This  is  the  peer  reviewed  version  of  the  following  article  Green  Chem.  2016,  18,  3507-­‐3512,  which  has  been  published  in   final  form  http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00792A#!divAbstract   Asymmetric  cross-­‐  and  self-­‐aldol  reactions  of  aldehydes  in  water  with  a  polystyrene-­‐ supported  triazolylproline  organocatalyst     a a  a a,b Patricia  Llanes,  Sonia  Sayalero,  Carles  Rodríguez-­‐Escrich  and  Miquel  A.  Pericàs*   a. Institute  of  Chemical  Research  of  Catalonia  (ICIQ),  The  Barcelona  Institute  of  Science  and  Technology.  Av.  Països  Catalans,  16,  43007  Tarragona,  Spain.  E-­‐mail:   mapericas@iciq.es.   b. Departament  de  Química  Orgànica,  Universitat  de  Barcelona  (UB),  08028  Barcelona,  Spain.     A   polystyrene-­‐immobilized   triazolylproline   has   been   prepared   by   a   bottom-­‐up   approach   involving   co-­‐polymerization   with   full   regiocontrol.   The   resulting   PS   resin   swells   in   water   and   has   been   applied   to   the   enantioselective   cross-­‐aldol   reaction   and   to   the   self-­‐aldol   reaction   of   aldehydes  under  essentially  neat  conditions,  excellent  yields  and  stereoselectivities  being  recorded.   Introduction   The   aldol   reaction   is   the   most   important   method  to   install   the   β-­‐hydroxycarbonyl   structural   unit,   very   common   in   fine   chemicals   1 and  pharmaceutically  active  compounds.   The  myriad  studies  devoted  to  the  topic  deal  almost  exclusively   with  ketone  donors   and   aromatic   aldehyde   acceptors.   In   contrast,   the   direct   asymmetric   cross-­‐aldol   coupling   between   non-­‐equivalent   aldehydes,   2 first  reported  by  MacMillan  and  co-­‐workers,  remains  a  synthetic  challenge.  Since  enolizable  aldehydes  can  play  a  double  role  as   3   nucleophiles  or  electrophiles,  controlling  reaction  pathways  is  crucial  to  achieve  the  desired  chemoselectivity.   The   use   of   proline   to   carry   out   this   transformation   in   a   stereoselective   manner   presents   several   advantages:   it   is   safe,   inexpensive   and   stable   to   moisture   and   air,   which   allows   this   metal-­‐free   process   to   take   place   in   very   benign   reaction   4 conditions.   Proline-­‐catalyzed   asymmetric   aldol   reactions   are   usually   carried   out   in   polar   solvents   such   as   DMSO   or   DMF.   5 However,   since   the   use   of   binary   mixtures   of   polar   aprotic   solvents   and   water   has   a   highly   beneficial   effect   in   the   reaction   rate, 6 the   possibility   of   using   water   as   reaction   medium   is   very   appealing   to   reduce   the   environmental   impact   of   the   process. In   addition,  the  undesired  formation  of  α,β-­‐unsaturated  aldehydes  arising  from  dehydration  of  the  initial  aldol  adduct,  is  minimized   7 under  aqueous  conditions.   Given  the  interest  in  the  asymmetric  aldol  reaction,  several  authors  have  described  the  immobilization  of  proline  derivatives  with   8 the   common   goal   of   increasing   their   sustainability   profile.   