Rapid access to pyrido[1,2,5]triazepin-4-ones through intramolecular nucleophilic aromatic substitution

Article abstract of DOI:10.1016/j.tetlet.2011.12.132

Several 3-substituted pyrido[1,2,5]triazepin-4-ones and their benzo counterparts have been prepared in three steps from commercial starting materials. The key step involves S_NAr-type intramolecular nucleophilic aromatic substitution of the appr

Full text of DOI:10.1016/j.tetlet.2011.12.132

Tetrahedron Letters 53 (2012) 1278–1281
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid access to pyrido[1,2,5]triazepin-4-ones through intramolecular
nucleophilic aromatic substitution
⇑
Shujuan Jin , Olivier St-Jean, Sandra I. Baltatu, Vijayaratnam Santhakumar, Mirosław J. Tomaszewski
Department of Medicinal Chemistry, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec, Canada H4S 1Z9
a r t i c l e i n f o
a b s t r a c t
Article history:
Several 3-substituted pyrido[1,2,5]triazepin-4-ones and their benzo counterparts have been prepared in
three steps from commercial starting materials. The key step involves SNAr-type intramolecular nucleo-
philic aromatic substitution of the appropriate hydrazone substrates.
Received 13 December 2011
Accepted 30 December 2011
Available online 8 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
a-Ketoamides
Microwave-assisted synthesis
Benzo[1,2,5]triazepin-4-ones
Benzodiazepines (BZDs) are among the most widely prescribed
drugs for the treatment of anxiety and related disorders.1 Classical
examples include diazepam and lorazepam (Fig. 1).2 The broad bio-
logical properties of BZDs are believed to arise, at least in part, from
the ability of the benzodiazepine nucleus to mimic a wide range of
b-turns, the proposed bioactive conformation of peptides.3 Related
fused heterocyclic systems, such as [1,2,5] or [1,3,4] benzotriaze-
pines (BTZs), can therefore be regarded as potentially useful
scaffolds for drug discovery. Notwithstanding the promising
biological properties of many such compounds, existing methods
for their synthesis are limited in number and scope.4,5
Cl
O
Cl
Cl
N
N
OH
N
N
H
O
Me
diazepam
lorazepam
Figure 1. Typical benzodiazepine drugs.
We have recently reported a five-step route to 3-substituted
benzo[1,2,5]triazepin-4-ones that makes use of intramolecular
imine formation as the key step6 (Path A; Scheme 1). While this
route proved effective for preparing several pyrido and benzotriaz-
epinones (1–2) from halonitroaromatics, it is somewhat lengthy
due to the need of protection/deprotection of the terminal hydra-
zine. Also, intramolecular imine formation requires long reaction
times and often proceeds with moderate efficiency.6 To overcome
these shortcomings, we decided to explore a new pathway that re-
lies on SNAr-type intramolecular nucleophilic aromatic substitu-
tion (IMNAS, Path B; Scheme 1).
Although SNAr-type IMNAS reactions are frequently used for
constructing 5 to 7-membered heterocycles,7 as well as hetero-
macrocycles,8 examples involving seven-membered ring formation
where the nucleophile is a nitrogen atom are extremely rare.9
Herein we report that such a process provides rapid access to a
6
Path A (previous work) :
R''
N
Y
Y
X
NH
2
R'
R'
imine
formation
NH
NO
2
O
O
R''
N
R
Y
N
R'
R
Path B (this work):
N
H
IMNAS
O
(SNAr)
R''
Y
X
Y
X
1 Y = N
2 Y = CH
R'
R'
-
N
N
NH
NH
2
O
R
Scheme 1. Synthetic approaches to benzotriazepines.
⇑
Corresponding author. Tel.: +1 514 832 3200; fax: +1 514 832 3232.
E-mail address: shujuan.jin@astrazeneca.com (S. Jin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.132

S. Jin et al. / Tetrahedron Letters 53 (2012) 1278–1281
1279
Table 1
Synthesis of a-ketoamides
the corresponding ketoamides (cf. 4f–g, entries 6 and 7). The latter
were ultimately prepared by adaptation of Tani’s procedure
(Method B).15,16
RCOCOCl, DMAP
(Method A)
N
Cl
N
Cl
With a range of a-ketoamide substrates in hand, attention was
or RCOCO2H, DCC
(Method B)
directed towards the preparation of hydrazones. After some
experimentation, we found that condensation with methylhydr-
azine could be conveniently achieved in ethanol under microwave
irradiation at 150 °C for 20–30 min, to afford hydrazones 5a–g of
over 90% purity (LC–MS) after a simple work-up17 (Table 2).
