Aminative Suzuki–Miyaura Coupling: Bond-Formation Order and Chemoselectivity Control in the Transformation from Ar–Ar′ to Ar–NH–Ar′
Aminative Suzuki–Miyaura Coupling: Bond-Formation Order and Chemoselectivity Control in the Transformation from Ar–Ar′ to Ar–NH–Ar′
Introduction
Suzuki–Miyaura coupling primarily uses aryl halides or aryl pseudohalides and organoboron reagents as coupling partners, and its typical outcome is the formation of a new C–C bond. In 2024, Onnuch, Ramagonolla, and Liu reported aminative Suzuki–Miyaura coupling, in which an NH unit is introduced between the two original coupling partners, changing the connectivity outcome of Ar–X + Ar′–B from Ar–Ar′ to Ar–NH–Ar′.[1] The core of this transformation is the alteration of competition among several bond-forming processes in the Pd-catalyzed system, allowing two consecutive C–N bond-forming events to replace the original direct C–C bond formation.[1]
The original study termed this net transformation formal nitrene insertion. Here, “insertion” describes the overall atomic connectivity: an NH unit is formally added between Ar and Ar′. Mechanistic studies showed that the two C–N bonds can be established in different orders and that the different pathways converge on the same diarylamine product.[1]
1. The C–C Bond-Formation Pathway in Suzuki–Miyaura Coupling
1.1 Oxidative Addition, Transmetalation, and Reductive Elimination
Classical Pd-catalyzed Suzuki–Miyaura coupling can be summarized in terms of three principal elementary processes:[8]
Oxidative addition
Ar–X + LₙPd(0) → LₙPd(II)(Ar)(X)
Transmetalation
LₙPd(II)(Ar)(X) + Ar′–B → LₙPd(II)(Ar)(Ar′)
Reductive elimination
LₙPd(II)(Ar)(Ar′) → Ar–Ar′ + LₙPd(0)
The actual transmetalating species is affected by the structure of the organoboron reagent, the base, the solvent, and the Pd coordination environment. The equations above represent the overall connectivity of the reaction rather than a single microscopic mechanism shared by all Suzuki–Miyaura systems.[8]
Modern Pd/phosphine catalytic systems can efficiently accomplish Ar–X oxidative addition, transmetalation of the arylboron reagent, and subsequent C–C reductive elimination. In aminative Suzuki–Miyaura coupling, this mature reactivity instead constitutes the principal competing pathway: once Ar′ enters the Pd coordination sphere in time and undergoes direct reductive elimination with Ar, the reaction reverts to the conventional Ar–Ar′ product.[1] At the reaction-design stage, the original paper therefore proposed that NH introduction requires a moderate reduction in the competitive advantage of the native Suzuki–Miyaura pathway while retaining the catalytic activity needed to form the second C–N bond.[1]
1.2 NH Bridging Changes the Connectivity Between the Two Aryl Groups
The net changes in the two types of reaction can be represented as follows:
Conventional Suzuki–Miyaura coupling
Ar–X + Ar′–B → Ar–Ar′
Aminative Suzuki–Miyaura coupling
Ar–X + Ar′–B + NH source → Ar–NH–Ar′
The original study used O-(diphenylphosphinyl)hydroxylamine as the formal NH source, abbreviated as DPPH, whose structure can be represented as:
H₂N–O–P(=O)Ph₂
Formation of Ar–NH–Ar′ requires the two aryl groups from different sources to form separate C–N bonds to nitrogen. The reaction selectivity therefore simultaneously involves multiple competing pathways, including direct Ar–Ar′ C–C bond formation, Ar–N bond formation, Ar′–N bond formation, and repeated incorporation of the same aryl group at the nitrogen center.
2. Competing Reactions in the Three-Component Assembly of Ar–NH–Ar′
2.1 The Efficient Conventional Suzuki Pathway Is the Primary Competing Reaction
The first conflict in the aminative reaction arises from the conventional Suzuki–Miyaura reaction itself. If transmetalation and C–C reductive elimination retain a strong competitive advantage, Ar and Ar′ are converted to Ar–Ar′ before DPPH enters the key bond-forming step.
