Expedited palladium-catalyzed amination of aryl nonaflates through the use of microwave-irradiation and soluble organic amine bases

Article abstract of DOI:10.1021/jo052131u

Microwave-assisted, palladium-catalyzed C-N bond-forming reactions with aryl/heteroaryl nonaflates and amines using the soluble amine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or MTBD (7-methyl-1,5,7-triazabicyclo[4.4. 0]dec-5-ene) and ligands (1-3) resulted in good to excellent yields (71-99%) of arylamines in short reaction times (1-45 min).

Full text of DOI:10.1021/jo052131u

some cases improve regio- and/or chemoselectivity.5 Reactions
that previously required hours to run to completion can now be
finished within minutes.6
Expedited Palladium-Catalyzed Amination of
Aryl Nonaflates through the Use of
Microwave-Irradiation and Soluble Organic
Amine Bases
In most cases, palladium-catalyzed C-N bond-forming
reactions using microwave irradiation employ highly polar
solvents and strong bases.7 Consequently, base-sensitive func-
tional groups are not tolerated, limiting the use and applications
of these protocols. The use of insoluble inorganic bases (e.g.,
Cs2CO3) has improved the substrate scope; however, efficient
stirring and heating can be problematic. Moreover, there are
limited examples of palladium-catalyzed amination of aryl
sulfonates using microwave-irradiation.7c,8 We thought that by
employing a soluble organic amine base, we could improve the
functional group tolerance and provide more efficient heating
and stirring in microwave-assisted Pd-catalyzed C-N bond-
forming reactions of aryl nonaflates (nonaflate ) -OSO2(CF2)3-
CF3).9,10 Herein, we report a general system to effect this using
a palladium catalyst comprised of Pd2dba3/1-3 and weak
organic amine bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene). These
catalytic systems successfully couple aryl/heteroaryl nonaflates
and aryl/heteroarylamines with excellent functional group
tolerance and fast reaction times, producing arylamines in good
to excellent yields.
Rachel E. Tundel, Kevin W. Anderson, and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed October 12, 2005
Microwave-assisted, palladium-catalyzed C-N bond-forming
reactions with aryl/heteroaryl nonaflates and amines using
the soluble amine bases DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene) or MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-
ene) and ligands (1-3) resulted in good to excellent yields
(71-99%) of arylamines in short reaction times (1-45 min).
XPhos 1, a bulky electron-rich monophosphine ligand that
has been successfully employed in C-N bond-forming reactions
of aryl sulfonates and halides, was used in our initial study which
examined the coupling of electronically neutral 4-tert-butylphen-
yl nonaflate and aniline (Table 1).2c Reactions that employed
DBU and MTBD gave the best results with this catalytic system
(Table 1, entries 3-5). Guanidine bases possessing a free N-H
moiety such as TBD or TMG failed to give any of the desired
diarylamine (Table 1, entries 8 and 9). In contrast, with hindered
secondary amine TMP as base, the desired arylated amine was
produced in an 80% yield (Table 1, entry 6). With DBU, toluene
was the best solvent for this reaction.11 Slightly higher reaction
temperatures were required when using N,N-DMF as the solvent
(Table 1 entries 13 and 14). Further, efficient coupling in the
absence of solvents was achieved in 1 min providing the
diarylamine in 87% yield (Table 1, entry 3).12
The palladium-catalyzed cross-coupling of aryl halides and
sulfonates with amines has become a common method in organic
synthesis.1 Recent efforts in this area have focused on the
development of more active catalyst systems that operate at
lower catalyst loadings and with shorter reaction times.2 Despite
many improvements to the substrate scope through the use of
weak inorganic bases such as K3PO4, Cs2CO3, or K2CO3, many
of these processes still require from 2 to 24 h to go to
completion, a problem that has been addressed through the use
of microwave irradiation.2c,3
The emergence of microwave technology as a tool for
increasing reaction rates is well documented.4 Microwave-
assisted reactions are extremely attractive to synthetic organic
chemists due to their ability to shorten reaction times and in
(5) (a) De La Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Curr. Org. Chem.
2004, 8, 903. (b) Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985.
