, 1H), 6.90 (d, J¼8.1 Hz, 1H),
6.81 (t, J¼7.9 Hz, 1H), 6.79 (t, J¼7.6 Hz, 1H), 6.70 (d, J¼7.8 Hz, 1H),
3.99 (d, J¼9.2 Hz,1H), 3.77 (s, 3H), 3.55 (d, J¼9.2 Hz,1H),1.76 (s, 3H).
NMR (150 MHz, CDCl3):
d
161.4 (J¼245 Hz), 150.6, 143.3 (J¼3.3 Hz),
136.7, 128.1 (J¼7.9 Hz), 127.8, 123.9, 119.1, 114.8 (J¼20.8 Hz), 110.0,
63.7, 49.1, 26.2. HRMS (ESI-TOF): calcd for C15H14FN [MþHþ]
228.1183, found 228.1188.
13C NMR (150 MHz, CDCl3):
d 157.7, 151.0, 136.6, 135.0, 127.9, 127.8,
127.5, 124.7, 120.2, 118.4, 111.8, 110.0, 60.8, 55.2, 49.0, 25.9. HRMS
(ESI-TOF): calcd for C16H17NO [MþHþ] 240.1383, found 240.1385.
Table 2 entry 1: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 26 mg,
98%. Physical state: colorless oil. Rf: 0.36 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3346, 1683 cmꢁ1. 1H NMR (600 MHz, CDCl3):
Table 1 entry 3: prepared according to the general procedure.
Purified on silica gel eluting with 9/1 hexanes/Et2O. Yield: 8.0 mg,
43%. Physical state: colorless oil. Rf: 0.53 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3379 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d 7.25
(d, J¼9.1 Hz, 4H), 7.10 (t, J¼7.7 Hz, 1H), 6.95 (d, J¼7.5 Hz, 1H), 6.78 (t,
J¼7.4 Hz, 1H), 6.73 (d, J¼7.7 Hz, 1H), 3.80 (br s, 1H), 3.67 (d,
J¼8.9 Hz,1H), 3.57 (d, J¼8.9 Hz,1H),1.70 (s, 3H). 13C NMR (150 MHz,
d mixture of rotomers (ratio: 2:1) 7.27–7.33 (m, 4H), 7.18–7.23 (m,
1H), 7.07 (t, J¼7.4 Hz,1H), 6.83–6.91 (m,1H), 6.69–6.77 (m,1H), 6.67
(d, J¼7.6 Hz, 1H), 3.97–4.15 (m, 1H), 3.71–3.89 (m, 1H), 3.36–3.56
(m, 3H), 3.18–3.29 (m, 1H), 2.42–2.50 (m, 1H), 2.11–2.19 (m, 1H),
CDCl3):
d 150.6, 146.2, 136.4, 131.9, 128.2, 128.0, 127.9, 123.9, 119.1,
110.0, 63.6, 49.2, 26.0. HRMS (ESI-TOF): calcd for C15H14ClN [MþHþ]
1.35–1.51 (m, 9H). 13C NMR (150 MHz, CDCl3):
d major rotomer
244.0887, found 244.0886.
156.1, 150.5, 147.1, 133.5, 128.4, 128.1, 126.8, 126.5, 124.3, 118.7, 109.6,
79.5, 66.5, 51.3, 43.4, 41.1, 31.3, 28.4. HRMS (ESI-TOF): calcd for
C22H26N2O2 [MþHþ] 351.2067, found 351.2072.
