A new approach to 1-substituted β-carbolines and isoquinolines utilizing tributyl[(Z)-2-ethoxyvinyl]stannane as a C-3,C-4 building block

Article abstract of DOI:10.1016/j.tet.2015.12.049

Starting from readily available indole-2-carboxylic acids, 1-substituted β-carbolines (among them the alkaloids harmane and isoharmine) are readily obtained via the corresponding 2-acylindoles, bromination at C-3, followed by a one-pot Stille cross-coupling with tributyl[(Z)-2-ethoxyvinyl]stannane, and ring closure with ammonium acetate. 1-Substituted isoquinolines are available in an analogous manner starting from 2-bromobenzoic acid.

Full text of DOI:10.1016/j.tet.2015.12.049

Accepted Manuscript
A new approach to 1-substituted β-carbolines and isoquinolines utilizing tributyl[(Z)-2-
ethoxyvinyl]stannane as a C-3,C-4 building block
Alexandra Kamlah, Florian Lirk, Franz Bracher
PII:
S0040-4020(15)30297-0
10.1016/j.tet.2015.12.049
TET 27375
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 November 2015
Revised Date: 18 December 2015
Accepted Date: 22 December 2015
Please cite this article as: Kamlah A, Lirk F, Bracher F, A new approach to 1-substituted β-carbolines
and isoquinolines utilizing tributyl[(Z)-2-ethoxyvinyl]stannane as a C-3,C-4 building block, Tetrahedron
(2016), doi: 10.1016/j.tet.2015.12.049.
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ACCEPTED MANUSCRIPT
Graphical Abstract
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ACCEPTED MANUSCRIPT
A
new approach to 1-substituted β-carbolines and isoquinolines utilizing tributyl[(Z)-2-
ethoxyvinyl]stannane as a C-3,C-4 building block
Alexandra Kamlah, Florian Lirk, and Franz Bracher*
Department für Pharmazie - Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München,
Butenandtstr. 5-13, D-81377 München, Germany
*Corresponding author. Email: Franz.Bracher@cup.uni-muenchen.de, Phone: +49-89-2180-77301, Fax: +49-89-
2180-77802
Abstract
Starting from readily available indole-2-carboxylic acids, 1-substituted β-carbolines (among them the alkaloids
harmane and isoharmine) are readily obtained via the corresponding 2-acylindoles, bromination at C-3, followed
by a one-pot Stille cross-coupling with tributyl[(Z)-2-ethoxyvinyl]stannane, and ring closure with ammonium
acetate. 1-Substituted isoquinolines are available in an analogous manner starting from 2-bromobenzoic acid.
Keywords: β-carbolines; isoquinolines; Stille cross-coupling; ethoxyvinylstannane; alkaloids
1. Introduction
The β-carbolines represent a very large and structurally diverse class of secondary metabolites from plants,
marine invertebrates, and microorganisms. A broad spectrum of biological activities has been demonstrated for
β-carbolines, e.g. antimicrobial, antiparasitic, antiviral, and cytotoxic, neuropharmocological [1], and
antiprotozoal [2] activities. In the past few years harmine (7-methoxy-1-methyl-β-carboline) attracted special
interest, since antidiabetic [3], antiinflammatory [4], and anti-Alzheimer [5] activities were demonstrated for this
simple alkaloid. Moreover, it was dentified as a potent inhibitor of several disease-relevant protein kinases
(DYRK1A [6], Haspin [7], PLK [8]). Unfortunately, harmine is also a nanomolar inhibtor of the enzyme
monoamineoxidase A (MAO A) [9], and the disturbances in neurotransmitter metabolism resulting from this
activity render harmine not applicable for therapy. Improvement of target selectivity and elimination of
undesired side effects of harmine is attempted by systematic structure modifications at all edges of the lead
structure. Such work has been performed by others [10] and us [11] by direct modification (ring substitution, N-
alkylations) of commercially available harmine, or by synthesizing novel 1-substituted β-carbolines following
established procedures. The most common approaches to the β-carboline ring system [12] start from tryptamine
or tryptophan, and involve construction of the pyridine ring under incorporation of either aldehyde (Pictet-
Spengler reaction) [13] or carboxylic acid (Bischler-Napieralski reaction) [14] building blocks, followed by
dehydrogenation of the resulting di- or tetrahydro-β-carbolines. Considerable time ago we introduced novel
strategies for the construction of 1-substituted β-carbolines, based on Pd-catalyzed cross-coupling of 1-
halogenated β-carboline building blocks [15], trapping of 1,9-dimetalated β-carboline with electrophiles [16], as
well as direct homolytic substitution of β-carbolines [17]. But once again, the central β-carboline building blocks
were derived from tryptamine precursors. Unfortunately, tryptamines bearing substituents on the benzene ring
are not freely accessible.
This prompted us to work out a novel approach to β-carbolines which on the one hand allows the flexible choice
of the substituent at C-1, and on the other hand starts from indole precursors which are available with a diverse
spectrum of substituents on the benzene partial structure (C-4 to C-7). For this purpose indole-2-carboxylates
were regarded as promising, since numerous methods (e.g. Hemetsberger-Knittel synthesis [18] and variants
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[19], Fischer indole synthesis, carboxylation of indoles [20]) are established for their synthesis. The prospective
substituent at C-1 was to be introduced in form of an organometallic species, by reaction with a Weinreb amide
derived from the respective indole-2-carboxylate. For completion of the pyridine moiety of the β-carboline ring
system, a C2 building block had to be introduced at C-3 of the indole in a manner that an an indole-3-
acetaldehyde (or an equivalent thereof) resulted, which in turn should give the fully aromatic β-carboline ring
system upon incorporation of ammonia. Examples for related cyclizations, starting from 1,5-dicarbonyl moieties
prepared on alternative routes are described in literature [21]. A cyclization of 2-acyl-3-alkynylindoles to give N-
protected 1,3-disubstituted β-carbolines has been reported [22]. This approach is presented in Figure 1.
Fig. 1: Our approach for the synthesis of 1-substituted β-carbolines.
In an analogous manner we intended to prepare 1-substituted isoquinolines. The isoquinoline alkaloids are one of
the largest classes of plant alkaloids, again with a broad panel of biological activities [23]. Total syntheses of 1-
substituted isoquinolines are commonly accomplished from appropriately substituted phenethylamines under
Pictet-Spengler or Bischler-Napieralski conditions, but here isomeric products can be obtained if the starting
phenethylamine bears two unsubstituted ortho-positions [24]. Direct substitution of 1-unsubstituted isoquinolines
(which are commonly prepared from phenethylamines) can be accomplished via 1-cyano-N-benzoyl
intermediates (Reissert synthesis) or via direct regioselective ring metalation at C-1 with amide bases [25]. For a
comprehensive overview on isoquinoline syntheses, see ref. [26]. Syntheses of 1-substituted isoquinolines
starting from 2-(alkoxyvinyl)benzonitriles, related to our approach, have been reported recently [27].
2. Results
2.1. Synthesis of 1-substituted β-carbolines
A first approach for the synthesis of the desired 1-substituted β-carbolines started from ethyl indole-2-
carboxylate (1a) (conversion of the ester group to ketones was to be performed later). For the introduction of the
C2 unit at C-3 we envisaged a two-step protocol comprising a direct allylation at C-3 with allyl bromide, and
later an ozonolysis of the terminal olefinic group to give the required indole-3-acetaldehyde moiety.
Electrophilic C-3 allylations of indoles are known from literature [28], typically the reactions are triggered by
Broensted or Lewis acids. However, no example is known for a respective allylation of an indole bearing an
electron-withdrawing substituent at C-2. To our disappointment we were not able to achieve considerable
conversion with allyl bromide or dimethylallyl bromide under a number of reaction conditions. In an alternative
approach we investigated a Stille cross-coupling of ethyl 3-iodoindole-2-carboxylate (1b) [29] with
allyltributylstannane [30]. The desired 3-allylindole 2 was obtained in 27% yield, but purification was extremely
tedious, and upscaling experiments gave frustrating yields (Scheme 1). This is in accordance with a related
observation for the C-3 allylation of an N-unprotected indolecarboxylate [31]. So we had to find an alternative
way for introduction of the C-3, C-4 unit of the β-carboline.
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Scheme 1: Allylation of indole-2-carboxylates
Tributyl[(Z)-2-ethoxyvinyl]stannane (7) can be reacted with haloarenes in a Stille cross-coupling to give 2-
ethoxyvinylarenes, which represent masked arylacetaldehyde equivalents [32]. So cross-coupling of 3-
halogenated 2-acylindoles with 7 was envisaged to open an access to masked 1,5-dicarbonyl compounds, which
should provide 1-substituted β-carbolines upon treatment with ammonia [21]. Representative 2-acylindoles 4a-d
were prepared by reaction of Weinreb amide 3a [33] with appropriate organolithium compounds. Bromination of
indoles 4a-d with NBS in DMF [33] gave the corresponding 3-bromo derivatives 5a-d in good to excellent
yields. Alternatively, Weinreb amide 3a was brominated at C-3 first, giving the advanced building block 6,
followed by reaction with the organolithium species. Surprisingly, the 3-bromo substituent was not affected in
this reaction. Comparable overall yields were obtained for 5a-d over the two steps on both routes.
In the same manner the 5-methoxy analogues 5e-h were obtained starting from 5-methoxyindole-2-carboxylic
acid via Weinreb amide 3b [34] and ketones 4e-h. But in this series the alternative route was not feasible, since
bromination of the Weinreb amide 3b failed to give the desired 3-bromo intermediate in acceptable yield due to
multiple bromination. Bromoketones 5a-h were conveniently coupled with tributyl[(Z)-2-ethoxyvinyl]stannane
(7), Pd2(dba)3, and S-Phos ligand [35] to give the 3-(2-ethoxyvinyl)indoles 8a-h. Heating the crude cross-
coupling products with ammonium acetate/glacial acetic acid gave the desired 1-substituted β-carbolines 9a-h,
among them the alkaloids harmane (9a) and isoharmine (9e) [35] in 35 - 54% overall yields from 5a-h (Scheme
2). No clear trend was observed for the impact of the substituents (R, R’) on the overall yields. Separation of
organotin by-products was critical in first experiments, but was accomplished in a satisfactory manner by
addition of triethylamine to eluents for column chromatography.
