Synthesis of 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazines by Sonogashira/copper(I)-catalyzed heteroannulation

Article abstract of DOI:10.1016/j.tetlet.2007.05.090

A Sonogashira/copper(I)-catalyzed heteroannulation sequence was developed to convert 3,5-diamino-6-chloro-1,2,4-triazines to the corresponding 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazine derivatives in good yields.

Full text of DOI:10.1016/j.tetlet.2007.05.090

Tetrahedron Letters 48 (2007) 5069–5072
Synthesis of 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazines
by Sonogashira/copper(I)-catalyzed heteroannulation
Coralie Nyffenegger, Guy Fournet and Benoˆıt Joseph*
Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires, Laboratoire de Chimie Organique 1, UMR—CNRS 5246,
Universite´ de Lyon, Universite´ Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Received 7 April 2007; revised 27 April 2007; accepted 15 May 2007
Available online 18 May 2007
Abstract—A Sonogashira/copper(I)-catalyzed heteroannulation sequence was developed to convert 3,5-diamino-6-chloro-1,2,4-tri-
azines to the corresponding 3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazine derivatives in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
+
3-Aminopyrrolo[2,3-d]pyrimidine ring 1 is present in
many anticancer agents recently described (dihydro-
folate reductase or thymidylate synthase inhibitors,
aurora kinase inhibitors, EGFR receptor inhibitors,
HSP-90 inhibitors).1 The pyrrolo[2,3-e]-1,2,4-triazine
moiety can be considered as a bioisostere of this nucleus
and is mainly encountered in 5H-1,2,4-triazino[5,6-b]-
indole derivatives which also displayed pharmacological
and biological properties.2 These latter compounds have
been widely prepared by condensation of isatine on thio-
carbazide. As part of our ongoing programme directed
towards the design of new kinase inhibitors, we have
developed the synthesis of 6-substituted 3-amino-5H-
pyrrolo[2,3-e]-1,2,4-triazines 2 as potential scaffolds for
new anticancer agents (Fig. 1).
N
N
N
N
N
pyrrolidine
N
Ph
Ph
N
N
N
Me
51%
-
BF4
Me
Scheme 1.
In 2003, the synthesis of 6-phenylpyrrolo[2,3-e]-1,2,4-tri-
azine was described through a fragmentation reaction
of 1-methyl-2-phenylpyrrolo[2,3-e]pyrido[1,2-b]-1,2,4-
triazinium tetrafluoroborate (Scheme 1).3c
The undeniable success of the synthesis of indoles,4
azaindoles4b–d,5 and other related heterocycles4b–d,6 by
cyclization of appropriately functionalized o-aminoacet-
ylenes, prepared by Sonogashira reaction of the corre-
sponding aryl halide and terminal alkyne, prompted us
to develop access to 6-substituted 3-amino-5H-pyr-
rolo[2,3-e]-1,2,4-triazine by the same way (Scheme 2).
Final cyclization of the alkyne intermediate to reach
the desired heterocycles should be effective either by iodo-
cyclization4e or by base-mediated4b–d,5c or, by transition
metal-mediated cyclization.5a
Few synthetic pathways of pyrrolo[2,3-e]-1,2,4-triazine
or related nuclei have been reported in the literature.3
7
N
N
N
R4
R1
R1
N
N
N
N
N
N
R3
R3
R2
R2
1
2
R3
N
N
N
N
N
R3
N
1,2,4-triazino[5,6-
b]indole
N
R1
R1
N
Bn
N
N
N
H
R2
N
N
NHBn
H
R2
Figure 1.
N
Cl
N
R3
+
Keywords: 1,2,4-Triazine; Alkyne; Palladium; Heteroannulation.
