Catalytic Enolate Arylation with 3-Bromoindoles Allows the Formation of β-Carbolines

Article abstract of DOI:10.1021/acs.joc.7b00299

Synthesis of substituted β-carbolines was accomplished by utilizing the catalytic enolate arylation reaction of ketones in conjunction with several 3-bromoindole derivatives. Quenching of the arylation reaction in situ with an electrophile allowed ready i

Full text of DOI:10.1021/acs.joc.7b00299

Note
pubs.acs.org/joc
Catalytic Enolate Arylation with 3‑Bromoindoles Allows the
Formation of β‑Carbolines
C. Henrique Alves Esteves,† Peter D. Smith,‡ and Timothy J. Donohoe*,†
†Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
‡AstraZeneca, Pharmaceutical Sciences, Silk Road Business Park, Macclesfield SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: Synthesis of substituted β-carbolines was accomplished by
utilizing the catalytic enolate arylation reaction of ketones in conjunction
with several 3-bromoindole derivatives. Quenching of the arylation reaction
in situ with an electrophile allowed ready incorporation of functionality at
the carboline C-4 position in an efficient one-pot protocol.
β-Carbolines are important N-heterocyclic aromatic com-
pounds that have been extensively studied for their wide-
ranging bioactivity.1 These compounds are also widely found in
natural products extracted from various sources such as the
dichotomides,2 from the roots of Stellaria dichotoma; the
metatacarbolines,3 from the fruiting bodies of Mycena metata;
hirsutaside D,4 from the leaves of Uncaria hirsute, hyrtiocarbo-
line,5 from the marine sponge Hyrtios reticulatus, and
stolonines,6 from the marine tunicate Cnemidocarpa stolonifera.
Some of the recently reported methodologies to prepare β-
carbolines involve the metal-catalyzed iminoannulation of
alkynes,7 the Rh-catalyzed cycloaddition of yne-ynamides with
methylcyanoformate,8 cascade annulation of alkynols,9 photo-
cyclization of anilinohalopyridines,10 coupling of anilines and
halopyridines,11 Pd-catalyzed ring-expansion of azidoalcohols,12
and cyclization of vinylindoles.13 While impressive, the main
limitations of these methods lie in the formation of
regioisomers or the limited accessibility of a variety of
substitution patterns in the heterocyclic ring.
Figure 1. Catalytic enolate arylation route to β-carbolines.
We sought a route to these heterocycles that would allow the
introduction of many different groups onto the aromatic
nucleus but without the complications arising from the
formation of regioisomers. In this regard, our approach to the
synthesis of carbolines relies on the use of catalytic enolate
arylation reaction of ketones,14 a powerful catalytic reaction still
underused in the synthesis of aromatic heterocycles.15 Previous
work from our group has shown that ketones can be easily
arylated by reaction of substituted aryl or vinyl halides so that
the products are ideally configured (masked 1,4-dicarbonyls)
for an aromatization step to furnish substituted isoquinolines16
or pyridines17 (Figure 1a).
Herein, we chose a 3-bromoindole partner A for the enolate
arylation (Figure 1b).18 The installation of a protected carbonyl
at C-2 of the indole bromide partner would provide the
functionality required to aromatize the ring after arylation was
complete (see B → C). Moreover, from previous prece-
dent,15,19 we anticipated that an ability to add an electrophile
directly to the catalytic arylation reaction would allow extra
functionalization to be added to the product (see R4 in B) that
would ultimately allow derivatization at the C-4 position of the
carboline without the addition of extra synthetic steps.
Initially, we selected 1-benzyl-3-bromo-2-(1,3-dioxolan-2-yl)-
1H-indole (1) and acetophenone (2) for optimization studies
using catalytic palladium (Table 1). Compound 1 was made in
high yield from the precursor indole-2-carboxaldehyde via
reaction with NBS, followed by N-benzylation with base and
BnBr and then acetal formation with ethylene glycol and
pTSA.20
We began our screening by treating 1 and acetophenone (2)
21
with catalytic Pd(dtbpf)Cl2 and NaOtBu in THF (Table 1),
which are conditions previously used for related arylations in
our laboratory,15 and they afforded product 3 in an encouraging
52% yield (entry 1). Pleasingly, compound 3 could be isolated
Received: February 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00299
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Table 1. Optimization Studies for the Pd-Catalyzed α-
Scheme 2. Synthesis of Substituted Indole Bromides
Arylation of 1
ketone
(equiv)
base
(2.5 equiv)
T
(°C)
yield
b
catalyst (mol %)
(%)
1
2
3
4
5
6
7
Pd(dtbf)Cl2 (5)
Pd(dtbf)Cl2 (5)
Pd(dtbf)Cl2 (5)
Pd(dtbf)Cl2 (2.5)
Pd(dtbf)Cl2 (2.5)
Pd(dtbf)Cl2 (5)
2
NaOtBu
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
50
50
50
50
50
RT
50
52
93
80
86
70
66
17
2
1.2
2
1.2
2
Table 2. Synthesis of Substituted β-Carbolines in Two
Steps
a
Pd(amphos)Cl2
(5)
2
a
b
Indole 1 (1.0 equiv),THF, 24 h. Isolated yields.
in 93% yield when the NaOtBu base was replaced by LiHMDS
(entry 2).
Further studies showed that the arylation was tolerant of
changes to the reaction parameters. For example, lower catalyst
loadings and/or ketone equivalents were examined, and these
delivered the desired product in good yields (entries 3−5).
Moreover, a reasonable yield of 3 (66%) was obtained when
the arylation reaction was carried out at room temperature
(entry 6). Finally, a different catalyst was screened with
Pd(amphos)2Cl2, (this was also previously very active in our
hands), delivering the product in a disappointing 17% yield
(entry 7).
Pleasingly, the reaction of arylated product 3 with
ammonium chloride in ethanol/water was sufficiently acidic
to deprotect the acetal and allow cyclization to give the
corresponding carboline 4 in 94% yield (Scheme 1), thus
validating our approach to these aromatic heterocycles.
Moreover, the N-benzyl group was easily removed from the
carboline products using AlCl3 (4 → 5 in 88% yield).22
Scheme 1. Cyclization of 3 to Furnish β-Carboline 4
a
Reaction conditions: (1) indole (1.0 equiv), Pd(dtbpf)Cl2 (5.0 mol
%), LiHMDS (2.5 equiv), ketone (2.0 equiv), THF, 50 °C, 24 h; (2)
b
NH4Cl (10 equiv); EtOH/H2O 3:1, 100 °C, 12 h. Solvent: EtOH/
c
H2O/DMF (3:1:2), 110 °C, 12 h. Isolated yields.
The next stage involved an exploration of the substrate
scope, and to do this, we prepared more substituted indole
bromides to be coupled with a selection of commercially
available ketones (Scheme 2). Our synthesis of the requisite
indole bromides began from readily available compound 6,23
which was N-benzylated (7) and then derivatized into two
different ketones (8 and 9) via reaction with a Grignard
reagent. After bromination at C-3 (10 and 11), ketone 10 was
protected as an acetal (12) under standard conditions.
With the key compounds in hand, we explored the substrate
scope, and Table 2 shows a set of carbolines (4, 14, 16, and 18)
that were prepared via this two-step sequence of enolate
arylation using the optimized conditions from Table 1, followed
by aromatization. Use of this methodology allowed substitution
at the carboline C-1, C-3, and C-4 positions simply by using a
substituted ketone or altering the substitution pattern of the
ketal protected indole bromide in the arylation step. Note that
some groups (e.g., Ph) could be introduced at the carboline C-
1 position without the need for ketal protection (see 11 → 17
→ 18); in this case, the conjugated nature of the ketone at C-2
of the indole makes it unreactive to competing aldol type side
reactions.
After these positive results, we then developed a one-pot
procedure for the arylation/aromatization sequence. This
B
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worked well, and starting from 1 and 2, we quenched the
arylation reaction directly with acid and then ammonia to
furnish carboline 4 in 68% yield for the one-pot process (Table
3). The one-pot sequence was optimal when it began with an
was more reliable across a wider range of ketones (for example,
compounds 19 and 20 were now formed in 53 and 73% yield,
respectively).
With these new arylation conditions, the one-pot synthesis of
various carbolines was then possible in excellent yields. Using
this approach, alkyl substituents could be incorporated with
ease at either the C-3 or C-4 positions on the carboline nucleus
(Table 3). Note that attempts at the one-pot synthesis of C-1
substituted carbolines from bromide 11 were unsuccessful.
Next, we examined the direct functionalization of the arylated
products in situ, which was accomplished by quenching the
arylation reaction of a methyl ketone with an electrophile (see 1
→ 27 with the addition of benzyl bromide, Scheme 3). This
a
Table 3. One-Pot Synthesis of Substituted β-Carbolines
Scheme 3. In Situ Enolate Alkyation to Furnish C-4
Substituted β-Carbolines
protocol works well because the initial arylation reaction
requires at least two equivalents of base to reach completion
and, therefore, the initial arylation product is actually present in
the reaction mixture as an enolate, which can be quenched. As
expected, the benzylated compound 27 was then easily
aromatized to carboline 28 under standard conditions (Scheme
3).
This precedent then provided the basis for a one-pot
arylation/enolate-quench/aromatization sequence starting from
1 and 2, that provided several C-4 derivatized products in good
yields (see 14 and 28−31, Table 4). This chemistry represents
a particularly convenient and short route to C-3,4-disubstituted
carbolines which installs the desired functionality with complete
control of regiochemistry.
