Desaturative Amination for the Synthesis of Amino Heteroarenes: Carbonyl-Site Predefinition of the C–N Bond-Forming Position and Subsequent Desaturative Aromatization
Desaturative Amination for the Synthesis of Amino Heteroarenes: Carbonyl-Site Predefinition of the C–N Bond-Forming Position and Subsequent Desaturative Aromatization
Introduction
Amino heteroarenes, including aminopyridines, aminopyrroles, aminofurans, and aminothiophenes, are widely found in pharmaceuticals and bioactive compounds. Although numerous methods are now available for C–N bond formation, a practical challenge in the synthesis of these structures often lies in obtaining suitably functionalized heteroaromatic precursors at the desired position.
In 2024, Javier Corpas, Alessandro Ruffoni, Daniele Leonori, and co-workers reported a desaturative amination method in Nature Catalysis. In this approach, carbonyl-containing saturated heterocycles are used as precursors to heteroarenes. A key C–N bond is first formed through condensation of the carbonyl group with an amine, followed by stepwise desaturation through photoredox catalysis and cobaloxime catalysis to construct C3- and C4-aminated pyridines, as well as C3-aminated pyrroles, furans, thiophenes, pyrazoles, and related structures [1]. This synthetic design builds on the authors’ previously developed desaturative amination of cyclohexanones [2].
The structural control achieved by this method can be summarized as two consecutive steps:
The position of the carbonyl group determines the C–N bond-forming position of the exogenous amine; subsequent desaturation establishes the π-conjugated system of the heteroaromatic ring.
As a result, some regioselectivity problems that would otherwise need to be addressed directly on the aromatic heterocycle can instead be handled at the stage of the saturated carbonyl precursor.
1. Where Does Regioselectivity in Heteroarene Amination Arise?
1.1 C3 and C4 Amination of Pyridines Is Limited by Precursor Preparation
Heteroarene amination commonly relies on nucleophilic aromatic substitution (S_NAr) or transition-metal-catalyzed C–N cross-coupling. These reactions generally require the heteroaromatic ring to bear a halogen or another suitable reactive functional group at the target position in advance.
The ring nitrogen of pyridine decreases the nucleophilicity of the aromatic π system. The original paper notes that amination at the C2 position of pyridine can be achieved through the Chichibabin reaction or by halogenation followed by S_NAr, whereas prefunctionalization at the C3 and C4 positions by reactions such as nitration or halogenation is comparatively difficult. Consequently, in the synthesis of such target structures, preparing heteroaryl precursors with the required substitution pattern can itself become a limiting step [1].
Electron-rich five-membered heteroarenes exhibit a different regioselectivity profile. Reactions such as halogenation of pyrroles, furans, and thiophenes generally favor the C2 position, whereas the C3 position is less reactive. The preparation of the corresponding C3-functionalized precursors and their subsequent C–N coupling can therefore also be challenging [1].
Although the specific electronic effects differ among heteroaromatic systems, they ultimately influence which substitution patterns can be readily accessed.
Target structure | Regioselectivity issue at the aromatic stage | Precursor used in desaturative amination |
C4-aminated pyridines | Prefunctionalization at C4 is restricted by the electronic properties of pyridine | N-Boc-4-piperidone |
C3-aminated pyridines | C3 prefunctionalization and preparation of multiply substituted structures are relatively difficult | N-Boc-3-piperidone |
C3-aminated pyrroles, furans, and thiophenes | Aromatic-ring functionalization generally favors the C2 position | Corresponding saturated five-membered 3-oxo heterocycles |
Desaturative amination establishes the regiochemical pattern before formation of the heteroaromatic ring, creating a direct correspondence between the position of the carbonyl group and the final position of the amino substituent.
2. How the Carbonyl Group Predefines the Final Amino-Substitution Position
2.1 The C–N Bond Is Formed before Aromatization
The reaction of N-tert-butoxycarbonyl (Boc)-protected 4-piperidone with morpholine can be used as an example.
The carbonyl carbon of 4-piperidone corresponds to the C4 position of the final pyridine framework. Condensation of the ketone with morpholine forms an enamine, at which point the C–N bond between the nitrogen atom of the exogenous amine and the original carbonyl carbon has already been established. Subsequent reactions sequentially generate new π bonds around the ring, ultimately affording 4-morpholinylpyridine. The C–N connectivity established during the condensation step is retained throughout aromatization [1].
