Catalytic regioselective 3,4-difunctionalization of 3-iodo-o-carborane via Pd migration

Abstract

A Pd-catalyzed one-pot regioselective difunctionalization of 3-iodo-o-carborane has been achieved for the synthesis of a wide variety of 3-alkyl-4-Nu-o-carboranes (Nu = aryl, alkyl, amino, or thio groups) in moderate to excellent yields. This protocol combines the sequential activation of cage B(3)–I and B(4)–H bonds via Pd 1,4-migration.

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Carboranes represent a unique class of polyhedral boron hydrides in which one or more BH vertices are replaced by CH units.¹ These molecules exhibit distinctive structural characteristics, including nearly spherical geometry and extensive three-dimensional electron delocalization, rendering them valuable building blocks for applications ranging from advanced materials to pharmaceuticals.^2,3 Although transition metal-catalyzed regioselective B–H functionalization of carboranes has witnessed remarkable progress, enabling access to structurally diverse derivatives that cannot be generated by other conventional methods,⁴ there remains significant interest in developing efficient, versatile methodologies for the synthesis of difunctionalized carboranes bearing different substituents.⁵ The metal migration strategy is a promising approach, which enables B–H functionalization at cage positions distinct from the initial site of bond activation.^6,7 In this context, the 1,2-metal migration strategy was first used in 2017 by the Spokoyny group, who reported sequential cage-walking during Pd-catalyzed B–Br/B–H activation of 9-Br-m-carborane, affording functionalization at B(2), B(4), B(5), and B(9) positions.⁸ Our group subsequently disclosed an acylamino-directed Pd cage-walking process from B(4) to B(8) in o-carboranes, enabling selective B(8)-arylation.⁹ On the other hand, B–I functionalization followed by 1,4-Pd migration can offer difunctionalized o-carborane in a one-pot reaction. We reported a Pd-catalyzed alkenylation-iodine migration cascade reaction of 3-iodo-o-carboranes with alkynes, which combines the sequential activation of cage B–I and B–H bonds via Pd 1,4-migration with excellent regioselectivity (Scheme 1).¹⁰ This prompted us to investigate whether alkenes could be employed to achieve regioselective B(3)-alkylation and B(4)-functionalization via a similar Pd 1,4-migration pathway (Scheme 1).¹¹ The results of our investigation are presented in this Communication.

Scheme 1 Carborane functionalization via Pd migration.

We first evaluated the feasibility of B(3)-alkylation and iodine migration in the reaction of 3-iodo-o-carborane (1) with alkenes. Norbornene (2) was selected as the model substrate to suppress β-hydride elimination during the alkylation process. In the presence of 10 mol% Pd(dba)₂ and 10 mol% PPh₃, treatment of 1 with 5.0 equivalents of 2 in toluene at 80 °C for 3 days afforded 3-(2-norbornyl)-4-iodo-o-carborane (3) in 46% yield (Table 1, entry 1). Other monodentate phosphine ligands such as PCy₃ and PPh₂Cy failed to produce 3 (Table 1, entries 2 and 3), while PPh₂Py led to a slightly improved yield of 53% (Table 1, entry 4). Bidentate ligands DPPB and DPPF afforded low yields (Table 1, entries 5 and 6), and bisphosphine L1 deactivated the catalyst entirely (Table 1, entry 7). The use of PhDavePhos (L2) gave a 16% yield (Table 1, entry 8), whereas the phosphine-amide ligand L3 significantly enhanced reaction efficiency (Table 1, entry 9). In addition, bisphosphine-amide ligand L4 enabled the formation of 3 in 92% yield with excellent regioselectivity (Table 1, entry 10). Screening of other Pd(0) catalysts did not yield better results, while Pd(II) was not suitable for this reaction (Table 1, entries 11, 12, 14 and 15). In the case of Pd(OAc)₂, the reaction can be initiated by reactive Pd(0) species generated in situ through reduction of Pd(II) by the phosphine ligand (Table 1, entry 13).¹² Reducing the catalyst or ligand loading or decreasing the amount of 2 led to diminished yields (Table 1, entries 16–18). Notably, no reactivity was observed with other alkenes, such as cyclohexene, 1-hexene, styrene, methyl acrylate, or 2-vinylpyridine, likely due to the unique ring strain and high reactivity of norbornene.

Table 1 Optimization of reaction conditions for Pd-catalyzed alkylation with iodine migration^a

Entry	L	[Pd]	Yield^b (%)
a Reactions were conducted on a 0.2 mmol scale of 1 in 2.0 mL of toluene; DPPB = 1,4-bis(diphenylphosphino)butane; DPPF = 1,1′-bis(diphenylphosphino)ferrocene. b Yield determined by ^1H NMR using 1,1,2,2-tetrachloroethane as the internal standard. c 5 mol% Pd2(dba)3. d 5 mol% Pd(dba)2. e 5 mol% L4. f 4 equiv. of 2.
1	PPh3	Pd(dba)2	46
2	PCy3	Pd(dba)2	Messy
3	PPh2Cy	Pd(dba)2	Messy
4	PPh2Py	Pd(dba)2	53
5	DPPB	Pd(dba)2	27
6	DPPF	Pd(dba)2	13
7	L1	Pd(dba)2	N.R.
8	L2	Pd(dba)2	16
9	L3	Pd(dba)2	72
10	L4	Pd(dba)2	92
11	L4	Pd2(dba)3 ^c	69
12	L4	Pd(PPh3)4	53
13	L4	Pd(OAc)2	56
14	L4	PdCl2(PPh3)2	N.R.
15	L4	[Pd(Allyl)2Cl]2	N.R.
16^d	L4	Pd(dba)2	80
17^e	L4	Pd(dba)2	42
18^f	L4	Pd(dba)2	72

