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C(sp2)-C(sp3) Cross-Coupling Reactions for Drug Discovery

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 amines11,12) 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.

C(sp2)-C(sp3) Cross-Coupling Reaction

Organometallic Reagents Halides, Carboxylic Acids and Amines
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.

Reductive C(sp2)-C(sp3) Cross-Electrophile Coupling (CEC)

X Y Reagents and Conditions Reference
Cl Cl
(primary alkyl chlorides,
secondary alkyl chlorides)
Ir[(ppy)2(dtbbpy)]PF6 [D4887] (cat.),
NiCl2(DME) (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
Br Br
(primary alkyl bromides,
secondary alkyl bromides)
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.),
NiCl2(DME) (cat.),
dtbbpy [D3134] (cat.),
TTMSS [T1463],
Na2CO3 [S0560],
DME, 34W blue LED, 25 °C
Br Br
(primary alkyl bromides,
secondary alkyl bromides)
NiCl2(DME) (cat.),
PyBCam·2HCl (cat.),
Zn [Z0015],
TFA [T0431],
NaI [S0564],
DMA, 60 °C
Cl Cl
(primary alkyl chlorides,
secondary alkyl chlorides)
NiBr2(DME) [N1050] (cat.) or NiI2·xH2O (cat.),
PyBCamCN (cat.),
Zn [Z0015],
LiCl [L0204],
NMP, 80 °C

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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.

Decarboxylative C(sp2)-C(sp3) Cross-Coupling

X R2-COOH Reagents and Conditions Reference
Br α-Heteroatom-substituted alkylcarboxylic acids Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.),
NiCl2(DME) (cat.),
dtbbpy [C2160] (cat.),
Cs2CO3 [A3462],
DMF, 26W CFL light, 23 °C
Br Primary alkylcarboxylic acids,
Secondary alkylcarboxylic acids
Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [D5817] (cat.),
NiCl2(DME) (cat.),
dtbbpy [D3134] (cat.),
Phthalimide [T1463],
BTMG [B6052],
DME, 34W blue LED, 25 °C
I, Br Tertiary alkylcarboxylic acids N-Hydroxyphthalimide [H0395] (cat.),
NiBr2(DME) [N1050] (cat.),
tBuBpyBCamCN (cat.),
Zn [Z0015],
DMA, rt

Decarboxylative C(sp2)-C(sp3) Cross-Coupling of azaarenes and alkylcarboxylic acids

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

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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.

Deaminative C(sp2)-C(sp3) Cross-Coupling

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

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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) Alkyl Iodides Download
Alkyl Bromides (169 items) Alkyl Bromides Download
Alkyl Chlorides (174 items) Alkyl Chlorides Download
Decarboxylative Cross-Coupling Alkyl Carboxylic Acids (185 items) Alkyl Carboxylic Acids Download
Deaminative Cross-Coupling Alkyl Amines (227 items) Alkyl Amines 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

Molecular Weight (MW) of 465 building blocks

MolLogP of 465 building blocks

Fraction of sp3 carbon atoms (Fsp3) of 465 building blocks

Rotatable Bond Count (RBC) of 465 building blocks

Hydrogen Bond Acceptor (HBA) of 465 building blocks

Hydrogen Bond Donor (HBD) of 465 building blocks

Topological Polar Surface Area (TPSA) of 465 building blocks

PMI (principal moment of inertia) plot of 465 building blocks

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