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Me
N
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N
H
O
1a
Figure 2. X-ray structure of benzotriazepinone 1a.
furnish the desired benzotriazepinones in yields of 33–76% after
purification by preparative HPLC (Table 3).19 The products (1a–h)
were readily identified by the characteristic 13C NMR signal of
the carbonyl carbon at ca. 163–166 ppm.20 As all of these com-
pounds were crystalline, we were able to secure irrefutable proof
for the proposed structures by performing X-ray diffraction analy-
sis of benzotriazepinone 1a (Fig. 2).21
Finally, it is worth mentioning that the choice of trifluoroacetyl
group for protecting the hydrazine moiety proved crucial for suc-
cess of the final step in the synthesis (cf. 6?1). Attempts to trans-
form either the Boc or Fmoc-protected analogues of 6a to
triazepinone 1a under acidic or basic conditions, respectively, led
to complex mixtures in which none of the desired product could
be detected by LC–MS.
In summary, a convenient synthesis of the previously unknown
3-aryl-substituted benzo and pyrido[1,2,5]triazepin-4-ones has
been developed. The key step involves one-pot deprotection-intra-
molecular imine formation of trifluoroacetylhydrazines 6, which
are prepared in four straightforward steps from commercial start-
ing materials. Efforts aimed at establishing shorter versions of this
pathway are currently underway.
18. Typical procedure: Preparation of
a-ketoamide 6d. To a solution of
trifluoroacetylhydrazide 3b (1.050 g, 3.02 mmol) in toluene (20 mL), Adam’s
catalyst (PtO2, 99.92 mg, 0.44 mmol) was added and the mixture was shaken
under hydrogen (50 psi) for 2 h. The reaction mixture was filtered through Celite
and the filtrate was concentrated under reduced pressure. The resulting crude
aniline product was used in the next step without purification. In a separate flask,
thionyl chloride (0.20 mL, 2.72 mmol) was added to a stirred solution of DMAP
(0.332 g, 2.72 mmol)inCH2Cl2 (10 mL)at À20 °Cundernitrogen. Tothis mixture,
a solution of 2-oxo-2-phenylacetic acid (0.353 g, 2.35 mmol) in CH2Cl2 (10 mL)
was added and the mixture was slowly warmed to rt and stirred for a further 3 h.
Then DMAP (0.332 g, 2.72 mmol) and a solution of crude aniline (0.545 g,
1.81 mmol) in CH2Cl2 (3 mL) were successively added and the resulting mixture
was stirred at rt for 24 h. After quenching with water, the aqueous layer was
extracted with CH2Cl2 (3 Â 10 mL) and the combined organic layers were
washed with brine, dried (Na2SO4), and the volatiles were removed under
reduced pressure. Purification of the residue by reverse phase preparative HPLC
(gradient 30–50% CH3CN in H2O containing 10 mM NH4HCO3 and 0.375% NH4OH
Acknowledgments
We thank Dr. Christopher Walpole for his support and encour-
agement during this work and Ms. May-BrittKary for the HRMSdata.
v/v) afforded
a-ketoamide 6d (0.783 g, 99%) as a light yellow solid (mp 168–
170 °C); 1H NMR (400 MHz, CDCl3) d 3.16 (s, 3H), 7.39–7.55 (m, 4H), 7.64 (t,
J = 7.42 Hz, 1H), 8.01 (s, 1H), 8.34 (d, J = 7.42 Hz, 2H), 8.82 (d, J = 1.95 Hz, 1H),
10.13 (s, 1H); 13C NMR (100 MHz, CDCl3) d 43.9, 105.0, 118.6 (q, J = 2 Hz), 119.5,
122.2 (q, J = 2 Hz), 128.8, 129.5 (q, J = 227 Hz), 131.5, 133.3 (q, J = 134 Hz), 135.0,
135.4, 139.1, 141.3, 154.6, 160.3, 186.9. HRMS (ESI, MH+) m/z 434.0938 (calcd for
C18H14F6N3O3: 434.0934).
References and notes
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49, 7174–7177. and references cited therein.
