β-Selective C?H Arylation of Electron-Deficient Thiophenes, Pyrroles, and Furans

Article abstract of DOI:10.1002/ijch.201900134

A general β-C?H arylation of electron-deficient thiophenes, pyrroles, and furans has been developed using ligand-modulated palladium catalyst. The use of a modified norbornene is crucial for reversing the conventional α-selectivity of these substrates. This method features good yields, high β-selectivity, and good tolerance of functional groups.

Full text of DOI:10.1002/ijch.201900134

Communication
DOI: 10.1002/ijch.201900134
β-Selective CÀ H Arylation of Electron-Deficient Thiophenes,
Pyrroles, and Furans
Luo-Yan Liu,[a] Jennifer X. Qiao,[b] William R. Ewing,[b] Kap-Sun Yeung,[c] and Jin-Quan Yu*[a]
Dedicated to 2019 Wolf Prize Awardees Professor Stephen L. Buchwald and Professor John F. Hartwig
Abstract: A general β-CÀ H arylation of electron-deficient selectivity of these substrates. This method features good
thiophenes, pyrroles, and furans has been developed using yields, high β-selectivity, and good tolerance of functional
ligand-modulated palladium catalyst. The use of a modified groups.
norbornene is crucial for reversing the conventional α-
Keywords: Thiophene · pyrrole · furan · palladium · arylation
Arylated five-membered heterocycles such as thiophenes,
pyrroles, and furans are important scaffolds in bioactive
molecules and natural products.[1] Although the α-arylation of
thiophenes, pyrroles, and furans have been extensively
developed due to the inherent reactivity,[2] β-selective arylation
of these heteroarenes, especially electron-deficient five-mem-
bered heterocycles, remains underdeveloped. In 2010, Itami
group reported a β-selective CÀ H arylation of thiophenes using
previously.[11] Disappointedly, the optimal pyridone ligand
could only afford the corresponding arylation product in 22%
yield. However, combination of quinoxaline (L21) and 5-CF3-
2-pyridone (L12) afforded substantial improvement in yield
(45%). Further screening of ligands identified a dual ligand
system of quinoxaline (L21) and 3-NHAc-5-CF3-2-pyridone
(L15), yielding the β-arylation product in 80%.
With the optimal ligands identified, we next examined
several modified norbornenes. The simple norbornene (NBE0)
only afforded the desired product in trace amount, although it
has been reported to assist directed meta CÀ H activation.[12] 2-
Carbomethoxynorbornene (NBE1) which has been extensively
explored by our group and others to achieve meta CÀ H
functionaliztion so far gave the highest yield.[13] Tuning the
methoxy group to bulkier but more electron-withdrawing
functional groups such as trifluoroethoxy and 1,1,1,3,3,3-
hexafluoroisopropoxy groups failed to further improve the
yield.
palladium catalysts and aryl iodides as coupling partners.[3]
A
number of related contributions on this subject from Studer,
Oi, Doucet and Glorius are also important.[4–8] In 2014,
Yamaguchi group published the first general method of β-
arylation of pyrroles using rhodium catalyst.[9] Although the β-
arylation of thiophenes and pyrroles have been successfully
achieved, one major limitation is the low reactivity of the
electron-deficient substrates. Herein we report a general β-
selective arylation of electron-deficient five-membered hetero-
cycles using a modified norbornene as the mediator.
It has been well documented that the CÀ H arylation of
these arenes preferably proceed at the α-positions.[2] To reverse
this conventional site-selectivity, a modified norbornene was
introduced, which has been employed as a mediator by our
group recently to realize a nondirected CÀ H activation on less
electronically favored positions.[10] With this design in mind,
we selected thiophene-2-carboxylic acid methyl ester as the
model substrate and began our study on ligand screening
(Table 1). Electron-deficient quinoline-type ligands which
demonstrated superior reactivity for nondirected CÀ H aryla-
tion of protected phenols yielded the desired β-arylation
product as the sole regioisomer in less than 10% yield.
Although the yield is quite low, the exclusive β-selectivity
corroborates our design of the norbornene relay pathway,
considering that direct CÀ H arylation of this substrate always
prefer the α-positions. Extensive screening of pyridine- and
quinoline-type ligands failed to further improve the yield. We
also tested the electron-deficient 2-pyridones that were proved
to accelerate nondirected CÀ H activation by our group
With the optimal conditions established, we set out to
explore the scope of heteroarenes and (hetero)aryl iodides
(Table 2). With 1a as the model substrate, a variety of (hetero)
aryl iodides were tested and thecorresponding β-arylated
products were obtained in good yields and with high β-
selectivity, regardless of their electronic properties (2aa–2ag).
