A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions

Article abstract of DOI:10.1039/c6ob02103d

Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS).

Full text of DOI:10.1039/c6ob02103d

Organic &
Biomolecular Chemistry
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A radical addition/cyclization of diverse ethers to
2-isocyanobiaryls under mildly basic aqueous
conditions†
Cite this: DOI: 10.1039/c6ob02103d
Cintia Anton-Torrecillas, Diego Felipe-Blanco and Jose C. Gonzalez-Gomez*
Received 27th September 2016,
Accepted 19th October 2016
Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogena-
tive addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic
studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution
(BHAS).
DOI: 10.1039/c6ob02103d
www.rsc.org/obc
Introduction
Phenanthridine is the scaffold of many naturally occurring
products1 that exhibit a wide range of bioactivities, such as
antitumor,2 antituberculosis,3 antimicrobial,4 antiviral,5 acari-
cidal,6 and fungicidal activities.7 Some phenanthridine deriva-
tives have also found application in biological chemistry as
dyes for cytofluorometric assays8 or even in materials science
due to their optoelectronic properties.9 Recently, the assembly
of the phenanthridine framework has been elegantly achieved
with a cascade that involves the addition of radicals to somo-
philic 2-isocyanobiphenyls, followed by intramolecular homo-
lytic aromatic substitution.10,11 In this context, and given the
progress made in the Cα–H oxidation of ethers with peroxides
to form radicals,12 the oxidative addition of ethers to
2-isocyanobiphenyls has been successfully achieved using
different conditions.13 This transformation requires a dual
selective C–H bond functionalization, and constitutes a power-
ful tool to increase molecular complexity with high atom-
economy, where only hydrogen is lost (Scheme 1). Moreover,
ethers are very important raw materials and they are also
common substructures of natural and synthetic bioactive
products.14 Consequently, the development of methods that
make use of relatively unreactive ethers to build complex mole-
cules, is highly demanded by organic and medicinal chemists.
It is worth noting that 1,4-dioxane is the model substrate
for C–H bond functionalization of ethers in most of the
reported studies.13 This symmetric ether presents all eight
C–H bonds adjacent to an oxygen atom, which stabilizes the
Scheme 1 Oxidative addition of 1,4-dioxane to 2-isocyanobiphenyls: a
radical cascade.
radical by hyperconjugation with the non-bonding electrons.
Moreover, theoretical studies suggest that the release of ring
strain upon radical formation is greater in 1,4-dioxane than in
other cyclic ethers such as tetrahydrofuran.15 As a matter of
fact, when TBPB was used as the oxidant in the insertion of
2-isocyanobiaryls with ethers, only 1,4-dioxane was successful
and THF failed.13a Notably, when benzoyl peroxide was used
in the same transformation, another three ethers could be
inserted with moderate results (40–45%).13b To the best of our
knowledge, the greatest number of ethers tolerated in this reac-
tion (seven examples) has been possible with the use of DTBP
as the oxidant, FeCl3 as the catalyst and DBU as the cocata-
lyst.13c With these precedents we decided to develop a new pro-
tocol for this reaction aimed at accommodating a range of
ethers, free of transition-metal catalysts and using economical
and environmentally friendly conditions (Scheme 2).
Results and discussion
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis
Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain.
E-mail: josecarlos.gonzalez@ua.es
To explore new reaction conditions we selected 2-isocyanobi-
phenyl (1a) and THF (2a) as model substrates. In a control
experiment we performed the reaction using BPO as the
oxidant at 100 °C and we obtained 35% yield of the desired
†Electronic supplementary information (ESI) available: Experimental details for
mechanistic studies and copies of NMR spectra. See DOI: 10.1039/c6ob02103d
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8–11). Similar results were obtained with Na2HPO4, and lower
yields were obtained for the desired product when non-nucleo-
philic organic bases were used in substoichiometric amounts
(entries 12–14).
Having found very simple optimized conditions for the
model reaction, we evaluated its scope using different 2-isocyano-
biaryls and THF (Scheme 3). We first examined substrates
with substituents on the upper aromatic ring. Methyl-substi-
tuted products 3ba and 3ca were obtained in good to moderate
yields, without observing any benzylic oxidation. During the
formation of 3ca, some compound 3aa was also observed
(GC-MS), likely by ipso-homolytic aromatic substitution, and
its isolated yield was affected due to difficulties in the chroma-
tographic purification. A more electron-donating group such
as methoxy was compatible with this protocol, affording com-
pound 3da in reasonably good yield, as well as the corres-
ponding byproduct 4d (detected by GC-MS and 1H-NMR).
Scheme 2 Previous results and our reaction conditions for THF.
product 3aa, a similar result to the one obtained by the Cheng
group,13b together with byproduct 4a (Table 1, entry 1).
Surprisingly, the addition of K2CO3 and H2O completely inhi-
bited the formation of 3aa (entry 2). Prompted by the excellent
results in oxidative transformations achieved with Bu4NI as the
catalyst and TBHP,16 we tried this combination, but 3aa was
obtained in low yield (entry 3). The use of DTBP or (NH4)2S2O8
in combination with Bu4NI was also unsuccessful in this trans-
formation (entries 4–6). It is reported that TBPB fails to afford
product 3aa in this reaction and that only compound 4a is
obtained.13a To our surprise, the inclusion of H2O in this reac-
tion mixture afforded product 3aa, although in low yield (entry
7). We were pleased to find that the same oxidant, but in the
presence of K2CO3 and H2O, allowed full conversion of 1a to
obtain compound 3aa in good yield (entry 10). While the
addition of Bu4NI had no important impact on the reaction,
the amount of base and the control of the reaction tempera-
ture were crucial to obtain good and reliable results (entries
Table 1 Screening of reaction conditions
Oxidant (mol%)/
Entry additive (mol%)
Conv.a
(%)
Base (mol%)
(3aa : 4a)b
1c
2
3
BPO (120)
BPO (120)
TBHP (300)/Bu4NI (20) K2CO3 (150)
DTBP (300)/Bu4NI (20) None
None
K2CO3 (150)
100
37
45
35 : 22
—
20 : 5
—
4
0
5
6
7
8
DTBP (300)/Bu4NI (20) K2CO3 (150)
0
0
100
55
70
100
100
90
100
100
—
(NH4)2S2O8 (220)
TBPB (220)
K2CO3 (150)
None
—
12 : 4c
—
TBPB (120)/Bu4NI (20)
TBPB (220)
K2CO3 (150)
K2CO3 (100)
K2CO3 (150)
K2CO3 (150)
Na2HPO4 (150)
DABCO (50)
DBU (50)
9
—
10d
11
12
13c
14c
TBPB (220)
77 : 23
75 : 25
75 : 25
18 : 0
40 : 0
TBPB (220)/Bu4NI (50)
TBPB (220)
TBPB (220)
TBPB (220)
1
a By GC of the crude reaction mixture. b Yield calculated by H-NMR of
the crude reaction mixture using durene as the internal standard.
c Formation of other products is observed by GC. d The conversion was
90% at 80 °C and 0% at 60 °C. BPO = benzoyl peroxide. DTBP = di-tert-
butylperoxide. TBPB = tert-butylperoxybenzoate. DABCO = 1,4-diazabi-
cyclo[2.2.2]octane. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Scheme 3 Scope of 2-isocyanobiaryls with THF. a Measured tempera-
ture of the sand bath. b Yields after purification of isolated products and
in parentheses are yields of 6-H phenanthridines 4 estimated by GC-MS
of crude reaction mixtures. c Product 3aa was also formed and purifi-
cation of 3ca was more difficult. *The other regioisomer isolated (3’).
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When 2-(2-isocyanophenyl)-naphthalene was used, compound yields, with linear n-Bu2O providing the best yield. 2-MeTHF
3ea was the only regioisomer isolated in moderate yield, (2f) was also examined, affording the more substituted com-
despite the steric hindrance between the ether moiety and the pound 3af as the major product and regioisomer 3′af as an
extra aromatic ring.17 Electron-withdrawing groups, such as inseparable trans/cis mixture. Surprisingly, when Bn2O (2h)
acetyl, trifluoromethyl, chloro and fluoro, were suitable substi- was examined, the expected product (3ah) was obtained in
tuents in the upper aromatic ring, furnishing products (3fa, only 17% yield and the addition of a benzyl radical took place
3ga, 3ha and 3ia) in good isolated yields. Interestingly, when preferentially (3′ah). It seems reasonable that after
meta-substituted substrates 1j and 1k were used, both possible H-abstraction from Bn2O, a β-fragmentation gives rise to the
regioisomers were isolated after column chromatography. benzyl radical, which is finally added to 1a. The addition of
While the ratio of 3ja/3′ja was 1 : 1, for 1k the major product phthalan (2i) was also possible, but compound 3ai was
was the most crowded regioisomer (3ka).18 We also examined obtained in lower yield. Importantly, acetals 2j and 2k led,
isocyanobiaryls substituted in the lower aromatic ring by elec- respectively, to products 3aj and 3ak in synthetically useful
tron-donating and electron-withdrawing groups, obtaining uni- yields. These compounds could be easily hydrolyzed to obtain
formly moderate yields in all cases (3la–3oa).
the corresponding 6-formylphenanthridine and the acetal
We further explore the performance of different ethers moiety has the potential to be transformed into other
using the optimized procedure (Scheme 4). 1,4-Dioxane (2b) functionalities.19
and THP (2c) were also suitable for this protocol, obtaining
Investigation of the reaction mechanism
products 3ab and 3ac in moderate yields after purification, as
well as compound 4a as the byproduct. With THP, minor
amounts of regioisomers were formed (see the ESI† for GC-MS
of isomers), complicating the isolation of 3ac in a pure form.