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Scheme 2: Synthesis of 1-substituted β-carbolines 9a-h via ethoxyvinylation of 2-acylindoles.
2.2. Synthesis of 1-substituted isoquinolines
This new protocol could, with minor modifications, also be applied to the synthesis of 1-substituted
isoquinolines 12a-c. The required ortho-brominated arylketones 11a-c were readily obtained by reaction of the
Weinreb amide 10, derived from 2-bromobenzoic acid, with Grignard reagents. Analogous conversion with
organolithium reagents however, failed to give appreciable amounts of the ketones. Annulation of the pyridine
ring was accomplished in good yields (67 - 82%) in the same manner as described above by cross-coupling with
ethoxyvinylstannane 7 and treatment of the crude reaction mixture with ammonium acetate/glacial acetic acid
(Scheme 3). Conversions of the bromoketones 11a-c were much cleaner than those in the indole series shown
above, resulting in significantly enhanced yields.
Scheme 3: Synthesis of 1-substituted isoquinolines 12a-c via ethoxyvinylation of (2-bromphenyl)ketones.
3. Conclusion
In conclusion, we have worked out a novel synthesis of β-carbolines and isoquinolines starting from readily
available aromatic carboxylic acids. Commercially available tributyl[(Z)-2-ethoxyvinyl]stannane (7) was utilized
as a versatile C2 building block for the introduction of the C-3,C-4 unit of the newly constructed heterocycles.
This protocol should facilitate the synthesis of differently substituted β-carbolines and isoquinolines in drug
development.
4. Experimental section
4.1. General Information
All solvents used were of HPLC grade or p.a. grade and/or purified according to standard procedures. Chemical
reagents were purchased from Sigma Aldrich (Schnelldorf, Germany), ABCR (Karlsruhe, Germany) and Acros
(Geel, Belgium). IR measurements were performed with a Perkin Elmer FT-IR Paragon 1000 spectrometer. All
melting points were determined by open tube capillary method on a Büchi melting point B-450 apparatus and are
uncorrected. NMR spectra were recorded on Jeol JNMR-GX 400 (400 MHz), Jeol JNMR-GX 500 (500 MHz),
Avance III HD Bruker BioSpin (400 MHz) and Avance III HD Bruker BioSpin (500 MHz) spectrometers.
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NMR-Spectra were recorded in deuterated solvents and chemical shifts are reported in parts per million (ppm). J
values are given in hertz. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. Signal assignments were carried out based on 1H, 13C, DEPT, HMQC, HMBC and COSY
spectra. Mass spectra (MS) were run by electrospray ionization (ESI) using a Thermo Finnigan LTQ FT Ultra
mass spectrometer or electron impact (EI) at 70 eV using a Hewlett Packard 5989A mass spectrometer with
59980B Particle Beam LC/MS. High-resolution mass spectra were performed by electrospray ionization (ESI)
using a Thermo Finnigan LTQ FT Ultra spectrometer or electron impact (EI) at 70 eV on a Jeol GCmate II or on
a Finnigan MAT 95 spectrometer. Microwave-accelerated reactions were carried out with a Discovery single-
mode microwave reactor. All reactions were monitored by thin-layer chromatography (TLC) using precoated
plastic sheets POLYGRAM® SIL G/UV254 from Macherey-Nagel (Düren, Germany). Compounds on TLC
plates were detected under UV light at 254 and 366 nm. Chromatographic purification of products was
performed by using flash column chromatography (FCC) on Merck silica gel 60 as stationary phase. Solutions
were concentrated in vacuo on a Heidolph rotary evaporator.
4.2. General Procedures
4.2.1. General Procedure 1: Synthesis of 2-acylindoles 4a-c, e-g, 5a-c from Weinreb amides 3a/3b/6
Under a nitrogen atmosphere the Weinreb aminde 3a/3b/6 was dissolved in anhydrous THF (2 mL/mmol educt).
After cooling to -80 °C, the appropriate organolithium reagent (2.0 equ.) was added. The mixture was stirred at -
80 °C for 2 hours, then 2M hydrochloric acid (5.0 mL/mmol educt) was added and the mixture extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were dried over MgSO4 and the solvents were
evaporated under reduced pressure. Purification was accomplished by FCC.
4.2.2. General Procedure 2: Bromination of 2-acylindoles 4a-h and Weinreb amide 3a
The 2-acylindole 4a-h and N-bromosuccinimide (1.0 equ.) were dissolved in DMF (5 mL/mmol educt) and
stirred at r.t. for 3 hours. Then the mixture was poured on crushed ice, and the precipitate was collected. The
filtrate was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over MgSO4 and
the solvents were evaporated under reduced pressure. This residue and the collected solid were combined and
purified by FCC.
4.2.3. General Procedure 3: Stille cross-coupling of the bromoarenes with ethoxyvinylstannane 7 and
subsequent cyclization to ß-carbolines/isoquinolines 9a-h/12a-c
The 3-bromo-2-acylindole 5a-h or 2-bromo-1-acylbenzene 11a-c, SPhos (8 - 12 mol%) and Pd2(dba)3ꢀCHCl3 (2 -
3 mol%) were dissolved in anhydrous DMF (4 mL/mmol educt) under a nitrogen atmosphere. Tributyl[(Z)-2-
ethoxyvinyl]stannane 7 (1.3 equ.) was added and the mixture was heated at 95 °C for 15 hours. Then a large
excess of ammonium acetate and glacial acetic acid (3 mL/mmol educt) were added. After heating at 120 °C for
7 hours aqueous ammonia (35%, 20 mL) was added and the mixture extracted with ethyl acetate (4 x 40 mL).
The combined organic layers were dried over MgSO4 and the solvents were evaporated under reduced pressure.
Purification was accomplished by FCC.
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4.2.4 General Procedure 4: Synthesis of acylbenzenes 11a-c from Weinreb amide 10
Under a nitrogen atmosphere 2-bromo-N-methoxy-N-methylbenzamide (10) (about 1 mmol) was dissolved in
anhydrous THF (3 mL). The solution was cooled to 0 °C and the appropriate Grignard reagent (3.0 equ.) was
added. The mixture was stirred for 15 hours, then 2M hydrochloric acid (10 mL) was added and extracted with
ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO4 and the solvents were
evaporated under reduced pressure. Purification was accomplished by FCC.
4.3. Compounds
4.3.1. Ethyl 3-allylindole-2-carboxylate (2)
Under a nitrogen atmosphere ethyl 3-iodo-1H-indole-2-carboxylate (170 mg, 0.54 mmol) and (Ph3P)2PdCl2 (24
mg, 0.034 mmol, 6 mol %) were dissolved in anhydrous dioxane (2.5 mL) and allyltributylstannane (0.20 mL,
0.68 mmol) was added. The mixture was heated in a sealed vial under microwave irradiation (300 W, 140 °C, 30
min). After cooling to r.t. aqueous sodium fluoride solution (10 %) (10 mL) was added and the mixture was
extracted with methylene chloride (3 x 15 mL). The combined organic layers were dried over MgSO4 and the
solvents were evaporated under reduced pressure. Purification was accomplished by FCC using 10:1 hexanes-
ethyl acetate to give 33 mg of 2 (0.14 mmol, 27 % yield) as a white solid. Mp 81 °C (lit.[31] 85 - 87 °C). 1H NMR
(500 MHz, CD2Cl2): δ = 8.91 (s, 1H, NH), 7.68 (dd, J = 8.1 Hz, 0.9 Hz, 1H, 4-H), 7.40 (dd, J = 8.3 Hz, 1.0 Hz,
1H, 7-H), 7.31 (ddd, J = 8.2 Hz, 6.9 Hz, 1.1 Hz, 1H, 6-H), 7.13 (ddd, J = 8.1 Hz, 7.0 Hz, 1.0 Hz, 1H, 5-H), 6.03
(ddt, J = 16.7 Hz, 10.0 Hz, 6.3 Hz, 1H, 2‘‘-H), 5.08 (ddt, J = 17.1 Hz, 3.4 Hz, 1.7 Hz, 1H, 3‘‘-H trans), 4.99 (ddt,
J = 10.0 Hz, 3.3 Hz, 1.7 Hz, 1H, 3‘‘-H cis), 4.40 (q, J = 7.1 Hz, 2H, O-CH2), 3.89 (dt, J = 6.3 Hz, 1.6 Hz, 2H,
1‘‘-H), 1.41 (t, J = 7.1 Hz, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 162.5 (C-1‘), 137.4 (C-2‘‘), 136.3
(C-7a), 128.2 (C-3a), 125.9 (C-6), 123.8 (C-2), 121.8 (C-4), 121.3 (C-3), 120.4 (C-5), 115.0 (C-3‘‘), 112.1 (C-7),
61.2 (O-CH2), 29.5 (C-1‘‘), 14.6 (CH3) ppm. IR: ṽ = 3340, 3062, 2981, 2927, 1687, 1540, 1455, 1443, 1381,
1331, 1257, 1130, 1020, 907, 773, 737 cm-1. MS (EI): m/z (%) = 229 (100) [M]+•, 183 (94), 154 (75). HRMS
(EI): calcd. for C14H15NO2: 229.1103 [M]+•; found 229.1102.