The structural conversion leading to C4-aminated pyridines can be represented as follows:
4-Piperidone + amine
↓ Carbonyl–amine condensation
C4 enamine
↓ Consecutive desaturation
C4-aminated pyridine
The same structural correspondence applies to 3-piperidone:
3-Piperidone + amine
↓ Carbonyl–amine condensation
C3 enamine
↓ Consecutive desaturation
C3-aminated pyridine
Two chemically distinct processes are involved:
① Carbonyl condensation forms the C–N bond between the exogenous amine and the cyclic framework and determines the ring position at which this bond is located;
② Desaturation generates new π bonds and converts the saturated heterocycle into an aromatic heterocycle.
Thus, the position of the target amino substituent is already determined when the enamine is formed, while the subsequent aromatization primarily converts the electronic structure of the cyclic framework into that of an aromatic system.
2.2 Synthetic Design from Cyclohexanones to Heterocyclic Ketones
In 2020, the Leonori group reported the synthesis of anilines using cyclohexanones as precursors to aromatic rings. Cyclohexanone first condenses with a primary or secondary amine to form an enamine, which then undergoes two rounds of photoredox activation and cobalt-mediated hydrogen atom transfer to accomplish desaturation and ultimately form an aniline [2].
The 2024 study applied the same type of retrosynthetic design to saturated cyclic ketones containing heteroatoms, directly linking carbonyl condensation with heteroarene construction. The heterocyclic nitrogen and its N-protecting group alter the electronic structure of the radical intermediates. Consequently, the second desaturation involved in aminopyridine formation differs markedly in mechanism from that previously established for the synthesis of anilines from cyclohexanones [1,2].
3. Aromatization Mechanism of C4-Aminated Pyridines
Formation of a C4-aminated pyridine requires the generation of two new degrees of unsaturation on the preformed enamine framework. Experimental studies, cyclic voltammetry, and computational results in the original paper support distinct mechanisms for the two desaturation events: the first involves cobalt-mediated hydrogen atom transfer, whereas the second involves cobalt-mediated single-electron oxidation [1].
3.1 Step 1: Condensation Generates a Photoxidizable Enamine
N-Boc-4-piperidone and morpholine form the electron-rich enamine 96 in the presence of a weak Brønsted acid.
The oxidation potential of this enamine was measured to be approximately +0.65 V versus the saturated calomel electrode (SCE). The excited-state iridium photocatalyst has sufficient oxidizing power to oxidize the enamine by single-electron transfer, producing enamine radical cation 97 [1].
Radical cation 97 subsequently undergoes deprotonation at C2 to form radical intermediate 98, in which the π-electron system is more extensively delocalized.
This stage converts a conventional enamine into a radical intermediate capable of undergoing the first desaturation.
3.2 Step 2: Cobalt-Mediated Hydrogen Atom Transfer Forms a Dienamine
Radical intermediate 98 cannot undergo desaturation across the C2–N region in the same manner as in the authors’ previous aniline synthesis. The original paper attributes this difference to Boc protection of the ring nitrogen.
Computational results indicate appreciable spin density at C4 in intermediate 98. On this basis, the authors proposed that the cobaloxime catalyst mediates hydrogen atom transfer (HAT) from the C5 position, removing a hydrogen atom from the C5–H bond while simultaneously establishing the C4=C5 double bond to form dienamine 99 [1].
The principal structural changes in this stage can be represented as follows:
Enamine 96
→ Photoinduced single-electron oxidation
→ Radical cation 97
→ C2 deprotonation
→ Radical 98
→ Cobalt-mediated HAT
→ Dienamine 99
According to the mechanism proposed by the authors, a cobalt hydride species is formed following HAT. The reaction was conducted in a sealed Young tube, and H₂ was detected immediately after the reaction by proton nuclear magnetic resonance spectroscopy, supporting the proposed cobalt-mediated dehydrogenation and hydrogen-evolution pathway [1].
At this point, the first new unit of unsaturation has been introduced into the ring, but the framework has not yet reached the aromatic state of pyridine.
3.3 Step 3: A Second Photooxidation Generates the Radical Precursor to Aromatization
Dienamine 99 undergoes a second round of photooxidation to form radical cation 100. Subsequent deprotonation at C6 generates radical 101 [1].
