photochemistry is among 
 the most powerful complexity generating 
 tools available to chemists . fundamentally groundbreaking reactions 
 such as di--methane rearrangements and arene olefin cycloadditions
have rarely 
 been exceeded in their potential to construct molecular architecture , 
 which would be unachievable in the absence of the reaction . however , 
 traditional batch - mode photochemistry has a number of disadvantages 
 that have hindered its implementation and development in traditional 
 synthetic organic laboratories .
typical batch reactor 
 systems often suffer from poor uv penetration , long diffusion lengths , 
 and poor temperature control .
while there have been a number of 
 examples utilizing flow chemistry to increase the effectiveness of 
 photochemistry , we have focused our application on reaction screening and discovery 
 of complex chemotypes . to this end , we have developed a microfluidic - based 
 photochemistry platform capable of running pulse or continuous flow 
 reactions , which is more suitable for high - throughput chemistry . in recent years
, a number of exciting 
 reaction discovery and development 
 paradigms have been highlighted in the literature .
examples such 
 as multidimensional reaction screening developed in our laboratory , mcmillan s advent of enabled serendipity , and hartwig s use of mass spectrometry 
 to analyze thousands of reaction mixtures are a testament to the potential of screening reactions in parallel . 
 over the past several years
, we have developed reaction screening 
 techniques that take advantage of analytical reaction scale and microfluidics .
herein , we report the expansion of our microfluidic platform to 
 incorporate photo - optics for higher levels of wavelength control and 
 its application to a multidimensional reaction screen .
we have developed a photochemical microfluidic platform utilizing 
 a 1 kw capillary mercury lamp and microreactor fabricated with schott 
 8337 , a uv transparent glass . in an effort 
 to advance the utility of photochemistry through expanded wavelength 
 control , we designed a system that also incorporates photo - optical 
 components ( figure 1 ) .
specifically , a plano - concave 
 lens focuses and collimates the beam , followed by a heat mirror that 
 reflects ir wavelengths . directly in front of the microfluidic device 

a wide range of uv 
 filters , both long - pass and band - pass , are commercially available .
one of the exciting applications 
 of our photochemical platform 
 is multidimensional reaction screening wherein multiple substrates 
 are evaluated in photochemical reactions with varying wavelength , 
 sensitizer , temperature , and solvent . with this in mind , we selected a variety of substrates ( 14 ) that 
 were part of the compound library collection in the cmld - bu ( figure 2 ) .
the absorption spectrum of each compound indicated 
 the presence of a chromophore that could potentially be excited under 
 photochemical conditions .
along with four long - pass uv filters , we 
 selected a series of sensitizers ( matched with appropriate uv filters ) 
 with triplet energies ranging from 41 to 74 kcal / mol , as well as two 
 electron - transfer sensitizers .
multidimensional reaction screening parameters . two temperatures ( room temperature 
 and 60 c ) and two solvents 
 ( ch3cn and thf ) were also screened .
each reaction was performed 
 on 100 g scale at a concentration of 0.05 m. the sensitizers 
 were utilized at 1.0 mol equiv .
the residence time within the microfluidic 
 device was 5 min ( 8 l / min ) .
the reactions were subsequently 
 collected into a 96 well - plate and analyzed by uplc / elsd .
each reaction 
 showing potential new products by uplc analysis was scaled up using 
 continuous flow and the same microfluidic device and photochemical 
 platform .
the continuous flow reactions afforded appropriate amounts 
 of material for structure elucidation . in total
however , while we were able to reproduce 
 reactions ( as shown by the identical uplc spectra ) , only four substrates 
 afforded isolable products .
the reaction 
 screen revealed multiple conditions leading to cyclopropane 5 via an oxa - di--methane rearrangement ( eq 1).1 the reaction was facilitated by both direct excitation and 
 triplet 
 sensitization .
further optimization of the reaction revealed that 
 reactions with a wavelength window of 340405 nm were not productive 
 unless sensitized with benzophenone , which has a triplet energy of 
 68 kcal / mol and marginal absorption in the uv filter window ( figure 3 ) . reaction screen profile .
however , when the reaction was carried out in absence of 
 a sensitizer 
 and a blue - shifted uv filter ( 305365 nm ) , it proceeded to 
 full conversion and was exceptionally clean . in this case , the reaction 
 was fully quenched in the presence of sensitizers with triplet energies 
 ranging from 41 to 53 kcal / mol .
the second reaction identified was a product derived from 
 substrate 2 ( scheme 1 ) . when heated 
 in acetonitrile 
 and irradiated at wavelengths > 280 nm , 2 undergoes 
 a 
 homolytic c  n bond fragmentation leading to diradical intermediate 6 followed by a 1,4-hydride shift to form isoquinoline 7 , which rapidly isomerizes to diastereomer 8 during column chromatography .
although this is a simple reaction , it was notable that 
 the original 
 reaction conditions from the reaction screen resulted in incomplete 
 conversion and significant decomposition .
utilizing the flexibility 
 of the platform , we were able to optimize the transformation with 
 a lower temperature and shorter residence time ( 10 c and 3 min ) 
 and slightly longer uv wavelength ( > 295 nm ) .
a third reaction was observed in the reaction screen 
 utilizing 
 tetracyclic scaffold 3 .
elucidation 
 of the purified material revealed cyclobutanone 9 , which 
 is derived from a 1,3-acyl shift ( eq 2 ) .
the reaction screen profile revealed that utilizing 
 a uv filter > 280 nm resulted in nearly complete conversion but 
 significant 
 decomposition by h nmr ( figure 4a ) . at wavelengths
the reaction screen 
 also revealed that the reaction was fully quenched by both acetophenone 
 and benzophenone ( triplet energies of 68 and 74 kcal / mol , respectively).2 ( a ) 
 reaction screen profile .
