Scope and mechanism of palladium-catalyzed amination of five-membered heterocyclic halides

Article abstract of DOI:10.1021/jo0266339

Detailed studies have been conducted to determine the activity of palladium catalysts for the amination of five-membered heterocyclic halides and to determine the factors that control the scope of this reaction. Palladium-catalyzed aminations of the electron-rich furanyl, thiophenyl, and indolyl halides and of the related 2-halogenated thiazoles, benzimidazole, and benzoxazole have been shown to occur with a subset of amines. Various combinations of palladium precursors and P^tBu₃ were tested as catalysts for reaction of 3-bromothiophene with N-methylaniline, and the fastest reactions occurred with the Pd(I) dimer, [PdBr(P^tBu₃)]2. The fastest aminations of thiazoles, benzimidazoles, and benzoxazoles occurred with the combination of palladium trifluoroacetate and P^tBu₃ as catalyst.

Full text of DOI:10.1021/jo0266339

Scop e a n d Mech a n ism of P a lla d iu m -Ca ta lyzed Am in a tion of
F ive-Mem ber ed Heter ocyclic Ha lid es
Mark W. Hooper, Masaru Utsunomiya, and J ohn F. Hartwig*
Department of Chemistry, P.O. Box 208107, Yale University, New Haven, Connecticut 06520-8107
john.hartwig@yale.edu
Received October 30, 2002
Detailed studies have been conducted to determine the activity of palladium catalysts for the
amination of five-membered heterocyclic halides and to determine the factors that control the scope
of this reaction. Palladium-catalyzed aminations of the electron-rich furanyl, thiophenyl, and indolyl
halides and of the related 2-halogenated thiazoles, benzimidazole, and benzoxazole have been shown
to occur with a subset of amines. Various combinations of palladium precursors and PtBu3 were
tested as catalysts for reaction of 3-bromothiophene with N-methylaniline, and the fastest reactions
occurred with the Pd(I) dimer, [PdBr(PtBu3)]2. The fastest aminations of thiazoles, benzimidazoles,
and benzoxazoles occurred with the combination of palladium trifluoroacetate and PtBu3 as catalyst.
In tr od u ction
tune the properties of the molecule.17 Heteroaromatic
amines also show novel intrinsic electronic properties.18-20
Many of the classical routes to heteroarylamines are
limited in scope or occur at high temperatures. Although
uncatalyzed amination of pyridyl and related six-
membered heterocyclic halides can occur at high tem-
peratures or pressures,21 direct amination of five-
membered heteroaryl halides containing a single hetero-
atom is restricted to systems containing strongly electron-
withdrawing substituents, such as nitro or acyl groups.22
Various systems have been developed for the arylation
of amines with stoichiometric amounts of copper and
heteroaryl boronic acids or tin reagents instead of het-
eroaryl halides.23,24 However, the substrate tolerance is
limited, and aryltin reagents are highly toxic. Some
electrophilic aminations of heteroaromatic carbanions
have also been performed.25,26 This reaction requires more
complex amine reagents and strongly basic conditions for
formation of the carbanions. Finally, some multistep,
indirect syntheses of heteroaromatic amines have been
reported.27,28
The palladium-catalyzed amination of aryl halides with
a large range of aryl halides and amines has been
extensively investigated in recent years.1-5 Third-genera-
tion ligands such as PtBu3,6-8 biphenylPtBu2,9 and het-
erocyclic carbenes10,11 create catalysts with increased
activity and allow milder conditions to be used. For
example, reactions can be run at room temperature, with
low catalyst loading, and with previously inactive sub-
strates, such as aryl chlorides.6-10,12 In contrast, the
application of this methodology to heteroaromatic sub-
strates such as halofurans, -thiophenes, -pyrroles, -in-
doles, -thiazoles, and -imidazoles has been limited.
Five-membered heteroaryl groups are common in
natural products and pharmaceutical targets.13-16 These
groups often act as surrogates for a phenyl group and
* Corresponding author.
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10.1021/jo0266339 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/13/2003
J . Org. Chem. 2003, 68, 2861-2873
2861

Hooper et al.
TABLE 1. Am in a tion of Heter oa r yl Ha lid es w ith
Watanabe reported that unfunctionalized bromo-
thiophenes react with diarylamines in the presence of
catalysts bearing PtBu3 as ligand, but yields were moder-
ate, and no reactions of furanyl or indolyl halides were
reported.29 Luker30 demonstrated that conjugated, electron-
deficient bromothiophenes react with a range of amines
in the presence of palladium and BINAP as catalyst and
Cs2CO3 as base but did not report reactions of electron-
neutral bromothiophenes. Rasmussen31 has shown that
palladium and PtBu3 is a superior catalyst for the
amination of 3-bromothiophene, but did not report reac-
tions of other isomers or other five-membered hetero-
cycles.
P d (d ba )2/P tBu 3
The amination of heteroaromatic halides containing
two oxygen, nitrogen, or sulfur atoms, such as halo-
thiazoles or -imidazoles, has been equally limited,32-34
despite the importance of 2-amino-thiazoles and -imida-
zoles in pharmaceutical applications.15,35 Most reported
aminations of these heterocyclic halides have been con-
ducted with BINAP as ligand; only one published33 and
one patented36 example conducted with palladium cata-
lysts bearing sterically hindered monodentate ligands
have been reported, and no studies that evaluate the
scope of these aminations with these recently developed
catalysts have been conducted. It is unclear if catalysts
containing these ligands would show high activity for
reactions of heteroaryl halides. They could display high
activity for the same reasons they are highly active for
reactions of deactivated aryl halides, or they could display
low activity if the hindered ligand is displaced by the
heterocyclic substrate.
This paper delineates in a more comprehensive manner
the scope of the formation of heteroarylamines from
halofurans, -thiophenes, -pyrroles, -indoles, -thiazoles,
and -imidazoles. In addition, we conducted both qualita-
tive and quantitative kinetic studies on the reactions
catalyzed by various combinations of palladium precur-
sors and PtBu3. These studies revealed the classes of
amines and five-membered heteroaryl halides that un-
dergo the amination and ruled out several likely pal-
ladium complexes as active species in these reactions.
Resu lts
Eva lu a tion of Rea ction Scop e. 1. Rea ction s of
Ha lofu r a n s, -th iop h en es, a n d -in d oles. Aminations
of simple, unactivated bromofurans and bromothiophenes
in the presence of catalytic amounts of Pd(dba)2 and PtBu3
in a 1:1 ratio are summarized in Table 1. Reactions of
bromofurans and -thiophenes with N-methylaniline oc-
curred at room temperature (Table 1, entries 1-4).
Reactions of chlorothiophenes with this amine required
a
b
Isolated yields (GC yields). 5 mol % of catalyst. c Average of
2 runs.
120 °C to ensure complete conversion (entries 13 and 14).