Although the hydrazones were obtained as mixtures of their Z
and E isomers, this was not a concern as such isomers are known
to undergo interconversion upon heating and/or treatment with
bases.18 We therefore reasoned that E to Z isomerization should
be achievable during the ensuing IMNAS reaction under SNAr con-
ditions. Accordingly, the crude E/Z hydrazone mixtures were used
directly in the next step.
Among the various conditions tried for the cyclization of 5a,
the use of NaHMDS in DMF (rt, 2 h) was found particularly effec-
tive, providing pyridotriazepinone 1a6 in a yield of 78% after chro-
matography (entry 1, Table 2).19 This procedure worked equally
well for making new pyridotriazepinones 1b–c19 in which the
C3-phenyl bears an electron-donating group (entries 2 and 3).
In sharp contrast, it failed when the C3-phenyl was equipped
with electron-withdrawing substituents, such as CF3 and NO2.
Nonetheless, we were able to prepare the corresponding pyrido-
triazepinones (1d–e), albeit in low yields, under microwave irra-
diation at 150 °C using N-methylpyrrolidone (NMP) as solvent,
and in the case of 1e, t-BuOK as base (entries 4 and 5).20 Alkyl
NH2
NH
3
4a-g
O
O
R
Entry
R
Method
% Yielda
1
2
3
4
5
6
7
Ph
A
A
A
A
A
B
B
79 (4a)
75 (4b)
72 (4c)
68 (4d)
91 (4e)
20 (4f)
69 (4g)
4-MePh
4-MeOPh
4-CF3Ph
4-NO2Ph
t-Bu
i-Pr
a
Yields of chromatographically isolated products.
range of 3-substituted pyridotriazepinones 1 and some of their
benzo analogues 2.
The synthesis of pyridotriazepinones (PTZs) began with the
preparation of
a-ketoamides 4a–g from commercially available
3-amino-2-chloropyridine (3, Table 1). While the fluoride would
be expected to be a better leaving group in the putative SNAr
reaction (F > Cl > Br),10,11 we chose 3 as the starting material for
two reasons: it is 20-fold less expensive than 3-amino-2-fluoropyr-
idine and obviates the problem of fluoride-induced glass etching of
pilot-scale reactors.12
a
-Ketoamides derived from aromatic ketoac-
substituents lacking
a-hydrogen atoms could be installed at C3,
ids (4a–e, entries 1–5) were obtained in good yields from 3 by
as demonstrated by the preparation of 3-t-butyl pyridotriazepi-
none 1f under standard conditions (58%, entry 6).21 However,
all attempts to prepare the 3-i-propyl analogue (1g, R = i-Pr) were
unsuccessful.
reaction with in situ generated a-ketoacid chlorides, according to
a recently conveyed procedure (Method A).6,13,14 However, this
protocol proved unsuitable for converting aliphatic ketoacids into
Table 2
Synthesis of pyridotriazepinones
Me
N
N
Cl
N
Cl
N
N
MeNHNH2
NaHMDS
R
EtOH, MW
150 °C, 0.5 h
DMF, rt, 2 h
NH NHMe
N
NH
N
H
O
O
O
O
R
4a-g
5a-g
(not purified)
R
1a-g
Entry
1
Product
% Yielda
Entry
4
Product
% Yielda
Me
N
Me
N
N
N
N
N
N
0b
78b
80b
83b
CF
3
41c
N
H
N
H
O
O
1d
1a
Me
N
Me
N
N
N
N
0b
Me
NO
2
2
3
5
6
12d
N
H
N
H
O
O
O
O
1b
1e
Me
N
Me
N
N
N
N
N
Me
Me
Me
58b
OMe
N
H
N
H
1c
1f
a
b
c
All yields refer to chromatographically isolated products after two steps.
Standard conditions (NaHMDS, DMF, rt) were used for the SNAr reaction.
SNAr conditions: NaHMDS, NMP, MW (150 °C), 1 h.
d
SNAr conditions: as in (c) but using t-BuOK as a base.

