Synthesis of indolo[2,1-a]isoquinolines via a triazene-directed C-H annulation cascade

Article abstract of DOI:10.1021/jo500807d

(Chemical Equation Presented) Indole-containing polyaromatic scaffolds are widely found in natural products, pharmaceutical agents, and π-conjugated functional materials. Often, the synthesis of these highly valuable molecules requires a multistep sequence. Therefore, a simple, one-step protocol to access libraries of polyaromatic indole scaffolds is highly desirable. Herein we describe the direct synthesis of polysubstituted indolo[2,1-a]isoquinoline analogues via a double C-H annulation cascade using triazene as an internally cleavable directing group. Evidence from HRMS and theoretical calculations suggests that an unprecedented 1,2-alkyl migration might be responsible for the in situ cleavage of the directing group. Both kinetic isotope effects and DFT calculations suggested that the alkyne insertion step is rate-limiting for the second C,N annulation reaction.

Full text of DOI:10.1021/jo500807d

Article
pubs.acs.org/joc
Synthesis of Indolo[2,1‑a]isoquinolines via a Triazene-Directed C−H
Annulation Cascade
Huan Sun, Chengming Wang, Yun-Fang Yang, Ping Chen, Yun-Dong Wu,* Xinhao Zhang,*
and Yong Huang*
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen Graduate
School, Shenzhen 518055, China
*
S Supporting Information
ABSTRACT: Indole-containing polyaromatic scaffolds are
widely found in natural products, pharmaceutical agents, and
π-conjugated functional materials. Often, the synthesis of these
highly valuable molecules requires a multistep sequence.
Therefore, a simple, one-step protocol to access libraries of
polyaromatic indole scaffolds is highly desirable. Herein we
describe the direct synthesis of polysubstituted indolo[2,1-
a]isoquinoline analogues via a double C−H annulation cascade using triazene as an internally cleavable directing group. Evidence
from HRMS and theoretical calculations suggests that an unprecedented 1,2-alkyl migration might be responsible for the in situ
cleavage of the directing group. Both kinetic isotope effects and DFT calculations suggested that the alkyne insertion step is rate-
limiting for the second C,N annulation reaction.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Indolo[2,1-a]isoquinolines are widely found in molecules with
One significant limitation of our original triazene-directed
indole synthesis was a very narrow substrate scope.
1
1b
1
The
various functions, including tubulin-binding drugs, HCV
2
3
reaction worked well only for triazenylbenzenes bearing
electron-neutral substituents. Strong electron-donating (e.g.,
MeO) and electron-withdrawing (e.g., Ac, CO Me, NO , etc.)
groups were not tolerated, and very low yields of the indole
products were obtained. Therefore, we decided to extend the
substrate scope for the crucial free NH indole synthesis before
attempting the cascade strategy. 2-Methoxy-4-nitrophenyltria-
zene 1aa, a modest substrate in our previous indole synthesis,
was chosen for development of the reaction conditions. Under
our previously identified conditions, substrate 1aa reacted with
replicon inhibitors, estrogen receptor modulators, solid-state
4
fluorescent materials, and organic semiconductors. The
2
2
specific functions of these molecules are often affected by the
substituents on the flat, electron-rich, polyaromatic ring
5
skeleton. Therefore, intensive research has been directed
toward the development of straightforward methods for the
synthesis of substituted indolo[2,1-a]isoquinoline analogues.
The recently reported C−H/N−H activation−annulation
reactions offer a very attractive approach to such scaffolds.
6
4
a,7
1
.1 equiv of diphenylacetylene (2a) in the presence of 5 mol %
The starting materials for these reactions, free NH indoles, can
also be synthesized through an analogous C−H/N−H
annulation reaction between an aniline derivative and an
[RhCp*Cl ] , 20 mol % AgSF , and 2.0 equiv of Cu(OAc) ·
2 2
6
2
H O in MeOH, yielding indole 3aa in 61% yield. Various
copper oxidants were examined, and Cu(OPiv) was found to
be significantly superior (Table 1, entry 5). Surprisingly, we
observed a profound solvent effect. A 1:1 MeOH/tAmOH
mixture led to a yield 30% higher than that with MeOH alone,
while tAmOH resulted in a very slow reaction (50% yield).
2
8
,9
2
internal alkyne. As common directing groups (DGs) for the
10
indole synthesis are noncleavable in situ, a separate synthetic
operation is required to remove the DG, rendering the overall
synthesis of indolo[2,1-a]isoquinolines a three-step sequence
(
Scheme 1a). Very recently, Glorius and our own group
Combining Cu(OPiv) and the solvent mixture improved the
2
reported the direct synthesis of free NH indoles using
yield of 3aa to 94%.
11
removable directing groups (Scheme 1b). Encouraged by
our recent discovery of the synthesis of free NH indoles using
Having identified the critical copper oxidant and solvent
combination, we examined many substrates beyond the scope
of the previous reaction conditions. As shown in Table 2, for
various triazenes examined, the yields were significantly higher
12
triazene as an “internally cleavable” directing group, we
decided to intercept the free NH indole product in situ with
another equivalent of the internal alkyne to generate the
corresponding indolo[2,1-a]isoquinoline directly. To the best
of our knowledge, this is the first direct synthesis of indolo[2,1-
a]isoquinolines from readily available aniline derivatives.
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: April 10, 2014
©
XXXX American Chemical Society
A
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Scheme 1. C−H Annulation Strategy for the Synthesis of Indolo[2,1-a]isoquinolines
Table 1. Investigation of Conditions for Triazene-Directed
Indole Synthesis
resolution ESI mass spectrometer, a peak at m/z = 321, which
a
+
might correspond to [(C H )RhN C H ] , was identified.
10
14
2
4
8
Collision-induced dissociation (CID) of this species (Figure
a) gave two major fragments at m/z = 292 and 237. The peak
1
+
13
at m/z = 237 was assigned as [Cp*Rh − H] (Figure 1c),
suggesting the loss of the N C H fragment. To confirm this
2
4
8
fragmentation, a 2-methylpyrrolidine-derivatized triazene sub-
strate was tested. As expected, a peak at m/z = 335 was found.
The CID mass spectrum of the peak at m/z = 335 (Figure 1b)
also showed a similar fragmentation pattern. On the basis of the
loss of 84/29 and 98/43/29, respectively, a cyclic azo species
from a 1,2-alkyl migration/ring expansion pathway was
proposed. Preliminary free energy profiling revealed that such
a process is highly exergonic (−44.4 kcal/mol).
entry
solvent
MeOH
oxidant
CuCl2
additive
yield (%)
1
2
3
4
5
6
7
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
trace
trace
trace
61
MeOH
CuO
MeOH
Cu(OTf)2
Cu(OAc) ·H O
MeOH
2
2
MeOH
Cu(OPiv)2
82
MeOH/tAmOH
MeOH/tAmOH
Cu(OAc) ·H O
91
2
2
Cu(OPiv)2
94
During the substrate scope survey, we noticed a minor side
product for the substrate bearing a p-Ac group. Isolation and
structure elucidation revealed that this was the indolo[2,1-
a]isoquinoline cascade product. We next surveyed various
reaction parameters for the direct synthesis of indolo[2,1-
a]isoquinolines (Table 3). It was found that combining the
indole synthesis and the second N−H/C−H annulation was
not trivial. Most of the conditions examined favored either the
indole synthesis or the indole−aryl annulation but not both,
and often, a large amount of indole or the triazene substrate
remained at the end of the cascade. Both steps appeared to be
most affected by the solvent. For 3-Ac-substituted triazenyl-
benzene 1q, low yields were observed in most solvents.
