2.1. Heteroarylzinc reagents
In general, the preparation of 2-pyridyl organometallics is mostly performed by lithiation of 2-halo-pyridine under cryogenic conditions followed by transmetallation with an appropriate metal halide. As mentioned above, this procedure imposes some limitations on the use of the 2-pyridyl organometallics. Treatment of readily available 2-bromopyridine with the active zinc gave the corresponding organozinc reagent. The oxidative addition of the active zinc to carbon-bromine bond was completed in an hour at refluxing temperature to give rise to the corresponding 2-pyridylzinc bromide (P1).
In order to investigate the reactivity of the 2-pyridylzinc bromide, it was treated with benzoyl chlorides. As summarized in
Table 1, the coupling ketone products were obtained in moderate yields. It should be emphasized that the coupling reaction with acid chlorides was carried out in the absence of any transition metal catalyst under mild conditions. Generally, a copper catalyst is widely used for the coupling reactions of organozinc reagents [
61]. Halobenzoyl chlorides were easily coupled with 2-pyridylzinc bromide (
P1) at rt to give the corresponding ketones (
1a,
1b,
1c,
1d and
1e,
Table 1) in moderate yields. Both benzoyl chlorides containing an electron-withdrawing group (CN and NO
2) and an electron-donating group (Me and MeO) also successfully afforded the corresponding ketones(
1f,
1g,
1h, and
1i,
Table 1). Even with nitrobenzoyl chloride, ketone (
1j,
Table 1) was obtained in moderate yield.
Table 1.
Coupling reaction with benzoyl chlorides. a
Table 1.
Coupling reaction with benzoyl chlorides. a
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More results obtained from the catalyst-free coupling reactions are shown in
Table 2. Treatment of
P1 with chloronicotinoyl chlorides and alkyl carbonyl chlorides provided the corresponding ketones. This result is particularly significant considering the fact that Fridel-Craft acylation can be accomplished on the pyridine ring.
Together with these results, the Pd-catalyzed C-C bond forming reaction of P1 was also explored. Even though 2-pyridylaryl derivatives were successfully prepared via the aforementioned direct arylation methods, relatively harsh conditions (excess amount of reactant, high temperature, protection/deprotection step and addition of additives) were required in these studies.
Prior to the Pd-catalyzed coupling reaction with a variety of arylhalides, an effort was executed to find out any effect of substitutents on the cross-coupling reactions. In general, good yields (entries 1, 3, and 4,
Table 1) were obtained from using 2-pyridylzinc bromide (
P1), 4-methyl-2-pyridylzinc bromide (
P3), and 5-methyl-2-pyridylzinc bromide (
P4).
Table 2.
Coupling reaction with acid chlorides. a
Table 2.
Coupling reaction with acid chlorides. a
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3-Methyl-2-pyridylzinc bromide (
P2), 6-methyl-2-pyridylzinc bromide (
P5), and 6-methoxy-2-pyridylzinc bromide (
P6) resulted in moderate yields (entries 2, 5, and 6,
Table 3).
Table 3.
Study of substitutent effect.
Table 3.
Study of substitutent effect.
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Entry | X | Product, X | Yield(%)a |
---|
1 | H(P1) | H (3a) | 85 |
2 | 3-CH3(P2) | 3-CH3 (3b) | 58 |
3 | 4-CH3(P3) | 4-CH3 (3c) | 77 |
4 | 5-CH3(P4) | 5-CH3 (3d) | 79 |
5 | 6-CH3(P5) | 6-CH3 (3e) | 57 |
6 | 6-OCH3(P6) | 6-OCH3 (3f) | 54 |
Additional studies have been performed to investigate the steric effect on cross-coupling reactions using 2-pyridylzinc bromides (
P2 and
P4). As shown in
Table 4, the effects of steric hindrance (76%
vs. 89%, 51%
vs. 84% isolated yield) were clearly observed from the coupling reactions with 5-bromofuran-2-carboxylic acid ethyl ester and 5-bromothiophene-2-carboxylic acid ethyl ester (entries 1, 2 and 3, 4,
Table 4), respectively. The results demonstrate that the steric bulk around the reaction site reduces the coupling ability of the corresponding organozinc reagents.
Table 4.
Steric effect on cross-coupling reaction.
Table 4.
Steric effect on cross-coupling reaction.
