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M. Shevlin et al.
Cluster
Synlett
(7) For selected examples of related [3,3]-sigmatropic rearrange-
ment/cyclization cascades, see: (a) Lovato, K.; Bhakta, U.; Ng, Y.
P.; Kürti, L. Org. Biomol. Chem. 2020, 18, 3281. (b) Gao, H.; Xu,
Q.-L.; Keene, C.; Kürti, L. Chem. Eur. J. 2014, 20, 8883.
(c) Contiero, F.; Jones, K. M.; Matts, E. A.; Porzelle, A.;
Tomkinson, N. C. O. Synlett 2009, 3003. (d) Wang, H.-Y.; Mueller,
D. S.; Sachwani, R. M.; Kapadia, R.; Londino, H. N.; Anderson, L.
L. J. Org. Chem. 2011, 76, 3203. (e) Wen, J.-J.; Tang, H.-T.; Xiong,
K.; Ding, Z.-C.; Zhan, Z.-P. Org. Lett. 2014, 16, 5940.
M.; Lee, C. H.; Cuff, J.; Sherer, E. C.; Kuethe, J.; Goble, S.; Perrotto,
N.; Pinto, S.; Shen, D.-M.; Nargund, R.; Balkovec, J.; DeVita, R. J.;
Dreher, S. D. J. Med. Chem. 2017, 60, 3594. (d) Grainger, R.;
Heightman, T. D.; Ley, S. V.; Lima, F.; Johnson, C. N. Chem. Sci.
2019, 10, 2264.
(17) For an example of [3,9]-sigmatropic rearrangement, see:
Kessler, S. N.; Neuburger, M.; Wegner, H. A. J. Am. Chem. Soc.
2012, 134, 17885.
(18) Synthesis of 2b – Typical Procedure
(8) For an example of a [3,3]-sigmatropic rearrangement of N-
alkenyloxybenzotriazoles that proceeds via bond formation at
C7 rather than N3, see: Kumar, M.; Scoble, M.; Mashuta, M. S.;
Hammond, G. B.; Xu, B. Org. Lett. 2013, 15, 724.
(9) For examples of [3,3]-sigmatropic rearrangements of N-alkeny-
loxyindoles have been previously reported to give low yields
due to competing byproduct formation, see: Duarte, M. P.;
Mendonça, R. F.; Prabhakar, S.; Lobo, A. M. Tetrahedron Lett.
2006, 47, 1173.
(10) For a related transformation that uses N–O bond cleavage in a
[3,3]-sigmatropic rearrangement to drive quaternary center for-
mation in spirocyclic pyrrolines, see: Alshreimi, A. S.; Zhang, G.;
Reidl, T. W.; Peña, R. L.; Koto, N.-G.; Islam, S. M.; Wink, D. J.;
Anderson, L. L. Angew. Chem. Int. Ed. 2020, 132, 15356.
(11) For other examples of dearomative [3,3]-sigmatropic rearrange-
ments that install quaternary centers, see: (a) An, J.; Parodi, A.;
Monari, M.; Reis, M. C.; Lopez, C. S.; Bandini, M. Chem. Eur. J.
2017, 23, 17473. (b) Gutierrez, O.; Hendrick, C. E.; Kozlowski, M.
C. Org. Lett. 2018, 20, 6539. (c) Zhao, W.; Huang, X.; Zhan, Y.;
Zhang, Q.; Li, D.; Zhang, Y.; Kong, L.; Peng, B. Angew. Chem. Int.
Ed. 2019, 58, 17210. (d) Peruzzi, M. T.; Lee, S. J.; Gagné, M. R.
Org. Lett. 2017, 19, 6256. (e) Huang, S.; Kötzner, L.; Kanta De, C.;
List, B. J. Am. Chem. Soc. 2015, 137, 3446. (f) Cao, T.; Linton, E. C.;
Deitch, J.; Berritt, S.; Kozlowski, M. C. J. Org. Chem. 2012, 77,
11034. (g) Susick, R. B.; Morrill, L. A.; Picazo, E.; Garg, N. K.
Synlett 2017, 28, 1. (h) Simmons, B. J.; Hoffmann, M.;
Champagne, P. A.; Picazo, E.; Yamakawa, K.; Morrill, L. A.; Houk,
K. N.; Garg, N. K. J. Am. Chem. Soc. 2017, 139, 14833.
(12) Son, J.; Reidl, T. W.; Kim, K. H.; Wink, D. J.; Anderson, L. L.
Angew. Chem. Int. Ed. 2018, 57, 6597.
(13) (a) Shevlin, M.; Guan, X.; Driver, T. G. ACS Catal. 2017, 7, 5518.
(b) Nicolaou, K. C.; Lee, S. H.; Estrada, A. A.; Zak, M. Angew.
Chem. Int. Ed. 2005, 44, 3736. (c) Li, B.; Williams, J. D.; Peet, N. P.
Tetrahedron Lett. 2013, 54, 3124.
