Br?nsted Acid-Catalyzed Tandem Pinacol-Type Rearrangement for the Synthesis of α-(3-Indolyl) Ketones by Using α-Hydroxy Aldehydes

Article abstract of DOI:10.1021/acs.joc.9b02474

A Br?nsted acid-catalyzed pinacol-type rearrangement pathway is reported here to synthesize various substituted α-(3-indolyl) ketones by employing unprotected indoles and α-hydroxy aldehydes as coupling partners. Utilization of economic and readily available Br?nsted acid catalyst and use of simple starting precursors exemplify the economic viability of this method. Under this developed protocol, selective migration of aryl over alkyl or a second aryl group is observed depending upon the migratory aptitude of the substituents. Applicability of this method was further demonstrated by synthesizing highly substituted carbazoles through a simple extension of this method to one-pot cascade annulation strategy.

Full text of DOI:10.1021/acs.joc.9b02474

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Article
A Brønsted Acid Catalyzed Tandem Pinacol-Type Rearrangement for
the Synthesis of #-(3-Indolyl) Ketones by Using #-Hydroxy Aldehydes
SAMRAT KUNDU, Ankush Banerjee, and Modhu Sudan Maji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02474 • Publication Date (Web): 21 Nov 2019
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A Brønsted Acid Catalyzed Tandem Pinacol-Type Rearrangement for the Synthesis of α-
(3-Indolyl) Ketones by Using α-Hydroxy Aldehydes
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Samrat Kundu, Ankush Banerjee, and Modhu Sudan Maji*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, W.B.,
India.
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ABSTRACT
A Brønsted acid catalyzed Pinacol-type rearrangement pathway is reported here to synthesize
various substituted α-(3-indolyl) ketones by employing unprotected indoles and α-hydroxy
aldehydes as coupling partners. Utilization of economic and readily available Brønsted acid
catalyst and use of simple starting precursors exemplifies the economic viability of this method.
Under this developed protocol, selective migration of aryl over alkyl or a second aryl group is
observed depending upon the migratory aptitude of the substituents. Applicability of this method
was further demonstrated by synthesizing highly substituted carbazoles through a simple
extension of this method to one-pot cascade annulation strategy.
KEYWORDS: α-Indolyl Ketones, Pinacol-Type Rearrangement, Indole, Brønsted Acid,
Annulation
INTRODUCTION
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Over the past decades, pinacol and semipinacol rearrangements have emerged as powerful
synthetic tools owing to their immense applicability in several fascinating organic
transformations as well as capability to fine-tune the synthesis of several important complex
molecular architectures.1-2 Besides the advantages, the reported pinacol rearrangements have
several major limitations, such as, poor regio- and diastereoselectivities, unpredictable side
reactions, kinetic versus thermodynamic product formations, and mechanistically stepwise
versus concerted pathways.3 These drawbacks can be circumvented by designing reactions based
on generation of the more predictable carbocation, thereby mitigating the regioselectivity issue
and served as a profound route to several important classes of molecules.4
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The construction of several indole based skeletons, particularly substituted α-(3-indolyl)
ketones have acquired significant attention for the concise synthesis of several medicinally
important compounds and alkaloids.5 Most importantly, it is one of the key intermediates to
achieve several important heterocycles like carbazoles, β-carbolines, spiroindolenines, and also
tryptamine and tryptophols.6-7 Despite their widespread applications, synthesis of this important
scaffold is of considerable challenge as reported methods suffer from limitations such as low
regio-selectivity for unsymmetrical ketones, multi-step synthesis, low yields, harsh reaction
conditions, limited substrate scopes, utilization of expensive catalyst.8-9
Scheme 1. Previous Reports and This Strategy
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In 2010, Antilla et al. developed an asymmetric version of the pinacol rearrangement to
accomplish chiral N-protected α-(3-indolyl) ketones, starting from prefunctionalized indolyl diol
derivatives (Scheme 1a).9d However, besides its advantages, this method was applicable only for
identical migratory groups with limited substrate scope. Recently, Macmillan et al. documented
an elegant method to access α-(3-indolyl) ketone via the generation of oxo-allyl cation
intermediate, which is primarily applicable for the synthesis of symmetrical ketones (Scheme
1b).8e You et al. reported N-heterocyclic carbene catalyzed umpolung reaction between aryl-
sulfonyl indoles and aldehydes to deliver aryl-substituted α-(3-indolyl) ketones (Scheme 1c).9b
Very recently, we have developed a Brønsted acid catalyzed tandem reaction to achieve α-(3-
indolyl) ketones by utilizing 2-benzyloxy aldehydes via the in situ generation of enol-ether
intermediate (Scheme 1d).10g
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Scheme 2. Working Hypothesis
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In our continuous efforts, to use in situ generated indolyl cations for the synthesis of
functionalized indoles,10 we envisioned that Brønsted acid catalyzed Pinacol-type rearrangement
can also be achieved by employing unprotected indoles and α-hydroxy aldehydes11 as coupling
partners to accomplish diversely substituted α-(3-indolyl) ketones.12 According to our
hypothesis, in the presence of a Brønsted acid catalyst, first indole 1 would react with α-hydroxy
aldehyde 2 to generate indolyl diol intermediate A which presumably would undergo
dehydration to form the vinylogous iminium intermediate B. After that, migration of the alkyl or
aryl group having greater migratory aptitude (R1>R2) via [1,2]-shift, would furnish the desired
product 3 (Scheme 2a). It should be mentioned here that the vinylogous intermediate B will be in
equilibrium with the bisindolylmethane C,13 and the formation of desired product 3 would
eventually shift the equilibrium towards B. So the generation of vinylogous intermediate B is the
driving force to facilitate the Pinacol-type pathway. The advantages of this protocol are; i) direct
use of unprotected indoles and easily available α-hydroxy aldehydes as coupling partners, ii) use
of cheap readily available Brønsted acid as catalyst, iii) this may open the route to the carbazoles
by one-pot cascade reactions, iv) easy to control the selective migration depending upon the
migratory aptitude.
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RESULTS AND DISCUSSION
Table 1: Optimization of Reaction Conditionsa
`
entry
1
cat. (mol %)
10
solvent
EtOAc
temp (oC)
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time (h)
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yield (%)b
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benzene
DCE
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ND
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toluene
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toluene
toluene
toluene
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rt
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aReaction Conditions: 1a (0.2 mmol), 2a (0.22 mmol). Isolated yield. 0.30 mmol 2a was
b
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used. dDiphenyl phosphate catalyst was used.
Keeping this synthetic strategy in mind, we focused on optimizing the reaction conditions by
choosing commercially available indole 1a (1.0 equiv) and α-hydroxy aldehyde 2a (1.1 equiv) as
model substrates. To our delight, commercially available and inexpensive PTSA·H2O (0.1 euuiv)
was an effective catalyst for this protocol. A brief optimization study revealed that toluene was
the ideal solvent (Table 1, entries 1-4) for this reaction. During the course of this study, it has
been observed that temperature plays a crucial role in this reaction as on increasing the
temperature, yields improve remarkably along with enhanced reaction rate (entries 5-7). Yields
of the reactions diminished drastically on either increasing or decreasing the catalyst loading
(entries 8-9). Increasing the amount of 2a did not provide a better result (entry 10). The reaction
did not show any incremental effect on changing the catalyst from PTSA·H2O to less acidic
diphenyl phosphate (entry 11). Hence the conditions reported under entry 7 is the optimal
reaction conditions (74%). It should be mentioned here that, in all the cases, reactions underwent
through the partial formation of bis-indolylmethane intermediate as depicted in our working
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hypothesis (Scheme 2a). To show the involvement of bisindolylmethane C (Scheme 2a) as one
of the intermediate, first, the bisindolylmethane C1 was isolated in 82% yield by conducting the
reaction at room temperature using indole 1b and aldehyde 2l (Scheme 2b). Then upon treatment
of the bisindolylmethane C1 under the standard reaction conditions, the desired product 3bl was
isolated in 90% yield and the 2-methylindole 1b was recovered in 84% yield.
