Direct regioselective phenylation of acridine derivatives by phenyllithium

Article abstract of DOI:10.1016/j.tetlet.2003.09.167

Acridine and acridine derivatives have been converted directly to phenyl derivatives regioselectively using phenyllithium.

Full text of DOI:10.1016/j.tetlet.2003.09.167

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8641–8643
Direct regioselective phenylation of acridine derivatives
by phenyllithium
Bishnupada Dutta, Gandhi K. Kar and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 31 July 2003; revised 8 September 2003; accepted 19 September 2003
Abstract—Acridine and acridine derivatives have been converted directly to phenyl derivatives regioselectively using phenyl-
lithium.
© 2003 Elsevier Ltd. All rights reserved.
Alkylation of acridine and acridine derivatives
improves their solubility in common organic solvents.1
Direct phenylation of acridine and its derivatives using
phenyllithium would generate phenylacridines which
are building blocks/motifs of various polycyclic natural
and unnatural products.1,2 Michael type 1,4-addition of
phenyllithium to the pyridine nucleus leads to the only
product isolated from the reaction mixture. Direct
phenylation will further help to prepare functionalised
aryl moieties which could be cyclised to generate aza-
congeners of polycyclic aromatic hydrocarbons (PAH).
As a part of our program on the synthesis of bioactive
acridines, we present here a general method for phenyl-
ation directed by the nitrogen of acridine derivatives at
specific sites. We are interested in applying the novel
phenylation protocol to the C-arylation of benz- and
dibenzacridines.
Similarly, benz[c]acridine4
2 upon treatment with
phenyllithium–TMEDA at 0°C followed by quenching
the reaction mixture with water produced 7-phenyl-
7,12-dihydrobenz[c]acridine 9a in 75% yield (Table 1,
entry 5). Incorporation of deuterium on the nitrogen
was observed, the product 9b being isolated in 67%
yield (Table 1, entry 6) when the reaction mixture was
quenched with D2O instead of water. Changing the
quenching agent to CH3I or C2H5Br led to the incorpo-
ration of a methyl or ethyl group onto the nitrogen
(Table 1, entries 7 and 8). However with isopropyl
bromide, N-alkylation was not observed. This may be
due to the bulkiness of the isopropyl group. In the
presence of a chiral diamine such as (−)-sparteine, the
reaction product from acridine derivatives with phenyl-
lithium showed optical activity, e.g. compound 10e
after reaction with phenyllithium in the presence of
(−)-sparteine5 in THF showed a specific rotation of +29
(CHCl3, c 0.008); (e.e. 20%).
When acridine 1 was treated with phenyllithium–
TMEDA, 0°C in THF, followed by quenching the
reaction mixture with water, 9-phenyl-9,10-dihydro-
acridine 8a was generated in 85% yield (Table 1, entry
1). This compound upon treatment with DDQ in
refluxing benzene produced 9-phenylacridine3 in 90%
yield. On changing the quenching agent from H2O to
D2O, incorporation of deuterium was observed on the
nitrogen leading to compound 8b in 82% yield (Table 1,
entry 2). Under identical conditions changing the
quenching agent from D2O to CH3I or C2H5Br gener-
ated 10-methyl-9-phenyl-9,10-dihydroacridine or 10-
ethyl-9-phenyl-9,10-dihydroacridine in 80 and 48%
yields, respectively (Table 1, entries 3 and 4).
The effect of ring substituents on this reaction was
studied and in many cases 1,4-addition of PhLi was
observed. Thus, dibenz[c,h]acridine6,7 3a, and 3-
methoxy dibenz[c,h]acridine 3b, when treated with PhLi
followed by quenching with H2O (Table 1, entries 9 and
10), D2O (Table 1, entries 11 and 12), CH3I (Table 1,
entries 13 and 14) and C2H5Br (Table 1, entries 15 and
16) produced 10a, 10e, 10b, 10f, 10c, 10g and 10d, 10h,
respectively.
An interesting observation was noticed in the case of
dibenz[c,f ]acridine 4, (Table 1, entry 17) where no
phenylation was observed. This may be due to the
bulkiness of the phenyl group, which inhibits the reac-
tion. In contrast, acenaphthoquinolines i.e., acenaph-
Keywords: phenyllithium; acridine.
* Corresponding author. Tel.: +91-3222-283326; fax: +91-3222-
282252; e-mail: jkray@chem.iitkgp.ernet.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.167

