Reductive Cyclization of o-Nitroarylated-α,β-unsaturated Aldehydes and Ketones with TiCl3/HCl or Fe/HCl Leading to 1,2,3,9-Tetrahydro-4 H-carbazol-4-ones and Related Heterocycles

Article abstract of DOI:10.1021/acs.joc.8b01940

Compounds such as 3, the product of a palladium[0]-catalyzed Ullmann cross-coupling of o-iodonitrobenzene and 2-iodocyclohex-2-en-1-one, undergo complementary modes of reductive cyclization depending upon the conditions employed. Thus, on treatment with hydrogen in the presence of palladium on carbon, the tetrahydrocarbazole 4 is formed, while reaction of the same substrate (3) with TiCl₃ in acetone affords the 1,2,3,9-tetrahydro-4H-carbazol-4-one 6.

Full text of DOI:10.1021/acs.joc.8b01940

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Article
The Reductive Cyclization of o-Nitroarylated-#,#-Unsaturated
Aldehydes and Ketones with TiCl3/HCl or Fe/HCl Leading to
1,2,3,9-Tetrahydro-4H-carbazol-4-ones and Related Heterocycles
Yun Qiu, Michael Dlugosch, Xin Liu, Faiyaz Khan, Jas S Ward, Ping Lan, and Martin G Banwell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01940 • Publication Date (Web): 05 Sep 2018
Downloaded from http://pubs.acs.org on September 8, 2018
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The Reductive Cyclization of o-Nitroarylated-α,β-Unsaturated Aldehydes and Ketones
with TiCl3/HCl or Fe/HCl Leading to 1,2,3,9-Tetrahydro-4H-carbazol-4-ones and
Related Heterocycles
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Yun Qiu,a,† Michael Dlugosch,b,† Xin Liu,b Faiyaz Khan,b Jas S. Ward,a Ping Lana and
Martin G. Banwellb,*
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aDepartment of Food Science and Engineering, Jinan University,
Guangzhou, 510632, China
bResearch School of Chemistry, Institute of Advanced Studies
The Australian National University, Canberra, ACT 2601, Australia
Compounds such as 3, the product of a palladium[0]ꢀcatalyzed Ullmann crossꢀ
coupling of oꢀiodonitrobenzene and 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone, undergo
complementary modes of reductive cyclization depending upon the conditions
employed. Thus, on treatment with hydrogen in the presence of palladium on carbon
the tetrahydrocarbazole 4 is formed while reaction of the same substrate (3) with
TiCl3 in acetone affords the 1,2,3,9ꢀtetrahydroꢀ4Hꢀcarbazolꢀ4ꢀone 6.
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Introduction
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Sometime ago1 we reported that ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (1) (Scheme 1) could be
efficiently crossꢀcoupled with oꢀiodonitrobenzene (2) in the presence of copper bronze and
catalytic quantities of palladium[0] at 50 °C. Catalytic hydrogenation of the resulting oꢀ
nitroarylated cyclohexenone 3 then afforded the tetrahydrocarbazole 4. We have since
extended this twoꢀstep and related reaction sequences in a variety of settings, including ones
that have led to a range of alkaloids as well as medicinally relevant heterocycles.2
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Scheme 1: The palladiumꢀcatalyzed Ullmann crossꢀcoupling/reductive cyclization sequence
leading to tetrahydrocarbazole 4
We now report that by treating crossꢀcoupling products such as 3 with titanium
trichloride3/HCl or iron/HCl4 then quite distinct reductive cyclization processes takes place to
give heterocyclic systems of biological interest.
Results and Discussion
As shown in Scheme 2, when compound 3 is treated with either titanium trichloride/HCl or
iron/HCl at ambient temperatures for brief periods then the primary product of reaction is the
Nꢀhydroxytetrahydroꢀ4Hꢀcarbazolꢀ4ꢀone 5, the structure of which was confirmed by singleꢀ
crystal Xꢀray analysis [see the Information (SI) for details]. Furthermore, when compound 3 or
5 was exposed to the same reagents for extended periods of time then the previously reported5
tetrahydroꢀ4Hꢀcarbazolꢀ4ꢀone 6 was obtained. Under optimal conditions (TiCl3/HCl is
generally the preferred reducing agent), the latter product could be obtained, as the exclusive
one, from precursor 3 in 82% yield. Fe/HCl was much less effective in these conversions (see
Experimental Section and SI for details). While the precise mode of formation of product 5
from substrate 3 remains to be established, it is clear that the former compound is a precursor
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to tetrahydrocarbazolꢀ4ꢀone 6. The formation of compound 6 by the means just described is
closely related to a protocol recently reported by Zhu and coꢀworkers as a key step in their
elegant total synthesis of aspidospermidine.3f
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Scheme 2: The reductive cyclization of compound 3, via Nꢀhydroxyindole 5, to
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1,2,3,9ꢀtetrahydroꢀ4Hꢀcarbazolꢀ4ꢀone 6 and the direct reduction of nitroarene 7 to aniline 8
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The cyclization process appears to be sensitive to stereoelectronic effects as evidenced by the
conversion of the cyclopentenoneꢀappended nitroarene 7 into the corresponding aniline 8
(80%) rather than the lower homologue of heterocycle 6. Interestingly, analogous treatment of
the cycloheptenoneꢀappended nitroarene (viz. the higher homologue of compound 3) only led
to complex mixtures of products.
The complementary nature of the original mode of reductive cyclization of the
palladiumꢀcatalyzed Ullmann crossꢀcoupling products and the one that can normally be best
effected using TiCl3/HCl is emphasized through the example shown in Scheme 3.
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Scheme 3: The complementary behaviors of the crossꢀcoupling product 10 under two distinct
reductive cyclization conditions
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Thus, crossꢀcoupling of electrophiles 96 and 2 using copper in the presence of catalytic Pd[0]
afforded product 10 (80%) and on treatment of this with hydrogen in the presence of 10%
palladium on carbon then the previously reported7 gemꢀdimethylated tetrahydrocarbazole 11 is
obtained in 92% yield. In contrast, on treating the same substrate with TiCl3/HCl in acetone at
ambient temperatures then compound 12, an established precursor to demethoxycarazomycin
B,8 is obtained in 82% yield.
The utility of the “new” mode of reductive cyclization in establishing multiꢀ
heteroatomꢀcontaining ring systems is revealed through the examples shown in Scheme 4.
Thus, exposure of the previously reported9 coupling product 13 with TiCl3/HCl gives the 7ꢀ
azaindole 14 (54%) while the products derived from the crossꢀcoupling of the homochiral
iodide 1510 with aryl iodides 2 and 16,9 namely compounds 17 (69%) and 18 (91%),
respectively, react with TiCl3/HCl (in the former case) or Fe/HCl (in the latter case) to afford
the tetracyclic products 19 (97% from 17) and 20 (58% from 18). The spectral data derived
from these products were in complete accord with the assigned structures and a singleꢀcrystal
Xꢀray analysis of compound 19 was obtained.
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Scheme 4: The reductive cyclization reactions of substrates 13, 17 and 18
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Acyclic ketones behave similarly as shown in Scheme 5. So, the Johnson αꢀ
iodination11 of chalcone (21) afforded a chromatographically separable mixture of compounds
2212 (58%) and 2312 (10%) that upon palladiumꢀcatalyzed Ullmann crossꢀcoupling with
compound 16 afforded the anticipated products 24 and 25 (59ꢀ85% combined yield). The
structure of the former product (24) was confirmed by singleꢀcrystal Xꢀray analysis. Since the
crossꢀcouplings of the geometrically pure Eꢀ and Zꢀisomeric forms of 22 and 23 are each
accompanied by some doubleꢀbond isomerization it was most convenient to carry the mixture
of iodinated products through the illustrated reaction sequence rather than separating these.
Subjection of these crossꢀcoupling products, either separately or as a mixture, to reductive
cyclization with hydrogen in the presence of 10% palladium on carbon afforded the 3ꢀbenzylꢀ
7ꢀazaindole 2613 (63ꢀ80%) while treatment of the same substrates with TiCl3 gave the 3ꢀ
benzoylꢀ7ꢀazaindole 27 in 15ꢀ49% yield. The structure of product 26 was confirmed by singleꢀ
crystal Xꢀray analysis.
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Scheme 5: The formation of the mixture of crossꢀcoupling products 24 and 25 and their
divergent reductive cyclizations to give 7ꢀazaindoles 26 and 27
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In contrast to the outcomes detailed immediately above, when the readily obtained αꢀiodinated
cinnamaldehyde 311 (Scheme 6) was subjected to palladiumꢀcatalyzed Ullmann crossꢀ
coupling with compound 2 and the ensuing product, 321 (77%), treated with TiCl3 then a
slowly interconverting mixture of the partially chromatographically separable and isomeric
cyclization products 3314 and 3414 was obtained (55% combined yield). The structure of
oxindole 33, a known antiproliferative agent,15 was confirmed by singleꢀcrystal Xꢀray
analysis.
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Scheme 6: The formation of cinnamaldehyde 32 and its reductive cyclization
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Very recently, we detailed16 the crossꢀcoupling of various βꢀiodoeneones and related
compounds with oꢀiodonitrobenzene (2) to afford products such as compound 35 (Scheme 7).
Accordingly, we sought to establish how this nitroarene and its homologue 36 would behave
on exposure to TiCl3/HCl. In the event, when treated under our now standard conditions each
produced the corresponding aniline, viz. compounds 37 (quant.) and 38 (98%), respectively,
with the structure of the latter being confirmed by singleꢀcrystal Xꢀray analysis.
Scheme 7: The reduction of nitroarenes 35 and 36 to the corresponding anilines
A more intriguing outcome was observed when an acetone solution of the nonꢀ
methylated crossꢀcoupling product 3916 (Scheme 8) was treated with TiCl3 at ambient
temperatures. Under these conditions the chromatographically separable products 4017 (40%)
and 41 (60%) were obtained and their structures established by singleꢀcrystal Xꢀray analysis.
Compound 40 is undoubtedly the primary product of reaction and the precursor to the other
through its Schiffꢀbase condensation with acetone to give imine 42 and electrocyclic ring
closure of this to give compound 43 that engages in a prototropic shift with accompanying reꢀ
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aromatization to deliver the secondary product 41. Consistent with this proposal, when THF
solutions of compound 40 are treated, at 22 °C, with methyl ethyl ketone, cyclohexanone or
benzaldehyde then the cycloadducts 44 (73%) 45 (64%), and 46 (quant.), respectively, are
obtained. The structures of products 44 and 45 were confirmed by singleꢀcrystal Xꢀray
analysis (see SI for details).
