T -BuONa-mediated direct C-H halogenation of electron-deficient (hetero)arenes

Article abstract of DOI:10.1039/c7ob03081a

An efficient halogenation of electron-deficient (hetero)arenes is described. The reaction utilizes common t-BuONa as a catalyst (for iodination) or a promoter (for bromination and chlorination), and perfluorobutyl iodide, CBr₄ or CCl₄ as the readily-available halogenating agents, respectively. The protocol features broad scope, high efficiency, mild conditions and gram scalability. An ionic pathway involving halogen bond formation and halophilic attack is proposed. The utility of the resulting iodinated heteroarenes is demonstrated in visible light-mediated C_aryl-C_aryl cross-coupling reaction.

Full text of DOI:10.1039/c7ob03081a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB03081A
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t-BuONa-mediated direct C-H halogenation of electron-deficient
(hetero)arenes†
Xia Liu,a,b Xin Zhao,a Fushun Liang ORCID*,a,b and Baoyi Ren ORCID *,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
chlorination) with broad halogen compatibility (Cl, Br and I).
The initial optimization started from benzothiazole and
An efficient halogenation of electron-deficient (hetero)arenes is
described. The reaction utilizes common t-BuONa as a catalyst (for
iodination) or a promoter (for bromination and chlorination), and perfluorobutyl iodide (Table 1). The reaction with t-BuONa (1.2
equiv) proceeded efficiently in DMF at room temperature, giving
2-iodobenzothiazole (3a) in nearly quantitative yield in 20 min
(entry 1). NaOH also worked well (entry 2), however, K2CO3
and DBU proved to be ineffective (entries 3 and 4). Solvent
screening indicated that DMSO, MeCN, DCM and toluene were
much less efficient than DMF (entries 5-8). It was interesting to
note that catalytic amount of t-BuONa of 50 mol% loading can
drive the reaction to completion, without sacrificing the yield
(entry 9). Comparatively, in the absence of tBuONa, no reaction
was observed (entry 10). All the reactions were conducted in the
open air and no precaution needs to be taken to exclude moisture
from the glassware.
perfluorobutyl iodide, CBr4 or CCl4 as the readily-available
halogenating agents, respectively. The protocol features broad
scope, high efficiency, mild conditions and gram scalability. An
ionic pathway involving halogen bond formation and halophilic
attack is proposed. The utility of the resulting iodinated
heteroarenes is demonstrated in visible light-mediated Caryl―Caryl
cross-coupling reaction.
(Hetero)aromatic halides are valuable and fundamental
building blocks that are used to construct new carbon–carbon and
carbon–heteroatom bonds in organic synthesis and drug design.1
Quite a few of important classical cross-coupling reactions such
as the Heck reaction, the Suzuki reaction and the Buchwald–
Hartwig reaction, require aryl halides as starting materials.2
Recently developed metal-free and electron transfer-mediated
cross-coupling occurs between halogenated (hetero)aromatics
and aromatics.3 Hence, it is always an important task to develop
efficient preparation methods of (hetero)aromatic halides. Till
now, there are many known methods for the preparation of
haloarenes from aromatics especially from electron-rich systems.
However, electron-deficient (hetero)arenes are difficult to be
halogenated,4 often suffering from harsh conditions (either strong
alkyllithium bases at extremely low temperature or relatively
weak bases upon heating), multi-steps and/or low yields. Among
all the halogenated aromatics, aryl iodides are less accessible and
particularly expensive due to the weakly electrophilic nature of
iodine. Based on our prehension on halogen-bonding
interaction/activation,5 herein, we would like to report an
efficient halogenation of electron-deficient (hetero)arenes under
mild conditions, employing common t-BuONa as the catalyst6
(for iodination) or the promoter (for bromination and
The survey of alternative iodination reagents revealed that N-
iodosuccinamide, iodine and C6F5I were not competent in the
reaction (Table 2, entries 1-3). As for bromination reaction, 2-
bromobenzothiazole (4a) could be obtained in 71% yield, using
perfluorooctyl bromide (1.1 equiv) as the bromine source (entry
4). Thus, other brominating reagents including CBr4, NBS and
BrCN were tried (entries 5-7). Delightly, CBr4 can be used as an
efficient bromine source, giving 4a in 93% yield (entry 5). Same
case was observed when CCl4 was employed as the chlorine
source (entries 8 and 9).
