Synthesis of tetracyclic indoles via intramolecular α-arylation of ketones

Article abstract of DOI:10.1021/jo300052z

Figure Persented: An intramolecular palladium(0)-mediated α-arylation of ketones applied to the synthesis of various substituted tetracyclic indoles is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to double α-arylation of ketones using one-pot reactions with either simultaneous addition or sequential addition of two aryl halides for producing aryl substituted tetracyclic indoles.

Full text of DOI:10.1021/jo300052z

Note
pubs.acs.org/joc
Synthesis of Tetracyclic Indoles via Intramolecular α-Arylation of
Ketones
Malik Hellal,† Shambhavi Singh,† and Gregory D. Cuny*,†,‡
†Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and
Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
‡Department of Pharmacological and Pharmaceutical Sciences, 549A Science and Research Bldg 2, College of Pharmacy,
University of Houston, Houston, Texas 77204, United States
S
* Supporting Information
ABSTRACT: An intramolecular palladium(0)-mediated α-arylation of ketones applied to the synthesis of various substituted
tetracyclic indoles is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated
Pd(0) complexes. This methodology was extended to double α-arylation of ketones using one-pot reactions with either
simultaneous addition or sequential addition of two aryl halides for producing aryl substituted tetracyclic indoles.
ndole is an important heterocycle found in a large number of
I
natural products and bioactive molecules.1 In particular,
carbo- or heterocycles joined at the indole 3,4-positions repre-
sent a common structural motif present in a variety of alkaloids.
Among these molecules are dragmacidin E,2 an inhibitor of
serine-threonine protein phosphatases, cycloclavine,3 N-meth-
ylwelwitindolinone C isothiocyanate,4 and 9-deacetylfumigacla-
vine C,5 which possess anticancer activities. These molecules
also present synthetic challenges that inspire the exploration of
various methodologies in order to achieve efficient syntheses of
the natural product and non-natural derivatives (Figure 1).
Various strategies have been used to affect the 3,4-indole con-
nectivity, including use of Pauson−Khand reactions,6 6π-electro-
cyclizations,7 Diels−Alder reactions,8 and aminocyclizations.9
The palladium-catalyzed α-arylation of carbonyl functional
groups has emerged as an attractive method for the rapid con-
struction of C−C bonds.10 Significant effort has been devoted
to developing this methodology. Numerous studies have shown
that this transformation is effective for the coupling of various
aryl halides with ketones in both intermolecular11 and intra-
molecular12 processes. Nevertheless, the Pd-catalyzed intra-
molecular α-arylation of ketones has not often been used in
indole chemistry,13 although it may allow the construction of
tetracyclic structures in only a few steps. We report herein a
concise approach that exploits a Suzuki−Miyaura coupling to
introduce ortho-ketoaryls, -ketoheteroaryls, or -ketocycloalkenes
at the 3-position of indoles, followed by intramolecular α-
arylation of the ketones to form tetracyclic derivatives.
Figure 1. Indole alkaloids joined at the 3,4-positions.
4-bromoindole (1) or 4-chloroindole (2). The products were
used without purification and subjected to regioselective halo-
genations at the 3-position using N-iodo- or N-bromosuccini-
mide generating 3a−c in 91%, 96%, and 97% overall yield,
respectively.14 Next, two different strategies were explored to
introduce the ortho-ketoaryl substituents. A Suzuki−Miyaura
coupling of 3a or 3b with commercially available 2-acetyl-
phenylboronic acid (4) gave indoles 7a and 7b in 52% and 71%
yield, respectively. However, this process was limited by the
The feasibility of this strategy is detailed in Scheme 1. N-
Benzyl-3,4-dihaloindoles 3a−c were prepared via a two-step
process involving nitrogen alkylation of commercially available
Received: January 11, 2012
Published: April 5, 2012
© 2012 American Chemical Society
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Note
Scheme 1. Preparation of the Key Intermediate 7a−b
access to various commercially available substituted boronic
acids necessitating several additional steps to prepare. In the
second strategy, the indole boronic ester 5 was prepared from
4-chloroindoles 3b or 3c in 61% and 62% yield, respectively.
Suzuki−Miyaura coupling of 5 with 2′-bromoacetophenone (6)
generated indole 7b in 92% yield.15
Optimization of the intramolecular α-arylation of indoles
7a−b was investigated using a variety of conditions as depicted
in Table 1. To our surprise, several of the previously reported
Table 1. Optimization of the Intramolecular Ketone α-
a
Arylation of 7
reaction
time (h)
yield
b
entry
substrate
catalyst
(%)
Figure 2. Various palladium catalysts and precatalysts.
1
2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
dtBPf PdCl2
0.5
16
3
50
25
31
94
time to 16 h was detrimental, presumably due to decom-
position of the tetracyclic indole product (entry 2). Indole 8
was obtained in only 31% yield with a palladium-N-heterocyclic
carbene catalyst, (SIPr)Pd(allyl)Cl, developed by Nolan and
co-workers (entry 3).18
dtBPf PdCl2
3
(SIPr)Pd(ally)Cl
XPhos precat.
Pd(OAc)2, XPhos
BrettPhos precat.
SPhos precat.
XPhos precat.
XPhos precat.
XPhos precat.
