Visible-Light-Mediated Radical Arylation of Anilines with Acceptor-Substituted (Hetero)aryl Halides

Article abstract of DOI:10.1021/acs.orglett.7b03001

A visible-light-mediated, catalyst-free, direct (hetero)arylation of anilines with mild reaction conditions has been developed. The formation of a donor-acceptor complex between electron-withdrawing substituted (hetero)aryl halides and anilines allows, under blue LED irradiation, the synthesis of ortho and para (hetero)arylated anilines in moderate to good yields. The reaction has a high functional group tolerance. Spectroscopic studies confirmed the donor-acceptor complex formation between aniline and aryl halide.

Full text of DOI:10.1021/acs.orglett.7b03001

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Visible-Light-Mediated Radical Arylation of Anilines with Acceptor-
Substituted (Hetero)aryl Halides
Leyre Marzo, Shun Wang, and Burkhard Konig*
̈
Institute of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany
S
* Supporting Information
ABSTRACT: A visible-light-mediated, catalyst-free, direct (hetero)arylation of anilines
with mild reaction conditions has been developed. The formation of a donor−acceptor
complex between electron-withdrawing substituted (hetero)aryl halides and anilines allows,
under blue LED irradiation, the synthesis of ortho and para (hetero)arylated anilines in
moderate to good yields. The reaction has a high functional group tolerance. Spectroscopic
studies confirmed the donor−acceptor complex formation between aniline and aryl halide.
Scheme 1. Metal-Mediated and Photochemical Arylation of
Anilines
niline is a frequent structural motif of antibacterial
Acompounds, analgesics, antifungal agents, or compounds
used as treatment for noninfectious diseases, such us
tranquilizers or anesthetics. In industry, anilines are used as
starting material or key intermediates for the synthesis of
pigments, dyestuffs, rubber products, or explosives, among
other uses.1 A typical approach for the arylation of aniline
derivatives is the Suzuki cross-coupling reaction, starting from
aryl halides or triflates and aniline boronic acids or boronates.2
Other approaches use the Stille cross-coupling reaction3 from
stannane derivatives or the Ullmann reaction4 from the
corresponding halides. These methods are well developed
and yield, in many cases, excellent results, but require transition
metals as catalyst and a prefunctionalization of the aniline.
More atom economic is the direct C−H functionalization of
anilines. However, only a small number of examples of this kind
of transformation have been reported so far. Greaney et al.
reported the direct C−H arylation of anilines via a benzyne
intermediate from 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate, as the benzyne precursor, and trityl aniline5a or N-
substituted arylsulfonamides.5b High temperatures are neces-
sary to obtain ortho-substituted anilines. Heinrich and co-
workers reported the radical ortho- and meta-arylation of para-
substituted anilines with aryldiazonium salts6a and arylhydrazi-
nes6b as precursors of a transient aryl radical, which is trapped
by aniline present in the reaction mixture. In both examples,
stoichiometric amounts of a reducing or oxidizing agent (TiCl3
and MnO2, respectively) are required. To overcome this
limitation,6c−e they developed a method starting from aryl
hydrazines as the radical source and dioxygen as the oxidant
under basic conditions (eq 1, Scheme 1).6d Using arylhy-
drazines as starting materials, Zou and co-workers have
reported the CoPc-catalyzed radical arylation of anilines (eq
2, Scheme 1).7 The reaction afforded good results when using
10 mol % of the transition metal catalyst at 80 °C. We report
here a practical alternative method for the arylation of anilines
at room temperature starting from commercially available
(hetero)aryl bromides or chlorides and anilines using visible
light as a traceless reagent (eq 3, Scheme 1).