Table 1. Optimization of the reaction conditions.a,b
yield
entry
1
base (equiv.)
solvent
DMF
t
(%)b
t-BuONa (1.2)
20 min
99
2
3
4
NaOH (1.2)
K2CO3 (2.2)
DBU (1.2)
DMF
DMF
DMF
25 min
6 h
98
0
a.College of Chemistry, Liaoning University, Shenyang 110036, China. E-mail:
fsliang@lnu.edu.cn.
b.Department of Chemistry, Northeast Normal University, Changchun 130024,
China.
c. College of Applied Chemistry, Shenyang University of Chemical Technology,
Shenyang 110142, China. E-mail: renbaoyi@syuct.edu.cn.
†Electronic Supplementary Information (ESI) available: [Experimental procedure,
and characterization data for all compounds (PDF)]. See DOI: 10.1039/x0xx00000x
6 h
trace
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Journal Name
5
6
t-BuONa (1.2)
DMSO
MeCN
DCM
6 h
6 h
6 h
6 h
50
trace
0
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DOI: 10.1039/C7OB03081A
t-BuONa (1.2)
t-BuONa (1.2)
t-BuONa (1.2)
t-BuONa (0.5)
7
8
toluene
DMF
0
9
25 min
99
10
DMF
6 h
nr
a Reaction conditions: 1a (0.1 mmol), 2a (1.1 equiv) and base in
solvent (0.5 mL). b Isolated yield. nr = no reaction.
Table 2. Investigation of the halogen sources.a
entry
halogen
source
yield
(%)
entry
halogen
source
yieldb
(%)
iodine source
5
6
7
CBr4
NBS
BrCN
93c
1
2
3
NIS
I2
0
0
0
trace
C6F5I
90
chlorine source
bromine source
C8F17Br
8
9
CCl4
NCP
88c
0
4
71
a Reaction conditions: 1a (0.1 mmol), 2 (1.1 equiv) and t-BuONa
(1.2 equiv) in DMF (0.5 mL). b Isolated yield. c t-BuONa (4 equiv)
was used.
aReaction conditions: 1 (0.1 mmol), t-BuONa and 2a (1.1 or 2.1
equiv) in DMF (0.5 mL). bIsolated yields. c In dry DMF (0.5 mL). d
In toluene (0.5 mL).
With the optimized conditions in hand, we examined the scope
of the halogenation reaction (Table 3). Electron-deficient
Monobromination for benzothiazole, benzoxazole, N-
methylimidazole and N-methylimidazole (4a-d), as well as
dibromination for thiazole and 5-phenyloxazole (4e and 4f) were
achieved in 63-93% yields. In the presence of 1.1 equiv of CCl4
and 4 equiv of t-BuONa, 2-chloro benzothiazole (5a) and 2-
chloro-1-methylbenzoimidazole (5b) were obtained in 88% and
51% yields, respectively. 2,4-Dichloro-5-phenyloxazole (5c)
were prepared with 2.1 equiv of CCl4 and 4 equiv of t-BuONa. It
is a major problem for bromonation and chlorination that t-
BuONa could not be loaded with catalytic amount, contrary to
that of iodination. Noteworthy that when pentafluorobenzene
was subjected to the reaction sequence, pentafluoro-6-
(hetero)aromatic hydrocarbons,
such as benzothiazole,
benzoxazole, N-methylbenzoimidazole and aromatics like
pentafluorobenzene and 1,4-dibromo-2-nitrobenzene could be
iodinated efficiently, giving products 3a-e in high to excellent
yields (81-99%). The amount of t-BuONa required can be as low
as 50 mol%. Using 2.1 equiv of perfluorobutyl iodide, thiazole,
5-phenyloxazole and pyridine N-oxide afforded diiodination
products 3f-h as the main products in excellent yields.