Reactions of bromofurans and -thiophenes with diaryl-
amines occurred at 100 °C. Isolated yields of 2-amino-
furans (entries 1 and 5) were somewhat lower than the
isolated yields of aminothiophenes because of the dif-
ficulty in isolating these acid and slightly air-sensitive
amines. In general, 3-bromothiophene reacted in higher
yields (entries 4 and 8) and broader scope than other five-
membered heteroaryl halides. Most striking, 3-bro-
mothiophene reacted with aniline (entries 9), but no
reaction was observed between 2-bromothiophene, 2-bro-
mofuran, or 3-bromofuran and aniline, even at 100 °C
over several days.
(29) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem. Commun.
2000, 133.
(30) Luker, T. J .; Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire,
D. R. Tetrahedron Lett. 2000, 41, 7731.
(31) Ogawa, K.; Radke, K. R.; Rothstein, S. D.; Rasmussen, S. C. J .
Org. Chem. 2001, 66, 9067.
(32) Hong, Y.; Tanoury, G. J .; Wilkinson, S. H.; Bakale, R. P.; Wald,
S. A.; Senanayake, C. H. Tetrahedron Lett. 1997, 38, 5607.
(33) Wang, Z.; Rizzo, C. J . Org. Lett. 2001, 3, 565.
(34) Schoffers, E.; Olsen, P. D.; Means, J . C. Org. Lett. 2001, 3, 4221.
(35) Young, R. C.; Mitchell, R. C.; Brown, T. H.; Ganellin, R. C.;
Griffiths, R.; J ones, M.; Rana, K. K.; Saunders, D.; Smith, I. R.; Sore,
N. E.; Wilks, T. J . J . Med. Chem. 1988, 31, 656.
(36) Akhavan-Tafti, H.; Eickholt, R. A.; Handley, R. S. U.S. 6,410,-
732, 2002.
Reactions of bromofurans and thiophenes with primary
or secondary alkylamines in the presence of PtBu3 and
Pd(dba)2 as catalyst were also evaluated. Little or no
2862 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
TABLE 2. Am in a tion of Heter oa r yl Br om id es w ith
P d (d ba )2/P tBu 3
F IGURE 1. Two ligands tested in the amination of heteroaryl
halides.
arylamine was observed from reaction of hexylamine,
dibutylamine, piperidine, or morpholine with most of the
heteroaryl halides. However, 3-halothiophenes did react
with cyclic secondary amines such as morpholine and
4-phenylpiperazine (entries 10, 11, and 15). Dibutylamine
and hexylamine also reacted with 3-bromothiophene, but
the yields (ca. 20-30%) were lower than those from
reactions of cyclic secondary amines.
Various alternative catalysts were tested for the ami-
nation of bromofurans and thiophenes. Complexes gener-
ated from PtBu3, and Pd(OAc)2 or Pd(dba)2 were tested
as catalysts for the reaction of 3-bromothiophene with
N-methylaniline. Similar yields of 3-(N-methyl-N-phen-
ylamino)thiophene were observed in both cases, but
significantly slower rates were observed for reactions
catalyzed by the combination of PtBu3 and Pd(OAc)2.
Reactions of bromothiophenes and bromofurans with
N-methylaniline in the presence of catalysts comprised
of Pd(dba)2 and the carbene or ferrocenyldi-tert-bu-
tylphosphine ligands in Figure 1 occurred in lower yields
than reactions of these heteroaryl bromides with N-
methylaniline in the presence of PtBu3 and Pd(dba)2. We
also evaluated reactions of N-methylaniline catalyzed by
the combination of DPPF or BINAP and Pd(dba)2 or Pd-
(OAc)2. Low to moderate yields and slow rates were
observed. Reactions attempted in the presence of triethyl-
amine, cesium carbonate, and sodium phenoxide as base
all failed to form any coupled product between this amine
and bromofurans or bromothiophenes.
a
Isolated yields (GC yields).
Table 2 summarizes our results on the amination of
some methyl-substituted bromofurans, methyl-substi-
tuted bromothiophenes, and N-methyl bromoindoles. This
simple substitution on the heterocycle led to differences
in rates and yields that were large in some cases and
that depended on the position of the methyl group. Again,
reactions of these heteroaromatic halides with N-methyl-
aniline proceeded to completion at room temperature,
whereas reactions of these substrates with diarylamines
required heating at 100 °C.
5-Methyl-2-bromofuran displayed similar reactivity to
the unsubstituted 2-bromofuran (Table 2, entries 1 and
2), and 5-methyl-2-bromothiophene displayed similar
reactivity to the parent 2-bromothiophene (Table 2,
entries 3 and 4). Isolated yields of the 5-methyl-2-
aminofurans were lower than the isolated yields of the
parent 2-aminofurans and 2-aminothiophenes simply
because the methyl-substituted products were more
prone to decomposition.
N-methylaniline. The major product was the amidine
PhNdC(H)NMePh formed from the known37 metal-
mediated disproportionation of the unstable imine CH2d
N(H)Ph, which would result from â-hydride elimination
of the palladium N-methylanilide intermediate. This
result is in contrast with the reactions of N-methylaniline
with o-tolyl bromides and phenyl bromide6-8 that both
occur in high yield; a single ortho-substituent often leads
to faster reductive elimination38 and higher yields in the
amination chemistry.8,9,39 In contrast to the reaction of
2-bromo-3-methylthiophene with N-methylaniline, the
reaction of 3-bromo-4-methylthiophene with N-methyl-
aniline provided a substantial 54% yield of the coupled
product. Thus, the position of the pseudo-ortho methyl
group has a larger affect on the yield of aminothiophenes
than does the position of the halide.
Reactivities of 2- and 3-bromo-N-methylindoles were
similar to those of 2- and 3-bromofurans and thiophenes
In contrast, a large difference was observed between
the reactivity of 3-methyl-2-bromothiophene (Table 2,
entry 7) and the reactivity of the unsubstituted parent
2-bromothiophene (Table 1, entry 3) toward N-methyl-
aniline. A low yield (6%) of coupled product was obtained
from the reaction of 2-bromo-3-methylthiophene and
(37) Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 7010.
(38) Mann, G.; Baran˜ano, D.; Hartwig, J . F.; Rheingold, A. L.; Guzei,
I. A. J . Am. Chem. Soc. 1998, 120, 9205.
(39) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144.
J . Org. Chem, Vol. 68, No. 7, 2003 2863

Hooper et al.
in amination reactions catalyzed by PtBu3 and Pd(dba)2.
N-Methylindoles were used instead of the parent indoles
to prevent competition between the reacting amine and
an indole N-H. Reactions of the free bromoindole with
amines did not produce any product from coupling with
the amine. Reactions of 2- and 3-bromo-N-methylindoles
with N-methylaniline occurred at room temperature,
whereas reactions of 2- and 3-bromo-N-methylindoles
with diphenylamine occurred at 100 °C. Little or no
reaction of these bromoindoles was observed with pri-
mary or secondary alkylamines or with primary aryl-
amines. The reaction of 2-bromo-N-methylindole with
N-methylaniline or diphenylamine produced slightly
higher yields of coupled product than did the reaction of
3-bromo-N-methylindole with these amines (Table 2,
entries 8-11). Studies on the reactions of 2- and 3-bro-
mopyrrole were not conducted because of the instability
of these substrates.
