Organic Letters
Letter
benzyl bromide. Similarly, as reported previously for organozinc
J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824. (c) Lopez, F.; Minnaard, A.
J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179.
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1b
reagents,
reaction with 4-chloro-1-phenylbutanone yielded
(3) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545.
tetrahydrofuran 12a. 1,4-Addition compounds on cyclohex-
(4) (a) Barl, N. M.; Werner, V.; Saemann, C.; Knochel, P. Heterocycles
anone were also obtained using copper iodide as catalyst to give
1
8
2014, 88, 827. (b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel,
F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
1
3a. Finally, flow Negishi coupling was attempted by mixing
the outcome with zinc chloride, iodoarene, and the correspond-
ing palladium catalyst following the procedure described by
2
(
003, 42, 4302.
5) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel,
19
Knochel and co-workers. In all examples mentioned above,
good to excellent yields of the corresponding products were
obtained.
P. Angew. Chem., Int. Ed. 2008, 47, 6802.
(6) (a) Kopach, M. E.; Cole, K. P.; Pollock, P. M.; Johnson, M. D.;
Braden, T. M.; Webster, L. P.; McClary Groh, J.; McFarland, A. D.;
Schafer, J. P.; Adler, J. J.; Rosemeyer, M. Org. Process Res. Dev. 2016, 20,
In summary, we have shown that insertion of magnesium into
various aryl and heteroaryl bromides and iodides, as well as alkyl
halides, takes place when the reactants flow through a
magnesium column. The approach can be easily scaled up by
simply flowing the solution through the column for a longer
period. Precise titration solutions were obtained and used in
either batch or flow protocols to yield a diverse set of compounds
with a wide range of functional groups. Alcohols, ketones, esters,
amides, ethers, and sulfones were all obtained in good to
1
581. (b) Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6, 906.
(c) Braden, T. M.; Johnson, M. D.; Kopach, M. E.; McClary Groh, J.;
Spencer, R. D.; Lewis, J.; Heller, M. R.; Schafer, J. P.; Adler, J. J. Org.
Process Res. Dev. 2017, 21, 317.
(7) (a) Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55, 4062.
(
(
b) Rasheed, M.; Wirth, T. Angew. Chem., Int. Ed. 2011, 50, 5943.
c) Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47,
4
583. (d) Newman, S. G.; Jensen, K. F. Green Chem. 2013, 15, 1456.
(8) (a) Grachev, A. A.; Klochkov, A. O.; Shiryaev, V. I. Russ. J. Appl.
Chem. 2012, 85, 629. (b) Storozhenko, P. A.; Grachev, A. A.; Klochkov,
A. O.; Shiryaev, V. I. Russ. J. Appl. Chem. 2013, 86, 387. (c) Goldbach,
2
3
2
excellent yields. Additionally, new C(sp )−C(sp ) and C(sp )−
2
C(sp ) bonds were formed in a single step from the Grignard
M.; Danieli, E.; Perlo, J.; Kaptein, B.; Litvinov, V. M.; Blu
Casanova, F.; Duchateau, A. L. L. Tetrahedron Lett. 2016, 57, 122.
̈
mich, B.;
reagents. A wide range of functional groups at the aromatic ring
were well-tolerated, and the methodology is also applicable for
heterocyclic systems as well as different functionalized alkyl
groups. Taking all of the results into consideration, the
methodology can be considered as an interesting tool for
(
(
(
9) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
10) Lin, H.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.
11) (a) Alonso, N.; Miller, L. Z.; de M. Munoz, J.; Alcazar, J.;
̃
́
McQuade, D. T. Adv. Synth. Catal. 2014, 356, 3737. (b) Huck, L.;
Berton, M.; de la Hoz, A.; Díaz-Ortiz, A.; Alcazar, J. Green Chem. 2017,
9, 1420.
(12) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry;
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diversity oriented synthesis of compounds with different
functional groups as well as for the diverse preparation of
intermediates for the synthesis of compounds with potential
biological activity, including new scaffolds like 2,2-disubstituted
tetrahydrofurans. The further applicability of this technology in
the field of drug discovery will be described in future
publications.
́
1
Wiley-VCH: Weinheim, 2003; p 46.
(13) Degennaro, L.; Maggiulli, D.; Carlucci, C.; Fanelli, F.; Romanazzi,
G.; Luisi, R. Chem. Commun. 2016, 52, 9554.
(
14) Stoner, E. J.; Cothron, D. A.; Balmer, M. K.; Roden, B. A.
Tetrahedron 1995, 51, 11043.
15) Leazer, J. L.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery, T.;
(
ASSOCIATED CONTENT
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Bachert, D. J. Org. Chem. 2003, 68, 3695.
(16) Williams, A. B.; Hanson, R. N. Tetrahedron 2012, 68, 5406.
*
S
Supporting Information
(
17) Deeming, A. S.; Russell, C. J.; Hennessy, A. J.; Willis, M. C. Org.
Lett. 2014, 16, 150.
18) Varchi, G.; Ricci, A.; Cahiez, G.; Knochel, P. Tetrahedron 2000,
56, 2727.
19) Petersen, T. P.; Becker, M. R.; Knochel, P. Angew. Chem., Int. Ed.
014, 53, 7933.
20) (a) Galloway, W. R. J. D.; Bender, A.; Welch, M.; Spring, D. R.
(
Experimental procedures, spectral data, and NMR spectra
(
2
(
AUTHOR INFORMATION
Chem. Commun. 2009, 2446. (b) Galloway, W. R. J. D.; Isidro-Llobet, A.;
Spring, D. R. Nat. Commun. 2010, 1, 80. (c) Kim, J. H.; Ko, Y. O.;
Bouffard, J.; Lee, S. Chem. Soc. Rev. 2015, 44, 2489.
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Corresponding Authors
ORCID
́
Notes
The authors declare no competing financial interest.
REFERENCES
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