Synthesis of phenanthridine derivatives via photolysis

Article abstract of DOI:10.1021/jo201542x

An improved photochemical method for producing the prolifically bioactive phenanthridine system is reported. A wide variety of derivatives were obtained in two steps in yields ranging from 31 to 95%.

Full text of DOI:10.1021/jo201542x

NOTE
pubs.acs.org/joc
Synthesis of Phenanthridine Derivatives via Photolysis
Anna M. Linsenmeier,†,‡ Craig M. Williams,*,† and Stefan Br€ase*,‡
†School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Queensland, Australia
‡Karlsruhe Institute of Technology (KIT), Campus South, Institute of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe,
Germany
S Supporting Information
b
ABSTRACT: An improved photochemical method for produc-
ing the prolifically bioactive phenanthridine system is reported.
A wide variety of derivatives were obtained in two steps in yields
ranging from 31 to 95%.
ur interest in the phenanthridine core stems from the
important role this system plays in a large number of natural
O
products. The diversity of these molecules is large and far
reaching from almost completely unsubstituted phenanthridines
cores like trispheridine (1)1 to more complex structures like
decarine (2)2 or chelerythrine (3) (Figure 1).2 Most of these
alkaloids demonstrate expansive biological activity including
nematodical, antitumor, antifungal, antibacterial, and cyto-
toxic activity.2,3
Figure 1. Examples for natural products containing a phenanthri-
dine core.
Recently, Pierini and Rossi et al.4 reported a new method for
synthesizing phenanthridines from the photolysis of N-(o-iodo-
benzyl)arylamines in liquid ammonia (or DMSO) and potassium
tert-butoxide (t-BuOK). In addition to the contribution of Pierini
and Rossi, other photochemical approaches to phenanthridines
have been reported. Badger and Lewis demonstrated the photo-
chemical cyclization of N-benzylideneaniline in concentrated
sulfuric acid,5 whereas Kessar,6 Park,7 and Sakurai8 showed later
that halobenzyl arylamines give phenanthridines under basic
conditions (NaOH) in waterÀacetonitrile on photolysis. More-
over, Rodríguez et al. and McBurney et al. irradiated acyloximes
and oxime carbonates affording phenanthridines.9
was heated for 15 min in the microwave at 170 °C, and the
desired product 6 was obtained, in most cases, in good to
excellent yields (Table 1, entries 1À13). Only the nitro derivative
gave a yield below 65% (entry 9, Table 1).
Initial attempts at photolysis were very promising. That is,
simple irradiation of 8 (entry 1, Table 1) in anhydrous acetoni-
trile under argon in a Rayonet photochemical reactor (254 nm)
gave the phenanthridine 21 in 85% in under 2 h. This was quite
surprising, especially considering previous reports suggest strong
base and aprotic solvents are required. This method was found to
be quite general, the results of which are shown in Table 1.
Overall, the photochemical cyclization gave products in high
yields, especially halides (26, 27), ester (22), and nitro groups
(29) which gave yields in the 95% range. Surprisingly, even the
phenol derivative 24 was obtained in 90% yield. Significantly
lower yields, 58% and 67%, respectively, were obtained with
methoxy (23) and methylthio (25) substituents. A possible
explanation could be that the newly formed products (i.e., 23
and 25) could be sensitive toward ultraviolet light, facilitating
decomposition on further irradiation. The side product phe-
nanthridine (21), obtained from the photolysis of the methoxy
aniline derivate 10, somewhat verifies this point (e.g., methoxy
radical production or hydrogen atom abstraction leading to
deformylation), although 21 was not observed in the case of the
Building on limited work in this area and the unfriendly
conditions so far required, we report herein a rapid, convenient,
and practical photolytic method to access the phenanthridine
core in yields ranging from 31 to 95%.
Taking inspiration from the work of Pierini and Rossi,4a
Kessar,6 Park,7 and Sakurai,8 we identified halogenated anilines
(6) as a strategic starting point but wanted to avoid the
requirement of strong base and undesirable solvents (i.e., DMSO
and liquid ammonia). To gain an understanding of why such
conditions were required, irradiation experiments with the
N-alkylated anilines 8À20 (Table 1, entries 1À13) were inves-
tigated. The method of Romera et al.10 was found to be superior
for the rapid N-alkylation of most anilines 4 accommodating
numerous functionalities such as a thioester, alkoxyl, halogen,
free OH, and nitro groups. An excess of the respective aniline 4
was introduced together with 2-iodobenzyl bromide (5) and a
catalytic amount of potassium iodide in acetonitrile. The mixture
Received: August 1, 2011
Published: September 21, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Table 1. Summary of N-Alkylation and Subsequent
Photolysis Giving Phenanthridines
Scheme 1. Product Mixture Obtained from the Photolysis
of 15
methylthio aniline derivative 12. In an attempt to gain further
insight into this question, the UV spectra (see the Supporting
Information) of the starting anilines (10, 12, 14, and 16) and
phenanthridine products (23, 25, 27, and 29) were compared
and showed that all compounds absorb strongly around
254 nm, suggesting additional photochemical transformations
are possible post-phenanthridine formation.
