Minisci reactions: Versatile CH-functionalizations for medicinal chemists

Matthew A. J. Duncton *
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. E-mail: mattduncton@yahoo.com; Tel: +1 917-345-3183

Received 24th May 2011 , Accepted 3rd July 2011

First published on 22nd August 2011


The addition of a radical to a heteroaromatic base is commonly referred to as a Minsici reaction. Such reactions constitute a broad-set of selective CH-functionalization processes. This review describes some of the major applications of Minisci reactions and related processes to medicinal or biological chemistry, and highlights some potential developments within this area.


Introduction

The aim of this review is to summarize the use of Minisci reactions within medicinal chemistry, and to highlight some future opportunities to continue progression of this chemistry. As such, it is not an aim that detailed mechanistic information, or a comprehensive list of examples be described. For this, the reader is directed to excellent articles from Minisci, Harrowven and Bowman.1–3 Rather, the review is written to show that Minisci reactions are extremely valuable CH-functionalization processes within medicinal chemistry. However, their use has been somewhat under-utilized when compared with other well-known selective transformations (e.g. COMPOUND LINKS

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palladium
-catalysed cross-couplings). Therefore, it is hoped that in the future, Minisci chemistry will continue to develop, such that the reactions become a staple-set of methods for medicinal and biological chemists alike.

To aid discussion, the review is divided in to several sections. First, some historical perspective is given. This is followed by a discussion of scope and limitations. The main-body of the review describes some specific examples of Minisci reactions and related processes, with a focus on their use within medicinal, or biological chemistry. Finally, brief mention is given to potential future applications, some of which may be beneficial in providing ‘high-content’ diverse libraries for screening.

1 Historical background

Additions of radicals to aromatic systems have an impressive history dating to an earlier era of organic chemistry. For example, the Gomberg-Bachmann reaction is a well-studied biaryl synthesis, involving the addition of aryl radicals to an aromatic system, such as COMPOUND LINKS

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benzene
, that dates from the early 1920's.4 However, as early as the 1890's, chemists had also been investigating similar reactions involving the addition of aryl radicals to heteroaromatic systems, such as COMPOUND LINKS

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pyridine
.2a,5 Over the ensuing half century or more, modest progress was made in developing this methodology as a synthetically-useful transformation for mainstream organic chemists. For example, by the early 1960's, a number of sources for producing phenyl radical had been uncovered, but the efficiency of the reaction with COMPOUND LINKS

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pyridine
remained low, and multiple regioisomers were produced in the addition process (Scheme 1).6 However, throughout the 1960's much progress began to be made in understanding and controlling the regioisomeric ratio encountered in the radical addition process. For example, in 1961 it was found that additions of phenyl radical to COMPOUND LINKS

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pyridine-N-oxide
occurred in both good yield, and with enhanced regioselectivity (for the 2-position of the pyridine ring), than the analogous reaction with COMPOUND LINKS

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pyridine
(Scheme 2).7

Gomberg-Bachmann raction (1924) and addition of aryl radicals to pyridine (ca. 1893–1960)2a,4,5
Scheme 1 Gomberg-Bachmann raction (1924) and addition of aryl radicals to COMPOUND LINKS

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pyridine
(ca. 1893–1960)2a,4,5

Use of pyridine-N-oxide to enhance regio-selectivity for aryl radical addition to pyridine (1961)2a,7
Scheme 2 Use of COMPOUND LINKS

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pyridine-N-oxide
to enhance regio-selectivity for aryl radical addition to COMPOUND LINKS

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pyridine
(1961)2a,7

A bigger breakthrough in understanding the rate of reaction, and in controlling the regiochemistry of aryl additions to heteroaromatic bases, emerged in 1964 from the work of Lynch and Chang,8,9 and later, from Lynch and Dou.10–13 For example, Lynch and Chang proposed that the rate of addition of phenyl radical to pyridinium (and imizolium) ions was greatly enhanced when compared to that of the neutral heteroaromatic base.9 By considering calculated localization energies for radical substitution of pyridinium and imidazolium ions, which strongly favored high reactivity at the 2-position,14 Lynch and Chang also proposed that ionic species could dominate the orientation of radical substitution in these heteroaromatic systems. This led to the proposal of investigating the reactivity and selectivity of conjugate acids of heteroaromatic compounds with phenyl radicals, in order to test the above predicitions.9 A short-time later, in 1965, Lynch and Dou published the first in a series of papers, in which they gained experimental support for this conjugate acid hypothesis.10–13 As well as radical phenylation undertaken with pyridines (Scheme 3), COMPOUND LINKS

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N-methylimidazole
and COMPOUND LINKS

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thiazole
, Dou and Lynch also found that protonation enhanced reaction rates and positional selectivity for phenyl radical addition to other heteroaromatic bases such as COMPOUND LINKS

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quinoline
, COMPOUND LINKS

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isoquinoline
, COMPOUND LINKS

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benzothiazole
, COMPOUND LINKS

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pyrazine
, COMPOUND LINKS

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pyrimidine
, COMPOUND LINKS

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quinoxaline
and COMPOUND LINKS

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N-methylbenzimidazole
.10 These results led Dou and Lynch to conclude that the use of acidic conditions would make radical additions to heteroaromatic bases a synthetically-viable transformation.10


Use of conjugate acids to enhamce regio-selectivity for radical addition to heteroaromatic bases (1964–1968)8–15
Scheme 3 Use of conjugate acids to enhamce regio-selectivity for radical addition to heteroaromatic bases (1964–1968)8–15

Later, Minisci would also demonstrate the benefit of acidic conditions to reaction rate and positional selectivity for radical additions to heteroaromatic bases.1,15 Through a series of developments and refinements that has persisted to the present day, Minisci and other organic chemists, have refined such reactions to the point where they constitute a very effective set of distinct transformations. For this reason, radical additions to heteroaromatic bases are sometimes referred to as “Minisci reactions” in the chemical literature (this description is used throughout this review). Formally, Minisci reactions represent a powerful method of CH-functionalization for heteroaromatic bases. The reactions are considered complementary to other CH-functionalization processes such as carbo-cation mediated reactions. For example, Punta and Minisci have desscribed the radical-based methods as, ‘a Friedel–Crafts-type process with opposite reactivity and selectivity’.1a

In the ensuing sections we attempt to demonstrate that Minisci reactions are attractive methods for medicinal chemists. We will detail some select examples of Minisci transformations within medicinal chemistry, and will consider some recent developments along the way, including the potential of such reactions for preparing diverse libraries from a common scaffold.

2 Scope and limitations

Minisci reactions are versatile transformations because they represent a diverse set of complementary and selective processes, making them ideal candidates for medicinal chemists looking to functionalize substances with pharmacological activity, or intermediates en-route to target compounds. In order to clearly illustrate the diversity and potential of Minisci chemistry, we will consider the heterocyclic base and radical partner in-turn.

2.1 The heterocyclic base

A large percentage of commerical drugs are based upon a heterocyclic core.16 Therefore, methodology to selectively functionalize a CH-bond within a heteroaromatic system should be very valuable. For Minisci chemistry, the range of heterocyclic core that has been utilized is vast. As can be seen in Table 1, 5-membered, 6-membered, 6,5-bicyclic, 6,6-bicyclic and other polycyclic heteroaromatics have all been successfully employed in Minisci transformations. Radicals can also add to non-basic heteroaromatics such as COMPOUND LINKS

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pyrrole
, COMPOUND LINKS

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thiophene
and COMPOUND LINKS

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furan
, together with annulated versions, such as indoles. We will not dwell too much on these variants, except for a small number of choice examples.
Table 1 Common heterocyclic partners encountered in Minisci reactions
5-Membered rings 6-Membered rings 6,5-Bicyclics 6,6-Bicyclics Polycyclic systems Non-basic systems


2.2 The radical partner

As is the case with the heteroaromatic base, a wide-array of radical groups can be utilized in Minisci reactions. Some of the more important examples for medicinal chemists are detailed in Table 2, together with some of the more common radical precursors from which they are derived.
Table 2 Representative groups added to heteroaromatics in Minisci chemistry
Functional group Common radical precursor(s)
R: Alkyl or Cycloalkyl R-CO2H R-I R-Br R-CHO RCH2OH RCH(OR)2
R-BF3K R-B(OH)2 RSePh Barton ester RSC(S)OR(xanthate)
Aryl Ar-N2+ Ar-I ArB (OH)2 Ar-M (M = COMPOUND LINKS

