pyridines and diazines 
 are among the most prevalent heterocycles 
 in biologically active compounds .
they are found in 2 of the 5 top - selling 
 pharmaceuticals and 6 of the 23 
 small molecules approved by the fda in 2013 . of course , the groups appended to the heteroarene and the 
 heteroarene core together affect the activity of the molecule , 
 not just the heteroarene itself .
thus , studies of the structure  activity 
 relationships ( sar ) require derivatives containing a range of substituents 
 attached to pyridines and diazines .
one potential method to create 
 these derivatives is c  h bond functionalization of the heteroarene . 

yet , few c  h bond functionalization reactions are amenable 
 to late - stage functionalization of heteroarenes . instead
, multistep 
 syntheses are typically conducted to study the effects of substituents 
 on the heteroarene units .
some c  h bond functionalization 
 reactions of heteroarenes 
 have been developed that exploit a directing group , but methods for 
 site - selective functionalization without the influence of such groups 
 would allow modifications at different positions and without the need 
 to install and remove such groups .
the first class comprises minisci - type 
 reactions , which occur by the addition of carbon - centered radicals 
 to heteroarenes ( scheme 1a ) .
these 
 reactions are versatile , but mixtures of isomers are formed in most 
 cases , and the regioselectivity depends on the steric and electronic 
 properties of both the heteroarene and the radical partner . a second class of heteroarene 
 c  h bond functionalization 
 reactions includes additions of nucleophiles to pyridine n - oxides in combination with a reagent to activate and dehydrate the 
 pyridine n - oxide ( scheme 1b ) . reactions of this type have been developed to install br , cl , 
 cn , amino , phenoxy , and nucleophiles derived from reagents containing 
 acidic c  h and n 
h bonds ( pka range of 1020 ) . in most 
 cases , the scope of the pyridine n - oxides that undergo 
 these reactions is limited to those containing ether , ester , and nitrile 
 substituents or halides at positions not reactive toward snar . in general
, functionalization occurs at the 2-position , but competing 
 functionalization at the 4-position or on pendant alkyl groups is 
 often observed .
in addition to these issues of functional group compatibility 
 and site selectivity , the need to prepare and isolate the n - oxides limits the use of these reactions .
most closely 
 related to the work reported here , c  h functionalization 
 reactions at the 2-position of pyridines and pyridine n - oxides have been developed with transition metal catalysts .
however , these reactions are limited to the formation 
 of c  c bonds , and the reaction conditions and scope suggest 
 that these reactions are not suitable for complex substrates .
other functionalizations of heteroaryl 
 c  h bonds involve cross - coupling at the most acidic c 
h 
 bond ; these methods occur most commonly with five - membered ring heteroarenes .
finally , c  h borylation reactions catalyzed by transition 
 metal complexes provide a means to install substituents onto heteroarenes 
 by conversion of the heteroarene to the corresponding heteroarylboronate 
 ester and subsequent transformations of the c  b bond .
however , borylations of pyridines occur predominantly 
 at the 3- and 4-positions and , therefore , are complementary to the 
 reactions at the 2-position described here .
we aimed to develop 
 a method for the late - stage functionalization 
 of pyridines and diazines that would address the limitations of the 
 regioselectivity and scope of c  h functionalizations 
 of heteroarenes .
our approach was inspired by the value of borylation 
 reactions developed in the authors laboratory to create synthetic 
 intermediates that can be converted to a variety of functionalized 
 products .
h 
 fluorination of pyridines and diazines at the position  to nitrogen with agf2 we developed 
 recently could be used for the late - stage functionalization of medicinally 
 relevant compounds because pyridines and diazines are contained in 
 many such compounds and the 2-fluoro group could be replaced with 
 a wide range of nucleophiles .
herein , we report mild conditions 
 for the snar reaction 
 of fluoroheteroarenes , an assessment of the potential 
 of the fluorination and snar reactions to be conducted 
 with complex structures , and the application of these findings to 
 the development of late - stage functionalizations of complex heterocyclic 
 compounds by the combination of c  h fluorination and snar reactions ( scheme 1c ) .
in addition 
 to revealing the potential of this reaction for the functionalization 
 of complex heteroarenes , we demonstrate how the combination of ch 
 bond fluorination and snar creates routes to several active 
 pharmaceutical ingredients that occur in higher yields and fewer steps 
 than previously reported syntheses of these molecules .
snar reactions of 2- or 4-halopyridines comprise 
 a site - specific method to synthesize substituted pyridines .
however , this approach requires initial synthesis 
 and isolation of halogenated pyridines that are typically prepared 
 from pyridine n - oxides or hydroxypyridines 
 with neat pox3 ( x = br , cl ) at high temperatures .
chloropyridines 
 are more available commercially than other halopyridines , but 
 the reactions of fluoropyridines are likely to be faster than 
 those of chloropyridines . as for snar reactions of 
 arenes , the snar reactions of pyridines and diazines are 
 likely to be accelerated by the high electronegativity of fluorine . 

