Tandem Oxidative Radical Halogenated Addition of Alkynyl Imines: Regioselective Synthesis of 3-Haloquinolines

Article abstract of DOI:10.1002/ejoc.201901395

A tandem oxidative radical halogenated addition of alkynyl imines for regioselective synthesis of 3-haloquinolines is described. Mechanism investigation suggests that the oxidation of halogen, 6-endo-trig cyclization and aromatization are involved in the process. Easily available starting materials, mild conditions, and a wide substrate scope make this approach potentially useful.

Full text of DOI:10.1002/ejoc.201901395

A Journal of
Accepted Article
Title: Tandem Oxidative Radical Halogenated Addition of Alkynyl
Imines: Regioselective Synthesis of 3-Haloquinolines
Authors: Dianpeng Chen, Jianming Li, Peiying Cui, Yingying Shan,
Yutong Zhao, and Guanyinsheng Qiu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901395
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
Tandem Oxidative Radical Halogenated Addition of Alkynyl
Imines: Regioselective Synthesis of 3-Haloquinolines
Dianpeng Chen,*[a] Jianming Li,[a] Peiying Cui[a] Yingying Shan,*[a] Yutong Zhao,[a] and Guanyinsheng
Qiu*[b]
Abstract: A tandem oxidative radical halogenated addition of alkynyl
(a) Direct Halogenations:
imines for regioselective synthesis of 3-haloquinolines is described.
X
electrophilic aromatic substitution
R1
X2
R1
Mechanism investigation suggests that the oxidation of halogen, 6-
+
N
N
endo-trig cyclization and aromatization are involved in the process.
Easily available starting materials, mild conditions, and a wide
substrate scope make this approach potentially useful.
(b) Electrophilic Cyclization (Zhou's work):
R3
R3
N
X
CuX
NXS
R1
R1
+
R2
N
R2
(c) Tandem Radical Cyclization (This Work):
Introduction
R3
R3
R3
N
6-endo-trig cyclization
X
X
+
R1
Quinolines represent an important class of nitrogen-containing
heterocycles that can be found in a wide range of interesting
compounds, including natural products, pharmaceuticals, and
functional materials.[1-3] In particular, 3-haloquinolines,[4] a member of
the family of privileged scaffold, occupy a significant place in
synthetic building blocks, due to the fact that halogen atom could
provide a further avenue for structural elaboration.[5]
X
R1
R1
regioselectivity
R2
N
R2
R2
N
X = Br or I
intermediate A
Scheme 1. Proposal for the Synthesis of 3-haloquinolines.
like to disclose our endeavor in the regioselective synthsis of 3-
haloquinolines (Scheme 1c). In this process, it was hypothesized
that the halogen radical,[12] deriving from the single electron oxidation
of halogen anions, was added to the triple bond to form a vinyl
radical intermediate A, which underwent 6-endo-trig cyclization to
achieve final products.
In view of the various applications, considerable research effort
had been devoted to the development of efficient methods for the
regioselective functionalization of quinolines (Scheme 1).[6] Classical
methods for the synthesis of 3-haloquinolines were predominantly
focused on direct halogenations via electrophilic aromatic
substitution (Scheme 1a).[7] However, progress in this area
frequently encountered the issue of over-halogenation and poor
regioselectivity.[7d,7e] Another alternative strategy was electrophilic
cyclization, which need halogen cations, for example NBS, I2, and
ICl etc. as electrophilic reagent (Scheme 1b).[4a,4d,8] For example,
Zhou and co-workers reported an efficient protocol for the
preparation 3-haloquinolines via electrophilic cyclization of alkynyl
imines using the NXS/CuX system.[4a] Although these methods were
efficient, the inferior of atom economy and poor tolerance of
functional groups might limit the synthetic applications in some
cases. Accordingly, developing new and regioselective approach for
the preparation of 3-haloquinolines remained a formidable challenge.
Results and Discussion
Stimulated by this proposal, we chose (Z)-N-(1,3-diphenylprop-2-
ynylidene)aniline (1a), an important dual-functionalized building
block,[13] as the starting material, which could be readily prepared via
the
treatment
of
(Z)-N-phenylbenzimidoyl
chloride
with
ethynylbenzene under Sonogashira conditions.[14] Based on our
previous work about tandem oxidative radical halogenated
addition,[15] an initial trial was occupied by the reaction of 0.2 mmol of
1a and 1.0 equiv of tetra-n-butylammonium bromide (TBAB) in 2 mL
of DCE:H2O (1:1, v/v) at 80 oC in the presence of 1.0 equiv of
K2S2O8 as an oxidant. To our delight, the desired product of 3-
bromo-2,4-diphenylquinoline (3a) was obtained in 32% isolated yield
(Table 1, entry 1), and the NMR data was consistent with the
literature reports.[4a]
On the other hand, tandem radical cyclization had been well-
recognized as a versatile tool to construct various useful cyclic
molecules.[9] In the past decade, its prosperous development had
emerged as a very attractive branch of modern organic synthesis.[10]
Considering our continuous interest in radical chemistry,[11] we would
Encouraged by this positive result, further optimization was then
carried out. Considering the high activity of bromo radical, increase
of K2S2O8 and TBAB dosage was evaluated at first. As expected, the
yield was improved apparently when both oxidant and bromo source
were increased to 2.0 equiv, leading to the final product 3a in 56%
yield (Table 1, entry 2). However, increase of K2S2O8 and TBAB
dosage to 3.0 equiv did not gave a better result (Table 1, entry 3).
