Combining Eosin y with Selectfluor: A Regioselective Brominating System for Para-Bromination of Aniline Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b01427

A mild, metal-free, and absolutely para-selective bromination of aniline derivatives has been developed in excellent yields, wherein the organic dye Eosin Y is employed as the bromine source in company with Selectfluor. Neither air nor moisture sensitive, this facile reaction proceeds smoothly at room temperature and completes within a short time. Mechanistic studies indicate a radical pathway; therefore, the existence of an in situ generated brominating reagent, "Selectbrom", is postulated, which may reasonably account for the unique regioselectivity for the para-bromination of N-acyl- as well as N-sulfonylanilines.

Full text of DOI:10.1021/acs.orglett.7b01427

Letter
pubs.acs.org/OrgLett
Combining Eosin Y with Selectfluor: A Regioselective Brominating
System for Para-Bromination of Aniline Derivatives
Binbin Huang,† Yating Zhao,† Chao Yang,† Yuan Gao,‡ and Wujiong Xia*,†
†State Key Lab of Urban Water Resource and Environment, School of Chemistry and Chemical Engineering, Harbin Institute of
Technology (Shenzhen), Shenzhen 518055, China
‡School of Chemistry and Chemical Engineering, Yantai University, 30 Qingquan Road, Laishan District, Yantai 264005, China
S
* Supporting Information
ABSTRACT: A mild, metal-free, and absolutely para-selective bromination of
aniline derivatives has been developed in excellent yields, wherein the organic
dye Eosin Y is employed as the bromine source in company with Selectfluor.
Neither air nor moisture sensitive, this facile reaction proceeds smoothly at
room temperature and completes within a short time. Mechanistic studies
indicate a radical pathway; therefore, the existence of an in situ generated
brominating reagent, “Selectbrom”, is postulated, which may reasonably
account for the unique regioselectivity for the para-bromination of N-acyl- as
well as N-sulfonylanilines.
groups has recently emerged as an attractive goal (Scheme
n the realm of organic synthesis, halogenated aromatic
Icompounds are widely accepted as significant building 1b).3 On the other hand, the commonly used electrophilic
halogenations generally yield the para-halogenated anilines as
major products; however, the ortho-position isomers are still
difficult to eliminate.4 Hence, we present here a new
brominating protocol for certain aniline derivatives with
absolute para-selectivity and high efficiency under mild
conditions (Scheme 1c).
As a kind of classic organic dye, Eosin Y has been well-known
and utilized in many fields. With the recent development of
visible-light photoredox reactions, it has been more frequently
applied as a visible-light photocatalyst owing to its comparable
photo and redox properties with the general Ru/Ir complexes.5
Selectfluor is a representative of a new class of electrophilic
fluorinating reagents. In addition to introducing fluorine
substituents to various substrates, it can also serve as an
oxidant or mediate other electrophilic additions in certain
transformations.6
Recently, we found that Selectfluor is able to activate the C−
Br bond of Eosin Y (in its basic form with two sodium
counteranions) and make it possible for Eosin Y to serve as a
bromine source, which had never been reported before. After
the cleavage of the C−Br bond, an elusive intermediate,
“Selectbrom”, is presumed formed in situ via a radical process,
which exhibits robust reactivity and unique regioselectivity as a
brominating reagent for aniline derivatives (Scheme 2).
At the initial stage of investigation, a negligible amount of
monobrominated N-acetylaniline was unexpectedly detected by
GC−MS in our tentative study of photoinduced fluorination of
N-acetylaniline (1a) employing Eosin Y as photocatalyst and
Selectfluor as fluorine source. Upon determination that the
blocks, mainly due to their versatile applications as key
precursors for a variety of cross-couplings, including the well-
established Suzuki, Heck, and Ullmann couplings and many
other newly developed methods.1 Thus, viable methods to
access this class of compounds are highly desirable, especially
the ones with high efficiency and excellent regioselectivity.
Despite the development of various methods, halogenation
of activated aromatic compounds such as aniline derivatives
remains challenging. Available classical methods generally suffer
from certain drawbacks such as application of hazardous
reagents and harsh conditions, poor tolerance of functional
groups, production of metal salts as stoichiometric byproducts,
and unavoidable overhalogenation. But above all, the most
important problem of these protocols is the poor regioselec-
tivity of halogenated products, which limits the synthetic
utilities of these procedures (Scheme 1a).2 In this regard,
considerable efforts have been made to overcome these
limitations. The application of metal or organocatalysts in
catalyzing the ortho-halogenation of anilines bearing directing
Scheme 1. Aromatic C−H Halogenation of Anilines
Received: June 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Mechanistic Hypothesis
Table 2. Scope of the Bromination
product was N-acetyl-4-bromoaniline (2a), the appropriate
input ratio of the two reagents, 2 equiv of Eosin Y and 4 equiv
of Selectfluor, was then settled. Furthermore, the reaction was
shown to occur without the need for light irradiation, additives,
and inert atmosphere (Table S1).7
To reach an optimal set of reaction conditions, various
oxidants and solvents were subsequently examined, and the
results are listed in Table 1. When oxidants other than
a
Table 1. Optimization of the Reaction Conditions
b
a
entry
oxidant
solvent
yield (%) of 2a
Reaction conditions: aniline substrate (0.1 mmol), Eosin Y (0.2
mmol), and Selectfluor (0.4 mmol) in acetonitrile (1.0 mL) stirred at
25 °C for the time listed. Isolated yields are given on the basis of the
substrates. Eosin Y (0.15 mmol) and Selectfluor (0.30 mmol) were
employed.
