Electron-transfer-mediated synthesis of phenanthridines by intramolecular arylation of anions from n-(ortho-Halobenzyl)arylamines: regiochemical and mechanistic analysis

Article abstract of DOI:10.1021/jo9025918

The synthesis of a series of substituted phenanthridines by photostimulated C-C cyclization of anions from N-(orrAo-halobenzyl)arylamines has been found to proceed in very good to excellent yields (79-95%) in liquid ammonia and in DMSO. The N-(ortho-halobenzyl)arylamines are obtained in good to very good isolated yields (44-85%) by nucleophilic substitution of orthohalobenzylchlorides with different arylamines. The reaction of the anions of a diverse set N-(orthohalobenzyl)arylamines was studied, and the methodology was extended to the synthesis of trispheridine, a natural product, in very good yield, In order to explain the regiochemical outcome of these reactions, a theoretical analysis was performed with DFT methods and the B3LYP functional.

Full text of DOI:10.1021/jo9025918

pubs.acs.org/joc
Electron-Transfer-Mediated Synthesis of Phenanthridines by
Intramolecular Arylation of Anions from N-(ortho-Halobenzyl)arylamines:
Regiochemical and Mechanistic Analysis
ꢀ
Marıa E. Buden, Viviana B. Dorn, Martina Gamba, Adriana B. Pierini,* and Roberto A. Rossi*
´
INFIQC, Departamento de Quımica Organica, Facultad de Ciencias Quımicas,
Universidad Nacional de Coꢀrdoba, Ciudad Universitaria, 5000 Coꢀrdoba, Argentina
ꢀ
´
rossi@fcq.unc.edu.ar
Received December 11, 2009
The synthesis of a series of substituted phenanthridines by photostimulated C-C cyclization of
anions from N-(ortho-halobenzyl)arylamines has been found to proceed in very good to excellent
yields (79-95%) in liquid ammonia and in DMSO. The N-(ortho-halobenzyl)arylamines are
obtained in good to very good isolated yields (44-85%) by nucleophilic substitution of ortho-
halobenzylchlorides with different arylamines. The reaction of the anions of a diverse set of N-(ortho-
halobenzyl)arylamines was studied, and the methodology was extended to the synthesis of tri-
spheridine, a natural product, in very good yield. In order to explain the regiochemical outcome of
these reactions, a theoretical analysis was performed with DFT methods and the B3LYP functional.
Introduction
Phenanthridines can be prepared by a number of methods
including (i) cyclization of N-(o-halobenzyl)arylamines
through a benzyne mechanism,4 (ii) reduction of phenanthri-
dones,5 (iii) intramolecular radical cyclizations of N-(o-
halobenzyl)arylamines,6 (iv) photocyclization of benzanilides
and benzylideneanilines,7 (v) Bischler-Napieralsky and di-
rected metalation for cyclization of 2-substituted biphenyls,8
(vi) microwave-mediated [2 þ 2 þ 2] cyclotrimerization of a
diyne,9 (vii) different photochemical approaches,10 and Pd
Phenanthridines are important core structures found in a
variety of natural products and other biologically important
molecules with a wide range of biological activities that confer
applications as antibacterial, antiprotozoal, and anticancer
agents, among others.1 A well-known member of this family
is ethidium (Figure 1), a common DNA intercalator. Trisphe-
ridine2 and bicolorine,3 also shown in Figure 1, are representa-
tive examples of natural products containing phenanthridine
core structures.
(5) Narasimham, N. S.; Chandrachood, P. S. Tetrahedron 1981, 37, 825–
827.
(1) (a) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223–
232. (b) Ishikawa, T. Med. Res. Rev. 2001, 21, 61–72. (c) Denny, W. A. Curr.
Med. Chem. 2002, 9, 1655–1665.
(2) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshi-
kawa, M. J. Nat. Prod. 2004, 67, 1119–1124.
(3) Viladomat, F.; Bastida, J.; Tribo, G.; Codina, C.; Rubiralta, M.
Phytochemistry 1990, 29, 1307–1310.
(4) (a) Kessar, S. V.; Gupta, Y. P.; Balakrishnan, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 1988, 53, 1708–1713. (b) Nakanishi,
T.; Suzuki, M. Org. Lett. 1999, 1, 985–987. (c) Kessar, S. V.; Gopal, R.; Singh,
M. Tetrahedron 1973, 29, 167–175. (d) Kessar, S. V.; Pal, D.; Singh, M.
(6) (a) Nakanishi, T.; Suzuki, M.; Mashiba, A.; Ishikawa, K.; Yokotsuka,
T. J. Org. Chem. 1998, 63, 4235–4239. (b) Rosa, A. M.; Lobo, A. M.; Branco,
S. P.; Pereira, A. M. D. L. Tetrahedron 1997, 53, 269–284.
(7) Mallory, F. B.; Mallory, C. Org. React. 1984, 30, 1.
(8) (a) Mamalis, P.; Petrow, V. J. J. Chem. Soc. 1950, 703–711. (b) Buu-Hoı,
N. P.; Jaquignon, P.; Long, C. T. J. Chem. Soc. 1957, 505–509. (c) Currie, K. S.;
Tennant, G. J. Chem. Soc., Chem. Commun. 1995, 2295–2296.
(9) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6, 263–
265.
(10) (a) Kessar, S. V.; Grupta, Y. P.; Dhingra, K.; Sharma, G. S.; Narula,
S. Tetrahedron Lett. 1977, 18, 1459–1462. (b) Androsov, D. A.; Neckers,
D. C. J. Org. Chem. 2007, 72, 1148–1152. (c) Alonso, R.; Campos, P. J.;
Garcıa, B.; Rodrıguez, M. A. Org. Lett. 2006, 8, 3521–3523.
ꢀ
Tetrahedron 1973, 29, 177–184. (e) Sanz, R.; Fernandez, Y.; Castroviejo, M.
P.; Perez, A.; Fananas, F. J. Eur. J. Org. Chem. 2007, 8, 62–69. (f) Barluenga, J.;
ꢀ
~
ꢀ
~
Fananas, F. J.; Sanz, R.; Fernandez, Y. Chem.;Eur. J. 2002, 8, 2034–2046.
ꢀ
ꢀ
2206 J. Org. Chem. 2010, 75, 2206–2218
Published on Web 03/08/2010
DOI: 10.1021/jo9025918
r
2010 American Chemical Society

