Cobalt-Catalyzed Selective Functionalization of Aniline Derivatives with Hexafluoroisopropanol

Article abstract of DOI:10.1021/acs.orglett.8b03666

A cobalt-catalyzed site-selective functionalization of aniline derivatives with hexafluoroisopropanol, which enables the synthesis of a wide array of fluoroalkylated anilines, a class of highly valuable building blocks for further preparation of fluorinated functional products, is reported. The developed transformation proceeds with operational simplicity, use of earth-abundant metal catalyst, broad substrate scope, good functional group tolerance, and mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.8b03666

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Selective Functionalization of Aniline Derivatives
with Hexafluoroisopropanol
He Zhao,† Shuo Zhao,‡ Xiu Li,† Yinyue Deng,‡ Huanfeng Jiang,† and Min Zhang*,†
†Key Lab of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510641, China
‡Guangdong Innovative and Entepreneurial Research Team of Sociomicrobiology Basic Science and Frontier Technology, College
of Agriculture, South China Agricultural University, Guangzhou 510642, China
S
* Supporting Information
ABSTRACT: A cobalt-catalyzed site-selective functionalization of aniline
derivatives with hexafluoroisopropanol, which enables the synthesis of a
wide array of fluoroalkylated anilines, a class of highly valuable building
blocks for further preparation of fluorinated functional products, is reported.
The developed transformation proceeds with operational simplicity, use of
earth-abundant metal catalyst, broad substrate scope, good functional group
tolerance, and mild reaction conditions.
Scheme 1. Existing Strategies
elective introduction of fluorinated substituents into an
Sorganic molecule is of particular importance in synthetic
chemistry, as it enables the electron distribution and the
lipophilicity of the entire molecule to be altered and
contributes to renewed applications in the fields of medicine,
agrochemicals, and material science.1 Among the various
related transformations, the study on direct synthesis of
hydroxyhexafluoroisopropyl (or bis(trifluoromethyl)carbinol)
group containing products is relatively rare.2 Nevertheless,
such compounds exhibit diverse biological and therapeutic
activities, and they have been applied for the treatment of
hepatitis C, cancer, dyslipidemia, inflammation, and diabetes.3
Moreover, they could be utilized for the preparation of
polymer,4 the development of ligands5 and chemical sensors,6
and the synthesis of spirosilanes.7
Anilines constitute a class of fundamental raw materials in
chemical industry, for instance, for large-scale production of
polymers and dyes. Moreover, they serve as highly useful
building blocks for the preparation of bioactive molecules,
pharmaceuticals, agrochemicals, dyes, and other functional
products.8 Because of the widespread applications, selective
installation of a hydroxyhexafluoroisopropyl group on the
aniline skeleton is of important significance, as it would pave
the way for further elaboration of various fluorinated functional
products. Despite the multidisciplinary impact of arylamino
and hexafluoroisopropanol motifs, there are very limited
strategies reported for the preparation of hydroxyhexafluor-
oisopropyl anilines, including the electrophilic substitution of
anilines with hexafluoroacetone under acidic conditions
(Scheme 1, eq 1)9a,b and the addition of organomagnesium
to hexafluoroacetone (eq 2).9c However, these methods suffer
from one or more limitations such as low regio- and
chemoselectivity, poor substrate and functional group compat-
ibility, the use of toxic2a and corrosive agents, and the need for
pre-preparation of air- and moisture-sensitive agents. As such,
the development of direct and selective methods for general
synthesis of hydroxyhexafluoroisopropyl anilines from readily
available feedstocks still remains a highly demanding goal.
As our sustained efforts toward the construction and
functionalization of N-heterocycles,10 we have recently
reported an aerobic copper-catalyzed α-amination of tetrahy-
dronquinolines (THQs) with various amines.10h Interestingly,
when the reaction of THQ 1a with O-(benzoyloxy)piperidine
(A1) as the aminating agent11 was performed in hexafluor-
oisopropanol (HFIP) by using as CuCl2 as a catalyst (Scheme
2), we observed that, instead of the anticipated α-C−H
Scheme 2. New Observation
Received: November 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03666
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Letter
a
amination product 3aA1, two hydroxyhexafluoroisopropyl
products (3a and 3a′), occurring at the sites para and ortho
to the N atom of the THQ 1a, were detected in 63% and 15%
yields, respectively. Moreover, a noncoupling quinoline 1a′ was
found in 5% yield. To the best of our knowledge, HFIP has
emerged as a solvent of choice for different reactions,12
whereas it has been scarcely utilized as a coupling agent for the
functionalization of C−H bonds. In particular, the new
observation on the formation products 3a and 3a′ has spurred
our interest, and we wished to develop a selective
fluoroalkylation reaction. Through a thorough investigation,
we report herein, for the first time, a cobalt-catalyzed direct
and selective functionalization of aniline derivatives with HFIP.
