Patent Description:
Nitrogen-containing compounds are prevalent in bioactive molecules, natural products and pharmaceutically important molecules. Such compounds can include vesicare (solifenacin), cryptostylines I-III, norlaudanosine, tadalafil, aspidospermidine, and sitagliptin (<NPL>. <NPL>) It is also important to consider methods relevant to the synthesis of such compounds.

As one example, the catalytic transfer of a nitrene moiety to C-H bonds is a useful tool in direct C-H amination because it avoids pre-functionalization of starting materials and/or the use of toxic reagents. Hence, it is regarded as both time- and atom-efficient (<NPL>; <NPL>; <NPL>). Over the past years, nitrene sources involved in this transformation have been used and explored including iminoiodinane (PhI=NTs, etc.) (<NPL>), oxidative amide salts (such as bromamine-T, chloramine-T, etc.) (<NPL>; <NPL>) to the use of organic azide (RN<NUM>) (<NPL>; <NPL>; <NPL>; <NPL>; <NPL>.

Following reports of the use of iron-dipyrrinato catalysts to realize intramolecular C(sp<NUM>)-H bonds of alkyl azides by Betley and co-workers (E. <NPL>; <NPL>), many types of catalysts including iron (<NPL>; <NPL>; <NPL>; <NPL>; <NPL>), cobalt (<NPL>; <NPL>; <NPL>; <NPL>; <NPL>. ), ruthenium (<NPL>; <NPL>. ), nickel (<NPL>), and palladium-based (<NPL>; <NPL>) catalysts have been extensively investigated. However, among the catalytic systems reported, the catalyst loadings remain high and use towards natural products synthesis has been lacking in general. You et al, Chem. , <NUM>, <NUM>, <NUM> describes a soluble iron (II)-phthalocyanine-catalyzed intramolecular C(sp<NUM>)-H amination with alkyl azides. <NPL> describes N-heterocyclic carbene iron(III) porphyrin-catalyzed intramolecular C(sp<NUM>)-H amination of alkyl azides.

Accordingly, there remains a need for improved methods for achieving intramolecular C(sp<NUM>)-H bonds of alkyl azides that require lower catalyst loadings, are applicable to a broad scope of substrates, and which are useful for producing natural product derivatives and late-stage functionalization of active pharmaceutical ingredients.

Therefore, it is an object of the present invention to provide such improved methods of catalyzed C-H bond amination.

It is a further object of the present invention to provide methods that function at lower catalyst loadings.

It is still a further object of the present invention to apply such methods towards the syntheses of natural product derivatives and late-stage functionalization of active pharmaceutical ingredients.

Methods of C-H amination are disclosed herein. The methods include the steps of:.

The product of the direct intramolecular C-H bond amination of the alkyl azide is considered a ring-closure amination product of the alkyl azide. It is believed that the methods described involve transition-metal catalyzed direct C-H bond amination proceeding via a nitrene transfer reaction to produce C-N bonds.

In some instances, the iron(II)-phthalocyanine catalyst has a chemical structure according to any one of Formulae A-D, shown below:
<CHM>
<CHM>
<CHM>
<CHM>
wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulae A-D are each independently selected from the group consisting of a hydrogen; halogen group (i.e., -F, -Cl, -Br, -I); a C<NUM>-C<NUM> alkyl group (linear or branched), such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group, such as methoxy, ethoxy, propoxy, or butoxy; an aryl group (i.e., a phenyl group); a heteroaryl group; a benzyl group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group (primary, secondary, or tertiary); an amide group; and a nitro group. In some instances, the Ra, Rb, Rd, Re, Rf, Rg, Ri, and Rj are hydrogens and Rc and Rh are substituted, preferably with the same substituent. In some instances, Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In some instances, Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In some instances, at least one of Ra, Rb, Rc, Rd, Re and at least one of Rf, Rg, Rh, Ri, and Rj are substituted.

In some instances, the iron(II)-phthalocyanine catalyst of Formula A is preferably:
<CHM>.

In step (b), the reaction mixture is heated to a temperature of at least <NUM> sufficient to induce a direct intramolecular C-H bond amination of the alkyl azide. In some instances, the temperature of the reaction mixture is selected to be sufficient to cause reflux of the one or more solvents selected. In some cases, the reaction mixture is heated to a temperature of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. In some other cases, the reaction mixture is heated to a temperature in a range of between <NUM> to <NUM>. The heating in step (b) can be performed for period of time ranging from between about <NUM> hour to <NUM> hours, <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours. In some instances, the heating of step (b) can be performed for period of time of at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> hours.

In some instances, the alkyl azide used in the method preferably contains a benzylic, tertiary, secondary, or primary C-H bond. In some other instances, the alkyl azide has a chemical structure of Formula I, as follows:
<CHM>.

In certain other instances, the alkyl azide has a chemical structure of Formula II, as follows:
<CHM>
wherein R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, and R<NUM> are each independently selected from the group consisting of hydrogen; halogen group (i.e., -F, -Cl, -Br, -I); a C<NUM>-C<NUM> alkyl group (linear or branched), such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group; an aryl group (i.e., a phenyl group); a heteroaryl group; a benzyl group; an oxo (=O) group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group; an amide group; and a nitro group.

In some cases, the ring-closure amination product of the methods disclosed has a chemical structure, as shown below:
<CHM>
wherein R is H, Me, OMe, Cl, Br, F, NO<NUM>, or N,N-dimethyl;
<CHM>
<CHM>
wherein each R is <NUM>-OMeC<NUM>H<NUM>;
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The C-H amination methods described are useful for the synthesis of various ring-closure amination products from a wide variety of organic azide starting materials. In particular, the methods can find application in catalytic transformations in the late-stage functionalization of active pharmaceutical ingredients (APIs) and the synthesis of natural products derivatives. Exemplary natural product derivatives (described, but not claimed) can include, for example, derivatives with a chemical structure shown below:
<CHM>
<CHM>
<CHM>.

<FIG> shows the x-ray crystallographic structures of sitagliptin derivatives 38b and 38b' prepared according to the C-H bond amination described in Example <NUM>.

An "aryl radical" or "aryl group" is understood to mean a radical containing a structure made up of <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, which is formed from one aromatic ring or a plurality of fused aromatic rings. Exemplary aryl radicals are, without limitation, phenyl, naphthyl, anthracenyl, or phenanthrenyl. Aryl radicals may be unsubstituted, where all carbon atoms which are substitutable bear hydrogen atoms. Alternatively, they may be substituted at one, greater than one, or at all substitutable positions therein. Suitable exemplary substituents include, without limitation, alkyl radicals, such as alkyl radicals having <NUM> to <NUM> carbon atoms, which may be selected from methyl, ethyl, i-propyl or t-butyl, aryl radicals (such as C<NUM>-aryl radicals, which may be substituted or unsubstituted), heteroaryl radicals (which may comprise at least one nitrogen atom, such as pyridyl radicals), alkenyl radicals (which may comprise one double bond and <NUM> to <NUM> carbon atoms), or groups with electron donating or electron accepting ability. Groups with electron donating ability are understood to mean groups which have a positive inductive (+I) and/or positive mesomeric (+M) effect, and groups with electron accepting ability are understood to mean groups which have a negative inductive (-I) and/or negative mesomeric (-M) effect. Suitable groups with donor or acceptor action are halogen radicals, such as F, Cl, Br, alkoxy radicals, aryloxy radicals, carbonyl radicals, ester radicals, amine radicals, amide radicals, CH<NUM>F groups, CHF<NUM> groups, CF<NUM> groups, CN groups, thio groups, or SCN groups.