(6) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
(7) (a) Poondra, K. R.; Turner, N. J. Org. Lett. 2005, 7, 863.(b) Shi, L.;
Wang, M.; Fan, C. A.; Zhang, F. M.; Tu, Y. Q. Org. Lett. 2003, 19, 3515.
(c) Jensen, T. A.; Liang, X.; Tanner, D.; Skjaerbaek, N. J. Org. Chem.
2004, 69, 4936. (d) Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels,
G.; Rombouts, G. Tetrahedron. 2004, 60, 11559. (e) Maes, B. U. W.;
Loones, K. T. J.; Lemie`re, G. L. F.; Dommisse, R. A. Synlett 2003, 12,
1822.
(8) Microwave-assisted amination of aryl triflates with alkylamines in
the absence of a catalyst and base has been accomplished; however,
arylamines failed and base-sensitive functional groups were not tolerated:
Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985.
(1) Reviews: (a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.: De Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, Germany, 2004; p 699. (b) Hartwig, J. F. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley-Interscience: New York, 2002; p 1051.
(2) (a) Shen, Q.; Shashank, S.; Stambuli, J. P.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2005, 44, 1371. (b) Lee, D.-Y.; Hartwig, J. F. Org. Lett.
2005, 7, 1169. (c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(3) (a) Anderson, K. W.; Mendes-Perez, M.; Priego, J.; Buchwald, S. L.
J. Org. Chem. 2003, 68, 9563 (b) Old, D. W.; Wolfe, J. P.; Buchwald, S.
L. J. Am. Chem. Soc. 1998, 120, 9722. (c) Wolfe, J. P.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6359.
(4) (a) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653. (b)
Olofsson, K.; Hallberg, A.; Larhed, A. In Transition Metal Catalysis and
MicrowaVe Flash Heating in Organic Chemistry; Loupy, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; p 379.
(9) Hayes, B. L. MicrowaVe Synthesis: Chemistry at the Speed of Light;
CEM Publishing: Matthews, NC, 2002.
(10) Aryl/heteroaryl nonaflates are generally more stable toward hy-
drolysis than the corresponding triflate and can easily be prepared from
the corresponding phenol by reacting with perfluoro-1-butanesulfonyl
fluoride. See ref 3a and the Supporting Information for more details.
(11) DBU and MTBD are good microwave absorbers, which allows the
reactions to attain higher temperatures faster in nonpolar solvents such as
toluene.
10.1021/jo052131u CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2005
430
J. Org. Chem. 2006, 71, 430-433

FIGURE 1. Supporting ligands and soluble organic amine bases used in this study.
TABLE 1. Screen of Bases and Solvents for the
TABLE 2. Palladium-Catalyzed Amination of Electron-Rich and
Palladium-Catalyzed Amination of 4-tert-Butylphenyl Nonaflatea
Electron-Neutral Aryl Nonaflatesa
entry
baseb
TEA
DABCO
DBU
DBU
MTBD
TMP
Proton Sponge
TBD
TMG
TMPMG
DBU
DBU
solvent
none
none
none
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
1,4-dioxane
DMF
conv (%)
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
>99
>99
>99
>99
>99
>99
37
12
10
90
56
0
0
87d
99
85
80
25
0
0
89
35
38e
86
92f
52
>99
92
>99
94
DBU
DBU
DBU
DMF
DMSO
a Reaction conditions: 1.0 equiv of Ar-ONf, 1.3 equiv of amine, 2.5
equiv of base, 0.05 equiv of 1, 0.0125 equiv of Pd2dba3, 2 mL of solvent/
mmol of Ar-ONf. b TEA ) triethylamine, DABCO ) 1,4-diazabicyclo-
[2.2.2]octane, DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene, MTBD )
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, TMP ) 2,2,6,6-tetrameth-
ylpiperidine, Proton Sponge ) 1,8-bis(dimethylamino)naphthalene, TBD
) 1,5,7-triazabicyclo[4.4.0]dec-5-ene, TMG ) N,N,N′,N′-tetramethylguani-
dine, TMPMG ) N,N,N′,N′-tetramethyl-N′′-(phenylmethyl)guanidine. c GC
yield. d Reaction was complete in 1 min; isolated yield. e Reaction was
conducted at 175 °C for 15 min. f Reaction was conducted at 175 °C for 5
min.
