Short syntheses of the indole alkaloids alocasin A, scalaridine A, and hyrtinadine A-B

Article abstract of DOI:10.1016/j.tet.2016.05.057

Expedient syntheses of the indole alkaloids alocasin A, scalaridine A, and hyrtinadine A-B are presented. All four natural products contain one or two 5-hydroxyindolyl units. Three palladium catalyzed reactions, an alkyne hydrostannylation, a Kosugi-Migita-Stille cross coupling and a reductive N-heterocyclization are the key steps in the syntheses.

Full text of DOI:10.1016/j.tet.2016.05.057

Accepted Manuscript
Short syntheses of the indole alkaloids alocasin A, scalaridine A, and hyrtinadine A-B
Nurul H. Ansari, Björn C.G. Söderberg
PII:
S0040-4020(16)30474-4
10.1016/j.tet.2016.05.057
TET 27784
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 April 2016
Revised Date: 18 May 2016
Accepted Date: 20 May 2016
Please cite this article as: Ansari NH, Söderberg BCG, Short syntheses of the indole alkaloids alocasin
A, scalaridine A, and hyrtinadine A-B, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.057.
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ACCEPTED MANUSCRIPT
Graphical abstract for:
Short syntheses of the indole alkaloids alocasin A, scalaridine A, and
hyrtinadine A-B
Nurul H. Ansari and Björn C. G. Söderberg1
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown,
West Virginia 26506-6045, USA
Keywords: annulation; palladium-catalyzed; alkaloid
1 Corresponding author. Tel.: +1-304-293-3435; fax: +1-304-293-4904; e-mail:
bjorn.soderberg@mail.wvu.edu

ACCEPTED MANUSCRIPT
Short syntheses of the indole alkaloids alocasin A, scalaridine A, and hyrtinadine A-B
Nurul H. Ansari and Björn C. G. Söderberg1
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West
Virginia 26506-6045, USA
Abstract Expedient syntheses of the indole alkaloids alocasin A, scalaridine A, and
hyrtinadine A-B are presented. All four natural products contain one or two 5-hydroxyindolyl
units. Three palladium catalyzed reactions, an alkyne hydrostannylation, a Kosugi-Migita-
Stille cross coupling and a reductive N-heterocyclization are the key steps in the syntheses.
Introduction Several bisindole alkaloid metabolites such as hamacanthins,1 dragmacidins,2
topsentins (spongetins),1a-b, 1e, 3 nortopsentins,4 and rhopaladins5 have been isolated from
marine sponges and tunicates.6 These metabolites exhibit diverse bioactivities such as
cytotoxic,1b, 1g, 2d, 3a, 4 antiviral,1g, 2b, 4 antifungal,7 antibacterial,7 and antiplasmodial8 activities.
The common feature of all these alkaloids is the presence of an imidazole/pyrazinone (or a
reduced derivative) linker either attached directly to the 3 positions of the two indoles or
attached via a carbonyl carbon and/or methine. In addition to a heterocyclic linker, the indole
fragments are usually brominated in one or both of the 6 positions. Hydroxylation in the 6 or
7 position can also be found in some of the metabolites.
Keywords: N-heterocyclization; palladium-catalyzed; indole; alkaloid synthesis
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In contrast to the marine natural products discussed above, an unusual alkaloid, alocasin A,
was recently isolated from the dried rhizomes of the herbaceous plant Alocasia macrorrhiza,
collected in the People Republic of China (Figure 1).9 To our knowledge, this is the only
heterocycle-linked bisindole isolated from a terrestrial source. The presence of hydroxylation
in the two 5-positions is also unusual for this type of bisindoles, but can also be found in
hyrtinadine A isolated from the marine sponge Hyrtios sp,10 and scalaridine A and hyrtinadine
B isolated from the marine sponge Scalarispongia sp11 (Figure 10 ). Hyrtinadine A and
scalaridine A are the only example of pyrimidine or pyridine linked bisindole alkaloids.
Figure 1. Structures of alocasin A, scalaridine A, hyrtinadine A-B.
alocasin A
scalaridine A
hyrtinadine A
hyrtinadine B
Total syntheses of alocasin A, scalaridine A, and hyrtinadine A using a cross-coupling strategy
have recently been reported. In three of the syntheses of these pyrazine, pyridine, and
pyrimidine linked bisindole alkaloids, a one-pot double Suzuki-Miyaura cross coupling of 1-t-
butoxycarbonyl-5-methoxy-3-boryl indole with 2,5-dibromopyrazine (alocasin A),12 3,5-
dibromopyridine (scalaridine A),13 and 2,5-dibromopyrimidine (hyrtinadine A)14 was used as
the key step. A palladium catalyzed double cross coupling of a triindolylindium reagent and 2-
1 Corresponding author. Tel.: +1-304-293-3435; fax: +1-304-293-4904; e-mail: bjorn.soderberg@mail.wvu.edu
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chloro-4-bromopyrimidine was used in a second synthesis of hyrtinadine A.15 Hyrtinadine B
has not yet been synthesized.
We report herein a different strategy for the synthesis of the four alkaloids seen in Figure 1.
The key indole forming reaction is a late stage palladium catalyzed N-heterocyclization of 2-
nitroaryl-substituted alkenes using carbon monoxide as the ultimate reducing agent. This
methodology is emerging as a powerful methodology for the synthesis of a variety of
substituted indoles.16 A number of naturally occurring indoles have been synthesized
including tjipanazoles,17 murrayaquinone,18 bauerine A,19 carbazole alkaloids,20 mushroom
metabolites,21 and the tetracyclic alkaloid ht-13-B22 using this methodology as the key indole
forming step.
