ly2784544 
 has been identified as a selective inhibitor of jak2-v617f 
 and has undergone clinical trials for the treatment of several myeloproliferative 
 disorders ( scheme 1 ) .
a significant challenge associated with the formation of the functionalized 
 imidazopyridazine is the introduction of the benzylic morpholine unit . 
 a first - generation synthesis employed a silver - catalyzed minisci radical 
 alkylation with n - phthaloylglycine 
 ( scheme 1 ) .
this method suffered from poor 
 selectivity for the desired c-8 position , as well as forming significant 
 quantities of a bis - alkylation product . at large 
 scale , the minisci chemistry proved challenging due to the insolubility 
 of the products and the thick mixtures that were formed .
additionally , 
 from a route design perspective , formation of the morpholine in this 
 fashion was undesirable due to the use of a protecting group . in order to address these concerns ,
a second - generation synthesis , which employed 
 a vanadium - catalyzed addition of n - methylmorpholine - n - oxide ( nmo ) was developed that displayed greater scalability , 
 improved yield , and product quality .
this method ultimately delivered 
 > 1 metric tonne of imidiazopyridizine 2 in a highly 
 reproducible 
 manner .
while the exact mechanistic pathway for this reaction has 
 not been elucidated , one possibility proceeds via the intermediacy 
 of an -amino radical .
other methods for generation of the intermediate 
 radical were subsequently investigated , including the use of photochemistry . 

initial studies found that under irradiation with a hg - lamp , a range 
 of sensitizers were successful in promoting the addition of n - methylmorpholine ( nmm ) to the pyridazine core , albeit 
 in low conversions and with relatively high levels of impurities . 

the use of nmm would represent a significant advantage as it is available 
 at greatly reduced cost and the safety and bulk sourcing concerns associated with anhydrous nmo would be 
 alleviated .
visible light - mediated photocatalysis has developed 
 into a defined 
 research field with a recent increase in both the number and diversity 
 of reported transformations . within this 
 arena
the generation 
 of -amino radicals has been demonstrated 
 from both unfunctionalized amines , and 
 those containing adjacent activating groups such as co2h or tms .
while most reports demonstrate the addition of -amino radicals 
 to activated alkenes , macmillan ( scheme 2a ) has shown the efficient arylation 
 of simple n - aryl amines with either cyano or chloro- 
 substituted arenes and heteroarenes . furthermore , given the quantity 
 of established methods for the functionalization of amine containing 
 compounds , there remain relatively few efforts that have demonstrated 
 the applicability of photocatalysis to a pharmaceutical or agrochemical 
 setting , especially with regard to the formation of challenging bond 
 constructs .
recent elegant studies by nagib and macmillan as well as dirocco and co - workers , among others have identified photocatalysis as an efficient strategy 
 for the functionalization of biologically relevant heterocycles ( scheme 2b ) .
these reported methods appear ideally suited 
 for the rapid generation of a collection of compounds during early 
 stage discovery chemistry .
later stage development demands a different 
 set of criteria , notably selectivity , efficiency , and scalability . 

a limited number of recent reports have demonstrated the use of photocatalysis 
 en route to known pharmaceutical compounds , such as the efficient 3-step synthesis of pregabalin , albeit in a racemic fashion and with the key 
 step conducted on < 100 mg scale .
considering the scarcity of industrially relevant examples 
 and 
 the unanswered questions of how visible light photocatalysis should 
 best be conducted at production scale , it currently remains unclear 
 whether it can be successfully applied in a process development setting . with these questions in mind
, we envisioned the introduction of 
 the benzylic morpholine in ly2784544 as an ideal opportunity to test 
 the viability of a photoredox transformation in a complex pharmaceutical 
 setting ( scheme 2c ) .
we were particularly drawn 
 to the mild reaction conditions and functional group tolerance typically 
 associated with visible light - mediated photocatalysis and furthermore 
 were encouraged by the precedent for the efficient formation of -amino 
 radicals .
we started with 
 initial conditions 
 similar to those reported for the -arylation of n - aryl amines but employed oxygen as 
 the terminal oxidant by running the reactions open to air .
our light 
 source consisted of 2  4 w blue led light strips which raised the temperature of the reaction 
 to 35 c . after 7 h , using 2 mol % of ir(ppy)3 , with 20 equiv of nmm , all of the imidazopyridazine 
 starting material had been consumed ( as measured by hplc ) .
the desired exo isomer 2 ( the product of addition from 
 a speculated radical at the exocyclic ch3 position ) was 
 identified as the major product ( 63% area / area ( a / a ) hplc ) ( scheme 3 ) .
an expected major impurity , the endo regioisomer 3 ( the product of addition from a speculated 
 radical at the endocyclic ch2 group ) , was present in 11% 
 ( or 5.7:1 exo : endo ) which is greater 
 than that observed in the second generation route employing nmo and 
 vo(acac)2 where the endo isomer was formed 
 in < 5% .
consistent with the previous minisci alkylation the competitive 
 addition of the -amino radical to the c-7 position of the imidazopyridazine 
 ( 4 ) was observed , albeit in greatly reduced quantity 
 ( 3% vs 25% ) .
further impurities unique to 
 the photocatalysis protocol were identified 
 as the reduction of the carbon - chlorine bond ( 5 ) ( 6% ) , 
 which is not unexpected given the precedent for photocatalysed aryl 
 halide bond reduction .
more interestingly 
 the product of formal methylation of the imidazopyridazine ( 6 ) ( 5% ) and of the addition of dma ( 7 ) ( 12% ) 
 were also present . while the crude 63% a /
a of the desired product 
 appeared high under these conditions , the reaction was inconsistent 
 and the isolation of pure 2 via chromatography proved 
 challenging .
furthermore , the bis - alkylation product 8 , a significant impurity in the n - phthaloylglycine 
 minisci reaction , could not be reliably resolved using the existing 
 hlpc method . in order to quantify the reaction products with 
 more certainty , 
 an analytical uplc ( ultra performance liquid chromatography ) method 
 was developed with both a photodiode array ( pda ) and mass detection 
 ( qda ) analyzer , which proved pivotal for the further optimization 
 of this reaction .
these analytical systems allowed the analysis of 
 a reaction mixture to a higher level of sensitivity in greatly reduced 
 time . at this juncture , we decided to control the reaction temperature 
 via the use of a jacketed beaker connected to a recirculating chiller . 

previously , the temperature of the reaction had been influenced by 
 the light - source , a feature that can be often overlooked .
running 
 the reaction at 22 c and using a 1 w led strip , while monitoring 
 with the updated analytical methods , the reaction was found to be 
 complete ( < 5% 1 remained ) in 16 h. the desired exo isomer 2 , was again the main component 
 in the reaction mixture ( 65% a /
a ) with a calculated uplc yield of 
 57% and 59% respectively , for the two quantitation methods ( uplc - pda 
 and uplc - qda ) ( table 1 entry 1 ) . under these conditions
the exo : endo ratio was 5.5:1 , while the other quantifiable 
 impurities were individually controlled to < 5% . through improved chromatography conditions , 2
this agreement between the two analytical 
 yields and the isolated material provided us with confidence in our 
 analytical method going forward .
we next sought to utilize the 
 jacketed beaker system by exploring the reaction at lower temperature . 
 at 5 c a similar yield and exo : endo ratio
could be obtained in only 8 h , potentially due to higher oxygen 
 solubility at this temperature ( table 1 , entry 
 2 ) .
further evidence of the important 
 role of oxygen was observed when the reaction was run at twice the 
 scale , resulting in a significant decrease in yield ( entry 3 ) .
this 
 is attributed to a decrease of relative surface area of solution exposed 
 to air . further probing the effect of 
 oxygen we found a deoxygenated reaction gave minimal product ( < 10% ) 
 ( entry 4 ) . conducting the reaction under an atmosphere of oxygen gave 
 both a reduction in the quantity of 2 and in the exo : endo ratio ( entry 5 ) .
furthermore , 
 a control reaction utilizing a balloon of air equally gave reduced 
 yield and exo : endo ratio ( entry 
 6 ) . in an effort to address the issue of scalability
, air was continuously 
 sparged through the reaction leading to identical reactions at different 
 scales , but with significantly decreased exo : endo ratio and with increased reaction time ( entries 7 and 
 8) .
the poor scalability of this batch reaction was not considered 
 a critical factor at this juncture .
any scale up would likely be more 
 efficiently conducted via continuous processing ; therefore , optimization was continued at the current scale .
the 
 reaction also showed a high degree of sensitivity to the light 
 source . in the absence of led light , or ir(ppy)3 , less 
 than <
5% 2 was observed . varying the total led power , 
 independently of temperature , showed that increasing led power had 
 a detrimental effect on selectivity ( figure 1 ) .
most strikingly , after 4 h with 9 
 w led irradiation < 10% 1 remained ; however , the exo product 2 was only observed in 23% yield . 

