Palladium-Catalyzed Aryl C–H Olefination with Unactivated, Aliphatic

Sep 4, 2014 - Arghya Deb, Sukdev Bag, Rajesh Kancherla, and Debabrata Maiti*. Department of Chemistry, Indian Institute of Technology Bombay, Powai, ...
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Palladium Catalyzed Aryl C–H Olefination with Unactivated, Aliphatic Alkenes Arghya Deb, Sukdev Bag, Rajesh Kancherla, and Debabrata Maiti J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5082734 • Publication Date (Web): 04 Sep 2014 Downloaded from http://pubs.acs.org on September 6, 2014

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Journal of the American Chemical Society

Palladium Catalyzed Aryl C–H Olefination with Unactivated, Aliphatic Alkenes Arghya  Deb,  Sukdev  Bag,  Rajesh  Kancherla,  Debabrata  Maiti*   Department  of  Chemistry,  Indian  Institute  of  Technology  Bombay,  Powai,  Mumbai-­‐400076,  India   Supporting  Information   ABSTRACT:  Palladium  catalyzed  coupling  between  aryl  hal-­‐ ides  and  alkenes  (Mizoroki-­‐Heck  reaction)  is  one  of  the  most   popular   reactions   for   synthesizing   complex   organic   mole-­‐ cules.    Limited  availability,  problematic  synthesis  and  higher   cost  of  aryl  halide  precursors  (or  their  equivalents)  have  en-­‐ couraged   exploration   of   direct   olefination   of   aryl   carbon-­‐ hydrogen   (C–H)   bonds   (Fujiwara-­‐Moritani   reaction).  Despite   significant   progress,   restricted   substrate   scope   in   particular   noncompliance  of  unactivated  aliphatic  olefins  restricted  the   usage   of   this   greener   alternative.     Overcoming   this   serious   limitation,   we   report   here   a   palladium-­‐catalyzed   chelation-­‐ assisted   ortho-­‐C–H   bond   olefination   of   phenyl   acetic   acid   derivatives   with   unactivated,   aliphatic   alkenes   in   good   to   excellent  yields  with  high  regio-­‐  and  stereoselectivities.    The   versatility   of   this   operationally   simple   method   has   been   demonstrated  through  drug  diversification  and  sequential  C– H  olefination  for  synthesizing  divinyl  benzene  derivatives.  

Despite   significant   efforts   for   alkenylation   using   palladium   catalysts,   previous   reports   are   limited   to   activated   or   elec-­‐ 5-­‐8 tronically   biased   olefins   like   acrylates   and   styrenes.     To   achieve   terminal   insertion,   pre-­‐installed   coordinating   11 groups  have  been  found  to  be  promising  for  selective  cases,   but   are   limited   in   application.     Till   date,   unbiased   alkenes   remain   the   most   challenging   partner   for   C–H   olefination   7,   9,   12 reaction  (Scheme  1).    In  addition,  regioselectivity  issues   due   to   lack   of   intrinsic   biasness   in   aliphatic   alkene   and   the   migration   of   C–C   double   bond   along   the   aliphatic   chain   re-­‐ 6k,  8h main  unsolved.       Me COOH Ibuprofen (analgesic and antipyretic)