ꢀ
Buden et al.
JOCArticle
simple, efficient, and general method to synthesize phenan-
thridines would be attractive.
The unimolecular radical nucleophilic substitution, or SRN
1
mechanism, stands as an interesting synthetic alternative to
phenanthridines. The mechanism, a chain process with radical
and radical anions as intermediates, affords the possibility to
achieve the nucleophilic substitution of compounds poorly reac-
tive in polar processes. The scope of the reaction has increased
considerably over the past decades, and nowadays, it serves as
an important synthetic route to different types of compounds. It
is compatible with many substituents, and moreover, several
nucleophiles, such as carbanions and heteroatomic anions, can
be used to form new C-C or C-heteroatom bonds in good
yields.21 One exception to this regiospecificity is the reaction of
the anions of aromatic amines with aromatic substrates in which
both C-N and C-C bond formation is achieved instead. For
instance, the intermolecular reaction of the phenylamide anion
with iodobenzene initiated by K metal in liquid ammonia
afforded diphenylamine (19%) and 2- (11%) and 4-biphenyla-
mines (11%).22 When 2-naphthylamide ions reacted by the
photostimulated SRN1 mechanism with iodoarenes, 1-aryl-2-
naphthylamines were regioselectively formed in 45-63% yields,
with only 3-6% N-arylation.23 Additionally, the anions of aza-
heterocycles such as pyrrole and 4-methylimidazole gave only
C-C bond formation.24,25
Furthermore, an SRN1 synthetic strategy to obtain hetero-
cyclic compounds was developed based on the intramolecular
cyclization of substrates bearing both the leaving group and
the nucleophilic center.26 This methodology has recently
been applied to the synthesis of 1-phenyl-1-oxazolinoindan
derivatives and related compounds,27 tetracyclic isoquino-
line derivatives,28 a series of substituted 9H-carbazoles,29
and aporphine and homoaporphine alkaloids.30
Beugelmans et al. applied this method to the synthesis of a
series of benzo[c]phenanthridines by reaction of substituted
iodobenzylamines with substituted tetralones. In this case,
an intermolecular SRN1 affords the products with modest
overall yields after several reactions.31
FIGURE 1. Selected phenanthridines.
catalysis routes.11 They can also be obtained with other
catalytic systems such as In(OTf)3, in the annulation between
o-alkynylanilines and o-alkynylbenzaldehydes,12 or by the
nickel-catalyzed iminoannulation of internal alkynes.13
Another procedure is the preparation of phenanthridines
using hypervalent iodine chemistry from N-(o-halobenzyl)-
arylamines as starting materials.14
6-Arylphenanthridines can be obtained from aromatic
aldehydes, anilines, and benzenediazonium-2-carboxylate via
a one-pot cascade process that involves the sequence of imine
and benzyne formation followed by a [4 þ 2] cycloaddition and
dehydrogenation.15 Very recently, Kohno et al. reported a new
synthetic strategy for antitumor benzo[c]phenanthridines using
a microwave-assisted electrocyclic reaction of the aza-6π-elec-
tron system.16 6-Substituted phenanthridines were prepared in
a one-pot procedure from 2-arylanilines and aryl aldehydes
with trifluoroacetic acid with good to very good yields.17
Fagnou et al. developed new conditions employing electron-
rich N-heterocyclic carbene (NHC) ligands to promote direct
arylation of a broad range of aryl chlorides to form six- and five-
membered ring biaryls.11f Recently, the Lautens group investi-
gated a C-H activation/cross-coupling approach toward the
synthesis of diversely substituted phenanthridine derivatives,
whereby a sequence of ortho-arylation and subsequent N-
arylation would provide the desired compounds in one step.18
Although a number of useful synthetic procedures to pre-
pare these compounds have been developed,4-18 still several
limitations remain, as well. For example, an efficient synthetic
method applicable to various phenanthridines has not been
developed.19 Most of the procedures involve several steps, and
the overall yields are usually not very good.20 Moreover, the
starting materials are not often readily available. Thus, a
Recently, we have proposed a new approach for the syntheses
of phenanthridines and benzophenanthridines by intramolecu-
lar ortho-arylation of benzylamide ions with aryl halides.32
~ꢀ~
(21) For reviews, see: (a) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem.
Rev. 2003, 103, 71–168. (b) Rossi, R. A.; Pierini, A. B.; Santiago, A. N. In Organic
Reactions; Paquette, L. A., Bittman, R., Eds.; Wiley & Sons: New York, 1999;
pp 1-271. (c) Rossi, R. A. In Synthetic Organic Photochemistry; Griesberck,
A. G., Mattay, J., Eds.; Marcel Dekker: New York, 2005; Vol. 12, Chapter 15,
pp 495-527.
(22) Kim, J. K.; Bunnet, J. F. J. Am. Chem. Soc. 1970, 92, 7464–7466.
(23) Pierini, A. B.; Baumgartner, M. T.; Rossi, R. A. Tetrahedron Lett.
1987, 28, 4653–4656.
(11) (a) Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720–7725.
(b) Li, D.; Zhao, B.; LaVoie, E. J. J. Org. Chem. 2000, 65, 2802–2805. (c) Xie,
C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431–5434. (d)
Bowman, W. R.; Lyon, J. E.; Gareth, J. P. Synlett 2008, 14, 2169–2171. (e)
Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett.
2004, 6, 2741–2744. (f) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org.
Lett. 2005, 7, 1857–1860. (g) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 581–590.
(12) Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minami, H.;
Yanada, K.; Ishikura, M.; Takemoto, Y. J. Org. Chem. 2008, 73, 5135–5138.
(13) Luo, Y.; Mei, Y.; Zhang, J.; Lua, W.; Tang, J. Tetrahedron 2006, 62,
9131–9134.
ꢀ
(24) Chahma, M.; Combellas, C.; Thiebault, A. Synthesis 1994, 366–368.
ꢀ
(25) Chahma, M.; Combellas, C.; Thiebault, A. J. Org. Chem. 1995, 60,
8015–8022.
(26) Rossi, R. A.; Baumgartner, M. T. Synthesis of Heterocycles by the
S
RN1 Mechanism. In Targets in Heterocyclic System: Chemistry and Proper-
ties; Attanasi, O. A., Spinelli, D., Eds.; Soc. Chimica. Italiana: Rome, Italy,
1999; Vol. 3, pp 215-243.
(27) Marshall, L. J.; Roydhouse, M. D.; Slawin, A. M. Z.; Walton, J. C.
J. Org. Chem. 2007, 72, 898–911.
(28) Roydhouse, M. D.; Walton, J. C. Eur. J. Org. Chem. 2007, 1059–1063.
(14) Moreno, I.; Tellitu, I.; Etayo, J.; San Martın, R.; Dominguez, E.
Tetrahedron 2001, 57, 5403–5411.
(15) Wang-Ge, S.; Yun-Yun, Y.; Yan-Guang, W. J. Org. Chem. 2006, 71,
9241–9243.
ꢀ
(16) Kohno, K.; Azuma, S.; Choshi, T.; Nobuhiro, J.; Hibino, S. Tetra-
hedron Lett. 2009, 50, 590–592.
(29) Buden, M. E.; Vaillard, V. A.; Martın, S. E.; Rossi, R. A. J. Org.
Chem. 2009, 74, 4490–4498.
(17) Youn, S. W.; Bihn, J. H. Tetrahedron Lett. 2009, 50, 4598–4601.
(18) Lautens, M.; Candito, D. A. Angew. Chem., Int. Ed. 2009, 48, 6713–6716.
(19) (a) Hilt, G.; Hess, W.; Schmidt, F. Eur. J. Org. Chem. 2005, 2526–
2533. (b) Mehta, B. K.; Yanagisawa, K.; Shiro, M.; Kotsuki, H. Org. Lett.
2003, 5, 1605–1608.
(30) Barolo, S. M.; Teng, X.; Cuny, G. D.; Rossi, R. A. J. Org. Chem.
2006, 71, 8493–8499.
(31) Beugelmans, R.; Chastanet, J.; Ginsburg, H.; Quintero-Cortes, L.;
Roussi, G. J. Org. Chem. 1985, 50, 4933–4938.
ꢀ
(32) For a preliminary communication, see: Buden, M. E.; Rossi, R. A.
Tetrahedron Lett. 2007, 48, 8739–8742.
(20) Ilka, K.; Bernd, C. Synthesis 2005, 7, 1052–1054.
J. Org. Chem. Vol. 75, No. 7, 2010 2207

