Cu-Catalyzed Cross-Coupling Reactions ~from Pd to Cu~

12th/May/2012 Ozawa un !M1"

1# 2# ,# -# 0#

$ntroduction +onogashira-type reactions +tille-type reactions .uchwald-/artwig-type reactions Perspecti1es

1# $ntroduction The discovery of a cross-coupling reaction is one of the most striking breakthrough in organic chemistry and it has brought us a lot of benefit: (i) it has expanded the scope for what we can synthesize and (ii) it has changed the methodology for the retrosynthesis, enabling us to shorten the synthetic procedures.

&

M easily accessible to biar yl str uctur es!

u-catalyzed coupling reactions have longer history than !d-catalyzed ones: for example, "laser coupling was reported in #$%&, almost #'' years before (izorogi-)eck reaction was reported in #&*#, #&*+. CuCl 2 Ph 'ase . "laser Ber. Dtsch. Chem. Ges. 1()*, 2, ,++ - 1/19 Ph Ph

-fter the discovery of !d-catalyzed couplings in #&*'s, !d chemistry has developed drastically: #&*#, #&*+ (izorogi-)eck (alkene) #&*+ .umada-Tamao- orriu (/-(g01) #&*2 3onogashira-)agihara (terminal alkyne) #&** 4egishi (/-5n01) #&**, #&*$ (igita-.osugi-3tille (/1-3n67) #&*& 3uzuki-(iyaura (/-86+) #&$$ )iyama (/1-3i67) #&&, 8uchwald-)artwig (/-4)/1 or /-9))

The !d reactions above achieve (i) catalytic amount of !d loading, (ii) low reaction temperature, and (iii) high yields. :hereas, the pioneering u reactions re;uired non-catalytic amount of reaction temperature (< +'' deg. or more). Then, u chemistry gradually got neglected. u source and 1ery high

?n these days, however, u is again attracting the attention of researchers around the world as an alterative of !d in coupling reactions, becouse !d is a precious metal and the reserve is much less than u, so it will cost more to use !d.

/ecently =oxidative= coupling reactions have been studied actively becouse they are benign to earth> no need for preparing organometallics and halides, which results in reducing wastes. 8ut it is still difficult in oxidative couplings to control reaction sites> therefore, they are hardly applicable to the syntheses in industry or labolatories. 3o usual non-oxidative coupling reactions are still in demand.

& $

Ph

+n.u,

Pd!Ph,P"Ph

The coupling reaction like this is difficult to conduct in an oxidative coupling manner.

- 2/19 -

2. Sonogashira-type reactions Pioneering work of alkyne couplings using Cu Glaser coupling CuCl 2 Ph aq NH3 C. Glaser Ber. Dtsch. Chem. Ges. 1869, 2, 422 Castro-Stephens coupling
I

2 Cu

Ph

)2

Ph

Ph * Cu2)

CuI Ph aq NH3 Cu Ph

8$ ! 12$ %eg. Py &sol'.( un%er N2

Ph * CuI # 7 ! 99" !

R. D. Stephens and C. E. Castro JOC, 1963, 28,

"oth reactions are the 2-step con#ersion and re$uire stoichio%etric a%ount of Cu&'( , that is, copper acetylides are isolated and they react with another reagent in the ne)t step. *he reactions +elow achie#e to conduct the coupling with a catalytic a%ount of Cu.

ho%ocoupling of alkynes CuI & +ol"(, )2 -./01 & +ol"( # acetone # 82 ! 97" ,. S. -ay JOC 1962, 27 , 2. #

CuI &2 +ol"(, )2 -./01 &1. +ol"( 023 or 012C) &1 eq( # .eCN # 4 ! 99" /. "eifuss JOC 2$$9, 74, 0142 #

- 3/19 -

heterocoupling of alkynes I # 5 CuI & +ol"(, 2Ph3P, 62C)3 # 0.7 ot 0.S), 12$ %eg. un%er N2 #8 2r #8 # 3. 3iura JOC 1993, 58, 44!1 I 5