The structure at this stage differs from that present before the first desaturation. Intermediate 101 lacks a suitably abstractable hydrogen atom that would allow the same cobalt-mediated HAT pathway to occur again. Consequently, the subsequent aromatization proceeds through a different oxidative pathway.
This step is central to understanding the overall mechanism: the two events that establish unsaturation proceed through different modes of electron transfer.
3.4 Step 4: Cobalt-Mediated Single-Electron Oxidation and Boc Transfer
The authors first used density functional theory (DFT) to examine the possibility of direct cleavage of the N–Boc bond in radical 101. This calculated pathway would generate CO₂ and a tert-butyl radical, with the latter expected to subsequently form isobutene.
No isobutene consistent with this pathway was detected experimentally. Instead, nearly stoichiometric formation of N-Boc-morpholine 103 was observed in the crude reaction mixture. This result suggests that the Boc group is transferred from the pyridine precursor to free morpholine [1].
Based on cyclic voltammetry and computational results, the authors proposed the following sequence:
Radical 101
↓ Co(II)-mediated single-electron transfer
N-Boc-pyridinium intermediate 102
↓ Boc transfer to the free amine
C4-aminated pyridine + N-Boc-amine
In this single-electron transfer (SET) step, Co(II) acts as an oxidant. Electrochemical measurements and DFT calculations reported in the paper indicate that this electron-transfer process is thermodynamically feasible [1].
Thus, the cobaloxime catalyst participates sequentially in two different types of reaction during the formation of C4-aminated pyridines:
Stage | Process involving the cobaloxime catalyst | Principal structural outcome |
First desaturation | HAT | Formation of a new C=C bond and a dienamine |
Second desaturation | SET oxidation | Formation of a pyridinium intermediate, followed by Boc transfer and completion of aromatization |
This dual role is an important mechanistic feature that distinguishes this reaction from the previously reported desaturative synthesis of anilines from cyclohexanones [1,2].
The mechanism described above is the reaction model proposed in the paper and is supported collectively by experimental and computational evidence. H₂ and N-Boc-morpholine were experimentally detected, whereas some of the radical and pyridinium intermediates were inferred from electrochemical measurements, computational studies, and product analysis [1].
4. Effect of N-Protecting Groups on the Reactivity of 4-Piperidones in Desaturative Amination
The substitution state of the ring nitrogen in 4-piperidones has a pronounced effect on desaturative amination. The authors first examined the reaction of unprotected 4-piperidone with an amine but obtained no target C4-aminated pyridine under the screened combinations of photoredox catalysts, cobaloxime catalysts, and additives. When N-Boc-protected 4-piperidone was used instead, the desired reaction proceeded efficiently [1].
Further screening of protecting groups revealed substantial differences in reactivity among different forms of N-substitution. N-Cbz-, N-Fmoc-, and N-Ac-protected 4-piperidones underwent the desired transformation to varying extents, whereas N-Ts-, N-Bn-, N-t-Bu-, and N-Me-substituted substrates showed substantially poorer reactivity [1].
These control experiments demonstrate that the substituent on the ring nitrogen does more than simply protect the substrate; its structure affects the ability of 4-piperidone to enter the desaturative amination sequence. The reactivity displayed by the N-Boc substrate also provided an important experimental basis for the subsequent mechanistic studies.
5. Desaturative Aromatization Pathways of Different Heterocyclic Precursors
Mechanistic studies of the 4-piperidone system indicate that formation of a six-membered pyridine ring requires two consecutive desaturation stages. The 3-piperidone system follows the same general sequence, although the site of the first deprotonation and the conjugation pattern of the dienamine intermediate differ. In contrast, after formation of an enamine, the corresponding saturated five-membered 3-oxo heterocycles can undergo aromatization through a single photooxidation–deprotonation–hydrogen atom transfer sequence [1].
5.1 Two-Stage Desaturation of C3-Aminated Pyridines
Condensation of 3-piperidone with an amine forms enamine 104. The oxidation potential of 104 was measured to be approximately +0.23 V versus SCE. Photoinduced single-electron oxidation then forms radical cation 105. Computational results gave calculated pK_a values of 10.7 and 15.7 for deprotonation of 105 at C4 and C6, respectively. Deprotonation at C4 is therefore computationally favored, generating radical 106 [1].
