Method for Iron-Catalyzed C-H Bond Amination

Abstract

This text describes the C−H amination of alkyl azides catalyzed by iron(II)−phthalocyanine. The catalyst can efficiently generate intramolecular amination of saturated C−H bonds in moderate to excellent yields, and this method is tolerant to a wide range of substrates. The method can be used for the synthesis of natural product derivatives and late-stage functionalization of drugs.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 236,050, filed on August 23, 2021, which is incorporated herein by reference in its entirety. Field of the invention

[0003] The disclosed invention generally pertains to the field of methods for transition - metal - catalyzed C - H amination. Background of the invention

[0004] Nitrogen - containing compounds are ubiquitous in bioactive molecules, natural products, and pharmaceutically important molecules. Such compounds can include Vesicare (solifenacin), cryptostylines I - III, norlaudanosoline, tadalafil, aspidospermidine, and sitagliptin (A.K. Mailyan et al., Chem. Rev., 2016, 116, 4441. R.D. Taylor, M. MacCoss; A.D.G. Lawson, J. Med. Chem., 2014, 57, 5845). It is also important to consider methods related to the synthesis of such compounds.

[0005] For example, the catalytic transfer of nitrene moieties to C–H bonds is a useful tool for direct C–H amination as it avoids pre-functionalization of starting materials and / or the use of toxic reagents. As such, it is considered time- and atom-efficient (B. Darses et al., Chem. Commun., 2017, 53, 493; Y. Liu et al., Chem. Soc. Rev., 2020, 49, 5310; Y. Liu et al., Tetrahedron, 2019, 75, 130607). In the past few years, nitrene sources involved in this transformation have been used and explored, including iminoiodinane (PhI=NTs, etc.) (B. Darses et al., Chem. Commun. 2017, 53, 493), oxidized amide salts (e.g., bromamine-T, chloramine-T, etc.) (J. D. Harden et al., Chem. Commun., 2007, 4644; T. Kawano et al., J. Am. Chem. Soc., 2010, 132, 6900) to the use of organic azides (RN3) (Y. M. Badiei et al., Angew. Chem. Int. Ed., 2008, 47, 9961; K. Shin et al., Acc. Chem. Res., 2015, 48, 1040; D. Intrieri et al., Chem. Commun., 2014, 50, 11440; T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831; B. Plietker et al., Catal. Sci. Technol., 2019, 9, 4188.).

[0006] Following the report by Betley and co-workers on the use of an iron-dipyrrinato catalyst to effect intramolecular C(sp 3)-H bonds (E. T. Hennessy et al., Science, 2013, 340, 591; D. A. Iovan et al., Angew. Chem. Int. Ed., 2017, 56, 15599), many types of catalysts including iron (B. Bagh et al., J. Am. Chem. Soc., 2017, 139, 5117; K.-P. Shing et al., Angew. Chem. Int. Ed., 2018, 57, 11947; Y.-D. Du et al., Org. Lett., 2019, 21, 895; Y.-D. Du et al., Chem. Sci., 2020, 11, 4680; S. Liang et al., Org. Lett., 2020, 22, 1961), cobalt (P. F. Kuijpers et al., Chem. Eur. J., 2017, 23, 7945; M. Goswami et al., Eur. J. Inorg. Chem., 2018, 2018, 617; Y. Baek et al., J. Am. Chem. Soc., 2019, 141, 7797; Y. Baek, J. Am. Chem. Soc., 2019, 141, 16944; Y. Baek et al., J. Am. Chem. Soc., 2020, 142, 11232.), ruthenium (J. Qin et al., Chem. Sci., 2019, 10, 3202; Z. Zhou et al., Angew. Chem. Int. Ed., 2019, 58, 1088.), nickel (Y. Dong et al., J. Am. Chem. Soc., 2020, 142, 10996) and palladium-based (D. L. J. Broere et al., J. Am. Chem. Soc., 2014, 136, 11574; D. L. J. Broere et al., Inorg. Chem., 2016, 55, 8603) catalysts have been extensively studied. However, in the reported catalytic systems, the catalyst loadings are still high and there is a general lack of catalysts for the synthesis of natural products.

[0007] Therefore, there is still a need for improved methods to achieve the intramolecular C(sp 3 )-H bond of alkyl azides, which require lower catalyst loadings, are applicable to a wide range of substrate scopes, and can be used for the late-stage functionalization of natural product derivatives and active pharmaceutical ingredients.

[0008] Accordingly, one object of the present invention is to provide an improved method for such catalytic C-H amination.

[0009] Another object of the present invention is to provide a method that operates at lower catalyst loadings.

[0010] Another object of the present invention is to apply these methods to the synthesis of natural product derivatives and the late-stage functionalization of active pharmaceutical ingredients. SUMMARY OF THE INVENTION

[0011] Methods for C-H amination are disclosed herein. The method comprises the following steps:

[0012] (a) forming a reaction mixture in a reaction vessel comprising an alkyl azide, an iron(II)-phthalocyanine catalyst, and one or more solvents; and

[0013] (b) heating the reaction mixture to a temperature of at least about 100 °C, sufficient to induce direct intramolecular C-H bond amination of the alkyl azide.

[0014] The product of the direct intramolecular C-H bond amination of the alkyl azide is believed to be the closed-loop amination product of the alkyl azide. It is believed that the described method involves transition metal-catalyzed direct C-H bond amination, proceeding through a nitrene transfer reaction to produce a C-N bond.

[0015] In some cases, the iron(II)-phthalocyanine catalyst has a chemical structure according to any one of Formulas A-D, as shown below:

[0016]

[0017]

[0018] wherein in each of the Formulas A-D, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj are each independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (linear or branched), such as methyl, ethyl, propyl, butyl, or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; aryl (i.e., phenyl); heteroaryl; benzyl; acyl; ester; carbonyl; carboxylate; amino (primary, secondary, or tertiary); amide; and nitro. In some cases, Ra, Rb, Rd, Re, Rf, Rg, Ri, and Rj are hydrogen and Rc and Rh are substituted, preferably with the same substituent. In some cases, Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re may together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms. In some cases, Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj may together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms. In some cases, at least one of Ra, Rb, Rc, Rd, Re and at least one of Rf, Rg, Rh, Ri, and Rj are substituted.

[0019] In some cases, the iron(II)-phthalocyanine catalyst of formula A is preferably:

[0020]

[0021] In step (b), the reaction mixture is heated to a temperature of at least about 100 °C, sufficient to induce direct intramolecular C-H bond amination of the alkyl azide. In some cases, the temperature of the reaction mixture is selected to be sufficient to cause reflux of one or more of the selected solvents. In some cases, the reaction mixture is heated to a temperature of about 105 °C, 110 °C, 115 °C, 120 °C, 125 °C or 130 °C. In some other cases, the reaction mixture is heated to a temperature in the range of about 105 °C to about 130 °C. The heating in step (b) can be carried out for a period of about 0.1 hours to 72 hours, 0.1 hours to 48 hours or 0.1 hours to 24 hours. In some cases, the heating in step (b) can be carried out for a period of at least about 10, 15, 20, 25, 30, 35, 40, 45 or 50 hours.

[0022] In some cases, the alkyl azide used in the method preferably contains a benzylic, tertiary, secondary or primary C-H bond. In some other cases, the alkyl azide has the chemical structure of formula I as follows:

[0023]

[0024] wherein R1, R2, R3 and R4 are each independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (straight or branched), such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl (i.e., phenyl); heteroaryl; benzyl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro; and

[0025] wherein L is a substituted or unsubstituted alkyl chain having 3, 4, 5, 6, 7 or 8 carbons, the chain being optionally interrupted by at least one heteroatom; and, when substituted, the substituents on each carbon present are independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (straight or branched), such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl (i.e., phenyl); heteroaryl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro.

[0026] In some other cases, the alkyl azide has the chemical structure of formula II as follows:

[0027]

[0028] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 are each independently selected from hydrogen; a halogen group (i.e., -F, -Cl, -Br, -I); a C2-C5 alkyl group (linear or branched), such as methyl, ethyl, propyl, butyl or pentyl; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkenyl group; a cycloalkynyl group; a hydroxyl group; an alkoxy group; an aryl group (i.e., phenyl); 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.

[0029] In some cases, the closed-loop amination product of the disclosed method has the chemical structure shown below: wherein R is H, Me, OMe, Cl, Br, F, NO2 or N,N-dimethyl; wherein each R is 4-OMeC6H4;

[0030] The C-H amination methods described herein can be used to synthesize a variety of closed-loop amination products from a variety of organic azide starting materials. In particular, these methods can find applications in the late-stage functionalization of active pharmaceutical ingredients (APIs) and the catalytic transformation in the synthesis of natural product derivatives. Exemplary natural product derivatives can include, for example, derivatives having the chemical structure shown below:

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 Shows the X-ray crystal structures of sitagliptin derivatives 38b and 38b' prepared by C-H bond amination as described in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0033] I. DEFINITIONS

[0034] "Aryl" shall be understood to mean a group containing a structure composed of 6 to 30 carbon atoms, 6 to 18 carbon atoms, which is formed by one aromatic ring or multiple fused aromatic rings. Exemplary aryls are, but not limited to, phenyl, naphthyl, anthryl or phenanthryl. The aryl can be unsubstituted, where all substitutable carbon atoms bear hydrogen atoms. Alternatively, they can be substituted at one, more than one or all substitutable positions therein. Suitable exemplary substituents include, but are not limited to, alkyl groups, such as alkyl groups having 1 to 8 carbon atoms, which can be selected from methyl, ethyl, isopropyl or tert-butyl, aryl (e.g., C6-aryl, which can be substituted or unsubstituted), heteroaryl (which can contain at least one nitrogen atom, such as pyridyl), alkenyl (which can contain one double bond and 1 to 8 carbon atoms), or groups having electron-donating or electron-accepting ability. A group having electron-donating ability is understood to mean a group having a positive inductive (+I) and / or positive mesomeric (+M) effect, and a group having electron-accepting ability is understood to mean a group having a negative inductive (-I) and / or negative mesomeric (-M) effect. Suitable groups having donor or acceptor effects are halogen groups, such as F, Cl, Br, alkoxy, aryloxy, carbonyl, ester, amine, amide, CH2F group, CHF2 group, CF3 group, CN group, thio group, or SCN group.

[0035] "Heteroaryl" shall be understood to differ from the above aryl in that at least one carbon atom in the structure constituting the aryl is replaced by at least one heteroatom. The heteroatom can have hydrogen substituents and / or any permitted substituents of the organic compound to satisfy the valence of the heteroatom. Exemplary heteroatoms include N, O and S. In most cases, one or two carbon atoms in the aryl structure are replaced by heteroatoms. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrimidinyl, pyrazolyl, triazolyl and five-membered heteroaromatic compounds, such as pyrrole, furan, thiophene, pyrazole, imidazole, triazole, oxazole, thiazole. The heteroaryl can be unsubstituted at the substitutable positions (unsubstituted), substituted at one, more than one or all substitutable positions. Suitable substituents are as defined above for aryl.

[0036] "Alkyl" is to be understood as referring to a group having from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 8 carbon atoms. The alkyl group may be branched or unbranched, and the carbon chain may optionally be interrupted by one or more heteroatoms such as N, O, or S. The heteroatom may have hydrogen substituents and / or any permissible substituents of the organic compound to satisfy the valence of the heteroatom. The alkyl group may optionally be substituted by one or more of the substituents mentioned above for the aryl group. The alkyl group may also contain one or more aryl groups thereon, where suitable aryl groups are as described above. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, and sec-hexyl.

[0037] "Alkenyl" is to be understood as referring to a group having from 2 to 20 carbon atoms, from 2 to 10 carbon atoms, or from 2 to 8 carbon atoms, which may be optionally substituted and has at least one carbon-carbon double bond.

[0038] "Alkynyl" is to be understood as referring to a group having from 2 to 20 carbon atoms, from 2 to 10 carbon atoms, or from 2 to 8 carbon atoms, which may be optionally substituted and has at least one carbon-carbon triple bond.

[0039] "Cycloalkyl" is to be understood as referring to a cyclic group having from 3 to 20 carbon atoms, from 3 to 10 carbon atoms, or from 3 to 8 carbon atoms. The carbon chain of the cycloalkyl group may optionally be interrupted by one or more heteroatoms such as N, O, or S. The heteroatom may have hydrogen substituents and / or any permissible substituents of the organic compound to satisfy the valence of the heteroatom. The cycloalkyl group may be unsubstituted or substituted, i.e., substituted by one or more of the substituents mentioned herein.

[0040] "Cycloalkenyl" is to be understood as referring to a cyclic group having from 4 to 20 carbon atoms, from 4 to 10 carbon atoms, or from 4 to 8 carbon atoms, which may be optionally substituted and has at least one carbon-carbon double bond.

[0041] "Cycloalkynyl" is to be understood as referring to a cyclic group having from 6 to 20 carbon atoms, from 6 to 10 carbon atoms, or from 6 to 8 carbon atoms, which may be optionally substituted and has at least one carbon-carbon triple bond.

[0042] As used herein, "carbonyl" is to be understood as referring to a moiety represented by the following general formula:

[0043]

[0044] wherein X is a chemical bond, or X represents oxygen or sulfur, and R represents 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, -(CH2) m-R”; wherein R' represents 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 -(CH2) m -R”; wherein R” represents hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, heterocycle or polycycle; and m is an integer of 0 or 1 - 8. When X is oxygen and R is as defined above, this moiety may be referred to as “carboxyl group”. When X is oxygen and R is hydrogen, this formula represents “carboxylic acid group”. When X is oxygen and R' is hydrogen, this formula represents “formate group”. When X is oxygen and neither R nor R' is hydrogen, this formula represents “ester group”. Generally, when the oxygen atom in the above formula is replaced by a sulfur atom, this formula represents “thiocarbonyl group”. When X is sulfur and neither R nor R' is hydrogen, this formula represents “thioester group”. When X is sulfur and R is hydrogen, this formula represents “thiocarboxylic acid group”. When X is sulfur and R' is hydrogen, this formula represents “thioformate group”. When X is a chemical bond and R is not hydrogen, the above formula represents “ketone group”. When X is a chemical bond and R is hydrogen, the above formula represents “aldehyde group”. The term “substituted carbonyl” refers to a carbonyl as defined above, wherein one or more hydrogen atoms in R, R' or the group connected to this moiety are independently replaced by suitable substituents as defined below.

[0045] “Amide group” or “amido” should be understood to refer to the moiety represented by the general formula:

[0046]

[0047] wherein, E does not exist, 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, E, R and R' each independently represent 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, -(CH2) m -R”’; or R and R' together with the N atom to which they are attached form a heterocycle having 3 to 14 atoms in the ring structure; R”’ may represent hydroxyl, substituted or unsubstituted carbonyl, aryl, cycloalkyl, heterocycle or polycycle; and m is an integer of 0 or 1 - 8. When E is oxygen, a “carbamate group” is formed. As understood by those of ordinary skill in the art, a carbamate cannot be connected to another chemical substance, such as forming an oxygen-oxygen bond or other unstable bonds.

[0048] 1. As used herein, the term "substituted" refers to all permissible substituents of the above compounds or functional groups. Exemplary substituents include, but are not limited to, halogen, hydroxyl, or any other organic group containing any number of carbon atoms (preferably 1-14 carbon atoms) and optionally containing one or more heteroatoms (such as oxygen, sulfur, or nitrogen groups), in the form of straight-chain, branched-chain, or cyclic structures. Representative substituents may include alkyl, substituted alkyl (such as -CF3 and -CD3), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halogen, hydroxyl, alkoxy, formyl, substituted alkoxy, phenoxy, substituted phenoxy, aryloxy, substituted aryloxy, mercapto (-SH), substituted mercapto, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, carboxylates, amino, substituted amino, amide, substituted amide, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, cyclic groups (such as C3-C 20 cyclic groups), substituted cyclic groups (such as substituted C3-C 20 cyclic groups), heterocyclic groups, substituted heterocyclic groups, deuterium, trihaloalkyl (trifluoromethyl), unsubstituted diarylamino, substituted diarylamino, unsubstituted dialkylamino, substituted dialkylamino, azo group, carbonate, nitro, nitroso, phosphino, pyridyl, NRR', SR, C(O)R, COOR, C(O)NR, SOR, and SOR groups, where R and R' are independently selected from a hydrogen atom, a deuterium atom, or any of the above substituents.

[0049] The numerical ranges disclosed in this application include, but are not limited to, ranges of carbon atoms, temperature ranges, concentration ranges, time ranges, and other ranges disclosed hereinafter. The disclosed ranges individually disclose such a range that can reasonably include every possible number, as well as any sub-ranges and combinations of sub-ranges contained therein. For example, in accordance with the disclosure herein, the disclosure of a range of carbon atoms is intended to individually disclose each possible value that the range may contain. For example, a carbon range of 1 to 10 carbons also separately discloses each carbon number within that range (1, 2, 3, 4, 5, 6, 7, 8, 9, 10 carbons), as well as any sub-ranges contained therein (2 to 4 carbons or 5 to 9 carbons).

[0050] The term "about" is intended to describe a value that is above or below a specified value, and the term "about" modifies it, with a range of about + / - 10%; in other cases, these values may be above or below the specified value, with a range of about + / - 5%. When the term "about" is used before a numerical range (i.e., about 1-5) or a series of numbers (i.e., about 1, 2, 3, 4, etc.), unless otherwise specified, it is intended to modify both ends of the numerical range and / or each number listed in the entire series.

[0051] II. Method for C-H Bond Amination

[0052] Methods for C-H amination are described herein. In some cases, the methods include the following steps:

[0053] (a) Forming a reaction mixture in a reaction vessel that includes an alkyl azide, an iron(II)-phthalocyanine catalyst, and one or more solvents; and

[0054] (b) Heating the reaction mixture to a temperature of at least about 100 °C, sufficient to induce direct intramolecular C-H bond amination of the alkyl azide.

[0055] The product of the direct intramolecular C-H bond amination of the alkyl azide is considered to be the closed-loop amination product of the alkyl azide. It is believed that the described method involves transition metal-catalyzed direct C-H bond amination, proceeding through a nitrene transfer reaction to produce a C-N bond.

[0056] The reaction mixture can be prepared in any known suitable reaction vessel according to standard synthetic practices known to those skilled in the art. The reaction mixture after step (b) can be worked up and purified using any standard synthetic workup and purification operations known to those skilled in the art to obtain a separated product of the direct intramolecular C-H bond amination of the alkyl azide. In some cases, steps (a) and / or (b) are carried out under an inert atmosphere, where the inert atmosphere can be selected from argon, nitrogen, or a combination thereof. Those skilled in the art can use any known synthetic characterization techniques (including but not limited to NMR, UV / Vis, mass spectrometry, elemental analysis, etc.) to characterize the product of the direct intramolecular C-H bond amination of the alkyl azide.

[0057] The concentration of the alkyl azide present in the reaction mixture can be any suitable concentration. In some cases, the concentration of the alkyl azide present in the reaction mixture is in the range of about 0.01 to 5 M, 0.01 to 4 M, 0.01 to 3 M, 0.01 to 2 M, or 0.01 to 1 M, and sub - ranges thereof. The amount of the iron(II)-phthalocyanine catalyst present in the reaction mixture can be in an amount of about 0.1 to 5 mol% of the amount of the alkyl azide present. In some other cases, the amount of the catalyst is at least about 1, 2, 3, 4, or 5 mol% of the amount of the alkyl azide present.

[0058] In some cases, the iron(II)-phthalocyanine catalyst is diamagnetic or paramagnetic. In certain cases, the catalyst is preferably diamagnetic. In certain cases, the catalyst is preferably diamagnetic. In some other cases, the catalyst is paramagnetic.

[0059] In some cases, the iron(II)-phthalocyanine catalyst has a chemical structure according to any one of Formulas A - D, as shown below:

[0060]

[0061]

[0062] Wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulas A - D are each independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2 - C5 alkyl (straight or branched), such as methyl, ethyl, propyl, butyl, or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy, such as methoxy, ethoxy, propoxy, or butoxy; aryl (i.e., phenyl); heteroaryl; benzyl; acyl; ester group; carbonyl; carboxylate group; amino (primary, secondary, or tertiary); amide group; and nitro. In some cases, Ra, Rb, Rd, Re, Rf, Rg, Ri, and Rj are hydrogen and Rc and Rh are substituted, preferably with the same substituent. In some cases, 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 5 to 10 carbon atoms. In other cases, 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 5 to 10 carbon atoms. In some cases, at least one of Ra, Rb, Rc, Rd, Re and at least one of Rf, Rg, Rh, Ri, and Rj are substituted.

[0063] The iron(II)-phthalocyanine catalyst used in the method includes a catalyst of any one of the above formulas A - D. In some cases, the catalyst used comprises a mixture of two or more catalyst compounds of formulas A - D. Those skilled in the art understand that mixtures of catalysts that can be considered isomers (such as those of formulas A - D) can be used in the method. Methods for synthesizing catalysts according to any one of formulas A - D are known in the art.

[0064] In some cases, the iron(II)-phthalocyanine catalyst of formula A has the following chemical structure:

[0065]

[0066]

[0067]

[0068]

[0069] The position of the tert-butyl group on the phthalocyanine in the above compound is the position shown in formula A above. As those of ordinary skill in the art will recognize and understand, equivalent isomeric structures with a tert-butyl group on the phthalocyanine (as shown in formulas B - D above) are also described and disclosed.

[0070] In some cases, the iron(II)-phthalocyanine catalyst of formula A is preferably:

[0071]

[0072] The catalyst t Bu4PcFe(py)2 is diamagnetic.

[0073] In other cases, the iron(II)-phthalocyanine catalyst can have one of the following chemical structures:

[0074]

[0075] In some cases, the reaction mixture further comprises at least one reagent for protecting amine groups. Suitable amine protecting groups are known in the art. In such cases, the reagent for protecting amine groups is present in an amount of about 1 to 3 equivalents based on the molar amount of alkyl azide present in the reaction mixture. In some cases, the reagent for protecting amine groups is fluorenylmethyloxycarbonyl (Fmoc) or preferably di-tert-butyl dicarbonate (Boc2O). Standard procedures for removing the protected amine groups are known to those of ordinary skill in the art and can be carried out after forming the intramolecular C - H bond amination product of the alkyl azide.

[0076] One or more solvents in the reaction mixture can be selected from any suitable solvent. The volume of one or more solvents in the reaction mixture can be any suitable amount, and the volume of the required solvent can be readily determined by those skilled in the art. In some cases, the one or more solvents are organic solvents selected from toluene, benzene, chlorobenzene, 1,2-dichlorobenzene, 1,2-dichloroethane. Preferably, the one or more solvents are used dry.

[0077] In step (b), the reaction mixture is heated to a temperature of at least about 100 °C, sufficient to induce direct intramolecular C-H bond amination of the alkyl azide. In some cases, the temperature of the reaction mixture is selected to be sufficient to cause reflux of the selected one or more solvents. In some cases, the reaction mixture is heated to a temperature of about 105 °C, 110 °C, 115 °C, 120 °C, 125 °C or 130 °C. In some other cases, the reaction mixture is heated to a temperature in the range of about 105 °C to about 130 °C. The heating in step (b) can be carried out for a period of about 0.1 hour to 72 hours, 0.1 hour to 48 hours or 0.1 hour to 24 hours. In some cases, the heating in step (b) can be carried out for a period of at least about 10, 15, 20, 25, 30, 35, 40, 45 or 50 hours.

[0078] In some cases, the alkyl azide used in the method preferably contains a benzylic, tertiary, secondary or primary C-H bond. In some other cases, the alkyl azide has a chemical structure of formula I as follows:

[0079]

[0080] wherein R1, R2, R3 and R4 are each independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (straight or branched), such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl (i.e., phenyl); heteroaryl; benzyl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro; and

[0081] wherein L is a substituted or unsubstituted alkyl chain having 3, 4, 5, 6, 7 or 8 carbons, the chain being optionally interrupted by at least one heteroatom; and, when substituted, the substituents on each carbon present are independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (straight or branched), such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl (i.e., phenyl); heteroaryl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro.

[0082] In some cases, at least one heteroatom (when present) on L can be selected from oxygen, sulfur, nitrogen atoms, or combinations thereof, provided that the valence requirements of the heteroatoms are satisfied.

[0083] In some cases, adjacent or proximate carbons of the substituted or unsubstituted alkyl chain L (i.e., separated by one or two atoms) can together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0084] In some cases, any one of R1, R2, R3, and R4 and a carbon of the substituted or unsubstituted alkyl chain L can independently together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0085] In some cases, R1 and R2 can together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms. In some cases, R3 and R4 can together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms. In other cases, R1 and R3 or R4 can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms. In other cases, R2 and R3 or R4 can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms. In some cases, R3 and R1 or R2 can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms. In other cases, R4 and R1 or R2 can be linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms.

[0086] In certain other cases, the alkyl azide has a chemical structure of Formula II as follows:

[0087]

[0088] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 are each independently selected from hydrogen; halogen groups (i.e., -F, -Cl, -Br, -I); C2-C5 alkyl (linear or branched), such as methyl, ethyl, propyl, butyl, or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl (i.e., phenyl); heteroaryl; benzyl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro.

[0089] In some cases, wherein R5 and R6, R6 and R7, R7 and R8, R8 and R9, or R9 and R 10Each of them can optionally form a saturated, unsaturated or aromatic optionally substituted ring which is optionally interrupted by a heteroatom and has a total of 5 to 18 carbon atoms and heteroatoms.

[0090] In some cases, the closed-loop amination product in the above method has the chemical structure shown below:

[0091] wherein R is H, Me, OMe, Cl, Br, F, NO2 or N,N-dimethyl; wherein each R is 4-OMeC6H4;

[0092] Those skilled in the art will understand that the closed-loop amination products formed according to the above method can 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 and are covered by the present disclosure. As used herein, the term "stereoisomer" refers to a compound composed of the same atoms having the same bond order but having different non-interchangeable three-dimensional arrangements of atoms. This three-dimensional structure is called configuration. As used herein, the term "enantiomer" refers to two stereoisomers that are non-overlapping mirror images of each other. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein, the term "diastereomer" refers to two stereoisomers that are neither mirror images nor overlapping. The terms "racemate", "racemic mixture" or "racemic variant" 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. Selecting a suitable chiral column, eluent and the conditions necessary to achieve the separation of enantiomer pairs using standard techniques is well known to those of ordinary skill in the art (see, for example, Jacques, J. et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981).

[0093] III. Uses of the C-H Bond Amination Method and Its Products

[0094] The above C-H amination method can be used to synthesize various closed-loop amination products from a variety of organic azide starting materials. In particular, these methods can find applications in the late-stage functionalization of active pharmaceutical ingredients (APIs) and catalytic transformations in the synthesis of natural product derivatives. Exemplary natural product derivatives can include, for example, derivatives having the chemical structure shown below:

[0095]

[0096] The above-mentioned compound can be used for manufacturing pharmaceutical products.

[0097] The disclosed method can be further understood by the following numbered paragraphs.

[0098] Paragraph 1. A method for C-H bond amination, the method comprising the following steps:

[0099] (a) Forming a reaction mixture in a reaction vessel, the reaction mixture comprising an alkyl azide, an iron(II)-phthalocyanine catalyst, and one or more solvents; and

[0100] (b) Heating the reaction mixture to a temperature of at least about 100 °C, sufficient to induce direct intramolecular C-H bond amination of the alkyl azide.

[0101] Paragraph 2. The method according to Paragraph 1, wherein the iron(II)-phthalocyanine catalyst is defined according to any one of Formulas A, B, C, or D:

[0102]

[0103]

[0104] Wherein Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, and Rj in each of Formulas A-D are each independently selected from hydrogen; a halogen group; a C2-C5 straight-chain or branched-chain alkyl group, such as methyl, ethyl, propyl, butyl, or pentyl; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkenyl group; a 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.

[0105] Paragraph 3. The method according to Paragraph 2, 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 5 to 10 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 5 to 10 carbon atoms.

[0106] Paragraph 4. The method according to any one of Paragraphs 2-3, wherein the iron(II)-phthalocyanine catalyst of Formula A has one of the following chemical structures:

[0107]

[0108]

[0109]

[0110]

[0111] Paragraph 5. The method according to any one of paragraphs 1-4, wherein the iron(II)-phthalocyanine catalyst is:

[0112]

[0113] Paragraph 6. The method according to any one of paragraphs 1-5, wherein the amount of the alkyl azide in which the iron(II)-phthalocyanine catalyst can be present is present in the reaction mixture in an amount of about 0.1 to 5 mol%; or is present in the reaction mixture in an amount of at least about 1, 2, 3, 4 or 5 mol% of the amount of the alkyl azide present.

[0114] Paragraph 7. The method according to any one of paragraphs 1-6, wherein the reaction mixture is heated to a temperature of about 105 °C, 110 °C, 115 °C, 120 °C, 125 °C or 130 °C.

[0115] Paragraph 8. The method according to any one of paragraphs 1-6, wherein the reaction mixture is heated to a temperature in the range of about 105 °C to about 130 °C.

[0116] Paragraph 9. The method according to any one of paragraphs 1-8, wherein the one or more solvents are organic solvents.

[0117] Paragraph 10. The method according to paragraph 6, wherein the organic solvent is selected from toluene, benzene, chlorobenzene, 1,2-dichlorobenzene, 1,2-dichloroethane.

[0118] Paragraph 11. The method according to any one of paragraphs 1-10, wherein step (a) and / or (b) is carried out under an inert atmosphere.

[0119] Paragraph 12. The method according to paragraph 11, wherein the inert atmosphere is selected from argon, nitrogen or a combination thereof.

[0120] Paragraph 13. The method according to any one of paragraphs 1-12, wherein the heating in step (b) is carried out for a period of about 0.1 hours to 72 hours, 0.1 hours to 48 hours or 0.1 hours to 24 hours.

[0121] Paragraph 14. The method according to any one of paragraphs 1-12, wherein the heating in step (b) is carried out for a period of at least about 10, 15, 20, 25, 30, 35, 40, 45 or 50 hours.

[0122] Paragraph 15. The method according to any one of paragraphs 1-14, wherein the reaction mixture further comprises at least one reagent for protecting amine groups.

[0123] Paragraph 16. The method according to paragraph 15, wherein the at least one reagent for protecting amine groups is present in an amount of about 1 to 3 equivalent moles of the alkyl azide.

[0124] Paragraph 17. The method according to any one of paragraphs 15-16, wherein the at least one reagent for protecting amine groups is fluorenylmethyloxycarbonyl (Fmoc) or di-tert-butyl dicarbonate (Boc2O).

[0125] Paragraph 18. The method according to any one of paragraphs 1-17, wherein the alkyl azide contains a benzylic, tertiary, secondary or primary C-H bond.

[0126] Paragraph 19. The method according to any one of paragraphs 1-17, wherein the alkyl azide has a chemical structure of formula I as follows:

[0127]

[0128] wherein R1, R2, R3 and R4 are each independently selected from hydrogen; halogen groups; C2-C5 alkyl groups, such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl; heteroaryl; benzyl; oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro; and

[0129] wherein L is a substituted or unsubstituted alkyl chain having 3, 4, 5, 6, 7 or 8 carbons, the chain being optionally interrupted by at least one heteroatom; and, when substituted, the substituents on each carbon present are independently selected from hydrogen; halogen groups; C2-C5 alkyl groups, such as methyl, ethyl, propyl, butyl or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl; heteroaryl; benzyl, oxo (=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro.

[0130] Paragraph 20. The method according to paragraph 19, wherein the at least one heteroatom (when present) is an oxygen atom, a sulfur atom or a nitrogen atom.

[0131] Paragraph 21. The method according to any one of paragraphs 19-20, wherein any two adjacent carbons of the substituted or unsubstituted alkyl chain together form a saturated, unsaturated or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0132] Paragraph 22. The method according to any one of paragraphs 19 - 21, wherein any one of R1, R2, R3, and R4 independently together with the carbon of a substituted or unsubstituted alkyl chain forms a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0133] Paragraph 23. The method according to any one of paragraphs 19 - 22, wherein R1 and R2 together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0134] Paragraph 24. The method according to any one of paragraphs 19 - 23, wherein R3 and R4 together form a saturated, unsaturated, or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0135] Paragraph 25. The method according to any one of paragraphs 19 - 22, wherein R1 and R3 or R4 are linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms.

[0136] Paragraph 26. The method according to any one of paragraphs 19 - 22, wherein R2 and R3 or R4 are linked together by a saturated, unsaturated, optionally substituted alkyl chain having a total of 3 to 10 carbon atoms.

[0137] Paragraph 27. The method according to any one of paragraphs 1 - 17, wherein the alkyl azide has a chemical structure of formula II as follows:

[0138]

[0139] wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 are each independently selected from hydrogen; halogen groups; C2 - C5 alkyl, such as methyl, ethyl, propyl, butyl, or pentyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxy; alkoxy; aryl; heteroaryl; phenyl; benzyl; oxo(=O) group; acyl; ester group; carbonyl; carboxylate group; amino; amide group; and nitro.

[0140] Paragraph 28. The method according to any one of paragraphs 1 - 27, wherein the direct intramolecular C - H bond amination of the alkyl azide gives a closed - loop amination product of the alkyl azide.

[0141] Paragraph 29. The method according to paragraph 28, wherein the closed - loop amination product has a chemical structure as shown below:

[0142] wherein R is H, Me, OMe, Cl, Br, F, NO2, or N,N - dimethyl; where each R is 4-OMeC6H4;

[0143] Paragraph 30. A natural product derivative prepared by the method of any one of Paragraphs 1-28, wherein the natural product derivative has the chemical structure shown below:

[0144]

[0145]

[0146] Paragraph 31. An iron(II)-phthalocyanine catalyst defined by any one of Formulae A, B, C or D:

[0147]

[0148]

[0149] wherein in each of Formulae A-D, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri and Rj are each independently selected from hydrogen; a halogen group; a C2-C5 straight-chain or branched alkyl group, such as methyl, ethyl, propyl, butyl or pentyl; an alkenyl group; an alkynyl group; a cycloalkyl group; a cycloalkenyl group; a 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.

[0150] Paragraph 32. The iron(II)-phthalocyanine catalyst according to Paragraph 31, wherein Ra and Rb, Rb and Rc, Rc and Rd, or Rd and Re may together form a saturated, unsaturated or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms; and / or Rf and Rg, Rg and Rh, Rh and Ri, or Ri and Rj may together form a saturated, unsaturated or aromatic optionally substituted ring having a total of 5 to 10 carbon atoms.

[0151] Paragraph 33. The iron(II)-phthalocyanine catalyst according to any one of Paragraphs 31-32, wherein the iron(II)-phthalocyanine catalyst has one of the following chemical structures:

[0152]

[0153]

[0154]

[0155] and its isomers.

[0156] The methods, compounds, and compositions described herein are further illustrated in the following examples, which are provided by way of illustration and are not intended to be limiting. It should be understood that variations in the proportions of the indicated components and substitutions of ingredients will be apparent to those skilled in the art and are within the scope of the disclosed forms. Theoretical aspects are presented with the understanding that the applicant does not seek to be bound by the proposed theory. Examples

[0157] Materials:

[0158] The chemical reagents used for the synthesis were purchased from commercial companies including Sigma - Aldrich, Acros Organics, and J&K Scientific. Unless otherwise stated, they were used directly without further treatment. The solvents used for the synthesis were purchased from Acros Organics, RCI Labscan, Scharlab, and J&K Scientific. Unless otherwise stated, they were used directly without further treatment.

[0159] Catalyst t Bu4PcFe(py)2 is a known compound and was prepared according to previous literature reports (Inorg. Chem. 1984, 23, 1065). The catalyst Bu4PcFe(py) was characterized by ESI mass spectrometry, UV / Vis, and 1 1H NMR spectroscopy. t 1H NMR (400 MHz, benzene - d6) δ 9.90–9.84 (m, 4H), 9.67 (dd, J = 8.0, 2.9 Hz, 4H), 8.00–7.93 (m, 4H), 4.60 (t, J = 7.5 Hz, 2H), 3.81 (t, J = 7.0 Hz, 4H), 2.43 (d, J = 5.4 Hz, 4H), 1.61–1.49 (m, 36H). 1 The 1H NMR spectra were recorded on a Bruker DPX - 500 or DPX - 400 NMR spectrometer. The chemical shifts of the proton signals were calibrated by the corresponding solvent residual signals. The ESI mass spectra were recorded on a Q Exactive mass spectrometer (Thermo Fisher Scientific, USA). The UV / Vis spectra were recorded on an Agilent Cary 8454 spectrometer. The X - ray crystallographic structures were recorded on a Bruker APEX - II CCD diffractometer.

[0160] 1 Example 1: Intramolecular C - H amination of (4 - azidobutyl)benzene:

[0161]

[0162]

[0163] Operation of the catalytic reaction: Under argon, (4-azidobutyl)benzene (0.2 mmol, 1.0 equiv), Boc2O (2.0 equiv), iron(II)-Pc catalyst t Bu4PcFe(py)2 (1 mol %) and dry toluene (2.0 mL) were charged into a dried Schlenk tube. The mixture was refluxed vigorously (130 °C) until the reaction was complete, as indicated by TLC (usually completed within 6 h). 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. The product was verified by NMR by comparison with the reported characterization data (Science, 2013, 340, 591).

[0164] Using the μ-oxo complex [(( t Bu4Pc)Fe III )2O] or the μ-imido complex [(( t Bu4Pc)Fe)2N] as the catalyst, the same reaction was carried out using the same procedure as above. [(( t Bu4Pc)Fe III )2O] and [(( t Bu4Pc)Fe)2N] are known compounds and were synthesized according to the references (C. Ercolani et al., J. Porphyrins Phthalocyanines, 2001, 05, 668; H. M. Neu et al., Adv. Synth. Catal., 2009, 351, 3168; A. B. Sorokin et al., Chem. Commun., 2008, 2562), respectively. It was found that the efficiency of this catalyst was lower than t Bu4PcFe(py)2. It was also observed that temperatures of about 100 °C or lower inhibited the C–H amination reaction, indicating that higher temperatures were required to provide satisfactory product yields.

[0165] Example 2: C–H amination of alkyl azides using an iron(II) catalyst

[0166] The C–H amination was carried out below using different alkyl azide starting reagents. It should be noted that organic azides are potentially explosive and should be handled with care. Although no problems were encountered during the synthesis, appropriate precautions should be taken throughout the handling of such compounds. After separation, the azides were stored in a -20 °C refrigerator.

[0167] The alkyl azides reported in the prior literature discussed in the examples are listed in Table 1 below. As described below, the detailed synthetic procedures and characterizations of other unknown azides are shown.

[0168] Table 1. Literature-reported azides

[0169]

[0170]

[0171] Synthesis of alkyl azides and their precursors:

[0172] General procedure A: Synthesis of alkyl azides from alkyl alcohols (two steps)

[0173]

[0174] Step 1: Triethylamine (1.5 equivalents) and 4-dimethylaminopyridine (0.1 equivalent) were added to a stirred solution of a primary or secondary alcohol (1 equivalent, 0.5 M) in anhydrous dichloromethane. 4-Toluenesulfonyl chloride (1.2 equivalents) was added at 0 °C. The reaction was warmed to room temperature and stirred overnight, and then the mixture was quenched with water after completion. The aqueous phase was extracted 3 times with dichloroethane. The combined organic phases were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography or used directly without further purification.

[0175] Step 2: Sodium azide (1.5 equivalents) was added to a stirred DMF solution of the above (purified or crude) tosylate (1 equivalent, 0.5 M) (or alkyl chloride, in a few cases alkyl chloride was obtained instead of tosylate), and the reaction was heated at 80 °C overnight. After completion of the reaction, water was added, and the mixture was extracted three times with Et2O. The combined organic phases were washed twice with water and brine, and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the desired azide.

[0176] General procedure B: Reduction of unsaturated precursors to synthesize saturated alkyl alcohols

[0177] 10% Pd / C (100 mg) was added to a MeOH solution of an unsaturated substrate (5 mmol, 0.1 M) containing a double bond or triple bond. Then the mixture was vigorously stirred overnight under a H2 atmosphere (1 atm). After completion, the reaction mixture was filtered through diatomaceous earth and washed with dichloroethane and ethyl acetate. Usually, after removing the solvent, a residue of sufficient purity could be obtained directly for the next step, and in a few cases, further purification was required before the next step.

[0178] General Procedure C: Synthesis of Alkyl Alcohols by Reduction of Alkyl Carboxylic Acids or Esters

[0179] Under an argon atmosphere, at 0 °C, LiAlH4 (379.5 mg, 10 mmol, 2 equiv) was added portionwise to a solution of the desired carboxylic acid or ester (5 mmol, 1 equiv, 0.5 M) in THF. The solution was then stirred at room temperature overnight. After completion, the reaction was terminated by adding aqueous NaOH solution (10% aqueous solution) until a solid precipitate formed. After filtration through MgSO4 and evaporation of the solvent, the crude alcohol was used directly in the next step without further purification.

[0180] General Procedure D: Cross-Coupling of Aryl Iodides with But-3-yn-1-ol (K. R. Roesch and R. C. Larock, J. Org. Chem., 2002, 67, 86)

[0181] To a solution of aryl iodide (1.0 equiv), PdCl2(PPh3)2 (0.05 - 0.1 equiv), CuI (0.15 - 0.3 equiv) in Et3N (0.25 M) was added but-3-yn-1-ol (1.3 equiv), and the mixture was stirred at room temperature under an argon atmosphere. After completion, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the desired coupling product.

[0182]

[0183] Alkyl Halide Characterization Data:

[0184]

[0185] 1-(4-Azidobutyl)-3,5-dimethylbenzene: Synthesized from 1-iodo-3,5-dimethylbenzene according to General Procedures D, B, and A, giving a colorless oil (46%, over four steps). 1 H NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 6.86 (s, 2H), 3.33 (t, J = 6.6 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 2.36 (s, 6H), 1.79–1.65 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 141.8, 137.9, 127.6, 126.3, 51.4, 35.3, 28.5, 21.3. HRMS (ESI) m / z: [M–N2+H] + [C 12 H 18 N] + Calculated: 176.1434, Found: 176.1434.

[0186]

[0187] 1-(4-Azidobutyl)-4-bromobenzene: Synthesized from 4-(4-bromophenyl)butan-1-ol according to General Procedure A, giving a colorless oil (78%, over two steps). 1 H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.28 (t, J = 6.6 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H), 1.71–1.58 (m, 4H). 13 C NMR (125 MHz, CDCl3) δ 140.8, 131.4, 130.1, 119.7, 51.3, 34.8, 28.4, 28.3. HRMS (ESI) m / z: [M–N2+H] + [C 10 H 13 NBr] + Calcd: 226.0226, Found: 226.0222.

[0188]

[0189] 1-(4-Azidobutyl)-4-nitrobenzene: Synthesized from 4-(4-nitrophenyl)butan-1-ol according to General Procedure A, giving a pale yellow oil (77%, over two steps). 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 3.32 (t, J = 6.6 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.80–1.60 (m, 4H). 13 C NMR (125 MHz, CDCl3) δ 149.7, 146.4, 129.2, 123.7, 51.2, 35.3, 28.4, 28.0. HRMS (ESI) m / z: [M–N2+H] + [C 10 H 13 O2N2] + Calcd: 193.0972, Found: 193.0971.

[0190]

[0191] 2-(4-Azidobutyl)-1,4-difluorobenzene: Synthesized from 1,4-difluoro-2-iodobenzene according to General Procedures D, B and A, giving a colorless oil (30%, over four steps). 11H NMR (400 MHz, CDCl3) δ 6.96 (td, J = 9.0, 4.6 Hz, 1H), 6.91–6.81 (m, 2H), 3.30 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H), 1.75–1.59 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 159.0 (dd, J = 159.2, 2.4 Hz), 156.6 (dd, J = 157.8, 2.4 Hz), 130.3 (dd, J = 18.8, 7.6 Hz), 116.7 (dd, J = 23.6, 5.4 Hz), 116.1 (dd, J = 25.4, 8.8 Hz), 113.9 (dd, J = 24.0, 8.5 Hz), 51.2, 28.5, 28.4, 27.0. 19 19F NMR (376 MHz, CDCl3) δ -119.62 (d, J = 17.6 Hz), -125.03 (d, J = 17.6 Hz).

[0192]

[0193] 1-(4-Azidobutyl)-2,4-dichlorobenzene: Synthesized from 2,4-dichloro-1-iodobenzene according to General Procedures D, B, and A, to give a colorless oil (45%, over four steps). 1 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 2.0 Hz, 1H), 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 3.32 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 7.3 Hz, 2H), 1.74–1.62 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 138.1, 134.5, 132.3, 131.1, 129.2, 127.1, 51.2, 32.5, 28.5, 26.8. HRMS (ESI) m / z: [M–N2+H] + [C 10 H 12 Cl2N] + Calcd: 216.0341, Found: 216.0342.

[0194]

[0195] (E)-Methyl 2-hydroxy-5-(4-(tosyloxy)but-1-en-1-yl)benzoate: Synthesized according to the general procedure of the reported Suzuki-Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407) to afford the desired compound as a colorless oil (77%). 1 H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.6, 2.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.6 Hz, 1H), 6.30 (d, J = 15.9 Hz, 1H), 5.89 (dt, J = 15.8, 7.0 Hz, 1H), 4.12 (t, J = 6.5 Hz, 2H), 3.95 (s, 3H), 2.53 (q, J = 6.5 Hz, 2H), 2.41 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 170.4, 160.9, 144.8, 133.1, 133.0, 131.8, 129.8, 128.5, 127.9, 127.5, 122.7, 117.8, 112.2, 69.7, 52.4, 32.4, 21.6.

[0196] Methyl 5-(4-azidobutyl)-2-hydroxybenzoate: Synthesized according to General Procedures B and A to afford a colorless oil (28%, over two steps). 1 H NMR (400 MHz, CDCl3) δ 10.60 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.5, 2.3 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.26 (t, J = 6.5 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H), 1.71–1.55 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 170.5, 159.9, 135.9, 132.5, 129.1, 117.5, 112.0, 52.2, 51.3, 34.3, 28.5, 28.3. HRMS (ESI) m / z: [M–N2+H] + [C 12 H 16 NO3] + Calcd: 222.1125, Found: 222.1123.

[0197]

[0198] (E)-4-methylbenzenesulfonic acid 4-(2-methylbenzo[d]thiazol-6-yl)but-3-en-1-yl ester: Synthesized according to the general procedure of the reported Suzuki-Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407), using 6-bromo-2-methylbenzo[d]thiazole (600 mg, 2.6 mmol, 1.0 equiv), (E)-4-methylbenzenesulfonic acid 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl ester (C.-B. Yi et al., Org. Lett., 2018, 20, 668) (1.21 g, 3.45 mmol, 1.3 equiv), SPhos-G3 (99 mg, 0.132 mmol, 0.05 equiv) and K2CO3 (1.09 g, 7.89 mmol, 3.0 equiv) in THF / H2O = 3:1 (0.3 M) at 60 °C for 6 h. The crude residue was purified by column chromatography to afford the desired compound as a colorless oil (600 mg, 61%). 1 H NMR (400 MHz, chloroform-d) δ 7.79 (dd, J = 8.4, 3.3 Hz, 1H), 7.76–7.70 (m, 2H), 7.61 (d, J = 2.7 Hz, 1H), 7.33–7.27 (m, 1H), 7.25–7.19 (m, 2H), 6.40 (d, J = 15.8 Hz, 1H), 6.05–5.91 (m, 1H), 4.11 (t, J = 6.4 Hz, 2H), 2.76 (s, 3H), 2.57–2.47 (m, 2H), 2.33 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 167.2, 152.6, 144.8, 136.1, 133.9, 132.9, 132.6, 129.8, 127.9, 124.5, 124.2, 122.1, 118.9, 69.6, 32.5, 21.6, 20.1. HRMS (ESI) m / z: [M+H] + [C 19 H 20 NO3S2] + Calcd: 374.0879, Found: 374.0876.

[0199] 6-(4-azidobutyl)-2-methylbenzo[d]thiazole: Synthesized according to general procedures B and A, to afford a colorless oil (97%, over two steps). 11H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.14 (dd, J = 8.3, 1.4 Hz, 1H), 3.15 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H), 2.62 (t, J = 7.5 Hz, 2H), 1.68–1.56 (m, 2H), 1.55–1.46 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 166.0, 151.8, 138.7, 135.9, 126.6, 122.0, 120.6, 51.2, 35.2, 28.6, 28.4, 20.0. HRMS (ESI) m / z: [M+H] + [C 12 H 15 N4S] + Calcd: 247.1012, found: 247.1009.

[0200]

[0201] (E)-5-(4-(Benzyloxy)but-1-en-1-yl)-2,2-difluorobenzo[d][1,3]dioxole: Synthesized according to the general procedure of the reported Suzuki–Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407), using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (600 mg, 2.53 mmol, 1.0 equiv), (E)-2-(4-(benzyloxy)but-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (C.-B. Yi et al., Org. Lett., 2018, 20, 668) (947 mg, 3.29 mmol, 1.3 equiv), SPhos-G3 (94.8 mg, 0.126 mmol, 0.05 equiv) and K2CO3 (1.047 g, 7.59 mmol, 3.0 equiv) in THF / H2O = 3:1 (0.3 M) at 60 °C for 6 h. The crude residue was purified by column chromatography to afford the desired compound (668 mg, 83%) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ 7.43–7.28 (m, 5H), 7.09 (d, J = 1.5 Hz, 1H), 7.00 (dd, J = 8.3, 1.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 6.17 (dt, J = 15.9, 6.9 Hz, 1H), 4.57 (s, 2H), 3.62 (t, J = 6.6 Hz, 2H), 2.55 (qd, J = 6.7, 1.3 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 144.3, 142.9, 138.5, 134.4, 131.8 (t, J = 254.8 Hz), 130.5, 128.6, 127.9, 127.8, 127.8, 122.0, 109.4, 106.6, 73.2, 69.7, 33.5. 19 19F NMR (376 MHz, CDCl3) δ -50.24.

[0202] 5-(4-Azidobutyl)-2,2-difluorobenzo[d][1,3]dioxole: Synthesized according to General Procedure B and A, obtained as a colorless oil (21%, over three steps). 1 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 8.1 Hz, 1H), 6.91–6.84 (m, 2H), 3.29 (t, J = 6.6 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.75–1.56 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 143.8, 142.0, 138.1, 131.7 (t, J = 254.1 Hz), 123.2, 109.5, 109.1, 51.2, 35.1, 28.6, 28.3. 19 19F NMR (376 MHz, CDCl3) δ -50.12. HRMS (ESI) m / z: [M–N2 + H] + [C 11 H 12 F2NO2] + Calcd: 228.0831, Found: 228.0829.

[0203]

[0204] tert-Butyl 5-(4-azidobutyl)-1H-indole-1-carboxylate: Synthesized from tert-butyl 5-iodo-1H-indole-1-carboxylate (J.E. Jakobsson et al., Chem. Commun., 2017, 53, 12906) according to the general procedures D, B and A, to give a colorless oil (68%, over four steps). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 3.4 Hz, 1H), 7.34 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 3.6 Hz, 1H), 3.27 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 1.83–1.56 (m, 4H + 9H). 13 C NMR (100 MHz, CDCl3) δ 149.9, 136.3, 133.8, 130.9, 126.2, 125.0, 120.4, 115.1, 107.2, 83.6, 51.5, 35.3, 29.0, 28.5, 28.3. HRMS (ESI) m / z: [M–N2+H] + [C 17 H 23 N2O2] + : Calcd: 287.1754, Found: 287.1752.

[0205]

[0206] (E)-4-Methylbenzenesulfonic acid 4-(1-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-5-yl)but-3-en-1-yl ester: Synthesized from 5-bromo-1-cyclopentyl-1H-pyrrolo[2,3-b]pyridine (M. Chen, S. Ichikawa and S.L. Buchwald, Angew. Chem. Int. Ed., 2015, 54, 263) according to the general procedure for the reported Suzuki–Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407) to afford the desired compound as a colorless oil (46%). 11H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.0 Hz, 1H), 7.82–7.74 (m, 3H), 7.29–7.26 (m, 2H), 7.25 (s, 1H), 6.47 (d, J = 15.9 Hz, 1H), 6.41 (d, J = 3.6 Hz, 1H), 5.95 (dt, J = 15.9, 7.0 Hz, 1H), 5.38–5.17 (m, 1H), 4.15 (t, J = 6.6 Hz, 2H), 2.65–2.50 (m, 2H), 2.35 (s, 3H), 2.27–2.17 (m, 2H), 1.96–1.67 (m, 6H). 13 13C NMR (100 MHz, CDCl3) δ 147.3, 144.8, 141.8, 133.1, 131.3, 129.8, 127.9, 125.7, 125.3, 125.1, 122.3, 120.6, 99.7, 69.9, 55.0, 32.9, 32.6, 24.1, 21.6.

[0207] 5-(4-Azidobutyl)-1-cyclopentyl-1H-pyrrolo[2,3-b]pyridine: Synthesized according to General Procedure B and A to give a colorless oil (69%, over two steps). 1 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H), 6.37 (d, J = 3.5 Hz, 1H), 5.35–5.18 (m, 1H), 3.23 (t, J = 6.7 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.28–2.13 (m, 2H), 1.89–1.79 (m, 4H), 1.78–1.65 (m, 4H), 1.64–1.56 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 146.7, 143.1, 128.6, 128.0, 125.1, 120.6, 99.0, 54.9, 51.3, 32.9, 32.6, 29.1, 28.3, 24.1. HRMS (ESI) m / z: [M + H] + [C 16 H 22 N5] + : Calcd: 284.1870, Found: 284.1867.

[0208]

[0209] (E)-tert-Butyl 4-(5-(4-(tosyloxy)but-1-en-1-yl)pyridin-2-yl)piperazine-1-carboxylate: Synthesized according to the general procedure of the reported Suzuki-Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407) to afford the desired compound as a colorless oil (39%). 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 6.60 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 15.9 Hz, 1H), 5.83 (dt, J = 15.8, 7.0 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.53 (s, 8H), 2.53 (q, J = 6.3 Hz, 2H), 2.43 (s, 3H), 1.49 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 158.5, 154.8, 146.6, 144.8, 134.4, 133.1, 129.8, 129.8, 127.9, 122.9, 121.5, 107.0, 80.0, 69.8, 45.1, 45.1, 32.6, 28.4, 21.7. HRMS (ESI) m / z: [M+H] + [C 25 H 34 N3O5S] + Calcd: 488.2214, Found: 488.2214.

[0210] tert-Butyl 4-(5-(4-azidobutyl)pyridin-2-yl)piperazine-1-carboxylate: Synthesized according to General Procedure B and A to afford a colorless oil (40%, over two steps). 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 8.5, 2.2 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 3.57–3.51 (m, 4H), 3.50–3.44 (m, 4H), 3.27 (t, J = 6.3 Hz, 2H), 2.52 (t, J = 6.9 Hz, 2H), 1.68–1.57 (m, 4H), 1.48 (s, 9H). 1313C NMR (100 MHz, CDCl3) δ 158.1, 154.8, 147.4, 137.7, 126.6, 107.2, 79.8, 51.2, 45.4, 31.4, 28.4, 28.4, 28.2. HRMS (ESI) m / z: [M+H] + [C 18 H 29 N6O2] + Calcd: 361.2347, Found: 361.2343.

[0211]

[0212] (E)-Methyl 4-(4-(tosyloxy)but-1-en-1-yl)furan-2-carboxylate: Synthesized according to the general procedure of the reported Suzuki–Miyaura coupling reaction (X.-J. Dai et al., Angew. Chem. Int. Ed., 2019, 58, 3407) to afford the desired compound as a colorless oil (44%). 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.46 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 6.21 (d, J = 15.9 Hz, 1H), 5.80 (dt, J = 15.8, 7.0 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 2.51 (q, J = 6.4 Hz, 2H), 2.44 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 159.0, 144.9, 144.9, 143.1, 133.0, 129.9, 127.9, 125.7, 121.7, 115.3, 69.3, 52.0, 32.3, 21.6. HRMS (ESI) m / z: [M+H] + [C 17 H 19 O6S] + Calcd: 351.0897, Found: 351.0894.

[0213] Methyl 4-(4-azidobutyl)furan-2-carboxylate: Synthesized according to General Procedure B and A to give a colorless oil (53%, over two steps). 11H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.98 (s, 1H), 3.79 (s, 3H), 3.21 (t, J = 6.1 Hz, 2H), 2.39 (t, J = 6.8 Hz, 2H), 1.60–1.50 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 159.1, 144.5, 142.9, 126.9, 118.8, 51.7, 51.1, 28.2, 26.8, 24.0. HRMS (ESI) m / z: [M–N2+H] + [C 10 H 14 NO3] + Calcd: 196.0968, found: 196.0968.

[0214]

[0215] (4-Azidopentyl)benzene: Prepared according to General Procedure A from 5-phenylpentan-2-ol (H. Ito et al., Org. Lett., 2012, 14, 890) to give a colorless oil (58%, over two steps). 1 1H NMR (400 MHz, CDCl3) δ 7.31–7.14 (m, 5H), 3.50–3.38 (m, 1H), 2.62 (t, J = 7.6 Hz, 2H), 1.82–1.62 (m, 2H), 1.59–1.45 (m, 2H), 1.24 (d, J = 6.5 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 142.0, 128.4, 125.9, 57.9, 35.8, 35.6, 27.9, 19.5. HRMS (ESI) m / z: [M–N2+H] + [C 11 H 16 N] + Calcd: 162.1277, found: 162.1277.

[0216]

[0217] Methyl 2-(2-(2-hydroxyethyl)phenyl)acetate: It was synthesized according to the reported procedure (H. Fuwa et al., Heterocycles, 2008, 76, 521). To a flask containing methyl 2-(2-vinylphenyl)acetate (N. Su et al., Angew. Chem. Int. Ed., 2015, 54, 12942) (1.19 g, 6.75 mmol) was added 9-BBN (a 0.5 M solution in THF, 27 mL, 13.5 mmol), and the solution was stirred at room temperature for several hours until TLC showed completion. The resulting mixture was cooled to 0 °C and treated with saturated aqueous NaHCO3 (27 mL) and 30% H2O2 (10 mL). After stirring overnight at room temperature, the resulting mixture was extracted with EtOAc, washed with saturated aqueous Na2SO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the alcohol (824 mg, 63%) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.25–7.17 (m, 4H), 3.81 (t, J = 6.7 Hz, 2H), 3.71 (s, 2H), 3.68 (s, 3H), 2.90 (t, J = 6.7 Hz, 2H), 2.13 (br s, 1H).

[0218] Methyl 2-(2-(2-azidoethyl)phenyl)acetate: It was synthesized from methyl 2-(2-(2-hydroxyethyl)phenyl)acetate according to General Procedure A, giving a colorless oil (86%, over two steps). 1 1H NMR (500 MHz, CDCl3) δ 7.29–7.19 (m, 4H), 3.70 (s, 3H), 3.69 (s, 2H), 3.50 (t, J = 7.4 Hz, 2H), 2.94 (t, J = 7.4 Hz, 2H). 13 13C NMR (125 MHz, CDCl3) δ 171.9, 136.6, 132.7, 131.0, 129.9, 127.8, 127.3, 52.2, 51.9, 38.6, 32.3. HRMS (ESI) m / z: [M+Na] + [C 11 H 13 N3NaO2] + : Calcd: 242.0900, Found: 242.0901.

[0219]

[0220] Methyl 2'-ethyl-[1,1'-biphenyl]-2-carboxylate: A mixture of methyl 2-iodobenzoate (524 mg, 2 mmol), (2-ethylphenyl)boronic acid (450 mg, 3 mmol, 1.5 equiv), toluene (15 mL), ethanol (6 mL), and 2 M Na2CO3 (2 mL, 4 mmol, 2 equiv) was degassed and then Pd(PPh3)4 (115.5 mg, 0.1 mmol, 0.05 equiv) and Bu4NBr (32 mg, 0.1 mmol, 0.05 equiv) were added under Ar. The mixture was heated at 95 °C for 3 - 4 h and 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 Na2SO4, filtered, and evaporated. The product was purified by silica gel chromatography to give the desired product as a colorless oil (388 mg, 81%). 1 H NMR (500 MHz, CDCl3) δ 7.96 (dd, J = 7.8, 1.4 Hz, 1H), 7.56–7.49 (m, 1H), 7.42 (td, J = 7.6, 1.3 Hz, 1H), 7.36–7.24 (m, 3H), 7.19 (td, J = 7.1, 2.1 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.59 (s, 3H), 2.49–2.31 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ 167.8, 142.8, 141.2, 140.9, 131.4, 131.2, 130.0, 128.7, 127.8, 127.5, 127.1, 125.1, 51.8, 26.2, 14.9. HRMS (ESI) m / z: [M+H] + [C 16 H 17 O2] + : Calcd: 241.1223, Found: 241.1221.

[0221] 2-(Azidomethyl)-2'-ethyl-1,1'-biphenyl: Synthesized according to General Procedures C and A to give a colorless oil (56%, over three steps). 1 H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.4 Hz, 1H), 7.42–7.31 (m, 4H), 7.26–7.19 (m, 2H), 7.10 (d, J = 7.3 Hz, 1H), 4.15–4.05 (m, 2H), 2.46–2.26 (m, 2H), 1.04 (t, J = 7.6 Hz, 3H). 1313C NMR (125 MHz, CDCl3) δ 141.9, 141.2, 139.0, 133.5, 130.2, 129.7, 128.8, 128.4, 128.1, 127.9, 127.8, 125.6, 52.5, 26.2, 15.2. HRMS (ESI) m / z: [M–N2+H] + [C 15 H 16 N] + Calcd for: 210.1277, Found: 210.1277.

[0222]

[0223] 1-(2-Azidoethyl)-2-benzylbenzene: Prepared according to General Procedure A from 2-(2-benzylphenyl)ethan-1-ol (M. Yus et al., Tetrahedron Lett., 2001, 42, 5721) to give a colorless oil (87%, over two steps). 1 1H NMR (400 MHz, CDCl3) δ 7.32–7.05 (m, 9H), 4.04 (s, 2H), 3.22 (t, J = 7.6 Hz, 2H), 2.86 (t, J = 7.6 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 140.6, 138.8, 136.4, 131.0, 130.0, 128.6, 128.6, 127.1, 126.2, 51.8, 39.2, 32.3. HRMS (ESI) m / z: [M+H] + [C 15 H 16 N3] + Calcd for: 238.1339, Found: 238.1336.

[0224]

[0225] Methyl 2-(2-(3,4-dimethoxybenzyl)-4,5-dimethoxyphenyl)acetate: At room temperature, methyl iodide (0.9 mL, 14.44 mmol, 2.0 equiv) was added to a stirred mixture of 2-(2-(3,4-dimethoxybenzyl)-4,5-dimethoxyphenyl)acetic acid (C. Legros et al., Int. J. Mol. Sci., 2013, 14, 8948) (2.5 g, 7.22 mmol, 1.0 equiv) and K2CO3 (3 g, 21.7 mmol, 3.0 equiv) in DMF (20 mL), and then the reaction mixture was stirred at room temperature for 5 h. After completion, the mixture was diluted with 100 mL of H2O. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over Na2SO4, evaporated to dryness, and the residue was purified by flash chromatography on silica gel to give the desired compound as an off-white solid (2.4 g, 92%). 1 H NMR (400 MHz, CDCl3) δ 6.79–6.76 (m, 2H), 6.67–6.63 (m, 2H), 6.61 (d, J = 8.3 Hz, 1H), 3.93 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.62 (s, 3H), 3.54 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ 172.2, 148.9, 148.1, 147.4, 147.3, 133.0, 131.6, 124.8, 120.5, 113.9, 113.7, 111.9, 111.2, 56.0, 55.9, 55.8, 52.0, 38.2, 38.1.

[0226] 1-(2-Azidoethyl)-2-(3,4-dimethoxybenzyl)-4,5-dimethoxybenzene: Synthesized according to General Procedures C and A to give a colorless oil (58%, over three steps). 1 H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 6.65 (d, J = 1.8 Hz, 1H), 6.61 (dd, J = 8.2, 1.8 Hz, 1H), 3.92 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.23 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H). 1313C NMR (100 MHz, CDCl3) δ 149.0, 147.7, 147.6, 147.4, 133.4, 131.1, 128.4, 120.4, 114.0, 113.3, 111.8, 111.3, 56.0, 55.9, 55.9, 55.8, 51.9, 38.2, 32.1. HRMS (ESI) m / z: [M+Na] + [C 19 H 23 N3O4Na] + Calculated: 380.1581, Found: 380.1580.

[0227]

[0228] (S)-1-(Benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-1λ 3 -pyrido[3,4-b]indole-3-carboxylic acid methyl ester: Trifluoroacetic acid (1.02 g, 8.93 mmol, 1.5 equiv) was added to a solution of (S)-tryptophan methyl ester (J. Ruchti et al., J. Am. Chem. Soc., 2014, 136, 16756) (1.3 g, 5.96 mmol, 1.0 equiv) and benzo[d][1,3]dioxole-5-carbaldehyde (1.08 g, 7.15 mmol, 1.2 equiv) in DCM (20 mL). The reaction mixture was stirred at room temperature for 1 day and then evaporated. The obtained residue was triturated with 5% aqueous K2CO3 solution (30 mL) and extracted with DCM. The organic layer was dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography to give the desired isomeric product (76%). The separation ratio of the two isomers was close to 1:1. Isomer a 1 1H NMR (400 MHz, CDCl3) δ 7.59–7.50 (m, 2H), 7.24–7.19 (m, 1H), 7.18–7.09 (m, 2H), 6.87 (dd, J = 7.8, 1.7 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.94 (s, 2H), 5.15 (t, J = 2.1 Hz, 1H), 3.94 (dd, J = 11.1, 4.2 Hz, 1H), 3.81 (s, 3H), 3.21 (ddd, J = 15.0, 4.2, 1.8 Hz, 1H), 3.06–2.94 (m, 1H), 2.43 (br s, 1H). 1313C NMR (100 MHz, CDCl3) δ 173.3, 148.3, 148.0, 136.3, 134.9, 134.8, 127.3, 122.1, 119.8, 118.4, 111.1, 109.0, 108.9, 108.5, 101.4, 58.6, 57.0, 52.4, 25.8. HRMS (ESI) m / z: [M+H] + [C 20 H 19 N2O4] + Calcd for: 351.1339, Found: 351.1333. Isomer b 1 1H NMR (400 MHz, CDCl3) δ 7.91–7.73 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.19–7.09 (m, 2H), 6.78–6.67 (m, 3H), 5.90 (s, 2H), 5.31–5.25 (m, 1H), 3.96 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.25 (dd, J = 15.4, 5.4 Hz, 1H), 3.10 (dd, J = 15.3, 6.7 Hz, 1H), 2.37 (br s, 1H). 13 13C NMR (100 MHz, CDCl3) δ 174.2, 148.1, 147.4, 136.2, 136.1, 133.3, 127.0, 122.0, 121.7, 119.5, 118.3, 111.0, 108.7, 108.3, 108.1, 101.2, 54.7, 52.5, 52.1, 24.7. HRMS (ESI) m / z: [M+H] + [C 20 H 19 N2O4] + Calcd for: 351.1339, Found: 351.1331.

[0229] (S)-Methyl 2-azido-3-(2-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-indol-3-yl)propionate: Step 1. To a solution of the above isomer (600 mg, 1.72 mmol) in MeOH (50 mL) was added 10% Pd / C (60 mg). The resulting solution was stirred at 50 °C under a hydrogen atmosphere for 3 days. The solution was concentrated to dryness. The residue was purified by column chromatography to give (S)-methyl 2-amino-3-(2-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-indol-3-yl)propionate as an off-white solid (450 mg, 74%). 11H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.73 (d, J = 8.2 Hz, 1H), 6.67 - 6.61 (m, 2H), 5.90 (s, 2H), 4.01 (s, 2H), 3.83 (dd, J = 7.9, 5.2 Hz, 1H), 3.70 (s, 3H), 3.30 (dd, J = 14.3, 5.1 Hz, 1H), 3.04 (dd, J = 14.3, 8.1 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 175.9, 148.0, 146.4, 135.6, 135.3, 132.3, 128.5, 121.6, 121.5, 119.5, 118.4, 110.7, 109.1, 108.4, 107.6, 101.0, 55.4, 52.1, 32.0, 30.1. HRMS (ESI) m / z: [M + H] + [C 20 H 21 N2O4] + Calcd: 353.1496, Found: 353.1489. Step 2. The desired azide was synthesized according to the reported procedure (E. D. Goddard - Borger et al., Org. Lett., 2007, 9, 3797) to give a brown oil (68%). 1 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.56 - 7.49 (m, 1H), 7.23 - 7.18 (m, 1H), 7.15 - 7.07 (m, 2H), 6.74 (d, J = 7.7 Hz, 1H), 6.66 (d, J = 7.8 Hz, 2H), 5.89 (s, 2H), 4.17 (dd, J = 8.5, 5.5 Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H), 3.36 (dd, J = 14.6, 5.5 Hz, 1H), 3.15 (dd, J = 14.6, 8.5 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 170.9, 148.1, 146.5, 135.6, 135.5, 132.0, 128.1, 121.8, 121.7, 119.7, 118.0, 110.8, 109.2, 108.5, 106.5, 101.1, 62.7, 52.7, 32.0, 27.2. HRMS (ESI) m / z: [M + H] + [C 20 H19 N4O4] + Calculated value: 379.1401, measured value: 379.1395.

[0230]

[0231] 2-(4,5-Dimethoxy-2-vinylphenyl)ethan-1-ol: It was synthesized from 2-(2-iodo-4,5-dimethoxyphenyl)ethan-1-ol (J. Ruiz et al., Tetrahedron, 2005, 61, 3311) according to the reported procedure (H. Liu et al., Org. Lett., 2015, 17, 4444). To a solution of vinylboronic acid pinacol cyclic ester (274 mg, 1.78 mmol, 2.2 equiv) in THF (10 mL) were successively added H2O (0.3 mL), PdCl2(dppf) (11.8 mg, 0.016 mmol, 0.02 equiv), and K3PO4 (515 mg, 2.4 mmol, 3 equiv). The resulting suspension was stirred for 15 minutes, and then 2-(2-iodo-4,5-dimethoxyphenyl)ethan-1-ol (250 mg, 0.811 mmol) was added. The reaction mixture was heated to 80 °C and stirred overnight, and then diluted with H2O (20 mL). The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired product as a yellow oil (157 mg, 93% yield). 1 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 6.92 (dd, J = 17.3, 10.9 Hz, 1H), 6.68 (s, 1H), 5.54 (d, J = 17.3 Hz, 1H), 5.19 (d, J = 11.0 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.73 (t, J = 7.2 Hz, 2H), 2.92 (br, 1H), 2.88 (t, J = 7.1 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 148.6, 147.5, 133.7, 128.9, 128.5, 113.4, 113.1, 108.4, 63.0, 55.7, 35.8, 24.5. HRMS (ESI) m / z: [M+H] + [C 12 H 17 O3] + Calculated value: 209.1172, measured value: 209.1170.

[0232] 2-(2-Ethyl-4,5-dimethoxyphenyl)ethan-1-ol: Synthesized according to General Procedure B, and the desired product was obtained as a yellow oil (69%) after flash chromatography. 1 H NMR (400 MHz, CDCl3) δ 6.73–6.66 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.76 (t, J = 7.2 Hz, 2H), 2.96 (br, 1H), 2.82 (t, J = 7.2 Hz, 2H), 2.59 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 147.5, 146.8, 134.8, 127.8, 113.4, 112.2, 63.4, 55.9, 55.9, 35.5, 25.3, 15.9. HRMS (ESI) m / z: [M+H] + [C 12 H 19 O3] + Calcd: 211.1329, found: 211.1325.

[0233] 1-(2-Azidoethyl)-2-ethyl-4,5-dimethoxybenzene: Synthesized from 2-(2-ethyl-4,5-dimethoxyphenyl)ethan-1-ol according to General Procedure A, and obtained as a colorless oil (59%, two steps). 1 H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.67 (s, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.42 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.59 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 147.9, 147.1, 134.6, 127.2, 113.0, 112.2, 56.0, 55.9, 52.3, 31.8, 25.3, 15.8. HRMS (ESI) m / z: [M–N2+H] + [C 12 H 18 NO2] + Calcd: 208.1332, found: 208.1330.

[0234]

[0235] 1-(2-Chloroethyl)-2-(3,4-dimethoxystyryl)-4,5-dimethoxybenzene: Synthesized from 2-(2-chloroethyl)-4,5-dimethoxybenzaldehyde (M. Yamato et al., Tetrahedron, 1990, 46, 5909) according to the reported procedure (J.D. Harling et al., Tetrahedron, 1998, 54, 14905), obtaining a pink solid (69%). 1 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 6.75–6.69 (m, 3H), 6.65 (s, 1H), 6.55 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.66 (s, 3H), 3.63 (t, J = 7.4 Hz, 2H), 3.56 (s, 3H), 3.02 (t, J = 7.4 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 148.4, 148.2, 148.0, 130.9, 129.7, 129.6, 128.6, 126.6, 122.4, 113.4, 112.7, 111.7, 110.8, 100.1, 56.1, 56.0, 55.9, 55.6, 44.6, 36.9.

[0236] 1-(2-Chloroethyl)-2-(3,4-dimethoxyphenethyl)-4,5-dimethoxybenzene: Synthesized according to General Procedure B, and the desired product was obtained after flash chromatography as a white solid (82%). 1 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 8.1 Hz, 1H), 6.69 (dd, J = 8.1, 2.0 Hz, 1H), 6.67 (s, 1H), 6.63 (s, 2H), 3.86 (s, 3H + 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.56 (t, J = 7.8 Hz, 1H), 2.96 (t, J = 7.9 Hz, 1H), 2.88–2.77 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 145.0, 148.0, 147.6, 147.4, 134.2, 132.2, 128.0, 120.5, 113.1, 113.0, 112.1, 111.5, 56.2, 56.2, 56.1, 56.0, 44.7, 37.7, 36.0, 34.7. HRMS (ESI) m / z: [M + Na] + [C 20 H 25 ClO4Na] +Calculated value: 387.1334, measured value: 387.1327.

[0237] 1-(2-Azidoethyl)-2-(3,4-dimethoxyphenethyl)-4,5-dimethoxybenzene: Synthesized according to the second step in General Procedure A (using alkyl chloride instead of tosylate), obtained as a white solid (93%). 1 H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 8.1 Hz, 1H), 6.69 (dd, J = 8.3, 1.8 Hz, 1H), 6.66 (s, 1H), 6.63 (s, 1H), 6.61 (d, J = 2.0 Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H + 3H), 3.35 (t, J = 7.5 Hz, 2H), 2.88–2.80 (m, 4H), 2.77 (t, J = 7.5 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 148.8, 147.7, 147.4, 147.3, 134.1, 132.0, 127.7, 120.4, 112.9, 112.8, 111.9, 111.3, 56.0, 56.0, 55.9, 55.8, 52.3, 37.6, 34.5, 31.8. HRMS (ESI) m / z: [M+Na] + [C 20 H 25 N3O4Na] + Calculated value: 394.1737, measured value: 394.1732.

[0238]

[0239] 1-(2-Azidoethyl)-2-benzylbenzene (3p) and (S)-(5-azidopentan-2-yl)benzene (S-3p): Synthesized according to General Procedure A from 4-phenylpentan-1-ol and (S)-4-phenylpentan-1-ol (D. J. Weix et al., J. Am. Chem. Soc., 2000, 122, 10027) respectively, obtained as colorless oils (71%, in two steps). 1 H NMR (400 MHz, CDCl3) δ 7.34–7.14 (m, 5H), 3.21 (t, J = 6.8 Hz, 2H), 2.76–2.63 (m, 1H), 1.70–1.61 (m, 2H), 1.59–1.41 (m, 2H), 1.26 (d, J = 6.9 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 146.8, 128.5, 126.9, 126.1, 51.6, 39.7, 35.3, 27.1, 22.4. The data is consistent with the literature values 5 The (S)-(5-azidopentan-2-yl)benzene was determined to be 98% ee by chiral HPLC analysis (CHIRALCEL OD-H, hexane, 0.9 mL / min, 210 nm, tr (minor) = 11.4 min, tr (major) = 12.1 min).

[0240] General procedure for catalytic C–H amination:

[0241] Iron-catalyzed intramolecular C–H amination of alkyl azides:

[0242] Under argon, an oven-dried Schlenk tube was charged with an organic alkyl azide (0.2 mmol, 1.0 equiv), Boc2O (2.0 equiv), the iron catalyst t Bu4PcFe(py)2 (1–3 mol %) and dry toluene (2.0 mL). The mixture was refluxed vigorously (130 °C) until the reaction was determined to be complete by TLC (usually within 6 h). The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography to afford the corresponding product. For the reported products, their characterization was accomplished by comparison with the 1 1H NMR data reported in the literature. For the new products, they were characterized by, for example 1 1H, 13 13C and 19 19F NMR spectroscopy and high-resolution mass spectrometry techniques. This represents the standard conditions. The following yields refer to isolated yields.

[0243] The C–H amination products 1b to 31b prepared according to the above standard conditions and their respective yields are as follows:

[0244]

[0245] Wherein b 3 mol % t Bu4PcFe(py)2, 24 h; c 5 mol % t Bu4PcFe(py)2, 24 h; and d 3 mol % t Bu4PcFe(py)2.

[0246] For the previously reported C–H amination products, their characterization is consistent with that in the references listed in Table 2 below.

[0247] Table 2. Products Reported in the Literature

[0248]

[0249]

[0250] Characterization Data of the New C-H Amination Products:

[0251]

[0252] tert-Butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate: 1 H NMR (400 MHz, CDCl3) δ 7.06–6.70 (m, 3H), 5.26–4.89 (br m, 1H), 3.73–3.40 (br m, 2H), 2.45–2.22 (m, 1H), 1.98–1.77 (m, 3H), 1.47 and 1.23 (br 2s, 3 + 6H). 13 C NMR (125 MHz, CDCl3) (minor rotamers shown in parentheses) δ 158.7 (d, J = 242.3 Hz), 155.6 (d, J = 240.5 Hz), 154.2 (154.3), 134.26–132.22 (m), 116.64–115.78 (m), 114.57–113.88 (m), 113.82–112.87 (m), 79.6 (79.7), 55.2 (55.3), 46.9 (47.2), 34.3 (33.3), 28.1 (28.5), 23.3 (23.6). 19 F NMR (376 MHz, CDCl3) δ -119.21 (d, J = 17.9 Hz), -119.29– -119.38 (m), -124.63– -124.73 (m), -125.83 (d, J = 17.8 Hz). HRMS (ESI) m / z: [M+Na] + [C 15 H 19 F2NO2Na] + Calculated: 306.1276, Found: 306.1277.

[0253]

[0254] tert-Butyl 2-(2,4-dichlorophenyl)pyrrolidine-1-carboxylate: 11H NMR (500 MHz, CDCl3) δ 7.28 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 28.3, 8.2 Hz, 1H), 5.16–5.00 (br m, 1H), 3.60–3.39 (br m, 2H), 2.35–2.23 (m, 1H), 1.85–1.75 (m, 2H), 1.73–1.67 (m, 1H), 1.39 (br s, 3H), 1.14 (br s, 6H). 13 13C NMR (125 MHz, CDCl3) (minor rotamer shown in parentheses) 13 13C NMR (126 MHz, chloroform-d) δ 154.3, 140.9 (139.8), 132.6 (132.8), 132.4, 129.6 (129.6), 129.1, 126.9 (127.3), 79.6 (79.7), 58.3, 47.1 (47.5), 33.9 (32.7), 28.1 (28.5), 23.0 (23.3). HRMS (ESI) m / z: [M+Na] + [C 15 H 19 Cl2NO2Na] + Calcd: 338.0685, found: 338.0684.

[0255]

[0256] tert-Butyl 2-(3-hydroxy-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate: 1 1H NMR (500 MHz, CDCl3) δ 10.66 (br s, 1H), 7.64 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 4.98–4.54 (br m, 1H), 3.94 (s, 3H), 3.69–3.47 (br m, 2H), 2.36–2.23 (br m, 1H), 1.94–1.76 (m, 3H), 1.50–1.15 (br m, 9H). 1313C NMR (125 MHz, CDCl3) (minor rotamer isomers shown in parentheses) δ 170.5, 160.3, 154.6, 135.8 (134.8), 133.2 (133.0), 126.6, 117.3 (117.6), 111.8 (112.0), 79.4, 60.5 (60.0), 52.3 (52.2), 47.0 (47.3), 35.9 (34.8), 28.2 (28.4), 23.2 (23.5). HRMS (ESI) m / z: [M+H] + [C 17 H 24 NO5] + Calcd for: 322.1649, Found: 322.1647.

[0257]

[0258] tert-Butyl 2-(2-methylbenzo[d]thiazol-5-yl)pyrrolidine-1-carboxylate: 1 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 5.14–4.80 (br m, 1H), 3.74–3.51 (br m, 2H), 2.82 (s, 3H), 2.43–2.28 (br m, 1H), 1.98–1.83 (br m, 3H), 1.50–1.07 (br m, 9H). 13 13C NMR (125 MHz, CDCl3) (minor rotamer isomers shown in parentheses) δ 166.6 (166.4), 154.6, 152.2 (152.3), 142.2 (141.2), 135.7 (135.8), 124.0 (123.7), 122.0 (122.2), 118.0, 79.4, 61.3 (60.7), 47.1 (47.5), 36.2 (35.1), 28.2 (28.5), 23.2 (23.5), 20.13. HRMS (ESI) m / z: [M+H] + [C 17 H 23 N2O2S] + Calcd for: 319.1475, Found: 319.1471.

[0259]

[0260] tert-Butyl 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrrolidine-1-carboxylate: 11H NMR (500 MHz, CDCl3) δ 6.98 (d, J = 8.4 Hz, 1H), 6.93–6.86 (m, 2H), 4.99–4.69 (br m, 1H), 3.70–3.45 (br m, 2H), 2.39–2.23 (br m, 1H), 1.93–1.83 (br m, 2H), 1.83–1.72 (br m, 1H), 1.52–1.17 (br m, 9H). 13 13C NMR (125 MHz, CDCl3) (minor rotamer shown in parentheses) δ 154.4 (154.5), 143.8 (143.9), 142.3 (142.4), 141.7 (140.7), 131.65 (t, J = 254.4 Hz), 120.4, 108.9 (109.2), 106.8, 79.6 (79.7), 60.98 (60.5), 47.1 (47.4), 36.1 (35.1), 28.2 (28.5), 23.0 (23.5). 19 19F NMR (376 MHz, CDCl3) δ -49.88 (d, J = 11.3 Hz), -50.17 (d, J = 9.1 Hz). HRMS (ESI) m / z: [M+Na] + [C 16 H 19 F2NO4Na] + Calcd: 350.1174, found: 350.1172.

[0261]

[0262] tert-Butyl 2-(1-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidine-1-carboxylate: 1 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.29 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 5.32–5.22 (br m, 1H), 5.16–4.86 (br m, 1H), 3.74–3.48 (br m, 2H), 2.43–2.17 (br m, 3H), 1.93–1.73 (br m, 9H), 1.50–1.15 (br m, 9H). 1313C NMR (125 MHz, CDCl3) (minor rotamer is shown in parentheses) δ 154.6 (154.6), 147.0, 141.2 (140.7), 132.2 (131.3), 125.4 (125.5), 125.3 (125.2), 120.3 (120.5), 99.2 (99.3), 79.3, 59.5 (59.1), 54.9, 47.0 (47.4), 36.3 (35.3), 32.9 (32.9), 28.3 (28.6), 24.1, 23.1 (23.4). HRMS (ESI) m / z: [M+H] + [C 21 H 30 N3O2] + Calcd for: 356.2333, Found: 356.2329.

[0263]

[0264] tert-Butyl 4-(5-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)pyridin-2-yl)piperazine-1-carboxylate: 1 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.7 Hz, 1H), 4.93–4.62 (br m, 1H), 3.62–3.45 (m, 10H), 2.34–2.19 (br m, 1H), 1.94–1.83 (br m, 2H), 1.82–1.75 (br m, 1H), 1.48 (s, 9H), 1.47–1.22 (m, 9H). 13 13C NMR (125 MHz, CDCl3) (minor rotamer is shown in parentheses) δ 158.5, 154.8, 154.5, 145.7 (145.1), 135.1 (135.5), 130.0, (129.0), 106.9 (107.1), 79.9, 79.4, 58.6 (58.2), 46.9 (47.1), 45.4, 43.8, 42.9, 35.7 (34.5), 28.4 (28.3), 23.2 (23.5). HRMS (ESI) m / z: [M+H] + [C 23 H 37 N4O4] + Calcd for: 433.2809, Found: 433.2807.

[0265]

[0266] tert-Butyl 2-(5-(methoxycarbonyl)furan-3-yl)pyrrolidine-1-carboxylate: 1 H NMR(500MHz,CDCl3)δ7.49–7.36(m,1H),7.08(s,1H),5.00–4.65(br m,1H),3.89(s,3H),3.59–3.34(br m,2H),2.30–2.12(br m,1H),1.95–1.85(m,3H),1.53–1.33(br m,9H). 13 C NMR(125MHz,CDCl3)(minor rotamer shown in parentheses)δ159.1,154.3(154.5),144.6,142.7(142.9),131.01(130.4),116.9(117.2),79.7,52.8(52.4),51.9,46.2(46.5),33.9(32.6),28.4,23.2(24.0).HRMS(ESI)m / z:[M+Na] + [C 15 H 21 NO5Na] + Calcd:318.1312,found:318.1310.

[0267]

[0268] tert-Butyl 2-benzamidopyrrolidine-1-carboxylate: 1 H NMR(400MHz,CDCl3)δ7.58–7.32(m,5H),5.67–5.03(br,m,2H),3.82–3.24(br,m,2H),2.42–1.70(br,m,4H),1.54–1.26(br,m,9H). 13 C NMR(125MHz,CDCl3)(minor rotamer shown in parentheses)δ171.1(170.0),154.9(153.2),136.5,130.1,128.3,127.3(126.7),79.7,66.7(66.1),50.0(45.9),34.5(30.7),28.3,24.5(21.3).HRMS(ESI):m / z:M + C 16 H 22 N2O3 Calcd:290.1630,found:290.1629.