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Bi
, COMPOUND LINKS

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Hg
, etc.)
CF3 F3C-I
F3C(CF2)n F3C(CF2)n-I
Oxetan-3-yl or Azetidin-3-yl
Acyl
Amide (CONR1R2)
Ester (CO2R)
CH2OH, CHR1OH, CR1R2OH H3COH HCHR1OH HCR1R2OH
CH2NR1R2 or CH2NR1Ac
SiR3 R3Si–H


When the examples in Table 1 and Table 2 are considered in combination, it is apparent that there is considerable scope to these reactions; essentially, any heteroaromatic system can be open to addition of a radical, providing that a suitable position for its attack is free. Likewise, the choice of radical coupling partner is huge and varied. Since radicals are involved as reactive intermediates, protection and deprotection strategies are rarely needed, as the rate of side-reactions arising from free functionalization, is slower than the rate of attack on the heteroaromatic system. This feature of Minisci chemistry makes the reactions especially appealing for industrial applications, since time is an important economic factor.

2.3 Limitations

Although Minisci reactions are very versatile, there are limitations. In the experience of this author, there are three major drawbacks with Minisci chemistry. First, there may be the possibility of obtaining regioisomeric products if more than one appropriate position of the heteroaromatic base is open to substitution. For example, reaction of COMPOUND LINKS

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quinoline
with methyl radical yields a mixture of regiosiomeric products (Scheme 4).17 Of course, a reaction providing more than one product can be an ‘opportunity’ for medicinal chemists, since more than one compound can be submitted for biological testing! None-the-less, the possibility of regioisomers may be a significant obstacle in some instances.

Regio-isomers encountred in a Minisci reaction17
Scheme 4 Regio-isomers encountred in a Minisci reaction17

The second issue with Minisci chemistry concerns the yields. In many cases, the isolated yields can be modest (<50%), even when an excess of the less valuable reacting partner (heteroaromatic base or radical precursor) is used. It is also our experience that reactions can progress to a certain point then stop - the addition or further reagents or heating making little, if any, difference. For example, in our studies on the addition of the oxetan-3-yl or azetidin-3-yl groups to heteroaromatic bases,18 the vast majority of reactions did not go to completion and starting material, along with desired product, was usually isolated. A neat solution to reactions that progress only so-far, then stop, can be found in the synthesis of CGS 19755 (section 3.7).

The final drawback is really a manifestation of the above two limitations. Since reactions do not always completely consume the starting material, and since more than one regioisomeric product can be obtained, purifying individual target compounds to a level suitable for biological testing can sometimes be challenging. As an example, consider the addition of the oxetan-3-yl group to COMPOUND LINKS

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hydroquinine
1 (Scheme 5).18 Although it was found that this reaction was very facile, and most of the starting material appeared to convert to addition products by LC/MS analysis, obtaining those products in a pure form required extensive purification by high-performance liquid chromatography. The result, was that a 27% yield of the 2-substituted product 2, together with a small quantity of the presumed 2,8-disubstituted isomer 3 were obtained, even though the reaction appeared to work better than the isolated yields would suggest.


Addition of an oxetane group to hydroquinine: a challenging separation of the products18
Scheme 5 Addition of an COMPOUND LINKS

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oxetane
group to COMPOUND LINKS

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hydroquinine
: a challenging separation of the products18

On balance, even with some genuine limitations in less favorable examples, Minisci reactions are extremely useful. It should also be remembered that this chemistry is used to undertake some very selective CH-functionalizations (vide infra), and that protection and deprotection sequences are not always required, potentially saving time. Additionally, a vast array of diverse functionalization processes can be undertaken, meaning that more ‘chemical space’ can be investigated by judicious choice of coupling partners. Taken together, the benefits of Minisci chemistry certainly outweigh the limitations.

In the next section the utility of Minisci methodology for medicinal chemists in illustrated by examining specific cases that have been used in medicinal or biological applications.

3 Medicinal or biological chemistry applications of Minisci chemistry

3.1 Introduction of alkyl and cycloalkyl groups

For the potential of Minisci reactions in medicinal and biological chemistry, one need look no further than their use in the synthesis of COMPOUND LINKS

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camptothecin
anti-cancer analogues. Such compounds are very important to medical science, due to their use as treatments for a variety of cancers, which is a consequence of their inhibition of Topoisomerase I.19 The synthesis of compound 5, an intermediate en-route to the marketed COMPOUND LINKS

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camptothecin
analogue Irinotecan 6, by Sawada and colleagues, provides a stunning example of this chemistry. Thus, reaction of unprotected 20(S)-camptothecin 4 with an ethyl radical (generated from an aldehyde precursor), gave 7-ethyl camptothecin in 77% yield (Scheme 6). Compound 5 could be elaborated to Irinotecan in 3 steps.20 Additionally, the same research group used this selective functionalization reaction to investigate structure–activity relationships about the 7-position of COMPOUND LINKS

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camptothecin
.21 Since these pioneering reports, Minisci reactions have been used extensively to prepare a multitude of other COMPOUND LINKS

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camptothecin
analogues, many of which are either marketed, or are being examined in clinical trials. It is beyond the scope of this review to detail every example of such reactions from the extensive patent and research literature. However, an illustration of some representative examples can be found in Scheme 7.22–26 Overall, the use of Minisci reactions in the COMPOUND LINKS

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camptothecin
arena provides a beautiful illustration of the utility and potential of this chemistry; one might describe this work as a text-book example of the functional group compatibility and selectivity of CH-functionalizations using radical processes in general, and Minisci chemistry in particular.

Synthesis of the marketed drug, Irinotecan, a Topoisomerase I inhibitor20
Scheme 6 Synthesis of the marketed drug, Irinotecan, a Topoisomerase I inhibitor20

Representative applications of Minisci chemistry to Topoisomerase I inhibitors22–26
Scheme 7 Representative applications of Minisci chemistry to Topoisomerase I inhibitors22–26

Subsequent to the very impressive Minisci chemistry used to prepare COMPOUND LINKS

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camptothecin
derivatives, there have been other noteworthy uses of the reaction to introduce alkyl groups to give compounds with pharmacological activity. For example, Jain has used Minisci reactions to effectively introduce alkyl and cycloalkyl groups in to histidines and histamines, in an unparalleled regio-specific manner.27–33 Similar reactions have also been used to introduce alkyl groups in to 1,2,4-triazoles.34 One application of this work is in the synthesis of selective Thyrotropin-Releasing Hormone (COMPOUND LINKS

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TRH
) Receptor 2 agonists with in vivo activity.30,32,33 Thus, compound 7 was synthesized using a Minisci reaction of a protected COMPOUND LINKS

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histidine
with a cyclopropyl radical (derived from COMPOUND LINKS

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cyclopropyl carboxylic acid
) as the key step (Scheme 8).31 Compound 7 was shown to be a potent agonist for THR-2 receptors (EC50 = 0.41 μM), with >250-fold selectivity over related THR-1 receptors.31 Additionally, 7 was active in an in vivo model of pentobarbitol-induced sleeping time at a dose of 10 μmol/kg. Interestingly, a close analogue 8, which was also prepared using a similar Minisci reaction as a key step (Scheme 8), showed an increase in pentobarbitol sleeping time.33


Synthesis of Thyrotropin-Releasing Hormone Receptor-2 agonists30,32,33
Scheme 8 Synthesis of Thyrotropin-Releasing Hormone Receptor-2 agonists30,32,33

Jain and colleagues have continued with their studies on the application of Minisci chemistry within a medicinal setting by preparing new COMPOUND LINKS

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quinoline
compounds with anti-tuberculosis activity.35–38 Such agents are sorely needed as TB kills many millions of individuals each year.39 Jain's work has led to the identification of several new anti-TB agents, such as compounds 9–11. These molecules are believed to exert their biological effect through a novel mechanism of action, since they do not inhibit M-tuberculosis-purified DNA-gyrase (a target of COMPOUND LINKS

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quinolone
anti-TB compounds). Some features of the Minisci reactions used to synthesize these analogues is worthy of discussion. As mentioned previously (Section 2.3), it is sometimes possible to obtain more than one addition product in certain instances. In the present work this ‘limitation’ of Minisci chemistry had a fortuitous outcome. Thus, radical alkylation of COMPOUND LINKS

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lepidine
under traditional Minisci conditions (a COMPOUND LINKS

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carboxylic acid
serving as the radical precursor), led to the isolation of mono- and di-alkylated products (Scheme 9). The di-alkylated product 10, was shown to have a more favorable biological profile than its mono-alkylated congener 9. Similarly, compounds 12 and 13 were shown to be particularly interesting analogues, from another set of Minisci reactions; other leading anti-TB compounds were also synthesized in an analogous manner (Scheme 10). Overall, the results from this work may open another avenue of opportunity for finding new treatments for TB patients.


