Cross-Coupling and Dehalogenation Reactions Catalyzed by (N-Heterocyclic carbene)Pd(allyl)Cl Complexes

Article abstract of DOI:10.1021/jo035834p

A series of well-defined, air- and moisture-stable (NHC)Pd(allyl)CI (NHC = N-heterocyclic carbene) complexes has been used in several catalytic reactions: Suzuki-Miyaura cross-coupling, catalytic dehalogenation of aryl halides, and aryl amination. The scope of the three processes using various substrates was examined. A general system involving the use of (IPr)Pd(allyl)Cl as catalyst and NaO^tBu as base has proven to be highly active for the Suzuki-Miyaura cross-coupling of activated and unactivated aryl chlorides and bromides, for the catalytic dehalogenation of aryl chlorides, and for the catalytic aryl amination of aryl triflates. All reactions proceed in short reaction times and at mild temperatures. The system has also proven to be compatible with the microwave-assisted Suzuki-Miyaura cross-coupling and catalytic dehalogenation processes, affording yields similar to those of the conventionally heated analogous reactions.

Full text of DOI:10.1021/jo035834p

Cr oss-Cou p lin g a n d Deh a logen a tion Rea ction s Ca ta lyzed by
(N-Heter ocyclic ca r ben e)P d (a llyl)Cl Com p lexes
Oscar Navarro, Harneet Kaur, Parisa Mahjoor, and Steven P. Nolan*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
Received December 17, 2003
A series of well-defined, air- and moisture-stable (NHC)Pd(allyl)Cl (NHC ) N-heterocyclic carbene)
complexes has been used in several catalytic reactions: Suzuki-Miyaura cross-coupling, catalytic
dehalogenation of aryl halides, and aryl amination. The scope of the three processes using various
substrates was examined. A general system involving the use of (IPr)Pd(allyl)Cl as catalyst and
NaOtBu as base has proven to be highly active for the Suzuki-Miyaura cross-coupling of activated
and unactivated aryl chlorides and bromides, for the catalytic dehalogenation of aryl chlorides,
and for the catalytic aryl amination of aryl triflates. All reactions proceed in short reaction times
and at mild temperatures. The system has also proven to be compatible with the microwave-assisted
Suzuki-Miyaura cross-coupling and catalytic dehalogenation processes, affording yields similar
to those of the conventionally heated analogous reactions.
In tr od u ction
coupling reactions have been communicated in prelimi-
nary form.10,11 We now wish to report an extended study
of the catalytic behavior of (NHC)Pd(allyl)Cl complexes
as catalysts in the Suzuki-Miyaura cross-coupling in-
volving aryl chlorides and bromides, aryl amination of
aryl triflates, and catalytic dehalogenation of aryl chlo-
rides.
Su zu ki-Miyau r a Cr oss-Cou plin g Reaction s. Cross-
coupling reactions represent an extremely versatile tool
in organic synthesis,12 since C-C bond formation is a key
step in a wide range of organic processes, from supramo-
lecular chemistry13 to natural product synthesis.14 These
reactions require the use of a transmetalating agent such
as an organomagnesium,15 organosilicon,16 organotin,17
or organozinc18 reagents. When organoboron reagents are
used in coupling with aryl halides or pseudohalides, the
process is known as the Suzuki-Miyaura reaction.19,20
N-Heterocyclic carbenes (NHC) have become increas-
ingly popular in homogeneous catalysis as they represent
a unique family of ligands possessing strong M-NHC
bonds and imparting thermal stability to organometallic
complexes.1,2 These important properties distinguish
them from tertiary phosphines.3 We have previously
reported on the use of palladium/imidazolium salt sys-
tems in dehalogenation reactions4 and cross coupling of
aryl halides with amines,5 organomagnesium,6 organo-
silicon,7 organotin,8 and organoboron9 reagents. Recently,
we have focused our research efforts on the design and
characterization of various monomeric (NHC)Pd(allyl)-
Cl species.10 Studies focusing on their reactivity in cross-
(1) (a) Regitz, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 725-728.
(b) Arduengo, A. J ., III; Krafczyc, R. Chem. Zeit. 1998, 32, 6-14. (c)
Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997, 36,
2163-2187.
(2) (a) Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.;
Grosche, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363-
1365. (b) Scholl, M.; Trnka, T. M.; Morgan, J . P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250. (c) Kucucbay, H.; Cetinkaya,
B.; Salaheddine, G.; Dixneuf, P. H. Organometallics 1996, 15, 2434-
2439. (d) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001, 3,
1077-1080. (e) Marshall, W. J .; Grushin, V. V.; Organometallics 2003,
22, 1591-1593.
(10) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens,
E. D.; Nolan, S. P. Organometallics 2002, 21, 5470-5472.
(11) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4,
4053-4056.