Radical 106 subsequently undergoes cobalt-mediated hydrogen atom transfer (HAT) to effect desaturation and form cross-conjugated dienamine 107. Formation of this structure represents one of the principal differences between the 3-piperidone and 4-piperidone systems during the first desaturation stage and is associated with the altered deprotonation site of the radical cation resulting from the change in carbonyl position [1].
This stage can be represented as follows:
Enamine 104
↓ Photoinduced single-electron oxidation
Radical cation 105
↓ C4 deprotonation
Radical 106
↓ Cobalt-mediated HAT
Cross-conjugated dienamine 107
Dienamine 107 has not yet formed a fully aromatic pyridine system. The paper proposes that 107 undergoes further photooxidation to form intermediate 108, followed by deprotonation to generate radical 109. Cobalt-mediated oxidation of 109 then forms pyridinium intermediate 110, after which Boc-group transfer occurs to generate the C3-aminated pyridine. The authors also obtained experimental evidence for H₂ formation and Boc transfer, supporting this mechanistic pathway [1].
Thus, both 3-piperidones and 4-piperidones undergo two stages of desaturation during the formation of aminated pyridines. A key feature of the 3-piperidone system is preferential C4 deprotonation after the first photooxidation, leading to formation of cross-conjugated dienamine 107. The subsequent oxidation, deprotonation, cobalt-mediated oxidation, and Boc transfer correspond to the second-stage aromatization pathway proposed in the paper for C4-aminated pyridines [1].
5.2 Desaturative Aromatization of C3-Aminated Five-Membered Heteroarenes
Saturated five-membered 3-oxo heterocycles can be used to construct C3-aminated pyrroles, furans, thiophenes, and pyrazoles. The paper demonstrated this reaction class using N-Boc-pyrrolidin-3-one and the corresponding saturated oxygen-, sulfur-, and nitrogen-containing heterocyclic precursors [1].
The authors proposed that these five-membered heterocycles first condense with amines to form enamine 112. Photooxidation of the enamine produces radical cation 113, which is then deprotonated at C3 to generate radical 114. The cobaloxime catalyst subsequently completes desaturation through HAT, forming the aromatic heterocycle [1].
The principal reaction sequence is:
Saturated five-membered 3-oxo heterocycle + amine
↓ Carbonyl–amine condensation
Enamine 112
↓ Photoinduced single-electron oxidation
Radical cation 113
↓ C3 deprotonation
Radical 114
↓ Cobalt-mediated HAT
C3-aminated five-membered heteroarene
Formation of the enamine has already established one C=C bond in the five-membered heterocycle. Subsequent HAT-mediated desaturation forms one additional unit of unsaturation, which is sufficient to generate the corresponding aromatic five-membered system. Therefore, the aromatization pathway proposed for the five-membered heterocycles does not involve the second round of photooxidation, cobalt-mediated oxidation, or Boc transfer required in the aminated pyridine systems [1].
5.3 Aromatization Pathways of Different Heterocyclic Precursors
Target structure | First desaturation | Subsequent aromatization |
C4-aminated pyridines | Photooxidation → deprotonation → cobalt-mediated HAT | Second photooxidation → deprotonation → cobalt-mediated oxidation → Boc transfer |
C3-aminated pyridines | Photooxidation → C4 deprotonation → cobalt-mediated HAT, forming a cross-conjugated dienamine | Second photooxidation → deprotonation → cobalt-mediated oxidation → Boc transfer |
C3-aminated five-membered heteroarenes | Photooxidation → C3 deprotonation → cobalt-mediated HAT | Aromatization is completed after HAT-mediated desaturation |
Both 3-piperidones and 4-piperidones require two stages of desaturation to form a six-membered aromatic pyridine system, although the position of the first deprotonation and the structure of the resulting dienamine differ. For the saturated five-membered 3-oxo heterocycles studied in the paper, formation of the enamine followed by one photooxidation, C3 deprotonation, and cobalt-mediated HAT is sufficient to reach the corresponding aromatic state [1].
6. Carbonyl Chemistry Can Also Predefine Additional Substituents
The role of saturated heterocyclic ketones is not limited to condensation with amines. The carbonyl group and its adjacent positions can also be structurally modified through reactions such as enolate chemistry and conjugate addition.