Quinolines with anti-tuberculosis activity35–38
Scheme 9 Quinolines with anti-tuberculosis activity35–38

Quinolines with anti-tuberculosis activity35–38
Scheme 10 Quinolines with anti-tuberculosis activity35–38

Another excellent example of the utility of Minisci chemistry for the introduction of alkyl or cycloalkyl groups, concerns the synthesis of selective GABAA α2/α3 selective agonists from Carling, Street, Castro and their colleagues at Merck.40 Such α2/α3 agonists were of interest as they were shown to retain anxiolytic properties, but were non-sedating in animal models. The synthesis of a development candidate TPA023 14 is shown in Scheme 11. It is noteworthy that the tert-butyl group could be introduced by Minisci chemistry at a late- or early-stage of the synthesis (radical precursor tBuCO2H), thus allowing for some flexibility in examing structure–activity relationships (SAR). Cycloalkyl groups were also introduced using the same methodology. However, the biological profile for these compounds was not as favorable to that of TPA023. A somewhat similar example concerns the investigation of COMPOUND LINKS

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Histamine
H2-Receptor antagonists as detailed by Lipinski, LaMattina and Hohnke (Scheme 12).41


Synthesis of TPA023, an α2/α3 selective GABAA agonist40
Scheme 11 Synthesis of TPA023, an α2/α3 selective GABAA agonist40

Minisci chemistry to provide an H2-Receptor antagonist41
Scheme 12 Minisci chemistry to provide an H2-Receptor antagonist41

The application of Minisci chemistry has also found novel uses in biological chemistry. For instance, Minisci reactions have been used to prepare functional organo-receptors via a tri-directional coupling of cis-1,3,5-cyclohexane-tri-COMPOUND LINKS

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carboxylic acid
and a heteroaromatic building block (Scheme 13). The resulting tripodal adducts functioned as carbohydrate receptors, with particular sensitivy for α-octyl-glucopyranoside. For example, receptor 15 displayed the highest binding affinity for noncovalent binding of an α-glucopyranoside in COMPOUND LINKS

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chloroform
, reported by 2008. Significantly, receptor 15 could also bind monosaccharides in polar solvents such as COMPOUND LINKS

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menthanol
.42


Preparation of carbohydrate organo-receptors42
Scheme 13 Preparation of carbohydrate organo-receptors42

As a final offering in this section, it has been shown that Barton esters and alkyl xanthates may be used as radical precursors for Minisci reactions.43–45 For example, Barton and co-workers showed that reactions may be used to introduce alkyl groups in to biologically-active molecules such as COMPOUND LINKS

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caffeine
, and other purines (Scheme 14). Jarman and colleagues have used this particular variant of Minisci chemistry to synthesize steroid 16, a relative of the marketed compound, Abiraterone 17, a recently approved treatment for prostate cancer (Scheme 15). Compound 16 was shown to be a reversible inhibitor of human cytochrome P45017α, (IC50 = 27nM), compared to the irreversible inhibition observed with Abiraterone (IC50 = 5nM).46


Barton esters in Minisci-type alkylations43–45
Scheme 14 Barton esters in Minisci-type alkylations43–45

Synthesis of reversible inhibitors of human cytochrome P45017α related to the marketed prostste cancer treatment Abiraterone46
Scheme 15 Synthesis of reversible inhibitors of human cytochrome P45017α related to the marketed prostste cancer treatment COMPOUND LINKS

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Abiraterone
46

3.2 Introduction of trifluoromethyl, difluoromethyl and perfluoroalkyl groups

The trifluoromethyl group is a very important substructural element within many drug molecules.47 A reason behind its success lies with the unique qualities of COMPOUND LINKS

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fluorine
in modulating numerous physicochemical and biological characteristics in an advantagous manner. For example, beneficial effects upon biological activity and metabolic stability are well-documented for many compounds.48 Recently, Yamakawa and co-workers have introduced some impressive trifluoromethylation procedures based upon a Minisci reaction with COMPOUND LINKS

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iodotrifluoromethane
(ICF3).49–51 For example, a 50kg-scale preparation of COMPOUND LINKS

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5-trifluoromethyluracil
(5-TFU) 19 from COMPOUND LINKS

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uracil
COMPOUND LINKS

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18
has been devised (Scheme 16).49 5-TFU is a valuable intermediate in both the medicinal and agricultural chemistry disciplines. The method could also be extended to other COMPOUND LINKS

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uracil
analogues, including nucleosides. For example, the mechanism-based thymidylate synthase inhibitor, COMPOUND LINKS

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Trifluridine
COMPOUND LINKS

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20
, could be synthesized using this methodology. Interestingly, COMPOUND LINKS

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iron
sources such as COMPOUND LINKS

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ferrocene
(Cp2Fe) could also be used in the reaction, and sometimes gave superior yields of trifluoromethylated product (Scheme 16).

Trifluoromethylation of uracils using Minisci chemistry49–51
Scheme 16 Trifluoromethylation of uracils using Minisci chemistry49–51

Yamakawa has also broadened the scope of this trifluoromethylation procedure, so that other heteroaromatic bases may be used as starting materials.50,51 For instance, pyridines, pyrimidines, pyrazines, thiazoles, triazoles, thiadiazoles, pyrazoles, COMPOUND LINKS

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pyrazolone
and oxazoles, amongst others, have all been successfully employed (Scheme 17). One important difference for the trifluoromethylation reactions, when compared to their traditional Minisci counterparts, concerns the nature of the radical intermediate. The introduction of COMPOUND LINKS

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fluorine
changes the nature of the COMPOUND LINKS

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carbon
-centered radical to an electrophilic species, rather than a nucleophilic radical encountered in most Minisci transformations.52 Thus, activating groups such as amino substituents were sometimes needed in order to increase the reactivity of the heteroaromatic base,51 although the role of these substituents may be somewhat more complicated (vide infra). The scope of such reactions has also been extended further to encompass the synthesis of ethoxycarbonyldifluoromethyl analogues. For example, a fluorinated COMPOUND LINKS

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azaindolone
derivative 21 could be prepared by reaction of a difluorocarboxylate radical with COMPOUND LINKS

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2-aminopyridine
(Scheme 18).53 As to be expected for an electrophilic process, reaction took place at the position ortho- to the amine substituent, in this case, the 3-position of a pyridine ring.


Trifluoromethylation of heteroaromatic systems using Minsci chemistry50,51
Scheme 17 Trifluoromethylation of heteroaromatic systems using Minsci chemistry50,51

Preparation of a fluorinated azaindolone,52
Scheme 18 Preparation of a fluorinated COMPOUND LINKS

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azaindolone
,52

The work from the above studies will undoubedly be useful, and will complement other methodology to introduce a trifluormethyl group based upon well-known cuprate and COMPOUND LINKS

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palladium
methodology.47 A couple of extensions for this chemistry may also be worthy of investigation. For example, it may be interesting to investigate the use of COMPOUND LINKS

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trifluoroacetic acid
rather than COMPOUND LINKS

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iodotrifluoromethane
as the radical precursor in Schemes 16 and 17. Second, extending the reaction to prepare COMPOUND LINKS

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pentafluorosulfur
analogues could also be considered, as COMPOUND LINKS

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bromopentafluorosulfane
(F5SBr) and COMPOUND LINKS

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chloropentafluorosulfane
(F5SCl) are known to be precursors of the F5S radical (F5S˙).54 Therefore, it may be possible to substitue CF3I for BrSF5, or ClSF5, in a Minisci-type reaction, to enable facile introduction of SF5 in to heteroaromatic systems. Since there has been increasing interest in the biological properties of SF5-containing molecules,55 a one-step process to introduce this group could present an interesting opportunity.