( b ) absorption spectrum of 3 with bars indicating that reactivity is wavelength dependent . on the basis of data from the 
 reaction screen
, we carried out further 
 optimization focused on wavelength variation . as summarized in figure 4b , reactions focused on a chromophore at 255 nm 
 resulted in no reaction .
significant loss of reactivity was observed 
 at wavelengths > 340 nm and no reactivity at wavelengths > 370 
 nm .
notably , 
 decomposition could be substantially avoided at wavelengths > 320 
 nm . utilizing the > 300 nm uv 
 filter
, we evaluated longer residence 
 times in order to drive the reaction to completion .
however , this 
 resulted in formation of a second product which was determined to 
 be tetrahydrofluorene 10 which was derived from a thermal 
 decarbonylation . because cyclobutanone 9 is extremely unstable and difficult to purify
thus , 
 microwave irradiation immediately following the photochemical transformation 
 afforded ketone 10 as a 1:1 mixture of diastereomers 
 in 27% yield ( scheme 2 ) .
we further evaluated 
 the scope of this reaction as a one - pot , two - step procedure utilizing 
 compounds 11,13 , and 15 .
reaction of substrate 11 afforded ketone 12 ( as a 1.5:1 mixture ) in 43% yield , whereas cyclobutanone 14 could be isolated cleanly from 13 and did 
 not decarbonylate under microwave radiations .
finally , ketol substrate 15 did not show any sign of reactivity under several photochemical 
 conditions .
a fourth reaction was identified 
 in the multidimensional reaction 
 screen involving glycal - derived substrate 4 ( eq 3 ) .
however , upon 
 scale - up and nmr analysis , it was apparent two products were present 
 and , upon isolation and elucidation , we determined that indole 16 and cyclobutane 17 were the major products . 

indole 16 is derived from a simple photo - fries migration of the sulfonyl moiety to c3 , while cyclobutane 17 may arise from an initial [ 2 + 2 ] cycloaddition followed 
 by migration of the sulfonate to the indole c7.3 close analysis of the reaction screening results 
 and follow - up 
 optimization suggested that the reaction pathways were wavelength 
 dependent .
as illustrated in figure 5 , a uv filter with 
 a window of 260300 nm resulted in the exclusive formation 
 of photo - fries product 16 .
a slightly red - shifted uv 
 filter ( > 275 nm ) resulted in a mixture of 16 and 17 ( favoring 16 ) , and a uv filter with a longer 
 wavelength window of 290340 nm favored formation of cyclobutane 17
the reaction was further 
 optimized by varying residence time and 
 temperature . thus ,
indole 16 could be isolated in 50% 
 yield when the reaction was carried out at 60 c with a 5 min 
 residence time , and cyclobutane 17 could be isolated 
 in 24% yield ( no indole 16 was observed ) when the reaction 
 was carried out at room temperature with a 10 min residence time . 

most notably , irradiation of 16 at various wavelengths 
 and conditions did not result in formation of 17 .
it has been shown that indoles bearing n - acyl 
 functionality can undergo [ 2 + 2 ] cycloadditions along with competing 
 photo - fries rearrangement . however ,
if the fries rearrangement occurs from a high energy singlet 
 excited state , longer wavelengths may favor [ 2 + 2]-cycloaddition , 
 which proceeds via a 1,4-diradical in the triplet excited state .
indeed , irradiation of boc - protected 18 and acetate - protected 20 at 290340 nm afforded 
 only cyclobutanes 19 and 21 ( scheme 3 ) .
however , reactions at shorter wavelengths did 
 not result in migration to c3 but only in decomposition .
indoles that 
 were not acylated ( n  h or n  ch3 ) were unreactive 
 under the photochemical reaction conditions .
changing the electronics 
 of the indole ring with 5-chloro substitution ( 22 ) resulted 
 in only the photo - fries product ( 23 ) in low yield . in conclusion , we have successfully 
 adapted a photochemical microfluidics 
 platform for use in multidimensional reaction screening . by adding 
 a photo - optics system , we are able to effectively control the wavelength 
 of the reactions utilizing uv filters .
such control allows for introduction 
 of irradiation wavelength as a screening variable as well as downstream 
 optimization of reactions that are highly dependent on wavelength . 
 utilizing the platform in a multidimensional reaction screen ,
we were 
 able to identify new chemotypes derived from photochemical transformations 
 of complex scaffolds .
most notably , we identified complex chemotypes 
 derived from an oxa - di--methane rearrangement of a bicyclo[3.2.1]octanoid 
 scaffold , a 1,3-acyl shift of bicyclic ketol , and a wavelength - dependent 
 photo - fries/[2 + 2]-cycloaddition .
the new scaffolds are currently 
 being used to develop methodologies and access additional complex 
 and unique molecules for use in high - throughput screening and medicinal 
 chemistry programs .
all reactions were 
 carried out in a flame - dried apparatus under an ar atmosphere , unless 
 otherwise noted .
solvents ( methylene chloride , thf , and acetonitrile ) 
 were dried by passage through columns of neutral alumina .
flash chromatography was performed 
 using silica gel ( siliaflash p60 , 230400 mesh ) purchased from 
 silicycle , or a flash chromatography system utilizing silica gel columns 
 from interchim .
analytical thin - layer chromatography was performed 
 on 0.25 mm sio2 60 f-254 plates .
tlc plates were analyzed 
 using uv illumination and staining with basic kmno4 solution . 

chemical shifts (  ) are reported in parts per million ( ppm ) 
 relative to the solvent ( cdcl3 at 7.27 ( 77.0 ) ppm or c6d6 at 7.16 ( 128 ) ppm ) .
coupling constants ( j ) are reported in hertz ( hz ) with multiplicities denoted 
 as br ( broad ) , s ( singlet ) , d ( doublet ) , t ( triplet ) , q ( quartet ) , 
 m ( multiplet ) .
stock solutions of substrate ( 0.1 m ) and sensitizers 
 ( 0.1 m ) were 
 prepared in ch3cn or thf ( anhydrous ) while maintaining 
 dry handling .
the solutions were placed in a custom - designed 96-well 
 aluminum holding block fitted with oven - dried glass sleeves .
the block was attached 
 to the microfluidics platform , and a slow , steady stream of argon 
 was passed through the inert gas chamber .
the system was fitted with 
 the appropriate uv filter , and the parameters were set to achieve 
 5 min residence time at the chosen temperature .
each reaction 
 was analyzed by uplc / ms / elsd ( 1090% ch3cn , 2 min ) . 