To conclude, we extended the enolate arylation/aromatiza-
tion sequence to accomplish the synthesis of carbolines by
using indole-based bromides as coupling partners. A variety of
(heterocyclic) substitution patterns were compatible with this
approach, either by arylation of a functionalized ketone or by a
direct enolate arylation and electrophilic quenching sequence.
The ability to combine an enolate arylation with a one-pot
aromatization sequence is particularly advantageous. This
convenient and modular approach allows access to a wide
range of carboline derivatives with many potential uses.
a
Reaction conditions: (1) indole (1.0 equiv), Pd(dtbpf)Cl2 (5.0 mol
%), NaOtBu (2.5 equiv), ketone (2.0 equiv), THF, 75 °C, 24 h; (2)
(aq) 1 M HCl; (3) NaHCO3 (20 equiv), NH3 (20 equiv, 7 M in
MeOH), EtOH, DMF, 100 °C, 12 h. LiHMDS (2.5 equiv) as base,
50 °C. Isolated yields.
b
c
enolate arylation, followed by the sequential addition of acid
(to hydrolyze the acetal), neutralization (NaHCO3), and then
addition of ammonia (7 M in MeOH) to perform the
aromatization.
However, as we switched to more substituted ketone
substrates to expand the methodology, we found the arylation
conditions that had proved optimal for acetophenone in Table
1 showed poor conversion (see 19 and 20 with 34 and 42%
yield, respectively). Therefore, we examined other conditions
from Table 1 that had also delivered arylated product and
found that a change of base to NaOtBu, together with an
increase in the temperature, delivered an arylation reaction that
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as purchased. Solvents
were dried using standard laboratory techniques. All reactions
requiring dry equipment were carried out in flame-dried glassware
under argon atmosphere. Flash column chromatography was
performed using Geduran silica gel 60 (40−63 μm). Thin layer
chromatography was performed on Merck Kieselgel 60 F254 0.25 mm
C
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mmol) and a 1 M solution of NH4Cl (4.1 mL, 10 equiv) in
EtOH:H2O 3:1. The mixture was stirred at 90 °C for 12 h. NH4HCO3
(6.97 g, 83.0 mmol, 20 equiv) was then added to the flask, and the
solution was stirred at 90 °C for 3 h. The crude product was
concentrated in vacuo, redissolved in pure EtOAc, and mixed with
water. The aqueous layer was extracted twice with EtOAc; the organic
extracts were combined, dried over MgSO4, filtered, and concentrated
in vacuo. The resulting solid was purified by flash column
chromatography (eluted with a mixture of petroleum ether:EtOAc)
to afford the β-carboline product.
Table 4. One-Pot Synthesis of C-4 Functionalized β-
Carbolines
a
General Procedure C for the Synthesis of Ketones from
Weinreb Amide 7. To a dry reaction flask were added indole 7 (2.00
g, 6.79 mmol) and dry THF (68 mL). A 3 M solution of the
appropriate Grignard reagent (6.8 mL, 20 mmol, 3 equiv) was slowly
added over 30 min at −78 °C and then allowed to stir at 0 °C for 1 h.
The mixture was then quenched at 0 °C with NH4Cl(aq), and the
aqueous layer was extracted twice with EtOAc. The organic extracts
were combined, dried over MgSO4, filtered, and concentrated in
vacuo. The resulting solid was purified by flash column chromatog-
raphy (eluted with a mixture of petroleum ether:EtOAc) to afford the
product ketone.
General Procedure D for the One-Pot Synthesis of β-
Carbolines. To a dry vial were added bromo indole 1 (110 mg, 307
μmol), Pd(dtbpf)Cl2 (10 mg, 15 μmol, 5 mol %), and NaOtBu (74
mg, 0.77 mmol, 2.5 equiv). The flask was sealed, evacuated, and
backfilled with argon twice and then dry THF (4 mL), and the
corresponding ketones (0.61 mmol, 2 equiv) were added in sequence.
The mixture was stirred for 24 h at 75 °C. After cooling to room
temperature, HCl(aq) (1 M, 10 equiv) was added, and the mixture was
stirred for 12 h at 90 °C. After cooling to room temperature, DMF (2
mL), EtOH (4 mL), NaHCO3 (516 mg, 6.14 mmol, 20 equiv), and
NH3 (7 M solution in MeOH, 0.88 mL, 6.1 mmol, 20 equiv) were
added, and the mixture was stirred at 110 °C for 24 h. The crude
product was concentrated in vacuo, redissolved in pure EtOAc, and
mixed with water. The aqueous layer was extracted twice with EtOAc,
and the organic extracts were combined, dried over MgSO4, filtered,
and concentrated in vacuo. The resulting solid was purified by flash
column chromatography (eluted with a mixture of petroleum
ether:EtOAc) to afford the β-carboline product.
General Procedure E for the Bromination of Keto-Indoles.
To a dry reaction flask were added the appropriate ketone (5.45
mmol) and DMF (3.9 mL). A solution of NBS (1.11 g, 6.27 mmol,
1.15 equiv) in DMF (3.9 mL) was added over 30 min at 0 °C, and the
resulting mixture was then stirred at room temperature for 2 h. H2O
(70 mL) was added, and the resulting slurry was extracted three times
with EtOAc; the organic extracts were combined and washed five
times with H2O, dried over MgSO4, filtered, and concentrated in
vacuo, affording the bromo indole product or, alternatively, were
purified by flash column chromatography (eluted with a mixture of
petroleum ether:EtOAc) to afford the bromo indole product.
General Procedure F for the One-Pot Synthesis of β-
Carboline with Addition of Electrophiles. A fresh solution of
LiHMDS was prepared in a dry vial adding sequentially dry THF (4
mL), HMDS (0.16 mL, 0.77 mmol, 2.5 equiv), and a 2.5 M solution of
nBuLi (0.31 mL, 0.77 mmol, 2.5 equiv) and stirring at −78 °C for 10
min. Acetophenone (72 μL, 0.61 mmol, 2.0 equiv) was then added at 0
°C and stirred for 15 min. In a second dry vial were added bromo
indole 1 (110 mg, 307 μmol) and Pd(dtbpf)Cl2 (10 mg, 15 μmol, 5
mol %). The flask was sealed, evacuated, and backfilled with argon.
The freshly formed enolate solution was then transferred via syringe to
the flask. The mixture was stirred at 50 °C for 24 h in an oil bath. After
cooling to room temperature, the appropriate electrophile (0.77 mmol,
2.5 equiv) was added, and the mixture was stirred at 90 °C for 24 h.
After cooling to room temperature, 1 M HCl(aq) (3.1 mL, 10 equiv)
was added, and the mixture was stirred for 12 h at 90 °C. After cooling
to room temperature, DMF (2 mL), EtOH (4 mL), NaHCO3 (516
mg, 6.14 mmol, 20 equiv), and NH3 (7 M solution in MeOH, 0.88
mL, 6.1 mmol, 20 equiv) were added, and the mixture was stirred at
110 °C for 24 h. The crude product was concentrated in vacuo,
redissolved in pure EtOAc, and mixed with water. The aqueous layer
a
Reaction conditions: (1) indole (1.0 equiv), Pd(dtbpf)Cl2 (5.0 mol
%), LiHMDS (2.5 equiv), ketone (2.0 equiv), THF, 50 °C, 24 h; then
electrophile, 90 °C. Isolated yields
b
precoated aluminum-backed plates. Product spots were visualized
under UV light (λmax = 254 nm) and/or by staining with vanillin,
phosphomolybdic acid, or basic potassium permanganate solutions. 1H
NMR spectra were recorded using a Bruker AVII400, AVIII400, or
AVII500 instruments at 400 or 500 MHz. 13C NMR spectra were
recorded at 100 or 125 MHz. 19F NMR spectrum was recorded at 376
MHz. Chemical shifts, δ, are reported relative to residual solvent peaks
1
and quoted in parts per million (ppm) to the nearest 0.01 for H and
to the nearest 0.1 ppm for 13C and 19F. Coupling constants, J, are
quoted to the nearest 0.1 Hz. Assignments were based upon DEPT,
COSY, HSQC, and HMBC experiments. High-resolution mass spectra
were acquired using electrospray ionization (ESI) as ionization source
and were recorded on a Fisons Platform II with TOF detector. IR
spectra were obtained from evaporated films using a Bruker Tensor 27
spectrometer equipped with a PIKE Miracle Attenuated Total
Reflectance (ATR) sampling accessory. Absorption maxima are
quoted in wavenumbers (cm−1) for the range 3500−600 cm−1.
Melting points (mp) were obtained by using a Leica VMTG heated-
stage microscope and are uncorrected.
General Procedure A for α-Arylation of Ketones. A fresh
solution of LiHMDS was prepared in a dry vial adding sequentially dry
THF (2 mL), HMDS (80 μL, 0.38 mmol, 2.5 equiv), a 2.5 M solution
of nBuLi (0.15 mL, 0.38 mmol 2.5 equiv) and stirring at −78 °C for 10
min. The ketone (0.31 mmol, 2.0 equiv) was then added at 0 °C and
stirred for 15 min. In a second dry vial were added bromo indole (0.15
mmol) and Pd(dtbpf)Cl2 (5 mg, 8 μmol, 5 mol %). The flask was
sealed, evacuated, and backfilled with argon. The freshly formed
enolate solution was then transferred via syringe to the flask. The
mixture was stirred at 50 °C for 24 h in an oil bath. The resulting
mixture was filtered through a plug of silica and concentrated in vacuo.
The crude product was purified by flash column chromatography
(eluted with a mixture of petroleum ether:EtOAc) to afford the ketone
product.