Related radical processes to selectively introduce perfluoroalkyl substituents in to electron-rich heteroaromatic systems such as COMPOUND LINKS

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pyrrole
are also known (Scheme 19).56 In contrast, perfluoroalkylation of electron-deficient heteroaromatic bases can result in poor chemo- and regio-selectivity. For example, perfluoroalkylation of COMPOUND LINKS

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quinoline
results in the formation of eight addition products by GC-MS analysis.57a This result was ascribed to enthalpic-effects acting as the driving-force for the reaction with the electrophilic perfluoroalkyl radical, as opposed to the usual situation in Minisci transformations, where kinetic polar-effects dominate, and selective reaction with nucleophilic radicals occurs.57a This suggested a method for controling the selectivity in the addition of perfluoroalkyl radicals to heteroaromatic bases, by undertaking the reaction in the presence of an alkene. The perfluoralkyl radical reacts faster with an electron-rich alkene, than with an electron-poor protonated heteroaromatic base (because both enthalpic and polar effects are favorable for reactions with alkenes). The new radical intermediate from addition of the perfluoroalkyl group to the alkene posesses sufficient nucleophilic character, such that kinetic polar-effects can control a further selective addition to a protonated heteroaromatic base, resulting in formation of a single perfluoralkylated addition adduct (Scheme 19).57a In a further demonstration of how consideration of enthalpic and polar effects can be utilized to control reactivity and selectivity with perfluoroalkyl radicals, Minisci and colleagues have also undertaken selective reactions with quinones.57b Since perfluoroalkyl groups are also useful in medicinal chemistry settings, and have also been used for separations by fluorous technology,58 perfluoroalkylation methodology will also be of interest to a broad chemistry audience. Presumably, consideration of enthalpic and polar effects for the transformations outlined in Schemes 16–18 may similarly account for the reactivity and selectivity observed in these processes.


Perfluoroalkylation using Minsci chemistry56,57
Scheme 19 Perfluoroalkylation using Minsci chemistry56,57

3.3 Introduction of aryl groups

As can be seen in Section 1 of this review, additons of aryl radicals to heteroaromatic bases have a long history. Some applications of this methodology to medicinal or biological chemistry can be seen in Scheme 20.59 For example, addition of aryl groups to COMPOUND LINKS

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pteridine
heteroaromatic cores gives a range of substituted products in ca. 15–65% yield. In the examples detailed in Scheme 20, the radical precursor is an arenediazonium salt, the radical being generated under traditional Meerwein conditions (base).

Radical addition to a pteridine heteroaromatic59
Scheme 20 Radical addition to a COMPOUND LINKS

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pteridine
heteroaromatic59

Recently, other methods for generating an aryl radical have been developed. For example, mild conditions to undertake radical formation from aryl iodides using COMPOUND LINKS

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potassium tert-butoxide
have been reported.60 The resulting radical could be added to heteroaromatic bases to give the coupled products in 56–98% yield, although the heteroaromatic base was used in a 40-fold excess (Scheme 21).


Radical addition to pyrazine promoted by potassium tert-butoxide60
Scheme 21 Radical addition to COMPOUND LINKS

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pyrazine
promoted by COMPOUND LINKS

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potassium tert-butoxide
60

At this juncture, it would also be appropriate to discuss some new developments using COMPOUND LINKS

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boron
species as radical precursors. Boranes, boronic acids or boronic esters are well-known radical precursors, although radical reactions with boranes or boronic esters are more common than other COMPOUND LINKS

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boron
species.61 Minisci-type chemistry with trialkylboranes has also been known for sometime. For instance, reaction of COMPOUND LINKS

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triethylborane
with COMPOUND LINKS

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lepidine
furnished a 62% yield of the addition adduct 22 using an aqueous acidic system (Scheme 22).62 More recently, a number of research groups have began to examine the use of boronic acids in Minisci-type reactions. Formally, such processes represent a change of the radical precursor from the commonly-encountered COMPOUND LINKS

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carboxylic acid
, to a COMPOUND LINKS

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boronic acid
. Demir, Reis and Emrullahoglu were the first to investigate these processes.63 They found that reaction of a heteroaromatic base with an aryl radical, generated from a COMPOUND LINKS

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boronic acid
precursor and 3 equivalents of Mn(OAc)3, furnished the expected biaryl products in moderate yield (Scheme 23). Similar results have been observed by Guchhait et al.,64 and again by Demir et al.,65 using a microwave-assisted variant of the reaction (Scheme 23). However, there are some drawbacks to the Mn(OAc)3 reactions as currently practised. For example, the heteroaromatic base tends to be used in large excess with respect to the COMPOUND LINKS

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boronic acid
radical precursor. Additionally, high temperatures are frequently used for the reactions. These limitations may restrict the above processes in medicinal chemistry applications.


Radical addition to lepidine using a borane as a radical precursor62
Scheme 22 Radical addition to COMPOUND LINKS

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lepidine
using a COMPOUND LINKS

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borane
as a radical precursor62

Boronic acids as radical precursors in Minisci-type reactions63–65
Scheme 23 Boronic acids as radical precursors in Minisci-type reactions63–65

Considerably more mild conditions to effect a Minisci-style arylation with boronic acids have recently been described by Baran and co-workers.66 The reactions employ 1.5 equivalents of an arylboronic acid, 1.0 equivalent of a protonated heteroaromatic base, and utilize Minisci's AgNO3 and K2S2O8 oxidation conditions at room temperature. Some impressive examples were undertaken. For instance, similar to our own experience of Minisci reactions with cinchona alkaloids,18 Baran found that unprotected substrates could participate in such reactions. For example, the anti-malarial natural product COMPOUND LINKS

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quinine
was cleanly arylated in 40% yield with 4-phenoxyboronic acid (Scheme 24).


Boronic acids as radical precursors in Minisci reactions66
Scheme 24 Boronic acids as radical precursors in Minisci reactions66

The use of COMPOUND LINKS

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boron
species in Minisci reactions will likely prove to be a valuable addition for medicinal chemists, since many departments carry large collections of these building blocks, due to their widespread use in Suzuki reactions. This area of Minisci chemistry is also ripe for further development. For example, it would be interesting to see whether other boronic acids such as alkyl-, cycloalkyl- (e.g. cyclopropyl), or heteroaryl-boronic acids can be used as radical precursors in Minisci reactions.67 Additionally, the possibility of using COMPOUND LINKS

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N-methyl iminodiacetic acid
(COMPOUND LINKS

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MIDA
) boronates, and COMPOUND LINKS

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potassium
trifluoroborates, as alternatives to boronic acids would also be worthwhile, as these compounds benefit from increased bench-top stability compared to their COMPOUND LINKS

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boronic acid
counterparts.68,69 On this theme, Molander has recently reported the use of alkyl trifluoroborates as radical precursors in Minisci reactions, the processes employing Mn(OAc)3 to promote radical formation (Scheme 25).70a Importantly, the trifluoroborates and heteroaromatic bases are used in equimolar quantities, and proceed under relatively mild conditions (AcOH, COMPOUND LINKS

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H2O
, COMPOUND LINKS

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TFA
, 50 °C).70a These features may render the Molander conditions more attractive for medicinal chemists than the alternative Mn(OAc)3 reactions described above. It will also be interesting to see whether Molander's conditions can be transferred to arylboronic species, be they trifluoroborates, boronic acids, or boronic esters (including COMPOUND LINKS

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MIDA
esters).