Reaction of compound 15 (entry 8, Table 1) gave a mixture of
four products: 4-bromophenanthridine (28), 3-bromophenan-
thridine (28b), phenanthridine (21), and an iodophenanthridine
28c (Scheme 1). It was possible to isolate 4-bromophenan-
thridine (28) in 31% yield and phenanthridine (21) in 29% yield,
but it was not possible to separate 3-bromophenanthridine (28b)
from the iodo compound 28c, both of which remain tentatively
assigned.
Interestingly, the pyridyl system 17 (entry 10, Table 1)
smoothly converted to the azaphenanthridine 30 (55%) but
the benzimidazole 20 failed to undergo cyclization, although
these systems are electronically different.
Of further intrigue was the cyclization performance of the
sensitive heterocylic systems 18 and 19 using these conditions.
The heterocycle isoxazolidinone 18 was found to be very
unstable and underwent ring-opening giving acid 31 in 63%
yield. The isatoic anhydride 19 on the other hand gave the
desired product 32 in 74% yield. Lastly, we discovered that (1)
photolysis could be performed in air using supplier-grade acet-
onitrile with only a slight reduction in yield (Table 1, entry 2) and
(2) even though photochemical reactions were generally per-
formed on small scale (e.g., 20 mg), when a reaction was
performed on larger scale (100 mgs) (i.e., fluoro derivative 13,
entry 6) the yield decreased only slightly.
Mechanistically, Rossi4 has nicely demonstrated that their
systems follow an SRN1 single electron transfer (SET) process,
induced by strongly basic conditions. In this case, shown in
Scheme 2, strongly basic conditions are absent suggesting a
preference for a classical photochemical radical cleavage of the
carbonÀiodine bond (i.e., 8) leading to cyclization of 34 and
removal of a hydrogen atom (i.e., 35) affording the dehydrophe-
nanthridine 36. It is possible that 35 could propagate the reaction
from SET to starting material 8 followed by elimination of
hydrogen iodide. Lastly, iodine (arising from hydrogen iodide)
or aerial oxidation on workup affords product (e.g., 21). Inter-
estingly, Pierini and Rossi4a also observed oxidation without
a N-Alkylation method: NaH, THF, 0 °C to rt, 3 h. b N-Alkylation
method: K2CO3, DMF, rt, 18 h. c Yield of reaction when conducted in air
and solvent directly from the supplier. d Yield using 100 mg of starting
material.
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The Journal of Organic Chemistry
NOTE
Scheme 2. Proposed Mechanism of the Photolysis
N-Alkylation General Procedure. A mixture of 2-iodobenzyl
bromide (1.00 equiv, 0.50 mmol, 149 mg), amine (3.00 equiv, 1.50 mmol),
and potassium iodide (0.10 equiv, 0.05 mmol, 8.00 mg) in acetonitrile
(1.50 mL) in a sealed vial was heated in a microwave reactor (200W,
ramp time 5À10 min) (170 °C, 15 min holdtime). After being cooled to
room temperature, the reaction mixture was diluted with dichloro-
methane (10 mL) and washed with an aqueous saturated sodium bi-
carbonate solution (10 mL) and brine (10 mL). Then the solution was
dried (MgSO4), and the solvent was evaporated. The crude product was
purified by flash chromatography.
N-(2-Iodobenzyl)aniline (8). The crude product was purified by flash
chromatography (pet. spirit/EtOAc = 5:1), and the product was ob-
tained as a white solid in 90% yield: Rf = 0.54 (pet. spirit/EtOAc = 5:1);
mp = 64À66 °C (lit. mp 1:13 66À68 °C, lit. mp 2:4a,14 62À64 °C); 1H
NMR (CDCl3, 400 MHz) δ = 7.87 (d, J = 7.8 Hz, 1H), 7.40 (dd, J =
7.6 Hz, J = 1.5 Hz, 1H), 7.31 (dt, J = 7.4 Hz, J = 1.0 Hz, 1H), 7.22À7.17
(m, 2H), 6.98 (dt, J = 7.5 Hz, J = 1.6 Hz, 1H), 6.74 (dt, J = 7.3 Hz, J =
0.9 Hz, 1H), 6.62 (dd, J = 8.5 Hz, J = 0.9 Hz, 1H), 4.33 (s, 2H), 4.19 (bs,
1H); 13C NMR (CDCl3, 100 MHz) δ = 147.5, 140.9, 139.4, 129.2,
128.9, 128.7, 128.3, 117.7, 112.9, 98.4, 53.1; HRMS (ESI) m/z [M + H]+
calcd for C13H13IN 310.0093, found 310.0087.