Cl
N
Cl
*
Corresponding author. Tel.: +33 472 448 135; fax: +33 472 431
214; e-mail: benoit.joseph@univ-lyon1.fr
Scheme 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.090

5070
C. Nyffenegger et al. / Tetrahedron Letters 48 (2007) 5069–5072
N
Cl
BnNH2 in excess, dioxane, rflx, overnight
N
93%
BnHN
N
NHBn
4a
BnNH2 (1 equiv)
Et3N, THF
-15 ºC to 0 ºC, 2 h
R1R2NH (2 equiv)
dioxane, rflx, 2 h
N
Cl
N
N
Cl
N
Cl
Cl
N
N
N
R1
N
N
NHBn
see Table 1
90%
Cl
NHBn
Cl
N
R2
5
3
4b-f
H
R3
R3
PdCl2(PPh3)2 (10 mol%)
CuI (10 mol%), Et3N
DMF, 50 ºC, 5h
CuI (10 mol%)
Et3N, MeOH
N
N
N
N
N
R3
rflx, 3 h
R1
R1
4
N
Bn
N
N
NHBn
N
see Table 2
R2
R2
6
7
Scheme 3.
Table 2. Synthesis of compounds 7a–i
3,5-Diamino-6-chloro-1,2,4-triazines 4 were first ob-
tained from the readily available 3,5,6-trichloro-1,2,4-
triazine 3 (Scheme 3). This key precursor was prepared
in two steps from the commercially available 6-azaura-
cil.7 Treatment of 3 with an excess of benzylamine
afforded N,N-dibenzyl derivative 4a8 in 93% yield.9
Benzylamine was also selectively introduced on C-5
position of 3.9,10 Thus, the reaction of 1 equiv of benzyl-
amine with 3 was carried out at À15 °C to afford 511 in
90% yield. 1,2,4-Triazines 4b–f12 were obtained in 57%
to 96% yields (Table 1) by treatment of 5 and various
amines R1R2NH (2 equiv) in dioxane at reflux
overnight.
R1
R2
R3
7—Yielda (%)
H
Bn
Propyl
7a—77
7b—73
7c—82
7d—71
7e—71
7f—62
7g—67
7h—72
7i—50
–(CH2)2–O–(CH2)2–
Propyl
H
Cyclopropyl
Propyl
–(CH2)4–
Propyl
H
4-MeO–Ph
Propyl
Me
H
H
H
H
Ph
Bn
Bn
Bn
Bn
Propyl
–CH2–N(Me)2
Ph
–CH2–O–THP
SiMe3
b
—
a Isolated yield.
b Complex mixture (not separable).
At this point, the Sonogashira cross-coupling reaction13
followed by heteroannulation on model derivative 4a
(pent-1-yne, PdCl2(PPh3)2, CuI, Et3N, DMF, 50 °C) in
a one pot reaction was investigated (Scheme 3). In our
hands, attempts to obtain 7a from 4a were not efficient.
Prolonged reaction times or elevated temperatures pro-
vided always a mixture of desired product 7a and acety-
lenic intermediate 6a. Cyclized compound was obtained
with an optimum yield when a two step procedure was
performed. Thus, derivatives 4a–f were first submitted
to Sonogashira reaction in the presence of pent-1-yne,
PdCl2(PPh3)2 (10 mol %) and CuI (10 mol %) for 5 h
at 50 °C. The mixture was then concentrated in vacuo
and the crude intermediates 6a–f were refluxed in
MeOH/Et3N solution (3:1) with a catalytic amount of
CuI for 3 h. By this way, compounds 7a–f14 were iso-
lated in 62–82% yields (typically 0.3 mmol scale, Table
2). Exemplification of the method was carried out
(Sonogashira reaction then Cu-mediated cyclization)
on 4a with miscellaneous alkynes (N,N-dimethylamino-
prop-1-yne, phenylethyne, 4-tetrahydropyran-2-yloxy-
but-1-yne and (trimethylsilyl)ethyne) to afford 7g–i in
fair yields (Table 2). It should be noted that the silyl
group does not tolerate the cyclization reaction condi-
tions. In this case, a complex mixture of silylated and
desilylated derivatives was obtained (not separable by
column chromatography). Iodocyclization of 6a was
investigated to reach 7-iodopyrrolo[2,3-e]-1,2,4-triazine
derivative. Unfortunately, in our hands, attempts (e.g.,
I2, CHCl3, room temperature) led to the degradation
of the starting material.
In summary, the Sonogashira/copper(I)-catalyzed
heteroannulation sequence was developed to convert
3,5-diamino-6-chloro-1,2,4-triazines to the 6-substituted
3-amino-5H-pyrrolo[2,3-e]-1,2,4-triazine
derivatives.