(12) (a) Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985. (b) Collman, J . P.; Hegedus, L. S.;
Norton, J . R.; Finke, R. G. In Principles and Applications of Organ-
otransition Metal Chemistry; University Science: Mill Valley, CA, 1987.
(c) Diederich, F., Stang, P. J . Metal-Catalyzed Cross-Coupling Reac-
tions; Wiley-VCH: Weinheim, 1998.
(13) (a) Roncali, J . J . Chem. Rev. 1992, 92, 711-738. (b) Yamamura,
K.; Ono, S.; Ogoshi, H.; Masuda, H.; Kuroda, Y. Synlett. 1989, 18-19.
(14) (a) Torssell, K. B. G. Natural Product Chemistry; Wiley:
Chichester, 1983. (b) Thomson, R. H. The Chemistry of Natural
Products; Blackie and Son: Glasgow, 1985. (c) Huth, A.; Beetz, I.;
Schumann, I. Tetrahedron 1989, 45, 6679-6682. (d) Ennis, D. S.;
McManus, J .; Wood-Kaczmar, W.; Richardson, J .; Smith, G. E.;
Carstairs, A. Org. Process Res. Dev. 1999, 3, 248-252. (e) Baudoin,
O.; Cesario, M.; Guenard, Daniel; Gueritte, F. J . Org. Chem. 2002,
67, 1199-1207.
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Chem. 1975, 91, C39-C42. (b) Tamao, K.; Kiso, Y.; Sumitani, K.;
Kumada, M. J . Am. Chem. Soc. 1972, 94, 9268-9269. (c) Sekiya, A.;
Ishikawa, N. J . Organomet. Chem. 1976, 118, 349-354.
(16) Hatanaka, Y.; Hiyama, T. Synlett. 1991, 845-853.
(3) Phosphine ligands in homogeneous catalysis: (a) Parshall, G.
W.; Ittel, S. D. Homogeneous Catalysis; J . Wiley and Sons: New York,
1992. (b) Pignolet, L. H., Ed. Homogeneous Catalysis with Metal
Phosphine Complexes; Plenum: New York, 1983.
(4) Viciu, M. S.; Grasa, G. A.; Nolan, S. P. Organometallics 2001,
20, 3607-3612.
(5) Huang, J .; Grasa, G. A.; Nolan, S. P. Org. Lett. 1999, 1, 1307-
1309.
(6) Huang, J .; Nolan, S. P. J . Am. Chem. Soc. 1999, 121, 9889-
9890.
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(8) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119-122.
(9) (a) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org.
Chem. 1999, 64, 3804-3805. (b) Grasa, G. A.; Viciu, M. S.; Huang, J .;
Zhang, C.; Trudell, M. L.; Nolan, S. P. Organometallics 2002, 21, 2866-
2873.
10.1021/jo035834p CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004
J . Org. Chem. 2004, 69, 3173-3180
3173

Navarro et al.
SCHEME 1. N-Heter ocyclic Ca r ben es Used a s
An cilla r y Liga n d s a n d Gen er a l Str u ctu r e of th e
(NHC)P d (a llyl)Cl Com p lexes
TABLE 1. Effect of th e Ba se on th e Su zu k i-Miya u r a
Cr oss-Cou p lin g Rea ction
base
yield (%)a
Cs2CO3
CsF
KF
K3PO4
KOtBu
NaOtBu
Ba(OH)2
47
66
39
20
65
74
62
a
GC yields, average of two runs.
TABLE 2. Effect of NHC Liga n d on th e
Su zu k i-Miya u r a Cr oss-Cou p lin g
Despite the fact that they are air-sensitive and degrade
at high temperatures,3 monodentate tertiary phosphines
are usually employed as ancillary ligands in the Suzuki-
Miyaura reaction. Most palladium/tertiary phosphine
systems require the use of excess ligand,21 and very active
systems achieve high performance at the expense of
complex stability.22 Some recent examples of the use of
bulky tertiary phosphines in this reaction are found in
the work of Hartwig, Buchwald, and Fu.22,23 The Fu group
has reported on methods to circumvent the air-sensitive
nature of trialkylphosphines.24 We have tested the per-
formance of (NHC)Pd(allyl)Cl catalysts as substitutes for
phosphine-based systems in the Suzuki-Miyaura reac-
tion.
(NHC)Pd(allyl)Cl
yield (%)a
(IMes)Pd(allyl)Cl (1)
(SIMes)Pd(allyl)Cl (2)
(IPr)Pd(allyl)Cl (3)
(SIPr)Pd(allyl)Cl (4)
(ItBu)Pd(allyl)Cl (5)
80
70
80
62
68
a
GC yields, average of two runs.