Results and Discussion Alocasin A was synthesized in 6 steps from 4-benzyloxy-2-bromo-1-
nitrobenzene (1) using a palladium catalyzed reaction in five of the steps (Scheme 1). The
synthesis commenced with a Sonogashira coupling of 1 with trimethylsilylethyne followed by
a tetrabutylammonium fluoride (TBAF) mediated deprotection affording the expected
products 2 and 3, respectively, in high isolated yields. Highly α-regioselective palladium
catalyzed hydrostannylations of ortho-substituted arylalkynes have been reported by Alami et
al.23 Following their procedure, regioselective hydrostannylation of 3 gave the expected
vinylstannane 4 in excellent yield.24
Palladium catalyzed reactions of halopyrazines25 including Sonogashira,26 Suzuki-Miura,27
Negishi,28 Kosugi-Migita-Stille29 cross couplings have been reported. A double Suzuki-Miura
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cross coupling of 2,5-dibromopyrazine with 3-borylated indoles was used to prepare 2,5-
bisindolopyrazines.14, 30 A sequential Suzuki-Miura and Kosugi-Migita-Stille cross coupling of
2,5-dibromo-3-methoxypyrazine was used in total synthesis of the bisindolepyrazine alkaloid
dragmacidine D.31 In the present synthesis of alocasin A, the central pyrazine ring was
installed by a one-pot double Kosugi-Migita-Stille cross coupling of vinylstannane 4 with 2,5-
dibromopyrazine (5) affording 6 in a relatively low isolated yield. In addition to the
anticipated coupling product, homo-coupling product 7 was also isolated in 40% yield. The
two products were readily separated by chromatography on silica gel. Cross couplings of
related styryltin derivatives with aryl bromides and iodides have been reported.32
A double palladium catalyzed reductive N-heterocyclization of pure 6 using a
bis(dibenzylidenacetone)palladium-1,3-bis(diphenyl)propane- 1,10-phenanthroline catalyst
system in the presence of carbon monoxide (pCO=6 atm, 120 oC ) in dimethylformamide,
furnished di-O-benzyl-protected alocasin A (8) in excellent yield. The benzyl groups were
smoothly removed by hydrogenolysis using Pd/C-H2 (10% Pd, pH2=4 atm) in ethanol at 60 oC
affording the naturally occurring bisindolopyrazine alocasin A. The synthesis was completed
using six different synthetic transformations in 21% overall yield starting from 1. It should be
noted that all transformations from 4 to alocasin A involved reactions at two different centers
making a total of nine connections/disconnections with an 84% average yield per step.
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Scheme 1. Synthesis of alocasin A.
1
2 (90%)
3 (90%)
4 (87%)
6 (39%)
7 (40%)
8 (89%)
alocasin A (86%)
Based on the successful completion of alocasin A, a similar sequence using a double Kosugi-
Migita-Stille cross coupling of 3,5-dibromopyridine (9) was envisioned for the synthesis of the
second alkaloid scalaridine A. While 3,5-dibromopyridine has previously been utilized in cross
coupling reactions with aryltin reagents,33 the use of vinyl tin reagents has not been reported.
Disappointingly, all attempted cross coupling experiments of 4 with 9, using a number of
palladium-based catalyst systems, were unsuccessful. The only product identified from these
reactions was the homo-coupled product 7 derived from 4 (Scheme 2). Low yields in addition
to a preference for cine-substitution34 have been observed in palladium catalyzed cross
coupling reactions using 1-trimethylstannyl-1-phenyl-ethene and 2- and 3-bromopyridines.35
Thus, a slightly different strategy was envisioned for the synthesis of scalaridine A wherein
the polarity of the cross coupling components was reversed that is, cross coupling of a
heterocyclic vinyltin reagent with a phenyl halide.
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Scheme 2. Attempted cross coupling of 4 with 3,5-dibromopyridine (9).
4
7 (30%)
Hydrostannylations of ethyne-substituted heterocycles are relatively rare in the literature. A
single example of a copper catalyzed, α-regioselective hydrostannylation, of 2-
ethynylpyridine using hexamethylditin was reported by Yoshida et al.32 A palladium catalyzed
hydrostannylation of an N-protected 3-ethynylindole also gave exclusively the α-stannylated
product.36 In contrast, palladium catalyzed hydrostannylation of 2-ethynylpyridine with an
ionic liquid supported stannane was shown to be relatively unselective having an α/β
= 38:62.37
In our case for the synthesis of scalaridine A, palladium catalyzed hydrostannylation of 3,5-
diethynylpyridine (10) gratifyingly furnished 11 with exclusively α-selectivity (Scheme 3).
Subsequent Kosugi-Migita-Stille cross coupling of 11 with 4-benzyloxy-2-iodo-1-nitrobenzene
(12) gave the expected product 13. Concluding the synthetic route, a reductive N-
heterocyclization to give the pyridine linked bisindole 14 and debenzylation gave scalaridine
A. Starting from 10, the overall yield was 13% in four synthetic transformations.
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Scheme 3. Synthesis of scalaridine A.
10
11 (69%)
13 (35%)
14 (67%)
scalaridine A (79%)
2,5-Dichloropyrimidine has been shown to participate in Kosugi-Migita Stille cross coupling
reactions with vinyl stannanes, reacting first in the 2-position then in the 5-position.38
However, the related compound 2,5-dibromopyrimidine (15) proved to be a problematic
substrate in cross coupling reactions (Scheme 4). Attempted coupling of 15 with 4 gave three
identifiable products, destannylated styrene 16, an inseparable mixture of homo-coupling
product 7 and an unknown impurity, and the monocoupled, debrominated pyrimidine 17. The
site of cross coupling was determined to be the 2-position based on 1H NMR wherein a
doublet resonance at δ 8.65 ppm integrating to two protons and a triplet at δ 7.10 ppm
integrating to one proton with a coupling constant of J=5.2 Hz was observed. Similar chemical
shifts and coupling constants have been reported for related 2-substituted pyrimidines.39
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Scheme 4. Attempted cross coupling of 4 with 2,5-dibromopyrimidine.
16 (10%)
7 (<9%)
17 (27%)
Instead of a cross coupling between 4 and 15, the bonds between the pyrimidine and indole
rings were again made by reversing the polarity of the coupling reagents. Double Sonogashira
coupling40 of 2,5-dibromopyrimidine (15) with trimethylsilylethyne gave the expected
product 18, which was desilylated using potassium carbonate in methanol to give 2,5-
diethynylpyrimidine (19). Palladium catalyzed hydrostannylation of 19 afforded the
divinyltin-substituted pyrimidine 20, again with excellent α-regioselectivity. The subsequent
steps, Kosugi-Migita-Stille cross coupling of 20 with 12, reductive N-heterocyclization, and
debenzylation proceeded uneventfully to give hyrtinadine A. The overall yield of hyrtinadine
A from 15 was 12% in five steps.