Acyclic ethers such as i-Pr2O (2d), n-Bu2O (2e) and t-BuOMe
(2g) afforded the corresponding products in good to excellent
To gain insight into the reaction mechanism we performed
some experiments. As shown in Scheme 5a, the use of TEMPO
as a radical scavenger in our model reaction, under standard
conditions, completely inhibited the formation of 3aa and the
coupling product 5 was detected by MS. Since compounds 4
are consistent byproducts of the radical cyclization studied
here, we were intrigued about their formation and we have not
found any experimental evidence of this in the literature.20
When the reaction was conducted using D2O and D8-THF
(Scheme 5b), the expected product D7-3aa was obtained,
Scheme 4 Scope of ethers. a Measured temperature of the sand bath.
b Yields after purification of isolated products and in parentheses are
yields of 4a.
Scheme 5 Mechanistic investigations.
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accompanied by phenanthridine 4a. Importantly, the bypro- that can easily transfer an electron to radical Bz• or to oxidant
duct of this reaction is not deuterated, indicating that neither TBPB, while generating product 3aa. In addition, intermediate
THF nor H2O is the source of hydrogen for the formation of I can transfer a hydrogen atom to 1a, which after a similar
this phenanthridine. We also studied the intermolecular BHAS process leads to the formation of byproduct 4a. This
kinetic isotopic effect (KIE) by competition experiments of explanation is consistent with our observation that neither
equimolar amounts of THF and D8-THF with 1a at the initial THF nor H2O was the hydrogen source of 4a.25
stage of the reaction (Scheme 5c). The large KIE obtained
(kH/kD = 3.16) suggests that the cleavage of the C(sp3)–H bond
is involved in the rate determining step of this reaction. In
addition, we also performed competition experiments at the
Conclusions
In conclusion, we have demonstrated that TBPB can be used
under mildly basic aqueous conditions to promote the radical
addition of a range of ethers to 2-isocyanobiaryls followed by
cyclization. Mechanistic investigations suggest that this trans-
formation is an example of BHAS and a plausible explanation
is provided for the formation of byproduct 4. Some salient fea-
tures of the developed methodology are: (a) neither transition
metals nor any expensive additives are needed; (b) the wastes
generated are harmless inorganic salts and can be easily
removed by aqueous workup; (c) the reaction medium is con-
stituted by the reactant ethers and water.
initial state of the reaction, using equimolar quantities of 1a
and 2-isocyanobiphenyls substituted in position 4′ by methyl
or fluoro groups. The results shown in Scheme 4d suggested
that electron-withdrawing substituents in the upper aromatic
ring accelerate the reaction. Since this class of group stabilizes
the LUMO of the upper aromatic ring, this result is also con-
sistent with a radical cyclization pathway.21
An important feature of this protocol is the crucial role of
K2CO3 and H2O in a successful transformation (Table 1,
entries 6 and 9). Since the seminal contribution of Studer and
Curran,22 several known reactions have been recognized as
“base promoted homolytic substitutions” (BHAS) and many
new transformations have been developed with this concept.11
Based on literature precedents and our own results, we believe
that this reaction is an example of BHAS. A possible reaction
mechanism is depicted in Scheme 6. Firstly, homolysis of
TBPB takes place upon heating. From the two generated rad-
icals, it is reported that t-BuO• abstracts a hydrogen atom from
THF faster than Bz•·to generate the α-furanyl radical.23
Addition of this intermediate to isonitrile 1a, followed by intra-
molecular addition to the upper aromatic ring, is well docu-
mented in a number of examples.11 DFT studies performed by
the Studer group indicate that cyclohexadienyl radicals, such
as I, are extremely strong acids (pKa ∼ −15 in H2O).24
Therefore, this radical intermediate can be deprotonated
under mild basic aqueous conditions (e.g. K2CO3 in H2O) to
generate a radical anion II. This species is a potent reductant
Experimental section
General remarks
All starting isonitriles were prepared according to a reported
method.10b TLC was performed on silica gel 60 F254, using alu-
minium plates and visualized by exposure to ultraviolet light.
Flash chromatography was carried out on hand-packed
columns of silica gel 60 (230–400 mesh). Infrared (IR) spectra
were recorded with a spectrophotometer equipped with an
ATR component; wavenumbers are given in cm−1. LRMS were
obtained using a mass spectrometer coupled with a gas chro-
matographer (GC); the mobile phase was helium (2 mL
min−1); HP-1 column of 12 m was used; temperature program
starts at 80 °C for 3 min, then up to 270 °C at a rate of 20 °C
min−1, and 17.5 min at 270 °C. HRMS analyses were carried
out using Electron Impact (EI) mode at 70 eV by Q-TOF.
1
1H NMR spectra were recorded at 300 or 400 MHz for H-NMR
and 75 or 100 MHz for 13C-NMR, using CDCl3 as the solvent
and TMS as an internal standard (0.00 ppm). The data are
being reported as (s = singlet, d = doublet, t = triplet, m =
multiplet or unresolved, br
s = broad signal, coupling
constant(s) in Hz, integration). 13C-NMR spectra were recorded
with 1H-decoupling at 100 MHz and referenced to CDCl3 at
77.16 ppm. DEPT-135 experiments were performed to assign
CH, CH2 and CH3.
General procedure for the synthesis of compounds 3
Into a pressure tube were added K2CO3 (103 mg, 0.75 mmol)
and H2O (0.82 mL). Then, to it were added sequentially the
2-isocyanobiaryl derivative 1 (0.50 mmol), ether 2 (2.5 mL) and
tert-butyl peroxibenzoate (TBPB) (213 µL, 1.10 mmol). The
reaction mixture was stirred under an Ar atmosphere for
12–14 h at 110 °C (sand bath temperature). Upon full conver-
Scheme 6 Plausible mechanism.
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sion of the isonitrile (TLC or GC), a saturated solution of
8-Methoxy-6-(tetrahydrofuran-2-yl)phenanthridine
(3da).
NaHCO3 (5 mL) and EtOAc (10 mL) was added to the reaction Following the general procedure, compound 3da was obtained
mixture. After phase separation, the aqueous phase was after column chromatography (hexane/EtOAc 95 : 5–75 : 25) as
extracted with EtOAc (3 × 15 mL) and the combined organic a white solid (78 mg, 0.28 mmol, 55%): Rf 0.20 (9 : 1 hexane/
1
layers were washed with brine (5 mL), dried over MgSO4 and EtOAc); H-NMR (300 MHz, CDCl3) δ 8.53 (d, J = 9.1 Hz, 1H),
concentrated under reduced pressure. The residue was purified 8.47–8.41 (m, 1H), 8.17–8.12 (m, 1H), 7.82 (d, J = 2.6 Hz, 1H),
by flash column chromatography on silica gel to give the 7.68–7.56 (m, 2H), 7.44 (dd, J = 9.1, 2.6 Hz, 1H), 5.69 (t, J = 6.9
desired product.
Hz, 1H), 4.24–4.12 (m, 1H), 4.12–4.01 (m, 1H), 3.98 (s, 3H),
6-(Tetrahydrofuran-2-yl)phenanthridine (3aa).13c Following 2.87–2.71 (m, 1H), 2.47–2.32 (m, 1H), 2.28–2.05 (m, 2H) ppm;
the general procedure, compound 3aa was obtained after 13C-NMR (101 MHz, CDCl3) δ 158.6 (C), 158.4 (C), 142.5 (C),
column chromatography (hexane/EtOAc 9 : 1) as a yellow pale 130.5 (CH), 127.8 (C), 127.6 (CH), 127.0 (CH), 126.3 (C), 124.3 (C),
solid (91 mg, 0.36 mmol, 73%): Rf 0.23 (95 : 5 hexane/EtOAc); 124.1(CH), 121.5 (CH), 120.8 (CH), 107.1 (CH), 80.1 (CH),
1H-NMR (300 MHz, CDCl3) δ 8.63 (dd, J = 8.2, 1.3 Hz, 1H), 8.55 69.1 (CH2), 55.6 (CH3), 29.8 (CH2), 26.2 (CH2) ppm; IR ν 3000,
(dd, J = 8.0, 1.5 Hz, 1H), 8.45 (dd, J = 8.7, 1.0 Hz, 1H), 8.19 (dd, 2964, 2858, 1571, 1059, 754 cm−1; LRMS (EI) m/z (%) = 279
J = 7.9, 1.6 Hz, 1H), 7.83 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), (M+, 12), 250 (8), 236 (100), 223 (44), 207 (35); HRMS (EI) m/z
7.75–7.61 (m, 3H), 5.78 (t, J = 6.9 Hz, 1H), 4.26–4.15 (m, 1H), calcd for C18H17NO2 279.1259, found 279.1261.
4.13–4.01 (m, 1H), 2.82–2.65 (m, 1H), 2.50–2.35 (m, 1H),
5-(Tetrahydrofuran-2-yl)benzo[i]phenanthridine
(3ea).