Pd(allyl)Cl (4) (SIPr ) (N,N′-bis(2,6-diisopropylphenyl)-
4,5-dihydroimidazol)-2-ylidene); (ItBu)Pd(allyl)Cl (5) (ItBu
) (N,N′-bis(2,6-tert-butyl)imidazol)-2-ylidene) (Scheme 1).
Results for the catalytic reactions after 20 min are
presented in Table 2. As observed in the in situ catalyst
generated palladium/imidazolium salt systems, catalysts
bearing IPr or IMes NHCs display the best catalytic
behavior.9b The use of 3 leads to complete conversion of
4-chlorotoluene after 1 h at 80 °C. When compared to the
palladium/imidazolium salt systems, a shorter reaction
time is required using the well-defined system. An
induction period was initially observed in the in situ
generated system since an interval was required to
generate the free NHC ligand. In the present case, the
active Pd(0) species is obtained rapidly from the (NHC)-
Pd(allyl)Cl complex by reaction with the alkoxide.
Under these reaction conditions, no sign of catalyst
decomposition (Pd black formation) was observed. To test
the activation threshold leading to a Pd-NHC species,
the reaction temperature was reduced to 60 °C. To
compensate for the decreased solubility of phenyl boronic
acid, the amount of solvent was increased to 1.5 mL. Both
factors led to a slower reaction yet a 90% conversion was
achieved in 2 h. The reaction did not proceed to comple-
tion even after longer reaction times. An increase in the
amount of benzene appearing in the GC at 60 °C in
comparison to the one at 80 °C indicated decomposition
of phenyl boronic acid; therefore, the boronic acid loading
was increased to 1.2 equiv. Under these conditions, the
reaction reached to completion in 4 h. Further reducing
Our studies began using (IMes)Pd(allyl)Cl (1) (IMes
) (N,N′-bis(2,4,6-trimethylphenyl)imidazol)-2-ylidene) and
a variety of bases (Table 1). 4-Chlorotoluene (1 equiv) was
coupled with phenylboronic acid in the presence of 1.5
equiv of base using 2 mol % of 1 at 80 °C in 3 mL of 1,4-
dioxane. Under these conditions of low base concentra-
tion, we found that NaOtBu and KOtBu were much more
efficient than the commonly used KF or Cs2CO3.
Once NaOtBu had been selected as the most effective
base, the next optimization step involved testing for the
optimum ancillary ligand. Several (NHC)Pd(allyl)Cl cata-
lysts were tested: (IMes)Pd(allyl)Cl (1); (SIMes)Pd(allyl)-
Cl (2) (SIMes ) (N,N′-bis(2,4,6-trimethylphenyl)-4,5-
dihydroimidazol)-2-ylidene); (IPr)Pd(allyl)Cl25 (3) (IPr )
(N,N′-bis(2,6-diisopropylphenyl)imidazol)-2-ylidene); (SIPr)-
(17) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-
524. (b) Farina, V.; Krishnamurthy, V.; Scott, W. Org. React. 1997,
50, 1-652. (c) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim,
1998; pp 167-202 and references therein. (d) Handy, S. T.; Zhang X.
Org. Lett. 2001, 3, 233-236.
(18) Erdik, E. Tetrahedron 1992, 48, 9577-9648.
(19) For reviews, see: (a) Miyaura, N. Top. Curr. Chem. 2002, 219,
11-59. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(c) Suzuki, A. J . Organomet. Chem. 1999, 576, 147-168.
(20) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J . Organomet.
Chem. 1998, 557, 93-96.
(21) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl.
1997, 36, 2163-2187.
(22) Stambuli, J . P.; Kuwano, R.; Hartwig, J . F. Angew. Chem., Int.
Ed. 2002, 41, 4746-4748.
(23) (a) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000,
122, 4020-4028 and references cited therein. (b) Netherton, M. R.;
Dai, C.; Neuschuetz, K.; Fu. G. C. J . Am. Chem. Soc. 2001, 123, 10099-
10100. (c) Yin, J .; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J . Am.
Chem. Soc. 2002, 124, 1162-1163.
(25) (IPr)Pd(allyl)Cl is now commercially available from Strem
Chemicals.
(24) Netherton, M. R.; Fu, G. C.; Org. Lett. 2001, 3, 4295-4298.
3174 J . Org. Chem., Vol. 69, No. 9, 2004

Reactions Catalyzed by (NHC)Pd(allyl)Cl Complexes
TABLE 3. Su zu k i-Miya u r a Cr oss-Cou p lin g of Ar yl
Ch lor id es w ith P h en ylbor on ic Acid
TABLE 4. Su zu k i-Miya u r a Cr oss-Cou p lin g of Ar yl
Br om id es w ith P h en ylbor on ic Acid
a
b
GC yield (isolated yield), average of two runs. 2 h.
