the success of a synthesis 
 is generally measured in terms of cost , 
 time , yield , waste , and length ; metrics influenced to varying degrees , 
 but mainly , by step economy . in general , 
 synthetic strategies with the greatest number of target relevant bond - forming 
 events per synthetic operation are the most step economical . however , most reactions , including the venerable 
 diels  alder cycloaddition , form at most only two new bonds 
 per operation . to achieve greater step economy in accessing targets 
 of value , new reactions , reagents , and strategies that would increase 
 this bonds - per - operation count are required . nature s solution 
 to this problem is instructive , often taking the form of recursive 
 reactions in which a single bond forming event is serially repeated . alkene cyclizations are 
 quintessential examples of how complexity is amplified through such 
 recursive processes . given the exceptional synthetic utility of the 
 diels  alder and related metal - catalyzed [ 4 + 2 ] cycloadditions , 
 we wondered whether they could be deployed recursively in a diene - based 
 cycloaddition that regenerates another diene . this 
 intriguing four - bond disconnection strategy to bicyclo[4.4.0]ring 
 systems  a common feature in natural products , materials , imaging agents , and potentially oligomeric acenes  leads conceptually to the 
 tetramethyleneethane diradical ( tme ) as a key species capable of connecting 
 back - to - back cycloadditions ( figure 1 ) . retrosynthetic 
 analysis of [ 4.4.0]bicycles into two dienophiles 
 and the tetramethyleneethane ( tme ) diradical . however , as shown in a brilliant series of studies by dowd , 
 tme 
 itself has a half - life of only 20 min at 196 c , and 
 preparations of its precursors can be lengthy . predating these studies , alder and ackermann serendipitously 
 uncovered a tme equivalent , reporting that allene and maleic anhydride 
 when heated in a bombenrohr  for 3 days at 175 c 
 produce an octahydronaphthalene product in 16% yield , putatively through 
 the formation and reaction of 1,2-bis - methylenecyclobutane ( bmcb ) . unfortunately , the volatility and reactivity 
 of bmcb limit its use in recursive processes . other creative concepts 
 for diene - generating diene cycloadditions have since been reported ; 
 however , these involve multistep sequences , harsh conditions , or volatile 
 or difficult to access reactants that limit utility . here we report the design and development of a versatile tme equivalent , 
 2,3-dimethylene-4-trimethylsilylbutan-1-ol ( dmtb , 1 ) , 
 that is readily prepared and safely handled on scale . this tme equivalent 
 efficiently engages dienophiles in an initial diels  alder or 
 metal - catalyzed [ 4 + 2 ] cycloaddition , which then allows for a catalyzed 
 vinylogous peterson elimination to produce 
 a second diene captured in a subsequent [ 4 + 2 ] cycloaddition ( figure 2 ) . a single dienophile can be used in both cycloadditions 
 to produce 2:1 products or different dienophiles can be deployed to 
 produce 1:1:1 bicyclic products . thus , in one synthetic operation , 
 this three component process involving as many as three catalytic 
 cycles efficiently produces four new bonds and a carbo- or hetero[4.4.0]bicyclic 
 product , a core subunit found in many synthetic targets , and here 
 applied to the synthesis of a new solvatochromic imaging agent with 
 excellent photophysical properties for biological applications . the synthesis of our parent tme reagent ( scheme 1 : dmtb , 1 ) uses a strategy that would be generally 
 applicable to the synthesis of many related reagents . commercially 
 available alkyne 3 is first alkylated using a previously 
 published procedure , and the resulting 
 alkyne 4 is converted to thp - dmtb ( 2 ) through 
 an enyne metathesis conducted under 1 atm of ethylene gas using grubbs 
 second generation catalyst . while previous studies have used higher 
 catalyst loadings and elevated temperatures for similar substrates , the conditions employed here for the synthesis of thp - dmtb ( 2 ) are unexpectedly efficient and can be conducted on a multigram 
 scale . the hydrolysis of thp - dmtb ( 2 ) to the desired 
 alcohol 1 was accomplished with boric acid in refluxing 
 ethanol which gave dmtb in 70% yield with a minor amount ( 6% ) of the 
 protodesilylated alcohol product . dmtb 
 can be prepared on gram - scale and is readily purified by column chromatography . it is an air - stable liquid and can be stored at 20 c 
 for months . in practice , the thp - dmtb is an effective storage point 
 and can be used as a tme equivalent on its own or converted as needed 
 to dmtb . tmsch2i , thf , 90% ; ( b ) grubbs ii , 1 atm ethylene , 
 dcm , rt , 16 h , 95% ; ( c ) b(oh)3 , etoh , reflux , 1 h , 70% . to investigate whether dmtb would serve as a 
 tme equivalent capable 
 of connecting back - to - back cycloadditions , we combined it with an 
 excess of n - phenylmaleimide in 1,2-dichloroethane 
 ( scheme 2 ) . after 4 h , cycloadduct 5 formed cleanly and was transformed to diene 6 upon 
 addition of [ ( naph)rh(cod)]sbf6 . over the course of 2 days at room temperature , diene 6 was converted to the 2:1 cycloadduct 7 in 96% overall 
 yield ( dr 8:1 favoring the cis  anti cis isomer , see supporting information ) . to determine whether 
 other conditions would effect the intervening peterson 1,4-elimination , cycloadduct 5 , obtained in 98% yield from the reaction 
 of dmtb with n - phenylmaleimide , both protic and lewis 
 acid catalysts were found to work well , leading , in the preferred 
 cases , to rapid ( <3 h ) and efficient ( > 90% ) conversion to diene 6 even at room temperature . all reactions in the table above 
 were monitored by tlc analysis for consumption of the cycloadduct 5 . the diverse and effective conditions for the vinylogous 
 peterson 
 elimination make possible a range of one - operation cycloaddition / elimination / cycloaddition 
 options , including consecutive diels  alder or metal - catalyzed 
 processes or a mixture of the two with the same or different dienophiles . alder 
 cycloadditions ; either with 2 equiv of a single dienophile or with 
 two different dienophiles added in a serialized fashion . thus , with 
 alcl3 as the lewis acid instead of rh(i ) , dmtb and n - phenylmaleimide provide compound 7 ( table 2 ) in one operation in greatly reduced reaction times 
 ( 1.5 h ) and in high yield ( 97% ) . similarly , the use of 1,4-naphthoquinone 
 as a dienophile and zncl2 as the lewis acid leads , in one 
 operation , to the hexacene precursor 8 , in 95% yield . complementing this route to 2:1 adducts , the 1:1:1 
 adduct 9 is obtained in 78% yield by using 1 equiv of n - phenylmaleimide first and then dimethyl fumarate as a 
 second component . interestingly , switching the order of the addition 
 ( dimethyl fumarate then n - phenylmaleimide ) results 
 in a similar outcome ( 73% ) . activated acetylenes ( e.g. , dimethyl acetylenedicarboxylate : 
 dmad ) were also shown to be effective diels  alder partners 
 in our system ( 10 ) . as exemplified by 11 and 12 ( table 2 ) , heteroatomic 
 dienophiles such as 4-phenyl-1,2,4-triazoline-3,5-dione and diethyl 
 oxomalonate both function effectively in this reaction , providing 
 facile access to a diverse array of heterocyclic compounds of the 
 isochromane and pyridazine families . we and others have previously 
 shown that certain transition metals 
 can effectively catalyze multistep diene alder 
 conditions due to a poor highest occupied molecular orbital  lowest 
 unoccupied molecular orbital gap . phenylacetylene , for example , is an ineffective dienophile under 
 conventional thermal diels  alder conditions involving 1 . when it is combined with an activated dienophile ( dmad ) 
 and 1 , cycloaddition occurs only with dmad . however , 
 addition of [ ( naph)rh(cod)]sbf6 to this mixture results 
 in elimination and subsequent rh(i ) catalyzed cycloaddition to afford 
 cycloadduct 13a in high yield . with rh(i ) catalysis , 
 a large variety of commercially available alkynes can be employed 
 in the same fashion as post - peterson elimination dienophiles providing 
 the corresponding cycloadducts in one operation in good to excellent 
 yields ( 13a  h , 14 , and 15 , table 2 ) . of further synthetic note , the resultant 
 tetrahydronaphthalenes can be readily transformed to the fully aromatic 
 naphthalene core using ddq , as exemplified by the transformation of 13a to its naphthalene derivative in 80% yield ( see supporting information ) . initial attempts 
 to perform sequential metal - catalyzed [ 4 + 2 ] 
 cycloadditions between dmtb and alkynes , i.e. , involving catalysis 
 of each step of the cycloaddition / elimination / cycloaddition sequence , 
 led to low yields due to decomposition of dmtb under the reaction 
 conditions . the use of thp - dmtb circumvented this problem and allowed 
 for successful conversion to 2:1 adducts of an alkyne and tme equivalent 
 ( 17 , table 2 ) . due to the facility 
 of the elimination at room temperature , the conditions used for the 
 synthesis of 17 were not amenable to accessing 1:1:1 
 adducts resulting from the use of different alkynes . however , a change 
 in solvent and reduction in temperature ( 0 c ) for the initial 
 cycloaddition markedly reduces the rate of elimination while allowing 
 the initial rhodium - catalyzed [ 4 + 2 ] cycloaddition to proceed . allowing the reaction to warm to room temperature and addition of a second 
 alkyne leads efficiently to 1:1:1 cycloadducts ( 16a  e , table 2 ) . utilizing this optimized 
 procedure in which a single catalyst under different conditions is 
 capable of effecting multiple reactions , a topic of understandably 
 great current interest , the synthesis 
 of a number of tetrahydronaphthalene structures resulting from unactivated 
 alkynes was achieved in high yield . this recursive process provides 
 highly step - economical access to 
 numerous targets of interest . pertinent to our studies on drug delivery , this process can be used to access solvatochromic 
 dyes ( e.g. , 6-dmn and anthradan ) . such agents report on their local molecular 
 environments through changes in their observable fluorescent properties 
 and have found considerable use in studies on dna binding to proteins ; protein  protein interactions ; membrane viscosity , dynamics , and permeation ; and protein structure . using our recursive 
 strategy , we set out to make 6-dma ( 21 ) a new and potentially 
 broadly useful solvatochromic dye , as it would be expected to exhibit 
 enhanced photophysical properties in biological applications relative 
 to 6-dmn ( scheme 3 ) . the synthesis of 
 the 6-dma fluorophore also presented a new direction 
 for our tme studies as it required compatibility between our reagent 
 and conditions required for aryne generation and cycloaddition . significantly , 
 in one synthetic operation , initiated by n - ethylmaleimide 
 cycloaddition with dmtb , followed by zinc catalyzed elimination and 
 tbaf triggered aryne formation using an easily synthesized chloroaryne 
 equivalent , 18 , afforded 
 the desired dye precursor 19 in 94% yield . to avoid an 
 undesirable exotherm on larger scales , a 1 m solution of dmtb and 
 the chloroaryne precursor 18 were added to a solution 
 of n - ethylmaleimide . under these conditions ( see supporting information ) , 1.2 g of the desired 
 hexahydroanthracene 19 was obtained in 86% yield . oxidation 
 of 19 utilizing a modified wohl  ziegler procedure 
 furnished the desired anthracene core 20(49 ) ( 96% yield ) and modified c  n coupling chemistry 
 readily produced the desired 6-dma ( 21 ) in 80% yield . this new fluorophore is thus formed in only 
 three synthetic operations in 72% overall yield from chloroaryne precursor 18 and dmtb . ( a ) i. dce , reflux , ii . 15% 
 zncl2 , 60 c , iii . tbaf , 0 c ; ( b ) i. nbs , ( phcoo)2 , ccl4 , reflux , 17 h , ii . net3 , rt , 
 20 min ; ( c ) hnme2 , 5% ruphos pd g2 , 5:1 toluene / t - buoh , cs2co3 , 100 c , 8.5 h the photophysical properties of the novel dye 21 are 
 summarized in figure 3 . the maximum emission occurs at 527 
 nm in toluene and 691 nm in methanol . this corresponds to a large 
 spectral red - shift of 164 nm in contrast to the lower benzolog 6-dmn , 
 which displays a spectral red - shift of only 100 nm in the same solvents . despite the large difference in emission , the 
 solvatochromic shift in absorption is minimal : changing only 7 nm 
 between the two solvents . in addition , the extension of the chromophore 
 from a naphthalene to an anthracene core results in approximately 
 a 40 nm increase in the wavelength of maximum absorption . this is 
 a useful property in that lower energy light minimizes stimulating 
 cellular autofluorescence . another important 
 quality of solvatochromic dyes is their ability to exhibit on / off 
 fluorescence between aprotic and protic environments , respectively . 