TABLE 3. Am in a tion of Heter oa r yl Ha lid es w ith
P d (O2CCF 3)2/P tBu 3
2. Am in a tion of Th ia zoles, Ben zim id a zoles, a n d
Oxa zoles. Substrates containing two heteroatoms in a
five-membered ring are less electron-rich than furans,
thiophenes, and indoles. Thus, we compared the pal-
ladium-catalyzed aminations of halothiazoles and -imi-
dazoles to those of halofurans and -thiophenes and to
those of uncatalyzed reactions (Table 3). Reaction condi-
tions that were different from those for the amination of
halothiophenes, furans, and indoles were required be-
cause 2-bromothiazole decomposed in the presence of the
strong base NaOtBu. The yield of coupled product in the
presence of NaOtBu and the combination of Pd(dba)2 and
PtBu3 as catalyst was less than 20%. After testing various
bases and palladium precursors, we obtained 70% yield
of coupled product from the reaction of 2-bromothiazole
with dibutylamine in the presence of K3PO4 and catalytic
amounts of Pd(O2CCF3)2 and PtBu3 (Table 3, entry 2).
This palladium precursor has rarely been used in coup-
ling chemistry, but did provide yields for these amination
processes that were superior to those obtained with Pd-
(OAc)2 (57%) or Pd(dba)2 (35%). The combination of Pd-
(O2CCF3)2 and PtBu3 was also effective for the reaction
of morpholine with 2-bromothiazole (Table 3, entry 1).
In contrast to reactions of furans, thiophenes, and in-
doles, which occurred in higher yield with N-methyl
aniline than with dialkylamines, reactions of bromothia-
zole with N-methyl aniline occurred in lower yield than
reactions with dialkylamines. Reactions of N-methyl-
aniline were most favorable with NaOtBu as base, Pd-
(OAc)2 as precursor, and ferrocenyl-di-tert-butylphos-
phine as ligand. Under these conditions, 46% yield of the
coupled product was isolated. Reactions of thiazoles and
imidazoles with primary alkyl- and arylamines in the
presence of catalysts containing Pd(dba)2, Pd(OAc)2, or
Pd(O2CCF3) and either PtBu3, ferrocenyl di-tert-butylphos-
phine, pentaphenylferrocenyl di-tert-butylphosphine, bi-
phenylPtBu2, BINAP, or DPPF occurred in low yields.
a
Isolated yields which are an average of 2 runs (yields without
catalyst). 4 equiv of amine was used. c Xylene was used as
solvent. Pd(OAc)2 and ferrocenyl di-tert-butylphosphine ligand
were used.
b
d
while the reaction of the benzimidazole with morpholine
(entry 8) was best conducted with K3PO4. In addition,
the reaction of 2-chlorobenzoxazole with morpholine gave
the coupled product in substantial yield (Table 3, entry
10). Reactions of other five-membered heterocyclic halides
were limited. Reactions of dibutylamine with 2-chloro-
imidazole and reactions of dibutylamine or N-methyl-
aniline with 2-chlorooxazole gave the heteroarylamine in
less than 30% yield. Moreover, reactions of amines with
4-bromo- or 5-bromoimidazoles and 3-choloro-isoben-
zothiazole did not occur in the presence of palladium and
PtBu3.
Many of the reactions of thiazoles and imidazoles with
amines proceeded to partial conversions without catalyst,
but the palladium-catalyzed reactions occurred under
milder conditions or in improved yields or both. In some
cases (Table 3, entries 3, 6, and 9), catalytic conditions
were required to generate any amination product. In no
case did reaction of the electron-rich halofurans or
thiophenes occur without catalyst, and the thermal
sensitivity limits direct aminations of 2- or 3-bromoin-
doles.
Reactions of related benzo-fused 2-haloheteroaryl com-
pounds with secondary amines were also evaluated
(Table 3, entries 4-10). 2-Chlorobenzothiazole and 2-chlo-
ro-N-methylbenzimidazole both reacted with the cyclic
secondary amine morpholine and the N-alkylarylamine
N-methyl aniline in good yield. 2-Chlorobenzothiazole
also reacted with dibutylamine. Reactions of the ben-
zothiazole were best conducted with NaOtBu as base,
2864 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
SCHEME 1
Mech a n istic Stu d ies. Catalytic reactions were moni-
tored in situ by 1H and 31P NMR spectroscopy to
determine how the catalyst resting state and the fate of
the catalyst and substrates varied between reactions that
formed coupled product and reactions that did not form
coupled product. In addition, the dependence of reaction
rate on the concentration of base and amine was evalu-
ated.
Gen er a tion of th e Ca ta lyst fr om P d (d ba )2 a n d
P tBu 3 a n d Rea ction s w ith Br om oth iop h en e. A 1:1
ratio of Pd(dba)2 and PtBu3 forms Pd(PtBu3)2 and leaves
half of the Pd(dba)2 unreacted.40,41 This equilibrium
required only 5 min to be established in tetrahydrofuran-
d8, but required about 1 h to be established in benzene-
d6 or toluene, most likely because of the lower solubility
of Pd(dba)2 in aromatic solvents. Reaction of the equili-
brated mixture of Pd(PtBu3)2 and Pd(dba)2 with 2-bro-
mothiophene formed a green solution containing [PdBr-
(PtBu3)]2 (eq 1).42-44 This material was isolated in 83%
yield as dark green crystals. 2,2′-Bithiophene was identi-
fied as a byproduct by 1H NMR spectroscopy. This
reaction provides a practical synthesis of the Pd(I) dimer
from commercially available materials. A similar reaction
was observed when aryl bromides were allowed to react
with a combination of Pd(dba)2 and PtBu3.44,45 However,
this reaction required an excess of aryl bromide and
heating to ensure complete conversion to [PdBr(PtBu3)]2.
The Pd(I) dimer is only moderately air-sensitive as a
solid. Standing in air for 72 h resulted in only about 25%
decomposition.
Reactions of 2-bromothiophene or phenyl bromide with
Pd(dba)2 and PtBu3 in the presence of N-methylaniline,
aniline, or hexylamine formed only small amounts of the
palladium(I) dimer [PdBr(PtBu3)]2. The same reactions
in the presence of NaOtBu instead of amine formed Pd-
(PtBu3)2 and no Pd(I) dimer. No reaction occurred be-
tween the isolated Pd(I) dimer and the heteroaryl halides.
Reaction of the dimer with hexylamine or NaOtBu
occurred slowly and with low conversion to Pd(PtBu3)2
(Scheme 1). In contrast, reaction of the dimer with
hexylamine and NaOtBu together formed Pd(PtBu3)2 at
F IGURE 2. Comparison of rates for reaction of arylamines
with 3-bromothiophene catalyzed by a combination of Pd(dba)2
and PtBu3.
room temperature. We did not determine the identity of
the remaining palladium in these transformations.