TABLE 5. Su zu k i-Miya u r a Cr oss-Cou p lin g of
4-Ch lor otolu en e w ith Differ en t Bor on ic Acid s
a
b
GC yield (isolated yield), average of two runs. 4 h.
the reaction temperature to 40 °C led to complete con-
version only after 20 h;26 thus, we conducted a substrate
survey at 60 °C. Substrates and reactions tested are
presented in Table 3. Both activated (entries 1-4) and
unactivated chlorides (entries 6-9) reached total conver-
sion in 4 h or less. When aryl bromides were used as
substrates, the amount of catalyst could be reduced to 1
mol % without loss of activity (Table 4). In all cases
examined (aryl chlorides and bromides), only traces of
homocoupling and dehalogenation products were formed
(<5%).
a
GC yield (isolated yield), average of two runs.
Aryl iodides, although not extensively tested here, are
also compatible with the catalyst system. Functional
group compatibility at the boronic acid was also tested
(Table 5). For demanding substrates, entries 3 (sterically
hindered) and 4 (with an electron-withdrawing substitu-
ent), good yields were obtained in 3 h.
Microwave-assisted reactions have gained popularity
as a facile screening method since it was first reported
in 1986.27 Since several microwave-assisted cross-coup-
ling reactions have been reported in the literature,28 we
decided to apply that concept to our system. Results are
listed in Table 6. Results very similar to the ones ob-
tained by conventional heating are obtained. Under these
high thermal conditions, the catalysts appear stable and
no palladium black is formed.
Ca ta lytic Deh a logen a tion of Ar yl Ch lor id es. The
dehalogenation of aryl halides, specifically aryl chlorides,
represents an important chemical transformation in
organic synthesis29 and due to the high toxicity of
polychlorinated biphenyls is of importance to environ-
mental remediation.30 Palladium is the most frequently
used transition metal in hydrodehalogenation reactions,
either in homogeneous or in heterogeneous processes, and
a plethora of systems and conditions have already been
reported to achieve dehalogenation.31 Fort and co-workers
recently reported a very efficient nickel(0)/imidazolium
(26) The reaction was done in 2 mL of 1,4-dioxane because of the
low solubility of the PhB(OH)2 at that temperature. This factor
certainly contributed to increase the reaction time.
(27) (a) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-
9584. (b) Larhed, M.; Hallberg, A.; Lindeberg, G. Tetrahedron Lett.
1996, 37, 8219-8222.
(28) (a) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg,
A. J . Org. Chem. 1997, 62, 5583-5587. (b) Erdelyi, M.; Gogoll, A. J .
Org. Chem. 2001, 66, 4165-4169. (c) Leadbeater, N. E.; Marco, M. J .
Org. Chem. 2003, 68, 888-892. (d) Blettner, C. G.; Koenig, W. A.;
Stenzel, W.; Schotten, T. J . Org. Chem. 1999, 64, 3885-3890.
(29) (a) Pinder, A. R. Synthesis 1980, 425-452 (b) Terstiege, I.;
Maleczka, R. E., J r. J . Org. Chem. 1999, 64, 342-343. (c) Parry, R. J .;
Li, Y.; Gomez, E. E. J . Am. Chem. Soc. 1992, 114, 5946-5959. (d)
Dorman, G.; Olszewski, J . D.; Prestwich, G. D.; Hong, Y.; Ahem, D. G.
J . Org. Chem. 1995, 60, 2292-2297.
J . Org. Chem, Vol. 69, No. 9, 2004 3175

Navarro et al.
TABLE 6. Micr ow a ve-Assisted Su zu k i-Miya u r a
Cr oss-Cou p lin g of Ar yl Ch lor id es w ith P h en ylbor on ic
Acid
TABLE 7. Effect of th e Ba se on th e Micr ow a ve-Assisted
Deh a logen a tion
base
yield (%)a
NaOtBu
KOtBu
NaOMe
KOMe
100
96
37
91
a
GC yields, average of two runs.
Studies were conducted in technical grade 2-propanol
with the idea of generating the working base (isopro-
poxide) in situ in an attempt to formulate an easy,
scalable, and economical process. The catalyst selected
was the one leading to the best results in the Suzuki-
Miyaura cross-coupling reaction since it has been sug-
gested that the rate-determining step for dehalogenation
is the oxidative addition of the aryl chloride.4,33 (IPr)Pd-
(allyl)Cl (3) was then the catalyst of choice for this
reaction.
a
b
GC yield, average of two runs. No catalyst added.