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With the preliminary results, this methodology was expanded to coupling reactions with a variety of haloaromatic compounds. The results are described in
Table 5. Interestingly, the mild conditions worked well allowing the coupling reactions of 2-pyridylzinc bromide (
P1) to go to completion. As shown in
Table 5, several different types of functionalized aryl halides and heteroaryl halides were coupled with
P1 in the presence of 1 mol% of Pd[P(Ph)
3]
4 at room temperature in THF.
More interesting materials were prepared by the coupling reaction of various 2-pyridylzinc bromides with halo heterocyclic derivatives and the results are summarized in
Table 6. A selective C-C bond forming occurred in the reactions with 2-bromo-3-hexyl-5-iodothiophene and 2-bromo-5-chlorothiophene. A slightly longer reaction time was required to complete the coupling reaction with 2-bromothiazole and 2-bromoquinoline with 4-methyl-2-pyridylzinc bromide (entries 2 and 3,
Table 6). Significantly, another selective C-C bond forming was achieved from the coupling reaction with symmetrically substituted thiophene, 2,5-dibromothiophene (entry 5,
Table 6). The resulting product,
6e, could be used for further application. Even though a little bit different reaction conditions (Pd-II catalyst and refluxing temperature) was applied to carry out the coupling reactions with dibromothiophenes, symmetrically disubstituted thiophene derivatives (
6g and
6h) were easily prepared by its 2-fold reaction (entries 7 and 8,
Table 6). These types of linear oligomers are important materials for optoelectronic device applications [
62].
Bipyridines are very important moiety for natural product as well as other material chemistry. For example, caerulomycins and collismycins contain pyridine unit as a key material [
63]. Therefore, it is worth to demonstrate to make these compounds by utilizing 2-pyridylzinc bromides used in this study.
Table 5.
Pd-catalyzed coupling of P1 with arylhalide.
Table 5.
Pd-catalyzed coupling of P1 with arylhalide.
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As described in
Table 7, not only symmetrical 2,2’-bipyridine (
7a) but several different types of unsymmetrical 2,2’-bipyridines
7b-7h were prepared in moderate yields. The preparation of bipyridines using readily available 2-pyridylzinc bromides
P1 ~
P6 could be a very practical approach because considerable effort has been directed toward the preparation of unsymmetrical 2,2’-bipyridines.
Scheme 1 shows two examples. 2,3-bipyridine (
s1a) was prepared by the coupling reaction of
P6 with in the presence of Pd(PPh
3)
4 in THF at refluxing temperature affording the coupling product in 64% isolated yield (route
A,
Scheme 1). Under the similar conditions, 2,2’-bipyridine (
s1b) was formed in moderate yield by Pd(0)-catalyzed cross-coupling reaction of
P1 (route
B,
Scheme 1). As described in
Scheme 1, further applications of
s1a and
s1b could result in the formation of interesting natural products.
Table 6.
More coupling reactions of 2-pyridylzincs with heteroaryl halides.
Table 6.
More coupling reactions of 2-pyridylzincs with heteroaryl halides.
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Table 7.
Preparation of 2,2’-bipyridinesa.
Table 7.
Preparation of 2,2’-bipyridinesa.
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Scheme 1.
Preparation of intermediates.
Scheme 1.
Preparation of intermediates.
Most of the electrophiles used in the transition metal-catalyzed cross-coupling reactions of 2-pyridylmetallics contain functional groups that are relatively non-reactive toward organometallics, such as ester, ketone, nitrile, halogen, and ether. For the preparation of a variety of 2-pyridyl derivatives, highly functionalized electrophiles are necessary as the coupling partner in the reactions. To this end, haloaromatic amines, phenols and alcohols are reasonable coupling reactant candidates. By utilizing this strategy, 2-substituted aminophenyl and hydroxyphenyl pyridines have been successfully prepared under mild conditions. Since Pd(II)-catalysts along with an appropriate ligand have been used in the coupling reactions of organozinc reagents with haloaromatic amines and alcohols [
64], it seemed reasonable to try these conditions. The coupling reactions worked well with 2-pyridylzinc bromide (
1a) and the results are summarized in
Table 8.
Methyl substituted 2-pyridylzinc bromide (
P3) with 4-iodoaniline and
P1 with 4-bromoaniline resulted in relatively low yields (entries 2, 3,
Table 8). However, a significantly improved yield was obtained by a simple change in reaction temperature (entry 4,
Table 8). An elevated reaction temperature also worked well for the reaction of
P3 with 3-iodoaniline leading
8c in 85% isolated yield (entry 5,
Table 8). As described in the previous report [
61,
62,
63,
64], the extra ligand (SPhos) was critical for the completion of the coupling reaction.