Potassium trifluoroborates as radical precursors in Minisci reactions70
Scheme 25 COMPOUND LINKS

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Potassium
trifluoroborates as radical precursors in Minisci reactions70

3.4 Introduction of oxetan-3-yl and azetidin-3-yl groups

The oxetan-3-yl substituent has recently been characterized as a privileged motif within medicinal chemistry.71 For example, introduction of an COMPOUND LINKS

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oxetane
module can result in changes to drug-like properties, resulting in improvements to characteristics such as metabolic stability and hERG activity by modulating log P, basicity and amphiphilicity.72 The oxetan-3-yl group has also been found to be acceptable when model compounds containing this group were screened for the formation of reactive metabolites.73 Azetidin-3-yl substituents are also prominent motifs within medicinal chemistry, being a common substructural feature of numerous agents that act through the central nervous system (CNS).74

Recently, our own research group has described the use of a Minisci reaction to introduce both oxetan-3-yl and azetidin-3-yl groups, using the appropriate iodides as the radical precursor (Scheme 26).18 The reactions could be undertaken on some highly functionalized substrates such as the anti-malarial, COMPOUND LINKS

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hydroquinine
1 (Scheme 5), and the marketed anti-cancer compound, COMPOUND LINKS

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Gefitinib
COMPOUND LINKS

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23
(Scheme 26). The product from the addition to COMPOUND LINKS

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Gefitinib
, compound 24, has been tested in biological screens and results will be disclosed soon. In addition to the reactions above, a wide-range of heteroaromatic bases could also be utilized, with isolated yields of the oxetan-3-yl, or azetidin-3-yl products ranging from 5–50%.


Introduction of the oxetan-3-yl and azetidin-3-yl groups18
Scheme 26 Introduction of the oxetan-3-yl and azetidin-3-yl groups18

3.5 Introduction of COMPOUND LINKS

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tetrahydrofuran
, furanoses and hexoses

Yokoyama, Vismara and Minisci have shown that a COMPOUND LINKS

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furan
, or furanose module, may be efficiently introduced in to a heteroaromatic base using a radical approach.75–77 The reaction may also be extended to hexoses. Thus, this methodology provides a unique synthesis of C-glycosides (Scheme 27), which are of interest for their potent anti-viral and anti-tumor activity, amongst others.78 For future applications, it would also be interesting to see whether di-saccharides and poly-saccharides could also be added to heteroaromatic bases using this methodology, since complex sugars are encountered in many biological processes.

Introduction of furanoses and hexoses to provide anti-viral compounds75–78
Scheme 27 Introduction of furanoses and hexoses to provide anti-viral compounds75–78

3.6 Introduction of aldehyde and ketone groups

The introduction of acyl groups to heteroaromatic bases was one of the early systems to be investigated by Minisci, despite the decarbonylation of acyl radicals being a facile process.1a,79 It should also be noted that the acyl products can be more open to radical attack than the starting material, leading to further reaction. In unfavourable examples, this is a limiting factor for such reactions.1a However, in many cases acylation reactions can be useful synthetically. For example, mono-acylation reactions have been employed to prepare compounds with biological activity, such as acyl purines, an aldehyde serving as the radical precursor (Scheme 28).80 Substituted pyrazines, which function as ant pheromones, have been synthesized in good yield using a complementary acylation method, starting from an α-ketoacid radical precursor (Scheme 29).81 Acylations using Minisci chemistry have also been utilized to synthsize potent anticonvulsants.82 For example, acylation of COMPOUND LINKS

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bromopyrimidine
COMPOUND LINKS

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25
afforded the COMPOUND LINKS

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benzoyl
adduct 26 in 61% yield on a 42g-scale (Scheme 30).82a Compound 26 could be elaborated to a potent COMPOUND LINKS

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triazole
anticonvulsant 27, which was shown to possess activity superior to COMPOUND LINKS

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valproic acid
(Depakene®) in two in vivo anticonvulsant screens. Similar reactions could yield COMPOUND LINKS

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pyrimido[1,4]diazepin-2-one
anticonvulsants.82b Acyl radicals have also been utilized to provide a number of acyl pteridines (Scheme 30).59b,83 Compounds containing the COMPOUND LINKS

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pteridine
structure have many biological functions, being present in important co-factors such as COMPOUND LINKS

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tetrahydrofolic acid
.84 Additionally, derivatives of acyl pteridines are known to possess a multitude of medicinal properties.85

Synthesis of acylpurines using Minisci chemistry80
Scheme 28 Synthesis of acylpurines using Minisci chemistry80

Preparation of ant phermones81
Scheme 29 Preparation of ant phermones81

Preparation of an anti-convulsant and a naturally-occurring pigment using Minisci acylations82,83
Scheme 30 Preparation of an anti-convulsant and a naturally-occurring pigment using Minisci acylations82,83

Radical-based formylation reactions have also been developed.86 Although there are few examples on the use of these reactions in medicinal chemistry, the aldehyde (or masked aldehyde) products are useful for reductive-amination chemistry, and other functionalizations (e.g. reaction with Grignard reagents and other organometallics).

3.7 Introduction of amide and ester groups

Primary, secondary and tertiary amides, as well as esters, can all be introduced using Minisci chemistry.1a,87 One of the first examples of an amide reaction being used in a medicinal setting, concerns a large-scale synthesis of the COMPOUND LINKS

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N-methyl-D-aspartate
(COMPOUND LINKS

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NMDA
) antagonist, CGS 19755 30.88 Thus, COMPOUND LINKS

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ethyl isonicotinate
COMPOUND LINKS

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28
(25g) was amidated to give 29 in 30–40% yield (Scheme 31). As mentioned in Section 2.3, one of the limitations with Minisci chemistry is that the reactions have a tendancy to progress so far, then stop. The authors of this present study partly overcame this limitation by working-up the reaction, then repeating the same transformation on the crude mixture (consisting of ca. 1[thin space (1/6-em)]:[thin space (1/6-em)]1 starting material COMPOUND LINKS

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28
and desired product 29). In this way, a 60% yield (19.3g) of desired amide 29 could be obtained after crystallization. The tactic employed above, of repeating a reaction after workup, may be a useful method for improving yields of other Minisci transformations that proceed in modest conversion.

Synthesis of the NMDA antagonist CGS 1975588
Scheme 31 Synthesis of the COMPOUND LINKS

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NMDA
antagonist CGS 1975588

Another important example for the introduction of an amide group concerns the synthesis of the marketed multi-kinase inhibitor, COMPOUND LINKS

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Sorafenib
COMPOUND LINKS

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31
, which is approved to treat advanced renal cell carcinoma and advanced primary hepatocellular carcinoma.89 COMPOUND LINKS

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Sorafenib
, which is classified as a multi-kinase inhibitor, can be prepared using Minisci chemistry on an early precursor, albeit in a very low 5% yield (Scheme 32).90 In an interesting modification, it has recently been shown that the primary amide can be introduced on a large-scale, the product also serving as a precursor to Sorafeninib (Scheme 32).91 Similar industrial utilities of Minisci chemistry to introduce amides have appeared frequently in both the patent and primary literature. For example, BAY 50-9193 33, an amide analogue of the clinical VEGFR-2 inhibitor, PTK787 32, was prepared in modest yield using Minisci chemistry (Scheme 33).92 The introduction of an amide group in to the pyridine ring of PTK787, to give compound 33, may have beneficial effects upon CYP3A4 inhibitory activity. In other examples, researchers from Roche have used an amidation reaction to prepare compound 34 (possibly, an intermediate to endothelin receptor antagonists) on a 132g scale (Scheme 33),93 and a group from BASF have used a Minisci amidation, on a 42kg-scale, in a synthesis of a highly potent thromin inhibitor 35 (Scheme 33).94


Preparation of Sorafenib, a marketed multi-kinase inhibitor using Minisci chemistry90,91
Scheme 32 Preparation of COMPOUND LINKS

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Sorafenib
, a marketed multi-kinase inhibitor using Minisci chemistry90,91

Preparation of kinase and thrombin inhibitors using Minisci chemistry92–94
Scheme 33 Preparation of kinase and thrombin inhibitors using Minisci chemistry92–94

Amidation reactions have also been useful to prepare natural products with pharmacological activity. For example, Göksh and colleagues have used an amidation process in their studies of Vertilecanin natural products, which have shown antibacterial activity against Bacilus subtilis (ATCC 6051), amongst other biological properties.95 Thus, amide 37 was synthesized in 50% yield from precursor 36 (Scheme 34). The amide product could be elaborated to Vertilecanin C 38 in one step. The methodology was short and flexible, which allowed for the synthesis of alternative analogues related to the Vertilecanin family. In a similar manner, amidation reactions can also be undertaken with the thioquinanthrene core (Scheme 34).96