the remaining material balance ( by uplc ) contained elevated amounts 
 of previously identified side products ( 5 5% , 4 7% ) but also comprised a large quantity of uncharacterized material 
 that made quantitation of other known impurities such as 6 and 7 difficult ( figure 1 right ) .
uplc chromatograms 
 showing reaction profile at 4 h using a 1 w 
 led ( left ) and a 9 w led ( right ) . while the exo product 2 is 
 stable 
 to the reaction conditions under 1 w led irradiation , increasing the 
 power to 8 w and resubjection to the reaction conditions gave ketone 
 reduction ( 9 ) as the major product ( 35% ) among a complex 
 mixture also containing 6 ( 7% ) and dechlorinated 2 ( 7% ) .
the addition of 5 equiv of formic acid provided a 
 cleaner reaction profile leading to methylation product 6 , isolated in 20% yield ( scheme 4 ) .
this strongly 
 suggests that 6 is derived from 2 and presumably 
 is formed via c 
no significant decomposition 
 of 2 was observed in the absence of ir(ppy)3 or nmm , and was greatly reduced in the absence of oxygen ( 72% 2 remained after 8 h ) suggesting this potentially useful transformation is a photocataylsed process . given the limited 
 solubility of naoac in dma a range of both organic 
 and inorganic bases were screened .
the 
 initial choice of 1 equiv of naoac proved optimal with other bases 
 delivering reduced yield , and surprisingly , reduced exo : endo ratio ( table 2 , entries 
 16 ) .
the exo : endo ratio 
 also varied with the amount of nmm . using 60 equiv a 1.2:1 exo : endo ratio was obtained ( entry 7 ) , 
 lowering the equivalents below 20 displayed a clear trend for increased exo : endo ratio with decreasing quantities 
 of nmm , albeit at the expense of 2 ( entries 810 ) . 

this is potentially rationalized by competition between radical addition 
 of the -amino radical and c  h abstraction from a molecule 
 of nmm .
the primary -amino radical could abstract the weaker 
 secondary c  h bond to give the secondary -amino radical 
 that then may add to the imidazopyridazine core to ultimately generate 
 the endo isomer 3 .
reactions performed 
 at a 0.231 mmol 
 scale , at 5 c with 1.0 mol % ir(ppy)3 , 1.0 equiv 
 of base , 20 equiv of nmm for 8 h unless otherwise stated . calculated 
 by uplc ( pda ) .
reaction 
 performed at a 0.774 mmol 
 scale , at 35 c with 2.0 mol % ir(ppy)3 , for 12 h. calculated via h nmr 
 analysis of the crude reaction mixture .
reaction time of 10 h. seeking to lower the cost burden associated with the 
 use of iridium , 
 we screened a wide range of other common photocatalysts .
all ruthenium complexes tested under the standard 
 reaction conditions returned only starting material ( table 3 , entries 12 ) .
these photocatalysts would 
 likely operate via reductive quenching of the excited state by nmm 
 and their consistent failure to promote the reaction may indicate 
 a general problem when applying reductive quenching to this particular 
 system .
more promisingly , 5 mol % of the organic photocatalyst eosin 
 y provided a 22% yield of 2 after 15 h , but with a reduced exo : endo ratio of 3.7:1 ( entry 3 ) .
other 
 iridium - based photocatalysts were capable of promoting the reaction 
 but in greatly reduced yield ( 1121% yield ) and with lower exo : endo selectivity ( entries 46 ) . 

the unique efficiency of ir(ppy)3 with regard to yield 
 and exo : endo selectivity is intriguing , 
 especially given the similar reduction potentials of ir(fppy)3 ( e1/2 reactions performed at a 0.231 mmol 
 scale , at 5 c with 1.0 mol % photocatalyst , 1.0 equiv of base , 
 20 equiv of nmm for 8 h unless otherwise stated .
reaction time of 
 10 h. reaction time of 15 
 h. screening a range of 
 solvents typically employed in visible light 
 photocatalysis revealed dmf as comparable to dma at room temperature 
 ( 53% , 5.3:1 exo : endo , 16 h ) .
dmso 
 provided an increased exo : endo ratio 
 but significantly lower conversion and yield ( 25% 1 , 
 38% 2 , 6.5:1 exo : endo , 16 h ) . increasing the reaction time to 24 h provided 50% yield 
 of 2 , with 13% 1 remaining , but further 
 increase in reaction time
mecn did not 
 efficiently solubilize 1 at 5 c and at 20 c 
 provided only 12% of the desired product 2 .
concentration 
 and analysis of the mecn reaction mixture revealed the presence of 
 nmo , the morpholine source in the corresponding 
 vo(acac)2 chemistry .
a subsequent control reaction showed 
 that nmo is not an effective starting material in this process .
interestingly 
 the use of dmpu gave 45% of the solvent addition products 10 and 11 .
excluding the nmm from the reaction provided 
 clean conversion to a 1:5 ratio of exo : endo with a combined 53% yield of the inseparable products ( scheme 5 ) .
h 
 abstraction of the solvent from the ho2 radical , generated following oxygen quenching of the ir(ppy)3 excited state and protonation , and could provide a method 
 for heterocyclic functionalization in its own right .
given the high exo : endo ratio 
 observed for the nmo / vo(acac)2 system run in etoh , we next 
 screened a range of polar protic solvent additives . while the addition of etoh or meoh had limited effect on 
 both the yield and exo : endo ratio , 
 the use of water ( 10:1 dma : h2o ) gave considerably improved exo : endo selectivity ( 12:1 ) at the expense 
 of reaction time , requiring 24 h to achieve 55% yield with 10% 1 remaining .
the increased reaction time is possibly due to 
 the lower solubility of ir(ppy)3 in the solvent mixture , 
 whereas the cause of increased in exo : endo remains to be elucidated .
further optimization of the dma : h2o conditions by reducing 
 the reaction temperature to 0 c and using only 0.5 mol % of 
 ir(ppy)3 resulted in a precipitation of 2 during 
 the course of the reaction . while this served to both ease isolation 
 and prevent the product from further reaction ,
premature precipitation 
 at moderate levels of conversion effectively blocked light penetration 
 and stalled the reaction .
the solids could be filtered and the filtrate 
 further progressed ; however , this method proved impractical and gave 
 material with reduced purity ( 8090% a / a uplc ) and yield ( 4549% ) . 