To a 40 mL vial equipped with a magnetic stirbar, 4.26 g (23.5
mmol) 1-fluoro-2-nitro-3-(prop-1-en-2-yl)benzene, 4.90
g
(25.9 mmol, 1.1 equiv) SnCl2, and 25 mL DMA were added to
give a homogeneous pale yellow solution. The mixture was
heated to 80 °C with stirring overnight, then transferred to a 1 L
separatory funnel containing 500 mL 10 wt% tartaric acid and
extracted three times with MTBE. The combined organics were
dried over MgSO4, concentrated on a rotary evaporator, and
chromatographed on a 220 g silica cartridge with a 2–20%
EtOAc/hexane gradient. The desired product fractions were
sequentially concentrated to approximately 50 mL volume and
diluted with hexane three times. The product solution was then
concentrated to approximately 10 mL volume and diluted with
a small amount of MTBE (to maintain solubility) to give 9.70 g
of a 32.5 wt% solution (81%). 1H NMR (400 MHz, DMSO-d6): =
11.28 (s, 1 H), 7.32–7.25 (m, 1 H), 7.24 (q, J = 1.1 Hz, 1 H), 6.98–
6.85 (m, 2 H), 2.22 (d, J = 1.1 Hz, 3 H). 13C{1H} NMR (101 MHz,
DMSO-d6): = 148.35 (d, J = 244.4 Hz), 128.31 (d, J = 4.9 Hz),
125.62, 121.65 (d, J = 9.6 Hz), 118.50 (d, J = 6.2 Hz), 114.74 (d, J =
3.5 Hz), 107.00 (d, J = 16.8 Hz), 106.06 (d, J = 1.8 Hz), 9.25. HRMS
(ESI/QTOF): m/z [M – H]– calcd for C9H7FNO: 164.0517; found:
164.0521.
(19) Synthesis of 4ba – Typical Procedure
To a 20 mL vial equipped with a magnetic stirbar, 165 mg (1.0
mmol) 2b, 10 mL DMF, and 183 mg (1.05 mmol, 1.05 equiv) 3a.
The reaction was cooled below 0 °C, and 200 L (1 M in THF,
200 mol, 20 mol%) KOt-Bu was added dropwise. The reaction
was stirred for 1 h and transferred to a 250 mL separatory
funnel containing 100 mL water, 10 mL saturated NH4Cl, and
MTBE. The aqueous layer was extracted twice with MTBE, and
the combined organics were dried over MgSO4, concentrated on
a rotary evaporator, and chromatographed on a 120 g silica car-
tridge with a 2–20% EtOAc/hexane gradient to give 243 mg
(72%) of a white solid. 1H NMR (500 MHz, CDCl3): = 7.61 (d, J =
7.6 Hz, 2 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.44–7.29 (m, 3 H), 6.98–
6.83 (m, 1 H), 6.83–6.69 (m, 1 H), 6.01 (d, J = 2.8 Hz, 1 H), 5.18 (s,
1 H), 4.19 (q, J = 7.1 Hz, 2 H), 1.80 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H).
19F{1H} NMR (471 MHz, CDCl3): = –135.67. 13C{1H} NMR (126
MHz, CDCl3): = 166.14, 164.80, 148.03 (d, J = 240.5 Hz), 136.72
(d, J = 3.5 Hz), 134.33 (d, J = 12.5 Hz), 130.63, 130.21, 129.27,
127.53, 120.57 (d, J = 3.1 Hz), 120.20 (d, J = 5.5 Hz), 114.65 (d, J =
16.9 Hz), 108.81, 103.63, 59.81, 59.24 (d, J = 2.1 Hz), 24.01,
14.00. HRMS (ESI/QTOF): m/z [M + H]+ calcd for C20H19FNO3:
340.1343; found: 340.1384.
(14) Stewart, G. W.; Shevlin, M.; Gammack Yamagata, A. D.; Gibson,
A. W.; Keen, S. P.; Scott, J. P. Org. Lett. 2012, 14, 5440.
(15) For recent reviews, see: (a) Shevlin, M. ACS Med. Chem. Lett.
2017, 8, 601. (b) Krska, S. W.; DiRocco, D. A.; Dreher, S. D.;
Shevlin, M. Acc. Chem. Res. 2017, 50, 2976.
(16) For recent examples, see: (a) Larson, H.; Schultz, D.; Kalyani, D.
J. Org. Chem. 2019, 84, 13092. (b) Becica, J.; Hruszkewycz, D. P.;
Steves, J. E.; Elward, J. M.; Leitch, D. C.; Dobereiner, G. E. Org.
Lett. 2019, 21, 8981. (c) Cernak, T.; Gesmundo, N. J.; Dykstra, K.;
Yu, Y.; Wu, Z.; Shi, Z.-C.; Vachal, P.; Sperbeck, D.; He, S.; Murphy,
B. A.; Sonatore, L.; Williams, S.; Madeira, M.; Verras, A.; Reiter,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E