reactions showing apparent reactivity were subsequently scaled up 
 and isolated , using the system in continuous flow , for further characterization .
the system was fitted with the appropriate optical filter and set 
 at the appropriate temperature .
a solution of substrate ( 1.0 equiv ) 
 in ch3cn was loaded into a syringe and flowed through the 
 device via a syringe pump set at the appropriate flow rate to obtain 
 the desired residence time .
the reactions were collected in a vial , 
 concentrated in vacuo , and purified by flash chromatography .
gly - omehcl ( 0.084 g , 
 0.666 mmol ) was added to a solution of aldehyde 24(51 ) ( 0.122 g , 0.444 mmol ) in dcm ( 2.2 ml ) , followed 
 by mgso4 ( 0.266 g , 2.22 mmol ) and et3n ( 0.08 
 ml , 0.666 mmol ) .
it was then concentrated in vacuo and dissolved in etoac 
 ( 5 ml ) , filtered , and concentrated in vacuo .
the resulting solid was 
 dissolved in dcm ( 1.5 ml ) and agotf ( 0.011 g , 0.044 mmol ) was added , 
 followed by molecular sieves ( 0.03 g ) and tfa ( 0.04 ml , 0.489 mmol ) . 

the resulting mixture was stirred at room temperature for 1 h and 
 filtered over a cotton plug .
the filtrate was concentrated in vacuo 
 to afford intermediate which was dissolved in phcf3 ( 4.4 
 ml ) to be used directly in the next step .
1-methyl-1h - pyrrole-2,5-dione ( 0.049 g , 0.444 mmol ) was then added followed 
 by hunig s base ( 0.09 ml , 0.489 mmol ) .
the reaction mixture 
 was stirred at room temperature for 3 h and concentrated in vacuo . 

purification by flash chromatography ( 5:1 hexanes / etoac ) afforded 2 as a white amorphous solid ( 0.063 g , 31% ) over 3 steps : rf = 0.58 ( 1:1 hexanes / etoac ) ; 
 ir ( thin film )  ( cm ) 2956 , 2924 , 1708 , 
 1435 , 1329 , 1118 ; h nmr ( cdcl3 , 400 mhz )  
 7.467.50 ( m , 2h ) , 7.397.42 ( m , 3h ) , 7.31 ( bs , 1h ) , 
 7.04 ( d , j = 7.6 hz , 1h ) , 5.36 ( s , 1h ) , 5.20 ( d , j = 7.6 hz , 1h ) , 4.91 ( s , 1h ) , 3.86 ( s , 3h ) , 3.74 ( d , j = 7.6 hz , 1h ) , 3.48 ( t , j = 7.6 hz , 1h ) , 
 2.89 ( s , 3h ) ; c nmr ( cdcl3 , 100 mhz )  
 176.3 , 174.7 , 170.4 , 148.7 , 136.1 , 135.9 , 132.1 , 129.6 , 129.2 , 128.8 , 
 127.8 ( d , jc 
f = 32 hz ) , 127.6 , 
 126.0 ( d , jc  f = 4 hz ) , 125.8 , 
 125.0 , 124.5 ( d , jc 
f = 281 hz ) , 
 124.3 ( d , jc  f = 4 hz ) , 102.0 , 
 67.1 , 63.4 , 53.6 , 51.5 , 46.5 ; hrms - esi ( m / z ) [ m + h ] calcd for c24h20f3n2o4 457.13785 , found 457.1362 .
( 1 ) prepared according 
 to general continuous flow procedure using 1(21 ) and benzophenone ( 1 equiv ) in ch3cn ( 0.05 m ) with a 340405 nm band - pass filter and a 2 min 
 residence time at room temperature .
( 2 ) prepared according to general continuous flow procedure using 1 in ch3cn ( 0.05 m ) with a 305365 nm band - pass 
 filter and a 2 min residence time at room temperature .
prepared 
 according to the general continuous flow procedure using 2 ( 0.0143 g , 0.031 mmol ) in ch3cn ( 1.24 ml ) with a 295 
 nm long pass filter and a 4 min residence time at 10 c .
the 
 reaction mixture was concentrated in vacuo to afford 7 ; h nmr ( cdcl3 , 500 mhz )  8.49 ( s , 
 1h ) , 8.10 ( s , 1h ) , 7.998.04 ( m , 2h ) , 7.857.89 ( m , 
 1h ) , 7.437.54 ( m , 4h ) , 5.35 ( d , j = 8.5 hz , 
 1h ) , 3.91 ( ddd , j = 11.0 , 8.5 , 4.0 hz , 1h ) , 3.23 
 ( s , 3h ) , 3.20 ( s , 1h ) , 2.99 ( dd , j = 18.0 , 4.0 hz , 
 1h ) , 2.25 ( dd , j = 17.5 , 11.0 hz , 1h ) ; c nmr ( cdcl3 , 125 mhz )  178.4 , 176.4 , 171.8 , 156.4 , 
 151.7 , 139.3 , 137.8 , 129.8 , 129.7 , 129.6 , 129.5 , 129.2 , 129.2 , 127.2 , 
 126.9 , 126.5 ( d , jc 
f = 2 hz ) , 
 125.8 , 123.1(d , jc  f = 4 hz ) , 116.1 , 
 51.9 , 47.6 , 42.3 , 30.4 , 25.7 .