Conversely, suppressing the Suzuki pathway must not deprive the Pd center of the reactivity required for the subsequent steps. After the first C–N bond is formed, the system must still introduce another carbon fragment and establish the second C–N bond. On this basis, the original study proposed three interdependent sets of reactivity requirements:[1]
Reaction Stage | Competition to Be Controlled |
Native Suzuki–Miyaura pathway | Prevent Ar and Ar′ from forming a C–C bond directly at an early stage |
Participation of the NH source | DPPH must be sufficiently reactive while avoiding premature consumption of Pd(0) before Ar–X oxidative addition |
Second C–N bond formation | Pd must retain the ability to continue coupling after the first amination |
Cross-selectivity | Reduce homocombinations such as Ar–NH–Ar or Ar′–NH–Ar′ |
The selectivity of this system is jointly determined by the relative rates of multiple pathways. Establishing the target reaction is not equivalent to increasing the rate of a single “amination step”; the competition among the native C–C pathway, the new C–N pathways, and processes such as reagent decomposition must lie within an appropriate range.
2.2 The NH Source Must Balance Migration Reactivity and Catalytic Compatibility
The N–O–P(O)Ph₂ structure of DPPH allows it to participate in aryl migration to nitrogen and subsequent Pd-mediated C–N bond formation. The original study also tested other nitrogen-containing reagents known to promote electrophilic amination of arylboronic acids, but these reagents did not produce the same effect in the three-component system.[1]
This distinction shows that the ability of a two-component Ar–B + NH-source system to undergo amination is not sufficient to ensure that the same nitrogen source can accomplish three-component cross-coupling of Ar–X + NH source + Ar′–B. The three-component reaction is simultaneously constrained by processes including Pd coordination, oxidative addition, aryl migration, transmetalation, and reductive elimination.
3. Regulation of C–C/C–N Bond-Formation Competition by Phosphine Ligands
3.1 Ligands Change the Connectivity of the Major Product
The original study compared different Pd/phosphine systems using 4-methoxyphenyl trifluoromethanesulfonate and 4-(trifluoromethyl)phenylboronic acid as model coupling partners. Changing the ligand produced marked differences in the ratio of the target aminative product to the conventional Suzuki–Miyaura product.[1]
Ligand System | Experimental Result |
RuPhos system | After 12 h, the reaction proceeded almost entirely through conventional Suzuki–Miyaura coupling, with no evident participation of DPPH observed |
t-BuBrettPhos system | Under optimized conditions, the aminative product 4a reached a 96% GC yield, while the conventional Suzuki product was approximately 3% |
t-BuXPhos system | Displayed similarly high aminative coupling efficiency to t-BuBrettPhos |
BrettPhos system | Approximately 70% aminative product was formed together with approximately 36% conventional Suzuki product |
With the same set of Ar–X, Ar′–B, and DPPH, merely changing the phosphine-ligand environment around Pd can shift the major product from Ar–Ar′ to Ar–NH–Ar′. Here, the ligand does more than “increase catalytic activity” in the general sense; it changes the competition between the two types of bond-forming processes, C–C and C–N.[1]
3.2 Effect of Bulky Ligands on Chemoselectivity
The original 2024 study directly demonstrated the pronounced effect of t-BuBrettPhos on aminative selectivity through the product distribution, but it did not attribute this phenomenon to a single, definitively established microscopic structural cause.[1]
Subsequent density functional theory (DFT) studies in 2026 further analyzed the ligand effect. One computational study proposed that bulky t-BuBrettPhos lowers the angular distortion required for a geometry favorable to C–N bond formation through geometric preorganization of a key Pd intermediate, whereas the smaller RuPhos favors competitive C–C coupling.[4] Another independent DFT study likewise identified the ligand as the principal determinant of C–N/C–C selectivity, but provided a different microscopic explanation for the specific interactions that stabilize the C–N bond-forming transition state.[5]
3.3 The Base and the Form of the Boron Reagent Jointly Regulate the Pathway
Representative conditions for aryl trifluoromethanesulfonates use t-BuBrettPhos Pd G3, K₃PO₄, and 2-methyltetrahydrofuran (2-MeTHF). Systems employing aryl bromides and chlorides require adjustment of the base conditions: 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) can support some reactions, whereas KOH has broader applicability.[1]
Aryl pinacol boronate esters (Ar–Bpin) can also participate in the reaction and, in the model system, give good conversion in combination with KOH. On the other hand, combinations of stronger bases with certain polar solvents increase the competing hydrolysis of aryl trifluoromethanesulfonates to phenols.[1]
The base does not serve a single function in this system. Activation of the boron species, deprotonation of nitrogen-containing species, Pd ligand exchange, and electrophile stability may all be affected by the combination of base and solvent. Accordingly, different types of Ar–X and Ar–B require an appropriate balance of conditions.