indeed , the reaction of 2-fluoropyridine with naoet in etoh 
 is 320 times faster than the reaction of 2-chloropyridine .
this higher reactivity of fluoropyridines 
 could allow snar reactions to occur under conditions that 
 are mild enough to allow this class of reaction to occur on complex 
 molecules ; however , a more detailed assessment of the rates and yields 
 for the snar reactions of fluoropyridines and diazines 
 would be needed to predict the scope of the snar process 
 and a method to create the 2-fluoropyridines and diazines that 
 could be conducted in a typical laboratory on complex pyridines and 
 diazines would be required .
h 
 bond fluorination and 
 snar , we first evaluated conditions to conduct snar reactions of 2-fluoropyridines .
although snar 
 reactions of electron - deficient fluoroarenes and 
 chloropyridines are commonplace , few studies have been performed on snar reactions of 
 fluoropyridines .
the majority of 
 the published reactions of 2-fluoropyridines have been conducted 
 with unsubstituted 2-fluoropyridine ; a few examples were conducted 
 with 2-fluoropyridines containing a single bromide substituent . 

moreover , these reactions were performed under conditions involving 
 strong nucleophiles and bases at high temperatures ( up to 130 c ) , 
 neat reagents , microwave heating , strong reducing agents ( libh3nr2 ) , or toxic solvents ( hmpa ) , and these conditions 
 are unlikely to tolerate the functional groups found in complex molecules 
 relevant to medicinal chemistry .
several snar reactions 
 of 2-fluoropyridines have been reported in the patent literature 
 on both simple and complex substrates .
however , the reactions described 
 in these documents for a given class of nucleophile occur under varying 
 conditions . therefore , the scope of each set of reaction conditions 
 is unclear , and the snar reactions were performed with 
 activated 2-fluoropyridines in most cases . from this body of 
 work , it was unclear whether mild and general snar reactions 
 with fluoroheteroarenes could be developed and if selectivity 
 could be obtained for substitution of fluoride over other halides . 

in fact , previous reports showed that the same forcing reaction conditions 
 lead to substitution of f , cl , br , and i. to identify conditions 
 for the snar reaction that would 
 tolerate common functionality , we studied reactions of unactivated 2-fluoropyridines with nucleophiles derived from alcohols , 
 phenols , amines , amides , n - heterocycles , cyanide , and thiols 
 under relatively mild conditions .
the reaction conditions we identified 
 afforded quantitative conversion to the substitution 
 products , as indicated by gc / ms and tlc ( table 1 ) .
variation 
 of the cyanide source , stoichiometry , temperature , and solvent did 
 not increase the yield , but the initial conditions did form the cyanopyridine 
 product in a synthetically useful yield . having
developed a set of 
 snar reactions that occur under mild conditions , we explored 
 the tandem fluorination  substitution process . for the snar reactions to occur 
 in tandem with c 
h 
 fluorination , the mecn and silver salts from the fluorination reaction 
 needed to be removed .
filtering the fluorination reactions through 
 a short silica - filled pipet and evaporating the solvent was sufficient 
 to perform the subsequent snar reactions .
yields of the 
 snar reactions conducted after filtering the fluorination 
 reaction through celite were low , due to the presence of soluble ag 
 salts . for the fluorination 
snar 
 sequence to be used broadly , procedures for conducting the reaction 
 without specialized equipment for excluding air and moisture are needed . 

