β-Hydrogen elimination and transmetalation from aliphatic compounds are regarded as bottlenecks, in the field of C-C bond formation between aromatic and aliphatic compounds (C(sp²)-C(sp³) cross-coupling reactions). Recently, a variety of C(sp²)-C(sp³) cross-coupling reactions utilizing the combination of visible light photoredox catalysts and transition metal catalysts like nickel catalysts have been reported.^1,2) Moreover, reductive cross-electrophile coupling (CEC) between aryl halides and alkyl halides enabled reproductive introduction of alkyl groups into (hetero)aromatic compounds. Alkyl halides,^3-6) alkylcarboxylic acids,^7-10) and alkyl amines^11,12) can be applied as coupling partners in these reactions. They are easier to find commercially than organozincs, organoboronic acids and Grignard reagents. Additionally, compared to organometal reagents, there are numerous benefits in terms of costs, stability, safety and handling.

Organometallic Reagents	Halides, Carboxylic Acids and Amines
Competitive side-reactions could proceed such as β-hydride elimination, demetallative protonation and so on. Unstable and difficult to handle due to sensitivity to air and water. Expensive and less available commercially. Few options of substituents. Reliable in the case of C(sp2)-C(sp2) cross-coupling.	Commercially available and inexpensive. Rich choice of substituents leading to diverse library. Stable and storable

Below are examples of representative C(sp²)-C(sp³) cross-coupling reactions using alkyl halides, alkyl carboxylic acids and alkyl amines as coupling partners. To learn more about detailed conditions, kindly refer to the original literature.

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Reductive Cross-Electrophile Coupling (CEC)

Reductive cross-electrophile couplings are nickel-catalyzed reactions between aryl halides and alkyl halides in the presence of reductants. These can be classified into two types; reactions promoted by Iridium photoredox catalysts and reactions using metals as reductants.

X	Y	Reagents and Conditions	Reference
Cl	Cl (primary alkyl chlorides, secondary alkyl chlorides)	Ir[(ppy)2(dtbbpy)]PF6 [D4887] (cat.), NiCl2(DME) [N1051] (cat.), 2,2’-Biimidazole [B2487] (cat.), N-(Adamantan-1-yl)-1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-amine [A3462], TMG [T0148], DMA / tert-Amyl alcohol, 34W blue LED, 55 °C	3)
Br	Br (primary alkyl bromides, secondary alkyl bromides)	Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.), NiCl2(DME) [N1051] (cat.), dtbbpy [D3134] (cat.), TTMSS [T1463], Na2CO3 [S0560], DME, 34W blue LED, 25 °C	4)
Br	Br (primary alkyl bromides, secondary alkyl bromides)	NiCl2(DME) (cat.), PyBCam·2HCl [P3015] (cat.), Zn [Z0015], TFA [T0431], NaI [S0564], DMA, 60 °C	5)
Cl	Cl (primary alkyl chlorides, secondary alkyl chlorides)	NiBr2(DME) [N1298] (cat.) or NiI2·xH2O (cat.), PyBCamCN [D6070] (cat.), Zn [Z0015], LiCl [L0204], NMP, 80 °C	6)

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Decarboxylative Cross-Coupling

Decarboxylative cross-couplings is a reaction to connect aryl halides and alkyl carboxylic acids. Though alkyl carboxylic acids require hetero atoms at α-position for good yields, use of phthalimide [P0402] as an additive⁸⁾ and N-hydroxyphthalimide [H0395] as an activator¹⁰⁾ can improve reactivity. Additionally, bond formations between carbon atoms and heteroatoms as well as carbon-carbon bond formations have been developed.⁹⁾ These reactions allow the N-alkylation of aromatic compounds containing nitrogen as well as the N-monoalkylation of carboxylic amides.