4. Two Orders of C–N Bond Formation
The original 2024 study did not restrict aminative Suzuki–Miyaura coupling to a single catalytic cycle. Instead, it proposed and experimentally supported two bond-formation sequences: electrophile-first and nucleophile-first.[1]
4.1 Electrophile-First: The First C–N Bond Is Formed on the Ar–X Side
The electrophile-first pathway begins with oxidative addition of Ar–X to Pd(0):
Ar–X + LPd(0)
→ LPd(II)(Ar)X
DPPH then enters the Pd coordination environment and undergoes deprotonation. The original paper proposed that the aryl group on Pd(II) may undergo 1,2-aryl migration to the coordinated nitrogen center, forming a Pd complex containing an Ar–NH unit:
LPd(II)(Ar)X + DPPH
→ LPd(II)(NHAr)(OPOPh₂)
The first C–N bond is formed from the aryl electrophile, Ar–X. Ar′–B subsequently enters the Pd coordination sphere through transmetalation, followed by C–N reductive elimination to generate Ar–NH–Ar′.[1]
The original study conducted a stoichiometric experiment using a Pd complex formed after oxidative addition. In the absence of an arylboronic acid, reaction of this Pd complex with DPPH and base afforded 3% aniline 6d and 25% diarylamine 7d. These results demonstrate that a C–N bond derived from the aryl electrophile can form before the other boronic-acid coupling partner is involved, thereby providing direct evidence for the chemical feasibility of the electrophile-first pathway.[1]
In 2025, Li and Liu extended aminative Suzuki–Miyaura coupling to primary and secondary alkyl boronate esters, achieving C(sp²)–NH–C(sp³) connectivity. Experimental and DFT results for this system further supported the feasibility of forming the C–N bond first from the electrophile-derived aryl group and proposed that this process may proceed through a double-migration-type rearrangement of an LPd(Ar)NHX intermediate.[3]
4.2 Nucleophile-First: The Ar′–B Side Participates in C–N Bond Formation First
The alternative sequence begins from the arylboron reagent.
The original study found that, for certain substrate combinations, the arylboron reagent and DPPH could form a certain amount of arylamine even in the absence of Pd. This gives rise to a formally more direct pathway:
Ar′–B + NH source
→ Ar′–NH₂
Ar′–NH₂ then undergoes Buchwald–Hartwig-type arylation with an Ar–Pd species[1]:
Ar′–NH₂ + Ar–Pd
→ Ar–NH–Ar′
The experiments also showed that the total number of C–N bonds formed on the boronate side increased with Pd loading, while the ratio of the target three-component product to the monoarylamine byproduct changed accordingly. This indicates that C–N bond formation at the boron terminus cannot be explained entirely by Pd-independent electrophilic amination of the arylboron reagent.[1]
On this basis, the original paper proposed a Pd-involved nucleophile-first pathway: an aryl-Pd(II) species, an arylboronic acid, and DPPH can form a combined reaction system in which the Lewis acidity of the metal center increases the electrophilic reactivity of the nitrogen center and promotes aryl migration from B to N. The specific coordination structure is a mechanistic model, but the Pd-loading experiments support the experimental conclusion that “Pd can promote C–N bond formation at the boron terminus.”[1]
4.3 Convergence of Multiple Pathways Rather Than a Fixed Bond-Formation Sequence
The two pathways can be summarized as follows:
Pathway I: Electrophile-first
Ar–X
→ Ar–Pd
→ Ar–N–Pd
→ introduction of Ar′–B
→ Ar–NH–Ar′
Pathway II: Nucleophile-first
Ar′–B
→ Ar′–N
→ combination with the Ar–Pd system
→ Ar–NH–Ar′
The original experiments confirm that both initial C–N bond-formation sequences are feasible.[1] The original paper also explicitly noted that multiple competing mechanisms may operate simultaneously. Subsequent experimental and theoretical studies of different model systems further indicate that the dominant pathway can be influenced by the type of carbon nucleophile, the ligand, and the specific substrate structure.[3–5]
Mechanistic evidence can be divided into three levels:
Conclusion | Nature of Evidence |
t-BuBrettPhos markedly changes the C–N/C–C product ratio | Direct experimental observation |
The electrophile-derived aryl group can form a C–N bond first | Supported by stoichiometric experiments |
The boron terminus can participate in C–N bond formation first, and Pd can promote this process | Supported by byproduct and Pd-loading experiments |
Specific Pd coordination structures, 1,2-migration geometries, and the dominant transition state | Mechanistic models or DFT calculations |
5. Chemical Basis for Migration of Arylboron Reagents to Nitrogen
The nucleophile-first pathway contains a key concept distinct from transmetalation in classical Suzuki–Miyaura coupling: Ar′ in the arylboron reagent need not first transfer from B to Pd; under appropriate conditions, it may instead migrate directly to an electrophilic nitrogen center.