Surprisingly, mixing MeOH and tAmOH in a 1:1 ratio led to a
very strong synergistic effect. The cascade reaction in either
alcohol alone gave a yield of ≤10% (Table 3, entries 4 and 5),
while a 65% yield was obtained using the solvent mixture
(Table 3, entry 6). This unexpected yield was attributed to the
difference in the rates of the two annulation steps in different
solvents. Separate experiments showed that the second N−H/
C−H annulation step was very slow in MeOH and quite facile
in tAmOH. In sharp contrast, the first NH indole formation
step was fast in MeOH and very slow in tAmOH. Therefore, a
1:1 MeOH/tAmOH mixture was required for the overall
a
Reactions were carried out on a 0.2 mmol scale at 90 °C for 24 h.
than those using the previous Cu(OAc) ·H O/MeOH
2
2
conditions. The nonsubstituted phenyltriazene resulted in a
6% yield, a more than 25% improvement. Substrates having
strong electron-withdrawing substituents (CO Me, Ac, NO )
7
2
2
were smoothly converted to the corresponding free NH indoles
in moderate to high yields. Electron-donating groups were also
tolerated. The reaction was slower when the other ortho
position of the substrate was substituted. For alkyl,aryl-
substituted asymmetric internal alkynes, excellent regioselectiv-
ity was observed.
The in situ cleavage of the N−N bond of triazene was
intriguing. To obtain insights into this puzzle, mass
spectrometry studies aimed at capturing the leaving fragment
were performed. Since a Ag salt was used to abstract chloride
from the catalyst precursor and a Cu salt acted as an oxidant,
stoichiometric RhCp*(OAc) was used for the mass spectrom-
2
etry experiments. This rhodium “catalyst” gave the desired
indole product in 47% yield under otherwise identical
conditions. When the diluted reaction mixture (see the
Supporting Information for details) was introduced to a high-
B
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a
Table 2. Extended Substrate Scope beyond That of the Previous Triazene-Directed NH Indole Synthesis
a
Reactions were carried out on a 0.3 mmol scale at 90 °C for 24 h; numbers in parentheses represent yields using the Cu(OAc) ·H O/MeOH
2
2
conditions.
Figure 1. CID-HRMS evidence for the 1,2-alkyl migration/ring expansion mechanism of the NN bond cleavage: (a) CID spectrum of the ion at
m/z = 321.1 at E = 15 eV; (b) CID spectrum of the ion at m/z = 335.1 at E = 15 eV; (c) CID spectrum of the ion at m/z = 297.0 at E = 10 eV.
lab
lab
lab
All of the CID experiments were performed with Ar as the collision gas.
cascade. Since the solvent mixture did not seem to slow down
either step, it is likely that both solvents participated in both
C−H activation processes. By contrast, when the non-
substituted triazenylbenzene was examined, the MeOH/
C
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Table 3. Investigation of Conditions for the Direct Synthesis
of Indolo[2,1-a]isoquinolines
indolo[2,1-a]isoquinoline product 5a obtained from dipheny-
lacetylene and 1,2-bis(4-bromophenyl)ethyne was isolated in
a
2
8% yield in the one-pot protocol. The efficiency of the
synthesis of hybrid products was significantly improved by
using a two-step sequence in which the free NH indole from
one alkyne was isolated and treated with another alkyne under
the cascade conditions (Scheme 2). Diphenylacetylenes bearing
various substituents were well-tolerated.
The reaction of the free NH indole and an alkyne under
either conditions A or B gave the desired indolo[2,1-
a]isoquinoline in good yield, indicating that indole is an
intermediate for this cascade reaction. The second catalytic
cycle leading to the polyaromatic indole scaffold was
investigated by density functional theory (DFT) calculations
yield
b
entry substrate
solvent
DCE
oxidant
additive
(%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1q
1q
1q
1q
1q
1q
1q
1a
1a
1a
1a
1a
1a
1a
Cu(OAc)2
Cu(OAc)2
AgSbF6
AgSbF6
8
22
7
CH CN
3
o-xylene
Cu(OAc)2
AgSbF6
tAmOH
Cu(OAc)2
AgSbF6
<5
10
65
79
15
25
49
20
46
<5
53
MeOH
Cu(OAc)2
Cu(OAc)2
Cu(OPiv)2
Cu(OAc)2
Cu(OPiv)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
(
see the Supporting Information for computational details). A
catalytic cycle with its free energy profile is depicted in Scheme
. The reaction is initiated by coordination of the indole to
MeOH/tAmOH
MeOH/tAmOH
MeOH
3
14
Cp*Rh(OAc)2. Deprotonation of N−H via a low-barrier
transition state (11.1 kcal/mol) gives INT2. Hence, N−Rh
moiety serves as a directing group for the following C−H bond
activation. A concerted metalation−deprotonation (CMD)
MeOH/tAmOH
tBuOH
1
1
1
1
1
iPrOH
DCE/tAmOH
MeOH/DCE
DCE
15
process then takes place with an activation free energy of
1
9.9 kcal/mol to afford intermediate INT3. It should be noted
that the N−Rh moiety may also direct the Rh center to another
adjacent C−H bond at the indole C7. However, the calculated
high barrier (35.9 kcal/mol) strongly discourages this
possibility. Through a dissociative ligand exchange step,
AcOH is replaced by an alkyne to form intermediate INT4.
Insertion of the alkyne into the Rh−C bond yields intermediate
INT5. The congested environment in TS3 causes repulsive
interactions and consequently results in a high barrier for the
insertion. The relative free energy of TS3 was calculated to be
24.2 kcal/mol, which is still accessible under the current
reaction conditions. Subsequently, INT5 undergoes reductive
elimination to release the product. Finally, Rh(I) in INT6 is
a
Reactions were carried out on a 0.2 mmol scale for 48 h using 3.5
b
1
equiv of alkyne. Conversion was calculated by H NMR analysis
using 1,3,5-trimethoxybenzene as the external standard.
tAmOH conditions resulted in a yield of only 25% (Table 3,
entry 9). For this substrate, the second step seemed to be
problematic, and after an extensive search, DCE was found to
be the best solvent (Table 3, entry 14). Eventually, we were
able to identify two sets of conditions for the direct synthesis of
indolo[2,1-a]isoquinolines. For triazenylbenzenes having an
strong electron-withdrawing substituent, Cu(OPiv) was used
2
as the oxidant and a 1:1 mixture of MeOH and tAmOH was
used as the solvent. For electron-neutral and -rich substrates,
Cu(OAc) ·H O and DCE were employed.
oxidized by Cu(OAc) to regenerate the active Rh(III) species.
2
Overall, the alkyne insertion is the rate-limiting step for this
catalytic cycle. The potential energy surface shows that the C−
H activation step is reversible, implying that the C−H
activation should not exhibit a kinetic isotope effect. The
small KIE of 1.1 measured experimentally (see the Supporting
Information for details) verified our theoretical prediction and
supported the proposed mechanism.
2
2
With the sets of optimized conditions in hand, we next
examined the scope and functional group tolerance for both
arenes and alkynes. As shown in Table 4, a number of triazenes
and alkynes were smoothly converted to the desired indolo[2,1-
a]isoquinolines. Triazenylbenzenes bearing electron-deficient
substituents reacted in moderate to good yields under
conditions A, while substrates having halogens, alkyls, and
other electron-donating groups yielded only trace amounts of
the desired polyaromatic products under the same conditions.
The reactions of these substrates proceeded well under
conditions B. Para, meta, or disubstituted triazenes were well-
tolerated. Substrates having one ortho position substituted
afforded low yields because of the unproductive indole
synthesis step. Diarylacetylenes tolerated various substituents.
Unfortunately, asymmetrically disubstituted acetylenes gave low
yields and mixtures of regioisomers. Alkynes bearing an
electron-withdrawing group such as ester, nitrile, etc. were
not tolerated for this reaction. Rigorous efforts to address the
selectivity issue of these substrates are currently ongoing.