Scheme 5. Synthesis of hyrtinadine A.
15
18 (R=TMS, 100%)
19 (R=H, 93%)
20 (40%)
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21 (53%)
22 (68%)
hyrtinadine A (87%)
Finally, 5-ethenylpyrimidine (23) served as the starting point for the synthesis of the
remaining alkaloid hyrtinadine B. Following the sequence of steps used in the synthesis of
hyrtinadine A, palladium catalyzed 1) hydrostannylation, 2) cross-coupling, 3) reductive
cyclization, and 4) debenzylation, hyrtinadine B was prepared from 23 in 28% overall yield in
four synthetic steps.
Scheme 6. Synthesis of hyrtinadine B.
23
24 (69%)
25 (53%)
26 (90%)
hyrtinadine B (84%)
In conclusion, short synthetic routes to four naturally occurring alkaloids, alocasin A,
scalaridine A, and hyrtinadine A-B have been described. The overall isolated yields were 27%
(six steps), 13% (four steps), 12% (five steps), and 28% (four steps), respectively. The results
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from the palladium catalyzed hydrostannylations seen in Schemes 3, 5, and 6 indicates that an
ortho-substituent is not a requirement for high α-selectivity when ethynyl substituted
heterocycles are used as the substrate systems as is the case for phenylethynes.
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Experimental Section
General Procedures. All NMR spectra were recorded in CDCl3 or CD3OD at 400/600 MHz (1H
NMR) and 100/150 MHz (13C NMR, 1H-broadband decoupled) at ambient temperature. The
chemical shifts are expressed in δ values relative to Me4Si (0.0 ppm, 1H and 13C), CD3OD (3.34
ppm, 1H; 49.9 ppm, 13C), or CDCl3 (77.0 ppm, 13C) internal standards.
Tetrahydrofuran (THF) was purified/dried via two consecutive columns composed
of activated alumina and Q5 catalyst on a Glass Contours solvent purification system.
Dichloromethane and toluene was purified/dried via two consecutive columns composed
of activated alumina on a Glass Contours solvent purification system. Hexanes, and ethyl
acetate were distilled from calcium hydride. Chemicals prepared according to literature
procedures have been footnoted first time used; all other reagents were obtained from
commercial sources and used as received. All reactions were performed under a nitrogen
atmosphere in oven-dried glassware unless otherwise stated. Solvents were removed from
reaction mixtures and products on a rotary evaporator at water aspirator pressure.
2-(5-Benzyloxy-2-nitrophenyl)-1-trimethylsilylethyne (2). 5-Benzyloxy-2-nitro-1-
bromobenzene41 (1) (3.91 g, 12.7 mmol) was dissolved in toluene (10 mL) and triethylamine
(NEt3, 40 mL) whereby bis(triphenylphosphinepalladium dichloride (PdCl2(PPh3)2, 0.62 g,
0.88 mmol) and copper iodide (CuI, 0.17 g, 0.89 mmol) were added successively. The reaction
mixture was stirred under a nitrogen atmosphere for five minutes. Trimethylsilylethyne (2.17
mL, 15.2 mmol) was added drop wise and the resulting mixture was stirred at 48 oC for 24 h.
After cooling to ambient temperature, the mixture was filtered through celite, and the celite
was washed with EtOAc. The solvents were removed from the filtrate under reduced pressure.
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The resulting residue was purified by chromatography (EtOAc/hexane, 1:9) affording 2 (3.71
g, 11.4 mmol, 90%) as a faint yellow solid. mp=96 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 (d,
J=9.2 Hz, 1H), 7.43-7.36 (m, 5H), 7.18 (d, J=2.8 Hz, 1H), 6.97 (dd, J=9.2, 2.8 Hz, 1H), 5.14 (s,
2H), 0.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.8, 143.2, 135.3, 128.8, 128.5, 127.5, 127.0,
120.7, 120.1, 115.4, 103.7, 99.9, 70.7, 0.4; IR (APT) 1572, 1515, 1333. 1248, 836 cm-1; HRMS
(ESI) calcd for C18H20NO3Si (M+H+) 326.1212, found 326.1195.
1-(5-Benzyloxy-2-nitrophenyl)ethyne (3). A solution of tetrabutylammonium fluoride (1M
in THF) was added drop wise to a 0 oC cold solution of 2 (2.32 g, 7.13 mmol) in THF (30 mL).
The resulting mixture was stirred at 0 oC for 30 min. The solvent was removed under reduced
pressure and the resulting residue was purified by chromatography (EtOAc/hexane, 2:8) to
give 3 (1.63 g, 6.44 mmol, 90%) as a white solid. mp=122 oC; 1H NMR (400 MHz, CDCl3) δ 8.10
(d, J=9.2 Hz, 1H), 7.45-7.35 (m, 5H), 7.22 (d, J=2.8 Hz, 1H), 7.02 (dd, J=9.2, 2.8 Hz, 1H), 5.15 (s,
2H), 3.52 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 161.9, 143.2, 135.1, 128.8, 128.7, 127.5, 127.1,
120.8, 119.7, 115.7, 85.0, 79.0, 70.8; IR (APT) 3284, 1579, 1507, 1327, 1249, 1073 cm-1; HRMS
(ESI) calcd for C15H12NO3 (M+H+) 254.0817, found 254.0805.