The method described here provides an efficient route
to obtain the 5H-pyrrolo[2,3-e]-1,2,4-triazine scaffold.
Further investigation on base-mediated cyclization of 6
will be reported in due course.
Acknowledgement
Table 1. Synthesis of compounds 4a–f
R1R2NH
R1
R2
4—Yielda (%)
Funding by the European Commission (Contract No.
LSHB-CT-2004-503467) is gratefully acknowledged.
BnNH2
H
Bn
4a—93
4b—89
4c—92
4d—96
4e—91
4f—57
Morpholine
Cyclopropylamine
Pyrrolidine
4-MeO–C6H4NH2
PhNHMe
–(CH2)2–O–(CH2)2–
Cyclopropyl
–(CH2)4–
H
References and notes
H
Me
4-MeO–Ph
Ph
1. (a) Gangjee, A.; Yu, J.; Kisliuk, R. L. J. Heterocycl.
Chem. 2002, 39, 833–840; (b) Gangjee, A.; Yang, J.; Ihnat,
a Isolated yield.

C. Nyffenegger et al. / Tetrahedron Letters 48 (2007) 5069–5072
5071
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for 2 h. After completion of the reaction, solids were
removed by filtration and the filtrate concentrated in
vacuo. The crude product was then recrystallized from
EtOH to give pure 5 (439 mg, 90%) as a solid. Mp 136–
137 °C (EtOH); IR (KBr) m 3220, 3160, 3080, 2975, 1600,
1495, 1370, 1255, 1200, 1050, 930 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d 4.72 (d, 2H, J = 5.6 Hz, CH2Bn),
6.15 (br s, 1H, NH), 7.34–7.44 (m, 5H, HAr); 13C NMR
(75 MHz, CDCl3) d 45.4 (CH2), 128.3 (2CH), 128.5 (CH),
129.1 (2CH), 135.7 (C), 142.8 (C), 152.3 (C), 161.8 (C);
HRMS (EI) for C10H8Cl2N4, Calcd: 254.0126. Found:
254.0127.
12. Compound 4b: A solution of 5 (182 mg, 0.71 mmol) and
morpholine (0.25 mL, 4 equiv) in THF (7 mL) was heated
at reflux overnight. After removing the solids, the filtrate
was concentrated in vacuo. The residue was purified by
column chromatography (PE/EtOAc 1:1) to give 4b
(194 mg, 89%) as a solid. Mp 145–146 °C (EtOH); IR
(KBr) m 3280, 3085, 3035, 2955, 2860, 1580, 1530, 1500,
2. (a) Kinsman, O. S.; Livermore, D. G.; Smith, C. Antimic-
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Natl. Acad. Sci. U.S.A. 2000, 97, 7981–7986; (c) Harris,
W.; John, D. E.; Firth-Clark, S. WO 2004096808; Chem.
Abstr. 2004, 141, 410968; (d) Kgokong, J. L.; Smith, P. P.;
Matsabia, G. M. Bioorg. Med. Chem. 2005, 13, 2935–2942.
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C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571–1587; (e) Dawei, Y.; Larock,
R. C. Org. Lett. 2004, 6, 1037–1040.
1450, 1275, 1250, 1120, 950, 890 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d 3.73–3.79 (m, 8H, CH2), 4.63 (d,
2H, J = 5.7 Hz, CH2Bn), 5.80 (br s, 1H, NH), 7.30–7.41
(m, 5H, HAr); 13C NMR (75 MHz, CDCl3) d 44.2 (2CH2),
44.6 (CH2Bn), 66.7 (2CH2), 127.7 (2CH), 127.9 (CH),
128.8 (2CH), 134.0 (C), 137.2 (C), 151.1 (C), 159.9 (C);
HRMS (EI) for C14H16ClN5O, Calcd: 305.1043. Found:
305.1045. Compound 4c: solid. Mp 147–148 °C (EtOH);
IR (KBr) m 3420, 3330, 3065, 3000, 1620, 1545, 1510, 1340,
1120, 770, 695 cmÀ1; 1H NMR (300 MHz, CDCl3) d 0.52–
0.58 (m, 2H, CH2), 0.76–0.82 (m, 2H, CH2), 2.71–2.80 (m,
1H, CH), 4.65 (d, 2H, J = 5.8 Hz, CH2Bn), 5.41 (br s, 1H,
NH), 5.87 (br s, 1H, NH), 7.31–7.36 (m, 5H, HAr); 13C
NMR (75 MHz, CDCl3) d 7.3 (2CH2), 24.0 (CH), 44.5
(CH2Bn), 128.0 (3CH), 128.9 (2CH), 134.4 (C), 137.3 (C),
151.6 (C), 161.8 (C); HRMS (EI) for C13H14ClN5, Calcd:
