Chemical synthesis of organic compounds is one of the fundamental components of the natural sciences in which the state of the art has a significant impact on many areas of science and technology. Increasing the efficiency of the syntheses of organic compounds, especially complex structures, as well as reducing the labor intensity required, creates a favorable basis for the accelerated emergence of qualitative new research results and their use in practice, especially in medicine, agriculture, and the sustainable preservation of habitats. For almost two centuries, numerous methodologies for the selective creation of various structural elements of organic compounds have been developed and applied to the synthesis of millions of individual substances. Nevertheless, in the preparation of organic compounds even of relatively simple structure, there are often obstacles to overcome that require a significant investment of both mental and physical labor. This has led organic chemists to identify new types of transformations of organic compounds, as well as to develop new reagents and catalysts for their effective and reliable implementation. A fruitful choice for such studies are cyclopropane compounds that are found in nature [1–3], and possess important and diverse biological activities [4–9], including their involvement in important biochemical processes [10–12].

In the development of efficient methods for the synthesis of cyclopropane derivatives considerable effort has been expended and impressive results have been achieved. It is equally important that these methods are also increasingly used for the preparation of many other types of organic compounds by involving the cyclopropane derivatives in the opening or fragmentation reactions of the three-carbon ring. Such transformations are promoted by high strain in the cyclopropane ring, caused by the inability to fully realize covalent bonding between the carbon atoms in the three-carbon ring and by the repulsion between sterically hindered substituents. These reactions often occur with high regio- and stereoselectivity and may lead to the formation of functionally substituted compounds with different carbon–carbon skeletons, enabling multipurpose uses of the cyclopropane derivatives as intermediates in target-directed organic synthesis.

Starting in the 1960s, work on the use of functionally substituted cyclopropanes in the synthesis of natural products has been carried out systematically in many research laboratories. As a result, consistent patterns for cyclopropane ring formation and cleavage reactions were identified which facilitated the successful syntheses of hundreds of natural and closely related products with various structures. However, only a small portion of the synthetic potential of the cyclopropane compounds has been implemented to date in these studies due, in part, to some difficulties in recognition in the target structures of suitable cyclopropane precursors because of the large number of the options available. Indeed, taking into account that cyclopropane rings can be opened or fragmented, any three carbon atoms of the organic compound may be mentally connected to the cyclopropane unit and, accordingly, such substances can be considered as potential precursors for the target molecule.

Part I of this book briefly considers the basic properties of the cyclopropane compounds and the cyclopropyl reaction intermediates, as well as the methods for the synthesis of cyclopropane derivatives. The most common organic synthesis data of the cyclopropane ring cleavage reactions are summarized as brief synopses of review articles and illustrated with appropriate examples from seminal and contemporary original publications. Since to date there is no published monograph on the application of the cyclopropane methodologies in target-directed organic synthesis, the main goal of this book is to systematize the data on their use in the synthesis of natural products as set out in Part II, which is opened by a brief description of the algorithm of retrosynthetic analysis, called retrosynthetic triangulation. Application of this algorithm to the retrosynthetic analysis of the natural and related compounds is illustrated by schemes in the corresponding tables that reflect the state of the art of the research in this area, and may be useful for the interested reader as a collection of exercises to obtain experience of routine handling to facilitate recognition of the suitable cyclopropane precursors for the target molecule. The author believes that it could contribute to the further development of cyclopropane synthetic methodologies as one of the fundamental bases of organic synthesis.

At the heart of this tutorial book are the author's lectures for advanced courses on the chemistry of organic compounds with small rings for students at the Belarusian State University and Tallinn University of Technology, as well his own research work in this area.