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Scheme 3. Scope of Indoles for Pinacol-type Rearrangementa
aReaction Conditions: 1a-1o (0.2 mmol), 2a (0.22 mmol), PTSA·H2O (10 mol %), toluene, 120
oC; isolated yield.
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With the optimized conditions in hand, the generality of this strategy was first investigated by
treating various functionalized indoles with α-hydroxy aldehyde 2a as a coupling partner. 2-
Methyl and 2-cyclopropyl indoles reacted efficiently to generate the desired α-(3-indolyl)
ketones in moderate to excellent yields (Scheme 3, 3ba-3ca, 69-95%). Even bulky tert-butyl as
well as adamantyl groups substituted indole did not hamper the reactivity and the corresponding
products 3da-3ea were isolated in 69-76% yields. Indoles bearing styryl-, phenyl-, thiophenyl-
groups at C2 position successfully took part in reaction to deliver 3fa-3ha in 29-84% yields.
Indoles, bearing electron-donating or withdrawing functional groups at the benzene ring
irrespective of their positions, underwent smooth conversion to provide the desired products in
moderate to good yields (3ia-3na, 32-70%). Although the primary goal of this protocol was to
employ NH free indoles, even the N-benzyl protected indole was also reactive enough to furnish
the product 3oa in 45% yield. Upon conducting the reaction on a gram scale, 0.92 g of the
product 3ba was isolated demonstrating the applicability of this method (95% yield). A sterically
hindered substitution at the C2-position retard the first nucleophilic attack leading to the
formation of products in low yields whereas in case of C2-unsubstituted one the formation of
bisindolyl methane C was one of the major intermediate at the beginning of the reaction also
leading to lower yield. In case of a sterically less demanding methyl substitution, an optimum
result was obtained at higher temperature probably due to the direct conversion to products 3ba
and 3bl through the intermediate B.
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Scheme 4. Scope of Aldehydes for Pinacol-type Rearrangementa
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aReaction Conditions: 1a-1b (0.2 mmol), 2b-2m (0.22 mmol), PTSA·H2O (10 mol %), toluene,
120 oC; isolated yield.
To further check the versatility of this method, the scope of electrophiles was next explored by
using indole (1a) or 2-methyl indole (1b) as model substrates. α-Hydroxy aldehydes bearing
identical aryl groups at the α-position were found to be elegant coupling partners and the
corresponding α-(3-indolyl) ketones were isolated in moderate to good yields (Scheme 4, 3ab-
3ae, 3bb, 3bd, 48-74%). Analogously, α-hydroxy aldehydes having similar alkyl substitutions at
the α-position were also well-tolerated to obtain the products 3af-3ag in 53-69% yields.
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Pleasingly, when aldehydes bearing two different functional groups at the α-centre, were
subjected to the optimized conditions, the group having greater migratory aptitude migrated
selectively to furnish the single regioisomer exclusively in moderate to good yields (3ah-3ak,
3bl, 45-96%). Analogously, preferential phenyl group migration over the allyl one, followed by
subsequent double bond migration delivered 3bm in 44% yield. Thus this present operationally
simple protocol provides an elegant route to several valuable building blocks α-(3-indolyl)
ketones in one step by employing simple precursors and catalyst.
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Scheme 5. Working Hypothesis for Cascade Annulation Strategy
After successfully accomplishing various structurally diverse α-(3-indolyl) ketones, next we
intended to explore the applicability of this newly developed protocol by exploiting the carbonyl
functionality in situ for the synthesis of highly substituted carbazoles through Brønsted acid
catalyzed cascade annulation pathway. It is noteworthy to mention that carbazole is a privileged
class of heterocycle present in various natural products and biologically active compounds.6a
Beside this, it exhibits ubiquitous applications in medicinal as well as material chemistry. In
order to execute our assumption, we planned to attach an alkene moiety at the C2 position of
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indole. Due to superior nucleophilic character of the indole nucleus, first nucleophilic addition
would occur via C3 position of indole generating α-(3-indolyl) ketone 3 through Pinacol-type
rearrangement pathway via the formation of indolyl diol intermediate A. After that, the second
nucleophilic addition would take place through the terminal C2ʹ position of alkene to generate
the desired functionalized carbazole 4 via intermediate B (Scheme 5).
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Scheme 6. Synthesis of Carbazole by Cascade Annulationa
o
aReaction Conditions: 1 (0.2 mmol), 2 (0.22 mmol), PTSA·H2O (20 mol %), toluene, 120 C;
isolated yield. bTo isolate pure carbazoles, N-methylation was carried out.
With this synthetic strategy in hand, the scope of carbazoles was next investigated by choosing
2-alkenyl indole 1p as a coupling partner with various aldehydes. Aldehyde bearing two benzyl
groups at the α-position was successfully participated in the reaction (4a, 69%, Scheme 6). To
our joy, aldehyde having two different substitutions at the α-centre also provided only one
isomer of carbazoles 4b-4c owing to the selective migration of the phenyl group over alkyl one.
However, due to the difficulties associated with the purification of carbazoles 4b-4c, probably
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due to the impurities generated via side reactions of aldehydes, N-methylation was performed
and pleasingly the carbazoles 5b-5c were isolated in pure form in 44-64% yields over two steps.
In a similar fashion, carbazoles 5d-5f were also isolated in 44-67% yields. It should be noted that
the presence of an aryl group at the C1ʹ position of alkene enhanced the nucleophilicity at the C2ʹ
position and also stabilized the Prins-type intermediate, thereby facilitated the formation of
carbazoles. Whereas, in case of 2-styryl indole 1f, the presence of sterically hindered phenyl ring
at the C2ʹ position prevents the intramolecular nucleophilic attack leading to the formation of
3fa.
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CONCLUSION
In conclusion, we have successfully developed a Brønsted acid catalyzed Pinacol-type
rearrangement for the synthesis of indoles to various functionally diverse α-(3-indolyl) ketones
by utilizing easily prepared α-hydroxy aldehydes and indoles as coupling partners. The method is
operationally simple and scalable. Common bottle reagent PTSA·H2O has been employed as
catalyst rendering this protocol economically viable. Various key functional groups such as
alkyl, aryl, alkenyl, thiophenyl, methoxy, nitro, and bromo are tolerated the reaction conditions
demonstrating the generality of this method. Selective migration of aryl groups for differently
substituted aldehydes eliminates the regioselectivity issue. The applicability of this strategy was
further demonstrated by synthesizing densely functionalized carbazoles by employing one-pot
cascade annulation strategy. The asymmetric version of this Pinacol-type rearrangement is
currently undergoing in our laboratory.
