A one-pot access to 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes

Article abstract of DOI:10.1021/ol026197c

A one-pot f-BuLi-induced synthesis of 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes is reported. Aryl-and hetaryl nitriles, cyanamides, and trimethylacetonitrile gave phenanthridine products. The method was extended to provide bisphenanthridine 10 by a one-pot bis-cyclization, using 1,3-dicyanobenzene and PhF in 1:5 ratio. Reaction of 1-fluoronaphthalene and 4-chlorofluorobenzene with benzonitrile afforded the regioisomerically pure products 11 and 12, respectively.

Full text of DOI:10.1021/ol026197c

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2687-2690
A One-Pot Access to 6-Substituted
Phenanthridines from Fluoroarenes and
Nitriles via 1,2-Arynes
Jan Pawlas* and Mikael Begtrup
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy,
UniVersitetsparken 2, DK-2100 Copenhagen, Denmark
japa@dfh.dk
Received May 16, 2002
ABSTRACT
A one-pot, t-BuLi-induced synthesis of 6-substituted phenanthridines from fluoroarenes and nitriles via 1,2-arynes is reported. Aryl- and
hetaryl nitriles, cyanamides, and trimethylacetonitrile gave phenanthridine products. The method was extended to provide bisphenanthridine
10 by a one-pot bis-cyclization, using 1,3-dicyanobenzene and PhF in 1:5 ratio. Reaction of 1-fluoronaphthalene and 4-chlorofluorobenzene
with benzonitrile afforded the regioisomerically pure products 11 and 12, respectively.
Chemistry of arynes provides a robust tool for synthetic
design and methodology.1 The recent reports concerned with
formation,2 reactivity,3 and in particular synthetic applica-
tions4 of arynes illustrate the continued interest in the area.
Biehl and others have shown that arynes can be employed
with outstanding success for the synthesis of various nitrogen
heterocycles.1c,5 Yet, despite apparent practical advantages
of such a strategy (see below), we are not aware of a route
to dibenzo-fused pyridine systems simply by reacting a nitrile
with two aryne molecules in a 2 + 2 + 2 fashion.6,7 Herein,
this goal is formally accomplished: we report a t-BuLi-
induced synthesis of 6-substituted phenanthridines (6SPs)
from nitriles and fluoroarenes, which presumably proceeds
via 1,2-aryne intermediates.
on multistep syntheses and often require harsh conditions.9
We reasoned that 6SPs (1) could be obtained by timely
addition of a nitrile to reactive 2-fluoro-2′-lithiobiphenyl 2
(Scheme 1).10 By this method, 1 would be formed by addition
of 2 to a nitrile, followed by an intramolecular SNAr reaction.
The salient aryllithium 2 would be generated by attack of a
(4) (a) Escudero, S.; Pe´rez, D.; Guitian, E.; Castedo, L. Tetrahedron Lett.
1997, 38, 5375-5378. (b) Cobas, A.; Guitian, E.; Castedo, L. J. Org. Chem.
1997, 62, 4896-4897. (c) Rigby, J. H.; Laurent, S. J. Org. Chem. 1998,
63, 6742-6744. (d) Bailey, W. F.; Longstaff, S. C. J. Org. Chem. 1998,
63, 432-433. (e) Frid, M.; Pe´rez, D.; Peat, A. J.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9469-9470. (f) Tripathy, S.; LeBlanc, R.; Durst, T.
Org. Lett. 1999, 1, 1973-1975. (h) Tomori, H.; Fox, J. M.; Buchwald, S.
L. J. Org. Chem. 2000, 65, 5334-5341. (i) Yoshikawa, E.; Radhakrishnan,
K. V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 7280-7286. (j) Beller,
M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403-
1412. (k) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S.
J. Am. Chem. Soc. 2001, 123, 12686-12687. (l) Rayabarapu, D. K.;
Majumdar, K. K.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem. 2001, 66,
3646-3649. (m) Rao, U. N.; Biehl, E. J. Org. Chem. 2002, 67, 3409-
3411. (n) Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.; Ferna´ndez, Y. Chem. Eur.
J. 2002, 8, 2034-2045.
(5) Biehl, E. R. In AdVances in Nitrogen Heterocycles; Moody, C. J.,
Ed.; JAI Press Inc: New York, 2000; Vol. 4, pp 251-293 and references
therein.
(6) (a) For a leading reference on metal-catalyzed pyridine formation
from two alkynes and a nitrile, see: Takahashi, T.; Tsai, F.-Y.; Li, Z.; Wang,
H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem.
Soc. 2002, 124, 5059-5067. (b) For a novel method to construct pyridines
from lithiobutadienes and nitriles, see: (1) Cheng, J.; Song, Q.; Wang, C.-
S.; Xi, Z. J. Am. Chem. Soc. 2002, 124, 6238-6239.
6SPs have recently found interesting applications,8 but
even the contemporary methods for their construction rely
(1) For reviews, see: (a) Hoffmann, R. W. Dehydrobenzene and
Cycloalkynes; Academic Press: New York, 1967. (b) Reinecke, M. G.
Tetrahedron 1982, 38, 427-498. (c) Biehl, E. R.; Khanapure, S. P. Acc.
Chem. Res. 1989, 22, 275-281. (d) Kessar, S. V. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, Chapter 2.3.
(2) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.; Meng,
Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674-11679.
(3) (a) Clark, A. E.; Davidson, E. R. J. Am. Chem. Soc. 2001, 123,
10691-10698. (b) Liu, H.-C.; Wang, C.-S.; Guo, W.; Wu, Y.-D.; Yang, S.
J. Am. Chem. Soc. 2002, 124, 3794-3798.
10.1021/ol026197c CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/03/2002