4
0.5
24
1
c
5
0
6
95
50
7
4
More recently, Buchwald and co-workers reported the
development of a new class of air- and moisture-stable Pd pre-
catalysts that are activated under standard reaction conditions
and ensure the formation of a monoligated active Pd(0)-
complex. The L1Pd(0) species offers the advantage of being
highly reactive due to less steric hindrance,19 which we hypo-
thesized may be beneficial for mediating the intramolecular α-
arylation of indoles 7. The use of these catalysts has also been
recently shown to be effective at mediating other processes,
including ortho- and para-arylations of phenols.20 In the
presence of the XPhos precatalyst (5 mol %), NaOt-Bu (1.1
equiv) in 1,4-dioxane at 60 °C for 0.5 h 8 was produced in 94%
yield (entry 4). For comparison, α-arylation was not observed
using Pd(OAc)2 and XPhos demonstrating the advantage of the
precatalyst (entry 5). When the reaction was performed at
room temperature, the conversion was very low after 24 h,
whereas higher temperatures (i.e., 80 °C) resulted in product
d
8
3
91
e
9
24
1
59
10
96
a
Reaction conditions: 7a or 7b (1 equiv), [Pd] (5 mol %), NaOtBu (1.1
equiv), 1,4-dioxane, 60 °C. Isolated yield. Pd(OAc)2 (5 mol %), XPhos
(10 mol %). XPhos precat. (3 mol %). XPhos precat. (1 mol %).
b
c
d
e
methods for α-arylation of ketones using either Pd(OAc)2 or
Pd2dba3 with BINAP, XantPhos, PPh3, or DPPF failed to yield
the desired product only rendering unreacted starting
material.16 However, dtBPfPdCl2, (SIPr)Pd(allyl)Cl, or pre-
catalysts (Figure 2) proved more efficient. For example,
using dtBPfPdCl2, a catalyst developed by Hartwig and co-
workers,17 indole 7a was converted to 8 in 50% yield in 0.5 h
(entry 1). This reaction also proved better in 1,4-dioxane
compared to THF or toluene. However, extending the reaction
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Note
a
Table 2. Substrate Scope of the Ketone α-Arylation
a
Reaction conditions. Suzuki coupling: 5 (1 equiv), 9a−i (1.5 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (3 equiv), Toluene, 90 °C, 4 h; α-arylation: 10a−i
b
(1 equiv), XPhos precat. (5 mol%), NaOtBu (1.1 equiv), 1,4-dioxane, 60 °C, 1 h. Isolated yield.
decomposition. Further investigation revealed that the reaction
was also dependent on the choice of ligand. For example, 8 was
obtained in only 50% yield using a precatalyst where the ligand
was SPhos (entry 6) but in 95% yield when the ligand was
BrettPhos (entry 7). Decreasing the catalyst loading to 3 mol %
resulted in 91% yield of 8 after 3 h (entry 8). However, the
reaction was less efficient with 1 mol % catalyst (entry 9). The
XPhos precatalyst was also effective at mediating the α-aryla-
tion of the 4-chloroindole substrate 7b giving 8 in 96% yield
after 1 h (entry 10). Unfortunately, to date indole 8 has not
been obtained via a one-step process utilizing boronic ester 5
and ketone 6.
With the optimized conditions identified, the scope of the
Suzuki coupling/ketone α-arylation sequence was examined. As
shown in Table 2, a variety of ortho-ketoaryls, -ketoheteroaryls,
and -ketocycloalkenes were tolerated in the Suzuki coupling
step. This allowed a phenyl, cyclopentenyl, cyclohexenyl, pyridyl,
and pyrazinyl containing indole substrate (10a−i) to be obtained
in 64−97% yields. These substrates were then subjected to the
ketone α-arylation conditions with XPhos precatalyst (5 mol %)
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Note
and NaOt-Bu (1.1 equiv), in 1,4-dioxane at 60 °C for 1 h.
Gratifyingly, various substituted (i.e., methyl, gem-dimethyl, or
phenyl) phenylketones could be efficiently coupled generating
tetracyclic indoles 11a−c in 89%, 99%, and 98% yields,
respectively (entries 1−3). However, 10d did not undergo ketone
α-arylation, possibly due to steric hindrance between the
methylenedioxy group and the 2-position of the indole (entry 4).
Cyclization of both the cyclopentenyl and cyclohexenyl substrates
10e−f gave 11e−f in excellent yields (entries 5 and 6).
Cyclization of the 3-pyridyl substrate 10g generated 11g in a
moderate 50% yield (entry 7). However, the 2-pyridyl and
pyrazinyl substrates 10h−i did not give the desired products
(entries 7−9), presumably due to chelation of nitrogen to the
palladium after metal insertion into the C−Cl bond.21 A number
of parameters were modified, including catalyst, solvent, temper-
ature, and addition of additives (i.e., Cu or Ag), in an attempt to
induce α-arylation of 10h−i, but so far all have failed.
chlorobenzene, bromobenzene, and 3-bromopyridine, giving
11c and 11k in good yields (entries 6−8). However, with 2-
bromopyridine the sequential one-pot reaction failed, again
probably due to nitrogen chelation by palladium following
metal insertion into the C−Cl bond (entry 9).
In summary, monoligated Pd(0) catalysts efficiently medi-
ated intramolecular α-arylation of ketones to generate a variety
of tetracyclic indoles in good to excellent yields. Low catalyst
loading (5 mol %) and short reaction times (≤1 h) were
generally sufficient to perform this process. The methodology
was also extended to double α-arylation of ketones by one-pot
procedures with either simultaneous or sequential additions of
the two aryl halides to yield aryl substituted tetracyclic indoles.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were purchased
from commercial sources and used without further purification. All
reactions were conducted under an argon atmosphere in flame-dried
or oven-dried glassware with magnetic stirring. Purification of products
was performed on an automated system using disposable silica gel
columns. Analytical thin layer chromatography was performed on
0.25 mm silica gel 60-F plates. Visualization was accomplished with
UV light and ninhydrin solution, KMnO4 or anisaldehyde staining
Next, more convergent syntheses using one-pot reactions
(with either simultaneous addition or sequential addition of the
two aryl halides) for producing aryl substituted tetracyclic
indoles (e.g., 11c) were investigated (Table 3). The efficiencies
Table 3. Double α-Arylation of Ketones
1
followed by heating. H NMR spectra were recorded on a 400 or
500 MHz spectrometer and are reported in ppm using solvent as the
internal standard (CDCl3 at 7.26 ppm). Data are reported as follows:
b = broad, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet; coupling constant(s) in Hz, integration. 13C NMR spectra
were recorded on a 100 or 125 MHz spectrometer. Chemical shifts are
reported in ppm from tetramethylsilane, with the solvent resonance
employed as the internal standard (CDCl3 at 77.0 ppm). High-
resolution mass spectra were obtained on MALDI-FT-ICR MS, using
150 mg/mL 2,5-dihydroxybenzoic acid dissolved in MeOH/H2O
(50:50) as the matrix.
