Angewandte Chemie International Edition
10.1002/anie.202000632
COMMUNICATION
heteroaryl iodides such as iodothiophene, -quinoline,
-
Acknowledgements
quinoxaline, -indole and -oxindole were also suitable coupling
partners (3ak-3ao), providing further support to the generality of
this protocol.
To demonstrate the practical application of this method, we
first turned to dihydrocholesterol as a substrate for C-H
functionalization. Following directing group installation, a short
sequence involving C−H arylation with 3-iodo-2-fluoropyridine,
We gratefully acknowledge Scripps Research and NIH (NIGMS,
R01GM084019) for financial support. We thank Dr. Jason Chen,
Ms. Brittany Sanchez and Ms. Emily Sturgell (Automated
Synthesis Facility, The Scripps Research Institute) for their
assistance with HRMS analysis.
directing group removal and S
dihydrofuro[2,3-b]pyridine cis-fused structure (5, 36% yield from
, Scheme 2a). The new C−H functionalization protocol was
N
Ar cyclization generated a novel
Conflict of interest
4
further showcased in the synthesis of 9, a known precursor of
englitazone (of antihyperglycemic activity),[18] via sequential -
The authors declare no conflict of interest.
and -C−H arylations. This route required
a total of 7
Keywords: aliphatic alcohol • C-H activation • directing group •
transformations and proceeded in 23% yield, comparing
favorably to the 11 steps and 4.5% overall yield previously
reported (Scheme 2b).[19]
ligand
[1]
For selected examples, see a) H.-X. Dai, A. F. Stepan, M. S. Plummer,
Y.-H. Zhang, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 7222–7228. b) B.
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Baran, Angew. Chem. Int. Ed. 2013, 52, 7317–7320. c) J. He, S. Li, Y.
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3
[
2]
3]
For recent reviews on C(sp )−H functionalization, see a) T. W. Lyons, M.
S. Sanford, Chem. Rev. 2010, 110, 1147–1169. b) L. Ackermann,
Chem. Rev. 2011, 111, 1315–1345. c) O. Daugulis, J. Roane, L. D.
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3
[
For examples on aza-cyclic substrate C(sp )–H functionalization, see a)
D. P. Affron, O. A. Davis, J. A. Bull, Org. Lett. 2014, 16, 4956−4959. b)
S. Ye, W. Yang, T. Coon, D. Fanning, T. Neubert, D. Stamos, J.-Q. Yu,
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Scheme 2. Practical application. Conditions: a) Substrate
iodobenzene (0.6 mmol), Pd(OAc) (10 mol%), L8 (40 mol%), AgTFA (1.5
equiv), in HFIP (3.0 mL), 100 oC, 4 h; then Pd(OH)
/C (20 mol%), H (1 atm),
in EtOH (2.0 mL), r.t., overnight, 65% yield over 2 steps; b) Ph P (1.2 equiv),
NHPI (1.2 equiv), DIAD (1.5 equiv), in THF (2 mL), r.t., 95% yield; c)
Hydrazine monohydrate (2.0 equiv), in CH Cl /MeOH, 2 h, then pyruvic acid (5
6 (0.5 mmol),
2
2
2
3
2
2
equiv),
1
h, 95% yield; d) Methyl 4-fluoro-3-iodobenzoate (1.5 equiv),
[
[
[
4]
5]
6]
For selected examples using heteroaryl iodides as coupling partners,
see a) Y.-Q. Chen, Z. Wang, Y. Wu, S. R. Wisniewski, J. X. Qiao, W. R.
Ewing, M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc. 2018, 140,
17884−17894. b) R.-Y. Zhu, L.-Y. Liu, H. S. Park, K. Hong, Y. Wu, C. H.
Senanayake, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 16080−16083. c)
R.-Y. Zhu, Z.-Q. Li, H. S. Park, C. H. Senanayake, J.-Q. Yu, J. Am.
Chem. Soc. 2018, 140, 3564−3658.
Pd(OAc)
2
(10 mol%), L8 (40 mol%), AgTFA (1.5 equiv), in HFIP (3.0 mL), 100
o
2 2 2
C, 4 h; then SOCl /MeOH, 49% yield; e) Pd(OH) /C (20 mol%), H (1 atm), in
EtOH (2.0 mL), r.t., overnight; then NaH (3.0 equiv), in THF, 70 oC, overnight,
1% yield over 2 steps.
8
3
In summary, we have developed a protocol for the -C(sp )−H
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protocol, leading notably to the activation of methylene β-C–H
bonds, is compatible with a wide range of substrates (including
aza-heterocycles), and coupling partners (including heteroaryl
iodides). Given the variety of commercially available aliphatic
alcohol substrates and suitable coupling partners, we anticipate
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3
that this C(sp )–H functionalization strategy will facilitate the
synthesis of novel chemical matter, particularly in the context of
drug discovery.
[
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