The amino-λ³-iodane-enabled electrophilic amination reported by Kiyokawa, Kawanaka, and Minakata in 2024 provides independent structural-chemical support for this reaction mode.[2] The nitrogen source used in that system differs from DPPH in aminative Suzuki–Miyaura coupling; its significance lies in demonstrating that the fundamental B–N coordination–1,2-aryl migration–C–N bond-formation sequence has a clear experimental and computational basis.[2]
5.1 B–N Coordination Brings the Migrating Aryl Group and Nitrogen into the Same Reactive Unit
The amino group of the amino-λ³-iodane first coordinates to the B center of the arylboronic acid, forming a tetracoordinate boronate-type intermediate:
Ar–B(OH)₂ + amino-λ³-iodane → B–N-coordinated intermediate
The aryl group then undergoes 1,2-migration from B to N, forming a new C–N bond.[2]
This shows that an organoboron reagent need not serve only its traditional role of “transferring an organic group to Pd.” In the presence of a suitably electrophilic nitrogen center and an appropriate coordination structure, it can also act as an Ar→N migration donor.
5.2 Cs⁺ Markedly Changes the Calculated Barrier for 1,2-Aryl Migration
The study used phenylboronic acid as the DFT model. In the absence of Cs₂CO₃, the calculated free-energy barrier for 1,2-aryl migration from the B–N-coordinated intermediate via TS1′ was 39.1 kcal/mol. After addition of Cs₂CO₃, nitrogen was deprotonated and the Cs⁺-involved, stabilized coordination structure INT2 was formed; the corresponding free-energy barrier for migration via TS1 decreased to 12.0 kcal/mol.[2]
The calculated TS1 simultaneously exhibits cleavage of the C–B and N–I bonds and formation of the C–N bond, supporting a concerted 1,2-aryl migration model.[2]
B–N coordination can establish the geometry required for aryl migration to electrophilic nitrogen; an appropriate base and Lewis-acidic cation can markedly alter the energetic requirements of the migration process.
6. Structural Changes, Synthetic Applications, and Applicable Conditions After NH Insertion
6.1 Conversion of Ar–Ar′ to Ar–NH–Ar′ Changes the Connectivity
Conventional Suzuki–Miyaura coupling and aminative coupling produce the following respective frameworks:
Ar–Ar′ and Ar–NH–Ar′
The bond connectivity, local geometry, mode of electron delocalization, and intermolecular interactions all change.
Structural Variable | Ar–Ar′ | Ar–NH–Ar′ |
Bond(s) between the two aryl groups | Direct C–C σ bond | Two C–N bonds |
Bridging atom | None | N |
N–H hydrogen-bond donor | None | Present |
Geometric relationship between the aryl groups | Controlled mainly by the biaryl C–C bond and ortho steric hindrance | Also influenced by the C–N bonds, the geometry of the N center, and aryl substitution |
Electronic structure | The degree of direct conjugation between the two aryl groups is affected by the torsion angle | The nitrogen lone pair can delocalize into the aromatic rings to varying degrees |
Acid–base properties | No amine center | A diarylamine center is introduced, and its properties vary markedly with the electronic effects of the aryl groups |
The N–H group in a diarylamine can act as a hydrogen-bond donor. The hydrogen-bond-accepting ability and basicity of the nitrogen are affected by the electronic effects of the aryl groups, while the overall molecular polarity must also be assessed in light of the specific substituents and conformation.[1]
6.2 Existing Suzuki Coupling Partners Can Be Directly Converted into NH-Insertion Analogues
The synthetic value of this reaction lies primarily in retaining the carbon fragments at both ends while changing how they are connected.
