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. Author manuscript; available in PMC: 2010 Oct 1.
Published in final edited form as: Org Lett. 2009 Oct 1;11(19):4330–4333. doi: 10.1021/ol901669k

Preparation of Potassium Azidoaryltrifluoroborates and Their Cross-Coupling with Aryl Halides

Young Ae Cho 1,, Dong-Su Kim 1,, Hong Ryul Ahn 1,, Belgin Canturk 1,, Gary A Molander 1,, Jungyeob Ham 1,
PMCID: PMC2751812  NIHMSID: NIHMS144872  PMID: 19736957

Abstract

graphic file with name nihms-144872-f0001.jpg Potassium azidoaryltrifluoroborates have been prepared from the corresponding haloaryltrifluoroborates in 73–98% yields. Also, we successfully cross-coupled the azido-functionalized organotrifluoroborates and carried out a one-pot sequential cross-coupling/1,3-dipolar cycloaddition and a one-pot cross-coupling/azide reduction process.


The azide functional group has been used as an important moiety for the formation of nitrogen-containing compounds in fields ranging from synthetic organic chemistry, to pharmaceutical chemistry, materials science, and biology. 1 Alkyl and aryl azides have gained prominence in particular because they may be used for the preparation of [1,2,3]-triazoles by Cu-catalyzed 1,3-dipolar cycloadditions onto terminal alkynes (via “Click” chemistry). 2 Unfortunately, the preparation of certain classes of organic azides has presented considerable challenges. Moreover, to the best of our knowledge, the Suzuki-Miyaura cross-coupling reaction with boron reagents bearing the azide functional group has not been reported, perhaps because of the inherent difficulty in preparing such bifunctional molecules and the perceived instability of the azide under cross-coupling reaction conditions.

Recently, organotrifluoroborate salts have been used as important synthetic reagents in the Suzuki-Miyaura cross-coupling reaction, providing many advantages over the corresponding boronic acids or boronate esters. 3 The organotrifluoroborates are air- and moisture-stable, crystalline solids that are inert to various nucleophilic reagents owing to the tetracoordinate nature of the boron.4

Consequently, it seemed likely that they would be tolerant of conditions allowing the incorporation of the azide functional group. Herein, we describe the first preparation of azidoaryltrifluoroborates from the corresponding haloaryltrifluoroborates and reaction conditions permitting Suzuki-Miyaura cross-coupling reactions of the azidoaryltrifluoroborates thus generated.

As a starting point, potassium haloaryltrifluoroborates were generated via the one-pot synthesis of aryl dihalides and B(OiPr)3 using 1.0 equiv of n-BuLi (Table 1). When dibromo or diiodobenzenes were used as starting materials, the target compounds were obtained in good yields except when 1,2-diiodobenzene was used. Interestingly, the reaction of dibromo pyridines gave the corresponding organotrifluoroborates in excellent yields. The reaction of 2,5-dibromo-p-xylene was also problematic, providing the desired product in much lower yield (Table 1, 5a 47%) under the same reaction conditions.

Table 1.

One-Pot Preparation of Potassium Haloaryltrifluoroborates from Various Aryl Dihalidesa

graphic file with name nihms-144872-f0002.jpg
entry X–Ar–X product yield
1 graphic file with name nihms-144872-t0003.jpg graphic file with name nihms-144872-t0004.jpg graphic file with name nihms-144872-t0005.jpg 1a-Br
1a-I
86%
90%
2 graphic file with name nihms-144872-t0006.jpg graphic file with name nihms-144872-t0007.jpg graphic file with name nihms-144872-t0008.jpg 2a-Br
2a-I
56%
85%
3 graphic file with name nihms-144872-t0009.jpg graphic file with name nihms-144872-t0010.jpg graphic file with name nihms-144872-t0011.jpg 3a
52%
4 graphic file with name nihms-144872-t0012.jpg graphic file with name nihms-144872-t0013.jpg 4a 81%
5 graphic file with name nihms-144872-t0014.jpg graphic file with name nihms-144872-t0015.jpg 5a 47%
6 graphic file with name nihms-144872-t0016.jpg graphic file with name nihms-144872-t0017.jpg 6a 82%
7 graphic file with name nihms-144872-t0018.jpg graphic file with name nihms-144872-t0019.jpg 7a 82%
8 graphic file with name nihms-144872-t0020.jpg graphic file with name nihms-144872-t0021.jpg 8a 72%
9 graphic file with name nihms-144872-t0022.jpg graphic file with name nihms-144872-t0023.jpg 9a 90%
10 graphic file with name nihms-144872-t0024.jpg graphic file with name nihms-144872-t0025.jpg 10a 87%
11 graphic file with name nihms-144872-t0026.jpg graphic file with name nihms-144872-t0027.jpg 11a 90%
12 graphic file with name nihms-144872-t0028.jpg graphic file with name nihms-144872-t0029.jpg 12a 85%
13 graphic file with name nihms-144872-t0030.jpg graphic file with name nihms-144872-t0031.jpg 13a 93%
14 graphic file with name nihms-144872-t0032.jpg graphic file with name nihms-144872-t0033.jpg 14a 94%
15 graphic file with name nihms-144872-t0034.jpg graphic file with name nihms-144872-t0035.jpg 15a 90%
16 graphic file with name nihms-144872-t0036.jpg graphic file with name nihms-144872-t0037.jpg 16a 80%
a

Reaction conditions: aryl dihalide (2.0 mmol), triisopropyl borate (2.0 mmol), and n-BuLi (2.0 mmol) at −78 °C to rt under N2 and then quenched with 1 N KHF2.