Synthesis of Vertilecanin natural products and thioquinathrece amides95, 96
Scheme 34 Synthesis of Vertilecanin natural products and thioquinathrece amides95, 96

Finally, in this section, Minisci reactions can be used to introduce both esters and amides (Scheme 35).83a,92 Such reactions may be valuable for gaining access to COMPOUND LINKS

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pteridine
analogues that function as Ricin A chain inhibitors.97


Minisci esterification and amidation applied to pteridine analogues83a,92
Scheme 35 Minisci esterification and amidation applied to COMPOUND LINKS

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pteridine
analogues83a,92

3.8 Introduction of hydroxymethyl, COMPOUND LINKS

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methoxymethyl
, aminomethyl and other functionalized methyl groups

The introduction of hydroxymethyl groups can be undertaken efficiently using Minisci chemistry. COMPOUND LINKS

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Hydrogen
abstraction from COMPOUND LINKS

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MeOH
yields the CH2OH radical. This radical is highly nucleophilic, and reacts with heteroaromatic bases very readily to give the expected substitution product(s).1a,98 However, the reaction may suffer from some drawbacks. For example, Minisci has found that an aldehyde by-product may also be formed in significant quantities, even when a large excess of COMPOUND LINKS

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methanol
is used.1a,99 Poly-hydroxymethylation can also occur when more than one free position is available for reaction. For example, in their studies of inhibitors of gastric acid secretion, Mitchell and co-workers found that mono-hydroxymethylation of COMPOUND LINKS

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4-chloropyridine
COMPOUND LINKS

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39
proceeded in 20–30% yield.100 One problem was the formation of a bis-hydromethylated product 41, together with unreacted starting material (Scheme 36). In order to improve the yield of desired product 40, an ingenious solution was devised. This involved using an N-methoxypyridinium salt starting material 42, to provide an electrophilic COMPOUND LINKS

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pyridine
that would react under neutral conditions. The thinking behind the use of this species was that if the pyridinium species lost the nitrogen substituent during the course of the hydroxymethylation, the product should be considerable less electrophilic than the starting material, thus allowing for the selective synthesis of compound 40. Further consideration of the reaction mechanism indicated that the process could be made catalytic in COMPOUND LINKS

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ammonium persulfate
. The results of the optimization were dramatic; hydroxymethylation of COMPOUND LINKS

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4-chloro-N-methoxypyridinium tetrafluoroborate
42 (made from COMPOUND LINKS

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4-chloropyridine-N-oxide
), with sub-stoichiometric amounts of COMPOUND LINKS

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ammonium persulfate
in refluxing COMPOUND LINKS

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MeOH
, gave the desired mono-hydroxymethylated product 40 in 71% isolated yield (Scheme 36). Other N-methoxypyridinium tetrafluoroborates could also be reacted efficiently.100 This general strategy of increasing the reactivity of heteroaromatic bases by using pyridinium salts (similar results can also be observed with N-oxides),101 may be worth remembering when other difficult Minisci procedures are encountered.

A modified Minisci hydroxymethylation reacion en route to inhibitors of gastric acid secretion100
Scheme 36 A modified Minisci hydroxymethylation reacion en route to inhibitors of gastric acid secretion100

Although bis-hydroxylation may be observed in some circumstances, it is not always encountered. For instance, an interesting example of a radical mono-hydroxymethylation was provided in the synthesis of a transition state analogue inhibitor of adenosine deaminase.102 Addition adducts 44–46 were synthesized by a UV-induced reaction of COMPOUND LINKS

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methanol
with purine ribonucleoside 43, a known reversible inhibitor of adenosine deaminase (Scheme 37). Similar to early results with radical additions to DNA-bases (Section 3.12), the products from the reaction were shown to be a diasteromeric mixture of dihydro-derivatives in a combined yield of 54% (25% diastereomer A COMPOUND LINKS

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44
and 29% diastereomer B 45), together with an oxidized addition product 46 (yield not disclosed). The diastereomers COMPOUND LINKS

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44
and 45 could be separated, and one diastereomer (COMPOUND LINKS

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44
) was shown to be an exceptionally potent inhibitor of adenosine deaminase from calf duodenum (Ki = 0.76 × 10−6).102


Preparation of inhibitors of adenosine deaminase102
Scheme 37 Preparation of inhibitors of adenosine deaminase102

Another application of the hydroxymethylation reaction has also been provided in the preparation of COMPOUND LINKS

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tetrahydro-1,8-naphthyridol
analogues of COMPOUND LINKS

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α-tocopherol
that function as antioxidants of lipid peroxidation. Since lipid peroxidation has been associated with pathologies such as cardiovascular disease, neurodegeneration and cancer,103 such compounds may be very valuable. For example, in the synthesis of a key compound known as N-TOH 49, a COMPOUND LINKS

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naphthyridine
starting material COMPOUND LINKS

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47
was selectively hydroxymethylated to provide addition adduct 48 in 88% yield (Scheme 38).104


Preparation of antioxidant N-TOH104
Scheme 38 Preparation of antioxidant N-TOH104

Introduction of aminomethyl groups has also been undertaken successfully. A particularly useful procedure was developed by Cowden at Merck and COMPOUND LINKS

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Co
.105 Thus, reaction of COMPOUND LINKS

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dichloropyrazine
with a protected amino acid affords the aminomethylated product 50 in good yield (Scheme 39). Minisci hydroxymethylation and aminomethylation reactions have been used extensively in COMPOUND LINKS

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camptothecin
, COMPOUND LINKS

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pteridine
and COMPOUND LINKS

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nicotine
chemisty (see also Sections 3.1, 3.6 and 3.7).21a,106–111 For instance, such reactions are used as key steps in the synthesis of gimatecan 51 and COMPOUND LINKS

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water
soluble aminomethyl camptothecin analogue 52 (Scheme 39). Gimatecan is currently being examined in clinical trials. Analogous reactions can also provide analogues of the natural COMPOUND LINKS

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pterin
, asperopterin-B, as well as intermediates en-route to COMPOUND LINKS

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folic acid
, and “aza-COMPOUND LINKS

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nicotine
” analogues 53 (Scheme 39). A further illustration of such chemistry, with many similarities to the chemistry outlined in Scheme 37, concerns the hydroxymethylation and aminomethylation of the natural nucleoside, COMPOUND LINKS

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nebularine
, protected as a tri-O-benzoate ester (compound 54).112 The benzoate esters were removed after the Minisci reactions to provide C-alkylated derivatives of COMPOUND LINKS

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nebularine
, such as COMPOUND LINKS

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55
and 56 (Scheme 39).


Synthesis of medicinally important compounds via Minisci aminomethylation or hydroxymethylation chemistry105,21a,106–112
Scheme 39 Synthesis of medicinally important compounds via Minisci aminomethylation or hydroxymethylation chemistry105,21a,106–112

Other useful applications of Minisci chemistry to introduce functionalized methyl groups include the synthesis of licofelone 59 (ML3000), a compound that recently completed Phase III clinical trials as an analgesic and anti-inflammatory agent.113 Thus, advanced intermediate 57 was alkylated under radical conditions using COMPOUND LINKS

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iodoacetonitrile
, or a haloacetate as the radical precursor, and a COMPOUND LINKS

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DMSO
/FeSO4.7H2O system (Fenton conditions) to provide addition adduct 58 (Scheme 40).114,115 Other sulfoxides were also investigated for an ability to promote the reaction of 57 to 58, but none proved as effective as COMPOUND LINKS

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DMSO
. The use of Minisci chemistry was especially noteworthy in the above synthesis, as previous transformations of 57 to licofelone 59 used COMPOUND LINKS

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diazoacetate
reagents, or COMPOUND LINKS

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oxalyl chloride
.113


Synthesis of the analgesic licofelone (ML3000) and a 13C-labelled bilin113,116
Scheme 40 Synthesis of the analgesic COMPOUND LINKS