A major limitation of the cascades described in Table 4 was
the necessity to use the same alkyne twice. When two different
alkynes were subjected to the conditions in Table 4, only the
product from the more reactive alkyne was observed. Next, we
tried sequential addition, where the second alkyne was
introduced after the first alkyne was consumed. The “hybrid”
The isolated products displayed strong fluorescent color in
both the solid and solution states. Variation of the substituents
influences the energy levels and/or dipole moments in the
ground and excited states of the core fluorophores, giving rise
to different optical and photochemical properties of the
16
fluorescent materials. As expected, electron-donating groups
blue-shifted the emission peaks by increasing the energy gap
between the HOMO and LUMO (3.75 eV for compound 4f;
Scheme 4), while electron-withdrawing substituents red-shifted
the emission peaks (3.29 eV for compound 4j; Scheme 4). The
fluorescence difference was more significant under UV light.
In summary, we have developed the first direct synthesis of
indolo[2,1-a]isoquinolines using a Rh(III)-catalyzed triple C−
H/N−H/C−H activation−annulation cascade. This trans-
formation utilizes an internally cleavable triazene directing
group. Collision-induced dissociation HRMS and theoretical
calculations suggested that an unprecedented 1,2-alkyl migra-
tion/ring expansion mechanism is responsible for the in situ
N−N cleavage. Detailed DFT studies of the second cascade
step were carried out. The fluorescent properties of the
D
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a
Table 4. Substrate Scope for the Synthesis of Indolo[2,1-a]isoquinolines via Cascade C−H Annulation
a
Reactions were carried out on a 0.2 mmol scale using 3.5 equiv of alkyne.
products are strongly influenced by the electronic character-
and AgSbF (0.060 mmol, 21 mg, 0.2 equiv) were weighed into an
6
istics of their substituents.
oven-dried Schlenk tube. The reaction vessel was capped and vacuum-
flushed with argon three times. A solution of alkyne (0.33 mmol, 1.1
equiv) in 1:1 MeOH/tAmOH (3.0 mL) was added through the side
arm using a syringe. The reaction mixture was stirred under an argon
atmosphere at 90 °C for 24 h and then cooled to room temperature.
Volatile solvent and reagents were removed by rotary evaporation, and
the residue was purified by silica gel flash chromatography using ethyl
acetate/petroleum ether (1:100 to 1:20) to afford product 3.
EXPERIMENTAL SECTION
■
General Methods and Materials. All of the reactions were
performed under an argon atmosphere (balloon) with dry solvents
under anhydrous conditions. Unless otherwise specified, all of the
reagents and starting materials were purchased from commercial
sources and used as received. The chromatography solvents were
technical grade and distilled prior to use. Flash chromatography was
performed using 200−300 mesh silica gel with the indicated solvent
system according to standard techniques. Analytical thin-layer
chromatography (TLC) was performed on precoated, glass-backed
silica gel plates. The developed chromatograms were visualized by UV
7
-Methoxy-5-nitro-2,3-diphenyl-1H-indole (3aa). Ethyl acetate/
petroleum ether = 1:9, 94% yield (97.0 mg), yellow solid, mp 170−
1
172 °C. H NMR (CDCl , 400 MHz): δ 8.82 (s, 1H), 8.29 (s, 1H),
3
1
3
7.58 (d, J = 1.2 Hz, 1H), 7.43−7.34 (m, 10H), 4.06 (s, 3H). C NMR
(CDCl , 100 MHz): δ 145.4, 143.1, 136.3, 133.6, 131.6, 130.1, 129.7,
3
1
13
absorbance (254 nm). The H and C NMR data were recorded on
00 MHz NMR spectrometers, unless otherwise specified. Chemical
shifts (δ) in parts per million are reported relative to the residual
1
29.0, 128.6, 128.4, 128.2, 127.2, 117.6, 110.9, 104.3, 98.1, 56.1.
4
+
HRMS (ESI): found 345.1231, calcd for C H N O ([M + H] )
21
17
2
3
−1
3
45.1239. IR (KBr) cm : 3345, 1526, 1476, 1337, 1130, 1072, 797,
1
13
signals of chloroform (7.26 ppm for H and 77.16 ppm for C).
Multiplicities are described as s (singlet), bs (broad singlet), d
7
66, 743, 702.
2
,3-Diphenyl-1H-indole (3a). Ethyl acetate/petroleum ether =
(
doublet), t (triplet), q (quartet), or m (multiplet), and coupling
1
1
(
7
:40, 76% yield (61.3 mg), yellow solid, mp 89−91 °C. H NMR
constants (J) are reported in hertz. HRMS (ESI) analysis with a
quadrupole time-of-flight mass spectrometer yielded ion mass/charge
CDCl , 400 MHz): δ 8.27 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50−
3
13
.27 (m, 12H), 7.18 (td, J = 8.0, 0.6 Hz, 1H). C NMR (CDCl , 100
3
(m/z) ratios in atomic mass units. IR spectra were measured as dry
−
1
MHz): δ 136.0, 135.2, 134.2, 132.8, 130.3, 128.9, 128.8, 128.7, 128.3,
films (KBr), and peaks are reported in terms of wavenumber (cm ).
1
27.8, 126.4, 122.8, 120.6, 119.8, 115.2, 111.0. HRMS (APCI): found
General Procedure for the Synthesis of Free NH Indoles.
+
−1
[
(
Cp*RhCl ] (0.0015 mmol, 9.3 mg, 5 mol %), triazene substrate 1
270.1278, calcd for C20H16N ([M + H] ) 270.1283. IR (KBr) cm :
2
2
0.3 mmol, 1.0 equiv), Cu(OPiv) (0.6 mmol, 159.5 mg, 2.0 equiv),
3410, 3057, 2926, 1506, 1456, 1423, 1250, 1070, 764, 698.
2
E
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Scheme 2. Synthesis of “Hybrid” Indolo[2,1-a]isoquinolines
Using Two Different Alkynes
Scheme 4. Fluorescent Colors of Indolo[2,1-a]isoquinolines
with Different Substituents: (top row) Under Natural Light;
(
bottom row) Under 254 nm UV Light
1
2
7
22 °C. H NMR (CDCl , 400 MHz): δ 8.56 (s, 1H), 8.42 (s, 1H),
3
1
3
.98 (dd, J = 1.4, 8.6 Hz, 1H), 7.46−7.31 (m, 11H), 3.92 (s, 3H).
NMR (CDCl , 100 MHz): δ 168.1, 138.5, 135.3, 134.3, 132.1, 130.2,
C
3
1
1
28.8, 128.7, 128.5, 128.1, 128.1, 126.7, 124.1, 122.7, 122.5, 116.2,
10.6, 51.9. HRMS (APCI): found 328.1332, calcd for C H NO
2
2
2
18
+
−1
(
[M + H] ) 328.1338. IR (KBr) cm : 3339, 1690, 1439, 1321, 1277,
261, 1109, 758, 694.
-(2,3-Diphenyl-1H-indol-5-yl)ethanone (3d). Ethyl acetate/petro-
1
1
leum ether = 1:9, 48% yield (44.8 mg), yellow solid, mp 233−235 °C.
1
2
,3-Diphenyl-1H-indole-5-carbonitrile (3b). Ethyl acetate/petro-
H NMR (CDCl , 400 MHz): δ 8.55 (s, 1H), 8.31 (s, 1H), 7.95 (dd, J
3
leum ether = 1:9, 51% yield (45.0 mg), yellow solid, mp 129−131 °C.
= 1.5, 8.6 Hz, 1H), 7.48−7.41 (m, 7H), 7.37−7.32 (m, 4H), 2.65 (s,
1
13
H NMR (CDCl , 400 MHz): δ 8.77 (s, 1H), 8.01 (s, 1H), 7.51−7.32
3H). C NMR (CDCl , 100 MHz): δ 198.3, 138.5, 135.5, 134.2,
3
3
(
1
m, 12H). 13C NMR (CDCl , 100 MHz): δ 137.5, 136.1, 133.6, 131.5,
30.0, 128.89, 128.86, 128.7, 128.5, 128.2, 127.0, 125.5, 125.4, 120.7,
132.0, 130.6, 130.1, 128.83, 128.80, 128.5, 128.15, 128.12, 126.8,
123.1, 121.9, 116.4, 110.8, 26.7. HRMS (APCI): found 312.1388, calcd
3
+
−1
1
15.5, 111.8, 103.4. HRMS (APCI): found 295.1227, calcd for
for C H NO ([M + H] ) 312.1388. IR (KBr) cm : 3331, 1661,
22
18
+
−1
C H N ([M + H] ) 295.1235. IR (KBr) cm : 3298, 2220, 1261,
1275, 1261, 766, 750, 698.