Table 1 entry 4: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 9.0 mg,
41%. Physical state: colorless oil. Rf: 0.53 (silica gel, 1:1 hexane/
Table 2 entry 2: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 28 mg,
96%. Physical state: colorless semisolid. Rf: 0.33 (silica gel, 1:1
hexane/Et2O). IR (film) nmax: 3346, 1684 cmꢁ1. 1H NMR (600 MHz,
Et2O). IR (film) nmax: 3378 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d 7.40
(d, J¼9.1 Hz, 2H), 7.19 (d, J¼9.1 Hz, 2H), 7.11 (t, J¼7.7 Hz, 1H), 6.95 (d,
J¼7.6 Hz, 1H), 6.77 (t, J¼7.6 Hz, 1H), 6.73 (d, J¼7.8 Hz, 1H), 3.67 (d,
J¼9.0 Hz, 1H), 3.57 (d, J¼8.9 Hz, 1H), 1.70 (s, 3H) [NHdtoo broad to
CDCl3):
d
mixture of rotomers (ratio: 2:1) 7.27 (d, J¼8.6 Hz, 2H), 7.23
identify conclusively]. 13C NMR (150 MHz, CDCl3):
d
150.6, 146.7,
(d, J¼8.5 Hz, 2H), 7.09 (t, J¼7.5 Hz,1H), 6.83–6.92 (m, 1H), 6.71–6.81
(m, 1H), 6.68 (d, J¼7.5 Hz,1H), 3.97–4.08 (m, 1H), 3.68–3.77 (m, 1H),
3.38–3.58 (m, 3H), 3.18–3.27 (m, 1H), 2.37–2.47 (m, 1H), 2.11–2.21
136.3, 131.2, 128.4, 127.9, 123.9, 120.1, 119.1, 110.0, 63.5, 49.3, 25.9.
HRMS (ESI-TOF): calcd for C15H14BrN [MþHþ] 288.0382, found
288.0377.
(m, 1H), 1.35–1.54 (m, 9H). 13C NMR (150 MHz, CDCl3):
d major
Table 1 entry 5: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 14 mg,
71%. Physical state: colorless semisolid. Rf: 0.62 (silica gel, 1:1
hexane/Et2O). IR (film) nmax: 3395 cmꢁ1. 1H NMR (600 MHz, CDCl3):
rotomer 156.0, 150.3, 145.8, 132.3, 128.5 (2C’s), 128.4, 128.0, 124.1,
118.8, 109.7, 79.7, 66.4, 51.0, 43.4, 41.0, 31.2, 28.4. HRMS (ESI-TOF):
calcd for C22H25ClN2O2 [MþHþ] 385.1677, found 385.1685.
Table 2 entry 3: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 18 mg,
60%. Physical state: white powder. Rf: 0.41 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3350, 1684 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d
7.85 (d, J¼8.2 Hz, 1H), 7.82 (d, J¼8.7 Hz, 1H), 7.76 (d, J¼8.2 Hz, 1H),
7.55 (d, J¼7.5 Hz,1H), 7.40 (t, J¼8.2 Hz,1H), 7.37 (t, J¼7.4 Hz,1H), 7.29
(t, J¼7.9 Hz, 1H), 7.10 (t, J¼7.9 Hz, 1H), 6.80 (d, J¼7.7 Hz, 1H), 6.77
(d, J¼7.7 Hz, 1H), 6.67 (t, J¼7.4 Hz, 1H), 4.28 (d, J¼9.4 Hz, 1H), 3.63
(d, J¼9.4 Hz, 1H), 1.90 (s, 3H) [NHdtoo broad to identify conclu-
d
mixture of rotomers (ratio: 2:1) 8.02 (d, J¼8.6 Hz, 1H), 7.84 (d,
J¼8.0 Hz, 1H), 7.76 (d, J¼8.3 Hz, 1H), 7.42–7.53 (m, 1H), 7.27–7.35
(m, 1H), 7.35–741 (m, 2H), 7.06–7.14 (m, 1H), 6.61–6.83 (m, 3H),
4.60–4.73 (m, 1H), 3.89–4.13 (m, 1H), 3.69–3.83 (m, 1H), 3.57–3.69
(m, 1H), 3.31–3.56 (m, 1H), 3.09–3.26 (m, 1H), 2.79–2.94 (m, 1H),
2.08–2.22 (m, 1H), 1.47–1.56 (m, 9H). 13C NMR (150 MHz, CDCl3):
sively]. 13C NMR (150 MHz, CDCl3):
d 149.7, 141.8, 138.2, 135.1, 131.2,
129.4, 128.2, 127.7, 126.2, 125.2, 124.9, 124.8 (2C’s), 123.9, 118.8,
109.7, 61.6, 50.3, 29.4. HRMS (ESI-TOF): calcd for C19H17N [MþHþ]
260.1434, found 260.1437.