A "heteroaryl radical" or "heteroaryl group" is understood to mean radicals which differ from the aryl radicals described above in that at least one carbon atom in the structure making up the aryl radical is otherwise replaced by at least one heteroatom. Heteroatoms may have hydrogen substituents and/or any permissible substituents of organic compounds in order to satisfy the valences of the heteroatoms. Exemplary heteroatoms include N, O, and S. In most instances, one or two carbon atoms of the structure of the aryl radicals are replaced by heteroatoms. Exemplary heteroaryls include, without limitation, pyridyl, pyrimidyl, pyrazyl, triazyl, and five-membered heteroaromatics, such as pyrrole, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole. Heteroaryls may be substituted at none (unsubstituted), one, more than one, or at all substitutable positions. Suitable substituents are as defined above for the aryl radicals.

An "alkyl radical" or "alkyl group" is understood to mean a radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms. The alkyl radical may be branched or unbranched. Modified versions of "alkyl", which do not fall under the definition of "alkyl" though, would be where the carbon chain may optionally be interrupted by one or more heteroatoms, such as N, O, or S. Heteroatoms may have hydrogen substituents and/or any permissible substituents of organic compounds in order to satisfy the valences of the heteroatoms. The alkyl radical may optionally be substituted by one or more of the substituents mentioned for the aryl radicals above. It is also possible that the alkyl radical contain one or more aryl groups thereon, where suitable aryl groups are described above. Exemplary alkyl radicals include, without limitation, methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, t-butyl, sec-butyl, i-pentyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, i-hexyl and sec-hexyl.

An "alkenyl radical" or "alkenyl group" is understood to mean a radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms, which may be optionally substituted and at least one carbon-carbon double bond.

An "alkynyl radical" or "alkynyl group" is understood to mean a radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms, which may be optionally substituted and at least one carbon-carbon triple bond.

A "cycloalkyl radical" or "cycloalkyl group" is understood to mean a cyclic radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms.

Modified versions of "cycloalkyl", which would not fall under the definition of "cycloalkyl" though, would be where the carbon chain of the cycloalkyl radical may optionally be interrupted by one or more heteroatoms, such as N, O, or S. Heteroatoms may have hydrogen substituents and/or any permissible substituents of organic compounds in order to satisfy the valences of the heteroatoms. The cycloalkyl radical may be unsubstituted or substituted, i.e. substituted by one or more of the substituents mentioned herein.

A "cycloalkenyl radical" or "alkenyl group" " is understood to mean a cyclic radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms, which may be optionally substituted and at least one carbon-carbon double bond.

A "cycloalkynyl radical" or "cycloalkynyl group" is understood to mean a cyclic radical having <NUM> to <NUM> carbon atoms, <NUM> to <NUM> carbon atoms, or <NUM> to <NUM> carbon atoms, which may be optionally substituted and at least one carbon-carbon triple bond.

"Carbonyl group," as used herein, is understood to mean moieties which can be represented by the general formula:
<CHM>
wherein X is a bond, or represents an oxygen or a sulfur, and R represents a hydrogen, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -(CH<NUM>)m-R''; wherein R' represents a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or -(CH<NUM>)m-R''; wherein R" represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl, a heterocycle, or a polycycle; and m is zero or an integer ranging from <NUM> to <NUM>. Where X is oxygen and R is defined as above, the moiety can be referred to as a "carboxyl group. " When X is oxygen and R is hydrogen, the formula represents a "carboxylic acid group. " Where X is oxygen and R' is hydrogen, the formula represents a "formate group. " Where X is oxygen and R or R' is not hydrogen, the formula represents an "ester group. " In general, where the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a "thiocarbonyl group. " Where X is sulfur and R or R' is not hydrogen, the formula represents a "thioester group. " Where X is sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid group. " Where X is sulfur and R' is hydrogen, the formula represents a "thioformate group. " Where X is a bond and R is not hydrogen, the above formula represents a "ketone group. " Where X is a bond and R is hydrogen, the above formula represents an "aldehyde group. " The term "substituted carbonyl" refers to a carbonyl, as defined above, wherein one or more hydrogen atoms in R, R' or a group to which the moiety is attached, are independently substituted with suitable substituents, as defined below.

An "amide group" or "amido" is understood to mean a moiety represented by the general formula:
<CHM>
wherein, E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein independently of E, R and R' each independently represent a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, -(CH<NUM>)m-R‴, or R and R' taken together with the N atom to which they are attached complete a heterocycle having from <NUM> to <NUM> atoms in the ring structure; R‴ can represent a hydroxy group, substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl group, a heterocycle, or a polycycle; and m is zero or an integer ranging from <NUM> to <NUM>. When E is oxygen, a "carbamate group" is formed. The carbamate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art.

Numerical ranges disclosed in the present application include, but are not limited to, ranges of carbon atoms, ranges of temperatures, ranges of concentrations, ranges of times, amongst other ranges disclosed below. The disclosed ranges, disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein. For example, disclosure of a range of carbon atoms is intended to disclose individually every possible value that such a range could encompass, consistent with the disclosure herein. For example, a carbon range of <NUM> to <NUM> carbons also discloses each number of carbons within the range individually (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> carbons), as well as any sub-range contained therein (<NUM> to <NUM> carbons or <NUM> to <NUM> carbons).

Use of the term "about" is intended to describe values either above or below the stated value, which the term "about" modifies, in a range of approx. +/- <NUM>%; in other instances the values may range in value either above or below the stated value in a range of approx. +/- <NUM>%. When the term "about" is used before a range of numbers (i.e., about <NUM>-<NUM>) or before a series of numbers (i.e., about <NUM>, <NUM>, <NUM>, <NUM>, etc.) it is intended to modify both ends of the range of numbers and/or each of the numbers recited in the entire series, unless specified otherwise.

Methods of C-H amination are described herein. In some instances, the methods described include the following steps:.

The product of the direct intramolecular C-H bond amination of the alkyl azide is considered a ring-closure amination product of the alkyl azide. It is believed that methods described involve transition-metal catalyzed direct C-H bond amination proceeding via a nitrene transfer reaction to produce C-N bonds.

The reaction mixture may be prepared according to standard synthetic practices known by the skilled person in any suitable reaction vessel known. The reaction mixture following step (b) can be worked up and purified using any standard synthetic workup and purification procedures known to the skilled person to obtain isolated product(s) of the direct intramolecular C-H bond amination of the alkyl azide. In some cases, steps (a) and/or (b) are performed under an inert atmosphere where the inert atmosphere can be selected from argon, nitrogen, or a combination thereof. The product of the direct intramolecular C-H bond amination of the alkyl azide can be characterized by the skilled person using any known synthetic characterization techniques (including, but not limited to, NMR, UV/Vis, mass spectrometry, elemental analysis, etc.).

The concentration of the alkyl azide present in the reaction mixture can be at any suitable concentration. In some instances, the concentration of the alkyl azide present in the reaction mixture is in a range of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>. , as well as sub-ranges within. The amount of the iron(II)-phthalocyanine catalyst present in the reaction mixture can be at an amount of <NUM> to <NUM> mol% of the amount of the alkyl azide present. In some other instances, the amount of the catalyst is at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> mol% of the amount of the alkyl azide present.

In some instances, the iron(II)-phthalocyanine catalyst is diamagnetic or paramagnetic. In certain cases, the catalyst is preferably diamagnetic. In certain other cases, the catalyst is paramagnetic.