1280
S. Jin et al. / Tetrahedron Letters 53 (2012) 1278–1281
7. Selected recent examples: (a) Chen, C.-y.; Reamer, R. A. Tetrahedron Lett. 2009,
Cl
Cl
50, 1529–1532; (b) Wilson, R. A.; Chan, L.; Wood, R.; Brown, R. C. D. Org. Biomol.
Chem. 2005, 3, 3228–3235; (c) Harrak, Y.; Weber, S.; Gomez, A. B.; Rosell, G.;
Pujol, M. D. Arkivoc 2007, Part: 4, 251–259; (d) Wen, L.-R.; Jiang, C.-Y.; Li, M.;
Wang, L.-J. Tetrahedron 2011, 67, 293–302; (e) Qin, L.-Y.; Cole, A. G.; Metzger,
A.; Brescia, M.-R.; Saionz, K. W.; Zhang, J. J.; Rigollier, P.; Wareing, J. R.; Gstach,
H.; Zimmermann, J.; Dolle, R. E.; Baldwin, J. J.; Henderson, I. Tetrahedron Lett.
2010, 51, 4486–4489; (f) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.;
Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao, M.;
Garattini, E. ACS Med. Chem. Lett. 2010, 1, 411–415.
RCOCOCl, DMAP
CH Cl , rt, 12 h
2
2
O2N
NH
O N
2
NH
2
O
6
7a (94%)
7b (68%)
O
R
a R = Ph
b R = 4-Me-Ph
MW, 150 °C
0.5 h
MeNHNH2
EtOH
8. Recent examples: (a) Comer, E.; Liu, H.; Joliton, A.; Clabaut, A.; Johnson, C.;
Akella, L. B.; Marcaurelle, L. A. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6751–6756;
(b) Mai, C.-K.; Sammons, M. F.; Sammakia, T. Angew. Chem., Int. Ed. 2010, 49,
2397–2400; (c) Wang, Q.; Zhu, J. Chimia 2011, 65, 168–174.
9. (a) Bunce, R. A.; Nago, T.; Sonobe, N.; Slaughter, L.-G. M. J. Heterocycl. Chem.
2008, 45, 551–557; (b) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C. Tetrahedron
Lett. 2003, 44, 1947–1950.
10. Although base-mediated IMNAS reactions are usually assumed to proceed
according to the classical SNAr mechanism, short-lived radical intermediates
may be involved in some cases: Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett.
2011, 13, 2876–2879.
Me
N
N
Cl
NaHMDS
DMF, rt, 2 h
R
O2N
NH NHMe
O2N
N
H
O
N
O
2a (84% from 7a)
2b (75% from 7b)
8a-b
(not purified)
R
Scheme 2. Synthesis of benzotriazepinones.
11. (a) Bowman, W. R.; Heaney, H.; Smith, P. H. G. Arkivoc 2003, Part: 10, 434–442;
(b) Sledeski, A. W.; Kubiak, G. G.; O’Brien, M. K.; Powers, M. R.; Powner, T. H.;
Truesdale, L. K. J. Org. Chem. 2000, 65, 8114–8118.
Next, the applicability of this methodology to the synthesis of
benzotriazepinones was briefly explored. Mindful of the need for
electron-deficient substrates for the eventual SNAr cyclization, we
chose commercially available 2-chloro-5-nitroaniline (6) as start-
ing point (Scheme 2). In a manner analogous to that described
earlier, ketoamides 7a–b were prepared without incident and
converted into new benzotriazepinones 2a–b in yields of 84 and
75%, respectively.22
In conclusion, a practical three-step synthesis of pyridotriazepi-
nones and their benzo counterparts has been developed. With the
exception of 1a, which was previously prepared in five steps from
2-chloro-3-nitropyridine,6 all triazepinones described herein are
new chemical entities. Also, some of these compounds (e.g., 2a–
b) are difficult to make by alternative methods.4,6 This work further
demonstrates the serviceability of hydrazones as nucleophiles in
IMNAS reactions along with the viability of the latter for construct-
ing seven-membered polynitrogen heterocycles. Complementary
annulation protocols aimed at expanding the substrate scope of
the present route are currently under investigation and the results
will be reported in due course.
12. Kruger, A. W.; Rozema, M. J.; Chu-Kung, A.; Gandarilla, J.; Haight, A. R.; Kotecki,
B. J.; Richter, S. M.; Schwartz, A. M.; Wang, Z. Org. Process Res. Dev. 2009, 13,
1419–1425.