Table 1 entry 6: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 6.0 mg,
36%. Physical state: colorless oil. Rf: 0.55 (silica gel, 1:1 hexane/
d major rotomer 156.1, 149.9, 141.2, 135.2, 131.3, 129.6, 128.6, 128.2,
125.5, 125.4, 125.3, 125.1, 124.7, 124.6, 124.1, 118.7, 109.3, 79.6, 63.9,
51.6, 43.0, 40.8, 33.3, 28.4. HRMS (ESI-TOF): calcd for C26H28N2O2
[MþHþ] 401.2223, found 401.2227.
Et2O). IR (film) nmax: 3382 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d 7.21
(d, J¼8.2 Hz, 2H), 7.10 (d, J¼8.0 Hz, 2H), 7.09 (t, J¼7.8 Hz, 1H), 6.96
(d, J¼7.8 Hz,1H), 6.76 (t, J¼7.9 Hz,1H), 6.72 (d, J¼7.8 Hz,1H), 3.77 (s,
1H), 3.70 (d, J¼8.9 Hz, 1H), 3.55 (d, J¼8.9 Hz, 1H), 2.31 (s, 3H), 1.70
Table 2 entry 4: prepared according to the general procedure.
Purified on silica gel eluting with 1:1 hexanes/Et2O. Yield: 11 mg,
40%. Physical state: colorless oil. Rf: 0.29 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3370, 1708 cmꢁ1. 1H NMR (600 MHz, CDCl3):
(s, 3H). 13C NMR (150 MHz, CDCl3):
d 150.7, 144.7, 137.2, 135.7, 128.9,
127.6, 126.5, 124.0, 119.0, 109.9, 63.8, 49.4, 26.2, 20.9. HRMS (ESI-
TOF): calcd for C16H17N [MþHþ] 224.1434, found 224.1438.
Table 1 entry 7: prepared according to the general procedure.
Purified on silica gel eluting with 9:1 hexanes/Et2O. Yield: 3.2 mg,
17%. Physical state: amber oil. Rf: 0.43 (silica gel, 1:1 hexane/Et2O).
d
7.76 (dd, J¼5.4, 3.1 Hz, 2H), 7.66 (dd, J¼5.4, 3.0 Hz, 2H), 7.39 (d,
J¼8.2 Hz, 2H), 7.23 (d, J¼7.9 Hz, 1H), 7.21 (t, J¼8.1 Hz, 2H), 7.08 (t,
J¼7.9 Hz, 1H), 7.07 (t, J¼7.9 Hz, 1H), 6.78 (t, J¼7.4 Hz, 1H), 6.70 (d,
J¼7.7 Hz, 1H), 3.82 (br s, 1H), 3.81 (s, 2H), 3.71–3.78 (m, 1H), 3.60–
3.78 (m, 1H), 2.43–2.58 (m, 2H). 13C NMR (150 MHz, CDCl3):
d 168.1,
IR (film) nmax: 3382 cmꢁ1. 1H NMR (600 MHz, CDCl3):
d
7.71 (br s,
150.9, 145.4, 133.7, 133.3, 132.1, 128.4, 128.1, 126.4, 126.3, 125.1,
123.0, 119.0, 110.2, 60.8, 52.3, 36.6, 34.8. HRMS (ESI-TOF): calcd for
C24H20N2O2 [MþHþ] 369.1597, found 369.1592.
0.5H), 7.53 (br s, 0.5H), 7.23 (d, J¼9.0 Hz, 2H), 7.08 (t, J¼7.4 Hz, 1H),
6.96 (d, J¼7.5 Hz, 1H), 6.82 (d, J¼8.9 Hz, 2H), 6.76 (t, J¼7.4 Hz, 1H),
6.72 (d, J¼7.6 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J¼8.8 Hz, 1H), 3.54 (d,
Table 2 entry 5: prepared according to the general procedure.