2.30–2.03 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) δ 159.4 Following the general procedure, compound 3ea was obtained
(C), 143.4 (C), 133.4 (C), 130.6 (CH), 130.4 (CH), 128.6 (CH), after column chromatography (hexane/EtOAc 98 : 2–95 : 5) as a
127.3 (CH), 127.0 (CH), 126.6 (CH), 124.9 (C), 124.2 (C), 122.5 white solid (57 mg, 0.19 mmol, 38%): Rf 0.35 (96 : 4 hexane/
1
(CH), 122.0 (CH), 79.7 (CH), 69.1 (CH2), 30.1 (CH2), 26.1 (CH2) EtOAc); H-NMR (400 MHz, CDCl3) δ 9.19 (H-1, d, J = 8.5 Hz,
ppm; IR ν 3073, 2981, 2881, 1583, 1444, 1300, 1057, 727 cm−1
;
1H), 8.57 (H-12 + H-4, dd, J = 8.7, 5.2 Hz, 2H), 8.23 (H-7, dd, J =
LRMS (EI) m/z (%) = 249 (M+, 5), 220 (15), 206 (100), 193 (48), 8.2, 1.1 Hz, 1H), 8.10 (H-11, d, J = 8.9 Hz, 1H), 7.98 (H-10, d, J =
178 (15).
8-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine
7.9 Hz, 1H), 7.78–7.71 (H-2 + H-8, m, 2H), 7.68–7.63 (H-3 +
(3ba). H-9, m, 2H), 5.91 (H-2′, t, J = 6.4 Hz, 1H), 4.47–4.38 (H-5′, m,
Following the general procedure, compound 3ba was obtained 1H), 4.20–4.13 (H-5′, m, 1H), 2.99–2.86 (H-3′, m, 1H), 2.59–2.37
after column chromatography (hexane/EtOAc 93 : 7) as a yellow (H-4′, m, 1H), 2.27–2.07 (H-3′ + H-4′, m, 2H) ppm; 13C-NMR
pale solid (80 mg, 0.31 mmol, 61%): Rf 0.20 (93 : 7 hexane/ (101 MHz, CDCl3) δ 157.7 (C), 144.0 (C), 133.8 (C), 133.2 (C),
EtOAc); 1H-NMR (400 MHz, CDCl3) δ 8.54–8.48 (m, 2H), 8.20 (br 131.9(C), 130.1 (CH), 129.9 (C), 128.8 (CH), 128.7 (CH), 128.4
s, 1H), 8.16 (dd, J = 8.1, 1.1 Hz, 1H), 7.71–7.59 (m, 3H), 5.79–5.74 (CH), 127.2 (CH), 126.9 (CH), 126.7 (CH), 123.7(C), 123.0 (C),
(m, 1H), 4.23–4.15 (m, 1H), 4.10–4.03 (m, 1H), 2.83–2.72 (m, 122.5 (CH), 120.2 (CH), 80.5 (CH), 69.4 (CH2), 31.3 (CH2), 26.8
1H), 2.60 (s, 3H), 2.46–2.35 (m, 1H), 2.27–2.17 (m, 1H), 2.17–2.06 (CH2) ppm; IR ν 3019, 2961, 2937, 1561, 1465, 1350, 1051,
(m, 1H) ppm; 13C-NMR (101 MHz, CDCl3) δ 159.0 (C), 143.1 (C), 750 cm−1; LRMS (EI) m/z (%) = 299 (M+, 14), 256 (100),
137.2 (C), 132.1 (CH), 131.2 (C), 130.5 (CH), 128.1 (CH), 126.9 242 (28), 227 (19); HRMS (EI) m/z calcd for C21H17NO
(CH), 126.0 (CH), 125.1 (C), 124.3 (C), 122.3 (CH), 121.8 (CH), 299.1310, found 299.1304.
79.5 (CH), 69.1 (CH2), 30.0 (CH2), 26.1 (CH2), 22.1 (CH3) ppm;
1-(6-(Tetrahydrofuran-2-yl)phenanthridin-8-yl)ethan-1-one (3fa).
IR ν 2955, 2867, 1577, 1460, 1052, 760 cm−1; LRMS (EI) Following the general procedure, compound 3fa was obtained
m/z (%) = 263 (M+, 6), 234 (10), 220 (100), 207 (57); HRMS (EI) after column chromatography (hexane/EtOAc 8 : 2) as a yellow
m/z calcd for C18H17NO 263.1310, found 263.1307.
10-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine
pale solid (77 mg, 0.27 mmol, 53%): Rf 0.20 (8 : 2 hexane/
(3ca). EtOAc); H-NMR (300 MHz, CDCl3) δ 9.10 (br s, 1H), 8.65 (d,
1
Following the general procedure, compound 3ca was obtained J = 8.7 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.35 (dd, 2H), 8.19 (dd,
after column chromatography (hexane/EtOAc 95 : 5–9 : 1) as a J = 8.1, 1.2 Hz, 1H), 7.77 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.67
yellow pale solid (54 mg, 0.20 mmol, 41%): Rf 0.20 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 5.77 (t, J = 7.0 Hz, 1H), 4.22–4.13
1
(95 : 5 hexane/EtOAc); H-NMR (300 MHz, CDCl3) δ 8.77 (br d, (m, 1H), 4.13–4.04 (m, 1H), 2.88–2.79 (m, 1H), 2.77 (s, 3H),
J = 8.2 Hz, 1H), 8.35 (dd, J = 8.1, 1.6 Hz, 1H), 8.23 (dd, J = 8.1, 2.52–2.37 (m, 1H), 2.31–2.10 (m, 2H) ppm; 13C-NMR
1.5 Hz, 1H), 7.70 (ddd, J = 8.2, 7.0, 1.4 Hz, 1H), 7.67–7.55 (m, (101 MHz, CDCl3) δ 197.5 (C), 159.8 (C), 144.2 (C), 136.5 (C),
3H), 5.81–5.75 (t, J = 6.8 Hz, 1H), 4.25–4.15 (m, 1H), 4.10–4.01 135.3 (C), 130.7 (C), 129.8 (CH), 128.8 (CH), 128.2 (CH), 127.4
(m, 1H), 3.11 (s, 3H), 2.84–2.67 (m, 1H), 2.48–2.32 (m, 1H), (CH), 124.5 (C), 123.5 (C), 122.9 (CH), 122.6 (CH), 79.9 (CH),
2.27–2.00 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) δ 159.6 (C), 69.2 (CH2), 29.9 (CH2), 26.9 (CH2), 26.2 (CH3) ppm; IR ν 2977,
144.5 (C), 135.6 (C), 134.6 (CH), 132.9 (C), 130.9 (CH), 2921, 2856, 1683, 1615, 1251, 1052, 760 cm−1; LRMS (EI) m/z
127.8 (CH), 126.7 (CH), 126.5 (CH), 126.4 (C), 126.1 (CH), 125.6 (C), (%) = 291 (M+, 5), 263 (20), 248 (100), 235 (65), 207 (17); HRMS
124.9 (CH), 79.7 (CH), 69.1 (CH2), 30.1 (CH2), 27.1 (CH2), (EI) m/z calcd for C19H17NO2 291.1259, found 291.1265.
26.1 (CH3) ppm; IR ν 3069, 2968, 2871, 1587, 1437, 1054,
6-(Tetrahydrofuran-2-yl)-8-(trifluoromethyl)phenanthridine
760 cm−1; LRMS (EI) m/z (%) = 263 (M+, 8), 234 (18), 220 (100), (3ga). Following the general procedure, compound 3ga was
207 (59), 204 (21), 165 (18); HRMS (EI) m/z calcd for C18H17NO obtained after column chromatography (hexane/EtOAc
263.1310, found 263.1306.
95 : 5–9 : 1) as a yellow pale solid (111 mg, 0.35 mmol, 70%):
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Rf 0.25 (95 : 5 hexane/EtOAc); 1H-NMR (400 MHz, CDCl3) δ 8.81 (98 : 2 hexane/EtOAc); H-NMR (400 MHz, CDCl3) δ 8.53 (d, J =
(s, 1H), 8.72 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.20 (d, 8.3 Hz, 1H), 8.51 (d, J = 8.3 Hz, 1H), 8.12 (dd, J = 8.1, 1.4 Hz,
J = 8.1 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 1H), 7.71–7.57 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 5.97 (dd, J =
7.69 (t, J = 7.5 Hz, 1H), 5.72 (t, J = 6.9 Hz, 1H), 4.19–4.12 (m, 6.9, 5.2 Hz, 1H), 4.20–4.12 (m, 1H), 4.04–3.95 (m, 1H), 3.09 (s,
1H), 4.12–4.03 (m, 1H), 2.88–2.75 (m, 1H), 2.48–2.35 (m, 1H), 3H), 2.89–2.80 (m, 1H), 2.32–2.12 (m, 2H), 2.11–1.96 (m, 1H)
2.30–2.08 (m, 2H); 13C-NMR (101 MHz, CDCl3) δ 159.2 (C), ppm; 13C-NMR (101 MHz, CDCl3) δ 159.4 (C), 142.5 (C), 136.5 (C),
144.0 (C), 135.6 (C), 130.7 (CH), 129.8 (CH), 129.1(CH), 129.0 134.9 (C), 132.0 (CH), 130.2 (CH), 129.6 (CH), 128.4 (CH),
2
3
(C-8, d, JC–F = 32.4 Hz), 127.6 (CH), 126.3 (CH, q, JC–F
=
126.9 (CH), 125.4 (C), 124.4 (C), 122.2 (CH), 120.9 (CH),
3
3.3 Hz), 124.5 (CH, q, JC–F = 4.3 Hz), 124.4 (CH), 124.25 (d, 80.3 (CH), 68.9(CH2), 30.3 (CH2), 25.8 (CH2), 25.2 (CH3) ppm;
1JC–F = 272.2 Hz), 123.5 (CH), 123.3 (C), 122.4 (CH), 80.0 (CH), IR ν 2959, 2874, 1573, 1449, 1286, 1048, 749 cm−1; LRMS (EI)
69.2 (CH2), 29.8 (CH2), 26.2 (CH2) ppm; IR ν 2966, 2874, 1722, m/z (%) = 263 (M+, 8), 248 (6), 234 (13), 220 (100), 207 (13),
1625, 1173, 1122, 763 cm−1; LRMS (EI) m/z (%) = 317 (M+, 4), 193 (19); HRMS (EI) m/z calcd for C18H17NO 263.1310, found
288 (8), 274 (100), 261 (73), 247 ([(M + 1)+ − THF], 14), 226 (12); 263.1312.