therefore , during our initial study , the fluorination 
 reactions were assembled in a glovebox with rigorously dried mecn . however , despite the water sensitivity of agf2 , simple procedures can be followed for conducting the reactions 
 without rigorous exclusion of air or moisture . to assess the 
 impact of water and oxygen on the yield of the fluorination reaction 
 of complex molecules
, we performed a series of experiments with ( co2me)-vismodegib , a drug recently approved for the treatment 
 of basal - cell carcinoma ( table 2 ) . assembling 
 the fluorination reaction in a glovebox ( oxygen and water content 
 < 1 ppm ) , in an oven - dried vial , with mecn
that had been rigorously 
 dried over cah2 , afforded the fluorinated vismodegib derivative 
 in 99% yield by f nmr spectroscopy .
reactions were 
 performed with 0.2 
 mmol of ( co2me)-vismodegib with 2 ml of mecn in 4 ml vials .
since the use of a glovebox 
 is not practical for all chemists , 
 we studied the effects of weighing the solid reagents in air and assembling 
 the reaction using standard air - free techniques .
a reaction was assembled 
 by adding the pyridine substrate to a dry vial in air and adding mecn 
 that had been dried over cah2 .
agf2 was weighed 
 quickly in air , added to the pyridine solution , and the vial was sealed 
 under an atmosphere of n2 .
the reaction assembled in this 
 manner afforded the 2-fluoropyridine product in 84% yield , only 
 a slight decrease in yield compared to the reaction assembled entirely 
 in the glovebox . performing the reaction in a similar manner with 
 a nondried vial and sealing the reaction under an atmosphere of air 
 ( 2 ml of mecn in a 4 ml vial ; 2 ml headspace of air ) resulted in a 
 similar yield of the fluoropyridine product ( 79% ) .
acetonitrile 
 dried with 5 wt % of 3  molecular sieves for 
 24 h was a suitable solvent ; the reaction of ( co2me)-vismodegib 
 with agf2 assembled by weighing the solid reagents in air 
 in a nondried vial sealed under an atmosphere of air afforded the 
 fluorinated product in 85% yield . the water content in mecn dried 
 over 5 wt % molecular sieves for 24 h is near 4 ppm , and the water 
 content further decreases with time .
mecn is below 
 10 ppm water and should be equally suitable for this reaction .
finally , the same reaction was assembled in air with acs grade 
 mecn directly from a commercial bottle that had been opened and used 
 over the course of a year ; a noticeable decrease in yield to 65% was 
 observed , but a substantial amount of product was still formed .
together , 
 these results demonstrate that these fluorination reactions can be 
 conveniently assembled completely in air , without the use of a glovebox 
 or air - free techniques , and with mecn dried over molecular sieves , 
 even though agf2 is sensitive to water and should be stored 
 under an inert atmosphere .
reactions performed on the benchtop occur 
 in yields that are comparable to those performed under rigorously 
 anhydrous reaction conditions .
agf2 is supplied as 
 a black , microcrystalline 
 solid , which should be stored under an inert atmosphere .
because agf2 undergoes decomposition with moisture , a noticeable color 
 change from black to yellow or brown is observed when it is stored 
 in air . for all reactions reported here , and in our previous paper , agf2 was used as received from alfa 
 aesar and stored under a nitrogen atmosphere in a plastic bottle . 
 in our experience , reactions with agf2 supplied from strem 
 occurred in comparable rates and yields to those performed with agf2 puchased from alfa aesar .
having identified convenient 
 methods for conducting both the fluorination and snar reactions 
 and having developed a protocol to conduct the two reactions in sequence , 
 we investigated the scope of the ch bond fluorination 
representative examples illustrating the scope 
 of the combined reactions are shown in tables 3 and 4 .
yields given are for isolated products 
 starting from the heteroarene . the yields for the fluorination 
 step are also shown to illustrate how the values for the two - step 
 process compare to those of the first step .
isolated yields 
 from the two - step 
 sequence for reactions performed with 0.2 mmol of heteroarene .
yields 
 in parentheses were determined by f nmr spectroscopy 
 for the independent fluorination reaction .
isolated yields from the two - step 
 sequence for reactions performed with 0.2 mmol of heteroarene . 

