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An Improved Method for the Palladium-Catalyzed Amination of Aryl Triflates
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TetrrrtwdronLetters, Vol. 38, No. 36, pp.6363-6366, 1997 01997 ElsevierScienceLtd All rightsreserved, Printedi“ GreatBritain 0040-4039/97$17,00+ 0,00
Pergamon
PII: SO040-4039(97)01464.()
An Improved Method for the Palladium-Catalyzed Amination of Aryl Triflates Jens~hmanandStephenL.Buchwald* Departmentof Chemistry MassachusettsInstituteof Technology Cambridge,MA02139
Abstract: Aryl triflatesare coupledwith tines
usingcatalyticamountsof Pd(OAc)2and BINAPand CS2C03 as a stoichiometricbase. This protocolallowsfor the efficientaminationof electron-pooras well as electron-rich aryl triflates and the reactionconditionsare compatiblewith a wide variety of fonctiond groups.@1997 E1sevierScienceLtd.
Recent reports from our laboratory and that of Hartwig described the palladium-catalyzed aminationof aryl triflates.l These protocolsemploypalladiumcatalystswith chelatingbis(phosphine) ligands and NaOt-Buas base to couple aryl triflates with amines(Scheme 1). These proceduresgive moderateto excellentyieldsfor electron-richandelectron-neutrrdaryltriflatesbut for electron-pooraryl triflatesonly modestyieldswereobtained. The low yieldswithelectron-poorsubstrateswere attributed to the rapid cleavageof the triflateby attackof NaOt-Buon sulfurleadingto the correspondingsodium phenoxide. The yields in these reactionscould sometimesbe improvedby slow addition of the aryl triflate, but the effect of this procedurewas very substratedependentand it did not providea general solution to the problem.lb Subsequentwork in our laboratoryled to the discovery that the use of CS2C03in place of NaOt-Buleads to improvedfunctionalgroupcompatibilityin the aminationof aql bromides.zHereinwe reportthe use of CS2C03as the basein the palladium-catalyzedaminationof aryl triflates.
Scheme 1.
We found that a catalyst system composedof 3 mol % Pd(OAc)2,4.5 mol % BINAP, and CS2C03as base is efficient for the couplingof electron-deficientaryl triflates with amines. Use of ligands such as DPPF, (rac)-PPF-OMe and P(o-tolyl)3 gave, along with the desired anilines, considerable amounts of the reduced arene side products.3Use of other palladium sources such as Pd2(dba)3and Pd(PPhJ4 resulted in lower reactionrates. The catalyst system described above gave greatly improved yields in the amination of electron-deficient aryl triflates, compared to the correspondingyieldsreportedfor arninationsusingNaOt-Buas base. Forexample,in the reactionsof 4benzoylphenyltriflatewithpyrrolidineandmorpholinethe yieldsincreasedfrom49%to 92% and47% 6363
6364
Table 1. Catalytic Aminationof Aryl Triflate#
Triflate
Entry
Amine
Product
Conditionsb Temp.
Time
Yield(%)*
1
HN
3
A
80“C
6h
92 (49)’
2
HNA w“
A
80“C
16 h
86 (47)f
~Nn L/”
A
80“C
16 h
84 (28)f
4
H NvPh Me’
A
80“C
5h
78
5
— HZN ~ 1 OMe u
B
65“C
4h
90
B’
65“C
4h
54
Bc,d
65“C
4h
46
A’
60“C
19 h
85
cd
80“C
5h
87
c
100 “c
16 h
91
Ac
80“C
5h
76
A
80“C
18 h
88
A’sd
100 “c
5h
90 (72)f
AC
100“c
5h
83
AC
100“c 7 h
78
3
u
NC
1. y
“’f
3
6
HN
7
WC6H,3NH*
8
-u
M~02c I
~ 0“ —
Me.[Vph
~c#,#@
9
MeO,C 1 i -o- — M@,~
NMe Lp~
— (ijH -c/
\
‘Hex
MeO&,
10
(2-
1 ~ OTf —
u u
n
‘NW” n
11
MeO j
~ OTf —
‘NW”
12
MeO I
~ OTf —
H Me’“Ph
— -0 — 6
/\ — Nno --u.
MeO
Me
13
Me ~ 1 OTf
H2NJ)
:1
Me
14
Me \
1 OTf
15
,—, oCaMe
oTf
3
HN
— u
HZN \
1 OMe
Pd(OAc)2,cat. BINAP a Reactionswereperformedwith1.0 equivtriflate,1.2 equivamine,1.4 equivCS2C03,cat. (1.5 ligancVPd) and2 mLsolvenV1.O mmoltriflate.bA = 3 mol% Pd(OAc)2,toluene,80 ‘C underAr;B = 3 mol% Pd(OAc)2,THF,85‘C, reactionrunina resealabletubeunderAr;C = 5 mol% Pd(OAc)2,1,4-dioxane,80 “C, of aminewere‘Sal. reactionrunina resealabletubeunderAr. cPerformedwith5 mol% Pd(OAc)2.d Two equiv ‘All yieldsare isolatedyields(averageoftworuns)ofcompounds estimatedto be 95% pureby ‘H NMR andGC orelementalanalysis. Yieldsm parenthesis wereobtainedusing NaOt-Buas base(see ref.1).
6365
to 86%,respectively(Table 1,entries 1-2).4,5In the reactionof 4-cyanophenyltriflatewithmorpholine, the yield increasedfrom28%to 84%(Table 1,entry 3).6The formationof phenolbyproductscould not be detectedwhen CS2C03was employedinsteadof NaOt-Bu. Use of CS2C03as base also allows for arninationof enolizableketones. For example 4-acetylphenyltriflate was coupledwithp-anisidinein 90% yield (Table 1, entry 5). With aminessuch as pyrrolidineand n-hexylamine5 mol % Pd(OAc)2 was requiredand the correspondinganilineswere obtainedonly in moderateyields of 54% and 46$Z0, respectively(Table 1, entries6 and 7).9 In contrastto our previousprocedure,methylesters were also compatiblewith these reactionconditions,but 5 mol Yo Pd(OAc)2was necessaryto preventbyproduct formation (Table 1, entries 8-10 and 15). Additionally, electron-rich aryl triflates, such as 4methoxyphenyltriflate, could also be aminated(Table 1, entries 11 and 12). Ortho-substitutedaryl triflates, such as 2,4-dimethylphenyltriflate and 2-carbomethoxyphenyl triflate, were transformedinto anlinesin high yields,but the reactionsrequiredhighertemperaturesand 5 mol % Pd(OAc)2to proceed to completion(Table 1,entries 13-15).10The reactionof aryltriflateswithprimarytines requiredthe use of 2 equivalents of the amine and a more polar solvent such as THF or 1,4-dioxanein order to minimizediarylation of the amine. Couplingreactionswith dibutylaminewere inefficientand did not proceedbeyond-75% conversion.Comparedto reactionswithmorpholineand pyrrolidine,aminations with piperidinewere much slower,and thesereactionsonly proceededto full conversionwith electronpooraryl triflates. Pd(OAc)2 + P-P —
ArN(R)R’
(P-P)Pd(OAc)2
II
ArOTf
“(P-P)Pd” v
1
[r (P-P)P‘? \ N(R)R’ 4 .SHC03+CSO+ CS2C03’
7
(P-P)Pd(A~ ‘-OTf
(W#J~TfJ2“ 3 H’
I
Scheme2.
The catalytic cycle for this reaction is probably very similar to the one proposed for aryl aminationusingNaOt-Buas the base and likelyinvolvesthe formationof zero valent Pd species 1 from Pd(OAc)2and the bidentatephosphineIigand(Scheme2).la Oxidativeadditionof the aryl triflate to 1 gives palladium aryl cation 2. Coordinationof amine followedby deprotonationby CS2C03 gives amidocomplex4. Reductiveeliminationfrom4 givesthe anilinewithconcomitantregenerationof the Pal(O)catalyst. In conclusionwe havedevelopeda generalandefficientmethodfor the couplingof aryl triflates with primaryand secondaryarninesand anilines. Withthis new protocola wider varietyof functional groupsare tolerated,and,in manyinstances,higheryieldscanbe obtained.
6366
Acknowledgments. We thankthe WallenbergFoundation,the NationalScienceFoundation,Pfizerand Eastman Kodakfor supportof this work. We thank John P. Wolfe for preparing2,4-dimethylphenyl triflate. J.~. is a WallenbergFoundationPostdoctoralFellow. References and Notes.
(1) (a) Wolfe, J. P.; Buchwald,S. L. 1 Org. Chem. 1997,62, 1264-1267.(b) Louie,J.; Driver,M. S.; Hamann,B. C.; Hartwig,J. F. J. Org. Chem. 1997,62, 1268-1273. (2) Wolfe,J. P.; Buchwald,S. L. TetrahedronLat. 1997, precedingpaperin this issue. (3) DPPF= 1,1’-bis(diphenylphophino)ferrocene, PPF-OMe= l-[2-(Diphenylphosphino)ferrocenyl]ethyl methylether. (4) All productswere characterizedby NMR(lH, 13C)and IR. Combustionanalyseswere obtainedfor new compounds. (5) Prevously reported compounds: (a) N+-benzoylphenyl)pyrrolidine (entry 1).la (b) N-(pbenzoylphenyl)morpholine (entry 2).la (c) N+-cyanophenyl)morpholine (entry 3).la (d) N-(4acetylphenyl)-p-anisidine(entry5): Itier, J.: Casadevall,A. Bull. Soc. Chim. Fr. 1969, 3523-3538. (e) N-(4-acetylphenyl)pyrrolidine (entry6): Ibata,T.; Isogarni,Y.; Toyoda,J. Bull. Chem. Soc. Jpn. 1991, 64, 4249. (f) 4-(4-carbomethoxyphenyl)morpholine (entry 10).2(g) N-(4-methoxyphenyl)morpholine (entry 11):Tuji, Y.; Huh, K. T.; Ohsugi,Y.; Watanabe,Y. J. Org. Chem. 1985,50, 1365-1370. (h) N(2,4-dimethylphenyl)benzylamine (entry 13).laN-(2,4-dimethylphenyl)pyrrolidine (entry 14):Walkup, R. E.; Seareles,S., Jr. Tetrahedron 1985,41, 101-106. (i) N-(2-carbomethoxymethylphenyl)-p-anisidine (entry 15).2 (6) Representativeprocedure: An oven-driedSchlenk tube was charged with CS2C03(456 mg, 1.4 rnrnol)in a nitrogen-filleddry box.7The tube was cappedwith a rubberseptum,removedfromthe dry box, and charged with Pd(OAc)2(6.7 mg, 0.03 mmol)and BINAP(28.2mg, 0.045 mmol). The tube was flushed with Ar for 5 rein, then a solution of 4-cyanophenyltriflate (251 mg, 1.0 mmol) and morpholine(105 @, 1.2mmol)in toluene(2 rnL)was added via cannulaand the resultingmixturewas first stirredunder Ar at roomtemperaturefor 30 ruinand then at 80 “C for 16h. The reactionmixture was allowedto cool to roomtemperature,dilutedwithether(15mL) and filteredthrougha pad of Celite and the filter cake was washed with ether (3 x 10 ruL). Concentrationand flash chromatographyon silicagel affordedN-(p-cyanophenyl)morpholine(164mg, 87%).la,8 (7) The CS2C03was weighedout in a dry box for reasonsof convenience.4-Cyarrophenyltriflate was coupledwith morpholineto givea 77%yieldof thecorrespondinganiline(entry3) usingCS2C03stored in a desiccatorand weighedin the air. Entries13-15wereset up withCS2C03weighedin the air. (8)Efficientstirringis importantin orderto ensureshortreactiontimesandoptimumyields. (9)We believethat the low yieldsare due to byproductsformedvia enolizationprocesses. (10)Attemptsto couple2-carbomethoxyphenyl triflatewithalkylarnines,suchas pyrrolidineand benzyl amine, gaveonly low yieldsof the desiredaniline.
