"This is the peer reviewed version of the following article: [Angew. Chem. Int. Ed. 2015, 54, 11686 –11690], which has been published in final form at [http://onlinelibrary.wiley.com/doi/10.1002/anie.201504956/abstract]. This article may be used for noncommercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving ."     A  New  and  Metal-­‐free  Synthesis  of  N−Aryl  Carbamates  under  Ambient  Conditions   Wusheng  Guo,[a]  Joan  Gónzalez-­‐Fabra,[a]  Nuno  A.  G.  Bandeira,[a]  Carles  Bo[a][b]  and  Arjan  W.  Kleij*[a][c]     Abstract:  The  first  chemo-­‐  and  site-­‐selective  process   for  the  formation  of  N-­‐aryl-­‐carbamates  from  cyclic   organic  carbonates  and  aromatic  amines  is  reported.   The  reactions  proceed  smoothly  under  extremely   mild/attractive  reaction  conditions  using  TBD   (triazabicyclodecene)  as  an  effective  and  cheap   organocatalyst  providing  a  sustainable  and  new   methodology  for  the  formation  of  a  wide  variety  of   useful  N-­‐aryl  carbamate  synthons  in  good  to  excellent   yields.  Computational  investigations  have  been   performed  showing  the  underlying  reason  for  the   observed  unique  reactivity  which  is  related  to  an   effective  proton-­‐relay  mechanism  mediated  by  the   bicyclic  guanidine  base.   The  conversion  of  carbon  dioxide  into  value-­‐added   organic  compounds  continues  to  be  a  vivid  area  of   research  in  academic  and  industrial  settings.[1]  The   valorization  of  CO2  is  important  to  create  value  from  a   waste  material,  and  currently  efforts  have  already   shown  great  potential  towards  the  use  of  CO2  to  store   energy,[2]  and  as  a  synthon  for  the  creation  of  new   polymers[3]  and  fine-­‐chemicals.[4]  Another  area  of   widespread  interest  and  importance  concerns  the   preparation  of  organic  carbonates.  More  recently,   focus  has  been  shifted  towards  the  use  of  these   carbonates  as  intermediates  in  organic  synthesis.[5]  An   [a] [b] [c] Dr. W. Guo, J. González-Fabra, Dr. N. A. G. Bandeira, Prof. Dr. C. Bo, Prof. Dr. A. W. Kleij, Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain E-mail: akleij@iciq.es Prof. Dr. C. Bo Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, Marcel•lí Domingo s/n, 43007 Tarragona, Spain Prof. Dr. A. W. Kleij Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain Supporting information for this article is given via a link at the end of the document attractive  route  towards  the  conversion  of  cyclic   carbonates  into  useful  products  concerns  their   aminolysis  by  aliphatic  amines  affording  N-­‐alkyl   carbamate  structures  (Scheme  1).[6]  However,  the   corresponding  site-­‐selective  aminolysis  induced  by   aromatic  amines  yielding  N-­‐aryl  carbamates  (NARCs)   is  surprisingly  unknown.   The  low  nucleophilic  character  of  aromatic  versus   aliphatic  amines  poses  a  huge  challenge  to  prepare   NARCs.  Recent  work[7]  concerning  the  catalytic   reaction  between  cyclic  carbonates  and  aromatic   amines  has  revealed  that  high  reaction  temperatures   (>140ºC)  are  needed  to  achieve  appreciable   conversion  rates.  However,  these  temperature   requirements  significantly  compromise  the  chemo-­‐ selectivity  of  the  process  with  no  observable   formation  of  the  NARC.  At  high  reaction  temperatures   aromatic  amines  prefer  the  attack  on  the  a-­‐carbon   (Scheme  1)  of  the  cyclic  carbonate  hence  yielding  a   plethora  of  decarboxylated  side-­‐products  including  N-­‐ alkylated  amines  and  their  derivatives.[7]  Relevant   studies[8]  concerning  the  reaction  of  non-­‐cyclic  dialkyl-­‐ carbonates  with  aromatic  amines  were  reported   although  with  quite  limited  scope  at  temperatures   >80oC.  Thus,  it  still  remains  highly  challenging  and   attractive  to  selectively  prepare  NARCs  through  a  site-­‐ specific  aminolysis  reaction  using  aromatic  amines   (Scheme  1,  below)  from  cyclic  carbonate  under  mild   reaction  conditions.  Such  a  new  and  sustainable   process  would  represent  a  valuable  alternative  to   reported  (metal-­‐based)  processes[9]  that  require   either  harsh  reaction  conditions  and/or  more   expensive  reagents/metal  precursors,  and   conventional  routes  to  NARCs  based  on   isocyanates.[10]     Furthermore,  the  NARC  compounds  may  offer   synthetically  attractive  scaffolds  as  they  partially   mimic  fragments  of  pharmaceutical  compounds  such   as  Efavirenz  and  Retigabine  (Scheme  1).[11]  Also,   thermolysis  of  NARCs  offers  a  useful,  phosgene-­‐free   route  towards  aryl  isocyanates  which  are  key  reagents   in  the  synthesis  of  polyurethane  polymers.[12]  Inspired   by  this  unresolved  challenge,  we  set  out  to  explore  a   new  preparative  method  towards  NARCs  and   envisioned  that  the  use  of  hydrogen-­‐bond  activation   of  cyclic  carbonates  could  offer  a  viable  substrate   conversion  strategy  as  recently  demonstrated  for   aminolysis  reactions  involving  alkyl-­‐amines.[6a]  Here   we  report  on  the  unprecedented  chemo-­‐selective   formation  of  (functionalized)  NARCs  from  cyclic   carbonates  under  extremely  mild  reaction  conditions   using  aryl-­‐amines  as  reagents  providing  a  highly   sustainable  method  for  these  important  scaffolds.   use  of  TBD  (5  mol%)  gave  an  appreciable  PC   conversion  of  60%  with  a  25%  yield  of  the  targeted   NARC  product  c.  However,  under  these  conditions   substantial  formation  of  the  diol  d  was  also  observed.   Performing  the  reaction  for  a  longer  period  of  time   gave  only  a  slightly  higher  conversion  at  higher  TBD   loading  (entry  3,  69%)  with  significantly  higher   amounts  of  undesired  diol  being  formed.  The  reaction   at  70ºC  (entry  4)  showed  a  promising  result  using  a   higher  amount  of  aniline:  while  maintaining  virtually   the  same  conversion  level  as  noted  at  100ºC  (60%),   the  chemo-­‐selectivity  for  the  NARC  c  was  markedly   improved.[13]     Table  1.  Selected  entries  from  the  optimization   of  conditions  for  the  organocatalyzed  N-­‐aryl   carbamate  formation  from  aniline  and  PC.[a]       ent ry   Our  initial  screening  phase  (see  Table  1  and   Supporting  Information,  Table  S1)  focused  on  the  use   of  aniline  (a)  and  propylene  carbonate  (PC,  b)  as   substrates  and  various  N-­‐heterocyclic  structures  as   potential  organocatalytic  activators.  It  is  important  to   emphasize  that  the  reaction  performed  at  100ºC  for   20  h  in  the  absence  of  any  catalyst  (entry  1)  did  not   show  any  observable  conversion  of  the  substrates  in   line  with  the  challenging  nature  of  this  conversion.   We  were  pleased  to  note  that  at  100ºC  (entry  2)  the   Cat.   T   Yiel d[b]   Yiel d[b]   b  [%]   c   [%]   d   [%]   Conv .[b]   [eq. ]   [mol  %]   [ oC ]   1   1.5   −   10 0   0   0   0   2[c]   1.2   TBD  5   10 0   60   25   31   3[d]   1.2   TBD  10   10 0   69   14   47   4   3   TBD  5   70   60   40   19   5   3   TBD  10   70   82   48   34   6   1.5   TBD  10   70   75   38   30   7   1.5   MTBD   70   26   10   15     Scheme  1.  Reaction  manifold  of  cyclic  organic   carbonates  with  amine  nucleophiles  and  new   reactivity  towards  NARC  formation  under  mild   conditions.   a   10   8   1.5   DBU  10   70   46   26   19   9   1.5   PG  10   70   0   0   0   10   1.5   DMAP   10   70   12   4   7   11   1.5   TMG  10   70   35   19   16   12   1.5   DABCO   10   70   <2   0   <2   13   1.5   HMTA   10   70   0   0   0   14   1.5   TBD  10   55   72   48   22   15[d ]   1.5   TBD  10   45   65   40   25   16   1.5   TBD  30   20   98   76[e]   21   17   3   TBD  30   20   99   70   20   18   1.5   TBD  40   20   98   75   20   19[f ]   1.5   TBD  30   14 0   94   0   trac e   20[g ]   1.5   TBD  30   20   95   77   diazabicyclo[2.2.2]octane,  DBU  =  1,8-­‐ diazabicyclo[5.4.0]-­‐undec-­‐7-­‐ene,  DMAP  =  4-­‐ dimethylamino-­‐pyridine,  MTBD  =  1-­‐methyl-­‐ 1,5,7-­‐triazabicyclo[4.4.0]-­‐dec-­‐5-­‐ene,  TBD  =   triazabicyclodecene,  TMG  =  1,1,3,3-­‐tetramethyl-­‐ guanidine,  PG  =  pyrogallol.  