Copper catalyzed reduction of azides with diboron under mild conditions

Journal Pre-proofs Copper Catalyzed Reduction of Azides with Diboron under Mild Conditions Liwen Liu, Qianwen Wang, Yu Liu, Xiao Zhang, Da Lu, Shengqi Deng, Yihua Gao, Yang Chen PII: DOI: Reference:

S0040-4039(20)30125-8 https://doi.org/10.1016/j.tetlet.2020.151702 TETL 151702

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Tetrahedron Letters

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12 December 2019 31 January 2020 2 February 2020

Please cite this article as: Liu, L., Wang, Q., Liu, Y., Zhang, X., Lu, D., Deng, S., Gao, Y., Chen, Y., Copper Catalyzed Reduction of Azides with Diboron under Mild Conditions, Tetrahedron Letters (2020), doi: https:// doi.org/10.1016/j.tetlet.2020.151702

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Copper Catalyzed Reduction of Azides with Diboron under Mild Conditions

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Liwen Liu, Qianwen Wang, Yu Liu, Xiao Zhang, Da Lu, Shengqi Deng, Yihua Gao and Yang Chen* R N3 1

CuCl, IAmd•HCl, B2pin2 KOtBu, toluene, 25 °C, 4 h

R NH2

R = alkyl, aryl, acyl; 20 examples, up to 96% yield.  Mild reaction conditions  Good functional group tolerance  High chemoselectivity  Applicable to sterically hindered azides

2

1

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Copper Catalyzed Reduction of Azides with Diboron under Mild Conditions Liwen Liua, Qianwen Wanga , Yu Liua , Xiao Zhanga , Da Lua , Shengqi Denga , Yihua Gaob and Yang Chena,  Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610052, PR China b Analysis Center, Guangdong Medical University, Dongguan, PR China a

———

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

We report herein the first Cu catalyzed reduction of azides with B2pin2 (pin = pinacolato) as the reductant under very mild conditions. A series of primary amines and amides were obtained in moderate to excellent yields with high chemoselectivity and good functional group tolerance. This reaction can be performed with a cheap copper salt, a simple NHC ligand and a diboron reagent.

 Corresponding author. E-mail address: [email protected] (Y. Chen)

2009 Elsevier Ltd. All rights reserved.

Keywords: azide diboron copper catalyzed reduction

Introduction Organic azides are valuable synthetic intermediates that have extensive use in the synthesis of nitrogen containing compounds [1]. The reduction of azides to the corresponding primary amines or amides represents a very important transformation in organic synthesis. Therefore, a large number of methods have been reported to achieve this conversion. Generally, hydrogen gas, triphenylphosphine and its derivatives, hydrosilanes, aluminum or boron hydrides, metals or metal salts and some radical reagents are employed as the most common reductants for this transformation [2]. Despite much progress has been made, there are still some limitations such as poor chemoselectivities, limited substrate scopes, harsh conditions and difficult workup procedures [3]. In fact, it is necessary to develop more simple, efficient and chemoselective synthetic procedures in the future. Diboron derivatives of the type B2(OR)4 are highly important reagents and widely used in synthetic and materials chemistry [4]. For instance, these compounds are often employed for the substitution, reduction or borylation of organic substrates such as aryl halides, alkenes, alkynes, unsaturated carbonyl and nitro compounds in many transition metal and/or Lewis base promoted reactions [5]. In the last few years, numerous N-Heterocyclic carbene ligated copper complexes acting as catalysts in a variety of reactions have been reported [6]. In 2005, Sadighi reported the preparation of the first well-defined copper boryl complex [(IPr)Cu(Bpin)] (IPr = N,N’-bis-(2,6diisopropylphenyl)imidazol-2-ylidene) and its reactivity studies. Since then, the CuX/NHC salt (X = I, Br, Cl; NHC = Nheterocyclic carbenes) catalyst precursors or well-defined NHC-