The known synthesis of sonidegib relies on a pair of Suzuki–Miyaura coupling partners. The original study directly used the same pair of partners and, under aminative coupling conditions with DPPH, obtained the NH-insertion analogue 4aj in 33% yield. A related pair of coupling partners used in the synthesis of etoricoxib afforded the modified intermediate 4ak in 50% yield on a 1 mmol scale.[1]
The study also performed late-stage functionalization of complex drugs containing aryl chloride motifs, affording NH-insertion products 4al and 4am from loratadine and fenofibrate in yields of 58% and 75%, respectively.[1]
6.3 Functional-Group Compatibility and Principal Limitations
The original study covered aryl trifluoromethanesulfonates, aryl bromides, aryl chlorides, and some aryl p-toluenesulfonates, and tested multiple classes of heteroaryl groups and functional groups. Nitro, cyano, amide, ketone, ester, and various ortho substituents could be incorporated into the corresponding reactions.[1]
The substrate scope also revealed several classes of limitations with clear chemical origins:
①Some highly electron-deficient, ortho-heteroatom-containing, or polyfluorinated arylboronic acids readily undergo competitive protodeboronation. In the original paper, converting two difficult substrates from the boronic acids to the corresponding Bpin derivatives increased the product yields to 79% and 45%, respectively.[1]
②Coupling is difficult when a pseudohalide is directly attached to certain five-membered heterocycles. The original paper related this behavior to known problems including catalyst deactivation, slower reductive elimination, and base-promoted ring fragmentation.[1]
③A representative substrate containing a primary alcohol gave only 36% yield. Possible competing processes include O-arylation and β-H elimination from Pd(II) alkoxide species.[1]
④Under stronger basic conditions, some aryl trifluoromethanesulfonates undergo competing hydrolysis to phenols. The base and solvent must be matched to the stability of the specific electrophile.[1]
These limitations again point to the same reaction characteristic: aminative Suzuki–Miyaura coupling is not simply an efficiency issue for a single elementary step, but the outcome of competition among C–C coupling, two C–N bond-forming events, deboronation, electrophile decomposition, and catalyst deactivation.
7. Reaction-Design Principles for Insertion of Bridging Components
7.1 Synthetic Variables Expand from “Building-Block Structure” to “Building-Block Connectivity”
When conventional cross-coupling is used to expand structural diversity, new products are often obtained by changing the substitution patterns of Ar–X or Ar′–B:
Ar₁–X + Ar₂–B
Ar₃–X + Ar₂–B
Ar₁–X + Ar₄–B
Aminative Suzuki–Miyaura coupling adds another type of variable:
Ar₁–X + Ar₂–B
→ Ar₁–Ar₂
→ Ar₁–NH–Ar₂
The principal fragments at both ends remain unchanged; what changes is the connecting unit between them.[1]
Further research in 2025 extended this concept from arylboron reagents to primary and secondary alkyl boronate esters, converting conventional C(sp²)–C(sp³) Suzuki connectivity into C(sp²)–NH–C(sp³) connectivity.[3]
This design is particularly suited to synthetic systems with large collections of standardized halide and organoboron building blocks, because the new structural space does not depend entirely on increasing the number of building blocks available for the two termini.
7.2 Reaction Optimization Can Target the Relative Rates of Competing Pathways
The markedly different C–C/C–N selectivities produced by RuPhos and t-BuBrettPhos show that development of the target reaction need not take the form of “accelerating all steps simultaneously.”
A general kinetic relationship is: the proportion of target product depends on the relative rates of the target and competing pathways.
When a new bridging component is introduced into an already highly efficient mature coupling reaction, an effective strategy is to reduce the competitive advantage of the native coupling pathway while maintaining the catalytic activity required for the new pathway to complete the subsequent bond-forming steps.
In the aminative Suzuki–Miyaura system[1,4,5]:
The ligand primarily changes the reactivity of Pd intermediates and the competition between C–C and C–N bond formation;
The base changes the states of the boron reagent, the NH source, and the Pd coordination system;
DPPH provides the NH unit that can participate in two C–N bond-forming events;
The electronic and steric properties of the substrates determine the relative feasibility of the different elementary processes.