EXPERIMENTAL SECTION
General Remarks. All reactions involving air or moisture-sensitive reagents were carried out in
flame dried glassware under nitrogen/argon atmosphere. Ethylacetate was obtained from SRL
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India. All other solvents were acquired from Merck India and were dried according to the
standard literature procedure. Reactions were monitored by thin-layer chromatography (TLC)
using Merck silica gel 60 F254 pre-coated plates (0.25 mm), and visualized under UV light or by
dipping into KMnO4 or DNP solution. Silica gel (particle size 100-200 mesh) was purchased
from SRL India for performing column chromatography by using mixture of hexanes and
ethylacetate eluent. The 1H NMR spectroscopic data were recorded with a Bruker 400 or 500 or
600 MHz instruments. Proton decoupled 13C NMR spectra (13C{1H}) were similarly recorded at
101 or 126 or 151 MHz instruments by using a broadband decoupled mode. Proton and carbon
NMR chemical shifts (δ) are reported in parts per million (ppm) relative to residual proton or
carbon signals in CDCl3 (δ = 7.26, 77.16) or DMSO-d6 (d= 2.50, 39.52). Coupling constants (J)
are reported in Hertz (Hz) and refer to apparent multiplicities. The following abbreviations are
used for the multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet of doublets, dt:
doublet of triplet, m: multiplet, br: broad. Infrared (IR) spectra were recorded by Perkin Elmer
FTIR spectrometer, and reported in terms of wave number (cm-1). High resolution mass spectra
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(HRMS) were recorded in ESI (+ Ve) method using a time-of-flight (TOF) mass analyzer.
11c, 11d
Aldehydes11b,
methods.
and 2-alkenyl indoles10b were synthesized according to the reported
Synthesis of α-(3-Indolyl) Ketones by Pinacol-type Rearrangement (GP I):
The indole 1 (0.2 mmol, 1.0 equiv) and p-toluenesulfonic acid·monohydrate (PTSA·H2O, 0.02
mmol, 10 mol %) were charged into an oven dried culture tube containing a stirring bar. To this
aldehyde 2 (0.22 mmol, 1.1 equiv, dissolved in 1.5 mL of toluene) was added dropwise at the
room temperature while stirring. The resulting mixture was then heated at 120 oC in oil bath for
0.5 to 6.5 h. Upon completion of the reaction (as monitored by TLC), the reaction mixture was
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transferred into a 25 mL round bottom flask by dissolving in ethyl acetate solvent and evaporated
under vacuum. The crude residue was purified by silica gel column chromatography using ethyl
acetate/hexane as an eluent to afford the desired products 3.
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2-(1H-Indol-3-yl)-1,2-diphenylethan-1-one (3aa):9b The titled compound 3aa was synthesized
according to the GP I (reaction time: 2.5 h), the product 3aa was isolated after column
1
chromatography using 5% ethyl acetate/hexane as eluent (46 mg, 74% yield). H NMR (400
MHz, CDCl3) δ (ppm) 8.17 (br s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 7.3 Hz, 2H), 7.44 –
7.30 (m, 7H), 7.26 – 7.18 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.30 (s,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 198.6, 139.0, 137.0, 136.6, 133.1, 129.2, 129.0,
128.74, 128.67, 127.2, 126.7, 124.0, 122.5, 119.9, 118.9, 114.5, 111.5, 50.8.
2-(2-Methyl-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ba):9b The titled compound 3ba was
synthesized according to the GP I (reaction time: 30 min), the product 3ba was isolated after
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column chromatography using 5% ethyl acetate/hexane as eluent (0.92 g, 95% yield). H NMR
(400 MHz, CDCl3) δ (ppm) 8.07 (d, J = 8.4 Hz, 2H), 8.01 (br s, 1H), 7.59 (d, J = 7.8 Hz, 1H),
7.48 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.32 – 7.23 (m, 5H), 7.21 (d, J = 7.7 Hz, 1H),
7.15 – 7.08 (m, 2H), 6.25 (s, 1H), 2.27 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 199.1,
139.4, 137.2, 135.3, 132.9, 129.2, 128.62, 128.57, 128.4, 128.0, 126.8, 121.3, 119.8, 118.6,
110.5, 108.4, 50.9, 12.4.
2-(2-Cyclopropyl-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ca): The titled compound 3ca was
synthesized according to the GP I (reaction time: 2 h), the product 3ca was isolated after column
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chromatography using 3-5% ethyl acetate/hexane as eluent (48 mg, 69% yield). H NMR (400
MHz, CDCl3) δ (ppm) 8.07 (d, J = 8.4 Hz, 2H), 7.81 (br s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.46 (t,
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J = 7.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.30 – 7.21 (m, 6H), 7.10 (t, J = 7.5 Hz, 1H), 7.04 (t, J =
7.4 Hz, 1H), 6.38 (s, 1H), 2.07 – 2.00 (m, 1H), 1.03 – 0.89 (m, 2H), 0.77 – 0.71 (m, 1H), 0.67 –
0.61 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 199.1, 139.5, 137.4, 134.9, 132.8,
129.3, 128.7, 128.5, 128.34, 128.25, 126.8, 121.6, 120.1, 119.3, 110.6, 110.1, 51.0, 7.9, 6.9, 6.6.
FTIR: (neat)/ cm-1 = 3375, 2923, 2854, 1669, 1447. HRMS (ESI) m/z: [M + H]+ calcd for
C25H22NO, 352.1696; found 352.1687.
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2-(2-(tert-Butyl)-1H-indol-3-yl)-1,2-diphenylethan-1-one (3da): The titled compound 3da was
synthesized according to the GP I (reaction time: 5 h), the product 3da was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (56 mg, 76% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.09 (br s, 1H), 8.00 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.9, 6.9 Hz, 1H),
7.37 – 7.32 (m, 3H), 7.27 – 7.22 (m, 4H), 7.18 (d, J = 7.3 Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.91
(t, J = 7.5 Hz, 1H), 6.44 (s, 1H), 1.481–1.478 (m, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ
(ppm) 200.5, 142.4, 140.6, 138.3, 134.4, 132.6, 129.3, 129.2, 128.6, 128.5, 128.4, 126.7, 121.4,
120.9, 120.0, 110.4, 107.9, 52.7, 33.4, 30.9. FTIR: (neat)/ cm-1 = 3390, 3054, 2960, 1671, 1450,
1208. HRMS (ESI) m/z: [M + H]+ calcd for C26H26NO, 368.2009; found 368.2000.
2-(2-((1s,3s)-Adamantan-1-yl)-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ea): The titled
compound 3ea was synthesized according to the GP I (reaction time: 6 h), the product 3ea was
isolated after column chromatography using 5% ethyl acetate/hexane as eluent (61 mg, 69%
yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (br s, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.44 (t, J
= 7.4 Hz, 1H), 7.34 (t, J = 7.3 Hz, 3H), 7.25–7.17 (m, 6H), 7.04 (t, J = 7.4 Hz, 1H), 6.90 (t, J =
13
7.5 Hz, 1H), 6.53 (s, 1H), 2.14 (s, 6H), 2.07 (s, 3H), 1.81–1.73 (m, 6H). C{1H} NMR (151
MHz, CDCl3): δ (ppm) 200.6, 142.4, 140.7, 138.2, 134.3, 132.7, 129.20, 129.15, 128.7, 128.5,
128.3, 126.7, 121.3, 120.9, 119.8, 110.4, 107.9, 52.5, 42.1, 36.7, 35.8, 28.6. FTIR: (neat)/ cm-1 =
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3404, 2902, 2851, 1671, 1448, 1199, 1007. HRMS (ESI) m/z: [M + Na]+ calcd for
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C32H31NNaO, 468.2298; found 468.2273.