8642
B. Dutta et al. / Tetrahedron Letters 44 (2003) 8641–8643
tho[1,2-b]benzo[ f ]quinoline
5,
acenaphtho[1,2-b]-
for Michael type addition, exclusive phenylation at C-6
quinoline 6 and acenaphtho[1,2-b]benzo[h]quinoline8 7
were phenylated, and oxidised presumably by aerial
oxidation during acidic workup, exclusively in the semi-
bay region of the acenaphthene moiety, which again
was influenced by the position of the heteroatom. This
was indicated by the disappearance of the doublet at l
8.40–8.51 and retention of the singlet at l 8.48–9.29 in
the 1H NMR spectrum, which demonstrated that in
compounds 5, 6 and 7 the 6 position is phenylated
exclusively. Although there are two positions available
is due to the ‘proximity effect’. This was further proved
by single-crystal X-ray analysis of butylated acenaph-
thoquinolines.9
In conclusion, this method is a simple one-pot, one-step
technique for preparing a wide variety of phenylacridi-
nes and N-substituted acridines. Increasing the reaction
time did not improve the yield. The N-methyldihydro-
acridine derivatives can also act as catalysts in photo
radical cyclisation reactions.10

B. Dutta et al. / Tetrahedron Letters 44 (2003) 8641–8643
8643
Table 1.
Entry
Compound
Reagents and conditions
Producta
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
3a
3b
3a
3b
3a
3b
3a
3b
4
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 1.5 h; (ii) D2O
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) CH3I
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) C2H5Br
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 1.5 h; (ii) D2O
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) CH3I
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) C2H5Br
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) D2O
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) D2O
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) CH3I
(i) PhLi–THF–TMEDA/0°C, 5 h; (ii) CH3I
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) C2H5Br
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) C2H5Br
(i) PhLi–THF–TMEDA/0°C, 2 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 5 h; (ii) H2O
(i) PhLi–THF–TMEDA/0°C, 4 h; (ii) H2O
8a
8b
8c
8d
9a
9b
9c
9d
10a
10e
10b
10f
10c
10g
10d
10h
85
82
80
48
75
67
52
42
71
70
51
63
55
60
58
45
–
9
10
11
12
13
14
15
16
17
18
19
20
No reaction
5
6
7
11
12
13
69
78
77
a Products were identified from analytical and spectroscopic data.
Acknowledgements
Typical experimental procedure: To an ice-cold solution
of the acridine (0.22 mmol) in dry THF (5–10 mL)
and TMEDA (0.5–0.8 mL) under an argon atmo-
sphere, 3–4 equiv. of PhLi solution in diethyl ether
was added dropwise. After stirring at 0°C for 0.5 h the
reaction mixture was quenched with the appropriate
electrophile. Stirring was continued until the comple-
tion of the reaction. The reaction mixture was poured
into ice-cold water and extracted with CHCl3. The
organic layer was washed with dil. HCl and water and
the solvent was dried over anhydrous Na2SO4.
Removal of the solvent furnished the crude product,
which was purified by column chromatography (neu-
tral alumina/n-hexane–ethyl acetate).
Financial support from CSIR and DRDO, New Delhi,
is greatly acknowledged. BPD is thankful to CSIR
(New Delhi) for his fellowship.
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Selected spectroscopic data for compound 8d:
1H NMR (CDCl3, 200 MHz): l 1.41 (t, 3H, J=7.0
Hz), 4.04 (q, 2H, J=7.0 Hz), 5.22 (s, 1H), 6.89 (dt,
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