4.3.2. 1-(1H-Indol-2-yl)ethan-1-one (4a)
Prepared from 3a (404 mg, 1.98 mmol) and methyllithium (1.6M in diethyl ether, 2.48 mL, 3.97 mmol)
following General Procedure 1. Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give
1
302 mg of 4a (1.9 mmol, 95 % yield) as a white solid. Mp 155 °C (lit.[37] 154 - 155 °C). H NMR (500 MHz,
CD2Cl2): δ = 9.10 (s, 1H, NH), 7.72 (dd, J = 8.1 Hz, 1.0 Hz, 1H, 4-H), 7.44 (dd, J = 8.4 Hz, 0.9 Hz, 1H, 7-H),
7.34 (ddd, J = 8.3 Hz, 7.0 Hz, 1.1 Hz, 1H, 6-H), 7.22 (dd, J = 2.1 Hz, 1.0 Hz, 1H, 3-H), 7.15 (ddd, J = 8.1 Hz, 7.0
Hz, 1.0 Hz, 5-H), 2.57 (s, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 190.6 (C-1‘), 137.6 (C-3a), 135.9
(C-2), 128.1 (C-7a), 126.6 (C-6), 123.4 (C-4), 121.3 (C-5), 112.5 (C-7), 109.8 (C-3), 26.1 (CH3) ppm. IR: ṽ =
3304, 1649, 1525, 1411, 1387, 1351, 1340, 1249, 1228, 1185, 1154, 1019, 940, 798 cm-1. MS (ESI): m/z = 160
[M + H]+.
4.3.3. 1-(1H-Indol-2-yl)pentan-1-one (4b)
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Prepared from 3a (613 mg, 3.01 mmol) and n-butyllithium (1.6M in hexanes, 3.75 mL, 6.08 mmol) following
General Procedure 1. Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 374 mg of
1
4b (1.86 mmol, 62 % yield) as a pale brown solid. Mp 114 °C (lit.[38] 113 - 115 °C). H NMR (400 MHz,
CD2Cl2): δ = 9.34 (s, 1H, NH), 7.72 (dd, J = 8.1 Hz, 0.9 Hz, 1H, 4-H), 7.46 (dd, J = 8.3 Hz, 0.9 Hz, 1H, 7-H),
7.34 (ddd, J = 8.4 Hz, 7.0 Hz, 0.9 Hz, 1H, 6-H), 7.23 (dd, 2.1 Hz, 0.9 Hz, 1H, 3-H), 7.14 (ddd, J = 8.1 Hz, 7.0
Hz, 0.9 Hz, 1H, 5-H), 3.00 - 2.92 (m, 2H, 2‘-H), 1.80 - 1.71 (m, 2H, 3‘-H), 1.49 - 1.38 (m, 2H, 4‘-H), 0.96 (t, J =
7.3 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 193.9 (C-1‘), 137.6 (C-7a), 135.8 (C-2), 128.0 (C-3a),
126.4 (C-6), 123.3 (C-4), 121.2 (C-5), 112.5 (C-7), 109.2 (C-3), 38.4 (C-2‘), 27.5 (C-3‘), 22.9 (C-4‘), 14.1 (CH3)
ppm. IR: ṽ = 3310, 2948, 1651, 1465, 1408, 1215, 1108, 790, 751, 729 cm-1. MS (ESI): m/z = 200 [M - H]-.
HRMS (ESI): calcd. for C13H14NO: 200.1075 [M - H ]-; found 200.1081
4.3.4. (1H-Indol-2-yl)(phenyl)methanone (4c)
Prepared from 3a (399 mg, 1.95 mmol) and phenyllithium (1.8M in dibutyl ether, 2.20 mL, 3.96 mmol)
following General Procedure 1. Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give
398 mg of 4c (1.80 mmol, 92 % yield) as a yellow solid. Mp 143 °C (lit.[39] 145 - 146 °C). 1H NMR (500 MHz,
CDCl3): δ = 9.42 (s, 1H, NH), 8.02 - 7.97 (m, 2H, 2‘‘-H, 6‘‘-H), 7.72 (dd, J = 8.2 Hz, 0.9 Hz, 1H, 4-H), 7.62 (tt,
J = 6.7 Hz, 1.3 Hz, 1H, 4‘‘-H), 7.56 - 7.51 (m, 2H, 3‘‘-H, 5‘‘-H), 7.49 (dd, J = 8.5 Hz, 1.0 Hz, 1H, 7-H), 7.38
(ddd, J = 8.2 Hz, 7.0 Hz, 1.0 Hz, 1H, 6-H), 7.19 - 7.15 (m, 2H, 3-H, 5-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
187.2 (C-1‘), 138.0 (C-1‘‘), 137.5 (C-7a), 134.3 (C-2), 132.3 (C-4‘‘), 129.2 (C-2‘‘, C-6‘‘), 128.5 (C-3‘‘, C-5‘‘),
127.7 (C-3a), 126.5 (C-6), 123.2 (C-4), 121.0 (C-5), 112.8 (C-3), 112.2 (C-7) ppm. IR: ṽ = 3313, 1622, 1568,
1514, 1341, 1318, 1129, 1013, 904, 819, 744, 725 cm-1. MS (ESI): m/z = 220 [M - H]-. HRMS (ESI): calcd. for
C15H10NO: 220.0762 [M - H]-; found 220.0769.
4.3.5. (1H-Indol-2-yl)(thiophen-2-yl)methanone (4d)
2-Thienyllithium was prepared in situ from 2-bromothiophene (0.12 mL, 1.23 mmol) and tert-butyllithium
(1.9M in pentane, 1.70 mL, 3.23 mmol) in anhydrous THF (1 mL) and was stirred for one hour at - 80 °C for 1
hour. To this solution 3a (125 mg, 0.61 mmol), dissolved in THF (3 mL), was added. Standard workup was
performed following General Procedure 1. Purification was accomplished by FCC using 6:1 hexanes-acetone to
1
give 88 mg (0.39 mmol, 63 % yield) of 4d as a yellow solid. Mp 155 °C (lit.[40] 152 - 155 °C). H NMR (400
MHz, CDCl3): δ = 9.44 (s, 1H, NH), 8.05 (dd, J = 3.8 Hz, 1.2 Hz, 1H, 5‘‘-H), 7.75 (dd, J = 8.1 Hz, 1.0 Hz, 1H,
4-H), 7.72 (dd, J = 5.0 Hz, 1.2 Hz, 1H, 3‘‘-H), 7.49 (dd, J = 8.4 Hz, 0.9 Hz, 1H, 7-H), 7.45 (dd, J = 2.1 Hz, 0.9
Hz, 1H, 3-H), 7.38 (ddd, J = 8.3 Hz, 7.0 Hz, 1.1 Hz, 1H, 6-H), 7.23 (dd, J = 5.0 Hz, 3.8 Hz, 1H, 4‘‘-H), 7.18
(ddd, J = 8.0 Hz, 7.0 Hz, 1.0 Hz, 1H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 178.0 (C-1‘), 142.6 (C-1‘‘),
137.5 (C-7a), 134.2 (C-2), 133.3 (C-3‘‘), 133.1 (C-5‘‘), 128.2 (C-4‘‘), 127.9 (C-3a), 126.6 (C-6), 123.3 (C-4),
121.2 (C-5), 112.3 (C-7), 110.8 (C-3) ppm. IR: ṽ = 3313, 1589, 1519, 1415, 1341, 1259, 1112, 1058, 839, 800,
742, 711 cm-1. MS (ESI): m/z = 228 [M + H]+. HRMS (ESI): calcd. for C13H10NOS: 228.0483 [M + H]+; found
228.0479.
4.3.6. 1-(5-Methoxy-1H-indol-2-yl)ethan-1-one (4e)
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Prepared from 3b (400 mg, 1.71 mmol) and methyllithium (1.6M in diethyl ether, 2.20 mL, 2.52 mmol)
following General Procedure 1. Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give
220 mg of 4e (1.16 mmol, 68 % yield) as a yellow solid. Mp 172 °C (lit.[41] 170 - 172 °C). 1H NMR (400 MHz,
CD2Cl2): δ = 9.15 (s, 1H, NH), 7.33 (dd, J = 9.0 Hz, 0.8 Hz, 1H, 7-H), 7.13 (dd, J = 2.2 Hz, 0.9 Hz, 1H, 3-H),
7.10 (d, J = 2.4 Hz, 1H, 4-H), 7.00 (dd, J = 9.0 Hz, 2.5 Hz, 6-H), 3.83 (s, 3H, OCH3), 2.55 (s, 3H, CH3) ppm. 13
C
NMR (100 MHz, CD2Cl2): δ = 190.5 (C-1‘), 155.2 (C-5), 136.4 (C-2), 133.1 (C-7a), 128.4 (C-3a), 118.3 (C-6),
113.4 (C-7), 109.4 (C-3), 103.1 (C-4), 56.0 (OCH3), 26.1 (CH3) ppm. IR: ṽ = 3309, 1636, 1525, 1450, 1357,
1297, 1216, 1151, 1117, 1029, 844, 823, 791, 711, 554 cm-1. MS (EI): m/z (%) = 189 (100) [M]+•,174 (100), 146
(50). HRMS (EI): calcd. for C11H11NO2: 189.0790 [M]+•; found 189.0782.
4.3.7. 1-(5-Methoxy-1H-indol-2-yl)pentan-1-one (4f)
Prepared following Procedure 1 from 3b (278 mg, 1.19 mmol) and n-butyllithium (2.5M in hexanes, 0.95 mL,
2.38 mmol). Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 197 mg of 4f (0.85
mmol, 71 % yield) as a yellow solid. Mp 120 °C. 1H NMR (500 MHz, CDCl3): δ = 9.16 (s, 1H, NH), 7.33 (d, J =
8.9 Hz, 7-H), 7.12 (d, J = 1.3 Hz, 1H, 3-H), 7.08 (d, J = 2.3 Hz, 1H, 4-H), 7.02 (dd, J = 8.9 Hz, 2.4 Hz, 1H, 6-H),
3.85 (s, 3H, OCH3), 2.95 - 2.90 (m, 2H, 2‘-H), 1.80 - 1.73 (m, 2H, 3‘-H), 1.48 - 1.39 (m, 2H, 4‘-H), 0.96 (t, J =
7.4 Hz, 3H, CH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 193.5 (C-1‘), 154.7 (C-5), 135.7 (C-2), 132.7 (C-7a),
127.9 (C-3a), 117.9 (C-6), 113.1 (C-7), 108.6 (C-3), 102.7 (C-4), 55.7 (OCH3), 38.1 (C-2‘), 27.3 (C-3‘), 22.5 (C-
4‘), 13.9 (CH3) ppm. IR: ṽ = 3312, 2963, 2935, 2864, 1644, 1523, 1456, 1412, 1353, 1295, 1264, 1202, 1174,
1145, 1032, 935, 840, 821, 733 cm-1. MS (EI): m/z (%) = 231 (70) [M]+•, 189 (100), 174 (85), 146 (27). HRMS
(EI): calcd. for C14H17NO2: 231.1259 [M]+•; found 231.1256.