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(E)-1,2-Diphenyl-2-(2-styryl-1H-indol-3-yl)ethan-1-one (3fa): The titled compound 3fa was
synthesized according to the GP I (reaction time: 4 h), the product 3fa was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (34 mg, 41% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.30 (br s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.8 Hz, 1H), 7.43 (d,
J = 7.3 Hz, 3H), 7.39 – 7.27 (m, 10H), 7.24 – 7.13 (m, 3H), 7.07 (t, J = 7.0 Hz, 2H), 6.84 (d, J =
16.6 Hz, 1H), 6.38 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) 198.7, 139.3, 137.3,
136.9, 136.7, 133.8, 133.0, 129.4, 129.3, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2,
127.1, 126.6, 123.6, 120.6, 119.9, 117.1, 112.9, 110.8, 51.1. FTIR: (neat)/ cm-1 = 3365, 3058,
2924, 2854, 1673, 1447, 1260, 1017. HRMS (ESI) m/z: [M + H]+ calcd for C30H24NO,
414.1852; found 414.1847.
1,2-Diphenyl-2-(2-phenyl-1H-indol-3-yl)ethan-1-one (3ga):9b The titled compound 3ga was
synthesized according to the GP I (reaction time: 2 h), the product 3ga was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (65 mg, 84% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.35 (br s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (br
s, 5H), 7.37 – 7.29 (m, 7H), 7.20 – 7.15 (m, 3H), 7.06 (t, J = 7.5 Hz, 1H), 6.30 (s, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ (ppm) 198.4, 140.0, 136.9, 136.8, 136.3, 132.7, 132.5, 129.4, 129.2,
128.7, 128.6, 128.6, 128.5, 128.3, 128.1, 126.9, 122.5, 121.4, 120.5, 111.0, 109.1, 51.2.
1,2-Diphenyl-2-(2-(phenylthio)-1H-indol-3-yl)ethan-1-one (3ha): The titled compound 3ha was
synthesized according to the GP I (reaction time: 2.5 h), the product 3ha was isolated after
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column chromatography using 5% ethyl acetate/hexane as eluent (24 mg, 29% yield). H NMR
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(400 MHz, DMSO-d6): δ (ppm) 11.81 (br s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.48 – 7.45 (m, 2H),
7.33 – 7.25 (m, 4H), 7.23 – 7.11 (m, 9H), 7.00 (d, J = 7.3 Hz, 2H), 6.56 (s, 1H). 13C{1H} NMR
(126 MHz, DMSO-d6): δ (ppm) 198.2, 139.5, 137.4, 136.5, 135.8, 133.0, 130.0, 129.2, 129.1,
128.5, 128.3, 128.1, 127.0, 126.5, 126.2, 123.1, 122.9, 119.9, 119.7, 118.8, 111.7, 51.0. FTIR:
(neat)/ cm-1 = 3386, 2923, 1678, 1447, 666, 612. HRMS (ESI) m/z: [M + H]+ calcd for
C28H22NOS, 420.1417; found 420.1398.
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2-(5-Methoxy-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ia): The titled compound 3ia was
synthesized according to the GP I (reaction time: 6.5 h), the product 3ia was isolated after
column chromatography using 10% ethyl acetate/hexane as eluent (38 mg, 55% yield). 1H NMR
(400 MHz, CDCl3): δ (ppm) 8.05 (d, J = 7.3 Hz, 1H), 8.01 (br s, 1H), 7.51 (t, J = 7.4 Hz, 1H),
7.41 (t, J = 7.7 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 – 7.22 (m, 2H),
7.00 (d, J = 2.5 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 6.22 (s, 1H),
3.78 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) 198.5, 154.5, 139.1, 137.2, 133.1,
131.8, 129.2, 129.0, 128.8, 128.7, 127.2, 127.2, 124.7, 114.3, 112.5, 112.1, 101.2, 56.1, 50.9.
FTIR: (neat)/ cm-1 = 3357, 2923, 2854, 1675, 1580, 1448, 1266, 1209, 1102, 1020. HRMS (ESI)
m/z: [M + Na]+ calcd for C23H19NNaO2, 364.1308; found 364.1302.
2-(4,7-Dimethyl-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ja): The titled compound 3ja was
synthesized according to the GP I (reaction time: 2.5 h), the product 3ja was isolated after
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column chromatography using 5% ethyl acetate/hexane as eluent (47 mg, yield 70%). H NMR
(400 MHz, CDCl3): δ (ppm) 8.03 (d, J = 7.8 Hz, 3H), 7.50 (t, J = 7.3 Hz, 1H), 7.39 (t, J = 7.3 Hz,
2H), 7.33 – 7.22 (m, 5H), 6.90 – 6.88 (m, 2H), 6.76 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 2.56 (s,
3H), 2.42 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 198.8, 139.8, 137.0, 136.7, 132.9,
129.4, 129.2, 128.8, 128.7, 128.2, 127.1, 124.6, 124.3, 123.1, 121.8, 118.4, 115.0, 52.3, 20.4,
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16.4. FTIR: (neat)/ cm-1 = 3856, 3753, 3651, 3358, 2931, 1718, 1673, 1425, 1259. HRMS (ESI)
m/z: [M + H]+ calcd for C24H22NO, 340.1696; found 340.1685.
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2-(6,7-Dimethyl-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ka): The titled compound 3ka was
synthesized according to the GP I (reaction time: 5 h), the product 3ka was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (21 mg, 32% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.04 (d, J = 7.6 Hz, 2H), 7.94 (br s, 1H), 7.50 (t, J = 7.3 Hz, 1H), 7.41 –
7.34 (m, 4H), 7.30 (d, J = 7.1 Hz, 2H), 7.26 – 7.20 (m, 2H), 6.99 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H),
6.25 (s, 1H), 2.38 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) 198.5, 139.2,
137.29, 136.9, 133.0, 130.1, 129.2, 129.0, 128.7, 128.6, 127.1, 124.7, 123.2, 122.9, 118.4, 116.1,
115.0, 51.0, 19.3, 13.1. FTIR: (neat)/ cm-1 = 3374, 2916, 2849, 1674, 1447, 1250. HRMS (ESI)
m/z: [M + H]+ calcd for C24H22NO, 340.1696; found 340.1682.
2-(5-Nitro-1H-indol-3-yl)-1,2-diphenylethan-1-one (3la): The titled compound 3la was
synthesized according to the GP I (reaction time: 6 h), the product 3la was isolated after column
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chromatography using 20% ethyl acetate/hexane as eluent (40 mg, 56% yield). H NMR (500
MHz, DMSO-d6): δ (ppm) 11.77 (br s, 1H), 8.61 (s, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.98 (d, J =
8.9 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.44 (d, J
= 7.9 Hz, 2H), 7.42 (s, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 6.9 Hz, 1H), 6.75 (s, 1H).
13C{1H} NMR (101 MHz, DMSO-d6): δ (ppm) 197.9, 140.6, 139.4, 139.3, 136.2, 133.3, 128.9,
128.84, 128.77, 128.5, 128.2, 126.8, 125.7, 116.8, 116.2, 115.9, 112.1, 49.0. FTIR: (neat)/ cm-1
= 3294, 3062, 2923, 2853, 1674, 1469, 1277, 1198, 1093, 981. HRMS (ESI) m/z: [M + H]+
calcd for C22H17N2O3, 357.1234; found 357.1231.