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Scheme 8: The formation of the dihydroquinolines 41 and 44ꢀ46
Conclusions
The reductive cyclization processes detailed above considerably enhance the utility of the
various products available through the palladiumꢀcatalyzed Ullmann crossꢀcoupling of oꢀ
halonitroarenes with either αꢀ or βꢀiodinatedꢀα,βꢀunsaturated enones and related systems.2
The resulting, and in some instances previously unreported, heterocyclic ring systems should
serve as useful scaffolds in a range of settings.
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Experimental Section
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General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded at room
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temperature in baseꢀfiltered CDCl3 on a spectrometer operating at 400 MHz for proton and
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100 MHz for carbon nuclei. For H NMR spectra, signals arising from the residual protioꢀ
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forms of the solvent were used as internal standards. H NMR data are recorded as follows:
chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. The signal due to residual CHCl3 appearing at δH 7.26 and the
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central resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to reference H and
13C NMR spectra, respectively. IR spectra were recorded, using neat samples, on an attenuated
total reflectance (ATR) infraꢀred spectrometer. Lowꢀresolution ESI mass spectra were
recorded on a single quadrupole liquid chromatographꢀmass spectrometer, while highꢀ
resolution measurements were conducted on a timeꢀofꢀflight instrument. Lowꢀ and highꢀ
resolution EI mass spectra were recorded on a magneticꢀsector machine. Melting points were
measured on an automated melting point system and are uncorrected. Analytical thin layer
chromatography (TLC) was performed on aluminumꢀbacked 0.2 mm thick silica gel 60 F254
plates. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolybdic acid : ceric sulfate :
sulfuric acid (conc.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium permanganate :
potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g : 20 g: 5 mL : 300
mL). column chromatographic separations were carried out following protocols defined by
Still et al.18 with silica gel 60 (40– 63 ꢁm) as the stationary phase and using the ARꢀ or
HPLCꢀgrade solvents indicated. Starting materials, reagents and drying agents as well as other
inorganic salts were generally available from commercial sources and used as supplied.
Tetrahydrofuran (THF), diethyl ether, methanol and dichloromethane were dried using a
solvent purification system that is based upon a technology originally described by Grubbs et
al.19 Where necessary, reactions were performed under a nitrogen atmosphere.
Specific Chemical Transformations
Compound 5. Method i: A magnetically stirred mixture of compound 31 (217 mg, 1.00
mmol) in acetone (5 mL) maintained at 22 °C was treated with titanium(III) chloride (5.0 mL
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of a 12% w/v solution in hydrochloric acid, 4.79 mmol). After 1 h the reaction mixture was
diluted with ethyl acetate (20 mL) and washed with water (3 x 10 mL) then dried (Na2SO4),
filtered and then concentrated under reduced pressure. The residue so obtained was subjected
to flash column chromatography (silica, 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether elution)
and thus affording, after concentration of the appropriate fractions (Rf = 0.2), compound 5
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(100 mg, 50%) as a white, crystalline solid, no m.p., decomposition 147 °C. H NMR (400
MHz, DMSOꢀd6) δ 11.70 (s, 1H), 7.99 (dd, J = 7.4 and 1.2 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H),
7.25–7.19 (complex m, 2H), 2.98 (t, J = 6.2 Hz, 2H), 2.44 (m, 2H), 2.20–2.08 (complex m,
2H); 13C NMR (100 MHz, DMSOꢀd6) δ 192.0, 148.4, 134.0, 122.7, 122.2, 120.5, 120.2,
108.8, 106.5, 37.6, 22.9, 20.3; IR (ATR) νmax 3062, 2946, 1710, 1575, 1462, 1311, 1256,
1182, 1096, 966, 741 cm–1; MS (ESI, +ve) m/z 224 [(M+Na)+, 100%], 202 [(M+H)+, 10];
HRMS (ESI, +ve) [M+H]+ Calcd for C12H12NO2 202.0863; Found 202.0860.
Method ii: A magnetically stirred solution of compound 31 (100 mg, 1.00 mmol) and
hydrochloric acid (3 mL of a 2 M aqueous solution) in THF (5 mL) maintained at 22 °C was
treated with iron powder (168 mg, 3.00 g.atom). After 18 h the reaction mixture was diluted
with ethyl acetate (20 mL) then filtered through a plug of TLCꢀgrade silica topped with
diatomaceous earth. The solids so retained were washed with ethyl acetate (1 x 10 mL) and
the combined filtrates were washed with water (2 x 20 mL) then brine (1 x 20 mL) before
being dried (Na2SO4), filtered, then concentrated under reduced pressure. The residue so
obtained was subjected to flash column chromatography (silica, 1:1 v/v ethyl acetate/40−60
petroleum ether elution) and thus affording, after concentration of the appropriate fractions (Rf
= 0.2), compound 5 (14 mg, 14%) as a white, crystalline solid. This material was identical, in
all respects, with that obtained by Method i.
Compound 6. Method i: A magnetically stirred mixture of compound 5 (50 mg, 0.25 mmol)
in acetone (1.3 mL) maintained at 22 °C was treated with titanium(III) chloride (1.3 mL of a
12% w/v solution in hydrochloric acid, 1.24 mmol). After 16 h the reaction mixture was
quenched with sodium carbonate (5 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through diatomaceous earth. The solids so retained were
washed with ethyl acetate (10 mL), the combined filtrates separated and the aqueous phase
extracted with ethyl acetate (2 × 5 mL). The combined organic phases were washed with brine
(20 mL) then dried (Na2SO4), filtered and then concentrated under reduced pressure. The
residue so obtained was subjected to flash column chromatography (silica, 1:1 v/v ethyl
acetate/40ꢀ60 petroleum ether elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.2), compound 65 (42 mg, 91%) as a white, crystalline solid, m.p.
= 174 °C (lit.5b m.p. = 225ꢀ228 °C). 1H NMR (400 MHz, DMSOꢀd6) δ 11.84 (s, 1H), 7.95 (m,
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1H), 7.39 (dd, J = 8.0 and 1.4 Hz, 1H), 7.15 (m, 2H), 2.96 (t, J = 6.2 Hz, 2H), 2.42 (t, J = 6.2
Hz, 2H), 2.10 (m, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 192.9, 152.3, 135.8, 124.5, 122.4,
121.5, 120.2, 111.7, 111.5, 37.8, 23.4, 22.7; IR (ATR) νmax 3056, 2954, 1604, 1576, 1462,
1445, 1411, 1251, 1177, 1145, 1016, 753 cm–1; MS (ESI, +ve) m/z 208 [(M+Na)+, 73%], 186
[(M+H)+, 100]; HRMS (ESI, +ve) [M+H]+ Calcd for C12H12NO 186.0913; Found 186.0912.
Method ii: A magnetically stirred solution of compound 5 (100 mg, 0.46 mmol) in
hydrochloric acid (5 mL of a 3 M aqueous solution) maintained at ca. 100 °C was treated with
iron powder (154 mg, 2.76 mmol). After 3 h the reaction mixture was cooled to 22 °C, diluted
with ethyl acetate (20 mL) then filtered through a plug of TLCꢀgrade silica topped with
diatomaceous earth and the solids so retained were washed with ethyl acetate (1 × 10 mL).
The combined filtrates were washed with water (2 × 20 mL) and brine (1 × 20 mL) before
being dried (Na2SO4), filtered, then concentrated under reduced pressure. The residue so
obtained was subjected to flash column chromatography (silica, ethyl acetate elution) and thus
affording, after concentration of the appropriate fractions (Rf = 0.1), compound 6 (10 mg,
12%) as a white, crystalline solid. This material was identical, in all respects, with that
obtained by Method i.
Compound 8. A magnetically stirred solution of compound 71 (108 mg, 0.53 mmol) in
acetone (5 mL) maintained at 22 °C was treated with titanium(III) chloride (3.3 mL of a 12%
w/v solution in hydrochloric acid, 3.18 mmol). After 19 h the reaction mixture was quenched
with sodium carbonate (10 mL of a saturated aqueous solution) and the resulting mixture
filtered through a pad of diatomaceous earth contained in a sintered glass funnel. The solids
thus retained were washed with ethyl acetate (20 mL). The separated aqueous phase associated
with the combined filtrates was extracted with ethyl acetate (2 x 10 mL) and the combined
organic phases washed with brine (1 × 50 mL) before being dried (Na2SO4), filtered then
concentrated under reduced pressure. The residue so obtained was subjected to flash column
chromatography (silica, 4:6 v/v ethyl acetate/40ꢀ60 petroleum ether elution) and thus
affording, after concentration of the appropriate fractions (Rf = 0.2), compound 8 (74 mg,
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80%) as a clear, red oil. H NMR (400 MHz, CDCl3) δ 7.76 (t, J = 2.9 Hz, 1H), 7.15ꢀ7.10
(complex m, 2H), 6.77 (m, 1H), 6.72 (m, 1H), 4.04 (broad s, 2H), 2.80 (m, 2H), 2.60 (m, 2H);
s13C NMR (100 MHz, CDCl3) δ 208.7, 162.7, 145.4, 144.8, 130.1, 129.6, 118.8, 118.7, 117.0,
35.2, 27.2; IR (ATR) νmax 3422, 3357, 2921, 1688, 1622, 1492, 1453, 1299, 1137, 935, 751
cm–1; MS (ESI, +ve) m/z 196 [(M+Na)+, 100%], 174 [(M+H)+, 5]; HRMS (ESI, +ve) [M+H]+
Calcd for C11H12NO 174.0913; Found 174.0910.
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Compound 9. A magnetically stirred mixture 4,4ꢀdimethylꢀ2ꢀcyclohexanꢀ1ꢀone (640 mg, 5.2
mmol) in THF/water (24 mL of a 1:1 v/v mixture) maintained at 0 °C was treated with K2CO3
(860 mg, 6.2 mmol), DMAP (127 mg, 1.0 mmol) and, in portions, powdered molecular iodine
(1.97 g, 7.8 mmol). The ensuing mixture was warmed to 22 °C and after 3 h the reaction
mixture was diluted with ethyl acetate (20 mL) before being quenched with sodium sulfite (50
ml of a saturated aqueous solution) then stirred vigorously until two clear layers were formed.