ꢀ
Buden et al.
JOCArticle
In order to address the overall performance of the new metho-
dology, to find the best conditions for the syntheses, and to
evaluate its scope and limitations, we now report new applica-
tions directed to the synthesis of substituted phenanthridines.
Furthermore, ab initio calculations are presented to inspect the
electronic and geometric factors responsible for the regiochem-
istry of these reactions.
well-knowninhibitorofSRN1reactions(entries2and3, Table 1).
These results indicate that product 4a could be formed by the
SRN1 mechanism following the steps presented in Scheme 2.
Compound 3a affords, in the presence of excess t-BuOK, the
amide anion 3a-. The initiation step is attributed to a photo-
induced ET to 3a- to yield its radical dianion 3a•2- 34
. Fragmen-
tation of the C-I bond of 3a•2- gives the distonic radical anion
6a•- and the I- anion. The intermediate radical anion 6a•-, via
an intramolecular C-C cyclization, yields the conjugated radi-
cal anion 7a•-. An ETfrom7a•- to 3a- affords the intermediate
7a and the radical dianion 3a•2-, which propagates the reaction
cycle. Under the basic reaction conditions, intermediate 7a gives
the anion 7a-. Upon acidification of the reaction media and
workup, product 8a was not isolated; instead, the oxidized
aromatized product 4a was obtained.
Results and Discussion
The nucleophilic substitution reaction of anilines with ben-
zylchloride was described as a synthetic method to obtain ben-
zylanilines.33 We use this reaction to prepare the expected o-
haloarylbenzylamines. When we carried out the reaction of 2-
iodobenzylchloride (1a) with aniline (2a) using NaHCO3 as
base, N-(2-iodobenzyl)benzenamide (3a) was obtained in 85%
isolated yield (Scheme 1). With the same procedure, the sub-
stituted nucleophilic reaction of 1a and anilines 2b-h afforded
the corresponding N-(ortho-iodobenzyl)arylamines, 3b-h, in
44-85% isolated yields.
SCHEME 2
SCHEME 1
The results of the photostimulated reaction (120 min) of
N-(ortho-iodobenzyl)arylamines 3a-h in liquid ammonia and
in the presence of excess t-BuOK (2.5 equiv) are presented in
Table 1. Under these reaction conditions, the anions 3a-f-
afford high yields of phenanthridines 4a-f and low yield of the
reduced products 5a-f (Table 1 and eq 1).
A reaction that competes with the cyclization of the radical
anion 6a•- is the reduction by hydrogen abstraction from the
solvent to yield 5a.
The reaction was not inhibited by radical traps, such as di-
tert-butyl nitroxide or TEMPO (entries 4 and 5, Table 1).
This suggests that the intramolecular cyclization of the
distonic radical anion 6a•- is faster than the intermolecular
reaction with the radical traps. When the reaction was
carried out with only 1 equiv of t-BuOK, 74% of 4a was
(33) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; John Wiley
& Sons: New York, 1989; p 902.
(34) Under excess t-BuO-, this anion as well as phenylamide ions can act as
electron donors in this step. Probably, t-BuO- (pKa of t-BuOH =32.2 in DMSO) is
a better electron donor than phenylamide ions (pKa of PhNH2 = 30.6 in DMSO).
See: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463 and references cited
therein.
There was no reaction in the dark (180 min), thus excluding a
benzyne mechanism. Besides, partial inhibition was observed
when 3a- was irradiated in the presence of 1,4-dinitrobenzene, a
2208 J. Org. Chem. Vol. 75, No. 7, 2010

ꢀ
Buden et al.
JOCArticle
TABLE 1. Intramolecular Photostimulated Reactions of o-Haloarylbenzylanilines in Liquid Ammonia: Syntheses of Phenanthridinesa
J. Org. Chem. Vol. 75, No. 7, 2010 2209

ꢀ
Buden et al.
JOCArticle
TABLE 1. Continued
aThe reactions were performed in 150 mL of liquid ammonia (or in 6 mL of DMSO), with 0.25 mmol of the substrate and 0.625 mmol of t-BuOK. Irradiation
b
was conducted in a photochemical reactor equipped with two 400 W Hg lamps emitting maximally at 350 nm (air and water refrigerated). Yields were
determined by GC (internal standard method). cHalide anions were determined potentiometrically. dThe substrate was recovered almost quantitatively. e1,4-
Dinitrobenzene (27 mol %) was added. The substrate was recovered in 39%. fDi-tert-butylnitroxide was added (30% mol). gTEMPO (2,2,6,6-tetramethylpi-
peridine-1-oxyl) was added (38% mol). hDMSO as solvent. iWith 0.25 mmol of t-BuOK, the substrate was recovered in 8%. jPhenanthridine was obtained in 7%
yield. k5,6-Dihydronaphtho[2,3-a]phenanthridine was detected. lTraces of reduced product (1-naphthylbenzylamine) was obtained. m1,4-Dinitrobenzene (30
mol %) was added. n1,3-Dinitrobenzene (30 mol %) was added. oReduced product (20% 1-naphthylbenzylamine) was obtained.
formed with 13% of 5a (entry 7). In DMSO as solvent, 4a
and 5a were obtained in 68 and 18% yields, respectively
(entry 6).
In the photostimulated reaction in liquid ammonia of anion
3g-, prepared from 3g and t-BuOK in excess, and after 120 min
of irradiation, 4-(1H-pyrrol-1-yl)phenanthridine (4g) was
2210 J. Org. Chem. Vol. 75, No. 7, 2010

ꢀ
Buden et al.
JOCArticle
obtained in 83% yield together with phenanthridine 3a in 7%
yield (entry 13, Table 1). In this system, we propose that once the
conjugated radical anion 7g•- is formed it can give 4g or can
fragment into radical 9• and the pyrrole anion 10- to finally
afford 3a (Scheme 3). This is the first report showing that the
anion of pyrrole can act as a leaving group under the reported
reaction conditions.
C-C coupling, can only be formed from 6h-syn•- with ΔE of
≈16.0 kcal/mol (Figure 2). This syn-anti isomerization barrier is
high because it involves the rotation around the C2(pyridine)-
N3 bond, which has partial double-bond character. These
theoretical results explain the regiochemistry observed experi-
mentally.
The development of this convenient and efficient synthetic
route to phenanthridines led us to test it as a synthetic route
to trispheridine, a phenanthridine alkaloid from the Amar-
yllidaceae plant family. In so doing, we evaluated the reac-
tivity of N-(ortho-iodobenzyl)arylamine 3i, which was
prepared in 62% isolated yield by a nucleophilic substitution
reaction of aniline with 5-bromo-6-(bromomethyl)benzo[d]-
[1,3]dioxole. In the photostimulated reaction of 3i with 2.5
equiv of t-BuOK in NH3 for 120 min, trispheridine (4i) was
obtained in 75% yield (entry 16 and eq 3).
SCHEME 3
Furthermore, other N-(ortho-halobenzyl)arylamines 12,
13, and 14a-c (Table 1) were obtained from 2-haloben-
zylchloride and the corresponding arylamines in very good
isolated yields (62-91%).
After 180 min of irradiation, in liquid ammonia, anion 3h-
afforded benzo[c][1,8]naphthyridine 4h and the isomeric
product 6H-pyrido[1,2-a]quinazoline 11 in 6 and 61% iso-
lated yield, respectively (entry 14, Table 1, and eq 2). In dark
conditions (180 min), there was no reaction (entry 15).
In the photoinitiated reaction of anion 12- in liquid
ammonia as a solvent (180 min), the novel naphtho[2,3-a]-
phenanthridine (15) was formed in 72% yield (entry 17,
Table 1, and eq 4). This reaction provides access to the
pentacyclic system 15 in very good yields.
The experimental behavior of the system was investi-
gated by molecular modeling calculations with the DFT
methodology and the B3LYP functional. In order to study
the system at first, we inspected the conformations in equilib-
rium of anion 3h-.35 The only conformer found (3h-syn-) is
responsible to give, after DET (dissociative electron transfer)
and C-I bond fragmentation, the more stable conformer of the
distonic radical anion 6h-syn•- (Figure 2), evaluated with the 6-
31þG* basis set. This radical anion affords, after internal
rotations, the conjugated radical anion 11•- (C-N cyclization)
with activation energy (ΔE) of ≈6.6 kcal/mol. The conformer
6h-anti•-, which affords the conjugated radical anion 7h•- by a
Using this methodology, the photostimulated reaction of
N-(2-iodobenzyl)naphthalen-2-amine (13) gave 98% yield of
benzo[a]phenanthridine 17 (entry 18, Table 1, and eq 5).
(35) Supporting Information shows a detailed reactions pathway and
intermediates of these processes.
J. Org. Chem. Vol. 75, No. 7, 2010 2211

ꢀ
Buden et al.
JOCArticle
FIGURE 2. Formation of radical anions by ET to the anion of 3h-. Anion (upper part, B3LYP/3-21G*X=I). Radical anions
(lower part, B3LYP/6-31þG*). All calculations include the solvent as a continuum model (Tomassi et al.). Distinguished reaction
coordinates: from 6h-syn•- to 6h-syn-b•-, rotation around the N3-C4 and C4-C5 bonds; from 6h-syn•- to 6h-anti•-, rotation around the
C2-N3 bond (more details are in the Supporting Information). Donor: t-BuO- (initiation step) or 11•- and 7h•- (along propagation
steps).
The regiochemistry of this reaction can also be explained
through theoretical calculations, as shown in Figure 3.
Radical anion 18-syn•-, formed after DET to 13-, presents
as 6h•- a syn conformation with a C1C2NC4 dihedral angle of
approximately 0° (Figure 3). This dihedral angle favors the
coupling at C1 to yield 17 (ΔE = 2.0 kcal/mol). The absence
of coupling at C3 of the naphthalene ring is ascribed to the
high activation barrier to form the radical anion 18-anti•-
(17.3 kcal/mol).
All other substrates investigated, 14a, 14b, and 14c,
yielded the expected ring closure product benzo[c]phena-
nthridine 19 and a rearranged product 20 in varying yields
(eq 6, and entries 19-28, Table 1). As shown, the nature
of the leaving group influences the relative ratio of both
As previously proposed, ET to the anions 14- may form
products. No reaction was observed in the dark (entries 20
and 25).
the dianion radicals, which by C-X bond fragmentation
2212 J. Org. Chem. Vol. 75, No. 7, 2010