3:4 ratio obtained under these conditions was not optimal:
according to GC-MS analysis, a large amount of tri-
phenylene 6 was formed, most likely by reaction of 2 with
4.13 Moreover, small amounts of imines 7 and 8 were also
detected by GC-MS, indicating the presence of PhLi at the
time PhCN was added.14 After some experimentation, we
found conditions that completely suppressed formation of 7
and 8 (entry 2). This in turn provided a slightly better yield
of 5, but 6 was again formed as the major product. In our
next attempt, we added PhCN before warming the reaction
to room temperature (entry 3). The yield of 5 was further
increased, and the arene 6 was not formed at all. In fact, the
only detectable byproduct was the imine 9. Through a series
of experiments varying temperature and timing of PhCN
addition, we established that the isolated yield of 5 is highest
when PhCN is added while the reaction is being warmed to
room temperature, ca. 1 min after the acetone-dry ice bath
keeping the reaction at low temperature is removed (entry
4). It is noteworthy that imine 9, which was invariably
obtained as a byproduct in these reactions, could be
hydrolyzed to the corresponding ketone at an acidic pH. This
ketone was in turn easily removed by extraction, circumvent-
ing use of chromatography during isolation of 5.15 Since
unreacted PhCN was always detected in the crude product
mixtures in the above experiments, we carried out reactions
using less PhCN (entries 5 and 6). Nevertheless, this had a
detrimental effect on the yield of 5, and arene 6 emerged as
a byproduct. Next, different lithium bases were screened
(entries 7 and 8),16 but these reactions provided 5 in lower
yields than experiments using t-BuLi as the base.
Scheme 1
o-fluorophenyllithium 311 on 1,2-aryne 4, which could be
formed either from 3 by loss of LiF (R1 ) R2), or from
another aryne precursor (R1 * R2). The latter approach would
allow installation of different substituents onto phenyl rings
in 6SPs. However, o-fluorophenyllithium is known to be
stable only at or below -70 °C.11 At higher temperaturess
presumably needed for addition of 3 to benzyne 4 at
sufficiently high ratessLiF elimination from 3 may occur
faster than attack on benzyne, preventing formation of
substantial amounts of aryllithium 2. Gratifyingly, our initial
attempt to prove the principle outlined in Scheme 1 did
provide the phenanthridine product, though in a modest yield
(Table 1, entry 1). Fluorobenzene, which served as the
Table 1. Base-Induced Formation of 6-Phenylphenanthridine
from Fluorobenzene and Benzonitrilea
time
temp
(°C)
equiv of
PhCNb
entry
base
(min)
% yield
1
2
3
4
5
6
7
8
t-BuLic
t-BuLie
t-BuLie
t-BuLie
t-BuLie
t-BuLie
s-BuLie
LTMPg
10
10
0
1
1
1
1
1
-78
-50
-50
-50
-50
-50
-50
-50
1.50
1.50
1.50
1.50
1.25
1.00
1.50
1.50
16d
19d
37f
63f
54f
49f
43f
40f
With the optimized conditions for the one-pot formation
of 6-phenylphenanthridine 5 (Table 1, entry 4),17 we
(8) (a) 6SPs as 5-HT3 receptor ligands: Cappelli, A.; Anzini, M.; Vomero,
S.; Mennuni, L.; Makovec, F.; Doucet, E.; Hamon, M.; Bruni, G.; Romeo,
M. R.; Menziani, M. C.; De Benedetti, P. G.; Langer, T. J. Med. Chem.
1998, 41, 728-741. (b) As topoisomerase inhibitors: Lynch, M. A.; Duval,
O.; Sukhanova, A.; Devy, J.; MacKey, S. P.; Waigh, R. D.; Nabiev, I.
Bioorg. Med. Chem. 2001, 11, 2643-2646. (d) As a tether in enzyme-
controlled cycloaddition: Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic,
Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2002, 41, 1053-1056.
(9) (a) For a recent three-step protocol, see: Lyse´n, M.; Kristensen, J.
L.; Vedsø, P.; Begtrup, M. Org. Lett. 2002, 4, 257-259. (b) Katritzky, A.
R.; Yang, B.; Dalal, N. S. J. Org. Chem. 1998, 63, 1467-1472. (c) Patra,
P. K.; Suresh, J. R.; H., I.; Junjappa, H. Tetrahedron 1998, 54, 10167-
10178; see also references therein for listing of earlier methods.
(10) For a route to pyrazoloquinolines by adding nitriles to a 2-fluoro-
phenylpyrazolyllithium, see: Pawlas, J.; Vedsø, P.; Jakobsen, P.; Huusfeldt,
P. O.; Begtrup, M. J. Org. Chem. 2001, 66, 4214-4219.
(11) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1955, 77, 3919-
3920.
a Reaction conditions: 3.2 mmol of PhF in 10 mL of THF under N2 at
temp, 3.2 mmol of base added. b Based on PhF being 2.0 equiv. c Added
over 10 min. d Calibrated GC-MS yield. e Added over 5 min, kept at -50
°C a further 10 min. f Isolated yield. g PhF (neat) added over 1 min to
premade LTMP in 10 mL of THF, kept at -50 °C a further 14 min.
precursor for both 3 and 4, was ortho-lithiated12 using t-BuLi
at -78 °C in dry THF. After 10 min at -78 °C, the reaction
was warmed to room temperature to generate 2, followed
by addition of 1.5 equiv of PhCN, which gave 5. Yet, the
(12) Snieckus, V. Chem. ReV. 1990, 90, 879-933.
(13) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217-
(7) For a benzyne-mediated pyridine formation in benzo[c]phenan-
thridines, see: Kessar, S. V.; Gupta, Y. P.; Balakrishnan, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 1988, 53, 1708-1713.
2222.
(14) PhLi can be formed from an alkylithium and benzyne: Franzen,
V.; Joschek, H.-I. Angew. Chem. 1960, 72, 564.
2688
Org. Lett., Vol. 4, No. 16, 2002