X	R2-COOH	Reagents and Conditions	Reference
Br	α-Heteroatom-substituted alkylcarboxylic acids	Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.), NiCl2(DME) [N1051] (cat.), dtbbpy [C2160] (cat.), Cs2CO3 [A3462], DMF, 26W CFL light, 23 °C	7)
Br	Primary alkylcarboxylic acids, Secondary alkylcarboxylic acids	Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.), NiCl2(DME) [N1051] (cat.), dtbbpy [D3134] (cat.), Phthalimide [T1463], BTMG [B6052], DME, 34W blue LED, 25 °C	8)
I, Br	Tertiary alkylcarboxylic acids	N-Hydroxyphthalimide [H0395] (cat.), NiBr2(DME) [N1298] (cat.), tBuBpyBCamCN [C3803] (cat.), Zn [Z0015], DMA, rt	10)

N-H	R2-COOH	Reagents and Conditions	Reference
Azaarenes	Primary alkylcarboxylic acids, Secondary alkylcarboxylic acids	Ir[(FMeppy)2(dtbbpy)]PF6 [B6258] (cat.), CuTC [C2312] (cat.), Bathophenanthroline [B6258] (cat.), Iodomesitylene Diacetate [I0479], Dioxane, blue LED, rt	9)

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Deaminative Cross-Coupling (C-N Bond Activation)

Alkyl amines can be utilizsed as coupling partners in C(sp²)-C(sp³) cross-coupling reactions, where they can be activated as pyridinium salts (Katritzky salts) by a pyrylium salt [T3968] beforehand.¹¹⁾ Primarily, this method can be mainly applied to primary and secondary alkyl amines. However, the 2,4,6-trimethoxybenzaldehyde [T2651] can be used to activate bulky tertiary alkyl groups into electron-rich imines.¹²⁾ Iridium photoredox catalyst is utilized in C-N bond activation.

X	R2-NH2	Reagents and Conditions	Reference
Br	Primary alkylamines, Secondary alkylamines	NiCl2(DME) [N1051] (cat.), diOMebpy [D3886] (cat.), Mn, 2,4,6-Triphenylpyrylium Tetrafluoroborate [T3968], MgCl2, NMP, 80°C	11)
Br	Tertiary alkylamines	Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.), Ni(TMHD)2 (cat.), 2,4,6-Trimethoxybenzaldehyde [T2651], TBAC [T0055], K2HPO4, DMSO, rt	12)

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Reagents

Iridium Complexes

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Nickel Catalyts and Copper Catalysts

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Ligands

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Activators and Bases

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Silane Reagents and Reductants

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Building Blocks

It is difficult to find the suitable building blocks because of extremely large number of products. In the phase of structure activation relationship research, adding inappropriate alkyl groups to drug candidates will cause an increase in molecular weight and lipophilicity. Finally, this could result in decreased oral absorption and an off-target effect, which would force the withdrawal of late-stage developments.
As indicators of ideal building blocks, 'Rule of 2' was put forward on the basis of estimable physical parameters.¹³⁾ According to the rule, good building blocks are regarded as good ones with molecular weight < 200, logP < 2, hydrogen bond donor (HBD) < 2 and hydrogen bond acceptor (HBA) < 4. We have extracted proper TCI's building blocks satisfying the Rule of 2, which can be used as coupling partners of C(sp²)-C(sp³) cross-coupling. Additionally, we have prepared SDF files of products whose core structures satisfy the Rule of 2 for your comparison and selection in your research.

Reaction	Building Blocks		SDF File
Reductive Cross-Electrophile Coupling	Alkyl Iodides (25 items)		Download
	Alkyl Bromides (169 items)		Download
	Alkyl Chlorides (174 items)		Download
Decarboxylative Cross-Coupling	Alkyl Carboxylic Acids (185 items)		Download
Deaminative Cross-Coupling	Alkyl Amines (227 items)		Download

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The following shows the table of calculated average value and histograms of 465 core structures possible to be introduced by C(sp²)-C(sp³) cross-coupling. The PMI (principal moment of inertia) plot is known as one of the methods to visualize three-dimensionality of structures.¹⁴⁾ When a dot is plotted into top-right zone, its structure is likely to be spherical.

