Synthesis of Carbamates and Ureas

In the previous chapter, we have discussed the catalytic systems leading to the direct synthesis of isocyanates. However, these processes are all plagued by insufficient selectivities, mainly due to self-condensation reactions of the product isocyanates [1]. In order to avoid this problem, most of the catalytic systems for the carbonylation of nitro compounds developed in the last years affords carbamates (RNHCOOR ) or ureas (RNHC(O)NHR) as products (eqs. 1,2)  

In the synthesis of ureas, an amine corresponding to the nitro compound employed is commonly used, but exceptions exists that will be discussed later. A different stoichiometry for eq. 2 is also possible (see later and Chapter 6). As for the synthesis of isocyanates, these reactions are essentially limited to aromatic nitro compounds, but the added amine may also be an aliphatic one. 

The reaction between an alcohol or an amine with an isocyanate is an exothermic reaction that, at least for aromatic isocyanates, occurs even in the absence of any catalyst, although Lewis acids such as BF3, ZnCL and others and even Lewis bases are known to accelerate it [2-6]. Under typical catalytic conditions, no catalyst for the condensation reaction is needed and isocyanates are never observed among the products if an excess of an alcohol or an amine is also present in the reaction medium. 

If the isocyanate is the desired product, carbamates can be then thermally decomposed to isocyanate and alcohol, a process that, analogously to the reverse reaction, can occur even without a catalyst (at 230-280 °C [7-12]), but which can also be catalysed by Lewis acids or metal oxides or other substances which probably afford metal oxides under the reaction conditions [8, 11, 13]. The reaction is a quite general one and it occurs even for the simplest of all carbamates, H2NC(0)0Et, which affords isocyanic acid when heated at 400 [14], In a typical process [11], diethyl-/ -toluen-2,4-dicarbamate is heated at 250 °C in hexadecane as solvent and in the presence of Mo(CO)s. Dinitrogen is continuously introduced into the reactor to remove the ethanol overhead. By this procedure, recombination of the isocyanate with ethanol is minimised. A further 

Carbamates can also be modified by transesterification [15, 16], An important example of this last reaction, which is already applied on an industrial scale for the synthesis of plasticizers, is the direct synthesis of polyurethanes from alkyl aryldicarbamates and diols, without the need for producing the diisocyanate at any stage of the process [16], 

---

Palladium-phenanthroline catalytic systems, which have been developed in the last decade, appear to be the most promising catalytic systems for possible industrial applications, due to their high activity, versatility and lack of corrosion problems. These systems can afford several products in excellent yields, depending on the reagents used together with the nitro compound. Their use for the synthesis of isocyanates and heterocyclic compound is discussed in Chapters 2 and 5 respectively. In this chapter, only the synthesis of carbamates and ureas (including acylureas) will be discussed. 

As previously mentioned in paragraph 3.2.1., many patents on the use of palladium-based catalytic systems containing a metallic cocatalyst also mention the use of rhodium compounds (usually RhCL) in place of PdCL, but lower yields are always reported. We will not mention again here the same patents and will discuss only the systems for which a rhodium compound is explicitly mentioned as the, or the best, catalyst. Compared to the number of patents dealing with palladium compounds and metal-containing cocatalysts, the number of reports on similar rhodium-based systems is much more limited, confirming that, at least for the synthesis of carbamates and ureas, the combination of... 

Very little has been done on the use of iron compounds in the synthesis of carbamates and ureas from nitro compounds. It has long been known [191] that heating aliphatic nitro compounds with an excess of Fe(CO)s (1.4 mol for 1.0 mol of nitro compound) in diglyme at 120-132 °C for 15-17 h affords low yields of formamides and ureas, but the yield of urea is at best 18.5 % (in the case of nitrocyclohexane yields were even lower for 1- or 2-nitropropane, 2-methyl-2-nitropropane, and 1-nitroadamantane). These experiments were among the first... 

As already discussed in previous chapters, some of the catalytic systems can produce both isocyanates and carbamates (or ureas) depending on the experimental conditions, whereas others only produce carbamates or ureas, but no isocyanate. When considering the synthesis of carbamates and ureas, one may expect isocyanates to be intermediates in the first type of catalytic system, but not in the second. However, this is not always true and the situation is more complex, as it will be reported in more detail in the discussion of the individual systems. 

Anilines are virtually always present as by-products, however, in some cases, they are also intermediates in the synthesis of carbamates and ureas. This last possibility will be discussed in more detail for the individual catalytic systems. When the aniline is a by-product, the necessary hydrogen atoms can originate from small amounts of water or H2 present as impurities in the solvent and/or the CO gas, but can also be produced by alcohol dehydrogenation (when an alcohol is present) or, to a minor extent, by direct hydrogen-atom abstraction from the solvent or from the nitro compound itself. Among primary alcohols, methanol is the less prone to be dehydrogenated [8]. 

Several other metal catalysts have also heen identified for use in this reaction. For example, catalytic zirconium te/t-butoxide is used in conjunction with 1-hydroxybenzotriazole (HOBt) or l-bydro3gr-7-azabenzotriazole (HOAt) as additive in order to achieve high yields in 4 hours in toluene. In addition, this same catalytic system can be applied to tbe synthesis of carbamates and ureas from carbonates, whereby substitution of only one ester moiety occurs. In this instance, the addition of methyl hydroxyquino-line (MeHYQ) is required. Although reaction times for this catalyst appear to be short and eliminate the need for the harsh conditions presented by acid or base catalysis, the additive is costly and high temperatures of 100 °C are still required. Other metal catalysts include Inlg and Cp 2Sm(THF)2 which also show potential in catalysing this reaction. 

---