In some instances, the iron(II)-phthalocyanine catalyst has a chemical structure according to any one of Formulae A-D, shown below:
<CHM>
<CHM>
<CHM>
<CHM>
wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulae A-D are each independently selected from the group consisting of a hydrogen; halogen group (i.e., -F, -Cl, -Br, -I); a C<NUM>-C<NUM> alkyl group (linear or branched), such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group, such as methoxy, ethoxy, propoxy, or butoxy; an aryl group (i.e., a phenyl group); a heteroaryl group; a benzyl group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group (primary, secondary, or tertiary); an amide group; and a nitro group. In some instances, the Ra, Rb, Rd, Re, Rf, Rg, Ri, and Rj are hydrogens and Rc and Rh are substituted, preferably with the same substituent. In some other instances, Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In still other instances, Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In some instances, at least one of Ra, Rb, Rc, Rd, Re and at least one of Rf, Rg, Rh, Ri, and Rj are substituted.

The iron(II)-phthalocyanine catalyst used in the methods described includes a catalyst of any one of Formulae A-D above. In some instances, the catalyst used contains a mixture of two or more catalyst compounds of Formulae A-D. The skilled person understands that such mixtures of catalysts, such as those of Formulae A-D, and which can be considered isomers can be used in the methods. Methods of synthesizing catalysts according to any one of Formulae A-D are known in the art.

In some instances, the iron(II)-phthalocyanine catalyst of Formula A has a chemical structure as follows:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
or
<CHM>
The positions of the tert-butyl groups on the phthalocyanine in the above compounds are those shown for Formula A above. The equivalent isomeric structures having the tert-butyl groups on the phthalocyanine, as shown in Formulae B-D above, are also described and disclosed, as would be recognized and understood by the person of ordinary skill in the art.

In some instances, the iron(II)-phthalocyanine catalyst of Formula A is preferably:
<CHM>
The catalyst tBu<NUM>PcFe(py)<NUM> is diamagnetic.

In still other instances, the iron(II)-phthalocyanine catalyst can have one of the following chemical structures:
<CHM>.

In some cases, the reaction mixture further contains at least one reagent for protecting amine groups. Suitable amine protecting groups are known in the art. In such instances, the reagent for protecting amine groups is present in an amount of about <NUM> to <NUM> equivalents of the molar amount of the alkyl azide present in the reaction mixture. In some instances, the reagent for protecting amine groups is fluorenylmethoxycarbonyl (Fmoc) or preferably di-tert-butyl dicarbonate (Boc<NUM>O). Standard procedures for removal of protecting amine groups are known to the person of ordinary skill in the art and may be performed following the formation of direct intramolecular C-H bond amination products of the alkyl azide.

The one or more solvents in the reaction mixture can be selected from any suitable solvent(s). The volume(s) of the one or more solvents in the reaction mixture may be any suitable amount and the volume of solvent(s) needed may be readily determined by the skilled person. In some instances, the one or more solvents are organic solvents selected from the group consisting of toluene, benzene, chlorobenzene, <NUM>,<NUM>-dichlorobenzene, <NUM>,<NUM>-dichloroethane. Preferably the one or more solvents are used dry.

In step (b), the reaction mixture is heated to a temperature of at least <NUM> sufficient to induce a direct intramolecular C-H bond amination of the alkyl azide. In some instances, the temperature of the reaction mixture is selected to be sufficient to cause reflux of the one or more solvents selected. In some cases, the reaction mixture is heated to a temperature of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>. In some other cases, the reaction mixture is heated to a temperature in a range of between <NUM> to <NUM>. The heating in step (b) can be performed for period of time ranging from between <NUM> hour to <NUM> hours, <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours. In some instances, the heating of step (b) can be performed for period of time of at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> hours.

In some instances, the at least one heteroatom on L, when present, can be selected from an oxygen, sulfur, nitrogen atom, or combination thereof with the proviso that valency requirements of the heteroatom(s) are satisfied.

In some instances, adjacent or close carbons (i.e., separated by one or two atoms) of the substituted or unsubstituted alkyl radical chain L can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of <NUM> to <NUM> carbon atoms.

In some instances, any one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> and a carbon of the substituted or unsubstituted alkyl radical chain L can independently together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms.

In some instances, R<NUM> and R<NUM> can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In some instances, R<NUM> and R<NUM> can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms. In still other instances, R<NUM> and R<NUM> or R<NUM> can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of from <NUM> to <NUM> carbon atoms. In yet other instances, R<NUM> and R<NUM> or R<NUM> can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of from <NUM> to <NUM> carbon atoms. In some instances, R<NUM> and R<NUM> or R<NUM> can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of from <NUM> to <NUM> carbon atoms. In still other instances, R<NUM> and R<NUM> or R<NUM> can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of from <NUM> to <NUM> carbon atoms.

In some instances, wherein each of R<NUM> and R<NUM>, R<NUM> and R<NUM>, R<NUM> and R<NUM>, R<NUM> and R<NUM>, or R<NUM> and R<NUM> can optionally form a saturated, unsaturated, or aromatic, optionally substituted ring, optionally interrupted by a heteroatom, and having a total of from <NUM> to <NUM> carbon atoms and heteroatoms.

In some cases, the ring-closure amination product of the above method has a chemical structure, as shown below:
<CHM>
wherein R is H, Me, OMe, Cl, Br, F, NO<NUM>, or N,N-dimethyl;
<CHM>
<CHM>
wherein each R is <NUM>-OMeC<NUM>H<NUM>;
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The skilled person understands that the ring-closure amination products formed according to the methods and described above may have one or more chiral centers and thus exist as one or more stereoisomers. Such stereoisomers can exist as a single enantiomer, a mixture of diastereomers or a racemic mixture are encompassed by the present disclosure. As used herein, the term "stereoisomers" refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers which are non-superimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein the term "diastereomer" refers to two stereoisomers which are not mirror images but also not superimposable. The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e.g. <NPL>).

The C-H amination methods described above are useful for the synthesis of various ring-closure amination products from a wide variety of organic azide starting materials. In particular, the methods can find application in catalytic transformations in the late-stage functionalization of active pharmaceutical ingredients (APIs) and the synthesis of natural products derivatives. Exemplary natural product derivatives can include, for example, derivatives with a chemical structure shown below:
<CHM>
<CHM>
<CHM>
The aforementioned are useful in the manufacture of pharmaceutical products. The disclosed methods can be further understood through the following numbered paragraphs. Paragraphs <NUM>-<NUM>, <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> align with the scope of the claims. The other paragraphs are presented herein only for information purposes.

Paragraph <NUM>. A method of C-H bond amination comprising the steps of:.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the iron(II)-phthalocyanine catalyst is defined according to any one of Formulae A, B, C, or D:
<CHM>
<CHM>
<CHM>
<CHM>
wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulae A-D are each independently selected from the group consisting of a hydrogen; halogen group; a C<NUM>-C<NUM> linear or branched alkyl group, such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group, such as methoxy, ethoxy, propoxy, or butoxy; an aryl group; a heteroaryl group; a benzyl group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group; an amide group; and a nitro group.

Paragraph <NUM>. The method of paragraph <NUM>, wherein Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms; and/or Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the iron(II)-phthalocyanine catalyst of Formula A has one of the following chemical structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
or
<CHM>.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the iron(II)-phthalocyanine catalyst is:
<CHM>.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture at an amount of <NUM> to <NUM> mol% of the amount of the alkyl azide present; or at an amount of at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> mol% of the amount of the alkyl azide present.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the reaction mixture is heated to a temperature of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the reaction mixture is heated to a temperature in a range of between <NUM> to <NUM>.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the one or more solvents are organic solvents.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the organic solvents are selected from the group consisting of toluene, benzene, chlorobenzene, <NUM>,<NUM>-dichlorobenzene, <NUM>,<NUM>-dichloroethane.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the steps (a) and/or (b) are performed under an inert atmosphere.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the inert atmosphere is selected from argon, nitrogen, or a combination thereof.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the heating of step (b) is performed for period of time ranging from between about <NUM> hour to <NUM> hours, <NUM> hour to <NUM> hours, or <NUM> hour to <NUM> hours.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the heating of step (b) is performed for period of time of at least about <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> hours.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the reaction mixture further comprises at least one reagent for protecting amine groups.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the at least one reagent for protecting amine groups is present in an amount of about <NUM> to <NUM> equivalents of the molar amount of the alkyl azide.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the at least one reagent for protecting amine groups is fluorenylmethoxycarbonyl (Fmoc) or di-tert-butyl dicarbonate (Boc<NUM>O).

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the alkyl azide comprises a benzylic, tertiary, secondary, or primary C-H bond.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the alkyl azide has a chemical structure of Formula I, as follows:
<CHM>.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the at least one heteroatom, when present, is an oxygen, sulfur, or nitrogen atom.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein any two adjacent carbons of the substituted or unsubstituted alkyl radical chain together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein any one of R<NUM>, R<NUM>, R<NUM>, and R<NUM> and a carbon of the substituted or unsubstituted alkyl radical chain independently together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein R<NUM> and R<NUM> together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein R<NUM> and R<NUM> or R<NUM> are linked by a saturated, unsaturated, optionally substituted alkyl chain having a total of from <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the alkyl azide has a chemical structure of Formula II, as follows:
<CHM>
wherein R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM>, and R<NUM> are each independently selected from the group consisting of hydrogen; halogen group; a C<NUM>-C<NUM> alkyl group, such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group; an aryl group; a heteroaryl group; a phenyl group; a benzyl group; an oxo (=O) group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group; an amide group; and a nitro group.

Paragraph <NUM>. The method of any one of paragraphs <NUM>-<NUM>, wherein the direct intramolecular C-H bond amination of the alkyl azide affords a ring-closure amination product of the alkyl azide.

Paragraph <NUM>. The method of paragraph <NUM>, wherein the ring-closure amination product has a chemical structure shown below:
<CHM>
wherein R is H, Me, OMe, Cl, Br, F, NO<NUM>, or N,N-dimethyl;
<CHM>
<CHM>
wherein each R is <NUM>-OMeC<NUM>H<NUM>;
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Paragraph <NUM>. A natural product derivative prepared using the method of any one of paragraphs <NUM>-<NUM>, wherein the natural product derivative has a chemical structure shown below:
<CHM>
<CHM>
<CHM>.

Paragraph <NUM>. An iron(II)-phthalocyanine catalyst defined according to anu one of Formulae A, B, C, or D:
<CHM>
<CHM>
<CHM>
<CHM>
wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulae A-D are each independently selected from the group consisting of a hydrogen; halogen group; a C<NUM>-C<NUM> linear or branched alkyl group, such as a methyl, ethyl, propyl, butyl, or pentyl group; alkenyl group; alkynyl group; cycloalkyl group; cycloalkenyl group; cycloalkynyl group; a hydroxyl group; an alkoxy group, such as methoxy, ethoxy, propoxy, or butoxy; an aryl group; a heteroaryl group; a benzyl group; an acyl group; an ester group; a carbonyl group; a carboxylate group; an amino group; an amide group; and a nitro group.

Paragraph <NUM>. The iron(II)-phthalocyanine catalyst of paragraph <NUM>, wherein Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms; and/or Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj can together form a saturated, unsaturated, or aromatic, optionally substituted ring having a total of from <NUM> to <NUM> carbon atoms.

Paragraph <NUM>. The iron(II)-phthalocyanine catalyst of any one of paragraphs <NUM>-<NUM>, wherein the iron(II)-phthalocyanine catalyst has one of the following chemical structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
and isomers thereof.

The methods, compounds, and compositions herein described are further illustrated in the following examples, which are provided by way of illustration and are not intended to be limiting. It will be appreciated that variations in proportions and alternatives in elements of the components shown will be apparent to those skilled in the art.

Theoretical aspects are presented with the understanding that Applicants do not seek to be bound by the theory presented.

The chemical reagents used for syntheses described were purchased from commercial including Sigma-Aldrich, Acros Organics, J&K Scientific. They were directly used without further process unless otherwise specified. The solvents used for syntheses described were purchased from Acros Organics, RCI Labscan, Scharlab and J&K Scientific. They were directly used without further process unless otherwise specified.

Catalyst tBu<NUM>PcFe(py)<NUM> is a known compound and was prepared according to a previous literature report (<NPL>). Catalyst tBu<NUM>PcFe(py) was characterized by ESI mass spectrometry, UV/Vis, and <NUM>H NMR spectroscopy. <NUM>H NMR (<NUM>, Benzene-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>H NMR spectra were recorded on either a Bruker DPX-<NUM> or DPX-<NUM> NMR spectrometer. The chemical shift of proton signals were calibrated by the corresponding solvent residual signals. ESI mass spectrometry was recorded on Q Exactive mass spectrometer (Thermo Fisher Scientific, USA) spectrometer. UV/Vis spectroscopy was recorded on an Agilent Cary <NUM> spectrometer. X-ray crystallography structures were recorded on a Bruker APEX-II CCD diffractometer.

Procedures for this catalysis reaction: an oven-dried Schlenk tube was charged with (<NUM>-azidobutyl)benzene (<NUM> mmol, <NUM> equiv. ), Boc<NUM>O (<NUM> equiv), iron(II)-Pc catalyst tBu<NUM>PcFe(py)<NUM> (<NUM> mol %), and dry toluene (<NUM>) under argon. The mixture was refluxed violently (<NUM>) until full completion, as revealed by TLC (usually completion within <NUM>). The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography to give the corresponding product. This product was verified by NMR by comparing to the reported characterization data (<NPL>).

The same reaction using the µ-oxo complex [((tBu<NUM>Pc)FeIII)<NUM>O] or µ-nitrido complex [((tBu<NUM>Pc)Fe)<NUM>N] as catalysts using the same procedure as described above. [((tBu<NUM>Pc)FeIII)<NUM>O] and [((tBu<NUM>Pc)Fe)<NUM>N] are known compounds and were synthesized according to literature references (<NPL>; <NPL>; <NPL>). The catalysts were found to be less efficient than tBu<NUM>PcFe(py)<NUM>. It was also observed that temperatures of about <NUM> or less inhibited the C-H amination reaction, which suggested that higher temperatures were needed to afford satisfactory product yields.

Different alkyl azide starting reagents are used below to undergo C-H amination. It is noted that organic azides are potentially explosive and should be handled with care. While no problems were encountered during their synthesis, proper precautions should be taken during the whole process of handling such compounds. Once isolated, azides were stored in a -<NUM> freezer.

Alkyl azides reported in previous literatures discussed in the Examples were as listed in Table <NUM> below. Detailed synthetic procedures and characterizations for other unknown azides are shown, as described below.

Step <NUM>: To a stirring solution of primary or secondary alcohol (<NUM> equiv. , <NUM>) in anhydrous dichloromethane, triethylamine (<NUM> equiv. ) and <NUM>-dimethylaminopyridine (<NUM> equiv. ) were added. <NUM>-Toluenesulfonyl chloride (<NUM> equiv. ) was added at <NUM>. The reaction was allowed to warm up to room temperature and stirred overnight, then the mixture was quenched with water once completion. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with sat. NaHCO<NUM> and brine, dried over Na<NUM>SO<NUM>, filtered and concentrated under reduced pressure. The residue was either purified by silica column chromatography or used without further purification.

Step <NUM>: To a stirring solution of the above (purified or crude) tosylate (<NUM> equiv. , <NUM>) (or alkyl chloride, in few cases alkyl chloride instead of tosylate was obtained) in DMF was added sodium azide (<NUM> equiv. ), and the reaction was heated at <NUM> overnight. After completion of the reaction water was added and the mixture was extracted with Et<NUM>O three times. The combined organic phases were washed twice with water and brine, and dried over Na<NUM>SO<NUM>. After removal of the solvent under reduced pressure the residue was purified by silica column chromatography to give the desired azide.

To a solution of unsaturated substrate containing double bond or triple bond (<NUM> mmol, <NUM>) in MeOH was added <NUM>% Pd/C (<NUM>). Then the mixture was stirred vigorously under H<NUM> atmosphere (<NUM> atm) for overnight. Upon completion, the reaction mixture was filtered through celite and washed with dichloromethane and ethyl acetate. Usually after removal of the solvent the residue can be obtained with enough purity for the next step directly and in few cases further purification is needed before next step.

To a solution of the desired carboxylic acid or ester (<NUM> mmol, <NUM> equiv. , <NUM>) in THF was added LiAlH<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) portionwise at <NUM> under argon atmosphere. Then the solution was stirred at rt for overnight. After completion, the reaction was quenched by adding a solution of NaOH aqueous (<NUM>% in water) until a solid precipitated. After filtration over MgSO<NUM> and evaporation of the solvent the crude alcohol was directly used for the next step without further purification.

To a solution of aryl iodide (<NUM> equiv), PdCl<NUM>(PPh<NUM>)<NUM> (<NUM>-<NUM> equiv. ), CuI (<NUM>-<NUM> equiv. ) in Et<NUM>N (<NUM>) was added but-<NUM>-yn-<NUM>-ol (<NUM> equiv) and the mixture was stirred at room temperature under argon atmosphere. After completion, the resulting mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel to give the desired coupling product.

<NUM>-(<NUM>-azidobutyl)-<NUM>,<NUM>-dimethylbenzene: Synthesized following the general procedures D, B and A from <NUM>-iodo-<NUM>,<NUM>-dimethylbenzene and obtained as a colorless oil (<NUM>% over four steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>N]+: <NUM>, found: <NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>-bromobenzene: Synthesized following the general procedure A from <NUM>-(<NUM>-bromophenyl)butan-<NUM>-ol and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>NBr]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>-nitrobenzene: Synthesized following the general procedure A from <NUM>-(<NUM>-nitrophenyl)butan-<NUM>-ol and obtained as a light yellow oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>O<NUM>N<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>,<NUM>-difluorobenzene: Synthesized following the general procedures D, B and A from <NUM>,<NUM>-difluoro-<NUM>-iodobenzene and obtained as a colorless oil (<NUM>% over four steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM> (d, J = <NUM>), -<NUM> (d, J = <NUM>).

<NUM>-(<NUM>-azidobutyl)-<NUM>,<NUM>-dichlorobenzene: Synthesized following the general procedures D, B and A from <NUM>,<NUM>-dichloro-<NUM>-iodobenzene and obtained as a colorless oil (<NUM>% over four steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>Cl<NUM>N]+ <NUM>, found : <NUM>.

methyl (E)-<NUM>-hydroxy-<NUM>-(<NUM>-(tosyloxy)but-<NUM>-en-<NUM>-yl)benzoate: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) to provide the desired compound as a colorless oil (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J= <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J= <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

methyl <NUM>-(<NUM>-azidobutyl)-<NUM>-hydroxybenzoate: Synthesized following the general procedures B and A, and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>]+: <NUM>, found <NUM>.

(E)-<NUM>-(<NUM>-methylbenzo[d]thiazol-<NUM>-yl)but-<NUM>-en-<NUM>-yl <NUM>-methylbenzenesulfonate: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) using <NUM>-bromo-<NUM>-methylbenzo[d]thiazole (<NUM>, <NUM> mmol, <NUM> equiv. ), (E)-<NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolan-<NUM>-yl)but-<NUM>-en-<NUM>-yl <NUM>-methylbenzenesulfonate(<NPL>) (<NUM>, <NUM> mmol, <NUM> equiv. ), SPhos-G3 (<NUM>, <NUM> mmol, <NUM> equiv. ), and K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF/H<NUM>O = <NUM>:<NUM> (<NUM>) at <NUM> for <NUM>. The crude residue was purified by column chromatography to provide the desired compound as a colorless oil (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, Chloroform-d) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>S<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>-methylbenzo[d]thiazole: Synthesized following the general procedures B and A, and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J= <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>S]+: <NUM>, found <NUM>.

(E)-<NUM>-(<NUM>-(benzyloxy)but-<NUM>-en-<NUM>-yl)-<NUM>,<NUM>-difluorobenzo[d][<NUM>,<NUM>]dioxole: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) using <NUM>-bromo-<NUM>,<NUM>-difluorobenzo[d][<NUM>,<NUM>]dioxol (<NUM>, <NUM> mmol, <NUM> equiv. ), (E)-<NUM>-(<NUM>-(benzyloxy)but-<NUM>-en-<NUM>-yl)-<NUM>,<NUM>,<NUM>,<NUM>-tetramethyl-<NUM>,<NUM>,<NUM>-dioxaborolane(<NPL>) (<NUM>, <NUM> mmol, <NUM> equiv. ), SPhos-G3 (<NUM>, <NUM> mmol, <NUM> equiv. ) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF/H<NUM>O = <NUM>:<NUM> (<NUM>) at <NUM> for <NUM>. The crude residue was purified by column chromatography to provide the desired compound (<NUM>, <NUM>%) as a colorless oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (qd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (t, J= <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>,<NUM>-difluorobenzo[d][<NUM>,<NUM>]dioxole: Synthesized following the general procedures B and A, and obtained as a colorless oil (<NUM>% over three steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM> (t, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>F<NUM>NO<NUM>]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-azidobutyl)-<NUM>H-indole-<NUM>-carboxylate: Synthesized following the general procedures D, B and A from tert-butyl <NUM>-iodo-<NUM>H-indole-<NUM>-carboxylate(<NPL>) and obtained as a colorless oil (<NUM>% over four steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM> + <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

(E)-<NUM>-(<NUM>-cyclopentyl-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)but-<NUM>-en-<NUM>-yl <NUM>-methylbenzenesulfonate: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) from <NUM>-bromo-<NUM>-cyclopentyl-<NUM>H-pyrrolo[<NUM>,<NUM>-b]pyridine(<NPL>) to provide the desired compound as a colorless oil (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

<NUM>-(<NUM>-azidobutyl)-<NUM>-cyclopentyl-<NUM>H-pyrrolo[<NUM>,<NUM>-b]pyridine: Synthesized following the general procedure B and A, and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>]+: <NUM>, found <NUM>.

tert-butyl (E)-<NUM>-(<NUM>-(<NUM>-(tosyloxy)but-<NUM>-en-<NUM>-yl)pyridin-<NUM>-yl)piperazine-<NUM>-carboxylate: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) to provide the desired compound as a colorless oil (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>S]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-(<NUM>-azidobutyl)pyridin-<NUM>-yl)piperazine-<NUM>-carboxylate: Synthesized following the general procedure B and A, and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM><NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

methyl (E)-<NUM>-(<NUM>-(tosyloxy)but-<NUM>-en-<NUM>-yl)furan-<NUM>-carboxylate: Synthesized following the reported general procedure for the Suzuki-Miyaura coupling reactions(<NPL>) to provide the desired compound as a colorless oil (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>O<NUM>S]+: <NUM>, found <NUM>.

methyl <NUM>-(<NUM>-azidobutyl)furan-<NUM>-carboxylate: Synthesized following the general procedure B and A, and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>]+: <NUM>, found <NUM>.