Mon itor in g by NMR Sp ectr oscop y of Am in a tion
Rea ction s Ca ta lyzed by P d (d ba )2 a n d P tBu 3. Ami-
1
nations of the heteroaryl halides were monitored by H
and 31P NMR spectroscopy with P(mesityl)3 as an internal
reference in benzene-d6 solvent. Prior to addition of the
reagents, the combination of Pd(dba)2 and PtBu3 was
allowed to stir for 1 h. In all reactions, the major
phosphine-ligated palladium complex in solution was Pd-
(PtBu3)2. This species accounted for greater than 90% of
the phosphorus signals. Approximately 5% of the signal
was due to free PtBu3. Integration of these signals vs that
of the internal standard showed that 75% or more of the
PtBu3 that was added to the system was present as Pd-
(PtBu3)2.
1. In flu en ce of th e Heter oa r yl Ha lid e. Both the
reactions that gave coupled product, such as the reaction
of 2-bromofuran with N-methylaniline, and the reactions
that gave little or no coupled product, such as the reaction
of 2-bromofuran with H2NPh, contained Pd(PtBu3)2 as the
major phosphine-ligated complex in solution. The reac-
tion of 2-bromofuran with N-methylaniline, which gener-
ated 80% yield of N-methyl N-phenyl-2-aminofuran, and
the reaction of 2-bromofuran with H2NPh, which gave
no N-phenyl-2-aminofuran, catalyzed by Pd(dba)2 and
PtBu3 at room temperature were monitored in detail by
1H NMR spectroscopy and by GC. The reaction of
N-methylaniline with 2-bromofuran was complete within
30 min, while the reaction of aniline with 2-bromofuran
consumed less than 10% of the heteroaryl bromide after
24 h at 100 °C. A similar difference in rate was observed
between reactions of 3-bromothiophene with N-methyl-
aniline and reactions of 3-bromothiophene with either
aniline or diphenylamine (Figure 2). These reactions all
produced coupled product, but the half-life for the reac-
tions catalyzed by a 1:1 combination of Pd(dba)2 and
PtBu3 differed by a factor of approximately 300 between
(40) Littke, A. F.; Dai, C. Y.; Fu, G. C. J . Am. Chem. Soc. 2000,
122, 4020.
(41) Beare, N. A.; Hartwig, J . F. J . Org. Chem. 2002, 67, 541.
(42) Dura-Vila, V.; Mingos, D. M. P.; Vilar, R.; Whiete, A. J . P.;
Williams, D. J . J . Organomet. Chem. 2000, 600, 198.
(43) Vilar, R.; Mingos, D. M. P.; Cardin, C. J . J . Chem. Soc., Dalton
Trans. 1996, 4313.
(44) Stambuli, J . P.; Kuwano, R.; Hartwig, J . F. Angew. Chem., Int.
Ed 2002, 41, 4746.
(45) Galardon, E.; Ramdeehul, S.; Brown, J . M.; Cowley, A.; Hii, K.
K.; J utand, A. Angew. Chem., Int. Ed. 2002, 41, 1760.
J . Org. Chem, Vol. 68, No. 7, 2003 2865

Hooper et al.
F IGURE 4. kobs vs [NaOCEt3] for the reaction of N-methyl-
aniline (0.025 M) with 2-bromothiophene (0.8 M) catalyzed by
10% of Pd(PtBu3)2 at 75 °C.
slower. Reactions conducted in the presence of a combi-
nation of Pd(PtBu3)2 and Pd(dba)2 were faster than those
catalyzed by Pd(PtBu3)2 alone, but they were slower than
those catalyzed by the Pd(I) species or mixtures of
Pd(dba)2 and PtBu3. Pd(dba)2, Pd(OAc)2, or Pd(trifluoro-
acetate)2 without added ligand did not catalyze the reac-
tion between any heteroaryl bromide and N-methyl-
aniline. Although large differences in rate were observed
for reactions containing these different catalyst composi-
tions, the fastest catalysts did not broaden the scope of
the reaction.
Mon itor in g of Rea ction s u n d er P seu d o-F ir st-
Or d er Con d ition s by 1H NMR Sp ectr oscop y. To
correlate aminations of the heteroaryl halides with
aminations of aryl halides, we measured the reaction
orders in amine and base. We have recently reported
kinetic studies on the reactions of N-methylbenzylamine
with phenyl chloride catalyzed by Pd(PtBu3)2 and by a
1:1 ratio of Pd(dba)2 and PtBu3.47 These studies revealed
a zero-order dependence of the rate on the concentration
of amine and a combination of first- and zero-order
dependence on the concentration of base. Rates for
reaction of 2-bromothiophene with N-methylaniline were
measured at 75 °C in benzene-d6 solvent in the presence
of NaOCEt3 as a soluble base and Pd(PtBu3)2 as catalyst.
Final concentrations of the reaction components were
2.50 mM Pd(PtBu3)2, 0.20-0.50 M NaOCEt3, 0.80 M
2-bromothiophene, and 0.025 M N-methylaniline. Both
decay of amine and appearance of product were moni-
tored.
F IGUR E 3. Reaction of 3-bromothiophene with N-methyl-
aniline in the presence of five different catalyst precursors
containing palladium and PtBu3.
the reaction of N-methylaniline, which was the fastest,
and the reaction of diphenylamine, which was the slow-
est.
A dramatic difference in rate was also detected for
reactions of isomeric halofurans and thiophenes. For
example, the palladium-catalyzed reaction of diphenyl-
amine with 2-bromofuran was faster than the reaction
of diphenylamine with 3-bromofuran. In contrast, the
palladium-catalyzed reactions of 3-bromothiophene with
diphenylamine or N-methylaniline were faster than the
reactions of 2-bromothiophene with these amines. These
differences in rates parallel the differences in yields for
catalytic reactions of the isomeric thiophenes in Table 1
and parallel the rates and yields for stoichiometric
reductive elimination from heteroarylpalladium amides
reported separately.46
2. In flu en ce of Ca ta lyst P r ecu r sor . To begin to
understand the relationship between the catalyst precur-
sor and the composition of the active catalyst, we
monitored the reaction of N-methylaniline with 3-bro-
mothiophene in benzene-d6 in the presence of five dif-
ferent combinations of PtBu3 and palladium. These data
are presented in Figure 3. Reactions catalyzed by the
42,44
palladium(I) dimer [PdBr(PtBu3)]2
were the fastest.
Reactions catalyzed by a 1:1 ratio of Pd(dba)2 and PtBu3
were slower but occurred to completion. With this com-
bination of precursors, the reaction rate depended on the
time that the catalyst and ligand were mixed prior to
addition of the reagents. As noted above, complete
conversion of Pd(dba)2 or Pd2(dba)3 and PtBu3 to Pd-
[P(tBu)]3 in toluene solvent required about 1 h because
the palladium precursor is only modestly soluble in
toluene. Catalytic reactions conducted after allowing
Pd(dba)2 and PtBu3 to mix for 5 min proceeded about
three times faster than reactions conducted after allowing
Pd(dba)2 and PtBu3 to mix for 1 h. Reactions conducted
in the presence of pure Pd(PtBu3)2 were considerably
Linear plots of the concentration of N-methylaniline
vs time were obtained for all reactions in the presence of
NaOCEt3 as base. These data are consistent with a
reaction that is zero order in amine. Figure 4 shows the
dependence of kobs on the concentration of NaOCEt3 for
the reaction of 2-bromothiophene with N-methylaniline
under the above conditions. The observed rate constant
was clearly smaller for reactions with higher concentra-
tions of base. Although evaluated in less detail, the
dependence of kobs on the concentration of NaOtBu for
(47) Alcazar-Roman, L. M.; Hartwig, J . F. J . Am. Chem. Soc. 2001,
123, 12905.
(46) Hooper, M.; Hartwig, J . F. Submitted for publication.
2866 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
should be faster than those of 3-bromofuran, and reac-
tions of 3-bromothiophene should be faster than those of
2-bromothiophene. This predicted reactivity was observed
experimentally. Finally, arylpalladium complexes with
two ortho substituents undergo reductive elimination
slower than those with one substituent, most likely
because the two ortho substituents inhibit binding of the
metal to the π-system at either C(ipso)-C(ortho) bond.
This effect was revealed by previous work on reductive
eliminations from heteroarylpalladium amides46 and on
reductive elimination from arylpalladium thiolates.38 An
analogous substituent effect with the heteroaromatic
substrates accounts for the larger difference in yield
between aminations of 3-methyl-2-bromothiophene and
2-bromothiophene with N-methylaniline than between
aminations of 4-methyl-3-bromothiophene and 3-bro-
mothiophene with N-methylaniline.
The origin of the effect of amine on reaction rate is less
straightforward. Reductive elimination of amine is un-
likely to be the turnover-limiting step of the catalytic
process because it is generally faster than oxidative
addition of electron-rich aryl or heteroaryl halides and
because Pd(0) complexes were observed as the major
species in solution. Thus, the rate of oxidative addition
and reductive elimination with the active catalyst does
not account for the differences in reactivity of amines
with the heteroaryl bromides. The reactions of some
amines consumed neither the heteroaryl halide nor the
amine. In these cases, the catalyst seemed to be poisoned,
as demonstrated by the interruption of an ongoing
catalytic reaction by addition of hexylamine. We cannot
explain the reversal of the relative reactivity of aryl- and
alkylamines toward the five-membered heteroaryl sys-
tems containing two heteroatoms, such as thiazoles,
benzimidazoles, and benzoxazoles, relative to the reactiv-
ity of these amines toward furans and thiophenes. These
substrates were more reactive toward alkylamines than
toward N-methylaniline, while the furans and thiophenes
were more reactive toward N-methylaniline and diphen-
ylamine than toward dialkylamines.
F IGURE 5. Reaction of N-methylaniline (0.025 M) with
2-bromothiophene (0.8 M) in the presence of NaOCEt3 (0.3 M)
catalyzed by 10% of Pd(PtBu3)2 at 75 °C. H2NHexyl (0.025 M)
was added at t ) 1600 s.
the same reaction was similar. Again, the observed rate
constant decreased with increasing concentrations of
base.
Reactions of 2-bromothiophene with N-methylaniline
were also monitored before and after adding hexylamine,
aniline, or piperidine (0.025 M). These amines were
added when approximately 50% of the heteroaryl bromide
had been consumed by reaction with N-methylaniline.
The reaction in which hexylamine was added at t ) 1600
s is shown in Figure 5. The reaction immediately stopped
upon addition of the unreactive amine. The same result
was observed when adding aniline and piperidine. Thus,
the amines that do not undergo coupling poison the
catalyst that is active for the coupling of heteroaryl
halides. An analogous experiment involving the addition
of hexylamine to the reaction of N-methylaniline with
bromobenzene did not show the same poisoning by the
primary alkylamine.
Several reactions were uncovered that accounted for
side products formed from reactions of N-methylaniline
that did consume the aryl bromide. Amidine and 2-me-
thylthiophene most likely form by â-hydrogen elimination
of the heteroarylpalladium amido intermediate and
reductive elimination of 2-methylthiophene. We previ-
ously showed that â-hydrogen elimination of an N-
methylanilide complex formed this amidine by formal
disproportionation of the resulting unstable imine PhNd
CH2.37 N-Methylaniline apparently forms by addition of
a proton from a source we did not identify. Bithiophene
was formed as an additional side product, and homocoup-
ling of both aryl51-53 and heteroaryl54,55 groups has been
observed previously. This homocoupling has been ratio-
nalized by disproportionation of arylpalladium halide
Discu ssion
Con n ection betw een th e Id en tity of th e Het-
er oa r yl Ha lid e a n d th e Yield s of Cou p led P r od u ct.
The yields for catalytic amination of thiophenyl and furyl
halides can be correlated with the yields obtained from
reductive eliminations of amine from DPPF-ligated aryl-
and heteroarylpalladium amides.46 Carbon-nitrogen bond-
forming reductive elimination is faster from complexes
with more electron-donating amido groups and less
electron-donating aryl groups.48 Because a furyl group
is less electron-rich at the 2-position and a thiophenyl
group is less electron-rich at the 3-position, aminations
of 2-bromothiophene and 3-bromofuran should occur in
higher yields than aminations of the isomeric heteroaryl
halides. Moreover, oxidative addition to palladium(0)
occurs faster with electron-poor aryl bromides.49,50 If
oxidative addition is the turnover limiting step in the
catalytic process, then the reactions of 2-bromofuran
(51) Penalva, V.; Hassan, J .; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 1998, 39, 2559.
(52) Albanese, D.; Landini, D.; Penso, M.; Petricci, S. Synlett 1999,
2, 199.
(53) Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett. 1999, 1
(8), 1205.
(48) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119, 8232.
(49) Alcazar-Roman, L. M.; Hartwig, J . F.; Rheingold, A. L.; Liable-
Sands, L. M.; Guzei, L. A. J . Am. Chem. Soc. 2000, 122, 4618.
(50) Fitton, P.; Rick, E. A. J . Organomet. Chem. 1971, 28, 287.
(54) Xie, Y.; Wu, B.-M.; Xue, F.; Ng, S.-C.; Mak, T. C. W.; Hor, T. S.
A. Organometallics 1998, 17, 3988.
(55) Xie, Y.; Tan, G. K.; Yan, Y. K.; Vittal, J . J .; Ng, S.-C.; Hor, T.
S. A. J . Chem. Soc., Dalton Trans. 1999, 5, 773.
J . Org. Chem, Vol. 68, No. 7, 2003 2867

Hooper et al.
SCHEME 2
complexes to form dihalo- and diarylpalladium com-
plexes,56 the latter of which forms biaryl by reductive
elimination.55
Id en tifyin g th e Restin g Sta te a n d Active Ca ta -
lyst. Identification of the true catalyst for the amination
of these five-membered, heteroaryl halides was difficult.