13. The preparation of ketoamide 4b has been described in a patent: Komori, T.;
Sakaguchi, H. PCT Int. Appl. WO 2004016594 (CA: 2004, 140, 217514).
14. Data for a-ketoamides 4a–e:
Compound 4a, white solid, mp 114.5–115.1 °C; 1H NMR (400 MHz, CDCl3)
d 7.27 (dd, J = 8.2, 4.7 Hz, 1H), 7.42–7.54 (m, 2H), 7.58–7.67 (m, 1H), 8.14 (dd,
J = 4.7, 1.6 Hz, 1H), 8.31–8.41 (m, 2H), 8.79 (dd, J = 8.0, 1.8 Hz, 1H), 9.52 (br s,
1H); 13C NMR (100 MHz, CDCl3) d 123.4, 128.7, 128.8, 131.1, 131.6, 132.7,
135.1, 141.1, 145.0, 159.4; 185.9; HRMS (ESI, MH+) m/z 261.0432 (calcd for
C
13H10ClN2O2 261.0425).
Compound 4b, white solid, mp 122.8–123.0 °C; 1H NMR (400 MHz, CDCl3) d
2.43 (s, 3H), 7.27–7.35 (m, 3H), 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 8.32 (d, J = 8.6 Hz,
2H), 8.83 (dd, J = 8.2, 1.6 Hz, 1H), 9.57 (br s, 1H); 13C NMR (100 MHz, CDCl3) d
22.2, 123.5, 128.7, 129.7, 130.3, 131.2, 131.9, 141.1, 144.9, 146.6, 159.7, 185.4;
MS (EI), m/z = 275.2 (M+1)+.
Compound 4c, white solid, mp 156.1–156.4 °C; 1H NMR (400 MHz, CDCl3) d
3.87 (s, 3H), 6.89–6.99 (m, 2H), 7.29 (dd, J = 8.2, 4.7 Hz, 1H), 8.15 (dd, J = 4.7,
2.0 Hz, 1H), 8.39–8.52 (m, 2H), 8.81 (dd, J = 8.2, 2.0 Hz, 1H), 9.61 (br s, 1H); 13
C
NMR (100 MHz, CDCl3) d 55.8, 114.3, 123.5, 125.8, 128.7, 131.3, 134.5, 141.1,
144.8, 160.1, 165.4, 183.8; MS (EI), m/z = 291.2 (M+1)+.
Compound 4d, light yellow solid, mp 111.1–112.4 °C; 1H NMR (400 MHz,
CDCl3) d 7.36 (dd, J = 8.0, 4.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 8.24 (dd, J = 4.7,
2.0 Hz, 1H), 8.55 (d, J = 8.2 Hz, 2H), 8.85 (dd, J = 8.2, 2.0 Hz, 1H), 9.58 (br s, 1H);
13C NMR (100 MHz, CDCl3) d 123.5, 123.6 (q, J = 274 Hz), 125.8 (q, J = 3 Hz),
128.8, 130.9, 132.0, 135.5, 136.1 (q, J = 33 Hz), 141.2, 145.3, 158.7, 185.3; MS
(EI), m/z = 329.1 (M+1)+.
Acknowledgments
Compound 4e, light yellow solid, mp 137.1–138.8 °C; 1H NMR (400 MHz,
CDCl3) d 7.34 (dd, J = 8.2, 4.7 Hz, 1H), 8.22 (dd, J = 4.7, 1.6 Hz, 1H), 8.29–8.40 (m,
2H), 8.53–8.63 (m, 2H), 8.81 (dd, J = 8.2, 1.6 Hz, 1H), 9.55 (br s, 1H); 13C NMR
(100 MHz, CDCl3) d 123.6, 123.9, 128.9, 130.8, 132.9, 137.4, 141.2, 145.5, 151.3,
158.3, 184.8; MS (EI), m/z = 306.3 (M+1)+.
We thank Professor Erik J. Sorensen of Princeton University for
his input. We also thank Ms. May-Britt Kary for the HRMS data and
Dr. Ralf Schmidt for translating some pertinent German literature.
15. Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata, T.; Tatsuno, Y.; Otsuka, S. J.
Organomet. Chem. 1989, 370, 203–221.