Then we began to optimize the reaction with respect to different
oxidants, bromo sources and solvents. Whereas subsequent
screening of oxidants, such as H2O2, MnO2 or DTBP (2-(tert-
butylperoxy)-2-methylpropane), offered unsatisfactory results (Table
[a]
[b]
Dr. D. Chen, J. Li, P. Cui, Dr. Y. Shan, Y. Zhao
Chemistry and Chemical Engineering,
Qufu Normal University, Qufu 273165, Shandong, China
E-mail: chendp@zju.edu.cn; shanyying@zju.edu.cn.
Prof. G. Qiu
College of Biological, Chemical Science and Engineering,
Jiaxing University, Jiaxing 314001, Zhejiang, China
E-mail: qiuguanyinsheng@mail.zjxu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
1, entries 4-6), Oxone (2KHSO5•KHSO4•K2SO4) was found to be an
appropriate oxidant for this reaction that afforded the product in 82%
yield (Table 1, entry 7). Replacing TBAB with halometallate gave
similar yields (Table 1, entries 8-9), and NBS (N-Bromosuccinimide)
showed poor reactivity (Table 1, entry 10). In addition, the effect of
water-containing co-solvents was also explored. From the results,
DCE : H2O (v/v, 1 : 1) was the best choice (Table 1, entry 7), which
was probably due to the improved solubility of bromide salt and
oxidant in the co-solvent system. No improvements were observed
when different co-solvents were screened (Table 1, entries 11-15).
Thus, the optimized reaction conditions were chosen as follows: 1a
(0.2 mmol), Oxone (2.0 equiv), TBAB (2.0 equiv) in 2 mL of DCE :
H2O (v/v, 1 : 1) were stirred at 80 oC.
under standard conditions. As shown in Table 3, a series of 3-
iodoquinolines were achieved in good yields. To our delight, the
reaction processed smoothly when R2 was tert-butyl (Table 3, 5g).
We reasoned that the result was ascribed to relatively easy
accessibility and high stability of iodo radical. Remarkably, this
approach was also applicable to the synthesis of 2-
iodobenzo[f]quinoline,[16] and produced the target molecule 5h in
66% yield.
Table 2. Synthesis of 3-bromoquinolines[a][b]
R3
R3
Oxone, 80 o
C
Br
+
TBAB
R1
R1
DCE:H2O (v/v, 1:1)
N
R2
N
R2
Table 1. Optimization of the reaction conditions.[a]
1
2
3
_________________________________________________________________________________________
R = 2-Cl, 3b, 68%
R = 3-Cl, 3c, 77%
Oxidant, Solvent
Br
Br
+
[Br]
Br
80 o
C
R = 4-Cl, 3d, 85%
N
N
N
N
R
R = 4-F, 3e, 81%
1a
2
3a
3a, 82%
R
Entry
Oxidant (equiv)
[Br] (equiv)
Solvent
Yield[b]
1
2
3
4
K2S2O8 (1.0)
K2S2O8 (2.0)
K2S2O8 (3.0)
H2O2 (2.0)
TBAB (1.0)
TBAB (2.0)
TBAB (3.0)
TBAB (2.0)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
32
56
43
18
R
Br
F
Br
Br
N
N
N
O
5
6
MnO2 (2.0)
DTBP (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
Oxone (2.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
KBr (2.0)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE:H2O (v/v, 1:1)
DCE
Trace
21
R = Et, 3f, 78%
R = H, 3h, 76%
3j, 80%
R = tBu, 3g, 75%
R = OMe, 3i, 84%
7
82
Cl
8
80
9
ZnBr2 (2.0)
NBS (2.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
77
Br
Br
Br
10
11
12
13
14
15
Trace
39
N
N
N
Cl
THF:H2O (v/v, 1:1)
MeCN:H2O (v/v, 1:1)
DMF:H2O (v/v, 1:1)
MeOH:H2O (v/v, 1:1)
58
3n, 73%
3m, 77%
R
35
R = H, 3k, 72%
R = OMe, 3l, 74%
13
_________________________________________________________________________________________
Complex
[a] Conditions: 1 (0.2 mmol), Oxone (2.0 equiv), TBAB (2.0 equiv) in 2 mL of
DCE : H2O (v/v, 1 : 1) were stirred at 80 oC. [b] Isolated yield based on 1.