The separated aqueous phase was extracted with ethyl acetate (2 × 20 mL) and the combined
organic phases washed with sodium sulfite (1 × 50 mL of a saturated aqueous solution),
hydrochloric acid (1 × 50 mL of a 0.5 M aqueous solution) and brine (1 × 50 mL) before being
dried (Na2SO4) then filtered through a plug of TLCꢀgrade silica. The filtrate was concentrated
under reduced pressure and the residue so obtained subjected to flash column chromatography
(silica, 1:7 v/v ethyl acetate/40ꢀ60 petroleum ether elution). Concentration of the appropriate
fractions (Rf = 0.2) then gave compound 96 (1.29 g, 91%) as a clear, yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.45 (broad s, 1H), 2.67 (t, J = 6.9 Hz, 2H), 1.92 (t, J = 6.9 Hz, 2H), 1.18
(broadened s, 6H); 13C NMR (100 MHz, CDCl3) δ 191.9, 168.0, 101.8, 38.0, 36.0, 33.3, 27.4;
IR (ATR) νmax 2959, 2926, 2864, 1687, 1583, 1317, 1142, 991, 957, 801, 724, 693 cm–1; MS
(ESI, +ve) m/z 273 [(M+Na)+, 100%], 251 [(M+H)+, 50]; HRMS (ESI, +ve) [M+H]+ Calcd for
C8H12IO 250.9927; Found 250.9925.
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Compound 10. A magnetically stirred suspension of compound 9 (1.17 g, 4.7 mmol), oꢀ
iodonitrobenzene (2) (2.33 g, 9.4 mmol) and copper powder (1.50 g, 23.5 mmol) in dry
DMSO (10 mL) maintained at 50 °C was treated with Pd(dppf)Cl2•CH2Cl2 (220 mg, 0.24
mmol). After 3 h the reaction mixture was cooled to 22 °C, diluted with ethyl acetate (10 mL)
before being filtered through a plug of TLCꢀgrade silica topped with diatomaceous earth. The
solids thus retained were washed with ethyl acetate (1 × 30 mL) and the combined filtrates
were washed with ammonia (2 × 50 mL of a 5% v/v aqueous solution), water (2 x 50 mL) and
brine (1 × 50 mL) before being dried (Na2SO4), filtered, then concentrated under reduced
pressure. The residue so obtained was subjected to flash column chromatography (silica, 1:5
v/v ethyl acetate/40ꢀ60 petroleum ether elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.2), compound 10 (920 mg, 80%) as a paleꢀyellow, crystalline
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solid, m.p. = 112 °C. H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.2 and 1.2 Hz, 1H), 7.59
(m, 1H), 7.46 (m, 1H), 7.24 (dd, J = 7.6 and 1.4 Hz, 1H), 6.65 (s, 1H), 2.61 (t, J = 6.8 Hz,
2H), 2.00 (m, 2H), 1.28 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 196.4, 155.5, 148.6, 136.6,
133.2, 132.1, 131.7, 128.7, 124.2, 35.8, 34.7, 33.4, 27.7; IR (ATR) νmax 2960, 1682, 1524,
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1351, 1145, 859, 787, 725 cm–1; MS (ESI, +ve) m/z 268 [(M+Na)+, 100%], 246 [(M+H)+, 56];
HRMS (ESI, +ve) [M+H]+ Calcd for C14H15NO3 246.1125; Found 246.1126.
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Compound 11. A magnetically stirred mixture of compound 10 (50 mg, 0.20 mmol) and 10%
palladium on carbon (10 mg) in dry methanol (5 mL) maintained at 22 °C was placed under a
hydrogen atmosphere. After 2 h the reaction mixture was filtered through a pad of
diatomaceous earth and the filtrate concentrated under reduced pressure. The residue thus
obtained was subjected to flash column chromatography (silica, 5:95 v/v ethyl acetate/40ꢀ60
petroleum ether elution) and thus affording, after concentration of the appropriate fractions (Rf
= 0.4 in 1:10 v/v ethyl acetate/40ꢀ60 petroleum ether elution), compound 117 (37 mg, 92%) as
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a white, crystalline solid, m.p. = 99 °C. H NMR (400 MHz, CDCl3) δ 7.66 (broad s, 1H),
7.45 (d, J = 7.6 Hz, 1H), 7.29 (m, 1H), 7.10–7.02 (complex m, 2H), 2.73 (t, J = 6.5 Hz, 2H),
2.52 (s, 2H), 1.68 (t, J = 6.5 Hz, 2H), 1.10 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 136.1,
132.8, 128.1, 120.9, 119.0, 117.6, 110.3, 109.7, 36.1, 34.9, 30.2, 28.2, 20.7; IR (ATR) νmax
3406, 2950, 1468, 1357, 1327, 1236, 1187, 1008, 740, 635 cm–1; MS (ESI, –ve) m/z 198 [(M–
H)–, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C14H18N 200.1434; Found 200.1433.
Compound 12. A magnetically stirred solution of compound 10 (50 mg, 0.20 mmol) in
acetone (3 mL) maintained at 50 °C was treated with titanium(III) chloride (1.25 mL of a 12%
w/v solution in hydrochloric acid, 1.20 mmol). After 16 h the reaction mixture was cooled to
22 °C then quenched with Na2CO3 (10 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through a pad of diatomaceous earth. The solids so retained
were washed with ethyl acetate (20 mL) and the aqueous phase associated with the combined
filtrates extracted with ethyl acetate (2 × 10 mL). The combined organic phases were washed
with brine (1 × 50 mL) then dried (Na2SO4) and filtered before being concentrated under
reduced pressure. The residue so obtained was subjected to flash column chromatography
(silica, 1:8 v/v ethyl acetate/dichloromethane elution) and thus affording, after concentration
of the appropriate fractions (Rf = 0.2), compound 128 (35 mg, 82%) as white, crystalline solid,
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m.p. = 258 °C (lit.8 m.p. = 270ꢀ274 °C). H NMR (400 MHz, CDCl3) δ 8.80 (broad s, 1H),
8.26 (m, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 2.68 (dd, J = 7.0 and 6.0 Hz, 2H), 2.10 (dd, J = 7.0
and 6.0 Hz, 2H), 1.48 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.0, 158.3, 135.6, 124.9,
123.4, 122.7, 121.7, 111.4, 111.0, 38.6, 35.4, 32.1, 27.4; IR (ATR) νmax 3186, 2962, 1625,
1615, 1582, 1474, 1453, 1415, 1201, 881, 756 cm–1; MS (ESI, +ve) m/z 449 [(2M+Na)+,
58%], 236 [(M+Na)+, 85] 214 [(M+H)+, 100]; HRMS (ESI, +ve) [M+H]+ Calcd for C14H16NO
214.1227; Found 214.1226.
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Compound 14. A magnetically stirred solution of compound 139 (109 mg, 0.50 mmol) in
acetone (2.5 mL) maintained at 22 °C was treated with titanium(III) chloride (2.5 mL of a
12% w/v solution in hydrochloric acid, 2.39 mmol). After 16 h the reaction mixture was
quenched with sodium carbonate (10 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through a pad of diatomaceous earth. The solids so retained
were washed with ethyl acetate (1 × 20 mL) and the aqueous phase associated with the
combined filtrates extracted with ethyl acetate (2 × 10 mL). The combined organic phases
were washed with brine (1 × 10 mL) then dried (Na2SO4) and filtered before being
concentrated under reduced pressure. The residue so obtained was subjected to flash column
chromatography (silica, ethyl acetate elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.2), compound 14 (50 mg, 54%) as white, crystalline solid, m.p. =
179 °C. 1H NMR (400 MHz, CDCl3) δ 13.01 (broad s, 1H), 8.55 (dd, J = 7.7 and 1.4 Hz, 1H),
8.31 (d, J = 4.9 Hz, 1H), 7.29 (m, 1H), 3.13 (t, J = 6.2 Hz, 2H), 2.65 (t, J = 6.4 Hz, 2H), 2.40–
2.26 (complex m, 2H); 13C NMR (100 MHz, CDCl3) δ 194.0, 152.5, 148.8, 141.8, 130.5,
118.5, 118.2, 111.7, 37.9, 23.5, 23.4; IR (ATR) νmax 3047, 2950, 2842, 1640, 1589, 1472,
1414, 1281, 1178, 1010, 776 cm–1; MS (ESI, +ve) m/z 209 [(M+H)+, 100%], 187 [(M+H)+,
60]; HRMS (ESI, +ve) [M+H]+ Calcd for C11H11N2O 187.0866; Found 187.0865.
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Compound 15. A magnetically stirred solution of levoglucosenone (1.50 g, 11.9 mmol) in dry
dichloromethane (15 mL) maintained at 22 °C was treated, in portions, with powdered
molecular iodine (4.53 g, 17.8 mmol) then pyridine (1.05 mL, 13.1 mmol). After 48 h the
reaction mixture was quenched with sodium sulfite (30 ml of a saturated aqueous solution)
then stirred vigorously until two clear layers were formed. The separated aqueous phase was
extracted with dichloromethane (2 × 20 mL) and the combined organic phases washed with
sodium sulfite (1 × 60 mL of a saturated aqueous solution), hydrochloric acid (1 × 100 mL of
a 0.5 M aqueous solution) and brine (1 × 100 mL) before being dried (Na2SO4) then filtered
through a plug of TLCꢀgrade silica. The filtrate was concentrated under reduced pressure and
the residue so obtained subjected to flash column chromatography (silica, 1:1 v/v diethyl
ether/40ꢀ60 petroleum ether elution). Concentration of the appropriate fractions (Rf = 0.3) then
gave compound 1510 (2.24 g, 75%) as a paleꢀyellow, crystalline solid, m.p. = 64 °C (lit.10 m.p.
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= 85ꢀ90 °C). H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 5.0 Hz, 1H), 5.57 (s, 1H), 4.93 (m,
1H), 3.89–3.78 (complex m, 2H); 13C NMR (100 MHz, CDCl3) δ 183.1, 155.5, 100.9, 99.8,
74.3, 66.5; IR (ATR) νmax 3063, 2973, 2899, 1699, 1575, 1329, 1175, 1104, 978, 916, 881
cm–1; MS (ESI, +ve) m/z 307 [(M+Na+MeOH)+, 100%], 275 [(M+Na)+, 55]; HRMS (ESI,
+ve) [M+H]+ Calcd for C6H6IO3 252.9356; Found 252.9361.