Physicochemical Parameter	Calculated Value	Ideal Value Based on Rule of 2
Molecular Weight (MW)	115.61±36.02	< 200
MolLogP	1.13±0.66	< 2
Fraction of sp3 carbon atoms (Fsp3)	0.66±0.33	─
Rotatable Bond Count (RBC)	1.48±1.47	─
Hydrogen Bond Acceptor (HBA)	1.77±1.03	≤ 4
Hydrogen Bond Donor (HBD)	0.43±0.65	≤ 2
Topological Polar Surface Area (TPSA)	24.67±15.68	─

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References

• 1) Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis
  • A. Y. Chan, I. B. Perry, N. B. Bissonnette, B. F. Buksh, G. A. Edwards, L. I. Frye, O. L. Garry, M. N. Lavagnino, B. X. Li, Y. Liang, E. Mao, A. Millet, J. V. Oakley, N. L. Reed, H. A. Sakai, C. P. Seath, D. W. C. MacMillan, Chem. Rev. 2022, 122, 1485.
• 2) Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)−C(sp³) Cross-Coupling Methods by Library Synthesis
  • A. W. Dombrowski, N. J. Gesmundo, A. L. Aguirre, K. A. Sarris, J. M. Young, A. R. Bogdan, M. C. Martin, S. Gedeon, Y. Wang, ACS Med. Chem. Lett. 2020, 11, 597.
• 3) Cross-Electrophile Coupling of Unactivated Alkyl Chlorides
  • H. A. Sakai, W. Liu, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2020, 142, 11691.
• 4) Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling
  • P. Zhang, C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138, 8084.
• 5) Coupling of Challenging Heteroaryl Halides with Alkyl Halides via Nickel-Catalyzed Cross-Electrophile Coupling
  • E. C. Hansen, C. Li, S. Yang, D. Pedro, D. J. Weix, J. Org. Chem. 2017, 82, 7085.
• 6) Nickel-Catalyzed Cross-Electrophile Coupling of Aryl Chlorides with Primary Alkyl Chlorides
  • S. Kim, M. J. Goldfpogel, M. M. Gilbert, D. J. Weix, J. Am. Chem. Soc. 2020, 142, 9902.
• 7) Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp³-carbons with aryl halides
  • Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D. W. C. MacMillan, Science 2014, 345, 437.
• 8) Accelerating reaction generality and mechanistic insight through additive mapping
  • C. N. P. Kullmer, J. A. Kautzky, S. W. Krska, T. Nowak, S. D. Dreher, D. W. C. MacMillan, Science 2022, 376, 532.
• 9) Decarboxylative sp³ C-N coupling via dual copper and photoredox catalysis
  • Y. Liang, X. Zhang, D. W. C. MacMillan, Nature 2018, 559, 83.
• 10) Control of Redox-Active Ester Reactivity Enables a General Cross-Electrophile Approach to Access Arylated Strained Rings
  • D. C. Salgueiro, B. K. Chi, I. A. Guzei, P. G. Reynaga, D. J. Weix, Angew. Chem. Int. Ed. 2022, 61, e202205673.
• 11) Deaminative Reductive Cross-Electrophile Couplings of Alkylpyridinium Salts and Aryl Bromides
  • J. Liao, C. H. Basch, M. E. Hoerrner, M. R. Talley, B. P. Boscoe, J. W. Tucker, M. R. Garnsey, M. P. Watson, Org. Lett. 2019, 21, 2941.
• 12) Photoredox-Catalyzed Deaminative Alkylation via C-N Bond Activation of Primary Amines
  • M. A. Ashley, T. Rovis, J. Am. Chem. Soc. 2020, 142, 18310.
• 13) Designing novel building blocks is an overlooked strategy to improve compound quality
  • F. W. Goldberg, J. G. Kettle, T. Kogej, M. W. D. Perry, N. P. Tomkinson, Drug Discov. Today 2015, 20, 11.
• 14) Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity
  • W. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comput. Sci. 2003, 43, 987.

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Related Product Category Pages

• Visible Light Photoredox Catalysts
• Nickel Catalysts [Cross-coupling Reaction using Transition Metal Catalysts]
• Copper Catalysts [Cross-coupling Reaction using Transition Metal Catalysts]
• Pyridine Ligands
• Bipyridine Ligands, Terpyridine Ligands
• Phenanthroline Ligands

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