1
(NH4)2S2O8
Oxone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
ND
ND
12
2
b
3
CBr4
4
Ph2IOTf
ND
>99
20
5
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
6
yield, along with a 2,4-dibrominated product 2g′ in 35% yield,
which was probably due to the electronic effect of the
additional methyl group compared to the reaction of 1f.
Changing the acetyl to other aliphatic acyl groups of substrates
1h−l showed no influence on the efficacy of these reactions,
and the desired products 2h−l were obtained in nearly
quantitative yields.
7
THF
6
8
CH2Cl2
EtOAc
CH3OH
H2O
23
9
ND
4
10
11
65
c
12
CH3CN
>99 (96)
a
Reactions were carried out on a 0.1 mmol scale of N-acetylaniline 1a.
GC yield; isolated yield is given in parentheses. Commercial
acetonitrile (AR) was directly used without further treatment. ND: not
detected.
A series of anilines with aromatic acyl groups on the nitrogen
atoms (1m−q) were also examined. Substituted with electron-
donating or -withdrawing groups at the para-position of
benzoyl groups, anilines 1n−q exhibited a small variation in
reaction rates, but no significant discrepancies of yields were
observed. Again, the brominations of 1r and 1s were found to
be highly efficient and selective. However, when it came to N-
furoylaniline (1t), byproducts of overbromination on the furan
ring were generated due to the high reactivity of the
heterocycle, but the yield could be improved by reducing the
feed amounts of Eosin Y and Selectfluor and prolonging
reaction time. Moreover, in the subsequent attempts of N-Boc-
aniline (1u), cyclic anilines (1v,w), and N-sulfonylanilines
(1x,y), the desired products 1u−y were successfully obtained in
good to excellent yields. Furthermore, N-acylanilines with their
protons of N−H replaced by alkyl groups (1aa−ac) were also
found to be capable of producing the para-brominated products
in excellent yields, indicating that the naked N−H is not a
prerequisite for this transformation. Interestingly, when
substrate 3a with its para-position occupied by a methyl
group was subjected to the standard conditions, the
bromination proceeded smoothly at the ortho-position instead
to furnish product 4a in 98% yield.
b
c
Selectfluor were applied, the formation of 2a was either not
detected or extremely sluggish (entries 1−4). Among all of the
employed solvents, the originally used acetonitrile gave the best
result, with no detectable signal of byproducts based upon GC
analysis (entries 5−11). It is worth noting that when water was
used as the reaction medium the reaction also proceeded to
give the product 2a in 65% yield (entry 11), which suggested
the system was not sensitive to water. Next, commercial
acetonitrile (AR, Analytical Reagent) was directly applied as
solvent, the reaction presented a quantitative GC yield, and
subsequent isolation afforded 2a in 96% yield (entry 12).
The scope of this para-bromination was then explored under
the optimized reaction conditions.8 As shown in Table 2, the
bromination occurred specifically at the para-position of N-
acyl- and N-sulfonylanilines and tolerated a wide range of
functional groups. When the N-acetylanilines bearing fluoride,
chloride, or methyl at the ortho- or meta-position (1b−f) were
applied, the corresponding brominated products 2b−f were
obtained in excellent yields. However, when N-acetyl-3,5-
dimethylaniline (1g) was subjected to the conditions, the
desired para-brominated product 2g was only acquired in 58%
To gain clearer insights into this transformation, mechanistic
studies were started with three sets of control experiments in
comparison with literature precedents to determine the
B
DOI: 10.1021/acs.orglett.7b01427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reaction pattern (Scheme 3). In these works, Selectfluor was
employed as an oxidant to achieve regioselective bromination
Eosin Y in which Selectfluor acts as the one-electron oxidant to
form a dicationic radical A, while Eosin Y serves as the
reductant undergoing a C−Br bond cleavage to produce a
bromine radical. The subsequent radical cross-coupling of A
and the bromine radical generates a putative in situ brominating
reagent, Selectbrom (B). When N-acetylaniline (1a) is
employed in this system, the bulky reagent B would preferably
draw close to the less hindered para-position to deliver C and
cationic intermediate D after the cleavage of N−Br bond. Then
D aromatizes after removal of the proton with the assistance of
C to yield the final brominated product 2a.