HRMS (EI) m/z calcd for C14H8F3N, 247.0609, found 247.0612.
9-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine (3′ja). From
8-Chloro-6-(tetrahydrofuran-2-yl)phenanthridine (3ha). the same reaction where compound 3ja was obtained, and
Following the general procedure, compound 3ha was obtained after column chromatography (hexane/EtOAc 95 : 5–100%
after column chromatography (hexane/EtOAc 95 : 5) as an EtOH), isomer 3′ja was isolated as a yellow pale solid (37 mg,
orange pale solid (92 mg, 0.32 mmol, 65%): Rf 0.25 0.14 mmol, 28%): Rf 0.19 (95 : 5 hexane/EtOAc); 1H-NMR
1
(95 : 5 hexane/EtOAc); H-NMR (300 MHz, CDCl3) δ 8.53 (d, J = (400 MHz, CDCl3) δ 8.52 (dd, J = 8.1, 1.5 Hz, 1H), 8.40 (H-10, s,
8.9 Hz, 1H), 8.46 (dd, J = 7.5, 1.8 Hz, 2H), 8.16 (dd, J = 8.1, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.1, 1.0 Hz, 1H), 7.68
1.1 Hz, 1H), 7.78–7.68 (m, 2H), 7.64 (ddd, J = 8.4, 7.1, 1.5 Hz, (ddd, J = 8.2, 7.1, 1.4 Hz, 1H), 7.60 (ddd, J = 8.3, 7.1, 1.4 Hz,
1H), 5.65 (t, J = 6.9 Hz, 1H), 4.20–4.11 (m, 1H), 4.11–4.01 (m, 1H), 7.50 (dd, J = 8.4, 1.4 Hz, 1H), 5.73 (t, J = 6.9 Hz, 1H),
1H), 2.87–2.71 (m, 1H), 2.47–2.30 (m, 1H), 2.29–2.00 (m, 2H) 4.23–4.16 (m, 1H), 4.11–4.00 (m, 1H), 2.76–2.65 (m, 1H), 2.62
ppm; 13C-NMR (101 MHz, CDCl3) δ 158.3 (C), 143.3 (C), (s, 3H), 2.46–2.32 (m, 1H), 2.27–2.04 (m, 2H) ppm; 13C-NMR
133.3 (C), 131.8 (C), 130.9 (CH), 130.7 (CH), 128.9 (CH), (101 MHz, CDCl3) δ 159.3 (C), 143.6 (C), 140.7 (C), 133.5 (C),
127.4 (CH), 126.2 (CH), 126.0 (C), 124.2 (CH), 123.6 (C), 130.5 (CH), 129.0 (CH), 128.4 (CH), 126.7 (CH), 126.4 (CH),
121.9 (CH), 79.8 (CH), 69.1 (CH2), 29.7 (CH2), 26.1 (CH2) ppm; 124.1 (C), 123.0 (C), 122.1 (CH), 121.9 (CH), 79.8 (CH), 69.1
IR ν 3063, 2939, 2839, 1617, 1460, 1220, 1038, 759 cm−1; LRMS (CH2), 30.2 (CH2), 26.1 (CH2), 22.3 (CH3) ppm; IR ν 2875, 2868,
(EI) m/z (%) = 283 (M+, 8), 254 (15), 240 ([M+ − C2H3O], 100), 1618, 1460, 1053, 760; LRMS (EI) m/z (%) = 263 (M+, 5),
217 (12), 207 (65), 177 (39); HRMS (EI) m/z calcd for C15H11ClN 234 (13), 220 (100), 207 (51), 192 (23); HRMS (EI) m/z calcd for
240.0580, found 240.0586.
C18H17NO 263.1310, found 263.1312.
8-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine
(3ia).
7-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine
(3ka).
Following the general procedure, compound 3ia was obtained Following the general procedure, compound 3ka was obtained
after column chromatography (hexane/EtOAc 95 : 5–8 : 2) as a after column chromatography (hexane/EtOAc 93 : 7) as a white
yellow pale solid (80 mg, 0.30 mmol, 60%): Rf 0.21 solid (51 mg, 0.19 mmol, 38%): Rf 0.19 (9 : 1 hexane/EtOAc);
1
(95 : 5 hexane/EtOAc); H-NMR (400 MHz, CDCl3) δ 8.60 (H-10, 1H-NMR (300 MHz, CDCl3) δ 8.49 (d, J = 8.2 Hz, 1H), 8.45 (d,
dd, JH–F = 9.1, 5.4 Hz, 1H), 8.46 (dd, J = 8.1, 1.1 Hz, 1H), 8.17 J = 8.4 Hz, 1H), 8.22 (dd, J = 8.2, 1.2 Hz, 1H), 7.82–7.70 (m,
(dd, J = 8.1, 1.2 Hz, 1H), 8.12 (H-7, dd, JH–F = 10.2, 2.6 Hz, 1H), 2H), 7.64 (ddd, J = 8.3, 7.1, 1.4 Hz, 1H), 7.36 (ddd, J = 12.5, 7.9,
7.70 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 7.64 (ddd, J = 8.3, 7.0, 1.0 Hz, 1H), 6.02 (dt, J = 8.2, 4.3 Hz, 1H), 4.43–4.32 (m, 1H),
1.5 Hz, 1H), 7.56 (H-9, ddd, JH–F = 9.1, 8.0, 2.7 Hz, 1H), 5.63 4.17–4.05 (m, 1H), 2.60–2.45 (m, 1H), 2.40–2.23 (m, 1H),
(H-2′, t, J = 6.9 Hz, 1H), 4.20–4.13 (H-5′, m, 1H), 4.09–4.02 2.13–1.96 (m, 1H) ppm; 13C-NMR (75 MHz, CDCl3) δ 160.2
1
3
(H-5′, m, 1H), 2.84–2.71 (m, 1H), 2.44–2.34 (m, 1H), 2.27–2.06 (C-7, d, JC–F = 255.2 Hz), 158.8 (C, d, JC–F = 7.9 Hz), 143.3
(m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) δ 161.33 (C-8, d, (CH), 136.0 (C, d, JC–F = 4.4 Hz), 131.0 (C-9, d, JC–F = 9.8 Hz),
4
3
1JC–F = 248.0 Hz), 158.53 (C, d, JC–F = 4.3 Hz), 142.94 (C), 130.8 (CH), 129.3 (CH), 127.3 (CH), 122.7 (C, d, JC–F = 2.7 Hz),
4
5
4
130.62 (CH), 130.11 (C), 128.51 (CH), 127.43 (CH), 126.24 122.3 (CH), 118.7 (C-10, d, JC–F = 4.0 Hz), 114.2 (CH), 114.1
(C-6a, d, 3JC–F = 7.8 Hz), 124.93 (C-10, d, 3JC–F = 8.5 Hz), 123.82 (C), (CH), 114.0 (C-6a, d, JC–F = 24.6 Hz), 81.9 (C-2′, d, JC–F
=
2
4
2
121.76 (CH), 119.64 (CH, d, JC–F = 23.9 Hz), 111.59 (CH, d, 14 Hz), 69.3 (CH2), 31.7 (CH2), 25.1 (CH2) ppm; IR ν 2970,
2JC–F = 21.8 Hz), 80.08 (CH), 69.14 (CH2), 29.79 (CH2), 26.08 2870, 1581, 1451, 1240, 757 cm−1; LRMS (EI) m/z (%) = 267
(CH2); IR ν 2958, 2873, 1773, 1697, 1480, 1196, 1054,759 cm−1
;
(M+, 2), 224 (100), 211 (64), 197 (19), 169 (9); HRMS (EI) m/z
LRMS (EI) m/z (%) = 267.1 (M+, 5), 238 (12), 224 (100), 211 (59), calcd for C17H14FNO 267.1059, found 267.1050.
197 (19), 169 (11); HRMS (EI) m/z calcd for C17H14FNO
267.1059, found 267.1042.
7-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine
9-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine
From the same reaction where compound 3ka was obtained,
(3ja). and after column chromatography (hexane/EtOAc 95 : 5),
(3′ka).