General Procedure B for the Cyclization of α-Arylated
Ketones. To a reaction flask were added the arylated ketone (4.15
D
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Note
was extracted twice with EtOAc and the organic extracts were
combined, dried over MgSO4, filtered, and concentrated in vacuo. The
resulting solids were purified by flash column chromatography (eluted
with a mixture of petroleum ether:EtOAc) to afford the β-carboline
product.
(1H, s, NH), 9.00 (1H, s, HC(1)), 8.77 (1H, s, HC(4)), 8.36 (1H, d, J
= 7.9 Hz, HCAr), 8.22 (2H, ddd, J = 8.3, 1.2, 1.0 Hz, 2 × HCAr), 7.66−
7.60 (1H, m, HCAr), 7.58 (1H, dd, J = 6.9, 1.2 Hz, HCAr), 7.54−7.48
(2H, m, 2 × HCAr), 7.41−7.35 (1H, m, HCAr), 7.28 (1H, ddd, J = 8.0,
6.9, 1.0 Hz, HCAr); 13C NMR (100 MHz, CDCl3); 13C NMR (100
MHz, DMSO-d6) δC: 146.0, 141.6, 140.6, 135.9 (4 × CAr), 134.0
(HC(1)), 129.3 (CAr), 129.1, 128.7, 127.9, 126.6 122.5, (5 × HCAr),
Synthesis of 1-Benzyl-3-bromo-2-(1,3-dioxolan-2-yl)-1H-in-
dole (1). To a dry reaction flask connected to a Dean−Stark apparatus
were added 1-benzyl-3-bromo-1H-indole-2-carbaldehyde (330 mg,
1.05 mmol), ethylene glycol (116 μL, 2.09 mmol, 2 equiv), p-
toluenesulfonic acid monohydrate (20 mg, 105 μmol, 10 mol %), and
toluene (10 mL). The resulting mixture was heated at reflux for 14 h
and then cooled to room temperature and quenched with
NaHCO3(aq). The aqueous layer was extracted twice with EtOAc,
and the organic extracts combined, dried over MgSO4, filtered, and
concentrated in vacuo. The resulting solid was purified by flash column
chromatography (eluted with 9:1 petroleum ether:EtOAc), affording 1
(350 mg, 93%) as a yellow solid. Mp: 64−67 °C. IR νmax (thin film):
3060, 2888, 1075 cm−1. HRMS: calcd for C18H17BrNO2, 358.04372
[M + H]+, found m/z 358.04379, Δ = 0.20 ppm. 1H NMR (400 MHz,
CDCl3) δH: 7.62−7.55 (1H, m, HCAr), 7.30−7.00 (8H, m, 8 × HCAr),
6.21 (1H, s, CH(OR)2), 5.46 (1H, s, PhCH2R), 4.06−3.86 (4H, m,
(OCH2)2); 13C NMR (100 MHz, CDCl3) δC: 137.9, 137.4, 129.3 (3 ×
CAr), 128.6 (HCAr), 127.3 (HCAr), 126.7 (CAr), 126.3, 124.3, 120.7,
120.0, 110.6 (5 × HCAr), 98.7 (CH(OR)2), 94.5 (C(3)), 65.2
((OCH2)2), 48.5 (PhCH2R).
1
121.5 (CAr), 119.8, 112.5 (2 × HCAr), 111.6 (HC(4)). H NMR data
were consistent with those previously reported.24
Synthesis of 1-Benzyl-N-methoxy-N-methyl-1H-indole-2-
carboxamide (7). To a dry reaction flask equipped with a reflux
condenser were added indole 6 (12.0 g, 58.7 mmol) and dry THF
(590 mL). NaH (60% in mineral oil, 2.82 g, 70.5 mmol, 1.2 equiv) was
added slowly at 0 °C over 10 min, and the resulting mixture was
heated at reflux for 30 min. After cooling to room temperature, benzyl
bromide (8.4 mL, 70 mmol, 1.2 equiv) was added, and the solution
was heated at reflux for 2 h and then cooled to 0 °C, when it was
quenched using NH4Cl(aq). The aqueous layer was extracted twice with
EtOAc, and the organic extracts were combined, dried over MgSO4,
filtered, and concentrated in vacuo. The resulting solid was purified by
flash column chromatography (eluted with 4:1 petroleum ether:-
EtOAc) to afford protected indole 7 (17.1 g, 99%) as a white solid.
Mp: 34−37 °C. IR νmax (thin film): 3060, 3030, 2931, 1632, 1453, 739
cm−1. HRMS: calcd for C18H18O2N2, 295.14410 [M + H]+, found m/z
1
295.14398, Δ = −0.41 ppm. H NMR (400 MHz, CDCl3) δH: 7.79−
7.40 (1H, m, HCAr), 7.44 (1H, dd, J = 8.4, 0.8 Hz, HCAr), 7.33 (1H,
ddd, J = 8.3, 7.0, 1.2 Hz, HCAr), 7.31−7.19 (5H, m, 6 × HCAr), 7.13
(2H, d, J = 6.6 Hz, 2 × HCAr), 5.77 (2H, s, PhCH2R), 3.53 (3H, s,
OCH3), 3.34 (3H, s, NCH3); 13C NMR (100 MHz, CDCl3) δC: 162.8
(C(O)), 138.6, 138.4, 129.6 (3 × CAr), 128.6, 127.3, 126.8 (3 × HCAr),
126.7 (CAr), 124.4, 122.3, 120.6, 110.6, 108.1 (5 × HCAr), 61.2
(OCH3), 47.9 (RCH2Ph), 33.9 (NCH3).
1-(1-Benzyl-1H-indol-2-yl)ethan-1-one (8). This compound was
prepared according to general procedure C, affording 8 (1.28 g, 76%)
as a white solid. Mp: 125−126 °C. IR νmax (thin film): 3061, 3031,
2924, 1657, 725 cm−1. HRMS: calcd for C17H161ON, 250.12264 [M +
H]+, found m/z 250.12302, Δ = 1.50 ppm. H NMR (400 MHz,
CDCl3) δH: 7.81−7.77 (1H, m, HCAr), 7.45−7.36 (3H, m, 3 × HCAr),
7.32−7.20 (4H, m, 4 × HCAr), 7.14−7.08 (2H, m, 2 × HCAr), 5.91 (s,
2H, NCH2Ph), 2.66 (s, 3H, C(O)CH3); 13C NMR (100 MHz,
CDCl3) δC: 191.3 (C(O)), 140.0, 138.4, 134.4 (3 × CAr), 128.5, 127.1,
126.5, 126.3 (4 × HCAr), 126.0 (CAr), 123.0, 121.1, 113.0, 111.0 (4 ×
HCAr), 48.2 (PhCH2N), 28.1 (C(O)CH3). 1H NMR data were
consistent with those previously reported.25
2-(1-Benzyl-2-(1,3-dioxolan-2-yl)-1H-indol-3-yl)-1-phenylethan-
1-one (3). This compound was prepared according to general
procedure A, affording 3 (57 mg, 93%) as a brown solid. Mp: 100−
102 °C. IR νmax (thin film): 3368, 3060, 2925, 1613, 1082, 745 cm−1.
HRMS: calcd for C26H24O3N, 398.17507 [M + H]+, found m/z
1
398.17496, Δ = −0.30 ppm. H NMR (400 MHz, CDCl3) δH: 8.15−
8.10 (2H, m, 2 × HCAr), 7.63−7.54 (2H, m, 2 × HCAr), 7.48 (2H, t, J
= 7.4 Hz, 2 × HCAr), 7.33−7.03 (9H, m, 9 × HCAr), 6.13 (1H, s,
CH(OR)2), 5.54 (1H, s, PhCH2R), 4.65 (2H, s, CH2C(O)), 4.05−
3.90 (4H, m, (OCH2)2); 13C NMR (100 MHz, CDCl3) δC: 196.7
(C(O)), 137.1, 136.4, 135.9 (3 × CAr), 131.8 (HCAr), 129.8 (CAr),
127.5, 127.5, 127.4 (3 × HCAr), 126.6 (CAr), 126.0, 125.0, 121.9, 118.7,
118.2, 109.0 (6 × HCAr), 108.2 (CAr), 97.9 (CH(OR)2), 63.9
((OCH2)2), 46.7 (RCH2Ph), 34.0 (CH2C(O)).