(Received in USA 27 May 1997;accepted 8 July 1997)
TetrrrtwdronLetters, Vol. 38, No. 36, pp.6363-6366, 1997 01997 ElsevierScienceLtd All rightsreserved, Printedi“ GreatBritain 0040-4039/97$17,00+ 0,00
Pergamon
PII: SO040-4039(97)01464.()
An Improved Method for the Palladium-Catalyzed Amination of Aryl Triflates Jens~hmanandStephenL.Buchwald* Departmentof Chemistry MassachusettsInstituteof Technology Cambridge,MA02139
Abstract: Aryl triflatesare coupledwith tines
usingcatalyticamountsof Pd(OAc)2and BINAPand CS2C03 as a stoichiometricbase. This protocolallowsfor the efficientaminationof electron-pooras well as electron-rich aryl triflates and the reactionconditionsare compatiblewith a wide variety of fonctiond groups.@1997 E1sevierScienceLtd.
Recent reports from our laboratory and that of Hartwig described the palladium-catalyzed aminationof aryl triflates.l These protocolsemploypalladiumcatalystswith chelatingbis(phosphine) ligands and NaOt-Buas base to couple aryl triflates with amines(Scheme 1). These proceduresgive moderateto excellentyieldsfor electron-richandelectron-neutrrdaryltriflatesbut for electron-pooraryl triflatesonly modestyieldswereobtained. The low yieldswithelectron-poorsubstrateswere attributed to the rapid cleavageof the triflateby attackof NaOt-Buon sulfurleadingto the correspondingsodium phenoxide. The yields in these reactionscould sometimesbe improvedby slow addition of the aryl triflate, but the effect of this procedurewas very substratedependentand it did not providea general solution to the problem.lb Subsequentwork in our laboratoryled to the discovery that the use of CS2C03in place of NaOt-Buleads to improvedfunctionalgroupcompatibilityin the aminationof aql bromides.zHereinwe reportthe use of CS2C03as the basein the palladium-catalyzedaminationof aryl triflates.
Scheme 1.
We found that a catalyst system composedof 3 mol % Pd(OAc)2,4.5 mol % BINAP, and CS2C03as base is efficient for the couplingof electron-deficientaryl triflates with amines. Use of ligands such as DPPF, (rac)-PPF-OMe and P(o-tolyl)3 gave, along with the desired anilines, considerable amounts of the reduced arene side products.3Use of other palladium sources such as Pd2(dba)3and Pd(PPhJ4 resulted in lower reactionrates. The catalyst system described above gave greatly improved yields in the amination of electron-deficient aryl triflates, compared to the correspondingyieldsreportedfor arninationsusingNaOt-Buas base. Forexample,in the reactionsof 4benzoylphenyltriflatewithpyrrolidineandmorpholinethe yieldsincreasedfrom49%to 92% and47% 6363
6364
Table 1. Catalytic Aminationof Aryl Triflate#
Triflate
Entry
Amine
Product
Conditionsb Temp.
Time
Yield(%)*
1
HN
3
A
80“C
6h
92 (49)’
2
HNA w“
A
80“C
16 h
86 (47)f
~Nn L/”
A
80“C
16 h
84 (28)f
4
H NvPh Me’
A
80“C
5h
78
5
— HZN ~ 1 OMe u
B
65“C
4h
90
B’
65“C
4h
54
Bc,d
65“C
4h
46
A’
60“C
19 h
85
cd
80“C
5h
87
c
100 “c
16 h
91
Ac
80“C
5h
76
A
80“C
18 h
88
A’sd
100 “c
5h
90 (72)f
AC
100“c
5h
83
AC
100“c 7 h
78
3
u
NC
1. y
“’f
3
6
HN
7
WC6H,3NH*
8
-u
M~02c I
~ 0“ —
Me.[Vph
~c#,#@
9
MeO,C 1 i -o- — M@,~
NMe Lp~
— (ijH -c/
\
‘Hex
MeO&,
10
(2-
1 ~ OTf —
u u
n
‘NW” n
11
MeO j
~ OTf —
‘NW”
12
MeO I
~ OTf —
H Me’“Ph
— -0 — 6
/\ — Nno --u.