ꢀ
Buden et al.
JOCArticle
FIGURE 3. Formation of radical anions by ET to the anion of 13-. Anion (upper part, B3LYP/LANL2DZ, X=I). Radical anions (lower
part, B3LYP/6-31þG*. All calculations include the solvent as a continuum model (Tomassi et al.). Distinguished reaction coordinates: from
18-syn•- to 18-anti•-, C2-N. Donor: t-BuO- (initiation step) or C1-cyclization•- (along propagation steps).
gives the distonic radical anion 21•-, which by an intramo-
lecular coupling followed by ET to the substrate will finally
give product 19 (eq 7).
Taking into account that there are precedents about ring
opening of cyclic radical anions to give benzyl radicals and
an anionic center,36 we propose that the formation of the
FIGURE 4. Main conformers for anions 14a- (X = I) evaluated by
B3LYP/LANL2DZ in the presence of a continuum solvent
rearranged product 20 is mediated by the conjugate radical
anion 23•-, which is formed by intramolecular cyclization at
the nucleophilic N of intermediate 21•- (eq 8). The formation
of 20 is inhibited by the presence of p-DNB and m-DNB
(methanol), 14a-P- (planar anion), 14a-O- (out of plane anion).
(Table 1, entries 26 and 27). Moreover, compounds 19 and 20
were observed when the reaction was carried out by solvated
electron initiation (Na metal in NH3(l)), which is strong
evidence favoring a radical anion intermediate route to
(36) Postigo, A.; Rossi, R. A. J. Chem. Soc., Perkin. Trans. 2 2000, 485–
490.
J. Org. Chem. Vol. 75, No. 7, 2010 2213

ꢀ
Buden et al.
JOCArticle
FIGURE 5. Conformers for radicals anions 21-O•-, 21-P•-, and 21-PR•- evaluated by B3LYP/6-31þG* in the presence of a continuum
solvent (methanol).
account for their formation. Intermediate 23•- may suffer
ring opening to give the distonic radical anion 24•- (eq 9); the
driving force of the reaction is the stability of the diaryl
amide moiety and the benzyl radical. Intermediate 24•- will
finally afford byproduct 20 by H abstraction and proto-
nation.
the SRN1 cycle, is evaluated as a dissociative exothermic reaction
that leads to the distonic radical anions 21•- (eq 10).37
The different conformers evaluated for 21•- are presented
in Figure 5. The nonplanar radical anion 21-O•-, formed by
dissociation from 14a,c-O-, cyclizes with very low activation
energy to form 22•-, the radical anion of the carbon-carbon
cyclized product (Figure 6).
As can be seen from Figure 5, the planar radical anion 21-P•-
can give 21-O•- (by rotation around the H2C-N bond)35 or
can give the planar radical anion 21-PR•- (by rotation around
the CPh-CH2 bond). From these intermediates, 21-PR•- has
the appropriate geometry to afford 20 (X = Br (34%), Cl
Furthermore, we evaluated the reactivity of 14a and 14c in
DMSO as a solvent. In this case, the photoinitiated reaction
afforded benzo[c]phenanthridine in 93 and 60% yield, re-
spectively (entries 22 and 28, Table 1).
In order to inspect the feasibility of the different steps
of the proposed mechanism (eqs 7-9), DFT calculations
were carried out for anions 14a- and 14c- taken as repre-
sentatives. The systematic inspection of the conformational
potential energy surface (PES) of both anions leads us to
conclude that mainly two conformers, P (benzyl system on
the naphthyl plane) and O (benzyl system out of the naphthyl
plane), are present under conformational equilibrium
(Figure 4).
On the basis of the energy differences between them, P pre-
vails for both anions (90%, X = I, 96%, X = Cl). The ET to
14a,c- from 22•-, the intermediate proposed as propagator of
(37) Although no radical dianions are located on the anionic potential
surfaces for both halogens with the LANL2DZ basis set, radical dianion
intermediates are obtained with the 6-31þG* basis set for X = Cl. These
intermediates dissociate with the following Ea values: 1.5 kcal/mol for
FIGURE 6. C-Cyclization from 21-O•- evaluated by B3LYP/6-
31þG* in the presence of a continuum solvent (methanol).
14c-O•2- and 4.5 kcal/mol for 14c-P•2-
.
2214 J. Org. Chem. Vol. 75, No. 7, 2010

ꢀ
Buden et al.
JOCArticle
FIGURE 7. N-Cyclization from 21-PR•- evaluated by B3LYP/6-31þG* in the presence of a continuum solvent (methanol).
(41%)) following the rearrangement routes propose in eqs 8
and 9 (Figure 7). The formation of 24•- from 21-PR•- is a
highly exothermic reaction, more exothermic than the C-
cyclization route (Figures 6 and 7, respectively). However, the
activation energy evaluated in going from 21-PR•- to 23•-
seems too high to compete with internal rotations or with C-
cyclization, and these B3LYP studies fail to explain this
experimental outcome under the conditions simulated in the
calculation, that is, free radical anions in a continuum media or
spheridine, a natural product, was carried out in a very good
yield. The synthetic strategy involves a first step nucleophilic
substitution of different anilines with 2-iodobenzylchloride
followed by an SRN1 substitution reaction in NH3 or DMSO
as solvent under photoinitiation.
The SRN1 mechanism accounts for the substitution reac-
tions, and the products are obtained in very good yields.
Considering the availability and/or simplicity of the starting
materials, and the mild conditions of the procedure, we have
demonstrated that this can be a general methodology for the
synthesis of this family of compounds.
The computational calculations seem to be a successful
approach for studying the conformational equilibrium of
anions and the distonic radical anions as well as to explain
the regiochemistry of C-C or C-N six-membered cycliza-
tions observed experimentally for pyridine, 1-naphthyl, and
2-napthyl systems in the presence of a solvent modeled as a
continuum. On the other hand, the theoretical design used
proved to be unsuccessful to explain the products from
rearrangements observed in the naphthyl system.
in the presence of discrete solvent (NH3) molecules.38
A
possibility of this failure could be related to the existence of
specific halogen effects that cannot be modeled under our
computational design.
Conclusions
In summary, in this work, we present a simple and transi-
tion-metal-free method for the synthesis of phenanthridine,
substituted phenanthridine, benzophenanthridine, and naph-
thophenanthridine using readily available N-(ortho-haloben-
zyl)arylamines as starting materials. The synthesis of tri-
Experimental Section
(38) (a) The activation energy from 21-PR•- to 23•- was also evaluated (16.7
kcal/mol) by inclusion of seven discrete molecules of solvent (NH3) (see ref 38b).
(b) The position of the solvent molecules was obtained from classical molecular
dynamic simulations of the anion (B3LYP geometry) within a box containing
8671 NH3 molecules. The dynamics were run with the Amber program. The
parameter file was generated with the Gaff Amber facility.
Computational Procedure. All calculations were performed
with the Gaussian03 program. First, the most stable conformers
of the anions RX- (X = Cl, I) were evaluated through an AM1
conformational search by scanning the two or three main
torsion angles (see Supporting Information). The conformers
J. Org. Chem. Vol. 75, No. 7, 2010 2215