1-(5-Benzyloxy-2-nitrophenyl)-1-tributylstannylethene (4). To a solution of 3 (1.60 g,
6.32 mmol) in THF (30 mL) under N2 was added PdCl2(PPh3)2 (0.44 g, 0.63 mmol) and
tributyltin hydride (2.76 g, 9.48 mmol). The resulting dark brown mixture was stirred at
ambient temperature under N2 for 24 h. The mixture was diluted with EtOAc (30 mL) and
washed with H2O (3x30 mL) and brine (30 mL), The organic layer was dried (MgSO4), filtered,
at the solvent was removed under reduced pressure. The residue was purified by
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chromatography (EtOAc/hexane, 1:19) affording 4 (2.99 g, 5.49 mmol, 87%) as a brown
viscous liquid. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=9.2 Hz, 1H), 7.45-7.33 (m, 5H), 6.86 (dd,
J=9.2, 2.4 Hz, 1H), 6.63 (d, J=2.0 Hz, 1H), 5.72 (d, J=2.4 Hz, 1H), 5.41 (d, J=2.0 Hz, 1H), 5.14 (s,
2H), 1.56-1.37 (m, 6H), 1.27 (sext, J=7.2 Hz, 6H), 0.95 – 0.84 (m, 15H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 155.7, 147.6, 139.1, 135.6, 128.7, 128.4, 127.5, 127.1, 124.8, 114.6, 112.7,70.5,
28.8, 27.3, 13.6, 11.0; IR (ATR) 2954, 2922, 1567, 1329, 1283, 1243, 1228, 694 cm-1; HRMS
(ESI) calcd for C27H40NO3Sn (M+H+) 546.2030, found 546.2025.
2,5-Di(1-(5-benzyloxy-2-nitrophenyl)-1-ethenyl)pyrazine (6) and 2,3-di(5-benzyloxy-
2-nitrophenyl)-1,3-butadiene (7). To a solution of 2,5-dibromopyrazine (5) (100 mg, 0.420
mmol) and 4 (458 mg, 0.841 mmol) in dry DMF (2 mL) was added
bis(dibenzylideneacetone)palladium (Pd(dba)2, 19.4 mg, 0.034 mmol), CuI (160 mg, 0.841
mmol), and PPh3 (35.3 mg, 0.135 mmol) respectively. The resulting brown mixture was
stirred under an atmosphere of N2 at 90 oC for 41 h. EtOAc (25 mL) was added and the
mixture was washed with H2O (3x25 mL) and brine (3x25 mL). The organic layer was dried
(MgSO4), filtered, and the solvents were removed under reduced pressure. The residue was
purified by chromatography on SiO2/K2CO3 (10% K2CO3, EtOAc/hexane, 1:9, then 2:8) to give,
in order of elution, 7 (85.5 mg, 0.168 mmol, 40%) followed by 6 (96 mg, 0.16 mmol, 39%)
both as white solids. Analytical data for 6: mp=186-187 oC; 1H NMR (400 MHz, CDCl3) δ 8.51
(s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.45-7.33 (m, 5H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 7.01 (d, J=2.4 Hz,
1H), 6.29 (s, 1H), 5.57 (s, 1H), 5.17 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.7, 149.9, 144.7,
141.2, 140.5, 137.8, 135.4, 128.8, 128.5, 127.6, 127.3, 118.8, 118.4, 114.6, 70.8; IR (APT) 1578,
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1508, 1326, 1242, 1001, 919, 750 cm-1; HRMS (ESI) calcd for C34H27N4O6 (M+H+) 587.1931,
found 587.1925.
Analytical data for 7: mp=158-160 oC; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=9.2 Hz, 1H), 7.48-
7.36 (m, 5H), 7.17 (d, J=2.8 Hz, 1H), 7.03 (dd, J=9.2, 2.8 Hz, 1H), 5.20 (s, 2H), 5.08 (s, 1H), 4.88
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.2, 145.6, 141.7, 138.3, 135.5, 128.7, 128.4, 127.8,
126.8, 117.5, 117.1, 114.9, 70.7; IR (ATR) 1573, 1513, 1343, 1230, 1007 cm-1; HRMS (ESI)
calcd for C30H25N2O6 (M+H+) 509.1713, found 509.1715.
5,5’-Dibenzyloxy-3,3’-(2,5-pyrazindiyl)bis-1(H)-indole (8). To a solution of 6 (114 mg,
0.194 mmol) in dry DMF (2 mL), in a treaded ACE-Glass pressure tube, was added 1,3-
bis(diphenylphosphino)propane (dppp, 6 mg, 0.014 mmol), 1,10-phenanthroline (phen, 5 mg,
0.027 mmol) and Pd(dba)2 (8 mg, 0.014 mmol). The tube was fitted with a pressure head, and
the solution was saturated with 3 cycles of CO (6 atm) and stirred at 120 oC (6 atm CO, 72 h).
The reaction mixture was cooled to ambient temperature, diluted with EtOAc (30 mL), and
washed with H2O (3x30 mL) and brine (3x30 mL). The organic layer was dried (MgSO4),
filtered, and the solvents were removed under reduced pressure. The residue was purified by
chromatography (EtOAc/hexane, 3:7, then 6:4) to afford 8 (90 mg, 0.172 mmol, 89%) as
yellow powder. mp=264-265 oC; 1H NMR (400 MHz, acetone-d6) δ 10.63 (s, 1H), 9.09 (s, 1H),
8.22 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.8 Hz, 1H), 7.58 (d, J=7.6 Hz, 2H), 7.46–7.29 (m, 5H), 6.98
(dd, J=8.8, 2.5 Hz, 1H), 5.22 (s, 2H); 13C NMR (100 MHz, acetone-d6) δ 155.0, 148.0, 141.0,
139.2, 133.6, 129.2, 128.6, 128.5, 127.2, 126.3, 114.5, 113.8, 113.2, 106.3, 71.3; IR (APT) 3228,
2927, 1546, 1478, 1154 cm-1; HRMS (ESI) calcd for C34H26N4O2 (M+H+) 523.2134, found
523.2116.
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Alocasin A. To a solution of 8 (41 mg, 0.078 mmol) in EtOH (2 mL), in a treaded pressure
tube, was added Pd/C (10%-Pd, 18 mg, 0.017 mmol). The tube was fitted with a pressure head
and the mixture was pressurized with H2 (4 atm) and stirred at 60 oC (12 h). After cooling to
ambient temperature, the mixture was filtered through a pad of celite and the celite was
washed with warm ethanol (5 mL). The solvent was removed under reduced pressure and
residue was purified by chromatography (EtOAc/hexane, 7:3) to afford alocasin A (23 mg,
0.067 mmol, 86%) as faint yellow solid. mp=244-245 oC (lit. mp=243-244 oC);9 1H NMR (400
MHz, CD3OD) δ 8.94 (s, 2H), 7.90 (s, 2H), 7.72 (d, J=2.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.79 (dd,
J=8.8, 2.4 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 152.8, 148.4, 141.4, 133.6, 127.3, 126.6,
113.8, 113.3, 113.2, 106.1; IR (ATR) 3298, 2927, 1551, 1466, 1154 cm-1; HRMS (ESI) calcd for
C20H15N4O2 (M+H+) 343.1195, found 343.1188.