We initiated this section of the study using microwave-
assisted heating. A minimum of 2 mL of solvent was
required because of the specifications of the microwave
reactor. By using 1.05 equiv of NaOtBu, the amount of
catalyst required to dehalogenate 1 equiv of 4-chloro-
toluene was reduced to 0.025 mol % of (IPr)Pd(allyl)Cl
(reaction at 120 °C, 120 s). Use of a larger amount of base
decreased the yields, presumably because of a competi-
tion between the tert-butoxide and the isopropoxide for
the addition to the metal center. To confirm the impor-
tance of the ancillary NHC ligand, a reaction was carried
out using 1 mol % of [Pd(allyl)Cl]2 as catalyst under these
same conditions and afforded the toluene product in only
45% yield with the concomitant formation of a large
amount of metallic palladium. Reactions without catalyst
or base afforded no product.
SCHEME 2. P r op osed Mech a n ism for th e
Ca ta lytic Deh a logen a tion of Ar yl Ha lid es
A survey of various bases was performed, and results
of this optimization exercise are shown in Table 7. Once
the optimum base was identified (NaOtBu), the scope of
the reaction was tested. Few examples of microwave-
assisted dehalogenation of aryl halides have been re-
ported. Such studies have mainly focused on bromides
and iodides and required much harsher reaction condi-
tions.32 With the present palladium system, several aryl
chlorides were successfully dehalogenated (Table 8).
Having demonstrated the compatibility of the system
with a microwave-assisted process, conventional heating
was also tested in these reactions. The optimization
process can be followed in Table 9, which shows temper-
atures and times to perform total conversion of 4-chlo-
rotoluene into toluene. It is important to remark that,
in all cases, the reaction reached 85% to 90% conversion
in half of the time required for complete conversion. The
subsequent reactions were carried at 60 °C with 0.5 mol
% of (IPr)Pd(allyl)Cl, affording very good results. Results
illustrating the scope of this reaction are presented in
Table 10.
chloride catalyzed reduction of aryl halides32 which is
very similar to the one we reported some time ago using
a palladium/imidazolium chloride system.4 In both sys-
tems, alkoxide attack at the metal center followed by
reductive elimination of the arene from the metal(II)-
hydride complex is suggested as a likely pathway (see
Scheme 2). While conducting our studies on the Suzuki-
Miyaura reaction, we noticed that, under certain condi-
tions, the dehalogenation of the aryl halide was promoted,
and we decided to examine the performance of the
present systems in dehalogenation chemistry.
(30) (a) Hutzinger, O.; Safe, S.; Zitko, V. The Chemistry of PCBs;
CRC Press: Cleveland, OH, 1974. (b) Mincher, B. J .; Curry, R. D.;
Clevenger, T. E.; Golden, J . U.S. Patent 6 132 561, 2000. (c) McNab,
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Rev. 2002, 102, 4009-4091.
(32) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y. Organometallics
2002, 21, 1554-1559.
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4211.
3176 J . Org. Chem., Vol. 69, No. 9, 2004

Reactions Catalyzed by (NHC)Pd(allyl)Cl Complexes
TABLE 8. Micr ow a ve-Assisted Deh a logen a tion of Ar yl
Ch lor id esa
TABLE 10. Con ven tion a lly Hea ted Deh a logen a tion of
Ar yl Ch lor id es
a
Reaction times not optimized. b GC yields, average of two runs.
c 0.05 mol % of catalyst, 2.1 equiv of base.
TABLE 9. Op tim iza tion Rea ction s for th e
Deh a logen a tion of Ar yl Ch lor id es w ith Con ven tion a l
Hea tin g
catalyst loading (mol %)
solvent (mL)
T (°C)
timea
1
1
0.5
0.5
0.25
2
60
60
60
50
60
40 min
40 min
90 min
8 h
a
b
GC yields, average of two runs. 1 mol % catalyst, 2.1 equiv
1.5
1.5
1.5
1.5
of base.
Suzuki-Miyaura couplings.37-39 Uncatalyzed coupling of
secondary amines with activated aryl triflates in polar
solvents is known but requires several days to lead to
product formation.40 Catalytic amination of aryl triflates
3.5 h
a
Times required to obtain >95% of toluene, GC yield; average
of two runs.
Ar yl Am in a tion of Ar yl Tr ifla tes. Several studies
have been reported on the palladium-catalyzed prepara-
tion of a wide variety of arylamines from aryl halides.34
Most of these reaction procedures make use of catalysts
bearing phosphine ligands.35 In the past few years, the
aryl amination reaction has been reported to be efficient
with aryl triflates as the coupling partner.36 The impor-
tance of aryl triflates is significant as they can be easily
synthesized from readily available phenols37 and their
use has already has been demonstrated in Stille and
(35) (a) Louie, J .; Hartwig, J . F. Tetrahedron Lett. 1995, 36, 3609-
3612. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348-1350. (c) Wolfe, J . P.; Wagaw, S.;
Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 7215-7216. (d) Driver,
M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 7217-7218. (e)
Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (f)
Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575-5580. (g) Kuwano,
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1267. (b) Ahman, J .; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363-
6366. (c) Louie, J .; Driver, M. S.; Hamann, B. C.; Hartwig. J . F. J .