attempts to increase the scale of the reaction while employing these 
 conditions , again proved problematic .
the scale of the reaction was 
 increased by a factor of 4 ( 300 mg , 0.92 mmol 1 ) and 
 the surface area by two , in an effort to mitigate the previously observed 
 rate decrease upon scale up . at this scale
the premature precipitation 
 of 2 was a more significant issue , and the reaction time 
 increased to 72 h. even after this duration only a 37% isolated yield 
 of 2 was obtained in 80% purity . returning to the standard 
 scale , and diluting the reaction to 0.09 m retained 2 in solution for an increased duration , allowing greater conversion 
 ( approximately 75% of 2 , 12:1 exo : endo ) .
under the fully optimized process , significant quantities 
 of 2 precipitated after 32 h. addition of a solution 
 of 3:1 h2o : etoh followed by filtration , provided 56% isolated 
 yield with a 90% purity ( a / a uplc ) ( scheme 6 ) .
the purity of this material could be further improved to > 98% 
 with simple extraction into a solution of 1 n hcl and reisolation 
 via basification to ph 12 . the final optimized reaction 
 is superior to the initial first generation 
 minisci route with regard to selectivity for 2 , step 
 efficiency , and yield .
furthermore , replacement of agno3 and tfa with 0.5 mol % ir(ppy)3 is an attractive prospect 
 from a waste management perspective , although the limited scalability 
 and cost concerns surrounding the use of iridium represent significant 
 issues to be addressed .
ultimately , any procedure on scale employing 
 photocatalysis would likely need to be conducted via continuous processing ; 
 this offers an exciting opportunity to address these current limitations 
 and research in this direction is underway . despite the 
 challenges that were encountered in attempts to scale 
 the methodology , the demonstration of efficiency and selectivity prompted 
 us to explore the reaction as a tool for discovery chemistry .
both 
 the previous routes are not ideal for the synthesis of analogues , 
 limited by high step count or the availability of the requisite amine - n - oxide . testing a range of simple , commercially available 
 tertiary amines
we were rapidly able to build a small collection of 
 imidazopyridizine analogues that would be difficult to prepare by 
 other means ( scheme 7 ) .
the isolated yields 
 were moderate ( 2056% ) , yet synthetically useful , and the scope 
 of the tertiary amine component encompassed aliphatic , benzylic , and 
 aromatic n - methyl tertiary amines .
in certain cases 
 ( such as 12 ) the reaction appeared to stall and increasing 
 both the catalyst loading and the equivalents of amine had limited 
 effect .
radical addition was selective through the n - methyl group when employing n , n - dimethylglycine methyl ester or n , n - dimethybenzylamine , possibly due to the increased nucleophilicity 
 of a primary radical when compared to the secondary radical . tetramethylethylenediamine ( tmeda ) proved a 
 particularly efficient 
 amine in terms of both reaction time and regioisomeric ratio ( r.r ) ( 14 , 7 h , > 10:1 r.r ) . 
 postulating that this may be due to an efficient intramolecular deprotonation 
 of the amine radical cation through a 5-membered transition state , 
 we tested tetramethylhexanediamine .
this amine proceeded with an equally 
 high regioisomeric ratio ( r.r > 10:1 ) but with 
 decreased 
 yield and increased reaction time ( 15 , 18 h , 24% ) suggesting 
 the improved selectivity is more likely the kinetic effect of an increased 
 number of n - methyl groups . in the case of n , n - dimethylethylamine
1.0 mol % ir(ppy)3 was employed to increase the reaction rate to compete productively 
 with evaporation of the amine ( bp 3638 c ) , a problem 
 not encountered with the other amines .
the configurational stability 
 of a stereogenic center alpha to nitrogen was also tested under the 
 reaction conditions , with minimal erosion of enantiomeric ratio ( e.r ) observed ( 21 ) .
this implies that radical 
 formation at this position is disfavored or the resultant radical 
 can not efficiently re - enter the catalytic cycle via h atom abstraction .
n - methylpyrrolidine , n - ethylmorpholine 
 and triethylamine failed to give any discernible product , while 1-methypiperizine 
 gave a complex mixture , presumably due to the presence of a secondary 
 amine .
intriguingly , given their reactivity in related systems employing 
 electron deficient alkenes or dicyanobenzene , diphenylmethylamine 
 and n - phenylmorpholine returned only starting material .
attempts were then made to assess the viability of the reaction to 
 a limited selection of other imidazopyridazines that are potential 
 intermediates in the synthesis of ly2784544 .
imidazopyridazine 22 ( scheme 8) with an ethyl ester at 
 c-3 has been extensively studied as an alternative precursor for the 
 nmo / vo(acac)2 chemistry , although it showed initially poor exo : endo selectivity ( 3:1 ) when compared 
 to 1 ( not shown ) .
similarly , 
 poor exo : endo selectivity was observed 
 in this visible light - mediated system giving a 1.1:1 exo : endo ratio and only moderate isolated yield ( 36% 22 , 19% 24 , not shown ) .
attempting to improve 
 the exo : endo ratio via the use of 
 the 10:1 dma : h2o solvent conditions employed previously 
 led to no improvement in selectivity ( scheme 8) .
interestingly under these conditions the formation of methylated 
 imidazopyridazine 25 , analogous to the formal methylation 
 product 7 , could also be observed ( scheme 8) .
furthermore , while no reaction was observed 
 on the parent heterocyclic 
 core 28 without substitution at the c-3 position , the 
 benzylic imidazopyridiazine 26 gave a low isolated 14% 
 yield of the exo product 27 .
the next 
 step in the synthesis of ly2784544 after 2 is the carbonyl 
 reduction giving 27 , a transformation that required significant 
 investigation .
the formation of the key 
 benzylic morpholine unit from 26 would therefore offer 
 the attractive prospect of eliminating the carbonyl reduction sequence . 
 additionally the reactivity of 26 , albeit moderate , suggested 
 the intriguing possibility of extending this reaction to less activated 
 heterocycles . to this end , a selection of pyridazines that have 
 previously been 
 shown to undergo minisci - type radical addition of n - protected amino acid derived radicals were initially tested .
unfortunately , no significant addition products 
 could be detected other than in the case of 3,6-dichloropyridazine 29 , where a mixture of products consistent with radical addition 
 were detected but proved difficult to isolate .
other simple heterocyclic scaffolds representative of common 
 fragments found in pharmaceutical and agrochemical compounds were 
 subsequently investigated ( scheme 8) .
in all 
 cases the majority of the starting material was recovered and no significant 
 formation of radical addition products could be detected .
the nmo / vo(acac)2 chemistry also displays limited substrate scope for the heterocyclic 
 portion , raising questions over the seemingly unique reactivity of 
 the substituted imidazopyridazine and the mechanistic pathways of 
 both these reactions . while the current methodology appears limited 
 with regards to the generality of the heterocyclic portion , the ease 
 and simplicity of the reaction set up , combined with the availability 
 of n - methyl tertiary amine coupling partners renders 
 this an attractive reaction to test on existing compound libraries .
given the demonstrated sensitivity 
 of this reaction to a range of factors such as oxygen , light source , 
 base , and photocatalyst , it is a strong possibility that multiple 
 reaction mechanisms may be operational .
one simplistic mechanistic 
 pathway is depicted in figure 2 whereby the 
 ir(ppy)3 undergoes initial photoexcitation to a long - lived 
 excited state that can undergo bimolecular quenching with oxygen to 
 generate ir(iv ) and the o2 radical . 

the resultant ir(iv ) ( e1/2 = + 0.77 vs sce ) may then oxidize nmm to the radical cation and return to the ground state .
the primary 
 -amino radical 30 is then generated via deprotonation 
 of the radical cation before addition to imidazopyridazine 1 and rearomatization to yield benzylic morpholine 2 .
volmer analysis , showed that imidazopyridazine 1 is a quencher 
 of the excited state ir(ppy)3 in the presence of oxygen , and therefore can not exclude mechanisms proceeding 
 from this initial event .
we probed the 
 possibility of radical propagation contributing to the mechanistic 
 complexity by conducting a lights - on - lights - off experiment .
minimal reaction was observed during the periods 
 of dark suggesting a long - lived radical propagation is not an major 
 pathway under these conditions .
additionally 
 the exo : endo selectivity observed 
 is opposed to that expected if the intermediate -amino radical 
 was formed via c  h abstraction .
a potential mechanism , which we 
 deem unlikely , is the generation 
 of an iminium species and friedel  crafts type addition of the 
 imidazopyridazine core .
the use of preformed iminium species 31 in the absence of photocatalyst gave no observable coupling 
 product .
however , the use of iminium 31 under photocatalytic 
 conditions in the absence of oxygen provided 2 with high 
 selectivity , albeit in low yield ( 13% , > 20:1 exo : endo , scheme 9 )
. this may 
 demonstrate 
 the possibility of a redox neutral process by which reduction of the 
 iminium by the excited state of ir(ppy)3 provides the -amino 
 radical 30 .
alternatively direct reduction of the imidazopyridazine 
 followed by addition to the iminium provides another mechanistic possibility 
 that can not be ruled out .
in conclusion , we have successfully developed 
 a visible light - mediated 
 photochemical transformation to address a challenging bond construction 
 en route to the jak2 inhibitor ly2784544 .
the introduction of this 
 benzylic morpholine unit occurs in moderate yield , with good selectivity 
 and product purity and is competitive with previously reported routes 
 in these respects .
importantly , nmm is utilized directly , which has 
 considerable benefit when compared to the nmm surrogates employed 
 in the first and second generation syntheses .
furthermore , the methodology 
 was amenable to a range of simple , commercially available tertiary 
 amines and delivered a range of analogues in synthetically useful 
 yields .
while the developed batch conditions are not currently scalable , 
 the potential application to continuous processing is an attractive 
 method to allow the further development of this step , and efforts 
 in this direction are ongoing . during the course of this investigation 
 a number of interesting photoredox transformations have been observed , 
 such as formal methylation via c  n bond cleavage , functionalization 
 of c 
overall , we believe that this initial demonstration 
 warrants the wider consideration of visible light - mediated photocatalysis 
 as a tool in process development as well as the potential application 
 of this specific transformation to the diversification of pharmaceutical 
 and agrochemical scaffolds .
solvents ( mecn , 
 dmf , dmso ) were obtained from a solvent purification system .
reactions 
 that were monitored by tlc were visualized by a dual short wave / long 
 wave uv lamp and stained with an ethanolic solution of potassium permanganate . 

column flash chromatography was performed using 230400 mesh 
 silica gel or via automated column chromatography .
jacketed beakers were 
 obtained from chemglass and connected to a recirculating heater chiller 
 with sil 180 silicone oil as the coolant .
h , c and f nmr spectra were recorded using an internal 
 deuterium lock on 400 , 500 , or a 700 mhz spectrometer .
all signals 
 are reported in ppm with the internal reference of the specified solvent .
data are presented as follows : 
 integration , multiplicity ( s = singlet , d = doublet , t = triplet , 
 q = quartet , m = multiplet , br = broad , app = apparent , dd = doublet 
 of doublet , dt = doublet of triplet , etc . ) and coupling constant ( j / hz ) .
infrared spectra were recorded on a ft - ir fitted 
 with an atr accessory . 