HMTA  =  hexamethyl-­‐ enetetramine.   14   An  increase  in  TBD  loading  (entries  5  and  6)  showed   higher  conversion  levels  but  still  with  substantial  diol   formation  and  therefore  we  decided  to  first  screen   other  nitrogen  bases  as  potential  catalysts  (entries   7−13)  and  a  previously  reported  hydrogen-­‐bond   activator,  PG.[14]  In  all  cases  studied  the  conversion   levels  were  (much)  lower  than  those  observed  for  TBD   under  similar  reaction  conditions  (cf.,  entry  6).  The   addition  of  a  solvent  gave  poorer  results  and  generally   we  performed  the  substrate  scope  reactions  under   neat  conditions;  in  some  cases  though  a  very  small   amount  of  CH3CN  (typically  20  mL)  was  necessary  to   maintain  a  liquid  phase  (Supporting  Information).     [a]  Reaction  conditions:  2  mmol  of  b,  indicated   equiv  of  a  and  catalyst,  solvent  free,  20  h;  see   ESI  for  more  entries  for  the  optimization   process  (Table  S1).  [b]  Based  on  1H  NMR   conversion  and  yield  determined  by  relative   integration  of  the  methyl  signals.  [c]  16  h.  [d]  40   h.  [e]  Isolated  yield  is  74%.  [f]  16  h,  complex   mixture  noted  by  1H  NMR.  [g]  Performed  under   anhydrous  conditions,  see  SI  for  details.   Abbreviations:  DABCO  =  1,4-­‐ Finally,  the  reaction  temperature  and  amount  of   aniline  were  further  optimized  (entries  14−18),  and   satisfying  results  were  finally  achieved  using  30  mol%   of  TBD  at  20ºC  and  1.5  equiv  of  aniline  providing  98%   PC  conversion  and  good  selectivity  for  the  NARC  c   (isolated  yield:  74%).  When  the  reaction  was   performed  at  140ºC  with  TBD  as  catalyst  (entry  19),  a   highly  complex  mixture  of  components  was  formed   with  only  trace  amounts  of  diol  being  present;  the   NARC  c  could  not  be  detected  in  the  crude  mixture.   This  strongly  suggests  that  for  high  chemo-­‐selectivity   towards  the  NARC  product  c  and  site-­‐selective  attack   of  the  aromatic  amine  onto  PC  (Scheme  1),  a  low   temperature  combined  with  a  sufficiently  high  loading   of  TBD  are  required.           Scheme  2.  TBD  catalysed  formation  of  NARCs  from   mono-­‐substituted  cyclic  carbonates  (only  the  major   isomer  is  shown).     cyclic  carbonates[15]  as  reaction  partners  (Scheme  2)   under  mild  reaction  conditions.  In  general,  good  to   excellent  isolated  yields  of  the  NARCs  1−19  up  to  93%   were  obtained.  A  variety  of  functional  groups  are   tolerated  using  this  procedure  including  electron-­‐ donating  and  remarkably  also  electron-­‐withdrawing   groups  [F  (3),  I  (5),  CN  (6)  and  Ph  (7)]  on  the  aniline   scaffold  with  reasonable  scope  in  the  position  (ortho,   meta  or  para)  of  the  substituent.  Of  further  note  is   that  the  synthesis  of  NARC  2  could  be  easily  scaled  up   (60  mmol,  9.2  g)  with  a  slightly  improved  isolated   yield  of  79%.  The  use  of  carbonates  other  than  PC  as   reagent  allows  for  introduction  of  various  groups  (cf.,   12−19)  including  useful  bromo-­‐aryl  (13),  morpholine   (14),  alkene  (16−17)  and  alkyne  (19)  groups.[16]  The   molecular  structure  of  13m  was  also  further   supported  by  X-­‐ray  analysis  (Supporting   Information).[17]  Apart  from  mono-­‐substituted   carbonates  also  di-­‐substituted  five/six-­‐membered   carbonates[5d,15a-­‐b]  showed  good  potential  as   substrates  in  the  formation  of  NARCs  (Scheme  3;   20−25).  The  formation  of  all  products  (except  24)   proceeded  with  high  levels  of  stereo-­‐retention.  