Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyl(tropone)iron

Summary

Representative experimental procedures for the addition of amine nucleophiles to tricarbonyl(tropone)iron and subsequent demetallation of the resulting complexes are presented in detail.

Abstract

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.

Introduction

Structurally complex amines containing a seven-membered carbocyclic ring are common to a number of biologically active molecules. Notable examples include the tropane alkaloids¹ and several members of the Lycopodium², Daphniphyllum³, and monoterpenoid indole alkaloid⁴ families. However, such compounds are often more difficult to synthesize compared to compounds of similar complexity containing only five- or six-membered rings. Thus, we sought to develop a new avenue towards such compounds by attaching diverse amine nucleophiles to tropone^....

Protocol

1. Synthesis of tricarbonyl(tropone)iron (1)¹⁹

1. In an argon-atmosphere glovebox, weigh out 4.1 g of diiron nonacarbonyl into an oven-dried 20 mL vial. Cap the vial and remove it from the glovebox.
   CAUTION: Prolonged storage of diiron nonacarbonyl leads to some deterioration to give triiron dodecacarbonyl and finely divided metallic iron²⁰. This deterioration is evidenced by the presence of a black solid within the shiny orange diiron nonacarbonyl. The iron impurity is pyrophoric and can ignite upon exposure to air. Storing the diiron nonacarbonyl under argon at 2-8 °C in a bottle sealed with electr....

Results

All novel compounds in this study were characterized by ¹H and ¹³C NMR spectroscopy and high resolution mass spectrometry. Previously reported compounds were characterized by ¹H NMR spectroscopy. NMR data for representative compounds are described in this section.

The ¹H NMR spectrum of tricarbonyl(tropone)iron is shown in Figure 3. The protons of the η⁴-diene ligand give rise to the signals at 6.39 ppm (.......

Discussion

Whether the solvent-free protocol involving direct addition to tricarbonyl(tropone)iron (Figure 2) or the indirect method utilizing the corresponding cationic complex as the electrophile (Figure 1) is to be employed depends on the amine substrate used. In general, the direct addition method is preferable since it requires fewer steps to generate the aza-Michael adducts from tropone and the overall yields are generally higher. However, this more direct m.......

Materials

Name	Company	Catalog Number	Comments
10 g SNAP Ultra silica gel columns	Biotage		for automated column chromatography
Acetic anhydride	Fisher Scientific	A10-500
Acetone	Fisher Scientific	A-16S-20	for cooling baths
Acetonitrile-D3	Sigma Aldrich	366544
Benzene, anhydrous, 99.8%	Sigma Aldrich	401765
Biotage Isolera Prime	Biotage	ISO-PSF	for automated chromatography
Celite; 545 Filter Aid	Fisher Scientific	C212-500	diatomaceous earth
Cerium(IV) ammonium nitrate, ACS, 99+%	Alfa Aesar	33254
Chloroform-D	Acros	209561000
Di-tert-butyl dicarbonate, 99%	Acros	194670250
Ethyl acetate	Fisher Scientific	E145-4
Ethyl alcohol, absolute - 200 proof	Greenfield Global	111000200PL05
Ethyl ether anhydrous	Fisher Scientific	E138-1
Hexanes	Fisher Scientific	H302-4
iron nonacarbonyl 99%	Strem	26-2640	air sensitive, synonymous with diiron nonacarbonyl
Magnesium sulfate	Fisher Scientific	M65-500
Methanol	EMD Millipore	MX0475-1
Methylene chloride	Fisher Scientific	D37-4
MP alumina, Act. II-III acc. To Brockmann	MP Biomedicals	4691	for column chromatography
o-toluidine 98%	Sigma Aldrich	466190
Phenethylamine 99%	Sigma Aldrich	128945	distill prior to use if not colorless
Sodium bicarbonate	Fisher Scientific	S233-500
Sodium carbonate anhydrous	Fisher Scientific	S263-500
Sodium chloride	Fisher Scientific	S271-500	dissolved in deionized water to perpare a saturated aqueous solution
Sodium sulfate anhydrous	Fisher Scientific	S415-500
Sonicator	Branson		model 2510
Sulfuric acid	Fisher Scientific	A300C-212
Tetrafluoroboric acid solution, 48 wt.%	Sigma Aldrich	207934	aqueous solution
TLC Aluminium oxide 60 F254, neutral	EMD Millipore	1.05581.0001	for thin layer chromatography
Tropone 97%	Alfa Aesar	L004730-06	Light sensitive