2,3-Di(5-benzyloxy-2-nitrophenyl)-1,3-butadiene (7). To a solution of 3,5-
dibromopyridine (9) (217 mg, 0.919 mmol) and 4 (1.00 g, 1.84 mmol) in dry DMF (6 mL) was
added Pd(dba)2 (52.8 mg, 0.092 mmol), CuI (350 mg, 1.84 mmol), and PPh3 (96.4 mg, 0.367
mmol) respectively. The resulting brown mixture was stirred under an atmosphere of N2 at 80
oC for 24 h. EtOAc (25 mL) was added and the mixture was washed with brine (6x50 mL).
The organic layer was dried (MgSO4), filtered, and the solvents were removed under reduced
pressure. The residue was purified by chromatography on SiO2/K2CO3 (10% K2CO3,
EtOAc/hexane, 1:9, then 2:8) to give 7 (139 mg, 0.273 mmol, 30%).
3,5-(1-Tributylstannyl-1-ethenyl)pyridine (11). Treatment of 3,5-diethynylpyridine (10)42
(150 mg, 1.18 mmol) with Bu3SnH (1.03 mg, 3.59 mmol) in the presence of PdCl2(PPh3)2 (100
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mg, 0.142 mmol) in THF (4 mL), as described for 4 (36 h), gave after work up and
chromatography (EtOAc/hexanes, 2:98) 11 (577 mg, 0.814 mmol, 69%) as yellow oil. 1H NMR
(400 MHz, CDCl3) δ 8.24 (d, J=2.4 Hz, 1H), 7.23 (t, J=2.0 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 5.51 (d,
J=2.4 Hz, 1H), 1.57-1.24 (m, 6H), 1.29 (sext, J=7.2 Hz, 6H), 1.07-0.79 (m, 15H); 13C NMR (100
MHz, CDCl3) δ 151.3, 145.4, 141.5, 130.4, 128.7, 29.0, 27.2, 13.6, 10.3; IR (ATR) 2956, 2925,
1463, 920 cm-1; HRMS (ESI) calcd for C33H62NSn2 (M+H+) 712.2926, found 712.2929.
2-Iodo-4-benzyloxy-1-nitrobenzene (12). A mixture of 3-iodo-4-nitrophenol (5.83 g, 22.0
mmol), benzyl bromide (4.86 g, 35.2 mmol) and K2CO3 (5.64 g, 40.8 mmol) in absolute EtOH
(50 mL) was heated ate reflux for 18 h. The resulting mixture was concentrated under
reduced pressure and EtOAc (50 mL) was added to the resulting residue. The mixture was
washed with water (3x40 mL), dried (MgSO4), and filtered. The filtrate was concentrated
under reduced pressure and the resulting residue was purified by chromatography
(EtOAc/hexanes, 2:8) to afford 12 (7.32 g, 20.6 mmol, 94%) as an orange-yellow solid.
mp=73-75 oC; 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=9.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 7.45-
7.36 (m, 5H), 7.00 (dd, J=8.8, 2.8 Hz, 1H), 5.12 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 161.6,
145.4, 135.0, 128.8, 128.6, 128.0, 127.5, 127.5, 114.7, 88.1, 70.8; IR (ATR) 1575, 1507, 1332,
1241, 982 cm-1; HRMS (ESI) calcd for C13H11INO3 (M+H+) 355.9784 , found 355.9785.
3,5-Di(5-benzyloxy-2-nitrophenyl)pyridine (13). Reaction of 11 (750 mg, 1.06 mmol) with
12 (1.13 g, 3.17 mmol) in the presence of Pd(dba)2 (61 mg, 0.11 mmol, PPh3 (111 mg, 0.423
mmol) and CuI (403 mg, 2.11 mmol) in DMF (6 mL), as described for 6 (120 oC, 48 h) gave
after work up and chromatography (EtOAc/hexanes, 2:8 then 3:7) 13 (216 mg, 0.369 mmol,
16

ACCEPTED MANUSCRIPT
35%) as viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=2.0 Hz, 2H), 8.07 (d, J=8.8
Hz, 2H), 7.51 (t, J=2.0 Hz, 1H), 7.46-7.37 (m, 10H), 7.04 (dd, J=9.2, 2.8 Hz, 2H), 6.98 (d, J=2.8
Hz, 2H), 5.73 (s, 2H), 5.36 (s, 2H), 5.17 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 162.4, 146.8,
144.1, 141.2, 138.4, 135.3, 134.4, 130.8, 128.8, 128.5, 127.6, 127.4, 118.2, 116.8, 114.7, 70.8;
IR (ATR) 1572, 1509, 1332, 1224 cm-1; HRMS (ESI) calcd for C35H28N3O6 (M+H+) 586.1978,
found 586.1979.
3,5-Bis(5-benzyloxy-3-indolyl)pyridine (14). Treatment of a solution of 13 (176 mg, 0.300
mmol) in the presence of Pd2(dba)3 (28 mg, 0.030 mmol), dppp (12 mg, 0.030 mmol), and
phen (11 mg, 0.060 mmol) in DMF (1.5 mL) with CO (6 atm), as described for 8 (120 oC, 68 h),
gave after work up and chromatography (EtOAc/hexanes, in order 7:3, 3:7) 14 (105 mg, 0.201
mmol, 67%) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.91 (br, s, 2H), 8.84 (d, J=2.0
Hz, 2H), 8.12 (t, J=2.0 Hz, 1H), 7.50 (d, J=2.4 Hz, 2H), 7.44-7.42 (m, 4H), 7.35-7.24 (m, 10H),
7.02 (dd, J=8.8, 2.4 Hz, 2H), 5.07 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 154.0, 145,2, 137.4,
132.6, 132.1, 131.9, 128.4, 127.7, 127.5, 125.9, 123.4, 114.1, 113.5, 112.4, 102.9, 70.9; IR
(ATR) 3427, 3287, 1594, 1477, 1196 cm-1; HRMS (ESI) calcd for C35H28N3O2 (M+H+) 522.2181,
found 522.2182.