Org. Chem. 1997, 62, 1268-1273. (d) Wolfe, J . P.; Tomori, H.; Sadighi,
J . P.; Yin, J .; Buchwald, S. L. J . Org. Chem. 2000, 65, 1158-1174.
(37) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987, 109,
5478-5486.
(34) See, for example: (a) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (b) Hartwig, J . F.
Acc. Chem. Res. 1998, 31, 852-860.
J . Org. Chem, Vol. 69, No. 9, 2004 3177

Navarro et al.
TABLE 11. Effect of Differ en t NHC on th e Ar yl
Am in a tion Rea ction
A variety of amines were coupled with aryl triflates in
the presence of NaOtBu as base using toluene as solvent.
Dialkylamines, secondary arylamines and primary amines
were suitable substrates for the amination reaction and
results are presented in Table 12.
Con clu sion s
(NHC)Pd(allyl)Cl
time (h)
yield (%)a
(IPr)Pd(allyl)Cl
(IMes)Pd(allyl)Cl
(ItBu)Pd(allyl)Cl
3
24
24
94
11
41
The catalytic behavior of a series of well-defined, air-
and moisture-stable (NHC)Pd(allyl)Cl complexes has
been examined. A general system involving the use of
(IPr)Pd(allyl)Cl and NaOtBu was shown to be suitable
for the Suzuki-Miyaura cross-coupling of activated and
unactivated aryl chlorides and bromides, also efficient
in the catalytic dehalogenation of aryl chlorides and in
the catalytic aryl amination involving aryl triflates. All
reactions proceed in short times and at mild tempera-
tures. Investigations focusing on mechanistic aspects and
reactivity of this series of complexes in related cross-
coupling reactions are ongoing in our laboratories.
a
GC yields.
has been previously achieved using systems involving Pd/
BINAP,36a,b Pd/dppf,36c and Pd/(o-biphenyl)P(tBu)2.36d The
active species in these systems is generated in situ;
however, the ligands employed are susceptible to thermal
degradation and are usually difficult to remove from the
product.
We turned our attention to triflates as substrates and
examined their compatibility with the (NHC)Pd(allyl) Cl
presented here. Various (NHC)Pd(allyl)Cl complexes
were tested in the coupling of morpholine and p-tolyl
triflate. From the results presented in Table 11, (IPr)-
Pd(allyl)Cl was selected to conduct the amination reac-
tions.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All aryl halides, boronic acids,
amines, and aryl triflates were used as received. Technical
grade 2-propanol was also used as received. 1,4-Dioxane
(anhydrous) and toluene were distilled under argon from
TABLE 12. Ca ta lytic Am in a tion of Ar yl Tr ifla tes
a
GC yield (isolated yield), average of two runs.
3178 J . Org. Chem., Vol. 69, No. 9, 2004

Reactions Catalyzed by (NHC)Pd(allyl)Cl Complexes
sodium benzophenone ketyl prior to use. Cesium carbonate,
potassium and cesium fluoride, potassium phosphate, potas-
sium and sodium tert-butoxide, and barium hydroxide were
stored under argon in an inert atmosphere glovebox or in
desiccators over anhydrous calcium carbonate. The palladium
complexes (IMes)Pd(allyl)Cl (1) (IMes ) (N,N′-bis(2,4,6-tri-
methylphenyl)imidazol)-2-ylidene), (SIMes)Pd(allyl)Cl (2) (SIM-
es ) (N,N′-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol)-2-
ylidene), (IPr)Pd(allyl)Cl (3) (IPr ) (N,N′-bis(2,6-diisopropyl-
phenyl)imidazol)-2-ylidene), (SIPr)Pd(allyl)Cl (4) (SIPr ) (N,N′-
bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol)-2-ylidene), and
(ItBu)Pd(allyl)Cl (5) (ItBu ) (N,N′-bis(2,6-tert-butylphenyl)-
imidazol)-2-ylidene) were prepared according to reported
procedures.10 All reactions were carried out under an atmo-
sphere of argon in screw cap vials and stirred in a Lab-Line
Orbit bench shaker if conventionally heated or in sealed cap
vials and placed in an Enrys Optimizer microwave reactor if
microwave heated. Flash chromatography was performed
using silica gel 60 (230-400 mesh) using hexanes/ethyl acetate
mixtures. NMR spectra were recorded on a 300 or 400 MHz
spectrometer at ambient temperature in CDCl3.