Purified on silica gel eluting with 1:1 hexanes/Et2O. Yield: 14 mg,
46%. Physical state: colorless oil. Rf: 0.29 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3378, 1707 cmꢁ1. 1H NMR (600 MHz, CDCl3):
J¼8.9 Hz, 1H), 1.69 (s, 3H). 13C NMR (150 MHz, CDCl3):
d 157.9, 150.6,
139.8, 137.3, 130.9, 127.6, 124.0, 119.0, 113.5, 109.9, 63.8, 55.2, 49.1,
26.2. HRMS (ESI-TOF): calcd for C16H17NO [MþHþ] 240.1383, found
240.1381.
d
7.76 (dd, J¼5.6, 3.0 Hz, 2H), 7.67 (dd, J¼5.5, 3.1 Hz, 2H), 7.32 (d,

3154
K. Eastman, P.S. Baran / Tetrahedron 65 (2009) 3149–3154
J¼8.6 Hz, 2H), 7.19 (d, J¼7.3 Hz, 1H), 7.16 (d, J¼8.7 Hz, 2H), 7.07 (t,
J¼7.4 Hz, 1H), 6.78 (t, J¼7.4 Hz, 1H), 6.69 (d, J¼7.6 Hz, 1H), 3.83 (br s,
1H), 3.79 (d, J¼9.2 Hz, 1H), 3.76 (d, J¼9.2 Hz, 1H), 3.74 (ddd, J¼15.6,
10.0, 5.5 Hz, 1H), 3.63 (ddd, J¼15.6, 9.5, 6.1 Hz, 1H), 2.53 (ddd,
J¼15.6, 9.8, 5.7 Hz, 1H), 2.44 (ddd, J¼15.6, 10.0, 5.8 Hz, 1H). 13C NMR
54.0, 52.9, 50.3, 37.5 HRMS (ESI-TOF): calcd for C30H24N2O4 [MþHþ]
477.1809, found 477.1804.
Acknowledgements
(150 MHz, CDCl3):
d 168.1, 150.8, 143.9, 133.9, 132.8, 132.2, 132.0,
Financial support for this work provided by the NSF and Bristol-
Myers Squibb.
128.5, 128.3, 127.8, 124.8, 123.0, 119.2, 110.3, 60.7, 51.9, 36.4, 34.7.
HRMS (ESI-TOF): calcd for C24H19ClN2O2 [MþHþ] 403.1208, found
403.1202.
Table 2 entry 6: prepared according to the general procedure.
Purified on silica gel eluting with 1:1 hexanes/Et2O. Yield: 17 mg,
47%. Physical state: white powder. Rf: 0.32 (silica gel, 1:1 hexane/
Et2O). IR (film) nmax: 3386, 1707 cmꢁ1. 1H NMR (600 MHz, CDCl3):
Supplementary data
Copies of all NMR spectra are included. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.09.028.
d
7.93 (d, J¼8.4 Hz, 1H), 7.81 (d, J¼7.4 Hz,1H), 7.76 (dd, J¼5.4, 3.0 Hz,
2H), 7.71 (d, J¼8.0 Hz, 1H), 7.66 (dd, J¼5.3, 3.0 Hz, 2H), 7.58 (d,
J¼7.6 Hz, 1H), 7.33–7.41 (m, 3H), 7.14 (d, J¼7.7 Hz, 1H), 7.10 (t,
J¼7.7 Hz, 1H), 6.77 (t, J¼7.8 Hz, 1H), 6.74 (d, J¼7.8 Hz, 1H), 4.26 (d,
J¼9.5 Hz, 1H), 4.12 (d, J¼9.5 Hz, 1H), 4.00 (br s, 1H), 3.90 (ddd,
J¼15.1, 10.0 5.0 Hz, 1H), 3.64 (ddd, J¼16.6, 10.1, 6.7 Hz, 1H), 2.64–
References and notes
1. (a) Rogers, E. F.; Snyder, H. R.; Fischer, R. F. J. Am. Chem. Soc. 1952, 74, 1987–
1989; (b) Snyder, H. R.; Fischer, R. F.; Walker, J. F.; Els, H. E.; Nussberger, G. A.