examined the scope of the cyclization using different nitriles
(Table 2). Arylnitriles with different steric and electronic
2-substituted benzonitriles afforded reasonable yields of
cyclized products (entries 6 and 7), but when the highly
hindered nitriles in entries 8 and 9 were used, the yields
dropped significantly. On the other hand, some base-sensitive
substituents were tolerated (entries 10 and 11).19 Also
hetarylnitriles could be incorporated (entries 12-15). As was
the case with arylnitriles, large differences in yields were
observed. For example 2-cyanopyridine afforded the cyclized
product in much higher yield than the 3-isomer (entries 12
and 13). Again, the lower yield with the latter is possibly
due to abstraction of an acidic proton from the nitrile by
2.18 In addition, by utilizing the bulky trimethylacetonitrile
in entry 16, we extended our method beyond aromatic
substrates. The lower yield in this case was primarily due to
preferential formation of 6, which was formed as the major
product.20 The extension to cyanamides is important despite
the modest yields obtained in these reactions (entries 17 and
18). This process constitutes a one-step entry to a medicinally
relevant structural class7a from readily available materials.
Furthermore, we were able to extend the method herein
to a facile one-pot bis-cyclization. Thus, bisphenanthridine
10 was obtained simply by changing the PhF to 1,3-
dicyanobenzene ratio from 4:3 (as in Table 2, entry 10) to
5:1 (eq 1).21 The phenanthridine shown in Table 2 was
Table 2. t-BuLi-Induced Synthesis of 6-Substituted
Phenanthridines from Fluorobenzene and Nitrilesa
a Reaction conditions: 3.2 mmol of PhF in 10 mL THF at -50 °C under
N2, 3.2 mmol of t-BuLi added. b t-BuLi added over 5 min. c 1.5 equiv, based
on PhF being 2.0 equiv. d Isolated yield, average of two runs. e Table 1,
entry 4. f Isolated as free amine.
present as a minor byproduct, and could be easily separated
by chromatography. Finally, we initiated studies using sub-
stituted fluorobenzenes. Not surprisingly,22 using 4-fluoro-
toluene, benzonitrile, and the conditions optimized in Table
1 afforded an inseparable, ca. 1:1 mixture of dimethylated
6-phenylphenanthridines in 41% overall yield.23 On the
contrary, both 1-fluoronaphthalene and 4-chlorofluoro-
benzene provided the phenanthridine products as single
regioisomers (Scheme 2).24 In the latter case, to obtain 12,
slightly modified conditions had to be employed.
properties participated in this cyclization (entries 1-11),
although the substitution pattern on the benzene moiety had
a profound effect on the yield of phenanthridine products.
For example, tolunitriles (entries 2, 4, and 6) and both 4-
and 2-chlorobenzonitrile (entries 3 and 7) provided 6SPs in
yields comparable to reactions using benzonitrile, but the
yield of phenanthridine product was substantially lower when
3-chlorobenzonitrile was employed (entry 5). Presumably,
this was due to competitive proton abstraction from the nitrile
by aryllithium 2.18 Furthermore, moderately congested
(15) Typical Procedure. 6-Phenylphenanthridine (Table 2, entry 1).
To a stirred solution of fluorobenzene (316 µL, 3.20 mmol) in 10.0 mL of
THF at -50 °C was added over 5 min dropwise 1.7 M t-BuLi in pentane
(1.88 mL, 3.20 mmol). After an additional 10 min at -50 °C, the acetone-
dry ice bath was removed. Exactly 1 min after removal of the acetone-dry
ice bath, benzonitrile (248 µL, 2.40 mmol) was added. The reaction was
allowed to warm to room temperature, 15 mL of 4 M HCl was added, and
the crude mixture was vigorously stirred overnight. The reaction was then
extracted with diethyl ether (3 × 150 mL), the pH of the aqueous phase
was adjusted to ca. pH 10 using 2 M NaOH, and the basic aqueous phase
was extracted with CH2Cl2 (3 × 150 mL). The combined CH2Cl2 extracts
were dried (MgSO4), ca. 50 mL EtOAc was added, and filtration through
a pad of silica gel (ca. 4 g) followed by evaporation afforded 257 mg (63%)
of the title compound as yellow crystals, mp 100-101 °C (EtOAc/heptane).
(16) According to GC-MS, n-BuLi, MeLi, PhLi, and LDA gave only
traces of 5.
Scheme 2
(17) Using DME, Et2O, or THF/dioxane as solvent gave <20% of 5,
while the reactions performed at concentrations higher than those given in
Table 1 provided 6 as the main product. Phenanthridine 5 was not obtained
when PhCl was used instead of PhF.
In summary, a one-pot, t-BuLi-induced process to con-
struct 6SPs from fluoroarenes and nitriles was developed.
Org. Lett., Vol. 4, No. 16, 2002
2689