Scalaridine A. Treatment of a solution of 14 (87 mg, 0.168 mmol) with Pd/C (10%, 21 mg,
0.020 mmol) in EtOH (1.5 mL), as decribed for alocasin A (4 atm, 60 oC, 12 h) gave after work
up and chromatography (EtOAc), scalaradine A (45 mg, 0.13 mmol, 79%) as yellow solid.
mp=321 oC dec. (lit. mp = 319-329 oC dec.);13 1H NMR (400 MHz, DMSO-d6) δ 11.26 (br, s, 2H),
8.80 (s, 2H), 8.69 (br, s, 2H), 8.18 (s, 1H), 7.78 (d, J=2.4 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 7.23 (d,
17

ACCEPTED MANUSCRIPT
J=2.4 Hz, 2H), 6.70 (dd, J=8.4, 2.0 Hz, 2H); 13C NMR (100 MHz,DMSO-d6) δ 151.6, 143.7, 132.0,
131.3, 130.0, 125.6, 124.5, 112.6, 112.0, 111.5, 102.6 ; IR (ATR) 3427, 3286, 1594, 1475, 1195
cm-1; HRMS (ESI) calcd for C21H16N3O2 (M+H+) 342.1243, found 342.1240.
(5-Benzyloxy-2-nitrophenyl)ethene (16), 2,3-di(5-benzyloxy-2-nitrophenyl)-1,3-
butadiene (7), 1-(5-benzyloxy-2-nitrophenyl)-1-(2-pyrimidyl)ethene (17). Reaction of
2,5-dibromopyrimidine (15) (300 mg, 1.26 mmol) and 4 (2.06 g, 3.78 mmol) in the presence
of Pd(dba)2 (73 mg, 0.13 mmol), CuI (720 mg, 3.78 mmol), and PPh3 (132 mg, 0.504 mmol) in
dry DMF (5 mL) under argon as described for 5 (100 oC, 48 h), gave after work up and
chromatography on SiO2/K2CO3 (10% K2CO3, EtOAc/hexane, 1:9, then 2:8), in order of elution,
16 (101 mg, 0.396 mmol, 10%) as a white solid, an inseparable mixture of 7 and an unknown
impurity (90 mg, <9%) as a white solid, and 17 (114 mg, 0.342 mmol, 27%) as a viscous
greenish-brown oil. Analytical data for 16:43 mp=58-59 oC; 1H NMR (400 MHz, CDCl3) δ 8.05
(d, J=9.2 Hz, 1H), 7.44-7.32 (m, 5H), 7.30 (dd, J=17.2, 10.8 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 6.94
(dd, J=9.2, 2.8 Hz, 1H), 5.65 (dd, J=17.2, 0.8 Hz, 1H), 5.46 (dd, J=11.2, 0.8 Hz, 1H), 5.17 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 162.3, 140.9, 136.7, 135.5, 133.7, 128.8, 128.5, 127.5, 127.3,
118.6, 114.4, 114.0, 70.6; IR (ATR) 1581, 1501, 1238, 1078, 987, 930 cm-1.
Analytical data for 17: 1H NMR (400 MHz, CDCl3) δ
d, J=5.2 Hz, 1H), 8.18 (d, J=8.8
Hz, 1H), 7.46-7.35 (m, 5H), 7.10 (t, J=5.2 Hz, 1H), 7.07 (d, J=2.8 Hz, 1H), 7.04 (dd, J=8.8, 2.8 Hz,
1H), 6.86 (d, J=1.2 Hz, 1H), 5.78 (d, J=1.2 Hz, 1H), 5.17 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
163.9, 162.6, 156.9, 146.9, 141.6, 138.2, 135.5, 128.7, 128.5, 127.6, 127.0, 122.4, 119.2, 118.4,
113.9, 70.6; IR (ATR) 1583, 1567, 1554, 1506, 1336, 1249, 758, 698 cm-1; HRMS (ESI) calcd for
C19H16N3O3 (M+H+) 334.1192, found 334.1190.
18

ACCEPTED MANUSCRIPT
2,5-Di(2-trimethylsilyl-1-ethynyl)pyrimidine (18). A solution of 15 (2.25 g, 9.49 mmol),
PdCl2(PPh3)2 (666 mg, 0.949 mmol), and CuI (362 mg, 1.90 mmol) in toluene (9 mL) was
stirred at ambient temperature under an atmosphere of N2 for 5 min. Triethylamine (25 mL)
and a solution of trimethylsilylethyne (2.52 g, 25.6 mmol) in NEt3 (4 mL) was added. The
resulting dark brown reaction mixture was stirred at 50 oC for 24 h. After cooling to ambient
temperature, the mixture was filtered through Celite and the bed was washed with Et2O (25
mL). The filtrate was concentrated under reduced pressure and the resulting residue was
purified by chromatography (EtOAc/hexanes, 5:95) to afford 18 (2.59 g, 0.949 mmol, 100%)
as pale green solid. mp=99-100 oC; 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 2H), 0.29 (s, 9H), 0.27
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.2, 149.9, 118.2, 104.6, 102.1, 97.6, 96.8, -0.4, -0.6; IR
(ATR) 2963, 2163,1413, 1245, 838 cm-1; HRMS (ESI) calcd for C14H21N2Si2 (M+H+) 273.1243,
found 273.1240.
2,5-Diethynylpyrimidine (19). A heterogeneous mixture of 18 (744 mg, 2.94 mmol), K2CO3
(2.43 g, 17.6 mmol) in MeOH/Et2O (1:2, 15 mL) was stirred at ambient temperature under an
N2 atmosphere for 1 h. Water (20 mL) was added and the mixture was extracted in EtOAc
(3x10 mL). The combined organic layer was concentrated under reduced pressure and the
resulting crude product was purified by chromatography (EtOAc/hexanes, 1:1) to afford 19
(326 mg, 2.54 mmol, 93%) as a white solid. mp=97-98 oC; 1H NMR (400 MHz, CDCl3) δ 8.79 (s,
2H), 3.49 (s, 1H), 3.26 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 159.6, 150.2, 117.8, 86.1, 81.5,
78.0, 76.7; IR (ATR) 3291, 3180, 2129, 2100, 1415 cm-1; HRMS (ESI) calcd for C8H5N2 (M+H+)
129.0452, found 129.0448.