purification by flash chromatography 
 ( 5:1 hexanes / etoac ) afforded 8 as an oil ( 0.0051 g , 36% ) : 
 rf = 0.71 ( 1:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 2958 , 2924 , 2852 , 1703 , 1635 , 1436 , 1329 , 1294 , 
 1122 ; h nmr ( cdcl3 , 400 mhz )  8.59 ( s , 
 1h ) , 8.11 ( m , 3h ) , 8.04 ( d , j = 8.4 hz , 1h ) , 7.90 
 ( d , j = 9.6 hz , 1h ) , 7.447.54 ( m , 4h ) , 5.01 
 ( d , j = 5.6 hz , 1h ) , 4.61 ( q , j = 
 6.0 hz , 1h ) , 3.64 ( s , 3h ) , 3.143.20 ( m , 1h ) , 3.12 ( s , 1h ) , 
 2.87 ( dd , j = 17.6 , 3.6 hz , 1h ) ; c
nmr 
 ( cdcl3 , 100 mhz )  178.6 , 175.4 , 171.9 , 155.2 , 151.7 , 
 139.4 , 138.3 , 129.7 , 129.2 , 128.8 , 127.3 , 126.5 , 126.3 , 124.1 , 124.0 , 
 116.5 , 52.4 , 50.1 , 41.7 , 33.2 , 25.8 ; hrms - esi ( m / z ) [ m + h ] calcd for c24h20f3n2o4 457.1375 , found 457.1373 .
prepared according to general continuous flow procedure using ketone 3(30 ) ( 0.0014 g , 0.05 mmol ) in ch3cn ( 1 ml ) with a 305365 nm band - pass filter and a 
 10 min residence time at 60 c .
the reaction mixture was then 
 transferred to a microwave flask and heated to 120 c for 15 
 min in a cem microwave .
purification by flash chromatography ( 15:1:1 
 hexanes / dcm / etoac ) afforded a 1:1 mixture of 10a and 10b .
10a : ( 0.002 g , 14% ) as a yellow oil ; rf = 0.53 ( 15:1:1 hexanes / dcm / etoac ) ; ir ( thin film )  
 ( cm ) 2960 , 2931 , 1816 , 1711 , 1460 , 1362 , 755 ; h nmr ( cdcl3 , 400 mhz )  7.137.20 
 ( m , 4h ) , 5.33 ( d , j = 4.4 hz , 1h ) , 3.87 ( d , j = 4.4 hz , 1h ) , 3.46 ( q , j = 7.2 hz , 1h ) , 
 3.07 ( dd , j = 15.2 , 8.0 hz , 1h ) , 2.943.00 
 ( m , 1h ) , 2.69 ( dd , j = 15.2 , 6.8 hz , 1h ) , 2.38 ( s , 
 3h ) , 2.34 ( dd , j = 16.8 , 7.2 hz , 1h ) , 2.172.24 
 ( m,1h ) , 2.10 ( dd , j = 17.2 , 6.0 hz , 1h ) , 0.94 ( d , j = 4.4 hz , 3h ) , 0.91 ( d , j = 5.2 hz , 3h ) ; c nmr ( cdcl3 , 100 mhz )  198.4 , 149.5 , 147.9 , 
 142.5 , 126.8 , 126.8 , 125.0 , 123.7 , 113.3 , 45.9 , 42.2 , 38.6 , 37.7 , 
 35.8 , 29.3 , 25.2 , 21.3 , 21.2 ; hrms - esi ( m / z ) [ m + h ] calcd for c18h23o 255.1749 , found 255.1773 .
10b : ( 0.0018 g , 13% ) as 
 a colorless oil ; rf = 0.5 ( 15:1 : hexanes / dcm / etoac ) ; ir 
 ( thin film )  ( cm ) 2960 , 2927 , 1709 , 1665 , 
 1459 , 1353 , 757 ; h nmr ( c6d6 , 400 
 mhz )  7.047.12 ( m , 4h ) , 5.29 ( d , j = 4.0 hz , 1h ) , 3.25 ( q , j = 6.8 hz , 1h ) , 2.822.92 
 ( m , 2h ) , 2.68 ( d , j = 4.4 hz , 1h ) , 2.57 ( dd , j = 14.4 , 4.8 hz , 1h ) , 2.19 ( dd , j = 17.2 , 
 7.6 hz , 1h ) , 2.05 ( sept , j = 7.2 hz , 1h ) , 1.97 ( dd , j = 16.8 , 5.2 hz , 1h ) , 1.78 ( s , 3h ) , 0.87 ( d , j = 6.4 hz , 6h ) ; c nmr ( c6d6 , 100 
 mhz )  207.2 , 148.1 , 146.8 , 143.1 , 127.1 , 127.1 , 125.5 , 123.8 , 
 116.5 , 54.0 , 42.8 , 39.1 , 38.8 , 35.9 , 28.9 , 28.2 , 21.5 , 21.4 ; hrms - esi 
 ( m / z ) [ m + h ] calcd 
 for c18h22o 255.1749 , found 255.1754 . prepared 

according to the general continuous flow procedure using ketone 11(30 ) ( 0.0125 g , 0.053 mmol ) in 
 ch3cn ( 1.1 ml ) with a 305365 nm band - pass filter 
 and a 10 min residence time at 60 c .
the reaction mixture was 
 then transferred to a microwave flask and heated to 120 c for 
 15 min in a cem microwave .
purification by flash chromatography ( 10:1 
 hexanes / etoac ) afforded a 1:1 mixture of 12a and 12b .
12a : ( 0.003 g , 26% ) as a yellow oil ; rf = 0.52 ( 5:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 2961 , 2872 , 1707 , 1665 , 1063 ; h nmr 
 ( c6d6 , 400 mhz )  5.43 ( d , j = 6.4 hz , 1h ) , 4.32 ( ddd , j = 7.8 , 5.1 , 3.1 hz , 
 1h ) , 3.75 ( dd , j = 6.4 , 2.9 hz , 1h ) , 3.68 ( td , j = 8.4 , 3.5 hz , 1h ) , 3.313.37 ( m , 1h ) , 2.58 ( qd , j = 7.8 , 3.1 hz , 1h ) , 2.21 ( dd , j = 16.8 , 
 3.2 hz , 1h ) , 2.002.08 ( m , 2h ) , 1.92 ( s , 3h ) , 1.571.64 
 ( m , 1h ) , 1.261.26 ( m , 1h ) , 0.86 ( t , j = 6.8 
 hz , 6h ) ; c nmr ( c6d6 , 100 mhz ) 
  198.2 , 150.2 , 113.2 , 77.5 , 67.1 , 46.2 , 37.3 , 36.0 , 33.6 , 30.7 , 
 24.6 , 21.2 , 21.1 ; hrms - esi ( m / z ) 
 [ m + h ] calcd for c13h21o2 209.1542 , found 209.1547 .