The original paper exploited this feature to prepare differently substituted piperidone precursors before carrying out desaturative amination. For example, the authors obtained C2-substituted piperidones through conjugate addition and subsequently prepared C2,C4-disubstituted aminopyridines. For electron-rich five-membered heterocycles, functionalization of saturated precursors was likewise used to access substitution patterns such as C3,C4 substitution [1].
The corresponding synthetic sequence is:
Saturated heterocyclic ketone
↓ Carbonyl-related reactions to install additional substituents
Substituted heterocyclic ketone
↓ Condensation with an amine
Enamine containing the target C–N bond
↓ Desaturation
Multiply substituted amino heteroarene
This sequence allows two structural problems to be addressed separately:
① The position of the carbonyl group determines where the exogenous amine is attached;
② Other functionalization reactions of the carbonyl precursor are used to position additional substituents on the ring.
The final desaturation preserves these previously established connectivities in the aromatic heterocycle.
This is also an important advantage of saturated heterocyclic ketones as synthetic precursors: the substitution pattern of a heteroaromatic ring can be constructed stepwise before aromaticity is established.
7. Relationship to Reductive Amination: The Same C–N Bond-Forming Step Can Lead to Different Skeletal Transformations
Piperidones and amines are also common starting materials for reductive amination in medicinal chemistry.
During reductive amination, condensation of the carbonyl compound with the amine is followed by reduction, and the product retains a saturated framework:
Piperidone + amine → condensation → reduction → saturated amine
Desaturative amination uses the same type of carbonyl–amine condensation to establish the C–N bond, but the subsequent reaction pathway proceeds toward consecutive desaturation:
Piperidone + amine → condensation → desaturation → aminated pyridine
The original paper illustrated this relationship using an N-Boc-piperidone and a complex amine. Reductive amination reported in the literature affords a saturated tertiary amine from this set of starting materials, whereas desaturative amination uses the same types of starting building blocks to generate the corresponding aminopyridine [1].
The two reaction pathways share the carbonyl–amine C–N bond-forming step but diverge in the subsequent direction of skeletal transformation. For synthetic programs that construct molecular libraries from ketones and amines, this means that the same classes of starting building blocks can be used to access either saturated nitrogen-containing frameworks or aromatic nitrogen-containing frameworks.
8. Reaction Efficiency Is Also Influenced by the Ability to Form the Enamine
Condensation of the carbonyl compound with the amine is the starting point of the entire desaturative reaction. Consequently, the efficiency of enamine formation directly affects the subsequent photooxidation and desaturation steps.
When examining C3-disubstituted aminopyridines, the paper found that the reaction yields of these substrates were generally lower than those of the C4-aminopyridine series. The authors suggested that slower enamine formation from 3-piperidones may be one factor affecting reaction efficiency. This behavior was associated with the preferential formation of a more stable but less reactive enol tautomer of the substrate [1].
These observations indicate that, when applying this type of desaturative amination in synthetic design, three chemical questions can be considered sequentially:
1. Can the saturated heterocyclic ketone efficiently form an enamine with the target amine?
2. Does the resulting enamine possess redox properties suitable for photooxidation?
3. Can the radical intermediate undergo the required desaturation through the corresponding HAT or SET process?
These three processes correspond, respectively, to C–N bond formation, radical generation, and establishment of aromaticity, and together determine the overall efficiency of the transformation.