Monitoring by NMR of reactions that formed coupled
product showed that Pd(PtBu3)2 was the major phosphorus-
containing species. Yet Pd(PtBu3)2 was also the major
phosphorus-containing species in reactions that did not
consume the heteroaryl halide or amine. Consistent with
this observation, Pd(PtBu3)2 was present in similar
concentrations before and after poisoning of the reactions
of N-methylaniline by addition of hexylamine. Thus, the
lack of reactivity of some amines toward the heteroaryl
bromides cannot be explained by precipitation of pal-
ladium or conversion of Pd(PtBu3)2 to a species that is
silent by 31P NMR spectroscopy. These results show that
Pd(PtBu3)2 is unlikely to lie directly on the catalytic cycle
or even to exist in dynamic equilibrium with the Pd(0)
species that does lie on the catalytic cycle. However,
several lines of evidence indicate that the reaction is
catalyzed by phosphine-ligated palladium: the product
distributions were affected by the identity of the ligand,
and systems with palladium but without added ligand
did not generate any coupled product.
to add the heteroaryl halide. The mechanism for genera-
tion of the Pd(PtBu3) from the Pd(I) dimer is unclear,
however.
The amount of the active catalyst also appears to be
influenced by the identity of the amine. The large
variation in rate for reactions of different amines with
the same heteroaryl halide indicates that the amine is
involved directly in the turnover-limiting step or that the
identity of the amine affects the concentration of the
palladium complex that lies on the catalytic cycle. We
suggest that the identity of the amine influences the
amount of active catalyst and that the amine does not
participate in the rate-determining step. Monitoring
under pseudo-first-order conditions the reactions that
occurred in good yield suggested that the reaction was
zero-order in amine. Moreover, reactions of an amine that
formed coupled product in good yield were poisoned by
addition of an amine that formed coupled product in low
yield.
The amount of active catalyst also appears to be
influenced by the concentration of base. The apparent
negative order of reaction in the presence of base implies
that high concentrations of base lead to low concentra-
tions of the active catalyst. Conversion of the active
catalyst to the inactive catalyst could not be observed
upon addition of the alkylamines or the base because the
active species is present in low concentration. However,
the presence of alkoxide base did accelerate the conver-
sion of PtBu3 and several catalyst precursors to Pd(Pt-
Bu3)2, which does not catalyze amination of these het-
eroaryl halides at these reaction temperatures. Reaction
of the heteroaryl halide with the combination of Pd(dba)2
and PtBu3 in the presence of NaOtBu rapidly generated
Pd(PtBu3)2. Reaction of the Pd(I) dimer with NaOtBu
formed Pd(PtBu3)2, and reaction of the Pd(I) dimer with
the combination of NaOtBu and amine formed Pd(PtBu3)2
even faster.
Previous results suggest that the palladium(0) complex
Pd(PtBu3)2 adds aryl halides fast enough and with
favorable enough thermodynamics to initiate aryl halide
amination.47,57,58 Yet, the oxidative addition of aryl ha-
lides to Pd(PtBu3)2 is thermodynamically unfavorable in
some cases59 and forms unusual three-coordinate mono-
phosphine complexes.58 The thermodynamics for addition
of the electron-rich heteroaryl halides may be even more
unfavorable. Thus, the unfavorable thermodynamics for
reaction of heteroaryl halides with Pd(PtBu3)2 to form a
monophosphine heteroarylpalladium complex may make
the addition too slow or the population of arylpalladium
halide complex too small to allow subsequent formation
of an arylpalladium amide complex and reductive elimi-
nation to form amine.
Thus, we suggest that the efficiency at which the
monoligated Pd(0) fragment Pd(PtBu3) is formed from the
combination of palladium catalyst precursor and PtBu3
controls the rates of the amination of five-membered
heteroaryl halides. Generation of this fragment from Pd-
(dba)2 and PtBu3 or from the Pd(I) dimer most likely
creates higher concentrations of this intermediate than
does ligand dissociation from Pd(PtBu3)2. The slow gen-
eration of Pd(PtBu3)2 from Pd(dba)2 and PtBu3 in toluene
solvent may allow for continuous generation of Pd(dba)-
(PtBu3), which could add heteroaryl halide faster than it
undergoes disproportionation to Pd(PtBu3)2 and Pd(dba)2.
The Pd(I) dimer should generate the catalyst efficiently
because it contains the same 1:1 ratio of ligand to
palladium that is present in the complex that is proposed
Our conclusions on the reaction mechanism are sum-
marized in Scheme 2. This mechanism parallels one of
the two mechanisms for coupling of aryl chlorides with
amines catalyzed by palladium complexes of PtBu3.47
However, the studies reported here suggest that efficient
generation of the Pd(PtBu3) intermediate is crucial to
observing amination with less reactive substrates, such
as bromothiophenes and bromofurans. It is clear that Pd-
(PtBu3)2 cannot initiate most of the couplings of the
heteroaryl bromides, and we suggest that unfavorable
(56) Ozawa, F.; Fujimori, M.; Yamamoto, T.; Yamamoto, A. Orga-
nometallics 1986, 5, 2144.
(57) Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2001, 123, 2719.
(58) Stambuli, J . P.; Bu¨hl, M.; Hartwig, J . F. J . Am Chem. Soc. 2002,
124, 9346.
(59) Roy, A. H.; Hartwig, J . F. J . Am. Chem. Soc. 2001, 123, 1232.
2868 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and purified by flash chromatography. Naph-
thalene or trimethoxybenzene were used as internal standards
when obtaining yields by GC.
Meth od B: In a drybox, aryl halide (1.0 mmol), NaOtBu or
K3PO4 (1.10 mmol), and amine (1.0-4.0 mmol) were added to
a suspension of Pd(dba)2 (0.02-0.05 mmol) or Pd(O2CCF3)2 and
PtBu3 (0.02-0.05 mmol) in 1.0-2.0 mL of toluene in a screw
capped vial. A small stirbar was added, and the vial was sealed
with a cap containing a PTFE septum. The mixture was
allowed to stir at room temperature in the drybox or at
elevated temperature outside of the drybox. After the reaction,
the mixture was adsorbed onto neutral alumina and purified
by flash chromatography. Dodecane was used as internal
standard when yields were determined by GC.
thermodynamics for ligand dissociation and oxidative
addition to Pd(PtBu3)2 makes the addition unfavorable
enough to prevent formation of the amido complex.
Instead, mixing of Pd(dba)2 and PtBu3 may feed the
system higher concentrations of Pd(PtBu3)(dba) and
Pd(PtBu3) than would be generated from full equilibration
of Pd(dba)2 and Pd(PtBu3)2 or from dissociation of ligand
from Pd(PtBu3)2. Consistent with the assertion that a 1:1
stoichiometry of ligand and metal is present in the active
catalyst, the palladium(I) dimer [Pd(Br)(PtBu3)]2 serves
as one of the most active precatalysts.
Con clu sion
Palladium-catalyzed amination has been shown to
proceed with a range of electron-rich heteroaromatic
bromides and chlorides with certain classes of amines.
The reactivity of heteroaryl bromides in palladium-
catalyzed amination appears to be controlled by several
factors. First, the concentration of catalyst that can add
the electron-rich, five-membered heteroaryl halides ap-
pears to be lower than the concentration of catalyst that
can add aryl halides. The concentration of this complex
that adds heteroaryl halides is apparently depleted in
the presence of alkylamines, aniline, or excess base.
Second, the scope of the catalytic reactions is controlled
not only by the concentration of the active catalyst, but
by the ability of the intermediate heteroarylpalladium
amides to undergo reductive elimination. The yields of
heteroarylamine formed during a study of reductive
elimination from DPPF-ligated complexes46 paralleled
closely the yields of heteroarylamine formed from reac-
tions catalyzed by complexes of palladium and PtBu3.
2-(N-Meth yl-N-p h en yla m in o)fu r a n (Ta ble 1, en tr y 1).
Method A of the above general procedure was followed with
2-bromofuran (368 mg, 221 µL, 2.5 mmol), 1.0 equiv of
N-methylaniline (268 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265
mg, 2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at room
temperature, the mixture was poured into pentane (15 mL),
filtered, and concentrated in vacuo. The crude product was
adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 242 mg (56%) of 2-(N-methyl-N-
phenylamino)furan as a colorless oil: 1H NMR (500 MHz,
C6D6) δ 7.23 (dd, J ) 7.3, 8.6 Hz, 2H), 7.00 (m, 1H), 6.94 (m,
3H), 6.21 (m, 1H), 5.74 (m, 1H), 2.99 (s, 3H); 13C{1H} NMR
(126 MHz, C6D6) δ 155.62, 148.38, 137.68, 129.60, 120.73,
116.58, 111.54, 97.67, 38.92; MS (EI) 173 (M+), 144, 130, 104,
77, 51. Anal. Calcd for C11H11NO: C, 76.30; H, 6.36; N, 8.09.
Found: C, 76.17; H, 6.35; N, 8.18.
3-(N-Meth yl-N-p h en yla m in o)fu r a n (Ta ble 1, en tr y 2).
Method A of the above general procedure was followed with
3-bromofuran (368 mg, 225 µL, 2.5 mmol), 1.0 equiv of
N-methylaniline (268 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265
mg, 2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at room
temperature, the mixture was poured into pentane (15 mL),
filtered, and concentrated in vacuo. The crude product was
adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 367 mg (85%) of 3-(N-methyl-N-
phenylamino)furan as a colorless oil: 1H NMR (500 MHz,
C6D6) δ 7.25 (dd, J ) 7.3, 8.7 Hz, 2H), 7.14 (m, 1H), 7.08 (m,
1H), 7.04 (m, 1H), 7.03 (m, 1H), 6.93 (m, 1H), 6.20 (m, 1H),
2.89 (s, 3H); 13C{1H} NMR (126 MHz, CD2Cl2) δ 149.67, 143.05,
137.00, 132.76, 129.67, 120.70, 118.15, 108.00, 40.87; MS (EI)
173 (M+), 144, 130, 77, 51. Anal. Calcd for C11H11NO: C, 76.30;
H, 6.36; N, 8.09. Found: C, 76.07; H, 6.60; N, 8.18.
2-(N-Meth yl-N-p h en yla m in o)th iop h en e (Ta ble 1, en tr y
3). Method A of the above general procedure was followed with
2-bromothiophene (408 mg, 244 µL, 2.5 mmol), 1.0 equiv of
N-methylaniline (268 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265
mg, 2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at room
temperature, the mixture was poured into pentane (15 mL),
filtered, and concentrated in vacuo. The crude product was
adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 387 mg (82%) of 2-(N-methyl-N-
phenylamino)thiophene as a colorless oil: 1H NMR (500 MHz,
C6D6) δ 7.22 (dd, J ) 7.4, 8.7 Hz, 2H), 6.99 (m, 2H), 6.92 (m,
1H), 6.73 (m, 1H), 6.70 (m, 1H), 6.57 (m, 1H), 3.02 (s, 3H);
13C{1H} NMR (126 MHz, CD2Cl2) δ 154.52, 150.13, 129.61,
127.24, 126.30, 120.69, 119.45, 117.12, 42.18; MS (EI) 189 (M+),
173, 147, 130, 77, 51. Anal. Calcd for C11H11NS: C, 69.84; H,
5.82; N, 7.41; S, 16.93. Found: C, 70.08; H, 5.84; N, 7.66; S,
16.98.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reactions
and manipulations were performed in an inert atmosphere
glovebox. All 31P{1H} NMR chemical shifts are reported in
parts per million relative to an 85% H3PO4 external standard.
Shifts downfield of the standard are reported as positive.
Benzene, toluene, and pentane solvents were distilled from
sodium/benzophenone prior to use. 3-Bromofuran was distilled
prior to use. 2-Bromofuran,60 2-bromo-5-methylfuran,60 2-bromo-
5-methylthiophene,60 2-bromo-N-methylindole61 3-bromo-N-
methylindole,62 2-chloro-N-methylbenzimidazole,63 and ferro-
cenyldi-tert-butylphosphine64 were all prepared according to
literature procedures. All other chemicals were used as
received from commercial suppliers.
Gen er a l P r oced u r e for Ca ta lytic Am in a tion of Het-
er oa r om a tic Ha lid es. Meth od A: In a drybox, aryl bromide
(0.5-2.5 mmol), amine (0.5-2.5 mmol), and NaOtBu (0.55-
2.75 mmol) were weighed directly into a screw capped vial. A
stir bar and 0.5-2.5 mL of toluene were added. Pd(dba)2 (2
mol %, 0.01-0.05 mmol) and PtBu3 (2 mol %, 0.01-0.05 mmol)
were weighed directly into a small vial and suspended in 0.5-
2.5 mL of toluene. The catalyst suspension was then added to
the reactants to give a purple mixture. The mixture was
allowed to stir for 16 h at room temperature in the drybox or
at 100 °C for 16 h outside the drybox. After this time, the
(60) Keegstra, M. A.; Klomp, A. J . A.; Brandsma, L. Synth. Commun.
1990, 20, 3371.
(61) Fukuda, T.; Maeda, R.; Iwao, M. Tetrahedron 1999, 55, 9151.
(62) Bocchi, V.; Palla, G. Synlett 1982, 1096.
(63) Iemura, R.; Kawashima, T.; Fukuda, T.; Ito, K.; Tsukamoto,
G. J . Med. Chem. 1986, 29, 1178.
3-(N-Meth yl-N-p h en yla m in o)th iop h en e (Ta ble 1, en tr y
4). Method A of the above general procedure was followed with
3-bromothiophene (408 mg, 234 µL, 2.5 mmol), 1.0 equiv of
N-methylaniline (268 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265
(64) Kataoka, N.; Shelby, Q.; Stambuli, J . P.; Hartwig, J . F. J . Org.
Chem. 2002, 67, 5553.