This reaction-design approach expands the optimization target from a “single transition state” to the distribution of flux across the entire network of competing reactions.
7.3 Multiple Bond-Formation Sequences Can Converge on the Same Target Structure
Both the electrophile-first and nucleophile-first pathways can lead to Ar–NH–Ar′. Different substrates need not rely on exactly the same mode of first C–N bond formation.[1]
This mechanistic feature also changes the information that can be used during reaction optimization. The conventional Suzuki byproduct reflects competition from the C–C pathway; a monoarylamine reflects formation of a C–N bond on one side without subsequent cross-coupling; and a protodeboronation product reflects insufficient stability of the organoboron reagent. The relative proportions of different byproducts can provide information about where competing steps occur.
In multicomponent coupling, the presence of multiple pathways that converge on the same product does not necessarily mean that the mechanism is uncontrolled. The key question is whether these pathways can collectively maintain cross-selectivity while limiting branches that do not generate the target structure.
7.4 Bridging Components Have Expanded from NH to O and CO + NH
Following the aminative reaction, the same research direction continued to develop different bridging components.
In 2025, Jiang, Kwan, Ping, and Liu reported formal oxygen insertion between Suzuki–Miyaura coupling partners, converting Ar–X and Ar′–B into the diaryl ether Ar–O–Ar′. The reaction uses N-methylmorpholine N-oxide (NMO) to oxidize the arylboron reagent, generating an aryloxyboronic ester intermediate in situ. Mechanistic studies indicated synergistic interplay between the Pd-independent organoboron oxidation step and the subsequent Pd-catalyzed step.[6]
In 2026, Zhou, Raykowski, and co-workers further reported carbonylative aminative Suzuki–Miyaura coupling, using Mo(CO)₆ as the CO source and DPPH as the NH source to insert CO and NH consecutively between conventional Suzuki coupling partners and directly form secondary amides.[7]
This series of reactions establishes a common structural-design relationship[1,6,7]:
Electrophilic coupling partner + nucleophilic coupling partner + bridging component → a new form of connectivity between the two terminal fragments
NH insertion:
Ar–X + Ar′–B + DPPH → Ar–NH–Ar′
O insertion:
Ar–X + Ar′–B + NMO → Ar–O–Ar′
CO + NH double insertion:
Ar/Vinyl–X + Ar′/Vinyl–B + Mo(CO)₆ + DPPH → secondary amide
These subsequent results further show that the outcomes of a mature cross-coupling system need not be expanded only by replacing the electrophile or nucleophile. By introducing bridging components and reorganizing the order and competition of elementary processes such as oxidative addition, migration, transmetalation, and reductive elimination, the same classes of mature building blocks can access new connectivity topologies.
8. Representative Chemicals Related to Aminative Suzuki–Miyaura Coupling: NH Transfer, Catalytic Control, Reaction Media, and Coupling Partners
Table 1. NH-Transfer Reagents and Structurally Differentiated Biarylphosphine Ligands
Classification | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Hydroxylamine-type electrophilic NH-transfer reagent | 72804-96-7 | O-(Diphenylphosphinyl)hydroxylamine | ≥98% | A representative NH source for aminative Suzuki–Miyaura coupling, participating in construction of a C–N–C bridge between two aryl groups; the reactivity of the nitrogen source directly affects aryl migration, C–N bond formation, and competition from conventional C–C coupling. | |
Bulky di-tert-butyl-BrettPhos-type biarylphosphine | 1160861-53-9 | 2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl | ≥97% | A bulky, electron-rich di-tert-butyl biarylphosphine ligand suitable for ligand screening in Pd-catalyzed aminative Suzuki–Miyaura coupling and for controlling C–N/C–C bond-forming selectivity; it can increase the proportion of aminative product formed. | |
Bulky di-tert-butyl-XPhos-type biarylphosphine | 564483-19-8 | 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl | ≥97% | Has bulky di-tert-butylphosphine features similar to t-BuBrettPhos and likewise displayed high aminative coupling selectivity in the original study; it can be used to compare the effect of methoxy substitution on the biaryl framework in pathway control. | |