[a] Conditions: 1a (0.2 mmol), Oxone (2.0 equiv), TBAB (2.0 equiv) in 2 mL of
DCE : H2O (v/v, 1 : 1) were stirred at 80 oC. [b] Isolated yield based on 1a.
Table 3. Synthesis of 3-iodoquinolines[a][b]
With the optimized conditions in hand, the scope of this tandem
oxidative radical brominative addition was investigated further. As
shown in Table 2, various alkynyl imines could be tolerated. The R1
group could be H (Table 2, 3a-3e, 3m), alkyl (Table 2, 3f-3i, 3k, 3l,
3n), or halogen (Table 2, 3j), and the yields were satisfactory. The
R2 group could be phenyl groups optionally substituted with an
electron-withdrawing (Table 2, 3b-3e, 3n) or an electron-donating
group (Table 2, 3f, 3g, 3j, 3l). Unfortunately, we failed to obtain
target products when R2 was an alkyl group, indicating that the
radical intermediate might be stabilized by aryl groups, which
probably due to the relative short life time of bromo radical.
Encouragingly, the reaction could proceed smoothly when R3 was
alkyl group, producing the corresponding product 3m and 3n in 77%
and 73% yield, respectively.
Then we turned our attention to explore the scope of tandem
oxidative radical iodinated addition, which just needed to utilize TBAI
(tetra-n-butylammonium iodide) as the iodo sources instead of TBAB
[a] Conditions: 1 (0.2 mmol), Oxone (2.0 equiv), TBAI (2.0 equiv) in 2 mL of
DCE : H2O (v/v, 1 : 1) were stirred at 80 oC. [b] Isolated yield based on 1.[c]
The substrate was (Z)-N-(3-cyclopropyl-1-phenylprop-2-ynylidene)naphthalen-
2-amine.
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
The halogen substituent was a vital part of the products and could
In light of the above results, a plausible mechanism was proposed
in Scheme 4. In this process, halogen radical was produced by the
oxidation of halogen anion, and added to the triple bond to form the
intermediate A. Cyclic intermediate B was obtained via 6-endo-trig
cyclization, which was oxidized to the intermediate C. In the
presence of base, intermediate C experienced aromatization to
furnish the final product 3 or 5.
be used as
a convenient chemical handle for other organic
conversion. According to the literature about carbonylation,[17] we
treated 5a with 4-chlorophenyl formate in the presence of Pd2(dba)3,
TBD (2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine) and DBU
(1,8-diazabicyclo[5.4.0]undec-7-ene) in toluene at 80 oC. As
envisaged,
carboxylate
4-chlorophenyl
6-methyl-2,4-diphenylquinoline-3-
6
was obtained in 65% yield, which provided
a
transformation from halogen atoms to a synthetically useful carbonyl
group (Scheme 2).
5 mmol % Pd2(dba)3
10 mmol % TBD
Cl
O
Cl
O
I
+
O
1.2 equiv of DBU
Toluene, 80 oC, 12h
H
O
N
N
5a
6
, 65%
Scheme 2. The carbonylation of the product
To understand the reaction, control experiments were conducted
as shown in Scheme 3. To clarify the radical process, the reactions
with excessive radical scavengers (2,2,6,6-tetramethylpiperidinyloxyl
and 1,1-diphenylethene) were carried out. The reaction was
prominently retarded, but not completely prevented (Scheme 3a and
3b). Interestingly, 2-bromo-1,1-diphenylethene 7 was observed in
36% yield. Supposing the reaction underwent a bromo cation
pathway, 1,1-diphenyl-based electrophilic addition products 8 and 9
should be detected. However, the addition products 8 and 9 were
not observed. As we know, the combination of bromide and H2O2
served as a well-known alternative.[18] The control experiment using
2.0 equiv of H2O2 as replacement, as noted in entry 3 of Table 1,
was also conducted, just providing the final 3a in 18% (Scheme 3c).
Further increase of H2O2 loading to 20 equiv gave rise to the final
product 3a in an improved yield as expected (Scheme 3d).
Scheme 4. Plausible mechanism.
Conclusions
In conclusion, we described a tandem oxidative radical halogenated
addition of alkynyl imines for regioselective synthesis of 3-
haloquinolines. In the transformation, halogen radical was produced
by the oxidation of halogen anion. The reaction proceeded smoothly
with good functional tolerance and efficiency. Further work toward
expanding on this protocol was currently underway.