ꢀ
Buden et al.
JOCArticle
thus obtained were then refined with complete geometry opti-
mization within the B3LYP39 DFT functional, the 6-31þG*
basis set for the chlorine compounds, and the LANL2DZ40 basis
set for the chlorine and iodine compounds. This effective core
potential (ECP) basis set41 was previously used in the evaluation
of the anionic surfaces of halobenzenes and afforded results of
acceptable quality in the comparison of electronic properties of
PhI with respect to PhX (X= F, Cl, Br).42
The radical anions formed, once the halides are released, were
fully optimized with the same functional and the 6-31þG* basis
set. The geometries thus found were used as starting points for
the evaluation of the potential surface of the different reaction
steps with the same functional and the latter basis set and the
reaction coordinate approach.
The effect of NH3 as polar protic solvent was evaluated for all
of the DFT calculations through Tomasi’s polarized continuum
model (PCM),43 as implemented in Gaussian03, using methanol
and complete geometry optimization. The inclusion of the
solvent in the calculations is a requisite to evaluate valence
radical anions.44
The characterization of stationary points was done by Hes-
sian matrix calculations. The energy informed for TSs, anions,
and radical anions includes zero-point corrections.
Synthesis of N-(2-Iodobenzyl)benzenamine (3a): The following
procedure is representative of all of these reactions. Aniline (273
μL, 3 equiv), 100.8 mg of NaHCO3 (1.2 equiv), and 0.5 mL of
H2O were added to a 10 mL round-bottom flask fitted with a
reflux condenser. The solution was heated to 100-110 °C,
stirred vigorously, and 2-iodobenzylchloride 1a (1 equiv, 252.5
mg) was added slowly. The heating and stirring continued for a
further 180 min. The solution was then allowed to cool. The
content was dissolved with water and then extracted with
CH2Cl2. The organic extract was dried with anhydrous MgSO4.
The solvent (CH2Cl2) was then evaporated, and the aniline was
N-(2-Iodobenzyl)-2-methylaniline (3b): o-Toluidine was dis-
€
tilled under reduced pressure using a Kugelrohr apparatus. The
amine 3b was purified by column chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (100:0 f
70:30) and recrystallized from petroleum ether as white crystals
and isolated in 72% yield (465.1 mg, 1.44 mmol): mp 74.0-75.0
°C; 1H NMR (CD3COCD3) δ 2.24 (3H, s), 4.38 (2H, d, J = 5.8
Hz), 5.10 (1H, s br), 6.34 (1H, d, J = 8.0 Hz), 6.57 (1H, t, J = 7.5
Hz), 6.94-7.04 (3H, m), 7.31 (1H, t, J = 7.5 Hz), 7.38 (1H, d,
J = 7.5 Hz), 7.88 (1H, dd, 1J = 8.0 Hz, 2J = 1.0 Hz); 13C NMR
(CD3COCD3) δ 17.9, 53.5, 98.8, 110.7, 117.6, 122.8, 127.7,
129.2, 129.3, 129.7, 130.8, 140.2, 142.3, 146.7; GC-MS (m/z)
324 (Mþ þ 1, 13), 323 (Mþ, 100), 217 (74), 96 (24), 195 (11), 194
(40), 181 (23), 180 (23), 120 (37), 118 (25), 106 (31), 91 (45), 90
(45), 89 (23), 77 (16), 65 (19); HRMS (ESI/APCI) calcd for
C14H15NI 324.0249, found 324.0242.
N-(2-Iodobenzyl)-4-methylbenzenamine (3c): p-Toluidine was
€
distilled under reduced pressure using a Kugelrohr apparatus.
The amine 3c was purified by column chromatography on silica
gel eluting with a petroleum ether/diethyl ether gradient (100:0
f 85:15) and recrystallized from petroleum ether as white
crystals and isolated in 75% yield (485.1 mg, 1.50 mmol): mp
51.0-52.0 °C; 1H NMR (CD3COCD3) δ 2.16 (3H, s), 4.28 (2H,
d, J = 6.0 Hz), 5.38 (1H, s br), 6.51 (2H, d, J = 8.5 Hz), 6.91 (2H,
d, J = 8.3 Hz), 6.98-7.02 (1H, m), 7.33 (1H, t, J = 7.3 Hz), 7.41
(1H, d, J = 7.3 Hz), 7.87 (1H, d, J = 7.8 Hz); 13C NMR (CD3-
COCD3) δ 20.8, 54.2, 99.2, 114.0, 126.8, 129.6, 129.8, 130.0,
130.7, 140.6, 143.0, 147.4; GC-MS (m/z) 324 (Mþ þ 1, 11), 323
(Mþ, 100), 322 (9), 217 (59), 196 (30), 195 (15), 194 (51), 181 (29),
180 (26), 120 (48), 118 (13), 106 (9), 91 (50), 90 (46), 89 (24), 77
(22), 65 (22), 63 (13), 51 (11); HRMS (ESI/APCI) calcd for
C14H15NI 324.0244, found 324.0246.
N-(2-Iodobenzyl)-2-methoxybenzenamine (3d): o-Anisidine
€
was distilled under reduced pressure using a Kugelrohr appa-
€
distilled under reduced pressure using a Kugelrohr apparatus.
ratus. The amine 3d was purified by column chromatography on
silica gel eluting with a petroleum ether/diethyl ether gradient
(100:0 f 90:10) as white crystals and isolated in 78% yield (528.8
mg, 1.56 mmol): mp 59.0-61.0 °C; H NMR (CCl3D) δ 3.87
(3H, s), 4.34 (2H, s), 4.79 (1H, s br), 6.47 (1H, d, J = 7.8 Hz),
6.66-6.70 (1H, m), 6.79-6.83 (2H, m), 6.94-6.97 (1H, m),
7.24-7.30 (1H, m), 7.36 (1H, d, J = 7.5 Hz), 7.85 (1H, d, J = 7.8
Hz); 13C NMR (CCl3D) δ 52.9, 55.5, 98.4, 109.5, 110.2, 116.8,
121.2, 128.3, 128.5, 128.8, 137.6, 139.3, 141.0, 146.8; GC-MS
(m/z) 340 (Mþ þ 1, 15), 339 (Mþ, 100), 324 (23), 217 (48), 210
(12), 196 (12), 180 (22), 136 (17), 120 (16), 94 (12), 92 (11), 91
(11), 90 (27), 89 (13), 77 (11), 65 (16); HRMS (ESI/APCI) calcd
for C14H15INO 340.0193, found 340.0198.
The amine 3a was purified by column chromatography on silica
gel eluting with a petroleum ether/dichloromethane gradient (100:0
f 70:30) and recrystallized from petroleum ether/diethyl ether as
white crystals and isolated in 85% yield (262.6 mg): mp 62.0-64.0
°C (lit.45 66-68 °C); 1H NMR (CCl3D) δ 4.17 (1H, s br), 4.32 (2H,
d, J = 5.5 Hz), 6.58-6.62 (2H, m), 6.72 (1H, tt, 1J = 7.3 Hz, 2J =
1.1 Hz), 6.96 (1H, td, 1J=7.7Hz, 2J=1.8Hz),7.12-7.21 (2H, m),
7.31 (1H, dd, 1J = 7.3 Hz, 2J = 1.1 Hz), 7.38 (1H, dd, 1J = 7.7 Hz,
2J = 1.8 Hz), 7.85 (1H, dd, 1J = 8.0 Hz, 2J = 1.1 Hz); 13C NMR
(CCl3D) δ 53.2, 98.5, 113.0, 117.8, 128.4, 128.8, 128.9, 129.3, 139.5,
141.0, 147.6; GC-MS (m/z) 310 (Mþ þ 1, 14), 309 (Mþ, 99), 308
(20), 218 (10), 217 (100), 207 (10), 183 (19), 182 (81), 181 (19), 180
(74), 179 (6), 178 (6), 167 (10), 165 (21), 154 (6), 153 (7), 152 (10),
151 (7), 128 (6), 127 (13), 107 (13), 106 (69), 105 (10), 104 (26), 102
(8), 92 (17), 91 (39), 90 (76), 89 (39), 78 (20), 77 (78), 76 (25), 75 (6),
65 (17), 64 (11), 63 (15), 62 (6), 52 (7), 51 (33), 50 (11).46
1
N-(2-Iodobenzyl)-4-methoxybenzenamine (3e): p-Anisidine
€
was distilled under reduced pressure using a Kugelrohr appara-
tus. The amine 3e was purified by column chromatography on
silica gel eluting with a petroleum ether/diethyl ether gradient
(100:0 f 90:10) as white crystals and isolated in 85% yield
1
(576.3 mg, 1.70 mmol): mp 47.0-49.0 °C; H NMR (CCl3D) δ
(39) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (b)
Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100. (c) Miehlich, B.; Savin, A.;
Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200–206.
(40) D95V for carbon and hydrogen atoms. See: Dunning, T. H., Jr.;
Hay, P. J. In Modern Theoretical Chemistry; Schaefer, H. F., III, Ed.; ;
Plenum: New York, 1976; Vol. 3, pp 1-28. Los Alamos ECP plus DZ on
Na-La, Hf-Bi for iodine: Hay, S. P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82,
270–283.
(41) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270–271.
(42) Pierini, A. B.; Vera, D. M. A. J. Org. Chem. 2003, 68, 9191–9199.
(43) (a) Miertus, S.; Scrocco, E.; Tomasi J. Chem. Phys. 1981, 55, 117–
129. (b) Miertus, S.; Tomasi J. Chem. Phys. 1982, 65, 239–245. (c) Cossi, M.;
Barone, V.; Cammi, R.; Tomasi J. Chem. Phys. Lett. 1996, 255, 327–335.
(44) Puiatti, M.; Vera, D. M. A.; Pierini, A. B. Phys. Chem. Chem. Phys.
2009, 11, 9013–9024.
3.75 (3H, s), 3.97 (1H, s br), 4.29 (2H, s), 6.57-6.61 (2H, m),
6.77-6.81 (2H, m), 6.98 (1H, td, 1J = 7.2 Hz, 2J = 1.2 Hz), 7.31
(1H, td, 1J = 7.2 Hz, 2J =1.2 Hz), 7.40 (1H, dd, 1J = 7.5 Hz, 2J =
1
2
1.2 Hz), 7.87 (1H, dd, J = 7.8 Hz, J = 1.2 Hz); 13C NMR
(CCl3D) δ 54.1, 55.8, 98.6, 114.3, 114.9, 128.4, 128.88, 128.91,
139.5, 141.2, 141.9, 152.4; GC-MS (m/z) 340 (Mþ þ 1, 14), 339
(Mþ, 100), 337 (36), 324 (11), 322 (14), 217 (44), 210 (20), 207 (16),
196 (13), 168 (10), 167 (28), 166 (10), 136 (11), 122 (99), 95 (11), 91
(13), 90 (25), 89 (17), 77 (12), 64 (14), 63 (18); HRMS (ESI/APCI)
calcd for C14H15INO 340.0193, found 340.0187.
N-(2-Iodobenzyl)biphenyl-2-amine (3f): Biphenyl-2-amine
€
was distilled under reduced pressure using a Kugelrohr appa-
(45) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578–
7584.
(46) Park, Y.-T.; Kim, K.-S.; Lee, I-H; Goo, C.-H.; Park, Y.-C. Bull.
Korean Chem. Soc. 1993, 14, 152–153.
ratus, and the amine 3f was purified by column chromatography
on silica gel eluting with a petroleum ether/dichloromethane
gradient (100:0 f 70:30) and recrystallized from diethyl ether as
2216 J. Org. Chem. Vol. 75, No. 7, 2010