References and notes
16. Typical procedure: To a mixture of 3-methyl-2-oxobutanoic acid sodium salt
(0.84 g, 6.0 mmol) in CHCl3 (5 mL) at rt was added 4 M HCl in dioxane (1.5 mL,
6.0 mmol). The mixture was stirred for 0.5 h at rt then cooled to À5 °C and was
added 3-amino-2-chloropyridine (0.77 g, 6.0 mmol), followed by DCC (1.24 g,
6.0 mmol) under N2 protection. The mixture was stirred at À5 °C for 2 h, then
concentrated. To the residue was added AcOEt (20 mL) and the white
precipitate was removed by filtration. The filtrate was concentrated. The
crude material was loaded on a 40 g silica gel column and purified on a
Teledyne Isco instrument, eluting with 0–30% ethyl acetate in heptane to
provide 4g (0.93 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) d 1.17 (dt, J = 7.0,
1.4 Hz, 6H), 3.53–3.71 (m, 1H), 7.24–7.29 (m, 1H), 8.13 (dq, J = 4.7, 1.6 Hz, 1H),
8.67–8.80 (m, 1H), 9.34 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 18.0, 34.1,
123.4, 128.5, 130.9, 141.0, 144.9, 157.8, 201.2. MS (ESI) m/z 227.1 (M+H)+.
1. (a) Rudolph, U.; Knofloch, F. Nat. Rev. Drug Disc. 2011, 10, 685–697; (b) Riss, J.;
Cloyd, J.; Gates, J.; Collins, S. Acta Neurol. Scand. 2008, 118, 69–86; (c)
Hadjipavlou-Litina, D.; Garg, R.; Hansch, C. Chem. Rev. 2004, 104, 3751–3793;
(d) Patchett, A. A.; Nargund, R. P. Ann. Rep. Med. Chem. 2000, 35, 289–298.
2. (a) Saari, T. I.; Uusi-Oukari, M.; Ahonen, J.; Olkkola, K. T. Pharmocol. Rev. 2011,
63, 243–267; (b) Mandrioli, R.; Mercolini, L.; Raggi, M. A. Curr. Drug Metab.
2008, 9, 827–844.
3. (a) Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.; Blaney, J. M.
Tetrahedron 1993, 49, 3593–3608; (b) Dziadulewicz, E. K.; Brown, M. C.;
Dunstan, A. R.; Lee, W.; Said, N. B.; Garratt, P. J. Bioorg. Med. Chem. Lett. 1999, 9,
463–468; (c) Martin, I. L.; Lattmann, E. Expert Opin. Ther. Patents 1999, 9, 1347–
1358; (d) Fecik, R. A.; Frank, K. E.; Gentry, E. J.; Menon, S. R.; Mitscher, L. A.;
Telikepalli, H. Med. Res. Rev. 1998, 18, 149–185.
4. For the synthesis of 1,2,5-BTZs, see: (a) Savelli, F.; Boido, A.; Ciarallo, G. J.
Heterocycl. Chem. 1999, 36, 857–862; (b) Schwesinger, H.; Sicker, D.; Wilde, H.
Pharmazie 1992, 47, 60–61; (c) Rossi, S.; Pirola, O.; Selva, F. Tetrahedron 1968,
24, 6395–6409.
5. For the synthesis of 1,3,4-BTZs, see: (a) Dong, C.; Xie, L.; Mou, X.; Zhong, Y.; Su,
W. Org. Biomol. Chem. 2010, 8, 4827–4830; (b) Yotphan, S.; Bergman, R. G.;
Ellman, J. A. Org. Lett. 2009, 11, 1511–1514; (c) McDonald, I. M.; Black, J. W.;
Buck, I. M.; Dunstone, D. J.; Griffin, E. P.; Harper, E. A.; Hull, R. A. D.; Kalindjian,
S. B.; Lilley, E. J.; Linney, I. D.; Pether, M. J.; Roberts, S. P.; Shaxted, M. E.;
Spencer, J.; Steel, K. I. M.; Sykes, D. A.; Walker, M. K.; Watt, G. F.; Wright, L.;
Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50, 3101–3112.