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licofelone
(ML3000) and a 13C-labelled COMPOUND LINKS

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bilin
113,116

Another particularly interesting application of a similar heteroaryl COMPOUND LINKS

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acetate
functionalization has been undertaken to provide 13C-labelled COMPOUND LINKS

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bilin
compounds, e.g.60 (Scheme 40).116 The labelled bilins synthesized in this study could be incorporated in to biological photoreceptors such as phytochromes, and may be useful for following conformational changes induced by photoisomerization of COMPOUND LINKS

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bilin
chromophores.116

3.9 Introduction of ketyl groups (Emmert reaction)

Related to the introduction of hydroxymethyl groups outlined in Section 3.8, and acyl groups outlined in Section 3.6, is the reaction of aldehydes or ketones with heteroaromatic bases, in the presence of aluminium or COMPOUND LINKS

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magnesium
, and mercuric salts (COMPOUND LINKS

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iodine
sometimes being used as an initiator). Such processes are known as Emmert reactions, and pre-date modern Minisci chemistry, as they were described in the late-1930's.117 Modern variants of the reaction can also be undertaken with COMPOUND LINKS

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lithium
or COMPOUND LINKS

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samarium(II) iodide
.118,119

An example from 1948 details the use of an Emmert reaction to prepare substituted pyridines as histamine antagonists.120 A key intermediate 61 was prepared from COMPOUND LINKS

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pyridine
and COMPOUND LINKS

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benzaldehyde
in 39% yield. Intermediate 61 could be elaborated to the desired target histamine antagonist 62 (Scheme 41). Similarly, α-methyl congener 63, which was also a potent histamine antagonist, was synthesized starting from COMPOUND LINKS

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pyridine
and COMPOUND LINKS

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acetophenone
, although a slightly modified procedure was used for the key radical-addition step. A similar use of an Emmert reaction has recently provided COMPOUND LINKS

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2-pyridyl-benzopyran
derviatives, such as COMPOUND LINKS

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64
, as potassium channel openers (Scheme 41).121


Use of Emmert reactions to provide histamine antagonists and potassium channel openers120,121
Scheme 41 Use of Emmert reactions to provide histamine antagonists and potassium channel openers120,121

3.10 Introduction of COMPOUND LINKS

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silicon
(and COMPOUND LINKS

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germanium
) groups

The use of COMPOUND LINKS

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silicon
within medicinal chemistry has been an active area of research, especially within recent years.122 An example of the advantageous use of COMPOUND LINKS

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silicon
within biologically-active scaffolds, is provided by the ‘Silatecans’ which constitute an important class of hydrophobic COMPOUND LINKS

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camptothecin
derivatives. The increased hydrophobicity of silatecans offers advantages over other COMPOUND LINKS

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camptothecin
derivatives, such as superior plasma stability, and an improved pharmacokinetic profile.26,123 A lead member of this group is DB-67 65, which is currently in Phase II clinical development.124 In a large-scale and practical synthesis of DB-67, and a series of closely-related analogues, Curran and colleagues developed a COMPOUND LINKS

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silicon
-variant of standard Minisci chemistry in order to functionalize COMPOUND LINKS

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camptothecin
COMPOUND LINKS

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44
or a COMPOUND LINKS

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diacetate
protected COMPOUND LINKS

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camptothecin
analogue 66 (Scheme 42).125 The method uses a silane as the radical precursor and a thiol/peroxide to facilitate H-abstraction, providing the R3Si radical (R3Si˙). The use of this protocol could be undertaken on a >50g scale. The reaction also provided small quantities of 12-substituted COMPOUND LINKS

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camptothecin
derivatives as minor by-products. Curran and colleagues concluded that this radical-addition method was shorter and higher-yielding than a previous total synthesis, even though the yields for the addition of R3Si radical were relatively modest. With this well-tried and trusted method in-hand, future studies may examine the generality of the process for introducting R3Si groups in to heteroaromatic systems other than the COMPOUND LINKS

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core. Another Silatecan in clinical studies is Karenitecan (BNP1350) 67 (Scheme 42), which is prepared in a similar manner to the chemistry originally utilized by Sawada and colleagues outlined in Section 3.1.126 A related analogue, which contains a novel “flipped” lactone E-ring, and a COMPOUND LINKS

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germanium
side-chain, can also be synthesized using similar methodology (Scheme 42).127

3.11 Intramolecular reactions

Intramolecular variants of Minisci's chemistry have been used extensively, most frequently as key-steps in total synthesis of natural products. The reader is directed towards reviews from Harrowven2a and Bowman3 for detailed discussion within this area; some representative examples of intramolecular reactions directly applicable to medicinal or biological chemistry are detailed below.

One of the earlier examples of an intramolecular Minisci reaction, in the synthesis of a biologically-important scaffold, was provided by the synthesis of an aza-COMPOUND LINKS

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ergoline
ring structure COMPOUND LINKS

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70
, available in three-steps from commercially-available COMPOUND LINKS

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indole-4-boronic acid
COMPOUND LINKS

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68
; the key cyclization step used a Minisci reaction of an acyl radical (Scheme 43).128 Of note, was the absence of an COMPOUND LINKS

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indole
protecting group in this short reaction sequence, clearly supporting the idea that Minisci chemistry does not necessarily benefit from a protecting group. Similar intramolecular radical reactions have very recently been described by Bennasar and Roca to obtain COMPOUND LINKS

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ergoline
-related COMPOUND LINKS

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indole
-fused isoquinolines (Scheme 43).129


Intramolecular Minisci reactions to provide “aza-ergoline” ring structures128,129
Scheme 43 Intramolecular Minisci reactions to provide “aza-COMPOUND LINKS

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ergoline
” ring structures128,129

Intramolecular Minisci chemistry is also useful for undertaking multi-step “tandem” syntheses. For example, González and Molina-Nazarro have described a beautiful cascade-sequence, terminating in a Minisci-type reaction, in their attempted synthesis of Spongidines (e.g. Spongidine A 74), which are a group of anti-inflammatory pyridinium alkaloids.130 Thus, reaction of keto-ester precuror 71, with Mn(OAc)3 in AcOH gave the tetracyclic product 72, in a very respectable 40% isolated yield (Scheme 44). Tetracycle 72 was isomeric with the Spongidine natural product, as the final cyclization had occurred exclusively at the 2-position of the pyridine ring, rather than the desired 4-position. The authors proceeded to prepare compound 73, an isomeric relative of Spongidine A, and are currently trying to prepare an appropriate derivative of 73 to measure its biological activity.


A cascade approach to a relative of the anti-inflammatory alkaloid, Spongidine A130
Scheme 44 A cascade approach to a relative of the anti-inflammatory alkaloid, Spongidine A130

In a similar vein to the work in Scheme 44, Rouden and colleagues have used an intramolecular Minisci cyclization to synthesize a COMPOUND LINKS

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cytisine
/COMPOUND LINKS

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epibatidine
hybrid, for in vivo imaging of nicotinic acetylcholine receptors (nAChRs), particularly those of the α4β2 subtype (Scheme 45). The desired cyclized compounds 75 and 76 were tested as racemic mixtures for inhibition of α4β2 nAChRs and showed Ki values of 3.5 nM and 0.5 nM respectively.131


Intramolecular Minisci reactions to provide ihibitors of nicotinic acetylcholine receptors131
Scheme 45 Intramolecular Minisci reactions to provide ihibitors of nicotinic acetylcholine receptors131

In a further demonstration of intramolecular Minisci reactions to prepare compounds of biological significance, Zard and Gagosz have provided compounds related to the anti-tumor agent PB1 77 (Scheme 46),132 and Bennesar et al. have synthesized the potent anti-malarial/anti-tumor COMPOUND LINKS

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quinone
Calothrixin B COMPOUND LINKS

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78
,133 and ellipticine quinones, such as 79 (Scheme 46), which may also be useful as anti-tumor agents, or as a precursor of ellipticine itself.134


Preparation of anti-tumor and anti-malarial agents by intramolecular radical additions132–134
Scheme 46 Preparation of anti-tumor and anti-malarial agents by intramolecular radical additions132–134