Cu complexes have been extensively studied as the catalysts for various reduction or borylation reactions using diboron reagents [7]. Although the reduction reactions of azides with boron hydrides are well studied [8], but to date, reaction of azides with diboron reagents has not been reported yet. In our previous work, we have discovered that the NHC⋅HCl/CuCl/KOtBu (NHC= NHeterocyclic carbene) system could efficiently catalyze the reduction of azides with hydrosilanes [2f, 2g]. Inspired by this work, we started to explore the Cu catalyzed reduction or borylation reactions of azides with diborons. Herein, we disclose for the first time a general CuCl/IAmd·HCl (IAmd = N,N’-bis(adamantyl)-imidazol-2ylidene) catalyzed reduction method of azides with B2pin2 (pin = pinacolato) under very mild conditions. Results and discussion Initially, 4-methoxylphenyl azide was used as a model substrate. Various reaction conditions including copper salts, ligands, bases, diborons, solvents, temperatures and reaction times were screened (Table 1). As we expected, the desired amine 2a could be obtained after workup procedures in moderate to high yields (33-96%) with CuCl/Imidazolium salt catalyst precursors (5 mol%) and B2pin2 (2 equiv) as the reducing agent in the presence of KOtBu (1 equiv) at 25 C (Table 1, entries 1–5). Obviously, the Imidazolium salt precursor IAmd·HCl which was converted to the NHC ligand IAmd after reaction with KOtBu was found to give optimal results (Table 1, Entry 5).

Tetrahedron Letters

2

Next, a screening of the solvents established that other solvents such as THF, 1,4-dioxane, and acetonitrile did not improve the reaction efficiency even with prolonged time and higher reaction temperatures (Table 1, entries 6–8). A survey of the bases revealed that KOtBu was superior to other bases, such as NaOtBu, NaOMe and NaOEt (Table 1, entries 9-11).

The diboron B2pin2 can be substituted by B2neop2 (neop = neopentyl glycolato) to give the corresponding amine 2a in a slightly lower yield than those observed for B2pin2. However, the diboronic acid B2(OH)4 was unreactive under the standard conditions, possibly due to poor solubility or formation of the unstable catalytic intermediates (Table 1, entries 12 and 13).

reaction time (6 h) (Table 1, entry 14). However, considering the operational simplicity, the catalyst loading of 10 mol% of CuCl/IAmd·HCl was selected as an optimum amount. Subsequently, different copper salts were screened. Other copper salts such as CuCl2, CuBr2, CuBr and CuI were significantly less effective than CuCl (Table 1, entries 15-18). In the control experiments, the reaction did not occur in the absence of any catalyst, ligand or KOtBu (Table 1, entries 19-21). Finally, we established the optimal protocol involving 10 mol% catalyst loading with B2pin2 (2 equiv) for 4 h at 25 C (Table 1, entry 5).

In additional, it is notable that 1a could be completely converted to 2a with 5 mol% of CuCl/IAmd·HCl with longer

Table 1. Optimization of the reaction conditions O +

Diboron

1), conditions

O

2), 1M HCl

NH2

N3 1a

2a

Entry

Copper salt

Imidazolium salt

Base

Diboron

Solvent

Temperature [C]

Reaction time [h]