21
15
2
1
472, 762, 750, 700.
Methyl 2,3-Diphenyl-1H-indole-5-carboxylate (3c). Ethyl acetate/
5-Bromo-6-methyl-2,3-diphenyl-1H-indole (3e). Ethyl acetate/
petroleum ether = 1:40, 71% yield (76.9 mg), yellow semisolid. H
1
petroleum ether = 1:9, 91% yield (89.3 mg), yellow solid, mp 220−
NMR (CDCl , 400 MHz): δ 8.18 (s, 1H), 7.64 (s, 1H), 7.51 (s, 1H)
3
Scheme 3. M06-Computed Free Energy Profile for the Formation of Indolo[2,1-a]isoquinolines
F
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1
3
7
1
1
.41−7.30 (m, 10H), 2.48 (s, 3H). C NMR (CDCl , 100 MHz): δ
General Procedures for the Direct Synthesis of Indolo[2,1-
3
35.2, 134.7, 134.7, 132.4, 130.1, 129.3, 128.7, 128.6, 128.5, 128.1,
27.9, 120.6, 119.2, 114.6, 114.3, 23.2. HRMS (ESI): found 362.0540,
calcd for C H BrN ([M + H] ) 362.0544. IR (KBr) cm : 3059,
a]isoquinolines. Conditions A. [Cp*RhCl
2
]
2
(0.0010 mmol, 6.4 mg,
(0.4
(0.040 mmol, 13.8 mg, 0.2
6
5 mol %), triazene substrate 1 (0.2 mmol, 1.0 equiv), Cu(OPiv)
2
+
−1
mmol, 106.3 mg, 2.0 equiv), and AgSbF
21
17
2
972, 1601, 1481, 1030, 982, 764, 698.
-Fluoro-5-methoxy-2,3-diphenyl-1H-indole (3f). Ethyl acetate/
petroleum ether = 1:40, 50% yield (47.5 mg), white solid, mp 59−61
equiv) were weighed into an oven-dried Schlenk tube. The reaction
vessel was capped and vacuum-flushed with argon three times. A
solution of alkyne (0.7 mmol, 3.5 equiv) in 1:1 MeOH/tAmOH (2.0
mL) was added through the side arm using a syringe. The reaction
mixture was stirred under an argon atmosphere at 90 °C for 48 h and
then cooled to room temperature. Volatile solvent and reagents were
removed by rotary evaporation, and the residue was purified by silica
gel flash chromatography using ethyl acetate/petroleum ether (1:100
to 1:10) to afford product 4.
7
1
°
C. H NMR (CDCl , 400 MHz): δ 8.29 (s, 1H), 7.44−7.31 (m,
3
1
3
1
1
0H), 6.90 (d, J = 1.8 Hz, 1H), 6.71 (dd, J = 2.0, 12.1 Hz, 1H), 3.83 (s,
H). 13C NMR (CDCl , 100 MHz): δ 155.0, 154.9, 150.4, 148.0,
35.6, 134.8, 132.3, 131.8, 131.7, 130.1, 128.7, 128.7, 128.1, 128.0,
26.5, 119.5, 119.4, 115.59, 115.56, 98.9, 98.7, 96.94, 96.91, 56.2.
3
+
HRMS (APCI): found 318.1289, calcd for C H FNO ([M + H] )
21
17
−1
318.1294. IR (KBr) cm : 3418, 1495, 1337, 1302, 1260, 1146, 859,
Conditions B. [Cp*RhCl
2
]
2
(0.0010 mmol, 6.4 mg, 5 mol %),
827, 770, 698.
triazene substrate 1 (0.2 mmol, 1.0 equiv), Cu(OAc)
2
·H O (0.4 mmol,
2
5
-Bromo-2,3-bis(4-(methylthio)phenyl)-1H-indole (3g). Ethyl ac-
80 mg, 2.0 equiv), and AgOAc (0.080 mmol, 13.4 mg, 0.4 equiv) were
weighed into an oven-dried Schlenk tube. The reaction vessel was
capped and vacuum-flushed with argon three times. A solution of
alkyne (0.7 mmol, 3.5 equiv) in DCE (2.0 mL) was added through the
side arm using a syringe. The reaction mixture was stirred under an
argon atmosphere at 90 °C for 48 h and then cooled to room
temperature. Volatile solvent and reagents were removed by rotary
evaporation, and the residue was purified by silica gel flash
chromatography using ethyl acetate/petroleum ether (0:100 to 1:10)
to afford product 4.
etate/petroleum ether = 1:40, 61% yield (80.3 mg), yellow solid, mp
1
1
=
2
1
1
18−120 °C. H NMR (CDCl , 400 MHz): δ 8.24 (s, 1H), 7.75 (d, J
3
1.7 Hz, 1H), 7.33−7.28 (m, 8H), 7.20−7.18 (m, 2H), 2.54 (s, 3H),
.49 (s, 3H). 13C NMR (CDCl , 100 MHz): δ 138.9, 136.549, 134.8,
3
34.548, 131.1, 130.5, 130.4, 128.5, 128.4, 126.9, 126.4, 125.5, 122.0,
13.9, 113.7, 112.3, 15.8, 15.4. HRMS (APCI): found 440.0137, calcd
for C H BrNS ([M + H] ) 440.0142. IR (KBr) cm : 3273, 2920,
591, 1504, 1186, 1013, 824, 795.
5
+
−1
22
19
2
1
-Bromo-2,3-di-m-tolyl-1H-indole (3h). Ethyl acetate/petroleum
1
ether = 1:40, 91% yield (102.4 mg), white solid, mp 152−154 °C. H
1-(5,6,12-Triphenylindolo[2,1-a]isoquinolin-9-yl)ethanone (4a).
NMR (CDCl , 400 MHz): δ 8.36 (s, 1H), 7.79 (s, 1H), 7.32−7.14 (m,
Conditions A, ethyl acetate/petroleum ether = 1:9, 79% yield (76.9
3
13
1
1
1
1
2
0H), 2.39 (s, 3H), 2.34 (s, 3H). C NMR (CDCl , 100 MHz): δ
mg), yellow solid, mp 234−236 °C. H NMR (DMSO- d
6
, 400 MHz):
3
38.4, 138.2, 135.3, 134.4, 134.3, 132.1, 130.7, 130.6, 128.8, 128.6,
28.50, 128.46, 127.4, 127.2, 125.4, 125.3, 122.2, 114.7, 113.6, 112.3,
1.5, 21.5. HRMS (ESI): found 376.0696, calcd for C H BrN ([M +
δ 7.87 (d, J = 8.0 Hz, 1H), 7.72−7.21 (m, 19H), 7.04 (d, J = 8.0 Hz,
1H), 6.56 (s, 1H), 2.03 (s, 3H). 13C NMR (DMSO-d
, 100 MHz): δ
6
197.0, 136.4, 136.2, 135.4, 135.1, 133.8, 133.3, 131.9, 131.5, 131.12,
131.08, 130.5, 130.0, 129.9, 129.6, 128.9, 128.5, 128.4, 127.7, 127.4,
22
19
+
−1
H] ) 376.0701. IR (KBr) cm : 3420, 1506, 1456, 1314, 795, 764, 669.
-Bromo-3-butyl-2-phenyl-1H-indole (3i). Ethyl acetate/petrole-
5
126.4, 125.1, 124.5, 122.6, 121.4, 118.7, 117.2, 112.3, 26.5. HRMS
1
+
um ether = 1:40, 61% yield (59.8 mg), yellow semisolid. H NMR
(APCI): found 488.2009, calcd for C36
IR (KBr) cm : 2920, 1670, 1263, 764, 714, 700.
