The strategy to make these bioactive pyrrolotriazines has
relied mainly on a pyrrole N-amination approach.8
Relying on pyrrole N-amination13 to install the key
NÀN bond, we were precluded from using the C2-
aldehyde due to conversion to the nitrile during amination.
Instead, we opted for the higher ester oxidation state; thus,
methyl-2-pyrrole carboxylate (7, Scheme 1) was treated
with chloramine and the crude material reacted with ben-
zoylisothiocyanate to give 8. Hydrolytic cyclization in 2 M
NaOH followed by methylation afforded 9. The choice of
the thiomethyl moiety at C2 was central to providing both
stability to the intermediates and latent reactivity. At this
stage, we required a lower oxidation state at C4 and
regioselective introduction of a halogen at C7. Attempted
bromination of 9 was severely limited by solubility; how-
ever, if chlorination was effected first, bromination pro-
ceeded smoothly to give 11 and with reasonable regio-
selectivity for C7 vs C5 (ca. 5:1); the regioisomers were
carried forward. Importantly, we had now clearly differ-
entiated C2, C4, and C7 and could take advantage of the
highly reactive C4 position. Interestingly, treatment of 11
with NaBH4 resulted in reduction of not only the chloride
but also the derived imine species. Fortunately, oxidation
to restore aromaticity was quite mild and facile with DDQ
to give the key intermediate 12 which was separated from
the 5-Br regiomer at this stage by chromatography.
Figure 1. Pyrrolo[2,1-f][1,2,4]triazine derivatives.
Recently, we reported novel diaminopyrimidine ATP-
competitive inhibitors of anaplastic lymphoma kinase
(ALK).10,11 In an effort to mimic the bioactive conforma-
tion we proposed constraining the diaminopyrimidine into
a 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazine (Figure 2)
which, tothebest ofourknowledge, isa novel modification
ofthis coretemplate and a new kinase inhibitorplatform.12
Scheme 1. Synthesis of Key 2,7-Substituted Intermediate
Figure 2. Initial design of novel 2-anilino-7-aryl-pyrrolo[2,1-f]-
[1,2,4]triazines.
Herein, we describe the discovery synthesis of this new
kinase inhibitor template which includes a late stage ortho-
gonally substituted core structure amenable to rapid diver-
sification as well as an optimized in situ triflate displace-
ment to install the C2-aniline. Furthermore, an efficient
scalable process approach will be described which begins
with readily available tert-butyl carbazate and benefits
from regioselective bromination and acylation culminating
in the formation of the preferred 2-oxo derivative 16.
The challenges associated with the initial synthesis in-
cluded incorporating the appropriate oxidation state at C4
and installation of orthogonally reactive groups at C2 and
C7 to support a late stage diversification strategy.
Intermediate 12 could be advanced to a target molecule
(15, Scheme 2) via orthogonal approaches. Suzuki cou-
pling to phenylboronic acid, followed by oxidation of the
sulfide to sulfoxide 13, provided an appropriate partner for
SNAr displacement with 3,4,5-trimethoxyaniline. Alterna-
tively, 15 was arrived at via the reverse process where the
phenyl group is installed in the final step. As we diversified
our appendages, especially with regard to poorly nucleo-
philic and/or sterically demanding anilines, the sulfoxide
displacement afforded poor yields with multiple side
products. To circumvent this limitation, we focused on
incorporating a more reactive nucleofuge at C2, namely a
triflate or the like. Toward this end we converted the
sulfoxide to the 2-oxo derivative 16. The in situ 16 to 15
transformation could be carried out by triflate formation
followed by SNAr displacement with the aniline. The
methodology offered significant advantages which in-
cluded a one-pot triflate formation/displacement and
milder reaction conditions (room temperature) and was
amenable to a wide variety of anilines. Furthermore, 12
could also be converted to 14 using this chemistry.
(11) Mesaros, E. F.; Burke, J. P.; Parrish, J. D.; Dugan, B. J.;
Anzalone, A. V.; Angeles, T. S.; Albom, M. S.; Aimone, L. D.; Quail,
M. R.; Wan, W.; Lu, L.; Huang, Z.; Ator, M. A.; Ruggeri, B. A.; Cheng,
M.; Ott, G. R.; Dorsey, B. D. Bioorg. Med. Chem. Lett. 2011, 21, 463–
466.
(12) Ott, G. R.; Wells, G. J.; Thieu, T. V.; Quail, M. R.; Lisko, J. G.;
Mesaros, E. F.; Gingrich, D. E.; Ghose, A. K.; Wan, W.; Lu, L.; Cheng,
M.; Albom, M. S.; Angeles, T. S.; Huang, Z.; Aimone, L. D.; Ator,
M. A.; Ruggeri, B. A.; Dorsey, B. D. J. Med. Chem. 2011, in press.
(13) (a) Hynes, J., Jr.; Doubleday, W. W.; Dyckman, A. J.; Godfrey,
J. D., Jr.; Grosso, J. A.; Kiau, S.; Leftheris, K. J. Org. Chem. 2004, 69,
1368–1371. (b) Bhattacharya, A; Patel, N. C.; Plata, R. E.; Peddicord,
M.; Ye, Q.; Parlanti, L.; Palaniswamy, V. A.; Grosso, J. A. Tetrahedron
Lett. 2006, 47, 5341–5343.
Org. Lett., Vol. 13, No. 16, 2011
4205