Table 8.
Coupling reaction with haloaromatic amines.
Table 8.
Coupling reaction with haloaromatic amines.
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Even though similar conditions as in the previous works [
64,
65,
66,
67] were used, it should be emphasized that a more practical procedure, especially for the large scale synthesis, has been demonstrated in this study. For example, the organozinc solution was added into the flask containing Pd(II)-catalyst, ligand (SPhos) and electrophile at a steady-stream rate at rt. According to Knochel’s report, a very slow addition of organozinc reagent into the reaction flask was crucial in order to obtain high yields [
68].
As mentioned above, the extra ligand (SPhos) was necessary when using the Pd(II)-catalysts for the coupling reactions. From an economic point of view as well as ease of work-up, a ligand-free reaction conditions would be highly beneficial. Thus the SPhos-free Pd-catalyzed coupling reactions of 2-pyridylzinc bromides with haloanilines were performed by employing a Pd(0)-catalyst and the results are summarized in
Table 8. Significantly, the Pd(0)-catalyzed coupling reactions were not affected by the presence of acidic protons (NH
2) [
69].
The reaction of
P1 with 4-iodoaniline in the presence of 1 mol% Pd[P(Ph)
3]
4 provided 2-(4-amino-phenyl)pyridine (
8a) with a compatible result (entry 6,
Table 8). Unfortunately, no satisfactory coupling reaction occurred with 4-bromoaniline using the Pd(0)-catalyst (entry 10,
Table 8). With the results obtained from the coupling reactions with haloaromatic amines, it can be concluded that Pd(0)-catalyzed reaction of 2-pyridylzinc bromides works effectively with iodoaromatic amines and also the relatively more reactive bromoaromatic amines.
Another interesting reaction of 2-pyridylzinc bromides would be the coupling reaction with phenols or alcohols, which also have an acidic proton. As shown in
Table 9, 4-iodophenol and 3-iodophenol were coupled with
P1 affording the corresponding hydroxyphenylpyridine products
9a and
9b in excellent yields (entries 1 and 2,
Table 9). A slightly disappointing result (25%) was obtained from 2-iodophenol (entry 3,
Table 9). The reason for this is not clear, but it is presumably because the coupling position was next to the hydroxy group. A similar outcome has also been reported in another study [
65]. In the case of bromophenolic alcohols, no coupling reaction took place with the Pd(0)-catalyst. Instead, the Pd(II)-catalyst was more efficient for the coupling reaction. Unlike the reactions with bromophenols, it is of interest that the coupling products (
9f and
9g) of
P5 and
P1 were efficiently achieved from the Pd(0)-catalyzed reactions with 4-bromobenzyl alcohol and 3-bromo-5-methoxybenzyl alcohol (entries 7 and 8,
Table 9), respectively.
Interestingly, unsymmetrical aminobipyridines were produced from the coupling reactions of 2-pyridylzinc bromides with halogenated aminopyridines under the conditions used above. As shown in
Scheme 2, 2-amino-5-iodopyridine reacted with
P1 to afford 2,3-bipyridine (
s2a) in 59% isolated yield in the presence of 1 mol% of Pd[P(Ph)
3]
4 catalyst (route A,
Scheme 2). However, in the case of 2-amino-5-bromopyridine, the Pd(II)-catalyst was more efficient for the coupling reaction and the reaction proceeded smoothly to give 2,3-bipyridine (
s2b, route
B,
Scheme 2). It is of interest that the bipyridylamines can be used as intermediates for the synthesis of highly functionalized molecules after transformation of the amino group to a halogen [
70].
Treatment of 2-pyridylzinc bromide (
P1) with a halopyridine bearing a hydroxyl group provided another functionalized bipyridine. Interestingly, the relatively reactive bromopyridyl alcohol, 2-bromo-5-hydroxypyridine, was coupled with
P1 using Pd(0)-catalyst. The hydroxyl group on 2,2’-bipyridine can also be converted to halogen to make halobipyridines using several different methods [
71].
Table 9.
Coupling reactions with haloaromatic alcohols.
Table 9.
Coupling reactions with haloaromatic alcohols.
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Scheme 2.
Preparation of amino and hydroxyl bipyridines.
Scheme 2.
Preparation of amino and hydroxyl bipyridines.