         Palladium  catalyzed  coupling  between  aryl  halide  and   alkene  (Mizoroki-­‐Heck  reaction)  has  traditionally  been  used   2 for   the   C–C   bond   formation   to   synthesize   arylated   alkenes.     Given   the   importance   of   this   reaction,   introduction   of   alkene   into  arene  C–H  bond  (Fujiwara-­‐Moritani  reaction)  to  prepare   the   same   carbogenic   scaffolds   offers   even   more   powerful   strategy   to   access   wide   array   of   pharmaceutical   precursors   3 and   drug   molecules.     However,   requirement   of   large   excess   of   the   arene   (often   solvent   amount)   and/or   the   regioselectivity   issues   has   impeded   the   practicality   of   the   Fujiwara-­‐Moritani   reaction.     To   address   these   issues,   directing   group   assisted   C(aryl)–H   olefination   reactions   are   adopted   in   recent   years.     The   usual   approach   is   to   use   σ-­‐ 4-­‐8 chelating  directing  groups  with  a  metal  center,  which  will   lead   to   ortho   selectivity   through   conformationally   rigid   5-­‐7   membered   rings.     Very   recently   meta-­‐selective   C(aryl)–H   bond  activation  and  oxidative  coupling  with  alkenes  has  also   10 been  reported  by  palladium  catalyst.     Scheme  1.  Arene  Ortho  C–H  Bond  Olefination     DG

DG

DG

DG R

different directing groups (DG) previous work

R = EWG (activated olefins)

R R DG = HN

N O

this work R = aliphatic (unactivated olefins)

 

O

COOH

MeO

Tiaprofenic acid (antiarthritic drug)

Naproxen (antiinflammatory drug)

O

COOH

Me

S

COOH

Me F

Me

O

S

COOH COOH

Unactivated   carbon-­‐hydrogen   bonds   (C–H)   are   present   in   every   naturally   occurring   organic   molecules.     Functionaliza-­‐ tion  of  these  C–H  bonds  is  arguably  of  highest  synthetic  im-­‐ portance.  Due  to  the  low  reactivity,  transition  metal  catalysts   have   been   extensively   employed   to   convert   them   to   carbon-­‐ 1 heteroatom  and  carbon-­‐carbon  (C–C)  bonds  of  interest.    

Me

Me Me

Flurbiprofen (antiarthritic drug)

Suprofen (eyedrop)

Ketoprofen (analgesic and antipyretic)

Me

 

Figure  1.    Commercial  drugs  with  aryl  acetic  acid  motif     Here   we   report   a   palladium   catalyzed   chelation-­‐assisted   C–H  olefination  reaction  between  unactivated,  aliphatic  ole-­‐ fins   and   synthetically   useful   phenyl   acetic   acid   substrates.     Notably,   only   activated   olefins   were   used   previously   for   oxi-­‐ 8h dative   Heck   coupling   of   phenyl   acetic   acids.     The   present   alkenylation   reaction   has   remarkably   broad   substrate   scope,   which   is   enabled   by   bidentate   directing   group   along   with   the   use   of   racemic   1,1'-­‐binaphthyl-­‐2,2'-­‐diamine   (rac-­‐BINAM)   lig-­‐ and  to  enhance  the  catalytic  activity  of  active  Pd(II)  species.     The  generality  of  this  protocol  is  demonstrated  here  by  pre-­‐ paring   an   exemplary   set   of   alkenylated   compounds   (45   ex-­‐ amples),  most  of  which  represent  new  chemical  entities.    The   versatility   of   the   protocol   is   shown   by   direct   olefination   of   commercial  drugs  (Figure  1)  with  aliphatic  olefins.       Scheme  2.    Alkenylation  with  1-­‐octene   10 mol% Pd(OAc)2 20 mol% rac-BINAM 1 equiv BQ, 2 equiv NaHCO3

O N H

N

O2, 1 mL DCE, 100 ºC, 24 h

CONHQ

CONHQ 4

major

Me

4 Me minor

+

1 (1 equiv)

+

4 (2 equiv)

Me

NH2 NH2 rac-BINAM

HN

N O CONHQ

  Conventional  monodentate  directing  groups  are  found  to   be   ineffective   in   palladium   catalyzed   C–H   bond   olefination   8 with   unactivated,   aliphatic   alkenes.     We   reasoned   that   a   rigid   coordination   to   palladium   with   a   bidentate   directing   13 14 groups  and  a  six-­‐membered  palladacycle  formation  during   C–H  olefination  of  arene  will  help  incorporating  unactivated   olefins   as   the   coupling   partner.     Although   benzoic   or   3-­‐

