Amination process

Details Amination process Amination process

2001-03-07

2003-12-30

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S334000, C546S268100

Reexamination Certificate

active

06670479

ABSTRACT:

FIELD OF THE INVENTION
The present invention belongs to the field of synthetic organic chemistry. In particular, it relates to a process for forming carbon-nitrogen bonds, particularly vinyl-nitrogen bonds and aryl-nitrogen bonds.
BACKGROUND OF THE INVENTION
The development of methods that effect the formation of carbon-nitrogen bonds is a challenge of broad interest due to the prevalence of the aniline subunit within many biologically-active natural products and medicinal agents (See, e.g.,
The Alkaloids: Chemistry and Biology,
Cordell, G. A., Ed.; Academic: San Diego, 1998, Vol. 50). Significantly, indole alkaloid syntheses frequently commence from one of many available aniline or indole derivatives. Although this strategy is inherently limited, its popularity is perhaps due to the fact that there are few methods available for forming aryl-nitrogen bonds. Moreover, existing technology generally fails to offer the mild conditions necessary for the highest degree of chemoselectivity. Transition-metal mediated aryl amination generally requires the use of a basic additive to promote the coupling process. Moreover, transition metal ligand selection is based upon consideration of the individual electronic nature of the aromatic halide (or triflate, etc.) and amine components.
Similar, but fewer, methods are available for vinyl amination. Again, the need for basic and/or nucleophilic addends limits the substrate generally of these methodologies. Metal-mediated alkyne amination offers alternative access to the products of vinyl amination (enamines), but functional group tolerance is attenuated further still. Notwithstanding the technological limitations, the products of these transformations are valuable both as synthetic intermediates and as targets themselves. Of particular importance is the pyrrolidine heterocyclic class and its oxidized variants (dihydropyrrole and pyrrole). For example, 2-carboxy pyrrolidine is also known as proline, an a-amino acid prevalent in biopeptides. The pyrrolidine backbone is also found in medicinal agents (i.e., drugs) and numerous classes of natural products displaying a range of biological activity.
SUMMARY OF THE INVENTION
The present invention provides methodology for carbon-nitrogen bond formation via vinyl or aryl amination. In the process of the invention, an sp
2
hybridized radical is reacted with an azomethine moiety to form dihydropyrrole, 2-methylenopyrrolidine, and indoline compounds. The methodology provides a facile process for the synthesis of compounds having the pyrroli dine or indoline subunit and is especially advantageous for compounds having acid or base labile functional groups and/or is comprised of chiral centers susceptible to acidbase epimerization.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention provides a process for forming an intramolecular carbon-nitrogen bond which comprises reacting an sp
2
hybridized carbon radical moiety with an azomethine moiety in the presence of a hydrogen atom donor, wherein said azomethine moiety possesses at least one radical stabilizing group, and the azomethine carbon is in the ketone oxidation state or higher. In this regard, suitable radical stabilizing groups are known in the art and include but are not limited to the following: phenyl, vinyl, trifluormethyl, carbonyl, and the like. In a preferred embodiment, the azomethine carbon will be in the ketone oxidation state and will be bonded by groups such as hydrocarbyl, substituted hydrocarbyl, aryl, and heteroaryl, provided that the atom bonded between such groups and the azomethine carbon is a carbon atom.
As used herein, the term “azomethine” preferably refers to the subunit having the Formula
wherein R
1
and R
2
are as defined herein.
In this process, the sp
2
hybridized radical can be formed using any number of methodologies, including but not limited to preparation of the desired carbon radical moiety by photolysis, thermal cleavage, or by homolytic transmetalation in the presence of a free radical initiator compound. In the latter case, the substituted carbon moiety will thus preferably be substituted by a suitable radical leaving group such as a halogen atom. The term “free radical intitiator” compound is any compound which is capable of facilitation of a free radical reaction via a homolytic mechanism. Examples include azonitrile compounds such as 2,2′-azobisisobutyronitrile (AIBN); peroxides; and the like. The carbon radical may also be produced via a prior homolytic reaction, including but not limited to a radical addition to an olefin or the thermal cyclization of an ene-diyne moiety.
Preferred “hydrogen atom donor” compounds include reactants or species which can be generated in situ which provide a hydrogen atom. Examples of suitable hydrogen donor compounds include organostannane hydrides, organosilyl silanes, organogermanium hydrides, 1,4-cyclohexadiene, &ggr;-terpinene, thiols, selenol, and the like. Examples of organostannane hydrides include compounds of the Formula (X′)
3
Sn—H, wherein X′ is an alkyl group, preferably a C
1
-C
6
alkyl group, aryl group, or a fluorous dervative thereof. Alternatively, such a compound can be generated in situ; for example, hexamethylditin can be photolyzed to provide the same tin radical as tri-n-butyl tin hydride plus a free radical initiator compound. Examples of alkylsilylsilanes include tris(trimethylsilyl)silane, triethylsilane, and the like.
The process of the invention is particularly well suited for the preparation of various pyrrolidine compounds. One such compound is proline (or its derivatives):
Thus, in a second aspect, the present invention provides a process for preparing a compound of Formula (2)
wherein each R is independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, heteroatom connected hydrocarbyl, heteroatom connected substituted hydrocarbyl, heteroatom connected aryl, heteroatom connected heteroaryl, heteroatom connected substituted aryl, heteroatom connected substituted heteroaryl, a group of the formula —C(O)R
1
, a group of the formula —O—R
1
, a group of the formula —NHR
1
, a group of the formula —N(R
1
)
2
, a group of the formula —Sn(R
1
)
3
, and a group of the formula —Si(R
1
)
3
;
wherein the R
1
and R
2
groups are independently selected from the group consisting of aryl, heteroaryl, hydrocarbyl, substituted aryl, substituted heteroaryl, and substituted hydrocarbyl; provided that said groups are bonded via a carbon atom;
each R
3
is independently selected from aryl; heteroaryl; hydrocarbyl; substituted aryl; substituted heteroaryl; substituted hydrocarbyl; heteratom connected aryl; heteroatom connected hydrocarbyl; heteroatom connected substituted hydrocarbyl; heteroatom connected heteroaryl; heteroatom connected substituted aryl; halo, preferably fluoro or chloro, most preferably fluoro; amino; cyano; hydroxy; carboxy; a group of the formula —C(O)O—C
1
-C
8
alkyl; a group of the formula —C(O)R
1
; a group of the formula —O—R
1
; a group of the formula —NHR
1
; a group of the formula —N(R
1
)
2
; C
1
-C
8
alkoxy; C
1
-C
8
alkylthio; and oxo (i.e., an in-line carbonyl group wherein the oxygen is doubly bonded with the carbon atom to which R
3
is attached, in which case n will of course be 1); or two R
3
groups taken together can form a divalent hydrocarbyl, substituted hydrocarbyl, or be bonded directly to a heteroatom such as oxygen, nitrogen, or sulfur; and n is from 0 to 6;
which comprises contacting a compound of Formula (1)
with a free radical initiator in the presence of a hydrogen atom donor, wherein R, R
1
, R
2
, R
3
, and n are as defined above.
In a third aspect, there is provided a process for preparing compounds of the formula
wherein each R is independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, heteroatom connected hydrocarbyl, heteroatom connected substituted hydrocarb

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