Following the general procedure, compound 3ja was obtained isomer 3′ka was isolated as a white solid (24 mg, 0.09 mmol,
1
after column chromatography (hexane/EtOAc 98 : 2–95 : 5) as a 18%): Rf 0.27 (9 : 1 hexane/EtOAc); H-NMR (300 MHz, CDCl3)
yellow pale solid (38 mg, 0.14 mmol, 28%): Rf 0.16 δ 8.52 (H-7, dd, J = 9.1, 5.8 Hz, 1H), 8.41 (H-1, dd, J = 8.2,
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1.1 Hz, 1H), 8.22 (H-10, dd, J = 10.5, 2.6 Hz, 1H), 8.17 (H-4, dd, 0.15 mmol, 50%): Rf 0.20 (93 : 7 hexane/EtOAc); 1H-NMR
J = 8.3, 1.2 Hz, 1H), 7.74 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 7.64 (300 MHz, CDCl3) δ 8.53 (d, J = 8.2 Hz, 1H), 8.48 (d, J = 2.1 Hz,
(ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.42 (H-8, ddd, J = 9.1, 8.2, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.87–7.79
2.6 Hz, 1H), 5.70 (H-2′, t, J = 6.9 Hz, 1H), 4.21–4.11 (H-5′, m, (m, 1H), 7.71 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.64 (dd, J = 8.7,
1H), 4.10–4.01 (H-5′, m, 1H), 2.88–2.71 (m, 1H), 2.47–2.31 (m, 2.3 Hz, 1H), 5.74 (t, J = 6.9 Hz, 1H), 4.24–4.14 (m, 1H),
1H), 2.29–2.05 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) 4.11–4.01 (m, 1H), 2.79–2.65 (m, 1H), 2.49–2.34 (m, 1H),
1
δ 163.70 (C-9, d, JC–F = 251.5 Hz); 158.7 (C), 143.6 (C), 135.9 2.28–2.03 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) δ 159.7
3
3
(C-10a, d, JC–F = 9.4 Hz), 130.6 (CH), 129.8 (C-7, d, JC–F
=
(C), 141.8 (C), 132.9 (C), 132.4 (C), 132.0 (CH), 130.7 (CH),
4
9.3 Hz), 129.3 (CH), 127.1 (CH), 123.8 (C-6a, d, JC–F = 4.1 Hz), 129.1 (CH), 128.0 (CH), 126.7 (CH), 125.3 (C), 125.1 (C), 122.5
5
122.2 (CH), 122.0 (C-6, d, JC–F = 2 Hz), 116.3 (C-10/C-8, d, (CH), 121.7 (CH), 79.6 (CH), 69.2 (CH2), 30.0 (CH2), 26.1(CH2)
2JC–F = 23.7 Hz), 107.5 (C-8/C-10, d, JC–F = 22.1 Hz), 80.0 (CH), ppm; IR ν 2967, 2869, 1584, 1495, 1255, 1054, 822, 767 cm−1
;
2
69.1 (CH2), 29.8 (CH2), 26.1 (CH2) ppm; IR ν 2962, 2877, 1619, LRMS (EI) m/z (%) = 283 (M+, 4), 254 (16), 240 ([M+ − C2H3O],
1496, 1195, 1052, 760 cm−1; LRMS (EI) m/z (%) = 267 (M+, 3), 100), 227 (51), 213 (13) 177 (29); HRMS (EI) m/z calcd for
238 (13), 224 (100), 211 (55), 197 (17), 169 (9); HRMS (EI) m/z C15H11ClN 240.0580, found 240.0576.
calcd for C17H14FNO 267.1059, found 267.1054.
3-Fluoro-6-(tetrahydrofuran-2-yl)phenanthridine
(3oa).
2-Methyl-6-(tetrahydrofuran-2-yl)phenanthridine
(3la). Following the general procedure, but from 0.30 mmol of 1o,
Following the general procedure, but from 0.30 mmol of 1l, compound 3oa was obtained after column chromatography
compound 3la was obtained after column chromatography (hexane/EtOAc 96 : 4) as a brown oil (36 mg, 0.13 mmol, 45%):
(hexane/EtOAc 94 : 6–93 : 7) as a yellow pale solid (43 mg, Rf 0.20 (93 : 7 hexane/EtOAc); 1H-NMR (300 MHz, CDCl3) δ 8.54
0.16 mmol, 55%): Rf 0.17 (93 : 7 hexane/EtOAc); 1H-NMR (d, J = 8.3 Hz, 1H), 8.49 (H-1, dd, J = 9.1, 5.9 Hz, 1H), 8.43 (d,
(300 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.42 (dd, J = 8.3, J = 8.2 Hz, 1H), 7.87–7.78 (m, 2H), 7.67 (ddd, J = 8.3, 7.0,
0.7 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.79 (ddd, J = 1.2 Hz, 1H), 7.38 (H-2, ddd, J = 8.9, 8.1, 2.7 Hz, 1H), 5.76 (t, J =
8.3, 7.0, 1.3 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.53 6.9 Hz, 1H), 4.24–4.14 (m, 1H), 4.11–4.01 (m, 1H), 2.78–2.64
(dd, J = 8.3, 1.6 Hz, 1H), 5.74 (t, J = 6.9 Hz, 1H), 4.25–4.14 (m, (m, 1H), 2.48–2.34 (m, 1H), 2.29–2.03 (m, 2H) ppm; 13C-NMR
1
1H), 4.11–4.00 (m, 1H), 2.83–2.66 (m, 1H), 2.61 (s, 3H), (101 MHz, CDCl3) δ 162.7 (C-3, d, JC–F = 247.6 Hz), 160.9 (C),
3
2.48–2.33 (m, 1H), 2.28–2.02 (m, 2H) ppm; 13C-NMR 144.7 (C-4a, d, JC–F = 11.9 Hz), 133.2 (C), 130.8 (CH), 127.2
4
(101 MHz, CDCl3) δ 158.3 (C), 141.7 (C), 136.8 (C), 133.1 (C), (CH), 126.7 (CH), 124.5 (C, d, JC–F = 1.0 Hz), 123.9 (C-1, d,
130.3 (CH), 130.3 (CH), 130.1(CH), 127.1 (CH), 126.5 (CH), 3JC–F = 9.5 Hz), 122.3 (CH), 120.9 (d, JC–F = 2.1 Hz), 116.0 (CH,
2
2
125.0 (C), 124.0 (C), 122.4 (CH), 121.6 (CH), 79.8 (CH), 69.1 d, JC–F = 23.7 Hz), 115.0 (CH, d, JC–F = 20.5 Hz), 79.5 (CH),
(CH2), 30.1 (CH2), 26.1 (CH2), 22.1 (CH3) ppm; IR ν 2971, 2923, 69.2 (CH2), 30.1 (CH2), 26.1(CH2) ppm; IR ν 2972, 2871, 1618,
2867, 1582, 1496, 1295, 1051, 822, 729 cm−1; LRMS (EI) 1580, 1484, 1459, 1053, 764 cm−1; LRMS (EI) m/z (%) = 267
m/z (%) = 263 (M+, 6), 234 (12), 220 (100), 207 (47), 192 (15), (M+, 5), 238 (15), 224 (100), 211 (55), 196 (17); HRMS (EI) m/z
165 (12); HRMS (EI) m/z calcd for C18H17NO 263.1310, found calcd for C17H14FNO 267.1059, found 267.1048.
263.1312.
6-(1,4-Dioxan-2-yl)phenanthridine (3ab).13a Following the
6-(Tetrahydrofuran-2-yl)-2-(trifluoromethoxy)phenanthridine general procedure, compound 3ab was obtained after column
(3ma). Following the general procedure, but from 0.45 mmol chromatography (hexane/EtOAc 85 : 15–75 : 25) as a white solid
of 1m, compound 3ma was obtained after column chromato- (69 mg, 0.26 mmol, 52%): Rf 0.25 (8 : 2 hexane/EtOAc).
graphy (hexane/EtOAc 94 : 6) as a red solid (84 mg, 0.25 mmol, 1H-NMR (300 MHz, CDCl3) δ 8.66 (d, J = 8.3 Hz, 1H), 8.60–8.52
55%): Rf 0.20 (93 : 7 hexane/EtOAc); 1H-NMR (400 MHz, CDCl3) (m, 1H), 8.48–8.39 (m, 1H), 8.26–8.15 (m, 1H), 7.90–7.80 (m,
δ 8.55 (d, J = 8.3 Hz, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 1H), 7.78–7.63 (m, 3H), 5.49 (p, J = 6.3 Hz, 1H), 4.34–4.29 (m,
1.7 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.87 (ddd, J = 8.4, 7.1, 2H), 4.21–4.06 (m, 2H), 3.99–3.88 (m, 2H) ppm; 13C-NMR
1.3 Hz, 1H), 7.75 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.57 (ddd, J = (75 MHz, CDCl3) δ 156.2 (C), 143.3 (C), 133.3 (C), 130.6 (CH),
8.9, 2.6, 1.1 Hz, 1H), 5.77 (t, J = 6.9 Hz, 1H), 4.23–4.15 (m, 1H), 130.6 (CH), 128.7 (CH), 127.5 (CH), 127.4 (CH), 126.2 (CH),
4.12–4.04 (m, 1H), 2.81–2.65 (m, 1H), 2.50–2.35 (m, 1H), 124.6 (C), 124.1 (C), 122.6 (CH), 122.0 (CH), 76.3 (CH), 70.2
2.31–2.06 (m, 2H) ppm; 13C-NMR (101 MHz, CDCl3) δ 160.1 (CH2), 67.9 (CH2), 66.7 (CH2) ppm; IR ν 2965, 2856, 1114,
(C), 147.7 (C), 141.7 (C), 132.8 (C), 132.5 (CH), 130.7 (CH), 10 856, 912, 759 cm−1; LRMS (EI) m/z (%) = 265 (M+, 4), 206
3
128.2 (CH), 126.8 (CH), 125.1 (C-2, d, JC–F = 10.5 Hz), 122.6 (100), 179 (24), 151 (12), 102 (5).