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phenylpropionic   acid   derived   8-­‐amino   quinolinamide   failed   15   to   provide   expected   olefination   product, phenyl   acetic   acid   derivative   (3a)  gave  the  alkenylated  product  with  1-­‐octene  in   40%   yield   (linear/branched,   4:1)   using   silver   acetate   as   co-­‐ oxidant.     In   order   to   increase   the   yield   and   to   reduce   the   branched   product,   we   thought   to   saturate   the   coordination   sites   of   palladium   by   incorporating   auxiliary   ligand.     Interestingly,   rac-­‐BINAM   provided   90%   GC   yield   with   8:1   selectivity   for   linear/branched   olefinated   product   with   1-­‐ octene  (Scheme  2).      

desired  product  with  different  internal  alkenes  (e.g.  (E)-­‐hex-­‐ 2-­‐ene,   cyclohexene,   1H-­‐indene   etc.)   as   well   as   1,1-­‐ disubstituted  alkenes  (e.g.  β-­‐pinene).     15

Table  3.    Scope  with  Substituted  Phenylacetic  Acids   CONHQ

+

R

H 1

(0.1 mmol)

2

15

+ H 1

(0.1 mmol)

10 mol% Pd(OAc)2 20 mol% rac-BINAM n R 1 equiv BQ, 2 equiv NaHCO3

major (isolated)

4

(0.2 mmol)

n

+

Me

n CONHQ

CONHQ

CONHQ

5e, R = 3,4-Cl, 49% (15:1) 5f, R = 2-Me, 58% (7:1) 5g, R = 3-Cl, 80% (10:1) 5h, R = 3-CF3, 65% (15:1)

Me

CONHQ Me 4

4

minor (isolated)

Cl

3d, n = 10, 84% (8:1) 3e, n = 12, 85% (8:1) 3f, n = 14, 86% (8:1)

Me

5j, 65%, single isomer

5k, 68% (8:1)

Me CONHQ

CONHQ Me

CONHQ

CONHQ

5

minor (isolated)

Me

5i, 55% (12:1)

3a, n = 4, 88% (8:1) 3b, n = 6, 85% (8:1) 3c, n = 8, 85% (9:1)

R

+ major (isolated)

5a, R = 4-NO2, 85% (9:1, E/Z, 5:1) 5b, R = 4-Cl, 78% (10:1) Me 5c, R = 4-Ph, 67% (8:1) 5d, R = 4-F, 55% (8:1)

R

CONHQ Me

R

1 equiv BQ, 2 equiv NaHCO3 O2, 1 mL DCE, 100 ºC, 24 h

CONHQ

nR

O2, 1 mL DCE, 100 ºC, 24 h

2

4

R

CONHQ

CONHQ

CONHQ

CONHQ

10 mol% Pd(OAc)2 20 mol% rac-BINAM

(0.2 mmol)

CONHQ

Table  1.    Scope  with  Unactivated  Aliphatic  Olefins   CONHQ

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4

Me

(X-ray) 3g, 75% (8:1)

3h, 78 % (10:1)

Me 3j, 50%, single isomer

3i, 62% (12:1)

  We  first  tested  different  alpha  olefins  (Table  1),  which  are   important   starting   materials   for   synthetic   lubricants,   synthetic  fatty  acids,  polymers  and  plasticizers.    Irrespective   of   the   chain   length   of   terminal   aliphatic   alkenes,   excellent   isolated   yields   (84-­‐88%,   3a-­‐3f)   were   obtained   with   high   linear/branched   selectivity.     With   different   vinyl   cycloalkanes,   regioselectivity   (linear/branched)   was   improved  with  increasing  cycloalkane  ring  size  (3g-­‐3i).    Such   observations   may   be   attributed   to   the   preferred   migratory   insertion  towards  linear  product  formation  with   α-­‐branched   olefins.     Olefination   product   with   vinyl   cyclooctane   was   characterized   by   X-­‐ray   crystallography   (3i),   which   further   15,  16 confirmed  the  trans-­‐geometry  of  the  desired  product.   Table  2.    Scope  with  Functionalized  Unactivated  Alkenes   CONHQ