Yield [%] a, b

1

CuCl

IMes·HCl

KOtBu

B2pin2

Toluene

25

8

85

2

KOtBu

B2pin2

Toluene

25

8

87

25

8

33

CuCl

IPr·HCl

3

CuCl

ItBu·HBF4

KOtBu

B2pin2

Toluene

4

CuCl

IXy·HCl

KOtBu

B2pin2

Toluene

25

8

76

5

CuCl

IAmd·HCl

KOtBu

B2pin2

Toluene

25

4

96

6

CuCl

IAmd·HCl

KOtBu

B2pin2

THF

55

16

85

7

CuCl

IAmd·HCl

KOtBu

B2pin2

1,4-Dioxane

65

16

83

8

CuCl

IAmd·HCl

KOtBu

B2pin2

Acetonitrile

40

16

78

9

CuCl

IAmd·HCl

NaOtBu

B2pin2

Toluene

25

8

85

10

CuCl

IAmd·HCl

NaOEt

B2pin2

Toluene

25

4

86

11

CuCl

IAmd·HCl

NaOMe

B2pin2

Toluene

25

4

74

12

CuCl

IAmd·HCl

KOtBu

B2neop2

Toluene

25

4

84

CuCl

IAmd·HCl

KOtBu

B2(OH)4

Toluene

25

4

trace

KOtBu

B2pin2

Toluene

25

6

90

25

4

74

13 14

CuCl

IAmd·HCl

15

CuCl2

IAmd·HCl

KOtBu

B2pin2

Toluene

16

CuBr2

IAmd·HCl

KOtBu

B2pin2

Toluene

25

4

71

17

CuBr

IAmd·HCl

KOtBu

B2pin2

Toluene

25

4

78

18

CuI

IAmd·HCl

KOtBu

B2pin2

Toluene

25

4

81

19

CuCl

none

KOtBu

B2pin2

Toluene

25

8

0

20

CuCl

IAmd·HCl

none

B2pin2

Toluene

25

8

0

21

none

none

KOtBu

B2pin2

Toluene

25

8

0

c

Reaction conditions: 1a (0.5 mmol), diboron (1.0 mmol), copper salt (0.05 mmol), Imidazolium salt (0.05 mmol), base (0.5 mmol) and solvent (2.0 mL) in a 10 mL Schlenk tube under Argon atmosphere. b Isolated yield. Workup procedures: The reaction was quenched by adding 1M HCl aqueous solution to adjust PH = 4.0. Then Na2CO3 was added to the mixture to adjust PH = 8.0. The mixture was extracted with ethyl acetate for two times. The organic phase was washed with brine and evaporated to dryness to afford the crude 2a which was finally purified by silica column chromatography. c 5 mol% CuCl/IAmd·HCl were used as the catalyst precursor. a

R 2,6-diisopropylphenyl R N

N R H Cl

2,6-dimethylphenyl 2,4,6-trimethylphenylphenyl adamantyl

NHC•HCl IPr•HCl IXy•HCl IMes•HCl IAmd•HCl

ItBu•HBF4 =

N

N H BF4

3 Having the best reaction condition in hand, the scope and limitations of the Cu catalyzed reduction of azides with B2pin2 were studied. Results are summarized in Table 2.

Table 2. Substrate scope of Cu catalyzed reduction of azides with diboron a, b CuCl, IAmd•HCl, B2pin2 R NH2 R N3 KOtBu, toluene, 25 °C, 4 h 1 2 F

O

Cl NH2

NH2 2a, 96%

NH2

2b, 52%

2c, 92%

Br NH2

NH2

NH2

2d, 85%

2e, 83%

NH2

NH2

NH2 2g, 87%

2i, 89%

2h, 94%

NH2 NH2

NH2 2j, 61%

The reduction reactions of aryl azides ran smoothly, and gave the anilines in moderate to excellent yields (52-96%) (Table 2, entries 2a-i). The halogen substituted phenyl azides could be converted to the corresponding anilines in moderate to good yields (Table 2, entries 2b-d). Reducible groups such as nitro, cyano and methoxycarbonyl remained unchanged during the reactions (Table 2, entries 2g-i). For the sterically hindered substituted 2,6-diisopropylphenyl azide (Table 2, entry 2f), the yield was 91%. Incorporated with the results of 2a-i, 2m, 2q and 2s, both electron-withdrawing and electron-donating substituents did not show any significant influence on the reduction (Table 2, entries 2a-i, 2m, 2q and 2s). It is noteworthy that the reactions of 2-nitrophenyl azide and 4-nitrobenzoyl azide also achieved (Table 2, entries 2g and 2q). These results showed that the nitro group was fully compatible with this reaction. The catalytic system was also adapted to aliphatic azides and given the corresponding amines in moderate to good yields (6195%) (Table 2, entries 2j-o). The C-C double bond was unaffected in this reaction (Table 2, entry 2o).