4.3.8. (5-Methoxy-1H-indol-2-yl)(phenyl)methanone (4g)
Prepared following General Procedure 1 from 3b (212 mg, 0.91 mmol) and phenyllithium (1.8M in dibutyl ether,
1.02 mL, 1.84 mmol). Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give 163 mg of
4g (0.65 mmol, 71 % yield) as a yellow solid. Mp 162 °C (lit.[42] 162 °C). 1H NMR (500 MHz, CD2Cl2): δ = 9.41
(s, 1H, NH), 8.00 - 7.96 (m, 2H, 2‘‘-H, 6‘‘-H), 7.66 - 7.61 (m, 1H, 4‘‘-H), 7.57 - 7.52 (m, 2H, 3‘‘-H, 5‘‘-H), 7.40
(dd, J = 9.0 Hz, 0.8 Hz, 1H, 7-H), 7.10 (d, J = 2.4 Hz, 1H, 4-H), 7.09 (dd, J = 2.2 Hz, 0.9 Hz, 1H, 3-H), 7.04 (dd,
J = 9.0 Hz, 2.5 Hz, 1H, 6-H), 3.83 (s, 3H, OCH3) ppm. 13C NMR (100 MHz, CD2Cl2): δ = 187.0 (C-1‘), 155.3
(C-5), 138.5 (C-1‘‘), 135.3 (C-2), 133.4 (C-7a), 132.6 (C-4‘‘), 129.5 (C-2‘‘, C-6‘‘), 128.8 (C-3‘‘, C-5‘‘), 128.5
(C-3a), 118.6 (C-6), 113.5 (C-7), 112.3 (C-3), 103.1 (C-4), 56.0 (OCH3) ppm. IR: ṽ = 3438, 3309, 1623, 1573,
1520, 1452, 1349, 1258, 1217, 1166, 1117, 1031, 903, 844, 815, 726 cm-1. MS (EI): m/z (%) = 251 (100) [M]+•,
236 (40), 208 (10), 174 (10). HRMS (EI): calcd. for C16H13NO2: 251.0946 [M]+•; found 251.0947.
4.3.9. (5-Methoxy-1H-indol-2-yl)(thiophen-2-yl)methanone (4h)
Prepared from 3b (360 mg, 1.54 mmol) and 2-thienyllithium, which was prepared in situ from 2-bromthiophene
(0.24 mL, 2.46 mmol) and tert-butyllithium (1.9M in pentane, 3.40 mL, 6.46 mmol) in the same manner as
1
described for 4d to give 198 mg of 4h (0.77 mmol, 50 % yield) as a yellow solid. Mp 152 °C. H NMR (400
MHz, CDCl3): δ = 9.38 (s, 1H, NH), 8.04 (dd, J = 3.8 Hz, 1.1 Hz, 1H, 5‘‘-H), 7.71 (dd, J = 5.0 Hz, 1.2 Hz, 1H,
3‘‘-H) 7.40 - 7.37 (m, 1H, 7-H), 7.36 (dd, J = 2.2 Hz, 0.9 Hz, 1H, 3-H), 7.22 (dd, J = 5.0 Hz, 3.8 Hz, 1H, 4‘‘-H),
9

ACCEPTED MANUSCRIPT
7.12 (d, J = 2.4 Hz, 1H, 4-H), 7.06 (dd, J = 8.9 Hz, 2.4 Hz, 1H, 6-H), 3.87 (s, 3H, OCH3) ppm. 13C NMR (100
MHz, CDCl3): δ = 177.6 (C-1‘), 154.9 (C-5), 142.5 (C-1‘‘), 134.5 (C-2), 133.1 (C-3‘‘), 132.9 (C-7a), 132.8 (C-
5‘‘), 128.1 (C-3a), 128.0 (C-4‘‘), 118.3 (C-6), 113.1 (C-7), 110.1 (C-3), 102.7 (C-4), 55.7 (OCH3) ppm. IR: ṽ =
3303, 2933, 1591, 1519, 1455, 1414, 1355, 1294, 1259, 1215, 1161, 1113, 1025, 842, 802, 753, 726 cm-1. MS
(ESI): m/z = 258 [M + H]+. HRMS (ESI): calcd. for C14H12NO2S: 258.0589 [M + H]+; found 258.0586.
4.3.10. 1-(3-Bromo-1H-indol-2-yl)ethan-1-one (5a)
Method A: Prepared following General Procedure 2 from 4a (504 mg, 3.17 mmol) and N-bromosuccinimide
(586 mg, 3.29 mmol). Purification was accomplished by using 4:1 hexanes-ethyl acetate to give 692 mg of 5a
(2.91 mmol, 93 % yield) as a pale yellow solid.
Method B: Prepared following General Procedure 1 from 3-bromo-N-methoxy-N-methyl-1H-indole-2-
carboxamide (6) (300 mg, 1.06 mmol) and methyllithium (1.6M in diethyl ether, 1.33 mL, 2.13 mmol).
Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give 173 mg of 5a (0.73 mmol, 69 %
yield). Mp 156 °C (lit.[43] 152 - 153 °C). 1H NMR (500 MHz, CD2Cl2): δ = 9.23 (s, 1H, NH), 7.69 (dd, J = 8.2
Hz, 0.9 Hz, 1H, 4-H), 7.43 (d, J = 8.2 Hz, 1H, 7-H), 7.42 - 7.38 (m, 1H, 6-H), 7.23 (ddd, J = 8.0 Hz, 6.6 Hz, 1.3
Hz, 1H, 5-H), 2.79 (s, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 190.0 (C-1‘), 135.8 (C-7a), 132.9 (C-
2), 128.5 (C-3a), 127.6 (C-6), 122.0 (C-4), 121.9 (C-5), 112.7 (C-7), 98.1 (C-3), 29.3 (CH3) ppm. IR: ṽ = 3316,
1640, 1505, 1409, 1386, 1336, 1250, 1227, 1151, 1020, 963, 745 cm-1. MS (ESI): m/z = 236, 238 [M - H]-.
HRMS (ESI): calcd. for C10H7BrNO: 235.9711 [M - H]-; found 235.9718.
4.3.11. 1-(3-Bromo-1H-indol-2-yl)pentan-1-one (5b)
Method A: Prepared following General Procedure 2 from 4b (73 mg, 0.36 mmol) and N-bromosuccinimide (67
mg, 0.38 mmol). Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 92 mg (0.33
mmol, 92 % yield) of 5b.
Method B: Prepared following General Procedure 1 from 6 (286 mg, 1.01 mmol) and n-butyllithium (1.6M in
hexanes, 1.26 mL, 2.02 mmol). Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give
1
185 mg of 5b (0.66 mmol, 66 % yield) as a white solid. Mp 127 °C. H NMR (500 MHz, CD2Cl2): δ = 9.47 (s,
1H, NH), 7.67 (dd, J = 8.2 Hz, 0.9 Hz, 1H, 4-H), 7.44 (dd, J = 8.4 Hz, 0.9 Hz, 1H, 7-H), 7.39 (ddd, J = 8.3 Hz,
6.9 Hz, 1.1 Hz, 1H, 6-H), 7.23 (ddd, J = 8.1 Hz, 6.9 Hz, 1.0 Hz, 1H, 5-H), 3.22 - 3.16 (m, 2H, 2‘-H), 1.80 - 1.74
(m, 2H, 3‘-H), 1.51 - 1.43 (m, 2H, 4‘-H), 0.98 (t, J = 7.4 Hz, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ =
193.1 (C-1‘), 135.8 (C-7a), 132.6 (C-2), 128.6 (C-3a), 127.4 (C-6), 121.9 (C-4, C-5), 112.7 (C-7), 97.4 (C-3),
41.1 (C-2‘), 26.6 (C-3‘), 22.8 (C-4‘), 14.1 (CH3) ppm. IR: ṽ = 3296, 2945, 2864, 1648, 1503, 1395, 1342, 1219,
1082, 975, 934, 743, 730 cm-1. MS (ESI): m/z = 280, 282 [M + H]+. HRMS (EI): calcd. for C13H14BrNO:
279.0259 [M]+•; found 279.0226.
4.3.12. (3-Bromo-1H-indol-2-yl)(phenyl)methanone (5c)
Method A: Prepared following General Procedure 2 from 4c (406 mg, 1.84 mmol) and N-bromosuccinimide
(375 mg, 2.1 mmol). Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give 545 mg of
5c (1.82 mmol, 99 % yield) as a yellow solid.
10

ACCEPTED MANUSCRIPT
Method B: Prepared following General Procedure 1 from 6 (458 mg, 1.62 mmol) and phenyllithium (1.8M in
dibutyl ether, 1.80 mL, 3.24 mmol). Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to
give 297 mg of 5c (0.99 mmol, 62 % yield). Mp 177 °C. 1H NMR (500 MHz, (CD3)2CO): δ = 11.28 (s, 1H, NH),
7.90 - 7.84 (m, 2H, H-2‘‘, H-6‘‘), 7.71 - 7.66 (m, 1H, H-4‘‘), 7.65 (d, J = 8.2 Hz, 1H, H-4), 7.63 - 7.58 (m, 1H,
H-7), 7.57 (d, J = 7.4 Hz, 2H, H-3‘‘, H-5‘‘), 7.42 (ddd, J = 8.3 Hz, 7.0 Hz, 1.1 Hz, 1H, H-6), 7.26 (ddd, J = 8.1
Hz, 7.0 Hz, 0.9 Hz, 1H, H-5) ppm. 13C NMR (125 MHz, (CD3)2CO): δ = 187.5 (C-1‘), 138.1 (C-1‘‘), 136.5 (C-
7a), 132.7 (C-4‘‘), 132.0 (C-2), 129.5 (C-2‘‘, C-6‘‘), 128.5 (C-3‘‘, C-5‘‘), 127.8 (C-3a), 126.6 (C-6), 121.5 (C-
5), 120.8 (C-4), 113.0 (C-7), 96.6 (C-3) ppm. IR: ṽ =3301, 3059, 1621, 1600, 1573, 1498, 1446, 1406, 1380,
1365, 1335, 1265, 1228, 1146, 1058, 940, 743, 733 cm-1. MS (ESI): m/z =298, 300 [M - H]-. HRMS (ESI): calcd.
for C15H9BrNO: 297.9868 [M - H]-; found 297.9879.