Dicyclohexyl-BrettPhos-type biarylphosphine | 1070663-78-3 | 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl | ≥97% | Retains the BrettPhos-type methoxy-substituted biaryl framework but uses a dicyclohexylphosphino group; in the original study it formed both aminative product and an appreciable amount of conventional Suzuki product, making it useful for studying how changes in the phosphine alkyl groups affect C–N/C–C chemoselectivity. | |
Dicyclohexyl-RuPhos-type biarylphosphine | 787618-22-8 | 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl | ≥98% | A typical dicyclohexyl biarylphosphine; in the model system of the original study it mainly promoted conventional Suzuki–Miyaura C–C coupling and can serve as a ligand control for comparing competition between the NH-insertion pathway and the native C–C pathway. |
Table 2. Bases and Solvents: Subclassification by Reaction Function and Medium Properties
Classification | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Phosphate inorganic base | 7778-53-2 | Potassium phosphate | Anhydrous grade, ≥98% | The base used in representative conditions for aminative coupling of aryl trifluoromethanesulfonates; used with a t-BuBrettPhos Pd catalytic system and 2-methyltetrahydrofuran in the model reaction and with multiple classes of trifluoromethanesulfonate substrates. | |
Strongly basic hydroxide | 1310-58-3 | Potassium hydroxide | Anhydrous grade, ≥99.95% metals basis | Used in systems involving aryl bromides, aryl chlorides, and pinacol boronate esters; it can promote activation of the boron reagent and regulate conversion in the three-component coupling. When aryl trifluoromethanesulfonates are used, competing hydrolysis must also be controlled. | |
Non-nucleophilic bicyclic organic base | 6674-22-2 | 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) | ≥99% | Can be used under aminative coupling conditions for some aryl trifluoromethanesulfonates and aryl halides, and is suitable for studying the effects of an organic base on activation of the nitrogen-containing reagent, substrate stability, and coupling efficiency. | |
Cesium carbonate promoter/base | 534-17-8 | Cesium carbonate | purum p.a., ≥98% (T) | A key promoter in mechanistic studies of electrophilic amination of arylboronic acids; Cs⁺ participates in stabilization of the B–N coordination system and regulation of the 1,2-aryl migration barrier, providing a related mechanistic reference for initial C–N bond formation at the boron terminus in aminative Suzuki–Miyaura coupling. | |
Ether reaction solvent | 96-47-9 | 2-Methyltetrahydrofuran | Anhydrous grade, ≥99%, unstabilized | The reaction medium used in the standard aminative coupling conditions for aryl trifluoromethanesulfonates in the original study, in combination with K₃PO₄ and a t-BuBrettPhos Pd catalytic system. | |
Polar aprotic nitrile solvent | 75-05-8 | Anhydrous acetonitrile (ACN) | Anhydrous grade, ≥99.8%, H₂O ≤0.003% | A representative reaction medium for aminative coupling of aryl bromides and chlorides that can be used with KOH; electrophile hydrolysis requires attention in strong-base/aryl-trifluoromethanesulfonate combinations. | |
Aromatic hydrocarbon reaction solvent | 108-88-3 | T399633 | Toluene (controlled precursor chemical) | Anhydrous grade, ≥99.8% | Used for aminative coupling of aryl trifluoromethanesulfonates under some DBU or KOH conditions; it can be used to compare the effects of a nonpolar reaction medium on substrate stability and three-component reaction selectivity. |
Table 3. Organoboron Coupling Partners: Subclassification by Electronic Properties, Heteroaryl Structure, and Boronate-Ester Form
Classification | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Unsubstituted reference arylboronic acid | 98-80-6 | Phenylboronic acid (PBA) (contains varying amounts of anhydride) | ≥99.5% | A structurally simple arylboron nucleophile that can serve as a reference substrate for organoboron reactivity; in the amino-λ³-iodane study, it was used in the DFT model of B–N coordination and B→N 1,2-aryl migration. | |
Electron-donating methoxyarylboronic acid | 5720-07-0 | 4-Methoxyphenylboronic acid (contains varying amounts of anhydride) | ≥95% | The para-methoxy group increases the electron density of the aromatic ring and can be used to examine the effects of electron donation on transmetalation of the arylboron reagent, electrophilic amination, and the tendency toward C–N bond formation at the boron terminus. | |
Monofluoro-substituted arylboronic acid | 1765-93-1 | 4-Fluorophenylboronic acid (contains varying amounts of anhydride) | ≥99% | Retains the arylboron reactive site while introducing a para-fluoro substituent; it can be used to construct fluorinated arylamine frameworks and to study halogen functional-group tolerance and electronic effects. | |
