Metal–free C5-H Bromination of Quinolines for One-pot C?X (X=C, O, S) Bond Formations

Article abstract of DOI:10.1002/adsc.201700391

We developed an efficient and convenient method for metal-free bromination of 8-aminoquinoline scaffolds on the C5 position that is geometrically inaccessible. And this bromination step can be followed in a one-pot manner with five kinds of C?X (X=C, O, S) cross-coupling reactions without any extra workup, such as removal of the solvent or filtration for the separation of intermediate. The reaction tolerates a wide scope of alkyl and aryl amides as well as (hetero)aryl boronic acids, generating the corresponding arylation products in good to excellent yields. Furthermore, the one-pot alkenylation, alkynylation, thiolation and phenoxylation of quinolines on the C5 position can be efficiently realized using this brominated quinoline amide molecular platform. Thus, the method shows high practical potential in industrial organic synthesis. (Figure presented.).

Full text of DOI:10.1002/adsc.201700391

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DOI: 10.1002/adsc.201700391
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Metal–free C5-H Bromination of Quinolines for One-pot CÀX
(X=C, O, S) Bond Formations
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You Li,+a Longzhi Zhu,+a Xin Cao,a Chak-Tong Au,b Renhua Qiu,a,* and Shuang-
Feng Yina,*
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a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha, 410082, People’s Republic of China
Phone and fax number: (+86)-731-8882-1546
E-mail: renhuaqiu@hnu.edu.cn; sf_yin@hnu.edu.cn
College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, Peopleꢀs Republic of
China
b
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These two authors contributed equally to this work.
Received: March 27, 2017; Revised: May 12, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201700391
Introduction
Abstract: We developed an efficient and conven-
Quinolines are important nitrogen-containing hetero-
ient method for metal-free bromination of 8-amino-
cycles widely existed in natural products, bio-active
quinoline scaffolds on the C5 position that is
molecules and agrochemicals (Figure 1).[1] And amino-
geometrically inaccessible. And this bromination
quinolines have been developed as important biden-
step can be followed in a one-pot manner with five
tate directing groups or ligand auxiliary in various
kinds of CÀX (X=C, O, S) cross-coupling reactions
kinds of organic reactions, especially in the area of
without any extra workup, such as removal of the
CÀH activation.[2] Therefore, the synthesis of this kind
solvent or filtration for the separation of intermedi-
of motifs, especially those with substituted quinolines,
ate. The reaction tolerates a wide scope of alkyl
is of great importance.
and aryl amides as well as (hetero)aryl boronic
In the past decade, efforts were put in for this kind
acids, generating the corresponding arylation prod-
of synthesis. Generally, there are two methods. One is
ucts in good to excellent yields. Furthermore, the
the ring-closing reaction of appropriate anilines with
one-pot alkenylation, alkynylation, thiolation and
carbonyl compounds or alkynes, and the desired
phenoxylation of quinolines on the C5 position can
products are generated with high efficiency.[3] How-
be efficiently realized using this brominated
ever, there are limitations and drawbacks. For exam-
quinoline amide molecular platform. Thus, the
ple, the reaction conditions are usually harsh and
method shows high practical potential in industrial
expensive multi-substituted anilines are required as
organic synthesis.
starting materials for the synthesis of multi-substituted
quinolines.
Keywords: Aminoquinoline; metal-free; one pot;
CÀH activation; cross-coupling
The other method is the direct late-stage and site-
selective CÀH functionalization of quinoline frame-
works that is suitable for straightforward synthesis of
complex molecules with a quinoline scaffold. Exam-
Figure 1. Representative molecules that contain quinoline scaffolds.