H
26NO ([M + H] ) 488.2014.
−1
(
(
2
CDCl , 400 MHz): δ 8.00 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.56−47
3
m, 4H), 7.42−7.38 (m, 1H), 7.30−7.22 (m, 2H), 2.84 (t, J = 7.9 Hz,
5,6,12-Triphenylindolo[2,1-a]isoquinoline (4b). Conditions B,
13
H), 1.71−1.66 (m, 2H), 1.45−1.36 (m, 2H), 0.97−0.92 (m, 3H).
C
ethyl acetate/petroleum ether = 1:100, 53% yield (47.2 mg), yellow
1
NMR (CDCl , 100 MHz): δ 135.5, 134.7, 133.1, 131.3, 129.1, 128.1,
solid, mp 186−188 °C. H NMR (CDCl
3
, 400 MHz): δ 7.99 (d, J =
3
1
(
28.0, 125.0, 122.0, 113.9, 112.8, 112.3, 33.3, 24.4, 23.1, 14.1. HRMS
APCI): found 328.0696, calcd for C H BrN ([M + H] ) 328.0701.
7.6 Hz, 1H), 7.69−7.63 (m, 4H), 7.61−7.52 (m, 2H), 7.41 (s, J = 9.5
+
Hz, 5H), 7.30−7.15 (m, 9H), 6.90−6.86 (m, 1H), 6.06 (d, J = 8.7 Hz,
18
19
−1
13
IR (KBr) cm : 3264, 2957, 1574, 1260, 1186, 974, 829, 704.
-Methoxy-2-(3-methoxyphenyl)-5-nitro-3-propyl-1H-indole (3j).
1H). C NMR (CDCl
3
, 100 MHz): δ 136.9, 136.5, 136.0, 135.6,
7
131.9, 131.6, 131.2, 131.1, 130.9, 130.7, 130.6, 129.1, 128.74, 128.69,
127.9, 127.3, 127.0, 126.8, 126.5, 126.1, 125.9, 124.5, 121.7, 121.6,
120.8, 119.0, 114.5, 112.1. HRMS (APCI): found 446.1901, calcd for
Ethyl acetate/petroleum ether = 1:9, 63% yield (64.3 mg), yellow
semisolid. H NMR (CDCl , 400 MHz): δ 8.57 (s, 1H), 8.29 (d, J =
.7 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.15 (d,
J = 7.7 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 6.98 (dd, J = 2.4, 8.2 Hz,
H), 4.04 (s, 3H), 3.88 (s, 3H), 2.87 (t, J = 7.9 Hz, 2H), 1.77−1.72
m, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl , 100 MHz): δ
60.1, 145.4, 142.3, 136.4, 133.6, 130.2, 129.7, 128.9, 120.5, 116.9,
13.9, 113.8, 110.7, 97.9, 56.1, 55.5, 26.8, 24.5, 14.5. HRMS (APCI):
found 341.1495, calcd for C H N O ([M + H] ) 341.1501. IR
1
3
+
−1
1
C H24N ([M + H] ) 446.1909. IR (KBr) cm : 2926, 1449, 1275,
34
1261, 750, 700.
1
(
1
1
10-Bromo-5,6,12-triphenylindolo[2,1-a]isoquinoline (4c). Condi-
tions B, ethyl acetate/petroleum ether = 1:100, 51% yield (53.3 mg),
3
1
yellow solid, mp 259−261 °C. H NMR (CDCl
, 400 MHz): δ 7.94
3
(d, J = 8.1 Hz, 1H), 7.63 (d, J = 4.4 Hz, 5H), 7.60−7.53 (m, 1H),
+
7.40−7.33 (m, 5H), 7.28−7.15 (m, 8H), 6.94−6.91 (dd, J = 1.9, 9.2
19
21
2
4
−1
13
(
KBr) cm : 3360, 2959, 1603, 1582, 1470, 1337, 1086, 872, 743.
-Bromo-3-cyclopropyl-2-phenyl-1H-indole (3k). Ethyl acetate/
Hz, 1H), 5.86 (d, J = 9.1 Hz, 1H). C NMR (CDCl , 100 MHz): δ
3
5
136.6, 135.7, 135.6, 135.2, 132.2, 131.8, 131.7, 131.13, 131.10, 130.8,
130.2, 129.3, 128.9, 128.8, 128.0, 127.6, 127.4, 126.9, 126.7, 126.3,
125.6, 124.7, 123.6, 122.2, 121.2, 115.9, 115.4, 111.4. HRMS (APCI):
1
petroleum ether = 1:40, 85% yield (79.3 mg), yellow oil. H NMR
(
7
1
CDCl , 400 MHz): δ 8.07 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.73−
3
+
.71 (m, 2H), 7.50−7.36 (m, 3H), 7.31−7.21 (m, 2H), 2.06−1.97 (m,
found 524.1015, calcd for C H BrN ([M + H] ) 524.1014. IR (KBr)
34
23
13
−1
H), 0.97−0.92 (m, 2H), 0.53−0.49 (m, 2H). C NMR (CDCl , 100
cm : 1591, 1443, 1373, 1339, 957, 866, 760, 704.
3
MHz): δ 137.0, 134.3, 132.5, 132.0, 131.9, 128.7, 128.0, 127.9, 125.1,
10-Chloro-5,6,12-triphenylindolo[2,1-a]isoquinoline (4d). Condi-
1
3
3
22.4, 122.1, 114.2, 113.0, 112.3, 6.9, 6.2. HRMS (APCI): found
tions B, ethyl acetate/petroleum ether = 1:100, 53% yield (50.8 mg),
+
−1
1
12.0382, calcd for C H BrN ([M + H] ) 312.0388. IR (KBr) cm :
yellow solid, mp 258−260 °C. H NMR (CDCl , 400 MHz): δ 7.96
17
15
3
285, 1574, 1514, 1493, 1379, 1184, 991, 829, 702.
2,3-Diphenyl-1H-indol-7-yl)methanol (3l). Ethyl acetate/petrole-
(dd, J = 0.5, 8.1 Hz, 1H), 7.62 (d, J = 4.3 Hz, 4H), 7.56−7.51 (m, 1H),
(
7.40 (d, J = 2.0 Hz, 1H), 7.41−7.34 (m, 5H), 7.31−7.15 (m, 8H), 6.81
1
13
um ether = 1:5, 47% yield (42.1 mg), white semisolid. H NMR
(dd, J = 2.2, 9.2 Hz, 1H), 5.92 (d, J = 9.2 Hz, 1H). C NMR (CDCl ,
3
(
CDCl , 400 MHz): δ 9.19 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.49−
100 MHz): δ 136.6, 135.8, 135.7, 135.2, 131.9, 131.8, 131.7, 131.1,
130.8, 129.9, 129.3, 128.9, 128.8, 128.0, 127.6, 127.4, 126.9, 126.7,
126.3, 125.6, 124.6, 122.2, 121.0, 118.0, 115.6, 111.5. HRMS (APCI):
3
13
7
1
1
.27 (m, 10H), 7.13−7.06 (m, 2H), 5.10 (s, 2H). C NMR (CDCl ,
3
00 MHz): δ 135.2, 134.7, 134.4, 132.7, 130.2, 129.3, 128.6, 128.5,
+
28.3, 127.7, 126.2, 123.1, 120.8, 120.1, 119.7, 115.0, 64.5. HRMS
found 480.1513, calcd for C H ClN ([M + H] ) 480.1519. IR (KBr)
3
4
23
+
−1
(
APCI): found 300.1391, calcd for C H NO ([M + H] ) 300.1388.
cm : 3065, 1595, 1443, 1072, 961, 872, 762, 704.