19

ACCEPTED MANUSCRIPT
2,5-Di(1-tributylstannyl-1-ethenyl)pyrimidine (20). THF (4 mL) was added to a flask
containing 19 (257 mg, 2.01 mmol) and PdCl2(PPh3)2 (169 mg, 0.241 mmol) under an
atmosphere of N2. The mixture was stirred at ambient temperature for 5 min followed by slow
addition of Bu3SnH (1.75 g, 6.03 mmol) dissolved in THF (1 mL). The resulting brown mixture
was stirred at the ambient temperature for 34 h. The mixture was then concentrated under
reduced pressure and the residue was purified by chromatography (EtOAc/hexanes, 2:98) to
give 20 (566 mg, 0.797 mmol, 40%) as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.47 (s,
2H), 7.10 (d, J=2.8 Hz, 1H), 6.12 (d, J=2.0 Hz, 1H), 5.86 (d, J=2.8 Hz, 1H), 5.56 (d, J=2.4 Hz, 1H),
1.58-1.43 (m, 12H), 1.30 (dhex, J=7.2, 3.2 Hz, 12H), 1.04-0.84 (m, 30H); 13C NMR (100 MHz,
CDCl3) δ 166.7, 154.4, 153.9, 147.8, 136.3, 132.4, 129.7, 29.1, 28.9, 27.3, 27.2, 13.7, 13.6, 10.4,
10.3; IR (ATR) 2955, 2922, 2852, 1427 cm-1; HRMS (ESI) calcd for C32H61N2Sn2 (M+H+)
713.2879, found 713.2883.
2,5-Di[1-(5-benzyloxy-2-nitrophenyl)-1-ethenyl]pyrimidine (21). Treatment of 20 (436
mg, 0.615 mmol) with 12 (655 mg, 1.84 mmol) in the presence of Pd2(dba)3 (56 mg, 0.061
mmol), PPh3 (65 mg, 0.25 mmol) and CuI (234 mg, 1.23 mmol) in DMF (5 mL), as described
for 5 (120 oC, 48 h), gave after work up and chromatography (EtOAc/hexanes, 1:9 then 8:2)
21 (189 mg, 0.323 mmol, 53%) as viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 2H),
8.16 (dd, J=8.0, 0.8 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.44-7.35 (m, 10H), 7.06-7.01 (m, 3H), 6.96
(d, J=2.4 Hz, 1H), 6.86 (d, J=1.2 Hz, 1H), 5.81 (s, 1H), 5.76 (d, J=1.2 Hz, 1H), 5.37 (s, 1H), 5.17 (s,
2H), 5.16 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 162.7, 162.5, 162.5, 154.0, 146.4, 141.5, 141.5,
140.7, 138.1, 137.5, 135.5, 135.1, 130.1, 128.8, 128.7, 128.5, 128.4, 127.6, 127.6, 127.5, 126.9,
20

ACCEPTED MANUSCRIPT
122.4, 118.2, 118.2, 116.9, 114.8, 114.0, 70.8, 70.6; IR (ATR) 1574, 1509, 1334, 1228, 1003 cm-
1; HRMS (ESI) calcd for C34H27N4O6 (M+H+) 587.1931, found 587.1934.
3-[2-(5-benzyloxy-1H-indol-3-yl)-5-pyrimidinyl]-5-benzyloxy-1H-indole (22).
Treatment of a solution of 21 (141 mg, 0.240 mmol) in the presence of
tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 22 mg, 0.024 mmol), dppp (10 mg, 0.024
mmol), and phen (9 mg, 0.048 mmol) in DMF (1.5 mL) with CO (6 atm), as described for 8
(120 oC, 60 h), gave after work up and chromatography (hexanes/EtOAc, 3:7) 22 (85 mg,
o
0.163 mmol, 68%) as a yellow solid. mp=199-200 C; 1H NMR (400 MHz, DMSO-d6) δ 11.54
(br, s, 1H), 11.46 (br, s, 1H), 9.09 (s, 2H), 8.26 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.55-7.32 (m,
13H), 6.94 (d, J=8.4 Hz, 2H), 5.20 (s, 2H), 5.17 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 160.6,
153.7, 154.4, 153.2, 137.8, 137.7, 132.3, 132.0, 129.0, 128.3, 128.3, 127.8, 127.7, 127.6, 127.6,
126.1, 125.0, 124.9, 124.6, 114.6, 112.8, 112.7, 112.5, 112.2, 109.3, 105.7, 102.3, 69.9, 69.9; IR
(ATR) 3409, 2884, 1543, 1447, 1199 cm-1; HRMS (ESI) calcd for C34H27N4O2 (M+H+) 523.2135,
found 523.2135.
Hyrtinandine A. Treatment of a solution of 22 (56 mg, 0.107 mmol) with Pd/C (10%-Pd, 14
mg, 0.013 mmol) in MeOH (2 mL), as described for alocasine A (4 atm H2, 60 oC, 14 h) gave
after work up and chromatography (EtOAc/hexanes, 9:1) hyrtinadine A (32 mg, 0.093 mmol,
87%) as a white solid. mp=290-291 oC (lit. mp = 296 oC);14 1H NMR (400 MHz, DMSO-d6) δ
11.38 (br s, 1H), 11.29 (br s, 1H), 8.99 (s, 2H), 8.84 (s, 2H), 8.11 (d, J=3.2 Hz, 1H), 7.97 (d, J=2.4
Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.30-7.25 (m, 2H), 7.20 (d, J=1.6 Hz, 1H), 6.73-6.68 (m, 2H); 13
C
NMR (100 MHz, DMSO-d6) δ 160.7, 153.5, 151.8, 151.6, 131.4, 131.3, 128.7, 126.4, 125.4,
21

ACCEPTED MANUSCRIPT
125.0, 124.2, 114.1, 112.6, 112.2, 112.1, 112.0, 108.6, 106.2, 102.7. IR (ATR) 3295, 1542, 1448,
1364, 1229 cm-1; HRMS (ESI) calcd for C20H15N4O2 (M+H+) 343.1195, found 343.1194.