9-Benzyl-3-phenyl-9H-pyrido[3,4-b]indole (4). This compound
was prepared according to general procedure B on a 4.15 mmol
scale, affording 4 (1.30 g, 94%) as a light brown solid. Mp: 143−146
°C. IR νmax (thin film): 3059, 3030, 1460, 733, 694 cm−1. HRMS:
calcd for C24H19N2, 335.15428 [M + H]+, found m/z 335.15350, Δ =
−2.3 ppm. 1H NMR (400 MHz, CDCl3) δH: 8.82 (1H, s, C(1)), 8.33
(1H, s, C(4)), 8.13 (1H, d, J = 7.8 Hz, HCAr), 8.08 (2H, d, J = 7.5 Hz,
HCAr), 7.55−7.43 (3H, m, 3 × HCAr), 7.40−7.31 (2H, m, 2 × HCAr),
7.30−7.15 (4H, m, 4 × HCAr), 7.14−7.05 (2H, m, 2 × HCAr), 5.41
(2H, s, PhCH2Ar); 13C NMR (100 MHz, CDCl3) δC: 147.9, 141.9,
140.6, 136.5, 136.0 (5 × CAr), 131.9 (HC(1)), 129.8 (CAr), 129.0,
128.8, 128.6, 127.9, 127.8, 126.9, 126.7, 122.0 (8 × HCAr), 121.7 (CAr),
(1-Benzyl-1H-indol-2-yl)(phenyl)methanone (9). This compound
was prepared according to general procedure C on a 10.2 mmol scale,
affording 9 (2.51 g, 79%) as a white solid. Mp: 107−110 °C. IR νmax
(thin film): 3060, 3030, 2923, 1633, 718, 694 cm−1. HRMS: calcd for
C22H17ONNa, 334.12024 [M + Na]+, found m/z 334.12023, Δ =
−0.02 ppm. 1H NMR (400 MHz, CDCl3) δH: 7.95−7.90 (2H, m, 2 ×
HCAr), 7.73 (1H, d, J = 8.0, HCAr), 7.65−7.58 (1H, m, HCAr), 7.54−
7.48 (2H, m, 2 × HCAr), 7.44 (1H, dd, J = 8.5, 0.7 Hz, HCAr), 7.38
(1H, ddd, J = 8.4, 6.9, 1.1 Hz, HCAr), 7.31−7.18 (4H, m, 4 × HCAr),
7.18−7.14 (2H, m, 2 × HCAr), 7.12 (1H, d, J = 0.6 Hz, C(3)), 5.91
(2H, s, PhCH2R); 13C NMR (100 MHz, CDCl3) δC: 188.6 (C(O)),
140.2, 139.4, 138.4, 134.7 (4 × CAr), 132.2, 129.8, 128.6, 128.2, 127.2,
126.6, 126.2 (7 × HCAr), 126.1 (CAr), 123.1,121.1,115.8, 111.1 (4 ×
1
120.0, 111.4, 109.9 (3 × HCAr), 47.0 (PhCH2Ar). H and 13C NMR
data were consistent with those previously reported.7c
Synthesis of 3-Phenyl-9H-pyrido[3,4-b]indole (5). To a dry
reaction flask were added freshly sublimed AlCl3 (287 mg, 2.15 mmol,
6 equiv) and toluene (1.8 mL). A solution of β-carboline 4 (120 mg,
359 μmol) in toluene (1.8 mL) was added at 0 °C over 10 min and
stirred at room temperature for 2 h. The resulting mixture was
quenched with NaHCO3(aq), and the aqueous layer was extracted twice
with EtOAc. The organic extracts were combined, dried over MgSO4,
filtered, and concentrated in vacuo. The resulting solids were purified
by flash column chromatography (eluted with a 19:1 mixture of
CHCl3:MeOH) to afford the β-carboline product 5 (71 mg, 88%) as a
white solid. Mp: 226−229 °C. IR νmax (thin film): 3125, 3018, 2923,
2755, 1137, 738, 696 cm−1. HRMS: calcd for C17H13N2, 245.10732 [M
1
HCAr), 48.1 (PhCH2R). H NMR data were consistent with those
previously reported.26
1-(1-Benzyl-3-bromo-1H-indol-2-yl)ethan-1-one (10). This com-
pound was prepared according to general procedure E, affording 10
(1.66 g, 93%) as a white solid. Mp: 118−120 °C. IR νmax (thin film):
3061, 3032, 2921, 16511, 726 cm−1. HRMS: calcd for C17H15ONBr,
328.03315 [M + H]+, found m/z 328.03348, Δ = 0.99 ppm. 1H NMR
(400 MHz, CDCl3) δH: 7.80−7.74 (1H, m, HCAr), 7.43−7.39 (2H, m,
2 × HCAr), 7.32−7.22 (4H, m, 4 × HCAr), 7.08−7.03 (2H, m, 2 ×
HCAr), 5.80 (2H, s, PhCH2N), 2.83 (3H, s, C(O)CH3); 13C NMR
(100 MHz, CDCl3) δC: 192.0 (C(O)), 138.4, 138.0, 132.6 (3 × CAr),
128.6, 127.3, 127.1 (3 × HCAr), 126.8 (CAr), 126.3, 121.9, 121.8, 111.0
(4 × HCAr), 100.0 (CAr), 48.9 (PhCH2N), 31.9 (C(O)CH3).
1
+ H]+, found m/z 245.10730, Δ = −0.10 ppm. H NMR (400 MHz,
CDCl3) δH: 8.99 (1H, s, HCAr), 8.57 (1H, bs, NH), 8.40 (1H, s,
HCAr), 8.20 (1H, d, J = 7.8 Hz, HCAr), 8.12−8.07 (2H, m, 2 × HCAr),
7.59−7.46 (4H, m, 4 × HCAr), 7.43−7.36 (1H, m, HCAr), 7.32 (1H,
dd, J = 8.1, 7.0 Hz, HCAr). 1H NMR (400 MHz, DMSO-d6) δH: 11.69
E
DOI: 10.1021/acs.joc.7b00299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(1-Benzyl-3-bromo-1H-indol-2-yl)(phenyl)methanone (11). This
compound was prepared according to general procedure E on a 4.17
mmol scale, affording 11 (1.62 g, 99%) as a white solid. Mp: 87−89
°C. IR νmax (thin film): 3060, 3030, 1719, 722, 692 cm−1. HRMS:
calcd for C22H17ONBr, 390.04880 [M + H]+, found m/z 390.04959, Δ
= 2.02 ppm. 1H NMR (400 MHz, CDCl3) δH: 7.82−7.78 (2H, m, 2 ×
HCAr), 7.68 (1H, d, J = 8.0 Hz, HCAr), 7.62−7.56 (1H, m, HCAr),
7.46−7.34 (4H, m, 4 × HCAr), 7.27 (1H, ddd, J = 8.0, 6.6, 1.3 Hz,
HCAr), 7.24−7.14 (3H, m, 3 × HCAr), 7.08−7.03 (2H, m, HCAr), 5.60
(2H, s, PhCH2R); 13C NMR (100 MHz, CDCl3) δC: 189.4 (C(O)),
138.0, 138.0, 137.5, 133.5 (4 × CAr), 133.3, 130.2, 128.7, 128.5, 127.6
(5 × HCAr), 126.8 (CAr), 126.7, 126.2, 121.6, 121.3, 110.9 (5 × HCAr),
98.1 (CAr), 48.3 (PhCH2R).
Synthesis of 1-Benzyl-3-bromo-2-(2-methyl-1,3-dioxolan-2-
yl)-1H-indole (12). To a dry reaction flask connected to a Dean−
Stark apparatus were added bromo indole 10 (3.00 g, 9.14 mmol),
ethylene glycol (5.1 mL, 91 mmol, 10 equiv), p-toluenesulfonic acid
monohydrate (175 mg, 914 μmol, 10 mol %), and toluene (91 mL).
The resulting mixture was heated at 120 °C for 60 h and then cooled
to room temperature and quenched with NaHCO3(aq). The aqueous
layer was extracted twice with EtOAc, and the organic extracts
combined, dried over MgSO4, filtered, and concentrated in vacuo. The
resulting solid was purified by flash column chromatography (eluted
with 1:0.8 petroleum ether:CHCl3), affording 12 (2.14 g, 63%) as a
white solid. Mp: 89−90 °C. IR νmax (thin film): 3031, 2990, 2892
cm−1. HRMS: calcd for C19H18O2NBr, 372.05937 [M + H]+, found m/
z 372.05930, Δ = −0.19 ppm. 1H NMR (400 MHz, CDCl3) δH: 7.59−
7.53 (1H, m, HCAr), 7.20−7.05 (6H, m, 6 × HCAr), 7.85−6.79 (2H,
m, 2 × HCAr), 5.60 (2H, s, PhCH2N), 3.95−3.83 (2H, m
CHaHbCHaHb), 3.65−3.53 (2H, m, CHaHbCHaHb); 1.60 (3H, s,
CCH3); 13C NMR (100 MHz, CDCl3) δC: 138.4, 137.1, 135.4 (3 ×
CAr), 128.6 (HCAr), 127.4 (CAr), 127.0, 125.7, 123.6, 120.7, 119.8,
110.3 (6 × HCAr), 106.4, 89.6 (2 × CAr), 64.6 (OCH2)2), 48.6
(PhCH2N), 26.4 (CCH3).
2-(1-Benzyl-2-(1,3-dioxolan-2-yl)-1H-indol-3-yl)-1-phenylpropan-
1-one (13). This compound was prepared according to general
procedure A, affording 13 (47 mg, 74%) as a yellow solid. Mp: 159−
164 °C. IR νmax (thin film): 3061, 2974, 2930, 2890, 1680, 1079, 745
cm−1. HRMS: calcd for C27H25O3N, 412.19072 [M + H]+, found m/z
412.19196, Δ = 3.0 ppm. 1H NMR (400 MHz, CDCl3) δH: 8.01 (2H,
d, J = 7.40 Hz, 2 × HCAr), 7.64 (1H, d, J = 7.6 Hz, HCAr), 7.34 (1H, t,
J = 7.4 Hz, HCAr), 7.24 (2H, t, J = 7.4 Hz, 2 × HCAr), 7.21−7.13 (3H,
m,3 × HCAr), 7.08−6.99 (3H, m, 3 × HCAr), 6.90−6.84 (2H, m, 2 ×
HCAr), 6.18 (1H, s, CH(OR)2), 5.42 (1H, s, PhCHaHbR), 5.41 (1H, s,
PhCHaHbR), 5.15 (1H, q, J = 6.8, CHCH3), 4.12−3.92 (4H, m,
(OCH2)2), 1.66 (3H, d, CH3CH); 13C NMR (100 MHz, CDCl3) δC:
201.1 (C(O)), 138.1, 137.64, 137.0 (3 × CAr), 132.4, 128.8 (2 ×
HCAr), 128.7 (CAr), 128.6, 128.2, 127.1, 125.9 (4 × HCAr), 125.8
(CAr), 123.1, 120.2, 119.9 (3 × HCAr), 116.7 (CAr), 110.1 (HCAr), 98.6
(CH(OR2)2), 65.2 (CHO2CaH2CbH2), 65.0 (CHO2CaH2CbH2), 47.7
(PhCH2R), 39.8 (CHCH3), 18.0 (CHCH3).