photocatalyst quenching was conducted on a fluorimeter and the values 
 represent an average of 3 samples .
uplc analysis was conducted on 
 a uplc with a beh c18 column ( 1.7 m 2.1  50 mm ) .
chiral 
 hplc analysis was conducted on a hplc with chiral pak od - h column 
 ( 4.6  250 mm ) at 254 nm at 22 c . to a 25 ml round bottom flask ( rbf ) open 
 to air
was added 1 ( 125 mg , 0.386 mmol , 1.0 equiv ) , ir(ppy)3 ( 5.00 mg , 0.008 
 mml , 0.02 equiv ) , sodium acetate ( 32.0 mg , 390 mmol , 1.0 equiv ) , dma 
 ( 2.5 ml ) and n - methylmorpholine ( 0.850 ml , 7.71 mmol , 
 20 equiv ) and the yellow heterogeneous solution was irradiated with 
 2  4 w led strips placed in a circular loop around the flask . 

aluminum foil was placed over the lights around the flask to contain 
 the light ( see figure s1 , supporting information ) .
after 1 h the internal temperature of the flask had stabilized 
 at 35 c .
max ( atr)/cm 3048 , 2361 , 1603 , 1569 , 1502 , 
 1479 , 
 1411 , 1318 , 1268 , 1197 , 914 , 887 , 806 , 761 and 611 ; h 
 nmr ( 500 mhz , cdcl3 ) h 8.26 ( 1h , dd , j 4.5 , 1.7 ) , 7.95 ( 1 h , dd , j 9.1 , 1.7 ) , 
 7.63 ( 1h , dd , j 8.2 , 7.5 ) , 7.29 ( 1h , dd , j 8.4 , 2.0 ) , 7.19 ( 1h , dd , j 9.1 , 4.5 ) , 
 7.10 ( 1h , dd , j 9.9 , 1.9 ) and 2.68 ( 3 h , s ) ; c nmr ( 126 mhz , cdcl3 ) c 180.3 , 
 160.4 ( d , j 255.4 ) , 153.0 , 143.0 , 140.3 , 138.9 ( d , j 10.4 ) , 131.4 ( d , j 3.7 ) , 127.2 ( d , j 14.0 ) , 125.3 ( d , j 3.5 ) , 125.2 , 119.9 , 
 116.6 ( d , j 25.5 ) and 16.45 ; f nmr ( 471 
 mhz , cdcl3 ) f 112.5 ( t , j 8.5 ) ; m / z ( esi+ ) hrms 
 [ m + h ] c14h10clfn3o found 
 290.0488 , calcd .
max ( atr)/cm 2927 , 1630 , 1601 , 1554 , 1504 , 1485 , 1396 , 1286 , 1217 , 1074 , 919 , 
 822 , and 623 ; h nmr ( 500 mhz , cdcl3 ) h 7.61 ( 1h , t , j 7.9 ) , 7.28 ( 1h , dd , j 8.3 , 1.8 ) , 7.11 ( 1h , dd , j 10.0 , 1.8 ) , 
 7.01 ( 1h , d , j 1.0 ) , 2.68 ( 3h , s ) and 2.66 ( 1h , d , j 1.0 ) ; c nmr ( 101 mhz , cdcl3 ) c 180.3 , 160.5 ( d , j 255 ) , 152.1 , 146.7 , 139.7 , 
 139.1 ( d , j 10.5 ) , 138.6 , 131.41 ( d , j 3.7 ) , 126.7 ( d , j 13.7 ) , 125.8 , 125.3 ( d , j 3.2 ) , 120.9 , 116.5 ( d , j 25.7 ) , 16.8 
 and 16.40 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 ( t , j 8.8 ) ; m / z ( esi+ ) hrms [ m + h ] c15h10cl2fn3o found 338.0263 , calcd . 
 338.0259 .
max ( atr)/cm 2925 , 1649 , 1630 , 1601 , 1554 , 1504 , 1396 , 1286 , 1074 , 919 , 822 and 
 617 ; h nmr ( 500 mhz , cdcl3 ) h ( as a mixture of rotamers confirmed by vt nmr ) 7.617.58 
 ( 1h , m ) , 7.307.26 ( 1h , m ) , 7.217.09 ( 1h , m ) , 7.01 
 ( 1h , s , major rotamer ) , 6.92 ( 1h , s , minor rotamer ) , 4.95 ( 2h , s ) , 
 3.18 ( 3h , s , major rotamer ) , 3.05 ( 3h , s , minor rotamer ) , 2.67 ( 3h , 
 s ) , 2.21 ( 3h , s , major rotamer ) and 2.14 ( 3h , s , minor rotamer ) ; c nmr ( 126 mhz , cdcl3 ) c data 
 for major rotamer 180.0 , 171.4 , 160.4 ( 1d , j 255.4 ) , 
 152.2 , 147.0 , 139.1 ( d , j 10.7 ) , 138.2 , 137.2 , 131.3 
 ( 1d , j 3.6 ) , 126.5 ( d , j 13.6 ) , 
 125.7 , 125.2 ( d , j 3.4 ) , 119.1 , 116.4 ( d , j 25.6 ) , 46.2 , 37.4 , 21.6 , and 16.2 ; f nmr 
 ( 471 mhz , cdcl3 ) f 112.4 ( t , j 8.6 ) ; m / z ( esi+ ) hrms 
 [ m + h ] c18h15cl2fn4o2 found 409.0625 , calcd .
was added 2 ( 97.8 mg , 0.231 mmol , 1.0 equiv ) , sodium 
 acetate ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 1.50 
 mg , 2.31 mol , 0.01 equiv ) , dma ( 1.50 ml ) and n - methylmorpholine ( 510 l , 4.63 mmol , 20 equiv ) to give a heterogeneous 
 yellow solution .
the flask was placed in a 25 ml jacketed beaker with iproh as the internal coolant connected to a recirculating 
 heater chiller set to 5 c .
the flask was stirred for 2 min open 
 to air before switching on 2  4w led strips and stirring for 
 8 h. uplc analysis ( figure s13 ) showed 
 27% a / a of starting material 1 , 33% a / a of the reduced 
 product 9 and also included the c6 carbon - chlorine bond 
 reduction [ ( 4-chloro-2-fluorophenyl)(2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-3-yl)methanone ] 10% a / a and the c  n bond 
 fragmentation product 6 9% a / a . while 9 could 
 not be efficiently isolated via chromatography , analysis of the h nmr spectrum of the crude reaction mixture following
work 
 up also confirmed its presence as the major compound among a complex 
 mixture . to a 10 ml rbf
was added 2 ( 97.8 mg , 0.231 
 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , 
 ir(ppy)3 ( 1.50 mg , 2.31 mol , 0.01 equiv ) , dma ( 1.50 
 ml ) , n - methylmorpholine ( 510 l , 4.63 mmol , 
 20 equiv ) and formic acid ( 44.0 l , 1.16 mmol , 5 equiv ) to give 
 a heterogeneous bright yellow / green solution . the flask was placed 
 in a 25 ml jacketed beaker with iproh as the internal 
 coolant connected to a recirculating heater chiller set to 5 c . 

the flask was stirred for 2 min open to air before switching on 2 
  4w led strips and stirring for 22 h. uplc analysis ( figure s14 ) showed 34% a / a of starting material 2 and
the reaction was worked up via the addition of etoac ( 50 
 ml ) followed by washing with water ( 50 ml ) and 5% licl ( 2  25 
 ml ) .
the organic phase was then dried ( na2so4 ) and concentrated in vacuo to give a crude product that was purified 
 via automated column chromatography ( 12 g silica column , 70:10:10 
 hexanes : etoac : ch2cl2 ) to give 6 ( 16.0 mg , 20% yield ) as a white solid with spectroscopic data in 
 accordance with that reported .
to four identical 
 10 ml rbfs was added 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , 
 sodium acetate ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 equiv ) , dma ( 1.50 ml ) and n - methylmorpholine ( 510 l , 4.63 mmol , 20 equiv ) to 
 give a heterogeneous yellow solution .
the flask was placed in a 25 
 ml jacketed beaker with iproh as the internal coolant 
 connected to a recirculating heater chiller set to 0 c .
the 
 flask was stirred for 2 min open to air before switching on a 1 w 
 led strips .
the reaction was stirred for 32 h before ( 3:1 water : etoh , 
 2.0 ml ) was added and the reaction was stirred for a further 30 min . 