Scheme 3. Comparative Experiments with Previous Works
Despite our efforts using 1H NMR and HRMS methods to in
situ detect the putative key intermediate Selectbrom (B), we
obtained no indicative evidence for this species. Nevertheless,
isolation attempts were also in vain, with compound C as the
only acquired product (Scheme S4).7
a
b
Detected by GC−MS. Starting material 1a was recovered in
quantitative yield.
To add more credence to the putative mechanism, further
control experiments were performed employing several selected
substrates with their potential reactive sites’ Mulliken charge
distributions calculated (Scheme S5).7 The common rules of
the well-known EAS (electrophilic aromatic substitution)-type
reaction may be found followed by this radical-involved
bromination.
Representing aniline derivatives bearing sensitive groups, N-
methacrylaniline (1h) was selected as a substrate to undergo
bromination under other conditions (Table S2).7 The
comparative results demonstrated the unique regio- as well as
chemoselectivity of the Selectfluor/Eosin Y combination.
A gram-scale reaction of 1a was next carried out to check the
synthetic potential of this methodology. The scaled-up reaction
with 5 mmol of 1a provided 2a in 98% yield within 1 h under
the standard conditions, showing no compromise in efficiency
when compared to the 0.1 mmol scale one (Table 2). As a
versatile building block, the resulting 2a is able to undergo a
variety of further transformations,10 and in a representative
Suzuki coupling with phenylboronic acid, the coupling product
was acquired in 90% yield (Scheme S6).7
In summary, a highly para-selective bromination of aniline
derivatives has been developed using a combination of
commercially available and user-friendly organic dye Eosin Y
and Selectfluor. This transformation has been proven to be
compatible with a wide range of anilines bearing various
functional groups. Mechanistic studies indicate a radical
pathway, and a reactive intermediate, Selectbrom, is postulated.
Owing to its broad substrate scope, mild reaction conditions,
high efficiency, and excellent selectivity, this method should be
of great synthetic potential.
with NaBr,6f KBr,6g and HBr (40% aqueous),6h respectively,
and either a Br+ or Br2 pathway was suggested. For example, the
double bond of styrene (3b) could be attacked by the in situ
generated Br+ and a nucleophile such as CH3OH and H2O to
afford the corresponding difunctionalized product (Scheme 3a,
3b).6g However, neither of 4b and 4c was detected in its
corresponding Selectfluor/Eosin Y system, indicating that Br+
formation is not likely to be included in this process (Scheme
3a, 3b). Moreover, although the addition of radical scavenger
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was proved
absolutely ineffective in the Selectfluor/HBr system,6h it
completely inhibited the bromination of 1a in our system,
suggesting that a radical process should be involved (Scheme
3c).
Furthermore, a series of fluorescence quenching experiments
were performed (Schemes S1−S3).7,9 The Stern−Volmer plots
revealed that Selectfluor was capable of quenching Eosin Y,
whereas 1a was not. Such a result suggested that the
mechanism should begin with the interaction of Eosin Y with
Selectfluor, most likely through a redox pathway with their
redox potentials taken into consideration (Ered = −1.11 V vs
SCE of Eosin Y5a and Ered = 0.33 V vs SCE of Selectfluor6b).
Accordingly, a plausible mechanism is proposed and
presented in Scheme 4. The initial step is assumed to be an
SET (single-electron transfer) process between Selectfluor and
Scheme 4. Proposed Mechanism
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.7b01427.
Experimental procedures and compound characterization
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiawj@hit.edu.cn.
ORCID
Yuan Gao: 0000-0002-6442-262X
C
DOI: 10.1021/acs.orglett.7b01427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with EtOAc/petroleum ether = 1:2) to afford the corresponding para-
brominated product 2a as a light yellow solid (20.6 mg, 96%).
(9) Huo, H.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016, 138,
6936.
(10) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550. (b) Kotadia, D. A.; Patel, U. H.; Gandhi,
S.; Soni, S. S. RSC Adv. 2014, 4, 32826. (c) Zhang, Q.; Wang, D.;
Wang, X.; Ding, K. J. Org. Chem. 2009, 74, 7187. (d) Xi, Z.; Liu, F.;
Zhou, Y.; Chen, W. Tetrahedron 2008, 64, 4254.
Wujiong Xia: 0000-0001-9396-9520
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the China NSFC
(Nos. 21372055, 21472030, and 21672047) and SKLUWRE
(No. 2018DX02). We thank Dr. Yuan Yao, School of
Chemistry and Chemical Engineering, Harbin Institute of
Technology, for theoretical calculations.