Data for a
-ketoamide 4f: White gum, 1H NMR (400 MHz, CDCl3) d 1.50 (s, 9H),
7.39 (dd, J = 8.2, 4.7 Hz, 1H), 8.26 (dd, J = 4.7, 2.0 Hz, 1H), 8.87 (dd, J = 8.2,
2.0 Hz, 1H) 9.52 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 26.5, 34.1, 123.4, 128.5,
131.1, 141.0, 144.8, 157.3, 201.9. MS (EI), m/z = 241.2 (M+1)+.
17. Typical procedure: The mixture of 4b (50 mg, 0.18 mmol) and methylhydrazine
(9.6 lL, 0.18 mmol) in EtOH (3 mL) was stirred at 150 °C under microwave
irradiation for 0.5 h. The crude mixture was concentrated under reduced
pressure to afford crude 5b (54.2 mg, 98%) as yellow solid, which was used as
obtained in the next step.
18. (a) Stassinopoulou, C. I.; Zioudrou, C.; Karabatsos, G. J. Tetrahedron 1976, 32,
1147–1151; (b) Frenna, V.; Buscemi, S.; Spinelli, D.; Consiglio, G. J. Chem. Soc.,
Perkin Trans. 2 1990, 215–221; (c) Landge, S. M.; Tkatchouk, E.; Benítez, D.;
Lanfranchi, D. A.; Elhabiri, M.; Goddard, W. A., III; Aprahamian, I. J. Am. Chem.
Soc. 2011, 133, 9812–9823.
6. Tomaszewski, M. J.; Boisvert, L.; Jin, S. Tetrahedron Lett. 2009, 50, 1435–1437.

S. Jin et al. / Tetrahedron Letters 53 (2012) 1278–1281
1281
19. Typical procedure: To a solution of 5a (34 mg, 0.12 mmol) in DMF (3 mL) was
added 1.0 M NaHMDS in THF (0.35 mL, 0.35 mmol) at rt and the mixture was
stirred at rt for 2 h and then water (5 mL) was added. The resulting mixture
was concentrated, the aq layer was extracted with CH2Cl2 (3 Â 5 mL) and the
combined organic layers were washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. Purification of the residue by
reverse phase preparative HPLC (gradient 40–60% CH3OH in H2O containing
10 mM NH4CO3 and 0.375% NH4OH v/v) afforded 1a6 (23 mg, 78%) as a yellow
solid. 1H NMR (400 MHz, CDCl3) d 3.41 (s, 3H), 6.99 (dd, J = 7.8, 4.7 Hz, 1H),
7.27–7.42 (m, 4H), 7.70–7.80 (m, 2H), 8.10 (dd, J = 5.1, 1.6 Hz, 1H), 9.03 (s, 1H).
MS (ESI) m/z 253.2 (M+H)+. Data for 1b: Yellow solid, mp 156.3 °C (decomp.);
1H NMR (400 MHz, CDCl3) d 2.32 (s, 3H), 3.39 (s, 3H), 6.97 (dd, J = 7.6, 4.9 Hz,
1H), 7.12 (d, J = 8.2 Hz, 2H), 7.30 (dd, J = 7.8, 1.6 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H),
8.09 (dd, J = 5.1, 1.6 Hz, 1H), 9.41 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 21.6,
41.0, 120.6, 126.6, 128.0, 129.2, 129.3, 130.5, 140.7, 143.7, 155.4, 155.5, 166.6;
HRMS (ESI, MH+) m/z 267.1245 (calcd for C15H15N4O 267.1240). Data for 1c:
Yellow solid, mp 215.6 °C (decomp.); 1H NMR (400 MHz, CDCl3) d 3.37 (s, 3H),
3.79 (s, 3H), 6.77–6.89 (m, 2H), 6.99 (dd, J = 7.6, 4.7 Hz, 1H), 7.29 (dd, J = 7.8,
CH3OH in H2O containing 10 mM NH4CO3 and 0.375% NH4OH v/v) afforded 1d
(20.0 mg, 41%) as yellow solid, mp 168.2–170.3 °C; 1H NMR (400 MHz, CDCl3) d
3.49 (s, 3H), 7.06 (dd, J = 7.6, 4.9 Hz, 1H), 7.32 (dd, J = 7.8, 1.6 Hz, 1H), 7.61 (d, J =
8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 8.15 (dd, J = 4.9, 1.4 Hz, 1H), 8.43–8.67 (m,
1H); 13C NMR (100 MHz, CDCl3) d 41.3, 124.1 (q, J = 273 Hz), 120.7, 125.3 (q, J =
4 Hz), 125.7, 128.3, 129.4, 131.6 (q, J = 32 Hz), 137.2, 143.9, 152.0, 154.8, 164.4;
HRMS (ESI, MH+) m/z 321.0957 (calcd for C15H12F3N4O 321.0958).
