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Application of Organic Azides for the Synthesis of Nitrogen-Containing Molecules

Shunsuke Chiba*

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore Fax +6567911961; E-mail: [email protected]

Received 31 May 2012

Organic azides possess diverse chemical reactivities.4 Owing to their 1,3-dipole character, they undergo [3+2] cycloaddition with unsaturated bonds, such as those in alkynes and alkenes as well as carbonitriles (Scheme 1, part a).5 Organic azides can also be regarded as nitrene equivalents (Scheme 1, part b).6 Accordingly, their reactions with nucleophilic anions, electrophilic cations, and radicals can formally provide the corresponding nitrogen anions, cations, and radicals, respectively, forming a new bond with the internal azido nitrogen and releasing molecular nitrogen. Moreover, the generation of anions, cations, and radicals at the a-position to the azido moiety can result in rapid denitrogenation to deliver the corresponding iminyl species, which can be used in further synthetic transformations (i.e., carbon–nitrogen bond formation).

Abstract: In this account, recent advances made on the reactions of several types of organic azides, such as vinyl azides, cyclic 2-azido alcohols, a-azido carbonyl compounds, towards the synthesis of nitrogen-containing molecules are described.

  • 1
  • Introduction

  • 2
  • Chemistry of Vinyl Azides

  • 2.1
  • Thermal [3+2]-Annulation of Vinyl Azides with 1,3-Dicar-

bonyl Compounds
2.2

2.3 2.4
Manganese(III)-Catalyzed Formal [3+2]-Annulation with 1,3-Dicarbonyl Compounds Manganese(III)-Mediated/Catalyzed Formal [3+3]-Annulation with Cyclopropanols Synthesis of Isoquinolines from a-Aryl-Substituted Vinyl Azides and Internal Alkynes by Rhodium–Copper Bimetallic Cooperation
33.1
Chemistry of Cyclic 2-Azido Alcohols Manganese(III)-Catalyzed Ring Expansion of 2-Azidocyclobutanols

(a) 1,3-Dipoles

N
R

N

N

  • 3.2
  • Palladium(II)-Catalyzed Ring Expansion of Cyclic 2-Azido

Alcohols

  • C
  • C

  • N
  • alkenes

alkynes nitriles
RR

NN

  • N
  • N

CCCCCN

R

N

C

Ntriazolines

44.1
Chemistry of a-Azido Carbonyl Compounds Orthogonal Synthesis of Isoindole and Isoquinoline Derivatives

+

C

Ntriazoles
R

N

C

N

  • N
  • N

N

tetrazoles

  • 4.2
  • Generation of Iminylcopper Species and Their Catalytic

Carbon–Carbon Bond Cleavage under an Oxygen Atmosphere

(b) Nitrene equivalents

+

N2

R

N

  • N
  • N
  • R

N

4.3 5
Copper(II)-Catalyzed Aerobic Synthesis of Azaspirocyclohexadienones Conclusion

nitrenes

with carbanions or other nucleophiles

R

N

  • N
  • N

X–

  • +
  • +

+
RR

N

XC

N2

Key words: azides, nitrogen-containing heterocycles, radical reactions, redox reactions, oxygenations

with carbocations

R

N

  • N
  • N

C+

+

N

N2 N2

with carbon radicals

+
R

N

  • N
  • N

C

  • +
  • R

N

C

  • 1
  • Introduction

chemistry of α-azido anions, cations, and radicals
CCC

NNN

NNNNNN
+++

CCC

NNN

N2 N2 N2

The chemistry of organic azides commenced with the synthesis of phenyl azide by Griess in 18641 and the discovery of the rearrangement of acyl compounds with hydrogen azide (HN3) by Curtius in 1890.2 Since 1950, various synthetic organic reactions have been developed using acyl, aryl, and alkyl azides, which have been extensively applied for the synthesis of nitrogen-containing azaheterocycles as well as peptides.3

Scheme 1

We have been interested in the intriguing chemical reactivity of organic azides, such as vinyl azides, cyclic 2-azido alcohols, and a-azido carbonyl compounds (Scheme 2). In this account, we describe recent advances made on the reactions of these organic azides towards the synthesis of nitrogen-containing molecules which have been developed in our research group.

SYNLETT 2012, 23, 21–44

  • x
  • x
  • .x
  • x
  • .2
  • 0
  • 1
  • 1

Advanced online publication: 09.12.2011 DOI: 10.1055/s-0031-1290108; Art ID: A59911ST © Georg Thieme Verlag Stuttgart · New York

22

S. Chiba

ACCOUNT

NN

N

inyl species serve for the formation of carbon–nitrogen bonds. In this section, we present the synthesis of azaheterocycles from vinyl azides via several types of reaction mode based on the above chemical reactivities.

NN

N

R

N

NN
HO
R'

R

O

a-azido carbonyl compounds cyclic 2-azido alcohols vinyl azides

  • 2.1
  • Thermal [3+2]-Annulation of Vinyl Azides

with 1,3-Dicarbonyl Compounds

Scheme 2

During the course of our study on the chemistry of 2H- azirine derivatives,11 it was found that the reaction of azirine 1 with acetylacetone (2) in 1,2-dichloroethane at room temperature gave tetrasubstituted pyrrole 3 in quantitative yield after 33 hours (Scheme 4).

  • 2
  • Chemistry of Vinyl Azides

Intermolecular annulation reactions can allow for the straightforward and selective construction of complex cyclic molecular structures in a one-pot manner from relatively simple building blocks, one of the most ideal processes in organic synthesis from an atom-7 and stepeconomical8 point of view. Inspired by this perspective, we have recently been interested in the application of vinyl azides as a three-atom unit including one nitrogen for various types of annulation reactions to prepare azaheterocycles.

EtO2C Cl
COMe Me
Cl

  • O
  • O
  • CO2Et

+

N

Cl

1

N

  • Me
  • Me

DCE r.t., 33 h

H

Cl

2 (1.2 equiv)
3 quant

Scheme 4

While the reaction of azirine 1 with acetylacetone (2) in tetrahydrofuran (THF) has been reported, the yield of pyrrole 3 was low.12 The generation of 3 in high yield in the above reaction (Scheme 4) led us to further investigate the pyrrole formation.
One of the attractive chemical properties of vinyl azides is their ability to undergo thermal decomposition to give highly strained three-membered cyclic imines, 2H-azirines, via vinylnitrene intermediates following denitrogenation (Scheme 3, part a).9 Moreover, the carbon–carbon double bond of vinyl azides can be used for the formation of new carbon–carbon bonds with appropriate organometallic compounds (R′–[M]) or radical species (R¢) which results in the generation of iminyl metals or iminyl radicals, respectively (Scheme 3, parts b and c).10 These im-
The reaction may proceed through the addition of acetylacetone (2) to the imino carbon of azirine 1,13 followed by nucleophilic attack of the nitrogen in the resulting aziridine to a carbonyl group with concurrent ring opening of the strained three-membered ring.14 However, the instability and poor accessibility of the 2H-azirines prevented us using this strategy as a synthetic method for pyrroles. Accordingly, we planned to use vinyl azides as precursors of 2H-azirines which can be easily synthesized15 and handled (Scheme 5).

R
R
R

Δ

N

NN
(a)

N

– N2

N

2H-azirines vinylnitrenes

R

R
R

As proposed in Scheme 5, simple heating of a mixture of ethyl 2-azido-3-(2,6-dichlorophenyl)acrylate (4) and acetylacetone (2) in toluene at 100 °C provided pyrrole 5 in 86% yield (Table 1, entry 1).16 Various 2-azido-substituted cinnamates possessing electron-donating and -withdrawing groups on the phenyl group (entries 2–8), as well as a derivative containing a pyridyl moiety (entry 9), reacted with acetylacetone (2) to give the corresponding 2-

R
R'
R'
R'–[M]
[M]

N

NN

N

NN
(b) (c)

N

[M]
– N2
R
R'
R'
R

N

NN

N

NN
R'
– N2

N

Scheme 3

Biographical Sketch

  • Shunsuke Chiba was born University of Tokyo (work- Nanyang
  • Technological

in Zushi, Kanagawa, Japan, ing under Professor Koichi University, Singapore, as an in 1978. He obtained his Narasaka). He was appoint- assistant professor. His reB.Eng. from Waseda Uni- ed as a research associate at search focus is methodology versity in 2001 and received the University of Tokyo in development in the area of his Ph.D. in 2006 from the 2005. In 2007, he moved to synthetic organic chemistry.

Synlett 2012, 23, 21–44

© Thieme Stuttgart · New York

ACCOUNT

Applications of Organic Azides for the Synthesis of Nitrogen-Containing Molecules

23

indoles via intramolecular C–H amination.17,18 It is noteworthy that the above intermolecular reactions of 2-azidosubstituted cinnamate derivatives with acetylacetone (2) gave pyrroles exclusively without any indole formation.

  • R2
  • R2

R1

COMe Me

R1

  • O
  • O

Δ

– N2 – H2O
+

N

  • Me
  • Me

N

N2

H

2

– N2
– H2O

As b-substituents (R1) of azidoacrylates, ethoxycarbonyl and alkyl groups could be introduced, giving the corresponding pyrroles in good yields (entries 12 and 13). Simple azidoacrylate 30 also reacted smoothly (entry 14). Using a-aryl-substituted vinyl azides, not only phenyl groups, but also naphthyl, indolyl, pyrrolyl, and benzothiophenyl moieties could be installed at the 3-position of the resulting trisubstituted pyrroles (entries 15–26). aAlkyl-substituted vinyl azide 56 reacted smoothly to give the corresponding pyrrole 57 in 82% yield (entry 27). An E,Z-mixture of 2-phenylvinyl azide (58) could also be used to prepare trisubstituted pyrrole 59 in 85% yield (entry 28). Tetrasubstituted pyrroles 61 and 63 were success-

R2

Me

  • R2
  • R2

R1

COMe

  • R1
  • R1

HN

  • O
  • Me

N

O
Me

OH
HO
H O

N

Me

H

Me

B
A

Scheme 5

arylpyrroles in good yields. Vinyl azides 22 and 24 bearing acetyl and (dimethylamino)carbonyl moieties instead of an a-ethoxycarbonyl group could be employed to give the corresponding pyrroles 23 and 25 (entries 10 and 11, respectively). It is known that the thermolysis of 2-azidosubstituted cinnamates and their derivatives delivers 1H-

Table 1 Synthesis of Pyrroles from Vinyl Azides and Acetylacetone (2)a

  • R2
  • R2

R1

COMe Me

R1

Δ

  • O
  • O

+

N

– N2 – H2O

  • Me
  • Me

N

N2

H

2

  • Entry
  • Vinyl azides
  • Pyrrolesb

Entry

24
Pyrrolesb
O
Vinyl azides

: R = 2,6-Cl

5 86% 7 93% 9 90% 11 89% 13 96% 15 90% 17 90% 19 81%
4

1234567

8c

2

6: R = H 8: R = 4-Me 10: R = 2-Me 12: R = 3-NO2 14: R = 4-Br 16: R = 4-CN 18: R = 4-MeO

  • EtO2C
  • COMe

Me
TsN

  • 51 92%
  • 50

Me Me

  • CO2Et
  • N

Ts
R

N3
N3

NH
N

  • H
  • R

O

O

EtO2C

COMe Me
TsN
Me

Me

52 54
53 92%

25 26
NTs
CO2Et

9

  • 20
  • 21 94%

NH

N3

NH

N3

N

N
S

R2

COMe Me

R2

  • 22: R2 = COMe
  • 23 74%

25 quant

10d 11
Me Me

N3

24: R2 = CONMe2

55 96%

S
NH
NH

N3

EtO2C

R1

COMe Me

26: R1 = CO2Et

28: R1 = CH2Ph 30: R1 = H

27 82% 29 96% 31 85%

  • 12
  • CO2Et

N3
R1

O
13e

14
Ph
Me

Me
Ph
N

56

27

57 82%

H

N3

32: R = H

33 75% 35 98% 37 95% 39 86% 41 92% 43 91% 45 86%

  • N
  • 15

16 17 18 19 20 21
R
H

34: R = 4-Me 36: R = 4-OMe 38: R = 2-OMe 40: R = 4-Br 42: R = 3-Br 44: R = 4-CO2Me

COMe Me
R
COMe

Me

N3

N

  • 58
  • 59 85%

61 66% 63 91%

28 29 30
N
H

N3

(E:Z = 1:1)
H

O
Me

Me
COMe Me

  • 47 94%
  • 46

48

22 23

60 62

N

N3
N3

H
NH

O
Me

COMe

Me
Me Me

49 65%

  • N3
  • N3

Me
N
N

  • H
  • H

a Unless otherwise noted, the reactions were carried out by heating a mixture of the vinyl azide (0.3–0.5 mmol) and acetylacetone (2) (1.2 equiv) in toluene at 100 °C for 2–24 h. b Isolated yields are shown. c The reaction was performed at 85 °C for 16 h. d The reaction was performed at 85 °C for 20 h in the presence of acetylacetone (2) (2 equiv). e The reaction was performed at reflux for 5 h.

© Thieme Stuttgart · New York

Synlett 2012, 23, 21–44

24

S. Chiba

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  • SODIUM AZIDE and HYDRAZOIC ACID in WORKPLACE ATMOSPHERES Method Number: ID-211 Matrix: Air Target Concentration: 0.3 Mg/M3 As So

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    SODIUM AZIDE and HYDRAZOIC ACID in WORKPLACE ATMOSPHERES Method Number: ID-211 Matrix: Air Target concentration: 0.3 mg/m3 as sodium azide (Ceiling) 0.1 ppm as hydrazoic acid (Ceiling) OSHA PEL: None Collection Device: An air sample is collected using a calibrated sampling pump and a glass tube containing impregnated silica gel (ISG). A pre-filter is used to collect particulate azide. Wipe samples can be taken to determine work surface contamination. Recommended Sampling Rate: 1 liter per minute (L/min) Recommended Minimum Sampling Time: 5 minutes Analytical Procedure: The sampling medium is desorbed using an aqueous solution which contains a mixture of 0.9 mM sodium carbonate (Na2CO3) and 0.9 mM sodium bicarbonate (NaHCO3). An aliquot of this solution is analyzed as azide (N3-) by an ion chromatograph equipped with a UV detector. Special Precautions: Ship samples to the laboratory as soon as possible after collection. Store samples under refrigeration when not in transit. Samples stored at room temperature need to be analyzed within 10 days. Detection Limit: 3 Qualitative: 0.001 ppm as HN3 or 0.003 mg/m as NaN3 (5-L air sample) 3 Quantitative: 0.004 ppm as HN3 or 0.011 mg/m as NaN3 (5-L air sample) Precision and Accuracy: Validation Range: 0.057 to 2.63 ppm CVT(pooled): 0.052 Bias: -0.022 Overall Error: ±12.6% Method Classification: Validated Method Chemist: James C. Ku Date: September, 1992 Commercial manufacturers and products mentioned in this method are for descriptive use only and do not constitute endorsements by USDOL-OSHA.
  • A Highly Efficient, Metal-Free, Heterogeneous Catalyst For

    A Highly Efficient, Metal-Free, Heterogeneous Catalyst For

    Article OSU-6: A Highly Efficient, Metal-Free, Heterogeneous Catalyst for the Click Synthesis of 5-Benzyl and 5-Aryl-1H-tetrazoles Baskar Nammalwar, Nagendra Prasad Muddala, Rajasekar Pitchimani and Richard A. Bunce * Received: 18 November 2015; Accepted: 11 December 2015; Published: 19 December 2015 Academic Editor: Derek J. McPhee Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA; [email protected] (B.N.); [email protected] (N.P.M.); [email protected] (R.P.) * Correspondence: [email protected]; Tel.: +1-405-744-5952; Fax: +1-405-744-6007 Abstract: OSU-6, an MCM-41 type hexagonal mesoporous silica with mild Brönsted acid properties, has been used as an efficient, metal-free, heterogeneous catalyst for the click synthesis of 5-benzyl and 5-aryl-1H-tetrazoles from nitriles in DMF at 90 ˝C. This catalyst offers advantages including ease of operation, milder conditions, high yields, and reusability. Studies are presented that demonstrate the robust nature of the catalyst under the optimized reaction conditions. OSU-6 promotes the 1,3-dipolar addition of azides to nitriles without significant degradation or clogging of the nanoporous structure. The catalyst can be reused up to five times without a significant reduction in yield, and it does not require treatment with acid between reactions. Keywords: 5-benzyl and 5-aryl-1H-tetrazoles; carboxylic acid bioisosteres; click 1,3-dipolar addition; heterogeneous catalysis; recyclable catalyst 1. Introduction Tetrazoles are versatile heterocyclic systems, which have attracted considerable interest in diverse applications ranging from pharmaceuticals [1–3] and agrochemicals [4] to photographic compounds [5], explosives [6], new materials [7–9], and ligands in coordination compounds [10,11].
  • Synthetic Approaches to Heterocyclic Bicyclo[2.1.0]Pentanes

    Synthetic Approaches to Heterocyclic Bicyclo[2.1.0]Pentanes

    SYNTHETIC APPROACHES TO HETEROCYCLIC BICYCLO[2.1.0]PENTANES Rabah N. Alsulami A THESIS Submitted to the Graduate College of Bowling Green State University in partial fulfillment of The requirements for the degree of MASTER OF SCIENCE August 2011 Committee: Thomas H. Kinstle (Advisor) Marshall Wilson Alexander N. Tarnovsky ABSTRACT Thomas H. Kinstle, Advisor Bicyclic systems such as bicyclo[2.1.0]pentanes and 5-oxabicyclo[2.1.0]pentanes are known to display a variety of unique chemical properties associated with their high strain energy. To the best of our knowledge, there were no reports regarding synthesis and investigation of 5- azabicyclo[2.1.0]pentanes. Therefore, the initial goal of this research was synthesis of 5-azabicyclo[2.1.0]pentane and investigation of its chemical properties. The cycloaddition reaction of azides (58, 59, 61) to olefins (54, 55) with further elimination of nitrogen was chosen as a synthetic method in order to obtain the compounds of interest. Starting olefins (3,3-dimethyl-1-cyclobutene-1-carboxylic acid (54) and methyl 3,3-dimethyl-1-cyclobutene-1-carboxylate (55) and azides phenyl azide (58), p- toluenesulfonyl azide (59), and picryl azide (61) were successfully synthesized and characterized by NMR spectroscopy and GCMS spectrometry. The addition reaction between azides and olefins was performed under various conditions, such as different solvents and temperature; however, according to NMR spectroscopy and GCMS spectrometry, olefins (54, 55) do not undergo cycloaddition reaction with azides (58, 59, 61). In order to investigate that behavior, cycloaddition reactions of more reactive olefins (66, 68) with azides (58, 59, 61) were performed under a variety of conditions.
  • A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-Deoxyribonucleosides

    A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-Deoxyribonucleosides

    Molecules 2014, 19, 2434-2444; doi:10.3390/molecules19022434 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article A Tractable and Efficient One-Pot Synthesis of 5'-Azido-5'-deoxyribonucleosides Theodore V. Peterson, Tobin U. B. Streamland and Ahmed M. Awad * Chemistry Program, California State University Channel Islands, One University Drive, Camarillo, CA 93012, USA; E-Mails: [email protected] (T.V.P.); [email protected] (T.U.B.S.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-805-437-2794; Fax: +1-805-437-8895. Received: 11 September 2013; in revised form: 11 February 2014 / Accepted: 12 February 2014 / Published: 21 February 2014 Abstract: Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions. Keywords: modified nucleosides; 5'-azido nucleosides; Appel reaction; Mitsunobu reaction; antisense oligonucleotides; ribonucleic guanidine (RNG) 1. Introduction The synthesis and chemical modification of nucleosides is a major research topic in medicinal and bioorganic chemistry. The vast utilization of nucleosides in most aspects of cellular function makes them a tantalizing target for a variety of therapies with potentially wide ranging physiological and pharmacological effects [1–4].