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Subsequently, the scope of the one-pot difunctionalization process was explored under the optimized conditions through Pd-catalyzed cage B–C coupling reactions of 3-iodo-o-carborane with Grignard reagents (Table 2).¹³ It was found that this method was quite general and a range of aryl Grignard reagents delivered the desired products 4a–4k in 81–92% yields, regardless of their electronic nature. The sterically demanding 2,6-dimethylphenyl Grignard reagent furnished the corresponding 4k in 82% yield, though 2-naphthyl Grignard reagents were incompatible. For substrates bearing heteroaryls, 2-thienyl successfully afforded 4m in 90% yield, while no coupling reaction occurred with 2-pyridyl substrates, likely due to nitrogen coordination inhibiting Pd catalysis. A variety of alkyl Grignard reagents also reacted to afford 4o–4t in 39–82% yields. Lower yields for 4q and 4t were attributed to β-H elimination, generating 3-(2-norbornyl)-o-carborane as a byproduct. Allyl and alkynyl Grignard reagents failed to react under the optimized conditions due to lower nucleophilicity.

Table 2 Substrate scope^a,b

a Reactions were conducted on a 0.2 mmol scale in 2 mL of toluene. b Yield of the isolated product.

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Given the utility of iodinated carboranes as key intermediates for boron vertex derivatization with the efficient construction of B–heteroatom bonds,¹⁴ we next examined the use of arylamino Grignard reagents for constructing B–N bonds (Scheme 2). One-pot reactions with phenylamino Grignard reagents afforded the difunctionalized product 5a in 64% yield. A series of substituted arylamino magnesium bromides bearing either electron-donating or -withdrawing groups were well tolerated, affording the corresponding 5b–g in 55%–68% isolated yields. Increasing steric hindrance on the aryl ring led to a reduced yield of 5h. Attempts to use alkylamino Grignard reagents resulted in complex mixtures.

Scheme 2 One-pot construction of B(3)–C and B(4)–N bonds.

After examining the one-pot B(3)-alkylation and B(4) cross-coupling reaction of 3-iodo-o-carborane and norbornene with Grignard reagents, we then evaluated the reactivity of sodium mercaptides as nucleophiles (Scheme 3). Reactions with these sulfur-based nucleophiles yielded B(4)-alkylthio derivatives 6a–6c in moderate to good yields. Sodium thiophenolate afforded 6d in 74% yield, while substrates bearing electron-donating (–OMe) or electron-withdrawing (–F) groups on the aryl ring also proved compatible, affording 6e and 6f in 35% and 47% yields, respectively.

Scheme 3 One-pot construction of B(3)–C and B(4)–S bonds.

All products 3, 4, 5 and 6 were fully characterized by ¹H, ¹³C, and ¹¹B NMR spectroscopy as well as high-resolution mass spectrometry. The molecular structures of 4i, 5f and 6b were further confirmed by single-crystal X-ray analyses.

Based on our previous studies¹⁰ and current observations, a plausible reaction mechanism is proposed in Scheme 4. The catalysis begins with oxidative addition of the B(3)–I bond in 3-iodo-o-carborane onto Pd(0), followed by norbornene insertion into the Pd–B bond to form a Pd(II) intermediate B. The subsequent 1,4-Pd migration from the alkyl carbon to the B(4) vertex furnishes intermediate C, which undergoes reductive elimination to deliver product 3 and regenerate Pd(0). Many attempts for the direct detection or characterization of the Pd–B intermediates failed.¹⁵ In the presence of nucleophiles, transmetallation and a second reductive elimination afford the difunctionalized products 4, 5, or 6, completing the catalytic cycle.

Scheme 4 Proposed reaction mechanism.

Conclusions

In summary, we have developed a Pd-catalyzed one-pot regioselective difunctionalization of 3-iodo-o-carborane via 1,4-Pd migration. This protocol enables the construction of a wide variety of 3-alkyl-4-Nu-o-carboranes (Nu = aryl, alkyl, amino, or thio groups) in moderate to excellent yields. The strategy integrates sequential B(3)–I and B(4)–H activation, followed by Pd-catalyzed B(4)–Nu bond formation, offering a powerful platform for diversifying o-carborane scaffolds.

Author contributions

Z. Q. and Z. X. directed and conceived this project. X. J. conducted the experiments. All authors discussed the results and wrote the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data for 4i, 5f and 6b have been deposited at the CCDC under deposition numbers 2442891 (4i), 2442892 (5f), and 2442893 (6b) and can be obtained from the CCDC viahttps://www.ccdc.cam.ac.uk/structures/.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Project No. 22371290 to Z. Q.; Project No. 22331005 to Z. X.), the Shenzhen Science and Technology Program (Project No. KQTD20221101093558015 to Z. X.), the Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, CAS, and the Hong Kong Research Grants Council (Project No. JLFS/P-404/24).

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Footnote

† Electronic supplementary information (ESI) available: Synthetic procedures and characterization data of compounds. CCDC 2442891–2442893. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5dt00981b

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