The   proposed  atom  connectivity  in  23  (only  one  regio-­‐ isomer  was  isolated)  was  fully  supported  by  2D  NMR   techniques.  Secondary  aromatic  amines  exhibited   much  lower  reactivity  under  the  present  conditions   (see  Table  S2).         Scheme  3.  TBD  catalysed  formation  of  NARCs  20−25   from  five-­‐  and  six-­‐membered  di-­‐substituted  cyclic   carbonates.     Encouraged  by  the  results  from  the  screening  phase,   the  substrate  scope  was  then  investigated  using   various  anilines  and  mono-­‐substituted,  functional     Scheme  4.  TBD  catalysed  formation  of  non-­‐ symmetrical  ureas  26  and  27  from  NARC  2   (concomitant  formation  of  diol  byproduct  observed).   Conditions:  100ºC,  20  h,  TBD  (30  mol%).     Hinted  by  the  screening  studies[13]  we  hypothesized   that  formation  of  non-­‐symmetrical  ureas  would  be   feasible  by  treatment  of  pure  NARCs  with  aniline   derivatives  under  appropriate  reaction  temperatures.   Indeed,  such  ureas  (cf.,  26  and  27)  are  the  major   product  noted  (Scheme  4;  beside  the  formation  of  diol   d,  Table  1)  when  2  is  treated  with  3  equiv  of  the   respective  aniline.  These  results  reinforce  the  idea   that  NARCs  are  indeed  intermediates  towards  urea   formation  under  high  temperature  conditions,  and   this  corroborates  well  with  the  observation  of  rather   chemo-­‐selective  formation  of  the  NARC  product   under  ambient  conditions.   In  order  to  get  a  better  insight  in  the  operative   mechanism  of  the  NARC  formation,  quantum   chemical  studies  were  performed  using  aniline  and   butylamine  as  representative  amine  nucleophiles  and   PC  as  carbonate  substrate.  This  demonstrates  that  the   reaction  of  aniline  with  PC  is  not  feasible  due  to  an   activation  barrier  of  40.9  kcal·∙mol-­‐1  (solid  red  line  in   Figure  S1).  Moreover,  the  calculations  also  point  out   that  a  direct  butylamine  attack  (dashed  red  line)  is  not   kinetically  favoured  at  room  temperature  with  a  free   energy  barrier  of  33.3  kcal·∙mol-­‐1.  Therefore,  the   presence  of  water  acting  as  a  proton-­‐relay  catalyst   was  considered  (blue  traces)  as  the  reactions  in   general  are  not  performed  under  anhydrous   conditions.  This  new  mechanism  indeed  decreases   significantly  the  barrier  for  the  aniline  pathway  from   40.9  to  33.9  kcal  mol-­‐1,  though  this  value  still  remains   considerably  high  for  the  reaction  to  occur  under   ambient  conditions.  For  the  butylamine  case,  the   barrier  was  also  effectively  lowered  to  24.2  kcal  mol-­‐1   confirming  the  experimental  observation  that  the   reaction  proceeds  smoothly  at  room  temperature.[6a]   To  reinforce  the  accuracy  of  the  computational   method,  the  obtained  structures  of  the  butylamine   pathway  underwent  single  point  CCSD(T)  calculations   (details  in  the  Supporting  Information;  Figure  S1).  The   obtained  absolute  barrier  was  determined  at  41.5  kcal   mol-­‐1  (orange  line)  thereby  unequivocally   demonstrating  that  the  presence  of  water  is  crucial   for  the  process  to  occur  and  also  revealing  that  the   B97-­‐D3  functional,  at  most,  only  slightly   underestimates  the  barriers.  The  calculated  energy   barrier  for  the  butylamine  attack  under  water   catalysis  using  CCSD(T)  is  33.2  kcal  mol-­‐1  and  thus  9.8   kcal·∙mol-­‐1  higher  than  observed  from  B97-­‐D3/6-­‐ 311G**  (cf.  Supporting  Information).     Figure  1.  Gibbs  free  energy  profile  for  the  TBD-­‐ catalyzed  reaction  mechanism  of  PC  with  aniline  (solid   line)  and  butylamine  (dashed  line).     The  results  for  the  TBD-­‐mediated  reactions  (depicted   in  Figure  1)  show  that  the  mechanism  for  the   transformation  of  butylamine  and  aniline  involves   several  steps.  Both  reactions  have  remarkably  similar   barriers,  viz.  18.1  and  17.5  kcal·∙mol-­‐1  for  aniline  and   butylamine,  respectively.  