Palladium-catalyzed heteroarylamination of ethyl 2-chloro-1-azaazulene-3-carboxylate and annulation of heteroarylamino-1-azaazulenes

Article abstract of DOI:10.3987/COM-08-S(D)6

The palladium catalyzed heteroarylamination of ethyl 2-chloro-l-azaazulene-3-carboxylate was achieved using a catalyst based on Pd₂(dba)₃/Xantphos system. Treatment of ethyl 2-(heteroarylamino)-1-aza-azulene-3-carboxylates with a PPA

Full text of DOI:10.3987/COM-08-S(D)6

HETEROCYCLES, Vol. 79, 2009
319
HETEROCYCLES, Vol. 79, 2009, pp. 319 - 324. © The Japan Institute of Heterocyclic Chemistry
Received, 30th July, 2008, Accepted, 1st September, 2008, Published online, 1st September, 2008.
DOI: 10.3987/COM-08-S(D)6
PALLADIUM-CATALYZED HETEROARYLAMINATION OF ETHYL
2-CHLORO-1-AZAAZULENE-3-CARBOXYLATE AND ANNULATION
OF HETEROARYLAMINO-1-AZAAZULENES†
Kazuya Koizumi,1 Kunitaka Shimabara,2 Aya Takemoto,2 Shinya
Yamazaki,1 Noriko Yamauchi,1 Hiroyuki Fujii,3 Masaki Kurosawa,4 Takeo
Konakahara,4 and Noritaka Abe1*
1 Applied Molecular Bioscience, Graduate School of Medicine, and Department
of Biology and Chemistry, Faculty of Science, Yamaguchi University, Yoshida,
Yamaguchi 753-8512, Japan
2 Department of Chemistry, Faculty of Science, Yamaguchi University, Yoshida,
Yamaguchi 753-8512, Japan
3 Science Research Center, Yamaguchi University, Yamaguchi 753-8512, Japan
4 Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science, Noda, Chiba 278-8510, Japan
Abstract
–
The palladium catalyzed heteroarylamination of ethyl
2-chloro-1-azaazulene-3-carboxylate was achieved using a catalyst based on
Pd2(dba)3 / Xantphos system. Treatment of ethyl 2-(heteroarylamino)-1-aza-
azulene-3-carboxylates with a PPA-POCl3 mixture gave corresponding annulation
products. 2-(2-Benzothiazolylamino)-1-azaazulene (3h) showed anticancer
activity against HeLa S3 cells (IC50: 6.5 µM).
In recent years Pd-catalyzed amination of aryl halides has attracted attention,1 because aryl amines have a
potential functionality in pharmaceutical drug candidates.2-6 The chemistry of azaazulenes7 is of interest
for their physiological properties8,9 as well as physical and chemical properties. Therefore, it is
expected that heteroarylamino-1-azaazulenes have potential bioactivities.
It is known that ethyl 2-chloro-1-azaazulene-3-carboxylate (1) reacted with good nucleophile, such as
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
† Dedicated to the memory of late Dr. John Daly.

