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Synlett 2024; 35(04): 459-463
DOI: 10.1055/a-2047-8355
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11th Singapore International Chemistry Conference (SICC-11)

Synthesis of 2,2′-Bipyridines via Dehydrogenative Dimerization of Pyridines Using Sodium Dispersion

Pinaki Bhusan De
a   RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
,
Laurean Ilies  ∗
a   RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
,
Kazuhiko Takai  ∗
b   Graduate School of Natural Science and Technology Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
,
Sobi Asako  ∗
a   RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
b   Graduate School of Natural Science and Technology Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
› Author Affiliations

We thank KOBELCO ECO-Solutions Co, Ltd. for financial support and for providing the sodium dispersion used in this study. This research was partially supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI Grant-in-Aid for Scientific Research (B) No. 22H02125 to S.A.) and the Naohiko Fukuoka Memorial Foundation.
› Further Information
 
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Dedicated to Professor Shigeru Yamago on the occasion of his 60th birthday

Abstract

2,2′-Bipyridine derivatives were synthesized by dehydrogenative dimerization of nonactivated pyridines using sodium dispersion. The reaction features operational simplicity, mild conditions, and the use of earth abundant and nontoxic sodium as the sole metal source. Importantly, transition metals are not required, which is beneficial in the fields of materials science and drug synthesis, where the contamination of the transition metals may cause significant problems.


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Key words

2,2′-bipyridine - sodium dispersion - dehydrogenative coupling - transition-metal-free - sustainable chemistry

Table 1 Synthesis of 4,4′-Di-tert-butyl-2,2′-bipyridine (2a) Using SDa

Entry

SD (X mol%)

THF (mL)

Yield of 2a (%)

Yield of 3a (%)

Yield of 1a (%)

1b

110

1.0

67

 5

10

2c

110

1.0

66

10

trace

3

110

1.0

83 (75)e

 8

 5

4d

110

1.0

80

10

 3

5d

110

2.0

78

 9

 4

6d

110

0.5

69

 7

 5

7

 50

1.0

49

trace

49

8

150

1.0

79

 5

 2

9f

110

0.5

34

 6

16

a The reaction of 1a was conducted in THF on a 0.5 mmol scale. Yields were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. 4,4′,4′′-Tri-tert-butyl-2,2′:6′,2′′-terpyridine (3a) was obtained as side product.

b Reaction time was 2 h.

c Air oxidation for 10 min.

d Yield determined by isolation.

e Air oxidation for 16 h.

f Sodium lump was used instead of SD; the reaction was conducted on a 0.3 mmol scale.

Bipyridines are privileged heterocyclic scaffolds of interest in various fields of chemistry,[1] a molecular motif often found in the structure of natural products and bioactive compounds.[2] The strong coordinating ability and high stability of 2,2′-bipyridine derivatives make them versatile bidentate ligands, and fine tuning of the substituents allows control of the catalytic properties of the corresponding metal complexes. While 2,2′-bipyridine derivatives are typically synthesized by selective halogenation or N-oxidation of the corresponding pyridines followed by transition-metal-catalyzed coupling (Scheme [1]A), there has been a considerable interest in developing a step- and atom-economical synthetic route without prefunctionalization. Thus, there are several reports on the direct use of pyridines as the starting materials via dehydrogenative dimerization in the presence of transition-metal catalysts such as ruthenium clusters,[3] palladium,[4] [5] or Raney nickel[6] (Scheme [1]B). Although these methods allow straightforward access to various 2,2′-bipyridines, they require harsh reaction conditions and long reaction times; more importantly, the transition-metal catalyst used for these reactions may coordinate to the 2,2′-bipyridine product, making purification tedious. The transition-metal-free dimerization of pyridines has been reported to proceed in the presence of expensive bases such as TMPMgX (2,2,6,6-tetramethylpiperidide, TMP)[7] or BuLi·LiDMAE (N,N-dimethylaminoethanol, DMAE),[8] or in the presence of NaNH2 [9] at high temperature (140 °C) and using an excess amount of substrate (Scheme [1]C). In continuation of our research program on the development of organic synthesis using sodium dispersion (SD),[10] which is a commercially available,[11] easy to handle, and highly reactive fine dispersion of sodium in paraffin oil, we report here an expedient route to access 2,2′-bipyridine derivatives by transition-metal-free dehydrogenative dimerization of pyridines under mild conditions, using sodium as the sole metal source (Scheme [1]D).

Zoom Image
Scheme 1 Synthetic routes to 2,2′-bipyridines

We commenced our study using 4-tert-butylpyridine (1a) as a model substrate, because the expected product, 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy, 2a), is an important ligand in transition-metal catalysis.[12] Compound 1a was reported to undergo dehydrogenative homocoupling in the presence of NaNH2 at 140 °C to afford 2a in 5–18% yield based on 1a,[9] while it was obtained in higher yields (8–76%) by the other methods.[3b] [4] [5] [7b] After extensive screening of various reaction parameters (Table [1]), we found that the use of 110 mol% of sodium dispersion in THF (0.5 M) was optimal and 2a was obtained in 75% yield (83% by 1H NMR) after heating the reaction mixture at 50 °C for 6 h, followed by oxidation under atmospheric air at room temperature (entry 3). Shorter time for the reaction (entry 1), or for the air oxidation step (entry 2), and higher concentration (entry 6) slightly decreased the yield. While a reduced amount of SD (50 mol%, entry 7) decreased the reaction efficiency, the use of excess SD (150 mol%, entry 8) did not affect the reaction too much. This supports the mechanism involving the formation of the putative dianionic intermediate A either via dimerization of radical anion species generated by single-electron reduction of pyridine with SD[10e] or the addition of a pyridyl radical anion to a neutral pyridine followed by another single-electron reduction. The reaction using sodium lump instead of SD gave lower yield (entry 9). Typically, 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine (3a) was obtained in ca. 10% as a side product (molar ratio of 2a:3a = 16:1 in entry 3). The reaction is operationally simple and easily scalable; the gram-scale reaction proceeded with 59% yield.

Zoom Image
Scheme 2 Synthesis of 2,2′-bipyridines via dehydrogenative dimerization of pyridines using SD. Pyridines 1 (typically 0.1–0.5 mmol) were reacted with SD (100–130 mol%) in THF at 50 °C for 6 h. a SD (150 mol%). b Pyridine (5 equiv), DMI (3 equiv), SD (1 equiv) reacted at 40 °C for 6 h, followed by addition of H2O and air oxidation for 12 h. Yields based on SD are shown.

With the optimized conditions in hand, we next explored the scope of the dimerization reaction (Scheme [2]). 4-Substituted pyridines underwent the coupling selectively at the 2-position to afford the corresponding 2,2′-bipyridines. The size of the substituent is important: tert-alkyl-substituted pyridines reacted more efficiently (2a–c) than secondary and primary alkyl-substituted pyridines (2e–i,k), partly because of the competing 4,4′-coupling of pyridines having a small substituent.[13] [14] The reaction of pyridines with bulky 4-trimethylsilyl (2d) and neopentyl group (2j) at the 4-position also proceeded smoothly. While the synthesis of 4,4′-di(1-adamantyl)-2,2′-bipyridine (2c) has not been reported, a related 4,4′-di(2-adamantyl)-2,2′-bipyridine was previously synthesized by a palladium-catalyzed cross-coupling between 2-adamantylzinc and 4,4′-dibromo-2,2′-bipyridine (89% yield).[15] 4,4′-Bis(trimethysilyl)-2,2′-bipyridine (2d) was previously synthesized from the corresponding dibromobipyridine using BuLi at –78 °C (12% yield)[16] or by Pd/C-catalyzed homocoupling of 4-trimethylsilylpyridine at 140 °C (42% yield).[4] Interestingly, 5,6,7,8-tetrahydroisoquinoline underwent the dimerization selectively at the more hindered 2-position to give 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-biisoquinoline (2l), whose structure was confirmed by X-ray crystallographic analysis (see the Supporting Information). This result suggests the importance of electronic factors, such as the spin density on the pyridyl radical anion and the relative stability of the dianion intermediate A, but mechanistic details are unclear at the moment. Compound 2l was previously synthesized by selective hydrogenation of the benzene rings “of 1,1’-biisoquinoline.[17] The reaction of 4-ethylpyridine (1k) proceeded poorly, together with recovery of the starting material and formation of unidentified side products in a small amount. The reaction of 3-trimethylsilylpyridine afforded the expected 5,5′-bis(trimethylsilyl)-2,2′-bipyridine (2m) along with the monodesilylation product (2m′). The reaction of nonsubstituted pyridine in 1,3-dimethyl-2-imidazolidinone (DMI)[10e] afforded 4,4′-bipyridine (2n),[14] while the reaction in THF afforded a trace amount of product. 2-Substituted pyridines reacted poorly (see the Supporting Information for less successful substrates).

In summary, we developed a simple synthetic method to access 2,2′-bipyridines through dehydrogenative coupling of nonactivated pyridines using sodium dispersion under mild conditions.[18] The reaction does not require the use of transition metals, which can be an advantage where the contamination of transition metals may cause significant problems, for example, in materials science and drug synthesis. In view of the sustainability and abundance of sodium,[19] as well as the convenience and user-friendliness of the finely dispersed sodium, further exploration of organic synthesis using sodium dispersion is underway in our laboratory.


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Conflict of Interest

S.A. and K.T. are listed as inventors on patent patent application PCT/JP2016/079887, submitted by KOBELCO ECO-Solutions CO., Ltd., which covers synthetic methods described in this manuscript.

Acknowledgment

We thank Dr. D. Hashizume and Dr. K. Adachi (Materials Characterization Support Team, CEMS, RIKEN, Japan) for X-ray crystallography, and Dr. Z. Hou and Dr. M. Takimoto (CSRS, RIKEN, Japan) for generously allowing us to use the mass spectrometer. We thank Mr. Naoki Okamoto and Mr. Mikio Sakka at Okayama University for preliminary experiments and Prof. Tharmalingam Punniyamurthy (Indian Institute of Technology Guwahati) for valuable assistance.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2047-8355.
  • Supporting Information

Corresponding Authors

Laurean Ilies
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako, Saitama 351-0198
Japan   

Sobi Asako
RIKEN Center for Sustainable Resource Science
2-1 Hirosawa, Wako, Saitama 351-0198
Japan   

Kazuhiko Takai
Graduate School of Natural Science and Technology Okayama University
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530
Japan   

Publication History

Received: 05 February 2023

Accepted after revision: 06 March 2023

Accepted Manuscript online:
06 March 2023

Article published online:
17 April 2023

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Zoom Image
Scheme 1 Synthetic routes to 2,2′-bipyridines
Zoom Image
Scheme 2 Synthesis of 2,2′-bipyridines via dehydrogenative dimerization of pyridines using SD. Pyridines 1 (typically 0.1–0.5 mmol) were reacted with SD (100–130 mol%) in THF at 50 °C for 6 h. a SD (150 mol%). b Pyridine (5 equiv), DMI (3 equiv), SD (1 equiv) reacted at 40 °C for 6 h, followed by addition of H2O and air oxidation for 12 h. Yields based on SD are shown.