Procedure for the Synthesis of Indoles 3a−c. 1-Benzyl-4-
bromo-3-iodoindole (3a). To a solution of 4-bromoindole (1.01 g,
5.0 mmol) in dry DMF (8 mL) at 0 °C was added NaH
(60% dispersal in mineral oil, 300 mg, 7.5 mmol). The mixture
was stirred at 0 °C for 10 min, and then it was allowed to warm
to ambient temperature and stirred for 30 min. The solution
was cooled to 0 °C, and then benzyl bromide (0.89 mL, 2.30
mmol) was added. The ice bath was removed, and the reaction
mixture was warmed to 45 °C and stirred for 1 h. The mixture
was cooled to room temperature, concentrated, and then
diluted with EtOAc and saturated NH4Cl. The organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated. The residue of 1-benzyl-4-bromoindole was
used without further purification.
To a solution at 0 °C of 1-benzyl-4-bromoindole (1.43 g, 5.0 mmol)
in dry DMF (10 mL) was added N-iodosuccinimide (1.30 g, 5.5
mmol). The reaction was stirred for 30 min and then quenched with
saturated NaHCO3, stirred for 10 min, concentrated, diluted with
H2O, and extracted with EtOAc. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated. Purification by chromatography (SiO2, 0−5% EtOAc in
cyclohexane) gave 3a (1.9 g, 4.6 mmol, 91% over two steps) as an
unstable white solid (stored at 0 °C). 1H NMR (500 MHz, CDCl3): δ
7.34−7.26 (m, 6H), 7.11−7.09 (m, 2H), 7.01 (t, J = 8.0 Hz, 1H), 5.28
(s, 2H). 13C NMR (125 MHz, CDCl3): δ 136.3, 135.5, 129.2, 128.3,
127.1, 125.6, 123.5, 110.0, 50.8.
yield
a
entry
route
X
Ar−Y
product
(%)
1
2
3
4
5
6
7
8
9
A
B
Cl or Br
Br
3-bromoanisole
3-bromoanisole
3-bromoanisole
3-bromoanisole
3-bromoanisole
chlorobenzene
bromobenzene
3-bromopyridine
2-bromopyridine
11j
11j
11j
11j
11j
11c
11c
11k
11l
94
64
0
B
Cl
C
C
C
C
C
C
Br
96
98
88
93
75
0
Cl
Cl
Cl
Cl
Cl
a
Isolated yield.
of these methods were compared to the stepwise process of
intramolecular ketone α-arylation of 7a−b to give 8 (isolated
and purified), followed by an intermolecular ketone α-arylation
with 3-bromoanisole to generate 11j in 94% overall yield
(entry 1), which used 10 mol % precatalyst over the two steps.
In the one-pot process (route B) using the bromine substrate
7a, the product 11j was obtained in 64% yield (entry 2).
However, no reaction was observed starting with the
chloroindole 7b (entry 3). Finally, sequential ketone α-
arylations (route C) of 7a and 7b were performed generating
11j in 96% and 95% yields, respectively (entries 4 and 5).
Route C was extended to other aryl halides, such as
1-Benzyl-3-bromo-4-chloroindole (3b). Unstable white solid (1.82
g, 5.7 mmol, stored at 0 °C), yield 96%. 1H NMR (500 MHz, CDCl3):
δ 7.34−7.27 (m, 3H), 7.19 (dd, J = 9.0 and 1.0 Hz, 1H), 7.16 (s, 1H),
7.13−7.05 (m, 4H), 5.26 (s, 2H). 13C NMR (125 MHz, CDCl3): δ
137.4, 136.4, 129.2, 128.3, 127.1, 123.4, 121.9, 109.3, 50.7.
1-Benzyl-4-chloro-3-iodoindole (3c). Unstable white solid (1.76
mmol, 4.8 mmol, stored at 0 °C), yield 97%.1H NMR (500 MHz,
CDCl3): δ 7.34−7.27 (m, 3H), 7.25 (s, 1H), 7.21 (dd, J = 8.0 and 1.0
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Note
Hz, 1H), 7.12−7.05 (m, 4H), 5.27 (s, 2H). 13C NMR (125 MHz,
CDCl3): δ 136.4, 135.0, 129.2, 128.3, 127.1, 123.2, 121.9, 109.3, 50.8.
1-Benzyl-4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-indole (5). To a solution of 3b (1.28 g, 4.0 mmol) in THF (40 mL)
at −78 °C was added t-BuLi (1.59 M in pentane, 5.53 mL, 8.8 mmol)
dropwise over 5 min. The reaction mixture was stirred for 15 min at
−78 °C, and then dioxaborolane (1.68 mL, 8.0 mmol) was added. The
mixture was stirred at −78 °C for 1 h, quenched with saturated
NH4Cl, and allowed to warm to room temperature. The aqueous layer
was extracted with Et2O. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated.
Purification by chromatography (SiO2, 0−10% EtOAc in cyclohexane)
gave 5 (896 mg, 2.44 mmol, 61% yield) as a moderately stable pale
yellow solid (stored at 0 °C). 1H NMR (500 MHz, CDCl3): δ 7.60 (s,
1H), 7.30−7.24 (m, 3H), 7.16−7.12 (m, 2H), 7.09−7.04 (m, 3H),
5.31 (s, 2H), 1.38 (s, 12H). 13C NMR (100 MHz, CDCl3): δ 139.0,
136.8, 129.9, 129.0, 128.0, 126.9, 122.8, 127.5, 108.7, 83.6, 50.8, 25.0.
HRMS (MALDI-TOF, M + Na) calcd for C21H23BClNNaO2
389.1439, found 389.1437.