320
HETEROCYCLES, Vol. 79, 2009
alkoxide, amine, and sulfoxide, to give corresponding 2-substituted-1-azaazulenes.7 Indeed, when 1 was
treated with aniline (2a) in EtOH under reflux for 30 min, ethyl 2-anilino-1-azaazulene-3-carboxylate
(3a) was obtained in 88% yield. Whereas, the reaction of 1 with inferior nucleophile did not undergo
well, and reactions of 1 with 2-aminopyridine (2b) or 4-aminopyridine (2c) did not give corresponding
substituted products.
CO2Et
CO2Et
∆
Cl
+
PhNH2
NH Ph
N
N
3a
1
2a
Therefore, we tried to use pyridinium aminide as superior nucleophile, which was produced by treating
aminopyridine with NaH in dioxane under argon atmosphere. Reaction of 1 with 2-aminopyridine (2b)
in the presence of NaH in dioxane at 120 ℃ for 24 h gave a complex mixture, and a trace amount of 3b
was isolated along with 1 (47%). On the other hand, when 1 was treated with 4-aminopyridine (2c) in
the presence of NaH in dioxane for 6 h at 140 ℃, 3c was isolated in 40% yield.
CO2Et
CO2Et
NaH
Cl
+
ArNH2
NH Ar
in dioxane
N
N
2b : Ar = 2-Py
1
3b : Ar = 2-Py
3c
2c
: Ar = 4-Py
: Ar = 4-Py
Recently, metal-catalyzed cross coupling of aryl halides with amines are extensively investigated.
Therefore, we adopted metal catalyzed amination of 2-chloro-1-azaazulene. At first, Ullmann-type
Cu-mediated cross coupling10,11 was examined. Treatment of 1 with 2b in the presence of CuI, PPh3,
t
and BuOK in toluene gave a complex mixture, and 3b was obtained only 1% yield together with 1
(55%).
CO2Et
Cl
CO2Et
NH Ar
CuI, PPh3
+
ArNH2
tBuOK in toluene
N
N
2b : Ar = 2-Py
1
3b : Ar = 2-Py
Next, we examined Pd-mediated amination.1 It is known that Pd2(dba)3-catalyzed amination of aryl
halides in the presence of Xantphos as a ligand is excellent method.12,13 Therefore, we treated 1 with 2b
in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 in dioxane at 120 ℃ for 24 h, and 3b was obtained
t
in 72% yield along with 1 (10%). When above reaction was carried out in the presence of BuOK as
base,
3b
was
obtained
in
40%
yield
together
with
1
(7%)
and
ethyl
2-oxo-1,2-dihydro-1-azaazulene-3-crboxylate (4) (15%). Similar reaction of 1 with 2c in the presence
of Pd2(dba)3, Xantphos, and Cs2CO3 in dioxane at 120 ℃ for 24 h, gave 3c in 59% yield.

HETEROCYCLES, Vol. 79, 2009
321
CO2Et
Cl
CO2Et
NH Ar
CO2Et
O
Pd catalyst
Xantphos, Base
+
ArNH2
N
N
N
H
1
2b-2j
3b-3j
4
Table 1. Coupling reaction of 1 with heteroaryl amines in the presence of Pd2(dba)3,
Xantphos, and Cs2CO3.
Entry
ArNH2
Product
Yield / % (recovery %)
CO2Et
N
N
H
N
NH2
1
2
3b
3c
: 72 (10)
: 59 ( - )
2b
N
CO2Et
H
N
N
NH2
NH2
N
N
2c
2d
CO2Et
N
N
N
N
H
N
3
3d : 50 (trace)
N
CO2Et
N
N
H
N
NH2
NH2
3e
4
5
: 73 ( - )
2e
2f
N
N
N
CO2Et
S
S
H
N
3f : 67 ( - )
N
N
N
H
N
CO2Et
H
N
H
N
6
7
NH2
3g : 52 (trace)
3h : 65 ( - )
N
N
2g
2h
N
CO2Et
S
N
S
N
H
N
NH2
N
CO2Et
N
8
9
H
N
NH2
3i : 70 ( - )
N
N
2i
Ph
N
CO2Et
NH2
3j : 52 ( - )
N
H
2j
N
N
Ph
O
N
N
N
NH2 2k
10
5k : 44 ( - )
N

322
HETEROCYCLES, Vol. 79, 2009
In a similar manner, reactions of 1 with some heteroarylamines were examined.14 Some results were
shown in Table 1. Interestingly, in the reaction of 1 with 2k, auto-Tandem catalysis15 occurred and
annulated product (5k) was obtained in 44% yield in one-pot.
Next, we examined the annulation of 3b-3i. When 3b was treated with polyphosphoric acid (PPA) at
150 ℃
for 5 h, cyclized product (5b) was obtained in 83% yield together with
2-(2-pyridylamino)-1-azaazulene (6) (10%), which was a deestrification product. For enhance the
annulation yield, we treated 3b with POCl3-PPA mixture at 150 ℃ for 5 h, and obtained 5b in 98%
yield. Similar treatment of 3c-3j gave corresponding annulated products (7 and 5d-5j) in moderate to
good yields.16
O
heteroaromatic
N
N
CO2Et
heteroaromatic
POCl3-PPA
N
H
N
∆
N
N
3b,3d-3i
5b,5d-5i
N
O
N
N
O
O
N
N
N
N
NH
N
N
NH
N
N
6
5d
7
: 63%
: 75%
5b : 98%
O
N
O
O
N
N
N
S
NH
N
N
N
N
N
N
5e
5g
: 91%
: 58%
5f
: 93%
Ph
O
O
O
N
N
N
N
S
N
N
N
N
N
5j
: 94%
5i
: 52%
5h
: 92%
Some newly synthesized products (3d, 3g, 3h) were evaluated for their anticancer activity (cytotoxic
activity) against HeLa S3 cells. The IC50 values [µM] are summarized in Table 2. In a case (denoted
>), the minimum inhibitory concentration could not be determined due to limited solubility of the