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2-(5-Bromo-1H-indol-3-yl)-1,2-diphenylethan-1-one (3ma): The titled compound 3ma was
synthesized according to the GP I (reaction time: 3 h), the product 3ma was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (41 mg, 53% yield). H NMR (400
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MHz, CDCl3); δ (ppm) 8.24 (br s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.54 (t,
J = 8.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.36 – 7.29 (m, 4H), 7.27 – 7.23 (m, 2H), 7.19 (d, J =
13
8.6 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.21 (s, 1H). C{1H} NMR (101 MHz, CDCl3): δ (ppm)
198.3, 138.6, 136.8, 135.2, 133.3, 129.04, 129.03, 128.9, 128.8, 128.4, 127.4, 125.5, 125.2,
121.4, 114.3, 113.3, 113.0, 50.6. FTIR: (neat)/ cm-1 = 3347, 2920, 2851, 1673, 1447, 793.
HRMS (ESI) m/z: [M + H]+ calcd for C22H17BrNO, 390.0488; found 390.0477.
2-(4-Bromo-1H-indol-3-yl)-1,2-diphenylethan-1-one (3na): The titled compound 3na was
synthesized according to the GP I (reaction time: 3 h), the product 3na was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (40 mg, 52% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.46 (br s, 1H), 8.10 (d, J = 7.7 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.41 (t,
J = 7.5 Hz, 2H), 7.34 – 7.31 (m, 4H), 7.28 – 7.18 (m, 3H), 7.00 (s, 1H), 6.95 (t, J = 7.8 Hz, 1H),
6.64 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) 198.8, 139.1, 138.1, 137.0, 132.9,
129.5, 129.4, 129.3, 128.9, 128.8, 128.7, 128.7, 127.2, 126.6, 124.6, 124.4, 123.2, 115.5, 114.0,
111.1, 51.1. FTIR: νmax (neat)/ cm-1 = 3334, 2923, 2853, 1676, 1596, 1335, 1182, 991, 909, 815.
HRMS (ESI) m/z: [M + H]+ calcd for C22H17BrNO, 390.0488; found 390.0465.
2-(1-Benzyl-1H-indol-3-yl)-1,2-diphenylethan-1-one (3oa):9d The titled compound 3oa was
synthesized according to the GP I (reaction time: 2 h), the product 3oa was isolated after column
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chromatography using 2% ethyl acetate/hexane as eluent (36 mg, 45% yield). H NMR (500
MHz, CDCl3): δ (ppm) 8.08 (d, J = 7.3 Hz, 2H), 7.56 – 7.53 (m, 2H), 7.45 – 7.40 (m, 4H), 7.33
(t, J = 7.5 Hz, 2H), 7.28 – 7.25 (m, 5H), 7.19 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.05 –
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7.04 (m, 3H), 6.33 (s, 1H), 5.29 (d, J = 4.4 Hz, 2H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm)
198.5, 139.1, 137.6, 137.2, 137.0, 133.0, 129.2, 129.0, 128.9, 128.73, 128.67, 128.2, 127.7,
127.5, 127.2, 126.7, 122.3, 119.8, 119.2, 113.6, 110.1, 50.9, 50.3.
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2-(1H-Indol-3-yl)-1,2-bis(4-methoxyphenyl)ethan-1-one (3ab): The titled compound 3ab was
synthesized according to the GP I (reaction time: 6 h), the product 3ab was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (36 mg, 49% yield). H NMR (400
MHz, CDCl3): δ (ppm) 8.10 (s, 1H), 8.05 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.35 (d, J
= 8.1 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.99 (d,
J = 2.2 Hz, 1H), 6.88 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.18 (s, 1H), 3.83 (s, 3H),
3.76 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 197.3, 163.5, 158.7, 136.6, 131.4,
131.3, 130.2, 130.0, 126.8, 123.8, 122.5, 119.9, 119.0, 115.3, 114.1, 113.9, 111.4, 55.6, 55.4,
49.6. FTIR: νmax (neat)/ cm-1 = 3348, 2925, 1668, 1597, 1509, 1457, 1269, 1027, 804. HRMS
(ESI) m/z: [M + H]+ calcd for C24H22NO3, 372.1594; found 372.1595.
1,2-bis(4-Methoxyphenyl)-2-(2-methyl-1H-indol-3-yl)ethan-1-one (3bb): The titled compound
3bb was synthesized according to the GP I (reaction time: 4 h), the product 3bb was isolated
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after column chromatography using 10% ethyl acetate/hexane as eluent (56 mg, 73% yield). H
NMR (600 MHz, CDCl3): δ (ppm) 7.97 (d, J = 9.0 Hz, 2H), 7.87 (br s, 1H), 7.51 (d, J = 7.9 Hz,
1H), 7.25 (d, J = 7.5 Hz, 1H)., 7.14 (d, J = 8.6 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.04 (t, J = 7.5
Hz, 1H), 6.82–6.80 (m, 4H), 6.08 (s, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 2.32 (s, 1H). 13C{1H} NMR
(151 MHz, CDCl3): δ (ppm) 197.7, 163.3, 158.4, 135.3, 132.5, 131.8, 131.0, 130.22, 130.19,
128.2, 121.4, 119.9, 118.8, 113.8, 113.7, 110.4, 109.6, 55.5, 55.4, 49.8, 12.7. FTIR: νmax (neat)/
cm-1 = 3310, 3057, 2932, 2838, 1661, 1597, 1509, 1460, 1214. HRMS (ESI) m/z: [M + H]+ calcd
for C25H24NO3, 386.1751; found 386.1752.
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2-(1H-Indol-3-yl)-2-(3-methoxyphenyl)-1-(4-methoxyphenyl)ethan-1-one (3ac): The titled
compound 3ac was synthesized according to the GP I (reaction time: 6 h), the product 3ac was
isolated after column chromatography using 5% ethyl acetate/hexane as eluent (48 mg, 64%
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yield). H NMR (600 MHz, CDCl3): δ (ppm) 8.15 (br s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.61 (s,
1H), 7.53 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.25 (t, J = 8 Hz,
1H), 7.21 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.09–7.07 (m, 1H), 7.04 (d, J = 2.2 Hz,
1H), 6.99 (d, J = 7.5 Hz, 1H), 6.95 (t, J = 1.8 Hz, 1H), 6.80 (dd, J = 8.3, 2.4 Hz, 1H), 6.25 (s,
1H), 3.81 (s, 3H), 3.76 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 198.2, 159.91,
159.88, 140.6, 138.4, 136.5, 129.7, 129.6, 126.7, 123.9, 122.6, 121.6, 120.0, 119.7, 118.9, 115.1,
114.5, 113.3, 112.5, 111.4, 55.5, 55.3, 50.9. FTIR: νmax (neat)/ cm-1 = 3354, 2925, 1675, 1597,
1456, 1335, 1246 1057, 850. HRMS (ESI) m/z: [M + H]+ calcd for C24H22NO3, 372.1594; found
372.1591.