yields in parentheses were determined by f nmr spectroscopy 
 for the independent fluorination reaction .
the isolated product contained 5% 
 of an inseparable impurity . a variety of pyridines that are sterically hindered ( 2 , 4 , 11 , 12 , 14 , 15 ) and/or electronically deactivated ( 2 , 9 , 13 , 15 ) toward snar reactions afforded the substitution products in good yields
. 
 substrates containing alkyl groups in the 2-position reacted selectively 
 at the 6-position ( 2 , 4 , 9 , 14 ) , while analogous reactions with pyridine n - oxides are known to result in substitution of a c  h bond 
 on the alkyl group ( scheme 1b ) .
a wide range 
 of functional groups were tolerated , including ethers , halides , ketones , 
 acetals , esters , amides , ethyl and t - butyl carbamates , 
 nitriles , and sulfones .
it is notable that the azetidine in 11 ( table 4 ) did not undergo ring opening , 
 a competing reaction observed under acidic conditions .
the reactions of chloropyridines 7 and 11 revealed a high selectivity for substitution 
 of a fluoride 
 over a chloride under conditions of the snar reactions 
 shown in table 1 .
this high selectivity , along 
 with the high functional group compatibility , is attributed to the 
 milder reaction conditions we developed for the snar reaction 
 at the 2-fluoro position , relative to the conditions typically used 
 to conduct substitutions with 2-fluoropyridines . in sum , this 
 work shows that fluoropyridines undergo substitution reactions 
 under conditions much milder than previously reported and can be performed 
 in the presence of a wide range of functional groups , including those 
 that are electrophilic .
six - membered heteroarenes containing two 
 nitrogen atoms ( diazines ) are prevalent subunits in medicinal chemistry . 

radical addition reactions to diazines are commonplace ( scheme 1a ) , but a single example 
 of ch bond functionalization by nucleophilic addition 
 of a heteroatom to a diazine n - oxide ( scheme 1b ) has been demonstrated . like pyridines , diazines react with agf2 with exclusive 
 selectivity for fluorination adjacent to nitrogen .
h 
 bond fluorination and snar reactions could be conducted 
 with these heterocycles to form functionalized diazine products .
indeed , pyrimidines ( 5 , 6 ) and pyrazines 
 ( 8) reacted in the two - step sequence following the standard 
 conditions we developed for the fluorination and snar reactions 
 reported in table 1 .
because the conditions for both the fluorination 
 and the snar reactions with diazines are the same as those 
 for pyridines , the tolerance of the reactions toward functional groups 
 on pyridines and diazines should be comparable .
this c  h fluorination  snar sequence was also applied to the synthesis of a reverse 
 transcriptase inhibitor containing a tetra - substituted pyrimidine 
 ( vide infra ) . with conditions established for the fluorination and snar reactions of pyridines and diazines
, we evaluated this sequence 
 for the late - stage functionalization of more complex molecules in 
 medicinal chemistry .
first , we used our tandem sequence to prepare 
 several 2-substituted derivatives of ( boc - protected ) betahistine ( 9 ) , a histamine agonist used in the treatment of mnire s 
 disease .
reaction of 9 with agf2 formed the 
 corresponding 2-fluoropyridine in nearly quantitative yield 
 ( 98% ) .
this electronically deactivated fluoropyridine intermediate 
 reacted with nucleophiles derived from butanol , morpholine , and indole 
 to provide several 2-substituted analogues of betahistine .
although 
 betahistine is a relatively simple compound that can be prepared in 
 one step from 2-vinylpyridine , the synthesis of derivatives 
 that are similar to those we report here would require 2-substituted 
 6-vinylpyridines .
thus , our ch bond fluorinationsnar strategy for late - stage functionalization avoids lengthy 
 synthetic sequences to prepare derivatives of betahistine .
