E
J. Richardson et al.
Letter
Synlett
Table 3 Further Optimization of the Monoarylation
O
P7, L7
OTBDPS
OTBDPS
OTBDPS
Br
K3PO4 (2.0 equiv)
acetone (2 mL/mmol)
co-solvent (2.5 mL/mmol)
50 °C
R
+
R
NH
NH
R
NH
3
4
5
Entry
Co-solvent
P7 loading (mol%)
L7 loading (mol%)
Base
4/5/3b
1
2
THF
5
5
5
5
5
–
–
–
–
–
–
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KH2PO4
K2HPO4
K2CO3
DBU
90:10:0
90:8:2
93:7:0
92:6:2
91:7:2
0:0:100
0:0:100
9:1:90
0:0:100
toluene
5
3
–
–
–
–
–
–
–
–
5
4
5
5
2.5
2.5
2.5
2.5
2.5
2.5
6
7
8
9
b
10
t-BuOK
–
a Determined by LC/MS.
b Complex mixture of products.
Acknowledgment
(9) MacQueen, P. M.; Chisholm, A. J.; Hargreaves, B. K. V.;
Stradiotto, M. Chem. Eur. J. 2015, 21, 11006.
(10) Gäbler, C.; Korb, M.; Schaarschmidt, D.; Hildebrandt, A.; Lang, H.
Adv. Synth. Catal. 2014, 356, 2979.
We thank Vladimir Larichev and Stephanos Ghilagaber for the prepa-
ration of compound 3.
(11) Zhong, W.; Hitchcock, S.; Albrecht, B. K.; Bartberger, M.; Brown,
J.; Brown, R.; Chaffee, S. C.; Cheng, Y.; Croghan, M.; Graceffa, R.;
Harried, S.; Hickman, D.; Horne, D.; Hungate, R.; Judd, T.; Kaller,
M.; Kreiman, C.; La, D.; Lopez, P.; Masse, C. E.; Monenschein, H.;
Nguyen, T.; Nixey, T.; Patel, V. F.; Pennington, L.; Weiss, M.; Xue,
Q.; Yang, B. WO 2007061670, 2007.
(12) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4,
916.
(13) Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. J. Org. Chem. 2014,
79, 4161.
References and Notes
(1) Hao, J.; Beck, J. P.; Schaus, J. M.; Krushinski, J. H.; Chen, Q.;
Beadle, C. D.; Vidal, P.; Reinhard, M. R.; Dressman, B. A.; Massey,
S. M.; Boulet, S. L.; Cohen, M. P.; Watson, B. M.; Tupper, D.;
Gardinier, K. M.; Myers, J.; Johansson, A. M.; Richardson, J.;
Richards, D. S.; Hembre, E. J.; Remick, D. M.; Coates, D. A.;
Bhardwaj, R. M.; Diseroad, B. A.; Bender, D.; Stephenson, G.;
Wolfangel, C. D.; Diaz, N.; Getman, B. G.; Wang, X.; Heinz, B. A.;
Cramer, J. W.; Zhou, X.; Maren, D. L.; Falcone, J. F.; Wright, R. A.;
Mitchell, S. N.; Carter, G.; Yang, C. R.; Bruns, R. F.; Svensson, K. A.
J. Med. Chem. 2019, 62, 8711.
(14) DeAngelis, A. J.; Gildner, P. G.; Chow, R.; Colacot, T. J. J. Org.
Chem. 2015, 80, 6794.
(15) 1-Arylacetones 7a–o; General Method
A 20 mL vial equipped with a stirrer bar and rubber seal was
charged with the appropriate (het)aryl bromide 6 (2.4 mmol),
K3PO4 (3 equiv), and P7 (2.5 mol%). The vial was sealed and
degassed by using three vacuum/N2 cycles before acetone (10.8
mL) was added and the resulting mixture was heated to 50 °C
for the appropriate time (Scheme 2). The mixture was then
cooled to rt, diluted with EtOAc, and filtered through Celite,
washing with additional EtOAc. The filtrate was evaporated to
dryness and purified by chromatography (silica gel).
1-(2-Methylphenyl)propan-2-one (7d)
Synthesized according to the general procedure from 2-bromo-
toluene (286 L, 2.38 mmol) as a colorless oil; yield: 245 mg
(70%). 1H NMR (400 MHz, CDCl3): = 7.21–7.12 (m, 4 H), 3.72 (s,
2 H), 2.25 (s, 3 H), 2.14 (s, 3 H). 13C NMR (100ꢀMHz, CDCl3):
= 19.8, 29.4, 49.3, 126.7, 127.5, 130.5, 130.6, 133.3, 137.0,
206.6.
(2) Eli Lilly and Company; A Study of LY3154207 in Participants with
Dementia Due to Lewy Body Dementia (LBD) Associated With
Idiopathic Parkinson’s Disease (PD) or Dementia With Lewy
Bodies (DLB) (PRESENCE); U.S. National Institutes of Health:
Bethesda,
2020;
NCT03305809 (accessed Jun 18, 2020)..
(3) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011,
133, 5194.
(4) Crawford, S. M.; Alsabeh, P. G.; Stradiotto, M. Eur. J. Org. Chem.
2012, 6042.
(5) Ackermann, L.; Mehta, V. P. Chem. Eur. J. 2012, 18, 10230.
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(7) Fu, W. C.; So, C. M.; Chow, W. K.; Yuen, O. Y.; Kwong, F. Y. Org.
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(8) Li, P.; Lü, B.; Fu, C.; Ma, S. Adv. Synth. Catal. 2013, 355, 1255.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E