the solids were filtered , washed with water then dissolved in ch2cl2 and dried with na2so4 .
the result material was dried overnight under a vacuum ( < 1 mbar ) 
 to give 2 ( 5256 mg , 56% average yield ) .
a portion 
 of this solid ( 50 mg ) was dissolved in etaoc ( 30 ml ) and extracted 
 twice with 1 n hcl ( 25 ml ) .
the aqueous hcl was basified to ph 12 
 with naoh and extracted twice with ch2cl2 , dried 
 ( na2so4 ) , filtered and concentrated to give 2 ( 29 mg , 58% recovery , > 98% a / a ) , in accordance 
 with 
 the literature.h nmr ( 500 mhz , cdcl3 ) h 7.62 ( 1h , t , j 7.9 ) , 7.38 ( 1h , td , j 0.7 , 0.3 ) , 7.30 
 ( 1h , dd , j 8.3 ) , 7.12 ( 1h , dd , j 10.0 , 1.9 ) , 4.00 ( 2h , s ) , 3.79 ( 4h , br s ) , 2.68 ( 3 h , s ) and 2.61 
 ( 3h , s ) . because of the limited 
 scalability of the reaction employing nmm , reactions employing other 
 amines were conducted at 0.231 mmol scale in triplicate and combined 
 prior to work up and isolation .
to a 10 ml rbf was added 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 
 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 
 0.005 equiv ) , dma ( 1.50 ml ) and amine ( 4.63 mmol , 20 equiv ) to give 
 a heterogeneous yellow solution .
the flask was placed in a 25 ml jacketed 
 beaker with iproh as the internal coolant connected 
 to a recirculating heater chiller set to 5 c .
the flask was 
 stirred for 2 min open to air before switching on a 1w led strip . 

the reaction was monitored via uplc and after a given time worked 
 up with the addition of etoac ( 50 ml ) followed by washing with water 
 ( 2  50 ml ) and 5% licl ( 2  25 ml ) .
the organic phase was 
 then dried ( na2so4 ) and concentrated in vacuo 
 to give a crude product that was purified via automated column chromatography 
 under the stated conditions . following the general procedure 
 with the absence of amine
; three identical reactions using 2 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 1.52 mg , 2.31 mol , 0.01 
 equiv ) , dmpu ( 1.50 ml ) for 41 h at 5 c were combined and worked 
 up together .
the resulting crude material ( 1:5 exo : endo ) was purified via automated column chromatography 
 ( 12 g silica column , 50:50 etoac : hexanes to etoac followed by a second 
 column 10:90 acetone : ch2cl2 to 20:80 acetone : ch2cl2 ) to give 10 and 11 ( 164 mg , 53% yield , 1:5 exo : endo ) as white solid .
h nmr ( 700 mhz , cdcl3 ) h 7.62 
 ( 1h , t , j 7.9 ) , 7.30 ( 1h , dd , j 8.2 , 
 1.7 ) , 7.11 ( 1h , dd , j 10.1 , 1.6 ) , 6.97 ( 1h , s ) , 5.19 
 ( 1h , d , j 3.9 ) , 3.143.07 ( 2h , m ) , 2.99 ( 3h , 
 s ) , 2.98 ( 3h , s ) , 2.66 ( 3h , s ) , 2.572.53 ( 1h , m ) and 2.38 
 ( 1h , dd , j 13.8 , 2.9 ) ; c nmr ( 176 mhz , 
 cdcl3 ) c 180.1 160.5 ( d , j 255 ) , 152.1 , 147.0 , 140.0 , 139.2 , ( d , j 10.6 ) , 
 138.8 , 131.4 ( d , j 3.6 ) , 126.7 ( d , j 14.1 ) , 125.5 , 125.3 ( d , j 3.2 ) , 120.0 , 116.5 ( d , j 25.6 ) , 65.4 , 64.6 , 55.4 , 54.8 , 27.3 , 23.7 , and 16.3 .
f nmr ( 377 mhz , cdcl3 ) f 112.4 
 ( t , j 8.8 ) ; m / z ( esi+ ) hrms [ m + h ] c20h19cl2fn5o2 found 450.0894 , calcd .
450.0894 . following 
 the general procedure three identical reactions using 1 ( 75.0 mg ,
0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and n - methylpiperidine ( 562 
 l , 4.63 mmol , 20 equiv ) for 40 h at 5 c were combined 
 and worked up together . prior to work up 12 was present 
 at 45% a / a ( uplc pda ) with > 10:1 exo : endo ( uplc ms ) .
the resulting crude material was purified 
 via automated column chromatography ( 24 g silica column , 80:20 hexanes : etoac 
 1% et3n ) to give 12 ( 87 mg , 30% yield ) as 
 a white solid .
max ( atr)/cm 2938 , 2360 , 2336 , 1636 , 1603 , 1417 , 1277 , 1074 , 918 , 856 and 622 ; h nmr ( 500 mhz , cdcl3 ) h 7.61 
 ( 1h , t , j 7.9 ) , 7.39 ( 1h , s ) , 7.30 ( 1h , dd , j 8.3 , 1.3 ) , 7.12 ( 1h , dd , j 10.0 , 1.7 ) , 
 3.94 ( 2h , s ) , 2.68 ( 4h , s ) , 2.53 ( 4h , br ) , 1.65 ( 4h , app quintet , j 5.6 ) and 1.521.50 ( 2h , m ) ; c nmr 
 ( 176 mhz , cdcl3 ) c 180.5 , 160.3 ( d , j 255 ) , 152.0 , 147.3 , 140.0 , 138.9 ( d , j 10.6 ) , 138.5 , 131.2 ( d , j 3.5 ) , 126.6 ( d , j 14.1 ) , 125.5 , 125.1 ( d , j 3.2 ) , 119.1 , 
 116.3 ( d , j 25.7 ) , 56.4 , 55.0 , 26.0 , 23.9 , and 16.3 .
f nmr ( 471 mhz , cdcl3 ) f 112.4 
 ( t , j 8.5 ) ; m / z ( esi+ ) hrms [ m + h ] c20h20cl2fn4o found 421.0992 , calcd .
421.0998 . following the general procedure three identical 
 reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium 
 acetate ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 
 mg , 1.16 mol , 0.005 equiv ) , dma ( 1.50 ml ) and n , n - dimethylglycine methylester ( 557 l , 4.63 
 mmol , 20 equiv ) for 28 h at 5 c were combined and worked up 
 together . prior to work up 13 was present at 60% 
 a / a ( uplc pda ) with 10:1 exo : endo ( uplc ms ) .
the resulting crude material was purified via automated 
 column chromatography ( 24 g silica column , 70:30 hexanes : etoac 1% 
 et3n ) to give 13 ( 172 mg , 56% yield ) as a 
 cream solid .
max ( atr)/cm 2948 , 2359 , 2335 , 1741 , 1634 , 1604 , 1505 , 1479 , 1415 , 1275 , 1074 , 
 917 , 872 , 817 , 736 , and 622 ; h nmr ( 500 mhz , cdcl3 ) h 7.62 ( 1h , t , j 7.9 ) , 
 7.45 ( 1h , t , j 1.1 ) , 7.30 ( 1h , dd , j 8.3 , 1.9 ) , 7.12 ( 1h , dd , j 10.0 , 1.9 ) , 4.19 ( 2h , 
 d j 1.1 ) , 3.74 ( 3h , s ) 3.45 ( 2h , s ) 2.67 ( 3h , s ) 
 and 2.51 ( 3h , s ) ; c nmr ( 176 mhz , cdcl3 ) c 180.0 , 171.0 , 160.3 ( d , j 255 ) , 152.1 , 147.3 , 
 139.0 ( d , j 10.6 ) , 138.9 , 138.3 , 131.2 ( d , j 3.5 ) , 126.6 ( d , j 14.1 ) , 125.5 , 125.1(d , j 3.2 ) , 119.3 , 116.3 ( d , j 25.7 ) , 58.2 , 
 54.5 , 51.7 , 42.7 , and 16.3 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 ( t , j 8.9 ) ; m / z ( esi+ ) hrms [ m + h ] 
 c19h18cl2fn4o3 found 439.0736 , calcd .
439.0740 . following 
 the general procedure two identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 (
0.8 mg , 1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and tetramethylenediamine ( 349 l , 2.31 
 mmol , 10 equiv ) for 7 h at 5 c were combined and worked up together . 
 prior to work up 14 was present at 70% a / a ( uplc 
 pda ) with >
the resulting crude material was purified via automated column chromatography 
 ( 24 g silica column , 10:90 hexanes : etoac 1% et3n ) to give 14 ( 88 mg , 44% yield ) as a light yellow solid .
max ( atr)/cm 2767 , 2361 , 1622 , 1601 , 1558 , 
 1507 , 1414 , 1289 , 1086 , 919 , 879 , 816 , 761 , and 596 ; h 
 nmr ( 700 mhz , cdcl3 ) h 7.62 ( 1h , t ) , 
 7.48 ( 1h , s ) , 7.30 ( 1h , dd , j 8.2 , 1.8 ) , 7.12 ( 1h , 
 dd , j 9.9 ) , 4.03 ( 2h , s ) , 2.68 ( 3h , s ) , 2.63 ( 2h , 
 t , j 6.8 , ) , 2.47 ( 2h , t , j 6.8 ) , 
 2.38 ( 3h , s ) and 2.25 ( 6h , s ) ; c nmr ( 176 mhz , cdcl3 ) c 180.1 , 160.3 ( d , j 255 ) , 
 152.1 , 147.4 , 140.1 , 139.0 ( d , j 10.4 ) , 138.5 , 131.2 
 ( d , j 3.5 ) , 126.6 ( d , j 14.2 ) , 125.6 , 
 125.1 ( d , j 3.2 ) , 119.4 , 116.4 ( d , j 25.6 ) , 57.6 , 56.0 , 55.7 , 46.0 , 43.2 , and 16.3 ; f nmr 
 ( 471 mhz , cdcl3 ) f 112.4 ( t , j 8.7 ) ; m / z ( esi+ ) hrms 