(<NUM>-azidopentyl)benzene: Synthesized following the general procedure A from <NUM>-phenylpentan-<NUM>-ol(<NPL>) and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>N]+: <NUM>, found <NUM>.

methyl <NUM>-(<NUM>-(<NUM>-hydroxyethyl)phenyl)acetate: Synthesized following the reported procedure(<NPL>). To a flask containing methyl <NUM>-(<NUM>-vinylphenyl)acetate(<NPL>) (<NUM>, <NUM> mmol) was added <NUM>-BBN (<NUM> solution in THF, <NUM>, <NUM> mmol), and the solution was stirred at rt for several hours until TLC completion. The resultant mixture was cooled to <NUM> and treated with saturated aqueous NaHCO<NUM> (<NUM>) and <NUM>% H<NUM>O<NUM> (<NUM>). After being stirred at rt overnight, the resultant mixture was extracted with EtOAc, washed with saturated aqueous Na<NUM>SO<NUM> and brine, dried over Na<NUM>SO<NUM>, filtered, and concentrated under reduced pressure. Purification of the residue by silica gel flash chromatography gave alcohol (<NUM>, <NUM>%) as a colorless oil. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>) , <NUM> (br s, <NUM>).

methyl <NUM>-(<NUM>-(<NUM>-azidoethyl)phenyl)acetate: Synthesized following the general procedure A from methyl methyl <NUM>-(<NUM>-(<NUM>-hydroxyethyl)phenyl)acetate and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>N<NUM>NaO<NUM>]+: <NUM>, found <NUM>.

methyl <NUM>'-ethyl-[<NUM>,<NUM>'-biphenyl]-<NUM>-carboxylate: A mixture of methyl <NUM>-iodobenzoate (<NUM>, <NUM> mmol), (<NUM>-ethylphenyl)boronic acid (<NUM>, <NUM> mmol, <NUM> equiv. ), toluene (<NUM>), ethanol (<NUM>) and <NUM> Na<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) was degassed, then Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) and Bu<NUM>NBr (<NUM>, <NUM> mmol, <NUM> equiv. ) were added under Ar. The mixture was heated at <NUM> for <NUM>-<NUM>, then stirred overnight at room temperature. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na<NUM>SO<NUM>, filtered and evaporated. The product was purified by silica gel chromatography to provide the desired product as a colorless oil (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM> Hz, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>O<NUM>]+: <NUM>, found <NUM>.

<NUM>-(azidomethyl)-<NUM>'-ethyl-<NUM>,<NUM>'-biphenyl: Synthesized following the general procedures C and A, and obtained as a colorless oil (<NUM>% over three steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>N]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidoethyl)-<NUM>-benzylbenzene: Synthesized following the general procedure A from <NUM>-(<NUM>-benzylphenyl)ethan-<NUM>-ol(<NPL>) and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>]+: <NUM>, found <NUM>.

methyl <NUM>-(<NUM>-(<NUM>,<NUM>-dimethoxybenzyl)-<NUM>,<NUM>-dimethoxyphenyl)acetate: To a stirred mixture of <NUM>-(<NUM>-(<NUM>,<NUM>-dimethoxybenzyl)-<NUM>,<NUM>-dimethoxyphenyl)acetic acid(<NPL>) (<NUM>, <NUM> mmol, <NUM> equiv. ) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> equiv. ) in DMF (<NUM>), methyl iodide (<NUM>, <NUM> mmol, <NUM> equiv. ) was added at room temperature, and then the reaction mixture was stirred at room temperature for <NUM>. After completion the mixture was diluted by <NUM> H<NUM>O. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over Na<NUM>SO<NUM>, and evaporated to dryness, and the residue was purified by silica gel flash chromatography to give the desired compound as an off-white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

<NUM>-(<NUM>-azidoethyl)-<NUM>-(<NUM>,<NUM>-dimethoxybenzyl)-<NUM>,<NUM>-dimethoxybenzene: Synthesized following the general procedures C and A and obtained as a colorless oil (<NUM>% over three steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>Na]+: <NUM>, found <NUM>.

methyl (S)-<NUM>-(benzo[d][<NUM>,<NUM>]dioxol-<NUM>-yl)-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydro-<NUM>H-1λ<NUM>-pyrido[<NUM>,<NUM>-b]indole-<NUM>-carboxylate: Trifluoroacetic acid (<NUM>, <NUM> mmol, <NUM> equiv. ) was added to a solution of (S)-tryptophan methyl ester(<NPL>) (<NUM>, <NUM> mmol, <NUM> equiv. ) and benzo[d][<NUM>,<NUM>]dioxole-<NUM>-carbaldehyde (<NUM>, <NUM> mmol, <NUM> equiv. ) in DCM (<NUM>). The reaction mixture was stirred for <NUM> day at room temperature and then evaporated. The obtained residue was triturated with a <NUM>% K<NUM>CO<NUM> aqueous solution (<NUM>) and extracted with DCM. The organic layer was dried over MgSO<NUM> and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to afford the desired products as isomers (<NUM>%). The isolated ratio of the two isomers is nearly <NUM>:<NUM>. Isomer a <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>. Isomer b <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (br s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

methyl (S)-<NUM>-azido-<NUM>-(<NUM>-(benzo[d][<NUM>,<NUM>]dioxol-<NUM>-ylmethyl)-<NUM>H-indol-<NUM>-yl)propanoate: Step <NUM>. To a solution of the above isomers (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added <NUM>% Pd/C (<NUM>). The resulting solution was stirred at <NUM> under atmospheric pressure of hydrogen for <NUM> days. The solution was concentrated to dryness. The residue was purified by column chromatography to afford methyl (S)-<NUM>-amino-<NUM>-(<NUM>-(benzo[d][<NUM>,<NUM>]dioxol-<NUM>-ylmethyl)-<NUM>H-indol-<NUM>-yl)propanoate as an off-white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>. Step <NUM>. Synthesized following the reported procedures(<NPL>), and the desired azide was afforded as a brown oil (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>,<NUM>-dimethoxy-<NUM>-vinylphenyl)ethan-<NUM>-ol: Synthesized following the reported procedure(<NPL>) from <NUM>-(<NUM>-iodo-<NUM>,<NUM>-dimethoxyphenyl)ethan-<NUM>-ol(<NPL>). To a solution of vinylboronic acid pinacol cyclic ester (<NUM>, <NUM> mmol, <NUM> equiv. ) in THF (<NUM>) was added H<NUM>O (<NUM>), PdCl<NUM>(dppf) (<NUM>, <NUM> mmol, <NUM> equiv. ), K<NUM>PO<NUM> (<NUM>, <NUM>, <NUM> equiv. mmol) in sequence. The resulting suspension was stirred for <NUM> and then added <NUM>-(<NUM>-iodo-<NUM>,<NUM>-dimethoxyphenyl)ethan-<NUM>-ol (<NUM>, <NUM> mmol). The reaction mixture was warmed to <NUM> and stirred overnight and then was diluted with H<NUM>O (<NUM>). The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (<NUM>×<NUM>). The combined organic layers were washed with NaCl (saturated aq. , <NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was subjected to purification by column chromatography on silica gel to afford desired product as a yellow oil (<NUM>, <NUM> % yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J= <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>O<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-ethyl-<NUM>,<NUM>-dimethoxyphenyl)ethan-<NUM>-ol: Synthesized following the general procedure B and the desired product was afforded as a yellow oil (<NUM>%) after flash chromatography. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>O<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidoethyl)-<NUM>-ethyl-<NUM>,<NUM>-dimethoxybenzene: Synthesized following the general procedure A from <NUM>-(<NUM>-ethyl-<NUM>,<NUM>-dimethoxyphenyl)ethan-<NUM>-ol and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M - N<NUM> + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-chloroethyl)-<NUM>-(<NUM>,<NUM>-dimethoxystyryl)-<NUM>,<NUM>-dimethoxybenzene: Synthesized following the reported procedures(<NPL>) from <NUM>-(<NUM>-chloroethyl)-<NUM>,<NUM>-dimethoxybenzaldehyde(<NPL>) and obtained as a pink solid (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