Methyl 2-(2-Iodobenzylamino)benzoate (9). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 40:1), and the prod-
uct was obtained as a white solid in 65% yield: Rf = 0.20 (pet. spirit/
EtOAc = 40:1); mp = 103À106 °C; 1H NMR (CDCl3, 400 MHz) δ = 8.27
(bs, 1H), 7.95 (dd, J = 7.9 Hz, J = 1.6 Hz, 1H), 7.86 (dd, J = 7.9 Hz, J =
1.0 Hz, 1H), 7.34À7.26 (m, 3H), 6.96 (dt, J = 7.7 Hz, J = 1.6 Hz, 1H),
6.65À6.60 (m, 1H), 6.51 (d, J = 8.4 Hz, 1H.), 4.43 (d, J = 5.9 Hz, 2H), 3.89
(s, 3H);13CNMR(CDCl3, 100MHz) δ= 169.0, 150.5, 140.2, 139.4, 134.6,
131.6, 128.8, 128.3, 128.0, 115.1, 111.7, 110.3, 98.2, 52.1, 51.5; HRMS (ESI)
m/z [M + Na]+ calcd for C15H14INNaO2 389.9967, found 389.9961.
N-(2-Iodobenzyl)-2-methoxyaniline (10). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 5:1), and the
product was obtained as a white solid in 94% yield: Rf = 0.57 (pet. spirit/
EtOAc = 5:1); mp = 59À62 °C (lit.4a mp 59À61°C); 1H NMR (CDCl3,
400 MHz) δ = 7.87 (dd, J = 7.8 Hz, J = 1.2 Hz, 1H), 7.38 (dd, J = 7.6 Hz,
J = 1.6 Hz, 1H), 7.30 (dt, J = 7.5 Hz, J = 1.2 Hz, 1H), 6.97 (dt, J = 7.6 Hz,
J = 1.7 Hz, 1H), 6.86À6.81 (m, 2H), 6.70 (dt, J = 7.7 Hz, J = 1.5 Hz, 1H),
6.49 (dd, J = 7.6 Hz, J = 1.4 Hz, 1H), 4.81 (bs, 1H), 4.36 (s, 2H), 4.34 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ = 146.7, 141.0, 139.3, 137.5,
128.7, 128.5, 128.3, 121.2, 116.8, 110.2, 109.4, 98.4, 55.4, 52.9; HRMS
(ESI) m/z [M + H]+ calcd for C14H15INO 340.0198, found 340.0193.
2-(2-Iodobenzylamino)phenol (11). The crude product was purified
by flash chromatography (pet. spirit/EtOAc = 5:1), and the product was
obtained as a green solid in 68% yield: Rf = 0.26 (pet. spirit/EtOAc =
5:1); mp = 85À87 °C; 1H NMR (CDCl3, 400 MHz): δ = 7.86 (dd, J =
7.8 Hz, J = 1.1 Hz, 1H), 7.38 (dd, J = 7.6 Hz, J = 1.5 Hz, 1H), 7.29 (dt, J =
7.5 Hz, J = 1.1 Hz, 1H), 6.97 (dt, J = 7.6 Hz, J = 1.6 Hz, 1H), 6.81 (t, J =
7.4 Hz, 1H), 6.75 (d, J= 7.4 Hz, 1H), 6.64 (t, J = 7.1 Hz, 1H), 6.56 (d, J =
7.7 Hz, 1H), 4.70 (bs, 1H, OH) 4.34 (s, 2H), 2.65 (s, 1H); 13C NMR
(CDCl3, 100 MHz): δ = 143.6, 140.9, 139.3, 136.3, 128.8, 128.7, 128.3,
121.5, 118.0, 114.3, 112.7, 98.6, 53.4; HRMS (ESI) m/z [M + H]+ calcd
for C13H13INO, 326.0042; found, 326.0036.
isolation of the dehydro analogue 36. Furthermore, they observed
on occasion dehalogenation, which we also see, but most promi-
nently with 20 (entry 13, Table 1) as 33b is the sole product. This
aspect supports a radical mechanism. Outright radical approaches
to this system have been reported by Nakanishi.11
In summary, a wide range of substituted phenanthridines were
rapidly synthesized in good to excellent yields. Systems contain-
ing electron-withdrawing groups were generally obtained in
higher yields as compared to systems containing electron-donat-
ing groups.
’ EXPERIMENTAL SECTION
All reactions were performed using dried glassware under a positive
pressure of argon unless otherwise stated. All reagents and solvents were
dried, distilled, or purified before use according to Perrin and Amarego’s
Purification of Laboratory Chemicals, 5th ed.12 Tetrahydrofuran was
freshly distilled from Na0/benzophenone. DMF and acetonitrile were
freshly distilled from CaH2. Thin-layer chromatography was performed
using E. Merck silica gel 60 F254 precoated plates. Column chroma-
tography was undertaken on silica gel (flash silica gel 230À400 mesh).