12b : ( 0.002 g , 17% ) as an 
 oil : rf = 0.47 ( 5:1 hexanes / etoac ) ; ir ( thin film )  
 ( cm ) 2962 , 2873 , 1708 , 1673 , 1355 , 1057 ; h nmr ( cd3cn , 500 mhz )  5.55 ( d , j = 5.0 hz , 1h ) , 4.07 ( ddd , j = 6.6 , 5.7 , 
 3.8 hz , 1h ) , 3.78 ( td , j = 8.0 , 4.7 hz , 1h ) , 3.56 
 ( dt , j = 8.5 , 7.5 hz , 1h ) , 3.05 ( t , j = 4.5 hz , 1h ) , 2.53 ( quint . , j = 7.0 hz , 1h ) , 2.172.27 
 ( m , 2h ) , 2.13 ( s , 3h ) , 1.992.08 ( m , 2h ) , 1.57 ( dtd , j = 11.9 , 7.7 , 6.6 hz , 1h ) , 0.99 ( d , j = 
 3.0 hz , 3h ) , 0.98 ( d , j = 2.0 hz , 3h ) ; c nmr ( cd3cn , 125 mhz )  209.5 , 146.9 , 116.5 , 77.3 , 
 67.1 , 54.2 , 38.4 , 36.2 , 33.6 , 30.9 , 29.1 , 21.6 , 21.6 ; hrms - esi ( m / z ) [ m + h ] calcd for c13h21o2 209.1542 , found 209.1545 . prepared 
 according to 
 general continuous flow procedure using ketone 13(33 ) ( 0.016 g , 0.055 mmol ) in ch3cn ( 2.3 
 ml ) , with a 290340 nm band - pass filter and a 10 min residence 
 time at 60 c .
purification by flash chromatography ( 6:1 hexanes / etoac ) 
 afforded 14 ( 0.0044 , 27% ) as a colorless oil : rf = 0.58 ( 3:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 3406 , 2958 , 2921 , 1710 , 1611 , 1512 , 1464 , 1247 , 1177 ; h nmr ( cdcl3 , 400 mhz )  7.17 ( d , j = 8.4 hz , 2h ) , 6.86 ( d , j = 8.4 hz , 2h ) , 5.615.64 
 ( m , 1h ) , 3.81 ( s , 3h ) , 3.113.13 ( m , 1h ) , 2.812.88 
 ( m , 1h ) , 2.30 ( sept . , j = 6.4 hz , 1h ) , 2.182.26 
 ( m , 4h ) , 2.042.11 ( m , 2h ) , 1.73 ( ddd , j = 
 12.9 , 11.3 , 6.3 hz , 1h ) , 1.06 ( d , j = 4.4 hz , 3h ) , 
 1.04 ( d , j = 4.0 hz , 3h ) ; c nmr ( cdcl3 , 100 mhz )  209.7 , 158.2 , 147.3 , 138.8 , 128.1 , 115.5 , 
 114.1 , 114.1 , 55.6 , 49.3 , 36.5 , 35.7 , 34.0 , 31.2 , 28.9 , 21.9 , 21.4 ; 
 hrms - esi ( m / z ) [ m - h2o ] calcd for c19h22o2 283.1698 , 
 found 283.1706 . prepared
according to the general continuous flow 
 procedure using 
 indole 4(34 ) in ch3cn ( 0.01 m ) and a 10 min residence time at room temperature .
purification 
 using flash chromatography ( 2:1 to 1:2 hexanes / etoac ) afforded a mixture 
 of indole 16 and cyclobutane 17 .
16 : colorless oil ; rf = 0.33 ( 1:1 hexanes / etoac ) ; ir ( thin 
 film )  ( cm ) 3286 , 2925 , 1723 , 1488 , 1454 , 
 1433 , 1305 , 1282 , 1135 , 1111 , 1087 ; h nmr ( cdcl3 , 500 mhz )  10.07 ( bs , 1h ) , 7.59 ( dd , j = 
 9.2 , 2.4 hz , 1h ) , 7.367.46 ( m , 5h ) , 7.287.29 ( m , 1h ) , 
 7.02 ( td , j = 9.0 , 2.4 hz , 1h ) , 6.196.26 
 ( m , 2h ) , 5.315.34 ( m , 2h ) , 5.16 ( d , j = 15.9 
 hz , 1h ) , 4.26 ( dd , j = 7.2 , 1.4 hz , 1h ) , 3.80 ( dt , j = 7.2 , 4.8 hz , 1h ) , 3.74 ( dd , j = 10.5 , 
 4 .
hz , 1h ) , 3.62 ( dd , j = 10.5 , 5.0 hz , 1h ) , 3.51 
 ( s , 3h ) , 3.13 ( s , 3h ) ; c nmr ( cdcl3 , 125 mhz ) 
  159.4 ( d , jc 
f = 238 hz ) , 
 143.5 , 139.2 , 131.1 , 131.0 , 128.8 , 128.6 , 128.5 , 128.3 , 126.4 ( d , jc  f = 11 hz ) , 125.7 , 112.9 ( d , jc 
f = 10 hz ) , 112.2 ( d , jc  f = 26 hz ) , 109.9 , 104.8 ( d , jc 
f = 25 hz ) , 74.5 , 73.3 , 73.1 , 69.8 , 63.0 , 59.7 , 
 45.5 ; hrms - esi ( m / z ) [ m + na ] calcd for c23h24fnnao5s 
 468.1257 , found 468.1269 .