19. Typical procedure: Preparation of benzotriazepinone 1a.
A mixture of a-
ketoamide 6a (20.9 mg, 0.55 mmol) and potassium carbonate (38.0 mg,
0.275 mmol) in MeOH (1 mL) and water (0.3 mL) was stirred at rt for
10 days. The volatiles were evaporated under reduced pressure and water
(5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 Â 5 mL) and
the combined organic layers were washed with brine, dried (MgSO4), filtered,
and the solvent was evaporated under reduced pressure. The residue was
purified by reverse phase preparative HPLC (10–30% MeCN/water containing
0.05% TFA) giving 1a (10.1 mg, 73%) as yellow crystals, mp 181–183 °C; 1H
NMR (400 MHz, CD3OD) d ppm 3.25 (s, 3H), 7.06–7.22 (m, 3H), 7.28–7.43 (m,
4H), 7.67–7.73 (m, 2H); 13C NMR (100 MHz, CD3OD) d ppm 41.1, 117.8, 121.4,
125.2, 125.3, 127.6, 128.1, 130.1, 132.4, 133.4, 145.8, 157.3, 166.2; HRMS (ESI,
MH+) m/z 252.1130 (calcd for C15H14N3O: 252.1131).
3. (a) Lynch, J. J., Jr.; Salata, J. J.; Wallace, A. A.; Stump, G. L.; Gilberto, D. B.;
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Bioorg. Med. Chem. Lett. 2007, 17, 1667–1670. and references cited therein.
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Vanmiddlesworth, F.; Sugg, E. E. Bioorg. Med. Chem. Lett. 2001, 11, 1145–1148.
6. Williams, T. M.; Stump, G. A.; Nguyen, D. N.; Quigley, A. G.; Bell, I. M.;
Gallicchio, S. N.; Zartman, C. B.; Wan, B.-L.; Penna, K. D.; Kunapuli, P.; Kane, S.
A.; Koblan, K. S.; Mosser, S. D.; Rutledge, R. Z.; Salvatore, C.; Fay, J. F.; Vacca, J. P.;
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8. For select examples of bioactive benzotriazepines see: (a) Stefancich, G.; Artico,
M.; Silvestri, R.; Pantaleoni, G. C.; Giorgi, R.; Palumbo, G. Farmaco 1990, 45, 7–
27; (b) Ashworth, D. M.; Pitt, G. R. W.; Hudson, P.; Yea, C. M.; Franklin, R. J. PCT
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200200626 (CA: 2002, 136, 69828).; (d) Silvestri, R.; Marfe, G.; Abruzzese, E.;
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20. Data for three other benzotriazepinones: Compound 1d: yellow crystals, mp 180–
181 °C; 1H NMR (400 MHz, CDCl3) d3.32 (s, 3H), 7.16–7.47 (m, 6H), 7.71–7.92 (m,
2H), 9.71 (s, 1H); 13C NMR (100 MHz, CDCl3) d 42.2, 118.5, 118.8 (q, J = 4 Hz),
122.8 (q, J = 4 Hz), 126.1 (q, J = 270 Hz), 127.9, 128.1, 128.6, 130.8, 132.4, 132.8,
148.2, 157.1, 166.3; HRMS (ESI, MH+) m/z 320.1010 (calcd for C16H13F3N3O
320.1005). Compound 1f: yellow crystals, mp 140–142 °C; 1H NMR (400 MHz,
CD3OD) d 3.33 (s, 3H), 7.11 (dd, J = 7.81, 1.95 Hz, 1H), 7.30–7.40 (m, 3H), 7.43 (dd,
J = 7.81, 1.95 Hz, 1H), 7.65–7.72 (m, 2H), 8.06 (dd, J = 4.88, 1.95 Hz, 1H), 8.52 (s,
1H); 13C NMR (100 MHz, CD3OD) d 40.0, 120.7, 127.2, 127.6, 128.1, 129.4, 130.1,
133.4, 143.0, 155.2, 156.4, 165.6; HRMS (ESI, MH+) m/z 253.1084 (calcd for
C14H13N4O 253.1084). Compound 1h: orange crystals; 1H NMR (400 MHz, CDCl3)
d 3.39 (s, 3H), 6.95–7.05 (m, 2H), 7.26-7.35 (m, 2H), 7.57 (d, J = 2.73 Hz, 1H), 8.11
(dd, J = 4.69, 1.56 Hz, 1H), 8.52 (s, 1H); 13C NMR (100 MHz, CDCl3) d 41.1, 120.6,
126.0, 127.7, 129.1, 129.2, 130.1, 137.1, 143.9, 149.9, 155.1, 164.1; HRMS (ESI,
MH+) m/z 259.0646 (calcd for C12H11N4OS 259.0648).
21. CCDC 677004 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic