Article pubs.acs.org/joc
TMSCl-Mediated Synthesis of α,β-Unsaturated Amides via C−C Bond Cleavage and C−N Bond Formation of Propargyl Alcohols with Trimethylsilyl Azide Xian-Rong Song, Bo Song, Yi-Feng Qiu, Ya-Ping Han, Zi-Hang Qiu, Xin-Hua Hao, Xue-Yuan Liu, and Yong-Min Liang* State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China S Supporting Information *
ABSTRACT: A new method with high efficiency for the synthesis of α,β-unsaturated amides from the easily prepared propargyl alcohols and TMSN3 using TMSCl as an acid promoter is developed. A wide variety of α,β-unsaturated amides were produced in moderate to excellent yields. Mechanistic studies indicate that this transformation involves TMSCl-mediated allenylazide intermediate formation, C−C bond cleavage, and C−N bond formation. Significantly, this reaction shows good functional group compatibility and high regioselectivity, with a relatively short reaction time and inexpensive reagents.
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INTRODUCTION In recent years, the transformations of vinyl azides have become powerful and novel methods for the constructions of various nitrogen-containing molecules and have attracted an increasing attention for their potential intrinsic reactivity.1 Furthermore, the azide group close to the alkene unit plays an important role in improving the reactivity of alkenes,2 which stimulates chemists to use vinyl azides as enamine-type nucleophiles to react with electrophiles for the efficient construction of bioactive compounds, especially amide derivatives. Amides are useful structural skeletons in a wide variety of pharmaceuticals, bioactive molecules, and functional materials.3 Therefore, the development of atom- and step-economical approaches to the synthesis of the amide-containing compounds has attracted considerable attention in organic chemistry.4,5 Recently, the Jiao group developed an interesting method for the synthesis of amides from alkynes.6 It was based on a gold-catalyzed transformation of alkynes with TMSN3, which involved a vinyl azide intermediate [Scheme 1, eq (1)]. More recently, Chiba and co-workers reported the remarkable conversion of vinyl azides into amides using carbon electrophiles (E+) and BF3·OEt2 as a Lewis acid promoter [Scheme 1, eq (2)].7 Inspired by these intriguing studies and based on our work on the application of propargylic alcohols in organic synthesis, we envisioned that it was possible for allenylazides instead of vinyl azides to react with electrophiles for their high nucleophilicities similar to alkene. Such transformations should be highly dependent on the synthesis of the allenylazides. However, the synthesis of allenylazides remained challenging due to their extreme instability.8 Fortunately, chemists have developed another strategy as an alternative method in situ to © 2014 American Chemical Society
form allenylazides by the nucleophilic addition of azides to propargyl alcohols. In 2013, Tanimoto and co-workers reported a Lewis acid mediated synthesis of trizoles from propargyl alcohols and organic azides via allenylazide intermediates [Scheme 1, eq (3)].9 In 2014, the Jiao group reported the reaction of terminal alkynols with TMSN3 in the presence of sulfuric acid to afford alkenyl nitriles via allenylazide intermediates [Scheme 1, eq (4)].10 Despite the significant progress in the area of C−N bond formation through allenylazides, the synthesis of amides from easily prepared propargyl alcohols and TMSN3 through C−C bond cleavage and C−N bond formation is still extremely attractive and challenging. More recently, our group reported Lewis acid mediated propargyl alcohols with TMSN3 through allenylazide intermediates to produce tetrazoles [Scheme 1, eq (5)].11The proposed mechanism involves the Schimidt-type rearrangement of allenylazide intermediate to form intermediate I. Thus, we envisioned that, if the intermediate I could be trapped by water, the overall transformation would lead to the formation of the α,β-unsaturated amides. Herein, we report a new method for the synthesis of amides by a C−C bond cleavage and C−N bond formation strategy that features allenylazides as intermediates through nucleophilic addition of azides to propargyl alcohols.
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RESULTS AND DISCUSSION Our study to explore the designed reaction started with propargyl alcohol 1a and TMSN3 in the presence of acid as the Received: June 23, 2014 Published: July 23, 2014 7616
dx.doi.org/10.1021/jo5013948 | J. Org. Chem. 2014, 79, 7616−7625
The Journal of Organic Chemistry
Article
Scheme 1. New Strategies for the Synthesis of Amides via C−C Bond Cleavage and C−N Bond Formation
Table 1. Optimization of the Reaction Conditionsa
yield (%) entry
acid (equiv)
TMSN3 (equiv)
solvent
2a
6
1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e 16f 17g 18h 19i 20j 21k 22l 23
TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TFA (1.0) BF3·OEt2 (1.0) p-TsOH (1.0) TMSCl (2.0) TMSCl (2.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) conc. HCl (3.0) AcCl (3.0)
2.0 2.0 2.0 2.0 2.0 3.0 3.0 3.0 3.0 3.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0
MeCN CH3NO2 HOAc toluene 1,4-dioxane HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc
35 45 50 traceb traceb 65 40
TMSCl-Mediated Synthesis of α,β-Unsaturated Amides via C−C Bond Cleavage and C−N Bond Formation of Propargyl Alcohols with Trimethylsilyl Azide Xian-Rong Song, Bo Song, Yi-Feng Qiu, Ya-Ping Han, Zi-Hang Qiu, Xin-Hua Hao, Xue-Yuan Liu, and Yong-Min Liang* State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China S Supporting Information *
ABSTRACT: A new method with high efficiency for the synthesis of α,β-unsaturated amides from the easily prepared propargyl alcohols and TMSN3 using TMSCl as an acid promoter is developed. A wide variety of α,β-unsaturated amides were produced in moderate to excellent yields. Mechanistic studies indicate that this transformation involves TMSCl-mediated allenylazide intermediate formation, C−C bond cleavage, and C−N bond formation. Significantly, this reaction shows good functional group compatibility and high regioselectivity, with a relatively short reaction time and inexpensive reagents.