1
(CH), 121.9 (CH), 120.8 (q, JC–F = 257.5 Hz), 113.7 (CH), 79.6
6-(Tetrahydro-2H-pyran-2-yl)phenanthridine
(3ac).13c
(CH), 69.2 (CH2), 30.1 (CH2), 26.1 (CH2) ppm; IR ν 2964, 2860, Following the general procedure, compound 3ac was obtained
1619, 1587, 1492, 1254, 1214 cm−1; LRMS (EI) m/z (%) = 333 after column chromatography (hexane/EtOAc 98 : 2–9 : 1) as a
(M+, 5), 304 (24), 290 (100), 277 (51), 263 (8); HRMS (EI) m/z white solid (57 mg, 0.22 mmol, 43%): Rf 0.20 (95 : 5 hexane/
calcd for C18H14F3NO2 333.0977, found 333.0950.
EtOAc); 1H-NMR (300 MHz, CDCl3) δ 8.62 (ddd, J = 8.2, 1.3,
2-Chloro-6-(tetrahydrofuran-2-yl)phenanthridine
(3na). 0.6 Hz, 1H), 8.56–8.50 (m, 2H), 8.25–8.19 (m, 1H), 7.80 (ddd, J =
Following the general procedure, but from 0.30 mmol of 1n, 8.3, 7.0, 1.3 Hz, 1H), 7.74–7.66 (m, 2H), 7.65–7.57 (m, 1H), 5.20
compound 3na was obtained after column chromatography (dd, J = 11.1, 2.2 Hz, 1H), 4.34–4.24 (m, 1H), 3.81 (td, J = 11.6,
(hexane/EtOAc 94 : 6–93 : 7) as
a white solid (42 mg, 2.4 Hz, 1H), 2.37–2.19 (m, 1H), 2.15–2.00 (m, 2H), 1.96–1.77
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(m, 2H), 1.74–1.63 (m, 1H) ppm; 13C-NMR (75 MHz, CDCl3) after column chromatography (hexane/EtOAc 99 : 1–9 : 1),
δ 159.6 (C), 143.4 (C), 133.5 (C), 130.5 (CH), 130.3 (CH), 128.6 isomer 3′af was isolated as a white solid (26 mg, 0.10 mmol,
(CH), 127.1 (CH), 127.0 (CH), 126.8 (CH), 124.5 (C), 124.1 (C), 21%) [trans/cis mixture in a 58 : 42 ratio (1H-NMR)]): Rf 0.75
1
122.4 (CH), 121.9 (CH), 80.7 (CH), 69.6 (CH2), 30.6 (CH2), 26.1 (9 : 1 hexane/EtOAc); H-NMR (400 MHz, CDCl3) δ 8.62 (d, J =
(CH2), 24.0 (CH2) ppm; IR ν 3075, 2930, 2839, 1083, 1039, 754, 8.3 Hz, 1.10H), 8.53 (d, J = 8.2 Hz, 1.51H), 8.46 (d, J = 7.9 Hz,
723 cm−1; LRMS (EI) m/z (%) = 262 (M+ − 1, 1), 235 (20), 206 0.6H), 8.21–8.15 (m, 1H), 7.81 (ddt, J = 8.3, 7.0, 1.3 Hz, 1.09H),
(100), 193 (12).
6-(2-Isopropoxypropan-2-yl)phenanthridine
7.75–7.59 (m, 3.58H), 5.91 (t, J = 6.9 Hz, 0.58H), 5.69 (t, J =
(3ad).13c 7.1 Hz, 0.42H), 4.53–4.43 (m, 0.64H), 4.37–4.27 (m, 0.47H),
Following the general procedure, compound 3ad was obtained 2.91–2.73 (m, 1.06H), 2.52–2.42 (m, 0.62H), 2.42–2.27 (m,
after column chromatography (100% hexane to hexane/EtOAc 1.02H), 2.27–2.14 (m, 0.44H), 1.87–1.67 (m, 1.5H), 1.39 (dd, J =
98 : 2) as a brown pale oil (79 mg, 0.28 mmol, 57%): Rf 0.29 6.1, 3.3 Hz, 3H) ppm; 13C-NMR (75 MHz, CDCl3) δ 159.9 (C),
(100% hexane); 1H-NMR (300 MHz, CDCl3) δ 9.25 (ddd, J = 8.5, 159.2 (C), 143.34 (C), 143.28 (C), 133.43 (C), 133.42 (C), 130.5
1.4, 0.6 Hz, 1H), 8.70–8.64 (m, 1H), 8.57 (dd, J = 8.0, 1.6 Hz, (CH), 130.4 (CH), 128.6 (CH), 128.6 (CH), 127.3 (CH), 127.3
1H), 8.17–8.12 (m, 1H), 7.81 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), (CH), 127.0 (CH), 126.9 (CH), 126.7 (CH), 125.1 (C), 124.9 (C),
7.77–7.61 (m, 3H), 3.75 (p, J = 6.1 Hz, 1H), 1.92 (s, 6H), 1.02 (d, 124.3 (C), 124.2 (C), 122.5 (CH), 122.4 (CH), 122.0 (CH), 80.6
J = 6.1 Hz, 6H) ppm; 13C-NMR (101 MHz, CDCl3) δ 163.7 (C), (CH), 79.2 (CH), 76.1 (CH2), 33.9 (CH2), 33.2 (CH2), 30.6 (CH2),
142.9 (C), 133.9 (C), 130.6 (CH), 130.3 (CH), 129.9 (CH), 128.5 30.0 (CH2), 21.6 (CH3), 21.4 (CH3) ppm; IR ν 3074, 2971, 2929,
(CH), 127.0 (CH), 126.1 (CH), 124.5 (C), 124.1 (C), 122.3 (CH), 2877, 2861, 1583, 1444, 1073, 725 cm−1; LRMS (EI) m/z (%) =
121.9 (CH), 81.8 (C), 67.0 (CH), 29.1 (CH3), 24.8 (CH3); 263 (M+, 11), 220 (72), 208 (100), 179 (58); HRMS (EI): calcd for
IR ν 2983, 2933, 1578, 1379, 1162, 1110, 996, 760, 730 cm−1
LRMS (EI) m/z (%) = 264 (M+, 0.2), 236 (18), 221 ([M+ − C5H7O],
;
C18H17NO 263.1310, found 263.1301.
6-(tert-Butoxymethyl)phenanthridine (3ag).13c Following the
100), 204 (34), 179 (54), 150 (18); HRMS (EI) m/z calcd for general procedure, compound 3ag was obtained after column
C16H14N 220.1126, found 220.1128. chromatography (hexane/EtOAc 95 : 5–93 : 2) as a yellow solid
6-(1-Butoxybutyl)phenanthridine (3ae).13b Following the (53 mg, 0.20 mmol, 40%): Rf 0.24 (9 : 1 hexane/EtOAc);
general procedure, compound 3ae was obtained after column 1H-NMR (300 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.53 (td,
chromatography (hexane/EtOAc 99 : 1–98 : 2) as a yellow oil J = 8.1, 1.3 Hz, 2H), 8.17 (dd, J = 7.8, 1.4 Hz, 1H), 7.87–7.79 (m,
(123 mg, 0.40 mmol, 80%): Rf 0.65 (9 : 1 hexane/EtOAc); 1H), 7.75–7.61 (m, 3H), 5.09 (s, 2H), 1.40 (s, 9H) ppm;
1H-NMR (300 MHz, CDCl3) δ 8.94–8.89 (m, 1H), 8.69–8.64 (m, 13C-NMR (75 MHz, CDCl3) δ 158.7 (C), 143.6 (C), 133.4 (C),
1H), 8.57 (dd, J = 8.0, 1.6 Hz, 1H), 8.20–8.15 (m, 1H), 7.84 130.6 (CH), 130.2 (CH), 128.6 (CH), 127.6 (CH), 127.3 (CH),
(ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.77–7.62 (m, 3H), 4.98 (dd, J = 127.1 (CH), 125.7 (C), 124.5 (C), 122.2 (CH), 122.0, 74.7 (CH),
8.8, 5.4 Hz, 1H), 3.52–3.33 (m, 2H), 2.28–2.13 (m, 1H), 66.9 (CH2), 27.9 (3CH3) ppm; IR ν 2974, 2932, 1719, 1364,
2.01–1.87 (m, 1H), 1.76–1.46 (m, 4H), 1.40–1.23 (m, 4H), 0.95 1145, 760 cm−1; LRMS (EI) m/z (%) = 265 ([(M + 1)+ − CH3], 1),
(t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H) ppm; 13C-NMR 235 (37), 208 (100), 192 (48), 180 (51), 165 (25).