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Compound 17. A magnetically stirred suspension of compound 15 (297 mg, 1.2 mmol), oꢀ
iodonitrobenzene (2) (200 mg, 0.79 mmol) and copper powder (250 g, 4.0 mmol) in dry
DMSO (6 mL) maintained at 80 °C was treated with Pd2(dba)3 (72 mg, 0.08 mmol). After 16
h the reaction mixture was cooled to 22 °C, diluted with ethyl acetate (5 mL) then filtered
through a plug of TLCꢀgrade silica topped with diatomaceous earth. The solids so retained
were washed with ethyl acetate (1 x 10 mL) and the combined filtrates washed with ammonia
(2 × 15 mL of a 5% v/v aqueous solution), water (2 × 15 mL) and then brine (1 × 15 mL)
before being dried (Na2SO4), filtered and concentrated under reduced pressure. The ensuing
residue was subjected to flash column chromatography (silica, 2:8 to 1:1 v/v diethyl ether/40ꢀ
60 petroleum ether elution) and thus affording, after concentration of the appropriate fractions
(Rf = 0.3 in 4:6 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 17 (135 mg, 69%) as a
white, crystalline solid, m.p. = 137 °C. 1H NMR (400 MHz, acetoneꢀd6) δ 7.92 (m, 1H), 7.53
(m, 1H), 7.27–7.18 (complex m, 2H), 5.88 (d, J = 4.5 Hz, 1H), 5.38 (s, 1H), 4.03 (dd, J = 7.1
and 4.5 Hz, 1H), 3.84 (d, J = 7.1 Hz, 1H) (resonance due to one proton not observed); 13C
NMR (100 MHz, acetoneꢀd6) δ 186.8, 151.6, 137.1, 125.1, 124.4, 123.3, 121.5, 113.4, 108.3,
103.2, 72.2, 68.0; IR (ATR) νmax 2967, 2899, 1703, 1523, 1354, 1108, 984, 895, 794 cm–1;
MS (ESI, +ve) m/z 270 [(M+Na)+, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C12H10NO5
248.0553; Found 248.0553.
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Compound 18. A magnetically stirred suspension of compound 15 (2.77 g, 11.0 mmol), 3ꢀ
bromoꢀ2ꢀnitropyridine (16)8 (1.0 g, 5.0 mmol), copper(I) iodide (1.43 g, 7.5 mmol) and copper
powder (250 g, 4.0 mmol) in dry DMSO (50 mL) maintained at 50 °C was treated with
Pd(dppf)Cl2•CH2Cl2 (204 mg, 0.25 mmol). After 5 h the reaction mixture was cooled to 22
°C, diluted with ethyl acetate (20 mL) then filtered through a plug of TLCꢀgrade silica topped
with diatomaceous earth. The solids so retained were washed with ethyl acetate (1 × 40 mL)
and the combined filtrates washed with ammonia (2 × 25 mL of a 5% v/v aqueous solution),
water (2 × 25 mL) then brine (1 × 25 mL) before being dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue so obtained was subjected to flash column
chromatography (silica, 1:4 v/v ethyl acetate/40ꢀ60 petroleum ether elution) and thus
affording, after concentration of the appropriate fractions (Rf = 0.2), compound 18 (135 mg,
69%) as a yellow, crystalline solid, m.p. = 170 °C. 1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J
= 4.7 and 1.7 Hz, 1H), 7.79 (dd, J = 7.6 and 1.7 Hz, 1H), 7.65 (dd, J = 7.6 and 4.7 Hz, 1H),
7.32 (d, J = 4.8 Hz, 1H), 5.51 (s, 1H), 5.20 (t, J = 4.6 Hz, 1H), 4.05–3.96 (complex m, 2H);
13C NMR (100 MHz, CDCl3) δ 185.4, 156.8, 148.8, 144.4, 141.6, 134.7, 128.1, 123.5, 101.3,
72.3, 66.9; IR (ATR) νmax 2971, 2888, 1702, 1541, 1407, 1364, 1101, 984, 930, 890, 819, 647
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cm–1; MS (ESI, +ve) m/z 271 [(M+Na)+, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for
C11H9N2O5 249.0506; Found 249.0509.
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Compound 19. A magnetically stirred solution of compound 18 (40 mg, 0.16 mmol) in THF
(1.7 mL) maintained at 22 °C was treated with titanium(III) chloride (0.85 mL of a 12% w/v
solution in hydrochloric acid, 0.81 mmol). After 18 h the reaction mixture was quenched with
sodium carbonate (5 mL of a saturated aqueous solution) and the resulting heterogeneous
mixture filtered through a pad of diatomaceous earth. The solids so retained were washed with
ethyl acetate (1 × 10 mL), the combined filtrates were separated and the aqueous phase
extracted with ethyl acetate (2 × 5 mL). The combined organic phases were washed with brine
(1 × 30 mL) then dried (Na2SO4), filtered and concentrated under reduced pressure. The
residue so obtained was subjected to flash column chromatography (silica, 4:6 v/v ethyl
acetate/40ꢀ60 petroleum ether elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.4), compound 19 (34 mg, 97%) as a white, crystalline solid, m.p.
>250 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.1 Hz, 1H), 7.65 (m, 1H), 7.56 (m, 1H),
7.28–7.24 (complex m, 2H), 5.51 (s, 1H), 5.19 (t, J = 4.6 Hz, 1H), 4.06–3.95 (complex m,
2H); 13C NMR (100 MHz, CDCl3) δ 185.7, 148.5, 142.7, 137.3, 133.5, 131.5, 129.8, 128.8,
124.6, 101.3, 72.1, 66.8; IR (ATR) νmax 3278, 2924, 1651, 1479, 1452, 1076, 869 cm–1; MS
(ESI, +ve) m/z 238 [(M+Na)+, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C12H10NO3
216.0655; Found 216.0858.
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Compound 20. A magnetically stirred solution of compound 18 (52 mg, 0.21 mmol) and
hydrochloric acid (9 mL of a 1 M aqueous solution) in 1,2ꢀdimethoxyethane (5 mL)
maintained at 50 °C was treated with iron powder (59 mg, 1.10 g.atom). After 18 h the
reaction mixture was cooled to 22 °C, diluted with ethyl acetate (10 mL) then filtered through
a plug of TLCꢀgrade silica topped with diatomaceous earth and the solids so retained were
washed with ethyl acetate (1 x 10 mL). The combined filtrates were washed with water (2 x
20 mL) and brine (1 x 20 mL) before being dried (Na2SO4), filtered, then concentrated under
reduced pressure. The residue so obtained was subjected to flash column chromatography
(silica, 2:1 v/v ethyl acetate/40−60 petroleum ether elution) and thus affording, after
concentration of the appropriate fractions (Rf = 0.2), compound 20 (26 mg, 58%) as a white,
crystalline solid, m.p. = 275 °C. 1H NMR (400 MHz, acetoneꢀd6) δ 8.37 (m, 1H), 8.25 (dd, J =
7.8 and 1.6 Hz, 1H), 7.29 (dd, J = 7.8 and 4.8 Hz, 1H), 5.95 (d, J = 4.6 Hz, 1H), 5.44 (s, 1H),
4.11 (dd, J = 7.2 and 4.6 Hz, 1H), 3.96 (d, J = 7.2 Hz, 1H) (signal due to NꢀH group proton
not observed); 13C NMR (100 MHz, acetoneꢀd6) δ 186.5, 152.2, 149.8, 145.6, 129.6, 119.4,
117.4, 107.1, 103.1, 72.1, 68.0; IR (ATR) νmax 2981, 2888, 1679, 1592, 1480, 1426, 1109,
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1075, 889, 805 cm–1; MS (ESI, +ve) m/z 239 [(M+Na)+, 100%], 217 [(M+H)+, 10]; HRMS
(ESI, +ve) [M+H]+ Calcd for C11H9N2O3 217.0608; Found 217.0609.
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Compounds 22 and 23. A magnetically stirred solution of transꢀchalcone (21) (475 mg, 2.28
mmol) in dry dichloromethane (7 mL) maintained at 22 °C was treated, in portions, with
powdered molecular iodine (2.00 g, 7.98 mmol) then pyridine (7 mL). After 0.5 h the reaction
mixture was quenched with sodium sulfite (30 ml of a saturated aqueous solution) and
vigorous stirring continued until two clear layers had formed. The separated aqueous phase
was extracted with dichloromethane (2 × 10 mL) and the combined organic phases washed
with sodium sulfite (1 × 60 mL of a saturated aqueous solution), hydrochloric acid (1 x 500
mL of a 0.5 M aqueous solution) and brine (1 × 50 mL) before being dried (Na2SO4) then
filtered through a plug of TLCꢀgrade silica. The filtrate was concentrated under reduced
pressure and the residue so obtained subjected to flash column chromatography (silica, 5:95 to
1:9 v/v diethyl ether/40ꢀ60 petroleum ether gradient elution). Two fractions, A and B, were
thus obtained.
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Concentration of fraction A (R = 0.5 in 1:9 diethyl ether/40ꢀ60 petroleum ether) gave
f
compound 2212 (439 mg, 58%) as a lightꢀyellow oil. 1H NMR (400 MHz, CDCl3) δ 8.01–7.92
(complex m, 2H), 7.58–7.40 (complex m, 6H), 7.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
193.0, 148.5, 135.5, 135.3, 132.7, 130.2, 130.0, 129.4, 128.5, 128.4, 103.5; IR (ATR) νmax
3057, 3024, 2923, 1657, 1595, 1446, 1238, 1176, 1059, 748, 689 cm–1; MS (ESI, +ve) m/z
357 [(M+Na)+, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C15H12IO 334.9927; Found
334.9916.
Concentration of fraction B (R = 0.6 in 1:9 diethyl ether/40ꢀ60 petroleum ether) gave
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compound 2312 (79 mg, 10%) as a lightꢀyellow oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (m,
2H), 7.53 (m, 2H), 7.40 (m, 2H), 7.16 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 193.6, 143.4,
136.0, 134.0, 132.5, 129.9, 128.8, 128.7, 128.5, 128.1, 92.7; IR (ATR) νmax 3058, 3024, 2924,
1659, 1596, 1447, 1221, 1173, 1012, 750, 685 cm–1; MS (ESI, +ve) m/z 357 [(M+Na)+,
100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C15H12IO 334.9927; Found 334.9916.
