A short route to the synthesis of pyrroloacridines via Ullmann-Goldberg condensation

Article abstract of DOI:10.1016/j.tetlet.2009.11.044

A concise method for the preparation of pyrroloacridines was reported via CuI mediated Ullmann-Goldberg condensation of 5-amino-2-methylindoles and o-halobenzoic acid derivatives followed by cyclization with POCl₃.

Full text of DOI:10.1016/j.tetlet.2009.11.044

Tetrahedron Letters 51 (2010) 422–424
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A short route to the synthesis of pyrroloacridines via Ullmann–Goldberg
condensation
*
Ramu Meesala, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Central University (PO), Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2009
Revised 7 November 2009
Accepted 11 November 2009
Available online 14 November 2009
A concise method for the preparation of pyrroloacridines was reported via CuI mediated Ullmann–Gold-
berg condensation of 5-amino-2-methylindoles and o-halobenzoic acid derivatives followed by cycliza-
tion with POCl3.
Ó 2009 Elsevier Ltd. All rights reserved.
Pyrroloacridines and pyrroloacridones are of particular interest
because they have a variety of interesting biological activities. Sig-
nificantly, members of this family are active in assays for antihel-
mintic,1 antitumor,1,2 antifungal,3 and DNA binding.4–6 These
abilities are specifically important in inhibiting the growth of can-
cerous cells, making these compounds ideal for developing novel
anticancer drugs. To date, the only pyrroloacridines that have been
published from marine sources are plakinidines A–E and alpkini-
dine.1,7–10 Only a few reports11 are available for the synthesis of
pyrroloacridines and therefore the synthetic versatility of these
compounds needs to be explored.
As a result of their significant potential as therapeutics, a con-
siderable synthetic attention has been directed at the development
of efficient methods toward the construction of pyrroloacridine
moiety. So, we became interested in synthesizing pyrroloacridines
which are isomeric analogues of bioactive pyrroloacridines such as
those shown in Figure 1. Our method is based on CuI mediated
N-arylation of 5-amino-2-methylindole with o-halobenzoic acids
by Ullmann–Goldberg condensation12 followed by intramolecular
Friedel–Crafts cyclization13 with POCl3.
As shown in Scheme 1, 5-amino-2-methylindole 1a was sub-
jected to Ullmann–Goldberg condensation with 2-iodobenzoic acid
2a in the presence of CuI (10 mol %) and K2CO3 (1.0 equiv) at 80 °C
in DMSO to give the condensation product14 3a. Due to the activa-
tion of halogens by the ortho-substituted carboxylic group, a facile
condensation occurred. The results, presented in Table 1, indicate
the condensation products are obtained in good yield. 2-Bromo-
benzoic and 2-chlorobenzoic acid required relatively longer reac-
tion time than their iodo analogue due to the order of halogen
displacement I > Br > Cl. Due to the further activation of iodide by
the strong electron-withdrawing nitro group, 2f requires only half
of the reaction time compared to 2c.
The condensation products 3a–i are subjected to cyclization
with POCl3 which results in the corresponding pyrroloacridones15
and pyrroloacridines15 depending on the reaction temperature.
As shown in Scheme 1, the condensation products 3a–f have pro-
duced the corresponding pyrroloacridones 4a–f after being treated
with an excess of POCl3 in good yields at 60 °C. The results are
summarized in Table 1. The condensation products 3g–i could
not give the corresponding pyrroloacridones at 60 °C. This may
be due to the strong electron-withdrawing nature of phenylsul-
phonyl group.
When the reaction was performed at 120 °C, the condensation
products 3a–i gave the corresponding pyrroloacridines 5a–i. The
absence of two singlets (due to 4th and 7th position protons of in-
dole) in the aromatic region of 1H NMR spectrum, clearly reveals
the exclusive formation of regioisomeric pyrroloacridines 5a–i.
This is further confirmed by the characterization of the structure
of 5g by the single crystal X-ray analysis.16 The ORTEP diagram
of 5g is shown in Figure 2.