REFERENCES

1. 1. Djerassi, C. and Doss, G.A. (1990) New Journal of Chemistry, 14, 713–719.
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3. 3. Boger, D.L. and Johnson, D.S. (1996) Angewandte Chemie International Edition, 35, 1438–1474.
4. 4. Ari, D., Jautelat, M., and Lantzsch, R. (1981) Angewandte Chemie International Edition, 20, 703–722.
5. 5. Liu, H.-U. and Walsh, C.T. (1987) In The Chemistry of the Cyclopropyl Group (eds S. Patai and Z. Rappoport), John Wiley & Sons, Ltd, New York, pp. 959–1025.
6. 6. Suckling, C.J. (1988) Angewandte Chemie International Edition, 27, 537–552.
7. 7. Salaun, J. and Baird, M.S. (1995) Current Medicinal Chemistry, 2, 511–542.
8. 8. Salaun, J. (2000) Topics in Current Chemistry, 207, 1–54.
9. 9. Schroder, F. (2014) Chemistry and Biodiversity, 11, 1734–1751.
10. 10. Wessjohann, L.A., Brandt, W., and Thiemann, T. (2003) Chemical Reviews, 103, 1625–1647.
11. 11. Poulter, C. (2009) Journal of Organic Chemistry, 74, 2631–2645.
12. 12. Nes, W. (2011) Chemical Reviews, 111, 6423–6451.

INTRODUCTION

The main feature of the structure of cyclopropane in comparison with other saturated carbocyclic compounds with larger ring size is the covalent bonding of the cyclopropane carbon atoms with each other. With this each carbon atom of the cyclopropane ring provides additional convergence between the other two carbons, acting in some respects like a π-bond in an ethylene molecule. It is revealed particularly in the shortening of internuclear carbon—carbon distances and in the manifestation of such unique properties of the cyclopropanes as the propensity to addition reactions, to stabilization of the cyclopropylcarbinyl cations, and to the ring cleavage of cyclopropyl cations, cyclopropylcarbinyl radical and ion intermediates. In almost 150 years of the chemistry of cyclopropanes, the first 35 years have been described in a review article [1], with many general and specific properties of these substances, including their biotransformations, being revealed.

An important prerequisite for the efficient application of cyclopropanes in a target directed organic synthesis is a high regioselectivity of three-carbon ring cleavage reactions. Therefore, the cyclopropanes bearing functional substituents that are able to promote a regioselective cleavage of one of the three carbon—carbon bonds in the cyclopropane ring are used mainly as the synthetic intermediates. The most important for the organic synthesis data on the structure and reactivity of cyclopropanes and related cyclopropane containing intermediates, which allow to correctly predict the regioselectivity of many cyclopropane ring opening reactions, are summarized in the first chapter of Part I. The next chapter is devoted to synthetically useful cyclopropane ring cleavage reactions in which the cyclopropane compounds have a predisposition owing to the internal strain of the small ring and to the high reaction susceptibility due to the influence of the attached substituents. In many cases, such thermally or catalytically induced transformations open effective ways to a wide variety of functionally substituted acyclic, carbocyclic, and heterocyclic derivatives.

The use of cyclopropanes as synthetic intermediates implies usually their availability from commercial precursors, and more than a dozen methods for the synthesis of cyclopropanes are recognized as reliable for general applications considered in the third chapter of Part I. It also covers the data on interconversion of cyclopropanes, which proceed with retention of the carbocycle and are also frequently used for the preparation of desired cyclopropane synthetic intermediates.

REFERENCE

1. 1. Contant, J.B. (1995) In The Chemistry of the Cyclopropyl Group, Vol. 2 (ed. Z. Rappoport), John Wiley & Sons, Ltd, London, pp. 1–41.

Numerous theoretical and experimental studies on cyclopropane compounds allow many of the specific properties of these substances to be elucidated, to synthesize a large number of their individual representatives, and to perform further conversion to other types of organic compounds. Consideration of the original publications on the studies of the structure and other physical and chemical properties of cyclopropane compounds and their reactive intermediates is beyond the scope of this chapter. However, references on the selected reviews of such publications together with a short synopsis from these reviews are provided instead.

1.1 GEOMETRY AND BONDING

Reviews: general [1–4]; theoretical models of bonding [3,5–8]; conjugative and substituent properties [7,9–13].