The scope of the method was examined using a variety of
nitriles. This chemistry also set up a one-pot formation of a
bis-cyclized product 10. A few substituted fluoroarenes were
examined, which in some cases afforded 6SPs as single
regioisomers. Experimental simplicity,15 abundance of in-
expensive readily available building blocks, and easy access
to diverse structural motifs compensate for the moderate
yields generally delivered by this method. Future studies will
focus on providing access to unsymmetrically substituted
6SPs (Scheme 1, R1 * R2), as well as on utilizing hetarynes1b
in the herein disclosed cyclization.
Acknowledgment. J.P. thanks The Graduate School of
Drug Research at The Royal Danish School of Pharmacy
for a Novo Nordisk Plus Prize.
(18) Large amounts of 2-fluorobiphenyl were detected in the crude
reaction mixture by GC-MS.
Supporting Information Available: Experimental de-
tails, characterization of all products, and NMR spectral data
of all new compounds are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Free amino, nitro, and ester groups are not compatible with this
chemistry.
(20) Expectedly, CH3CN did not give 6-methylphenanthridine. An
R-proton was abstracted by 2 instead to give 2-fluorobiphenyl as the major
product. See ref 9a for a method enabling introduction of R-hydrogen-
containing alkyl groups.
(21) Bisphenanthridines of type 10 are unknown, and the potential uses
of such systems are thus unexplored. On the other hand, the related
terpyridines are well-known and have been used, e.g., in Ru-based
cyclometalated complexes. See for example: (a) Beley, M.; Collin, J.-P.;
Louis, R.; Metz, B.; Sauvage, J.-P. J. Am. Chem. Soc. 1991, 113, 8521-
8522. (b) Beley, M.; Chodorowski, S.; Collin, J.-P.; Sauvage, J.-P.
Tetrahedron Lett. 1993, 2933-2936. (c) Chavarot, M.; Pikramenou, Z.
Tetrahedron Lett. 1999, 6865-6868.
OL026197C
(23) Both 3- and 2-fluorotoluenes also provided ca. 1:1 mixtures of
regioisomers, but in much lower yields than 4-fluorotoluene.
(24) While it is known that additions of nucleophiles to 1-naphthyne
and 4-chlorobenzyne may lead to mixtures of regioisomers, additions to
the 2-position of the former and the 4-position of the latter are generally
favored for a variety of nucleophiles.22
(22) For a general discussion on addition of nucleophiles to unsym-
metrically substituted arynes, see ref 1a, pp 134-150.
2690
Org. Lett., Vol. 4, No. 16, 2002