1,2-bis(4-(tert-Butyl)phenyl)-2-(1H-indol-3-yl)ethan-1-one (3ad): The titled compound 3ad was
synthesized according to the GP I (reaction time: 5 h), the product 3ad was isolated after column
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chromatography using 2% ethyl acetate/hexane as eluent (36 mg, 48% yield). H NMR (500
MHz, CDCl3): δ (ppm) 8.10 (br s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.41
(d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.31 – 7.28 (m, 4H), 7.18 (t, J = 7.5 Hz, 1H), 7.08
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(t, J = 7.5 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.25 (s, 1H), 1.30 (s, 9H), 1.27 (s, 9H). C{1H}
NMR (126 MHz, CDCl3): δ (ppm) 198.3, 156.7, 149.8, 136.6, 136.1, 134.6, 129.0, 128.8, 126.8,
125.7, 125.6, 123.9, 122.5, 119.9, 119.0, 115.0, 111.4, 50.1, 35.2, 34.6, 31.5, 31.2. FTIR: νmax
(neat)/ cm-1 = 3357, 2960, 1673, 1603, 1107, 997, 793. HRMS (ESI) m/z: [M + H]+ calcd for
C30H34NO, 424.2635; found 424.2641.
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1,2-bis(4-(tert-Butyl)phenyl)-2-(2-methyl-1H-indol-3-yl)ethan-1-one (3bd): The titled compound
3bd was synthesized according to the GP I (reaction time: 1.5 h), the product 3bd was isolated
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after column chromatography using 5% ethyl acetate/hexane as eluent (82 mg, 74% yield). H
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NMR (600 MHz, CDCl3): δ (ppm) 7.96 (d, J = 8.4 Hz, 2H), 7.91 (br s, 1H), 7.59 (d, J = 7.9 Hz,
1H), 7.37 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.3
Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.17 (s, 1H), 2.37 (s, 3H), 1.30 (s, 9H),
1.29 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 198.4, 156.3, 149.2, 136.4, 135.2,
134.6, 132.6, 128.7, 128.6, 128.2, 125.5, 125.2, 121.3, 119.8, 118.9, 110.2, 109.0, 50.1, 35.0,
34.4, 31.4, 31.1, 12.6. FTIR: νmax (neat)/ cm-1 = 3354, 2963, 1673, 1603, 1426, 1335, 1246,
1107. HRMS (ESI) m/z: [M + H]+ calcd for C31H36NO, 438.2791; found 438.2781.
2-(1H-Indol-3-yl)-1,2-di(naphthalen-1-yl)ethan-1-one (3ae): The titled compound 3ae was
synthesized according to the GP I (reaction time: 6 h), the product 3ae was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (52 mg, 64% yield). H NMR (500
MHz, CDCl3): δ (ppm) 8.61 - 8.59 (m, 1H), 8.18 (br s, 1H), 8.10 (d, J = 7.2 Hz, 1H), 8.04 (d, J =
8.5 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.87 – 7.85 (m, 1H), 7.79 (d, J =
8.0 Hz, 1H), 7.53 – 7.49 (m, 3H), 7.47 – 7.44 (m, 2H), 7.41 – 7.35 (m, 4H), 7.23 (t, J = 7.6 Hz,
1H), 7.08 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3): δ (ppm) 202.3, 136.8, 135.7, 135.5, 134.3, 133.1, 131.8, 130.9, 129.2, 128.6, 128.4,
128.3, 128.2, 128.1, 127.2, 126.9, 126.63, 126.60, 126.2, 125.8, 125.7, 124.9, 124.6, 123.4,
122.7, 120.1, 119.1, 114.4, 111.5, 50.5. FTIR: νmax (neat)/ cm-1 = 3375, 3054, 2923, 2853, 1674,
1506, 1457, 1228, 1093, 907. HRMS (ESI) m/z: [M + Na]+ calcd for C30H21NNaO, 434.1515;
found 434.1503.
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3-(1H-Indol-3-yl)-1,4-diphenylbutan-2-one (3af): The titled compound 3af was synthesized
according to the GP I (reaction time: 1.5 h), the product 3af was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (38 mg, 69% yield). H NMR (600
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MHz, CDCl3): δ (ppm) 8.21 (br s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.28
(d, J = 6.7 Hz, 1H), 7.29 – 7.19 (m, 8H), 7.09 (d, J = 7.2 Hz, 2H), 6.99 (s, 1H), 6.96 (d, J = 4.6
Hz, 2H), 4.37 (t, J = 7.3 Hz, 1H), 3.66 (dd, J = 36.6, 15.7 Hz, 2H), 3.51 (dd, J = 13.6, 8.2 Hz,
1H), 3.11 (dd, J = 13.7, 6.5 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 207.7, 140.2,
136.5, 134.3, 129.6, 129.1, 128.6, 128.3, 126.8, 126.5, 126.1, 123.1, 122.5, 120.0, 119.0, 113.0,
111.5, 51.0, 48.9, 38.1. FTIR: νmax (neat)/ cm-1 = 3369, 3029, 1704, 1454, 1321, 1095. HRMS
(ESI) m/z: [M + Na]+ calcd for C24H21NNaO, 362.1515; found 362.1512.
8-(1H-Indol-3-yl)tetradecan-7-one (3ag): The titled compound 3ag was synthesized according to
the GP I (reaction time: 1.5 h), the product 3ag was isolated after column chromatography using
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5% ethyl acetate/hexane as eluent (35 mg, 53% yield). H NMR (600 MHz, CDCl3): δ (ppm)
8.14 (br s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13
(t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 3.90 (t, J = 7.4 Hz, 1H), 2.44 – 2.34 (m, 2H), 2.12 – 2.06 (m,
1H), 1.84 – 1.78 (m, 1H), 1.51 – 1.42 (m, 2H), 1.30 – 1.17 (m, 13H), 0.85 (t, J = 7.0 Hz, 3H),
0.80 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 211.7, 136.3, 126.9, 122.3,
122.2, 119.7, 119.1, 114.3, 111.2, 50.0, 41.1, 31.7, 31.6, 31.5, 29.3, 28.76, 27.81, 23.9, 22.6,
22.4, 14.1, 14.0. FTIR: (neat)/ cm-1 = 3348, 2926, 2854, 1693, 1459, 1342, 1100, 1012. HRMS
(ESI) m/z: [M + Na]+ calcd for C22H33NNaO, 350.2454; found 350.2438.
2-(1H-Indol-3-yl)-2-(4-methoxyphenyl)-1-phenylethan-1-one (3ah):9b The titled compound 3ah
was synthesized according to the GP I (reaction time: 1.5 h), the product 3ah was isolated after
column chromatography using 10% ethyl acetate/hexane as eluent (47 mg, yield 69%). 1H NMR
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(400 MHz, CDCl3): δ (ppm) 8.10 (br s, 1H), 8.05 (d, J = 7.3 Hz, 2H), 7.53 – 7.48 (m, 2H), 7.41
(t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.29–7.25 m, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.09 (t, J
= 7.4 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.22 (s, 1H), 3.76 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 198.8, 158.8, 137.1, 136.6, 133.1, 131.1, 130.2,
129.0, 128.7, 126.7, 123.8, 122.6, 120.0, 119.0, 115.1, 114.2, 111.4, 55.4, 50.0. FTIR: (neat)/
cm-1 = 3485, 3055, 2926, 2852, 1686, 1511, 1265.
