Transition-metal-free site-selective C–F bond activation for synthesis of 8-aminoquinolines

Article abstract of DOI:10.1016/j.tetlet.2017.09.069

An efficient and general selective method for the synthesis of 8-aminoquinoline derivatives has been disclosed through transition metal direct C–N coupling from fluoroquinolines and arylamines. Significantly, good chemo- and regio-selectivity was observed

Full text of DOI:10.1016/j.tetlet.2017.09.069

Accepted Manuscript
Transition-Metal-Free Site-Selective C-F Bond Activation for Synthesis of 8-
Aminoquinolines
Jianping Chen, Dongyang Huang, Yuqiang Ding
PII:
S0040-4039(17)31205-4
https://doi.org/10.1016/j.tetlet.2017.09.069
TETL 49339
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
28 July 2017
19 September 2017
22 September 2017
Please cite this article as: Chen, J., Huang, D., Ding, Y., Transition-Metal-Free Site-Selective C-F Bond Activation
for Synthesis of 8-Aminoquinolines, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.09.069
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Transition-Metal-Free Site-Selective C-F
Bond Activation for Synthesis of
8-Aminoquinolines
Jianping Chen,Dongyang Huang, Yuqiang Ding*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Wuxi 214122, Jiangsu Province, China
An efficient and general selective method for the synthesis of 8-aminoquinoline derivatives has been disclosed through
transition metal direct C-N coupling from fluoroquinolines and arylamines. Significantly, good chemo- and
regio-selectivity were observed for polyfluoroquinolines in which only C-F bond on 8-substituted position was broken.
Thus, this methodology proves its value as an inexpensive and efficient synthetic way to access quinolin-8amine
derivatives in moderate to good yields.

1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
Transition-Metal-Free Site-Selective C-F Bond Activation for Synthesis of
8-Aminoquinolines
Jianping Chen, Dongyang Huang, Yuqiang Ding*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi 214122, Jiangsu Province, China
Email: yding@jiangnan.edu.cn
Tel./fax: +86 510 85917763
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and general selective method for the synthesis of 8-aminoquinoline
derivatives has been disclosed through transition metal direct C-N coupling from
fluoroquinolines and arylamines. Significantly, good chemo- and regio-selectivity
was observed for polyfluoroquinolines in which only C-F bond on 8-substituted
position was broken. Thus, this methodology proves its value as an inexpensive
and efficient synthetic way to access quinolin-8amine derivatives in moderate to
good yields.
Available online
Keywords:
C-N bond coupling
C-F bond activation
Metal free
fluoroquinoline
selectivity
2016 Elsevier Ltd. All rights reserved.
Over the past few decades, transition-metal-catalyzed C-N
bond formation has been broadly employed to construct
effective pharmacophore and drug analogues.[1] These
transformations include Ullmann, Chan-Lam and Buchwald-
Hartwig reactions.[2] Generally, electrophiles applied in these
kinds of coupling reactions are aryl chlorides, bromides,
iodides and boric acid. However, aryl fluorides remain limited
on account of superior bond-dissociation energy.[3] Therefore,
the functionalization methodologies of C-F bond have brought
attention towards mechanistic investigation and synthetic
application.[4] Furthermore, transition-metal-free C-F bond
activation can reduce the cost of catalyst. Especially, for
expensive metal catalyst used for C-F bond activation, and
should find its application in industry. [5]
Scheme 1. C-N coupling of fluoroquinolines with arylamines.
Recently, 8-aminoquinoline derivatives received extensive
attention as important structural motifs in polyolefin catalyst
families.[6] In 2003, Hamann et al. showed a rapid synthesis
of amidoquinolines through microwave assisted Pd-catalyzed
amination of 8-bromoquinoline with amines.[7] In 2014,
Pitchumani et al. reported a mild protocol for synthesis of
halogenate aminoquinolines by using copper catalyst
supported by triazine-based mesoporous covalent imine
polymers.[8] Despite scientists successfully developing the
diverse ways for 8-aminoquinoline derivatives, the synthetic
procedures so far adopted mainly rely on traditional palladium
catalyzed C-N coupling tactics (Scheme 1).[9] Herein, we
have developed a convenient transition-metal direct C-N bond
coupling reaction from fluoroquinolines.
Initially, we began this study on the basis of the reaction
mechanism that the reactivity of the aryl halides decreases in
the order of fluoride > chloride > bromide > iodide in a
process of nucleophilic substitution (SNAr).[4a] Then,
8-fluoroquinoline and aniline were chosen as model substrates
to optimize reaction conditions. Because the base plays an
important role in the formation of aniline salt, we speculated
that seeking a suitable base would be highly rewarding in the
process of optimized reaction. Therefore, we started our trials
with common carbonates. (Table 1, Entry 1, 2, 3)
Unfortunately, no desired product was detected. Next, our
investigation focused on the use of strong bases including
LiOtBu, NaOtBu, KOtBu. However, still no product was
obtained. (Table 1, Entry 4, 5, 6). We surmised that further
reactions might be prevented by the byproducts (carbonic acid
or tertiary butanol). Along this train of thought, LiH, NaH,