4.3.13. (3-Bromo-1H-indol-2-yl)(thiophen-2-yl)methanone (5d)
Method A: Prepared following General Procedure 2 from 4d (53 mg, 0.23 mmol) and N-bromosuccinimide (44
mg, 0.24 mmol). Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 68 mg of 5d
(0.22 mmol, 94 % yield) as a yellow solid.
Method B: Prepared from 6 (202 mg, 0.71 mmol) and 2-thienyllithium, which was prepared in situ from 2-
bromthiophene (0.12 mL, 1.23 mmol) and tert-butyllithium (1.9M in pentane, 1.70 mL, 3.23 mmol) in the same
manner as described for 4d. Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 142
mg of 5d (0.46 mmol, 65 % yield) as a yellow solid. Mp 166 °C. 1H NMR (400 MHz, CD2Cl2): δ = 9.31 (s, 1H,
NH), 8.02 (dd, J = 3.8 Hz, 1.1 Hz, 1H, 5‘‘-H), 7.85 (dd, J = 5.0 Hz, 1.1 Hz, 1H, 3‘‘-H), 7.75 (dd, J = 8.2 Hz, 0.9
Hz, 1H, 4-H), 7.53 (dd, J = 8.3 Hz, 0.9 Hz, 1H, 7-H), 7.46 (ddd, J = 8.3 Hz, 6.9 Hz, 1.1 Hz, 1H, 6-H), 7.32 (ddd,
J = 8.0 Hz, 6.9 Hz, 1.1 Hz, 1H, 5-H), 7.27 (dd, J = 4.9 Hz, 3.8 Hz, 1H, 4‘‘-H) ppm. 13C NMR (100 MHz,
CD2Cl2): δ = 179.2 (C-1‘), 142.6 (C-1‘‘), 136.1 (C-7a), 136.0 (C-5‘‘), 134.9 (C-3‘‘), 132.1 (C-2), 128.5 (C-3a),
128.4 (C-4‘‘), 127.3 (C-6), 122.2 (C-5), 121.7 (C-4), 112.7 (C-7), 97.4 (C-3) ppm. IR: ṽ = 3290, 2980, 2360,
1601, 1512, 1491, 1413, 1334, 1264, 1225, 1055, 1029, 912, 887, 851, 781, 740, 673 cm-1. MS (ESI): m/z = 304,
306 [M - H]-. HRMS (ESI): calcd. for C13H7BrNOS: 303.9432 [M - H]-; found 303.9440.
4.3.14. 1-(3-Bromo-5-methoxy-1H-indol-2-yl)ethan-1-one (5e)
Prepared following General Procedure 2 from 4e (110 mg, 0.58 mmol) and N-bromosuccinimide (106 mg, 0.590
mmol). Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give 116 mg of 5e (0.43 mmol,
74 % yield) as a pale yellow solid. Mp 167 °C. 1H NMR (500 MHz, CD2Cl2): δ = 9.26 (s, 1H, NH), 7.30 (d, J =
9.0 Hz, 1H, 7-H), 7.06 (dd, J = 9.0 Hz, 2.4 Hz, 1H, 6-H), 7.00 (d, J = 2.4 Hz, 1H, 4-H), 3.89 (s, 3H, OCH3), 2.79
(s, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 189.7 (C-1‘), 155.4 (C-5), 132.7 (C-2), 130.8 (C-7a), 128.5
(C-3a), 119.6 (C-6), 113.4 (C-7), 101.0 (C-4), 97.5 (C-3), 55.7 (OCH3), 29.0 (CH3) ppm. IR: ṽ = 3312, 2932,
2831, 1630, 1510, 1489, 1402, 1387, 1283, 1248, 1225, 1207, 1169, 1113, 1036, 1012, 965, 820, 806, 694, 658
cm-1. MS (ESI): m/z = 266, 269 [M - H]-. HRMS (EI): calcd. for C11H10BrNO2 : 266.9895 [M]+•; found 266.9897.
4.3.15. 1-(3-Bromo-5-methoxy-1H-indol-2-yl)pentan-1-one (5f)
Prepared following General Procedure 2 from 4f (200 mg, 0.86 mmol) and N-bromosuccinimide (159 mg, 0.89
mmol). Purification was accomplished by FCC using 9:1 hexanes-ethyl acetate to give 258 mg of 5f (0.83 mmol,
11

ACCEPTED MANUSCRIPT
96 % yield) as a pale brown solid. Mp 153 °C. 1H NMR (400 MHz, CDCl3): δ = 9.29 (s, 1H, NH), 7.30 (dd, J =
8.9 Hz, 0.5 Hz, 7-H), 7.05 (dd, J = 8.9 Hz, 2.5 Hz, 1H, 6-H), 7.00 (d, J = 2.4 Hz, 1H, 4-H), 3.89 (s, 3H, OCH3),
3.20 - 3.14 (m, 2H, 2‘-H), 1.82 - 1.74 (m, 2H, 3‘-H), 1.52 - 1.42 (m, 2H, 4‘-H), 0.99 (t, J = 7.4 Hz, 3H, CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 192.7 (C-1‘), 155.4 (C-5) 132.4 (C-2), 130.7 (C-7a), 128.5 (C-3a), 119.4
(C-6), 113.4 (C-7), 101.0 (C-4), 96.7 (C-3), 55.7 (OCH3), 40.5 (C-2‘), 26.4 (C-3‘), 22.5 (C-4‘), 14.0 (CH3) ppm.
IR: ṽ = 3294, 2950, 1642, 1511, 1454, 1211, 1170, 1031, 979, 822 cm-1. MS (ESI): m/z = 308, 310 [M - H]-.
HRMS (EI): calcd. for C14H16BrNO2 : 309.0364 [M]+•; found 309.0374.
4.3.16. (3-Bromo-5-methoxy-1H-indol-2-yl)(phenyl)methanone (5g)
Prepared following General Procedure 2 from 4g (172 mg, 0.68 mmol) and N-bromosuccinimide (122 mg, 0.68
mmol). Purification was accomplished by FCC using 4:1 hexanes-ethyl acetate to give 147 mg of 5g (0.44
mmol, 65 % yield) as a yellow solid. Mp 159 °C. 1HNMR (400 MHz, CD2Cl2): δ = 9.32 (s, 1H, NH), 8.87 - 7.82
(m, 2H, 2‘‘-H, 6‘‘-H), 7.66 - 7.61 (m, 1H, 4‘‘-H), 7.56 - 7.50 (m, 2H, 3‘‘-H, 5‘‘-H), 7.37 (dd, J = 9.0 Hz, 0.5 Hz,
1H, 7-H), 7.07 (dd, J = 9.0 Hz, 2.5 Hz, 1H, 6-H), 7.02 (d, J = 2.4 Hz, 1H, 4-H), 3.88 (s, 3H, OCH3) ppm. 13C
NMR (100 MHz, CD2Cl2): δ = 188.1 (C-1‘), 156.0 (C-5), 138.1 (C-1‘‘), 132.9 (C-4‘‘), 132.3 (C-2), 131.7 (C-
7a), 129.9 (C-2‘‘, C-6‘‘), 129.0 (C-3a), 128.7 (C-3‘‘, C-5‘‘), 119.7 (C-6), 113.9 (C-7), 101.1 (C-4), 98.2 (C-3),
56.0 (OCH3) ppm. IR: ṽ = 3285, 3061, 3008, 2925, 1614, 1576, 1506, 1480, 1449, 1398, 1380, 1282, 1265,
1213, 1166, 1122, 1057, 1024, 970, 918, 830, 804, 729, 694 cm-1. MS (ESI): m/z = 330, 332 [M + H]+. HRMS
(ESI): calcd. for C16H13BrNO2: 330.0130 [M + H]+; found 330.0126.
4.3.17. (3-Bromo-5-methoxy-1H-indol-2-yl)(thiophen-2-yl)methanone (5h)
Prepared following General Procedure 2 from 4h (145 mg, 0.57 mmol) and N-bromosuccinimide (106 mg, 0.59
mmol). Purification was accomplished by FCC using 4:1 hexanes-acetone to give 174 mg of 5h (0.52 mmol, 92
% yield) as a yellow solid. Mp 148 °C. 1HNMR (400 MHz, CD2Cl2): δ = 9.26 (s, 1H, NH), 7.95 (dd, J = 3.8 Hz,
1.1 Hz, 1H, 5‘‘-H), 7.79 (dd, J = 4.9 Hz, 1.1 Hz, 1H, 3‘‘-H), 7.38 (dd, J = 8.5 Hz, 1.0 Hz, 1H, 7-H), 7.22 (dd, J =
5.0 Hz, 3.8 Hz, 1H, 4‘‘-H), 7.08 - 7.04 (m, 2H, 4-H, 6-H), 3.89 (s, 3H, OCH3) ppm. 13C NMR (100 MHz,
CD2Cl2): δ = 178.9 (C-1‘), 156.1 (C-5), 142.8 (C-1‘‘), 135.7 (C-5‘‘), 134.7 (C-3‘‘), 132.4 (C-2), 131.4 (C-7a),
128.9 (C-3a), 128.3 (C-4‘‘), 119.3 (C-6), 113.9 (C-7), 101.0 (C-4), 96.9 (C-3), 56.1 (OCH3) ppm. IR: ṽ = 3288,
2921, 1590, 1505, 1481, 1448, 1414, 1378, 1359, 1281, 1262, 1213, 1169, 1119, 1054, 1036, 1021, 965, 889,
856, 829, 803, 757, 718 cm-1. MS (ESI): m/z = 336, 338 [M + H]+. HRMS (ESI): calcd. for C14H11BrNO2S:
335.9694 [M + H]+; found 335.9690.
4.3.18. 3-Bromo-N-methoxy-N-methyl-1H-indole-2-carboxamide (6)
Prepared following General Procedure 2 from 3a (1.50 g, 7.35 mmol) and N-bromosuccinimide (1.33 g, 7.47
mmol). Purification was accomplished by FCC using 7:3 hexanes-acetone to give 1.78 g of 6 (6.30 mmol, 86 %
1
yield) as a yellow solid. Mp 121 °C. H NMR (500 MHz, CD2Cl2): δ = 9.72 (s, 1H, NH), 7.63 (dd, J = 8.1 Hz,
1.0 Hz, 1H, 4-H), 7.44 (d, J = 8.3 Hz, 1H, 7-H), 7.34 (ddd, J = 8.3 Hz, 7.0 Hz, 1.2 Hz, 1H, 6-H), 7.22 (ddd, J =
8.0 Hz, 7.0 Hz, 1.0 Hz, 1H, 5-H), 3.71 (s, 3H, OCH3), 3.40 (s, 3H, NCH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ
= 160.8 (C-1’), 135.5 (C-7a), 127.4 (C-3a), 126.3 (C-2), 125.9 (C-6), 121.6 (C-5), 120.7 (C-4), 112.5 (C-7), 96.8
(C-3), 62.3 (OCH3), 34.5 (NCH3) ppm. IR: ṽ = 3201, 3174, 2932, 1704, 1639, 1534, 1425, 1386, 1341, 1228,
12

ACCEPTED MANUSCRIPT
1034, 989, 914, 880, 747 cm-1. MS (EI): m/z % = 282 (20) [M]+•, 224 (96), 222 (100), 194 (20), 192 (22), 169
(18), 167 (16). HRMS (EI): calcd. for C11H11BrN2O2 : 282.0004 [M]+•; found 282.0028.
4.3.19. 1-Methyl-9H-pyrido[3,4-b]indole (harmane) (9a)
Prepared following General Procedure 3 from 5a (252 mg, 1.06 mmol), SPhos (60 mg, 0.15 mmol),
Pd2(dba)3ꢀCHCl3 (39 mg, 0.04 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.46 mL, 1.39 mmol) and
ammonium acetate (1.43 g, 18.57 mmol). Purification was accomplished by FCC using 1:3 hexanes-ethyl acetate
and 5 % triethylamine to give 90 mg of 9a (0.49 mmol, 47 % yield) as a pale brown solid. Mp 219 °C (lit.[15b]
231 °C). 1H NMR (500 MHz, CD2Cl2): δ = 8.98 (s, 1H, NH), 8.32 (d, J = 5.3 Hz, 1H, 3-H), 8.13 (d, J = 7.9 Hz,
1H, 5-H), 7.84 (d, J = 5.3 Hz, 1H, 4-H), 7.58 - 7.51 (m, 2H, 7-H, 8-H), 7.28 (ddd, J = 8.0 Hz, 6.5 Hz, 1.6 Hz, 1H,
6-H), 2.81 (s, 3H, CH3) ppm. 13C-NMR (125 MHz, CD2Cl2): δ = 142.5 (C-1), 140.8 (C-8a), 138.6 (C-3), 135.1
(C-9a), 128.5 (C-4a, C-7), 122.3 (C-4b), 122.1 (C-5), 120.3 (C-6), 113.2 (C-4), 112.1 (C-8), 20.5 (CH3) ppm. IR:
ṽ = 3315, 2923, 1642, 1505, 1410, 1387, 1336, 1250, 1227, 1152, 964, 745 cm-1. MS (ESI): m/z = 181 [M - H]-.
HRMS (ESI): calcd. for C12H9N2: 181.0766 [M - H]-; found 181.0772.
4.3.20. 1-Butyl-9H-pyrido[3,4-b]indole (9b)
Prepared following General Procedure 3 from 5b (151 mg, 0.54 mmol) SPhos (29 mg, 0.071 mmol),
Pd2(dba)3ꢀCHCl3 (19 mg, 0.018 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.24 mL, 0.71 mmol) and
ammonium acetate (476 mg, 6.18 mmol). Purification was accomplished by FCC using 1:2 hexanes-ethyl acetate
and 5 % triethylamine to give 66 mg of 9b (0.29 mmol, 54 % yield) as a brown solid. Mp 162 °C (lit.[44] 166 °C).
1H NMR (500 MHz, CD2Cl2): δ = 8.89 (s, 1H, NH), 8.33 (d, J = 5.4 Hz, 1H, 3-H), 8.13 (d, J = 7.9 Hz, 1H, 5-H),
7.84 (d, J = 5.4 Hz, 1H, 4-H), 7.59 - 7.53 (m, 2H, 7-H, 8-H), 7.29 (ddd, J = 8.0 Hz, 6.1 Hz, 1.9 Hz, 1H, 6-H),
3.17 - 3.06 (m, 2H, 1‘-H), 1.91 - 1.80 (m, 2H, 2‘-H), 1.46 - 1.37 (m, 2H, 3‘-H), 0.94 (t, J = 7.3 Hz, 3H, CH3)
ppm. 13C NMR (125 MHz, CD2Cl2): δ = 146.4 (C-1), 140.8 (C-8a), 138.4 (C-3), 134.6 (C-9a), 128.9 (C-4a),
128.6 (C-7), 122.3 (C-4b), 122.0 (C-5), 120.4 (C-6), 113.1 (C-4), 112.1 (C-8), 34.2 (C-1‘), 31.1 (C-2‘), 23.2 (C-
3‘), 14.2 (CH3) ppm. IR: ṽ = 3061, 2957, 2925, 2869, 1667, 1625, 1601, 1566, 1502, 1455, 1428, 1324, 1241,
1116, 1043, 741 cm-1. MS (EI): m/z (%) = 224 (7) [M]+•, 182 (100). HRMS (EI): calcd. for C15H16N2: 224.1314
[M]+•; found 224.1316.
4.3.21. 1-Phenyl-9H-pyrido[3,4-b]indole (9c)
Prepared following General Procedure 3 from 5c (545 mg, 1.82 mmol), SPhos (88 mg, 0.21 mmol),
Pd2(dba)3ꢀCHCl3 (57 mg, 0.055 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.80 mL, 2.37 mmol) and
ammonium acetate (1.45 g, 18.83 mmol). Purification was accomplished by FCC using 1:2 hexanes-ethyl acetate
and 5 % triethylamine to give 215 mg of 9c (0.88 mmol, 48 % yield) as a brown solid. Mp 241 °C (lit.[15a] 243 -
245 °C). 1H NMR (500 MHz, (CD3)2SO): δ = 11.52 (s, 1H, NH), 8.46 (d, J = 5.1 Hz, 1H, 3-H), 8.27 (d, J = 7.9
Hz, 1H, 5-H), 8.12 (d, J = 5.2 Hz, 1H, 4-H), 8.06 - 8.02 (m, 2H, 2’-H, 6’-H), 7.67 - 7.59 (m, 3H, 8-H, 3’-H, 5’-
H), 7.58 - 7.51 (m, 2H, 7-H, 4’-H), 7.27 (ddd, J = 7.9 Hz, 7.1 Hz, 0.9 Hz, 1H, 6-H) ppm. 13C NMR (125 MHz,
(CD3)2SO): δ = 142.2 (C-1), 141.1 (C-8a), 138.4 (C-3, C-1‘), 133.0 (C-9a), 129.1 (C-4a), 128.7 (C-3‘, C-5‘),
128.5 (C-2‘, C-6‘), 128.4 (C-4‘), 128.1 (C-7), 121.6 (C-5), 120.8 (C-4b), 119.5 (C-6), 113.9 (C-4), 112.4 (C-8)
ppm. IR: ṽ = 3060, 1625, 1563, 1497, 1469, 1456, 1447, 1416, 1323, 1278, 1235, 1140, 1065, 1019, 739 cm-1.
13

ACCEPTED MANUSCRIPT
MS (EI): m/z (%) = 244 (100) [M]+•, 231 (22), 181 (35), 169 (54), 119 (38). HRMS (EI): calcd. for C17H12N2:
244.1001 [M]+•; found 244.1040.
4.3.22. 1-(Thiophen-2-yl)-9H-pyrido[3,4-b]indole (9d)
Prepared following General Procedure 3 from 5d (136 mg, 0.44 mmol), SPhos (14 mg, 0.034 mmol),
Pd2(dba)3ꢀCHCl3 (9 mg, 0.0087 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.19 mL, 0.57 mmol) and
ammonium acetate (612 mg, 7.95 mmol). Purification was accomplished by FCC using 4:1 hexanes-acetone and
5 % triethylamine to give 43 mg of 9d (0.17 mmol, 39 % yield) as a yellow solid. Mp 145 °C (lit.[45] 148 - 149
°C). 1H NMR (500 MHz, CD2Cl2): δ = 8.79 (s, 1H, NH), 8.45 (d, J = 5.2 Hz, 1H, 3-H), 8.18 - 8.14 (m, 1H, 5-H),
7.92 (d, J = 5.2 Hz, 1H, 4-H), 7.77 (dd, J = 3.6 Hz, 1.0 Hz, 1H, 5‘-H), 7.62 - 7.55 (m, 2H, 7-H, 8-H), 7.53 (dd, J
= 5.1 Hz, 1.0 Hz, 1H, 3‘-H), 7.33 (ddd, J = 8.0 Hz, 6.3 Hz, 1.7 Hz, 1H, 6-H), 7.27 (dd, J = 5.1 Hz, 3.7 Hz, 1H,
4‘-H) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 143.9 (C-1‘), 141.1 (C-8a), 139.8 (C-3), 137.5 (C-1), 132.6 (C-
9a), 130.8 (C-4a), 129.2 (C-7), 128.6 (C-4‘), 127.8 (C-3‘), 125.4 (C-5‘), 122.3 (C-4b), 122.2 (C-5), 121.1 (C-6),
114.3 (C-4), 112.4 (C-8) ppm. IR: ṽ = 3357, 2971, 2932, 2884, 1626, 1565, 1467, 1409, 1379, 1341, 1309, 1161,
1130, 853, 817 cm-1. MS (ESI): m/z = 251 [M + H]+. HRMS (ESI): calcd. for C15H11N2S: 251.0643 [M + H]+;
found 251.0638.