Solid-­‐supported   catalysts   are   easily   separated   from   the   reaction   mixture,   thereby   facilitating   product   isolation   and   opening   up   the   possibility   of   recovery   and   reuse. Indeed,   excellent   results   9 10 have  been  achieved  using  insoluble  supports  such  as  mesoporous  silica   and   different  classes  of  nanostructured  or  polymeric   11,  12   materials. Lightly  cross-­‐linked  PS  (1-­‐2%  DVB)  has  good  swelling  characteristics  in  a  variety  of  organic  solvents,  which  generates  a  gel-­‐type   material.   However,   the   limited   compatibility   of   water   with   polystyrene   (PS)   resins   usually   hampers   the   use   of   PS-­‐supported   catalysts  in  an  aqueous  environment,  albeit  this  issue  can  be  circumvented.  For  instance,  we  have  previously  demonstrated  that,   with   the   appropriate   design,   PS-­‐supported   organocatalysts   can   generate   a   hydrophilic   pocket,   akin   to   that   of   aldolases,   that   11a-­‐c allows  working  in  water  with  high  efficiency.  To  this  end,  it  would  be  desirable  to  develop  more  efficient  synthetic  methods   to  prepare  these  catalytic  resins  without  having  to  resort  to  pre-­‐functionalized  commercially  available  materials.  This  approach   would   significantly   lower   the   cost   of   the   catalytic   material,   an   important   parameter   when   large   scale   applications   are   conceived,   and   introduce   the   possibility   of   preparing   custom-­‐made   resins   with   fully   controllable   parameters   like   loading,   cross-­‐linking   level,   12g,h and   site-­‐selective   functionalization.   In   this   last   respect,   it   has   been   normally   overlooked   that   commercial   Merrifield   resins,   the   most   usual   starting   materials,   contain   in   their   structures   variable   mixtures   of   para-­‐   and   meta-­‐chloromethyl   substituted   phenyl  rings,  this  fact  being  a  potential  origin  of  reproducibility  issues  in  their  preparation  and  catalytic  applications.   Results  and  discussion   Herein   we   wanted   to   evaluate   the   possibility   of   a   bottom-­‐up   approach   towards   catalytic   resins,   where   a   p-­‐vinyl   substituted   monomeric   species   would   be   co-­‐polymerized   with   styrene   and   divinylbenzene   (DVB)   in   order   to   achieve   strictly   p-­‐phenyl   functionalized   copolymers.   Bearing   in   mind   our   ultimate   goal   of   efficient   operation   in   water,   we   decided   to   introduce   a   light   11a-­‐c   cross-­‐linking  level  (2%  DVB),  with  the  aim  of  generating  a  microporous  resin  that  could  swell  in  that  media. handle for copolymerization HO NaH, DMF + 1 Cl O 0 ºC, 2 h 3 94% 2 O N3 spacer CO 2t-Bu N Boc 4 CuSO 4!5H 2O ascorbic acid t-BuOH/H 2O MW 200 W 80 ºC, 90 min 70% N N handle for catalyst immobilization linker N N Boc CO 2t-Bu 5   Scheme  1  Synthesis  of  the  functional  monomer  5   To   this   end,   a   proline   derivative   bearing   a   pendant   vinyl   group   was   prepared   as   indicated   in   Scheme   1.   First,   p-­‐ chloromethylstyrene   (1)   was   reacted   with   alcohol   2   to   give   the   bifunctional   linker   3.   The   terminal   alkyne   was   clicked   with   the   11b azidoproline  derivative  4,  yielding  5  in  70%  yield.  This  monomer  features  the  desired  catalytic  unit  bound  to  a  polymerizable   13 vinyl   group   through   a   robust   triazole   unit,   whose   function   is   providing   optimal   hydrophobic/hydrophilic   balance   in   the   resin.   