Synopsis. The C—C and C—H bonds in cyclopropane are shorter than in ethane (Figure 1).

The Coulson-Moffitt and Walsh theoretical models are usually used to describe the bonding in cyclopropane molecules. The Coulson-Moffitt model suggests the change in hybridization of the carbon orbitals toward increasing p-character of the C—C bonds resulted in a minimization of the difference between the conventional interorbital angles and the cyclopropane bond angles. This leads to the concept of bent C—C bonds and the formation of C—H orbitals which are relatively rich in s-character of the carbon atom. X-ray crystallographic data of cyclopropane derivatives agree with the deformation density of the C—C bond outside the triangle which includes the three carbons of the cyclopropane ring (Figure 2).

The Walsh model for cyclopropane also suggests the increased s-character of the C—H bonds are formed by sp² orbitals of the carbon atoms. The remaining carbon sp² orbitals are directed towards the center of the ring to form one bonding and two antibonding molecular orbitals. In turn, the overlap of p orbitals, which are in the plane of the cyclopropane ring, results in the formation of two C—C bonding and one antibonding bent interactions (Figure 2). The Walsh model more clearly describes the effect of substituents on the structure and conformational properties of functionally substituted cyclopropanes.

The conjugation of the cyclopropyl group with a carbonyl and other π-acceptor substituents in the preferred bisected conformation results in a lengthening of the adjacent bonds and in a shortening of the distal cyclopropane C—C bond. The influence of p-donating heteroatom substituents on the geometry of the cyclopropane ring is not so definite and it is likely that inductive effects of the heteroatom interfere with p-conjugation in these cases. For cyclopropanes bearing p-donor and π-acceptor substituents in vicinal positions, a lengthening of the C—C bond adjacent to both substituents takes place.

1.2 ENERGY

Reviews: general [3,7,14–17]; effect of the strain upon reactivity [5,6,18].

Synopsis. The ring cleavage reactions in cyclopropane compounds proceed in milder conditions than the corresponding cleavage reactions of ordinary C—C bonds in other carbocyclic compounds and this difference is attributed to lower strength of the bent bond and to some other electron factors, which collectively are reflected in strain energy. Its amount is calculated as the difference between the observed heat of formation of the cyclopropane and that estimated for a strain-free model. Taking the expiremental heat of formation of cyclohexane as −29.4 kcal/mol and that of cycloopropane as +12.7 kcal/mol allow the strain energy of cyclopropane to be estimated as (12.7 + 29.4:2) kcal\mol = 27.4 kcal/mol (Figure 3).

1.3 SPECTRA

Reviews: NMR spectra [19,20]; vibrational and ultraviolet spectra [7,20]; photoelectron spectra [21–23]; chiroptical spectra [24].

Synopsis. NMR spectra of cyclopropanes have remarkable upfield chemical shifts in comparison with homologues with larger ring size. Thus, the ¹H NMR chemical shift of cyclopropane (δ 0.22) is shifted upfield considerably with respect to cyclohexane (δ 1.43), and the ¹³C chemical shift for cyclopropane (δ −2.8) is also shifted upfield with respect to cyclohexane (δ 27.0) (Figure 4). The shielding of the protons is conventionally attributed to the magnetic induction of the aromatic-like ring current in cyclopropane, involving six electrons in the three C—C bonds. The opposite direction of the ¹H NMR shift for benzene to down field in comparison with the upper field cyclopropane shift is attributed to the different geometrical disposition of the hydrogens toward the rings. The lowered chemical shifts of the cyclopropane signals in ¹H NMR spectra considerably facilitates identification and structural determination of cyclopropane containing compounds.

Vibrational and electronic spectra of cyclopropanes are usually less informative for synthetic organic chemists than NMR spectra, however their use could be also valuable for experimental and theoretical studies. The absorptions in the region of 1020 and 865 cm⁻¹ are typical for the cyclopropane ring, and the first band is assigned to a symmetric vibration of the cyclopropane ring. The cyclopropane C—H stretching absorption lies in the range 3000–3100 cm⁻¹. The absorption bands in the ultraviolet spectra which are correspond to the σ–σ* transition from occupied and unoccupied orbitals in cyclopropane are observed in a non-characteristic area below 210 nm.