Differently, the iodination of N-methylimidazole did not proceed
well in DMF solution. Instead, taking toluene as the solvent, the
iodination reaction goes facilely, with monoiodination and
diiodination as a mixture. We think the reaction performed in
toluene may undergo a different pathway from that in DMF.
(tribromomethyl)benzene
(6)
and
pentafluoro-6-
(trichloromethyl)benzene (7), rather than the corresponding
brominated and chlorinated products, were achieved in 92% and
77% yields, respectively (eqs 1 and 2).7,8
Table 3. Halogenation of heteroarenes.a,b
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examined the reactions in the presence of a siVnigewleArteiclleecOtnrloinne
transfer (SET) inhibitor, p-dinitrobenzeneD(pO-ID: 1N0.1B0)3,9a/Cn7dOnBo03y0i8e1lAd
decrease was observed. On the contrary, in the case of
trihalogenative methylation reaction to form compounds 6 and 7,
the reactions were partly or completely quenced in the presence
of TEMPO or p-DNB (eq 7, Scheme 2).
On the basis of all the experimental results, as well as
literature report,4e an ionic mechanism was proposed, which
involves the formation of t-butyl hypohalide from the metathesis
of tBuONa and C4F9I10 and subsequent halogen bond adduct A
leading to the C-H of 1a more acidic.11,12 Thus, hydrogen
abstraction by C4F9Na becomes feasible, and carboanion B is
generated. The final iodinated product 3a is formed via
halophilic attack (for example, via an three-membered iodonium
ion intermediate),13 along with the liberation of t-BuONa, to
finish the catalytic cycle (Scheme 3).
Scheme 1. Gram-scale reaction
Scheme 3. Proposed mechanism for the halogenation
Scheme 4. Visible light-mediated cross-coupling of
halogenated heteroaryls
Scheme 2. Control experiment
To demonstrate the practicality of this protocol, large scale
reactions were conducted under otherwise identical conditions
(Scheme 1). 10 g 1a reacted with perfluorobutyl iodide (28.15 g)
to give 3a (17.57 g) in 91% yield (eq 3). In the mixture of 1a (5 g,
36.99 mmol) with CBr4 (13.49 g, 40.68 mmol) and t-BuONa (4
equiv) in DMF, product 4a (6.05 g) was obtained in 76% yield
(eq 4).
To gain insight into the reaction mechanism, a control
experiment was conducted (Scheme 2). The main question is
whether radical intermediates are involved in the reaction. Thus,
2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), an efficient free
radical scavenger, was introduced as an additive under the
standard conditions.9 As a result, compounds 3a and 4a were
produced with almost same efficiency, suggesting that TEMPO
has no effect on the reactions (eq. 5 and 6). Furthermore, we
Scheme 5. Possible mechanism for the cross-coupling
Finally, the utility of the halogenated heterocycles was
illustrated by performing visible-light mediated cross-coupling
reaction, which is quite attractive in current organic synthetic
chemistry.14 In the presence of t-BuOK (4 equiv), the cross-
coupling of 2-iodobenzothiazole with 1,3,5-trimethoxybenzene
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O. Daugulis, Org. Lett., 2009, 11, 421; (f) J.-M. L'HelgouVaile'cw,AArti.cSleeOgngliinoe,