4.3.23. 6-Methoxy-1-methyl-9H-pyrido[3,4-b]indole (isoharmine) (9e)
Prepared following General Procedure 3 from 5e (157 mg, 0.59 mmol), SPhos (19 mg, 0.046 mmol),
Pd2(dba)3ꢀCHCl3 (12 mg, 0.012 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.25 mL, 0.75 mmol) and
ammonium acetate (482 mg, 6.26 mmol). Purification was accomplished by FCC using 1:2 hexanes-ethyl acetate
and 5 % triethylamine to give 44 mg of 9e (0.21 mmol, 35 % yield) as a brown solid. Mp 166 °C (lit.[36] 200 °C).
1H NMR (500 MHz, (CD3)2SO): δ = 11.36 (s, 1H, NH), 8.15 (d, J = 5.3 Hz, 1H, 3-H), 7.89 (d, J = 5.3 Hz, 1H, 4-
H), 7.73 (d, J = 2.3 Hz, 1H, 5-H), 7.50 (d, J = 8.8 Hz, 1H, 8-H), 7.17 (dd, J = 8.8 Hz, 2.5 Hz, 1H, 7-H), 3.85 (s,
3H, OCH3), 2.74 (s, 3H, CH3) ppm. 13C NMR (125 MHz, (CD3)2SO): δ = 153.3 (C-6), 142.2 (C-1), 136.9 (C-3),
135.2 (C-8a), 135.0 (C-9a), 126.7 (C-4a), 121.4 (4b), 117.8 (C-7), 112.7 (C-8), 112.6 (C-4), 103.5 (C-5), 55.6
(OCH3), 20.4 (CH3) ppm. IR: ṽ = 3341, 2954, 2929, 2858, 1599, 1581, 1565, 1496, 1478, 1438, 1291, 1216,
1177, 1027, 824, 619 cm-1. MS (EI): m/z (%) = 212 (100) [M]+•, 197 (20). HRMS (EI): calcd. for C13H12N2O:
212.0950 [M]+•; found 212.0951.
4.3.24. 1-Butyl-6-methoxy-9H-pyrido[3,4-b]indole (9f)
Prepared following General Procedure 3 from 5f (150 mg, 0.48 mmol), SPhos (17 mg, 0.041 mmol),
Pd2(dba)3ꢀCHCl3 (11 mg, 0.011 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.22 mL, 0.65 mmol) and
ammonium acetate (493 mg, 6.40 mmol). Purification was accomplished by FCC using 1:1 hexanes-ethyl acetate
and 5 % triethylamine to give 50 mg of 9f (0.19 mmol, 40 % yield) as a yellow solid. Mp 174 °C. 1H NMR (400
MHz, (CD3)2CO): δ = 10.55 (s, 1H, NH), 8.26 (d, J = 5.3 Hz, 1H, 3-H), 7.86 (d, J = 5.3 Hz, 1H, 4-H), 7.73 (d, J
= 2.5 Hz, 1H, 5-H), 7.50 (d, J = 8.8 Hz, 1H, 8-H), 7.16 (dd, J = 8.8 Hz, 2.5 Hz, 1H, 7-H), 3.90 (s, 3H, OCH3),
3.17 - 3.10 (m, 2H, 1‘-H), 1.91 -1.82 (m, 2H, 2‘-H), 1.48 - 1.39 (m, 2H, 3‘-H), 0.93 (t, J = 7.4 Hz, 3H, CH3)
ppm. 13C NMR (125 MHz, (CD3)2CO): δ = 155.0 (C-6), 147.1 (C-1), 138.5 (C-3), 136.4 (C-8a), 135.9 (C-9a),
128.6 (C-4a), 123.0 (C-4b), 118.7 (C-7), 113.5 (C-8), 113.2 (C-4), 104.1 (C-5), 56.1 (OCH3), 34.4 (C-1‘), 31.3
14

ACCEPTED MANUSCRIPT
(C-2‘), 23.4 (C-3‘), 14.3 (CH3) ppm. IR: ṽ = 3114, 3043, 2952, 2925, 2857, 1596, 1580, 1563, 1493, 1477, 1438,
1416, 1290, 1213, 1177, 1125, 1027, 823 cm-1. MS (ESI): m/z = 253 [M - H]-. HRMS (ESI): calcd. for
C16H17N2O: 253.1341 [M - H]-; found 253.1348.
4.3.25. 6-Methoxy-1-phenyl-9H-pyrido[3,4-b]indole (9g)
Prepared following General Procedure 3 from 5g (100 mg, 0.35 mmol), SPhos (16 mg, 0.039 mmol),
Pd2(dba)3ꢀCHCl3 (10 mg, 0.0097 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.13 mL, 0.39 mmol) and
ammonium acetate (249 mg, 3.23 mmol). Purification was accomplished by FCC using 1:1 hexanes-ethyl acetate
and 5 % triethylamine to give 44 mg of 9g (0.16 mmol, 52 % yield) as a brown solid. Mp 175 °C (lit.[46] 181 -
1
184 °C). H NMR (400 MHz, CDCl3): δ = 8.54 (d, J = 5.3 Hz, 1H, 3-H), 8.48 (s, 1H, NH), 7.98 - 7.93 (m, 2H,
2‘-H, 6‘-H), 7.89 (d, J = 5.3 Hz, 1H, 4-H), 7.60 - 7.53 (m, 3H, 5-H, 3‘-H, 5‘-H), 7.46 (t, J = 7.4 Hz, 1H, 4‘-H),
7.39 (d, J = 8.8 Hz, 1H, 8-H), 7.20 (dd, J = 8.8 Hz, 2.5 Hz, 1H, 7-H), 3.95 (s, 3H, OCH3) ppm. 13C NMR (125
MHz, CDCl3): δ = 154.3 (C-6), 143.2 (C-1), 139.1 (C-3), 138.6 (C-1‘), 135.2 (C-8a), 134.1 (C-9a), 129.6 (C-4a),
129.2 (C-3‘, C-5‘), 128.8 (C-4‘), 128.1 (C-2‘, C-6‘), 122.2 (C-4b), 118.5 (C-7), 113.6 (C-4), 112.4 (C-8), 103.5
(C-5), 56.0 (OCH3) ppm. IR: ṽ = 3056, 2926, 1561, 1497, 1470, 1436, 1410, 1285, 1215, 1178, 1130, 1037, 816,
759, 695, 645, 624 cm-1. MS (EI): m/z (%) = 274 (100) [M]+•, 259 (90), 231 (20). HRMS (EI): calcd. for
C18H14N2O: 274.1106 [M]+•; found 274.1106.
4.3.26. 6-Methoxy-1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole (9h)
Prepared following General Procedure 3 from 5h (164 mg, 0.49 mmol), SPhos (17 mg, 0.041 mmol),
Pd2(dba)3ꢀCHCl3 (11 mg, 0.011 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.22 mL, 0.64 mmol) and
ammonium acetate (522 mg, 6.78 mmol). Purification was accomplished by FCC using 7:3 hexanes-acetone and
1
5 % triethylamine to give 51 mg of 9h (0.18 mmol, 37 % yield) as a yellow solid. Mp 141 °C. H NMR (500
MHz, CD2Cl2): δ = 9.09 (s, 1H, NH), 8.37 (d, J = 5.2 Hz, 1H, 3-H), 7.83 (d, J = 5.2 Hz, 1H, 4-H), 7.81 (dd, J =
3.6 Hz, 0.9 Hz, 1H, 5‘-H), 7.55 (d, J = 2.5 Hz, 1H, 5-H), 7.50 (d, J = 8.8 Hz, 1H, 8-H), 7.46 (dd, J = 5.1 Hz, 0.9
Hz, 1H, 3‘-H), 7.19 - 7.16 (m, 2H, 7-H, 4‘-H), 3.90 (s, 3H, OCH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ =
155.1 (C-6), 143.7 (C-1‘), 138.8 (C-3), 137.6 (C-1), 136.2 (C-8a), 133.2 (C-9a), 130.8 (C-4a), 128.6 (C-4‘),
127.7 (C-3‘), 125.7 (C-5‘), 122.6 (C-4b), 119.1 (C-7), 114.2 (C-4), 113.4 (C-8), 103.8 (C-5), 56.4 (OCH3) ppm.
IR: ṽ = 3210, 2954, 2830, 1581, 1561, 1492, 1463, 1435, 1414, 1285, 1206, 1126, 1110, 1071, 1029, 820, 704
cm-1. MS (EI): m/z (%) = 280 (100) [M]+•, 237(25). HRMS (EI): calcd. for C16H12N2OS: 280.0670 [M]+•; found
280.0660.
4.3.27. 1-(2-Bromophenyl)ethan-1-one (11a)
Prepared following General Procedure 4 from 2-bromo-N-methoxy-N-methylbenzamide (10) (256 mg, 1.05
mmol) and methylmagnesium bromide (3.0M in diethyl ether, 1.05 mL, 3.15 mmol). Purification was
accomplished by FCC using 4:1 hexanes-ethyl acetate to give 152 mg of 11a (0.76 mmol, 72 % yield) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.62 (dd, J = 8.0 Hz, 1.1 Hz, 1H, 3-H), 7.46 (dd, J = 7.6 Hz, 1.8 Hz,
1H, 6-H), 7.37 (td, J= 7.5 Hz, 1.2 Hz, 1H, 5-H), 7.30 (td, J = 7.8 Hz, 1.8 Hz, 1H, 4-H), 2.63 (CH3) ppm. 13C
NMR (125 MHz, CDCl3): δ = 201.5 (C-1‘), 141.6 (C-1), 134.0 (C-3), 131.9 (C-4), 129.0 (C-6), 127.6 (C-5),
119.0 (C-2), 30.5 (CH3) ppm. IR: ṽ = 3060, 1702, 1588, 1563, 1465, 1427, 1356, 1283, 1242, 1164, 1125, 1091,
15

ACCEPTED MANUSCRIPT
1026, 959, 759 cm-1. MS (EI): m/z (%) = 198 (20), 200 (19) [M]+•, 185 (97), 183 (100), 157 (31), 155 (33).