Initially, we chose the reaction of substrate 1a in HFIP (2)
as a model system to screen an efficient catalyst system (Table
1). Gratifyingly, in the presence of catalytic amount of cobalt
Scheme 3. Variation of Benzocyclic Amines
a
Table 1. Optimization of the Reaction Conditions
a
Standard conditions: 1 (0.25 mmol), A1 (0.25 mmol), Co(OAc)2·
4H2O (2 mol %), HFIP 2 (0.5 mL), 70 °C, under air, 5 h. Isolated
yield.
b
entry
catalyst
additive
3a, yield (%)
1
2
3
4
5
6
7
8
9
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
Co(OAc)2·4H2O
−
A1
A2
A3
A4
A5
A6
98
94
trace
34
34
trace
−
smooth hydroxyhexafluoroisopropylation at the site para to the
N atom of substrates 1 and furnished the desired products in
good to excellent yields upon isolation (Scheme 3, 3a−i). The
electronic properties of the substituents on the aryl ring of
THQs affected the product yields to some extent. In particular,
THQs containing an electron-donating group afforded the
products (3b−g) in relatively higher yields than those of with
electron-deficient THQs (3h,i). This phenomenon is attribut-
able to the fact that the electron-rich THQs enhance the
electron density of the aryl ring and favor the coupling step. In
addition to THQs, other types of secondary and tertiary
benzocyclic amines, such as benzomorpholine (1j), benzothia-
zine (1k), 1,2,3,4-tetrahydroquinoxaline (1l), 2,3,4,5-tetrahy-
dro-1H-benzo[b]azepine (1m), indolines (1n and 1o), and N-
methyl-1,2,3,4-tetrahydroquinoline (1p), were also amenable
to the transformation, affording the desired products in
satisfactory yields (3j−p). Intriguingly, THQs (1q and 1r)
substituted with a methyl group at position 6 resulted in 8-
hydroxyhexafluoroisopropyl products 3q and 3r in excellent
yields. It is important to note that, in all cases studied, no
dehydrogenation on the cyclic amine motifs was found,
showing that the reaction proceeds in a chemoselective
manner. The retention of such structural units has the
potential for further elaboration of functional frameworks.10
Next, we focused on the variation of aniline derivatives with
different substitution patterns. As shown in Scheme 4, primary,
secondary, and tertiary anilines (4a−o) were reacted with
HFIP 2, which generated the desired products in the moderate
to good isolated yields (5a−o). Similar to the results described
in Scheme 4, electron-rich anilines gave relatively higher yields
(5c, 5k, and 5m) than those of electron-deficient ones (5j, 5l,
and 5n). It is noteworthy that various functional groups, as
shown in Schemes 3 and 4, were well tolerated, which offers
(−, TBHP, H2O2)
A1
A1
A1
15
c
Co(OAc)2·4H2O
Co(OAc)2·4H2O
47
d
10
44
a
Reaction conditions: 1a (0.25 mmol), additive (0.25 mmol),
Co(OAc)2·4H2O (2 mol %), HFIP 2 (0.5 mL), 70 °C, under air, 5
b
c
d
h. Isolated yield. Catalyst loading: 1 mol %. Additive loading: 0.5
equiv.
acetate and O-(benzoyloxy)piperidine (A1) as the additive,
performing the reaction at 70 °C for 5 h gave product 3a in
almost quantitative yield (Table 1, entry 1:98%), and its
structure was confirmed by X-ray diffraction (Figure S1 and
Table S3). Then a series of O-benzoyl hydroxylamines were
tested (A2−A6). The results showed that they were inferior to
A1 (entries 1−6). However, the absence of additive A1 or
catalyst, or the use of other common oxidants (e.g., TBHP and
H2O2), led to no product formation or poor yield (entries 7
and 8), showing that the combination of A1 and Co(OAc)2 is
critical to constitute an efficient catalyst system. Further, a
decrease of catalyst or additive loading significantly diminished
the product yield. Thus, the optimal conditions are as
described in entry 1 (standard conditions).
With the availability of the optimal conditions, we then
evaluated the substrate scope of the synthetic protocol.