21
18
−1
IR (KBr) cm : 3441, 3354, 3057, 2926, 1614, 1267, 1026, 768, 745,
5,6,10,12-Tetraphenylindolo[2,1-a]isoquinoline (4e). Conditions
698.
B, ethyl acetate/petroleum ether = 1:50, 46% yield (47.9 mg), yellow
G
dx.doi.org/10.1021/jo500807d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
solid, mp 230−232 °C. H NMR (CDCl , 400 MHz): δ 7.97 (d, J =
135.82, 135.78, 135.51, 133.48, 133.22, 133.17, 131.6, 131.5, 131.2,
130.17, 130.15, 129.8, 128.0, 127.7, 127.6, 127.3, 127.1, 126.7, 126.6,
3
8
7
9
1
1
1
5
3
.2 Hz, 1H), 7.71−7.68 (m, 3H), 7.65−7.64 (t, J = 3.7 Hz, 2H), 7.62−
.53 (m, 3H), 7.41−7.36 (m, 7H), 7.30−7.13 (m, 10H), 6.09 (d, J =
125.9, 123.9, 122.0, 121.1, 120.0, 119.8, 119.6, 119.5. HRMS (APCI):
.0 Hz, 1H). 13C NMR (CDCl , 100 MHz): δ 141.9, 136.9, 136.3,
found 498.1420, calcd for C H ClFN ([M + H] ) 498.1425. IR
(KBr) cm : 3057, 2922, 1443, 1024, 758, 696.
+
3
34 22
−1
35.9, 135.5, 134.9, 131.9, 131.4, 131.3, 131.1, 131.02, 130.96, 129.2,
28.81, 128.75, 128.6, 127.9, 127.4, 127.1, 126.8, 126.6, 126.5, 126.2,
25.9, 124.6, 121.8, 120.5, 117.0, 114.7, 112.5. HRMS (APCI): found
22.2214, calcd for C H N ([M + H] ) 522.2222. IR (KBr) cm :
057, 1599, 1452, 1375, 1263, 1028, 878, 760, 700.
0-Methoxy-5,6,12-triphenylindolo[2,1-a]isoquinoline (4f). Con-
10-Bromo-9-methyl-5,6,12-triphenylindolo[2,1-a]isoquinoline
(4l). Conditions B, ethyl acetate/petroleum ether = 1:100, 46% yield
+
−1
1
(49.4 mg), yellow solid, mp >270 °C. H NMR (CDCl
, 400 MHz): δ
40
28
3
7.91 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 4.3 Hz, 4H), 7.54−7.52 (m, 1H),
1
7.45−7.40 (m, 3H), 7.36−7.13 (m, 11H), 6.07 (s, 1H), 2.39 (s, 3H).
13
ditions B, ethyl acetate/petroleum ether = 1:50, 35% yield (33.2 mg),
C NMR (CDCl , 100 MHz): δ 136.7, 136.0, 135.7, 135.1, 131.8,
3
1
yellow solid, mp 212−214 °C. H NMR (CDCl , 400 MHz): δ 7.92
131.2, 130.7, 130.5, 130.0, 129.0, 128.9, 127.9, 127.4, 127.2, 126.987,
126.6, 126.2, 125.7, 124.5, 121.6, 119.3, 118.1, 117.5, 111.4, 23.1.
3
(
7
d, J = 7.7 Hz, 1H), 7.67−7.60 (m, 4H), 7.55−7.53 (m, 1H), 7.39−
+
.35 (m, 5H), 7.28−7.14 (m, 8H), 6.89 (d, J = 2.5 Hz, 1H), 6.52−6.49
dd, J = 2.6, 9.4 Hz, 1H), 5.91 (d, J = 9.1 Hz, 1H), 3.75 (s, 3H). 13
NMR (CDCl , 100 MHz): δ 155.3, 137.0, 136.6, 135.8, 135.5, 131.9,
HRMS (APCI): found 538.1166, calcd for C H BrN ([M + H] )
538.1170. IR (KBr) cm : 2918, 1441, 764, 739, 721, 698.
35
25
−1
(
C
1-(3-Methyl-5,6,12-tri-p-tolylindolo[2,1-a]isoquinolin-9-yl)-
3
1
1
1
31.40, 131.38, 131.2, 131.0, 130.9, 129.2, 128.74, 128.71, 127.9,
27.3, 126.9, 126.8, 126.7, 126.3, 126.1, 125.6, 124.4, 121.2, 115.4,
11.7, 111.2, 99.5, 55.6. HRMS (APCI): found 476.2008, calcd for
C H NO ([M + H] ) 476.2014. IR (KBr) cm : 2920, 1611, 1441,
375, 1227, 1200, 1126, 1032, 764, 723, 700.
ethanone (4m). Conditions A, ethyl acetate/petroleum ether = 1:9,
1
60% yield (65.2 mg), orange solid, mp 207−209 °C. H NMR
(CDCl , 400 MHz): δ 7.91 (d, J = 8.3 Hz, 1H), 7.81−7.94 (d, J = 8.6
3
+
−1
Hz, 1H), 7.49−7.46 (m, 3H), 7.41−7.39 (d, J = 7.6 Hz, 2H), 7.30−
7.27 (m, 4H), 7.10−7.05 (m, 5H), 6.98 (s, 1H), 6.60 (s, 1H), 2.53 (s,
35
26
1
1
3
5
,6,12-Triphenylindolo[2,1-a]isoquinoline-9-carbonitrile (4g).
Conditions A, ethyl acetate/petroleum ether = 1:9, 58% yield (54.5
3H), 2.42 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H). C NMR
(CDCl , 100 MHz): δ 197.9, 139.0, 137.8, 137.1, 136.4, 136.0, 134.5,
3
1
mg), yellow solid, mp 234−236 °C. H NMR (CDCl , 400 MHz): δ
133.8, 133.5, 132.7, 132.6, 131.8, 131.5, 130.9, 130.7, 130.4, 129.9,
128.7, 128.1, 126.2, 124.9, 123.1, 122.4, 120.7, 118.4, 117.7, 111.7,
25.8, 21.7, 21.5, 21.4, 21.3. HRMS (APCI): found 544.2635, calcd for
3
13
7
.97 (d, J = 7.9 Hz, 1H), 7.61−7.20 (m, 20H), 6.23 (s, 1H). C NMR
(
CDCl , 100 MHz): δ 136.2, 135.6, 135.2, 134.6, 134.1, 133.0, 131.6,
3
+
−1
1
1
1
31.5, 131.0, 130.6, 130.2, 129.5, 129.4, 129.3, 128.2, 128.1, 127.9,
27.1, 127.0, 126.5, 125.2, 125.0, 124.1, 123.2, 120.7, 119.8, 119.6,
12.6, 102.6. HRMS (APCI): found 471.1855, calcd for C H N
2
[M + H] ) 471.1861. IR (KBr) cm : 2920, 1597, 1472, 1454, 1339,
22, 762, 700.
-Bromo-5,6,12-triphenylindolo[2,1-a]isoquinoline (4h). Condi-
C H34NO ([M + H] ) 544.2640. IR (KBr) cm : 2920, 1668, 1595,
40
1558, 1472, 1395, 951, 816, 739.
1-(3-(Methylthio)-5,6,12-tris(4-(methylthio)phenyl)indolo[2,1-a]-
isoquinolin-9-yl)ethanone (4n). Conditions A, ethyl acetate/petro-
35
23
+
−1
(
leum ether = 1:9, 72% yield (96.6 mg), yellow solid, mp 216−218 °C.
