Old and new Aryne precursor, anthranilic acid: Multicomponent reaction of benzyne with quinolines or imines and pronucleophiles

Article abstract of DOI:10.1246/cl.190944

An operationally simple one-pot protocol for the synthesis of a variety of trichloromethylated tertiary amines from anthranilic acid, imines, and chloroform was achieved. This reaction proceeds via in situ imine formation followed by the addition of benzyne prepared from anthranilic acid with concomitant proton abstraction from chloroform. By employing this method, a series of β-trichloromethylated anilines were synthesized in moderate to good yields in gram scale. Basic hydrolysis of trichloromethylated dihydoquinoline gave dichloromethylene-1-phenylquinoline in quantitative yield.

Full text of DOI:10.1246/cl.190944

Advance Publication Cover Page
Old and New Aryne Precursor, Anthranilic Acid: Multicomponent Reaction of Benzyne with
Quinolines or Imines and Pronucleophiles
Kentaro Okuma,* Yuxuan Qu, Nonoka Fujiie, and Noriyoshi Nagahora
Advance Publication on the web February 20, 2020
doi:10.1246/cl.190944
© 2020 The Chemical Society of Japan
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1
Old and NewAryne Precursor, AnthranilicAcid: Multicomponent Reaction of Benzyne with
Quinolines or Imines and Pronucleophiles
Kentaro Okuma,* Yuxuan Qu, Nonoka Fujiie, and Noriyoshi Nagahora
Department of Chemistry, Fukuoka University, Jonan-ku, Fukuoka 814-0180
E-mail: kokuma@fukuoka-u.ac.jp
1
2
3
4
5
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7
8
9
An operationally simple and one-pot protocol for the
synthesis of a variety of trichloromethylated tertiary amines
from anthranilic acid, imines, and chloroform was achieved.
This reaction proceeds via in situ imine formation followed
by the addition of benzyne prepared from anthranilic acid
with concomitant proton abstraction of chloroform. By
employing this method, a series of -trichloromethylated
anilines were synthesized in moderate to good yields with
gram scale.
Basic hydrolysis of trichloromethylated
10 dihydoquinoline gave dichloromethylene-1-phenylquinoline
11 in quantitative yield.
12 Keywords: Benzyne, Imine, Multicomponent reaction
13
.
14
Arynes are one of the oldest, most interesting and
50
15 useful intermediates, and powerful reactive electrophiles that
16 have received great attention for the formation of conjugated
17 heterocycles via intramolecular cycloaddition.1 Recent
18 progress of aryne chemistry is mainly due to the aryne
19 precursor, 2-(trimethylsilyl)phenyl triflate (triflate), which
51 Figure 1. Three-component reaction of triflate, imines,
52 and chloroform
53
54
Anthranilic acid 1a, a typical benzyne precursor, is
55 well known to react with dienes in the presence of alky nitrite
56 to afford the corresponding Diels-Alder adducts in moderate
57 yields.7 [2+2] or [4+2] Cycloaddition reactions of benzyne
58 derived from benzenediazonium 2-carboxylate with imines
59 were reported: [4+2] cycloaddition of benzyne with
o
o
20 produces benzyne under mild conditions (0 C to 80 C,
21 neutral conditions).2 This reagent has some advantages on
22 the formation of arynes compared to typical benzyne
23 precursors such as aryl halides, ortho-dihalobenzenes, and
24 diphenyliodonium carboxylate, which generally required
25 harsh reaction conditions (elevated reaction temperature or
26 use of strong base).1 Due to the low-lying LUMO of benzyne,
27 the neutral nucleophiles add to benzyne generating
28 zwitterions, which are reactive toward the electrophiles or
29 pronucleophiles. For example, Hu et al., Biju et al. and Tan
30 et al. have reported three-component reaction of aryne
31 derived from triflate with quinolines and pronucleophiles to
32 give the corresponding three-component products.3 Three-
33 component reactions of arynes with imines, and
34 pronucleophiles (chloroform, acetonitrile, terminal alkynes)
35 to afford the corresponding tertiary anilines were also
36 reported by Tian and coworkers (Figure 1).4 We have also
37 reported the three-component reaction of arynes with cyclic
38 ethers or imines, and chloroform to afford the corresponding
39 terminal trichloroalkyl phenyl ethers and amines.5 Generally,
40 these reactions were performed within 1 mmol scale due to
41 the use of expensive triflate derivatives. For this reason, there
42 is no report on the large scale synthesis of three-component
43 reaction. Additionally, fluoride salts such as CsF, KF, and
44 TBAF must be required for the formation of benzyne, which
45 have to remove inorganic byproducts as waste materials that
46 are difficult to recycle. In some cases, 18-crown-6 would be
47 required to solubilize these fluoride sources.6 Therefore, the
48 development of a simple, inexpensive, and readily available
49 reagent would extend the scope of this transformation.
60 benzylideneanilines by Nakayama et al.,8
[2+2]
61 cycloaddition of benzyne with benzylideneanilines by Singal
62 and Kaur,9 and [4+2] reaction of benzyne with in situ formed
63 benzylideneanilines by Shou et al. (Figure 2).10 However,
64 there are relatively few reports on the multicomponent
65 reaction of benzyne starting from anthranilic acid
66 derivatives.11,12 These results prompted us to investigate
67 the multi-component reaction of several imines containing
68 quinoline derivatives with in situ formed benzyne from
69 anthranilic acid and isoamyl nitrite and pronucleophiles
70 whether gram scale synthesis of multi-component
71 products would be accomplished.
Since isolated
72 benzenediazonium 2-carboxylate decomposes explosively
73 on being heated or scraped against a hard surface,13 we
74 have tried the thermal reaction of in situ formed
75 benzenediazonium 2-carboxylate with imines, and
76 chloroform.
77
Three-component reaction products were obtained by
78 the reaction of benzyne prepared from triflate with imines and
79 chloroform4, whereas, benzylideneaniline 2 react with
80 benzyne prepared from benzenediazonium 2-carboxylate to
81 give [4+2] and [2+2] cyloadducts.8-10 Thus, we first tried the
82 reaction of benzylideneaniline 2 with in situ formed
83 benzenediazonium 2-carboxylate in chloroform whether
84 three-component reaction or [4+2] cycloaddition would
85 proceed.