Experimental Section
General information: All reactions were carried out in oven-dried
glassware sealed with rubber septa under nitrogen condition. All
solvents were distilled under nitrogen atmosphere prior to use.
Purification of products was conducted by flash chromatography on
silica gel (200-300 mesh). NMR spectra were measured on a Bruker
magnetic resonance spectrometer (1H at 500 MHz, 13C at 126 MHz).
Chemical shifts are reported in ppm using tetramethylsilane as
internal standard (s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublets, m = multiplet). MS data were obtained on an
Agilent 5975C inert 350 EI mass spectrometer (GC-MS). HRMS data
were obtained on a VG ZAB-HS mass spectrometer, Brucker Apex
IV FTMS spectrometer. Compounds described in the literature were
characterized by the comparison of 1H and/or 13C NMR spectra to
the previously reported data.
General procedure for 3-bromoquinolines: Alkynyl imine 1 (0.2
mmol), TBAB 2 (128 mg, 0.4 mmol), Oxone (246 mg 0.4 mmol) and
solvent DCE : H2O (v/v = 1:1, 2 mL) were added to a test tube. The
mixture was stirred at 80 °C for 8 h, diluted with water (10 mL) and
extracted with EtOAc (3×5 mL). The combined organic layer was
dried over Na2SO4, and concentrated in vacuo. The resulting crude
product was purified by column chromatography to afford the pure
product 3.
Scheme 3. Control experiments.
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
General procedure for 3-iodoquinolines: Alkynyl imine 1 (0.2
mmol), TBAI 4 (148 mg, 0.4 mmol), Oxone (246 mg 0.4 mmol) and
solvent DCE : H2O (v/v = 1:1, 2 mL) were added to a test tube. The
mixture was stirred at 80 °C for 8 h, diluted with water (10 mL) and
extracted with EtOAc (3×5 mL). The combined organic layer was
dried over Na2SO4, and concentrated in vacuo. The resulting crude
product was purified by column chromatography to afford the pure
product 5.
(m, 2H), 7.37–7.32 (m, 2H), 7.21–7.16 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 163.1 (J = 247 Hz), 157.9, 149.9, 146.4, 138.0, 137.0,
131.5 (J = 8 Hz), 129.8 (J = 50 Hz), 129.3, 128.6, 128.5, 128.0,
127.5, 126.5, 118.4, 115.0 (J = 21 Hz); IR (neat) 2359, 1612, 915
cm-1; HRMS (EI-TOF) calcd for C21H13BrFN 377.0215, found
377.0218.
3-bromo-6-ethyl-4-phenyl-2-p-tolylquinoline (3f): Amorphous
1
solid, 63 mg, 78% yield; H NMR (500 MHz, CDCl3) δ 8.10 (d, J =
General procedure for ester 6: To a test tube sealing with 3-
iodoquinoline 5a (210 mg, 0.5 mmol) in toluene (5 mL) was added
Pd2(dba)3 (22 mg, 0.025 mmol), TBD (2 mg, 0.0125 mmol) and DBU
(91 mg, 0.6 mmol). The 4-chlorophenyl formate (234 mg, 1.5 mmol)
was added at last, and the solution was stirred for 12 hours at 80 oC.
Then the reaction was quenched with water (10 mL), extracted with
DCM (3×5 mL), dried with anhydrous Na2SO4. After evaporation,
chromatography on silica gel of the reaction mixture afforded desired
ester 6.
8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 (dd, J = 12.0, 4.0 Hz, 2H),
7.54 (dd, J = 9.0, 5.0 Hz, 2H), 7.38–7.33 (m, 2H), 7.30 (d, J = 8.0 Hz,
2H), 7.15 (s, 1H), 2.70 (q, J = 8.0 Hz, 2H), 2.43 (s, 3H), 1.20 (t, J =
8.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 158.0, 149.1, 143.6,
138.5, 138.4, 130.9, 129.4, 129.3, 129.2, 128.7, 128.6, 128.5, 128.4,
127.9, 123.9, 118.7, 29.1, 21.4, 15.5; IR (neat) 2357, 1615, 908 cm-1;
HRMS (EI-TOF) calcd for C24H20BrN 401.0779, found 401.0776.
3-bromo-6-tert-butyl-4-phenyl-2-p-tolylquinoline
(3g):
1
Amorphous solid, 64 mg, 75% yield; H NMR (500 MHz, CDCl3) δ
8.13 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 9.0, 2.0 Hz, 1H), 7.62 (d, J =
8.0 Hz, 2H), 7.60–7.51 (m, 3H), 7.36 (d, J = 7.0 Hz, 2H), 7.33–7.28
(m, 3H), 2.43 (s, 3H), 1.26 (s, 9H); 13C NMR (126 MHz, CDCl3) δ
158.3, 150.2, 149.5, 145.0, 138.5, 138.3, 129.4, 129.3, 129.0, 128.7,
128.6, 128.5, 128.4, 127.6, 121.3, 118.6, 35.1, 31.0, 21.4; IR (neat)
2357, 1609, 912 cm-1; HRMS (EI-TOF) calcd for C26H24BrN 429.1092,
found 429.1091.