ꢀ
Buden et al.
JOCArticle
white crystals and isolated in 82% (315.7 mg): mp 98.8-100.2
139.5, 140.7, 145.2; GC-MS (m/z) 360 (Mþ þ 1, 12), 359 (Mþ,
62), 233 (10), 232 (50), 231 (32), 230 (100), 229 (12), 217 (44),
215 (19), 202 (15), 156 (21), 128 (18), 127 (38), 126 (10), 116 (14),
115 (69), 114 (10), 91 (13), 90 (43), 89 (23), 77 (14), 63 (16),
51 (10).32
1
°C; H NMR (DMSO-d6) δ 4.22 (2H, s), 5.37 (1H, s br), 6.34
(1H, d, J = 7.5 Hz), 6.67 (1H, s), 7.01-7.07 (3H, m), 7.33-7.48
(7H, m), 7.85 (1H, d, J = 5.5 Hz); 13C NMR (DMSO-d6) δ 52.1,
98.6, 110.5, 116.7, 127.0, 127.1, 128.2, 128.4, 128.5, 128.9, 129.1,
130.2, 139.1, 139.2, 140.9, 144.2; GC-MS (m/z) 386 (Mþ þ 1, 18),
385 (Mþ, 100), 258 (27), 257 (13), 256 (34), 254 (10), 232 (11), 217
(26), 182 (24), 181 (10), 180 (57), 168 (40), 167 (45), 166 (15), 165
(10), 152 (21), 139 (10), 128 (10), 127 (13), 91 (17), 90 (37), 89
(19), 77 (7), 65 (6).32
N-(2-Iodobenzyl)naphthalen-1-amine (14a): 1-Naphthylamine
€
was distilled under reduced pressure using a Kugelrohr appa-
ratus. The amine 14a was purified by column chromatography
on silica gel eluting with a petroleum ether/CH2Cl2 gradient
(90:10 f 70:30) as a yellow crystal and isolated in 74% yield
(531.4 mg): mp 102-103 °C; 1H NMR (CCl3D) δ 4.49 (2H, s),
4.88 (1H, s br), 6.50 (1H, d, J = 7.2 Hz), 6.98 (1H, t, J = 7.5 Hz),
N-(2-Iodobenzyl)-2-(1H-pyrrol-1-yl)benzenamine (3g): o-Pyr-
rolylaniline was distilled under reduced pressure using a
Kugelrohr apparatus. The amine 3g was purified by column
7.23-7.32 (3H, m), 7.39-7.46 (3H, m), 7.79-7.89 (3H, m); 13
C
€
chromatography on silica gel eluting with a petroleum ether/
CH2Cl2 gradient (85:15 f 65:35) as white crystals and isolated in
69% yield (516.1 mg, 1.38 mmol): mp 127.0-128.0 °C; 1H NMR
(CCl3D) δ 4.32 (2H, d, J = 5.8 Hz), 4.45 (1H, s br), 6.39-6.41
(2H, m), 6.61 (1H, d, J = 7.9 Hz), 6.79 (1H, t, J = 7.6 Hz),
6.90-6.92 (2H, m), 6.98-7.02 (1H, m), 7.20-7.24 (2H, m),
7.28-7.35 (2H, m), 7.87 (1H, d, J = 7.6 Hz); 13C NMR (CCl3D)
δ 52.7, 98.2, 109.5, 111.5, 116.9, 121.9, 127.1, 127.2, 128.1, 128.3,
128.9, 128.9, 139.5, 140.2, 143.0; GC-MS (m/z) 375 (Mþ þ 1, 16),
374 (Mþ, 100), 373 (43), 247 (12), 245 (23), 217 (25), 180 (17), 171
(28), 169 (18), 157 (68), 156 (23), 91 (14), 90 (27), 89 (15), 77 (14);
HRMS (ESI/APCI) calcd for C17H16IN2 375.0353, found
375.0357.
NMR (CCl3D) δ 53.3, 98.7, 105.0, 117.8, 119.8, 123.3, 124.8,
125.7, 126.5, 128.4, 128.7, 128.8, 129.0, 134.3, 139.5, 140.6,
142.6; GC-MS (m/z) 361 (Mþ þ 2, 2), 360 (Mþ þ 1, 15), 359
(Mþ, 100), 233 (11), 232 (50), 231 (28), 230 (90), 217 (66), 215
(22), 202 (12), 154 (10), 142 (28), 128 (13), 127 (26), 126 (9), 116
(9), 115 (68), 114 (11), 101 (10), 91 (11), 90 (34), 89 (20), 77 (10),
63 (9); HRMS (ESI/APCI) calcd for C17H15IN 360.0249, found
360.0245.
N-(2-Chlorobenzyl)naphthalen-1-amine (14c): The amine 14c
was purified by column chromatography on silica gel eluting
with a petroleum ether/dichloromethane gradient (100:0 f
50:50) and recrystallized from petroleum ether/dichloro-
methane as white crystals in 91% (242.6 mg): mp 109.0-110.2
°C; 1H NMR (CCl3D) δ 4.49 (2H, s), 4.69 (1H, s br), 6.63 (1H, d,
J = 7.5 Hz), 7.24-7.46 (8H, m), 7.78-7.83 (2H, m); 13C NMR
(CCl3D) δ 46.1, 105.1, 117.9, 119.8, 123.4, 124.8, 125.7, 126.5,
126.9, 128.5, 128.7, 129.1, 129.6, 133.4, 134.3, 136.2, 142.6; GC-
MS (m/z) 269 (Mþ þ 2, 25), 268 (15), 267 (Mþ, 70), 266 (11), 265
(5), 233 (8), 232 (48), 230 (25), 156 (6), 154 (8), 143 (8), 142 (61),
140 (6), 129 (7), 128 (16), 127 (44), 126 (13), 125 (73), 116 (11),
115 (100), 114 (9), 102 (6), 101 (11), 99 (6), 89 (24), 77 (10), 75 (7),
63 (10), 51 (6).32
Representative Procedure for Photostimulated Reactions: Pre-
paration of Phenanthridine (4a) in Liquid Ammonia. The follow-
ing procedure is representative of all of these reactions. Liquid
ammonia (150 mL), previously dried over Na metal, was
distilled into a 250 mL three-necked, round-bottomed flask
equipped with a coldfinger condenser and a magnetic stirrer
under a nitrogen atmosphere. The base t-BuOK (2.5 equiv,
56.0 mg) and then the substrate N-(2-iodobenzyl)aniline (3a)