2989, 2891, 1691, 1197, 742 cm−1. HRMS: calcd for C27H25O3NNa,
434.17266 [M + Na]+, found m/z 434.17270, Δ = 0.08 ppm. 1H NMR
(400 MHz, CDCl3) δH: 8.15−8.11 (2H, m, 2 × HCAr), 7.63−7.56
(1H, m, HCAr), 7.55−7.46 (3H, m, 3 × HCAr), 7.30−7.12 (6H, m, 6 ×
HCAr), 6.98−6.93 (2H, m, 2 × HCAr), 5.67 (2H, s, PhCH2N), 4.72
(2H, s, ArCH2C(O)), 3.88−3.80 (2H, m CHaHbCHaHb), 3.68−3.62
(2H, m, CHaHbCHaHb), 1.65 (3H, s, CCH3); 13C NMR (100 MHz,
CDCl3) δC: 198.2 (C(O)), 139.0,137.5, 137.4, 136.6 (4 × CAr), 132.8,
128.6, 128.5 (3 × HCAr), 128.4 (CAr), 128.3, 126.7, 125.8, 122.5, 119.8,
118.6, 110.3 (7 × HCAr), 107.3, 106.8 (CAr + CCH3), 64.8 (OCH2)2),
48.0 (PhCH2N), 35.2 (ArCH2C(O)), 27.2 (CCH3).
9-Benzyl-1-methyl-3-phenyl-9H-pyrido[3,4-b]indole (16). This
compound was prepared according to a modification of general
procedure B on a 85 μmol scale, affording 16 (28 mg, 94%) as a brown
solid. A mixture of EtOH:H2O:DMF (3:1:2) was used as solvent, and
the temperature was kept at 110 °C for this cyclization. Mp: 127−129
°C. IR νmax (thin film): 3060, 3030, 1472, 734, 694 cm−1. HRMS:
calcd for C25H21N2, 349.16993 [M + H]+, found m/z 349.16943, Δ =
1
−1.41 ppm. H NMR (500 MHz, CDCl3) δH: 8.31 (1H, s, HC(4)),
8.22 (1H, d, J = 7.7 Hz, HCAr), 8.16−8.12 (2H, m, 2 × HCAr), 7.56−
7.48 (3H, m, 3 × HCAr), 7.41−7.35 (2H, m, 2 × HCAr), 7.34−7.22
(4H, m, 5 × HCAr), 7.05−7.00 (2H, m, 2 × HCAr), 5.81 (2H, s,
PhCH2N), 2.95 (3H, s, CH3); 13C NMR (125 MHz, CDCl3) δC:
145.9, 141.3, 140.2, 139.4, 137.0, 133.9, 129.2 (7 × CAr), 127.9, 127.6,
127.3, 126.5, 126.5, 125.7, 124.4 (7 × HCAr), 120.7 (CAr), 120.4, 119.0,
108.9 (3 × HCAr), 108.5 (C(4)), 47.2 (PhCH2N), 22.4 (CH3).
2-(2-Benzoyl-1-benzyl-1H-indol-3-yl)-1-phenylethan-1-one (17).
This compound was prepared according to general procedure A on
a 6.36 mmol scale, affording 17 (1.75 g, 64%) as a yellow solid. Mp:
132−134 °C. IR νmax (thin film): 3059, 3030, 1689, 1637, 745, 729
cm−1. HRMS: calcd for C30H23O2NNa, 452.16210 [M + Na]+, found
1
m/z 452.16183, Δ = −0.59 ppm. H NMR (400 MHz, CDCl3) δH:
7.78 (2H, ddd, J = 8.0, 1.3, 0.9 Hz, 2 × HCAr), 7.74−7.69 (2H, m, 2 ×
HCAr), 7.58 (1H, d, J = 8.0 Hz, HCAr), 7.54−7.48 (1H, m, HCAr),
7.43−7.13 (11H, m, 11 × HCAr), 7.05−7.00 (2H, m, 2 × HCAr), 5.59
(2H, s, PhCH2Ar), 4.26 (2H, s, CH2C(O)); 13C NMR (100 MHz,
CDCl3) δC: 196.4, 190.2 (2 × C(O)), 139.6, 138.8, 138.0, 136.6, 134.5
(5 × CAr), 133.0, 132.8, 129.4, 128.6, 128.6, 128.5, 128.1 (7 × HCAr),
127.5 (CAr), 127.3, 126.5, 125.6, 121.1, 120.9 (5 × HCAr), 116.1 (CAr),
110.9 (HCAr), 48.1 (PhCH2Ar), 36.0 (CH2C(O)).
9-Benzyl-1,3-diphenyl-9H-pyrido[3,4-b]indole (18). This com-
pound was prepared according to a modification of general procedure
B on a 0.17 mmol scale, affording 18 (61 mg, 85%) as a yellow solid. A
mixture of EtOH:H2O:DMF (3:1:2) was used as solvent, and the
temperature was kept at 110 °C for this cyclization. Mp: 170−174 °C.
IR νmax (thin film): 3058, 3031, 1468, 1450, 737, 694 cm−1. HRMS:
calcd for C30H22N2, 411.18558 [M + H]+, found m/z 411.18452, Δ =
1
−2.57 ppm. H NMR (400 MHz, CDCl3) δH: 8.48 (1H, s, HC(4)),
8.30 (1H, ddd, J = 7.8, 1.2, 0.8 Hz, HCAr), 8.23−8.18 (2H, m, 2 ×
HCAr), 7.58−7.47 (5H, m, 5 × HCAr), 7.45−7.30 (6H, m, 6 × HCAr),
7.20−7.10 (3H, m, 3 × HCAr), 6.68−6.62 (2H, m, 2 × HCAr), 5.25
(2H, s, PhCH2N); 13C NMR (100 MHz, CDCl3) δC: 147.1, 144.0,
143.2, 140.3, 139.9, 137.1, 134.0, 131.8 (8 × CAr), 129.6, 128.7, 128.6,
128.4, 128.3, 128.0, 127.8, 127.1, 127.0, 125.8 (10 × HCAr), 122.0
(CAr), 121.6, 120.3 (2 × HCAr), 110.8 (C(3)), 110.2 (HCAr), 48.2
(PhCH2N).
9-Benzyl-4-methyl-3-phenyl-9H-pyrido[3,4-b]indole (14). This
compound was prepared according to general procedure B on a
0.15 mmol scale, affording 14 (50 mg, 94%) as a yellow solid. Mp:
164−167 °C. IR νmax (thin film): 3055, 3030, 2924, 1454, 737, 701
cm−1. HRMS: calcd for C25H21N2, 349.16993 [M + H]+, found m/z
1
349.16946, Δ = −1.3 ppm. H NMR (400 MHz, CDCl3) δH: 8.82
9-Benzyl-3-(tert-butyl)-9H-pyrido[3,4-b]indole (19). This com-
pound was prepared according to general procedure D, affording 19
(51 mg, 53%) as a brown solid. Mp: 132−134 °C. IR νmax (thin film):
3030, 2956, 2864, 1468, 740, 698 cm−1. HRMS: calcd for C22H23N2,
(1H, s, HC(1)), 8.33 (1H, d, J = 8.0 Hz, HCAr), 7.65−7.60 (2H, m, 2
× HCA), 7.59 (1H, ddd, J = 8.3, 7.1, 1.2 Hz, HCA), 7.54−7.47 (3H, m,
3 × HCA), 7.45−7.39 (1H, m, HCAr) 7.34 (1H, t, J = 8.0 Hz, HC(6)),
7.32−7.25 (3H, m, 3 × HCAr), 7.22−7.17 (2H, m, 2 × HCAr), 5.58
(2H, s, PhCH2R), 2.91 (3H, s, RCH3); 13C NMR (100 MHz, CDCl3)
δC: 149.2, 141.7, 141.2, 136.6, 135.6 (5 × CAr), 130.0, 129.3 (2 ×
HCAr), 129.0 (C(1)), 128.4 (CAr), 128.1, 127.8, 127.8, 127.2, 126.6 (5
× HCAr), 124.9 (CAr), 124.2 (C(5)), 122.4 (CAr), 119.9 (C(6)), 109.6
(HCAr), 46.9 (PhCH2R), 17.6 (RCH3).
1
315.18558 [M + H]+, found m/z 315.18530, Δ = −0.86 ppm. H
NMR (400 MHz, CDCl3) δH: 8.82 (1H, d, J = 0.9 Hz, HC(1)), 8.19
(1H, d, J = 7.8 Hz, HCAr), 8.19 (1H, d, J = 0.9 Hz, HC(4)), 7.55 (1H,
ddd, J = 8.3, 7.1, 1.2 Hz, HCAr), 7.43 (1H, d, J = 8.3 Hz, HCAr), 7.32−
7.18 (6H, m, 6 × HCAr), 5.53 (2H, s, PhCH2N), 1.51 (9H, s,
(CH3)3C); 13C NMR (100 MHz, CDCl3) δC: 159.0, 141.8, 136.7,
135.0 (4 × CAr), 130.8 (C(1)), 129.3 (CAr), 128.9, 128.2, 127.8, 126.7,
121.8 (5 × HCAr), 121.6 (CAr), 119.6, 109.6 (2 × HAr), 109.4 ((4)),
47.1 (PhCH2N), 37.2 ((CH3)3C), 30.9 ((CH3)3C).
