There are basically four different ways to construct the C₅ skeleton from smaller carbon units, two of which are still being used commercially:
1.Addition of acetone to acetylene to form 2-methyl-3-butyne-2-ol followed by partial hydrogenation and dehydration.
2.Dimerization of propene to isohexene followed by demethanation.
3.Double addition of formaldehyde to isobutene resulting in 4,4-dimethyl-1 ,3-dioxane followed by dehydration and cleavage of formaldehyde.
4.Dismutation of isobutene and 2-butene to form 2-methyl-2-butene followed by dehydrogenation.

The acetone-acetylene process was developed by Snamprogetti, and was used in a 30000 tonne-per-year plant in Italy until 1982. In the first step, acetone and acetylene are reacted together at 10-40°C and 20 bar in liquid ammonia, with KOH as the catalyst. The product methylbutynol is selectively hydrogenated to methylbutenol, which is dehydrated at 250-300 °C on Al₂O₃ at atmospheric pressure to give :



Overall selectivity to isoprene is 85% (based on CH₃COCH₃, C₂H₂).

The Goodyear-Scientific Design process operates according to the second principle, the isohexene route. The dimerization of propene on a Ziegler catalyst (e.g., tri-n-propylaluminum) leads to the formation of 2-methvl-1-oentene. which is then isomerized to 2-methyl-2-pentene with a supported acidic catalyst. This can be cracked with superheated steam and catalytic amounts of HBr at 650-800 °C to give isoprene and methane:



Isoprene selectivity is about 50% (based on propene).

Goodyear operated a plant in Texas for several years using this process. It was shut down for economic reasons.

The third route with m-dioxane as intermediate has been extensively studied and also developed into industrial processes by various companies (Bayer, IFP, Marathon Oil, Kuraray and in the CIS).

The first step is a Prins reaction between formaldehyde and isobutene. It takes place in the presence of a strong mineral acid such as H₂SO₄ or on acidic ion-exchangers at 70-95°C and about 20 bar. Aqueous formaldehyde reacts with the isobutene present in a butadiene-free C, fraction to form 4,4-dimethyl-1,3-dioxane:

In the next step, the dioxane derivative is cracked at 240-400°C on a H₃PO₄/charcoal or Ca₃(PO₄)₂ catalyst in the presence of additional water:



The total selectivity to isoprene is about 77% (based on isobutene).

Polyols are formed as byproducts in both steps, and the amounts formed strongly influence the economic viability. Kuraray operates a 30000 tonne-per-year plant in Japan using this process. Kuraray also uses the 4,4-dimethyl-l,3-dioxane to manufacture 3-methyl-3-methoxybutanol, an economical solvent, by selective hydrogenolysis:

There are also several plants operating in the CIS and Eastern Europe. Recently, several firms have made proposals to simplify the process and improve the profitability of the m-dioxane route.

According to Takeda Chemical, isoprene can be manufactured from isobutene and formaldehyde in the gas phase at 300 °C and 1 bar in a single-step process with catalysts such as oxides of silicon, antimony or the rare earths. Instead of formaldehyde, Sun Oil proposes using methylal H₂C(OCH₃)₂ for the single-step reaction with isobutene, since it is more stable than formaldehyde and less decomposes into CO+H₂. e, another formaldehyde source, has been suggested by Sumitomo Chemical.

Another improvement and simplification is also said to result from Sumitomo Chemical's single-step reaction of isobutene with methanol and O₂ which goes through a formaldehyde intermediate:



H₃PO₄-MoO₃/SiO₂ and mixed oxide systems based on Mo-Bi-P-Si, Mo-Sb-P-Si, or H₃PO₄-V-Si are the catalysts used. At 250 °C, the isobutene conversion is 12%, with selectivity to isoprene of 60% (based on isobutene) and 40% (based on methanol). Most of the methanol is oxidized to formaldehyde.

The potential advantages of this process, such as less expensive C₁ components and the lower investment costs of a single-step process, are still to be confirmed in an industrial plant.

The fourth synthetic route to an isoprene precursor has not yet been employed industrially although it is the subject of great interest. This method is analogous to the dismutation of propene to 2-butene and ethylene developed by Phillips and extended by other firms. In this case, a dismutation takes place between isobutene and 2-butene. These starting materials can be obtained from the butadiene raffinate:



The resulting 2-methyl-2-butene can be dehydrogenated to isoprene.