3-bromo-2,4-diphenylquinoline (3a): Amorphous solid, 59 mg,
1
82% yield; H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.0 Hz, 1H),
7.76–7.71 (m, 3H), 7.59–7.55 (m, 2H), 7.54–7.49 (m, 3H), 7.48–7.46
(m, 1H), 7.45–7.41 (m, 2H), 7.37–7.34 (m, 2H); 13C NMR (126 MHz,
CDCl3) δ 159.0, 149.8, 146.4, 140.9, 138.1, 129.6, 129.5, 129.4,
129.3, 128.7, 128.6, 128.5, 128.0, 127.9, 127.4, 126.4, 118.6; IR
(neat) 2360, 1568, 912 cm-1; HRMS (EI-TOF) calcd for C21H14BrN
359.0310, found 359.0311.
3-bromo-6-methyl-2,4-diphenylquinoline (3h): Pale yellow solid,
1
3-bromo-2-(2-chlorophenyl)-4-phenylquinoline (3b): Pale yellow
57 mg, 76% yield; Mp 79−81 °C; H NMR (500 MHz, CDCl3) δ 8.09
1
oil, 53 mg, 68% yield; H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 8.0
(d, J = 9.0 Hz, 1H), 7.76–7.69 (m, 2H), 7.61–7.52 (m, 4H), 7.52–7.46
Hz, 1H), 7.74 (m, 1H), 7.58–7.46 (m, 7H), 7.44–7.37 (m, 3H), 7.33 (d, (m, 3H), 7.37–7.32 (m, 2H), 7.15 (s, 1H), 2.42 (s, 3H); 13C NMR (126
J = 7.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 157.7, 149.2, 146.4,
140.2, 137.6, 133.0, 130.3, 130.0, 129.9, 129.7, 129.6, 129.2, 128.7,
128.6, 128.5, 128.2, 126.9, 126.5, 119.5; IR (neat) 2359, 1551, 916
cm-1; HRMS (EI-TOF) calcd for C21H13BrClN 392.9920, found
392.9923.
MHz, CDCl3) δ 157.9, 149.1, 144.9, 140.9, 138.3, 137.5, 132.2,
129.5, 129.3, 129.2, 128.6, 128.5, 128.4, 128.0, 127.9, 125.1, 118.6,
21.8; IR (neat) 2360, 1513, 911 cm-1; HRMS (EI-TOF) calcd for
C22H16BrN 373.0466, found 373.0469.
3-bromo-4-(4-methoxyphenyl)-6-methyl-2-phenylquinoline (3i):
1
3-bromo-2-(3-chlorophenyl)-4-phenylquinoline (3c): Pale yellow
Yellow solid, 68 mg, 84% yield; Mp 86−88 °C; H NMR (500 MHz,
1
oil, 61 mg, 77% yield; H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.0
CDCl3) δ 8.07 (d, J = 9.0 Hz, 1H), 7.74–7.68 (m, 2H), 7.55 (d, J = 9.0
Hz, 1H), 7.47 (m, 3H), 7.27 (d, J = 9.0 Hz, 2H), 7.22 (s, 1H), 7.09 (d,
J = 9.0 Hz, 2H), 3.92 (s, 3H), 2.43 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 159.6, 158.0, 148.9, 145.0, 141.1, 137.4, 132.1, 130.7,
130.5, 129.5, 129.3, 128.6, 128.3, 128.0, 125.2, 119.1, 114.0, 55.3,
21.9; IR (neat) 2358, 1526, 910 cm-1; HRMS (EI-TOF) calcd for
C23H18BrNO 403.0572, found 403.0574.
Hz, 1H), 7.75 (dd, J = 11.0, 4.0 Hz, 2H), 7.66–7.61 (m, 1H), 7.55 (m,
3H), 7.49–7.42 (m, 4H), 7.35 (d, J = 7.0 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 157.4, 150.0, 146.3, 142.5, 137.9, 134.0, 130.1, 129.7,
129.5, 129.3, 129.2, 128.9, 128.6, 128.6, 128.1, 127.8, 127.7, 126.5,
118.1; IR (neat) 2358, 1549, 912 cm-1; HRMS (EI-TOF) calcd for
C21H13BrClN 392.9920, found 392.9924.