HETEROCYCLES, Vol. 79, 2009
323
compound in the testing medium. The results revealed that the compound (3h) showed moderate
activity and the compound (3d) showed weak activity against HeLa S3 cells (It is considered that IC50 >
30 µM is inactive).
Table 2. Cytotoxic evaluation of compounds (3d, 3g, 3h) expressed in µM.
3d
3g
3h
IC50
>7.5
23±3
6.5±1.4
In summary, the Pd-mediated coupling of ethyl 2-chloro-1-azaazulene-3-carboxylate (1) with wide range
of heteroarylamines was described. Annulation of ethyl heteroarylamino-1-azaazulene-3-carboxylates
using a POCl3-PPA mixture is useful for preparing new numerical heterocycles. Some ethyl
heteroarylamino-1-azaazulene-3-carboxylates showed anticancer activity against HeLa S3 cells.
REFERENCES AND NOTES
1. For the reviews on the Pd-catalyzed amination reactions, see (a) J. F. Hartwig, Angew. Chem. Int. Ed.,
1998, , 2046; (b) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, and S. L. Buchwald, Acc. Chem. Res.,
37
1998, , 805; (c) B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999,
31
, 125; D. Prim,
576
J.-M. Campagne, D. Joseph, and B. Andrioletti, Tetrahedron, 2002, , 2041.
58
2. D. Lednicer, Strategies for Organic Drug Synthesis and Design; John Wiley and Sons, New York,
1998.
3. S. Tasler, J. Mies, and M. Lang, Adv. Synth. Catal., 2007, 349, 2286.
4. R. Jiang, D. Duckett, W. Chen, J. Habel, Y. Y. Ling, P. Lograsso, and T. M. Kamenecka, Bioorg.
Med. Chem. Lett., 2007, 17, 6378.
5. W. Huang, W. Zheng, D. J. Urban, J. Inglese, E. Sidransky, C. P. Austin, and C. J. Thomas, Bioorg.
Med. Chem. Lett., 2007, 17, 5783.
6. P. Ballard, B. C. Barlaam, R. H. Bradbury, A. Dishington, L. F. A. Hennequin, D. M. Hickinson, I.
M. Hollingsworth, J. G. Kettle, T. Klinowska, D. J. Oglivie, S. E. Pearson, J. S. Scott, A. Suleman, R.
Whittaker, E. J. Williams, R. Wood, and L. Wright, Bioorg. Med. Chem. Lett., 2007, 17, 6326.
7. For reviews see, N. Abe, ‘Recent Research Developments in Organic and Bioorganic Chemistry’
2001, 4, 14, Transworld Research Network; T. Nishiwaki and N. Abe, Heterocycles, 1981, 15, 547;
M. Kimura, Yuki Gosei Kagaku Kyokai Shi, 1981, 39, 690.
8. T. Ishikawa and A. Zeimoto, Jpn. Kokai Tokkyo Koho, JP 1999, 11,255,746.