Based on our experience in the photoreduction of aryl8 and
heteroaryl halides9 with rhodamine 6G (Rh-6G), we inves-
tigated the reaction between bromothiophene 1A and aniline
2a using the previously reported9 catalytic system and obtained
product 3Aa in 66% yield (entry 1, Table 1). However, control
experiments revealed that the photocatalyst is not necessary
(entry 2, Table 1). Irradiation with 455 nm light is crucial for
the reaction (entry 3, Table 1). To understand this result, we
measured the absorption spectra of 1A (see Supporting
Information (SI), Figure S1). At the concentration of the
reaction mixture, 1A absorbs visible light until 600 nm, which
allows the initiation of the observed reaction. The reaction
proceeds in the absence of DIPEA (entry 4, Table 1), but its
presence accelerates the initial reaction (see kinetic measure-
ments in the SI, Figure S4), resulting in higher product yields.
Further experiments using different solvents as well as
equivalents of DIPEA and aniline revealed as the optimal
Received: September 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions for the
Direct Heteroarylation of Anilines
Scheme 2. Scope of Aniline Derivatives 2 under Optimal
Reaction Conditions with 1A
a
a
b
entry
solvent
DIPEA (equiv)
2a (equiv)
yield 3Aa (%)
c
1
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
1.2
1.2
1.2
−
1.2
1.2
1.2
1.2
1.2
0.5
0.2
0.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
5.0
66
60
0
2
d
3
4
62
0
5
6
0
7
THF
0
8
CH2Cl2
EtOH
50
0
9
10
11
12
CH3CN
CH3CN
CH3CN
70
64
77
a
Reaction conditions: 0.1 mmol of 1A, in 1 mL of CH3CN, 20 h,
under N2 at room temperature and 455 nm LED irradiation.
b
Determined by GC analysis with benzophenone as internal standard.
c
d
Using 10 mol % Rh-6G. No light.
reaction conditions the use of 0.5 equiv of DIPEA, 5.0 equiv of
the aniline derivative in acetonitrile (0.1 M) under nitrogen
atmosphere, 25 °C, and 455 nm irradiation (for further details
see SI, Table S1).
With the optimized conditions in hand, we studied the
reaction of different anilines with 1A (Scheme 2). Aniline 2a
and N-substituted anilines 2b and 2c afforded a mixture of the
ortho and para regioisomers in high yields (3Aa, 3Ab, 3Ac,
Scheme 2), while para-substituted anilines (2d, 2e, 2f) gave the
ortho adducts as single regioisomers in moderate yields (3Ad,
3Ae, 3Af, Scheme 2). With 2g, bearing bulky alkyl groups in the
two ortho positions, 3 equiv of the aniline are enough to obtain
the para adduct in good yield (3Ag, Scheme 2). However, the
presence of double bonds in the molecule diminishes the
reactivity.10 Thus, with 2h a 32% yield of the two possible
regioisomers was obtained (3Ah, Scheme 2). Benzene diamine
derivative 2i afforded 3Ai in 76% yield as a single regioisomer.
The steric hindrance by the dimethylated amines blocks
position C-2, forcing the substitution reaction to position C-4
(3Ai, Scheme 2). The reaction tolerates para-halogenated
anilines. Thus, 2j and 2k gave the ortho-substituted products as
single regioisomers in moderate yields (3Aj, 3Ak, Scheme 2).11
However, halogens in the ortho position and electron-
withdrawing groups at the nitrogen atom completely suppress
the reactivity by diminishing the electron density (3Al, 3Am,
Scheme 2). Anilines bearing ester substituents (2n and 2o)
show low reactivity, but the expected regioselectivity. Thus,
3An was obtained as a mixture of regioisomers in moderate
yield, while benzocaine 2o, an aniline derivative employed as a
topical anesthetic,12 affords the ortho adduct 3Ap in low yield
(Scheme 2). Naphthalene-2-amine 2p gave 3Ap in 54% yield,
but 2q did not react, due to low solubility and overlapping
absorption in the visible region of 2q and 1A.13
a
Reaction conditions: 0.1 mmol of 1A, 0.5 mmol of 2, 0.05 mmol of
DIPEA, 1 mL of CH3CN, blue LED irradiation (455 nm), under
nitrogen atmosphere and 25 °C. 0.2 equiv of DIPEA were used
instead of 0.5 equiv. 3.0 equiv of 2 were used. 8.0 equiv of 2 were
b
c
d
e
used. 10.0 equiv of 2 were used.