3-bromo-2-(4-chlorophenyl)-4-phenylquinoline (3d): Pale yellow
solid, 67 mg, 85% yield; Mp 87−89 °C; 1H NMR (500 MHz, CDCl3) δ
8.16 (d, J = 8.0 Hz, 1H), 7.76–7.68 (m, 3H), 7.55 (m, 3H), 7.50–7.41
(m, 4H), 7.34 (d, J = 7.0 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ
157.7, 150.0, 146.4, 139.3, 138.0, 134.9, 131.0, 130.0, 129.6, 129.2,
128.6, 128.5, 128.3, 128.0, 127.6, 126.5, 118.2; IR (neat) 2360,
1611, 910 cm-1; HRMS (EI-TOF) calcd for C21H13BrClN 392.9920,
found 392.9923.
3-bromo-6-fluoro-2-(4-methoxyphenyl)-4-p-tolylquinoline
(3j):
Yellow solid, 67mg, 80% yield; Mp 80−82 °C; 1H NMR (500 MHz,
CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.21 (d, J
= 9.0 Hz, 2H), 7.19–7.13 (m, 2H), 7.09 (s, 1H), 6.87 (d, J = 9.0 Hz,
2H), 3.82 (s, 3H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 161.7
(J = 287 Hz), 160.3, 158.8, 146.2, 142.2, 131.8, 131.5, 130.4, 130.2,
129.6, 128.4, 122.0, 121.4 (J = 8 Hz), 115.2 (J = 21 Hz), 113.9,
113.7, 109.6, 55.4, 21.6; IR (neat) 3416, 1625, 1116 cm-1; HRMS
(EI-TOF) calcd for C23H17BrFNO 421.0478, found 421.0477.
3-bromo-2-(4-fluorophenyl)-4-phenylquinoline (3e): Pale yellow
solid, 61 mg, 81% yield; Mp 81−83 °C; 1H NMR (500 MHz, CDCl3) δ
8.16 (d, J = 8.0 Hz, 1H), 7.78–7.71 (m, 3H), 7.56 (m, 3H), 7.48–7.40
3-bromo-4-(4-chlorophenyl)-8-methyl-2-phenylquinoline
(3k):
Pale yellow oil, 59 mg, 72% yield; 1H NMR (500 MHz, CDCl3) δ
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
7.90–7.82 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 11.0, 7.0
Hz, 4H), 7.47 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 6.0 Hz, 3H), 2.82 (s,
3H), 2.80 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 158.9, 153.7, 146.0,
142.1, 140.9, 137.8, 134.7, 134.6, 131.3, 130.6, 130.4, 129.0, 128.0,
3H); 13C NMR (126 MHz, CDCl3) δ 155.9, 149.9, 145.5, 139.7, 138.6, 127.4, 127.3, 124.5, 97.6, 18.0; IR (neat) 2358, 1379, 1082 cm-1;
137.8, 134.7, 131.5, 131.4, 130.0, 129.3, 128.5, 128.4, 128.0, 127.3,
124.4, 117.9, 18.1; IR (neat) 2356, 1612, 913 cm-1; HRMS (EI-TOF)
calcd for C22H15BrClN 407.0076, found 407.0073.
HRMS (EI-TOF) calcd for C22H14Cl2IN 488.9548, found 488.9546.
4-(4-chlorophenyl)-3-iodo-2-(4-methoxyphenyl)-8-
methylquinoline (5d): Yellow solid, 75mg, 77% yield; Mp 82−84 °C;
1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz, 2H), 7.51–7.45 (m,
1H), 7.37 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 4.0 Hz, 2H), 7.10 (d, J =
9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 2.71 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 158.5, 157.8, 153.8, 145.0, 141.3, 136.5,
134.0, 133.5, 130.3, 129.4, 129.1, 126.9, 126.8, 126.0, 124.0, 112.9,
97.5, 54.3, 17.0; IR (neat) 2359, 1508, 1026 cm-1; HRMS (EI-TOF)
calcd for C23H17ClINO 485.0043, found 485.0041.
3-bromo-4-(4-chlorophenyl)-2-(4-methoxyphenyl)-8-
methylquinoline (3l): Yellow solid, 65 mg, 74% yield; Mp 66−68 °C;
1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.56 (d, J =
6.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.32 (q, J = 9.0 Hz, 2H), 7.26–
7.21 (m, 2H), 7.07 (d, J = 9.0 Hz, 2H), 3.91 (s, 3H), 2.81 (s, 3H); 13
C
NMR (126 MHz, CDCl3) δ 159.6, 155.9, 149.8, 145.5, 139.8, 137.7,
134.7, 131.4, 130.8, 130.6, 129.9, 128.4, 128.0, 127.2, 124.6, 118.5,
113.9, 55.3, 18.1; IR (neat) 2362, 1608, 905 cm-1; HRMS (EI-TOF)
calcd for C23H17BrClNO 437.0182, found 437.0185.