and N-methylindole was successful, giving the coupled
products 8a and 8b in moderate yields. (Scheme 4). The
possible mechanism for the metal-free cross-coupling reaction
F. Chevallier, M. Yonehara, E. Jeanneau, M. Uchiyama and F. Mongin,
DOI: 10.1039/C7OB03081A
J. Org. Chem., 2008, 73, 177; (g) X. Zhao, F. Ding, J. Li, K. Lu, X. Lu,
B. Wang and P. Yu, Tetrahedron Lett., 2015, 56, 511; (h) C. Boga, E.
Del Vecchio, L. Forlani and P. E. Todesco, J. Organomet. Chem. 2000,
601, 233; (i) I. Popov, H.-Q. Do and O. Daugulis, J. Org. Chem., 2009,
74, 8309; (j) L. Li, W. Liu, H. Zeng, X. Mu, G. Cosa, Z. Mi and C.-J. Li,
J. Am. Chem. Soc., 2015, 137, 8328.
was given in Scheme 5. A halogen bond adduct
C can be
formed between sodium t-butoxide and 2-iodobenzothiazole.
Under the action of visible light, single-electron-transfer occurs,
yielding radical anion
D with the liberation of t-BuO radical.
(5) Selected halogen bonding-mediated reactions from our group: (a)
Y. Wei, S. Lin and F. Liang, Org. Lett. 2012, 14, 4202; (b) Y. Wei, S.
C―I bond cleavage leads to persistent benzothiazole radical
E 15
radical
,
which would add to (hetero)aromatics, giving carbon Lin, F. Liang, J. Zhang, Org. Lett. 2013, 15, 852; (c) Y. Wei, F. Liang
and X. Zhang, Org. Lett. 2013, 15, 5186; (d) M. Li, H. Yuan, B. Zhao, F.
F
. Hydrogen abstraction by t-BuO radical, affords the
Liang and J. Zhang, Chem. Commun. 2014, 50, 2360; (e) H. Tan, M. Li
and F. Liang, RSC Adv. 2014, 4, 33765; (f) L. Zhang, Y. Li, L.-Y. Jin
and F. Liang, RSC Adv. 2015, 5, 65600; (g) R. Wang, W. Guan, Z.-B.
Han, F. Liang, T. Suga, X. Bi and H. Nishide, Org. Lett. 2017, 19, 2358.
(6) t-BuONa is abundant, inexpensive, commercially available and
bench stable. For t-BuONa(K)-catalyzed reactions, see: (a) A. A. Toutov,
W.-B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz and R. H. Grubbs,
Nature, 2015, 518, 80; (b) X. Shi, J. Guo, J. Liu, M. Ye and Q. Xu,
Chem. Eur. J. 2015, 21, 9988.
(7) A radical pathway is most possibly involved in the reaction. P. R.
Schreiner, O. Lauenstein, I. V. Kolomitsyn, S. Nadi and A. A. Fokin,
Angew. Chem. Int. Ed., 1998, 37, 1895. See Scheme S1 for the possible
mechanism.
(8) A. Orlinkov, I. Akhrem, S. Vitt and M. Vol'pin, Tetrahedron Lett.,
1996, 37, 3363.
(9) For alkane radical iodination by t-BuOI, see: R. Montoro and T.
Wirth, Org. Lett., 2003, 5, 4729.
(10) A distinct coloration was observed when mixing tBuONa and
C4F9I in DMF solution. For the formation of tBuOI, see: (a) C. Walling
and B. B. Jacknow, J. Am. Chem. Soc. 1960, 82, 6108; (b) C. Walling
and A. Padwa, J. Org. Chem., 1962, 27, 2976; (c) S. Zhu, C. Qing, C.
Zhou, J. Zhang and B. Xu, J. Fluorine Chem., 1996, 79, 77; (d) P. Feng,
K. N. Lee, J. W. Lee, C. Zhan and M.-Y. Ngai, Chem. Sci., 2016, 7,
424; (e) S. Okumura, C.-H. Lin, Y. Takeda and S. Minakata, J. Org.
Chem., 2013, 78, 12090.
final C―C coupling products. The role of t-BuOK in the cross-
coupling is a halogen bond acceptor as well as an electron
donor.16
Conclusions
In conclusion, we have developed a novel method for the
halogenation of an array of electron-deficient (hetero)arenes.
