1860
P. Mukashyaka, G. L. Hamilton
Letter
Synlett
vation with hygroscopic lanthanide salts. Finally, the fluo-
renylidene activating group can be removed under condi-
tions compatible with many functional groups, leading to
useful hydrazine or amine products. We hope that all of
these features will make the method attractive to others,
especially for medicinal chemistry.
(7) Notte, G. T.; Leighton, J. L. J. Am. Chem. Soc. 2008, 130, 6676.
(8) Addition of carbon radicals to hydrazones is possible when the
substrate is quite electrophilic, e.g., 1,2-dicarbonyl- or alde-
hyde-derived. See for example: (a) Nam, T. K.; Jang, D. O. J. Org.
Chem. 2018, in press; DOI: 10.1021/acs.joc.7b03193.
(b) Friestad, G. K.; Ji, A. Org. Lett. 2008, 10, 2311. (c) Miyabe, H.;
Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324.
(9) (a) Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735.
(b) Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.;
Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276. (c) Shapiro, R.
H. Org. React. 1976, 23, 405.
Supporting Information
Supporting information for this article is available online at
(10) (a) Overberger, C. G.; DiGiulio, A. V. J. Am. Chem. Soc. 1958, 80,
6562. (b) Cram, D. J.; Bradshaw, J. S. J. Am. Chem. Soc. 1963, 85,
1108.
S
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(11) Nishino, T.; Miyaji, K.; Iwamoto, S.; Mikashima, T.; Saruhashi,
K.; Kishikawa, Y. WO 2012074067, 2012.
References and Notes
(12) Johns, A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem. Int. Ed. 2007, 46,
7259.
(13) General Procedure for Reactions of Azine Substrates with
Grignard Reagents
(1) (a) Lai, Y.-H. Synthesis 1981, 585. (b) Wakefield, B. J. Organomag-
nesium Methods in Organic Chemistry; Academic Press: San
Diego, CA, 1995. (c) Silverman, G. S.; Rakita, P. E. Handbook of
Grignard Reagents; Marcel Dekker: New York, 1996. (d) Richey,
H. G. Grignard Reagents: New Developments; Wiley: Chichester,
2000. (e) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int.
Ed. 2003, 42, 4302. (f) Knochel, P. Handbook of Functionalized
Organometallics; Wiley-VCH: Weinheim, 2005.
(2) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Kobayashi, S.; Mori,
Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.
(c) Yamada, K.; Tomioka, K. Chem. Rev. 2008, 108, 2874.
(d) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853.
(e) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (f) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645.
(3) Allyl Grignards are well-known to be particularly nucleophilic
and less basic, reacting with even very hindered electrophiles.
See for example: DeMeester, W. A.; Fuson, R. C. J. Org. Chem.
1965, 30, 4332.
(4) (a) Lu, A.; Huang, D.; Wang, K.-H.; Su, Y.; Ma, J.; Xu, Y.; Hu, Y.
Synthesis 2016, 48, 293. (b) Cui, Y.; Li, W.; Sato, T.; Yamashita, Y.;
Kobayashi, S. Adv. Synth. Catal. 2013, 355, 1193. (c) Yue, X.; Qiu,
X.; Qing, F. Chin. J. Chem. 2009, 27, 141. (d) Schneider, U.; Chen,
I.-H.; Kobayashi, S. Org. Lett. 2008, 10, 737. (e) Garcia-Flores, F.;
Flores-Michel, L.-S.; Juaristi, E. Tetrahedron Lett. 2006, 47, 8235.
(f) Ding, H.; Friestad, G. K. Synthesis 2004, 2216. (g) Berger, R.;
Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686.
(h) Hirabayashi, R.; Ogawa, C.; Sugiura, M.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 9493.
(5) (a) Marques-Lopez, E.; Herrera, R. P.; Fernandez, R.; Lassaletta, J.
M. Eur. J. Org. Chem. 2008, 3457. (b) Konishi, H.; Ogawa, C.;
Sugiura, M.; Kobayashi, S. Adv. Synth. Catal. 2005, 347, 1899.
(c) Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153. (d) Chiba,
T.; Okimoto, M. Synthesis 1990, 209.
To a solution of azine substrate in anhydrous THF (ca. 0.2 M)
cooled to 0 °C was added slowly a solution of Grignard reagent
(1–5 equiv). After addition, the reaction mixture was allowed to
warm to room temperature and stir for 16 h. After this time, the
reaction was quenched with 5% aqueous citric acid, and the
mixture was extracted with isopropyl acetate (3×). The com-
bined organics were washed with water and brine, dried over
sodium sulfate, and concentrated. The resulting crude material
was purified by column chromatography. NOTE: The azine sub-
strates were generally found to be hygroscopic. Therefore, best
yields were obtained when the azines were dried overnight in a
vacuum dessicator over anhydrous calcium sulfate prior to use.
(14) Analytical Data for Example Azine 1b
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.6 Hz, 1 H), 7.86 (d,
J = 7.4 Hz, 1 H), 7.61 (dd, J = 11.1, 7.5 Hz, 2 H), 7.39 (tt, J = 7.5, 1.3
Hz, 2 H), 7.34–7.21 (m, 2 H), 4.05–3.93 (m, 4 H), 2.81–2.69 (m, 4
H), 2.04–1.95 (m, 2 H), 1.87–1.78 (m, 2 H). 13C NMR (101 MHz,
CDCl3): δ = 164.25, 155.11, 142.27, 141.01, 136.86, 131.54,
131.06, 130.55, 129.43, 128.01, 127.99, 122.48, 119.96, 119.75,
108.00, 64.56, 34.70, 33.73, 32.15, 25.06. LRMS: m/z [M + H]+
calcd for C21H21N2O2+: 333; found: 333.
(15) Analytical Data for Example Product 2b
1H NMR (400 MHz, CDCl3): δ = 7.83–7.73 (m, 3 H), 7.71–7.62 (m,
1 H), 7.40 (td, J = 7.5, 1.1 Hz, 1 H), 7.34 (td, J = 7.5, 1.3 Hz, 1 H),
7.33–7.23 (m, 2 H), 6.68 (s, 1 H), 3.96 (s, 3 H), 2.16–2.06 (m, 2
H), 1.96–1.85 (m, 2 H), 1.82–1.72 (m, 3 H), 1.72–1.62 (m, 4 H),
0.84 (t, J = 7.5 Hz, 3 H). 13C NMR (101 MHz, CDCl3); δ = 140.63,
138.76, 138.47, 137.30, 130.35, 128.47, 127.46, 127.37, 127.10,
123.87, 120.48, 120.25, 119.35, 108.96, 64.28, 64.28, 57.78,
32.77, 31.55, 30.61, 7.55. LRMS: m/z [M
C
+
H]+ calcd for
23H27N2O2+: 363; found: 363.
(6) (a) Prieto, A.; Bouyssi, D.; Monteiro, N. Asian J. Org. Chem. 2016,
5, 742. (b) Dilman, A. D.; Arkhipov, D. E.; Levin, V. V.; Belyakov,
A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A. J. Org.
Chem. 2008, 73, 5643.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 1857–1860