6-fluoro-3-iodo-4-phenyl-2-p-tolylquinoline (5e): Yellow solid, 63
mg, 72% yield; Mp 99−101 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (dd,
J = 9.0, 6.0 Hz, 1H), 7.61–7.53 (m, 5H), 7.51–7.45 (m, 1H), 7.34–
7.27 (m, 4H), 7.03 (dd, J = 10.0, 3.0 Hz, 1H), 2.45 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 161.3, 160.7 (J = 248 Hz), 154.1 (J = 6 Hz),
144.1, 141.8, 140.6, 138.6, 131.9 (J = 10 Hz), 129.2, 129.0, 128.8,
128.7, 128.6, 127.9 (J = 8 Hz), 120.3 (J = 25 Hz), 110.3 (J = 22 Hz),
100.0, 21.5; IR (neat) 3416, 1512, 1184 cm-1; HRMS (EI-TOF) calcd
for C22H15FIN 439.0233, found 439.0234.
3-bromo-4-cyclopropyl-2-phenylquinoline (3m): Amorphous solid,
1
50 mg, 77% yield; H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 9.0 Hz,
1H), 8.12 (d, J = 8.0 Hz, 1H), 7.74–7.68 (m, 1H), 7.65 (dd, J = 8.0,
1.0 Hz, 2H), 7.61–7.55 (m, 1H), 7.47 (m, 3H), 2.13 (m, 1H), 1.45–
1.39 (m, 2H), 0.92 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 159.2,
148.1, 146.4, 141.2, 130.1, 129.4, 129.3, 129.1, 128.5, 128.0, 126.7,
124.6, 122.2, 15.0, 10.1; IR (neat) 2360, 1615, 916 cm-1; HRMS (EI-
TOF) calcd for C18H14BrN 323.0310, found 323.0313.
3-iodo-4-phenyl-2-(thiophen-2-yl)quinoline (5f): Amorphous solid,
1
3-bromo-2-(4-chlorophenyl)-4-cyclopropyl-6-methylquinoline
(3n): Pale yellow oil, 54 mg, 73% yield; 1H NMR (500 MHz, CDCl3) δ
8.28 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 18.0, 8.0 Hz, 3H),
7.45 (d, J = 8.0 Hz, 2H), 2.60 (s, 3H), 2.15–2.05 (m, 1H), 1.46–1.38
(m, 2H), 0.93–0.87 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 156.8,
147.9, 144.6, 137.1, 134.7, 132.0, 131.0, 129.5, 129.2, 128.2, 123.5,
121.8, 22.2, 14.9, 10.2; IR (neat) 2356, 1612, 913 cm-1; HRMS (EI-
TOF) calcd for C19H15BrClN 371.0076, found 371.0077.
65 mg, 79% yield; H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz,
1H), 7.89 (d, J = 3.0 Hz, 1H), 7.71 (dd, J = 11.0, 4.0 Hz, 1H), 7.59–
7.53 (m, 3H), 7.51 (d, J = 5.0 Hz, 1H), 7.36 (dd, J = 13.0, 7.0 Hz, 2H),
7.30–7.26 (m, 2H), 7.15 (dd, J = 5.0, 4.0 Hz, 1H); 13C NMR (126
MHz, CDCl3) δ 155.5, 154.5, 146.8, 145.2, 142.5, 130.3, 130.1,
129.2, 129.1, 128.7, 128.5, 128.1, 127.4, 127.3, 126.9, 126.8, 97.3;
IR (neat) 2358, 1526, 912 cm-1; HRMS (EI-TOF) calcd for C19H12INS
412.9735, found 412.9731.
3-iodo-6-methyl-2,4-diphenylquinoline (5a): Yellow solid, 60 mg,
2-tert-butyl-4-cyclopropyl-3-iodoquinoline (5g): Amorphous solid,
1
1
71% yield; Mp 83−85 °C; H NMR (500 MHz, CDCl3) δ 8.06 (d, J =
44mg, 63% yield; H NMR (500 MHz, CDCl3) δ 8.42 (d, J = 9.0 Hz,
9.0 Hz, 1H), 7.64 (d, J = 7.0 Hz, 2H), 7.59–7.52 (m, 4H), 7.50–7.43
(m, 3H), 7.28 (d, J = 7.0 Hz, 2H), 7.14 (s, 1H), 2.40 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 161.0, 154.0, 145.5, 143.8, 142.4, 137.4, 132.4,
129.4, 129.2, 129.1, 128.7, 128.5, 128.4, 128.0, 127.4, 125.6, 98.6,
21.8; IR (neat) 2358, 1535, 1084 cm-1; HRMS (EI-TOF) calcd for
C22H16IN 421.0327, found 421.0325.