General Procedure for the Preparation of Ketones 9d−h. To
a solution of aldehyde (1 equiv) in dry THF (2 mL/1 mmol of starting
material) under an argon atmosphere at −78 °C was added dropwise a
Grignard reagent (1.1 equiv). After stirring at room temperature for
18 h, the reaction mixture was quenched with saturated NH4Cl and
extracted twice with EtOAc. The organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purifica-
tion by chromatography (SiO2, 10−50% EtOAc in cyclohexane) afforded
the alcohol as a colorless oil.
was heated at 110 °C for 2 h. After cooling, the reaction mixture was
quenched with saturated NH4Cl and extracted with EtOAc. The organic
layers were combined, washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by chromatography (SiO2, 0−5%
EtOAc in cyclohexane) gave 2-chloro-3-(1-ethoxyprop-1-enyl)pyrazine
(339 mg, 1.71 mmol, 43%) as a yellow oil.
To a solution of 2-chloro-3-(1-ethoxyprop-1-enyl)pyrazine (330
mg, 1.66 mmol) in DME (2 mL) was added 2 N HCl (2 mL). The
reaction mixture was heated at 60 °C for 2 h and then allowed to cool
to room temperature, neutralized with saturated NaHCO3, and
extracted with EtOAc. The organic layers were combined, washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated.
Purification by chromatography (SiO2, 0−5% EtOAc in cyclohexane)
1
gave 9i (240 mg, 1.41 mmol, 85%) as a pale yellow solid. H NMR
(500 MHz, CDCl3): δ 8.54 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz,
1H), 3.12 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 200.8, 148.5, 146.6, 145.7, 141.6, 33.9, 7.8.
1-(2-(1-Benzyl-4-bromoindol-3-yl)phenyl)ethanone (7a). A
Schlenk flask was charged with 3a (1.0 g, 2.43 mmol), 4 (609 mg,
3.64 mmol), and PdCl2dppf (178 mg, 0.24 mmol). The flask was
evacuated and backfilled with argon (3 times), and then DME (20
mL) followed by a solution of Na2CO3 (514 mg, 4.86 mmol) in water
(4 mL) was added. The reaction mixture was sparged with argon and
then heated to 80 °C for 6 h. After cooling, the reaction mixture was
dissolved with water and extracted with EtOAc. The organic layers
were combined, washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated. Purification by chromatography
(SiO2, 5−20% EtOAc in cyclohexane) gave 7a (510 mg, 1.26 mmol,
52%) as a yellowish solid. 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J =
7.0 Hz, 1H), 7.47−7.40 (m, 3H), 7.34−7.27 (m, 5H), 7.14−7.11 (m,
2H), 7.06 (t, J = 8.0 Hz, 1H), 7.05 (s, 1H), 5.34 (s, 2H), 2.07 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 204.1, 142.3, 137.5, 136.8, 134.2,
133.3, 129.9, 129.6, 129.2, 1127.4, 127.0, 125.7, 124.8, 123.4, 116.8,
114.8, 109.7, 50.7, 30.3. HRMS (MALDI-TOF, M + H) calcd for
C23H19BrNO 404.0644, found 404.0642.
To a solution of alcohol (1 equiv) in dry CH2Cl2 (3 mL/1 mmol of
starting material) at 0 °C under an argon atmosphere was added Dess-
Martin periodinane (1.6 equiv). The reaction mixture was stirred at
0 °C for 1 h and then overnight at room temperature. The reaction
mixture was concentrated, and the residue was purified by chro-
matography (SiO2, 10−25% EtOAc in cyclohexane) to give the
corresponding ketone.
1-(4-Bromo-benzo[1,3]dioxol-5-yl)-propan-1-one (9d). Colorless
1-(2-(1-Benzyl-4-chloroindol-3-yl)phenyl)ethanone (7b). A
Schlenk flask was charged with 3b (1.84 g, 5.74 mmol), 4 (1.44 g,
8.61 mmol), and Pd(PPh3)4 (332 mg, 0.29 mmol). The flask was
evacuated and backfilled with argon (3 times), and then DME
(40 mL) followed by a solution of Na2CO3 (445 mg, 4.20 mmol) in
water (4 mL) was added. The reaction mixture was sparged with argon
and then heated to 80 °C for 18 h. After cooling, the reaction was
dissolved with water and extracted with EtOAc. The organic layers were
combined, washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated. Purification by chromatography (SiO2, 5−20%
EtOAc in cyclohexane) gave 7b (1.46 g, 4.05 mmol, 71%) as a
1
oil (214 mg, 0.83 mmol), yield 56%. H NMR (400 MHz, CDCl3): δ
7.05 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H), 2.89
(q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 201.6, 147.6, 146.0, 126.4, 124.2, 110.6, 109.7, 102.4, 37.4,
7.8. HRMS (EI, M+) calcd for C10H9BrO3 255.9735, found 255.9738.
1-(2-Bromo-cyclopent-1-enyl)-propan-1-one (9e). Colorless oil
1
(180 mg, 0.87 mmol), yield 52%. H NMR (400 MHz, CDCl3): δ
2.88−2.81 (m, 4H), 2.68−2.63 (m, 2H), 1.97−1.89 (m, 2H), 1.11 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 199.6, 140.2, 129.1,
44.1, 35.5, 33.7, 21.6, 7.9. HRMS (EI, M+) calcd for C8H11BrO
201.9993, found 201.9990.
1
yellowish solid. H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 7.5 Hz,
1-(2-Bromo-cyclohex-1-enyl)-propan-1-one (9f). Colorless oil
1H), 7.49−7.39 (m, 3H), 7.34−7.32 (m, 4H), 7.15−7.10 (m, 4H),
7.03 (s, 1H), 5.34 (s, 2H), 2.08 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 204.1, 142.0, 137.9, 136.8, 133.7, 133.6, 130.0, 129.4, 129.2,
128.2, 127.4, 127.3, 127.0, 126.8, 124.3, 123.1, 121.3, 116.1, 109.1,
50.7, 30.2. HRMS (MALDI-TOF, M + H) calcd for C23H19ClNO
360.1150, found 360.1153.
1
(147 mg, 0.68 mmol), yield 77%. H NMR (400 MHz, CDCl3): δ
2.70 (q, J = 7.2 Hz, 2H), 2.54−2.50 (m, 2H), 2.26−2.24 (m, 2H),
1.75−1.68 (m, 4H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 207.8, 139.8, 119.7, 36.2, 34.9, 29.0, 24.3, 21.5, 7.8. HRMS
(EI, M+) calcd for C9H13BrO 216.0150, found 216.0145.