1.4 CYCLOPROPYL CATIONS

Reviews: general [10,25]; cyclopropyl cations [26]; cyclopropyl to allyl rearrangements [27–29]; protonated cyclopropanes [30,31]; cyclopropyl cation radicals [32–36].

Synopsis. The generation of cyclopropyl cations is usually accompanied by cleavage of the opposite C—C bond affording allyl cations (Scheme 1a). This cationic cyclopropyl–allyl rearrangement proceeds in a concerted disrotatory fashion in agreement with the Woodward–Hoffman principle of the conservation of orbital symmetry. Of the two possible directions of disrotatory rotation, one of them is more favorable, namely if ionization and ring opening occur synchronously. The reason for this can be best understood by the better overlap of the bonding orbital of the breaking C—C bond with the antibonding orbital of the breaking orbital of the leaving group through a two-electron cyclic aromatic transition state (Scheme 1b).

If two leaving groups are present in the molecule, for example at cyclopropyl–allyl isomerization of gem-dihalocyclopropanes, the ionization is usually initiated by the leaving group which leads to the formation of the less hindered allylic cation (Scheme 1c). The cationic cyclopropyl–allyl isomerization may be prevented by the presence in the cyclopropane ring in α-position to the leaving group of a strong p-electron donor substituent, for example an alkoxide group.

1.5 СYCLOPROPYL ANIONS

Reviews: general [10,25]; basicity [30]; organometallic derivatives [37–41]; anion radicals [32,35].

Synopsis. Cyclopropane is relatively more acidic than other saturated cycloalkanes with larger ring size and is estimated to have a pK_a of about 50. At the same time cyclopropanes bearing π-acceptor substituents appear to have diminished acidity relative to the corresponding isopropyl analogs because planarization of the carbanionic center increases bond angle distortion thus resulting in greater internal strain (I-strain). Theoretical calculations predict essentially the same geometry for cyclopropane and the cyclopropyl anion. For the same reason, the barrier for inversion of the cyclopropyl anion estimated to be near 20 kcal/mol is much high than the barrier for inversion of open chain carbanions (~5 kcal/mol) (Scheme 2). The higher configurational stability of the cyclopropyl anion system allows a configurationally stable cyclopropyl carbanionic species to be generated at lowered or ordinary temperatures. Such species also have a low reactivity to isomerization to the corresponding allyl anions, with the exception of those products which are strongly stabilized by π-acceptor substituents.

1.6 CYCLOPROPYL RADICALS

Reviews: general [10,25]; special [42]; ion radicals [32–35].

Synopsis. The cyclopropyl radical, as well as the cyclopropyl anion, exists as a pyramidal species, however its configuration inversion proceeds considerably faster. For unconstrained cyclopropyl radicals the inversion proceeds rapidly (k_{1 ~}10⁸ s⁻¹, ΔE^# _~1 kcal/mol) through a plane p-centered radical transition state configuration that creates difficulties for performing radical substitution reactions (e.g., Hunsdiecker reaction) at the cyclopropane ring with maintaining or inversion configuration of a chiral center (Scheme 3). Electronegative heteroatom substituents (F, Cl, alkoxy group) at the α-position of the radical center sufficiently increase the configurational stability of the cyclopropyl radicals. The rearrangement of the cyclopropyl radicals to the corresponding allyl radicals occurs when a highly delocalized radical intermediate is formed and these reactions, as well as in the anionic cyclopropyl–allyl rearrangements, have no high synthetic importance. Notably, the gas-phase chemistry of the cyclopropyl cation radicals generated in a mass spectrometer, by radiolysis or other methods, sufficiently differs from the chemistry of cyclopropyl cations and cyclopropyl radicals.

1.7 CYCLOPROPYLIDENES

Reviews: general [10–25]; special [43].