J. Am. Chem. Soc. 1954, 76, 2819–2825; (c) Snyder, H. R.; Fischer, R. F.; Walker,
J. F.; Els, H. E.; Nussberger, G. A. J. Am. Chem. Soc. 1954, 76, 4601–4605; (d)
Snyder, H. R.; Strohmayer, H. F.; Mooney, R. A. J. Am. Chem. Soc. 1958, 80, 3708–
3710; (e) Cava, M. P.; Talapatra, S. K.; Nomura, K.; Weisbach, J. A.; Douglas, B.;
Shoop, E. C. Chem. Ind. 1963, 30, 1242–1243; (f) Rae, I. D.; Rosenberger, M.; Szabo,
A. G.; Willis, C. R.; Yates, P.; Zacharias, D. E.; Jeffrey, G. A.; Douglas, B.; Kirkpatrick,
L. L.; Weisbach, J. A. J. Am. Chem. Soc.1967, 89, 3061–3062; (g) Zacharias, D. E. Acta
Crystallogr., B 1970, 26, 1455–1464; (h) Yates, P.; MacLachlan, F. N.; Rae, I. D.;
Rosenberger, M.; Szabo, A. G.; Sillis, C. R.; Cava, M. P.; Behforouz, M.; Lakshmi-
kantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842–7850.
2. Kam, T.-S.; Tan, S.-J.; Ng, S.-W.; Komiyama, K. Org. Lett. 2008, 10, 3749–3752.
3. Overman, L. E.; Sato, T. Org. Lett. 2007, 9, 5267–5270.
4. Kodanko, J. J.; Hiebert, S.; Peterson, E. A.; Sung, L.; Overman, L. E.; de Moura
Link, V.; Goerck, G. C.; Amador, T. A.; Leal, M. B.; Elisabetsky, E. J. Org. Chem.
2007, 72, 7909–7914.
2.77 (m, 2H). 13C NMR (150 MHz, CDCl3):
d 168.1, 150.6, 141.1, 135.2,
133.7, 133.4, 132.1, 131.0, 129.5, 128.3, 128.2, 125.7, 125.6, 125.3,
125.2, 124.9, 124.8, 123.0, 118.9, 109.9, 58.8, 53.1, 38.7, 34.8. HRMS
(ESI-TOF): calcd for C28H22N2O2 [MþHþ] 419.1754, found 419.1756.
Table 2 entry 7: prepared according to the general procedure.
Purified on silica gel eluting with 5% Et2O in DCM. Yield: 12 mg,
34%. Physical state: colorless semisolid. Rf: 0.38 (silica gel, 2:1
hexane/EtOAc). IR (film) nmax: 3382, 1744, 1711 cmꢁ1
.
1H NMR
(600 MHz, CDCl3): major diastereomer (ratio: 3:2) 7.60–7.66 (m,
d
4H), 7.42 (d, J¼7.4 Hz, 1H), 7.30 (d, J¼8.0 Hz, 2H), 7.04 (t, J¼7.8 Hz,
2H), 6.91 (t, J¼7.5 Hz, 1H), 6.82 (t, J¼7.6 Hz, 1H), 6.63 (t, J¼7.6 Hz,
1H), 6.61 (d, J¼7.6 Hz, 1H), 5.09 (d, J¼11.5 Hz, 1H), 3.83 (br s, 1H),
3.79 (d, J¼9.2 Hz, 1H), 3.67 (s, 3H), 3.62 (d, J¼9.2 Hz, 1H), 3.23 (dd,
J¼15.3, 11.6 Hz, 1H), 3.03 (d, J¼15.2 Hz, 1H). 13C NMR (150 MHz,
5. Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem., Int. Ed.
2007, 46, 4715–4718.
6. Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Synlett 2007, 3137–3140.
7. Barton, D. H. R.; Finet, J.-P.; Giannotti, C.; Halley, F. J. Chem. Soc., Perkin Trans. 1
1987, 241–245.