 to investigate the potential of 6-dma as an on / off fluorophore , the 
 quantum yields were determined in a number of common solvents . the 
 highest quantum yield ( qy ,  ) observed for 6-dma was in 1,4-dioxane 
 (  = 0.48 ) , and the lowest was in methanol (  = 0.0027 ) . the difference in quantum yields corresponds to a 180-fold decrease 
 in fluorescence intensity , which is an order of magnitude more than 
 6-dmn ( 18-fold decrease in qy ) . research is currently underway for 
 the derivatization of this new class of solvatochromic dyes to allow 
 for incorporation into biological systems and will be reported on 
 in due course . , we have introduced recursive 
 reagents that function like 
 tetramethyleneethane equivalents , bringing together , through back - to - back 
 cycloadditions , common building blocks in the form of alkynes , alkenes , 
 arynes , and heteroatomic dienophiles and efficiently producing in 
 one operation polycyclic ring systems of potential use in the synthesis 
 of natural and designed molecules . the reagents allow for the coupling 
 of two diels  alder cycloadditions , a diels  alder cycloaddition 
 and a metal - catalyzed cycloaddition , or two metal - catalyzed cycloadditions 
 with the same or different dienophiles . a range of conditions for 
 the crucial 1,4-peterson elimination enables these recursive cycloadditions 
 to be achieved in one operation . the use of [ ( naph)rh(cod)]sbf6 provides a highly effective example of a catalytic cascade 
 in which three operations are controlled by the same catalyst . these 
 new reagents allow facile access to commonly encountered ring systems , 
 herein illustrated in a three - step synthesis of a promising new solvatochromic 
 fluorophore ( 21 ) . further studies on these fluorophores 
 and other applications of this methodology are ongoing in our laboratory 
 and will be reported in due course .
new reactions and reagents that allow 
 for multiple bond - forming 
 events per synthetic operation are required to achieve structural 
 complexity and thus value with step- , time- , cost- , and waste - economy . 
 here 
 we report a new class of reagents that function like tetramethyleneethane 
 ( tme ) , allowing for back - to - back [ 4 + 2 ] cycloadditions , thereby amplifying 
 the complexity - increasing benefits of diels  alder and metal - catalyzed 
 cycloadditions . the parent recursive reagent , 2,3-dimethylene-4-trimethylsilylbutan-1-ol 
 ( dmtb ) , is readily available from the metathesis of ethylene and thp - protected 
 4-trimethylsilylbutyn-1-ol . 
 dmtb and related reagents engage diverse 
 dienophiles in an initial diels  alder or metal - catalyzed [ 4 
 + 2 ] cycloaddition , triggering a subsequent vinylogous peterson elimination 
 that recursively generates a new diene for a second cycloaddition . 
 overall , this multicomponent catalytic cascade produces in one operation 
 carbo- and heterobicyclic building blocks for the synthesis of a variety 
 of natural products , therapeutic leads , imaging agents , and materials . 
 its application to the three step synthesis of a new solvatochromic 
 fluorophore , n - ethyl(6-n , n - dimethylaminoanthracene-2,3-dicarboximide ) ( 6-dma ) , and 
 the photophysical characterization of this fluorophore are described .