Initially, a variety of benzocyclic amines 1 (for their structures,
see Scheme S1), a class of specific aniline derivatives, were
tested. As shown in Scheme 3, all the reactions proceeded with
B
DOI: 10.1021/acs.orglett.8b03666
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Letter
a
Scheme 4. Variation of Aniline Derivatives
Figure 1. Representative cyclic voltammogram of A1 and A3
measured in HFIP with 0.1 M TBAPF6 at 25 °C.
On the basis of the above findings, three possible reaction
pathways are depicted in Scheme 6. Initially, the single-
Scheme 6. Plausible Reaction Pathways
a
Standard conditions: 4 (0.25 mmol), A1 (0.25 mmol), Co(OAc)2·
4H2O (2 mol %), HFIP 2 (0.5 mL), 70 °C, under air, 5 h. Isolated
yield.
the potential for the construction of complex molecules via
further chemical transformations.
To gain mechanistic insights into the reaction, we conducted
several control experiments. As illustrated in Scheme 5, the
Scheme 5. Control Experiments
electron transfer from [CoII] to A1 forms the [CoIII] species,
PhCOO− (A), and piperidyl radical B. Then the interaction
between B and HFIP gives radical C along with elimination of
piperidine. In path a, the electron-deficient radical C is trapped
by electron-rich aniline 1 at the sterically less hindered para-
site (see the zwitterionic form D),10d which then gives
intermediate E via single-electron oxidation (SEO) by
[CoIII]- and PhCOO−-assisted deprotonation. Finally, the
tautomerization of E generates product 3 or 5. In path b, direct
SEO of aniline 1 followed by deprotonation and radical−
radical coupling between G and C would give rise to the
desired product. Alternatively, direct addition of C to aniline
on the aryl ring followed by SEO and elimination of proton
also rationalizes the product formation (path c). It is
noteworthy that when the site para to the N-atom of aniline
1 is blocked, the fluoroalkylation occurs at the o-position.
Finally, we were interested in demonstrating the utility of
the developed chemistry. The reaction of substrate 4c was
scaled up to 10 mmol under the standard conditions, which
still gave product 5c in good isolated yield. Further, the
treatment of compound 5c with benzoyl chloride in dichloro-
methane (DCM) by using NEt3 as a base resulted in the N-
acylated product 6c, a potent inhibitor of hepatitis C virus,8b in
excellent yield (Scheme 7).
addition of 3 equiv of butylated hydroxytoluene (BHT) or 1,1-
diphenylethylene (DPE) into the model reaction completely
suppressed the formation product 3a (eqs 1 and 2), whereas
the products of BHT trapping THQ 1a at position 6 (3s) and
a piperidyl motif from additive A1 (3t) were detected in 60%
and 20% yields, respectively (eq 1), and DPE combined with a
HFIP unit was produced in 80% yield. These two experiments
show that the reaction involves piperidyl, tetrahydroquinolyl,
and hydroxyhexafluoroisopropyl radicals. Further, the reaction
of THQ 1a and hexafluoroacetone yielded a mixture of 6-
functionalized quinoline 3a-1 (51%) and 6,8-difunctionalized
THQ 3a-2 (39%), but it failed to give even trace of product 3a
(eq 3). Thus, the reaction involving hexafluoroacetone as an
intermediate can be ruled out.
To better understand the role of the additive, we analyzed
the redox potentials of compounds A1 and A3. As shown in
Figure 1, in sharp contrast with the weak signal of A3, A1
exhibits a significant redox potential and a larger surface area
under the same conditions, which indicate that A1 has stronger
oxidizing capacity than that of A3, and compound A3 is not an
applicable oxidant for the reaction.
Scheme 7. Synthetic Utility of the Developed Chemistry
C
DOI: 10.1021/acs.orglett.8b03666
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Letter
Furthermore, we evaluated the in vitro cytotoxicity of all the
obtained products by the methylthiazoltetrazolium (MTT)
assay on the human hepatoma carcinoma cell (HepG-2),
human cervical cancer cell (Hela), human lung carcinoma cell
(A549), and human skin fibroblasts (HSF) cell lines. The
detailed results are listed in Scheme 8 and Table S2.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program of China (2016YFA0602900), 1000 Youth Talents
Plan, the Fundamental Research Funds for the Central
Universities (2017ZD060), the National Natural Science
Foundation of China (21472052), the Science and Technology
Program of Guangzhou (201607010306), and the Science
Foundation for Distinguished Young Scholars of Guangdong
Province (2014A030306018) for financial support.