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2-(1H-Indol-3-yl)-2-(naphthalen-1-yl)-1-phenylethan-1-one (3ai): The titled compound 3ai was
synthesized according to the GP I (reaction time: 4.5 h), the product 3ai was isolated after
column chromatography using 10% ethyl acetate/hexane as eluent (51 mg, 71% yield). 1H NMR
(500 MHz, CDCl3): δ (ppm) 8.52 – 8.35 (m, 1H), 8.15 (br s, 1H), 7.97 (dd, J = 15.4, 7.7 Hz, 2H),
7.86– 7.84 (m, 1H), 7.53–7.48 (m, 3H), 7.45–7.42 (m, 3H), 7.38 (d, J = 8.2 Hz, 1H), 7.31 (t, J =
7.5 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.28 (s, 1H).
13C{1H} NMR (126 MHz, CDCl3): δ (ppm) 202.5, 139.1, 136.8, 136.5, 134.1, 132.6, 130.7,
129.2, 128.8, 128.5, 128.0, 127.7, 127.3, 126.9, 126.6, 126.0, 124.6, 123.9, 122.6, 120.0, 119.1,
114.8, 111.4, 54.4. FTIR: νmax (neat)/ cm-1 = 3410, 3058, 1678, 1508, 1457, 1230, 1093. HRMS
(ESI) m/z: [M + Na]+ calcd for C26H19NNaO, 384.1359; found 384.1360.
1-(1H-Indol-3-yl)-1-phenylhexan-2-one (3aj): The titled compound 3aj was synthesized
according to the GP I (reaction time: 30 min), the product 3aj was isolated after column
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chromatography using 2% ethyl acetate/hexane as eluent (26 mg, yield 45%). H NMR (400
MHz, CDCl3): δ (ppm) 8.17 (br s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.36–
7.35 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.15 (d, J =
2.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 5.38 (s, 1H), 2.64 (dt, J = 7.2, 3.1 Hz, 2H), 1.63 – 1.58 (m,
2H), 1.36 – 1.25 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ (ppm)
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209.0, 138.8, 136.4, 129.0, 128.7, 127.2, 127.0, 123.4, 122.5, 119.9, 119.0, 114.0, 111.4, 55.8,
42.3, 26.4, 22.4, 13.9. FTIR: (neat)/ cm-1 = 3408, 2957, 2871, 1708, 1457, 1339, 1098. HRMS
(ESI) m/z: [M + H]+ calcd for C20H22NO, 292.1696; found 292.1680.
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2-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (3ak): The titled compound 3ak was synthesized
according to the GP I (reaction time: 1.5 h), the product 3ak was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (42 mg, yield 65%). H NMR (400
MHz, CDCl3) δ (ppm) 8.10 (br s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.44 –
7.40 (m, 1H), 7.34 – 7.29 (m, 3H), 7.23 – 7.13 (m, 7H), 6.97 (d, J = 2.5 Hz, 1H), 5.15 (dd, J =
8.2, 6.0 Hz, 1H), 3.65 (dd, J = 13.7, 8.3 Hz, 1H), 3.23 (dd, J = 13.7, 6.0 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ (ppm) 199.8, 140.6, 137.0, 136.5, 132.8, 129.2, 128.6, 128.5, 128.4, 126.3,
126.2, 122.9, 122.4, 120.0, 118.9, 114.3, 111.5, 47.1, 39.3. FTIR: (neat)/ cm-1 =3372, 2928,
1667, 1446, 1341, 1266, 1181, 1103, 977, 931, 874. HRMS (ESI) m/z: [M + Na]+ calcd for
C23H19NNaO, 348.1359; found 348.1353.
1,1-bis(2-Methyl-1H-indol-3-yl)-2-phenylbutan-2-ol (C1): The 2-methylindole 1b (0.2 mmol, 1.0
equiv) and p-toluenesulfonic acid·monohydrate (PTSA·H2O, 0.02 mmol, 10 mol %) were
charged into an oven dried culture tube containing a stirring bar. To this aldehyde 2l (0.22 mmol,
1.1 equiv, dissolved in 1.5 mL of toluene) was added dropwise at the room temperature while
stirring. The resulting mixture was then stirred for 8 h at the room temperature. Upon completion
of the reaction (as monitored by TLC), the reaction mixture was transferred into a 25 mL round
bottom flask by dissolving in ethyl acetate and evaporated under vacuum. The crude residue was
purified by silica gel column chromatography using 5-10% ethyl acetate in hexane as an eluent to
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afford the desired bisindolylmethane product C1 (67 mg, 82% yield). H NMR (400 MHz,
CDCl3) δ (ppm) 10.66 (br s, 1H), 10.23 (br s, 1H), 8.05 (br s, 1H), 7.98 (br s, 1H), 7.48 (d, J = 6.6
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Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 2H), 7.01 – 6.90 (m, 4H), 6.77 (t, J = 7.3
Hz, 1H), 6.70 (t, J = 7.2 Hz, 1H), 4.93 (br s, 1H), 4.48 (br s, 1H), 2.39 (s, 3H), 2.08 (s, 3H), 1.91
– 1.85 (m, 2H), 0.50 (t, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO) δ (ppm) 151.2, 146.6,
135.1, 134.8, 133.2, 131.9, 128.6, 126.8, 126.2, 125.1, 121.1, 119.2, 118.8, 117.8, 117.1, 112.2,
111.9, 110.3, 109.9, 109.5, 80.5, 44.8, 34.7, 12.8, 8.1. FTIR: (neat)/ cm-1 = 3559, 3398, 2973,
1460, 1368, 1308, 1247, 1174, 1126, 1025, 904, 811. HRMS (ESI) m/z: [M + Na]+ calcd for
C28H28N2NaO, 431.2094; found 431.2097.
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Synthesis of compound 3bl from bisindolylmethane C1: The compound C1 (0.1 mmol, 1.0 equiv)
and p-toluenesulfonic acid·monohydrate (PTSA·H2O, 0.01 mmol, 10 mol %) were charged into
an oven dried culture tube containing a stirring bar. To this 1.0 mL of toluene was added at the
o
room temperature while stirring. The resulting mixture was then heated at 120 C in oil bath for
20 min. Upon completion of the reaction (as monitored by TLC), the reaction mixture was
transferred into a 25 mL round bottom flask by dissolving in ethyl acetate solvent and evaporated
under vacuum. The crude residue was purified by silica gel column chromatography using 5%
ethyl acetate/hexane as an eluent to afford the desired product 3bl (25 mg, 90% yield). In a
second fraction the indole 1b was also isolated (11 mg, 84% yield).
1-(2-methyl-1H-indol-3-yl)-1-phenylbutan-2-one (3bl): The titled compound 3bl was synthesized
according to the GP I (reaction time: 30 min), the product 3bl was isolated after column
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chromatography using 5% ethyl acetate/hexane as eluent (53 mg, yield 96%). H NMR (400
MHz, CDCl3) δ (ppm) 7.99 (br s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.27 –
7.25 (m, 2H), 7.23 – 7.17 (m, 3H), 7.13 (t, J = 8.1 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H), 5.30 (s, 1H),
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2.63 – 2.46 (m, 2H), 2.36 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ
(ppm) 210.0, 138.8, 135.4, 133.4, 129.0, 128.3, 128.1, 126.8, 121.5, 120.0, 119.1, 110.5, 108.4,
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55.0, 35.3, 12.4, 8.4. FTIR: (neat)/ cm-1 =3350, 2922, 1699, 1461, 1310, 1247, 1115, 917, 842.
HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO, 278.1539; found 278.1538.