9. Classification and Research Applications of Representative Chemicals Related to the Desaturative Amination Synthesis of Amino Heteroarenes
Table 1. Saturated Heterocyclic Ketones and Heteroarene Precursors
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Protected six-membered nitrogen-containing cyclic ketone | 204376-55-6 | N-Fmoc-4-piperidone | ≥98% (HPLC) | A 4-piperidone precursor that can be used to investigate the effects of ring-nitrogen protecting groups on enamine formation and desaturative amination reactivity, as well as for studies on the construction of C4-aminopyridine scaffolds | |
Six-membered nitrogen-containing cyclic ketone | 98977-36-7 | 1-(tert-Butoxycarbonyl)-3-piperidone | ≥97% | A saturated heterocyclic ketone precursor for the synthesis of C3-aminopyridines; the carbonyl site is used to establish the C–N bond with the exogenous amine, followed by desaturation to form the pyridine framework | |
Five-membered nitrogen-containing cyclic ketone | 101385-93-7 | 1-Boc-3-pyrrolidinone | ≥97% | A saturated nitrogen-containing heterocyclic ketone precursor for the synthesis of C3-aminopyrroles; it can undergo condensation with an amine to form an enamine, followed by further desaturative aromatization | |
Five-membered oxygen-containing cyclic ketone | 22929-52-8 | Tetrahydrofuran-3-one | ≥98% (GC) | A saturated oxygen-containing heterocyclic ketone for constructing C3-aminofurans, suitable for studies of carbonyl–amine condensation and subsequent photoredox desaturation | |
Five-membered sulfur-containing cyclic ketone | 1003-04-9 | Tetrahydrothiophen-3-one | ≥98% | A saturated sulfur-containing heterocyclic ketone for constructing C3-aminothiophenes, suitable for studies of enamine formation and desaturative aromatization reactions |
Table 2. Photoredox–Cobalt Catalytic System and Reagents Used in the Reaction Conditions
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Photoredox catalyst | 676525-77-2 | Bis(2-pyridyl)phenyliridium(III) hexafluorophosphate | ≥99% | A visible-light-driven iridium photoredox catalyst used for single-electron oxidation of enamines and generation of radical cations; a key component of the photocatalytic cycle for desaturative aromatization | |
Cobaloxime catalyst | 483979-48-2 | Chlorobis(dimethylglyoximato)[4-(dimethylamino)pyridine]cobalt(III) | ≥95% | A cobaloxime desaturation catalyst used in reaction systems such as C4-aminopyridine synthesis; it works in concert with the photocatalytic cycle in hydrogen atom transfer, desaturation, and oxidation processes | |
Cobaloxime catalyst | 23638-66-6 | Dichloro(dimethylglyoxime)(dimethylglyoxime)cobalt(III) | ≥97% | A cobaloxime catalyst that can be used to investigate desaturation conditions for systems such as C3-aminopyridines and is suitable for photoredox–cobalt cooperative aromatization systems | |
Basic additive | 280-57-9 | 1,4-Diazabicyclo[2.2.2]octane (DABCO) | Moligand™, ≥98% | A basic additive used in desaturative amination systems for C4-aminopyridines and amino-substituted five-membered heteroarenes and associated with deprotonation of radical cations | |
Carboxylate base | 19455-23-3 | Potassium pivalate | ≥98% (T) | A basic reagent used in 3-piperidone desaturative amination systems for post-photooxidation deprotonation and studies of related aromatization reaction conditions | |
Acidic additive | 64-19-7 | Glacial acetic acid | Premium-grade reagent, ≥99.5% | A weakly acidic additive used in C4-aminopyridine and five-membered heteroarene systems to promote condensation of carbonyl compounds with amines to form reactive enamines | |
Acidic additive | 76-05-1 | Trifluoroacetic acid (TFA) | AR, ≥99% | An acidic additive used in 3-piperidone desaturative amination systems, participating in carbonyl–amine condensation and reaction-condition control | |
Lewis acid additive | 144026-79-9 | Scandium(III) triflate | ≥99.995% metals basis | Used as a Lewis acid additive in modified reaction conditions for the desaturative coupling of certain primary amines and arylamines | |
Reaction solvent | 75-05-8 | Anhydrous acetonitrile (ACN) | Anhydrous grade, ≥99.8%, H₂O ≤0.003% | A solvent for photoredox–cobalt-catalyzed desaturation reactions used in the synthesis of C4-aminopyridines and amino-substituted five-membered heteroarenes; anhydrous conditions are favorable for carbonyl–amine condensation and control of photochemical reactions | |
Reaction solvent | 98-08-8 | Trifluoromethylbenzene | Anhydrous grade, ≥99% | A reaction solvent used in C3-aminopyridine desaturative amination systems and suitable for studies of photocatalytic aromatization of 3-piperidones with primary or secondary amines |
Table 3. Cyclic Amine Substrates and Medicinal Chemistry Building Blocks
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Four-membered cyclic secondary amine | 503-29-7 | Azetidine | ≥98% | A small-ring secondary amine building block that can serve as the amine nucleophile in desaturative amination and be used to examine the effects of ring size on C–N bond formation and aminopyridine formation | |