REFERENCES
■
(1) (a) Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116,
12564. (b) Weix, D. J. Acc. Chem. Res. 2015, 48, 1767. (c) Tellis, J. C.;
Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A.
Acc. Chem. Res. 2016, 49, 1429. (d) Johansson Seechurn, C. C. C.;
Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed.
2012, 51, 5062. (e) Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219.
(2) (a) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116,
̌
8003. (b) Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed.
2009, 48, 8424. (c) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.;
Bedekar, A. V. Tetrahedron 1999, 55, 11127. (d) Jereb, M.; Zupan, M.;
Stavber, S. Chem. Commun. 2004, 22, 2614. (e) Zhao, Y.; Li, Z.; Yang,
C.; Lin, R.; Xia, W. Beilstein J. Org. Chem. 2014, 10, 622.
(3) (a) Xiong, X.; Yeung, Y. Y. Angew. Chem., Int. Ed. 2016, 55,
16101. (b) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew. Chem., Int. Ed.
2013, 52, 4440. (c) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am.
̈
́
Chem. Soc. 2012, 134, 8298. (d) Monzo̧ n, G.; Tirotta, I.; Knochel, P.
Angew. Chem., Int. Ed. 2012, 51, 10624. (e) Bedford, R. B.; Haddow,
M. F.; Mitchell, C. J.; Webster, R. L. Angew. Chem., Int. Ed. 2011, 50,
5524. (f) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z.
J. Am. Chem. Soc. 2006, 128, 7416.
(4) (a) Hering, T.; Muhldorf, B.; Wolf, R.; Konig, B. Angew. Chem.,
̈
̈
Int. Ed. 2016, 55, 5342. (b) Chen, A.-J.; Wong, S.-T.; Hwang, C.-C.;
Mou, C.-Y. ACS Catal. 2011, 1, 786. (c) Chretien, J.-M.; Zammattio,
́
F.; Le Grognec, E.; Paris, M.; Cahingt, B.; Montavon, G.; Quintard, J.-
P. J. Org. Chem. 2005, 70, 2870. (d) Smith, M. B.; Guo, L. C.; Okeyo,
S.; Stenzel, J.; Yanella, J.; LaChapelle, E. Org. Lett. 2002, 4, 2321.
(5) (a) Hari, D. P.; Konig, B. Chem. Commun. 2014, 50, 6688.
̈
(b) Majek, M.; Jacobi von Wangelin, A. Acc. Chem. Res. 2016, 49,
2316. (c) Ravelli, D.; Fagnoni, M. ChemCatChem 2012, 4, 169.
́
(d) Quint, V.; Morlet-Savary, F.; Lohier, J.-F.; Lalevee, J.; Gaumont,
A.-C.; Lakhdar, S. J. Am. Chem. Soc. 2016, 138, 7436. (e) Davies, J.;
Booth, S. G.; Essafi, S.; Dryfe, R. A. W.; Leonori, D. Angew. Chem., Int.
Ed. 2015, 54, 14017. (f) Li, J.; Zhang, J.; Tan, H.; Wang, D. Z. Org.
Lett. 2015, 17, 2522.
́
(6) (a) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192. (b) Singh, R. P.;
Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31. (c) Xia, J.-B.; Zhu, C.;
Chen, C. J. Am. Chem. Soc. 2013, 135, 17494. (d) Rueda-Becerril, M.;
́
Mahe, O.; Drouin, M.; Majewski, M. B.; West, J. G.; Wolf, M. O.;
Sammis, G. M.; Paquin, J.-F. J. Am. Chem. Soc. 2014, 136, 2637.
(e) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2015, 137, 5654. (f) Syvret, R. G.; Butt, K. M.; Nguyen, T. P.;
Bulleck, V. L.; Rieth, R. D. J. Org. Chem. 2002, 67, 4487. (g) Ye, C.;
Shreeve, J. M. J. Org. Chem. 2004, 69, 8561. (h) Liang, D.; Li, X.;
Wang, C.; Dong, Q.; Wang, B.; Wang, H. Tetrahedron Lett. 2016, 57,
5390.
(7) For details, see the Supporting Information.
(8) Representative procedure for the bromination of N-acylanilines
(taking 1a as an example): A suspension of N-acetylaniline (1a, 13.5
mg, 0.1 mmol), Eosin Y (138.4 mg, 0.2 mmol), and Selectfluor (141.6
mg, 0.4 mmol) in acetonitrile (1.0 mL) was stirred at 25 °C for 1 h.
Upon completion, the reaction mixture was filtered through a plug of
silica gel. The resulting mixture was concentrated under reduced
pressure and purified by column chromatography on silica gel (eluted
D
DOI: 10.1021/acs.orglett.7b01427
Org. Lett. XXXX, XXX, XXX−XXX