[a] L.-Y. Liu, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
[b] Dr. J. X. Qiao, Dr. W. R. Ewing
Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Prince-
ton, New Jersey 08543, United States
[c] K.-S. Yeung
Discovery Chemistry, Bristol-Myers Squibb Research and Devel-
opment, 100 Binney Street, Cambridge, MA 02142
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201900134
©
Isr. J. Chem. 2020, 60, 1–4
2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Evaluation of ligands and modified norbornenes.[a,b]
Table 2. Substrates Scope.[a,b]
[a] Conditions: 1a (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%),
modified norbornene (1.5 equiv.), L1x (20 mol%), L2x (20 mol%),
°
AgOAc (3.0 equiv), HFIP (0.25 mL), 100 C, under air, 18 h. [b] The
yield was determined by GC-Mass using mesitylene as the internal
standard.
[a] Conditions: 1a (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%),
NBE1 (1.5 equiv.), L15 (20 mol%), L21 (20 mol%), AgOAc
Various 2-substituted pyridine-based heteroaryl iodides also
gave good reactivity under this condition (2ah–2aj). In
addition, the heteroaryl iodide derived from N-protected 2-
pyridone was also compatible with this reaction and yielded
the desired product in 66% yield (2ak). 2-Acetyl-5-iodothio-
phene provided the corresponding β-arylation product 2al in
52% yield. After evaluation of (hetero)aryl iodides, a variety
of electron-deficient (carbonyl-substituted) thiophenes, pyr-
roles, and furans were subsequently examined, using methyl 4-
iodobenzoate as the model aryl iodide substrate. 2-Acetyl
thiophene was smoothly coupled with the model aryl iodide,
yielding the desired product in 80% (2b). Several aryl
carbonyl-substituted thiophenes were also evaluated and
showed good reactivity and high selectivity (2c, 2d). Furans
are more challenging substrates for β-arylation. Tsukada group
reported the only example of direct β-arylation of furans in
2017, however, the reaction is highly α-selective with 2-
carbonyl furans as the substrates.[14] We employed furan-2-
carboxylic acid methyl ester as the substrate, a moderate yield
was obtained under our optimal conditions (2e). Moreover, β-
arylation of carbonyl-substituted pyrroles also proceeded in
good yields. everal carbonyl-substituted pyrrole substrates
°
(3.0 equiv), HFIP (0.25 mL), 100 C, under air, 18 h. [b] The yield
was determined by H NMR using CH2Br2 as the internal standard.
[c] 20 mol% of L15 was used as ligand.
1
with different carbonyl groups and N-protecting groups were
tested, affording the corresponding arylation products in 55–
69% yields (2f–2i). Gram-scale reactition using 1a as the
substrate affforded the desired product in 74% yield, which
further showcases the utility of this protocol (Scheme 1). A
plausible mechanism is outlined in Scheme 2. Modified
norbornene was employed to reverse the inherent α-selectivity
Scheme 1. Gram-Scale Reaction.
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Isr. J. Chem. 2020, 60, 1–4
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References
[1] a) T. Y. Zhang, J. O’Toole, C. S. Proctor, Sulfur Rep. 1999, 22, 1;
b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
103, 893; c) A. Kamboj, H. Randhawa, J. Pharm. Res. 2012, 5,
2676; d) I. S. Young, P. D. Thornton, A. Thompson, Nat. Prod.
Rep. 2010, 27, 1801; e) B. D. Roth, Prog. Med. Chem. 2002, 40,
1; f) A. Fürstner, M. M. Domostoj, B. Scheiper, J. Am. Chem.
Soc. 2005, 127, 11620; g) W. Zhang, Z. Liu, S. Li, T. Yang, Q.
Zhang, L. Ma, X. Tian, H. Zhang, C. Huang, S. Zhang, J. Ju, Y.
Shen, C. Zhang, Org. Lett. 2012, 14, 3364; h) B. E. Beck, R.
Hatley, M. J. Gaunt, Angew. Chem. 2008, 120, 3046; Angew.
Chem. Int. Ed. 2008, 47, 3004; i) R. A. Davis, M. S. Buchanan,
S. Duffy, V. M. Avery, S. A. Charman, W. N. Charman, K. L.
White, D. M. Shackleford, M. D. Edstein, K. T. Andrews, D.
Camp, R. J. Quinn, J. Med. Chem. 2012, 55, 5851.
[2] a) L. Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673;
b) F. Bellina, R. Rossi, Tetrahedron 2009, 65, 10269; c) T. Satoh,
M. Miura, Chem. Lett. 2007, 36, 200.
[3] K. Ueda, S. Yanagisawa, J. Yamaguchi, K. Itami, Angew. Chem.
2010, 122, 9130; Angew. Chem. Int. Ed. 2010, 49, 8946.
[4] a) S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer, K.
Itami, Angew. Chem. 2011, 123, 2435; Angew. Chem. Int. Ed.
2011, 50, 2387; b) K. Yamaguchi, J. Yamaguchi, A. Studer, K.
Itami , Chem. Sci. 2012, 3, 2165.