It has also been found that Rieke zinc in the presence of certain additives exhibits a very high reactivity towards 3-bromopyridine. The corresponding 3-pyridylzinc bromide was easily prepared by the direct insertion of active zinc and the resulting 3-pyridylzinc bromide was successfully applied to the cross-coupling reaction with a variety of electrophiles under mild conditions.
The first attempt to synthesize 3-pyridylzinc bromide from the direct reaction of active zinc and 3-bromopyridine in THF at either rt or refluxing temperature resulted in low conversion to the desired organozinc reagent. Almost the same result was obtained after an extended reaction time (reflux/24h). However, a dramatic improvement in the oxidative addition of active zinc has been achieved by adding 10–20 mol% of lithium chloride to the reaction mixture. Even though the role of lithium chloride has not been totally explained, more than 99% conversion of 3-bromopyridine to 3-pyridylzinc bromide was obtained in 2h at refluxing temperature in THF. As was pointed out in 1989, the rate limiting step in the oxidative addition is electron transfer [
72]. Accordingly, this process will be accelerated by the presence of alkali salts which are generated in the reduction process of forming the active metals or additional salts can be added to the reaction mixture [
61].
In order to confirm the formation of 3-pyridylzinc bromide, the resulting organozinc reagent was first treated with iodine, affording 90% 3-iodopyridine and 3% pyridine. The resulting 3-pyridylzinc bromide (
P7) was added to a variety of different electrophiles to give the corresponding coupling products in moderate to good yields. The results are summarized in
Table 10. Palladium catalyzed cross-coupling reactions with aryl iodides (
a ~
c,
Table 10) were completed in 1h at rt to give 3-pyridylbenzene derivatives
10a,
10b, and
10c in good yields (entries 1 ~ 3,
Table 10). A longer reaction time was required with aryl iodides
d and
e, bearing a substitutent in the 2-position (entries 4 and 5,
Table 10). This is probably due to steric hindrance. Even though a low yield was obtained from 2,6-dibromopyridine (
j), the coupling product
10j bearing a bromine atom can serve as a valuable intermediate for the preparation of a variety of materials. Interestingly, it was also possible to obtain an aromatic ketone
10k in moderate yield from the reaction of
P7 with benzoic acid anhydride in the presence of Pd(0) catalyst.
Table 10.
Pd-Catalyzed coupling reactions of 3-pyridylzinc bromide (P7).
Table 10.
Pd-Catalyzed coupling reactions of 3-pyridylzinc bromide (P7).
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To expand the applications of 3-pyridylzinc bromide, several other copper-catalyzed coupling reactions were also investigated and the results are summarized in
Table 11. S
N2’-type reactions have been tried with allyl halides affording the resulting products (
11a and
11b,
Table 11) in moderate to good yields. In the presence of TMSCl, silyl enol ether
11c (
Table 2) was obtained from the conjugate addition intermediate. Like other general organozinc reagents, 3-pyridylzinc bromide (
P7) was successfully used for the copper-catalyzed synthesis of ketone compounds.
Table 11.
Copper-catalyzed coupling reaction of 3-pyridylzinc bromide.
Table 11.
Copper-catalyzed coupling reaction of 3-pyridylzinc bromide.
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This study was expanded to several analogues of 3-bromopyridine. As described in
Table 12, 3-bromoquinoline (
Q1) and 3-bromoisoquinoline (
Q2) were treated with active zinc along with 20 mol% of lithium chloride. It was found that the oxidative addition of active zinc was completed in 2h at refluxing temperature to give the corresponding organozinc reagents. The subsequent coupling reactions of
Q1 were performed with aryl iodide (entry 1,
Table 12) and heteroaryl iodides (entries 2 and 3,
Table 12) in the presence of palladium catalyst affording the corresponding products (
12a ~
12c) in moderate to good isolated yields.
Table 12.
Preparation of quinoline and isoquinoline derivatives via heteroarylzinc reagent.
Table 12.
Preparation of quinoline and isoquinoline derivatives via heteroarylzinc reagent.
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Along with the successful results from the coupling reaction of 2-pyridylzinc bromides with aromatic haloamines and alcohols, the readily available 3-pyridylzinc bromide was easily coupled with haloaromatic compounds bearing relatively acidic protons under mild conditions affording the corresponding cross-coupling products in the moderate to excellent yields. Of primary interest, the general procedure for the transition metal-catalyzed cross-coupling reactions of 3-pyridylzinc bromides with haloanilines and halophenols providing 3-(aminophenyl)pyridines and 3-(hydroxyl-phenyl) pyridines were reported. The results also include the preparation of quinoline and isoquinoline derivatives as well as other pyridine derivatives.