Con ven tion a l a n d Micr ow a ved -Assisted Su zu k i-
Miya u r a Cr oss-Cou p lin g Rea ction s. Effect of th e Ba se
on th e Su zu k i-Miya u r a Cr oss-Cou p lin g. Gen er a l P r o-
ced u r e. In a glovebox, 1 (2 mol %, 9.8 mg), base (1.5 mmol),
and phenylboronic acid (1 mmol, 122 mg) were added in turn
to a vial and closed with a screw cap fitted with a septum.
Outside the glovebox, 4-chlorotoluene (1 mmol, 118 mL) and
1,4-dioxane (3 mL) were injected into the vial in that order.
The vial was then placed in a benchtop shaker set at 80 °C
for 4 h. The mixture was then analyzed by gas chromatogra-
phy.
Effect of Differ en t NHC on th e Su zu k i-Miya u r a
Cr oss-Cou p lin g. Gen er a l P r oced u r e. In a glovebox, cata-
lyst (2 mol %), NaOtBu (3 mmol, 288 mg), and phenylboronic
acid (1.1 mmol, 134 mg) were added in turn to a vial that was
then closed with a screw cap fitted with a septum. Outside
the glovebox, 4-chlorotoluene (1 mmol, 118 µL) and 1,4-dioxane
(1 mL) were injected into the vial in that order. The vial was
then placed in a benchtop shaker set at 80 °C for 20 min. The
mixture was then analyzed by gas chromatography.
Ca ta lytic Su zu k i-Miya u r a Cr oss- Cou p lin g of Ar yl
Ch lor id es w ith P h en ylbor on ic Acid . Gen er a l P r oced u r e.
In a glovebox, 3 (2 mol %, 11.4 mg), NaOtBu (3 mmol, 288
mg), and phenylboronic acid (1.2 mmol, 146 mg) were added
in turn to a vial that was then closed with a screw cap fitted
with a septum. Outside the glovebox, the aryl chloride (1
mmol) and 1,4-dioxane (1.5 mL) were injected into the vial in
that order. The vial was then placed in a benchtop shaker set
at 80 °C for 3-4 h and subsequently allowed to cool to room
temperature. After analysis by gas chromatography, silica gel
was added to the vial, the solvent was evaporated in vacuo,
and the product was isolated by flash chromatography. The
isolated product yields are the average of two runs.
Ca ta lytic Su zu k i-Miya u r a Cr oss-Cou p lin g of 4-Ch lo-
r otolu en e w ith Differ en t Bor on ic Acid s. Gen er a l P r o-
ced u r e. In a glovebox, 3 (2 mol %, 11.4 mg), NaOtBu (3 mmol,
288 mg), and the boronic acid (1.2 mmol) were added in turn
to a vial that was then closed with a screw cap fitted with a
septum. Outside the glovebox, 4-Cl-toluene (1 mmol, 120 mL)
and 1,4-dioxane (1.5 mL) were injected into the vial in that
order. The vial was then placed in a benchtop shaker set at
60 °C for 3 h and subsequently allowed to cool to room
temperature. After analysis by gas chromatography, silica gel
was added to the vial, the solvent was evaporated in vacuo,
and the product was isolated by flash chromatography. The
amounts of isolated product are the average of two runs.
Micr ow a ve-Assisted Ca ta lytic Su zu k i-Miya u r a Cr oss-
Cou p lin g of Ar yl Ch lor id es w ith P h en ylbor on ic Acid .
Gen er a l P r oced u r e. In a glovebox, 3 (2 mol %, 11.4 mg),
NaOtBu (3 mmol, 288 mg), and phenylboronic acid (1.2 mmol,
146 mg) were added in turn to a microwave vial containing a
magnetic stirring bar and the vial sealed with a cap fitted with
a septum. Outside the glovebox, the aryl chloride (1 mmol)
and 1,4-dioxane (2 mL) were injected into the vial in that order.
The vial was then placed in a microwave reactor set at 120 °C
for 90 s and subsequently allowed to cool to room temperature.
The mixture was then analyzed by gas chromatography.
Con ven tion a l a n d Micr ow a ve-Assisted Ca ta lytic De-
h a logen a tion of Ar yl Ch lor id es. Effect of th e Ba se on
th e Micr ow a ve-Assisted Deh a logen a tion . Gen er a l P r o-
ced u r e. In a glovebox, base (1.05 mmol) was added to a
microwave vial containing a magnetic stirring bar and the vial
sealed with a cap fitted with a septum. Outside the glovebox,
4-chlorotoluene (1 mmol, 118 µL) and 2 mL of a stock solution
of 3 in technical grade 2-propanol (1.5 mg in 20 mL, 0.025 mol
% in 2 mL) were injected into the vial in that order. The vial
was then placed in a microwave reactor set at 120 °C for 120
s and subsequently allowed to cool to room temperature. The
mixture was analyzed by gas chromatography and compared
with an authentic sample of the product.