Compounds 24 and 25. Method i: A magnetically stirred mixture of compound 22 (160 mg,
0.48 mmol), 3ꢀbromoꢀ2ꢀnitropyridine (16) (155 mg, 0.76 mmol) and copper powder (182 mg,
4.0 mmol) in dry DMSO (5 mL) maintained at 80 °C was treated with Pd2(dba)3 (43 mg, 0.05
mmol). After 16 h the reaction mixture was cooled to 22 °C, diluted with ethyl acetate (10
mL) then filtered through a plug of TLCꢀgrade silica topped with diatomaceous earth. The
solids so retained were washed with ethyl acetate (1 × 5 mL) and the combined filtrates
washed with ammonia (2 × 10 mL of a 5% v/v aqueous solution), water (2 × 10 mL) and brine
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(1 × 10 mL) before being dried (Na2SO4), filtered, then concentrated under reduced pressure.
The residue so obtained was subjected to flash column chromatography (silica, 3:7 to 1:1 v/v
diethyl ether/40ꢀ60 petroleum ether gradient elution) and so affording two fractions, A and B.
Concentration of fraction A (R = 0.3 in 3:7 ethyl acetate/40ꢀ60 petroleum ether) gave
f
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compound 24 (122 mg, 77%) as a lightꢀyellow oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J
= 4.6 and 1.8 Hz, 1H), 8.16 (dd, J = 7.8 and 1.8 Hz, 1H), 7.90 (m, 2H), 7.62 (dd, J = 7.8 and
4.6 Hz, 1H), 7.40 (m, 1H), 7.29–7.22 (complex m, 3H), 7.17–7.08 (complex m, 5H); 13C
NMR (100 MHz, CDCl3) δ 195.6, 156.4, 147.8, 141.9, 138.3, 135.9, 134.3, 133.7, 133.4,
130.0, 129.4, 129.1, 128.3, 128.2(1), 128.9(9), 127.3; IR (ATR) νmax 3060, 2982, 1734, 1646,
1540, 1447, 1359, 1245, 694 cm–1; MS (ESI, +ve) m/z 353 [(M+Na)+, 100%]; HRMS (ESI,
+ve) [M+H]+ Calcd for C20H15N2O3 331.1077; Found 331.1080.
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Concentration of fraction B (R = 0.4 in 3:7 ethyl acetate /40ꢀ60 petroleum ether) gave
f
compound 25 (12 mg, 8%) as a lightꢀyellow oil. 1H NMR (400 MHz, CDCl3) δ 8.63 (dd, J =
4.6 and 1.9 Hz, 1H), 7.92 (m, 2H), 7.73 (m, 1H), 7.60 (m, 2H), 7.53 (m, 2H), 7.48 (s, 1H),
7.29 (m, 1H), 7.23 (m, 2H), 7.00 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 195.6, 156.4, 148.3,
143.8, 143.5, 137.4, 135.9, 133.3, 132.4, 130.1, 129.9, 129.8, 128.7, 128.4, 128.3, 127.9; IR
(ATR) νmax 3060, 2981, 1647, 1541, 1447, 1365, 1231, 695 cm–1; MS (ESI, +ve) m/z 353
[(M+Na)+, 100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C20H15N2O3 331.1077; Found
331.1079.
Method ii: Compound 23 was subjected to crossꢀcoupling with bromopyridine 16 in the same
manner as described immediately above in Method i. Subjection of the product mixture
obtained on workup to flash column chromatography (silica, 3:7 to 1:1 v/v diethyl ether/40ꢀ60
petroleum ether gradient elution) afforded two fractions, A and B.
Concentration of fraction A (R = 0.3 in v/v 3:7 ethyl acetate/40ꢀ60 petroleum ether)
f
gave compound 24 (18%) as a lightꢀyellow oil. This material was identical, in all respects,
with that obtained by Method i.
Concentration of fraction B (R = 0.4 in 3:7 v/v ethyl acetate/40ꢀ60 petroleum ether)
f
gave compound 25 (41%) as a lightꢀyellow oil. This material was identical, in all respects,
with that obtained by Method i.
Compound 26. Method i: A magnetically stirred mixture of compound 24 (23 mg, 0.07
mmol) and 10% palladium on carbon (10 mg) in ethyl acetate (5 mL) maintained at 22 °C was
placed under a hydrogen atmosphere. After 16 h the reaction mixture was flushed with
nitrogen then filtered through a pad of diatomaceous earth and the filtrate concentrated under
reduced pressure. The residue thus obtained was subjected to flash column chromatography
(silica, 3:7 to 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether gradient elution) and thus affording,
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after concentration of the appropriate fractions (Rf = 0.4 in 3:7 v/v ethyl acetate/40ꢀ60
petroleum ether), compound 2613 (13 mg, 63%) as a white, crystalline solid, no m.p.,
1
decomposition above 120 °C. H NMR (400 MHz, CDCl3) δ 11.77 (broad s, 1H), 8.18 (m,
1H), 7.69 (m, 3H), 7.50 (m, 2H), 7.42 (m, 1H), 7.32–7.15 (complex m, 5H), 6.99 (m, 1H),
4.32 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1, 140.9, 136.9, 132.3, 130.1, 129.6, 128.9,
128.6, 128.5, 128.3(1), 128.2(9), 128.2, 126.0, 115.5, 109.1, 30.5; IR (ATR) νmax 3026, 2920,
2849, 1739, 1579, 1600, 1490, 1461, 1411, 765, 699 cm–1; MS (ESI, +ve) m/z 285 [(M+H)+,
100%]; HRMS (ESI, +ve) [M+H]+ Calcd for C20H17N2 285.1386; Found 285.1388.
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Method ii: Compound 25 was subjected to reductive cyclisation in the same manner as
described immediately above in Method i. Subjection of the product mixture obtained on
workup to flash column chromatography (silica, 3:7 to 1:1 v/v diethyl ether/40ꢀ60 petroleum
ether gradient elution) afforded, after concentration of the appropriate fractions (Rf = 0.4 in
3:7 to 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 26 (80%) as a white, crystalline
solid. This material was identical, in all respects, with that obtained by Method i.
Compound 27. A magnetically stirred mixture of compound 24 (45 mg, 0.14 mmol) in THF
(5 mL) maintained at 22 °C was treated with titanium(III) chloride (0.9 mL of a 12% w/v
solution in hydrochloric acid, 0.86 mmol). After 16 h the reaction mixture was quenched with
sodium carbonate (10 mL of a saturated aqueous solution) and the resulting heterogeneous
mixture filtered through a pad of diatomaceous earth. The solids so retained were washed with
ethyl acetate (1 × 20 mL), the combined filtrates separated and the aqueous phase extracted
with ethyl acetate (4 × 10 mL). The combined organic phases were washed with brine (1 × 50
mL) then dried (Na2SO4) and filtered before being concentrated under reduced pressure. The
residue so obtained was subjected to flash column chromatography (silica, 2:8 to 1:1 v/v ethyl
acetate/40ꢀ60 petroleum ether gradient elution) and thus affording, after concentration of the
appropriate fractions (Rf = 0.2 in 3:7 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 27
(20 mg, 49%) as yellow, crystalline solid, m.p. = 159 °C. 1H NMR (400 MHz, CDCl3) δ 8.37
(d, J = 7.9 Hz, 1H), 8.15 (broad s, 1H), 7.64 (m, 2H), 7.52 (m, 2H), 7.34 (m, 4H), 7.21 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 192.7, 148.1, 145.4, 142.5, 139.3, 131.7, 131.5, 131.1,
129.8, 129.6, 129.3, 128.4, 127.8, 117.9, 111.6 (one signal obscured or overlapping); IR
(ATR) νmax 2917, 2849, 1615, 1459, 1435, 1292, 936, 896, 766, 730, 698 cm–1; MS (ESI, +ve)
m/z 321 [(M+Na)+, 100%], 299 [(M+H)+, 70%]; HRMS (ESI, +ve) [M+H]+ Calcd for
C20H15N2O 299.1179; Found 299.1181.
Method ii: Compound 25 was subjected to reductive cyclisation in the same manner as
described immediately above in Method i. Subjection of the product mixture obtained on
workup to flash column chromatography (silica, 2:8 to 1:1 v/v ethyl acetate/40ꢀ60 petroleum
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ether gradient elution) afforded, after concentration of the appropriate fractions (Rf = 0.2 in
3:7 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 27 (15%) as a yellow, crystalline
solid. This material was identical, in all respects, with that obtained by Method i.
Compound 32. A magnetically stirred mixture of compound 311 (516 mg, 2.00 mmol), oꢀ
iodonitrobenzene (2) (996 mg, 4.00 mmol) and copper powder (636 mg, 10.0 mmol) in dry
DMSO (10 mL) maintained at 50 °C was treated with Pd(dppf)Cl2•CH2Cl2 (82 mg, 0.10
mmol). After 4 h the reaction mixture was cooled to 22 °C then diluted with ethyl acetate (10
mL) before being filtered through a plug of TLCꢀgrade silica topped with diatomaceous earth.
The solids so retained were washed with ethyl acetate (1 × 30 mL) and the combined filtrates
were washed with ammonia (2 × 40 mL of a 5% v/v aqueous solution), water (2 × 40 mL) and
brine (1 × 40 mL) before being dried (Na2SO4), filtered, then concentrated under reduced
pressure. The residue so obtained was subjected to flash column chromatography (silica,
toluene elution) and thus affording, after concentration of the appropriate fractions (Rf = 0.3),
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compound 321 (390 mg, 77%) as a clear, yellow oil. H NMR (400 MHz, CDCl3) δ 9.73 (s,
1H), 8.23 (m, 1H), 7.63–7.56 (complex m, 2H), 7.54 (s, 1H), 7.37–7.22 (complex m, 3H),
7.17 (complex m, 3H); 13C NMR (100 MHz, CDCl3) δ 191.8, 148.9, 139.7, 133.9, 133.3,
132.0, 130.5, 130.4, 129.6(1), 129.5(9), 128.7, 125.0 (one signal obscured or overlapping); IR
(ATR) νmax 3348, 3062, 2830, 1682, 1627, 1521, 1346, 1110, 1062, 856, 713 cm–1; MS (ESI,
+ve) m/z 276 [(M+Na)+, 100%], 254 [(M+H)+, 8]; HRMS (ESI, +ve) [M+H]+ Calcd for
C15H12NO3 254.0182; Found 254.0182.