2-(1-Benzyl-2-(2-methyl-1,3-dioxolan-2-yl)-1H-indol-3-yl)-1-phe-
nylethan-1-one (15). This compound was prepared according to
general procedure A on 0.15 mmol scale, affording 15 (50 mg, 84%) as
an off-white solid. Mp: 128−131 °C. IR νmax (thin film): 3058, 3029,
F
DOI: 10.1021/acs.joc.7b00299
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The Journal of Organic Chemistry
Note
9-Benzyl-4-isopropyl-3-phenyl-9H-pyrido[3,4-b]indole (20). This
compound was prepared according to general procedure D, affording
20 (84 mg, 73%) as a brown solid. Mp: 170−171 °C. IR νmax (thin
film): 3055, 3030, 2990, 2958, 2929, 2872, 1439, 741, 701 cm−1.
HRMS: calcd for C27H24N2, 377.20123 [M + H]+, found m/z
377.20139, Δ = 0.42 ppm. 1H NMR (500 MHz, CDCl3) δH: 8.89 (1H,
s, HC(1)), 7.62−7.53 (3H, m, 3 × HCAr), 7.46−7.37 (4H, m, 4 ×
HCAr), 7.33−7.23 (5H, m, 5 × HCAr), 6.95 (1H, dd, J = 8.0, 6.9 Hz,
HCAr), 6.83 (1H, d, J = 8.0 Hz, HCAr) 5.53 (2H, s, PhCH2N), 3.18
(1H, hept, J = 6.8 Hz, CH(CH3)2), 1.29 (6H, d, J = 6.8 Hz,
CH(CH3)2); 13C NMR (100 MHz, CDCl3) δC: 153.9, 141.8, 138.6,
136.7, 134.9 (5 × CAr), 130.9, 129.3, 128.9, 128.9 (4 × HCAr), 128.9
128.8 (2 × CAr), 127.8, 127.8, 127.8, 126.8, 123.5 (5 × HCAr), 121.6
(CAr), 119.4, 109.3 (2 × HCAr), 47.0 (PhCH2N), 30.9 (CH(CH3)2),
23.2 (CH(CH3)2).
9-Benzyl-3-(furan-2-yl)-4-methyl-9H-pyrido[3,4-b]indole (21).
This compound was prepared according to general procedure D,
affording 21 (78 mg, 75%) as a brown solid. Mp: 156−159 °C. IR νmax
(thin film): 3141, 2918, 1488, 1301, 733, 696 cm−1. HRMS: calcd for
C23H119ON2, 339.14919 [M + H]+, found m/z 339.14883, Δ = −1.05
ppm. H NMR (500 MHz, CDCl3) δH: 8.63 (1H, s, HC(1)), 8.19
(1H, d, J = 8.0 Hz, HCAr), 7.50 (1H, dd, J = 1.9, 0.7 Hz, OCH), 7.44
(1H, ddd, J = 8.2, 7.2, 1.1 Hz, HCAr), 7.33 (1H, d, J = 8.3 Hz, HCAr),
7.20 (1H, ddd, J = 8.0, 7.3, 0.6 Hz, HCAr), 7.16−7.09 (3H, m, 3 ×
HCAr), 7.03−6.99 (2H, m, 2 × HCAr), 6.67 (1H, dd, J = 3.3, 0.7 Hz,
OCCH), 6.46 (1H, dd, J = 3.3, 1.9 Hz, OCHCH), 5.39 (2H, s,
PhCH2N), 2.89 (3H, s, CH3); 13C NMR (125 MHz, CDCl3) δC: 154.1
(CAr), 142.2 (OCH), 141.6, 139.1, 136.4, 135.3 (4 × CAr), 129.6
(C(1)), 128.9 (HCAr), 128.3 (CAr), 127.8, 127.8, 126.5 (3 × HCAr),
125.4 (CAr), 124.2 (HCAr), 122.4 (CAr), 120.1 (HCAr), 111.2
(OCHCH), 109.7 (HCAr), 109.6 (OCCH), 46.8 (PhCH2N), 16.8
(CH3).
9-Benzyl-4-ethyl-3-phenyl-9H-pyrido[3,4-b]indole (22). This com-
pound was prepared according to general procedure D, affording 22
(76 mg, 68%) as a brown solid. Mp: 136−138 °C. IR νmax (thin film):
3056, 2969, 2933, 2873, 1441, 730, 700 cm−1. HRMS: calcd for
C26H23N2, 363.18558 [M + H]+, found m/z 363.18530, Δ = −0.75
ppm. 1H NMR (500 MHz, CDCl3) δH: 8.81 (1H, s, C(1)), 8.28 (1H,
d, J = 8.0 Hz, HCAr), 7.61−7.55 (3H, m, 3 × HCAr), 7.52−7.46 (3H,
m, 3 × HCAr), 7.44−7.39 (1H, m, HCAr), 7.35 (1H, ddd, J = 8.0, 7.1,
1.0 Hz, HCAr), 7.32−7.26 (3H, m, 3 × HCAr), 7.24−7.20 (2H, m, 2 ×
HCAr), 5.60 (2H, s, PhCH2N), 3.26 (2H, q, J = 7.5 Hz, CH2CH3), 1.44
(3H, t, J = 7.5 Hz, CH2CH3); 13C NMR (125 MHz, CDCl3) δC: 149.1,
141.7, 141.5, 136.6, 136.2 131.2 (6 × CAr), 129.5 (C(1)), 129.4, 129.0,
128.1, 127.8, 127.8 (5 × HCAr), 127.4 (CAr), 127.2, 126.6, 124.2 (3 ×
HCAr), 121.5 (CAr), 120.1, 109.7 (2 × HCAr), 46.9 (PhCH2N), 23.4
(CH2CH3), 14.5 (CH2CH3).
(1H, ddd, J = 8.3, 7.2, 1.1 Hz, HCAr), 7.43 (1H, d, J = 8.3 Hz, HCAr),
7.30−7.23 (4H, m, 4 × HCAr), 7.22−7.18 (2H, m, 2 × HCAr), 5.53
(2H, s, PhCH2N), 2.19−2.15 (3H, m, 3 × CH), 2.14 (6H, d, J = 2.9
Hz, RC(CH2)3), 1.84 (6H, t, J = 3.1, 3 × CH2); 13C NMR (125 MHz,
CDCl3) δC: 158.0, 140.7, 135.7, 134.0 (4 × CAr), 129.9 (C(1)), 128.3
(CAr), 127.8, 127.1, 126.7, 125.7, 120.7 (5 × HCAr), 120.6 (CAr), 118.5
(HCAr), 108.5 (C(4)), 108.2 (HCAr), 46.0 (PhCH2N), 41.6 (RC-
(CH2)3), 37.6 (RC(CH2)3), 35.9 (CH2), 28.0 (CH).
9-Benzyl-3-(4-fluorophenyl)-4-methyl-9H-pyrido[3,4-b]indole
(25). This compound was prepared according to general procedure D,
affording 25 (58 mg, 52%) as a brown solid. Mp: 183−185 °C. IR νmax
(thin film): 3056, 1455 1219, 731, 699 cm−1. HRMS: calcd for
C25H119FN2, 367.16050 [M + H]+, found m/z 367.16034, Δ = −0.45
ppm. H NMR (500 MHz, CDCl3) δH: 8.78 (1H, s, HC(1)), 8.32
(1H, d, J = 7.8 Hz, HCAr), 7.62−7.54 (3H, m, 3 × HCAr), 7.49 (1H, d,
J = 8.2, HCAr), 7.35 (1H, t, J = 7.6 Hz, HCAr), 7.37−7.24 (3H, m, 3 ×
HCAr), 7.21−7.14 (4H, m, 4 × HCAr), 5.59 (2H, s, PhCH2N), 2.89
(3H, s, CH3); 13C NMR (125 MHz, CDCl3) δC: 161.2 (d, J = 246 Hz,
CF), 147.0, 140.6 (2 × CAr), 136.1 (d, J = 3.3 Hz, CCHCHCF), 135.4,
134.6 (2 × CAr) 130.5 (d, J = 8.1 Hz, CHCF), 128.2 (HCAr), 127.9
(HC(1)), 127.4 (CAr), 126.8 (d, J = 6.2 Hz, CHCHF), 125.5 (HCAr),
123.8 (CAr), 123.1 (HCAr), 121.2 (CAr), 118.9, 114.0, 113.8, 108.6 (4 ×
HCAr), 45.8 (PhCH2N), 16.5 (CH3); 19F NMR (376 MHz, CDCl3) δ
F: 115.4 (tt, J = 8.8, 5.5 Hz).
3-(Benzo[d][1,3]dioxol-5-yl)-9-benzyl-4-methyl-9H-pyrido[3,4-b]-
indole (26). This compound was prepared according to general
procedure D, affording 26 (71 mg, 61%) as a brown solid. Mp: 152−
155 °C. IR νmax (thin film): 2890, 1459, 725 cm−1. HRMS: calcd for
C25H191N2, 379.14410 [M + H]+, found m/z 379.14352, Δ = −1.53
ppm. H NMR (500 MHz, CDCl3) δH: 8.84 (1H, d, J = 0.9 Hz,
HC(1)), 8.30 (1H, d, J = 0.9 Hz, HC(4)), 8.20 (1H, d, J = 7.8 Hz,
HCAr), 7.64−7.54 (3H, m, 3 × HCAr), 7.43 (1H, d, J = 8.3 Hz, HCAr),
7.34−7.22 (4H, m, 4 × HCAr), 7.20−7.16 (2H, m, 2 × HCAr), 6.94
(1H, d, J = 8.1 Hz, HCAr), 6.01 (2H, s, O2CH2), 5.54 (2H, s,
PhCH2N); 13C NMR (125 MHz, CDCl3) δC: 148.2, 147.5, 147.5,
141.9, 136.5, 135.8, 135.1 (7 × CAr), 131.6 (HC(1)), 129.8 (CAr),
129.0, 128.6, 127.9, 126.6, 121.9 (5 × HCAr), 121.6 (CAr), 120.4, 120.0
(2 × HCAr), 110.8 (HC(4)), 109.8, 108.5, 107.4 (3 × HCAr), 101.2
(O2CH2), 47.0 (PhCH2N).