we 
 also conducted the fluorination of compound 10 , the direct 
 precursor to loratadine ( claritin ) and desloratadine ( clarinex ) , two 
 common antihistamines .
compound 10 is prepared 
 in two steps from 3-methylpicolinic acid under relatively harsh 
 reaction conditions ( buli , kobu for the first step ; socl2 , alcl3 for the second step ) .
therefore , 
 the synthesis of 2-substituted derivatives of 10 would 
 require access to the appropriately substituted 3-methylpicolinic 
 acid , which could require several steps to prepare , and an additional 
 two - step sequence to construct the tricycle for each derivative .
we 
 prepared various analogues of 10 more directly through 
 fluorination and snar reactions to form the corresponding 
 2-alkoxy- , 2-amino- , and 2-pyrazolyl - substituted derivatives .
it is 
 worthy to note that the substituents we installed in 10a10c would be unlikely to tolerate the conditions 
 of a de novo synthesis of similar analogues of 10 .
our c  h functionalization method also gave access to a series 
 of ( boc - protected ) derivatives of tebanicline ( 11 ) , a 
 potent non - opiod analgesic that is structurally related to several 
 nicotinic acetylcholine receptor agonists .
as mentioned above , 
 no ring opening of the azetidine or substitution of the chloride was 
 observed .
de novo syntheses of compounds similar to 11a11c would require access to 2-substituted 3-hydroxy-6-chloropyridine 
 substrates and an additional c  o bond - forming reaction to complete 
 the synthesis of each derivative . the sequence of c 
h 
 bond fluorination and snar 
 also led to a convenient synthesis of 2-alkoxy and 2-amino analogues 
 of roflumilast ( 12 ) .
roflumilast is a recently approved 
 pde-4 inhibitor used in the treatment of chronic obstructive pulmonary 
 disease .
thus , the syntheses 
 of the 2-substituted analogues we report would require access to 2-alkoxy 
 or 2-amino-3,5-dichloro-4-aminopyridine , for which none 
 are commercially available .
therefore , preparing derivatives of roflumilast 
 would mandate multistep syntheses of the appropriate pyridine , in 
 addition to performing the subsequent amide bond formation for each 
 derivative .
in contrast , the ch fluorinationsnar strategy we report allows rapid access to analogues that 
 would otherwise require several synthetic steps to prepare . in a similar manner , analogues of the precursor to pirenzepine 
 ( 13 )
, a benzodiazepine - based m1-selective antagonist 
 used for the treatment of ulcers , were prepared .
the sequence was 
 used to install alkoxy , thio , and aryloxy substituents at the 2-position 
 in good overall yields .
the synthesis of the core of 13 requires three steps from 2-chloro-3-aminopyridine . because many medicinally 
 important compounds contain multiple heteroaryl rings , it would be 
 valuable if the fluorination was selective for the functionalization 
 of one type of ring system over another . the proposed mechanism for the fluorination of pyridines and diazines 
 with agf2
( eq 1 ) is initiated by 
 coordination of the basic nitrogen to silver .
this coordination could 
 cause a more basic heterocycle to be more reactive than a less 
 basic heterocycle .
however , the second step in the proposed 
 mechanism is addition of fluoride to the  system , which would 
 be favored for a more electron - deficient heteroarene .
finally , the 
 third step , a formal oxidation of the heterocycle through hydrogen 
 atom abstraction , would likely be favored for a more electron - rich 
 substrate .
our previous studies of the selectivity between pyridine 
 and pyridine - d5 demonstrated that coordination 
 of agf2 to pyridine is reversible and that cleavage of 
 the c  h bond is irreversible.1 to determine how the electronic properties 
 of the heteroarene influence the relative rates of fluorination , we 
 conducted a series of competition experiments . in these experiments , 