*
5

Cu&phen(&Ph3P(2r &1$ +ol"( 62C)3 toluene, 11$ %eg. un%er 1r 5 7$ ! 97"

D. 5enkatara%an OL 2$$1, 26, 4 !0

su+strate scope of 3iura6s case

- 4/19 -

I )2N 1a I 19

I Cl 1c

I .e 1%

I ).e 1e

2r )2N

2r

2r N)2

1:

1g

1h

1i

1;

Ph 2a

C H11 29

H) 2c

-HP) 2%

t 2u)

1c) 2e 2:

-HP) 2g

Ph 19a

2r

Ph 199

Ph 19c

nC

H11 19%

nC H 6 13

i Pr

I 19:

19e

Copper acetylides are poly%eric +y nature and are al%ost insolu+le in %any organic sol#ents7 they don6t dissol#e e#en in D38 co%pletely without ligands. "y adding so%e appropriate ligands in ad#ance, copper acetylides %ake co%ple)es with the% and +eco%e %ono%eric species that are solu+le in organic sol#ents, resultig in these 9catalytic9 reactions.

'n the step 2 to 26, one ligand %ust lea#e fro% 2 , so e)cess e$ui#alent of ligands or %ore electron-donating ligands are ineffecti#e7 2 e$ of Ph P is the +est for 3iura6s conditions.

- 5/19 -

Do Cu&'''( species generate fro% Cu&'( like ,r-:2Pd&''(-&alkyne( in Pd-cataly;ed crosscoupling< *he fact is #erifted that the o)idati#e addition and reducti#e eli%ination of Cu&'( can occur in the presence of ,r=, so it is possi+le that Cu&'( undergoes the steps si%ilar to Pd&.( in cross-coupling reactions.

S. S. Stahl and =. Ri+as Chem. Sci. 2$1$, 1, 21

N -,rylation of pyridone occurs with ,r"r and catalytic a%ount of >Cu&3eC?(4P81@ - 6/19 -

other e)a%ples

) * # Cl #8

CuCl &1$ +ol"( /t3N &1 eq( # 9en>ene 4 ! 6$ %eg., 1 ! 1$ hr

#8 63 ! 92"

#, #8 @ alAyl

,. S. Aanina Mendeleev Comm nic!tions 1994, 4, 2.4

C)2 &1 at+(

* #8

CuI &8+ol"( /t3P or 9ipy &8+ol"( Cs2C)3 &3 eq( #) 0.1, r.t., 24 hr

# @ alAyl, allyl, 9en>yl #8 @ 1r, alAyl ? @ I, 2r

#8 ! 91"

B. 'na%oto and C. Bondo Or". Biomol. Chem. 2$12, 1#, !0!4

I * # )H # @ alAyl, 1r, halogens 1r

<Cu&phen(&PPh3(2=N)3 &1$ +ol"( Cs2C)3 &2 eq( toluene 11$ %eg., 24 or 48 hr # ) 62 ! 96"

1r

D. 5enkatara%an OL. 2$$2, 4, 4424

- 7/19 -

5. Perspectives Cross-coupling reactions catalyzed by Cu have been growing steadily, but there're still some disadvantages: (i) large catalyst loading The Cu-catalyzed couplings usually require 1 1! mol" o# Cu source$ on the other hand, the %d-catalyzed couplings need !&!1 ' mol" o# %d source& (ven though Cu itsel# is cheaper than %d (%d()*c)+: ,-'!! yen.1! g, Cu()*c)+: +--!! yen.1!! g at /igma *ld&), large catalyst loading o##sets the merit o# lower price o# Cu&

%d catalyst is outstanding&&&

Br

B(OH)2

50 ppb ~ 2.5 ppm Pd H2O, w, Na2CO3 R ~ R' ! "ie#d

+
R R'