1H), 7.99 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0
Hz, 1H), 2.11–2.01 (m, 1H), 1.72 (s, 9H), 1.49–1.43 (m, 2H), 0.77 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 165.2, 152.7, 145.5, 129.7, 128.9,
128.1, 125.8, 124.1, 99.4, 41.3, 30.1, 21.1, 12.9, 8.7; IR (neat) 2358,
1532, 935 cm-1; HRMS (EI-TOF) calcd for C16H18IN 351.0484, found
351.0487.
3-iodo-4-(4-methoxyphenyl)-6-methyl-2-phenylquinoline
(5b):
1-cyclopropyl-2-iodo-3-phenylbenzo[f]quinoline (5h): Yellow
solid, 56 mg, 66% yield; Mp 103−105 °C; 1H NMR (500 MHz, CDCl3)
δ 9.29 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 7.86 (d, J = 7.0
Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 7.0 Hz, 2H), 7.68–7.59
(m, 2H), 7.50 (dd, J = 15.0, 7.0 Hz, 3H), 2.22–2.07 (m, 1H), 1.49 (m,
2H), 0.88 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 160.6, 152.0, 145.3,
144.2, 133.3, 131.6, 130.0, 128.4, 128.3, 127.7, 127.6, 127.5, 127.0,
126.6, 125.2, 121.9, 102.3, 20.0, 12.1; IR (neat) 2358, 11503, 909
cm-1; HRMS (EI-TOF) calcd for C22H16IN 421.0327, found 421.0325.
1
Yellow solid, 67 mg, 74% yield; Mp 96−98 °C; H NMR (500 MHz,
CDCl3) δ 8.04 (d, J = 9.0 Hz, 1H), 7.66–7.59 (m, 2H), 7.52 (dd, J =
9.0, 2.0 Hz, 1H), 7.49–7.38 (m, 3H), 7.20 (t, J = 7.0 Hz, 3H), 7.06 (d,
J = 9.0 Hz, 2H), 3.88 (s, 3H), 2.39 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 161.0, 159.6, 153.9, 145.6, 144.0, 137.3, 134.7, 132.4,
130.5, 129.4, 129.2, 128.5, 128.0, 127.8, 125.7, 114.1, 99.6, 55.4,
21.9; IR (neat) 2359, 1612, 910 cm-1; HRMS (EI-TOF) calcd for
C23H18INO 451.0433, found 451.0431.
2,4-bis(4-chlorophenyl)-3-iodo-8-methylquinoline (5c): Yellow
solid, 67 mg, 68% yield; Mp 85−87 °C; 1H NMR (500 MHz, CDCl3) δ
7.68 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 8.0 Hz,
2H), 7.46 (d, J = 8.0 Hz, 2H), 7.34–7.28 (m, 1H), 7.21 (d, J = 8.0 Hz,
4-chlorophenyl 6-methyl-2,4-diphenylquinoline-3-carboxylate (6):
Pale yellow oil, 58 mg, 65% yield; 1H NMR (500 MHz, CDCl3) δ 8.02
(d, J = 9.0 Hz, 2H), 7.59 (q, J = 8.0 Hz, 6H), 7.44 (t, J = 9.0 Hz, 2H),
7.36 (t, J = 7.0 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 6.51 (d, J = 10.0 Hz,
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10.1002/ejoc.201901395
European Journal of Organic Chemistry
COMMUNICATION
2H), 6.40 (d, J = 10.0 Hz, 2H), 2.35 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 161.5, 149.3, 143.2, 139.2, 133.6, 132.0, 131.3, 130.9,
130.8, 130.0, 129.8, 128.8, 128.7, 127.7, 127.6, 127.5, 127.1, 126.5,
125.3, 124.8, 120.3, 21.6; IR (neat) 3415, 1516, 1182 cm-1; HRMS
(EI-TOF) calcd for C29H20ClNO2 449.1183, found 449.1185.
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Acknowledgements
This work was supported by the Natural Science Foundation of
Shandong Province (No. ZR2018BB029, No. ZR2019PB004), and
National Natural Science Foundation of China (21772067).
Conflict of interest
The authors declare no conflict of interest.
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Regioselective halogenation*
Dianpeng Chen,* Jianming Li, Peiying
Cui, Yingying Shan,* Yutong Zhao, and
Guanyinsheng Qiu*
Tandem Oxidative Radical
Halogenated Addition of Alkynyl
Imines: Regioselective Synthesis of
3-Haloquinolines
Text for Table of Contents (about 350 characters)
A tandem oxidative radical halogenated addition of alkynyl imines for regioselective synthesis of 3-haloquinolines was described. In
this process, it is believed that the oxidation of halogen, 6-endo-trig cyclization and aromatization were involved in the process. With
the advantages of simple operation, mild conditions and useful products, this protocol should be of great significance not only for
laboratory synthesis but also helpful for industrial production.
*Halogen Radical
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