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ples of the modification of quinoline scaffolds are Results and Discussion
mainly on the C2,[4] C3,[5] C4[6] and C8[7] positions that
are easily accessible. As for the C5 position that is We first attempted the synthesis of C5-arylated
geometrically inaccessible,[8] it was not until 2013 that quinoline 4a by treating 8-aminoquinoline amide (1a)
Stahl et al. reported the first chlorination of quinoline with aryl reagent directly via C5-H arylation similar to
framework via a Cu(I)-catalyzed single electronic that of C5-H chalcogenation reported by us (Table 1,
transient (SET) mechanism using LiCl as chloride entries 1–3).[11a] The result was that there is no
source.[9] Since then, several methods efficient for C5 formation of 4a. Nonetheless, unexpected C5-bromi-
modification have been disclosed, such as the reac- nated quinoline 2a was obtained when CuBr2 was
10 tions of allylation (Zeng[10]), chalcogenation (Zhu,[11a] used. To investigate whether a cascade Suzuki cross
11 Baidya[11b] and Xu[12]), halogenation (Xie[13] and many coupling[32] can proceed in a one-pot manner after
12 others[14]), sulfonylation (Wei[15] and many others[16]), bromination, we combined the bromination with a Pd-
13 amination (Baidya[17] and others[18]), azidation catalyzed Suzuki cross-coupling reaction without any
14 (Zhu[19]), fluoroalkylation (Huang[20] and others[21]), workup for 2a isolation. To our delight, 4a could be
15 nitration (Ribas[22] and others[23]), esterification (Xia[24] obtained in 27% yield (entry 4) using Pd(PPh3)4 as
16 and others[25]), methoxylation (Shi[26] and You[27]), catalyst. The use of PdCl2 or Pd(PPh3)2Cl2 as catalyst
17 homo-coupling (Watkins[28]) and alkylation (Song[29a,b] resulted in low efficiency (entries 5–6). We then
18 and others[29c]). Although great progresses on remote turned our attention to metal-free halogenation using
19 C5-H functionalization of quinoline have been made, NXS (X=Cl, I, Br) (entries 7–9) and found that
20 there are still drawbacks: (1) The reaction conditions Suzuki coupling proceeded with high efficiency. The
21 are different, and it is not easy to extend a particular results imply that the metal salts from the bromination
22 system to another by simple modification, and that process have a negative effect on the Suzuki cross
23 developed by Zhang et al.[16c] for sulfonalyation is the coupling that follows. And we found that NBS is the
24 only exception. Therefore, it is desirable to develop a best choice for the formation of 4a (entry 8), while
25 general and simple method to realize the transforma- DMF is the best among the solvents tested (entries
26 tions. (2) A number of direct remote CÀH functional- 10–12). Further optimization of reaction conditions
27 ization on C5 position of quinoline have not been resulted in 90% yield of 4a when bromination was
28 demonstrated, including arylation, alkynylation, alke- conducted at 508C for 1 h (entries 13–18). Note that
29 nylation, etc. (3) The harsh reaction conditions for the second step was performed with simple addition of
30 remote C5-H functionalization of quinoline, such as the required chemicals into the mixture obtained at
31 those adopted in thiolation,.[11a]should be replaced by the end of the metal-free brominating reaction. And
32 some milder ones. (4) Recently, Baidya et al.[14d] there is no need of solvent removal or material
33 disclosed an efficient two-step transformation com- isolation. Such convenient transformation cannot be
34 bined with metal-catalyzed remote C5-H iodination realized in the metal-catalyzed halogantion processes.
35 followed by a traditional cross-coupling process. For example, we performed a number of metal-
36 However, in the method the iodide produced in the catalyzed/mediated bromination that were reported to
37 first step has to be isolated. And the protocol is not be efficient,[14a,d,h] and had the Suzuki cross coupling
38 appropriate for one-pot synthesis, because the metal reaction followed as shown in Scheme 1. It was found
39 for the first step might have negative effect on the that Suzuki cross coupling failed to proceed in such an
40 transformation that follows. As a result, there is a approach.
41 need for the isolation of the halogenation intermedi-
42 ate (vide infra).
With the optimized reaction conditions in hand, we
explored the applicability of the protocol and exam-
43
Compared to analogs such as iodoarene (less stable ined a series of aryl boronic acids (Table 2). It was
44 and with heavier molecular weight) and chloroarene found that aryl boronic acid bearing electron-donating
45 (less active), bromoarene is more stable and reactive, or electron-withdrawing groups on the benzene ring
46 making it a good intermediate for the generation of are well tolerated (4a–4s). With electron-donating
47 various kinds of functional molecules that are widely (4b–4i) and electron-withdrawing groups (4j–4p), the
48 used in organic synthesis.[30] Herein, we report an corresponding products are obtained in moderate to
49 efficient protocol that combines fast and efficient good yields. The para, meta or ortho substitution of
50 metal-free[31] bromination on C5 position of quinolines aryl rings with a methyl group does not significantly
51 with traditional CÀX (C, O, S) cross-coupling reac- affect the arylation reaction (4b, 4h and 4i). 1-
52 tions, including arylation, alkynylation, alkenylation, Naphthylboronic acid could react smoothly to give 4q
53 phenoxylation, and thiolation. Without the need for in 75% yield. When a methyl group is on the C2 (4r)
54 intermediate isolation, materials that were previously or a methoxyl group on the C6 position (4s), the
55 inaccessible by metal-catalyzed halogenation process corresponding product can be obtained in good yield.