a Reaction Conditions: 1.0 equiv of Ar-ONf, 1.3 equiv of amine, 2.5
equiv of DBU, 0.06 equiv of 1, 0.015 equiv of Pd2dba3, 2 mL of toluene/
mmol of Ar-ONf. b Yields (isolated) represents an average of two runs.
c MTBD was used as the base. d 2 was used.
and the nonaflates derived from 3-hydroxy acetophenone or
N-methyl-5-hydroxyindole. In these instances, a protocol with
use of 2 provided the products in excellent yield (Table 3, entries
4 and 6). The synthesis of heterocyclic compounds is important
due to their common place in numerous pharmaceutical and
natural products. Heteroaryl nonaflates derived from 3-hydroxy-
pyridine and 5-hydroxyquinoline react efficiently with aniline
providing the N-heteroarylamines in 93% and 80% yields,
respectively (Table 3, entries 8 and 9).
One of the limitations of using DBU as the base is that it
was only effective in the coupling of primary anilines to aryl
nonaflates; N-alkyl anilines, benzophenone imine, and amides
proved to be less successful substrates. Fortunately, through the
use of MTBD, an effective base in the coupling of aryl
nonaflates and anilines in the initial optimization/base study
(Table 1), the substrate scope was expanded to include a variety
of nitrogen nucleophiles.14 Under these new reaction conditions,
N-methyl aniline could be coupled with a functionalized aryl
nonaflate (Table 3, entry 3), using 3 as the supporting ligand.
Further, benzophenone imine could be combined successfully
with an assortment of aryl nonaflates, including heteroaryl
nonaflates and functionalized aryl nonaflates (Table 4). As we
With DBU as the base, the amination of various aryl
nonaflates with anilines was explored. For combinations of
unactivated electron-rich and electron-neutral aryl nonaflates,
ligand 1 was used (Table 2). The coupling of an ortho-
substituted aryl nonaflate and aniline was accomplished in 15
min providing excellent yields of the corresponding diarylamine
(Table 2, entries 1). Interestingly, use of MTBD as the base for
the amination of electron-rich 4-methoxyphenyl nonflate with
aniline was crucial to the success of the reaction.
Aryl nonaflates and anilines featuring an assortment of
functional groups (e.g., -CN, -NO2, -CO2Me, -C(O)Me)
coupled successfully under similar reaction conditions with use
of 2, the more hindered analogue of XPhos 1, or XantPhos 3
(Table 3). When functional groups were present in the ortho
position of the aryl nonaflate, it was essential that the bidentate
ligand 3 be employed (Table 3, entries 1-2 and 7). The
amination of 2-chlorophenyl nonaflate with aniline is particularly
useful since it can be used in the synthesis of carbazoles through
C-H activation, a process that has been demonstrated by several
research groups (Table 3, entry 7).13 Interestingly, the use of 3
as a supporting ligand was unsuccessful for reactions of anilines
(13) (a) Ferreira, I. C. F. R.; Queiroz, M. R. P.; Kirsch, G. Tetrahedron
2002, 58, 7943. (b) Ferreira, I. C. F. R.; Queiroz, M. R. P.; Kirsch, G.
Tetrahedron 2003 59, 3737.
(14) For a comparison of the basicity of organic amines, see: Kaljurand,
I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets, V.; Leito, I.; Koppel, I. A.
J. Org. Chem. 2005, 70, 1019.
(12) When DBU was used as the base/solvent for more challenging
substrate combinations, decomposition of the aryl nonflate predominated.
J. Org. Chem, Vol. 71, No. 1, 2006 431

TABLE 3. Palladium-Catalyzed Amination of Functionalized Aryl Nonaflatesa
a Reaction conditions: 1.0 equiv of Ar-ONf, 1.3 equiv of amine, 2.5 equiv of DBU, 0.10 equiv of ligands 2 or 3, 0.025 equiv of Pd2dba3, 2 mL of
toluene/mmol of Ar-ONf. b Yield (isolated) represents an average of two runs. c MTBD used as the base.