Scheme 8. Anticancer Activity of Compounds 3o, 5g, and 5i
REFERENCES
■
(1) For selected reviews, see: (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang,
S.; Zhu, W.; Acen
Rev. 2016, 116, 422. (b) Vitale, A.; Bongiovanni, R.; Ameduri, B.
Chem. Rev. 2015, 115, 8835. (c) Mishra, S.; Daniele, S. Chem. Rev.
̃
a, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem.
Gratifyingly, compounds 5i (IC50 = 11.731 μM) and 5g
(IC50 = 6.718 μM) exhibit potent inhibitory activities against
HepG-2 cell lines, product 5i (IC50 = 3.96 μM) shows high
inhibitory efficiency in A549 cell lines, and compound 3o (IC50
= 11.36 μM) is a powerful cytotoxic agent against these cell
lines except for HepG-2 (Scheme 8). This study has
demonstrated the potential of hydroxyhexafluoroisopropyl
anilines in the discovery of new potent anticancer agents.
In summary, we have developed a new cobalt-catalyzed
selective functionalization of aniline derivatives with hexa-
fluoroisopropanol, which enables to access a wide array of
fluoroalkylated anilines, a class of highly valuable building
blocks for further preparation of fluorinated functional
products. The catalytic transformation proceeds with good
functional group and substrate compability, high regio and
chemoselectivity, mild conditions, and operational simplicity,
which offers the potential for the discovery of functional
molecules such as new anticancer agents and sheds new light
on further introduction of other fluoroalkyl groups into
electron-rich organic systems via a radical-coupling strategy.
́
́
2015, 115, 8379. (d) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del
̃
Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2014, 114, 2432. (e) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (f) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) (a) Domino, K.; Veryser, C.; Wahlqvist, B. A.; Gaardbo, C.;
Neumann, K. T.; Daasbjerg, K.; De Borggraeve, W. M.; Skrydstrup, T.
Angew. Chem., Int. Ed. 2018, 57, 6858. (b) Xu, Z.-B.; Hang, Z. J.; Chai,
L.; Liu, Z.-Q. Org. Lett. 2016, 18, 4662.
(3) (a) Li, L.; Liu, J.; Zhu, L.; Cutler, S.; Hasegawa, H.; Shan, B.;
Medina, J. C. Bioorg. Med. Chem. Lett. 2006, 16, 1638. (b) Kumar, N.;
Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.;
Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. Mol. Pharmacol.
2010, 77, 228. (c) Wang, Y.; Kumar, N.; Nuhant, P.; Cameron, M. D.;
Istrate, M. A.; Roush, W. R.; Griffin, P. R.; Burris, T. P. ACS Chem.
Biol. 2010, 5, 1029. (d) Bourbeau, M. P.; Ashton, K. S.; Yan, J.; St.
Jean, D. J., Jr J. Org. Chem. 2014, 79, 3684. (e) Li, Y.; Xia, G.; Guo,
Q.; Wu, L.; Chen, S.; Yang, Z.; Wang, W.; Zhang, Z.-Y.; Zhou, X.;
Jiang, Z.-X. MedChemComm 2016, 7, 1672. (f) Peng, Q.; Yuan, Y.;
Zhang, H.; Bo, S.; Li, Y.; Chen, S.; Yang, Z.; Zhou, X.; Jiang, Z.-X.
Org. Biomol. Chem. 2017, 15, 6441.
(4) (a) Cassidy, P. E.; Aminabhavi, T. M.; Reddy, V. S.; Fitch, J. W.,
III Eur. Polym. J. 1995, 31, 353. (b) Fitch, J. W.; Bucio, E.; Martinez,
L.; Macossay, J.; Venumbaka, S. R.; Dean, N.; Stoakley, D.; Cassidy,
P. E. Polymer 2003, 44, 6431. (c) Miyasaka, M.; Koike, N.; Fujiwara,
Y.; Kudo, H.; Nishikubo, T. Polym. J. 2011, 43, 325.
(5) (a) Morikawa, S.; Michigami, K.; Amii, H. Org. Lett. 2010, 12,
2520. (b) O’Reilly, M. E.; Ghiviriga, I.; Abboud, K. A.; Veige, A. S. J.
Am. Chem. Soc. 2012, 134, 11185. (c) Ratjen, L.; van Gemmeren, M.;
Pesciaioli, F.; List, B. Angew. Chem., Int. Ed. 2014, 53, 8765.