HRMS (EI): calcd. for C8H7BrO: 197.9680 [M]+•; found 197.9678.
4.3.28. 1-(2-Bromophenyl)heptan-1-one (11b)
Prepared following General Procedure 4 from 2-bromo-N-methoxy-N-methylbenzamide (10) (226 mg, 0.93
mmol) and hexylmagnesium bromide (2.0M in diethyl ether, 1.40 mL, 2.79 mmol). Purification was
accomplished by FCC using 9:1 hexanes-acetone to give 114 mg of 11b (0.42 mmol, 47 % yield) as a pale
yellow oil. 1H NMR (500 MHz, CD2Cl2): δ = 7.62 - 7.60 (m, 1H, 3-H), 7.40 - 7.34 (m, 2H, 5-H, 6-H), 7.30 (ddd,
J = 8.0 Hz, 6.7 Hz, 2.4 Hz, 1H, 4-H), 2.90 - 2.86 (m, 2H, 2‘-H), 1.71 - 1.64 (m, 2H, 3‘-H), 1.40 - 1.28 (m, 6H,
4‘-H, 5‘-H, 6‘-H), 0.91 - 0.86 (m, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 204.8 (C-1‘), 142.7 (C-1),
134.1 (C-3), 131.8 (C-4), 128.7 (C-6), 128.0 (C-5), 118.9 (C-2), 43.3 (C-2‘), 32.2 (C-5‘), 29.4 (C-4‘), 24.5 (C-
3‘), 23.1 (C-6‘), 14.4 (CH3) ppm. IR: ṽ = 3066, 2955, 2929, 2857, 1702, 1588, 1563, 1465, 1428, 1402, 1360,
1281, 1221, 1201, 1113, 1058, 1026, 980, 757 cm-1. MS (ESI): m/z = 269, 271 [M + H]+. HRMS (ESI): calcd. for
C13H18BrO: 269.0541 [M + H]+; found 269.0542.
4.3.29. (2-Bromophenyl)(phenyl)methanone (11c)
Prepared following General Procedure 4 from 2-bromo-N-methoxy-N-methylbenzamide (10) (244 mg, 1.01
mmol) and methylmagnesium bromide (3.0M in diethyl ether, 1.0 mL, 3.03 mmol). Purification was
accomplished by FCC using 4:1 hexanes-ethyl acetate to give 196 mg of 11c (0.75 mmol, 75 %) as a pale yellow
oil. 1H NMR (500 MHz, CDCl3): δ = 7.76 - 7.72 (m, 2H, 2‘‘-H, 6‘‘-H), 7.57 (d, J = 8.0 Hz, 3-H), 7.55 - 7.50 (m,
1H, 4‘‘-H), 7.42 - 7.36 (m, 2H, 3‘‘-H, 5‘‘-H), 7.34 (dd, J = 6.9 Hz, 1.5 Hz, 1H, 5-H), 7.30 - 7.25 (m, 2H, 4-H, 6-
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 196.0 (C-1‘), 140.8 (C-1), 136.2 (1‘‘), 133.9 (C-4‘‘), 133.3 (C-3),
131.3 (C-4), 130.3 (C-2‘‘, C-6‘‘), 129.1 (C-6), 128.8 (C-3‘‘, C-5‘‘), 127.3 (C-5), 119.6 (C-2) ppm. IR: ṽ = 3059,
1671, 1595, 1581, 1466, 1448, 1430, 1315, 1287, 1250, 1153, 1046, 1024, 927, 762, 737, 701 cm-1. MS (EI): m/z
(%) = 260 (90) [M]+•, 185 (97), 183 (95). HRMS (EI): calcd. for C13H9BrO: 259.9837 [M]+•; found 259.9845.
4.3.30. 1-Methylisoquinoline (12a)
Prepared following General Procedure 3 from 11a (128 mg, 0.64 mmol), SPhos (26 mg, 0.063 mmol),
Pd2(dba)3ꢀCHCl3 (15 mg, 0.014 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.28 mL, 0.83 mmol) and
ammonium acetate (504 mg, 6.55 mmol). Purification was accomplished by FCC using 4:1 hexanes-acetone and
5 % triethylamine to give 61 mg of 12a (0.43 mmol, 67 % yield) as a yellow oil. 1H NMR (500 MHz, CD2Cl2): δ
= 8.35 (d, J = 5.8 Hz, 1H, 3-H), 8.11 (dd, J = 8.4 Hz, 0.9 Hz, 1H, 8-H), 7.81 (d, J = 8.2 Hz, 1H, 5-H), 7.67 (ddd,
J = 8.2 Hz, 6.9 Hz, 1.2 Hz, 1H, 6-H), 7.59 (ddd, J = 8.3 Hz, 6.9 Hz, 1.3 Hz, 1H, 7-H), 7.50 (d, J = 5.8 Hz, 4-H),
2.92 (s, 3H, CH3) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 159.0 (C-1), 142.2 (C-3), 136.2 (C-4a), 130.2 (C-6),
127.8 (C-8a), 127.5 (C-5), 127.3 (C-7), 126.0 (C-8), 119.4 (C-4), 22.6 (CH3) ppm. IR: ṽ = 3064, 2925, 2853,
1704, 1588, 1563, 1531, 1494, 1438, 1357, 1308, 1243, 1205, 1134, 1026, 827, 780, 759, 734 cm-1. MS (EI): m/z
(%) = 143 (100) [M]+•, 115 (24). HRMS (EI): calcd. for C10H9N: 143.0735 [M]+•; found 143.0719.
4.3.31. 1-Hexylisoquinoline (12b)
16

ACCEPTED MANUSCRIPT
Prepared following General Procedure 3 from 11b (275 mg, 1.02 mmol), SPhos (34 mg, 0.083 mmol),
Pd2(dba)3ꢀCHCl3 (21 mg, 0.020 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.45 ml, 1.34 mmol) and
ammonium acetate (1.17 g, 15.19 mmol). Purification was accomplished by FCC using 6:1 hexanes-acetone and
1
5 % triethylamine to give 161 mg of 12b (0.75 mmol, 74 % yield) as a pale yellow oil. H NMR (500 MHz,
CDCl3): δ = 8.42 (d, J = 5.7 Hz, 1H, 3-H), 8.14 (d, J = 8.4 Hz, 1H, 8-H), 7.78 (d, J = 8.1 Hz, 1H, 5-H), 7.63 (ddd,
J = 8.2 Hz, 6.9 Hz, 1.3 Hz, 1H, 6-H), 7.56 (ddd, J = 8.3 Hz, 6.9 Hz, 1.3 Hz, 1H, 7-H), 7.47 (d, J = 5.7 Hz, 1H, 4-
H), 3.31 - 3.25 (m, 2H, 1‘-H), 1.89 - 1.81 (m, 2H, 2‘-H), 1.52 - 1.43 (m, 2H, 3‘-H), 1.37 - 1.29 (m, 4H, 4‘-H, 5‘-
H) , 0.89 (t, J = 7.1 Hz, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.4 (C-1), 141.9 (C-3), 136.2 (C-4a),
129.7 (C-6), 127.3 (C-5), 126.9 (C-7, C-8a), 125.3 (C-8), 119.1 (C-4), 35.6 (C-1‘), 31.7 (C-4‘), 29.8 (C-2‘), 29.6
(C-3‘), 22.6 (C-5‘), 14.1 (CH3) ppm. IR: ṽ = 3051, 2980, 2954, 2927, 2857, 1621, 1586, 1562, 1502, 1464, 1387,
1357, 1339, 1239, 1141, 1105, 1017, 867, 822, 746 cm-1. MS (ESI): m/z = 214 [M + H]+. HRMS (ESI): calcd.
for C15H20N: 214.1596 [M + H]+; found 214.1591.
4.3.32. 1-Phenylisoquinoline (12c)
Prepared following General Procedure 3 from 11c (140 mg, 0.54 mmol), SPhos (27 mg, 0.066 mmol),
Pd2(dba)3ꢀCHCl3 (17 mg, 0.016 mmol), tributyl[(Z)-2-ethoxyvinyl]stannane (7) (0.25 mL, 0.75 mmol) and
ammonium acetate (595 mg, 7.72 mmol). Purification was accomplished by FCC using 3:1 hexanes-ethyl acetate
and 5 % triethylamine to give 90 mg of 12c (0.44 mmol, 82 % yield) as a pale yellow solid. Mp 93 °C (lit.[47] 93-
94 °C). 1H NMR (500 MHz, CDCl3): δ = 8.62 (d, J = 5.7 Hz, 1H, 3-H), 8.11 (d, J = 8.5 Hz, 1H, 8-H), 7.89 (d, J =
8.2 Hz, 5-H), 7.73 - 7.68 (m, 3H, 6-H, 2‘-H, 6‘-H), 7.66 (d, J = 5.7 Hz, 4-H), 7.56 - 7.52 (m, 3H, 7-H, 3‘-H, 5‘-
H), 7.52 - 7.48 (m, 1H, 4‘-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.9 (C-1), 142.4 (C-3), 139.7 (C-1‘),
137.0 (C-4a), 130.1 (C-6, C-2‘, C-6‘), 128.7 (C-4‘), 128.5 (C-3‘, C-5‘), 127.7 (C-8), 127.3 (C-7), 127.1 (C-5),
126.9 (C-8a), 120.0 (C-4) ppm. IR: ṽ = 3053, 2928, 2854, 1618, 1582, 1553, 1499, 1440, 1382, 1353, 1319,
1245, 1167, 1021, 876, 824, 168, 754, 700, 675 cm-1. MS (ESI): m/z = 206 [M + H]+. HRMS (ESI): calcd. for
C15H12N: 206.0967 [M + H]+; found 206.0964.
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