Scheme 3. Scope of Brominated (Hetero)Arenes 1 Reacting
with Diphenylamine 2c
a
a
Reaction conditions: 0.1 mmol of 1, 0.5 mmol of 2c, 0.05 mmol
DIPEA, 1 mL of CH3CN, blue LED irradiation (455 nm), under
nitrogen atmosphere and 25 °C. The reaction was carried out with
the chlorinated starting material and under 400 nm LED irradiation.
b
Next, we investigated the (hetero)aryl halide scope of the
reaction (Scheme 3). 2-Bromothiophene 1B and the electron-
deficient 2-bromopyridine 1C did not react with 2c (3Bc, 3Cc,
Scheme 3), suggesting that the presence of an electron-
withdrawing substituent in 1 is essential for the reaction. 1D
and 1E, bearing an aldehyde or a nitrile group, react smoothly
affording 3Dc and 3Ec as a mixture of regioisomers in excellent
B
DOI: 10.1021/acs.orglett.7b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yields (Scheme 3). However, in the presence of a nitro
substituent (1F) the reaction does not take place, due to the
ability of the nitro group to strongly stabilize the radical anion
intermediate inhibiting the C−Br bond scission (3Fc, Scheme
3). Chlorinated thiophenes 1G and 1H afforded a mixture of
the ortho/para adducts in moderate to good yields under 400
nm LED irradiation (3Gc, 3Hc, Scheme 3).14 2-Bromofurfural
1I also reacts under these conditions affording 3Ic in 78%
yield.15 The reaction was also applied to aryl bromides 1J and
1K, which afforded 3Jc and 3Kc as a single regioisomer in low
yield due to lower reactivity. 4-Bromobenzonitrile 1L gave 3Lc
as an ortho/para mixture in 66% yield (Scheme 3).
6, 7, and 8 for Job plots, association constants, and NMR
titration experiments of EDA complexes 1D/2c and 1G/2c).
To elucidate the role of DIPEA as a base or as a sacrificial
electron donor, we ran the reaction in the presence of other
bases that cannot act as sacrificial electron donors.20 The
reaction in standard conditions with DBU and K2CO3 afforded
3Aa in 75% and 76% yield, respectively (measured by GC),
similar to the yield observed for the standard reaction
conditions using 0.5 equiv of DIPEA (77%), thus suggesting
that DIPEA is acting as a base and not as a sacrificial electron
donor, and that DIPEA is able to accelerate the process by
neutralizing the HBr formed in the reaction.
The reaction mixture turns yellow upon mixing of the
starting materials (Figure 1a, picture). Compounds 1D−1L
Our proposed mechanistic model starts with the formation of
the excited donor−acceptor complex I* by absorption of one
photon under blue LED irradiation (Scheme 4). Single electron
Scheme 4. Mechanism of the Visible-Light-Mediated Direct
(Hetero)Arylation of Anilines
transfer (SET), followed by C−Br bond scission, affords the
radical intermediate II.21 Next, the radical intermediate II reacts
with 2, generating the radical intermediate III. Final hydrogen
atom transfer (HAT) regenerates the aromaticity and yields
compound 3. The quantum yield of the reaction was
determined to be Φ = 1%, indicating that the mechanism
does not contain significant radical chains. In addition, we
illuminated the reaction with successive intervals of light and
dark periods (see SI, Figure S12). The experiment showed
complete interruption of the reaction in the dark periods and
restart of the reaction under irradiation, thus confirming light as
an indispensable parameter of the reaction.