438.1264 . following 
 the general procedure three identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and tetramethyl-1,6-hexanediamine ( 991 l , 

4.63 mmol , 20 equiv ) for 20 h at 5 c were combined and worked 
 up together . prior to work up 15 was present at 55% 
 a / a ( uplc pda ) with > 10:1 exo : endo ( uplc ms ) .
excess tetramethyl-1,6-hexanediamine was removed via 
 kugelrohr distillation at 5060 c and < 1 mbar .
the 
 resulting crude material was purified via automated column chromatography 
 ( 24 g silica column , etoac 1% et3n ) to give 15 ( 82 mg , 24% yield ) as a light brown solid .
max ( atr)/cm 2923 , 2775 , 1636 , 1610 , 1506 , 1414 , 
 1214 , 1074 , 920 and 818 ; h nmr ( 700 mhz , cdcl3 ) h 7.60 ( 1h , t , j 7.9 ) , 7.38 
 ( 1h , s ) , 7.28 ( 1h , dd , j 8.3 , 1.87.11 ( 1h , dd , j 9.9 ) , 3.95 ( 2h , s ) , 2.49 ( 2h , t , j 7.4 ) 
 2.29 ( 3h , s ) , 2.22 ( 2h , t , j 7.4 ) , 2.21 ( 6h , s ) , 
 1.53 ( 2h , dt , j 14.7 , 7.3 ) , 1.45 ( 2h , dt , j 14.7 , 7.3 ) and 1.361.29 ( 4h , m ) ; c nmr ( 176 mhz , cdcl3 ) c 180.2 , 160.4 
 ( d , j 255 ) , 152.1 , 147.4 , 140.5 , 138.9 ( d , j 10.3 ) , 138.5 , 131.2 ( d , j 3.5 ) , 126.6 
 ( d , j 14.0 ) , 125.5 , 125.1 ( d , j 3.3 ) , 
 119.2 , 116.3 ( d , j 25.4 ) , 59.8 , 58.1 , 55.3 , 45.5 , 
 42.8 , 27.7 , 27.4 , 27.4 , 27.3 and 16.3 ; f nmr ( 471 mhz , 
 cdcl3 ) f 112.4 ( t , j 8.9 ) ; m / z ( esi+ ) hrms [ m + h ] 
 c24h31cl2fn5o found 494.1890 , calcd .
494.1884 . following 
 the general procedure three identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 1.52 mg , 2.31 mol , 0.01 
 equiv ) , dma ( 1.50 ml ) and dimethylethylamine ( 502 l , 4.63 mmol , 
 20 equiv ) for 8 h at 5 c were combined and worked up together . 
 prior to work up 16 was present at 63% a / a ( uplc 
 pda ) with 67:1 exo : endo ( uplc ms ) .
the resulting crude material was purified via automated 
 column chromatography ( 24 g silica column , 80:20 hexanes : etoac 1% 
 et3n ) to give 16 ( 145 mg , 53% yield ) as a 
 cream solid .
max ( atr)/cm 2804 , 1634 , 1603 , 1507 , 1414 , 1278 , 1213 , 1077 , 1039 , 919 , 859 , 
 and 734 ; h nmr ( 500 mhz , cdcl3 ) h 7.62 ( 1h , t , j 7.9 ) , 7.40 ( 1h , t , j 1.3 ) , 7.30 ( 1h , dd , j 8.3 , 1.9 ) , 7.12 
 ( 1h , dd , j 9.9 , 1.9 ) , 3.98 ( 2h , d , j 1.3 ) , 2.68 ( 3h , s ) , 2.59 ( 2h , q , j 7.1 ) , 2.33 ( 3h , 
 s ) and 1.14 ( 3h , t , j 7.1 ) ; c nmr ( 176 
 mhz , cdcl3 ) c 180.2 , 160.3 ( d , j 255 ) , 152.1 , 147.4 , 140.5 , 139.0 ( d , j 10.4 ) , 138.5 , 131.2 ( d , j 3.5 ) , 126.6 ( d , j 14.0 ) , 125.5 , 125.1 ( d , j 3.3 ) , 119.3 , 
 116.4 ( d , j 25.6 ) , 54.9 , 52.0 , 42.3 , 16.3 , and 12.6 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 
 ( t , j 8.5 ) ; m / z ( esi+ ) hrms [ m + h ] c18h18cl2fn4o found 395.0840 , calcd .
395.0842 . following 
 the general procedure three identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and 1,4-dimethylpiperizine ( 621 l , 4.63 
 mmol , 20 equiv ) for 18 h at 5 c were combined and worked up 
 together . prior to work up 17 was present at 55% 
 a / a ( uplc pda ) with 56:1 exo : endo ( uplc ms ) .
the resulting crude material was purified 
 via automated column chromatography ( 12 g silica column , etoac 1% 
 et3n ) to give 17 ( 109 mg , 36% yield ) as a 
 light brown solid .
max ( atr)/cm 2797 , 1629 , 1603 , 1498 , 1414 , 1271 , 1224 , 1212 , 1075 , 1013 , 917 , 
 826 and 764 ; h nmr ( 700 mhz , cdcl3 ) h 7.63 ( 1h , t , j 7.9 ) , 7.36 ( 1h , s ) , 7.29 
 ( 1h , dd , j 8.3 , 1.7 ) , 7.11 ( 1h , dd , j 9.9 , 1.7 ) , 4.00 ( 2h , d , j 1.0 ) , 2.67 ( 3h , s ) overlapping 
 2.64 ( 4h , br s ) , 2.51 ( 4h , br s ) and 2.32 ( 3h , s ) ; c 
 nmr ( 176 mhz , cdcl3 ) c 180.2 , 160.4 ( d , j 255 ) , 152.1 , 147.3 , 139.3 , 139.0 ( d , j 10.3 ) , 138.4 , 131.3 ( d , j 3.5 ) , 126.6 ( d , j 14.1 ) , 125.6 , 125.1 ( d , j 3.3 ) , 119.1 , 
 116.4 ( d , j 25.6 ) , 55.5 , 55.0 , 53.4 , 46.0 and 16.3 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 
 ( t , j 8.8 ) ; m / z ( esi+ ) hrms [ m + h ] c20h21cl2fn5o found 436.1102 , calcd .
436.1107 . following the general procedure three identical reactions 
 using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate 
 ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 
 mol , 0.005 equiv ) , dma ( 1.50 ml ) and bu-4-methylpiperazine-1-carboxylate 
 ( 695 mg
, 3.47 mmol , 15 equiv ) for 20 h at 5 c were combined 
 and worked up together . prior to work up 18 was present 
 at 55% a / a ( uplc pda ) with 34:1 exo : endo ( uplc pda ) .
the resulting crude material was 
 purified via automated column chromatography ( 12 g silica column , 
 90:10 dcm : etoac to 50:50 etoac : dcm ) to give 18-exo ( 99 mg , 27% yield ) as a light cream solid and 18-endo ( 56 mg , 15% yield ) as a cream solid .
max ( atr)/cm 1694 , 1634 , 1604 , 1418 , 1238 , 
 1164 , 1128 , 1073 , 1008 , 920 , 850 , and 831 ; h nmr ( 400 
 mhz , cdcl3 ) h 7.62 ( 1h , t , j 7.9 ) , 7.37 ( 1h , s ) , 7.30 ( 1h , dd , j 8.2 , 1.9 ) , 
 7.12 ( 1h , dd , j 10.0 , 1.8 ) , 4.01 ( 2h , d , j 0.9 ) , 3.51 ( 4h , t , j 4.8 ) 2.68 ( 3h , s ) , 
 2.55 ( 4h , t , j 4.8 ) and 1.47 ( 9h , s ) ; c nmr ( 176 mhz , cdcl3 ) c 180.2 , 160.5 
 ( d , j 255 ) , 154.8 , 152.3 , 147.4 , 139.3 ( d , j 10.4 ) , 139.0 , 138.5 , 131.4 ( d , j 3.5 ) , 
 126.7 ( d , j 14.0 ) , 125.8 , 125.3 ( d , j 3.3 ) , 119.2 , 116.5 ( d , j 25.5 ) , 80.1 , 55.8 , 53.4 , 
 20.6 , and 16.4 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 ( t , j 8.6 ) ; m / z ( esi+ ) hrms [ m + h ] c24h26cl2fn5o3 found 522.1481 , 
 calcd .
max ( atr)/cm 1696 , 
 1636 , 1604 , 1415 , 1270 , 
 1147 , 1077 , 920 , 860 , and 728 ; h nmr ( 500 mhz , cdcl3 ) h 7.62 ( 1h , t , j 7.9 ) , 
 7.34 ( 1h , s ) , 7.31 ( 1h , dd , j 8.3 , 1.9 ) , 7.13 ( 1h , 
 dd , j 9.9 , 1.8 ) , 4.16 ( 2h , s ) , 3.96 ( 1h , dd , j 10.2 , 2.8 ) , 3.05 ( 1h , br s ) , 2.94 ( 1h , d , j 11.4 ) , 2.77 ( 1h , br s ) , 2.68 ( 3h , s ) , 2.39 ( 1h , td , j 11.9 , 3.3 ) , 2.17 ( 3h , s ) , 1.63 ( 1h , br s ) and 1.46 ( 9h , s ) ; c nmr ( 176 mhz , cdcl3 ) c 180.2 , 
 160.5 ( d , j 255 ) , 152.7 ( 2  c ) , 147.3 , 140.6 , 
 139.2 ( d , j 10.4 ) , 138.0 , 131.4 ( d , j 3.5 ) , 126.7 ( d , j 13.9 ) , 126.0 , 125.3 ( d , j 3.2 ) , 119.1 , 116.6 ( d , j 25.6 ) , 61.2 , 
 54.6 , 43.8 , 28.5 , 28.5 , and 16.5 ; f nmr ( 471 mhz , cdcl3 ) f 112.4 ( app m ) ; m / z ( esi+ ) hrms [ m + h ] c24h26cl2fn5o3 found 522.1479 , 
 calcd .
522.1469 . following 
 the general procedure three identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg ,
1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and dimethylanaline ( 441 l , 3.47 mmol , 
 15 equiv ) for 15 h at 5 c were combined and worked up together . 
 prior to work up 19 was present at 60% a / a ( uplc 
 pda ) .
the resulting crude material was purified via automated column 
 chromatography ( 12 g silica column , 0% etoac to 30% etoac ) to give 19 ( 123 mg , 40% yield ) as a light yellow solid that was contaminated 
 with 5% of n - methyl - n - phenylformamide .
max ( atr)/cm 2888 , 2360 , 
 2330 , 1632 , 1599 , 1505 , 1417 , 1204 , 1075 , 917 , 848 , 817 , and 748 ; h nmr ( 700 mhz , cdcl3 ) h 7.64 
 ( 1h , t , j 7.9 ) , 7.31 ( 1h , dd , j 8.3 , 
 1.8 ) , 7.277.24 ( 2h , m ) , 7.13 ( 1h , dd , j 9.9 , 
 1.7 ) , 7.00 ( 1h , s ) , 6.80 ( 1h , t , j 7.3 ) , 6.71 ( 2h , d , j 8.2 ) , 4.95 ( 2h , d , j 0.7 ) , 3.15 ( 3h , s ) and 2.72 ( 3h , s ) ; c nmr 
 ( 176 mhz , cdcl3 ) c 180.3 , 160.4 ( d , j 255 ) , 152.3 , 148.7 , 147.4 , 139.5 , 139.1 ( d , j 10.7 ) , 137.7 , 131.3 ( d , j 3.7 ) , 126.5 ( d , j 14.0 ) , 125.9 , 125.2 ( d , j 3.3 ) , 118.1 , 
 117.9 , 116.4 ( d , j 25.6 ) , 112.3 , 52.4 , 39.4 , and 
 16.4 ( one c was not be resolved ) ; f nmr ( 377 mhz , cdcl3 ) f 112.3 ( t , j 8.8 ) ; m / z ( esi+ ) hrms [ m + h ] 
 c22h18cl2fn4o found 443.0837 , calcd .
443.0836 . following the general procedure three identical 
 reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium 
 acetate ( 19.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 
 mg ,
1.16 mol , 0.005 equiv ) , dma ( 1.50 ml ) and dimethylbenzylamine 
 ( 346 l , 2.31 mmol , 10 equiv ) for 15 h at 5 c were combined 
 and worked up together . prior to work up 20 was present 
 at 70% a / a ( uplc pda ) and in > 10:1 exo : endo ( uplc ms ) .
the resulting crude material was 
 purified 
 via automated column chromatography ( 12 g silica column , 50:50 ch2cl2:hexanes then a gradient of etoac : hexanes ) to 
 give 20 ( 171 mg , 54% yield ) as a light yellow solid .
max ( atr)/cm 2794 , 2361 , 1634 , 
 1604 , 1413 , 1285 , 1076 , 919 , 732 , and 698 ; h nmr ( 500 
 mhz , cdcl3 ) h 7.61 ( 1h , t , j 7.9 ) , 7.46 ( 1h , dt , j , 1.9 , 1.3 ) , 7.397.37 
 ( 2h , m ) , 7.33 ( 2h , dd , j 7.0 , 1.6 ) , 7.317.24 
 ( 3h , m ) , 7.11 ( 1h , dd , j 9.9 , 1.9 ) , 4.00 ( 2h , s ) , 
 3.70 ( 2h , s ) , 2.67 ( 3h , s ) and 2.35 ( 3h , s ) ; c nmr ( 176 
 mhz , cdcl3 ) c 180.1 160.3 ( d , j 255 ) , 152.1 , 147.4 , 140.4 , 139.0 ( d , j 10.6 ) , 138.5 , 131.2 ( d , j 3.6 ) , 126.6 ( d , j 13.9 ) , 127.5 , 126.7 , 126.3 , 125.6 , 125.1 ( d , j 3.2 ) , 119.2 , 116.3 ( d , j 25.6 ) , 62.6 , 54.5 , 43.2 , 
 and 16.4 ; f nmr ( 377 mhz , cdcl3 ) f 112.4 ( t , j 8.8 ) ; m / z ( esi+ ) hrms [ m + h ] c23h19cl2fn4o found 457.0993 , calcd . 

