Cascade reaction of arylboronic acid and 2'-cyano-biaryl-2-aldehyde

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Cascade reaction of arylboronic acid and 2'-cyano-biaryl-2-aldehyde Ntosylhydrazones: Access to functionalized 9-amino-10-arylphenanthrenes Yueqiang Liu, Lingjuan Chen, Zhong Wang, Ping Liu, Yan Liu, and Bin Dai J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02605 • Publication Date (Web): 11 Dec 2018 Downloaded from http://pubs.acs.org on December 11, 2018

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The Journal of Organic Chemistry

Cascade reaction of arylboronic acid and 2'-cyano-biaryl-2-aldehyde N-tosylhydrazones:

Access

to

functionalized

9-amino-10-arylphenanthrenes Yueqiang Liu, Lingjuan Chen, Zhong Wang, Ping Liu*, Yan Liu*, and Bin Dai School of Chemistry and Chemical Engineering, the Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi City, 832004, China E-mail: [email protected] and [email protected]; Tel.: +86 0993 2057213; fax: +86 0993 2057270. CN Ar TsHNN

H 2N

1

Ar2

+ Ar3B(OH)2

Ar3

Na2CO3 Ar1

Ar2

27 examples 36-81% yields

Abstract: An efficient, general and convenient protocol for the synthesis of functionalized 9-amino-10-arylphenanthrene derivatives using a catalyst-free cascade reaction of arylboronic acid and 2'-cyano-biaryl-2-aldehyde N-tosylhydrazone is described. The synthesis was carried out using simple experimental conditions using Na2CO3 in 1,4-dioxane as a solvent. Moreover, the 9-amino-10-arylphenanthrene compounds were also obtained on a gram scale and further derivatized to synthesize the fused phenanthrene derivatives. Keywords: N-tosylhydrazones; arylboronic acid; phenanthrene; cascade reaction.

Introduction

ACS Paragon Plus Environment

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9-Aminophenanthrene proves to be an important structural scaffold frequently found in natural products,1 medicinal chemistry,2 and functional materials.3 Furthermore, 9-aminophenanthrene derivatives represent important synthons widely used in organic reactions due to the presence of easily accessible amino groups and other active sites.4 Classical

ways

to

access

9-aminophenanthrenes

include

nitro-reduction,5

amide-hydrolysis,6 and intramolecular cyclization.7 More recently, amination reactions of phenanthryl boronic acids or phenanthryl halides have been reported.8 In addition, coupling reactions prove to be effective for the construction of 9-aminophenanthrene derivatives.9 Despite significant advances that have been achieved in this field, the methods developed to date often suffer from limitations including poor accessibility of the starting materials, harsh reaction conditions, a narrow substrate scope, and the use of transition metal catalysts and/or organometallic reagents. Therefore, the development of an efficient, general and convenient protocol towards the synthesis of functionalized 9-aminophenanthrene derivatives remains a desirable target in synthetic organic chemistry. N-Tosylhydrazones, a class of readily accessible and excellent bench-stable diazo precursors, have been extensively used in organic synthesis.10,11 Since 2012, numerous applications have been reported in the literature describing the use of N-tosylhydrazones as starting materials in cross-coupling, insertion, olefination, alkynylation, and other reaction types.12-14 In particular, reactions generating various structurally important units in a one-pot and cascade manner proves to be critical in this field. Likewise, cyclization reactions using N-tosylhydrazone substrates offer an important method for the construction of phenanthrene ring systems. Wang et al. developed a Cu-catalyzed tandem reaction ACS Paragon Plus Environment

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between N-tosylhydrazones and terminal alkynes to generate substituted phenanthrenes (Scheme

1a

and

1b).15,16

In

addition,

a

metal-catalyzed

cyclization

of

bis(N-tosylhydrazone)s provided various polycyclic aromatic compounds (Scheme 1c).17,18 In 2013, Wang et al. reported a new cyclization process involving an diazo carbon insertion into a keto C-C bond as the key step to afford 9-hydroxy-phenanthrene derivatives (Scheme 1d).19

However,

to

the

best

of

our

knowledge,

tandem

reaction

involving

N-tosylhydrazones to construct 9-aminophenanthrene derivatives have never been reported to date. Scheme 1. Synthesis of phenanthrene derivatives via cyclization reactions involving N-tosylhydrazones. NNHTs Ar Ar1

Ar2

cat. CuBr2 (a)

Ar2

Rh2(OAc)4 (c)

TsHNN R

X=H X

Ar1

NNHTs Ar1

Ar X=H

X=H

R

NNHTs cat. CuI (b)

R = H, aryl, alkyl, alkenyl, alkynyl


Ar2

R

Ar2 X = OH

Ar1

O metal-free 1,2-shift (d)

Ar1 TsHNN

Ar2


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Scheme 2. Cyclization reactions of cyano-N-tosylhydrazones with boronic acids. (a) Valdés' work: NNHTs