In conclusion, we have developed the first catalyst-free,
visible-light-mediated approach for the direct radical (hetero)-
arylation of aniline derivatives. The reaction proceeds smoothly
under blue LED irradiation at room temperature, affording the
final products in good to very good yields. The scope of the
reaction comprises anilines bearing electron-withdrawing or
electron-donating substituents in the arene, but N-acetylated or
ortho-halogenated anilines do not react. On the other hand, a
variety of electron-poor substituted (hetero)arenes were
converted with good results. The arylation products are
obtained as a mixture of regioisomers or a single isomer
depending on the starting aniline. Mechanistic investigations
support the formation of a donor−acceptor complex to be
responsible for the observed reactivity.
Figure 1. Experimental observations supporting the EDA complex
formation: (a) Visible appearance of starting materials and reaction
mixture; (b) Comparison of the UV−vis absorption spectra of
solutions of CH3CN containing 1A, 2a, and the mixture of 1A + 5.0
equiv of 2a; (c) Job plot of ratio between 1A and 2a; (d) NMR
titration experiment between 1A and 2a.
absorb only slightly in the visible region (see SI, Figure S2).
However, when 5 equiv of 2a were added to the solution of 1A,
a significant extinction in the visible part of the spectrum arises,
which indicates the formation of a donor−acceptor complex16
(Figure 1b; see also SI Figure S3 for changes in the absorption
spectra of compounds 1D, 1G, and 1L in the presence of 5
equiv of 2c).17 The emission intensity of compound 1A is
quenched upon addition of compound 2c (see SI, Figure S5).
However, its emission lifetime was determined to be shorter
than 1 ns; therefore, diffusion controlled quenching of the
singlet state of 1A is unlikely, and an interaction between the
two molecules via the formation of a donor−acceptor complex
is more probable.
NMR titration experiments showed that the H1 NMR
resonance signal of the proton α to the electron-withdrawing
group in 1A shifts downfield upon addition of 2a (Figure 1d).
The stoichiometry of the donor−acceptor complex was
investigated by a Job plot analysis of UV−vis and NMR
data.18 The Job plot analysis of the EDA complex 1A/2a yields
a 1:1 ratio of the two components (Figure 1c), and the
association constant KEDA was derived to be 0.18 M−1 in
CH3CN by the Benesi−Hildebrand method19 (see SI sections
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.7b03001.
C
DOI: 10.1021/acs.orglett.7b03001
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Full experimental data (PDF)
AUTHOR INFORMATION
Letter
(13) Zeng, K.; Hwang, H.-M.; Dong, S.; Shi, X.; Wilson, K.; Green, J.;
Jiao, Y.; Yu, H. Environ. Toxicol. Chem. 2004, 23, 1400.
(14) The reaction under blue LED (455 nm) also worked, but in
lower conversion than under 400 nm irradiation.
■
(15) Although other heterocycles were studied in the reaction, the
scope is limited to furane and thiophene derivatives.
(16) (a) Rosokha, S. V.; Kochi, J. K. Acc. Chem. Res. 2008, 41, 641.
Corresponding Author
*E-mail: Burkhard.Koenig@ur.de.
ORCID
́
́
(b) Arceo, E.; Jurberg, I. D.; Alvarez-Fernandez, A.; Melchiorre, P. Nat.
Chem. 2013, 5, 750.
Burkhard Konig: 0000-0002-6131-4850
̈
(17) In the case of 1C and 1K this complex is able to absorb at 455
nm irradiation. However, in the case of 1F, the complex shows little
absorption at 455 nm vs 400 nm, explaining the better conversion
observed with 400 nm LED irradiation.
Notes
The authors declare no competing financial interest.
(18) MacCarthy, P. Anal. Chem. 1978, 50, 2165.
(19) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71,
2703.
(20) The reaction was carried out with DBU and K2CO3 under the
optimized reaction conditions (entry 12, Table 1).
(21) To probe the radical character of the reaction, we ran the
reaction of 1A with 2a in the standard reaction conditions, adding 10
equiv of TEMPO after 1 h of irradiation, and irradiating for an
additional 20 h. Compound 3Aa was obtained with a 26% yield, which
means that the reaction was suppressed by the addition of TEMPO,
confirming the radical character of the reaction.