have previously described, benzophenone imine is an effective
ammonia equivalent and the initially formed coupling product
can be easily converted to the corresponding free amine with
use of aqueous HCl or NH2OH-HCl (Table 4, entries 1, 2,
and 4).15 For these processes, 3 was the most effective
supporting ligand. Aryl nonflates containing an ester or nitrile
group in the meta position were successfully combined with
benzophenone imine (Table 4, entries 1 and 2). Additionally,
heteroaryl nonaflates coupled successfully to benzophenone
imine in good to excellent yields within 30 min (Table 4, entries
3 and 4); previously, these processes could take up to 24 h to
go to completion and/or required a strong inorganic base.15
Further expanding the substrate scope, an aliphatic primary
amide is combined with 2-naphthyl nonaflate providing the
secondary N-aryl amide in 92% yield (Table 4, entry 5). Primary
amides benzamide and 3-chlorobenzamide were efficiently
combined with 3-trifluoromethylphenyl nonaflate and 2-cyano-
phenyl nonaflate, respectively, using 3 as the supporting ligand
(Table 4, entries 6 and 7).
We have shown that through the use of ligand 3 and MTBD
as the base, various heterocyclic amines were coupled success-
fully to aryl/heteroaryl nonaflates (Table 4, entries 8-11). Of
note, 2-aminopyrimidine and 2-amino-N-methylbenzimidazole
were successfully combined with 3-pyridyl and 5-quinolyl
nonaflates, respectively, providing the diheteroarylamines in
high yields within 30 min (Table 4, entries 10 and 11).
Previously, efficient palladium-catalyzed C-N bond-forming
reactions of heteroarylamines required long reaction times (15-
23 h) and a weak inorganic base.16
In conclusion, we have developed a fast and efficient protocol
for the microwave-assisted, palladium-catalyzed coupling of
aryl/heteroaryl nonaflates and anilines, amides, benzophenone
imine, and heteroarylamines. This method expands the utility
of microwave-assisted C-N bond-forming processes by allow-
ing substrates with a broad scope of functional groups, both on
the amine and aryl nonaflate, to be utilized. Additionally, the
use of a soluble, weak amine base is beneficial in preserving
the homogeneity of the reaction mixture for more efficient
heating and stirring. Further investigations are underway to apply
this system in microwave-assisted palladium-catalyzed C-N
bond-forming reactions of aryl halides and aryl tosylates.
Experimental Section
General Procedure for Tables 2-4. An oven-dried disposable
microwave tube containing a stir bar was charged with Pd2dba3
and ligand. The vessel was sealed with a plastic microwave septum
and then evacuated and backfilled with argon; this sequence was
repeated two additional times. The aryl/heteroaryl nonaflate (1.0
equiv), amine (1.3 equiv), DBU or MTBD (2.5 equiv), and toluene
(2 mL/mmol) were successively added via syringe (aryl/heteroaryl
nonaflates or amines that were solids at room temperature were
added prior to the evacuation and backfill sequence). The vessel
was submitted to microwave irradiation with stirring until the
starting aryl/heteroaryl nonaflate had been completely consumed
as judged by GC analysis. The mixture was cooled to room
temperature and then diluted with water and ethyl acetate. The
organic layer was separated, dried over anhydrous MgSO4, and
concentrated. The crude material was purified by column chroma-
tography on silica gel (eluting with ethyl acetate/hexanes mixtures).
The typical procedure is given for N-methyl-N-(3-carboxymethyl)-
aniline (Table 3, entry 3) and (2-ethyl-2H-pyrazol-3-yl)naphthalen-
2-ylamine (Table 4, entry 9.)
(15) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett. 1997, 38, 6367.
(16) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org. Lett.
2002, 4, 3481.
N-Methyl-N-(3-carboxymethyl)aniline (Table 3, Entry 3).