agf2 was allowed to react with a 1:1 mixture of two different 
 pyridines and diazines . because the yield of the fluorination reactions 
 conducted with a large excess of pyridine , relative to agf2 , is low
, reactions containing 1 equiv of each heteroarene 
 ( 0.1 mmol each ) and 2 equiv of agf2 ( 0.2 mmol ) were run , 
 and the reactions were quenched after 15 min so that the selectivities 
 were being measured at low conversion ( 25  2% ) .
competition 
 experiments between 2-ethyl , 2-methoxy , and 2-chloropyridine 
 were conducted ; the steric properties of these substrates are similar 
 to each other , but the basicity of the heterocycles differ incrementally 
 from each other by 2.6 pka units . 

competition experiments were also conducted between alkyl - substituted 
 pyridines , pyrimidines , and pyrazines containing two available c 
these data show that 
 more lewis basic pyridines undergo the c  h fluorination reactions 
 in preference to less lewis basic pyridines .
moreover , exclusive selectivity 
 for fluorination of a 4-alkylpyridine over two alkyl - substituted 
 diazines was observed ; the competition between 2-methylpyrimidine 
 and 2,3-dimethylpyrazine showed that the pyrimidine was 
 the more reactive diazine by a factor of 3.3 .
product ratios were determined by f nmr spectroscopy of the crude reaction mixture after quenching 
 with aqueous nahco3 .
the results of these competition experiments contrast with what 
 would be predicted based only on the relative rates of independent 
 reactions between each substrate and agf2 .
2-ethylpyridine 
 reacts with 2 equiv of agf2 to give 38% yield of the 6-fluoropyridine 
 after 15 min .
similarly , 2-methoxypyridine reacts in 36% yield , 
 and 2-chloropyridine reacts in 9% yield after 15 min . because 
 the rates for fluorination of 2-ethylpyridine and 2-methoxypyridine 
 are comparable , and because agf2 is present in excess , 
 little selectivity for 2-ethylpyridine over 2-methoxypyridine 
 would be expected based on these data alone .
however , agf2 has negligible solubility in mecn ; therefore , competitive binding 
 of the two substrates to the limited amount of available agf2 likely results in fluorination of the more basic pyridine.2 to assess the relative reactivity of multiple pyridines in 
 the 
 context of a medicinally important compound , we conducted the fluorination 
 and snar reaction of etoricoxib ( eq 2 ) , a selective cox-2 inhibitor used in the treatment of arthritis . 

the more electron - rich 
 ring contains methyl and 2-pyridyl substituents , and the less electron - rich 
 ring contains chloro , aryl , and 3-pyridyl substituents .
this molecule 
 reacted with agf2 with complete selectivity 
 for fluorination of the more basic pyridine system , as predicted from 
 the results in table 5 .
following 
 this site - selective fluorination , several derivatives of etoricoxib 
 containing pendant alkoxy , amino , cyano , and pyrazolyl units were 
 prepared .
many medicinally active pyridines contain two inequivalent c  h 
 bonds that could undergo fluorination with agf2 .
we previously 
 demonstrated that several 3-substituted 
 pyridines undergo fluorination with exclusive selectivity to form 
 the 2-fluoro-3-substituted pyridine product .
the 3-substituted pyridines 
 that react selectively at the 2-position include those containing 
 3-halo , alkoxy , cyano , or cf3 groups . 3-substituted pyridines 
 that give a mixture of 2-fluoropyridine isomers include those 
 containing 3-alkyl , 3-co2r , and 3-c(o)nr2 substituents . 