(6) (a) Kong, L.; Wang, J.; Fu, X.; Zhong, Y.; Meng, F.; Luo, T.; Liu,
J. Carbon 2010, 48, 1262. (b) Kong, L.; Wang, J.; Luo, T.; Meng, F.;
Chen, X.; Li, M.; Liu, J. Analyst 2010, 135, 368.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03666.
Experimental details, NMR spectra, and single-crystal X-
ray diffraction data of 3a (PDF)
Accession Codes
CCDC 1875943 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
(7) (a) Lenormand, H.; Corce, V.; Sorin, G.; Chhun, C.;
Chamoreau, L.-M.; Krim, L.; Zins, E.-L.; Goddard, J.-P.;
Fensterbank, L. J. Org. Chem. 2015, 80, 3280. (b) Perozzi, E. F.;
Martin, J. J. Am. Chem. Soc. 1979, 101, 1591.
(8) (a) Mintzer, M. A.; Simanek, E. E. Chem. Rev. 2009, 109, 259.
(b) Birch, A. M.; Groombridge, S.; Law, R.; Leach, A. G.; Mee, C. D.;
Schramm, C. J. Med. Chem. 2012, 55, 3923. (c) Hutchby, M. Novel
Synthetic Chemistry of Ureas and Amides; Springer: Berlin, 2012.
(9) (a) Zelenin, A.; Chkanikov, N.; Umnov, A.; Kolomiets, A.;
Fokin, A. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1986, 35, 1890.
(b) Matsuno, K.; Ueda, Y.; Fukuda, M.; Onoda, K.; Waki, M.; Ikeda,
M.; Kato, N.; Miyachi, H. Bioorg. Med. Chem. Lett. 2014, 24, 4276.
(c) Satou, M.; Kakizawa, T. WO2014133048A1, 2014.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: minzhang@scut.edu.cn.
ORCID
Yinyue Deng: 0000-0003-1511-0870
Huanfeng Jiang: 0000-0002-4355-0294
Min Zhang: 0000-0002-7023-8781
Notes
(10) (a) Chen, X.-W.; Zhao, H.; Chen, C.-L.; Jiang, H.-F.; Zhang, M.
Angew. Chem., Int. Ed. 2017, 56, 14232. (b) Xie, F.; Chen, Q.-H.; Xie,
R.; Jiang, H.-F.; Zhang, M. ACS Catal. 2018, 8, 5869. (c) Liang, T.;
Tan, Z.; Zhao, H.; Chen, X.; Jiang, H.; Zhang, M. ACS Catal. 2018, 8,
2242. (d) Chen, X.; Zhao, H.; Chen, C.; Jiang, H.; Zhang, M. Chem.
Commun. 2018, 54, 9087. (e) Chen, X.; Zhao, H.; Chen, C.; Jiang, H.;
The authors declare no competing financial interest.
D
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Letter
Zhang, M. Org. Lett. 2018, 20, 1171. (f) Tan, Z.; Jiang, H.; Zhang, M.
Org. Lett. 2016, 18, 3174. (g) Xie, F.; Xie, R.; Zhang, J.-X.; Jiang, H.-
F.; Du, L.; Zhang, M. ACS Catal. 2017, 7, 4780. (h) Liang, Y.; Jiang,
H.; Tan, Z.; Zhang, M. Chem. Commun. 2018, 54, 10096.
(11) Zhao, H.; Chen, X.-W.; Jiang, H.-F.; Zhang, M. Org. Chem.
Front. 2018, 5, 539.
́
(12) For selected examples, see: (a) Holloczki, O.; Berkessel, A.;
Mars, J.; Mezger, M.; Wiebe, A.; Waldvogel, S. R.; Kirchner, B. ACS
Catal. 2017, 7, 1846. (b) Berkessel, A.; Kramer, J.; Mummy, F.;
Neudorfl, J. M.; Haag, R. Angew. Chem., Int. Ed. 2013, 52, 739.
(c) Broese, T.; Francke, R. Org. Lett. 2016, 18, 5896. (d) Richmond,
́
E.; Yi, J.; Vukovic, V. D.; Sajadi, F.; Rowley, C. N.; Moran, J. Chem.
Sci. 2018, 9, 6411. (e) Imada, Y.; Rockl, J. L.; Wiebe, A.; Gieshoff, T.;
Schollmeyer, D.; Chiba, K.; Franke, R.; Waldvogel, S. R. Angew.
Chem., Int. Ed. 2018, 57, 12136.
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