56 can be synthesized in a one-pot manner.
However, alkyl boronic acid (3t) is less reactive in this
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catalytic system, but it can be successfully synthesized
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Table 1. Optimization of reaction conditions.[a]
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[a] 1a (0.2 mmol), [X] (equiv.), [Ar] (3, 0.4 mmol), solvent (1.0 mL), N2;
[b] GC yield, using n-tridecane as internal standard; the number in parentheses is isolated yield;
[c] at 1608C;
[d] in this run, 2a can be isolated in 96% yield at the end of the brominating step.
43 via a two-step manner by isolating 2a with EtMgBr in quinoline ring is favored over the metalation–deproto-
44 Et2O at room temperature for 24 h (4t, 41%). None- nation (CMD) process at the ortho-position of
45 theless, heterocyclic boronic acid such as thienyl-, benzamide.[14b] Furthermore, arylated product in mod-
46 furyl-, and pyridinyl-boronic acids are all compatible, erate yield can be obtained in the two cases of
47 giving the target products in excellent yields (4u–4y). heterocyclic amides (5h and 5i).
48
Then the scope of 8-aminoquinoline amides was
To demonstrate the synthetic utility of this method,
49 explored under the adopted reaction conditions we carried out the reaction on 5 mmol scale, and the
50 (Table 3). A number of aliphatic amides give the desired product was obtained in 78% yield (1.186 g of
51 products in moderate to good yields (5a–5d). More- 4a) (Scheme 2a). The amide bond could be readily
52 over, the system could be applied to a variety of cleaved without damaging the CÀC bond that is newly
53 benzamides, generating the desired products in good formed to obtain 83% yield of 6. Followed by
54 yields (5e–5i). The result is in sharp contrast with that sulfonylation of amino group (85% yield of 7), a drug
55 of our thiolation system in which only a mixture of candidate for inhibiting ubiquitination was synthesized
56 thiolated products (on benzamides or quinoline motif) in a “one-pot” manner to give 7 in a yield of 55%. The
57 can be obtained.[11a] Herein, the bromination of approach is superior to the procedures patented by
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Scheme 1. Suzuki cross coupling following reported bromination methods.
26 Rigel Pharmaceuticals Inc.,[33] thereby providing a at 1608C for 24 h) (Scheme 3b),[11a] the present proto-
27 feasible protocol for concise synthesis of biologically col exhibits higher yield (12, 90%) with lower metal
28 relevant arylated substances. Furthermore, by using loading (0.2 equivalent of CuI) and under milder
29 this platform molecule, one can realize one-pot reaction conditions (bromination at 508C for 1 h,
30 remote alkenylation (CÀH bromination and Heck followed by CÀS cross-coupling at 1008C for 18 h)
31 reaction[34]), alkynylation (CÀH bromination and So- (Scheme 3a, Condition B).
32 nogashira cross-coupling reaction[35]), and phenoxyla-
Studies were performed to obtain insight into the
33 tion (CÀH bromination and Ullmann-type CÀO cross- reaction mechanism (Scheme 4). The addition of a
34 coupling reaction[36]) of 8-aminoquinoline scaffolds on radical
inhibitor, 2,6-diisopropyl-4-methylphenol
35 the C5 position (Scheme 2b), with the desired prod- (BHT) or (2,2,6,6-tetramethyl-piperidin-1-yl)oxidanyl
36 ucts 8, 9 and 10 obtained in 80%, 83% and 67% yield, (TEMPO), resulted in inhibition of reaction (Sche-
37 respectively. It is worth pointing out that to the best of me 4a), indicating the involvement of a radical step.