Synthesis of 2-(1-Benzyl-2-(1,3-dioxolan-2-yl)-1H-indol-3-
yl)-1,3-diphenylpropan-1-one (27). A fresh solution of LiHMDS
was prepared in a dry vial, adding sequentially dry THF (7.3 mL),
HMDS (290 μL, 1.39 mmol, 2.5 equiv), and a 2.5 M solution of nBuLi
(1.39 mmol, 558 μL, 2.5 equiv) and stirring at −78 °C for 10 min.
Acetophenone (130 μL, 1.07 mmol, 2 equiv) was then added at 0 °C
and stirred for 15 min. In a second dry vial were added bromo indole 1
(200 mg, 558 μmol) and Pd(dtbpf)Cl2 (18 mg, 27.9 μmol, 5 mol %).
The flask was sealed, evacuated, and backfilled with argon twice. The
freshly formed enolate solution was then transferred via syringe to the
flask. The mixture was stirred at 50 °C for 24 h in an oil bath. After
cooling to room temperature, benzyl bromide (166 μL, 1.39 mmol, 2.5
equiv) was added, and the mixture was stirred at 90 °C for 24 h. The
resulting mixture was filtered through a plug of silica and concentrated
in vacuo. The crude product was purified by flash column
chromatography (eluted with 9:1 petroleum ether:EtOAc) to afford
product 27 (177 mg, 65%) as a brown solid. Mp: 134−135 °C. IR νmax
(thin film): 3060, 3027, 2924, 1679, 1083, 742, 697 cm−1. HRMS:
calcd for C33H30O3N, 488.22202 [M + H]+, found m/z 488.22195, Δ
= −0.14 ppm. 1H NMR (400 MHz, C6D6) δH: 8.24 (2H, ddd, J = 8.2,
1.9, 1.5 Hz, HCAr), 8.05 (1H, d, J = 8.05 Hz, HCAr), 7.17−7.14 (1H,
m, HCAr), 7.12−6.89 (12H, m, HCAr), 6.86 (1H, d, J = 8.2 Hz, HCAr),
6.72 (2H, ddd, J = 7.6, 1.9, 1.3 Hz, 2 × HCAr), 5.92 (1H, s,
CH(OR)2), 5.39 (1H, dd, J = 8.4, 6.0 Hz, CH2CHC(O)), 5.15 (1H, d,
J = 17.1 Hz, PhCHaHbAr), 5.09 (1H, d, J = 17.1 Hz, PhCHaHbAr),
3.99 (1H, dd, J = 13.5, 6.0 Hz, PhCHaHbCH), 3.59 (1H, dd, J = 13.5,
8.4 Hz, PhCHaCHbCH), 3.36−3.13 (4H, m, (OCH2)2); 13C NMR
(100 MHz, C6D6) δC: 198.9 (C(O)), 140.8, 138.3, 137.6, 137.3 (4 ×
CAr), 132.0 (HCAr), 129.9, (CAr), 129.4, 128.8, 128.3, 128.0, 128.0,
126.7 (6 × HCAr), 126.3 (CAr), 125.9, 125.8, 123.1, 120.5, 120.3 (5 ×
HCAr), 113.9 (CAr), 110.3 (HCAr), 99.5 (CH(OR)2), 64.6
9-Benzyl-3-(2-methoxyphenyl)-9H-pyrido[3,4-b]indole (23). This
compound was prepared according to general procedure D, affording
23 (83 mg, 74%) as a yellow solid. Mp: 95−97 °C. IR νmax (thin film):
3030, 2935, 2834, 1491, 727, 700 cm−1. HRMS: calcd for C25H20N2O,
1
365.16484 [M + H]+, found m/z 365.16464, Δ = −0.54 ppm. H
NMR (500 MHz, CDCl3) δH: 8.94 (1H, d, J = 1.0 Hz, HC(1)), 8.51
(1H, d, J = 1.0 Hz, HC(4)), 8.22 (1H, ddd, J = 7.8, 1.2, 0.7 Hz, HCAr),
7.84, (1H, dd, J = 7.6, 1.8 Hz, HCAr), 7.57 (1H, ddd, J = 8.3, 7.1, 1.2
Hz, HCAr), 7.46−7.42 (1H, m, HCAr), 7.38 (1H, ddd, J = 8.3, 7.4, 1.8
Hz, HCAr), 7.34−7.18 (6H, m, 6 × HCAr), 7.14−7.09 (1H, m, HCAr),
7.06 (1H, dd, J = 8.3, 1.0 Hz, HCAr), 5.58 (2H, s, PhCH2N), 3.91 (3H,
s, CH3O); 13C NMR (125 MHz, CDCl3) δC: 156.8, 146.0, 141.8,
136.6, 135.7 (5 × CAr), 131.6 (HCAr), 131.5 (C(1)), 130.2, 129.0 (2 ×
CAr), 128.9, 128.9, 128.4, 127.8, 126.7, 122.0 (6 × HCAr), 121.7 (CAr),
121.1, 119.8 (2 × HCAr), 115.9 (C(4)), 111.5, 109.7 (2 × HCAr), 55.8
(CH3O), 47.0 (PhCH2N).
3-((3r,5r,7r)-Adamantan-1-yl)-9-benzyl-9H-pyrido[3,4-b]indole
(24). This compound was prepared according to general procedure D,
affording 24 (73 mg, 61%) as a brown solid. Mp: 241−243 °C. IR νmax
(thin film): 2901, 2846, 1464, 1452, 738, 698 cm−1. HRMS: calcd for
C28H30N2, 393.23253 [M + H]+, found m/z 393.23257, Δ = 0.12 ppm.
1H NMR (500 MHz, CDCl3) δH: 8.82 (1H, d, J = 1.0 Hz, HC(1)),
8.17 (1H, d, J = 7.8 Hz, HCAr), 7.96 (1H, d, J = 1.0 Hz, HC(4)), 7.54
G
DOI: 10.1021/acs.joc.7b00299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(O2CaH2CbH2), 64.3 (O2CaH2CbH2), 48.0 (CH2CHC(O)), 47.5
(PhCH2Ar), 38.2 (CH2CH)
AUTHOR INFORMATION
Corresponding Author
*E-mail: timothy.donohoe@chem.ox.ac.uk.
ORCID
Timothy J. Donohoe: 0000-0001-7088-6626
Notes
The authors declare no competing financial interest.
■
4,9-Dibenzyl-3-phenyl-9H-pyrido[3,4-b]indole (28). This com-
pound was prepared according to general procedure B on a 0.18
mmol scale, affording 28 (75 mg, 96%) as an off-white solid. Mp:
201−204 °C. IR νmax (thin film): 3056, 3026, 1448, 740, 728, 699
cm−1. HRMS: calcd for C31H25N2, 425.20123 [M + H]+, found m/z
1
425.20102, Δ = −0.48 ppm. H NMR (400 MHz, CDCl3) δ H: 8.95
(1H, s, HC(1)), 7.89 (1H, d, J = 8.0 Hz, HCAr), 7.55−7.44 (4H, m, 4
× HCAr), 7.42−7.10 (14H, m, 14 × HCAr), 5.64 (2H, s, PhCH2N),
4.68 (2H, s, PhCH2Ar); 13C NMR (100 MHz, CDCl3) δC: 150.3,
141.8, 141.0, 139.7, 136.5, 136.0 (6 × CAr), 130.3 (HC(1)), 129.5,
129.0 (2 × HCAr), 128.9 (CAr), 128.7, 128.2, 128.0, 128.0, 127.9, 127.4,
126.7, 126.1 (8 × HCAr), 126.0 (CAr), 124.4 (HCAr), 121.5 (CAr),
120.1, 109.6 (2 × HCAr), 47.0 (PhCH2N), 36.4 (PhCH2Ar).
ACKNOWLEDGMENTS
■
We thank CAPES, Coordenaca
̧
o de Aperfeico
̧
amento de
̃
́
Pessoal de Nivel Superior, Brazil and AstraZeneca for
supporting this project.
4-Allyl-9-benzyl-3-phenyl-9H-pyrido[3,4-b]indole (29). This com-
pound was prepared according to general procedure F, affording 29
(62 mg, 54%) as an off-white solid. Mp: 156−158 °C. IR νmax (thin
film): 3056, 2926, 1487, 739, 700 cm−1. HRMS: calcd for C27H23N2,
REFERENCES
■
(1) (a) Freedland, C. S.; Mansbach, R. S. Drug Alcohol Depend. 1999,
54, 183. (b) Hassani, M.; Cai, W.; Koelsch, K. H.; Holley, D. C.; Rose,
A. S.; Olang, F.; Lineswala, J. P.; Holloway, W. G.; Gerdes, J. M.;
Behforouz, M.; Beall, H. D. J. Med. Chem. 2008, 51, 3104. (c) Dai, J.-
K.; Dan, W.-J.; Li, N.; Du, H.-T.; Zhang, J.-W.; Wang, J.-R. Bioorg.