2f, 91% MeOOC

NO2 NC

Most of the aromatic, aliphatic and acyl azides could be converted to the corresponding primary amines and amides in moderate to excellent yields. Functional groups like halide, nitro, ester, cyano and alkenyl were all fully compatible with the employed reaction conditions (Table 2, entries 2b-d, 2g-i, 2o and 2q).

It is important to point out that the sterically hindered amines 2f, 2l and 2n were obtained in excellent yields (91-95%) (Table 2, entries 2f, 2l and 2n). These results indicated that the catalytic system might be more suitable for the reduction of azides with bulky substituents.

NHC•HCl + CuCl 2l, 92%

2k, 73%

R N N

NH2

NH2

NH2

A

KOtBu

Bpin Bpin

LCuOtBu B2pin2 LCuBpin

R N N2

B2pin2 LCu

2m, 78%

L = NHC

2n, 95%

2o, 87%

LCu

R N Bpin

Bpin

R N N2

O2N NH2 O 2p, 88%

NH2 O 2q, 92%

O

O NH2 O 2s, 94%

NH2 O

-N2

2r, 91%

O NH2

2t, 93%

a Reaction conditions: 1 (1.0 mmol), B pin (2.0 mmol), CuCl (0.1 mmol), 2 2 IAmd·HCl (0. 1 mmol), KOtBu (1.0 mmol) and toluene (2 mL) in a 10 mL Schlenk tube at 25 C for 4 h under Argon atmosphere. b Isolated yield after workup and purification.

R N

Bpin

HCl, H2O

R NH2 Bpin 2 A Scheme 1. Proposed reaction mechanism. Furthermore, the reactions of acyl azides afforded the corresponding primary amides in good to excellent yields (8894%) (Table 2, entries 2p-t). These reactions were carried out under very mild conditions (25 C, 4 h) and the common Curtius rearrangement by-product was completely not formed. The heterocyclic furan ring was stable during the reaction (Table 2, entry 2t). This type of reaction provides a synthetically useful

Tetrahedron

4

and mild alternative method for the synthesis of primary amides from acyl azides. Other azide substrates with aldehyde, ketone, carboxyl, hydroxyl and alkynl groups were also investigated. Unfortunately, the results showed that this method was not compatible with those functional groups. A proposed mechanism for the reduction is illustrated in Scheme 1. The key active catalyst, a copper boryl species (IPr)CuBpin is formed via a σ-bond metathesis reaction.[7] The reaction between this copper boryl complex and the azide would generate a copper (II) amide. In the last step, this copper amide reacts with B2pin2 to form the diborylamine compound A and regenerate the active catalyst. The compound A is hydrolyzed to give the amine product. All attempts to isolate the diborylamine intermediate A have so far failed, possibly due to its high air and moisture sensitivities [9]. In conclusion, we have reported the first NHC-copper catalyzed reduction of azides to amines/amides by reaction with diborons. The most efficient CuCl/IAmd·HCl catalytic system by employing B2pin2 as the reducing agent is developed. This method can perform the reductions of aromatic, aliphatic and acyl azides to the corresponding amines/amides with good chemoselectivity and high functional group tolerance under very mild conditions. The reaction employs a cheap copper salt as the catalyst, a simple NHC as the ligand, a safe diboron B2pin2 as the reducing agent, is chemoselective and convenient for work-up and purification. Further investigations on the synthetic applications of this method are in progress in our laboratory.

3. 4.

5.

6.

Acknowledgments 7.

We gratefully acknowledge grants from the Sichuan Science and Technology Program (2019YJ0284), the Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province (ARRLKF18-04), the Educational Commission of Sichuan Province of China (18ZB0134) and Chengdu University (2081916036). Supplementary data 8.

Supplementary data to this article can be found online at References and notes 9. 1.

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• Mild reaction conditions, good functional group tolerance, high chemoselectivity. • Applicable to sterically hindered azides Declaration of interests

5  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: