Efficient one-pot synthesis of dan-substituted organo- and silyl-boron compounds

Abstract

Direct, transition metal-free B(dan)-installation into organic frameworks has been developed. Heteroaryl–H bonds were transformable into the respective heteroaryl–B(dan) bonds through deprotonation. The resulting heteroaryl–B(dan) compounds, which are otherwise difficult to access, can undergo the direct Suzuki–Miyaura coupling. The method was demonstrated to apply to a silicon nucleophile, giving Lewis acidity-diminished stable silyl–B(dan) and –B(aam) in one pot.

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Installation of a naphthalene-1,8-diaminato (dan) substituent on boron centers significantly diminishes the boron-Lewis acidity,¹ thus providing transmetalation-resistant properties to the respective organoboron compounds [R–B(dan)] that are conventionally synthesized by dehydration condensation of organoboronic acids [R–B(OH)₂] and 1,8-diaminonaphthalene (danH₂) (Scheme 1A).² The characteristic feature has been utilized for the boron-masking strategy in the iterative Suzuki–Miyaura coupling (SMC),² where the B(dan) moieties remain intact during the cross-coupling event at Lewis acidic B(OH)₂ or pinacol boronates [B(pin)]. On the other hand, we have disclosed that the B(dan) moieties can be activated toward transmetalation by treatment with t-BuOK, leading to the direct SMC of aryl–^3,4 and cyclopropyl–B(dan).⁵ In addition to the inactive/active flexible properties in the SMC depending on bases, dan-installation also endows organoboron compounds with air- and water-resistant properties: protodeborylation is substantially suppressed with 2-pyridyl–B(dan),^3,6 and PhMe₂Si–B(dan)⁷ becomes stable in air, while their B(OH)₂/B(pin) counterparts usually suffer from serious decomposition under these conditions.^8,9 In this regard, the development of a direct method of synthesizing dan-substituted organoboron compounds,¹⁰ especially heteroaryl ones that are often unstable in their Lewis acidic –B(OH)₂ forms,¹¹ would be an important subject, since it could open the way to synthetic transformations with heteroaryl–B(dan). We have previously reported on a reaction of Grignard reagents with H–B(dan) that directly produces various R–B(dan) including 2-pyridyl– and 2-thienyl–B(dan) under transition metal-free conditions (Scheme 1B);⁶ however, this reaction requires organic bromides (R–Br for preparing R–MgBr) and pre-prepared H–B(dan), which would leave something to be desired.¹² Hence, our attention was focused on the use of borates [R–B(OR′)₃⁻], one of the most common intermediates in the synthesis of organoboronic acid derivatives, generated from readily accessible B(OR′)₃ and carbon nucleophiles (R–M, M = Li, MgX) for their direct conversion to R–B(dan). Here we disclose an improved approach to prepare R–B(dan) by using only commercially available reagents, wherein deprotonation of R–H moieties is also usable for generating the requisite carbon nucleophiles (Scheme 1C).

Scheme 1 Transition metal-free synthesis of Ar–B(dan).

We first conducted a reaction (5 mmol scale) of 5-pyrazolyl lithium, prepared readily by deprotonation of 1-methyl-1H-pyrazole (1a), with triethylborate [B(OEt)₃]; subsequent treatment of the resulting pyrazoylborate [5-pyrazolyl–B(OEt)₃⁻] with 1,8-diaminonaphthalene and acetic acid, in a similar way to the direct transformation of trialkyl borates [R–B(OR′)₃⁻] into pinacol boronates [R–B(pin)],¹³ provided 5-pyrazolyl–B(dan) (2a) in 88% yield (Scheme 2).¹⁴ Because the one-pot direct conversion of a heteroaryl–H bond into a heteroaryl–B(dan) bond can be carried out under non-aqueous conditions, 5-thiazolyl–B(dan) (2b and 2c) could also be synthesized, avoiding the intermediary formation of their protodeborylation-prone B(OH)₂ counterparts.^11b An acidic C–H moiety of furan (1d) or thiophene (1e) was also convertible into the respective C–B(dan) (2d: 75% and 2e: 70%), and 4,4-dimethyl-2-phenyl-2-oxazoline (1f) and 1,3-dimethoxybenzene (1g) could participate in the reaction via directed ortho metalation. Owing to the diminished boron Lewis acidity, all the heteroaryl–B(dan) and other products mentioned below exhibit sufficient stability under ambient conditions, allowing for their isolation by column chromatography. The use of 1,1′-dilithioferrocene generated by dual deprotonation of ferrocene (1h) resulted in the formation of 1,1′-B(dan)-substituted ferrocene (2h) in 59% yield, and the procedure was also applicable to phenylacetylene (1i) or 1,3-dithiane (1j), giving phenylethynyl–B(dan) (2i) or 1,3-dithian-2-yl–B(dan) (2j) as air/water-stable compounds.¹⁵

Scheme 2 Synthesis of R–B(dan) from R–H.

Organic bromides (1k–1q) were naturally usable as starting materials (Scheme 3), and thus 2-fluorophenyl–B(dan) (2k), 2-pyridyl–B(dan) (2l) and 2,2′-B(dan)-substituted 1,1′-binaphthyl (2m) were produced through lithium–bromine exchange. In addition, various aryl–B(dan) (2n–2p)¹⁶ and alkyl–B(dan) (2q and 2r¹⁷) could be synthesized with the respective Grignard reagents.¹⁸ A carbon nucleophile used for B(dan)-installation was also available by lithium–tin exchange of 2,5-bis(tributylstannyl)thiophene (1s) to afford a 63% yield of 2s bearing B(dan) and SnBu₃ functionalities on the thiophene ring (Scheme 4).

Scheme 3 Synthesis of R–B(dan) from R–Br.

Scheme 4 B(dan)-installation via lithium–tin exchange.

It should be noted that the present method could also be applied to capturing a silicon nucleophile: air-resistant PhMe₂Si–B(dan) (2t) became straightforwardly accessible in 40% yield by treating PhMe₂SiLi with B(OEt)₃ (Scheme 5),^19,20 while the previous multistep method⁷ required the use of air/water-sensitive reagents and intermediates [BCl₃, (i-Pr₂N)₂BCl and PhMe₂Si–B(Ni-Pr₂)₂]. A new air-resistant silylborane bearing an anthranilamide substituent on the boron center [PhMe₂Si–B(aam) (2u)] was generated by extending the direct synthesis, although the yield was relatively low.²¹ According to the previous procedure using PhMe₂Si–B(Ni-Pr₂)₂, the yield was improved to 65%.

Scheme 5 Synthesis of PhMe₂Si–B(dan) and –B(aam).

To gain insight into the reaction pathway, we carried out ¹¹B NMR experiments using n-BuLi as a carbon nucleophile (Fig. 1). Treatment of B(OEt)₃ (18.3 ppm, Fig. 1A) with n-BuLi resulted in the generation of an upfield-shifted species (3.0 ppm, Fig. 1B), being in a typical chemical shift range of a tetracoordinate borate.²² The resulting borate [n-Bu–B(OEt)₃⁻] remained unchanged upon mixing with 1,8-diaminonaphthalene (Fig. 1C), while further addition of acetic acid led to the formation of n-Bu–B(dan) (2v) with complete disappearance of the borate (Fig. 1D).²³ These results imply that dan-installation on the boron center does not occur at the tetracoordinate borate stage; the intermediary formed neutral species [R–B(OEt)₂] via protonation of the borates would immediately undergo ligand exchange to afford R–B(dan) (Scheme 6).

Fig. 1 ¹¹B NMR experiments on the reaction pathway.

Scheme 6 Proposed reaction pathway.

Finally, the synthetic utility of heteroaryl–B(dan) was demonstrated by the direct SMC: treatment of 2a with 4-bromoanisole and Ba(OH)₂ under Pd–dppf catalysis³ quantitatively provided the coupling product (3a), which verifies the protodeborylation-resistant yet enough reactive property of the C–B(dan) bond (Scheme 7). Furthermore, chemoselective cross-coupling at the SnBu₃ moiety of 2s gave a 95% yield of 3b, whose thienyl–B(dan) bond was then coupled with 4-(trifluoromethyl)bromobenzene efficiently under the Ba(OH)₂ conditions.

Scheme 7 Direct SMC of heteroaryl–B(dan).

Conclusions

We have developed a one-pot direct method for installing the B(dan) moiety without the intermediary formation of sometimes unstable organoboronic acids. The present transition metal-free method is superior to our previous H–B(dan) one⁶ in that organolithium reagents directly generated by deprotonation are usable as carbon nucleophiles;¹² diverse R–B(dan) (R = heteroaryl, aryl, alkynyl, alkyl) endowed with air/water-resistant characters have become accessible in good yields. Moreover, the method was demonstrated to apply to a silicon nucleophile to lead to the direct synthesis of PhMe₂Si–B(dan) and –B(aam). Further studies on the synthetic utilization of the resulting R–B(dan) especially for catalytic carbon–carbon bond-forming reactions are in progress.

Author contributions

K.T. and H.Y. conceived the concept and wrote the manuscript. K.T. conducted most of the experiments and data collection. Y.I. synthesized 2u according to the previous method. K.N. performed the X-ray crystal structure analysis of 2u. M.N. provided advice for the research. H.Y. directed the project. All authors have approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Fukuoka Naohiko Memorial Foundation and the Nagase Science and Technology Foundation.

References

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12. The reaction of organolithium reagents with H–B(dan) was unsuccessful.
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14. Depending on the substrates, various reaction conditions (molar ratio, temperature, and time) were employed. See the ESI† for details.
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17. A tert-butyl Grignard reagent was used as the starting material.
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19. Acetic acid was added first to the silylborate intermediate in this case; the reaction conducted in the usual manner resulted in a slightly decreased yield (38%).
20. Using a silyl Grignard reagent (PhMe₂SiMgBr) instead of PhMe₂SiLi resulted in an almost similar yield (42%). For the generation of silyl Grignard reagents, see: W. Xue, R. Shishido and M. Oestreich, Angew. Chem., Int. Ed., 2018, 57, 12141–12145.
21. The use of acetic acid instead of TMSCl gave 2u in only trace amounts.
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23. See the ESI† for the assignment of other 11B NMR signals.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2121000. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ob00613a

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