MeO
Me
13
Me ~ 1 OTf
H2NJ)
:1
Me
14
Me \
1 OTf
15
,—, oCaMe
oTf
3
HN
— u
HZN \
1 OMe
Pd(OAc)2,cat. BINAP a Reactionswereperformedwith1.0 equivtriflate,1.2 equivamine,1.4 equivCS2C03,cat. (1.5 ligancVPd) and2 mLsolvenV1.O mmoltriflate.bA = 3 mol% Pd(OAc)2,toluene,80 ‘C underAr;B = 3 mol% Pd(OAc)2,THF,85‘C, reactionrunina resealabletubeunderAr;C = 5 mol% Pd(OAc)2,1,4-dioxane,80 “C, of aminewere‘Sal. reactionrunina resealabletubeunderAr. cPerformedwith5 mol% Pd(OAc)2.d Two equiv ‘All yieldsare isolatedyields(averageoftworuns)ofcompounds estimatedto be 95% pureby ‘H NMR andGC orelementalanalysis. Yieldsm parenthesis wereobtainedusing NaOt-Buas base(see ref.1).
6365
to 86%,respectively(Table 1,entries 1-2).4,5In the reactionof 4-cyanophenyltriflatewithmorpholine, the yield increasedfrom28%to 84%(Table 1,entry 3).6The formationof phenolbyproductscould not be detectedwhen CS2C03was employedinsteadof NaOt-Bu. Use of CS2C03as base also allows for arninationof enolizableketones. For example 4-acetylphenyltriflate was coupledwithp-anisidinein 90% yield (Table 1, entry 5). With aminessuch as pyrrolidineand n-hexylamine5 mol % Pd(OAc)2 was requiredand the correspondinganilineswere obtainedonly in moderateyields of 54% and 46$Z0, respectively(Table 1, entries6 and 7).9 In contrastto our previousprocedure,methylesters were also compatiblewith these reactionconditions,but 5 mol Yo Pd(OAc)2was necessaryto preventbyproduct formation (Table 1, entries 8-10 and 15). Additionally, electron-rich aryl triflates, such as 4methoxyphenyltriflate, could also be aminated(Table 1, entries 11 and 12). Ortho-substitutedaryl triflates, such as 2,4-dimethylphenyltriflate and 2-carbomethoxyphenyl triflate, were transformedinto anlinesin high yields,but the reactionsrequiredhighertemperaturesand 5 mol % Pd(OAc)2to proceed to completion(Table 1,entries 13-15).10The reactionof aryltriflateswithprimarytines requiredthe use of 2 equivalents of the amine and a more polar solvent such as THF or 1,4-dioxanein order to minimizediarylation of the amine. Couplingreactionswith dibutylaminewere inefficientand did not proceedbeyond-75% conversion.Comparedto reactionswithmorpholineand pyrrolidine,aminations with piperidinewere much slower,and thesereactionsonly proceededto full conversionwith electronpooraryl triflates. Pd(OAc)2 + P-P —
ArN(R)R’
(P-P)Pd(OAc)2
II
ArOTf
“(P-P)Pd” v
1
[r (P-P)P‘? \ N(R)R’ 4 .SHC03+CSO+ CS2C03’
7
(P-P)Pd(A~ ‘-OTf
(W#J~TfJ2“ 3 H’
I
Scheme2.
The catalytic cycle for this reaction is probably very similar to the one proposed for aryl aminationusingNaOt-Buas the base and likelyinvolvesthe formationof zero valent Pd species 1 from Pd(OAc)2and the bidentatephosphineIigand(Scheme2).la Oxidativeadditionof the aryl triflate to 1 gives palladium aryl cation 2. Coordinationof amine followedby deprotonationby CS2C03 gives amidocomplex4. Reductiveeliminationfrom4 givesthe anilinewithconcomitantregenerationof the Pal(O)catalyst. In conclusionwe havedevelopeda generalandefficientmethodfor the couplingof aryl triflates with primaryand secondaryarninesand anilines. Withthis new protocola wider varietyof functional groupsare tolerated,and,in manyinstances,higheryieldscanbe obtained.