0& (& 1eadbeater JOC, 2003, 68, '22! 0& (& 1eadbeater JOC, 2005, 70, 121 The %d loading is 0.000000$ m%#! and turnover number is &2500003 (ii) lac4 o# understanding o# the ligand e##ect The catalytic systems are usually developed by random tryals because it is still in a blac4 bo5 what we should ta4e care about when tuning the system& the ligands shown in this paper

P'3P

N N N N N

OH (t3P

O N(t2

NH)e N H CO2H P' N P' NH)e

NH)e NH)e

- 8/19 -

4. Buchwald-Hartwig-type reactions Pioneering wor !"ing #! Ullmann conden"ation NH2 Br Cu "0.1 e#$ % 200 deg. H N & !Br C
2H

&
C
2!

F. Ullmann Ber. Dtsch. Chem. Ges. 1903, 36, 2382 (amination) F. Ullmann Chem. Ber. 1905, 38, 2211 (etherification) I. Goldberg Chem. Ber. 1906, 39, 1691 (amination, amidation) $hi" Ullmann%Goldberg conden"ation ha" been !"ed !ntil mo"t recentl&, 199', among other #!%(romoted co!(ling", to obtain diar&l% or triamine" beca!"e there wa" no other (ractical method. )!t the reaction" al"o re*!ire har"h (rolonged heating at 2++ deg. or higher, "o it" a((lication i" limited. ,an& bidentate ligand" ha-e been recentl& re(orted a" efficient ligand" for the amination reaction" and tho"e "&"tem" are o-ercoming "!ch limitation". .r&lation of al &l amine" Primar& and c&clic "econdar& amine" can be ar&lated, b!t "econdar& non%c&clic amine" "how" low reacti-it&, mo"t li l& d!e to "teric rea"on". Cu, "5 -ol.$ * "5-20 -ol.$ !3/ 4 "2 e#$ 90 deg0 11 % 22 hr 234 or neat '

Br & '( '

NH2

NH '( 51 % 95.

*+

N)t2

/. 0. )!chwald OL 2003, 5, 193 "!b"trate "co(e

N %ar&lation occ!r" in the (re"ence of 23 (entr& 2).

- 9/19 -

N % -" O%ar&lation (0. /. )!chwald JACS 2005, 129, 3'9+)

*1

*2

2ther non%linear aminoalcohol" with more than ' atom" between 4 and 2 can be al"o ar&lated "electi-el& (#%45 !( to 6 7+ 518 #%25 !( to 2+5 1).

*2 i" !"ed for -ario!" O%ar&lation of al &l alcohol". (0. /. )!chwald JOC 2001, 73, 28') Cu, "5 -ol.$0 *2 "10 -ol.$ Cs2C 3 "1.5 e#$ toluene ' '(

6 '

& '(

$hi" "&"tem i" not efficient for "econdar& non%c&clic alcohol".

- 10/19 -

9hat bring" the"e N :O "electi-itie"; #om(!tational "t!d& wa" cond!cted b& )!chwald (0. /. )!chwald JACS 2010, 132, 62+7). $here were "e-eral (o""ible (ahtwa&" to (rod!ce .r%4!c com(o!nd".

/n#!I

3%4!c

$he free energ& of each (athwa& wa" calc!lated. the coordination "te(

$he coordination of an alcohol i" m!ch more fa-orable than that of an amine in each ca"e. $hi" "te( i" not "electi-it&%determining. the "te(", (a), (b), (d), (e)
(a) (e) (d) (b)

$he energie" of $02. and $00ig are m!ch higher than I.$ or 0<$, "o I.$ of 0<$ i" more fa-orable than the other 2 (athwa&". In the ca"e of ( et)#! com(le=e", 0<$ i" (referred both when > i" 2 and > i" 438 ((hen)#! com(le=e" al"o fa-or 0<$ when > i" 43, b!t don?t when > i" 2 and then I.$ i" (referable.
@I.$5 Iodine .tom $ran"fer

- 11/19 -

$he energi" of the "te(" after I.$ or 0<$.