+ H 1

2

(0.1 mmol)

nR

CONHQ

CONHQ

CONHQ

n

+

major (isolated)

4

(0.2 mmol)

CONHQ

CONHQ

10 mol% Pd(OAc)2 20 mol% rac-BINAM n R 1 equiv BQ, 2 equiv NaHCO3 O2, 1 mL DCE, 100 ºC, 24 h

minor (isolated)

CONHQ O

Br 7

4a, 72% (11:1)

4b, 63%, single isomer

CONHQ

4c, 65% (8:1)

CONHQ 6

CO2Me

4e, 68% (10:1, E/Z - 5:1)

R

5

4d, 65% (8:1) CONHQ

6

4f, 61%, single isomer

OH

CO2Me 4g, 80%, single isomer

           The   scope   of   the   position-­‐selective   alkenylation   reaction   was   further   extended   to   various   functionalized   aliphatic   olefins   (Table   2).     Allyl   benzene   produced   72%   yield   (4a)   with   11:1   selectivity   for   linear/branched   products.     An   unconjugated  terminal  alkene  moiety  can  be  incorporated  in   arene   (4b)   from   allyl   bromide   via   a   concerted   elimination   upon  insertion  of  alkene  in  the  initially  generated  palladium-­‐ aryl  species.    Arene  C–H  bond  can  be  selectively  reacted  with   aliphatic   alkene   bearing   bromo   substituent   (4c).   An   epoxy   (4d),   an   ester   (4e)   and   a   hydroxyl   group   (4f)   containing   alkenylated   products   were   isolated   in   synthetically   useful   yields.     Unfortunately,   present   strategy   failed   to   provide  

5l, 50% (8:1)

5m, 62%, single isomer

  To  obtain  insights  into  the  electronic  and  steric  effect  on   this  direct  oxidative  coupling  of  C(aryl)–H  bonds  and  olefins,   1-­‐octene  was  reacted  with  functionalized  phenylacetamide  of   8-­‐aminoquinoline   under   the   optimized   reaction   conditions   (Table   3).     Notably,   meta   substituted   phenyl   acetic   acid   derivatives   employed   in   this   study   gave   alkenylated   product   exclusively   at   the     6-­‐position   (5f-­‐5h).     Halogenated   arenes   not  only  underwent  coupling  at  the  ortho  position  selectively   and   efficiently   (5b,   and   5d-­‐5g),   but   also   did   not   suffer   any   Heck  coupling  or  protodehalogenation  reactions.    Although  a   moderate   yield   of   olefin   insertion   into   1-­‐naphthylacetamide   was  attained  (5l  and  5m),  complete  selectivity  for  2-­‐position   vs.   8-­‐position   was   noteworthy.     Further   no   branched   alkenylated   product   was   detected   for   this   case.   This   olefination   reaction   was   also   successfully   extended   to   α-­‐ substituted   phenyl   acetic   acid   substrate   (5k).     Selectively   linear   olefinated   product   was   also   obtained   for   commercial   drugs   (Figure   1),   such   as   Ibuprofen   (5j)   and   Naproxen   (5n).   Therefore,   in   combination   with   previous   Rh-­‐catalyzed   7 method,   this   report   demonstrated   the   use   of   a   variety   of   unactivated   aliphatic   olefins   for   the   generation   of   valuable   linear  alkenylated  products.   In   Tables   1-­‐3,   a   variety   of   mono-­‐alkenylated   products   have  been  synthesized  without  any  need  for  ortho-­‐  or  meta-­‐   substituent   to   prevent   the   bis-­‐alkenylation.     Encouraged   by   these   results,   we   thought   to   provide   divinylbenzene   derivatives   since   they   are   widely   used   as   building   blocks   in   17 synthetic   chemistry   and   materials   research.     Traditionally   dihaloarenes   were   used   (Mizoroki-­‐Heck   reaction)   as   the   18 precursor   for   these   commonly   occuring   carbogenic   motifs.     In   order   to   obtain   sequential   functionalization   with   unactivated   olefins   by   position   selective   manner,   mono-­‐ olefinated  products  have  been  utilized  following  the  present   method.     Second   olefination   reaction   is   expected   to   be   problematic   since   electronic   and   steric   properties   of   mono   olefinated   species   will   be   completely   different   than   the   8g   starting   materials.   Further,   the   ability   of   the   monoalkenylated   product   to   coordinate   with   the   palladium   centers   may   hinder   the   catalyst   to   achieve   the   second   19 alkenylation.    