(1 equiv, 61.8 mg) were added to the liquid ammonia, and the
solution was irradiated for 120 min. Irradiation was conducted
in a reactor equipped with two 400 W lamps emitting maximally
at 350 nm (refrigerated with air and water). The reaction was
quenched with an excess of ammonium nitrate, and the liquid
ammonia was allowed to evaporate. Water was added to the
residue, and the mixture was extracted with CH2Cl2 (3 ꢀ 30 mL).
The organic extract was dried over anhydrous MgSO4 then
filtered, and the solvent was removed to leave the crude pro-
ducts. The products were separated and isolated by radial thin-
layer chromatography on silica gel. In other similar experi-
ments, the products were quantified by GC by using the internal
standard method. The yield of halide ions in the aqueous
solution was determined potentiometrically.
N-(2-Iodobenzyl)pyridin-2-amine (3h): The pyridine-2-amine
€
was distilled under reduced pressure using a Kugelrohr appa-
ratus. The amine 3h was purified by column chromatography on
silica gel eluting with a petroleum ether/diethyl ether gradient
(75:25 f 50:50) as yellow crystals and isolated in 44% yield
(272.8 mg, 0.88 mmol): mp 98.0-100.0 °C; 1H NMR (CCl3D) δ
4.56 (2H, d, J = 5.5 Hz), 6.29 (1H, s), 6.53 (1H, ddd, 1J = 7.0
Hz, 2J = 5.0 Hz, 3J = 0.9 Hz), 6.58 (1H, dd, 1J = 8.4 Hz, 2J =
0.7 Hz), 7.00 (1H, dt, 1J = 7.8 Hz, 2J = 1.7 Hz), 7.33 (1H, td,
2
1J = 7.5 Hz, J = 1.1 Hz), 7.37-7.44 (2H, m), 7.86 (1H, dd,
1J = 7.9 Hz, 2J = 1.1 Hz), 7.99 (1H, dd, 1J = 5.0 Hz, 2J = 1.0
Hz); 13C NMR (CCl3D) δ 51.1, 98.6, 106.9, 113.4, 128.4, 128.8,
129.0, 137.5, 139.5, 140.9, 148.2, 158.3; GC-MS (m/z) 310 (Mþ,
5), 184 (14), 183 (100), 182 (11), 181 (19), 91 (17), 90 (14), 89 (10),
79 (11), 78 (21), 51 (9); HRMS (ESI/APCI) calcd for C12H12IN2
311.0040, found 311.0048.
N-(2-Chlorobenzyl)anthracen-2-amine (12): The amine 12 was
purified by column chromatography on silica gel eluting with a
petroleum ether/CH2Cl2 gradient (80:20 f 50:50) as yellow
crystals and isolated in 72% yield (456.5 mg, 1.44 mmol): mp
144.0-146.0 °C; 1H NMR (CD3COCD3) δ 4.63 (2H, d, J = 5.7
Hz), 6.01 (1H, t, J = 5.4 Hz), 6.79 (1H, d, J = 2.1 Hz), 7.22 (1H,
1
2
dd, J = 9.1 Hz, J = 2.3 Hz), 7.25-7.34 (3H, m), 7.34-7.41
(1H, m), 7.44-7.52 (1H, m), 7.53-7.61 (1H, m), 7.87 (2H, d, J =
9.0 Hz), 7.93 (1H, d, J = 8.3 Hz), 8.06 (1H, s), 8.29 (1H, s); 13
C
NMR (CD3COCD3) δ 46.8, 102.6, 122.5, 124.0, 125.2, 127.0,
127.8, 128.9, 129.1, 129.4, 130.0, 130.3, 130.9, 131.0, 131.2,
131.3, 134.4, 134.8, 135.8, 138.6, 147.3; GC-MS (m/z) 319 (Mþ
þ 2, 23), 318 (15), 317 (Mþ, 67), 283 (8), 282 (35), 280 (21), 192
(16), 176 (8), 166 (14), 165 (100), 125 (10), 89 (5); HRMS (ESI/
APCI) calcd for C21H17ClN 318.1044, found 318.1048.
N-(2-Iodobenzyl)naphthalen-2-amine (13): 2-Naphthylamine
€
4-Phenylphenanthridine (4f): The product 4f was purified by
column chromatography on silica gel eluting with a petroleum
ether/dichloromethane gradient (80:20 f 0:100): white crystals;
was distilled under reduced pressure using a Kugelrohr appa-
ratus. The amine 13 was purified by column chromatography on
silica gel eluting with a petroleum ether/diethyl ether gradient
(90:10 f 70:30) as a yellow crystal and isolated in 80% yield
(287.2 mg): mp 73.0 °C (decomposed); 1H NMR (CCl3D) δ 4.29
(1H, s br), 4.40 (2H, s), 6.74 (1H, d, J = 2.2 Hz), 6.89 (1H, dd,
1J = 8.8 Hz, 2J = 2.2 Hz), 6.97 (1H, dd, 1J = 7.7 Hz, 2J = 1.8
Hz), 7.14-7.41 (4H, m), 7.54-7.67 (3H, m), 7.86 (1H, dd, 1J =
1H NMR (CCl3D) δ 7.46 (1H, tt, J = 7.4 Hz, J = 1.3 Hz),
7.53-7.57 (2H, m), 7.73-7.81 (5H, m), 7.89-7.93 (1H, m), 8.07
(1H, d, J = 8.0 Hz), 8.65 (1H, dd, 1J = 7.8 Hz, 2J = 2.0 Hz), 8.70
(1H, d, J = 8.3 Hz), 9.32 (1H, s); 13C NMR (CCl3D) δ 121.7,
122.1, 124.5, 126.1, 126.6, 127.2, 127.5, 127.9, 128.6, 130.0,
130.7, 130.9, 132.7, 140.1, 141.7, 142.0, 153.1; GC-MS (m/z)
256 (Mþ þ 1, 5), 255 (Mþ, 35), 254 (100), 253 (9), 252 (9), 127
(34), 126 (10), 112 (10).32
1
2
2
8.0 Hz, J = 1.1 Hz); 13C NMR (CCl3D) δ 53.2, 98.6, 105.0,
117.7, 122.2, 126.0, 126.3, 127.6, 128.4, 128.8, 129.0, 135.1,
J. Org. Chem. Vol. 75, No. 7, 2010 2217