6366
Acknowledgments. We thankthe WallenbergFoundation,the NationalScienceFoundation,Pfizerand Eastman Kodakfor supportof this work. We thank John P. Wolfe for preparing2,4-dimethylphenyl triflate. J.~. is a WallenbergFoundationPostdoctoralFellow. References and Notes.
(1) (a) Wolfe, J. P.; Buchwald,S. L. 1 Org. Chem. 1997,62, 1264-1267.(b) Louie,J.; Driver,M. S.; Hamann,B. C.; Hartwig,J. F. J. Org. Chem. 1997,62, 1268-1273. (2) Wolfe,J. P.; Buchwald,S. L. TetrahedronLat. 1997, precedingpaperin this issue. (3) DPPF= 1,1’-bis(diphenylphophino)ferrocene, PPF-OMe= l-[2-(Diphenylphosphino)ferrocenyl]ethyl methylether. (4) All productswere characterizedby NMR(lH, 13C)and IR. Combustionanalyseswere obtainedfor new compounds. (5) Prevously reported compounds: (a) N+-benzoylphenyl)pyrrolidine (entry 1).la (b) N-(pbenzoylphenyl)morpholine (entry 2).la (c) N+-cyanophenyl)morpholine (entry 3).la (d) N-(4acetylphenyl)-p-anisidine(entry5): Itier, J.: Casadevall,A. Bull. Soc. Chim. Fr. 1969, 3523-3538. (e) N-(4-acetylphenyl)pyrrolidine (entry6): Ibata,T.; Isogarni,Y.; Toyoda,J. Bull. Chem. Soc. Jpn. 1991, 64, 4249. (f) 4-(4-carbomethoxyphenyl)morpholine (entry 10).2(g) N-(4-methoxyphenyl)morpholine (entry 11):Tuji, Y.; Huh, K. T.; Ohsugi,Y.; Watanabe,Y. J. Org. Chem. 1985,50, 1365-1370. (h) N(2,4-dimethylphenyl)benzylamine (entry 13).laN-(2,4-dimethylphenyl)pyrrolidine (entry 14):Walkup, R. E.; Seareles,S., Jr. Tetrahedron 1985,41, 101-106. (i) N-(2-carbomethoxymethylphenyl)-p-anisidine (entry 15).2 (6) Representativeprocedure: An oven-driedSchlenk tube was charged with CS2C03(456 mg, 1.4 rnrnol)in a nitrogen-filleddry box.7The tube was cappedwith a rubberseptum,removedfromthe dry box, and charged with Pd(OAc)2(6.7 mg, 0.03 mmol)and BINAP(28.2mg, 0.045 mmol). The tube was flushed with Ar for 5 rein, then a solution of 4-cyanophenyltriflate (251 mg, 1.0 mmol) and morpholine(105 @, 1.2mmol)in toluene(2 rnL)was added via cannulaand the resultingmixturewas first stirredunder Ar at roomtemperaturefor 30 ruinand then at 80 “C for 16h. The reactionmixture was allowedto cool to roomtemperature,dilutedwithether(15mL) and filteredthrougha pad of Celite and the filter cake was washed with ether (3 x 10 ruL). Concentrationand flash chromatographyon silicagel affordedN-(p-cyanophenyl)morpholine(164mg, 87%).la,8 (7) The CS2C03was weighedout in a dry box for reasonsof convenience.4-Cyarrophenyltriflate was coupledwith morpholineto givea 77%yieldof thecorrespondinganiline(entry3) usingCS2C03stored in a desiccatorand weighedin the air. Entries13-15wereset up withCS2C03weighedin the air. (8)Efficientstirringis importantin orderto ensureshortreactiontimesandoptimumyields. (9)We believethat the low yieldsare due to byproductsformedvia enolizationprocesses. (10)Attemptsto couple2-carbomethoxyphenyl triflatewithalkylarnines,suchas pyrrolidineand benzyl amine, gaveonly low yieldsof the desiredaniline.
(Received in USA 27 May 1997;accepted 8 July 1997)