324
HETEROCYCLES, Vol. 79, 2009
9. M. Nagahara, J. Nakano, M. Miura, T. Nakamura, and K. Uchida, Chem. Pharm. Bull., 1994, 42,
2491.
10. For reviews see, S. V. Ley and A. W. Thomas, Angew. Chem. Int. Ed., 2003, 42, 5400.
11. Z. Lu, R. J. Twieg, and S. D. Huang, Tetrahedron Lett., 2003, 44, 6289, and references therein.
12. J. Yin, M. M. Zhao, A. Huffman, and M. McNamara, Org. Lett., 2002, 4, 3481.
13. S. B. Larsen, B. Bang-Andersen, T. N. Johansen, and M. Jφrgensen, Tetrahedron, 2008, 64, 2938.
14. A representative procedure of the amination: A mixture of 1 (0.2228 g, 0.95 mmol),
2-aminobenzo-thiazol (3e) (0.1402 g, 0.093 mmol), Xantphos (0.0533 g, 0.0092 mmol), Pd2(dba)3
(0.0580 g, 0.0063mmol), Cs2CO3 (0.3176 g, 0.980 mmol), and dry 1,4-dioxane (2.5 mL) in a sealed
tube under argon atmosphere was heated at 120 ℃ for 22 h under stirring, then water (20 mL) was
added. The mixture was extracted with CHCl3. The extract was dried over Na2SO4, and
evaporated. Chromatography of the residue with EtOAc-hexane (1 : 8) gave 3h (0.2106 g, 65%).
3h : Orange needles (from CH2Cl2-hexane), mp 177-178 ℃; 1H NMR (CDCl3) δ 10.71 (1H, s, NH),
9.09 (1H, d, J = 10.0, H-4), 8.48 (1H, d, J = 9.6, H-8), 7.82 (1H, d, J = 8.0, H-7’), 7.81 (1H, dd, J =
10.0, 9.6, H-7), 7.77 (1H, dd, J = 10.0, 9.6, H-5), 7.74 (1H, dd, J = 7.2, 1.2, H-4’), 7.71 (1H, dd, J =
10.0, 9.6, H-6), 7.43 (1H, t, J = 7.2, H-5’), 7.27 (1H, ddd, J = 8.0, 7.2, 1.2, H-6’), 4.53 (2H, q, J = 7.2,
CH2), 1.52 (3H, t, J = 7.2, CH3); 13C NMR (CDCl3) δ 165.2, 161.7, 159.4, 159.2, 149.6, 147.1, 135.1,
133.7, 133.5, 133.3, 133.2, 132.7, 126.0, 123.1, 121.0, 120.5, 99.1, 60.7, 14.7; νmax / cm-1 1653
(C=O), 3249 (NH); λmax nm (log ε) 277 (4.59), 308 (4.45, sh), 393 (4.78), 444 (3.71, sh). Anal.
Calcd for C19H15N3O2S: C, 65.31; H, 4.33; N, 12.03. Found: C, 65.73; H, 4.32; N, 11.88.
15. C. Mayers, G. Rombouts, K. T. J. Loones, A. Coelho, and B. U. W. Maes, Adv. Synth. Catal., 2008,
350, 465.
16. A representative procedure of the annulation: A mixture of 3h (0.0735 g, 0.21 mmol), PPA (5 mL),
and POCl3 (1.5 mL) was heated at 150 ℃ for 4 h under stirring, and then ice-water (20 mL) was
added. The mixture was neutralized with Na2CO3. Then the precipitate was collected by filtration,
1
and 5h (0.0589g, 92%) was obtained. 5h : Yellow prisms (CHCl3-EtOH), mp 259-261 ℃; H
NMR (DMSO-d6) δ 9.50 (1H, dd, J = 9.2, 1.6, H-12), 9.08 (1H, dd, J = 8.4, 1.2, H-1), 8.84 (1H, dd, J
= 10.0, 1.6, H-8), 8.32-8.24 (3H, m, H-9,11,12), 8.10 (1H, dd, J = 8.4, 1.2, H-4), 7.66 (1H, ddd, J =
13
8.4, 7.6, 1.2, H-3), 7.58 (1H, ddd, J = 8.4, 7.6, 1.2, H-2); CNMR (TFA-d) δ 172.2, 159.1, 158.9,
151.7, 147.7, 144.6, 144.6, 144.4, 144.0, 137.6, 136.2, 131.1, 130.9, 125.4, 124.6, 121.9, 103.7; νmax
/ cm-1 1690 (C=O); λmax nm (log ε) 288 (4.27), 322 (4.45), 375 (3.60, sh), 458 (3.14). Anal. Calcd
for C17H9N3OS: C, 67.31; H, 2.99; N, 13.85. Found: C, 67.25; H, 3.22; N, 14.11.