Compounds 33 and 34. A magnetically stirred solution of compound 32 (134 mg, 0.53
mmol) in acetone (5 mL) maintained at 22 °C was treated with titanium(III) chloride (3.3 mL
of a 12% w/v solution in hydrochloric acid, 3.18 mmol). After 23 h the reaction mixture was
quenched with sodium carbonate (10 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through a pad of diatomaceous earth. The solids so retained
were washed with ethyl acetate (1 × 20 mL), the combined filtrates separated and the aqueous
phase extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed
with brine (1 × 50 mL) then dried (Na2SO4) and filtered before being concentrated under
reduced pressure. The residue so obtained was subjected to flash column chromatography
(silica, 1:9 v/v diethyl ether/dichloromethane elution) and thus affording a partially separable,
ca. 5ꢀ3:1 and slowly interconverting mixture of compounds 3314 and 3414 (64 mg, 55%) as an
1
oily solid, R
f
= 0.2 and 0.4, respectively. H NMR (400 MHz, CDCl3) δ (for compound 33)
8.20 (broad s, 1H), 7.85 (s, 1H), 7.70–7.60 (complex m 3H), 7.52–7.41 (complex m, 3H), 7.22
(m, 1H), 6.88 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (for compound 33) 170.1, 141.6,
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137.7, 135.0, 130.0, 129.8, 129.5, 128.8, 127.6, 123.2, 122.0, 121.9, 110.2; 13C NMR (100
MHz, CDCl3) δ (for a ca. 3:1 mixture of compounds 33 and 34) 170.0, 167.7, 141.4, 139.6,
137.6(1), 137.5(9), 134.8, 133.7, 131.9, 130.6, 139.9, 129.7, 129.3, 128.9, 128.6, 128.3,
127.4, 126.2, 125.3, 123.0, 121.8(1). 121.7(9), 121.7, 119.3, 110.1, 109.5; IR (ATR) νmax (for
a mixture) 3222, 3062, 1704, 1613, 1463, 1329, 1202, 781, 747, 722, 696 cm–1; MS (ESI,
+ve) m/z (for a mixture) 465 [(2M+Na)+, 60%], 244 [(M+Na)+, 100], 222 [(M+H)+, 13];
HRMS (ESI, +ve) [M+H]+ Calcd for C15H12NO 222.0913; Found 222.0906.
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Crystals of compound 33 suitable for Xꢀray analysis was grown from diethyl ether (m.p. = 169
°C).
Compound 36. A magnetically stirred mixture of 3ꢀiodoꢀ2ꢀmethylcyclohexꢀ2ꢀenone16 (213
mg, 0.90 mmol), oꢀiodonitrobenzene (2) (449 mg, 1.80 mmol) and copper powder (286 mg,
4.5 mmol) in dry DMSO (10 mL) maintained at 80 °C was treated with Pd2(dba)3 (77 mg,
0.08 mmol). After 16 h the reaction mixture was cooled to 22 °C, diluted with ethyl acetate
(10 mL) before being filtered through a plug of TLCꢀgrade silica topped with diatomaceous
earth and the solids so retained were washed with ethyl acetate (1 x 10 mL). The combined
filtrates were washed with ammonia (2 x 40 mL of a 5% v/v aqueous solution), water (2 x 40
mL) and brine (1 x 40 mL) before being dried (Na2SO4), filtered, then concentrated under
reduced pressure. The residue so obtained was subjected to flash column chromatography
(silica, 1:4 to 1:1 v/v diethyl ether/40ꢀ60 petroleum ether elution) and thus affording, after
concentration of the appropriate fractions (Rf = 0.3 in 2:3 v/v diethyl ether/40ꢀ60 petroleum
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ether elution), compound 36 (120 mg, 61%) as a clear, lightꢀyellow oil. H NMR (400 MHz,
CDCl3) δ 8.18 (dd, J = 8.3 and 1.3 Hz, 1H), 7.71 (m, 1H), 7.55 (m, 1H), 7.24 (dd, J = 7.6 and
1.6 Hz, 1H), 2.65 (m, 2H), 2.59–2.46 (m, 2H), 2.27 (m, 1H), 2.15 (m, 1H), 1.52 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 198.8, 153.9, 146.3, 136.7, 134.0, 131.8, 129.1, 128.8, 124.9,
37.8, 32.5, 23.0, 12.5; IR (ATR) νmax 2947, 2870, 1665, 1523, 1344, 1111, 908, 727 cm–1; MS
(ESI, +ve) m/z 254 [(M+Na)+, 100%], 232 [(M+H)+, 15]; HRMS (ESI, +ve) [M+H]+ Calcd for
C13H14NO3 232.0968; Found 232.0966.
Compound 37. A magnetically stirred solution of compound 3516 (150 mg, 0.69 mmol) in
acetone (7 mL) maintained at 22 °C was treated with titanium(III) chloride (3.6 mL of a 12%
w/v solution in hydrochloric acid, 3.45 mmol). After 16 h the reaction mixture was quenched
with sodium carbonate (15 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through a pad of diatomaceous earth. The solids so retained
were washed with ethyl acetate (1 × 20 mL) and the aqueous phase associated with combined
filtrates extracted with ethyl acetate (4 × 10 mL). The combined organic phases were washed
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with brine (1 × 50 mL) then dried (Na2SO4) and filtered before being concentrated under
reduced pressure. The residue so obtained was subjected to flash column chromatography
(silica, 2:3 v/v ethyl acetate/40ꢀ60 petroleum ether elution) and thus affording, after
concentration of the appropriate fractions (Rf = 0.3), compound 37 (130 mg, quant.) as yellow,
crystalline solid, m.p. = 108 °C. 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 7.06 (dd, J = 7.6
and 1.7 Hz, 1H), 6.82 (m, 1H), 6.77 (m, 1H), 3.64 (broad s, 2H), 2.84 (m, 2H), 2.51 (m, 2H),
1.73 (t, J = 2.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.6, 167.7, 142.5, 138.6, 129.7,
127.4, 122.2, 118.1, 115.7, 34.4, 30.8, 9.5; IR (ATR) νmax 3453, 3357, 2917, 1689, 1686,
1622, 1494, 1451, 1342, 1222, 1094, 1061, 747 cm–1; MS (ESI, +ve) m/z 210 [(M+Na)+,
100%], 188 [(M+H)+, 17]; HRMS (ESI, +ve) [M+H]+ Calcd for C12H14NO 188.1070; Found
188.1069.
Compound 38. Method i: A magnetically stirred solution of compound 3616 (45 mg, 0.19
mmol) in THF (2 mL) maintained at 22 °C was treated with titanium(III) chloride (1.0 mL of a
12% w/v solution in hydrochloric acid, 0.96 mmol). After 16 h the reaction mixture was
quenched with sodium carbonate (5 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through a pad of diatomaceous earth. The solids so retained
were washed with ethyl acetate (1 × 10 mL), the phases associated with the combined filtrates
separated and the aqueous one extracted with ethyl acetate (4 × 10 mL). The combined
organic phases were washed with brine (1 × 50 mL) then dried (Na2SO4) and filtered before
being concentrated under reduced pressure. The residue so obtained was subjected to flash
column chromatography (silica, 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether elution) and thus
affording, after concentration of the appropriate fractions (Rf = 0.6), compound 38 (40 mg,
98%) as lightꢀyellow crystals, m.p. = 73 °C. 1H NMR (400 MHz, CDCl3) δ 7.13 (m, 1H), 6.92
(dd, J = 7.6 and 1.7 Hz, 1H), 6.79 (m, 1H), 6.74 (dd, J = 7.9 and 1.1 Hz, 1H), 3.57 (broad s,
2H), 2.55 (m, 4H), 2.10 (m, 2H), 1.65 (t, J = 2.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
199.6, 154.9, 141.5, 133.6, 128.8, 127.1, 126.6, 118.4, 115.5, 37.9, 31.9, 22.9, 12.3; IR (ATR)
νmax 3459, 3362, 2945, 2923, 1660, 1618, 1494, 1452, 1354, 1106, 750 cm–1; MS (ESI, +ve)
m/z 224 [(M+Na)+, 100%], 202 [(M+H)+, 28]; HRMS (ESI, +ve) [M+H]+ Calcd for C13H16NO
202.1226; Found 202.1219.
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Method ii: Reduction of compound 36 with TiCl3/HCl in the same manner as detailed above
but using acetone instead of THF as solvent gave, after workup and flash chromatography,
compound 38 (80%) as lightꢀyellow crystals. This material was identical, in all respects, with
that obtained by Method i.
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Compounds 40 and 41. A magnetically stirred mixture of compound 3916 (200 mg, 0.92
mmol) in acetone (10 mL) maintained at 22 °C was treated with titanium(III) chloride (5.0 mL
of a 12% w/v solution in hydrochloric acid, 4.79 mmol). After 16 h the reaction mixture was
quenched with sodium carbonate (20 mL of a saturated aqueous solution) and the resulting
heterogeneous mixture filtered through diatomaceous earth. The solids so retained were
washed with ethyl acetate (40 mL), the combined filtrates separated and the aqueous phase
extracted with ethyl acetate (4 × 10 mL). The combined organic phases were washed with
brine (1 × 100 mL) then dried (Na2SO4), filtered and then concentrated under reduced
pressure. The residue so obtained was subjected to flash column chromatography (silica, 1:9
to 4:6 v/v ethyl acetate/40ꢀ60 petroleum ether elution) and so affording, two fractions, A and
B.