Other chromatographic methods involved using Celite 545. 1H and 13
C
NMR spectra were recorded on 400.13 and 100.62 MHz (or 125.76
MHz) spectrometers, respectively. Coupling constants are given in Hz,
and chemical shifts are reported in δ values in ppm with the solvent
resonance as the internal standard (1H NMR: CDCl3: δ 7.26; 13C NMR:
CDCl3: δ 77.0). Data are reported as follows: chemical shift, multiplicity
(s = singlet, bs = broad singlet, d = doublet, t = triplet, dd = double
doublet, dt = double triplet, ddd = double double doublet, m =
multiplet), coupling constants (Hz), and integration. High-resolution
electrospray ionization (HRESIMS) accurate mass measurements
were recorded in positive or negative mode on a quadrupole-time of
flight instrument with a ESI source using sodium formate as a reference
calibrant. For microwave-assisted reactions the CEM discover micro-
wave was used.
N-(2-Iodobenzyl)-2-(methylthio)aniline (12). The crude product
was purified by flash chromatography (pet. spirit/EtOAc = 5:1) and
the product was obtained as a white solid in 66% yield: Rf = 0.47 (pet.
spirit/EtOAc = 5:1); mp = 61À64 °C; 1H NMR (CDCl3, 400 MHz) δ =
7.87 (d, J = 7.7 Hz, 1H), 7.44 (dd, J = 7.6 Hz, J = 1.4 Hz, 1H), 7.34À7.28
(m, 2H), 7.17À7.11 (m, 1H), 6.98 (dt, J = 7.5 Hz, J = 2.0 Hz, 1H), 6.68
(dt, J = 7.4 Hz, J = 1.1 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 5.52 (bs, 1H),
4.39 (d, J = 5.8 Hz, 2H), 2.37 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ =
147.6, 140.6, 139.4, 134.2, 129.5, 128.9, 128.5, 128.4, 119.8, 117.4, 110.4,
98.4, 53.0, 18.4; HRMS (ESI) m/z [M + H]+ calcd for C14H15INS
355.9970, found 355.9964.
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NOTE
2-Fluoro-N-(2-iodobenzyl)aniline (13). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 10:1), and the
product was obtained as a white solid in 86% yield: Rf = 0.50 (pet. spirit/
EtOAc = 10:1); mp =80À83 °C; 1H NMR (CDCl3, 400 MHz) δ = 7.86
(d, J = 7.7 Hz, 1H), 7.39À7.28 (m, 2H), 7.03À6.91 (m, 3H), 6.68À6.61
(m, 1H), 6.61À6.54 (m, 1H), 4.47 (bs, 1H), 4.37 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 151.5 (d, 1J = 283.4 Hz), 140.4, 139.5, 136.0 (d,
J = 11.4 Hz), 129.0, 128.5, 128.4, 124.6 (d, J = 3.3 Hz), 117.1 (d, J = 6.8
Hz), 114.4 (d, J = 18.3 Hz), 112.4 (d, J = 3.0 Hz), 98.4, 52.7; HRMS
(ESI) m/z [M + H]+ calcd for C13H12FIN 327.9998, found 327.9993.
4-Chloro-N-(2-iodobenzyl)aniline (14). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 5:1), and the
product was obtained as a brown solid in 71% yield: Rf = 0.50 (pet. spirit/
EtOAc = 5:1); mp = 57À59 °C; 1H NMR (CDCl3, 400 MHz) δ = 7.86
(d, J = 7.8 Hz, 1H), 7.36À7.28 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.98
(t, J = 7.3 Hz, 1H), 6.52 (d, J = 8.2 Hz, 2H), 4.29 (s, 2H), 4.21 (bs, 1H);
13C NMR (CDCl3, 100 MHz) δ = 146.1, 140.3, 139.5, 129.0, 128.6,
128.4, 122.3, 114.0, 98.4, 53.2; HRMS (ESI) m/z [M +H]+ calcd for
C13H12ClIN 343.9703, found 343.9697.
3-Bromo-N-(2-iodobenzyl)aniline (15). The crude product was pur-
ified by flash chromatography (pet. spirit/EtOAc = 5:1), and the product
was obtained as a yellow oil in 78% yield: Rf = 0.55 (pet. spirit/EtOAc =
5:1); 1H NMR (CDCl3, 400 MHz) δ = 7.87 (dd, J = 7.7 Hz, J = 1.0 Hz,
1H), 7.36À7.29 (m, 2H), 7.04À6.97 (m, 2H), 6.84 (ddd, J = 7.8 Hz, J =
1.7 Hz, J = 0.8 Hz, 1H), 6.76 (t, J = 2.0 Hz, 1H), 6.50 (ddd, J = 8.1 Hz, J =
2.3 Hz, J = 0.8 Hz, 1H), 4.30 (s, 2H), 4.22 (bs, 1H); 13C NMR (CDCl3,
100 MHz) δ = 148.8, 140.2, 139.5, 130.5, 129.1, 128.7, 128.4, 123.2, 120.5,
115.5, 111.5, 98.5, 52.9; HRMS (ESI) m/z [M + H]+ calcd for
C13H12BrIN 387.9198, found 387.9192.