following 
 the general procedure three identical reactions using 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and n - methyl - l - prolinol 
 ( 555 l , 4.63 mmol , 20 equiv ) for 15 h at 5 c were combined 
 and worked up together . prior to work up 21 was present 
 at 25% a / a ( uplc pda ) and in > 10:1 exo : endo ( uplc ms ) .
the resulting crude material was 
 purified 
 via automated column chromatography ( 12 g silica column , 20:80 etoac : hexanes 
 to 40:60 etoac : hexanes ) to give 21 ( 60 mg , 20% yield ) 
 as a light brown oil .
+ 19.6 ( c 1.0 , chcl3 ) ; chiral hplc analysis chiralpak od - h ( 5% ipa : hexane , flow rate 
 1.0 ml min , 254 nm ) tr major ( s ) 13.8 min , tr minor ( r ) 16.5 min 96:4 er . the 
 racemic standard was prepared in an identical fashion from ( rac)-n - methyl - prolinol to give a light brown solid .
max ( atr)/cm 2946 , 2361 , 1335 , 1634 , 1602 , 
 1558 , 1506 , 1418 , 1286 , 213 , 1077 , 919 , 821 , and 735 ; h nmr ( 700 mhz , cdcl3 ) h 7.60 ( 1h , t , j 7.8 ) , 7.29 ( 1h , dd , j 8.2 , 1.2 ) , 7.11 
 ( 1h , dd , j 9.9 , 1.3 ) , 7.10 ( 1h , s ) , 5.32 ( 1h , br 
 s ) , 4.63 ( 1h , d , j 14.1 ) , 3.82 ( 1h , dd , j 11.7 , 2.7 ) , 3.58 ( 1h , d , j 14.1 ) , 3.52 ( 1h , dd , j 11.7 , 5.5 ) , 2.992.96 ( 1h , m ) , 2.952.92 
 ( 1h , m ) , 2.68 ( 3h , s ) , 2.392.36 ( 1h , m ) , 1.941.89 
 ( 1h , m ) , 1.791.71 ( 2h , m ) , 1.701.64 ( 1h , m ) ; c nmr ( 176 mhz , cdcl3 ) c 180.1 
 160.5 ( d , j 255 ) , 152.1 , 147.0 , 140.0 , 139.2 , ( d , j 10.6 ) , 138.8 , 131.4 ( d , j 3.6 ) , 126.7 
 ( d , j 14.1 ) , 125.5 , 125.3 ( d , j 3.2 ) , 
 120.0 , 116.5 ( d , j 25.6 ) , 65.4 , 64.6 , 55.4 , 54.8 , 
 27.3 , 23.7 , and 16.3 ; f nmr ( 377 mhz , cdcl3 ) f 112.2 ( t , j 8.7 ) ; m / z ( esi+ ) hrms [ m + h ] c20h20cl2fn4o2 found 
 437.0943 , calcd .
437.0942 . following 
 the general procedure two identical reactions using 1 ( 55.4 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19.0 mg , 0.231 
 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg ,
1.16 mol , 0.005 
 equiv ) , dma ( 1.50 ml ) and n - methylmorpholine ( 510 
 l , 4.63 mmol , 20 equiv ) for 12 h at 5 c were combined 
 and worked up together .
the resulting crude material ( 1:1 exo : endo ) was purified via automated column 
 chromatography ( 12 g silica column , 50:20:30 hexanes : etoac : ch2cl2 ) to give exo-23 ( 57 mg , 36% yield ) as a white solid and endo-24 that was further purified via acid base extraction to give 
 ( 29 mg , 19% ) h nmr ( 500 mhz , cdcl3 ) h 7.40 ( 1h , s ) , 
 4.46 ( 2h , q , j 7.1 ) , 3.98 ( 2h , s ) , 3.78 ( 4h , t , j 4.4 ) , 2.72 ( 3h , s ) , 2.60 ( 4h , t , j 4.4 ) 
 and 1.43 ( 3h , t , j 7.1 ) .
max ( atr)/cm 2982 , 2851 , 1696 , 1230 , 1417 , 
 1288 , 1225 , 1115 , 989 , 952 , 876 , 758 , and 636 ; h nmr ( 500 
 mhz , cdcl3 ) h 7.39 ( 1h , s ) , 4.46 ( 2h , 
 q , j 7.1 ) , 4.13 ( 1h , d , j 8.2 ) , 
 3.99 ( 1h , dd , j 11.2 , 2.9 ) , 3.96 ( 1h , d , j 11.4 ) , 3.74 ( 1h , t j 11.4 ) , 3.29 ( 1h , 
 t , j 9.8 ) , 2.88 ( 1h , d , j 11.7 ) , 
 2.73 ( 3h , s ) , 2.56 ( 1h , d , j 10.6 ) , 2.17 ( 3h , s ) 
 and 1.43 ( 3h , t , j 7.1 ) ; c nmr ( 176 
 mhz , cdcl3 ) c 159.5 , 151.6 , 147.9 , 139.3 , 
 139.1 , 118.8 , 117.9 , 71.5 , 67.4 , 61.0 , 54.6 , 43.8 , 16.8 , and 14.5 
 ( one c was not resolved ) ; m / z ( esi+ ) 
 hrms [ m + h ] c15h20cln4o3 found 339.1226 , calcd .
339.1218 . following 
 the general procedure two identical 
 reactions using 22 ( 55.4 mg , 0.231 mmol , 1.0 equiv ) , 
 sodium acetate ( 19,0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 0.005 equiv ) , dma ( 1365 l ) , water 
 ( 137 l ) and n - methylmorpholine ( 510 l , 