2
KH were chose as perfect bases to optimize reaction
conditions (Table 1, Entry 7, 8, 9) To our delight, LiH gave
highly conversion desired product 3a with the yield of 84%.
To further investigate the solvent effect, THF, DMF and
DMSO were examined successively. However, no satisfactory
responds were given.
with Grignard reagents.[11]
Table 2. Substrate scope studies a
a
Table 1. Screening of reaction conditions.
Entry
Base
Li2CO3
Na2CO3
K2CO3
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF[f]
Yield[%] b
1
2
nd
nd
3
nd
t
4
LiO Bu
nd
5
NaOtBu
KOtBu
LiH
nd
6
nd
a
Reagents and conditions: 1 (0.3 mmol), 2 (0.6 mmol), LiH (0.9
mmol), Toluene (2 mL), 12 h, nitrogen atmosphere. Isolated yield
based on 1.
7
84%
10%
5%
nd
8
NaH
KH
Additionally, we also explored the generality of the optimal
condition for the reaction of a series of 2-substituted
fluoroquinolines(Table 3). Chlorine substituted arylamines in
different positions (ortho, meta, para) could be arylated with
similar yields. However, compared to 3, the yield of 5 sharply
reduced due to the steric effect, which further proved that the
cleavage of C-F bond was connected with the nitrogen
heterocyclic ring .
9
10[c]
11[d]
12[e]
LiH
LiH
DMF[g]
DMSO[h]
nd
LiH
nd
[a] Reaction conditions (unless otherwise specified): 1 (0.3 mmol), 2a (2.0 equiv),
base (3.0 equiv), solvent (2.0 mL), reaction temperature (110 oC), reaction time (12
h), nitrogen atmosphere. [b] Isolated yield based on 1. [c] Reaction conducted at 60
oC. [d] Reaction conducted at 130 oC. [e] Reaction conducted at 140 oC. [f] THF,
tetrahydrofuran. [g] DMF, N,N-dimethyl-formamide. [h] DMSO, dimethyl
sulfoxide.
Table 3. Substrate scope studies a
With the optimal conditions in hand, we explored the scope
of the coupling reactions. As shown in Table 2, a variety of
o
arylamines (110 C) were coupling with fluoroquinolines to
afford the diarylamines in good yields. (2a-2k). Among these,
the arylamine equipped with strong electronic donating group,
such as 4-methoxyl aniline, gave moderate yield (Table 3, 3e).
However, with electronic withdrawing group, such as
4-cyanoaniline, 4-nitroaniline, 4-trifluoromethylaniline did
not afford the desired products. It is worth mentioning that
ortho-bis-substituted
arylamine
(2c)
reacted
with
8-fluoroquinoline in slightly low yield, which could be
explained by the steric effect. Moreover, halo-substituted
diarylamines are valuable building blocks for further
transformations. To our surprise, when polyfluoroquinolines
were treated as reaction substrates, good region-selectivity
were observed for polyfluoroquinolines, in which only the
8-position C-F bond on the benzene ring were replaced by a
C-N bond. We speculated that it might be the cross-coupling
reaction of polyfluoroquinolines with arylamines via
heterocycle-directed cleavage of 8-position C-F bond. Similar
results had been reported in previous papers. For examples, in
2013, cao and coworkers reported pyridyl-directed alkylation
and arylation C-F bond of polyfluoroarenes with Grignard
reagents.[10] In 2014, Li and coworkers demonstrated that
selective imino-directed alkylation and arylation of C-F bond
a
Reagents and conditions: 4 (0.3 mmol), 2 (0.6 mmol), LiH (0.9
mmol), Toluene (2 mL), 12 h, nitrogen atmosphere. Isolated Yield
based on 4.
As shown in the Table 1, compared to the LiH, both NaH
and KH gave lower yields. Generally, the reactivity observed
for the counterion corresponds to the strength of the M-F
bond.[12] Distinctly, the Li-F bond (138 kcal/mol) is stronger
than a Na-F (124 kcal/mol) bond and a K-F bond (119
kal/mol). Furthermore, the reaction using LiH as a base
resulted in no reaction in the presence of lithium ion selective
[12]crown-4, which directly verified the importance of Li/F
interaction for the C-N bond coupling reaction.[13] The
position of nitrogen atom was also examined, when