1-(3-Bromopyridin-4-yl)propan-1-one (9g). Colorless oil (65 mg,
0.30 mmol), yield 45%. 1H NMR (500 MHz, CDCl3): δ 8.79 (s, 1H),
8.60 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.91 (q, J = 7.0 Hz,
2H), 1.23 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 203.3,
153.1, 148.8, 148.7, 121.8, 116.3, 36.1, 7.9. HRMS (EI, M+) calcd for
C8H8BrNO 212.9789, found 212.9788.
1-(2-Bromopyridin-3-yl)propan-1-one (9h). Colorless oil (237 mg,
1.11 mmol), yield 56%. 1H NMR (500 MHz, CDCl3): δ 8.44 (dd, J =
4.5 and 2.0 Hz, 1H), 7.66 (dd, J = 7.5 and 2.0 Hz, 1H), 7.35 (dd, J =
7.5 and 4.5 Hz, 1H), 2.98 (q, J = 7.0 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 203.6, 151.3, 139.2, 137.9, 136.9,
122.9, 36.3, 8.3.
General Procedure for the Synthesis of Indoles 10a−i. A
Schlenk flask was charged with 5 (1 equiv), the corresponding aryl,
vinyl or heteroaryl halide 6 or 9a−i (1.5 equiv), anhydrous K3PO4
(3 equiv), and Pd(PPh3)4 (5 mol %). The flask was evacuated and
backfilled with argon (3 times), and then dry toluene (1 mL/0.1 mmol
of starting material) was added. The reaction mixture was sparged with
argon and then heated at 90 °C for 4−24 h. After cooling, the reaction
mixture was diluted with EtOAc and then filtered through a pad of
Celite. The solvent was removed in vacuo. Purification by
chromatography (SiO2, 5−20% EtOAc in cyclohexane) gave 10a−i.
1-(2-(1-Benzyl-4-chloroindol-3-yl)phenyl)propan-1-one (10a).
1
Pale yellow solid (64 mg, 0.17 mmol), yield 86%. H NMR (500
1-(3-Chloropyrazin-2-yl)propan-1-one (9i). A Schlenk flask was
charged with 2,3-dichloropyrazine (596 mg, 4.0 mmol), Pd2dba3 (83
mg, 0.08 mmol), PPh3 (84 mg, 0.32 mmol), and dry toluene (8 mL).
The reaction vessel was flushed with argon for 5 min, and then
(1-ethoxypropenyl)tributyltin (1.5 g, 4.0 mmol) was added. The reaction
MHz, CDCl3): δ 7.57−7.48 (m, 2H), 7.45 (ddd, J = 8.0, 7.5, and 1.5
Hz, 1H), 7.39 (ddd, J = 8.0, 7.5, and 1.5 Hz, 1H), 7.33−7.27 (m, 3H),
7.25 (dd, J = 7.0 and 2.0 Hz, 1H), 7.15−7.10 (m, 4H), 7.01 (s, 1H),
5.32 (s, 2H), 2.39 (q, J = 7.5 Hz, 1H), 0.84 (2, J = 7.5 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 208.2, 142.3, 137.9, 136.8, 133.8, 132.8,
4127
dx.doi.org/10.1021/jo300052z | J. Org. Chem. 2012, 77, 4123−4130

The Journal of Organic Chemistry
Note
129.6, 129.4, 129.2, 128.2, 127.2, 127.0, 126.9, 124.2, 123.1, 121.4,
115.8, 109.1, 50.7, 35.8, 8.7. HRMS (MALDI-TOF, M + H) calcd for
C24H21ClNO 374.1306, found 374.1307.
NMR (100 MHz, CDCl3): δ 202.8, 149.8, 148.0, 144.6, 140.9, 138.0,
136.4, 131.1, 129.2, 128.2, 127.2, 126.2, 124.0, 123.2, 121.7, 114.2,
109.5, 51.0, 33.3, 8.1. HRMS (MALDI-TOF, M + H) calcd for
C22H19ClN3O 376.1211, found 376.1215.
1-(2-(1-Benzyl-4-chloroindol-3-yl)phenyl)-2-methylpropan-1-one
1
(10b). Pale yellow solid (40 mg, 0.10 mmol), yield 82%. H NMR
General Procedure for the Intramolecular α-Arylations. A
reaction tube was charged with the corresponding indole (1 equiv),
Xphos precat. (5 mol %), and NaOtBu (1.1 equiv). The tube was
evacuated and backfilled with argon (3 times), and then dry 1,4-
dioxane (1 mL/0.1 mmol of starting material) was added. The reaction
mixture was sparged with argon and then heated to 60 °C for 0.5−1 h.
After cooling, the reaction was quenched with saturated NH4Cl and
extracted with EtOAc. The organic layers were combined, washed with
brine, dried over anhudrous Na2SO4, filtered, and concentrated.
Purification by chromatography (SiO2, 5−25% EtOAc in cyclohexane)
gave the products.
(500 MHz, CDCl3): δ 7.51 (d, J = 7.5 Hz, 1H), 7.46−7.35 (m, 3H),
7.32−7.24 (m, 4H), 7.16 (m, 4H), 6.98 (s, 1H), 5.30 (s, 2H), 2.69−
2.60 (m, 1H), 0.94−0.67 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
212.7, 142.2, 137.9, 136.7, 133.8, 132.2, 129.9, 129.1, 128.9, 128.2,
127.1, 126.9, 124.2, 123.2, 121.4, 115.4, 109.1, 50.7, 39.9, 19.7. HRMS
(MALDI-TOF, M + H) calcd for C25H23ClNO 388.1463, found
388.1464.