4.63 mmol , 20 equiv ) for 16 h at 5 c were combined and worked 
 up together .
the resulting crude material ( 1:1.3 exo : endo ) was purified via automated column chromatography 
 ( 12 g silica column , 50:20:30 hexanes : etoac : ch2cl2 ) to give 25 ( 7 mg , 6% yield ) , 23-exo that was further purified via acid base extraction to 
 remove ethyl 2-methylimidazo[1,2-b]pyridazine-3-carboxylate 
 ( s3 ) to give ( 26 mg , 17% ) and 24-endo ( 37 mg , 24% yield ) max ( atr)/cm 1679 , 
 1528 , 1417 , 1347 , 1295 , 1252 , 1143 , 1130 , 11063 , 
 930 , 884 765 and 715 h nmr ( 500 mhz , cdcl3 ) 
 h 7.04 ( 1h , d , j 1.1 ) , 4.46 ( 2h , 
 q , j 7.1 ) , 2.73 ( 3h , s ) , 2.66 ( 3h , d , j 1.1 ) and 1.44 ( 3h , t , j 7.1 ) ; c nmr 
 ( 176 mhz , cdcl3 ) c 159.6 , 151.1 , 147.3 , 
 140.2 , 138.2 , 120.4 , 117.6 , 60.9 , 16.7 , 16.7 , and 14.5 ; m / z ( esi+ ) hrms [ m + h ] c11h13cln3o2 found 254.0693 , calcd . 254.0691 .
max ( atr)/cm 3113 , 2934 , 1703 , 1425 , 1385 , 1323 , 1266 , 1188 , 1083 , 
 1040 , 805 , and 768 h nmr ( 500 mhz , cdcl3 ) h 8.56 ( 1h , dd , j 4.5 , 1.7 ) , 7.97 ( 1 h , dd , j 9.1 , 1.7 ) , 7.22 ( 1h , dd , j 9.1 , 4.5 ) , 
 4.49 ( 2h , q , j 7.1 ) , 2.77 ( 3h , s ) and 1.45 ( 3h , t , j 7.1 ) ; c nmr ( 176 mhz , cdcl3 ) c 159.8 , 151.8 , 143.6 , 140.7 , 124.9 , 119.1 , 117.0 , 60.8 , 16.9 , 
 and 14.5 m / z ( esi+ ) hrms [ m + h ] 
 c10h12n3o2 found 206.0926 , calcd . 206.0924 . following the general procedure five identical reactions using 27 ( 71.6 mg , 0.231 mmol , 1.0 equiv ) , sodium acetate ( 19,0 
 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 0.8 mg , 1.16 mol , 
 0.01 equiv ) , dma ( 1365 l ) , water ( 137 l ) and n - methylmorpholine ( 510 l , 4.63 mmol , 20 equiv ) for 
 20 h at 5 c were combined and worked up together .
the resulting 
 crude material ( 1.2:1 exo : endo ) 
 was purified via automated column chromatography ( 12 g silica column , 
 50:40:10 hexanes : etoac : ch2cl2 ) to give 27 ( 64 mg , 14% yield in accordance with the literature.h nmr ( 500 
 mhz , cdcl3 ) h 7.19 ( 1h , t , j 1.3 ) , 7.16 ( 1h , d , j 8.2 ) , 7.06 ( 1h , dd , j 9.7 and 2.1 ) , 7.01 ( 1h , ddd , j 8.2 , 2.1 
 and 0.7 ) , 4.27 ( 2 h , s ) , 3.96 ( 2h , d , j 1.3 , ) , 3.77 
 ( 4h , t , j 4.6 ) , 2.59 ( 4h , t , j 4.6 ) , 
 2.46 ( 3h , d , j 0.5 ) . following the general 
 procedure 1 ( 75.0 mg , 0.231 mmol , 1.0 equiv ) , ir(ppy)3 ( 2.27 mg , 3.47 mol , 0.015 equiv ) , 31 ( 627 
 mg , 4.63 mmol , 20 equiv ) , made via the literature report of shustov 
 and khlebnikov anhydrous dma ( 5 ml ) , 
 gave a slurry that was sparged with nitrogen for 15 min and then sealed . 

a 1 w led strip was turned on for 24 h at 22 c before the reaction 
 was worked up and purified to give 2 ( 13 mg , 13% yield ) . 

prior to purification h nmr spectroscopic analysis and 
 uplc pda analysis of the crude reaction mixture showed a exo : endo ratio of > 20:1 .
 we 
 report a detailed investigation into the application of visible 
 light - mediated photocatalysis to a challenging bond construction in 
 a complex pharmaceutical target . 
 the optimized reaction allowed the 
 direct coupling of n - methylmorpholine with an unfunctionalized 
 pyridazine in good yield and selectivity , and with high purity of 
 the product isolated via crystallization . 
 the reaction also facilitated 
 the expedient synthesis of a range of analogues via the use of other 
 commercially available n - methyl substituted tertiary 
 amines , and therefore it represents an attractive tool for medicinal 
 chemistry . 
 furthermore , a number of other interesting photoredox reactions 
 were discovered during the course of this investigation , such as a 
 formal methylation reaction via c  n bond cleavage , functionalization 
 of c  
 h bonds alpha to amides , and a visible light - mediated 
 iminium ion reduction . 
Introduction
Results and Discussion
Conclusion
Experimental Section