2
25
We then tried the reaction of quinoline 4 with
26 anthranilic acid and chloroform in the presence of isoamyl
27 nitrite whether the corresponding three-component products
28 would be formed. Recently, Tan et al. have found that three-
29 component products were obtained by the reaction of
30 quinolines 4 with triflate and chloroform, whereas only 0.15
31 mmol scale reaction was performed.14 Treatment of
32 anthranilic acid 1a in dioxane with quinoline 4a and isoamyl
33 nitrite in refluxing chloroform resulted in the formation of 2-
34 trichloromethyl-1-phenyl-1,2-dihydroquinoline 5a in 89%
35 yield. (Scheme 2). Other heterocyclic compounds such as
36 isoquinoline also reacted with benzyne and chloroform to
37 give three-component products 5b-5d in good yields
38 (Scheme 2).
39
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Figure 2．Cycloaddition of benzyne derived from
anthranilic acid with benzylideneanilines and this work
Treatment of anthranilic acid 1a with 4,4’-
dimethoxybenzylideneaniline 2a and isoamyl nitrite in
refluxing chloroform resulted in the formation of 4-methoxy-
N-phenyl-N-2,2,2-trichloro-1-(4-methoxyphenyl)ethyl-
40
41
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43
Reaction conditions: 1a (5 mmol) in dioxane (5 mL), quinoline 4 (3
10 aniline 3a in 21% yield. 4-Anisaldehyde (25%) and 4-
11 anisidine (22%) along with unreacted 2a (15%) were
12 obtained as byproducts, which suggested that in situ formed
13 water prevent the reaction to complete. When molecular
14 sieves 4A (MS4A) was added to the solution, aniline 3a was
15 obtained in 51% yield, which clearly shows that not
16 cycloaddition but three-component reaction proceeded
17 preferentially under these conditions (Scheme 1). Although
18 the yield of 3a is moderate, compound 1a found to be a useful
19 and inexpensive precursor for aryne mediated three-
20 component reaction.
mmol), MS4A, and chloroform (7 mL), reflux 1 h.
44 Scheme 2. Reaction of quinoline 4 with benzyne prepared
45 from anthranilic acid 1a and chloroform
46
47
We switched the focus of our investigation to the four-
48 component reaction of primary amines, aromatic aldehydes,
49 with anthranilic acid and chloroform in the presence of
50 isoamyl nitrite. In situ formation of imines by the reaction of
51 primary amines with aldehydes were already reported.4, 15
52 Treatment of MS4A and in situ formed imines from
53 methylamine 6a and p-methylbenzaldehyde 7a with isoamyl
54 nitrite followed by the addition of anthranilic acid 1a in
55 refluxing chloroform gave the corresponding four-
56 component product 3b in 75% yield (Table 1, Entry 1). When
57 p-methoxybenzaldehyde 7b was used, a similar yield of 3c
58 was obtained in 73% (Entry 2). When butylamine 6b was
59 used as a primary amine, the four-component products 3d and
60 3e were obtained in moderate yields (Entry 3 and 4). Allyl
61 amine 6c gave moderate yields of products (Entry 5-6).
62 Benzylamine 6d gave much better yields of products 3h and
63 3i (Entry 7-8), whereas aromatic aldehydes with electron
64 withdrawing groups at para position gave lower yields of
65 products (Entry 10-12). The present reaction has a broad
66 scope, and various primary amines and aromatic aldehydes
67 can be converted very efficiently into the corresponding
68 trichloromethylated tertiary anilines 3.
21
22
23 Scheme 1. Reaction of 2 with benzyne prepared from
24 anthranilic acid 1a in chloroform
69