1-(2-(1-Benzyl-4-chloroindol-3-yl)phenyl)-2-phenylethanone
(10c). Pale yellow solid (43 mg, 0.10 mmol), yield 79%. 1H NMR (500
MHz, CDCl3): δ 0.56−7.33 (m, 4H), 7.31−7.24 (m, 4H), 7.19−7.07
(m, 7H), 6.91 (s, 1H), 6.83−6.77 (m, 2H), 5.29−5.16 (m, 2H), 3.75−
3.55 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 204.9, 142.1, 138.0,
136.6, 134.8, 133.9, 132.9, 130.1, 129.6, 129.2, 128.4, 128.2, 127.3,
127.2, 127.1, 126.9, 126.7, 124.1, 123.3, 121.6, 115.4, 109.2, 50.6, 49.3.
HRMS (MALDI-TOF, M + H) calcd for C29H23ClNO 436.1463,
found 436.1457.
2-Benzyl-2,6-dihydro-2-aza-dibenzo[cd,h]azulen-7-one (8).
1
White solid (345 mg, 1.07 mmol), yield 96%. H NMR (500 MHz,
CDCl3): δ 7.81 (d, J = 7.5 Hz, 1H), 7.63 (dd, J = 7.5 and 1.5 Hz, 1H),
7.55 (s, 1H), 7.43 (ddd, J = 8.0, 7.5, and 1.5 Hz, 1H), 7.35−7.27
(m, 3H), 7.25−7.15 (m, 5H), 7.00−6.96 (m, 1H), 5.37 (s, 2H), 4.32
(s, 2H). 13C NMR (100 MHz, CDCl3): δ 198.9, 139.4, 137.1, 136.9,
132.6, 131.5, 129.5, 129.2, 128.2, 127.3, 127.1, 126.9, 125.4, 124.6,
124.4, 123.7, 120.2, 115.8, 109.0, 51.3, 50.7. HRMS (MALDI-TOF,
M + Na) calcd for C23H17NNaO 346.1202, found 346.1209.
1-[4-(1-Benzyl-4-chloroindol-3-yl)-benzo[1,3]dioxol-5-yl]-propan-
1
1-one (10d). Pale yellow solid (55 mg, 0.13 mmol), yield 88%. H
NMR (400 MHz, CDCl3): δ 7.33−7.25 (m, 3H), 7.22−7.17 (m, 1H),
7.12−7.06 (m, 4H), 7.01 (s, 1H), 6.89 (dd, J = 12.4 and 8.0 Hz, 2H),
6.06 (s, 2H), 5.30 (s, 2H), 2.59−2.43 (m, 2H), 0.88 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 203.8, 147.2, 145.0, 137.6,
136.9, 129.5, 129.1, 128.1, 126.9, 126.7, 126.3, 124.7, 12.6, 122.8,
121.1, 115.0, 109.0, 101.8, 50.6, 37.1, 8.1. HRMS (MALDI-TOF,
M + H) calcd for C25H21ClNO3 418.1204, found 418.1197.
1-[2-(1-Benzyl-4-chloroindol-3-yl)-cyclopent-1-enyl]-propan-1-
one (10e). White solid (51 mg, 0.14 mmol), yield 94%. 1H NMR (400
MHz, CDCl3): δ 7.33−7.27 (m, 3H), 7.24−7.20 (m, 1H), 7.13−7.08
(m, 4H), 6.96 (s, 1H), 5.31 (s, 2H), 2.94−2.86 (m, 2H), 2.82−2.76
(m, 2H). 2.20 (q, J = 7.2 Hz, 2H), 2.00−1.93 (m, 2H), 0.82 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 202.7, 147.0, 142.1, 138.0,
1136.8, 129.1, 128.2, 127.0, 126.9, 126.6, 124.4, 123.1, 121.1, 113.1,
109.0, 50.5, 44.5, 34.5 (2C), 22.3, 8.4. HRMS (MALDI-TOF, M + H)
calcd for C23H23ClNO 364.1463, found 364.1464.
1-[2-(1-Benzyl-4-chloroindol-3-yl)-cyclohex-1-enyl]-propan-1-
one (10f). White solid (56 mg, 0.15 mmol), yield 97%. 1H NMR (400
MHz, CDCl3): δ 7.31−7.25 (m, 3H), 7.17−7.03 (m, 5H), 6.85 (s,
1H), 5.22 (s, 2H), 2.89−2.51 (m, 2H), 2.20−2.02 (m, 4H), 1.90−1.56
(m, 2H), 0.70 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
210.8, 139.6, 136.8, 135.1, 129.1, 128.3, 128.1, 126.9, 126.5, 124.5,
123.1, 120.9, 117.3, 108.9, 50.5, 35.5, 34.7, 26.7, 22.8, 22.4, 8.5. HRMS
(MALDI-TOF, M + H) calcd for C24H25ClNO 378.1619, found
378.1613.
2-Benzyl-6-methyl-2,6-dihydro-2-aza-dibenzo[cd,h]azulen-7-one
1
(11a). White solid (56 mg, 0.17 mmol), yield 89%. H NMR (500
MHz, CDCl3): δ 7.81 (d, 1H, J = 8.0 Hz), 7.61 (dd, 1H, J = 8.0 and
1.5 Hz), 7.59 (s, 1H), 7.43 (ddd, 1H, J = 8.0, 8.0, and 1.5 Hz), 7.35−
7.27 (m, 3H), 7.25−7.21 (m, 3H), 7.19−7.16 (m, 2H), 7.07−7.03 (m,
1H), 5.37 (s, 2H), 4.29 (q, 1H, J = 7.0 Hz), 1.41 (d, 3H, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): δ 203.5, 137.5, 137.4, 136.8, 133.2,
132.2, 131.2, 130.0, 129.2, 128.2, 127.3, 127.2, 125.6, 124.1, 123.7,
123.2, 119.0, 115.4, 109.0, 54.8, 50.7, 20.3. HRMS (MALDI-TOF, M +
Na) calcd for C24H19NNaO 360.1359, found 360.1363.