Synopsis. Cyclopropyl carbene, or cyclopropylidene transforms to allene at low temperatures spontaneously via cleavage of the C—C bond distal to the carbenic center. Ab initio calculations provide evidence for cyclopropylidene in a singlet ground state, and various mechanisms were proposed for cyclopropylidene–allene isomerization. It is conventional that in the initial stages the disrotatory cleavage of the C—C bond takes place, probably due to operation of the driving forces which promote a disrotatory ring cleavage in the isoelectronic cyclopropyl cation in accordance with the Woodward–Hoffmann rules (Scheme 4). At the same time the ring opening of cyclopropylidene involves four electrons and the disrotatory motion to be interrupted to afford the overall conrotatory motion affording allenes in a stereoselective or nonstereoselective manner. Thus, the rearrangement of cis-2,3-dimethylcyclopropylidene is nonstereoselective whereas that for the trans isomer is highly stereoselective. Steric effects and other factors can play an important role in determining the stereochemical result.

1.8 CYCLOPROPYLCARBINYL CATIONS

Reviews: general [10,25,28]; special [44–48]; cation radicals [35].

Synopsis. The study of cyclopropylcarbinyl cations using various techniques, including highly informative low-temperature NMR spectroscopy, has a rich history which about 50 years ago led to proposals for the existence of these species as an equilibrated mixture of the delocalized bisected cyclopropylcarbinyl cation and nonclassical bicyclobutonium ion. This model still remains a topic for discussion and development, centered on the structure and relative energies of the rapidly equilibrating carbenium ions. The most important features of the cyclopropylcarbinyl cations for synthetic organic chemists are their easy generation due to a high internal stabilization, as well as their ability for selective conversion in reactions with nucleophiles to synthetically valued homoallyl and cyclobutane derivatives. Notably, comparative NMR studies of the protonated cyclopropyl carbinols and cyclopropyl ketones show in the latter species much smaller delocalization of the cationic charge at the cyclopropane ring, as indicated by the mainly double bond character of the carbonyl group (Scheme 5).

1.9 CYCLOPROPYLCARBINYL ANIONS

Reviews: general [10,25]; organometallic derivatives [37]; homoenolate anions [49–51]; anion radicals [35].

Synopsis. Cyclopropylcarbinyl anions have a tendency to undergo cyclopropane ring opening giving the but-3-enyl anions (Scheme 6a). In contrast to the easy formation of cyclopropylcarbinyl cations in solvolytic conditions, the generation of cyclopropylcarbinyl anions by deprotonation does not exhibit large kinetic effects of the cyclopropyl group. Rate data for base-catalyzed hydrogen exchange in benzylcyclopropane and related compounds suggest that cyclopropyl exerts only a weak stabilizing effect on an adjacent carbanion, much smaller than the effects of vinyl or phenyl groups. At the same time the cyclopropylmethyl anion is 5–15 kcal/mol more stable than primary and secondary alkyl anions. Anionic cyclopropylcarbinyl–homoallyl rearrangement impedes the preparation and synthetic applications of cyclopropylcarbinyl organometallic compounds which are usually transformed in the reaction conditions to the corresponding homoallyl derivatives. In turn, isotopic labeling experiments demonstrate that the α- and β-carbon atoms of 3-butenyl magnesium bromide interchange their positions presumably via reverse formation of the cyclopropylmethyl magnesium bromide (Scheme 6b). Heteroatom substituted cyclopropanes are also involved in isoelectronic cyclopropylcarbinyl–homoallyl rearrangement. For example, the base-catalyzed cyclopropane ring cleavage in cyclopropanols leading to the corresponding carbonyl compounds proceeds at a rate several orders faster than for the cleavage of cyclobutanols (Scheme 6c).

1.10 CYCLOPROPYLCARBINYL RADICALS

Reviews: general [10,25,36]; special [52–56]; ion radicals [33,34].