3
1
2
3
4
Table 1. Four-component reaction of primary amines 6 with
aldehydes 7 followed by the addition of anthranilic acid 1a
in refluxing chloroform
29
30 Scheme 4. Four-component reaction of benzyne with
31 methylamine, aldehyde, and carbon tetrachloride
32
33
To confirm substituted anthranilic acid also play as aryne
34 precursor, we then tried the reaction of 2-amino-4,5-
35 dimethoxybenzoic acid 1b with 3-bromoquinoline in the
36 presence of isoamyl nitrite was carried out. When a solution
37 of anthranilic acid 1b in dioxane was added to a refluxing
38 solution of 3-bromoquinoline and isoamyl nitrite in
39 chloroform
for
overnight,
3-bromo-1-(3’,4’-
40 dimethoxyphenyl)-2-trichloromethyl-1,2-dihydroquinoline
41 5e was obtained in 45% yield (Scheme 5).
42
5
6
7
8
9
To confirm benzyne insertion to carbon-hydrogen bond
of chloroform, the reaction of methylamine 6a with p-
methoxybenzaldehyde 7b in chloroform-d followed by the
43
44
Scheme 5. Reaction of quinoline 4b with benzyne
10 addition of anthranilic acid 1a in the presence of isoamyl
11 nitrite was carried out. As expected, 93% of deuterated 3c-d
12 was isolated (Scheme 3).
45 prepared from anthranilic acid 1b and chloroform
46
47
To further demonstrate the practical utilization of this
48 newly developed methodology, multi-gram scale reaction of
49 3-bromoquinoline 4b with anthranilic acid and isoamyl nitrite
50 in chloroform by using 30 mmol of anthranilic acid, quinoline
51 4b (15 mmol), and chloroform was performed, which
52 resulted in the isolation of three-component product 5b
53 without any chromatographic separation in 74% (4.46 g, 11.1
54 mmol). Work-up process was simple; after finishing the
55 reaction, the filtered solution was concentrated and added a
56 small amount of methanol to give precipitated products.
57 Separation of the precipitate afforded almost pure three-
58 component product 5b. Previous reports on the three-
59 component reaction by using triflate were generally
60 performed under 1 mmol scales.3-4,6 The obtained products
61 would not be applied to the starting materials for further
62 reaction.
13
14 Scheme 3. Reaction of 6a with 7b followed by the addition
15 of anthranilic acid 1a in refluxing chloroform-d.
16
17
Recently, Yu et al. have extended this reaction to the
18 synthesis of ortho-chloroaniline derivatives by using carbon
19 tetrachloride instead of chloroform, which are useful
20 precursors for pharmaceutical products.16 We have also
21 applied this reaction to the synthesis of ortho-chlorinated
22 phenylation. Treatment of in situ formed imine and isoamyl
23 nitrite with anthranilic acid in refluxing carbon tetrachloride
24 resulted in the formation of 2-chlorophenyl derivatives 8a
25 and 8b in 79 % and 68 % yields, respectively (Scheme 4).
26 However, when acetonitrile and bromoform were used as
27 pronucleophiles, the corresponding three component
28 products were not obtained.
63
Since large scale synthesis of trichloromethylated
64 quinoline 5b was accomplished, the reaction of 5b with base
65 was tried. Hydrolysis by KOH in dioxane gave 2-
66 (dichloromethylene)-1-phenyl-3-bromo-1,2-dihydro-
67 quinoline 9 in almost quantitative yield. Treatment of 5b
68 with DBU in CH2Cl2 at rt or 24h gave the same product 9 in
69 95% yield. Reaction of 9 with methanol gave the
70 corresponding adduct 10 in quantitative yield (Scheme 6).
71 The structures of 9 and10 were determined by spectroscopic
72 analysis.

4
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9
K. K. Singal, J. Kaur, Synth. Commun. 2001, 31, 2809.
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10 W. -G. Shou, Y. -Y. Yang, Y. -G. Wang, J. Org. Chem. 2006, 71,
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69
2
3
Scheme 6. Reaction of 5b with KOH in dioxane
4
5
6
7
8
9
In conclusion, the first multi-component reaction of in
situ formed benzyne with imines and pronucleophiles was
successfully developed with the assistance of anthranilic acid
as a starting benzyne precursor. In situ formed imines also
reacted with benzyne to give the corresponding four-
10 component products. Multi-gram scale synthesis was
11 successfully accomplished and applied in the facile
12 construction
of
2-(dichloromethylene)-1-phenyl-1,2-
13 dihydro-quinoline.
14
15 References and Notes
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