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Concentration of fraction A (R = 0.4 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether
f
elution) gave compound 4017 (80 mg, 40%) as orangeꢀcolored crystals, m.p. = 90 °C. 1H NMR
(400 MHz, CDCl3) δ 7.16 (m, 1H), 7.07 (dd, J = 7.8 and 1.7 Hz, 1H), 6.78 (m, 1H), 6.73 (dd,
J = 8.1 and 1.2 Hz, 1H), 6.26 (t, J = 1.6 Hz, 1H), 3.84 (broad s, 2H), 2.67 (m, 2H), 2.51 (m,
2H), 2.15 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 199.6, 161.2, 142.8, 129.7, 127.9, 127.7,
125.5, 118.3, 116.2, 37.3, 30.2, 23.1; IR (ATR) νmax 3443, 3354, 2925, 1655, 1608, 1490,
1449, 1244, 1188, 747 cm–1; MS (ESI, +ve) m/z 210 [(M+Na)+, 100%], 188 [(M+H)+, 9];
HRMS (ESI, +ve) [M+H]+ Calcd for C12H14NO 188.1070; Found 188.1072.
Concentration of fraction B (R = 0.5 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether
f
elution) gave compound 41 (135 mg, 60%) as redꢀcolored crystals, m.p. = 113 °C. 1H NMR
(400 MHz, CDCl3) δ 7.21 (dd, J = 7.9 and 1.5 Hz, 1H), 7.11 (m, 1H), 6.65 (m, 1H), 6.45 (dd,
J = 8.0 and 1.2 Hz, 1H), 3.64 (broad s, 1H), 2.69 (t, J = 6.1 Hz, 2H), 2.43 (dd, J = 7.4 and 6.1
Hz, 2H), 2.03 (m, 2H), 1.52 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 196.8, 148.2, 145.2,
133.8, 131.7, 125.2, 120.2, 117.5, 113.8, 53.8, 38.7, 29.0, 25.9, 21.6; IR (ATR) νmax 3336,
2952, 2925, 1637, 1607, 1380, 1269, 743 cm–1; MS (ESI, +ve) m/z 250 [(M+Na)+, 100%], 228
[(M+H)+, 70%]; HRMS (ESI, +ve) [M+H]+ Calcd for C15H18NO 228.1383; Found 228.1384.
Compound 44. A magnetically stirred solution of compound 40 (35 mg, 0.19 mmol, 1.0 eq.)
in butanone (5 mL) was treated with HCl (100 ꢀl of a 12 M aqueous solution) and the ensuing
mixture was maintained at 22 °C for 16 h. The resulting mixture was quenched with sodium
carbonate (5 ml of a saturated aqueous solution) and the separated aqueous layer extracted
with ethyl acetate (3 × 5 mL). The combined organic phases were then dried (Na2SO4),
filtered and concentrated under reduced pressure. The residue so obtained was subjected to
flash column chromatography (silica, 5:35 v/v diethyl ether/40ꢀ60 petroleum ether elution) to
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afford, after concentration of the appropriate fractions (Rf = 0.6 in 3:7 v/v diethyl ether/40ꢀ60
petroleum ether elution), compound 44 (33 mg, 73%) as a red, crystalline solid, m.p. = 118
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°C. H NMR (400 MHz, CDCl3) δ 7.19 (dd, J = 7.9 and 1.3 Hz, 1H), 7.07 (m, 1H), 6.59 (m,
1H), 6.41 (dd, J = 8.0 and 1.1 Hz, 1H), 3.54 (broad s, 1H), 2.70 (m, 2H), 2.45 (m, 3H), 2.04
(m, 2H), 1.49 (s, 3H), 1.34 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
197.1, 149.2, 145.8, 131.9(1), 131.8(9), 125.3, 119.5, 116.9, 113.3, 57.3, 38.8, 33.8, 28.5,
26.1, 21.7, 9.3; IR (ATR) νmax 3349, 2957, 2932, 2871, 1638, 1609, 1566, 1455, 1378, 1262,
1152 cm–1; MS (ESI, +ve) m/z 264 [(M+Na)+, 100%], 242 [(M+H)+, 37]; HRMS (ESI, +ve)
[M+H]+ Calcd for C16H20NO 242.1545; Found 242.1547.
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Compound 45. A magnetically stirred solution of compound 40 (65 mg, 0.35 mmol, 1.0 eq.)
and cyclohexanone (136 mg, 1.39 mmol, 4.0 mole eq.) in THF (5 ml) was treated with HCl
(100 ꢀl of a 12 M aqueous solution) and the ensuing mixture stirred at 22 °C for 16 h. The
resulting mixture was quenched with sodium carbonate (5 mL of a saturated aqueous solution)
and the separated aqueous layer extracted with ethyl acetate (3 × 5 mL). The combined
organic layers were then dried (Na2SO4), filtered and concentrated under reduced pressure.
The residue thus obtained was dissolved in methanol/CH2Cl2 (5 mL of a 1:1 v/v mixture), the
resulting solution cooled to –78 °C and NaBH4 (58 mg, 1.55 mmol, 5.0 mole eq.) then added.
The reaction mixture was stirred at –78 °C for 1 h then treated with acetone (5 mL) and
warmed to 22 °C before being concentrated under reduced pressure. The residue so obtained
was subjected to flash column chromatography (silica, 3:7 v/v diethyl ether/40ꢀ60 petroleum
ether elution) and so affording, after concentration of the appropriate fractions (Rf = 0.6),
compound 45 as orange crystals (59 mg, 64%), m.p. = 136 °C. 1H NMR (400 MHz, CDCl3) δ
7.20 (d, J = 7.8 Hz, 1H), 7.11 (m, 1H), 6.66 (m, 1H), 6.52 (dd, J = 8.0 and 1.1 Hz, 1H), 4.57
(broad s, 1H), 2.68 (t, J = 6.1 Hz, 2H), 2.51–2.34 (complex m, 4H), 2.01 (m, 2H), 1.79 (dm, J
= 13.2 Hz, 2H), 1.70–1.56 (complex m, 3H), 1.47–1.31 (complex m, 3H); 13C NMR (100
MHz, CDCl3) δ 196.9, 149.1, 144.8, 134.1, 131.6, 125.3, 121.1, 117.7, 114.2, 55.4, 39.1, 32.7,
26.3, 24.7, 21.5, 21.0; IR (ATR) νmax 3382, 2920, 2854, 1637, 1605, 1374, 1311, 1198 cm–1;
MS (ESI, +ve) m/z 290 [(M+Na)+, 100%], 268 [(M+H)+, 9]; HRMS (ESI, +ve) [M+H]+ Calcd
for C18H22NO 268.1701; Found 268.1697.
Compound 46. A magnetically stirred solution of compound 40 (35 mg, 0.19 mmol, 1.0 eq.)
and benzaldehyde (1.0 mL, 9.72 mmol, 52 mole eq.) in THF (3 mL) was maintained at 22 °C
for 16 h then concentrated under reduced pressure. The ensuing residue was subjected to flash
column chromatography (silica, 1:4 to 1:1 v/v diethyl ether/40ꢀ60 petroleum ether gradient
solution) and so affording, after concentration of the appropriate fractions (Rf = 0.5 in 2:3 v/v
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diethyl ether/40ꢀ60 petroleum ether), compound 46 (51 mg, quant.) as a lightꢀyellow oil. H
NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.87 (dd, J = 7.5 and 2.1 Hz, 2H), 7.56–7.44
(complex m, 3H), 7.40 (m, 1H), 7.33–7.24 (complex m, 2H), 7.04 (dd, J = 7.8 and 1.1 Hz,
1H), 6.13 (broad s, 1H), 2.80 (m, 2H), 2.47 (m, 2H), 2.09 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 199.8, 163.2, 160.4, 149.5, 136.0, 134.8, 131.6, 129.9, 129.0, 128.8(1), 128.7(9),
128.1, 125.9, 118.7, 37.5, 30.7, 23.3; IR (ATR) νmax 3060, 2943, 1661, 1625, 1578, 1451,
1188, 888, 764, 754, 691 cm–1; MS (ESI, +ve) m/z 298 [(M+Na)+, 100%], 276 [(M+H)+, 15];
HRMS (ESI, +ve) [M+H]+ Calcd for C19H18NO 276.1383; Found 276.1382.
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X-ray Crystallographic Studies
Crystallographic Data
Crystallographic Data for Compound 5.
C12H11NO2, M = 201.22, T = 150 K, monoclinic, space group P21/c, Z = 8, a = 8.6966(2), b =
12.4116(4), c = 21.1857(7) Å; β = 96.602(3)°; V = 2271.59(12) Å3, Dx = 1.177 g cm–3, 4391
unique data (2θmax = 144.0°), R = 0.057 [for 3120 reflections with I > 2.0σ(I)]; Rw = 0.164
(all data), S = 1.03.
Crystallographic Data for Compound 19.
C12H9NO3, M = 215.20, T = 150 K, orthorhombic, space group P212121, Z = 4, a = 6.7281(1),
b = 9.5441(2), c = 15.1689(4) Å; V = 974.08 Å3, Dx = 1.467 g cm–3, 1951 unique data (2θmax
= 147.4°), R = 0.038 [for 1890 reflections with I > 2.0σ(I)]; Rw = 0.101 (all data), S = 1.05.
Crystallographic Data for Compound 24.
C20H14N2O3, M = 330.33, T = 150 K, monoclinic, space group P21/c, Z = 4, a = 12.5226(3), b
=12.7446(3), c = 10.8100 Å; β = 107.865(2)°; V = 1642.04 Å3, Dx = 1.336 g cm–3, 3297
unique data (2θmax = 147.6°), R = 0.046 [for 3062 reflections with I > 2.0σ(I)]; Rw = 0.129
(all data), S = 1.03.
Crystallographic Data for Compound 26.
C20H16N2, M = 284.35, T = 150 K, triclinic, space group P , Z = 4, a = 10.2371(7), b =
12.0551(8), c = 12.5051(9) Å; α = 93.572(6)°, β = 105.062(6)°, γ = 99.112(6) °; V = 1462.73
(18) Å3, Dx = 1.291 g cm–3, 5940 unique data (2
θ
max = 52.8°), R = 0.046 [for 4420 reflections
with I > 2.0σ(I)]; Rw = 0.120 (all data), S = 1.04.
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Crystallographic Data for Compound 33.
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C15H11NO, M = 221.25, T = 150 K, monoclinic, space group P21/c, Z = 4, a = 4.0072(1), b =
22.2268(5), c = 12.2592(3) Å; β = 95.112(2)°; V = 1087.55(5) Å3, Dx = 1.351 g cm–3, 2147
unique data (2θmax = 148.4°), R = 0.052 [for 2026 reflections with I > 2.0σ(I)]; Rw = 0.144
(all data), S = 1.04.