8
1
9
H NMR (CDCl , 400 MHz): δ 7.93 (d, J = 8.6 Hz, 1H), 7.84 (d, J =
3
tions B, ethyl acetate/petroleum ether = 1:100, 47% yield (49.2 mg),
8.4 Hz, 1H), 7.51−7.46 (m, 5H), 7.33−7.29 (m, 4H), 7.18−7.10 (m,
1
yellow solid, mp 257−259 °C. H NMR (CDCl , 400 MHz): δ 7.94
5H), 7.01 (s, 1H), 6.67 (s, 1H), 2.63 (s, 3H), 2.53 (s, 3H), 2.50 (s,
3
3H), 2.35 (s, 3H), 2.17 (s, 3H). 13C NMR (CDCl
, 100 MHz): δ
(
7
d, J = 7.8 Hz, 1H), 7.62−7.60 (m, 4H), 7.55−7.52 (m, 1H), 7.46−
3
13
.14 (m, 15H), 6.03 (d, J = 1.3 Hz, 1H). C NMR (CDCl , 100
197.7, 140.8, 139.1, 137.9, 137.5, 136.2, 134.1, 133.7, 132.5, 132.0,
131.94, 131.90, 131.4, 131.3, 131.0, 130.5, 129.8, 127.1, 126.4, 125.9,
125.2, 124.9, 122.9, 122.5, 121.7, 121.1, 118.4, 117.4, 111.4, 26.0, 15.7,
15.39, 15.37, 15.2. HRMS (APCI): found 672.1517, calcd for
3
MHz): δ 136.6, 135.8, 135.7, 135.0, 131.9, 131.8, 131.2, 131.1, 131.0,
30.8, 129.3, 129.2, 129.0, 128.9, 128.0, 127.5, 127.3, 126.9, 126.7,
26.3, 125.7, 124.8, 124.5, 122.1, 120.0, 117.6, 114.1, 112.0. HRMS
APCI): found 524.1007, calcd for C H BrN ([M + H] ) 524.1014.
IR (KBr) cm : 3057, 1458, 1369, 1335, 1277, 955, 764, 702.
-(5,6,12-Triphenylindolo[2,1-a]isoquinolin-10-yl)ethanone (4i).
Conditions A, ethyl acetate/petroleum ether = 1:9, 50% yield (48.7
1
1
(
+
+
−1
C H34NOS ([M + H] ) 672.1523. IR (KBr) cm : 1667, 1593,
34
23
40 4
−1
1470, 1435, 1265, 1098, 816, 768, 750.
1-(3-Methoxy-5,6,12-tris(4-methoxyphenyl)indolo[2,1-a]-
isoquinolin-9-yl)ethanone (4o). Conditions A, ethyl acetate/petro-
1
1
mg), yellow solid, mp 246−248 °C. H NMR (CDCl , 400 MHz): δ
leum ether = 1:9, 63% yield (76.5 mg), yellow solid, mp 227−229 °C.
3
1
8
7
7
.1 (s, 1H), 7.9 (d, J = 4.3 Hz, 1H), 7.65 (d, J = 4.4 Hz, 4H), 7.58−
H NMR (CDCl , 400 MHz): δ 7.94 (d, J = 9.0 Hz, 1H), 7.83 (dd, J =
3
.56 (m, 1H), 7.49−7.48 (d, J = 1.8 Hz, 1H), 7.47−7.35 (m, 5H),
1.2, 8.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 1H),
7.31 (d, J = 8.6 Hz, 2H), 7.13 (t, J = 8.2 Hz, 4H), 6.99 (d, J = 8.6 Hz,
2H), 6.86−6.82 (m, 3H), 6.68−6.66 (m, 2H), 3.96 (s, 3H), 3.86 (s,
13
.30−7.13 (m, 8H), 6.04 (d, J = 9.1 Hz, 1H), 2.56 (s, 3H). C NMR
(
CDCl , 100 MHz): δ 198.3, 136.5, 135.6, 135.5, 135.2, 133.7, 132.1,
3
3H), 3.81 (s, 3H), 3.69 (s, 3H), 2.17 (s, 3H). 13C NMR (CDCl
, 100
1
1
1
+
31.7, 131.1, 131.0, 130.9, 130.2, 129.3, 129.0, 128.8, 128.0, 127.7,
27.5, 127.0, 126.8, 126.4, 125.7, 124.7, 122.9, 120.7, 120.5, 114.4,
13.4, 26.7. HRMS (APCI): found 488.2007, calcd for C H NO ([M
H] ) 488.2014. IR (KBr) cm : 3057, 2924, 2853, 1676, 1437, 1256,
64, 700.
-Nitro-5,6,12-triphenylindolo[2,1-a]isoquinoline (4j). Conditions
3
MHz): δ 197.8, 160.0, 159.12, 159.05, 158.3, 136.5, 134.7, 133.8,
132.6, 132.2, 132.0, 130.4, 129.2, 128.7, 127.8, 126.5, 122.2, 120.8,
119.3, 118.2, 117.5, 114.7, 114.6, 114.5, 113.6, 110.5, 109.5, 55.4, 55.4,
55.2, 55.1, 26.0. HRMS (APCI): found 608.2432, calcd for
36
26
+
−1
7
+
−1
9
C H NO ([M + H] ) 608.2437. IR (KBr) cm : 2934, 1663,
40 34 5
A, ethyl acetate/petroleum ether = 1:4, 50% yield (49.0 mg), orange
1605, 1512, 1290, 1211, 1032, 831.
1-(3-(tert-Butyl)-5,6,12-tris(4-(tert-butyl)phenyl)indolo[2,1-a]-
isoquinolin-9-yl)ethanone (4p). Conditions A, ethyl acetate/petro-
1
solid, mp 222−224 °C. H NMR (CDCl , 400 MHz): δ 7.81 (d, J =
3
2
.0 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.64−7.50 (m, 9H), 7.49−7.46
13
1
(
m, 3H), 7.40−6.98 (m, 7H), 6.97 (s, 1H). C NMR (CDCl , 100
leum ether = 1:9, 56% yield (79.6 mg), yellow solid, mp >270 °C. H
3
MHz): δ 141.4, 136.0, 136.0, 135.8, 135.0, 134.3, 134.3, 131.7, 131.5,
NMR (CDCl , 400 MHz): δ 8.00 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.3
3
1
1
31.0, 130.4, 129.73, 129.68, 129.5, 129.4, 128.5, 128.1, 128.0, 127.2,
Hz, 1H), 7.62−7.50 (m, 5H), 7.41−7.22 (m, 8H), 7.09 (d, J = 7.6 Hz,
27.1, 126.6, 125.2, 125.1, 123.5, 118.4, 116.9, 112.7, 112.4. HRMS
2H), 6.97 (s, 1H), 2.06 (s, 3H), 1.49 (s, 9H), 1.31 (s, 9H), 1.28 (s,
+
13
(
APCI): found 491.1759, calcd for C H N O ([M + H] ) 491.1760.
9H), 1.21 (s, 9H). C NMR (CDCl
3
, 100 MHz): δ 197.8, 151.9,
34
23
2
2
−1
IR (KBr) cm : 3360, 2920, 2849, 1645, 1470, 1329, 706.
-Chloro-10-fluoro-5,6,12-triphenylindolo[2,1-a]isoquinoline
4k). Conditions B, ethyl acetate/petroleum ether = 1:100, 53% yield
150.8, 150.3, 149.5, 135.9, 134.4, 133.9, 133.3, 132.62, 132.59, 131.3,
130.7, 130.5, 130.4, 129.3, 126.0, 125.6, 124.6, 124.5, 124.4, 123.3,
123.2, 122.6, 120.5, 118.6, 117.8, 111.7, 34.9, 34.77, 34.75, 34.4, 31.6,
9
(
(
1
52.7 mg), yellow solid, mp 256−258 °C. H NMR (CDCl , 400
31.3, 31.1, 26.1. HRMS (APCI): found 712.4510, calcd for C H NO
3
52 58
+
−1
MHz): δ 7.93 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.32−7.27
(
5
1
([M + H] ): 712.4518. IR (KBr) cm : 2966, 2923, 1676, 1404, 1366,
m, 5H), 7.21−7.19 (m, 7H), 7.06 (t, J = 7.5 Hz, 1H), 6.93−6.84 (m,
1271, 1116, 1023, 823.
10-Bromo-12-phenyl-5,6-dipropylindolo[2,1-a]isoquinoline (5a).