■
INTRODUCTION In recent years, the transformations of vinyl azides have become powerful and novel methods for the constructions of various nitrogen-containing molecules and have attracted an increasing attention for their potential intrinsic reactivity.1 Furthermore, the azide group close to the alkene unit plays an important role in improving the reactivity of alkenes,2 which stimulates chemists to use vinyl azides as enamine-type nucleophiles to react with electrophiles for the efficient construction of bioactive compounds, especially amide derivatives. Amides are useful structural skeletons in a wide variety of pharmaceuticals, bioactive molecules, and functional materials.3 Therefore, the development of atom- and step-economical approaches to the synthesis of the amide-containing compounds has attracted considerable attention in organic chemistry.4,5 Recently, the Jiao group developed an interesting method for the synthesis of amides from alkynes.6 It was based on a gold-catalyzed transformation of alkynes with TMSN3, which involved a vinyl azide intermediate [Scheme 1, eq (1)]. More recently, Chiba and co-workers reported the remarkable conversion of vinyl azides into amides using carbon electrophiles (E+) and BF3·OEt2 as a Lewis acid promoter [Scheme 1, eq (2)].7 Inspired by these intriguing studies and based on our work on the application of propargylic alcohols in organic synthesis, we envisioned that it was possible for allenylazides instead of vinyl azides to react with electrophiles for their high nucleophilicities similar to alkene. Such transformations should be highly dependent on the synthesis of the allenylazides. However, the synthesis of allenylazides remained challenging due to their extreme instability.8 Fortunately, chemists have developed another strategy as an alternative method in situ to © 2014 American Chemical Society
form allenylazides by the nucleophilic addition of azides to propargyl alcohols. In 2013, Tanimoto and co-workers reported a Lewis acid mediated synthesis of trizoles from propargyl alcohols and organic azides via allenylazide intermediates [Scheme 1, eq (3)].9 In 2014, the Jiao group reported the reaction of terminal alkynols with TMSN3 in the presence of sulfuric acid to afford alkenyl nitriles via allenylazide intermediates [Scheme 1, eq (4)].10 Despite the significant progress in the area of C−N bond formation through allenylazides, the synthesis of amides from easily prepared propargyl alcohols and TMSN3 through C−C bond cleavage and C−N bond formation is still extremely attractive and challenging. More recently, our group reported Lewis acid mediated propargyl alcohols with TMSN3 through allenylazide intermediates to produce tetrazoles [Scheme 1, eq (5)].11The proposed mechanism involves the Schimidt-type rearrangement of allenylazide intermediate to form intermediate I. Thus, we envisioned that, if the intermediate I could be trapped by water, the overall transformation would lead to the formation of the α,β-unsaturated amides. Herein, we report a new method for the synthesis of amides by a C−C bond cleavage and C−N bond formation strategy that features allenylazides as intermediates through nucleophilic addition of azides to propargyl alcohols.
■
RESULTS AND DISCUSSION Our study to explore the designed reaction started with propargyl alcohol 1a and TMSN3 in the presence of acid as the Received: June 23, 2014 Published: July 23, 2014 7616
dx.doi.org/10.1021/jo5013948 | J. Org. Chem. 2014, 79, 7616−7625
The Journal of Organic Chemistry
Article
Scheme 1. New Strategies for the Synthesis of Amides via C−C Bond Cleavage and C−N Bond Formation
Table 1. Optimization of the Reaction Conditionsa
yield (%) entry
acid (equiv)
TMSN3 (equiv)
solvent
2a
6
1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e 16f 17g 18h 19i 20j 21k 22l 23
TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TMSCl (1.0) TFA (1.0) BF3·OEt2 (1.0) p-TsOH (1.0) TMSCl (2.0) TMSCl (2.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) TMSCl (3.0) conc. HCl (3.0) AcCl (3.0)
2.0 2.0 2.0 2.0 2.0 3.0 3.0 3.0 3.0 3.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0
MeCN CH3NO2 HOAc toluene 1,4-dioxane HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc HOAc
35 45 50 traceb traceb 65 40