N-(2-Iodobenzyl)-4-nitroaniline (16). The crude product was pur-
ified by flash chromatography (pet. spirit/EtOAc = 5:1), and the product
was obtained as a yellow solid in 31% yield: Rf = 0.27 (pet. spirit/
EtOAc = 5:1); mp = 139À142 °C; 1H NMR (CDCl3, 400 MHz): δ =
8.08 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.35À7.28 (m, 2H),
7.02 (dt, J = 7.7 Hz, J = 2.1 Hz, 1H), 6.56 (d, J = 9.1 Hz, 2H), 4.98 (bs,
1H), 4.43 (d, J = 5.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ = 152.5,
139.8, 139.0, 138.6, 129.5, 128.6, 128.5, 126.3, 111.4, 98.4, 52.5 (2
quaternary carbons not detected); HRMS (ESI) m/z [M + H]+ calcd for
C13H12IN2O2 354.9943, found 354.9938.
5-Chloro-N-(2-iodobenzyl)pyridin-2-amine (17). The crude product
was purified by flash chromatography (pet. spirit/EtOAc = 5:1), and the
product was obtained as a white solid in 82% yield: Rf = 0.38 (pet. spirit/
EtOAc = 5:1); mp = 95À97 °C; 1H NMR (CDCl3, 400 MHz) δ = 8.04
(bd, J = 2.1 Hz, 1H), 7.84 (dd, J = 7.8 Hz, J = 1.1 Hz, 1H), 7.38À7.31 (m,
2H), 7.29 (dt, J = 7.5 Hz, J = 1.2 Hz, 1H), 6.97 (dt, J = 7.6 Hz, J = 1.7 Hz,
1H), 5.10 (bs, 1H), 4.48 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ = 156.5, 146.5, 140.5, 139.5, 137.2, 129.1, 128.8, 128.4, 120.1, 107.7,
98.6, 51,1; HRMS (ESI) m/z [M + H]+ calcd for C12H11ClIN2
344.9655, found 344.9650.
1H), 7.38 (dt, J = 7.5 Hz, J = 1.1Hz, 1H), 7.31À7.26 (m, 2H), 7.05 (dt, J =
7.6 Hz, J = 1.5 Hz, 1H), 4.71 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ =
167.6, 157.0, 139.6, 136.2, 135.1, 130.5, 130.0, 128.5, 125.8, 124.4, 113.1,
112.0, 99.4, 65.0; HRMS (ESI) m/z [M + Na]+ calcd for C14H10INNaO2
373.9654, found 373.9648.
1-(2-Iodobenzyl)-1H-benzo[d][1,3]oxazine-2,4-dione (19). Isatoic
anhydride (109 mg, 0.67 mmol) was dissolved in DMF (7.0 mL), and
2-iodobenzyl bromide (200 mg, 0.67 mmol) and K2CO3 (111 mg,
0.80 mmol) were added. The mixture was stirred at room temperature
for 18 h. Then water (10 mL) was added to the solution. The solution
was extracted with dichloromethane (3 Â 20 mL), washed with water
(3 Â 10 mL), and dried (MgSO4) and the solvent evaporated under
vacuum. The crude product was purified by flash chromatography (pet.
spirit/EtOAc = 5:1). The product was obtained as a white solid in 38%
yield: Rf = 0.24 (pet. spirit/EtOAc = 5:1); mp =194À196 °C; 1H NMR
(CDCl3, 400 MHz) δ = 8.19 (dd, J = 7.9 Hz, J = 1.3 Hz, 1H), 7.92 (dd,
J = 7.9 Hz, J = 1.1 Hz, 1H), 7.66À7.62 (m, 1H), 7.32À7.24 (m, 2H),
7.05À6.99 (m, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H),
5.26 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ = 158.1, 148.2, 141.0,
139.9, 137.4, 135.4, 130.8, 129.6, 128.8, 126.0, 124.3, 114.8, 111.7, 97.0,
53.8; HRMS (ESI) m/z [M + Na]+ calcd for C15H10INNaO3 401.9603,
found 401.9598.
1-(2-Iodobenzyl)-1H-benzo[d]imidazole (20). The crude product
was purified by flash chromatography (pet. spirit/EtOAc = 1:1), and the
product was obtained as a yellow solid in 64% yield: Rf = 0.29 (pet. spirit/
EtOAc = 1:1); mp = 119À121 °C (lit.16 mp = 102À104 °C); 1H NMR
(CDCl3, 400 MHz) δ = 7.94 (s, 1H), 7.91 (dd, J = 7.9 Hz, J = 1.1 Hz,
1H), 7.87À7.84 (m, 1H), 7.32À7.25 (m, 3H), 7.22 (dt, J = 7.5 Hz, J =
1.1 Hz, 1H), 7.01 (dt, J = 7.8 Hz, J = 1.6 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H),
5.35 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ = 143.8, 143.3, 139.8, 137.5,
133.8, 129.8, 128.8, 127.9, 123.2, 122.4, 120.5, 109.9, 97.6, 53.5; HRMS
(ESI) m/z [M + H]+ calcd for C14H12IN2 335.0045, found 335.0040.