CDCl3):
d mixture of diastereomers (ratio: 3:2) 169.9, 167.3, 151.2,
8. Eastman, K. J.; Baran, P. S., unpublished results.
133.6, 131.7, 131.66. 131.3, 128.2, 128.16, 128.1, 128.0, 127.98, 126.1,
125.9, 125.6, 125.59, 123.6, 123.0, 122.9, 119.2, 118.7, 110.6, 110.3,
61.6, 57.8, 52.9, 52.6, 51.4, 49.3, 49.28, 36.7, 36.4. HRMS (ESI-TOF):
calcd for C26H22N2O4 [MþHþ] 427.1652, found 427.1651.
9. Ebno¨therand co-workersdemonstrated the formation of an sp2 arylated product,
but not a 3,3-disubstituted indole. The presumed mechanism follows: initial
deprotonation of indole, followed by arylation at C-3, and finally retro-Mannich
to give the observed product. This work does not represent the first example of
the direct arylation of an indole to give a C-3 quaternary center, rather, it was the
‘presumed’ intermediate that served as precedent for the reaction of bis-aryl
iodide salts with indole derivatives. Our work is first to isolate and characterize
C-3 quaternary indolines prepared by reaction of an indole and a bis-aryl iodide.
Ebno¨ther, A.; Niklaus, P.; Su¨ess, R. Helv. Chim. Acta 1969, 629–638.
Table 2 entry 8: prepared according to the general procedure.
Purified on silica gel eluting with 5% Et2O in DCM. Yield: 11 mg,
40%. Physical state: colorless semisolid. Rf: 0.41 (silica gel, 2:1
hexane/EtOAc). IR (film) nmax: 3379, 1743, 1711 cmꢁ1 1H NMR
.
10. (a) Barton, D. H. R.; Blazejewski, J.-C.; Charpiot, B.; Motherwell, W. B. J. Chem.
Soc., Chem. Commun. 1981, 503–504; (b) Barton, D. H. R.; Yadav-Bhantagar, N.;
Blazejewski, J.-C.; Charpoit, B.; Finet, J.-P.; Lester, D. J.; Motherwell, W. B.;
Papoula, M. T. B.; Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1985, 2657–2665;
(c) Barton, D. H. R.; Yadav-Bhatnagar, N.; Finet, J.-P.; Khamsi, J.; Motherwell, W.
B.; Stanforth, S. P. Tetrahedron 1987, 43, 323–332; (d) Barton, D. H. R.; Finet, J.-P.;
Giannotti, C. F.; Halley, F. Tetrahedron 1988, 44, 4483–4494; (e) Fedorov, A.;
Combes, S.; Finet, J.-P. Tetrahedron 1999, 55, 1341–1352.
11. (a) Beringer, F. M.; Forgione, P. S.; Yudis, M. D. Tetrahedron 1960, 49–63;
(b) Beringer, F. M.; Galton, S. A.; Huang, S. J. J. Am. Chem. Soc. 1962, 84, 2819–
2823; (c) Beringer, F. M.; Forgione, P. S. J. Org. Chem. 1963, 28, 714–717;
(d) Beringer, F. M.; Daniel, W. J.; Galton, S. A.; Rubin, G. J. Org. Chem. 1966, 31,
4315–4318; (e) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 431–447; (f) Chen, K.;
Koser, G. F. J. Org. Chem. 1991, 56, 5764–5767; (g) Ryan, J. H.; Stang, P. J. Tetra-
hedron Lett. 1997, 38, 5061–5064; (h) Ochiai, M.; Shu, T.; Nagaoka, T.; Shiro, M. J.
Org. Chem. 1997, 62, 2130–2138; (i) Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem.
1999, 64, 1338–1340; (j) Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.;
Shiro, M. J. Am. Chem. Soc. 1999, 121, 9233–9234; (k) Ochiai, M.; Kitagawa, Y.;
Toyonari, M. ARKIVOC 2003, 43–48; (l) Ochiai, M. Top. Curr. Chem. 2003, 224,
5–68; (m) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893–2903; (n) Ozanne-
Beaudenon, A.; Quideau, S. Angew. Chem., Int. Ed. 2005, 44, 7065–7069.
12. Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
4972–4973.
(600 MHz, CDCl3):
d major diastereomer (ratio: 3:2) 7.63–7.70 (m,
4H), 7.44 (d, J¼7.7 Hz, 1H), 7.23 (d, J¼7.8 Hz, 2H), 6.98 (d, J¼7.9 Hz,
2H), 6.94 (t, J¼7.9 Hz, 1H), 6.65 (t, J¼7.5 Hz, 1H), 6.64 (d, J¼7.7 Hz,
1H), 5.06 (d, J¼11.5 Hz, 1H), 3.83 (br s, 1H), 3.77 (d, J¼9.5 Hz, 1H),
3.67 (s, 3H), 3.56 (d, J¼9.4 Hz, 1H), 3.17 (dd, J¼15.1, 11.7 Hz, 1H), 3.01
(d, J¼15.2 Hz, 1H). 13C NMR (150 MHz, CDCl3):
d mixture of di-
astereomers (ratio: 3:2) 169.7, 169.6, 167.3, 167.28, 151.1, 149.6,
143.3, 141.4, 134.0, 133.95, 132.0, 131.8, 131.6, 131.4, 130.7, 128.3,
128.24,128.2, 127.7, 127.0, 123.2, 123.0, 119.4, 118.9, 110.7, 110.3, 61.2,
57.4, 53.0, 52.2, 50.9, 49.2, 49.0, 36.6, 36.4. HRMS (ESI-TOF): calcd
for C26H21ClN2O4 [MþHþ] 461.1263, found 461.1260.
Table 2 entry 9: prepared according to the general procedure.
Purified on silica gel eluting with 5% Et2O in DCM. Yield: 13 mg,
47%. Physical state: yellow semisolid. Rf: 0.46 (silica gel, 2:1 hexane/
EtOAc). IR (film) nmax: 3389, 1741, 1711 cmꢁ1 1H NMR (600 MHz,
.
CDCl3):
d
major diastereomer (ratio: 2:1) 7.88 (d, J¼8.3 Hz, 1H),
7.82–7.87 (m, 3H), 7.71–7.77 (m, 3H), 7.65 (d, J¼7.4 Hz, 1H), 7.34–
7.43 (m, 3H), 7.09 (d, J¼7.4 Hz, 1H), 7.06 (t, J¼7.6 Hz, 1H), 6.71 (t,
J¼7.4 Hz, 1H), 6.67 (d, J¼7.8 Hz, 1H), 4.89 (d, J¼10.5 Hz, 1H), 4.04 (d,
J¼10.0 Hz,1H), 3.91 (dd, J¼15.6,10.4 Hz,1H), 3.84 (d, J¼10.0 Hz,1H),
3.76 (br s, 1H), 3.63 (s, 3H), 3.13 (d, J¼15.2 Hz, 1H). 13C NMR
13. Ochiai, M.; Toyonari, M.; Nagaoka, T.; Chen, D.-W.; Kida, M. Tetrahedron Lett.
1997, 38, 6707–6712; When unavailable commercially, bisacetoxy aryl iodides
were prepared in one step according to Skulski’s protocol: Kazmierczak, P.;
Skulski, L.; Kraszkiewicz, L. Molecules 2001, 6, 881–891. All boronic acids used
are commercially available.
14. As it pertains to the conversion from skatole to the unstable indolenine.
15. Experiments with the fully protected tryptophan 30 were conducted with the
(150 MHz, CDCl3):
d major diastereomer (ratio: 2:1) 193.8, 170.3,
use of 2 equiv of the bisaryl
16. Reduction to the indoline is aided by the addition of silica gel.
l
3-iodane.
167.7, 150.6, 135.3, 134.0, 132.0, 130.9, 129.5, 128.5, 128.4, 126.0,
125.9, 125.3, 125.0, 124.94, 124.9, 123.4, 118.8, 110.6, 105.2, 58.6,