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Journal of the American Chemical Society

Table  4.    Synthesis  of  Bis-­‐alkenylated  Products   CONHQ R

+

5

(0.1 mmol)

Me

R1

10 mol% Pd(OAc)2 20 mol% rac-BINAM

R1

1 equiv BQ, 2 equiv NaHCO3 (0.2 mmol) O2, 1 mL DCE, 100 ºC, 24 h R3 CONHQ 2

4

4

4

Me

R4

O

4

4

Me O

6l, 47%, single isomer CONHQ CO2Me

4

(A)

N

HOAc

L

6

Br

H

NH

O

O

PdII

L

HOAc

N NH

Me

4

Me

6m, 48% (10:1) CONHQ CO2Me

(X-ray)

O

N

O

N

O N

N N PdII L

N PdII L

olefin coordination

A  stable  six-­‐membered  palladacycle  intermediate  (C)  was   proposed  with  chelating  auxiliary  8-­‐aminoquinoline  through   13,   14a position-­‐selective   C–H   activation   (Scheme   3).     Upon   olefin   coordination   with   C,   intermediate   D   will   be   formed.     BINAM   (L)   is   unlikely   to   bind   to   the   palladium   center   throughout   the   catalytic   cycle   in   presence   of   strongly   coordinating  substrates.    Upon  olefin  binding  in  D,  bidentate   BINAM   may   act   as   monodentate   ligand   in   order   to   stabilize   21 complex   D.     Unlike   activated   or   electronically   biased   olefins,   migratory   insertion   may   occur   to   both   sides   of   aliphatic  alkene.    Nonetheless,  linear  olefinated  product  was   obtained   in   major   quantity   compared   to   branched   product.     These   unsymmetrical   ratios   of   olefinated   product   are   likely   due   to   the   preferential   attack   by   C–Pd   bond   to   the   less   hindered  site  of  olefin.    Depending  on  preference,  two  eight   membered   cyclometallated   intermediate   (E   or   F)   has   been   proposed   to   form   after   1,2-­‐insertion.     Finally   the   N–H   bond   formation   will   generate   Pd(0),   which   will   be   oxidized   to   Pd(II)  with  the  help  of  benzoquinone  and  oxygen.    

PdII L

(C)

R

R

  Sequential  olefinated  product  (e.g.  6g,  Scheme  4)  can  be   hydrogenated   with   Pd/C/H2.     In   this   way,   different   long   chain   alkyl   groups   can   be   incorporated   to   arene.   The   resulting   product   may   further   be   applied   for   iterative   8g   olefination.   Notably,   the   8-­‐aminoquinoline   moiety   can   be   15   easily  removed  by  acid  catalyzed  hydrolysis. Scheme  4.    Hydrogenation  of  Bis-­‐olefinated  Product   R

Me

(F)

Minor

(D)

Me

5

CONHQ Pd/C H2 CO2Bn

6n, 81% (10:1)