ꢀ
Buden et al.
JOCArticle
4-(1H-Pyrrol-1-yl)phenanthridine (4g): The product was puri-
fied by radial thin-layer chromatography on silica gel eluting
with petroleum ether/diethyl ether (95:5): white crystals; mp
97.0-98.5 °C; 1H NMR (CCl3D) δ 6.46 (2H, t, J = 2.2 Hz), 7.28
(2H, dd, 1J = 8.1 Hz, 2J = 6.0 Hz), 7.72-7.78 (3H, m),
7.89-7.93 (1H, m), 8.07 (1H, d, J = 8.0 Hz), 8.55-8.58 (1H,
m), 8.66 (1H, d, J = 8.3 Hz), 9.34 (1H, s); 13C NMR (CCl3D) δ
109.3, 120.7, 122.2, 123.4, 124.4, 125.4, 126.3, 126.7, 128.0,
128.8, 131.2, 132.3, 138.5, 139.1, 153.6; GC-MS (m/z) 245
(Mþ þ 1, 14), 244 (Mþ, 83), 243 (100), 242 (12), 217 (12), 151
(7), 122 (22); HRMS (ESI/APCI) calcd for C17H13N2 245.1073,
found 245.1080.
121.0, 7.13/131.1, 7.19/128.3, 7.19/152.4, 7.24/121.0, 7.24/121.2,
7.24/152.4, 7.64/148.7, 7.64/155.9, 8.21/114.9, 8.21/137.7, 8.21/
155.9; GC-MS (m/z) 183 (Mþ þ 1, 7), 182 (Mþ, 60), 181 (100), 91
(17), 78 (11), 51 (7); HRMS (ESI/APCI) calcd for C12H11N2
183.0917, found 183.0921.
Naphtho[2,3-a]phenanthridine (15): The product was purified
by radial thin-layer chromatography on silica gel eluting with
petroleum ether/diethyl ether gradient (70:30 f 30:70): yellow
1
crystals; mp 210.4-211.3 °C; H NMR (CCl3D) δ 7.61-7.65
(2H, m), 7.77-7.80 (1H, m), 7.97-8.01 (1H, m), 8.04 (1H, d, J =
9.0 Hz), 8.13-8.15 (2H, m), 8.18-8.24 (2H, m), 8.57 (1H, s),
9.29 (1H, d, J = 8.7 Hz), 9.43 (1H, s), 9.63 (1H, s); 13C NMR
(CCl3D) δ 120.7, 126.1, 126.2, 126.3, 126.7, 126.8, 127.3, 127.8,
128.0, 128.6, 128.8, 130.1, 131.1, 131.5, 131.6, 131.9, 132.9,
144.7, 152.6; GC-MS (m/z) 280 (Mþ þ 1, 22), 279 (Mþ, 100),
278 (20), 277 (11), 251 (10), 250 (14), 139 (19), 125 (19), 113 (8),
111 (7); HRMS (ESI/APCI) calcd for C21H14N 280.1126, found
280.1127.
Benzo[c][1,8]naphthyridine (4h): The product was purified by
radial thin-layer chromatography on silica gel eluting with
1
1
methanol: yellow oil; H NMR (CCl3D) δ 7.66 (1H, dd, J =
2
8.0 Hz, J = 4.4 Hz), 7.79-7.83 (1H, m), 7.93-7.97 (1H, m),
8.15 (1H, d, J = 8.0 Hz), 8.62 (1H, d, J = 8.0 Hz), 8.96 (1H, d,
J = 8.0 Hz), 9.12 (1H, dd, 1J = 4.6 Hz, 2J = 1.9 Hz), 9.56 (1H,
s); H-1H COSY NMR (CCl3D) δH/δH 7.81/7.95, 7.81/8.15,
1
N-o-Tolylnaphthalen-1-amine (20): Yellow oil; 1H NMR
(CD3COCD3) δ 2.30 (3H, s), 2.78 (1H, s), 6.83-7.13 (4H, m),
7.96/8.15, 8.14/8.62, 7.96/8.62, 7.83/8.62, 7.66/8.90, 7.65/9.12,
8.90/9.12, 8.62/9.56; 1H-13C HSQC NMR (CCl3D) δH/δC
7.66/122.1, 7.81/128.6, 7.96/131.6, 8.15/129.3, 8.63/122.2, 8.96/
7.23-7.53 (5H, m), 7.85-7.90 (1H, m), 8.15-8.20 (1H, m); 13
C
NMR (CD3COCD3) δ 18.1, 114.3, 121.6, 121.9, 123.0, 123.3,
125.9, 126.7, 127.0, 127.5, 127.7, 129.1, 130.4, 131.7, 135.8,
141.9, 143.9; DEPT 135° (CD3COCD3) δ 18.1, 114.3, 121.6,
121.9, 123.0, 123.3, 125.9, 126.7, 127.0, 127.5, 129.1, 131.7; GC-
MS (m/z) 235 (1), 234 (Mþ þ 1, 17), 233 (Mþ, 100), 232 (35), 230
(13), 218 (39), 217 (38), 128 (15), 115 (38), 109 (18).32
1
131.8, 9.12/151.5, 9.56/157.4; H-13C HMBC NMR (CCl3D)
δH/δC 7.66/151.5, 7.81/122.1, 7.81/126.5, 7.96/129.3, 7.96/
132.9, 8.16/131.8, 8.15/157.4, 8.62/126.5, 8.62/128.6, 9.56/
126.6, 9.56/129.3, 9.56/132.7; GC-MS (m/z) 181 (Mþ þ 1, 13),
180 (Mþ, 100), 179 (44), 153 (12), 152 (10), 127 (11), 126 (11), 90
(8), 76 (8), 63 (9); HRMS (ESI/APCI) calcd for C12H9N2
181.0760, found 181.0765.
Acknowledgment. This paper is dedicated to Professor
Pelayo Camps on the occasion of his 65th birthday. This
ꢀ
work was supported in part by the Agencia Cordoba Ciencia,
the Consejo Nacional de Investigaciones Cientıficas y
6H-Pyrido[1,2-a]quinazoline (11): The product was purified
by radial thin-layer chromatography on silica gel eluting with
petroleum ether/diethyl ether (80:20): yellow oil; 1H NMR
(CD3COCD3) δ 5.05 (2H, s), 6.77 (1H, dd, 1J = 7.1 Hz, 2J =
5.0 Hz), 6.85 (1H, d, J = 8.3 Hz), 6.91 (1H, t, J = 7.5 Hz), 7.13
(1H, d, J = 7.6 Hz), 7.19 (1H, d, J = 7.0 Hz), 7.24 (1H, t, J = 7.7
Hz), 7.56-7.68 (1H, m), 8.21 (1H, d, J = 4.8 Hz); 13C NMR
(CD3COCD3) δ 59.7, 107.2, 109.3, 114.9, 121.0, 121.2, 128.3,
131.1, 137.7, 148.7, 152.4, 155.9; 1H-1H COSY NMR
(CD3COCD3) δH/δH 6.77/6.85, 6.77/7.64, 6.77/8.21, 6.85/
7.64, 6.85/8.21, 6.91/7.13, 6.91/7.19, 6.91/7.24, 7.13/7.24, 7.64/
8.21; 1H-13C HSQC NMR (CD3COCD3) δH/δC 5.05/59.7,
6.77/114.9, 6.85/107.2, 6.91/121.0, 7.13/109.3, 7.19/121.2, 7.24/
128.3, 7.64/137.7, 8.21/148.7; 1H-13C HMBC NMR (CD3CO-
CD3) δH/δC 5.05/121.2, 5.05/131.1, 5.05/152.4, 6.77/107.2,
6.77/148.7, 6.85/114.9, 6.91/109.3, 6.91/128.3, 6.91/131.1, 7.13/
ꢀ
Tecnicas (CONICET), SECYT, Universidad Nacional de
ꢀ
Cordoba, and FONCYT, Argentina. M.E.B. and V.B.D.
gratefully acknowledge receipt of fellowships from CON-
ICET.
Supporting Information Available: General experimental
methods, materials, characterization data (for 3i, 14b, 4a-e, 4i,
17, 19), copies of 1H and 13C NMR spectra for previously
reported and unreported compounds; xyz coordinates and total
energies in atomic units of the species calculated and the
schematic profiles. This material is available free of charge via
the Internet at http://pubs.acs.org.
2218 J. Org. Chem. Vol. 75, No. 7, 2010