Baldwins Cyclization Rules

Whereas the cyclization of chalcones or analogous compounds leads to six-membered rings, in accordance with the Baldwin rules [182], the same reaction with a triple bond can afford compounds with six-membered (6-endo-dig) or five-membered (5-exo-dig) rings, depending on the reaction conditions. This property... 

While the Baldwin rules [44] indicate both 5-exo-tri and 6-endo-in modes of cycliz-ation are favorable, only the latter is observed in the following reaction [45]. 

According to the Baldwin rule, the exo cyclization mode is favored in intramolecular reactions of alkynyloxiranes with alcohols to afford cyclic ethers. However, the unfavorable endo cyclization mode is observed by the complexation. Thus exclusive endo cyclization of epoxide complex 146 takes place regioselectively to give 147, without forming the five-membered ether 148 by exo mode reaction [37]. 

In summary, certain reactions with diterpenoid alkaloid imines proceeded by a disfavored 5-endo-trigonal process, whereas in other cases, such as the reactions with glycidol, a favored 6-endo-trigonal process was followed. The Baldwin rules should be modified to accomodate the exceptional behavior of the tertiary immonium salts. Recently, examples of similar reactions demonstrating the violation of the Baldwin cyclization rules have been reported (156-158). 

Cyclocondensation reactions starting from two components are possible only when both have two reactive centers. By far the most common version is an initial electrophilic/nucleophilic interaction yielding a linear product, followed by a second electrophilic/nucleophilic interaction in the final cyclization step (85MI2). The ring-forming condensation step is controlled by a series of rules (Baldwin rules 76CC734). There are various types of such interactions (Scheme 19). 

Generation of a radical in a molecule that contains a site of unsaturation presents an opportunity for (yclization. These types of radical cyclizations have been developed into very useful synthetic reactions. The synthetic utility of these cyclizations is enhanced by the abhity to predict the regiochemistry of cyclization by applying the Baldwin rules. The Baldwin rules cover the formation of three- to seven-membered rings by various reactions and are based on consideration of both kinetic and thermodynamic factors. (See Beckwith, A. L. J. Easton, D. J. Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482-483, and Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.)... 

It should be noted that the radical cyclization proceeds to yield a five-membered ring and not a six-membered one. This is predicted by the Baldwin rules for ring-closure and is classified as a 5-exo-trig closure ". LiAlH4 has also been used to generate the cyclopropyl radical which also underwent a 5-exo-trig ring-closure. ... 

These findings have been rationalized by the rule offive (Srinivasan and Carlough, 1967), according to which five-membered cyclic biradicals are preferentially formed, as shown in Scheme 15. (Cf. also the Baldwin rules for radical cyclizations, Baldwin, 1976.)... 

Piccirilli, J. A. Do enzymes obey the Baldwin rules A mechanistic imperative in enzymic cyclization reactions. Chem. Biol. 1999, 6, R59-R64. 

These types of intramolecular cyclizations offer an excellent opportunity to test the Baldwin rules <76CC734> for ring closure. Such studies have been undertaken on furans and pyrroles carrying a (CH2) -epoxyalkyl tether at the 3-position of the furan and 1-position of the pyrrole, respectively (Scheme 9) <83JOC4572, 87JOC819). 

Epoxy-arene cyclizations have been studied extensively by Taylor et al. <87JOC425>. The reaction to give six-membered rings can be specific (Scheme 10). The yields for (3) and (4) are lower than for (2), and this is in accord with the Baldwin rules the former reaction is exo, whereas the latter reactions are endo. 

In a classic 1976 paper, Baldwin used the Biirgi-Dunitz trajectory to define the well-known rules for the design of cyclizations (the Baldwin rules). However, stereoelectronic factors for a bond formation to alkynes have been controversial. Originally, the rules for alkyne cyclizations were based on the assumption that nucleophiles add to alkynes along an acnte trajectory, instead of the obtuse Biirgi-Dunitz angle of attack. Subsequent experimental and computational analysis suggested that this trajectory is stereoelectronically... 

Alabugin, I. V., Timokhin, V. I., Abrams, 1. N., Manoharan, M., Ghiviriga, L, Abrams, R. (2008). In Search of Efficient 5-Endo-dig Cyclization of a Carbon-Centered Radical 40 Years from a Prediction to Another Success for the Baldwin Rules. Journal of the American Chemical Society, 130, 10984-10995. 

Intramolecular Mizoroki-Heck reactions via S-cndo-cyclization, disfavoured according to the Baldwin rules, are by far not as common as the cxo-cyclic variant. There are, nevertheless, some cases where this cyclization type can occur, notably when substrates of substructure E (Figure 6.3) are used in the presence of Mizoroki-Heck conditions. 

The B aldwin rules indicate which cyclizations of acyclic precursors are favored and which are not [6-8]. It is important to note the substantial difference to the Woodward-Hoffimann mles [9-11], based on the theoretical concept staling which reactions are "allowed and which are forbidden by the orbital symmetry. The Baldwin rules are based on experimental observations and indicate the relative prrf-erence of the acyclic precursor to form cyclic compounds. Therefore, the expressions favored" and disfavored" indicate enCTgetically convenient and inconvenient cyclization. These rules refer predominantly to nucleophilic intramolecular reactions where the nucleophile approaches the C atom, which can be tetrahedral (tet, sp ), trigonal (trig, sp ) or diagonal (dig, sp). Based on experimental experience, they provide a particularly important guide for synthetic organic chemists. 

On the other hand, cyclization to TM 7.8 requires the approach of the nucleophile under a small angle, approximately 90°, and the endb-position of the double bond, both stereoelectronically unfavorable. Generally, the Baldwin rules state that cyclization to a five-membered ring is favored when the reacting double bond on the trigonal C-atom is exo and disfavored when it is endo. In Table 7.1, the Baldwin... 

Table 7.1 Baldwin rules for favored and disfavored cyclizations...

Scheme 7.16 Cyclization to TM 7.10 is disfavored according to the Baldwin rules...

The next three examples refer to syntheses of generic drugs developed by technological processes by chemists at the PLIVA Co. (Croatia). In all three examples, the heterocyclic unit is formed on cyclization according to the Baldwin rules. Since they were not postulated at the time these processes were developed, the authors might only speculate why they are Tavored ... 

Let us now reconsider the cyclization of the isoxazole derivative on the route to sulfisoxazole TM 7.2, Scheme 7.4. Cyclization to TM 7.2b mns under slighdy basic conditions and follows the Baldwin rules. The intermediary anion of ketoxime approaches as a nucleophile cyano group in the favored 5-exo-dig path (Scheme 7.23). 

Further uses of tricarbonylcyclohexadienylium iron complexes have appeared throughout the year. Spirocyclization of the complex (5) by triethylamine at -78 C leads to the product arising from carbon-carbon coupling, whereas the complex (6) gave exclusive cyclization via the oxygen atom, in accord with Baldwin rules (Scheme 12). 

The predictions for cyclization developed by Baldwin ( ) are rather vague when applied to these mercury initiated cyclizations. The rules, as stated for nucleophilic attack on 3-membered rings, "seem to lie between those for tetrahedral and trigonal systems, generally preferring exo modes." From our limited observation of peroxide attack on the three-membered ring mercurinium... 

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