Data for 1e: Yellow solid, mp 243.9–245.5 °C (decomp.); 1H NMR (400 MHz,
CDCl3) d 3.52 (s, 3H), 7.07 (dd, J = 7.8, 4.7 Hz, 1H), 7.28 (dd, J = 7.8, 1.6 Hz, 1H),
7.59 (br s, 1H), 7.88–7.97 (m, 2H), 8.14 (dd, J = 4.7, 1.6 Hz, 1H), 8.15–8.22 (m,
2H); 13C NMR (100 MHz, DMSO-d6) d 41.7, 122.0, 124.1, 127.1, 129.5, 130.8,
140.5, 143.4, 148.4, 152.5, 154.4, 163.5; HRMS (ESI, MH+) m/z 298.0935 (calcd
for C14H12N5O3 298.0933).
21. Data for 1f: Yellow solid, mp 144.1–144.3 °C; 1H NMR (400 MHz, CDCl3) d 1.20
(s, 9H), 3.20 (s, 3H), 6.99 (dd, J = 7.6, 4.9 Hz, 1H), 7.26 (dd, J = 7.8, 1.6 Hz, 1H),
8.09 (dd, J = 5.1, 1.6 Hz, 1H), 8.69 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 28.7,
37.6, 40.3, 120.2, 126.9, 128.3, 143.6, 155.5, 166.7, 167.3; HRMS (ESI, MH+) m/z
233.1406 (calcd for C12H17N4O 233.1397).
1.6 Hz, 1H), 7.66–7.81 (m, 2H), 8.10 (dd, J = 4.7, 1.6 Hz, 1H), 8.63 (br s, 1H); 13
C
22. Data for 2a: Orange solid, mp 251.3–252.8 °C (decomp.); 1H NMR (400 MHz,
CD3OD) d 3.34 (s, 3H), 7.31–7.43 (m, 3H), 7.47 (d, J = 8.9 Hz, 1H), 7.67–7.77 (m,
2H), 7.94 (d, J =2.5 Hz, 1H), 8.04 (dd, J = 8.9, 2.5 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) d 31.0, 116.8, 119.5, 120.9, 128.3, 129.0, 131.2, 133.1, 133.6, 144.5,
150.3, 157.8, 164.6; HRMS (ESI, MH+) m/z 297.0981 (calcd for C15H13N4O3
297.0982). Data for 2b: Yellow solid, mp 216.7–218.3 °C (decomp.); 1H NMR
(400 MHz, CDCl3) d 2.36 (s, 3H), 3.36 (s, 3H), 7.17 (d, J = 8.2 Hz, 2H), 7.29 (d,
J = 9.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 2.7 Hz, 1H), 8.04 (dd, J = 9.0,
2.3 Hz, 1H), 8.52 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 21.6, 42.3, 116.7,
118.4, 121.3, 128.0, 129.4, 129.5, 132.3, 141.6, 144.6, 150.5, 157.7, 164.9;
HRMS (ESI, MH+) m/z 311.1140 (calcd for C16H15N4O3 311.1139).
NMR (100 MHz, CDCl3) d 40.9, 55.5, 113.9, 120.4, 125.6, 126.5, 129.0, 129.8,
143.8, 155.3, 155.5, 161.6, 166.0; HRMS (ESI, MH+) m/z 283.1191 (calcd for
C
15H15N4O2 283.1190).
20. Preparation of pyridotriazepinone 1d: A solution of 5d (54.3 mg, 0.15 mmol) in
NMP (1 mL) was purged with nitrogen in a 5 mL microwave vial and then 1.0 M
NaHMDS in THF (457 lL, 0.46 mmol) was added and the mixture was stirred
under microwave irradiation at 150 °C for 1 h. Saturated NaHCO3 (10 mL) and
CH2Cl2 (10 mL) were added and the phases were separated. The aq phase was
extracted with CH2Cl2 (3 Â 10 mL) and the combined organics were washed
with brine, dried (MgSO4), filtered and concentrated under reduced pressure.
Purification of the residue by reverse phase preparative HPLC (gradient 50–70%