R

N2

base

CN

CN

I

R

R

B(OH)2

R N B(OH)2

B(OH)2 CN

II

O

H 2O IV

III

(b) current prosposal: TsHNN

N2

R

RB(OH)2

base

B(OH)2

-N2 CN

HO

N II'

CN I' O

Ar

(HO)2B N

Ar

Ar

H 2O route 1 III'

IV'

V'

route 2 H 2N

Ar

(HO)2B NH

Ar

H 2O VI'

VII'

In 2016, Valdés et al. reported the carbocyclization of γ- or δ- cyano-N-tosylhydrazones with alkenylboronic acids to afford a series of cyclic ketone products.20 The mechanism proposed for this cascade reaction involved the addition of boronic acid to the diazo compound, nucleophilic attack of the allylboronic acid II to the cyano group, and hydrolysis of the imine III that provided the final product IV (Scheme 2a). Inspired by this work,

we

envisioned

that

the

cascade

reaction

of

boronic

acid

with

2'-cyano-biphenyl-2-aldehyde N-tosylhydrazones could proceed in a similar manner to ACS Paragon Plus Environment

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provide intermediate III’. Instead of the formation of ketone IV’ via hydrolysis (Scheme 2b, route 1), intermediate III’ was hypothesized to form intermediate VI’ via tautomerization and due to the stabilization of the entire conjugated structure. Subsequent hydrolysis may furnish the 9-aminophenanthrene compound VII’ (Scheme 2b, route 2). Herein, we report the realization of this hypothesis and the corresponding 9-amino-10-arylphenanthrene derivatives were readily synthesized through the catalyst-free tandem reaction of arylboronic acid and 2′-cyano-biaryl-2-aldehyde N-tosylhydrazones.

Results and Discussion Optimization of the reaction conditions Various 2'-formyl-[1,1'-biaryl]-2-carbonitrile derivatives 1 as starting material could be readily prepared in good yields by Suzuki-Miyaura reaction. The corresponding derivatives could then be transformed to N-tosylhydrazones in almost quantitative yields via reaction with p-toluenesulfonyl hydrazine in methanol. The solvent was then removed by rotary evaporation and the residual was dried in vacuo to obtain the tosylhydrazone 2. The latter compound was then used in the next step without further purification (Scheme 3). Scheme 3. Preparation of 2'-formyl-[1,1'-biaryl]-2-carbonitrile derivatives Bpin Ar1

+

O

Ar2

CN

Br or

Ar2

O Bpin

Br +

Ar1 CN

Suzuki coupling

CN

CN Ar

1

O

TsNHNH2 Ar2

1, 30-98% yields

MeOH

Ar

1

TsHNN

Ar2

2, >95% yields

The reaction of N-tosylhydrazone 2a with phenylboronic acid was employed as a model reaction to assess the optimal reaction conditions (Table 1). Using K2CO3 as a base,



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reaction in 1,4-dioxane at 110 ºC for 5 hours afforded the targeted cyclization product 3a in 56% yield and the coupling byproduct 3a′ in 33% yield (entry 1). In an effort to further improve the yield of intermediate 3a, various bases and solvents were screened. Among the studied bases, Na2CO3 provided the highest yield of compound 3a (76%, entry 9). Other bases, including Cs2CO3, K3PO4, Li2CO3, NaHCO3, CH3COONa, t-BuOK and organic bases did not result in a further yield increase (entries 2-8). Moreover, the use of different solvents (entries 10-13) did not lead to a further increase in yield. Further adjustments of the

reaction

temperature

resulted

in

lower

reaction

yields

(entries

14-16).

4,4,5,5-Tetramethyl-2-phenyl-1,3,2-dioxaborolane proved to ineffective for this reaction (entry

17).

When

N-4-methoxybenzenesulfonyl

4-methoxybenzenesulfonyl

hydrazone

derived

from

hydrazine

2'-formyl-4',5'-dimethoxy-[1,1'-biphenyl]-2-carbonitrile

was

with employed

instead

of

N-tosylhydrazone 2a, the yield was not improved (entry 18). The optimal condition was obtained using Na2CO3 as a base, 1,4-dioxane as a solvent at a reaction temperature of 110 ºC (entry 9). Table 1. Optimization of the reaction conditionsa. H 2N

CN OMe TsHNN

Ph

CN

PhB(OH)2 conditions

OMe

OMe

OMe

2a

+

OMe Ph

3a

OMe 3a'

Entry Solvent

Base

Yield/3a(%)a Yield/3a′(%)a

1

K2CO3

56

1,4-Dioxane


33

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2

1,4-Dioxane

Cs2CO3

55

35

3

1,4-Dioxane

K3PO4

26

56

4

1,4-Dioxane

Li2CO3

0

0

5

1,4-Dioxane

NaHCO3

Cascade reaction of arylboronic acid and 2'-cyano-biaryl-2-aldehyde

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