In summary, we have developed a simple and efficient two-step
method for the synthesis of pyrroloacridones and pyrroloacridines
via N-arylation of 5-amino-2-methylindole derivatives with 2-
halobenzoic acids by Ullmann–Goldberg condensation followed
by intramolecular Friedel–Crafts cyclization with POCl3. This meth-
od provides a new entry to the synthesis of pyrroloacridone and
pyrroloacridine derivatives of biological importance.
HN
N
N
O
HN
O
H2N
O
H3C
N
N
N
O
NH
Plakinidine E
Figure 1. Representative pyrroloacridines isolated from marine sources.
NH
NH
Plakinidine A
Plakinidine D
* Corresponding author. Tel.: +91 040 66794831; fax: +91 040 23012460.
E-mail addresses: rnsc@uohyd.ernet.in, naga_indole@yahoo.co.in (R. Nagarajan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.044

R. Meesala, R. Nagarajan / Tetrahedron Letters 51 (2010) 422–424
423
R1
R1
COOH
O
X
HN
H2N
HN
POCl3
60 o
COOH
CuI, K2CO3
DMSO, 80 o
+
C
CH3
CH3
N
R
CH3
C
N
R
N
R
R = H, CH3
R1
4a-f
1a-i
3a-i
2a-i
R = H
= CH3
= SO2Ph
R1 = Cl
= Br
= NO2
= OMe
R = H, CH3,
SO2Ph
POCl3,
120 o
C
R1
Cl
N
CH3
N
R
5a-i
Scheme 1. Synthesis of pyrroloacridones and pyrroloacridines.
Table 1
Synthesis of pyrroloacridones and pyrroloacridines
S.No.
1
R
R1
H
X
I
Condensed product
Time (h)
0.5
Yield (%)
86
Cyclized product
Time (h)
Yield (%)
H
3a
4a
5a
4a
5a
4b
5b
4c
5c
4c
5c
4d
5d
4e
5e
4f
0.5
3.0
0.5
3.0
0.5
3.0
0.5
3.0
0.5
3.0
0.5
3.0
0.5
3.0
0.5
3.0
3.0
3.0
3.0
3.0
3.0
75
76
75
76
74
71
72
75
72
75
77
77
76
73
79
82
73
73
73
72
75
2
3
3
4
5
6
7
H
H
Br
Br
I
3a
3b
3c
3c
3d
3e
3f
2.0
2.0
0.5
2.0
0.5
0.5
0.25
80
81
91
82
87
79
84
H
OMe
H
CH3
CH3
CH3
CH3
CH3
H
Br
I
Cl
Br
I
NO2
I
5f
8
9
10
11
12
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
H
H
H
Cl
Br
I
3g
3g
3g
3h
3i
0.5
2.0
3.0
0.5
0.5
71
68
65
75
77
5g
5g
5g
5h
5i
Br
Cl
I
I
Acknowledgments
We thank the Department of Science and Technology (DST), In-
dia for providing financial assistance (Project No. SR/SI/OC-70/
2008). We also greatly acknowledge DST for providing single crys-
tal X-ray spectrometer in our school. R.M. thanks the Council of
Scientific and Industrial Research (CSIR), India for providing
fellowship.
Supplementary data
Characterization data for all compounds, 1H and 13C NMR spec-
tra of all compounds. LC–MS and elemental analysis of 3d, 4c, 4e,
5d, and 5i are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.044.
Figure 2. ORTEP diagram of 5g.

424
R. Meesala, R. Nagarajan / Tetrahedron Letters 51 (2010) 422–424
14. Typical procedure for the preparation of 5-chloro-2-(1,2-dimethyl-1H-5-
indolylamino)benzoic acid (3d): mixture of 5-amino-1,2-dimethylindole
References and notes
A
(1.0 mmol), 5-chloro-2-iodobenzoic acid (1.0 mmol), CuI (0.1 mmol), and
K2CO3 (1.0 mmol) in DMSO was heated at 80 °C for 0.5 h. Then the reaction
mixture was poured into water and extracted with ethylacetate (3 Â 20 mL).