Cyclization General Procedure. N-Alkylated material (20 mg)
was dissolved in anhydrous acetonitrile in a quartz flask. The mixture was
irradiated [irradiation conditions: Rayonet photochemical reactor using
254 nm lamps (16 lamps)] under an argon atmosphere for 2 h. The
solvent was evaporated, and the crude product was purified by flash
chromatography. Most compounds were isolated as white or yellow solids
but turned brown after a short time on exposure to the atmosphere.
Phenanthridine (21). The crude product was purified by flash
chromatography (pet. spirit/EtOAc = 5:1), and the product was ob-
tained as a yellow solid in 85% yield: Rf = 0.29 (pet. spirit/EtOAc = 5:1);
mp = 104À106 °C (lit.17 mp 104À105 °C); 1H NMR (CDCl3, 400 MHz)
δ = 9.30 (s, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.59 (dd, J = 8.0 Hz, J = 1.3 Hz,
1H), 8.20 (dd, J = 8.1 Hz, J = 1.3 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H),
7.90À7.85 (m, 1H), 7.78À7.68 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ = 153.5, 144.3, 132.5, 131.0, 130.0, 128.8, 128.7, 127.5, 127.1, 126.3,
124.1, 122.2, 121.6; HRMS (ESI) m/z [M + H]+ calcd for C13H10N
180.0813, found 180.0808.
1-(2-Iodobenzyl)benzo[c]isoxazol-3(1H)-one (18). Isoxazolidinone15
(181 mg, 1.34 mmol) was dissolved in anhydrous THF (30 mL). The
solution was cooled to 0 °C, and washed sodium hydride (38.6 mg,
1.61 mmol) was added in one portion. The solution was stirred at 0 °C for
30 min, and then 2-iodobenzyl bromide (478 mg, 1.61 mmol) was added.
The solution was stirred at0 °C for 1 h, warmed to room temperature, and
stirredfor a further 2 h. Thesolution was cooled to 0 °C, and anice-cooled
solution of diethyl ether/water =1/1 (15 mL) was added to the reaction
mixture. The resolution was extracted with diethyl ether (3 Â 20 mL),
washedwithbrine(10mL), anddried(MgSO4) and the solvent evaporated
under vacuum. The crude product was purified by flash chromatography
(pet. spirit/EtOAc = 5:1). The product was obtained as a white solid
in 22% yield: Rf = 0.39 (pet. spirit/EtOAc = 5:1); mp = 142À145 °C;
1H NMR(CDCl3, 400 MHz) δ=7.89(dd, J =7.9Hz, J= 1.0 Hz, 1H), 7.83
(d, J = 7.8 Hz, 1H), 7.78À7.65 (m, 1H), 7.57 (dd, J = 7.6 Hz, J = 1.4 Hz,
Methyl Phenanthridine-4-carboxylate (22). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 2:1), and the
product was obtained as a yellow oil in 95% yield: Rf = 0.21 (pet. spirit/
EtOAc = 2:1); 1H NMR (CDCl3, 400 MHz) δ = 9.40 (s, 1H), 8.71 (dd,
J = 8.3 Hz, J = 1.2 Hz, 1H), 8.61 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 7.9 Hz,
1H), 7.99 (dd, J = 7.3 Hz, J = 1.3 Hz, 1H), 7.92À7.87 (m, 1H),
7.78À7.73 (m, 1H), 7.73À7.68 (m, 1H), 4.08 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 168.9, 154.4, 141.6, 132.5, 132.1, 131.4, 128.9,
128.8, 128.0, 126.2, 126.1, 125.1, 124.4, 121.9, 52.7; HRMS (ESI) m/z
[M + H]+ calcd for C15H12NO2 238.0868, found 238.0863.
4-Methoxyphenanthridine (23). The crude product was purified by
flash chromatography (pet. spirit/EtOAc = 1:1), and the product was
obtained as a yellow solid in 67% yield: Rf = 0.15 (pet. spirit/EtOAc =
1:1); mp =75À78 °C (lit.18 mp 73À77 °C); 1H NMR (CDCl3,
400 MHz): δ = 9.32 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.5 Hz,
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The Journal of Organic Chemistry
NOTE
1H), 8.07 (d, J = 7.9 Hz, 1H), 7.89À7.84 (m, 1H), 7.75À7.70 (m, 1H),
7.62 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 4.13 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 156.0, 152.1, 135.4, 132.4, 130.9, 128.7, 127.6,
127.3, 126.5, 125.3, 122.3, 114.0, 108.2, 56.1; HRMS (ESI) m/z [M + H]+
calcd for C14H12NO 210.0919, found 210.0913.