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft DFG GRK 1626, Chemical Photocatalysis. L.M. thanks
the Alexander von Humboldt Foundation for a postdoctoral
fellowship. S.W. thanks the China Scholarship Council (CSC)
for a predoctoral fellowship. We thank Dr. Rudolf Vasold
(University of Regensburg) for his assistance in GC−MS
measurements and Ms. Regina Hoheisel (University of
Regensburg) for her assistance in cyclic voltammetry measure-
ments.
REFERENCES
■
(1) Travis, A. S. Manufacture and Uses of the Anilines: A Vast Array
of Processes and Products. In Patai’s Chemistry of Functional Groups;
Rappoport, Z., Ed.; John Wiley & Sons, Ltd.: Chichester, U.K., 2009.
(2) (a) Bao, X.; Yao, W.; Zhu, Q.; Xu, Y. Eur. J. Org. Chem. 2014,
2014, 7443. (b) Akula, M.; Yogeeswari, P.; Sriram, D.; Jha, M.;
Bhattacharya, A. RSC Adv. 2016, 6, 46073. (c) Monti, F.; Baschieri, A.;
Matteucci, E.; Mazzanti, A.; Sambri, L.; Barbieri, A.; Armaroli, N.
Faraday Discuss. 2015, 185, 233. (d) Piątek, P.; Słomiany, N. Synlett
2006, 13, 2027.
(3) (a) Izgu, E. C.; Hoye, T. R. Tetrahedron Lett. 2012, 53, 4938.
(b) Junk, L.; Kazmaier, U. Synlett 2016, 27, 1531.
(4) Nelson, T. D.; Crouch, R. D. Cu, Ni, and Pd Mediated
Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction.
In Organic Reactions; Denmark, S. E., Ed.; John Wiley & Sons: 2004;
pp 265−555.
(5) (a) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.;
Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006. (b) Holden, C.
M.; Sohel, S. M. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2016, 55,
2450.
(6) (a) Wetzel, A.; Ehrhardt, V.; Heinrich, M. R. Angew. Chem., Int.
Ed. 2008, 47, 9130. (b) Jasch, H.; Scheumann, J.; Heinrich, M. R. J.
Org. Chem. 2012, 77, 10699. For methods that do not require the use
of a stoichiometric oxidant or reductant, see: (c) Pratsch, G.;
Wallaschkowski, T.; Heinrich, M. R. Chem. - Eur. J. 2012, 18, 11555.
(d) Hofmann, J.; Jasch, H.; Heinrich, M. R. J. Org. Chem. 2014, 79,
2314. (e) Hofmann, J.; Gans, E.; Clark, T.; Heinrich, M. R. Chem. -
Eur. J. 2017, 23, 9647.
(7) Jiang, T.; Chen, S.-Y.; Zhang, G.-Y.; Zeng, R.-S.; Zou, J.-P. Org.
Biomol. Chem. 2014, 12, 6922.
(8) Ghosh, I.; Konig, B. Angew. Chem., Int. Ed. 2016, 55, 7676.
̈
(9) Marzo, L.; Ghosh, I.; Esteban, F.; Konig, B. ACS Catal. 2016, 6,
6780.
̈
(10) Although competition between hydrogen abstraction and radical
addition can be expected for compounds 3Ag and 3Ah, we did not
observe any product formation coming from the hydrogen abstraction
process. For HAT processes, see: (a) Huang, X.; Groves, J. T. ACS
Catal. 2016, 6, 751. (b) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2017, 56, 1960.
(11) A likely reason for the reduced product yield is the electron-
withdrawing character of the halogen atom that deactivates the
aromatic ring.
(12) Tetzlaff, J. E. Anesthesiol. Clin. North Am. 2000, 18, 217.
D
DOI: 10.1021/acs.orglett.7b03001
Org. Lett. XXXX, XXX, XXX−XXX