Then the solvent was evaporated under reduced pressure and the crude
material was purified by column chromatography (15% ethylacetate/hexane).
Mp: 223–224 °C; IR (KBr): 3350, 2916, 2550, 1657, 1502, 1440, 1332, 1280,
1. Inman, W. D.; O’Neill-Johnson, M.; Crews, P. J. Am. Chem. Soc. 1990, 112, 1–4.
2. Gimenez-Arnau, E.; Missailidis, S.; Stevens, M. F. G. Anti-Cancer Drug Res. 1998,
13, 431–451.
3. McCarthy, P. J.; Pitts, T. P.; Gunawardana, G. P.; Kelly-Borges, M.; Pomponi, S. A.
J. Nat. Prod. 1992, 55, 1664–1668.
4. Shochet, N. R.; Rudi, A.; Kashman, Y.; Hod, Y.; El-Maghrabi, M. R.; Spector, I. J.
Cell. Physiol. 1993, 157, 481–492.
5. Tasdemir, D.; Marshall, K. M.; Mangalindan, G. C.; Concepción, G. P.; Barrows, L.
R.; Harper, M. K.; Ireland, C. M. J. Org. Chem. 2001, 66, 3246–3248.
6. McDonald, L. A.; Eldredge, G. S.; Barrows, L. R.; Ireland, C. M. J. Med. Chem. 1994,
37, 3819–3827.
1161, 812, 738, 657 cmÀ1 1H NMR (400 MHz, TMS, CDCl3): d 9.5 (1H, s, NH),
;
7.76 (1H, s), 7.37 (1H, d, J = 7.6 Hz), 7.26 (2H, s), 6.91 (2H, d, J = 6.4 Hz), 6.16
(1H, s), 3.64 (3H, s, CH3), 2.37 (3H, s, CH3); 13C NMR (100 MHz, TMS, CDCl3): d
175.2, 142.8, 140.0, 138.4, 136.5, 133.2, 130.6, 129.3, 123.2, 120.3, 119.8, 116.3,
115.1, 114.4, 104.3, 34.3, 17.5; LC–MS: m/z = 314.5 (M), 316.5 (M+2); Anal.
Calcd for molecular formula C17H15ClN2O2: C, 64.87; H, 4.8; N, 8.9. Found: C,
64.81; H, 4.85; N, 8.98.
7. West, R. R.; Mayne, C. L.; Ireland, C. M.; Brinen, L. S.; Clardy, J. Tetrahedron Lett.
1990, 31, 3271–3274.
15. Typical procedure for the preparation of 9-chloro-2,3-dimethyl-6,11-dihydro-3H-
pyrrolo[3,2-a]acridin-11-one (4d) and 9,11-dichloro-2,3-dimethyl-3H-pyrrolo[3,2-
a]acridine (5d): 5-Chloro-2-(1,2-dimethyl-1H-5-indolylamino)benzoic acid
(1.0 mmol) in excess of POCl3 (5 mL) was heated for 0.5 h at 60 °C. Then the
reaction mixture was poured onto the crushed ice and then neutralized with 10%
aq NaOH solution. Then it was extracted with dichloromethane (3 Â 10 mL) and
the solvent was evaporated and the crude material was purified by column
chromatography(30%ethylacetate/hexane) to obtainthepure product4d. When
the reaction was performed at 120 °C for 3 h, 5d was obtained. The crude
material was purified by column chromatography (5% ethylacetate/hexane).
Compound 4d: mp: 147–148 °C; IR (KBr): 3477, 1635, 1560, 1475, 1415, 1016,
8. (a) Smith, C. J.; Venables, D. A.; Hopmann, C.; Salomon, C. E.; Jompa, J.; Tahir, A.;
Faulkner, D. J.; Ireland, C. M. J. Nat. Prod. 1997, 60, 1048–1050; (b) Ford, P. W.;
Davidson, B. S. J. Nat. Prod. 1997, 60, 1051–1053.