275.0938. Found: 275.0937.
5. (a) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B.
Tetrahedron Lett. 1998, 39, 5159–5162; (b) Mazeas, D.;
Guillaumet, G.; Viaud, M.-C. Heterocycles 1999, 50,
1065–1080; (c) Harcken, C.; Ward, Y.; Thomson, D.;
Riether, D. Synlett 2005, 3121–3125.
13. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467–4470.
6. (a) Ames, D. E.; Brohi, M. I. J. Chem. Soc., Perkin Trans.
1 1980, 7, 1384–1389; (b) Ames, D. E.; Bull, D. Tetrahe-
dron 1982, 38, 383–387; (c) Norman, M. H.; Chen, N.;
Chen, Z.; Fotsch, C.; Hale, C.; Han, N.; Hurt, R.; Jenkins,
T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.; Santora, V.
J.; Sonnenberg, J. D.; Karbon, W. J. Med. Chem. 2000, 43,
4288–4312.
7. Loving, B. A.; Snyder, C. E., Jr.; Whittier, G. L.;
Fountain, K. R. J. Heterocycl. Chem. 1971, 8, 1095–1096.
8. Compound 4a: solid. Mp 142–144 °C (EtOH), IR (KBr) m
3405, 3240, 3185, 3070, 1615, 1555, 1420, 1340, 1275, 1140,
1060, 745, 716, 700 cmÀ1; 1H NMR (300 MHz, DMSO-d6)
d 4.38 (br s, 2H, CH2Bn), 4.50 (d, 2H, J = 5.6 Hz,
CH2Bn), 7.19–7.26 (m, 10H, HAr), 7.76 (br s, 1H, NH),
8.28 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d
43.1 (CH2), 44.0 (CH2), 126.6 (CH), 126.9 (CH), 127.2
(2CH), 127.4 (2CH), 128.1 (2CH), 128.3 (2CH), 133.0 (C),
138.6 (C), 140.1 (C), 151.1 (C), 160.6 (C); HRMS (EI) for
C17H16ClN5, Calcd: 325.1094. Found: 325.1094.
14. Compound 7a: To a solution of 4a (127 mg, 0.39 mmol),
CuI (6 mg, 10 mol %) and PdCl2(PPh3)2 (27 mg, 10 mol %)
in DMF (0.65 mL) was added Et3N (0.22 mL, 4 equiv)
and pent-1-yne (0.19 mL, 5 equiv). The mixture was
stirred at 50 °C for 5 h and concentrated in vacuo. The
crude product was then refluxed with CuI (7.6 mg,
10 mol %) in MeOH/Et3N (3.6 mL, 7/3 v/v) for 3 h.