(101 MHz, CDCl3) δ 161.9 (C), 143.4 (C), 133.5 (C), 130.5 (CH),
6-((Benzyloxy)(phenyl)methyl)phenanthridine
(3ah).
130.2 (CH), 128.7 (CH), 127.0 (CH), 124.5 (C), 124.1 (C), 122.4 Following the general procedure, compound 3ah was obtained
(CH), 122.0 (CH), 86.5 (CH), 69.5 (CH2), 38.3 (CH2), 32.2 (CH2), after column chromatography (hexane/EtOAc 99 : 1–98 : 2) as a
20.0 (CH2), 19.5 (CH2), 14.1 (CH3), 14.0 (CH3) ppm; IR ν 2957, yellow solid (32 mg, 0.08 mmol, 17%): Rf 0.5 (9 : 1 hexane/
2932, 2870, 1759, 1459, 1092, 727 cm−1; LRMS (EI) m/z (%) = EtOAc); 1H-NMR (300 MHz, CDCl3) δ 8.65–8.55 (m, 3H),
265 (M+ − C3H6, 12), 250 (9), 235 (37), 206 (100), 151 (9).
8.30–8.25 (m, 1H), 7.81–7.66 (m, 3H), 7.57–7.43 (m, 3H),
6-(2-Methyltetrahydrofuran-2-yl)phenanthridine
(3af). 7.39–7.25 (m, 7H), 7.24–7.19 (m, 1H), 6.27 (s, 1H), 4.73 (d, J =
Following the general procedure, compound 3af was obtained 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H) ppm; 13C-NMR
after column chromatography (hexane/EtOAc 99 : 1–9 : 1) as a (101 MHz, CDCl3) δ 159.9 (C), 143.4 (C), 140.8 (C), 138.3 (C),
colorless oil (43 mg, 0.16 mmol, 33%): Rf 0.75 (9 : 1 hexane/ 133.9 (C), 130.5 (CH), 130.5 (CH), 128.8 (CH), 128.4 (CH), 128.3
1
EtOAc); H-NMR (300 MHz, CDCl3) δ 9.14 (d, J = 8.4 Hz, 1H), (CH), 128.0 (CH), 127.7 (CH), 127.4 (CH), 127.1 (CH), 126.3
8.63 (d, J = 8.3 Hz, 1H), 8.53 (dd, J = 8.1, 1.5 Hz, 1H), 8.12 (d, (CH), 124.5 (C), 124.3 (C), 122.3 (CH), 122.1 (CH), 86.5 (CH),
J = 8.0 Hz, 1H), 7.78 (ddd, J = 8.1, 6.6, 1.2 Hz, 1H), 7.72–7.58 71.7 (CH2) ppm; IR ν 3060, 3029, 2915, 2850, 1572, 1449, 1067,
(m, 3H), 4.14–4.03 (m, 1H), 3.80–3.69 (m, 1H), 3.66–3.56 (m, 722 cm−1. LRMS (EI-DIP) m/z (%) = 284 (M+ − C7H7, 52), 269
1H), 2.10–1.88 (m, 3H), 1.83 (s, 3H) ppm; 13C-NMR (75 MHz, (100), 268 (52), 178 (16), 91 (32); HRMS (EI) calcd for
CDCl3) δ 163.1, 142.9, 134.0, 130.4, 130.0, 129.3, 128.4, 126.9, C27H21NO 375.1623, found 375.1605.
126.6, 124.4, 124.1, 122.4, 121.9, 88.7, 68.1, 37.4, 28.2,
25.2 ppm; IR ν 3065, 2970, 2930, 2872, 1570, 1097, 758 cm−1
6-Benzylphenanthridine (3′ah).26 From the same reaction
where compound 3ah was obtained, and after column chrom-
;
LRMS (EI) m/z (%) = 263 (M+, 18), 235 (48), 207 (86), 179 (55), atography (hexane/EtOAc 99 : 1–98 : 2), compound 3′ah was iso-
85 (100); HRMS (EI) calcd for C18H17NO 263.1310, found lated as a yellow solid (62 mg, 0.23 mmol, 46%): Rf 0.5
263.1308.
(9 : 1 hexane/EtOAc); 1H-NMR (300 MHz, CDCl3) δ 8.56 (br d,
6-(5-Methyltetrahydrofuran-2-yl)phenanthridine (3′af). From J = 8.3 Hz, 1H), 8.51 (dd, J = 8.2, 1.4 Hz, 1H), 8.18 (ddd, J = 9.7,
the same reaction where compound 3af was obtained, and 8.1, 1.3 Hz, 2H), 7.72 (ddd, J = 8.2, 7.0, 1.4 Hz, 2H), 7.61 (ddd,
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J = 8.3, 7.0, 1.4 Hz, 1H), 7.53 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H),
Phenanthridine (4a).13a This compound was obtained as the
7.33–7.28 (m, 2H), 7.26–7.10 (m, 4H), 4.74 (s, 2H) ppm; by-product of 3aa and of all compounds represented in
13C-NMR (101 MHz, CDCl3) δ 160.2 (C), 143.8 (C), 139.2 (C), Scheme 3. After purification by column chromatography
133.3 (C), 130.4 (CH), 129.9 (CH), 128.7 (CH), 128.6 (2CH), (hexane/EtOAc 9 : 1), it was isolated as a white solid. Rf 0.25
1
127.4 (CH), 127.1 (CH), 126.7 (CH), 126.4 (CH), 125.4 (C), (9 : 1 hexane/EtOAc); H-NMR (300 MHz, CDCl3) δ 9.28 (s, 1H),
124.0 (C), 122.5 (CH), 122.0 (CH), 43.2 (CH2) ppm; IR ν 3062, 8.63–8.54 (m, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H), 8.03 (br d, J =
3025, 1684, 1581, 1362, 723 cm−1. LRMS (EI-DIP) m/z (%) = 269 7.9 Hz, 1H), 7.84 (ddd, J = 8.4, 7.1, 1.4 Hz, 1H), 7.78–7.63 (m,
(M+, 41), 268 (M+ − 1, 100), 254(6), 134 (11), 57 (6).
2H) ppm; 13C-NMR (75 MHz, CDCl3) δ 153.7 (CH), 144.6 (C),
6-(1,3-Dihydroisobenzofuran-1-yl)phenanthridine
(3ai). 132.7 (C), 131.1 (CH), 130.3 (CH), 128.9 (CH), 128.8 (CH), 127.6
Following the general procedure, compound 3ai was obtained (CH), 127.2 (CH), 126.5 (C), 124.2 (C), 122.3 (CH), 122.0 (CH)
after column chromatography (hexane/EtOAc 99 : 1–98: 2) as a ppm; IR ν 2924, 2851, 1457, 1245, 890, 745 cm−1; LRMS (EI)
yellow crystalline solid (52 mg, 0.17 mmol, 35%): Rf 0.4 m/z (%) = 179 (M+, 100), 151 (13), 76(100), 179 (8).
(9 : 1 hexane/EtOAc); mp 120–121 °C (3 : 1 EtOAc/MeOH);
1H-NMR (400 MHz, CDCl3) δ 8.65 (br d, J = 8.3 Hz, 1H), 8.56
(dd, J = 8.1, 1.4 Hz, 1H), 8.25 (br d, J = 8.3 Hz, 1H), 8.17 (dd, J =
8.0, 1.2 Hz, 1H), 7.80 (s, 1H), 7.72 (ddd, J = 8.2, 7.0, 1.6 Hz,
Acknowledgements
1H), 7.66 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.59 (ddd, J = 8.3, 7.0, We thank the Ministerio de Economia y Competitividad
1.2 Hz, 1H), 7.41–7.37 (m, 1H), 7.35–7.30 (m, 1H), 7.23–7.13 (CTQ2015-66624-P) and the University of Alicante
(m, 2H), 6.97 (t, J = 2.5 Hz, 1H), 5.59 (dd, J = 12.3, 2.7 Hz, 1H), (VIGROB-173) for financial support. C. A.-T. thanks the ISO for
5.42 (dd, J = 12.3, 2.0 Hz, 1H) ppm; 13C-NMR (101 MHz, a grant.
CDCl3) δ 158.8 (C), 143.4 (C), 140.9 (C), 139.2 (C), 133.9 (C),
130.7 (CH), 130.4 (CH), 128.7 (CH), 128.0 (CH), 127.5 (CH),
127.3 (CH), 127.3 (CH), 126.6 (CH), 124.6 (C), 124.4 (C), 122.8
Notes and references
(CH), 122.6 (CH), 122.0 (CH), 121.3(CH), 87.8 (CH), 73.8 (CH2)
ppm; IR ν 3074, 2851, 1572, 1027, 720 cm−1. LRMS (EI) m/z (%) =
297 (M+, 2), 268 (100), 251 (3), 119 (12); HRMS (EI) calcd for
C21H15NO 297.1154, found 297.1141.
1 Examples can be found in: O. B. Abdel-Halim, T. Morikawa,
S. Ando, H. Matsuda and M. Yoshikawa, J. Nat. Prod., 2004,
67, 1119.