Strongly electron-withdrawing trifluoromethyl arylboronic acid | 128796-39-4 | 4-(Trifluoromethyl)phenylboronic acid (contains varying amounts of anhydride) | ≥98% | The model boronic-acid substrate used in reaction development in the original study; combined with 4-methoxyphenyl trifluoromethanesulfonate to establish aminative Suzuki–Miyaura coupling and investigate ligand selectivity. | |
Electron-withdrawing cyano arylboronic acid | 126747-14-6 | 4-Cyanophenylboronic acid (contains varying amounts of anhydride) | ≥97% | The cyano group exerts a pronounced electron-withdrawing effect and can serve as a site for subsequent functional-group transformations. It is suitable for studying the coupling reactivity of electron-deficient arylboron reagents and cyano-group tolerance under C–N–C construction conditions; the substrate scope in the original study confirmed that cyano groups are compatible. | |
Strongly electron-withdrawing nitro arylboronic acid | 24067-17-2 | 4-Nitrophenylboronic acid (contains varying amounts of anhydride) | ≥95% | The nitro group markedly lowers the electron density of the aromatic ring and can be used to study C–N bond formation, competing deboronation, and functional-group tolerance with electron-deficient arylboron substrates; the original study confirmed that nitro-containing substrates can participate in the aminative coupling. | |
Nitrogen-containing heteroarylboronic acid | 1692-25-7 | Pyridine-3-boronic acid (contains varying amounts of anhydride) | ≥98% | The pyridine nitrogen can alter the electronic properties of the heteroaryl group and engage in coordination interactions with the metal center. This reagent is suitable for evaluating the reactivity, catalyst compatibility, and deboronation tendency of heteroarylboron reagents in Pd-catalyzed C–N–C construction. | |
Stable aryl pinacol boronate ester | 24388-23-6 | Phenylboronic acid pinacol ester | ≥98% | Exhibits hydrolysis and transmetalation behavior different from that of the free boronic acid; the original study demonstrated that aryl Bpin reagents can enter aminative coupling under KOH conditions and can improve the performance of some substrates prone to competing deboronation. |
Table 4. Aryl Electrophilic Coupling Partners: Subclassification by Leaving-Group Type and Arene Electronic Properties
Classification | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Electron-rich aryl trifluoromethanesulfonate | 66107-29-7 | 4-Methoxyphenyl trifluoromethanesulfonate | ≥97% (GC) | The model aryl electrophile used for reaction development and ligand screening in the original study; combined with 4-(trifluoromethyl)phenylboronic acid and DPPH to form a representative three-component system for comparing conventional C–C coupling with the NH-insertion C–N–C pathway. | |
Electron-rich aryl bromide | 104-92-7 | p-Bromoanisole | ≥99% | A methoxy-substituted aryl bromide that can serve as an electron-rich Ar–Br electrophilic partner for studies of Pd oxidative addition, aminative coupling of aryl bromides, and electronic effects. | |
Electron-rich aryl chloride | 623-12-1 | 4-Chloroanisole | ≥99% | Combines the electron-donating effect of a methoxy group with a relatively less reactive C–Cl bond and can be used to compare oxidative addition and three-component C–N–C construction conditions for aryl chlorides and aryl bromides. | |
Electron-withdrawing cyano aryl bromide | 623-00-7 | 4-Bromobenzonitrile | ≥97% (GC) | The cyano group lowers the electron density of the aromatic ring, while C–Br can serve as the Pd oxidative-addition site; this reagent is suitable for aminative coupling of electron-deficient aryl electrophiles and studies of cyano-group functional-group tolerance. | |
Electron-withdrawing cyano aryl chloride | 623-03-0 | p-Chlorobenzonitrile | ≥98% | Combines an electron-withdrawing cyano group with a C–Cl reactive site and can be used to study the oxidative addition of electron-deficient aryl chlorides, ligand dependence, and the conditions required for participation of aryl chlorides in C–N–C coupling. |
Note: The products listed above are representative Aladdin research-related products. Their specific use should be determined in conjunction with the product specifications, batch COA, and the target 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
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