In all the (athwa&", the generation of #(III) "(ecie" i" not de"irable and in"tead #!(I):#!(II) mediated (athwa&" are (referred.

- 12/19 -

0!mmariAed free%energ& (rofile"

<lctron%rich ligand" (romote 0<$ machani"m, where e% i" tran"ferred from the #!(I)%4!c com(le=. 4%bo!nd #!(I) com(le=e" are rather e% rich and !ndergo 0<$ (athwa& e-en if the ligand i" (hen or "imilar one"8 2%bo!nd com(le=e" !ndergo I.$ (athwa& when the ligand i" not%"o%electron%donating, beca!"e al o=ide" are wor"e electron donor than amide". $he (athwa&" -ia #!(III) "(ecie" are !nfa-orable "!rel& beca!"e #!(III) i" !n"table, "o #!(II) intermediate ret!rn" to rather "table #!(I) in"tead. $ol!ene, the "ol-ent !"ed for O%ar&lation (I.$, non%anionic:cationic (athwa&), ma& "low down N %ar&lation (0<$, anionic:cationic (athwa&) relati-el&.

- 13/19 -

other N%ar&lation .r&lation of ar&lamine" diar&lamine" Cu, "10 -ol.$ * "20 -ol.$ !3/ 4 "2 e#$ 237 0 50 % 100 deg.0 24 hr '( "2 e#$ *+
N H C
2H

NH2 & '

H N

'

'(

0. /. )!chwald JOC, 2001, 73, 7161 triar&lamine" N Cu, "4 -ol.$ * "4 -ol.$ ! t Bu "3 e#$ toluene0 115 deg.0 3.5 hr ' '( "2.1 e#$ *+
/h N /h

NH2 &

' H N

'(

'

'(

triaryl8diaryl ratios are up to 9582 B. C. #ha!dhari T L 2002, 43, 11'3 B. C. #ha!dhari J. Mol. C t l. A! Chem. 2004, 223, '7 $he a!thor" don?t mention in the (a(er" abo!t what re"!lt" in the "electi-it&, di% or triar&ltion. .r&lation of amide" Cu, "0.2 % 10 -ol.$ * "5 % 20 -ol.$ !3/ 4 "2 e#$ 9r 6 & 'HN '( dio:ane0 110 deg.0 24 hr
NH3e NH3e

9r

'( N ' % 100.

*+
NH3e

or
NH3e

" $ 0. /. )!chwald JACS 2002, 124, 1'21

- 14/19 -

$he rate" of N %ar&lation deffer a" the t&(e of amine" differ5 normal amine", aniline deri-ati-e", and amide"

H2N , & HN

Cu, "5 -ol.$ * "10 -ol.$ !3/ 4 "2 e#$ toluene 100 deg.0 11 hr
NH3e

H2N N 95. 0. /. )!chwald JACS 2002, 124, 1'21

*+
NH3e

NH2

Cu, "5 -ol.$ * "20 -ol.$ !3/ 4 "2 e#$ & Br H2N 2340 90 deg. 11 % 20 hr
H

NH2

N H 10.

*+

N)t2

0. /. )!chwald OL 2003, 5, 193

after all, aniline deri;ati;es < nor-al a-ines < a-ides

$hi" i" (robabl& d!e to the difference of "Da" and n!cleo(hilicitie" of BB?43. .mide" are the wor"t n!cleo(hile" b!t "how the lowe"t "Da8 in contra"t, normal amine" are the be"t n!cleo(hile b!t "how the highe"t "Da, which ma& re"!lt in the order of the N % ar&lation rate".