The protocol exhibits broad scope and is efficient and practical.
Among them, t-BuONa-catalyzed iodination by harnessing
perfluorobutyl iodide as the iodination reagent was
unprecedented. The utility of the halogenated products is
demonstrated by visible light-mediated and metal-free cross-
coupling reaction with (hetero)arenes.
ORCID
Fushun Liang: 0000-0003-4195-3863
Baoyi Ren: 0000-0001-5879-3291
(11) For the halogen bond adduct formation, see: P. Metrangolo and G.
Resnati, Halogen Bonding: Fundamentals and Applications; Springer:
Berlin, 2008. In some cases, the strength of halogen bonding is
comparable to that of Ag(I) coordination. See: S. M. Walter, F. Kniep, E.
Herdtweck and S. M. Huber, Angew. Chem. Int. Ed. 2011, 50, 7187.
(12) S. I. Gorelsky, Organometallics, 2012, 31, 794. Direct hydrogen
abstraction was difficult, by comparing the pKa values of benzothiazole
and benzoazole and the base used. The pKa of benzothiazole and
benzoxazole are 24.4 and 27.0 (in DMSO), while the pKa of t-BuOH
(conjugate acid of tBuONa) is 29.4 in DMSO. See: (a) F. G. Bordwell,
Acc. Chem. Res., 1988, 21, 456; (b) K. Shen, Y. Fu, J.-N. Li, L. Liu and
Q.-X. Guo, Tetrahedron, 2007, 63, 1568. Thus, we think that the
formation of halogen bond adduct in the first step, followed by
deprotonation and iodination, would be much reasonable.
(13) N. S. Zefirov and D. I. Makhon’kov, Chem. Rev. 1982, 82, 615.
(14) For visible light-induced C–C coupling, see: (a) A. Arora and J.
D. Weaver, Acc. Chem. Res., 2016, 49, 2273; (b) J. Xuan, Z.-G. Zhang
and W.-J. Xiao, Angew. Chem. Int. Ed. 2015, 54, 15632; (c) F. Yang, J.
Koeller and L. Ackermann, Angew. Chem. Int. Ed. 2016, 55, 4759; (d) I.
Ghosh, R. S. Shaikh and B. König, Angew. Chem. Int. Ed. 2017, 56,
8544.
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
Financial support from NSFC (21172034 and 21372039) is greatly
acknowledged.
Notes and references
(1) (a) R. Taylor, Electrophilic Aromatic Substitution, Wiley, New
York, 1990; (b) P. B. De La Mare, Electrophilic Halogenation,
Cambridge University Press, Cambridge, 1976, chapt. 5.
(2) (a) A. de Meijere, S. Bräse and M. Oestreich, Metal Catalyzed
Cross-Coupling Reactions and More, 3 Volume Set. Wiley: 2013. (b) I. J.
S. Fairlamb, Chem. Soc. Rev. 2007, 36, 1036.
(3) For a review: see: (a) C. L. Sun and Z. J. Shi, Chem. Rev., 2014,
114, 9219. For selected papers: (b) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X.
Zhou, X.-Y. Lu, K. Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nature
Chem. 2010, 2, 1044; (c) J. Chen and J. Wu, Angew. Chem. Int. Ed.,
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Org. Lett., 2008, 10, 4673.
(4) Selected examples: (a) Q. Q. Shi, S. Y. Zhang, J. X. Zhang, V. F.
Oswald, A. Amassian, S. R. Marder and S. B. Blakey, J. Am. Chem. Soc.,
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(16) J. P. Barham, G. Coulthard, K. J. Emery, E. Doni, F. Cumine, G.
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DOI: 10.1039/C7OB03081A
t-BuONa
(Het)Ar
Het)Ar
(
H
X
halogenating agent
(C4F9I, CBr4, or CCl4)
(X = I, Br and Cl)
high efficiency
gram scalable
broad scope
mild conditions