3
3. a) Daasbjerg, K. J. Chem. Soc. Perkin Trans. 2 1994,
8-fluoroisoquinoline was chosen as substrate, no desired
product was obtained, suggesting the nitrogen directing effect
probably serves to facilitate the reaction. Furthermore, we
also investigated 8-chloro, bromo and iodo-quinolines as the
substrates in the same reaction condition. However, no
reactions were observed.
1275-1277. b) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res.
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A possible reaction mechanism for the C-N bond coupling
of 8-fluoroquinoline was proposed (Scheme 2).[5f] Initially,
lithium ion prioritized coordination with the lone-pair
electrons at the nitrogen atom of pyridine. Furthermore, the
C-F bond was activated upon coordination of lithium toward
nucleophilic attack by the anilide. Subsequently, the addition
of amino to benzene ring led to the formation of C-N bond
(Scheme 2, A). Finally, cleavage of the C-F bond of analogue
of Meisenheimer complex afforded the target product along
with releasing LiF.
5. Selected examples in 2017: a) Wang L.; Sun H.; Zuo Z.; Xue B.;
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Eur. J. Org. Chem. 2017, 4300-4304. g) Zell D. Müller V.;
Dhawa U.; Bursch M.; Presa R. R.; Grimme S.; Ackermann L.
Chem. Eur. J. 2017, 23, 1-5. h) Wilklow-Marnell M.;
Brennessel W. W.; Jones W. D. Organometallics 2017, 36,
3125-3134
6. For selected examples, see a) Ittel, S. D.; Johnson, L. K.;
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Scheme 2. The proposed possible mechanism.
In conclusion, an efficient and general selective method for
the synthesis of 8-aminoquinoline derivatives has been
disclosed through transition metal direct C-N bond coupling
from fluoroquinolines and arylamines. Notably, this protocol
has demonstrated its value as a versatile synthetic route for
8-aminoquinoline derivatives.
Kuhlman, R. L.; Wenzel, T. T. Science 2006, 312, 714−719. d)
De Waele, P.; Jazdzewski, B. A.; Klosin, J.; Murray, R. E.;
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Acknowledgements
We gratefully acknowledge financial support of this work
by the National Natural Science Foundation of China (No.
21371080) and the Fundamental Research Funds for the
Central Universities (JUSRP51627B).
Supplementary data
Supplementary data associated with this paper can be found,
in the online version, at http://
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897-900.
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4
Convenient synthesis of 8-aminoquinolines from
fluoroquinolines
Selective C-F bond activation by heterocycle
directing effect and Li/F interaction
Good function group flexibility for coupling
arylamines
Steric effect has an impact on the reaction yield