[0269]

[0270] (10R,11aR)-10-(2,4,5-Trifluorobenzyl)-3-(trifluoromethyl)-5,6,9,10,11,11a-hexahydro-8H-[1,2,4]triazolo[3',4':3,4]pyrazino[1,2-a]pyrimidin-8-one: 1 H NMR(500MHz,CDCl3)δ7.13(q,J=8.8Hz,1H),6.94(q,J=9.4Hz,1H),5.70(d,J=8.6Hz,1H),5.14(dd,J=14.3,4.0Hz,1H),4.22(dd,J=12.6,4.0Hz,1H),4.12(td,J=12.3,4.3Hz,1H),3.55–3.43(m,1H),3.18–3.08(m,1H),2.99(dd,J=13.9,6.1Hz,1H),2.92(t,J=8.9Hz,1H),2.85(dd,J=13.9,7.2Hz,1H),2.48(dd,J=17.2,3.3Hz,1H),2.25(dd,J=17.2,11.8Hz,1H). 13 C NMR(125MHz,CDCl3)δ167.0,156.1(ddd,J=244.6,9.3,2.4Hz),151.4,149.1(dt,J=250.8,13.4Hz),146.7(ddd,J=245.4,12.5,3.5Hz),143.9(q,J=40.1Hz),120.2(dt,J=18.3,4.6Hz),119.0(dd,J=19.0,5.6Hz),118.0(q,J=270.8Hz),105.7(dd,J=28.6,20.8Hz),67.1,51.3,43.4,38.1,35.9,34.4. 19 F NMR(376MHz,CDCl3)δ-63.16,-118.56–-118.68(m),-134.84–-135.00(m),-142.23–-142.44(m).

[0271]

[0272] (10R,11aS)-10-(2,4,5-Trifluorobenzyl)-3-(trifluoromethyl)-5,6,9,10,11,11a-hexahydro-8H-[1,2,4]triazolo[3',4':3,4]pyrazino[1,2-a]pyrimidin-8-one: 11H NMR (500 MHz, CDCl3) δ 7.17 (q, J = 8.7 Hz, 1H), 6.93 (td, J = 9.6, 6.6 Hz, 1H), 5.77 (s, 1H), 5.06 (d, J = 13.6 Hz, 1H), 4.15 (d, J = 6.1 Hz, 2H), 3.32–3.19 (m, 2H), 2.95 (dd, J = 14.1, 6.3 Hz, 1H), 2.82 (dd, J = 14.1, 6.7 Hz, 1H), 2.73–2.52 (m, 1H), 2.43 (dd, J = 16.7, 3.3 Hz, 1H), 2.27 (dd, J = 16.7, 10.5 Hz, 1H). 13 13C NMR (125 MHz, CDCl3) δ 167.7, 156.1 (ddd, J = 244.1, 9.0, 2.4 Hz), 152.8, 149.1 (dt, J = 251.3, 13.4 Hz), 146.8 (ddd, J = 245.4, 12.2, 3.2 Hz), 144.8 (q, J = 39.4 Hz), 119.8 (dt, J = 18.3, 4.7 Hz), 118.9 (dd, J = 19.2, 5.8 Hz), 118.0 (q, J = 270.4 Hz), 105.7 (dd, J = 28.7, 20.7 Hz), 66.8, 49.4, 42.8, 38.5, 38.3, 33.4. 19 19F NMR (376 MHz, CDCl3) δ -63.43, -118.32–-118.44 (m), -134.68–-134.83 (m), -141.99–-142.29 (m). HRMS (ESI) m / z: [M+H] + [C 16 H 14 F6N5O] + Calcd: 406.1097, Found: 406.1088.

[0273]

[0274] tert-Butyl 1-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (M. Kaur et al., Eur. J. Org. Chem., 2016, 2016, 4159): 11H NMR (500 MHz, CDCl3) δ 6.96 (s, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.68 (s, 1H), 6.61 (d, J = 6.7 Hz, 1H), 6.52 (s, 1H), 6.43–6.05 (br m, 1H). 4.22–3.94 (br m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.12–3.00 (br m, 1H), 2.99–2.86 (br m, 1H), 2.73–2.60 (br m, 1H), 1.52 (s, 9H). 13 13C NMR (125 MHz, CDCl3) (minor rotamer shown in parentheses) δ 154.7 (154.3), 148.7, 148.2, 147.9, 147.3, 135.8, 127.3, 127.1, 120.8, 111.8, 111.2, 111.1, 110.3, 79.9, 57.1, 55.9, 55.8, 55.8, 55.8, 37.8 (36.5), 28.6, 28.1. HRMS (ESI) m / z: [M+H] + [C 24 H 32 NO6] + Calcd for: 430.2224, Found: 430.2224.

[0275] Discussion:

[0276] As shown above, various alkyl azides with different electronic properties and functional groups underwent C–H amination in moderate to excellent yields to afford compounds 1b to 31b.

[0277] Electron-donating and electron-withdrawing substituents on the phenyl moiety of the model substrate did not make a difference, all of which led to high yields of benzylic C–H amination pyrrolidine products (1b to 7b).

[0278] Amination of secondary azides with benzylic, tertiary, secondary, and primary C–H bonds gave pyrrolidine products (9b to 12b) in 95% to 23% yields, indicating the following reactivity order: benzylic > 3°–2° > 1° C–H bonds.

[0279] When the alkyl azide precursor of product 13b was treated according to this system, the tropane derivative 13b was synthesized in good yield using 3 mol% catalyst. Similarly, the α-azido ketone precursors were well aminated to tropane analogs 14b and 19b in 69% and 74% yields, respectively.

[0280] In addition, functional groups such as indole, amide, ester, ether, thiazole, furan, and phenol show good tolerance in the catalytic system, and the corresponding pyrrolidines (20b - 31b) are formed in yields of 30% to 87%.

[0281] The seven - membered ring product of azepine analogue 28b was obtained in 62% yield using this method.

[0282] Notably, to the best of our knowledge and as of the filing of this application, the intramolecular C - H amination of alkyl azides to produce products 20b to 31b has not been reported in previous work.

[0283] In summary, the iron(II) - phthalocyanine complex t Bu4PcFe(py)2 is a useful catalyst that can react with various alkyl azides having benzylic, tertiary, secondary, and primary C - H bonds, thereby inducing intramolecular C–H insertion and providing the cyclized amination products in moderate to excellent yields.

[0284] Example 3: Large - scale C - H amination of azacycloheptane

[0285] Procedure: Under argon, an oven - dried Schlenk flask was charged with azacycloheptane (3 mmol; 417 mg), Boc2O (2.0 equiv), the iron catalyst t Bu4PcFe(py)2 (3 mol%) and dry toluene (15 mL). The reaction was refluxed vigorously (130 °C) for 2 days, then cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography to give the amination product. The product was characterized by comparison with literature data (Angew. Chem. Int. Ed., 2018, 57, 11947). The product (13b) was obtained in 90% 1 1H NMR yield and 61% isolated yield.

[0286] Discussion:

[0287] To demonstrate the synthetic application of the C - H amination reaction, a large - scale reaction was carried out by scaling up the catalysis 15 - fold, providing the tropane derivative in 90% 1 1H NMR yield. The tropane derivative has the following chemical structure:

[0288]

[0289] Example 4: Synthesis of complex molecules and late - stage functionalization of active pharmaceutical ingredients using C - H amination

[0290] Using the standard reaction conditions given in Example 2 above, the following natural product derivatives were formed in the specified yields, as shown below:

[0291]

[0292]

[0293] Discussion:

[0294] The characterization of the above compounds was given in Example 2 above. The application of catalytic transformation in the late-stage functionalization of active pharmaceutical ingredients and the synthesis of alkaloid-related natural product derivatives was explored. For example, cyclization reaction of an azide derived from dehydroabietylamine gave 32b in 69% yield. In another example, N-Boc-1-phenyltetrahydroisoquinoline (33b), a key intermediate for the preparation of the potent antimuscarinic drug Vesicare (also known as solifenacin) with urinary antispasmodic properties, was constructed using this method. Similarly, N-Boc-protected salsolidine (35b), norlaudanosoline (36b), and cryptostyline II (34b) derivatives were also constructed from their azide precursors, although with lower efficiency compared to the first two molecules. Product 37b (which can be converted to tadalafil (Cialis) in three steps (Tetrahedron: Asymmetry, 2009, 20, 2090)) could be obtained from an azide derived from L-tryptophan. Finally, late-stage amination of the drug molecule sitagliptin was achieved from the derived azide precursor to give 38b and 38b’, and the structures of the corresponding products were confirmed by X-ray analysis, as Figure 1 shown.

[0295] The above examples show that the catalytic transformation for C-H amination using the iron(II)-phthalocyanine complex t Bu4PcFe(py)2 catalyst can also be successfully applied to the synthesis of natural product derivatives and the late-stage functionalization of commercially available acyclic amines to obtain the corresponding alkaloids.

[0296] Example 5: Comparison of Catalyst Performance for C-H Amination

[0297] In 2013, Betley and his colleagues applied the iron-dipyrrinato catalyst (1) to the intramolecular amination of the C(sp 3 )-H bond of alkyl azides. Several groups have also developed other catalysts with different catalytic reactivities for the amination of alkyl azides. The catalytic performances of some representative iron catalysts (1 - 4) were compared with t those of Bu4PcFe(py)2 (5). Table 3 provides the chemical structures of the known catalysts.

[0298] Table 3. Iron Catalysts

[0299]

[0300]

[0301] As discussed in the above examples, compounds 12b, 10b, 13b and 32b were synthesized using catalysts 1 - 5 by the C-amination method. The compounds are shown below.

[0302]

[0303] Table 4. Reaction results

[0304]

[0305] "-" indicates that the reaction was not carried out.

[0306] As shown in Table 4, compared with catalysts 1 - 4, catalyst 5 ( t Bu4PcFe(py)2) showed good catalytic reactivity to obtain the corresponding products 12b, 10b, 13b and 32b with lower catalyst loading and / or higher yields.

[0307] Example 6: Mechanistic study

[0308] To understand the mechanism of the catalytic amination process described herein, three reactions shown in Scheme 2 below were carried out.

[0309]

[0310] The standard conditions were those of Example 2 above. In (a), (S)-(5-azidopentan-2-yl)benzene (98% ee) was treated according to this method to obtain tert-butyl (R)-2-methyl-2-phenylpyrrolidine-1-carboxylate (94% ee) with stereochemical retention, which was similar to the reported results (Science, 2013, 340, 591).

[0311] In (b), the addition of 5 equivalents of TEMPO to the catalytic system did not stop the amination reaction, and no radical-trapping products were detected.

[0312] In (c), when the monodeuterated azide 1-azido-4-deuterio-4-phenylbutane was subjected to the standard conditions, the intramolecular kinetic isotope effect (KIE) value was calculated to be 4.0, which was less than the data of 5.1 reported by Betley at 60 °C (Science, 2013, 340, 591), but greater than the data of 1.9 reported by the Che group at 115 °C (Angew. Chem. Int. Ed., 2018, 57, 11947). This indicates that the catalytic reaction involves a stepwise mechanism.

[0313] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention pertains. Publications and materials cited herein are specifically incorporated by reference.

[0314] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A method for C-H amination, the method comprising the following steps: (a) forming a reaction mixture in a reaction vessel comprising an alkyl azide, an iron(II)-phthalocyanine catalyst, at least one reagent for protecting an amine, and one or more solvents, wherein the iron(II)-phthalocyanine catalyst is: and the at least one reagent for protecting an amine is selected from fluorenylmethyloxycarbonyl (Fmoc) and di-tert-butyl dicarbonate (Boc2O); and (b) heating the reaction mixture to a temperature of at least 100 °C to induce direct intramolecular C-H amination of the alkyl azide, producing a cyclic amination product of the alkyl azide, Among them, the closed-loop amination product has the chemical structure shown below: wherein R is H, Me, OMe, Cl, Br, F, NO2 or N,N-dimethyl; Each R is 4-OMeC6H4; 2. The method according to claim 1, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of 0.1 to 5 mol% of the amount of alkyl azide present.

3. The method according to claim 2, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of at least 1 mol% of the amount of alkyl azide present.

4. The method according to claim 1, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of at least 2 mol% of the amount of alkyl azide present.

5. The method according to claim 2, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of at least 3 mol% of the amount of alkyl azide present.

6. The method according to claim 2, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of at least 4 mol% of the amount of alkyl azide present.

7. The method according to claim 2, wherein the iron(II)-phthalocyanine catalyst is present in the reaction mixture in an amount of 5 mol% of the amount of alkyl azide present.

8. The method according to claim 1, wherein the reaction mixture is heated to a temperature of 105 °C to 130 °C.

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