17 : colorless oil ; rf = 0.16 ( 1:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 3387 , 2925 , 2854 , 1461 , 1300 , 1133 ; h nmr ( cdcl3 , 500 mhz )  7.337.44 ( m , 6h ) , 6.97 ( dd , j = 8.5 , 3.0 hz , 1h ) , 5.49 ( ddd , j = 7.8 , 
 2.6 , 0.9 hz , 1h ) , 5.01 ( d , j = 4.0 hz , 1h ) , 4.39 
 ( t , j = 4.7 hz , 1h ) , 4.15 ( d , j = 
 7.9 hz , 1h ) , 3.87 ( d , j = 9.5 hz , 1h ) , 3.693.73 
 ( m , 3h ) , 3.49 ( d , j = 9.2 hz , 1h ) , 3.36 ( s , 3h ) , 
 3.163.20 ( m , 1h ) , 2.99 ( s , 3h ) , 2.64 ( ddd , j = 8.4 , 6.9 , 4.0 hz , 1h ) ; c nmr ( cdcl3 , 125 
 mhz )  155.3 ( d , jc  f = 239 
 hz ) , 147.5 , 140.4 , 137.5 ( d , jc  f = 8 hz ) , 128.6 , 127.6 , 125.5 , 118.0 ( d , jc 
f = 7 
 hz ) , 111.4 ( d , jc  f = 26 hz ) , 74.6 , 
 74.3 , 73.8 , 72.5 , 71.3 , 70.0 , 59.4 , 44.3 , 43.9 , 43.0 , 40.0 ; hrms - esi 
 ( m / z ) [ m + h ] calcd 
 for c23h25fno5s 446.1437 , found 446.1433 .
tbaf ( 0.54 ml , 0 . 539 mmol , 
 1.0 m solution in thf ) was added dropwise to a solution of indole 4 ( 0.12 g , 0.269 mmol ) in thf ( 5 ml ) .
the reaction mixture 
 was stirred at room temperature overnight . a saturated solution ( 5 
 ml ) of nh4cl
the mixture was extracted 
 with etoac ( 3 5 ml ) , washed with brine ( 2 3 ml ) , dried 
 over na2so4 , and concentrated in vacuo .
purification 
 by flash chromatography ( 2:1 hexanes / etoac ) afforded indole 25 ( 0.075 g , 75% ) as a colorless oil : rf = 0.65 
 ( 1:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 3316 , 2922 , 2853 , 1486 , 1452 , 1318 , 1169 , 1078 ; h nmr 
 ( cdcl3 , 500 mhz )  8.69 ( bs , 1h ) , 7.227.44 
 ( m , 2h ) , 7.317.39 ( m , 3h ) , 7.217.25 ( m , 2h ) , 6.92 
 ( td , j = 9.1 , 2.6 hz , 1h ) , 6.39 ( d , j = 1.2 hz , 1h ) , 6.11 ( m , 1h ) , 5.30 ( m , 1h ) , 4.85 ( d , j = 12.8 hz , 1h ) , 4.78 ( d , j = 13.1 hz , 1h ) , 4.224.24 
 ( m , 1h ) , 3.69 ( dt , j = 7.6 , 3.8 hz , 1h ) , 3.63 ( dd , j = 10.4 , 4.3 hz , 1h ) , 3.51 ( dd , j = 10.4 , 
 3.4 hz , 1h ) , 3.37 ( s , 3h ) ; c nmr ( cdcl3 , 125 
 mhz )  158.1(d , jc 
f = 232 
 hz ) , 139.4 , 137.5 , 133.1 , 130.2 , 128.8 ( d , jc 
f = 10 hz ) , 128.7 , 128.3 , 126.8 , 111.6 ( d , jc  f = 10 hz ) , 110.5 ( d , jc  f = 26
hz ) , 105.5 ( d , jc  f = 23 hz ) , 101.6 , 101.5 , 74.4 , 72.4 , 70.9 , 70.4 , 
 64.5 , 59.5 ; hrms - esi ( m / z ) [ m + 
 h ] calcd for c22h23fno3 368.1662 , found 368.1658 .
boc2o ( 0.036 g , 0.163 
 mmol ) and dmap ( 0.001 g , 0.008 mmol ) were added to a solution of indole 25 ( 0.03 g , 0.082 mmol ) in dcm ( 2 ml ) .
the mixture was extracted with dcm ( 3 5 ml ) , 
 washed with brine ( 2 3 ml ) , dried over na2so4 , and concentrated in vacuo .
purification by flash chromatography 
 ( 3:1 hexanes / etoac ) afforded indole 18 ( 0.023 g , 61% ) 
 as a yellow oil : rf = 0.71 ( 1:1 hexanes / etoac ) ; ir ( thin 
 film )  ( cm ) 2978 , 2930 , 1731 , 1471 , 1446 , 
 1369 , 1258 , 1155 , 1155 , 1111 ; h nmr ( cdcl3 , 
 500 mhz )  8.03 ( dd , j = 9.2 , 4.6 hz , 1h ) , 
 7.447.46 ( m , 2h ) , 7.307.39 ( m , 3h ) , 7.16 ( dd , j = 8.5 , 2.4 hz , 1h ) , 6.99 ( td , j = 9.0 , 
 2.5 hz , 1h ) , 6.63 ( s , 1h ) , 6.106.19 ( m , 2h ) , 5.315.34 
 ( m , 1h ) , 5.05 ( d , j = 14.3 hz , 1h ) , 4.92 ( d , j = 14.3 hz , 1h ) , 4.26 ( dd , j = 7.9 , 1.5 
 hz , 1h ) , 3.663.69 ( m , 1h ) , 3.60 ( dd , j = 
 10.4 , 4.6 hz , 1h ) , 3.52 ( dd , j = 10.2 , 2.6 hz , 1h ) , 
 3.353.38 ( m , 1h ) , 3.31 ( s , 3h ) , 1.69 ( s , 9h ) ; c nmr ( cdcl3 , 100 mhz )  160.7 , 158.3 , 150.3 , 149.2 , 
 140.1 , 139.7 , 133.2 , 130.2 , 130.1 , 129.9 128.7 , 128.4 , 128.2 , 127.4 , 
 116.7 ( d , jc  f = 9 hz ) , 111.8 ( d , jc 
f = 4 hz ) , 106.1 ( d , jc  f = 23 hz ) , 84.7 , 74.5 , 72.0 , 70.6 , 70.5 , 66.1 , 59.5 , 28.5 ; hrms - esi 
 ( m / z ) [ m + na ] calcd 
 for c27h30fnnao5 490.2006 , found 
 490.2004 .