6o, 72%, single isomer   Despite   several   potential   challenges   as   outlined   above,   20 (homo)di-­‐alkenylated   products   were   obtained   with   1-­‐ octene   and   styrene   derivatives   (Table   4,   6a-­‐6d).     Subsequently,   we   focused   on   synthesizing   differentially   substituted   diolefinated   compounds.     Generation   of   unsymmetrical  diolefinated  products  (Table  4)  indicated  that   the   present   catalytic   system   is   indeed   very   reactive   and   effective   for   both   mono-­‐   and   di-­‐olefination.     With   pre-­‐ installed   1-­‐octene   olefinated   product   3a,   styrene,   ethyl   acrylate   and   benzyl   acrylate   were   incorporated   (6e-­‐6g,   70-­‐ 85%   yields).     A   variety   of   alkenes   including   alpha   olefin,   α-­‐ branched   olefin,   allyl   benzene,   aliphatic   alkene   possessing   bromo,   ester   and   epoxy   groups   were   reacted   with   1-­‐octene-­‐ olefinated   product   3a   to   produce   unsymmetrical   divinylbenzene  compounds  (6h-­‐6o,  Table  4).      

(B)

C-H activation

Major

O

L

(E)

R

1,2-migratory insertion

Me

OAc

PdII

N

N

Me

R

N

O

R

4

6

N

!-hydride elimination

6k, 50% (14:1; E/Z, 5:1b) CONHQ Me

Pd(OAc)2

N

6i, 55% (8:1) CONHQ

6j, 48% (8:1; E/Z, 5:1b) CONHQ

Me

4

Me

6h, 52% (10:1) CONHQ 4

HN H

reoxidation

O

R4 = Me, 6f, 70%, single isomer R4 = Ph, 6g, 81%, single isomer CONHQ

CONHQ 4

HO O

R2

CONHQ

O

OH

Pd(0)

6e, 85%, single isomer

O

H2O

R (isolated) 6

R2 = R3 = H, 6b, 68%, single isomer R2 = R3 = Cl, 6c, 78%, single isomer R2 = R3 = Br, 6d, 75%, single isomer CONHQ O

CONHQ

8

O2 + H+ + e

Me

6a, 65% (8:1)

MeO

Scheme  3.    Proposed  Mechanism  

CONHQ

CONHQ

6

Me

6

CONHQ

CO2H

CO2H

  In   summary,   we   have   developed   an   effective   method   of   olefination   for   acetic   acid   derivatives   by   using   palladium-­‐ catalyzed   chelation-­‐assisted   ortho-­‐C–H   bond   functionaliza-­‐ tion  technique.    The  applicability  of  this  present  protocol  was   also  demonstarted  by  the  sequential  bis-­‐olefination  reaction.     Synthetic  applications  based  on  present  strategy  and  detailed   mechanistic  investigations  are  currently  underway.   6g

50 %

R

ASSOCIATED CONTENT Supporting Information Experimental  procedures  and  characterization  data.  This  material  is   available  free  of  charge  via  the  Internet  at  http://pubs.acs.org.   AUTHOR INFORMATION Corresponding  Author   [email protected]   ACKNOWLEDGMENT This   activity   is   supported   by   SERB,   India   (SB/S5/GC-­‐05/2013).   Financial   support   received   from   CSIR-­‐India   (fellowship   to   A.D.),   UGC-­‐India  (S.  B.)  and  DST-­‐Fast  Track  Scheme  (R.  K.)  are  gratefully   acknowledged.   Palladium   catalysts   were   obtained   as   a   gift   from   Johnson  Matthey  Chemicals,  MIDC  Taloja,  India.   REFERENCES  

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Journal of the American Chemical Society

TOC Graphic : Pd HN

HN O H

N

O nR

nR

Unactivated alkenes High yield Drug diversification

N

45 examples

Excellent regioselectivity Sequential bisolefination

 

ACS Paragon Plus Environment