Next, using conditions previously developed for the preparation of aryl azides with aryl halide and Cu/amine-ligand,1, 5 we attempted the formation of azidoaryltrifluoroborates (Table 2).

Table 2.

Optimization of Reaction Conditions for the Preparation of Potassium 4-Azidophenyltrifluoroborate (1b)a

graphic file with name nihms-144872-f0038.jpg
entry CuX ligand base reaction time (h) conversion yield (%)b
1 CuI a K2CO3 24 66
2 CuI b K2CO3 5 98
3 CuI c K2CO3 16 100
4 CuI d K2CO3 24 81
5 CuI e K2CO3 15 100
6 CuI f K2CO3 1 100 (88)c
7 CuI g K2CO3 24 trace
8 CuI h K2CO3 48 68
9 CuId f K2CO3 2 100 (89)c
10 CuBr f K2CO3 1 100 (92)c
11 CuBr f Cs2CO3 0.5 100 (94)c
12e CuBr f Cs2CO3 2.5 100
a

All reactions were performed on a 0.05 mmol scale in 0.5 mL of DMSO-d6 in an NMR tube.

b

Percent conversions were determined by 1H NMR of the reaction mixtures. The conversion yield was based on the integration of peaks at 7.14 (1a-I) ppm and 6.85 (1b) ppm, respectively.

c

Reactions were performed on a 0.1 mmol scale and isolated yields are reported.

d

5 mol % of CuI was used.

e

Reaction was performed in DMF-d7.

We first carried out the reaction of potassium 4-azidophenyltrifluoroborate (1b) generated in situ by treatment of 1a-I with 1.0 equiv of NaN3 in the presence of 10 mol % of Cu(I) and various amine ligands.

A number of different amine ligands were screened for their efficacy in promoting the azidation, and it was found that N,N’-dimethylethylenediamine (ligand f) provided the fastest reaction time and the highest converted yield (Table 2, entry 6). Although both CuI and CuBr catalysts generated the target compound 1b under the same reaction conditions (Table 2, entries 6 and 10), the isolated yield and purity of compound 1b using CuBr were better than those of using CuI. A decrease in the catalyst loading from 10 to 5 mol % effectively doubled the reaction time (Table 2, entries 6 and 9).

When Cs2CO3 was used as a base instead of K2CO3, the reaction time decreased from 1 h to 30 min (Table 2, entries 10 and 11), and DMSO-d6 appeared to be a better solvent than DMF-d7 (Table 2, entries 11 and 12). Using these conditions (Table 2, entry 11), the azidation of various potassium haloaryltrifluoroborates was examined (Table 3). As a general rule, isolated yields and reaction rates of the corresponding azidophenyltrifluoroborates increased in the order para > meta > ortho under the same conditions (Table 3, 1b3b). Both mono- and dimethyl-substituted aryltrifluoroborates afford the corresponding azidoaryltrifluoroborates in satisfactory yields (Table 3, 4b5b). Surprisingly, when organotrifluoroborates 7a, 8a, and 13a were used as starting materials, aminoaryltrifluoroborates were generated in good yields instead of azidoaryltrifluoroborates.

Table 3.