<NUM>-(<NUM>-chloroethyl)-<NUM>-(<NUM>,<NUM>-dimethoxyphenethyl)-<NUM>,<NUM>-dimethoxybenzene: Synthesized following the general procedure B and the desired product was obtained as a white solid (<NUM>%) after flash chromatography. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>+<NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>ClO<NUM>Na]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidoethyl)-<NUM>-(<NUM>,<NUM>-dimethoxyphenethyl)-<NUM>,<NUM>-dimethoxybenzene: Synthesized following the second step in the general procedure A (the tosylate was replaced by alkyl chloride) and obtained as a white solid (<NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>+<NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>Na]+: <NUM>, found <NUM>.

<NUM>-(<NUM>-azidoethyl)-<NUM>-benzylbenzene (3p) and (S)-(<NUM>-azidopentan-<NUM>-yl)benzene (S-3p): Synthesized following the general procedure A from <NUM>-phenylpentan-<NUM>-ol and (S)-<NUM>-phenylpentan-<NUM>-ol respectively(<NPL>) and obtained as a colorless oil (<NUM>% over two steps). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. Data is consistent with literature values<NUM>. (S)-(<NUM>-azidopentan-<NUM>-yl)benzene was determined to be <NUM>% ee by chiral HPLC analysis (CHIRALCEL OD-H, Hexanes, <NUM>/min, <NUM>, tr (minor) = <NUM>, tr (major) = <NUM>).

An oven-dried Schlenk tube was charged with organic alkyl azides (<NUM> mmol, <NUM> equiv. ), Boc<NUM>O (<NUM> equiv), iron catalyst tBu<NUM>PcPe(py)<NUM> (<NUM>-<NUM> mol %), and dry toluene (<NUM>) under argon. The mixture was refluxed violently (<NUM>) until full completion as detected by TLC (usually completion within <NUM>). The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography to give the corresponding products. For reported products, their characterization are done by comparing with literature reported <NUM>H NMR data. For new products, they were characterized by techniques such as <NUM>H, <NUM>C and <NUM>F NMR spectroscopy and high-resolution mass spectrometry. This represents the standard condition. Yields below refer to isolated yields.

C-H amination products 1b to 31b, produced according to the standard condition above and their respective yields, were as follows:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
where b<NUM> mol% tBu<NUM>PcFe(py)<NUM> for <NUM>; c<NUM> mol% tBu<NUM>PcFe(py)<NUM> for <NUM> hours; and d<NUM> mol% tBu<NUM>PcFe(py)<NUM>.

For previously reported C-H amination products, the characterization was consistent with the characterization in the references listed in Table <NUM> below.

tert-butyl <NUM>-(<NUM>,<NUM>-difluorophenyl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> and <NUM> (br <NUM>, <NUM>+<NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (d, J = <NUM>), <NUM> (d, J = <NUM>), <NUM> (<NUM>), <NUM> - <NUM> (m), <NUM> - <NUM> (m), <NUM> - <NUM> (m), <NUM> - <NUM> (m), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM> (d, J = <NUM>), -<NUM> - -<NUM> (m), -<NUM> - -<NUM> (m), -<NUM> (d, J = <NUM>). HRMS (ESI) m/z: [M+Na]+ calcd. for [C<NUM>H<NUM>F<NUM>NO<NUM>Na]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>,<NUM>-dichlorophenyl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (br s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) <NUM>C NMR (<NUM>, Chloroform-d) δ <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>). HRMS (ESI) m/z: [M+Na]+ calcd. for [C<NUM>H<NUM>Cl<NUM>NO<NUM>Na]+ <NUM>, found : <NUM>.

tert-butyl <NUM>-(<NUM>-hydroxy-<NUM>-(methoxycarbonyl)phenyl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM>, <NUM>, <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>). HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-methylbenzo[d]thiazol-<NUM>-yl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>S]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>,<NUM>-difluorobenzo[d][<NUM>,<NUM>]dioxol-<NUM>-yl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (t, J = <NUM>), <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM> (d, J = <NUM>), -<NUM> (d, J = <NUM>). HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>F<NUM>NO<NUM>Na]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-cyclopentyl-<NUM>H-pyrrolo[<NUM>,<NUM>-b]pyridin-<NUM>-yl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>). HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-(<NUM>-(tert-butoxycarbonyl)pyrrolidin-<NUM>-yl)pyridin-<NUM>-yl)piperazine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM>, <NUM>, <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, (<NUM>), <NUM> (<NUM>), <NUM>, <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM>, <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>). HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>N<NUM>O<NUM>]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>-(methoxycarbonyl)furan-<NUM>-yl)pyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>). HRMS (ESI) m/z: [M + Na]+ calcd. for [C<NUM>H<NUM>NO<NUM>Na]+: <NUM>, found <NUM>.

tert-butyl <NUM>-benzamidopyrrolidine-<NUM>-carboxylate: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (br, m, <NUM>), <NUM> - <NUM> (br, m, <NUM>), <NUM> - <NUM> (br, m, <NUM>), <NUM> - <NUM> (br, m, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM>, <NUM>, <NUM> (<NUM>), <NUM>, <NUM> (<NUM>), <NUM> (<NUM>), <NUM> (<NUM>), <NUM>, <NUM> (<NUM>). HRMS (ESI): m/z: M+ calcd. for C<NUM>H<NUM>N<NUM>O<NUM>: <NUM>, found <NUM>.

(<NUM>R,11aR)-<NUM>-(<NUM>,<NUM>,<NUM>-trifluorobenzyl)-<NUM>-(trifluoromethyl)-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-[<NUM>,<NUM>,<NUM>]triazolo[<NUM>',<NUM>':<NUM>,<NUM>]pyrazino[<NUM>,<NUM>-a]pyrimidin-<NUM>-one: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (q, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM> (ddd, J = <NUM>, <NUM>, <NUM>), <NUM>, <NUM> (dt, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>), <NUM> (dt, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>, - <NUM> - -<NUM> (m), -<NUM> - -<NUM> (m), -<NUM> - -<NUM> (m).