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Crystallographic Data for Compound 38.
C13H15NO, M = 201.26, T = 150 K, monoclinic, space group P21/c, Z = 12, a = 13.9326(3), b
= 31.3218(6), c = 7.6013(1) Å; β = 98.270(2)°; V = 3282.67(11) Å3, Dx = 1.222 g cm–3, 6363
unique data (2θmax = 144.2°), R = 0.058 [for 5008 reflections with I > 2.0σ(I)]; Rw = 0.163
(all data), S = 1.07.
Crystallographic Data for Compound 40.
C12H13NO, M = 187.23, T = 150 K, monoclinic, space group P21, Z = 2, a = 7.0538(7), b =
8.4543(7), c = 8.3005(10) Å; β = 99.725(10)°; V = 487.89(9) Å3, Dx = 1.275 g cm–3, 1859
unique data (2
θmax = 52.8°), R = 0.038 [for 1663 reflections with I > 2.0σ(I)]; Rw = 0.081 (all
data), S = 1.09.
Crystallographic Data for Compound 41.
C15H17NO, M = 227.29, T = 150 K, monoclinic, space group P21/n, Z = 4, a = 8.8038(8), b =
12.8773(9), c = 11.2318(10) Å; β = 109.578(10)°; V = 1199.72(19) Å3, Dx = 1.258 g cm–3,
2446 unique data (2θmax = 52.8°), R = 0.039 [for 2055 reflections with I > 2.0σ(I)]; Rw =
0.107 (all data), S = 1.04.
Crystallographic Data for Compound 44.
C16H17NO, M = 239.30, T = 150 K, monoclinic, space group P21/n, Z = 4, a = 9.3856(3), b =
12.2110(3), c = 12.1822(4) Å; β = 108.645(4)°; V = 1322.90(7) Å3, Dx = 1.202 g cm–3, 2640
unique data (2θmax = 147.2°), R = 0.082 [for 2373 reflections with I > 2.0σ(I)]; Rw = 0.244
(all data), S = 1.06.
Crystallographic Data for Compound 45.
C18H21NO, M = 267.36, T = 150 K, monoclinic, space group P21/n, Z = 4, a = 11.0667(3), b =
10.0284(2), c = 14.0170(3) Å; β = 112.696(3)°; V = 1435.16(6) Å3, Dx = 1.237 g cm–3, 2883
unique data (2θmax = 148.0°), R = 0.047 [for 2635 reflections with I > 2.0σ(I)]; Rw = 0.132
(all data), S = 1.06.
Structure Determinations
The images for compounds 5, 19, 24, 26, 33, 38, 40, 41, 44 and 45 were measured on either a
SuperNova (Cu Kα, mirror monochromator, λ = 1.54184 Å) or Xcalibur (Mo Kα, mirror
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monochromator, λ = 0.71073 Å) diffractometer fitted with an area detector and the data
extracted using the CrysAlis package. The structures of these compounds were solved with
ShelXT20 and refined using ShelXL21 in OLEX2.22 Atomic coordinates, bond lengths and
angles, and displacement parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC no. 1852687–1852695 and 1855327). These data can be obtained freeꢀofꢀ
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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Associated Content
Supporting Information
The Supporting Information is available freeꢀofꢀcharge on the ACS Publications website at
DOI: 10.1021/acs.joc.XXXXXX.
Xꢀray derived plots for compounds 5, 19, 24, 26, 33, 38, 40, 41, 44 and 45 and copies of
the NMR spectra of compounds 5, 6, 8ꢀ12, 14, 15, 17ꢀ20, 22ꢀ27, 32ꢀ34, 36ꢀ38, 40, 41 and
44ꢀ46 (PDF).
Accession Code
CCDC 1852687ꢀ1852695 and 1855327 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by eꢀmailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
Author Information
Corresponding Author
*Eꢀmail: Martin.Banwell@anu.edu.au
ORCID Martin G. Banwell: 0000ꢀ0002ꢀ0582ꢀ475X
Author Contributions
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The manuscript was written through contributions of all authors. All authors have given
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approval to the final version of the manuscript. Y.Q. and M.D. contributed equally to this
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work.
Notes
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The authors declare no competing financial interest.
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Acknowledgements
We thank the Australian Research Council, the Institute of Advanced Studies, Jinan
University, the Pearl River Scholar Program of Guangdong Province and the Famous Foreign
Supervisor Program (Grant 2018ꢀHWMS001) of the Ministry of Education, People’s Republic
of China for financial support.
References
1. Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Synthesis of Indoles via
Palladium[0]ꢀMediated UllmannꢀCross Coupling of oꢀHalonitroarenes with αꢀHaloꢀ
enones or –enals. Org. Lett., 2003, 5, 2497ꢀ2500.
2. Khan, F.; Dlugosch, M.; Liu, X.; Banwell, M. G. The PalladiumꢀCatalyzed Ullmann
CrossꢀCoupling Reaction: A Modern Variant on a TimeꢀHonored Process. Acc. Chem.
Res., 2018, 51, 1784ꢀ1795.
3. (a) Ho, TꢀL.; Wong, C. M. Reduction of Aromatic Nitro Compounds by Titanium(III)
Chloride. Synthesis, 1974, 45; (b) Somei, M.; Kato, K.; Inoue, S. Titanium (III)
Chloride for the Reduction of Heteroaromatic and Aromatic Nitro Compounds. Chem.
Pharm Bull. 1980, 28, 2515ꢀ2518; (c) Moody, C. J.; Rahimtoola, K. F. DielsꢀAlder
Reactivity of Pyrano[4,3ꢀb]indolꢀ3ꢀones, Indole 2,3ꢀQuinomethane Analogues. J.
Chem. Soc., Perkin Trans. 1 1990, 673ꢀ679; (d) Iwama, T.; Birman, V. B.; Kozmin, S.
A.; Rawal, V. H. Regiocontrolled Synthesis of CarbocycleꢀFused Indoles via Arylation
of Silyl Enol Ethers with oꢀNitrophenylphenyliodonium Fluoride. Org. Lett. 1999, 1,
673ꢀ676; (e) Harvey, M. J.; Banwell, M. G.; Lupton, D. W. The Synthesis of
Compounds Related to the IndoleꢀIndoline Core of the Vinca Alkaloids (+)ꢀ
Vinblastine and (+)ꢀVincristine. Tetrahedron Lett. 2008, 49, 4780ꢀ4783; (f) Tong, S.;
Xu, Z.; Mamboury, M.;, Wang, Q.; Zhu, J. Aqueous Titanium Trichloride Promoted
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5
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7
8
Reductive Cyclization of oꢀNitrostyrenes to Indoles: Development and Application to
the Synthesis of Rizatriptan and Aspidospermidine, Angew. Chem. Int. Ed., 2015, 54,
11809ꢀ11812; (g) Yang, R.ꢀS.; Beard, A.; Sheng, H.; Zhang, L.ꢀK.; Helmy, R.
Applications of TiCl3 as a Diagnostic Reagent for the Detection of Nitroꢀ and Nꢀ
OxideꢀContaining Compounds as Potentially Mutagenic Impurities Using Ultrahighꢀ
Performance Liquid Chromatography Coupled with HighꢀResolution Mass
Spectrometry. Org. Process Res. Dev. 2016, 20, 59ꢀ64.
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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4. For particularly relevant examples of the application of this reagent combination, see:
Janreddy, D.; Kavala, V.; Bosco, J. W. J.; Kuo, C.ꢀW.; Yao, C.ꢀF. An Easy Access to
Carbazolones and 2,3ꢀDisubstituted Indoles. Eur. J. Org. Chem. 2011, 2360ꢀ2365.
5. For related but longer and technically more complex routes to this and related
compounds, see: (a) Scott, T. L.; Söderberg, B. C. G. Novel PalladiumꢀCatalyzed
Synthesis of 1,2ꢀDihydroꢀ4(3H)ꢀcarbazolones. Tetrahedron Lett. 2002, 43, 1621ꢀ1624;
(b) Scott, T. L.; Söderberg, B. C. G. PalladiumꢀCatalyzed Synthesis of 1,2ꢀDihydroꢀ
4(3H)ꢀcarbazolones. Formal Total Synthesis of Murrayaquinone A. Tetrahedron 2003,
59, 6323ꢀ6332; (c) Scott, T. L.; Burke, N.; CarreroꢀMartínez, G.; Söderberg, B. C. G.
Synthesis of 1,2,3,4ꢀTetrahydrocarbazoles and Related Tricyclic Indoles. Tetrahedron,
2007, 63, 1183ꢀ1190; (d) Bunce, R. A.; Nammalwar, B. 1,2,3,9ꢀTetrahydroꢀ4Hꢀ
carbazolꢀ4ꢀone and 8,9ꢀDihydropyrido[1,2ꢀa]indolꢀ6(7H)ꢀone from 1HꢀIndoleꢀ2ꢀ
butanoic Acid. J. Heterocyclic Chem., 2009, 46, 172ꢀ177.
6. Jan, N.ꢀW.; Liu, H.ꢀJ. An Enantioselective Total Synthesis of (+)ꢀRicciocarpin A. Org.
Lett. 2006, 8, 151ꢀ153.
7. Rice, L. M.; Sheth, B. S.; Wheeler, J. W. Spirans XVIII. gemꢀDialkyl and
Spirotetrahydrocarbazoles. J. Heterocyclic Chem. 1971, 8, 751ꢀ754.
8. Bergman, J.; Venemalm, L. Synthesis of Cyclopent[b]indolones. Tetrahedron, 1990,
46, 6067ꢀ6084.
9. Yan, Q.; Gin, E.; Banwell, M. G.; Willis, A. C.; Carr, P. D. A Unified Approach to the
αꢀ, βꢀ, γꢀ and δꢀCarbolines via their 6,7,8,9ꢀTetrahydrocounterparts. J. Org. Chem.
2017, 82, 4328ꢀ4335.
10. Bamba, M.; Nishikawa, T.; Isobe M. Stereoelectronic and Steric Control in Chiral
Cyclohexane Synthesis Toward (–)ꢀTetrodotoxin. Tetrahedron, 1998, 54, 6639ꢀ6650.
11. Johnson, C. R.; Adams, J. P.; Brian, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.;
Uskokovic, M. R. Direct αꢀIodination of Cycloalkenones. Tetrahedron Lett. 1992, 33,
917ꢀ918.
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