Using the general procedure, a mixture of 3-carboxymethylphenyl
432 J. Org. Chem., Vol. 71, No. 1, 2006

TABLE 4. Palladium-Catalyzed Imination, Amidation, and Amination of Aryl/Heteroaryl Nonaflatesa
a Reaction conditions: 1.0 equiv of Ar-ONf, 1.3 equiv of amine, 2.5 equiv of MTBD, 0.10 equiv of XantPhos 3, 0.025 equiv of Pd2dba3, 2 mL of
toluene/mmol of Ar-ONf. b Yield (isolated) represents an average of two runs. c 0.06 equiv of XantPhos 3 and 0.015 equiv of Pd2dba3 used. d 125 °C, 30
min. e 140 °C, 20 min. f 150 °C, 15 min. g 150 °C, 30 min. h 175 °C, 30 min. i Isolated as the free amine after hydrolysis of the imine with HCl (1.0 M).
j Isolated as the free amine after hydrolysis of the imine with NH2OH-HCl.
nonaflate (177 mg, 0.250 mmol), Pd2dba3 (5.8 mg, 0.0063 mmol),
XantPhos (14.5 mg, 0.0250 mmol), N-methyl-p-toluidine (41 µL,
0.33 mmol), and MTBD (90 µL, 0.63 mmol) in toluene (0.5 mL)
was subjected to microwave irradiation for 30 min at 175 °C. The
crude material was purified by column chromatography on silica
gel (eluting with ethyl acetate/hexanes, 1:4) to give the title
(t, J ) 6 Hz, 1H), 7.13 (t, J ) 7.2 Hz, 1H), 7.02 (d, J ) 2 Hz, 1H),
6.08 (d, J ) 2 Hz, 1H), 4.06 (q, J ) 7.2 Hz, 2H), 1.33 (t, J ) 7.2
Hz, 3H). 13C NMR (100 MHz, d4-MeOH) δ 144.4, 142.7, 139.8,
136.3, 130.3, 130.2, 128.7, 127.6, 127.4, 124.1, 119.0, 109.5, 99.1,
43.6, 15.6. IR (neat, cm-1) 3248, 1632, 1462,1403, 928, 747. Anal.
Calcd for C15H15N3: C, 75.92; H, 6.37. Found: C, 75.73; H, 6.45.
1
compound as a yellow oil (56 mg, 89%). H NMR (400 MHz,
CDCl3) δ 7.47 (m, 1H), 7.40 (d, J ) 8.4 Hz, 1H), 7.15 (m, 1H),
7.06 (d, J ) 8 Hz, 2H), 6.94 (d, J ) 8 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 167.9, 149.8, 146.4, 133.8, 131.3, 130.6, 129.3,
124.2, 121.8, 120.5, 117.6, 52.5, 40.8, 21.3. IR (neat, cm-1) 2949,
1721, 1598, 1511, 1446, 1348, 1106, 753. Anal. Calcd for C16H17-
NO2: C, 75.27; H, 6.71. Found: C, 75.07; H, 6.65.
(2-Ethyl-2H-pyrazol-3-yl)naphthalen-2-ylamine (Table 4, En-
try 9). Using the general procedure, a mixture of 2-naphthyl
nonaflate (107 mg, 0.250 mmol), Pd2dba3 (5.8 mg, 0.0063 mmol),
XantPhos (14.5 mg, 0.0250 mmol), 5-amino-1-ethylpyrazole (36
mg, 0.33 mmol), and MTBD (90. µL, 0.63 mmol) in toluene (0.5
mL) was subjected to microwave irradiation for 30 min at 150 °C.
The crude material was purified by column chromatography on
silica gel (eluting with ethyl acetate/hexanes, 1:2) to give the title
compound as an off-white solid (44 mg, 74%). Mp 78-79 °C. 1H
NMR (400 MHz, d4-MeOH) δ 7.69-7.72 (m, 2H), 7.53 (d, J )
8.4 Hz, 1H), 7.47 (d, J ) 2 Hz, 1H), 7.31 (t, J ) 6.4 Hz, 1H), 7.20
Acknowledgment. We thank the National Institutes of
Health (GM 58160) and the National Cancer Institute (Cancer
Training Grant GM 5-T32-CAO9112-30) for support of this
work. R.E.T. would like to thank Pfizer for the 2005 summer
undergraduate fellowship and MIT (UROP) for financial sup-
port. We are grateful to Merck and CEM (microwave reactor
and supplies) for additional support. The Bruker Advance-400
MHz instrument used in this work was purchased with funding
from the National Institutes of Health (GM 1S10RR13886-01).
Supporting Information Available: Experimental procedures
as well as characterization data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052131U
J. Org. Chem, Vol. 71, No. 1, 2006 433