Synopsis. The cyclopropylmethyl radical rapidly rearranges at ordinary temperature to the but-3-enyl radical with a rate constant ~10⁸ s⁻¹ (Scheme 7a). A strong dependence of the rate constants on the substituents in easily available cyclopropylcarbinyl radical precursor substituents led to widespread use of these compounds as “radical clocks” for studies of organic and bioorganic reaction mechanisms. Spectral data evidence shows that the preferred conformation of the cyclopropylmethyl radicals is bisected, however in contrast to the rearrangements of cyclopropylcarbinyl cations, cyclopropylmethyl radicals have no tendency to rearrange in the cyclobutane derivatives. The regioselectivity of the ring opening of conformationally labile systems usually corresponds to the formation of the more stabilized butenyl radicals, or depends on kinetic effects connected to the reversibility of the rearrangement. For bicyclic cyclopropylcarbinyl radicals regioselectivity of the ring opening may also be determined by stereoelectronic factors or relief of internal strain (Scheme 7b and c). Cyclopropylcarbinyl radicals generated by one-electron reduction of the cyclopropylcarbinyl compounds, or the related isoelectronic species by one-electron oxidation of hetero-substituted cyclopropanes, are also readily involved in the rearrangement affording synthetically value functionalized olefins.

1.11 CYCLOPROPYLCARBENES

Reviews: general [10,25,37]; complexes with transition metals [57–59].

Synopsis. Singlet cyclopropylcarbene undergoes a ring enlargement reaction to cyclobutenes spontaneously (Scheme 8a) and disproportionates in a minor side reaction to ethylene and acetylene. The ring expansion reactions of substituted cyclopropylcarbenes often proceed with high regio- and stereoselectivity and are used for the synthesis of cyclobutenes (Scheme 8b). The theoretical calculations predict the preference of a bisected conformation for the ground singlet state, which changed on completion of the rearrangement via 1,2-sigmatropic shift of the proximal cyclopropane C—C bond to the carbene carbon. The reaction includes an electrophilic phase when the ordinary C—C bond is formed with participation of the empty p atomic orbital and a nucleophilic phase for the formation of the olefin bond.

Nowadays, considerable development has led to understanding the chemistry of easily available cyclopropylcarbene-metal complexes (Scheme 8c) which in addition to rearrangement into cyclobutane derivatives can be involved in various other synthetically useful reactions.

1.12 CONCLUSION

Specific properties of cyclopropane compounds, as well as cyclopropyl and cyclopropylcarbinyl reactive species, often determine the results of the transformations of functionally substituted cyclopropanes on treatment with various reagents. Table 1 summarizes the data on the stability of cyclopropyl and cyclopropylcarbinyl cations, anions, radicals, and carbenes in the temperature ranges commonly used in organic synthesis, as well as examples of their most synthetically useful transformations. The knowledge of the properties of these species greatly facilitates the understanding of the reaction mechanisms of functionally substituted cyclopropanes and facilitates the planning of the target-directed synthesis of organic compound by using the versatility of the regio- and stereoselective ring cleavage reactions of suitable cyclopropane synthetic intermediates.

Reactive intermediate	Stability at temperatures commonly used for synthetic transformations	Synthetically useful transformation
Cyclopropyl cations	Usually unstable	Disrotatory cyclopropyl–allyl isomerization
Cyclopropyl anions	Usually stable	α- and β-Elimination
Cyclopropyl radicals	Stable (configurationally unstable)	Abstraction of the hydrogen or halogen atom
Cyclopropylidenes	Unstable	Cyclopropylidene–allene isomerization
Cyclopropylmethyl cations	Usually unstable	Cationic cyclopropylcarbinyl–homoallyl and cyclopropylcarbinyl–homoallyl isomerization
Cyclopropylmethyl anions	Unstable	Anionic cyclopropylcarbinyl–homoallyl isomerization
Cyclopropylmethyl radicals	Very unstable	Radical cyclopropylcarbinyl–homoallyl isomerization (radical clocks)
Cyclopropyl carbenes	Unstable	Cyclopropyl carbene–cyclobutene isomerization