11b-­‐d According  to  precedents,  this  situation  gives  rise  to  a  hydrogen  bond  network  that  connects  the  linker  with  the  amino  acid,   which  explains  why  the  resin,  in  spite  of  its  highly  lipophilic  backbone,  swells  perfectly  in  water.  On  the  other  hand,  a  suitable   spacer   ensures   enough   distance   between   the   catalytic   site   and   the   polymeric   matrix,   thus   avoiding   undesirable   interactions   which  might  affect  the  catalytic  activity  and/or  selectivity.   The   heterogeneous   catalyst   with   the   desired   morphology   and   properties   was   obtained   by   AIBN-­‐initiated   radical   copolymerization   of   the   proline   derivative   5   with   styrene   and   DVB   under   the   usual   conditions   for   a   suspension-­‐type   14,15   polymerization   (Scheme   2). Trifluoroacetic   acid-­‐mediated   deprotection   of   both   the   Boc   group   and   the   tert-­‐butyl   ester   in   6   furnished  the  catalytically  active  resin  7  (Scheme  2),  which  was  finally  treated  with  a  buffer  solution  (pH  5)  to  ensure  proline  is  in   its  zwitterionic  form.               O H 2O/Toluene boric acid AIBN, PVA 80 ºC, 16 h N N N N Boc 5 + + CO 2t-Bu O O TFA, CH 2Cl 2 Et 3SiH, rt, 16 h N N N N N Boc 6 N CO 2t-Bu N N H 7 CO 2H   Scheme  2  Synthesis  of  the  regioisomerically  defined  polystyrene-­‐supported  catalyst  7   -­‐1   An  86%  of  the  monomer  was  incorporated  to  resin  7,  giving  a  functionalization  level  of  0.9  mmol  g . Solvent  uptake  data  of  resin   7   were   recorded   for   water,   and   aqueous   mixtures   of   THF,   DMF   or   DMSO   (see   Supporting   Information).   Notably,   this   new   11b,c polymer   proved   to   swell   in   water   thanks   to   the   cooperative   effect   between   the   triazole   and   the   amino   acid   unit.   This   reveals   the   amphiphilic   nature   of   the   polymer:   on   the   one   hand   it   displays   a   hydrophobic   matrix   and,   on   the   other   hand,   hydrophilic   reactive  centres  are  regularly  scattered  within  its  structure.     The  asymmetric  cross-­‐aldol  reaction  between  butanal  and  2-­‐nitrobenzaldehyde  was  chosen  as  a  model  to  optimize  the  reaction   conditions.   As   highlighted   in   Table   1,   the   reaction   takes   place   at   room   temperature   with   10   mol%   of   7   in   different   aqueous   solvent  systems.  To  our  delight,  using  water  as  the  only  solvent  (entry  1)  the  cross-­‐aldol  product  was  obtained  in  80%  yield  and   excellent  stereoselectivity  (93:7  anti/syn,  95%  ee).  A  similar  result  was  obtained  with  DMSO  containing  6%  of  water  (entry  2)  or   in  a  DMSO/water  1:1  mixture  (entry  3).  With  wet  DMF  and  THF  the  stereoselectivities  were  also  very  good,  albeit  the  yield  was   lower   in   the   latter   case   (entries   4-­‐7). Using   butanal   in   excess ensured   excellent   yields   of   the   desired   product   while   its   homodimerization  was  practically  negligible. For  the  sake  of  comparison,  an  analogous  PS-­‐supported  triazolylproline  previously   11c reported  by  our  group ,  derived  from  commercial  Merrifield  resin  (mixture  of  meta  and  para  regioisomers)    was  tested  in  the   benchmark  reaction,  giving  the  desired  product  in  85%  yield,  but  only  84%  ee.   a Table  1  Solvent  effects  on  the  cross-­‐aldol  reaction  of  2-­‐nitrobenzaldehyde  with  butanal  catalyzed  by  resin  7   O NO 2 O NO 2 1) 7 (10 mol%) OH OH solvent, rt, 24 h + 2) NaBH 4, EtOH 0 ºC, 1 h Entry 1 2 3 4 5 6 7 a Solvent H2 O DMSO/H2O (94:6) DMSO/H2O (50:50) DMF/H2O (94:6) DMF/H2O (50:50) THF/H2O (94:6) THF/H2O (50:50) Yield [%]b 80 80 79 80 81 56 72 8 anti/sync 93:7 93:7 93:7 92:8 93:7 93:7 92:8   ee anti [%]d 95 96 93 95 87 96 91   Reactions   were   performed   with   resin   7   (0.02   mmol),   2-­‐nitrobenzaldehyde   (0.2     mmol)   and   butanal   (0.6   mmol)   in   different   solvents   (67   μL).   