6-(1,3,5-Trioxan-2-yl)phenanthridine (3aj). Following the
general procedure, compound 3aj was obtained after column
chromatography (100% hexane to hexane/EtOAc 8 : 2) as a
white solid (96 mg, 0.26 mmol, 52%): Rf 0.2 (9 : 1 hexane/
EtOAc); 1H-NMR (300 MHz, CDCl3) δ 9.10–9.04 (m, 1H), 8.64
(d, J = 8.3 Hz, 1H), 8.60–8.55 (m, 1H), 8.23–8.18 (m, 1H),
7.90–7.83 (m, 1H), 7.79–7.67 (m, 1H), 6.48 (s, 1H), 5.50 (q, J =
6.5 Hz, 4H) ppm; 13C-NMR (75 MHz, CDCl3) δ 153.6 (C),
142.8 (C), 134.0 (C), 131.0 (CH), 130.6 (CH), 128.9 (CH),
128.3 (CH), 128.1 (CH), 127.4 (CH), 125.0 (C), 123.7 (C),
122.2 (2CH), 106.1(CH), 94.2 (2CH2) ppm; IR ν 3037, 2884,
1418, 1199, 1100, 1047, 944, 750, 723 cm−1; LRMS (EI) m/z (%) =
267 (M+, 1), 208 (67), 179 (100), 151 (31); HRMS (EI) calcd for
C16H13NO3 267.0895, found 267.0879.
2 (a) Y. L. Janin, A. Croisy, J.-F. Riou and E. Bisagni, J. Med.
Chem., 1993, 36, 3686; (b) S. D. Fang, L. K. Wang and
S. M. Hecht, J. Org. Chem., 1993, 58, 5025; (c) T. Nakanishi,
M. Suzuki, A. Saimoto and T. Kabasawa, J. Nat. Prod., 1999,
62, 864; (d) I. Slaninova, K. Pencikova, J. Urbanova,
J. Slanina and E. Taborska, Phytochem. Rev., 2014, 13, 51.
3 T. Ishikawa, Med. Res. Rev., 2001, 21, 61.
4 (a) X. Yang, Y. Yao, Y. Qin, Z. Hou, R. Yang, F. Miao and
L. Zhou, Chem. Pharm. Bull., 2013, 61, 731; (b) J. Hu, X. Shi,
J. Chen, X. Mao, L. Zhu, L. Yu and J. Shi, Food Chem., 2014,
148, 437.
5 E. Vanquelef, M. Amoros, J. Boustie, M. A. Lynch,
R. D. Waigh and O. Duval, J. Enzyme Inhib. Med. Chem.,
2004, 19, 481.
6-(Benzo[d][1,3]dioxol-2-yl)phenanthridine (3ak). Following
the general procedure, compound 3ak was obtained after
column chromatography (hexane/EtOAc 99 : 1–98 : 2) as a white
crystalline solid (90 mg, 0.3 mmol, 60%): Rf 0.49 (9 : 1 hexane/
EtOAc); mp 105–107 °C (MeOH); 1H-NMR (300 MHz, CDCl3)
δ 8.64 (br d, J = 8.3 Hz, 1H), 8.56 (dd, J = 8.0, 1.4 Hz, 1H),
8.30–8.21 (m, 2H), 7.82 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H),
7.79–7.66 (m, 2H), 7.60 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.43 (s,
1H), 7.04–6.91 (m, 4H) ppm; 13C-NMR (75 MHz, CDCl3)
6 F. Miao, X.-J. Yang, Y.-N. Ma, F. Zheng, X.-P. Song and
L. Zhou, Chem. Pharm. Bull., 2012, 60, 1508.
7 M. Zhang, L. Liu, H. Xiao, T. Zhao, L. Yang and X. Xu,
J. Heterocycl. Chem., 2016, 53, 234.
8 H. Lecoeur, Exp. Cell Res., 2002, 277, 1.
9 (a) N. Stevens, N. O’Connor, H. Vishwasrao, D. Samaroo,
E. Kandel, D. L. Akins, C. M. Drain and N. J. Turro, J. Am.
Chem. Soc., 2008, 130, 7182; (b) Y. Chen, W. Huang, C. Li
and Z. Bo, Macromolecules, 2010, 43, 10216.
δ 152.5 (C), 147.5 (2C), 142.9 (C), 133.9 (C), 130.9 (2CH), 10 For pioneer studies, see: (a) D. Nanni, P. Pareschi,
129.0 (CH), 128.4 (CH), 127.7 (CH), 125.9 (CH), 125.0 (C),
123.8 (C), 122.6 (CH), 122.3 (2CH), 122.1 (CH), 112.2 (CH),
C. Rizzoli, P. Sagarabotto and A. Tundo, Tetrahedron, 2010,
51, 9045; (b) M. Tobisu, K. Koh, T. Furukawa and
N. Chatani, Angew. Chem., Int. Ed., 2012, 51, 11363.
109.4 (2CH) ppm; IR ν 3078, 2909, 1479, 1338, 1229, 724 cm−1
;
LRMS (EI) m/z (%) = 299 (M+, 2), 270 (100), 241 (9), 178 (7); 11 For a recent comprehensive review, see: B. Zhang and
HRMS (EI) calcd for C20H13NO2 299.0946, found 299.0949.
A. Studer, Chem. Soc. Rev., 2015, 44, 3505.
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12 For some selected examples, see: (a) T. Yoshimitsu, 19 For selected examples, see: (a) T. Akindele, Y. Yamamoto,
Y. Arano and H. Nagaoka, J. Org. Chem., 2005, 70, 2342;
(b) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu
M. Maekawa, H. Umeki, K.-I. Yamada and K. Tomioka, Org.
Lett., 2006, 8, 5729; (b) I. Hayakawa, H. Watanabe and
H. Kigoshi, Tetrahedron, 2008, 64, 5873.
and X. Wan, Chem.
–
Eur. J., 2011, 17, 4085;
(c) G. S. Kumar, B. Pieber, K. R. Reddy and C. O. Kappe, 20 It is worth noting that compound 4a is significantly
Chem. – Eur. J., 2012, 18, 6124; (d) Z.-Q. Liu, L. Zhao,
X. Shang and Z. Cui, Org. Lett., 2012, 14, 3218;
(e) S.-R. Guo, Y.-Q. Yuan and J.-N. Xiang, Org. Lett., 2013,
15, 4654; (f) D. Liu, C. Liu, H. Li and A. Lei, Angew. Chem.,
Int. Ed., 2013, 52, 4453.
formed with TBPB in the absence of base (ref. 13a and
checked by us in Table 1, entry 7); or with BPO in
neutral media (ref. 13b and checked by us in Table 1,
entry 1).
21 S. Z. Zard, Radical Reactions in Organic Synthesis, Oxford
University Press, 2003, pp. 26–30.
13 (a) J.-J. Cao, T.-H. Zhu, S.-Y. Wang, Z.-Y. Gu, X. Wang and
S.-J. Ji, Chem. Commun., 2014, 50, 6439; (b) L. Wang, 22 (a) A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011,
W. Sha, Q. Dai, X. Feng, W. Wu, H. Peng, B. Chen and
J. Cheng, Org. Lett., 2014, 16, 2088; (c) C. Pan, J. Han and
50, 5018; (b) For a recent excellent review, see: A. Studer
and D. P. Curran, Nat. Chem., 2014, 6, 765.
Z. ChengJian, Sci. China: Chem., 2014, 57, 1172; (d) During 23 The following rate constants are reported for α-hydrogen
the preparation of the manuscript, the following paper was
published: Y. Xu, Y. Chen, W. Li, Q. Xie and L. Shao, J. Org.
Chem., 2016, 81, 8426.
abstraction of THF: k (t-BuO•) ∼ 8.3 × 106 vs. k (PhCOO•) ∼
2.5 × 103 M−1 s−1. See: J. Fossy, D. Lefort and J. Sorba, Free
Radicals in Organic Chemistry, John Wiley & Sons, 1995,
p. 290.
14 For reviews on the synthesis of oxacyclic natural products,
see: (a) E. Kang and E. Lee, Chem. Rev., 2005, 105, 4348; 24 B. Zhang, C. Mück-Lichtenfeld, C. D. Daniliue and
(b) T. Nakata, Chem. Rev., 2005, 105, 4314. A. Studer, Angew. Chem., Int. Ed., 2013, 52, 10792.
15 F. Agapito, B. J. Costa Cabral and J. A. Martinho Simoes, 25 An intramolecular electrophilic aromatic substitution
J. Mol. Struct.: THEOCHEM, 2005, 719, 109.
16 For a recent review, see: X.-F. Wu, J.-L. Gong and X. Qi, Org.
Biomol. Chem., 2014, 12, 5807.
17 A similar result was observed by the group of Ji (ref. 13a)
with 1,4-dioxane and TBPB as the oxidant.
18 This regiochemistry was observed by the group of Chen,
might also be considered as a plausible pathway for the
formation of byproduct 4a. Due to the extremely high
acidity of cyclohexadienyl radical I, a proton transfer to the
isonitrile moiety of 1a would form a cationic intermediate
that could undergo Friedel–Crafts-type cyclization to
give 4a.
using 1,4-dioxane and BPO as the oxidant. A plausible 26 Z. Liang, L. Ju, Y. Xie, L. Huang and Y. Zhang, Chem. – Eur.
explanation is given in ref. 13b.
J., 2012, 18, 15816.
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