' "Da n!cleo(hilicit& rate

N H H 11 low fa"t

/h

H N H

H2N H

21 middle "low

37 high middle

- 15/19 -

3. Stille-type reactions

Pioneering work to obtain biaryl comopunds using Cu Ullmann coupling O2N Br 2 NO2 + 2Cu 200 deg. or more NO2 + 2CuBr

F. Ullmann Chem. Ber. 1901, 34, 2174 Biaryl compounds can be synthesi ed using Cu, but the reaction re!uires stoichiometric amount o" Cu and #ery high reaction temperature, and is not applicable to heterocoupling, say, $ryl1-$ryl2, or $ryl%#inyl coupling.

&n 'tille coupling, additional Cu(&) is known to accelerate the reaction* +. Farina and ,. '. ,iebeskind reported in 1--4 that Cu(&) sca#enges ligands o" Pd and accelerates the rate%determining transmetalation. +. Farina and ,. '. ,iebeskind JOC 1994, 59, 6-36

.ne o" the ligand must be dissociated so that the transmetalation can occur, and Cu& helps the step.

/hey also reported in the paper, this is more important "or the de#elopment o" Cu%cataly ed couplings, that 'n0Cu transmetalation does occur only in highly polar sol#ents like 12P, and it is an e!uilibrium reaction. (&n 2334 organotin reagents are re#ealed to be independent o" the rate enhancement* P. 5spinet Organometallics 2003, 22, 1436.)

- 16/19 -

/o enhance the transmetalation in Cu%cataly ed coupling, there7re 2 choices* (i) using an e8cess o" Cu9 to dri#e the transmetalation or (ii) adding some reagent(s) that sca#enge Bu4'n9. Both cases were tryed by ,. '. ,iebeskind. Cu#C $1.% e&' (i) SnBu3 + !" N()* 0 deg. + r.t. - !

SnBu3

CuBr $0.2 e&'* Cs- $1.2 e&' +

" ),

Cl ),

(ii)
Cl

N()* 60 deg. . ,r 91/

,. '. ,iebeskind JACS 1996, 118, 274: substrate scope o" (i)

/he reactions "inish within minutes under low temperatures with high yields. Carbonyl groups and $r9, e#en $ryl iodides (e8cept o%iodonitroben ene, entry 14), are tolerated in this reaction, which results in the chemoselecti#ity that is not achie#ed under typical 'tille reaction conditions. /he reactions are e8cellently stereoretenti#e, precluding a radical chain mechanism (entries 1, 1% and 12, 13). - 17/19 -

/he Cu/C%cataly ed coupling was employed in some total syntheses.

Con#entional 'tille conditions brought lower than 43? yield at prolonged reaction time and <3 deg.. Cu#C

N()* -10 deg. 1 ,r* .0/

U. ;oert ACIE 2001, 40, 23<4

Cu#C N()* 0 deg. to r.t. 4% min* 60/

&t took 1. ,ours "or the con#entional 'tille coupling to "inish though the yield was almost the same.

=. 5. 2alec ka, >r. O 2002, 4, 2:41

- 18/19 -

/he cross%coupling reactions using other organometallics are also de#eloped. ;umada%/amao%Corriu%type

7i2CuCl4 5cO O#s + (e$C62'.(gBr #6-

5cO $C62'9(e

;. 2ori E"r. J. Org. Chem. 2001, 47-7

'u uki%2iyaura%type O 5l9yl 0 + 5r B O Cu" $10 mol/' 7iOt Bu $2 e&' 3(-* 12 ,r 60 or .0 deg. 5l9yl 5r + .:/

5l9yl

5r

9-BBN

5l9yl 5l9yl + :1/ ,. ,iu ACIE 2011, 50, 4-34

0 8 "* Br* Cl* O#s$* O(s' /his reactions don7t proceed when Cu& is replaced with Pd(.$c)2A

@iyama%type 2- $1.2 e&' Cu" $1.% e&' 0 + C-3Si1t3 3(-4N() $141' .0 deg.* 24 ,r C-3 + 94/ /. Fuchikami ! , 1991, 32, -1

8 5r or Bn 0 8 " or Br

- 19/19 -