These  values  are  consistent   with  the  reactions  taking  place  at  room  temperature   (cf.,  Table  1  and  S1).  The  mechanistic  pathways  are   slightly  different  for  each  substrate.  The  first   intermediate  (INT-­‐0)  could  only  be  optimized  for  the   butylamine  pathway.  In  this  step,  the  amine   approaches  the  carbonate  group,  with  the  carbon   centre  adopting  a  tetrahedral  geometry.  Next,  TS-­‐1  is   a  mutual  step  and  rate-­‐determining  for  both   pathways.  This  transition  state  constitutes  an  ion  pair   comprising  of  a  protonated  TBDH+  and  an  alkoxide   (INT-­‐1).  Formation  of  INT-­‐2  is  characterised  by  an   elongated  C−O  bond  (1.66  Å)  in  the  cyclic  species  and   is  stabilised  by  two  hydrogen  bonds  with  the  TBDH+.   In  the  subsequent  step,  INT-­‐3  is  produced  and  the   substrate  is  now  linear  retaining  still  an  alkoxide   character.  The  final  step  is  the  proton  transfer  from   TBDH+  to  the  substrate  through  transition  state  TS-­‐2.   Compared  with  the  reaction  assisted  by  water,  the   TBD  is  a  much  more  effective  proton-­‐relay  catalyst[18]   providing  significantly  lower  kinetic  barriers.  Also,   when  MTBD  (methylated  TBD)  is  used,  much  poorer   catalysis  behaviour  was  noted  (Table  1,  cf.  entries  6   and  7)  clearly  indicating  that  H-­‐bonding  stabilization  is   also  crucial  in  this  reaction.   In  summary,  we  here  present  a  new  and  highly   attractive  route  towards  the  challenging  formation  of   N-­‐aryl  carbamates  derived  from  readily  available   cyclic  carbonates  and  aromatic  amines  under  virtually   solvent-­‐free  and  metal-­‐free  conditions.  TBD  is  shown   to  be  an  effective  organocatalyst  for  the  site-­‐selective   and  chemo-­‐selective  formation  of  the  N-­‐aryl   carbamate  products  and  DFT  studies  have  revealed  an   interesting  proton-­‐relay  mechanism.  The  present   methodology  is  operationally  simple,  easily  scalable   and  has  large  potential  in  synthetic  chemistry.   Experimental  Section   Typical  NARC  formation:  the  respective  carbonate  (2   mmol,  1  equiv.),  amine  (1.5  equiv.)  and  TBD  (30  mol%)   were  charged  into  a  5  mL  round  bottom  flask  and  the   reaction  mixture  was  stirred  at  rt  for  the  required   time.  The  analytically  pure  N-­‐aryl  carbamate  product   was  then  isolated  by  flash  chromatography.  The   NARCs  were  fully  characterized  by  1H/13C  NMR,  2D   NMR  (COSY,  HSQC,  HMBC  and  DEPTQ135  when   necessary),  IR  and  HRMS.  Full  details  are  provided  in   the  Supporting  Information.   Acknowledgements   We  thank  ICIQ,  ICREA,  and  the  Spanish  Ministerio  de   Economía  y  Competitividad  (MINECO)  through   projects  CTQ-­‐2014–60419-­‐R  and  CTQ2014–52824-­‐R,   and  the  Severo  Ochoa 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 been  reported,  see  for  instance:  A.  Chuma,   H.  W.  Horn,  W.  C.  Swope,  R.  C.  Pratt,  L.  Zhang,  B.  G.  G.   Lohmeijer,  C.  G.  Wade,  R.  M.  Waymouth,  J.  L.  Hedrick,   J.  E.  Rice,  J.  Am.  Chem.  Soc.  2008,  130,  6749-­‐6754.       Entry  for  the  Table  of  Contents:     COMMUNICATION   The  previously  unknown  site-­‐   selective  attack  of  arylamine     on  cyclic  carbonates  to  deliver   N-­‐aryl  carbamates  as  the   principal  product  is  reported.   The  organocatalyst  TBD   guides  an  effective  proton-­‐ relay  process  mediating  a   chemo-­‐selective  formation  of   the  carbamate  target  under   extremely  mild  conditions.   The  new  methodology     represents  a  sustainable,     cheap  and  attractive  process   towards  these  important  N-­‐ aryl  carbamate  synthons.       Wusheng  Guo,  Joan  Gónzalez-­‐ Fabra,  Nuno  A.  G.  Bandeira,   Carles  Bo  and  Arjan  W.  Kleij*     Page  No.  –  Page  No.           A  New  and  Metal-­‐free   Synthesis  of  N-­‐Aryl   Carbamates  under  Ambient   Conditions