ac2o ( 0.04 ml , 0.441 
 mmol ) and et3n ( 0.02 ml , 0.165 mmol ) were added to a solution 
 of indole 25 ( 0.0405 g , 0.11 mmol ) and dmap ( 0.003 g , 
 0.022 mmol ) in dce ( 0.5 ml ) .
the resulting mixture was heated to 60 
 c for 18 h. a saturated solution ( 1 ml ) of nh4cl 
 was then added .
the mixture was extracted with etoac ( 3 2 ml ) , 
 washed with brine ( 2  3 ml ) , dried over na2so4 , and concentrated in vacuo .
purification by flash chromatography 
 ( 3:1 hexanes / etoac ) afforded indole 20 ( 0.03 g , 66% ) 
 as a yellow oil : rf = 0.64 ( 1:1 hexanes / etoac ) ; ir ( thin 
 film )  ( cm ) 2925 , 2892 , 1705 , 1614 , 1601 , 
 1470 , 1448 , 1372 , 1309 , 1205 , 1090 ; h nmr ( cdcl3 , 400 mhz )  7.98 ( dd , j = 9.0 , 4.3 hz , 1h ) , 
 7.297.45 ( m , 5h ) , 7.19 ( dd , j = 8.6 , 2.7 
 hz , 1h ) , 7.04 ( td , j = 9.1 , 2.5 hz , 1h ) , 6.69 ( s , 
 1h ) , 6.106.13 ( m , 2h ) , 5.31 ( s , 1h ) , 5.03 ( d , j = 14.5 hz , 1h ) , 4.92 ( d , j = 14.1 hz , 1h ) , 4.27 
 ( dd , j = 7.8 , 2.0 hz , 1h ) , 3.543.67 ( m , 2h ) , 
 3.48 ( dd , j = 10.2 , 2.7 hz , 1h ) , 3.29 ( s , 3h ) , 2.82 
 ( s , 3h ) ; c nmr ( cdcl3 , 125 mhz )  170.2 , 
 159.3 ( d , jc 
f = 223 hz ) , 139.6 , 
 133.6 , 130.7 , 130.2 , 128.7 , 128.3 , 128.2 , 126.9 , 116.7(d , jc  f = 11 hz ) , 112.5 ( d , jc 
f = 31 hz ) , 111.2 ( d , jc  f = 4.5 hz ) , 106.6 ( d , jc 
f = 29 hz ) , 74.5 , 72.0 , 70.6 , 70.2 , 65.9 , 59.5 , 26.8 ; hrms - esi ( m / z ) [ m + na ] calcd for c24h24fnnao4 432.1587 , found 432.1574 .
4-fluoro-2-iodo - n - methylaniline 
 ( 0.164 g , 0.652 mmol ) was added dropwise to a solution 
 of alkyne 26(6 ) ( 0.252 g , 0.978 
 mmol ) , pd(pph3)2cl2 ( 0.023 g , 0.033 
 mmol ) , and cui ( 0.006 g , 0.033 mmol ) in et2nh ( 7 ml ) at 
 50 c .
the resulting mixture was stirred at 50 c for 2 
 h. the solution was then cooled to room temperature , and the solvent 
 was evaporated .
purification by flash chromatography ( benzene then 
 4:1 hexanes / etoac ) afforded 27 ( 0.169 g , 68% ) as a brown 
 oil : rf = 0.71 ( 1:1 hexanes / etoac ) ; ir ( thin film )  
 ( cm ) 2916 , 2849 , 1515 , 1488 , 1451 , 1315 , 1265 , 
 1166 , 1076 ; h nmr ( cdcl3 , 400 mhz )  
 7.297.45 ( m , 6h ) , 7.02 ( dd , j = 8.8 , 2.9 
 hz , 1h ) , 6.97 ( td , j = 8.7 , 2.9 hz , 1h ) , 6.49 ( dd , j = 9.0 , 4.3 hz , 1h ) , 6.126.22 ( m , 2h ) , 5.325.34 
 ( m , 1h ) , 4.55 ( s , 2h ) , 4.334.36 ( m , 1h ) , 3.633.68 
 ( m , 2h ) , 3.523.56 ( m , 1h ) , 3.35 ( m , 3h ) , 2.87 ( s , 3h ) ; c nmr ( cdcl3 , 100 mhz )  147.2 , 139.5 , 130.4 , 
 128.7 , 128.6 , 128.4 , 128.4 , 128.3 , 128.2 , 126.9 , ( d , jc  f = 24 hz ) , 117.4 ( d , jc  f = 22 hz ) , 110.0 ( d , jc  f = 8 hz ) , 91.9 , 82.4 , 74.4 , 71.8 , 70.5 , 70.0 , 59.6 , 57.6 , 31.0 ; hrms - esi 
 ( m / z ) [ m + h ] calcd 
 for c23h25fno3 382.1818 , found 382.1213 . prepared according to general 
 continuous flow procedure using indole 18 ( 0.015 g , 0.031 
 mmol ) in ch3cn ( 3.1 ml ) with a 290340 nm band - pass 
 filter and a 10 min residence time at room temperature .