Phenanthridin-4-ol (24). The crude product was purified by flash
chromatography (pet. spirit/EtOAc = 1:1), and the product was
obtained as a yellow solid in 90% yield: Rf = 0.69 (pet. spirit/EtOAc =
1:1); mp = 179À183 °C (lit.19 mp 188À189 °(C); 1H NMR (CDCl3,
400 MHz) δ = 9.15 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 7.4 Hz,
1H), 8.04 (d, J = 8.3 Hz, 1H), 7.90À7.85 (m, 1H), 7.75À7.70 (m, 1H),
7.59 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ = 153.0, 150.9, 133.4, 132.7, 131.2, 128.9, 128.1, 127.6,
126.8, 124.5, 122.4, 112.7, 110.8; HRMS (ESI) m/z [M + H]+ calcd for
C13H10NO 196.0762, found 196.0757.
4-(Methylthio)phenanthridine (25). The crude product was purified
by flash chromatography (pet. spirit/EtOAc = 5:1), and the product was
obtained as a yellow solid in 58% yield: Rf = 0.38 (pet. spirit/EtOAc =
5:1); mp = 169À173 °C; 1H NMR (CDCl3, 400 MHz) δ = 9.32 (s, 1H),
8.60 (d, J = 8.3 Hz, 1H), 8.33 (dd, J = 8.2 Hz, J = 1.0 Hz, 1H), 8.08 (d, J =
7.9 Hz, 1H), 7.90À7.85 (m, 1H), 7.75À7.70 (m, 1H), 7.64 (t, J = 7.9 Hz,
1H), 7.46 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 2.61 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ = 152.1, 141.2, 140.6, 132.5, 131.0, 128.8, 127.6,
127.1, 126.5, 124.0, 122.4, 122.3, 117.9, 14.4; HRMS (ESI) m/z [M + H]+
calcd for C14H12NS 226.0690, found 226.0685.
4-Fluorophenanthridine (26). The crude product was purified by
flash chromatography (pet. spirit/EtOAc = 5:1), and the product was
obtained as a yellow solid in 95% yield: Rf = 0.19 (pet. spirit/EtOAc =
5:1); mp =94À98 °C; 1H NMR (CDCl3, 400 MHz) δ = 9.33 (s, 1H),
8.59 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H),
1H), 8.02 (t, J = 7.7 Hz, 1H), 7.87 (t, J = 7.4 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ = 156.4, 146.2, 146.2, 133.0, 132.7, 130.9, 129.8, 129.3,
126.3, 124.3, 122.8, 122.3, 119.0; HRMS (ESI) m/z [M + H]+ calcd for
C13H9N2O2 225.0664, found 225.0659.
2-Chlorobenzo[c][1,8]naphthyridine (30). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 1:1), and the product
was obtained as a yellow solid in 55% yield: Rf = 0.22 (pet. spirit/EtOAc =
1
1:1); mp = 234À236 °C (lit.21 mp 231À233 °C); H NMR (CDCl3,
400 MHz) δ = 9.51 (s, 1H), 9.00 (d, J = 2.5 Hz, 1H), 8.87 (d, J = 2.5 Hz,
1H), 8.54 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.98À7.93 (m, 1H),
7.86À7.81 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ = 157.2, 151.9, 150.3,
131.8, 131.7, 130.4, 130.0, 129.1, 129.0, 126.5, 122.1, 119.6; HRMS (ESI)
m/z [M + Na]+ calcd for C12H7ClNaN2 237.0195, found 237.0190.
Phenanthridine-4-carboxylic Acid (31). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 1:1), and the
product was obtained as a white solid in 63% yield: Rf = 0.31 (pet. spirit/
1
EtOAc = 1:1); mp = 238À241 °C (lit.22 mp 242À243°C); H NMR
(CDCl3, 400 MHz) δ = 9.32 (s, 1H), 8.85 (dd, J = 8.3 Hz, J = 1.3 Hz,
1H), 8.81 (dd, J = 7.5 Hz, J = 1.3 Hz, 1H), 8.70 (d, J = 8.3 Hz, 1H), 8.20
(d, J = 7.9 Hz, 1H), 8.07À8.02 (m, 1H), 7.92À7.84 (m, 2H); 13C NMR
(CDCl3, 100 MHz) δ = 167.5, 152.0, 141.4, 133.5, 133.1, 132.8, 129.8,
128.7, 127.7, 127.2, 125.5, 125.3, 124.4, 122.3; HRMS (ESI) m/z[M+Na]+
calcd for C14H9NNaO2 246.0531, found 246.0525.