1-(5-Pyrimidyl)-1-tributylstannylethene (24). Treatment of 5-ethynylpyrimidine 2344
(388 mg, 3.73 mmol) with tributyltin hydride (1.63 g, 5.59 mmol) in the presence of
PdCl2(PPh3)2 (262 mg, 0.373 mmol) in THF (9 mL), as described for 4 (ambient temperature,
36 h), gave after work up and chromatography (EtOAc/hexanes, 5:95) 24 (1.02 g, 2.57 mmol,
1
69%) as pale yellow oil. H NMR (600 MHz, CDCl3) δ 9.04 (s, 1H), 8.52 (s, 2H), 6.10 (d, J=1.8
Hz, 1H), 5.62 (d, J=2.4 Hz, 1H), 1.52-1.42 (m, 6H), 1.29 (sext, J=7.8 Hz, 6H), 1.06-0.84 (m, 15H);
13C NMR (100 MHz, CDCl3) δ 156.4, 153.9, 147.5, 139.7, 130.9, 28.8, 27.1, 13.5, 10.2; IR (APT)
2956, 2925, 1544, 1407 cm-1; HRMS (ESI) calcd for C18H33N2Sn (M+H+) 397.1666, found
397.1666.
1-(5-Benzyloxy-2-nitrophenyl)-1-(4-pyrimidyl)ethene (25). To mixture of 12 (584 mg,
1.64 mmol), PPh3 (66 mg, 0.25 mmol), CuI (241 mg, 1.26 mmol) and Pd2dba3 (58 mg, 0.063
mmol) in DMF (5 mL) at ambient under an atmosphere of N2, was added a solution of 24 (500
mg, 1.26 mmol) in DMF (1 mL). The resulting brown reaction mixture was heated at 120 oC for
36 h. After cooling to ambient temperature, the mixture was diluted with EtOAc (30 mL) and
the organic layer was washed with water (4x20 mL) and brine (20 mL). The organic phase
was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The
crude product was purified by column (EtOAc/hexanes, 3:7, then 1:1) to afford 25 (223 mg,
0.669 mmol, 53%) as viscous pale brown oil that slowly solidified. mp=113 oC; 1H NMR (400
MHz, CDCl3) δ 9.11 (s, 1H), 8.62 (s, 2H), 8.17 (d, J=8.8, 1H), 7.45-7.37 (m, 5H), 7.09 (dd, J=8.8,
22

ACCEPTED MANUSCRIPT
2.4 Hz, 1H), 6.99 (d, J=2.8 Hz, 1H), 5.82 (s, 1H), 5.44 (s, 1H), 5.19 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 162.5, 157.7, 153.9, 141.5, 137.3, 135.0, 132.6, 128.7, 128.5, 127.7, 127.4, 118.4,
117.7, 114.6, 70.7; IR (APT) 1575, 1510, 1340, 1223 cm-1; HRMS calcd for C19H16N3O3 (M+H+)
334.1192, found 334.1190.
5-Benzyloxy-3-(4-pyrimidyl)indole (26). Treatment of a solution of 25 (200 mg, 0.600
mmol) in the presence of Pd2(dba)3 (33 mg, 0.036 mmol), dppp (15 mg, 0.036 mmol), and
phen (13 mg, 0.072 mmol) in DMF (2 mL) with CO (6 atm), as described for 8 (120 oC, 28 h),
gave after work up and chromatography (EtOAc/hexanes, 7:3) 26 (163 mg, 0.540 mmol, 90%)
as a white solid. mp=189 oC; 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 9.00 (s, 2H), 8.52 (br, s,
1H), 7.48 (d, J=7.2 Hz, 2H), 7.45 (d, J=2.8 Hz, 1H), 7.42-7.31 (m, 5H), 7.05 (dd, J=8.4, 2.0 Hz,
1H), 5.12 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 156.0, 154.5, 154.4, 137.2, 131.9, 129.9, 128.6,
127.9, 127.6, 125.5, 123.3, 114.2, 112.6, 110.7, 102.3, 70.9; IR (ATR) 3017,1533, 1486, 1157
cm-1; HRMS (ESI) calcd for C19H16N3O (M+H+) 302.1293 , found 302.1291.
Hyrtinadine B. Treatment of a solution of 21 (90 mg, 0.30 mmol) with Pd/C (10%, 28 mg,
0.026 mmol) in MeOH (1.5 mL), as described for alocasin A (4 atm H2, 60 oC, 6 h) gave after
work up and chromatography (EtOAc) hyrtinadine B (53 mg, 0.251 mmol, 84%) as a white
solid. mp=289-290 oC; 1H NMR (400 MHz, CD3OD) δ 9.05 (s, 2H), 8.89 (s, 1H), 7.62 (s, 1H), 7.24
(d, J=8.4 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.72 (dd, J=8.8, 2.0 Hz, 1H); 13C NMR (100 MHz,
CD3OD) δ 155.5, 155.0, 153.3, 133.7, 133.1, 127.0, 126.1, 113.8, 113.8, 109.5, 103.8; IR (ATR)
3327, 2727, 1557, 1420, 1386 cm-1; HRMS (ESI) calcd for C12H10N3O (M+H+) 212.0824, found
212.0821.
23

ACCEPTED MANUSCRIPT
Supporting Information
Supplementary data associated with this article including 1H NMR and 13C NMR spectra can
be foundin the online version, at http://dx.doi
Acknowledgements. We gratefully acknowledge the C. Eugene Bennett Department of
Chemistry for generous support. The National Science Foundation-MRI program is also
gratefully acknowledged for the funding of a 400 MHz NMR system (CHE-1228366) and a
single-crystal X-ray diffractometer (CHE-1336071). The authors would like to thank Dr.
Gregory Donohoe for HRMS analyses.
References and notes
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43 Compound 14 has been described in a patent but only a very cursory 1H NMR was reported.
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44 The compound is commercially available however it was prepared in two steps from 4-
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