(<NUM>R,11aS)-<NUM>-(<NUM>,<NUM>,<NUM>-trifluorobenzyl)-<NUM>-(trifluoromethyl)-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,11a-hexahydro-<NUM>H-[<NUM>,<NUM>,<NUM>]triazolo[<NUM>',<NUM>':<NUM>,<NUM>]pyrazino[<NUM>,<NUM>-a]pyrimidin-<NUM>-one: <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (q, J = <NUM>, <NUM>), <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM> (ddd, J = <NUM>, <NUM>, <NUM>), <NUM>, <NUM> (dt, J = <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>), <NUM> (q, J = <NUM>), <NUM> (dt, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>), <NUM> (dd, J = <NUM>, <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>, -<NUM> - -<NUM> (m), -<NUM> - -<NUM> (m), -<NUM> - -<NUM> (m). HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>F<NUM>N<NUM>O]+: <NUM>, found <NUM>.

tert-butyl <NUM>-(<NUM>,<NUM>-dimethoxyphenyl)-<NUM>,<NUM>-dimethoxy-<NUM>,<NUM>-dihydroisoquinoline-<NUM>(<NUM>H)-carboxylate (<NPL>): <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>). <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> - <NUM> (br m, <NUM>), <NUM> (s, <NUM>). <NUM>C NMR (<NUM>, CDCl<NUM>) (minor rotamer was shown in the parentheses) δ <NUM> (<NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (<NUM>), <NUM>, <NUM>. HRMS (ESI) m/z: [M + H]+ calcd. for [C<NUM>H<NUM>NO<NUM>]+: <NUM>, found <NUM>.

As shown above, a variety of alkyl azides bearing different electronic properties and functional groups underwent C-H amination in moderate to excellent yields to afford compounds 1b to 31b.

Both electron-donating and withdrawing substituents on the phenyl moiety in the model substrate produced no difference, all leading to the benzylic C-H aminated pyrrolidine products in high yields (1b to 7b).

The aminations of secondary azides with benzylic, tertiary, secondary, and primary C-H bonds, afforded pyrrolidine products (9b to 12b) in <NUM>% to <NUM>% yields, indicating the following reactivity order: benzylic > <NUM>° ~ <NUM>° > <NUM>° C-H bonds.

When the alkyl azide precursor to product 13b was treated according to the system, tropane derivative 13b was synthesized in good yield when utilizing <NUM> mol% catalyst. Similarly, α-azido ketone precursors were well aminated to tropane analogues 14b and 19b in <NUM>% and <NUM>% yield, respectively.

Additionally, functional groups like indole, amide, ester, ether thiazole, furan and phenol were well tolerated in the catalytic system, yielding the corresponding pyrrolidines in yields of <NUM>% to <NUM>% (20b-31b).

A seven-member ring product of azepine analogue 28b was obtained using the instant method in <NUM>% yield.

Notably intramolecular C-H aminations of alkyl azides producing products 20b to 31b have not, to the best of our knowledge and as of the filing of this application, been reported in previous works.

In summary, the iron (II)-phthalocyanine complex tBu<NUM>PcFe(py)<NUM> is a useful catalyst which can be reacted with various alkyl azides featuring benzylic, tertiary, secondary, and primary C-H bonds to induce intramolecular C-H insertion and afford the ring-closure amination products in moderate to excellent yields.

Procedure: An oven-dried Schlenk flask was charged with azidocycloheptane (<NUM> mmol; <NUM>), Boc<NUM>O (<NUM> equiv), iron catalyst tBu<NUM>PcFe(py)<NUM> (<NUM> mol %), and dry toluene (<NUM>) under argon. The reaction was refluxed violently (<NUM>) for <NUM> days, and then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give the amination product. The characterization of this product was done by comparing with literature data (<NPL>). The product (13b) was obtained in <NUM>% (<NUM>H NMR yield) and <NUM>% isolated yield.

To demonstrate the synthetic application of the C-H amination reaction, a large-scale reaction was carried out to afford the tropane derivative in <NUM>% <NUM>H NMR yield by scaling up the catalytic by <NUM>-fold. The tropane derivative had the following chemical structure:
<CHM>.

Using the standard reaction conditions given in Example <NUM> above, the following natural product derivatives were formed at the specified yields, as follows:
<CHM>
<CHM>
<CHM>.

Characterization for the compounds above is given in Example <NUM> above. The application of the catalytic transformation was explored for late-stage functionalization of active pharmaceutical ingredients and the synthesis of alkaloids related natural products derivatives. For example, a cyclization reaction afforded 32b in <NUM>% yield from an azide derived from leelamine. In another instance, N-Boc-<NUM>-phenyltetrahydroisoquinoline (33b), the key intermediate for preparation of vesicare (also called solifenacin), a potent antimuscarinic medication with urinary antispasmodic properties, was constructed using this method. Similarly, N-Boc-protected salsolidine (35b), norlaudanosine (36b) and cryptostyline II (34b) derivatives were also constructed from their azides precursors, albeit with less efficiency as compared to the former two molecules. Product 37b, which can be converted to tadalafil (cialis) in three steps (<NPL>), can be obtained from the azides derived from L-tryptophan. Lastly, late-stage amination of the drug molecule sitagliptin was realized from a derived azide precursor to afford 38b and 38b' where the structures of the corresponding products was confirmed by x-ray analysis, as shown in <FIG>.

The above example demonstrates that the catalytic transformation using the iron (II)-phthalocyanine complex tBu<NUM>PcFe(py)<NUM> catalyst for C-H amination could also be successfully applied in the synthesis of natural product derivatives and late-stage functionalization of commercially available acyclic amines to gain the corresponding alkaloids.

Iron-dipyrrinato catalyst (<NUM>) was applied in intramolecular amination of C(sp<NUM>)-H bonds of alkyl azides by Betley and co-workers in <NUM>. Other catalysts with different catalytic reactivities for amination of alkyl azides have also been developed by several groups. Some representative iron catalysts (<NUM>-<NUM>) are compared with the catalysis performance of tBu<NUM>PcFe(py)<NUM> (<NUM>). Table <NUM> provides the chemical structures of known catalysts.

Compounds 12b, 10b, 13b, and 32b, as discussed in above examples, were synthesized using the C-H amination method using catalysts <NUM>-<NUM>. The compounds are shown below.

As shown in Table <NUM>, catalyst <NUM> (tBu<NUM>PcFe(py)<NUM>) showed good catalytic reactivity to obtain corresponding products 12b, 10b, 13b and 32b with lower catalyst loading and/or higher yields, as compared to catalysts <NUM>-<NUM>.

In order to gain an understanding of the mechanism of the catalytic amination process described herein, three reactions were performed as shown in Scheme <NUM> below.

The standard conditions were those of Example <NUM> above. In (a) (S)-(<NUM>-azidopentan-<NUM>-yl)benzene (<NUM>% ee) was treated according to the method and resulted in tert-butyl (R)-<NUM>-methyl-<NUM>-phenylpyrrolidine-<NUM>-carboxylate (<NUM>% ee) with retention of stereochemistry, which is similar with the reported result (<NPL>).

In (b) adding <NUM> equivalents of TEMPO to the catalytic system did not shut down the amination reaction, and no radical trapped products were detected.

In (c), the intramolecular kinetic isotope effect (KIE) value was calculated as <NUM> when monodeuterated azide <NUM>-azido-<NUM>-deutero-<NUM>-phenylbutane was subjected to standard conditions, which was smaller than the reported data <NUM> at <NUM> by <NPL>) but larger than the value <NUM> at <NUM> by Che's group (<NPL>). This was indicative that a stepwise mechanism was involved in the catalytic reaction.

Claim 1:
A method of C-H bond amination comprising the steps of:
(a) forming a reaction mixture comprising an alkyl azide, an iron(II)-phthalocyanine catalyst, and one or more solvents in a reaction vessel; and
(b) heating the reaction mixture to a temperature of at least <NUM> sufficient to induce a direct intramolecular C-H bond amination of the alkyl azide.