4H-[1,3]Oxazino[5,4,3-de]phenanthridine-4,6(8H)-dione (32). The
crude product was purified by flash chromatography (pet. spirit/EtOAc =
5:1), and the product was obtained as a white solid in 74% yield: Rf = 0.18
(pet. spirit/EtOAc = 5:1); mp = 245À249 °C; 1H NMR (CDCl3, 400
MHz) δ = 8.17 (dd, J = 7.8 Hz, J = 1.3 Hz, 1H), 8.04 (dd, J = 7.9 Hz,
J = 1.4 Hz, 1H), 7.82À7.79 (m, 1H), 7.45À7.36 (m, 2H), 7.32 (t, J =
7.7 Hz, 1H), 7.28À7.25 (m, 1H), 5.22 (s, 2H); 13C NMR (CDCl3,
125 MHz) δ = 158.0, 147.3, 137.3, 130.0, 129.7, 129.6, 128.8, 128.2,
127.0, 126.9, 124.4, 122.7, 122.3, 111.5, 46.6; HRMS (ESI) m/z [M + Na]+
calcd for C15H9NNaO3 274.0480, found 274.0475.
1-Benzyl-1H-benzo[d]imidazole (33b). The crude product was
purified by flash chromatography (pet. spirit/EtOAc = 1:1), and the
product was obtained as a yellow solid in 54% yield: Rf = 0.13 (pet.
spirit/EtOAc = 1:1); mp =114À116 °C (lit.23 mp 115À116°C); 1H
NMR (CDCl3, 400 MHz) δ = 8.17 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H),
7.38À7.28 (m, 6 H), 7.23À7.20 (m, 2H), 5.40 (s, 2H); HRMS (ESI)
m/z [M + H]+ calcd for C14H13N2 209.1079, found 209.1073.
7.92À7.87 (m, 1H), 7.78À7.74 (m, 1H), 7.62 (dt, JHH = 8.1 Hz, JHF
=
5.2 Hz, 1H), 7.46 (ddd, JHF = 10.2 Hz, JHH = 7.9 Hz, JHH = 1.1 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ = 158.7 (d, 1J = 255.0 Hz), 153.7 (d, J =
2
1.7 Hz), 134.0 (d, J = 10.6 Hz), 131.9 (d, J = 2.8 Hz), 131.5, 129.0,
128.1, 127.0 (d, J = 8.4 Hz), 126.5, 126.1, 122.2, 117.8 (d, J = 4.2 Hz),
113.6 (d, 2J = 19.8 Hz); HRMS (ESI) m/z [M + Na]+ calcd for
C13H8FNaN 220.0538, found 220.0533.
2-Chlorophenanthridine (27). The crude product was purified by
flash chromatography (pet. spirit/EtOAc = 2:1), and the product was
obtained as a yellow solid in 95% yield: Rf = 0.39 (pet. spirit/EtOAc =
1
2:1); mp = 154À157 °C (lit.19 155À156°C); H NMR (CDCl3, 400
MHz) δ = 9.26 (s, 1H), 8.53À8.50 (m, 2H), 8.12 (d, J = 8.7 Hz, 1H),
8.06 (d, J = 7.8 Hz, 1H), 7.91À7.86 (m, 1H), 7.78À7.73 (m, 1H), 7.68
(dd, J = 8.7 Hz, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ = 153.6,
142.6, 133.1, 131.5, 131.4, 131.4, 129.2, 128.8, 128.2, 126.4, 125.2, 121.9,
121.8; HRMS (ESI) m/z [M + H]+ calcd for C13H8ClN 214.0424,
found 214.0418.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra and
S
b
UV spectra of compounds 10, 12, 14, 16, 23, 25, 27, and 29. This
material is available free of charge via the Internet at http://pubs.
acs.org.
3-Bromophenanthridine (28). The crude product was purified by
flash chromatography (pet. spirit/EtOAc = 5:1). A product mixture of
four compounds was obtained. Pure 28 could be isolated as a yellow
solid in 31% yield: Rf = 0.35 (pet. spirit/EtOAc = 5:1); mp =
206À209 °C; 1H NMR (CDCl3, 400 MHz) δ = 9.29 (s, 1H), 8.58 (d,
J = 8.1 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.07 (d,
J = 7.4 Hz, 1H), 7.91À7.87 (m, 1H), 7.78 (dd, J = 8.7 Hz, J = 2.0 Hz,
1H), 7.77À7.73 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ = 153.6,
143.4 (Cquart., bs, quadrupole), 132.6, 132.5, 131.4, 131.0, 129.5, 128.3,
125.8, 123.8, 123.1, 123.0, 121.9; HRMS (ESI) m/z [M + H]+ calcd for
C13H9BrN 257.9918, found 257.9913.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: c.williams3@uq.edu.au; stefan.braese@kit.edu.
’ ACKNOWLEDGMENT
We acknowledge financial support from the Deutscher
Akademischer Austauschdienst (DAAD), Karlsruhe Institute of
Technology, and the University of Queensland.
2-Nitrophenanthridine (29). The crude product was purified by flash
chromatography (pet. spirit/EtOAc = 2:1), and the product was
obtained as a yellow solid in 95% yield: Rf = 0.29 (pet. spirit/EtOAc =
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NOTE
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