[5] K. Yamaguchi, H. Kondo, J. Yamaguchi, K. Itami, Chem. Sci.
2013, 4, 3753.
[6] K. Funaki, T. Sato, S. Oi, Org. Lett. 2012, 14, 6186.
[7] K. Yuan, H. Doucet, Chem. Sci. 2013, 5, 3495.
[8] D. T. Tang, K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem.
Int. Ed. 2014, 53, 1809; Angew. Chem. 2014, 126, 1840.
[9] K. Ueda, K. Amaike, R. M. Maceiczyk, K. Itami, J. Yamaguchi,
J. Am. Chem. Soc., 2014, 136, 13226.
[10] L.-Y. Liu, J. X. Qiao, K.-S. Yeung, W. R. Ewing, J.-Q. Yu, J. Am.
Chem. Soc. 2019, 141, 14870.
[11] P. Wang, P. Verma, G.-Q. Xia, J. Shi, J. X. Qiao, S. Tao, P. T. W.
Cheng, M. A. Poss, M. E. Farmer, K.-S. Yeung, J.-Q. Yu, Nature
2017, 551, 489.
[12] Early examples on simple norbornene-assisted meta CÀ H
activation: a) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S.
Li, K. M. Engle, J.-Q. Yu, Nature 2015, 519, 334; b) Z. Dong, J.
Wang, G. Dong, J. Am. Chem. Soc. 2015, 137, 5887.
Scheme 2. Proposed Mechanism.
to β. The dual ligands are believed to promote the non-directed
CÀ H activation.
In summary, we have developed a general method of Pd-
catalyzed β-arylation of electron-deficient thiophenes, pyr-
roles, and furans, using the modified norbornene (NBE1) as
the mediator. High site-selectivity on the β-carbon was
achieved and a series of (hetero)aryl iodides were coupled in
moderate to good yields. This work provides a practical and
concise method to synthesize 4-arylated 2-carbonyl substituted
thiophenes, pyrroles, and furans that are difficult to access
otherwise.
Experimental Section
General procedure: Heteroarenes (0.1 mmol), aryl iodides
(2.0 equiv.), Pd(OAc)2 (10 mol%), modified norbornene NBE1
(1.5 equiv.), L15 (20 mol%), L21 (20 mol%), AgOAc (3.0 equiv.), and
HFIP (0.25 mL) were added to a 10 ml-reaction vial. The vial was
capped and closed tightly. Then the reaction mixture was stirred at
[13] Selected examples on modified norbornene-assisted meta CÀ H
activation: a) P.-X. Shen, X.-C. Wang, P. Wang, R.-Y. Zhu, J.-Q.
Yu, J. Am. Chem. Soc. 2015, 137, 11574; b) P. Wang, M. E.
Farmer, X. Huo, J. Pankaj, P.-X. Shen, M. Isoloey, J. E. Bradner,
S. R. Wisniewski, M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc.
2016, 138, 9269; c) P. Wang, G.-C. Li, J. Pankaj, M. E. Farmer, J.
He, P.-X. Shen, J.-Q. Yu, J. Am. Chem. Soc. 2016, 138, 14092;
d) S. Hang, P. Wang, S. Suzuki, M. E. Farmer, J.-Q. Yu, J. Am.
Chem. Soc. Soc. 2016, 138, 14876.
°
100 C for 18 hours. After cooling to room temperature, the mixture
was passed through a pad of Celite with ethyl acetate as the eluent to
remove the insoluble precipitate. The resulting solution was concen-
trated and purified by preparative thin-layer chromatography to afford
the desired product.
[14] T. Goto, H. Kato, N. Tsukada, Heterocycles 2017, 94, 2222.
Acknowledgement
We gratefully acknowledge The Scripps Research Institute, the
NIH (National Institute of General Medical Sciences grant
R01GM102265) and Bristol-Myers Squibb for financial
support. We gratefully acknowledge Dr. Jason Chen (TSRI),
Brittany Sanchez (TSRI) and Emily Sturgell (TSRI) for
HRMS analysis and compound purification.
Manuscript received: October 26, 2019
Revised manuscript received: December 15, 2019
Version of record online: ■■■, ■■■■
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Isr. J. Chem. 2020, 60, 1–4
2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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COMMUNICATION
L.-Y. Liu, Dr. J. X. Qiao, Dr. W. R.
Ewing, K.-S. Yeung, Prof. Dr. J.-Q.
Yu*
1 – 4
β-Selective CÀ H Arylation of
Electron-Deficient Thiophenes,
Pyrroles, and Furans
A general β-CÀ H arylation of electron-
deficient thiophenes, pyrroles, and
furans has been developed using ligand-
modulated palladium catalyst. The use
of a modified norbornene is crucial for
reversing the conventional α-selectivity
of these substrates. This method
features good yields, high β-selectivity,
and good tolerance of functional
groups.