Solvents were removed in vacuo and the residue purified
by column chromatography (PE/EtOAc 1:1) to give 7a
(107 mg, 77%) as a solid. Mp 150–151 °C; IR (KBr) m
3230, 3030, 2960, 1600, 1525, 1410, 1080, 765, 725,
1
700 cmÀ1; H NMR (300 MHz, DMSO-d6) d 0.91 (t, 3H,
J = 7.3 Hz, CH3), 1.59 (hex, 2H, J = 7.3 Hz, CH2), 2.58 (t,
2H, J = 7.3 Hz, CH2), 4.54 (d, 2H, J = 6.2 Hz, CH2Bn),
5.26 (s, 2H, CH2Bn), 6.44 (s, 1H, CHAr), 7.05–7.08 (m,
2H, HAr), 7.18–7.34 (m, 8H, HAr), 7.82 (br s, 1H, NH); 13
C
NMR (75 MHz, DMSO-d6) d 13.6 (CH3), 20.3 (CH2), 28.0
(CH2), 43.5 (CH2Bn), 44.2 (CH2Bn), 96.9 (CH), 126.5
(CH), 126.7 (2CH), 127.3 (2CH), 127.4 (CH), 128.1 (2CH),
128.7 (2CH), 137.2 (C), 140.4 (C), 140.9 (C), 144.1 (C),
145.2 (C), 159.1 (C); HRMS (EI) for C22H23N5, Calcd:
357.1953. Found: 357.1951. Compound 7b: amorphous
solid; IR (KBr) m 3085, 3030, 2960, 2840, 1605, 1500, 1415,
9. (a) Neunhoeffer, H.; Lehmann, B. Chem. Ber. 1976, 109,
1113–1119; (b) Sanemitsu, Y.; Nakayama, Y.; Tanabe, Y.;
Matsumoto, H.; Hashimoto, S. Agric. Biol. Chem. 1990,
54, 3367–3369.
10. Nakayama, Y.; Sanemitsu, M.; Nagano, Y.; Hashimoto,
S. Matsumoto, K. Japan Patent JP 57082378; Chem.
Abstr. 1982, 97, 182463.
1350, 1260, 1245, 1105, 1085, 955 cmÀ1 1H NMR
;
(300 MHz, CDCl3) d 0.95 (t, 3H, J = 7.4 Hz, CH3), 1.66
(hex, 2H, J = 7.4 Hz, CH2), 2.52 (t, 2H, J = 7.4 Hz, CH2),
3.79–3.87 (m, 8H, CH2), 5.26 (s, 2H, CH2Bn), 6.43 (s, 1H,
CHAr), 7.05–7.07 (m, 2H, HAr), 7.21–7.33 (m, 3H, HAr);
13C NMR (75 MHz, CDCl3) d 13.8 (CH3), 20.6 (CH2),
28.9 (CH2), 44.2 (CH2Bn), 44.7 (2CH2), 66.8 (2CH2), 97.8
(CH), 126.6 (2CH), 127.7 (CH), 128.8 (2CH), 136.8 (C),
11. Compound 5: To a solution of 3,5,6-trichloro-1,2,4-
triazine
3 (353 mg, 1.91 mmol) and Et3N (0.32 mL,
1.2 equiv) in THF (19 mL) was added dropwise benzyl-
amine (0.21 mL, 1.02 equiv) at À15 °C. The solution was
stirred for 30 min at this temperature and warmed to 0 °C

5072
C. Nyffenegger et al. / Tetrahedron Letters 48 (2007) 5069–5072
141.7 (C), 144.8 (C), 146.3 (C), 158.9 (C); HRMS (EI) for
(m, 1H, CH), 5.28 (s, 2H, CH2Bn), 6.08 (br s, 1H, NH),
6.44 (s, 1H, HAr), 7.11–7.14 (m, 2H, HAr), 7.26–7.31 (m,
3H, HAr); 13C NMR (75 MHz, CDCl3) d 7.4 (2CH2), 13.9
(CH3), 20.6 (CH2), 24.1 (CH), 29.1 (CH2), 44.7 (CH2Bn),
98.3 (CH) 127.0 (2CH), 128.1 (CH), 129.0 (2CH), 136.3
(C), 141.3 (C), 145.8 (C), 148.4 (C), 158.9 (C); HRMS (EI)
for C18H21N5, Calcd: 307.1797. Found: 307.1799.
C19H23N5O, Calcd: 337.1903. Found: 337.1905. Com-
pound 7c: amorphous solid; IR (KBr) m 3210, 3080, 2960,
1600, 1520, 1385, 1090, 770,700 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d 0.60 (br s, 2H, CH2), 0.79–0.87 (m,
2H, CH2), 0.98 (t, 3H, J = 7.4 Hz, CH3), 1.69 (hex, 2H,
J = 7.4 Hz, CH2), 2.56 (t, 2H, J = 7.4 Hz, CH2), 2.78–2.88