1
375.18558 [M + H]+, found m/z 375.18552, Δ = −0.16 ppm. H
NMR (400 MHz, CDCl3) δH: 8.75 (1H, s, HC(1)), 8.09 (1H, d, J =
8.0 Hz, HCAr), 7.52 (2H, d, J = 7.0 Hz, 2 × HCAr), 7.44 (1H, t, J = 7.5
Hz, HCAr), 7.39−7.25 (4H, m, 4 × HCAr), 7.23−7.05 (6H, m, 6 ×
HCAr), 6.23−6.10 (1H, m, ArCH2CHCH2), 5.48 (2H, s, PhCH2N),
5.08 (1H, dd, J = 10.3, 1.3 Hz, CHcisHtransCHAr), 4.87 (1H, dd, J = 17,
1.3 Hz, CHcisHtransCHAr), 3.92−3.84 (2H, m, ArCH2CHCH2); 13C
NMR (100 MHz, CDCl3) δC: 149.8, 141.8, 141.1, 136.5, 135.9 (5 ×
CAr), 135.6 (ArCH2CHCH2), 130.0, 129.5, 129.0 (3 × HCAr), 128.4
(CAr), 128.0, 128.0, 127.9, 127.4, 126.6 (5 × HCAr), 125.9 (CAr), 124.6
(HCAr), 121.4 (CAr), 120.0 (HCAr), 116.8 (ArCH2CHCH2), 109.7
(HCAr), 47.0 (PhCH2N), 34.5 (ArCH2CHCH2).
9-Benzyl-4-(4-methoxybenzyl)-3-phenyl-9H-pyrido[3,4-b]indole
(30). This compound was prepared according to general procedure F,
affording 30 (74 mg, 53%) as a yellow solid. Mp: 208−209 °C. IR νmax
(thin film): 3058, 2932, 2835, 1244, 735, 699 cm−1. HRMS: calcd for
C32H216N2O, 455.21179 [M + H]+, found m/z 455.21158, Δ = −0.46
ppm. H NMR (400 MHz, CDCl3) δH: 8.80 (1H, s, HC(1)), 7.78
(1H, d, J = 8.0 Hz, HCAr), 7.42−7.30 (4H, m, 4 × HCAr), 7.28−7.08
(8H, m, 8 × HCAr), 7.05−6.98 (1H, m, HCAr), 6.94 (2H, d, J = 8.6 Hz,
2 × HCAr), 6.70−6.65 (2H, m, 2 × HCAr), 5.49 (2H, s, PhCH2N),
4.47 (2H, s, PMBCH2Ar), 3.63 (3H, s, CH3O); 13C NMR (100 MHz,
CDCl3) δC: 157.9, 150.2, 141.8, 141.0, 136.5, 136.0, 131.7 (7 × CAr),
130.3 (C(1)), 129.5, 129.1, 129.0 (3 × HCAr), 128.9 (CAr), 128.0,
128.0, 127.9, 127.4, 126.7 (5 × HCAr), 126.4 (CAr), 124.5 (HCAr),
121.5 (CAr), 120.1, 114.1, 109.6 (3 × HCAr), 55.2 (CH3O), 47.0
(PhCH2N), 35.6 (PMBCH2Ar).
́ ́ ̀
Med. Chem. Lett. 2016, 26, 580. (d) Frederick, R.; Bruyere, C.;
Vancraeynest, C.; Reniers, J.; Meinguet, C.; Pochet, L.; Backlund, A.;
Masereel, B.; Kiss, R.; Wouters, J. J. Med. Chem. 2012, 55, 6489.
(2) Sun, B.; Morikawa, T.; Matsuda, H.; Tewtrakul, S.; Wu, L. J.;
Harima, S.; Yoshikawa, M. J. Nat. Prod. 2004, 67, 1464.
(3) Jaeger, R. J. R.; Lambshoft, M.; Gottfried, S.; Spiteller, M.;
Spiteller, P. J. Nat. Prod. 2013, 76, 127.
̈
(4) Xin, W.-B.; Chou, G.-X.; Wang, Z.-T. Phytochem. Lett. 2011, 4,
380.
(5) Inman, W. D.; Bray, W. M.; Gassner, N. C.; Lokey, R. S.; Tenney,
K.; Shen, Y. Y.; TenDyke, K.; Suh, T.; Crews, P. J. Nat. Prod. 2010, 73,
255.
(6) Tran, T. D.; Pham, N. B.; Ekins, M.; Hooper, J. N. A.; Quinn, R.
J. Mar. Drugs 2015, 13, 4556.
(7) (a) Too, P. C.; Chua, S. H.; Wong, S. H.; Chiba, S. J. Org. Chem.
2011, 76, 6159. (b) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540.
(c) Zhang, H.; Larock, C. J. Org. Chem. 2002, 67, 9318.
(8) Nissen, F.; Richard, V.; Alayrac, C.; Witulski, B. Chem. Commun.
2011, 47, 6656.
(9) Dhiman, S.; Mishra, U. K.; Ramasastry, S. S. V. Angew. Chem., Int.
Ed. 2016, 55, 7737.
(10) Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem.
2011, 76, 6421.
(11) Namjoshi, O. A.; Gryboski, A.; Cook, J. M. J. Org. Chem. 2011,
76, 4721.
9-Benzyl-4-(naphthalen-2-ylmethyl)-3-phenyl-9H-pyrido[3,4-b]-
indole (31). This compound was prepared according to general
procedure F, affording 31 as a brown solid (70 mg, 48%). Mp: 181−
183 °C. IR νmax (thin film): 3052, 734, 699 cm−1. HRMS: calcd for
C35H217N2, 475.21688 [M + H]+, found m/z 475.21644, Δ = −0.91
ppm. H NMR (500 MHz, CDCl3) δH: 9.01 (1H, s, HC(1)), 7.88
(1H, d, J = 8.1 Hz, HCAr), 7.85−7.81 (2H, m, 2 × HCAr), 7.61 (1H, d,
J = 7.8 Hz, HCAr), 7.57−7.52 (2H, m, 2 × HCAr), 7.51−7.46 (3H, m, 3
× HCAr), 7.45−7.25 (11H, m, 11 × HCAr), 7.09−7.03 (1H, m, HCAr),
5.66 (2H, s, PhCH2N), 4.84 (2H, s, C10H7CH2Ar); 13C NMR (125
MHz, CDCl3) δC: 150.3, 141.9, 140.9, 137.4, 136.5, 136.1, 133.8, 132.2
(8 × CAr), 130.5 (C(1)), 129.5, 129.0 (2 × HCAr), 129.0 (CAr), 128.5,
128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.0, 126.7, 126.3, 126.0 (11
× HCAr), 125.8 (CAr), 125.4, 124.4 (2 × HCAr), 121.5 (CAr), 120.5,
109.6 (2 × HCAr), 47.1 (PhCH2N), 36.8 (C10H7CH2Ar).
(12) Chiba, S.; Xu, Y.-J.; Wang, Y.-F. J. Am. Chem. Soc. 2009, 131,
12886.
(13) Kamlah, A.; Lirk, F.; Bracher, F. Tetrahedron 2016, 72, 837−
845.
(14) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382. (b) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108. (c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1740−1742. For reviews, see:
(d) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (e) Johansson, C.
C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676.
(15) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org. Biomol.
Chem. 2015, 13, 4367.
(16) (a) Donohoe, T. J.; Pilgrim, B. S.; Jones, C. R.; Bassuto, J. A.
Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 11605. (b) Pilgrim, B.;
Gatland, A. E.; McTernan, C.; Procopiou, P.; Donohoe, T. J. Org. Lett.
2013, 15, 6190. (c) Gatland, A. E.; Pilgrim, B. S.; Procopiou, P. A.;
Donohoe, T. J. Angew. Chem., Int. Ed. 2014, 53, 14555. (d) Pilgrim, B.
S.; Esteves, C. H. A.; McTernan, C. T.; Jones, G. R.; Tatton, M. R.;
Procopiou, P. A.; Donohoe, T. J. Org. Biomol. Chem. 2016, 14, 1065.
(17) Hardegger, L. A.; Habegger, J.; Donohoe, T. J. Org. Lett. 2015,
17, 3222.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00299.
(18) Sole,
9, 4535−4544.
́
D.; Bennasar, M.-L.; Jimen
́
ez, I. Org. Biomol. Chem. 2011,
Spectroscopic data for all new compounds (PDF)
H
DOI: 10.1021/acs.joc.7b00299
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(19) (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(b) Si, C.; Myers, A. G. Angew. Chem., Int. Ed. 2011, 50, 10409.
(20) Biswas, S.; Batra, S. Adv. Synth. Catal. 2011, 353, 2861−2867.
(21) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(22) Suzuki, H.; Iwata, C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.;
Hanada, M.; Yokoyama, Y.; Murakami, Y. Tetrahedron 1997, 53,
1593−1606.
(23) Kolhatkar, R. B.; Ghorai, S. K.; George, C.; Reith, M. E. A.;
Dutta, A. K. J. Med. Chem. 2003, 46, 2205−2215.
(24) Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55,
3257−3269.
(25) Sechi, M.; Derudas, M.; Dallocchio, R.; Dessì, A.; Bacchi, A.;
Sannia, L.; Carta, F.; Palomba, M.; Ragab, O.; Chan, C.; Shoemaker,
R.; Sei, S.; Dayam, R.; Neamati, N. J. Med. Chem. 2004, 47, 5298−
5310.
(26) Miki, Y.; Hachiken, H.; Yoshikawa, I. Heterocycles 1997, 45,
1143−1150.
I
DOI: 10.1021/acs.joc.7b00299
J. Org. Chem. XXXX, XXX, XXX−XXX