b   Isolated   yield.   c   Determined  by  1H  NMR  on  a  crude  sample  of  the  1,3-­‐diol.  d    Determined  by  chiral  HPLC  .   A   representative   family   of   aromatic   aldehydes   was   then   reacted   with   donor   aliphatic   aldehydes   under   the   two   best   sets   of   conditions   (A:   water;   B:   wet   DMSO;   Table   2).   Electron-­‐deficient   aromatic   aldehydes   such   as   o-­‐nitro-­‐,   p-­‐nitro-­‐,   p-­‐cyano-­‐,   p-­‐ trifluoromethyl-­‐   and   o-­‐chlorobenzaldehyde   reacted   with   butanal   or   propanal   in   very   good   yields   and   ee’s,   regardless   of   the   substitution   pattern   (products   8-­‐12,   conditions   A).   The   use   of   wet   DMSO   (containing   6%   of   water)   as   solvent   gave   the   corresponding   adducts   with   similar   results   (conditions   B).   Remarkably,   the   concentration   of   the   limiting   aldehyde   was   3   M   in   both  solvent  systems.   When  benzaldehyde  was  employed  as  the  reaction  partner  the  use  of  water  gave  much  higher  yield  than  wet  DMSO,  albeit  the   stereoselectivities  were  almost  identical  (product  13).  3-­‐Methoxybenzaldehyde  and  furfural  (which  required  48  h  reaction  time)   were   also   suitable   substrates,   providing   the   aldol   product   in   good   to   excellent   yields   and   stereoselectivities   (products   14-­‐16).   Again  water  gave  much  higher  yields  than  wet  DMSO  (conditions  A  vs  B),  which  seems  to  be  a  trend  for  electron  rich  aromatic   aldehydes.  In  the  latter  case,  neat  conditions  proved  to  be  also  suitable  to  carry  out  the  reaction.   It   is   important   to   note   that   all   the   scope   in   Table   2   was   carried   out   with   two   samples   of   7   that   were   repeatedly   reused.   This   illustrates  the  robustness  of  the  resin,  which  displays  excellent  results  with  a  wide  variety  of  substrates.     a Table  2  Asymmetric  direct  cross-­‐aldol  reaction  of  non-­‐equivalent  aldehydes  catalyzed  by  resin  7   O R1 1) 7 (10 mol%) O H H 0 NO 2 OH OH OH F 3C OH OH Me OH NC 9   OH 10 A yield 85% anti/syn 92:8 ee 93% OH B yield 98% anti/syn 90:10 ee 95% OH OH Me 11 12 A B yield 85% yield 84% anti/syn 93:7 anti/syn 82:18 ee 81% ee 97% OH OH A B yield 88% yield 82% anti/syn 87:13 anti/syn 90:10 ee 96% ee 96% Cl R2 8-16 1h OH O2N 8 A B yield 80% yield 80% anti/syn 93:7 anti/syn 93:7 ee 95% ee 96% R1 2) NaBH4, EtOH oC, OH OH solvent, rt, 24 h R2 + 13 A B yield 99% yield 60% anti/syn 89:11 anti/syn 94:6 ee 95% ee 99% OH OH OH A yield 92% anti/syn 91:9 ee 89% B yield 32% anti/syn 97:3 ee 90% OH OH MeO O 14 A B yield 59% yield 43% anti/syn 97:3 anti/syn 97:3 ee 81% ee 95% Me 15 Ab yield 52% anti/syn 83:17 ee 82% O 16 Ab Bb Neat b yield 70% yield 30% yield 69% anti/syn 80:20 anti/syn 70:30 anti/syn 70:30 ee 77% ee 78% ee 82%   a  Typical  reaction  conditions:  resin  7  (0.02  mmol),  aromatic  aldehyde  (0.2  mmol)  and  aliphatic  aldehyde  (0.6  mmol)  in  water  (67  μL,  Conditions  A)  or  in  a  mixture  of   DMSO/water  (94:6,  67  μL,  Conditions  B);  isolated  yield;  anti/syn  diastereomeric  ratio  was  determined  by  1H  NMR  on  a  crude  sample  of  the  1,3-­‐diol;  ee  was  determined   by  chiral  HPLC.  b  48  h  reaction  time.     