2-Benzyl-6,6-dimethyl-2,6-dihydro-2-aza-dibenzo[cd,h]azulen-7-
one (11b). White solid (18 mg, 0.05 mmol), yield 99%. 1H NMR (500
MHz, CDCl3): δ 7.78 (d, 1H, J = 8.0 Hz), 7.60 (s, 1H), 7.51 (dd, 1H,
J = 7.5 and 1.5 Hz), 7.41 (ddd, 1H, J = 8.0, 7.5, and 1.5 Hz), 7.35−7.28
(m, 3H), 7.26−7.20 (m, 4H), 7.18−7.14 (m, 2H), 5.38 (s, 2H), 1.57
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 206.1, 138.4, 137.4, 137.2,
136.8, 131.7, 130.6, 129.3, 129.2, 128.2, 127.1, 127.0, 125.6, 123.4,
123.3, 115.9, 115.7, 109.2, 51.8, 50.7, 27.0. HRMS (MALDI-TOF, M +
Na) calcd for C25H21NNaO 374.1515, found 374.1516.
2-Benzyl-6-phenyl-2,6-dihydro-2-aza-dibenzo[cd,h]azulen-7-one
(11c). Pale yellow solid (18 mg, 0.04 mmol), yield 98%. 1H NMR (500
MHz, CDCl3): δ 7.76 (d, 1H, J = 8.0 Hz), 7.59 (s, 1H), 7.45 (dd, 1H,
J = 8.0 and 1.5 Hz), 7.37−7.27 (m, 6H), 7.22−7.19 (m, 2H), 7.11−
7.03 (m, 5H), 6.96−6.92 (m, 2H), 5.58 (s, 1H), 5.42 (AB, 2H, J=16.0
and 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ 200.9, 139.5, 137.5,
137.4, 136.8, 131.4, 131.1, 130.8, 129.4, 129.2, 128.6, 128.3, 128.0,
127.5, 127.2, 127.1, 125.5, 124.7, 124.3, 124.0, 123.8, 121.6, 115.8,
109.5, 67.4, 50.8. HRMS (MALDI-TOF, M + Na) calcd for
C29H21NNaO 422.1515, found 422.1515.
1-(3-(1-Benzyl-4-chloroindol-3-yl)pyridin-4-yl)propan-1-one
1
(10g). Pale yellow solid (30 mg, 0.08 mmol), yield 64%. H NMR
(500 MHz, CDCl3): δ 8.78 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H), 7.34−
7.26 (m, 5H), 7.18−7.10 (m 4H), 7.08 (s, 1H), 5.35 (s, 2H), 2.43 (q,
J = 7.5 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 206.4, 154.1, 148.6, 147.9, 137.9, 136.5, 130.2, 129.2, 128.3,
127.3, 127.0, 126.7, 124.3, 123.5, 121.6, 120.0, 111.6, 109.3, 50.8, 35.7,
8.1. HRMS (MALDI-TOF, M + H) calcd for C23H20ClN2O 375.1259,
found 375.1268.
2-Benzyl-6-methyl-2,8,9,10-tetrahydro-6H-2-aza-benzo[cd]-
cyclopenta[h]azulen-7-one (11e). White solid (17 mg, 0.05 mmol),
yield 96%. 1H NMR (400 MHz, CDCl3): δ 7.35−7.28 (m, 3H), 7.25−
7.15 (m, 5H), 7.02−6.99 (m, 1H), 5. 31 (s, 2H), 4.09 (q, J = 7.2 Hz,
1H), 3.06−2.88 (m, 3H), 2.77−2.70 (m, 1H), 2.08−1.88 (m, 2H),
1.40 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 198.5,
144.6, 137.4, 136.7, 134.4, 134.0, 129.2, 128.8, 128.2, 127.2, 124.6,
123.8, 120.8, 114.0, 108.7, 56.2, 50.7, 36.0, 34.8, 23.9, 22.0. HRMS
(MALDI-TOF, M + H) calcd for C23H22NO 328.1696, found
328.1699.
1-(2-(1-Benzyl-4-chloroindol-3-yl)pyridin-3-yl)propan-1-one
1
(10h). Pale yellow solid (196 mg, 0.52 mmol), yield 65%. H NMR
(500 MHz, CDCl3): δ 8.77 (dd, J = 5.0 and 2.0 Hz, 1H), 7.87 (dd, J =
7.5 and 2.0 Hz, 1H), 7.35−7.23 (m, 5H), 7.18 (s, 1H), 7.16−7.11 (m,
4H), 5.34 (s, 2H), 2.45 (q, J = 7.5 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 206.2, 151.8, 150.5, 138.0, 137.6,
136.5, 135.3, 130.3, 129.2, 128.2, 127.0, 126.7, 124.5, 123.5, 121.8,
121.8, 116.1, 109.1, 50.8, 35.5, 8.6. HRMS (MALDI-TOF, M + H)
calcd for C23H20ClN2O 375.1259, found 375.1259.
2-Benzyl-6-methyl-2,6,8,9,10,11-hexahydro-2-aza-dibenzo[cd,h]-
1
azulen-7-one (11f). White solid (16 mg, 0.05 mmol), yield 94%. H
NMR (400 MHz, CDCl3): δ 7.34−7.28 (m, 4H), 7.22−7.13 (m, 4H),
6.99−6.97 (m, 1H), 5.35−5.24 (m, 2H), 4.10 (q, J = 7.2 Hz, 1H),
2.85−2.77 (m, 1H), 2.71−2.66 (m, 2H), 2.32−2.24 (m, 1H), 1.82−
1.68 (m, 4H), 1.42 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 203.7, 137.1, 137.0, 134.3, 133.7, 131.2, 129.1, 128.1, 127.3, 127.1,
1-(3-(1-Benzyl-4-chloroindol-3-yl)pyrazin-2-yl)propan-1-one
(10i). Pale yellow solid (53 mg, 0.14 mmol), yield 93%. 1H NMR (400
MHz, CDCl3): δ 8.68 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H),
7.46 (s, 1H), 7.35−7.22 (m, 4H), 7.21 (m, 2H), 7.13−7.06 (m, 2H),
5.38 (s, 2H), 3.17 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C
4128
dx.doi.org/10.1021/jo300052z | J. Org. Chem. 2012, 77, 4123−4130

The Journal of Organic Chemistry
Note
123.9, 123.4, 119.0, 117.5, 108.5, 55.7, 50.6, 28.0, 27.7, 22.8, 22.6, 20.8.