9. Thale, Z.; Johnson, T.; Tenney, K.; Wenzel, P. J.; Lobkovsky, E.; Clardy, J.; Media, J.;
Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P. J. Org. Chem. 2002, 67, 9384–9391.
10. Ralifo, P.; Sanchez, L.; Nadine, C. G.; Karen, T.; Scott Lokey, R.; Theodore, R. H.;
Frederick, A. V.; Crews, P. J. Nat. Prod. 2007, 70, 95–99.
11. (a) Munawar, M. A.; Groundwater, P. W. Bull. Korean Chem. Soc. 1999, 20, 456–
458; (b) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron 1994, 50, 12959–
12972; (c) Alyab’eva, T. M.; Khoshtariya, T. E.; Vasil’ev, A. M.; Tret’yakova, L. G.;
Efimova, T. K.; Suvorov, N. N. Khim. Geterotskl. Soedin 1979, 8, 1092–1097; (d)
Suvorov, N. N.; Alyab’eva, T. M.; Khoshtariya, T. E. Khim. Geterotskl. Soedin 1978,
9, 1277; (e) Wardani, A.; Lhomme, J. Tetrahedron Lett. 1993, 34, 6411–6414.
12. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384; (b) Goldberg, I. Ber.
Dtsch. Chem. Ges. 1906, 39, 1691–1692; (c) Goodbrand, H. B.; Hu, N.-X. J. Org.
Chem. 1999, 64, 670–674; (d) Arterburn, J. B.; Pennala, M.; Gonzalez, A. M.
Tetrahedron Lett. 2001, 42, 1475–1477; (e) Lang, F.; Zewge, D.; Houpis, I. N.;
Volante, R. P. Tetrahedron Lett. 2001, 42, 3251–3254; (f) Lindley, J. Tetrahedron
1984, 40, 1433–1456; (g) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4120–4121; (h) Klapars, A.; Xiaohua, H.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 7421–7428; (i) Meesala, R.; Nagarajan, R. Tetrahedron
2009, 65, 6050–6056.
655 cmÀ1 1H NMR (400 MHz, TMS, CDCl3): d 11.4 (1H, s, NH), 8.37 (1H, d,
:
J = 4.0 Hz), 7.61 (1H, t, J = 8.0 Hz), 7.53–7.45 (3H, m), 7.22 (1H, d, J = 8.0 Hz), 3.76
(3H, s), 2.50 (3H, s); 13C NMR (100 MHz, TMS, CDCl3): d 181.9, 143.2, 143.0, 142.3,
136.7, 136.4, 130.3, 129.9, 128.7, 127.0, 123.7, 121.3, 117.8, 114.5, 108.0, 34.5,
17.9; LC–MS: m/z = 296.5 (M), 298.5 (M+2). Compound 5d: mp 202–203 °C; IR
(KBr): 2924, 1628, 1520, 1415, 1261, 1080, 866, 802, 767, 663, 601 cmÀ1 1HNMR
;
(400 MHz, TMS, CDCl3): d 8.45 (1H, s), 8.31 (1H, d, J = 8.4 Hz), 7.96 (1H, d,
J = 8.8 Hz), 7.83 (1H, d, J = 9.2 Hz), 7.69 (1H, d, J = 8.8 Hz), 7.50 (1H, s), 3.8 (3H, s),
2.54 (3H, s); 13C NMR (100 MHz, TMS, CDCl3): d 138.5, 136.1, 134.0, 133.6, 132.1,
132.0, 127.4, 126.6, 123.7, 121.79, 121.75, 120.2, 119.3, 116.2, 107.5, 31.2, 14.0;
LC–MS: m/z
= 315 (M), 317 (M+2); Anal. Calcd for molecular formula
C17H12N2Cl2: C, 64.78; H, 3.84; N, 8.89. Found: C, 64.81; H, 3.88; N, 8.93.
13. Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S.. In Comprehensive Organic synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 3, pp 293–339.
16. CCDC number of 5g is 737672.