The first approach included the reaction of 3-pyridylzinc bromide (
P7) with 4-iodoaniline in the presence of 1% of Pd(OAc)
2 along with 2% of SPhos in THF (enty1,
Table 13). Even though a little longer reaction time was required, the coupling product
13a was also obtained in good yield from the reaction with 4-bromoaniline under the same conditions (entry 2,
Table 13). Interestingly, trace amounts of coupling product was detected by GC from the reaction with 4-iodophenol using the same conditions (entry 3,
Table 13). A protected bromophenol gave rise to the coupling product
13b in moderate yield under the same conditions (entry 4,
Table 13). As described in the previous report, the critical role of an extra ligand (SPhos) for the completion of the coupling reaction was observed. Trace amount of product formation was detected in the absence of SPhos (entry 5,
Table 13). It was also found that a Pd(0)-catalyst was not effective for the coupling with a protected bromophenol (entry 6,
Table 13).
Table 13.
Preliminary test for the coupling reaction.
Table 13.
Preliminary test for the coupling reaction.
![Molecules 15 08006 i013]() |
Again, extra ligand-free coupling reactions were also successfully performed in the case of 3-pyridylzinc with iodoanilines. The results are summarized in
Table 14. No significant effect of the presence of acidic protons was observed in the Pd(0)-catalyzed coupling reactions.
The coupling reactions were easily accomplished by the addition of 3-pyridylzinc bromide into the mixture of haloaniline and Pd(0)-catalyst in THF. The organozinc solution was added into the reaction flask in one portion via a syringe at room temperature. The lack of a large heat of reaction should be a useful feature for large scale synthesis. For the sterically hindered 4-methyl-3-pyridylzinc bromide (
P8), slightly more severe conditions (refluxing for 6 h) were required to complete the coupling. Unfortunately, no satisfactory coupling reaction occurred with 2-methoxy-5-pyridylzinc bromide (
P13) using the Pd(0)-catalyst (entry 9,
Table 14). From the results described above, it can be concluded that Pd(0)-catalyzed coupling reactions of 3-pyridylzinc bromides work effectively with iodoanilines under mild conditions.
Table 14.
Preparation of aminophenylpyridines.
Table 14.
Preparation of aminophenylpyridines.
![Molecules 15 08006 i014]() |
Another interesting reaction of 3-pyridylzinc bromide would be the coupling reaction with phenols, which also have an even more acidic proton [
69]. The coupling reactions with iodophenols were carried out using Pd(0)-catalyst. As shown in
Table 15, 2.0 equivalent of organozinc reagent was reacted with halophenols at refluxing temperature in the presence of 1 mol% of Pd(PPh
3)
4 in THF. In the case of
P7, even though the coupling reaction with iodophenol worked fairly at rt, increasing the reaction temperature worked more effectively to complete the coupling reaction. Unlike the reaction with 4-bromoaniline, treatment of
P7 with 4-bromophenol gave rise to the product
15a in moderate yield (entry 3,
Table 15).
Table 15.
Preparation of hydroxyphenylpyridines.
Table 15.
Preparation of hydroxyphenylpyridines.
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With the successful results described above, several analogues of 3-bromopyridine was also tried. The results are described in
Table 16. Quinolinylzinc bromide (
Q1) and isoquinolinylzinc bromide (
Q2) were easily prepared and then the subsequent coupling reactions with 4-iodoaniline and 4-iodophenol afforded the corresponding products,
16a and
16b.
Table 16.
Preparation of quinoline and isoquinoline derivatives.
Table 16.
Preparation of quinoline and isoquinoline derivatives.
![Molecules 15 08006 i016]() |
Scheme 3.
Expanded examples of coupling reactions.
Scheme 3.
Expanded examples of coupling reactions.
Further application of this practical synthetic approach has been performed by the coupling reaction with different types of alcohols. 2-Methoxy-5-bromobenzyl alcohol and 6-bromo-2-naphthol were nicely coupled with
P7 under the reaction conditions given in
Scheme 3. Interestingly, unsymmetrical amino-bipyridines were produced from the coupling reactions of
P7 with 2-amino-6-bromopyridine (route C,
Scheme 3). It is of interest that the resulting product (
s3c) can be utilized for further applications after transformation of the amino group to a halogen [
70].