HRMS (MALDI-TOF, M + H) calcd for C24H24NO 342.1852, found
342.1859.
Notes
The authors declare no competing financial interest.
2-Benzyl-6-methyl-2,6-dihydro-2,10-diaza-dibenzo[cd,h]azulen-
ACKNOWLEDGMENTS
1
■
7-one (11g). Yellow solid (18 mg, 0.05 mmol), yield 50%. H NMR
(500 MHz, CDCl3): δ 9.16 (s, 1H), 8.47 (d, 1H, J = 5.0 Hz), 7.71 (s,
1H), 7.44 (d, 1H, J = 5.0 Hz), 7.37−7.30 (m, 3H), 7.28−7.27 (m,
2H), 7.21−7.18 (m, 2H), 7.09−7.07 (m, 1H), 5.40 (s, 2H), 4.29 (q,
1H, J = 7.0 Hz), 1.40 (d, 3H, J = 7.0 Hz). 13C NMR (100 MHz,
CDCl3): δ 201.5, 146.5, 146.4, 142.2, 137.4, 136.4, 132.5, 129.3, 128.4,
127.2, 127.1, 126.9, 124.2, 123.4, 122.6, 119.6, 112.0, 109.5, 54.6, 50.9,
20.0. HRMS (MALDI-TOF, M + H) calcd for C23H19N2O 339.1492,
found 339.1487.
2-Benzyl-6-(3-methoxyphenyl)-2,6-dihydro-2-aza-dibenzo[cd,h]-
azulen-7-one (11j). Route A. A reaction tube was charged
with 8 (33 mg, 0.1 mmol), Xphos precat. (3.7 mg, 0.005 mmol),
3-bromoanisole (14 μL, 0.2 mmol), and NaOt-Bu (11 mg,
0.11 mmol). The tube was evacuated and backfilled with argon
(3 times), and then dry 1,4-dioxane (1 mL) was added. The
reaction mixture was sparged with argon and then heated to
60 °C for 1 h.
Route B. A reaction tube was charged with 7a (40 mg, 0.1 mmol),
Xphos precat. (3.7 mg, 0.005 mmol), 3-bromoanisole (14 μL, 0.2
mmol), and NaOt-Bu (21.4 mg, 0.22 mmol). The tube was evacuated
and backfilled with argon (3 times), and then dry 1,4-dioxane (1 mL)
was added. The reaction mixture was sparged with argon and then
heated to 60 °C for 2 h.
Route C. A reaction tube was charged with 7b (36 mg, 0.1 mmol),
Xphos precat. (3.7 mg, 0.005 mmol). and NaOt-Bu (21.4 mg, 0.12
mmol). The tube was evacuated and backfilled with argon (3 times)
and then dry 1,4-dioxane (1 mL). The reaction mixture was sparged
with argon and then heated to 60 °C for 1 h. Then, 3-bromoanisole
(14 μL, 0.2 mmol) was added, and the mixture was heated for an
additional 1 h.
The authors appreciate financial support from the Harvard
NeuroDiscovery Center. The authors also thank Prof. Stephen
L. Buchwald for providing several of the precatalysts.
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After cooling, the reaction mixtures were quenched with saturated
NH4Cl and extracted with EtOAc. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated. Purification by chromatography (SiO2, 5−25% EtOAc in
cyclohexane) gave 11j (94%, 64% and 98% for routes A, B, and C,
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1
respectively) as a yellow solid. H NMR (500 MHz, CDCl3): δ 7.66
(d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.46 (dd, J = 8.0 and 1.5 Hz, 1H),
7.37−7.26 (m, 6H), 7.21−7.17 (m, 2H), 7.09−7.05 (m, 2H), 7.00 (t,
J = 8.0 Hz, 1H), 6.58 (dd, J = 8.0 and 2.5 Hz, 1H), 6.54 (d, J = 8.0 Hz,
1H), 6.49 (s, 1H), 5.55 (s, 1H), 5.41 (dd, J = 15.5 and 7.5 Hz, 2H),
3.59 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 200.7, 159.7, 141.1,
137.6, 137.3, 136.8, 131.5, 131.1, 130.8, 129.5, 129.3, 129.2, 128.2,
127.5, 127.2, 125.5, 124.7, 124.0, 123.8, 121.7, 120.5, 115.7, 113.8,
112.5, 109.5, 67.4, 55.2, 50.7. HRMS (MALDI-TOF, M + Na) calcd
for C30H23NNaO2 452.1621, found 452.1623.
2-Benzyl-6-pyridin-3-yl-2,6-dihydro-2-aza-dibenzo[cd,h]azulen-
7-one (11k). 1H NMR (400 MHz, CDCl3): δ 8.31 (dd, J = 4.8 and 1.6
Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H); 7.68 (d, J = 8.0 Hz, 1H), 7.61 (s,
1H), 7.46 (dd, J = 8.0 and 1.2 Hz, 1H), 7.38−7.26 (m, 7H), 7.22−7.18
(m, 2H), 7.09 (ddd, J = 8.0, 8.0, and 1.2 Hz, 1H), 7.05−7.01 (m, 2H),
5.59 (s, 1H), 5.46−5.38 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
199.6, 149.6, 148.5, 137.5, 137.1, 136.6, 135.7, 135.0, 131.5, 130.6,
129.3, 128.3, 127.8, 127.2, 125.7, 124.4, 124.2, 123.9, 123.5, 121.3,
115.5, 109.9, 64.7, 50.8. HRMS (MALDI-TOF, M + H) calcd for
C28H21N2O 401.1648, found 401.1644.
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ASSOCIATED CONTENT
* Supporting Information
́
Tetrahedron 2004, 60, 11783−11803. (e) Sole, D.; Serrano, O. J. Org.
■
S
Chem. 2008, 73, 2476−2479. (f) Powell, N. A.; Hagen, T. J.; Ciske, F.
L.; Cai, C.; Duran, J. E.; Holsworth, D. D.; Leonard, D.; Kennedy, R.
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Supporting Information, including NMR spectra of the
compounds, is provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gdcuny@central.uh.edu.
■
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The Journal of Organic Chemistry
Note
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