Micr ow a ve-Assisted Deh a logen a tion of Ar yl Ch lo-
r id es. Gen er a l P r oced u r e. In a glovebox, NaOtBu (1.05
mmol, 101 mg) was added to a microwave vial containing a
magnetic stirring bar and the vial sealed with a cap fitted with
a septum. Outside the glovebox, aryl chloride (1 mmol) and 2
mL of a stock solution of 3 in technical grade 2-propanol (1.5
mg in 20 mL, 0.025 mol % in 2 mL) were injected into the vial
in that order. The vial was then placed in a microwave reactor
set at 120 °C for 120 s and subsequently allowed to cool to
room temperature. The mixture was analyzed by gas chroma-
tography and compared with an authentic sample of the
product.
Deh a logen a tion of Ar yl Ch lor id es. Gen er a l P r oce-
d u r e. In a glovebox, NaOtBu (1.05 mmol, 101 mg) was added
to a vial that was then closed with a screw cap fitted with a
septum. Outside the glovebox, the aryl chloride (1 mmol) and
1.5 mL of a stock solution of 3 in technical grade 2-propanol
(57 mg in 30 mL, 0.5 mol % in 1.5 mL) were injected into the
vial in that order. The vial was then placed in a benchtop
shaker set at 60 °C for 1.75 h and subsequently allowed to
cool to room temperature. The mixture was analyzed by gas
chromatography and compared with an authentic sample of
the product.
Ca ta lytic Su zu k i-Miya u r a Cr oss-Cou p lin g of Ar yl
Br om id es w ith P h en ylbor on ic Acid . Gen er a l P r oced u r e.
In a glovebox, 3 (1 mol %, 5.7 mg), NaOtBu (3 mmol, 288 mg),
and phenylboronic acid (1.2 mmol, 146 mg) were added in turn
to a vial that was then closed with a screw cap fitted with a
septum. Outside the glovebox, the aryl bromide (1 mmol) and
1,4-dioxane (1.5 mL) were injected into the vial in that order.
The vial was then placed in a benchtop shaker set at 60 °C
for 3 h and subsequently allowed to cool to room temperature.
After analysis by gas chromatography, silica gel was added to
the vial, the solvent was evaporated in vacuo, and the product
was isolated by flash chromatography. The amounts of isolated
product are the average of two runs.
Ca ta lytic Am in a tion of Ar yl Tr ifla tes. Effect of Dif-
fer en t NHC on th e Ca ta lytic Am in a tion of Ar yl tr ifla tes.
In a glovebox, catalyst (1 mol %), NaOtBu (1.05 mmol, 101 mg),
and dry toluene (4 mL) were added in turn to a vial which
was closed with a screw cap fitted with a septum. Outside the
glovebox, p-tolyl triflate (1 mmol, 179 µL) and morpholine (1.2
mmol, 105 µL) were injected into the vial in that order. The
vial was then placed in a benchtop shaker set at 70 °C, and
the reaction was monitored by gas chromatography.
(38) Oh-e, T.; Miyaura, N.; Suzuki. A. J . Org. Chem. 1993, 58, 2208-
2201.
(39) Ritter, K. Synthesis 1993, 735-762.
(40) Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, H. Syn-
thesis 1990, 1145-1147.
Ca ta lytic Am in a tion of Ar yl Tr ifla tes. Gen er a l P r o-
ced u r e. In a glovebox, 3 (1 mol %), NaOtBu (1.05 mmol, 101
J . Org. Chem, Vol. 69, No. 9, 2004 3179

Navarro et al.
mg), and dry toluene (4 mL) were added in turn to a vial that
was then closed with a screw cap fitted with a septum. Outside
the glovebox, aryl triflate (1 mmol) and amine (1.2 mmol) were
injected into the vial in that order. The vial was then placed
in a benchtop shaker set at 70 °C. After analysis by gas
chromatography, silica gel was added to the vial, the solvent
was evaporated in vacuo, and the product isolated by flash
chromatography. The amounts of isolated product reported are
the average of two runs.
this work. Eli Lilly and Co. and the Lonza Group are
gratefully acknowledged for the generous gift of chemi-
cals and metal salts. Personal Chemistry, Inc., is
gratefully acknowledged for the loan of the Enrys
Optimizer microwave reactor.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and product isolation protocol. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The National Science Founda-
tion is gratefully acknowledged for financial support of
J O035834P
3180 J . Org. Chem., Vol. 69, No. 9, 2004