it was unclear from these results if 3,5-disubstituted pyridines would 
 undergo the fluorination selectively .
a set of 3,5-disubstituted pyridines 
 containing phenyl , cyano , benzyloxy , bromo , methyl , and cf3 substituents was prepared .
the fluorination of the 15 unsymmetrical 
 pyridines containing these substituents occurred with poor site selectivity 
 ( from 1:1 up to 6:1 ) , with the exception of the benzyloxy - substituted 
 pyridines .
the 3-benzyloxy - substituted pyridines containing various 
 substituents in the 5-position reacted with agf2 with modest 
 to high selectivity ( 4.2:1 to 20:1 ) for fluorination adjacent to the 
 ether substituent ( table 6 ) .
having shown that an 
 alkoxy group can lead to selective fluorination 
 of a 3,5-disubstituted pyridine , we exploited this selectivity to 
 conduct the late - stage fluorination of a medicinally relevant , 3,5-disubstituted 
 pyridine .
the core of crizotinib ( eq 3 ) , a drug 
 used for the treatment of metastatic non - small cell lung cancer , contains 
 such a heteroaromatic unit .
reaction of 15 with 
 agf2 gave products reflecting a 7.2:1 selectivity for fluorination 
 adjacent to oxygen .
this selectivity is lower than that observed for 
 the fluorination of 3-bromo-5-benzyloxypyridine ( table 6 ) , likely due to the steric hindrance of the arylethoxy 
 substituent . to determine
if the lower selectivity of this substrate 
 is due to the greater steric hindrance of the benzyloxy group of 15 than that of a simple benzyloxy substrate , the fluorination 
 reaction was also performed with a 2,6-dimethylphenyl arylethoxy 
 substrate .
this compound reacted in 62% yield with similar 5.9:1 selectivity 
 for fluorination adjacent to the ether substituent .
thus , the selectivity 
 is lower for reactions of pyridines containing more hindered benzyloxy 
 groups but is still significant .
the steric hindrance of the arylethoxy 
 substrates disfavors both the second and third steps in our proposed 
 mechanism ( eq 1 ) 3leading to an increase in the relative amount 
 of product from fluorination adjacent to the bromide .
even though 
 the 2-fluoro-3-benzyloxypydridine intermediate 
 is both sterically and electronically deactivated toward snar , several 2-substituted derivatives were prepared under the standard 
 conditions for the snar step shown in table 1 .
even a secondary amine reacted with the 2-fluoropyridine 
 to form the sterically congested product 15c .
snar reactions were not separable by standard silica gel chromatography , 
 even though the 2-fluoropyridine isomers could be separated 
 by hplc and gc . although we have demonstrated 
 that the c 
h 
 fluorination and snar reactions occur with broad scope 
 and can be conducted on complex molecules , there are some limitations . 
 as we reported previously ,
the fluorination 
 reaction is not compatible with free amines or alcohols , carboxylic 
 acids , aldehydes , or electron - rich five - membered heterocycles ; however , 
 several protected derivatives of these groups are tolerated by agf2 .
in addition , we have found that pyridines or diazines containing 
 multiple electron - withdrawing substituents undergo the fluorination 
 reaction in lower yields than those containing electron - neutral or 
 electron - donating groups .
examples of substrates that reacted with 
 agf2 in low yields ( 030% ) are shown in table 7 .
although the boc - protected derivative of hg-10 - 102 - 01 
 reacted with agf2 in low yield , a similar tetra - substituted 
 pyrimidine reacted in high yield for the synthesis of etravirine ( vide 
 infra ) .
we have demonstrated that 
 a simple set of snar reaction 
 conditions can be employed for substitution reactions on a variety 
 of 2-fluoroheteroarenes .
however , we did find substrates 
 that underwent competing side reactions faster than they underwent 
 snar ( table 7 ) .
fluorinated analogues 
 of tropicamide underwent retro - michael addition under the basic reaction 
 conditions .
although we demonstrated that tert - butyl 
 esters remain intact during the snar reactions ( table 3 , substrate 3 ) , we found that aryl 
 acetates are cleaved faster than substitution of fluoride .
finally , very electron - rich and sterically hindered pyridines , such 
 as the precursor to nexium , underwent the snar step in 
 low yields ; more forcing conditions resulted in the formation of side 
 products .
snar 
 sequence for the late - stage derivatization of medicinally important 
 compounds , we sought to evaluate whether the same strategy could create 
 shorter and higher - yielding synthetic routes to the same types of 
 compounds .
although this chemistry requires stoichiometric silver 
 and is not designed for process - scale chemistry , the strategy of c  h 
 fluorination and snar can be useful in discovery chemistry . 

one example of a synthesis that could be simplified by the fluorination 
 and substitution process is the synthesis of the simple compound 6-(methylamino)-2-pyridineethanol 
 ( scheme 2 , 16 ) .
compound 16 is a precursor to several important compounds , including 
 the integrin inhibitor sb-273005 ( scheme 2c ) . 

although 16 is structurally simple , the two reported 
 syntheses of 16 by medicinal chemists were conducted 
 in five and seven steps from 2-amino-6-methylpyridine ( scheme 2a ) .
we considered that the 2-methylamino group 
 could be installed through c  h bond fluorination and snar from a derivative of 2-pyridineethanol .
fluorination did not occur on the free alcohol , but it 
 did occur 
 after protecting the alcohol as an ester . an acetyl protecting group 
 was chosen because it could be cleaved in concert with the snar reaction .
the fluorination of acetylated 2-pyridineethanol 
 occurred in 88% yield ( by f nmr spectroscopy ) .
treatment 
 of the crude mixture from the fluorination step with aqueous menh2 in dmso led to formation of the methylaminopyridine 
 unit and cleaveage of the acetyl group to reveal 
 the free alcohol .
this route gave 16 with only two isolations 
 in 64% overall yield , a significantly shorter and higher - yielding 
 approach than the reported syntheses requiring five or seven steps . 

although our route requires stoichiometric silver , it is worthy 
 to note that an improved process used to prepare 30 g of 16 still required four steps and occurred in only 39% overall yield .
the combination of c  h bond fluorination 
 and snar also shortened the synthesis of pf-1247324 , a 
 potent and selective 
 nav1.8 inhibitor ( scheme 3 ) .
the medicinal chemistry route to this compound 
 comprised six steps and occurred in less than 1% yield ; an advanced 
 intermediate was outsourced for the kilogram - scale synthesis of pf-1247324 .
the fluoropyridine intermediate 
 contains two electrophilic sites for nucleophilic substitution : a 
 methyl ester and a 2-fluoropyridine .
we demonstrated ( tables 3 and 4 ) that substitution 
 at the fluorine of a 2-fluoropyridine can occur in the presence 
 of auxiliary electrophilic functional groups , including a tert - butyl ester .
however , we considered that conditions 
 could be identified to transform the methyl ester to the n - methyl amide without substitution of the fluoride .
the reaction 
 between the fluoropyridine methyl ester with aqueous menh2 in thf formed a mixture of products resulting from substitution 
 of both methoxide and fluoride .
however , simply changing the reaction 
 solvent from thf to meoh allowed for the selective transformation 
 of the methyl ester to the n - methyl amide without substitution of the fluoride .
after aqueous workup , the crude reaction mixture was treated 
 with 
 ammonium hydroxide in dmso to substitute an nh2 group for 
 the fluoride .
finally , the 3-bromopyridine was subjected to 
 the reported suzuki cross - coupling reaction conditions to provide the title compound . by our route
, 
 the synthesis of pf-1247324 involving c  h fluorination was 
 completed with just three total isolations in 51% overall yield , a 
 major improvement in yield and step count over the published synthesis . 

furthermore , the route performed by medicinal chemists required 120 
 h of total reaction time , while the route we report here required 
 less than 18 h. finally , we used our chemistry to prepare the 
 non - nucleoside reverse 
 transcriptase inhibitor intelence ( etravirine , scheme 4 ) , a compound used in the treatment of hiv .
the route to this 
 compound developed by medicinal chemists occurred in five steps and 
 9% yield from n-(4-cyanophenyl)guanidine hydrochloride .
an alternative route used to prepare etravirine 
 on kilogram scale required four steps and occurred in 30% yield .
our synthesis of etravirine began with substitution of 
 the 4-chloro 
 substituent in 2,4-dichloro-5-bromopyrimidine with 2,6-dimethyl-4-cyanophenol , 
 from which the solid product was isolated after the addition of water . 

next , substitution with 4-aminobenzontirile and boc protection 
 in situ was conducted , and the product was isolated in 88% yield . 
 the installation of a protecting group for the n 
the 
 synthesis of etravirine was then completed by c  h fluorination 
 of the pyrimidine ( 71% yield by f nmr spectroscopy ) , 
 substitution with aqueous ammonia , and addition of hcl(aq ) to cleave the boc group . through this route , etravirine was prepared 
 with three total isolations in 45% overall yield in under 6 h of total 
 reaction time .
in summary , we have developed 
 a broadly applicable strategy for 
 the diverse , site - selective c  h functionalization of pyridines 
 and diazines .
the reaction sequence occurs to provide alkoxy- , aryloxy- , 
 amino- , amido- , heteroaryl- , thio- , and cyano - substituted heterocycles 
 that can be difficult to access through traditional methods .
this 
 tandem sequence is attractive for the direct diversification 
 of heteroarenes , due to the exquisite site selectivity for c 
in addition , high site selectivity for the fluorination 
 of substrates containing more than one heteroarene or more than one 
 reactive c  h bond is possible using this chemistry .
finally , 
 the process of fluorination and snar can allow medicinal 
 compounds containing substituted pyridines and diazines to be prepared 
 by short synthetic routes .
we anticipate that these reactions will 
 find immediate use for both late - stage functionalization and efficient syntheses of complex molecules .
 we report the late - stage functionalization 
 of multisubstituted 
 pyridines and diazines at the position  to nitrogen . by this 
 process 
 , a series of functional groups and substituents bound to the 
 ring through nitrogen , oxygen , sulfur , or carbon are installed . 
 this 
 functionalization is accomplished by a combination of fluorination 
 and nucleophilic aromatic substitution of the installed fluoride . 
 
 a diverse array of functionalities can be installed because of the 
 mild reaction conditions revealed for nucleophilic aromatic 
 substitutions ( snar ) of the 2-fluoroheteroarenes . 
 
 an evaluation of the rates for substitution versus the rates for competitive 
 processes provides a framework for planning this functionalization 
 sequence . 
 this process is illustrated by the modification of a series 
 of medicinally important compounds , as well as the increase in efficiency 
 of synthesis of several existing pharmaceuticals . 
Introduction
Results and Discussion
Summary