38 our knowledge there are no reports on direct C5-H We found that the arylation reaction is of low
39 functionalization for the synthesize of 8, 9, 10.
efficiency with N-(naphthalen-1-yl)pivalamide 1b or
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To further demonstrate the advantage of using this N-protected amide 1b’, yielding the corresponding
41 one-pot method, we attempted the Ullmann-type CÀS product with no regioselectivity (Schemes 4b). When
42 cross-coupling[37] using the recently reported approach analog N,O-bidentate directing group 1c is used, the
43 of metal-free bromination of quinolines under aque- quinoline is hydrolyzed and no desired product is
44 ous condition,[14k] and obtained no CÀS cross coupling obtained (Schemes 4c), which confirms the indispen-
45 product (Scheme 3a, Condition A). However, using sable role of the 8-aminoquinoline skeleton for this
46 our one-pot protocol, desired product 11 and 12 can reaction. The protocol is also ineffective with 1d,
47 be obtained in 85% and 90% yield, respectively giving 1da in low yield and poor regioselectivity
48 (Scheme 3a, Condition B). The above results indicate (Schemes 4d), plausibly due to the low efficiency and
49 that the solution of the first reaction has a significant poor regioselectivity of the first bromination step.
50 effect on the Ullmann-type CÀS bond cross coupling Thus, the acyl group is important in the control of
51 reaction that follows, and the DMF in the solution can regioselectivity. In Scheme 4e, the two-step reaction is
52 be directly used in the cross coupling reaction without of high efficiency, giving 2a and 4a in 96% and 96%
53 any workup processes such as isolation and evapo- yield, respectively. The molecular structure of 2a has
54 ration that are essential if the reaction were per- been unambiguously confirmed by single crystal X-ray
55 formed in aqueous solution. Compared to our work diffraction study (Figure 2) (CCDC 1497054).[38]
56 on CÀH direct thiolation of quinolines on C5 position
On the basis of the results of the control experi-
57 (12, 88%, in the presence of 1.5 equivalents of CuBr2 ments and those of literatures,[9,13—14] we propose a
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Table 2. Scope investigation of arylboronic acids.
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Reaction conditions: 1 (0.2 mmol), NBS (0.22 mmol), DMF (1.0 mL), 508C, 1 h, N2; then RB(OH)2 (3, 0.4 mmol), Pd(PPh3)4
(10 mol%), Na2CO3 (2 equiv.), DMSO (1.0 mL), 1408C, 6 h, N2, isolated yield; a in a two-step manner followed by treatment of
isolated 2a with EtMgBr in Et2O at room temperature for 24 h.
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Table 3. Scope investigation of Amides.
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Reaction conditions: 1 (0.2 mmol), NBS (0.22 mmol), DMF (1.0 mL), 508C, 1 h, N2; then PhB(OH)2 (3a, 0.4 mmol), Pd(PPh3)4
(10 mol%), Na2CO3 (2 equiv.), DMSO (1.0 mL), 1408C, 6 h, N2, isolated yield.
Conclusion
In summary, we developed an efficient method for the
synthesis of 5-(hetero)arylated quinoline motifs via a
cascade reaction of metal-free radical C5–H bromina-
tion and Suzuki-coupling reaction without isolation of
the intermediate bromide. The system is applicable to
a variety of boronic acids and amides, giving the target
products in good yields. Furthermore, through this
platform molecule, the alkenylation, alkynylation and
thiolation, and phenoxylation of quinolines on the C5
position can also be efficiently realized. Thus, this
protocol shows high practical potential in industrial
orgnanic synthesis.
Figure 2. X-ray of 2a
Experimental Section
49 pathway for arylation on the C5 position of quinolines
50 (Scheme 5). First, Br· radical is generated from NBS General Procedure for One-Pot Arylation of
51 upon heating. Then the quinoline ring is brominated Quinolines
52 to generate 2a. After Suzuki coupling, the desired
53 product 4a is obtained.
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To a 10 mL screw capped vial equipped with a magnetic
stirring bar was added 8-aminoquinolines amide (1)
(0.2 mmol), N-bromosuccinimide (0.22 mmol), and DMF
(1.0 mL) under N2 atmosphere. The reaction mixture was
placed in a pre-heated oil bath at 508C and vigorously stirred
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Scheme 2. Gram-scale and synthesis application.
Scheme 3. Comparison of Ullmann-type CÀS cross-coupling performed under the different conditions.
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Scheme 4. Control experiments.
Scheme 5. Possible pathway.
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for 1 h to generate brominated quinoline 2. Afterward the
reaction mixture was cooled down to ambient temperature
and added boronic acid derivatives (0.4 mmol), sodium
carbonate (0.4 mmol), Pd(PPh3)4 (0.02 mmol), and DMSO
(1.0 mL) under N2 atmosphere. The mixture was placed in an
oil bath pre-heated at 1408C and vigorously stirred for 6 h.
Subsequently it was cooled down to room temperature,
filtered through a plug of celite and then washed with
saturated brine and extracted with ethyl acetate (33 5.0 mL).
The solvents were removed under reduced pressure and the
crude reaction mixture was purified by chromatography on
silica gel using PE/EtOAc as eluent to obtain the desired
product 4 or 5.
[4] Selected examples of C2 functionalization of quinoline,
see: a) A. M. Berman, J. C. Lewis, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2008, 130, 14926–14927;
b) M. Tobisu, I. Hyodo, N. Chatani, J. Am. Chem. Soc.
2009, 131, 12070–12071; c) D. Zhao, W. Wang, F. Yang,
J. Lan, L. Yang, G. Gao, J. You, Angew. Chem., Int. Ed.
2009, 48, 3296–3300.
[5] Selected example of C3 functionalization of quinoline,
see: M. Wasa, B. T. Worrell, J. Q. Yu, Angew. Chem.,
Int. Ed. 2010, 49, 1275–1277.
[6] Selected examples of C4 functionalization of quinoline,
see: a) C.-C. Tsai, W.-C. Shih, C.-H. Fang, C.-Y. Li, T.-G.
Ong, G. P. Yap, J. Am. Chem. Soc. 2010, 132, 11887–
11889; b) Q. Chen, X. M. du Jourdin, P. Knochel, J. Am.
Chem. Soc. 2013, 135, 4958–4961.
[7] Selected examples of C8 functionalization of quinoline,
see: a) N. Boudet, J. R. Lachs, P. Knochel, Org. Lett.
2007, 9, 5525–5528; b) J. Kwak, M. Kim, S. Chang, J.
Am. Chem. Soc. 2011, 133, 3780–3783.
[8] Selected reviews for synthesis of substituted quinoline
via CÀH activation, see: a) T. Iwai, M. Sawamura, ACS
Catal. 2015, 5, 5031–5040; b) D. E. Stephens, O. V.
Larionov, Tetrahedron 2015, 71, 8683–8716; c) L. Zhu,
X. Cao, Y. Li, T, Liu, X. Wang, R. Qiu, S.-F. Yin, Chin.
J. Org. Chem. 2017, DIO: 10.6023/cjoc201703020.
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aminoquinoline on C5-position, see: A. M. Suess, M. Z.
Ertem, C. J. Cramer, S. S. Stahl, J. Am. Chem. Soc. 2013,
135, 9797–9804.
[10] The first example of remote CÀH allylation of 8-
aminoquinoline on C5-position, see: X. Cong, X. Zeng,
Org. Lett. 2014, 16, 3716–3719.
[11] The two examples of remote CÀH chalcogenation of 8-
aminoquinoline on C5-position, see: a) L. Zhu, R. Qiu,
X. Cao, S. Xiao, X. Xu, C. T. Au, S.-F. Yin, Org. Lett.
2015, 17, 5528–5531; b) H. Sahoo, A. Mandal, J.
Selvakumar, M. Baidya, Eur. J. Org. Chem. 2016, 2016,
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[12] The first example of thio/salenocyanation on C5 posi-
tion of quinoline: J. Chen, T. Wang, T. Wang, A. Lin, H.
Yao, J. Xu, Org. Chem. Front. 2017, 4, 130–134;
[13] The first example of two remote CÀH halogenation of
8-aminoquinoline on C5 and C7-position together, see:
H. Guo, M. Chen, P. Jiang, J. Chen, L. Pan, M. Wang, C.
Xie, Y. Zhang, Tetrahedron 2015, 71, 70–76.
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Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21373003 and 21676076), the Natural Science Founda-
tion of Hunan Province (2016JJ3034), and Hunan Youth
Talent (2016RS3023) for financial support. C.T. Au thanks
the Hunan University for an adjunct professorship. We thank
Prof. Nobuaki Kambe and Prof. Takanori Iwasaki (Osaka
University), Prof. Akihiro Orita (Okayama University of
Science), and Prof. Li-Biao Han (AIST, Tsukuba, Japan),
and Prof. Wai-Yeung Wong (Hong Kong Polytechnic Uni-
versity) for helpful discussion.
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