As mentioned in Section 2.1, radicals can add to heteroaromatic systems that are not basic. Intramolecular variants of this reaction have provided some of the earliest examples on the use of Minisci reactions to prepare cyclic structures. For example, a number of cyclized products, including the ant pheromone (-)-Monomorine 80 were prepared using this method (Scheme 47).135–137 Similar reactions could also be extended to the cyclization of COMPOUND LINKS

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quinone
and COMPOUND LINKS

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pyridone
derivatives (Scheme 47).138,139 As another illustration of this chemistry, albeit using traditional radical-generating conditions, potent tricyclic 5-HT2C agonists, such as 81, were synthesized from N-substituted indoles (Scheme 47).140 The cyclization conditions were based upon prior work by Moody and Norton.141 More recently, similar chemistry has been used to prepare other bicyclic COMPOUND LINKS

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azole
derivatives, such as Withasomnine 82, which is used in ayurvedic alternative medicine (Scheme 47).142


Intramolecular radical additions providing biologically-active natural products and 5-HT2C agonists135–142
Scheme 47 Intramolecular radical additions providing biologically-active natural products and 5-HT2C agonists135–142

3.12 Reaction with DNA or RNA-bases

Finally, in section 3, we change track and consider the reaction of a class of heteroaromatics with COMPOUND LINKS

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carbon
-centered radicals, rather than the introduction of a specific group.

The reaction of nucleic heteroaromatics with alkyl radicals is a huge and diverse field. A full discussion of this chemistry, which is important in biological systems, is well-beyond the scope of this review, and readers are directed to a selection of other articles for a more in-depth account of these processes.143 However, a few selective examples are shared here for illustrative purposes.

The addition of COMPOUND LINKS

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carbon
-centered radicals to DNA or RNA bases has been known for over 40 years. For example, in 1968 Linschitz and Connolly reported the addition of alkoxymethyl radicals to COMPOUND LINKS

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purine
, to give COMPOUND LINKS

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dihydro-purine
products (Scheme 48).144 Contemporaneous studies were also reported by Yang et al., and by Elad and colleagues, who examined the reaction of purines, or purine nucleosides, with amines and alcohols respectively, under the influence of UV-radiation. The products from these reactions were also shown to be addition adducts resulting from radical attack on the heteroaromatic base (Scheme 48).145,146 Subsequently, modifications of nucleic acid bases with other alkyl and aryl radicals have been investigated by those in the chemical toxicology and biological chemistry fields. For example, in 1974 Kawazae and co-workers detailed the addition of methyl and amide groups to various nucleic acid bases, using Minisci's conditions for radical-formation, as a model of DNA-damage caused by carcinogenic peroxides (Scheme 49).147,148 Further studies have elucidated the site of radical attack for all four DNA-heteroaromatics (Scheme 50).149 The relevance of these radical reactions to in vivo biology is an area of current interest.143 Thus, the study of Minisci-type reactions in biological systems provides a nice illustration of how a one-time nineteenth century chemical curiosity, rarely encountered in simply-equipped organic chemistry laboratories, has blossomed, to encompass the modern-day study of such processes in highly-sophisticated cellular systems (complex chemistry laboratories!).


Radical additions to bases found in DNA or RNA144–146
Scheme 48 Radical additions to bases found in DNA or RNA144–146

Use of Minisci methylation and amidation to model DNA damage with radicals147,148
Scheme 49 Use of Minisci methylation and amidation to model DNA damage with radicals147,148

Site of radical reactions for bases found in DNA143,149
Scheme 50 Site of radical reactions for bases found in DNA143,149

4 Future developments

4.1 ‘High Content’ libraries

An under-utilized, yet potentially powerful application of Minisci chemistry, is in the production of chemical libraries. There are at least two themes that could be developed further. The first, involves the use of a single Minisci reaction, undertaken in a parallel manner, to prepare small arrays. Such an approach was recently used by Baran and colleagues to prepare a 17-membered 2-aryl-4-tert-butylpyridine library (Scheme 51).66
Library synthesis using Baran's version of a Minisci reaction66
Scheme 51 Library synthesis using Baran's version of a Minisci reaction66

The second approach, and one highlighted by our own research group, is to use different variations of Minisci functionalization to introduce diverse substituents within a pharmacologically-active scaffold.18 Thus, one could introduce diverse substituents such as alkyl, cycloalkyl (e.g. cyclopropyl), fluoroalkyl (e.g. CF3), aryl, carbamoyl, oxetan-3-yl, azetidin-3-yl, trialkylsilyl, hydroxymethyl, C-glycoside, and other groups, from a common starting material (Scheme 52). One possible application of such a strategy would be the functionalization of approved drugs containing appropriate heteroaromatic cores. Since it has been said that the best way to find a new drug is to start from an existing one,150 such an exercise may give-rise to a ‘high-content’ library for screening against multiple biological targets, with an aim of unearthing new pharmacology, or optimizing against a known biological target. The adoption of Minisci chemistry to introduce diverse substituents is also attractive from a synthetic perspective. As has recently been discussed, medicinal chemists tend to use a relatively small variety of reactions in their syntheses.151 Minisci chemistry provides a formidible set of transformations which would make a fine addition to the compendium of routine organic reactions employed by medicinal chemists.


Potential synthesis of a ‘high content’ library by functionalization of pharmacologically-active heteroaromatics using Minisci chemistry to introduce multiple and diverse substituents18
Scheme 52 Potential synthesis of a ‘high content’ library by functionalization of pharmacologically-active heteroaromatics using Minisci chemistry to introduce multiple and diverse substituents18

Conclusions

In conclusion, this review describes the addition of radicals to heteroaromatic bases, which are commonly referred to as Minisci reactions, and details specific examples of these methods to the fields of medicinal and biological chemistry. Rather than describing one particular transformation, Minisci chemistry encompasses a whole set of related CH-functionalization processes for the introduction of diverse functional groups in to heteroaromatic systems. In many cases, these processes are highly chemo- and regio-selective, which makes them ideal for industrial applications, since complicating factors like protecting group strategies can be avoided. Like any synthetic procedure, there are limitations; the most frequently encountered with Minisci chemistry being a modest yield of product after purification, which itself may sometimes be cumbersome. The versatility of Minisci chemistry is exemplified by the successful use of these reactions to prepare marketed COMPOUND LINKS

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camptothecin
analogues, as key-steps in the synthesis of compounds undergoing clinical evaluation, and for the introduction of privileged motifs such as trifluoromethyl, COMPOUND LINKS

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oxetane
and COMPOUND LINKS

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azetidine
groups, amongst others. Although there is ample evidence that Minisci chemistry is particularly suited for medicinal and biological applications, its widespread use by chemists working in these areas is far from routine. New developments, such as the use of boronic acids and COMPOUND LINKS

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potassium
trifluoroborates as radical precursors may be helpful in promoting these reactions to a wider audience. Similarly, an increased use in library synthesis may also assist in the utilization of this methodology. Looking ahead, there are many more new developments and uses of Minisci reactions within medicinal and biological chemistry settings. In order to realize the potential of these reactions, medicinal chemists are encouraged to use this chemistry fequently. Indeed, it is not hard to envisage a time when Minisci reactions become a routine set of transformations for chemists looking to functionalize a heteroaromatic compound with biological activity.

Acknowledgements

We thank Amelia Cervantes and Rigel Pharmaceuticals, Inc. for obtaining a small selection of references used in this review. Jing Zhang is thanked for translation of a Chinese patent application (ref. 91). We also thank a referee for highlighting the relative contributions of enthalpic and polar effects in perfluoroalkylation reactions of heteroaromatic bases, and recommending ref. 57a and 57b for further reading.

Notes and references

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    camptothecin
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    MIDA
    boronates in cross-coupling reactions see: M. P. Gillis and M. D. Burke, Aldrichchimica Acta, 2009, 42, 17–27 Search PubMed.
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    trifluoroborates in organic chemistry see: (a) S. Darses and J. P. Genêt, Chem. Rev., 2008, 108, 288–325 CrossRef CAS; (b) G. A. Molander and E. Noel, Acc. Chem. Res., 2007, 40, 275–286 CrossRef CAS.
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    ethylene glycol
    as the hydroxymethyl radical precursor, rather than COMPOUND LINKS

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    methanol
    .
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