Ethyl acetate/petroleum ether = 1:20, 84% yield (19.1 mg), yellow
H), 6.69 (d, J = 7.7 Hz, 1H). 13C NMR (CDCl , 100 MHz): δ 156.2,
3
53.6, 143.8, 139.7, 139.7, 139.32, 139.30, 138.8, 138.6, 138.5, 138.3,
H
dx.doi.org/10.1021/jo500807d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
solid, mp 183−185 °C. H NMR (CDCl , 400 MHz): δ 7.86 (t, J = 9.1
3
REFERENCES
■
Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.59−7.55
(
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(
3
1
m, 2H), 7.52−7.48 (m, 3H), 7.44−7.37 (m, 2H), 7.14−7.10 (m, 1H),
.38 (t, J = 8.2 Hz, 2H), 2.93 (t, J = 8.1 Hz, 2H), 1.99−1.93 (m, 2H),
.75−1.69 (m, 2H), 1.28 (t, J = 7.3 Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H).
(
1
3
C NMR (CDCl , 100 MHz): δ 136.3, 136.2, 132.6, 132.2, 131.2,
3
2
(
1
1
29.9, 129.6, 129.4, 127.63, 127.56, 125.8, 125.7, 125.4, 124.0, 123.4,
21.6, 117.3, 116.2, 115.2, 111.1, 31.7, 30.0, 23.7, 21.8, 14.7, 14.1.
+
HRMS (APCI): found 456.1322, calcd for C H BrN ([M + H] )
28
27
(
2
−
1
4
1
8
56.1327. IR (KBr) cm : 3671, 3057, 2953, 2877, 2315, 1947, 1886,
707, 1593, 1540, 1439, 1366, 1320, 1274, 1228, 1157, 1058, 945, 900,
67, 750, 699, 487.
(
2
́
as, J.-L. Adv. Mater.
4
,4′-(12-Phenylindolo[2,1-a]isoquinoline-5,6-diyl)dibenzonitrile
(
5b). Ethyl acetate/petroleum ether = 1:9, 40% yield (10.0 mg), yellow
1
2003, 5, 1131. (c) Marsden, J. A.; Miller, J. J.; Shirtcliff, L. D.; Haley,
M. M. J. Am. Chem. Soc. 2005, 127, 2464.
(6) (a) Reboredo, F. J.; Treus, M.; Estevez, J. C.; Castedo, L.;
Estevez, R. J. Synlett 2003, 1603. (b) Mamane, V.; Hannen, P.;
solid, mp >270 °C. H NMR (CDCl , 400 MHz): δ 7.94 (d, J = 7.8
3
Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.62−7.47 (m, 10H), 7.31−7.20
13
(
m, 5H), 6.98−6.91 (m, 2H), 5.99 (d, J = 8.7 Hz, 1H). C NMR
(
CDCl , 100 MHz): δ 141.7, 139.7, 135.8, 134.1, 132.9, 132.7, 132.2,
3
Fu
̈
rstner, A. Chem.Eur. J. 2004, 10, 4556. (c) Bressy, C.; Alberico,
1
1
1
31.8, 131.3, 131.1, 131.0, 130.5, 129.7, 129.4, 127.8, 127.7, 127.6,
26.3, 125.8, 124.9, 122.4, 121.7, 120.7, 119.7, 118.6, 118.2, 113.7,
13.5, 113.3, 111.7. HRMS (APCI): found 496.1810, calcd for
C H N ([M + H] ) 496.1814. IR (KBr) cm : 3657, 3060, 2982,
892, 2391, 2226, 1926, 1807, 1731, 1602, 1555, 1445, 1384, 1332,
246, 1149, 1105, 1024, 961, 842, 742, 673, 619, 554, 498, 436.
,6-Bis(4-(tert-butyl)phenyl)-12-phenylindolo[2,1-a]isoquinoline
5c). Ethyl acetate/petroleum ether = 1:20, 58% yield (16.2 mg),
D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (d) Loetter, A. N.
C.; Pathak, R.; Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de
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Lett. 2013, 54, 5597.
+
−1
36
22
3
2
1
5
(
1
yellow solid, mp >270 °C. H NMR (CDCl , 400 MHz): δ 7.96 (d, J =
3
8
(
.0 Hz, 1H), 7.67−7.59 (m, 4H), 7.53 (d, J = 7.8 Hz, 2H), 7.34−7.15
m, 10H), 7.08 (d, J = 7.8 Hz, 2H), 6.87 (t, J = 7.9 Hz, 1H), 6.20 (d, J
8.7 Hz, 1H), 1.33 (s, 9H), 1.28 (s, 9H). 13C NMR (CDCl , 100
MHz): δ 151.7, 149.4, 136.7, 136.4, 134.0, 132.8, 131.7, 131.6, 131.4,
30.9, 130.7, 130.6, 129.2, 127.3, 127.0, 126.3, 126.0, 125.3, 124.61,
=
3
(
1
7) (a) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3,
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1
1
24.57, 121.9, 121.7, 120.7, 118.9, 114.9, 112.0, 34.8, 34.5, 31.4.
+
HRMS (APCI): found 558.3157, calcd for C H N ([M + H] )
42
40
−
1
5
1
1
58.3161. IR (KBr) cm : 3060, 3033, 2960, 2903, 2869, 2313, 1911,
770, 1669, 1607, 1557, 1449, 1386, 1333, 1258, 1213, 1152, 1110,
022, 839, 747, 707, 622, 574, 433, 408.
7
1
(
487. (e) Zhu, C.; Wang, R.; Falck, J. R. Chem.Asian J. 2012, 7,
502.
8) For recent reviews of directed C−H annulation reaction with
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ASSOCIATED CONTENT
(
6
■
̈
*
S
Supporting Information
H and 13C NMR spectra of new compounds, CID-HRMS
data, and computational details. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
2
́
2
(
AUTHOR INFORMATION
■
9) For the synthesis of N-protected indoles using directed C−H
activation reactions, see: (a) Stuart, D. R.; Bertrand-Laperle, M.;
Corresponding Authors
*
*
*
E-mail: wuyd@pkusz.edu.cn.
E-mail: zhangxh@pkusz.edu.cn.
E-mail: huangyong@pkusz.edu.cn.
Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474.
(b) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc.
2
010, 132, 18326. (c) Huestis, M. P.; Chan, L. N.; Stuart, D. R.;
Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338. (d) Feng, Z.; Han,
X. L.; Lu, X. Y. Tetrahedron Lett. 2011, 52, 4681. (e) Ackermann, L.;
Lygin, A. V. Org. Lett. 2012, 14, 764. (f) Wang, C.; Huang, Y. Org. Lett.
Notes
The authors declare no competing financial interest.
2
013, 15, 5294. (g) Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am.
Chem. Soc. 2013, 135, 16625. (h) Cajaraville, A.; Lopez, S.; Varela, J.
A.; Saa, C. Org. Lett. 2013, 15, 4576. (i) Gong, T.-J.; Cheng, W.-M.;
́
ACKNOWLEDGMENTS
■
́
This work was financially supported by grants from the
National Natural Science Foundation of China (21372013), the
National Basic Research Program of China (2010CB833201,
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(
b) Wang, C.; Huang, Y. Synlett 2013, 24, 145.
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(
1
2
012CB722602), the Shenzhen Peacock Program
(
KQTD201103), and the Shenzhen Technology Innovation
Program (CXZZ20130517152257071). Y.H. thanks the MOE
for the Program for New Century Excellent Talents in
University. The Shenzhen Municipal Development and Reform
Commission is acknowledged for their public service platform
program.
(
+
(
̧
15, 345. (b) Gibson, J. K.; Haire, R. G. Organometallics 2005, 24, 119.
I
dx.doi.org/10.1021/jo500807d | J. Org. Chem. XXXX, XXX, XXX−XXX

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6
J
dx.doi.org/10.1021/jo500807d | J. Org. Chem. XXXX, XXX, XXX−XXX