Having  established  that  resin  7  effectively  promoted  the  cross-­‐aldol  reaction  of  aldehydes  in  the  presence  of  small  amounts  of   aqueous  solvents  at  room  temperature,  these  conditions  were  applied  to  the   self-­‐aldol  reaction  of  aldehydes  using  water  as  the   only   solvent.   Initial   investigations   revealed   that   in   the   presence   of   7   the   self-­‐aldol   reaction   of   propanal   works   satisfactorily   in   water   (Table   3).   In   these   conditions,   the   self-­‐aldol   product   undergoes   hemiacetal   formation   with   the   starting   aldehyde,   which   protects  the  product  from  epimerization  or  participation  in  further  aldol  processes.  However,  this  consumes  up  to  one  third  of   the   starting   material   and   thus   the   yields   in   Table   3   refer   to   this   hemiacetal   product.   To   our   convenience,   diol   17   could   be   obtained  in  good  yield  and  with  good  stereoselectivity  after  in  situ  reduction.  As  shown  in  Table  3,  the  reactions  gave  moderate   to  good  yields  but  high  enantioselectivities  with  propanal,  butanal  and  3-­‐phenylpropanal.   a Table  3  Self-­‐aldol  reaction  of  aldehydes  catalyzed  by  resin  7   R OH O R 7 (10 mol%) H2O, rt, 24 h O R R R Me Et Bn Bn 17-19 Yield [%]b 30 82 61 70 Product 17 18 19 19 OH R EtOH OH 0 ºC, 1 h R 3 equiv Entry 1 2 3 4f NaBH4 O anti:sync 70:30 60:40 79:21 56:44   ee anti [%]d 91 87 96e 73 a   Reactions   were   performed   in   water   (0.4   mL)   with   aldehyde   (1   mmol)   and   resin   7   (0.1   mmol).   b   Isolated   yield.   c   Determined   by   1H   NMR   on   a   crude   sample   of   the   1,3-­‐ diol  (entries  1,  2)  or  non  chiral  HPLC  (entries  3,  4).   d    Determined  by  chiral  HPLC  after  conversion  to  the  monobenzoate.   e  Determined  by  chiral  HPLC  of  the  1,3-­‐diol.   f   With  2-­‐methyltetrahydrofuran  as  the  solvent.     11b,16 7h Previous   studies   on   the   proline-­‐mediated   self-­‐aldol   reaction of   propanal   or   butanal   in   water   indicated   that   the   reaction   hardly  proceeds  in  the  presence  of  10  mol%  of  proline.  In  contrast,  polymer  7  proved  useful  in  the  formation  of  the  β-­‐hydroxy   aldehyde   adducts   with   high   stereoselectivity   in   an   aqueous   environment.   Furthermore,   dehydration   products   were   not   observed,   probably   as   a   consequence   of   the   aqueous   reaction   conditions:   in   the   presence   of   water,   dehydration   is   much   less   favourable  than  when  dry  organic  solvents  are  used.  The  role  of  water  looks  even  more  crucial  if  we  consider  that  employing  2-­‐ methyltetrahydrofuran  as  the  solvent  the  stereoselectivities  decrease  significantly  (Table  3,  entry  4).       As  a  demonstration  of  the  synthetic  potential  of  immobilized  proline  7,  the  self-­‐aldol  reaction  of  butanal  was  scaled  up  using  50   mmol  of  the  aldehyde  (Scheme  3).  