purification 
 by flash chromatography ( 5:1 hexanes / etoac ) afforded indole 19 ( 0.0059 g , 40% ) as a yellow oil : rf = 0.71 ( 1:1 
 hexanes / etoac ) ; ir ( thin film )  ( cm ) 3429 , 
 2971 , 2930 , 2881 , 1707 , 1479 , 1452 , 1369 , 1260 , 1140 , 1089 ; h nmr ( cdcl3 , 500 mhz )  7.70 ( bs , 1h ) , 7.387.43 
 ( m , 4h ) , 7.337.37 ( m , 1h ) , 6.71 ( t , j = 7.8 
 hz , 1h ) , 5.29 ( dd , j = 8.1 , 2.6 hz , 1h ) , 5.00 ( d , j = 4.0 hz , 1h ) , 4.42 ( t , j = 5.0 hz , 1h ) , 
 4.064.15 ( m , 2h ) , 3.703.75 ( m , 3h ) , 3.60 ( d , j = 7.0 hz , 1h ) , 3.343.39 ( m , 4h ) , 2.58 ( td , j = 7.7 , 4.1 hz , 1h ) , 1.58 ( s , 9h ) ; c nmr ( cdcl3 , 125 mhz )  161.0 , 159.9 , 158.1 , 151.9 , 140.3 , 128.6 , 
 127.6 , 125.6 , 116.1 ( d , jc 
f = 
 8 hz ) , 113.7 ( d , jc  f = 22 hz ) , 
 111.2 ( d , jc 
f = 30 hz ) , 81.5 , 
 74.2 , 73.6 , 73.2 , 72.4 , 69.9 , 59.4 , 43.7 , 39.9 , 38.6 , 28.8 ; hrms - esi 
 ( m / z ) [ m + na ] calcd 
 for c27h30fnnao5 490.2006 , found 
 490.2013 .
prepared 
 according to the 
 general continuous flow procedure using indole 20 ( 0.016 
 g , 0.038 mmol ) in ch3cn ( 0.01 m , 3.8 ml ) with a 290340 
 nm band - pass filter and a 10 min residence time at room temperature . 

purification using flash chromatography ( 2:1:1 hexanes / etoac / dcm ) 
 afforded indole 21 ( 0.0023 g , 16% ) as a yellow oil : rf = 0.35 ( 2:1:1 hexanes / etoac / dcm ) ; ir ( thin film )  
 ( cm ) 3403 , 2923 , 2853 , 1737 , 1462 , 1127 ; h nmr ( c6d6 , 500 mhz )  7.007.38 
 ( m , 6h ) , 6.79 ( dd , j = 10.1 , 2.6 hz , 1h ) , 5.72 ( dd , j = 8.1 , 2.4 hz , 1h ) , 4.84 ( d , j = 3.9 
 hz , 1h ) , 4.40 ( t , j = 4.6 hz , 1h ) , 3.78 ( d , j = 8.1 hz , 1h ) , 3.67 ( d , j = 6.8 hz , 1h ) , 
 3.48 ( d , j = 9.0 hz , 1h ) , 3.23 ( dd , j = 10.5 , 4.4 hz , 1h ) , 3.13 ( dd , j = 10.5 , 5.4 hz , 
 1h ) , 2.892.90 ( m , 4h ) , 2.63 ( t , j = 7.5 hz , 
 1h ) , 2.27 ( td , j = 7.6 , 3.9 hz , 1h ) , 1.99 ( s , 3h ) ; c nmr ( cdcl3 , 125 mhz )  198.5 , 155.1 , 153.2 , 
 151.0 , 140.6 , 136.4 ( d , jc 
f = 
 8 hz ) , 128.6 , 127.5 , 125.6 , 117.6 ( d , jc 
f = 6 
 hz ) , 112.2 ( d , jc  f = 23 hz ) , 105.3 , 
 74.3 , 73.8 , 73.3 , 72.7 , 71.1 , 70.0 , 59.4 , 44.1 , 43.4 , 39.7 , 29.9 ; 
 hrms - esi ( m / z ) [ m + h ] calcd for c24h25fno4 410.1768 , 
 found 410.1762 .
prepared 
 according to the general 
 continuous flow procedure using indole 22(34 ) ( 0.014 g , 0.03 mmol ) in ch3cn ( 3 
 ml ) with a 305 nm long - pass filter and a 10 min residence time at 
 room temperature .
purification by flash chromatography ( 3:1 hexanes / etoac ) 
 afforded indole 23 ( 0.023 g , 16% ) as a yellow oil : rf = 0.38 ( 1:1 hexanes / etoac ) ; ir ( thin film )  ( cm ) 3335 , 2925 , 1722 , 1681 , 1449 , 1420 , 1302 , 1146 , 
 1125 ; h nmr ( cdcl3 , 500 mhz )  10.13 
 ( bs , 1h ) , 7.83 ( d , j = 8.5 hz , 3h ) , 7.367.46 
 ( m , 6h ) , 7.34 ( dd , j = 1.8 , 0.6 hz , 1h ) , 6.196.25 
 ( m , 2h ) , 5.315.36 ( m , 2h ) , 5.15 ( d , j = 15.9 
 hz , 1h ) , 4.244.26 ( m , 1h ) , 3.77 ( d , j = 7.9 
 hz , 1h ) , 3.58 ( d , j = 7.0 hz , 1h ) , 3.49 ( d , j = 7.0 hz , 1h ) , 3.25 ( dd , j = 10.5 , 4.1 
 hz , 1h ) , 3.13 ( dd , j = 10.5 , 5.0 hz , 1h ) , 2.92 ( s , 
 3h ) , 2.50 ( t , j = 7.8 hz , 1h ) , 2.30 ( s , 3h ) , 2.10 
 ( ddd , j = 8.5 , 6.6 , 4.1 hz , 1h ) ; c nmr 
 ( cdcl3 , 125 mhz )  142.8 , 139.1 , 131.0 , 129.7 , 128.8 , 
 128.5 , 128.3 , 125.7 , 124.2 , 123.4 , 120.3 , 111.9 , 110.0 , 74.5 , 73.4 , 
 73.2 , 69.7 , 62.9 , 59.8 , 53.7 , 45.7 , 31.2 ; hrms - esi ( m / z ) [ m + na ] calcd for c23h24clnnao5s 484.0961 , found 484.0965 .
 we 
 have developed an automated photochemical microfluidics platform 
 that integrates a 1 kw high - pressure hg vapor lamp and allows for 
 analytical pulse flow or preparative continuous flow reactions . 
 herein , 
 we will discuss the use of this platform toward the discovery of new 
 chemotypes through multidimensional reaction screening . 
 we will highlight 
 the ability to discretely control wavelengths with optical filters , 
 allowing for control of reaction outcomes . 
Introduction
Results and Discussion
Experimental Section