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synthesized according to the GP I (reaction time: 1 h), the product 3bm was isolated after
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column chromatography using 5% ethyl acetate/hexane as eluent (25 mg, yield 44%). H NMR
(400 MHz, CDCl3): δ (ppm) 8.04 (br s, 1H), 7.39 (dd, J = 11.4, 6.1 Hz, 1H), 7.29 (d, J = 7.3 Hz,
2H), 7.23 – 7.19 (m, 3H), 7.13 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.97 (dd, J = 14.7, 7.7
Hz, 1H), 6.27 (dd, J = 15.3, 1.5 Hz, 1H), 5.40 (s, 1H), 2.33 (s, 3H), 1.78 (dd, J = 7.0, 1.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 197.6, 142.6, 138.7, 135.4, 133.5, 130.6, 129.2,
128.7, 128.4, 128.3, 127.1, 126.8, 121.5, 119.9, 119.0, 110.5, 107.7, 54.0, 18.3, 12.5. FTIR:
(neat)/ cm-1 = 3348, 2922, 2852, 1685, 1625, 1459, 1291, 964. HRMS (ESI) m/z: [M + H]+ calcd
for C20H20NO, 290.1539; found 290.1534.
Synthesis of Carbazoles by Formal [4+2] Benzannulation (GP II): The indole 1p (0.2 mmol,
1.0 equiv) and p-toluenesulfonic acid·monohydrate (PTSA·H2O, 0.04 mmol, 20 mol %) were
charged into an oven dried culture tube containing a stirring bar. To this aldehyde 2 (0.22 mmol,
1.1 equiv, dissolved in 1.5 mL of toluene) was added dropwise at the room temperature while
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stirring. The resulting mixture was then heated at 120 C in oil bath over 24 to 48 h. Upon
completion of the reaction (as monitored by TLC), the reaction mixture was transferred into a 25
mL round bottom flask using ethyl acetate solvent and evaporated under vacuum. The crude
residue was purified by silica gel column chromatography using hexane as an eluent to afford the
desired products 4a-4f. As carbazoles 4b-4f were isolated along with inseparable impurities, they
were subjected to the N-methylation conditions to obtain pure N-methylated products 5b-5f in
44-67% yields over two steps.
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Procedure for N-Methylation Reaction: The carbazoles 4b-4f (1.0 equiv) was dissolved in 3
mL dimethyl sulfoxide, solid potassium hydroxide (1.2 equiv) was added and the mixture was
stirred for 30 min at room temperature. Then methyl iodide (1.5 equiv) was added at room
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temperature and heated at 90 C in oil bath for 2 to 3 h. Upon completion of the reaction as
indicated by TLC, water was added to the reaction mixture and extracted with ethyl acetate. The
organic layers were dried over Na2SO4, evaporated under vacuum and purified by silica gel
column chromatography using hexane as an eluent to afford the desired products 5b-5f.
3,4-Dibenzyl-2-methyl-1-phenyl-9H-carbazole (4a): The titled compound 4a was synthesized
according to the GP II (reaction time: 24 h), the product 4a was isolated after column
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chromatography using hexane as eluent (59 mg, yield 69%). H NMR (400 MHz, CDCl3): δ
(ppm) 7.98 (d, J = 8.0 Hz, 1H), 7.81 (br s, 1H), 7.60 – 7.56 (m, 2H), 7.50 – 7.48 (m, 3H), 7.34 –
7.33 (m, 2H), 7.29 – 7.26 (m, 6H), 7.22 – 7.20 (m, 2H), 7.11–7.09 (m, 3H), 4.66 (s, 2H), 4.24 (s,
2H), 2.21 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) 140.9, 139.8, 139.7, 138.6, 137.9,
133.3, 133.0, 130.4, 129.4, 129.2, 128.7, 128.5, 128.4, 128.0, 127.6, 126.1, 125.8, 125.0, 123.9,
123.8, 122.5, 120.7, 119.5, 110.5, 36.4, 35.0, 17.8. FTIR: (neat)/ cm-1 = 3421, 2915, 1600, 1451,
1328, 1254, 1103, 1028, 957. HRMS (ESI) m/z: [M + H]+ calcd for C33H28N, 438.2216; found,
438.2199.
2,3,9-Trimethyl-1,4-diphenyl-9H-carbazole (5b): The titled compound 5b was synthesized
according to the GP II (reaction time: 24 h) and followed by subsequent methyl protection. The
product 5b was isolated along with its minor regioisomer (generated due to the migration of
methyl group over phenyl one) in 3.5:1 ratio after column chromatography using hexane as
eluent (46 mg, 64% combined yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.59 – 7.46 (m, 5H),
7.44 – 7.41 (m, 5H), 7.32 – 7.28 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.58
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(d, J = 7.9 Hz, 1H), 3.13 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
(ppm) 142.3, 141.7, 140.3, 137.3, 135.7, 133.6, 131.2, 130.6, 129.7, 129.0, 128.3, 127.5, 127.3,
125.6, 124.8, 124.5, 122.8, 122.0, 118.5, 108.3, 32.0, 18.0, 17.1. FTIR: (neat)/ cm-1 = 3054,
2923, 2854, 1573, 1463, 1388, 1311, 1070, 1024, 894, 846. HRMS (ESI) m/z: [M + H]+ calcd
for C27H24N, 362.1903; found 362.1900.
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3-Butyl-2,9-dimethyl-1,4-diphenyl-9H-carbazole (5c): The titled compound 5c was synthesized
according to the GP II (reaction time: 32 h) and followed by subsequent methyl protection. The
product 5c was isolated after column chromatography using hexane as eluent (33 mg, yield 44%
over two steps). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.57 – 7.47 (m, 5H), 7.46 – 7.42 (m, 5H),
7.28 –7.25 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H),
3.12 (s, 3H), 2.60 – 2.57 (m, 2H), 2.21 (s, 3H), 1.49 – 1.41 (m, 2H), 1.26 – 1.17 (m, 2H), 0.77 (t,
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J = 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3): δ (ppm) 142.3, 141.4, 140.4, 137.2, 135.7,
133.0, 131.2, 130.7, 129.7, 128.8, 128.4, 127.4, 127.3, 124.83, 124.82, 122.9, 122.0, 120.2,
118.5, 108.2, 33.3, 32.0, 30.3, 23.2, 17.4, 13.9. FTIR: (neat)/ cm-1 = 3055, 2922, 2852, 1569,
1457, 1384, 1312, 1027. HRMS (ESI) m/z: [M + H]+ calcd for C30H30N, 404.2373; found
404.2371.
3,4-Dihexyl-2,9-dimethyl-1-phenyl-9H-carbazole (5d): The titled compound 5d was synthesized
according to the GP II (reaction time: 48 h) and followed by subsequent methyl protection. The
product 5d was isolated after column chromatography using hexane as eluent (58 mg, 67% yield
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over two steps). H NMR (400 MHz, DMSO-d6): δ (ppm) 8.00 (d, J = 7.8 Hz, 1H), 7.51 – 7.43
(m, 3H), 7.39 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.29 (dd, J = 7.7, 1.6 Hz, 2H), 7.17 (dt, J
= 6.5, 1.3 Hz 1H), 3.18 – 14 (m, 2H), 2.75 – 2.70 (m, 2H), 2.05 (s, 3H), 1.67 – 1.56 (m, 4H), 1.32
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– 1.20 (m, 4H), 0.90 (t, J = 4.6 Hz, 3H), 0.87 (t, J = 4.8 Hz, 3H). C{1H} NMR (101 MHz,
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