Lowering  the  catalyst  loading  to  only  0.2  mol%  of  resin  7  and  under  essentially  neat  conditions   (just  0.3  mL  of  water  were  used),  the  reaction  proceeded  in  4  days  to  furnish  the  desired  product   15  in  49%  yield  (1.17  g  isolated   product).     The   operational   simplicity   associated   to   the   catalytic   use   of   resin   7   (simply   adding   a   sample   of   wet   resin  7   to   the   flask   containing   the   aldehyde)   is   truly   remarkable,   with   a   behaviour   reminiscent   to   the   alchemysts'   philosophers   stone   or   to   the   brewers'   ferments.       1) 7 (0.2 mol%) O OH OH H2O, rt, 4 d H 49% yield 2) NaBH4, EtOH 67:33 anti/syn 50 mmol 0 ºC, 1 h 15 82% ee   Scheme  3  Asymmetric  self-­‐aldol  reaction  of  neat  butanal  using  wet  7.     To  further  confirm  the  recyclability  of  7,  the  dimerization  of  butanal  was  performed  during  ten  consecutive  runs  with  the  same   sample  of  this  catalytic  resin.  After  each  run,  it  was  recovered  by  simple  filtration,  rinsed  with  EtOAc,  dried  and  directly  reused  in   the   next   cycle   (see   Supporting   Information   for   more   details).   Under   these   conditions,   only   a   moderate   decrease   of   catalytic   activity  was  recorded  at  the  end  of  the  recycling  test  (Table  4).     a Table  4  Recycling  experiments  of  catalyst  7  in  the  self-­‐aldol  reaction  of  butanal   O OH 7 (10 mol%) H2O, rt, 24 h 3 equiv O O OH NaBH4 EtOH OH 0 ºC, 1 h 18   Cycle 1 2 3 4 5 6 7 8 9 10 a Yield [%]b 75 85 96 94 95 94 87 75 85 83 anti/sync 60:40 68:32 70:30 70:30 63:37 68:32 73:27 75:25 73:26 70:30 ee anti [%]d 87 92 91 90 88 86 85 84 84 83  Reactions  were  performed  in  water  (0.4  mL)  with  butanal  (1  mmol)  and  resin  7  (0.1  mmol).  b  Isolated  yield.  c  Determined  by  1H  NMR  on  a  crude  sample  of  the  1,3-­‐diol.    Determined  by  chiral  HPLC  after  conversion  to  the  monobenzoate.   d   Conclusions   We  have  developed  a  polystyrene-­‐supported  organocatalyst  based  on  proline  (7)  using  a  simple  copolymerization  strategy.  The   catalyst  thus  obtained  is  suitable  for  work  under  wet  conditions,  is  notably  robust  and  can  be  repeatedly  reused  with  minimal   loss   of   activity.   Resin   7,   which   displays   a   completely   regiodefined   structure   unlike   analogous   polymers   based   on   commercial   Merrifield   resins,   represents   an   innovative   and   sustainable   catalyst   design   that   shows   excellent   performance   in   both   the   self-­‐ aldolization  and  the  cross-­‐aldol  reaction  of  aldehydes  by  simply  using  a  small  volume  of  water  as  solvent.  From  the  operational   point  of  view,  the  asymmetric  direct  coupling  of  aldehyde  substrates  mediated  by  7  thus  represents  a  green  alternative  for  the   rapid  production  of  a  range  of  enantiomerically  and  diastereomerically  enriched  1,3-­‐diols.  In  particular,  the  possibility  of  using   the  wet  resin  7  as  a  catalyst  (ferment)  to  induce  the  asymmetric  self-­‐aldol  reaction  of  aliphatic  aldehydes  under  essentially  neat   conditions   represents,   in   our   opinion,   an   important   step   towards   the   development   of   truly   practical   catalytic   asymmetric   processes  fulfilling  all  the  requirements  of  sustainable  chemistry.     Acknowledgments   This  work  was  funded  by  the  Institute  of  Chemical 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