Five-membered cyclic secondary amine | 123-75-1 | Pyrrolidine | ≥99% | A five-membered cyclic secondary amine substrate that can condense with piperidones to form enamines and be used in the synthesis of aminopyridines and related nitrogen-containing heteroaromatic derivatives | |
Six-membered cyclic secondary amine | 110-89-4 | P1506301 | Piperidine (controlled precursor chemical) | AR, ≥99.5% | A six-membered cyclic secondary amine building block used in substrate-scope studies of desaturative C–N coupling and in the construction of piperidinyl-substituted amino heteroarenes |
Oxygen-containing six-membered cyclic secondary amine | 110-91-8 | Morpholine | Refined grade, ≥99.5% | A representative amine used in reaction development, substrate-scope studies, and mechanistic investigations in the paper; applicable to studies of the desaturative synthesis of C4- and C3-aminopyridines and amino-substituted five-membered heteroarenes | |
Seven-membered cyclic secondary amine | 111-49-9 | H157403 | Hexamethyleneimine (HMI) | ≥98% (GC) | A seven-membered cyclic secondary amine building block that can be used to investigate condensation and desaturative amination reactions of larger cyclic amines with piperidones |
Protected piperazine | 57260-71-6 | 1-(tert-Butoxycarbonyl)piperazine | ≥98% | A mono-protected piperazine building block that can be used in desaturative amination studies of aminopyridines and related heteroarenes and to evaluate the chemoselectivity of protected diamines | |
Fluorinated six-membered cyclic secondary amine | 21987-29-1 | 4,4-Difluoropiperidine | ≥98% | A cyclic amine building block containing a gem-difluoro motif that can be used to evaluate the compatibility of fluorinated functional groups under desaturative amination conditions and to construct fluorinated amino heteroarenes | |
Sulfur-containing six-membered cyclic secondary amine | 123-90-0 | Thiomorpholine | ≥98% | A sulfur-containing cyclic secondary amine that can be used in desaturative coupling studies such as C3-aminopyridine synthesis and to examine the compatibility of sulfur-containing heterocyclic amines under photoredox conditions |
Table 4. Primary Amines, Arylamines, and Acyclic Amine Substrates
Category | CAS No. | Aladdin Cat. No. | Name | Specification or Purity | Product Features and Applications |
Branched aliphatic primary amine | 75-64-9 | tert-Butylamine (TBA) | Refined grade, ≥99.5% | A sterically hindered aliphatic primary amine that can be used in C3-aminopyridine desaturative coupling and in studies of C–N bond-forming reactivity with branched primary amines | |
Rigid aliphatic primary amine | 768-94-5 | 1-Adamantanamine | Moligand™, ≥98% | A rigid cage-like primary amine building block that can be used in desaturative pyridine-forming reactions involving complex amines and in derivatization studies of highly saturated nitrogen-containing structures | |
Aromatic primary amine | 62-53-3 | Aniline | AR, ≥99.5% | A benchmark aromatic primary amine substrate that can be used to evaluate the reactivity of arylamines under carbonyl condensation and desaturative C–N coupling conditions | |
Substituted aromatic primary amine | 104-94-9 | p-Anisidine | ≥99% | An aromatic primary amine bearing an electron-donating substituent that can be used to investigate electronic effects in arylamine substrates and to construct amino heteroarene derivatives | |
Heteroaromatic primary amine | 462-08-8 | 3-Aminopyridine | ≥99% | A heteroaromatic primary amine containing a pyridine nitrogen, suitable for studies of the desaturative coupling reactivity of heteroarylamines and also usable as a building block for aminopyridine derivative synthesis and structural comparison | |
Acyclic secondary amine | 103-49-1 | Dibenzylamine | ≥98% | An acyclic secondary amine substrate that can be used to evaluate condensation of noncyclic secondary amines with piperidones, enamine formation, and subsequent desaturative aromatization |
Note: The products listed above are representative Aladdin products relevant to scientific research. Specific applications should be determined in conjunction with product specifications, batch-specific COAs, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the product name, CAS number, or catalog number.
References
[1] Corpas J, Caldora H P, Di Tommaso E M, Hernandez-Perez A C, Turner O, Azofra L M, Ruffoni A, Leonori D. A general strategy for the amination of electron-rich and electron-poor heteroaromatics by desaturative catalysis. Nature Catalysis, 2024, 7: 593–603. DOI: 10.1038/s41929-024-01152-1.
[2] Dighe S U, Juliá F, Luridiana A, Douglas J J, Leonori D. A photochemical dehydrogenative strategy for aniline synthesis. Nature, 2020, 584: 75–81. DOI: 10.1038/s41586-020-2539-7.
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