One-Pot Preparation of Potassium Azidoaryltrifluoroboratesa

graphic file with name nihms-144872-f0039.jpg
entry X–Ar–BF3K reaction time (h) product yield
1 graphic file with name nihms-144872-t0040.jpg 1a-Br
1a-I
7
1
graphic file with name nihms-144872-t0041.jpg 1b 95%
95%b
2 graphic file with name nihms-144872-t0042.jpg 2a-Br
2a-I
9
6
graphic file with name nihms-144872-t0043.jpg 2b 90%
93%
3 graphic file with name nihms-144872-t0044.jpg 3a 24 graphic file with name nihms-144872-t0045.jpg 3b 73%
4 graphic file with name nihms-144872-t0046.jpg 4a 8 graphic file with name nihms-144872-t0047.jpg 4b 93%
5 graphic file with name nihms-144872-t0048.jpg 5a 12 graphic file with name nihms-144872-t0049.jpg 5b 90%
6 graphic file with name nihms-144872-t0050.jpg 6a 4 graphic file with name nihms-144872-t0051.jpg 6b 92%c
7 graphic file with name nihms-144872-t0052.jpg 7a 12 graphic file with name nihms-144872-t0053.jpg 7b 83%c
8 graphic file with name nihms-144872-t0054.jpg 8a 12 graphic file with name nihms-144872-t0055.jpg 8b 91%c
9 graphic file with name nihms-144872-t0056.jpg 9a 1 graphic file with name nihms-144872-t0057.jpg 9b 98%
10 graphic file with name nihms-144872-t0058.jpg 10a 1 graphic file with name nihms-144872-t0059.jpg 10b 98%
11 graphic file with name nihms-144872-t0060.jpg 11a 3 graphic file with name nihms-144872-t0061.jpg 11b 95%
12 graphic file with name nihms-144872-t0062.jpg 12a 3 graphic file with name nihms-144872-t0063.jpg 12b 95%
13 graphic file with name nihms-144872-t0064.jpg 13a 12 graphic file with name nihms-144872-t0065.jpg 13b 90%
14 graphic file with name nihms-144872-t0066.jpg 14a 10 graphic file with name nihms-144872-t0067.jpg 14b (82%)c,d
15 graphic file with name nihms-144872-t0068.jpg 15a 13 graphic file with name nihms-144872-t0069.jpg 15b (82%)e
16 graphic file with name nihms-144872-t0070.jpg 16a 5 min graphic file with name nihms-144872-t0071.jpg 16b 96%
a

All reactions were performed on a 1.0 mmol scale in 4 mL of DMSO and monitored by 1H NMR in D2O. Yields are given for isolated products.

b

Reaction was performed on a 3.0 mmol scale.

c

Products were obtained as amorphous solids.

d

Product was contaminated with about 10% of 14a.

e

Product was contaminated with about 15% of the azide product.

On the other hand, the azidation reactions of bromopyridinyl and iodonaphthyl organotrifluoroborates proceeded readily to give the desired azide compounds in excellent yields (Table 3, 9b12b and 16b). Naphthyl organotrifluoroborates were not suitable for this azidation because the resulting products were contaminated with the starting material or mixtures of azido- and aminoaryltrifluoroborates (Table 3, 14b and 15b).

We next examined the Suzuki-Miyaura cross-coupling reaction of 4-azidophenyltrifluoroborate (1b) and various aryl halides in the presence of Pd catalyst and 3.0 equiv of Cs2CO3 (Table 4). As expected, the coupling of aryl and heteroaryl bromides led to the corresponding target products in good yields. Aryl chlorides were generally ineffective as coupling partners.

Table 4.

Cross-Coupling Reactionsa

graphic file with name nihms-144872-f0072.jpg
entry R-X reaction conditions reaction time (h) product yield
1 graphic file with name nihms-144872-t0073.jpg A
B
graphic file with name nihms-144872-t0074.jpg 0.5
6
graphic file with name nihms-144872-t0075.jpg 17 85%
2 graphic file with name nihms-144872-t0076.jpg A
B
graphic file with name nihms-144872-t0077.jpg 1
6
graphic file with name nihms-144872-t0078.jpg 18 83%
48%
3 graphic file with name nihms-144872-t0079.jpg A
B
graphic file with name nihms-144872-t0080.jpg 0.5
3
graphic file with name nihms-144872-t0081.jpg 19 58%
45%
4 graphic file with name nihms-144872-t0082.jpg A 3 graphic file with name nihms-144872-t0083.jpg 20 81%
a

Reaction conditions A: potassium 4-azidophenyltrifluoroborate (1b, 0.2 mmol), aryl bromide (0.2 mmol), 10 mol % of PdCl2(dppf)·CH2Cl2, Cs2CO3 (0.6 mmol), MeOH (1.5 mL), 80 °C.; B: 1b (0.2 mmol), aryl chloride (0.2 mmol), 3 mol % of Pd(OAc)2, 6 mol % of XPhos, Cs2CO3(0.6 mmol), 1,4-dioxane/H2O (10/1, 1.5 mL), 100 °C. Yields are given for isolated products.

Finally, we examined one-pot sequential reactions that incorporated cross-coupling followed by 1,3-dipolar cycloaddition or NaBH4 reduction to the amine (eqs 1 and 2).6 These processes provided the desired compounds in good overall yields.

graphic file with name nihms-144872-f0084.jpg

In summary, we have developed a new synthetic method for the preparation of potassium azidoarytrifluoroborates from the corresponding haloaryltrifluoroborates. Additionally, we successfully cross-coupled the azido-functionalized organotrifluoroborates and carried out a one-pot sequential cross-coupling/1,3-dipolar cycloaddition and a one-pot cross-coupling/azide reduction process. Further investigations on transformations of azido-substituted trifluoroborates are currently underway in our laboratory.

Supplementary Material

1_si_001

Acknowledgment

This research was supported by KIST Institutional Program (2Z03270) and a grant from Marine Biotechnology Program funded by Ministry of Land, Transport and Maritime Affairs, Republic of Korea. Support from the NIH General Medical Sciences Institute (USA) is also acknowledged.

Footnotes

Supporting Information Available: General experimental procedures, compound characterization data, and NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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  • 6.For detailed procedures, see Supporting Information.

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