J . Org. Chem, Vol. 68, No. 7, 2003 2869

Hooper et al.
mg, 2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at room
temperature, the mixture was poured into pentane (15 mL),
filtered, and concentrated in vacuo. The crude product was
adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 439 mg (93%) of 3-(N-methyl-N-
phenylamino)thiophene as a colorless oil: 1H NMR (500 MHz,
C6D6) δ 7.12 (m, 2H), 6.92 (m, 2H), 6.84 (t, J ) 8.4 Hz, 1H),
6.79 (dd, J ) 3.2 Hz, 5.2 Hz, 1H), 6.70 (dd, J ) 1.5, 5.2 Hz,
1H), 6.24 (dd, J ) 1.5, 3.1 Hz, 1H), 2.87 (s, 3H); 13C{1H} NMR
(126 MHz, CD2Cl2) δ 150.15, 149.14, 129.69, 125.39, 123.85,
121.46, 119.69, 108.35, 41.13; MS (EI): 189 (M+), 173, 156,
144, 130, 77, 51. Anal. Calcd for C11H11NS: C, 69.84; H, 5.82;
N, 7.41; S, 16.93. Found: C, 70.10; H, 5.89; N, 7.58; S, 16.90.
to give 601 mg (97%) of 3-(diphenylamino)thiophene as a white
solid: 1H NMR (500 MHz, CDCl3) δ 7.19-7.15 (m, 5H), 7.03
(d, J ) 8.6 Hz, 4H), 6.93 (t, J ) 7.3 Hz, 2H), 6.81 (dd, J ) 1.4,
5.2 Hz, 1H), 6.59 (dd, J ) 3.7, 5.6 Hz, 1H); 13C{1H} NMR (126
MHz, CDCl3) δ 148.24, 146.96, 129.54, 125.54, 125.28, 123.50,
123.02, 113.26; MS (EI) 251 (M+), 217, 174, 77, 51. Anal. Calcd
for C16H13NS: C, 76.49; H, 5.18; N, 5.58; S, 12.75. Found: C,
76.59; H, 5.09; N, 5.59; S, 12.75.
3-(N-P h en ylam in o)th ioph en e (Table 1, en tr y 9). Method
A of the above general procedure was followed with 3-bro-
mothiophene (408 mg, 234 µL, 2.5 mmol), 1.0 equiv of aniline
(233 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265 mg, 2.8 mmol),
2 mol % of Pd(dba)2, and 2 mol % of tri-tert-butylphosphine in
5 mL of toluene. After 16 h at 100 °C, the mixture was poured
into pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 386 mg (88%) of 3-(N-
phenylamino)thiophene as a colorless oil: 1H NMR (400 MHz,
C6D6) δ 7.12 (m, 2H), 6.80 (m, 2H), 6.75 (m, 1H), 6.74 (m, 1H),
6.54 (dd, J ) 1.5, 5.1 Hz, 1H), 6.34 (dd, J ) 1.5, 4.3 Hz, 1H),
4.92 (br s, 1H); 13C{1H} NMR (101 MHz, C6D6) δ 145.42,
142.20, 129.92, 125.41, 123.44, 120.41, 116.27, 106.88; MS (EI)
175 (M+), 130, 77, 51. Anal. Calcd for C10H9NS: C, 68.55; H,
5.18; N, 8.00. Found: C, 68.99; H, 5.40; N, 7.72.
2-(Dip h en yla m in o)fu r a n (Ta ble 1, en tr y 5). Method A
of the above general procedure was followed with 2-bromofuran
(368 mg, 221 µL, 2.5 mmol), 1.0 equiv of diphenylamine (423
mg, 2.5 mmol), 1.1 equiv of NaOtBu (265 mg, 2.8 mmol), 2 mol
% of Pd(dba)2, and 2 mol % of tri-tert-butylphosphine in 5 mL
of toluene. After 16 h at 100 °C, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 300 mg (51%) of
1
2-(diphenylamino)furan as a white solid: H NMR (400 MHz,
3-(Mor p h olin o)th iop h en e65 (Ta ble 1, en tr y 10). Method
B of the above general procedure was followed with 3-bro-
mothiophene (162 mg, 1.0 mmol), 1.0 equiv of morpholine (87.2
µL, 1.0 mmol), 1.1 equiv of NaOtBu (106 mg, 1.1 mmol), 2 mol
% of Pd(dba)2, and 2 mol % of tri-tert-butylphosphine in 1 mL
of xylene. After 24 h at 120 °C, the mixture was adsorbed onto
neutral alumina and eluted with 10% ethyl acetate in hexanes
to give 134 mg (80%) of 3-(morpholino)thiophene as a solid:
1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J ) 5.4, 3.1 Hz, 1H),
6.85 (dd, J ) 5.2, 1.3 Hz, 1H), 6.19 (dd, J ) 3.0, 1.6 Hz, 1H),
3.84 (t, J ) 4.8 Hz, 4H), 3.08 (t, J ) 4.8 Hz, 4H); 13C{1H} NMR
(101 MHz, CDCl3) δ 152.4, 125.5, 119.6, 100.4, 66.6, 50.7.
3-(4-P h en ylp ip er a zin o)th iop h en e (Ta ble 1, en tr y 11).
Method B of the above general procedure was followed with
3-bromothiophene (163 mg, 1.0 mmol), 1.0 equiv of N-phen-
ylpiperazine (153 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106 mg,
1.1 mmol), 5 mol % of Pd(dba)2, and 5 mol % of tri-tert-
butylphosphine in 1 mL of xylene. After 24 h at 120 °C, the
mixture was adsorbed onto neutral alumina and eluted with
10% ethyl acetate in hexanes to give 103 mg (42%) of 3-(4-
phenylpiperazino)thiophene as a solid: 1H NMR (400 MHz,
CDCl3) δ 7.9 (m, 3H), 6.99 (dd, J ) 7.8, 0.9 Hz, 2H), 6.90 (m,
2H), 6.26 (dd, J ) 3.1, 1.7 Hz, 1H), 3.33 (m, 4H), 3.25 (m, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ 152.2, 151.2, 129.2, 125.5,
C6D6) δ 709-7.01 (m, 8H), 6.86 (m, 1H), 6.84 (m, 1H), 6.81
(m, 1H), 6.05 (dd, J ) 3.3, 2.1 Hz, 1H), 5.76 (dd, J ) 3.2, 1.0
Hz, 1H); 13C{1H} NMR (101 MHz, C6D6) δ 153.76, 146.99,
138.70, 129.88, 123.61, 122.66, 111.82, 101.48; MS (EI) 235
(M+), 206, 77, 51. Anal. Calcd for C16H13NO: C, 81.70; H, 5.53;
N, 5.96. Found: C, 81.44; H, 5.53; N, 5.88.
3-(Dip h en yla m in o)fu r a n (Ta ble 1, en tr y 6). Method A
of the above general procedure was followed with 3-bromofuran
(368 mg, 225 µL, 2.5 mmol), 1.0 equiv of diphenylamine (432
mg, 2.5 mmol), 1.1 equiv of NaOtBu (265 mg, 2.8 mmol), 2 mol
% of Pd(dba)2, and 2 mol % of tri-tert-butylphosphine in 5 mL
of toluene. After 16 h at 100 °C, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 324 mg (55%) of
3-(diphenylamino)furan as a white solid: 1H NMR (400 MHz,
CDCl3) δ 7.28 (t, J ) 1.7 Hz, 1H), 7.19-7.15 (m, 5H), 7.04 (m,
4H), 6.92 (t, J ) 7.3 Hz, 2H), 6.25 (m, 1H); 13C{1H} NMR (126
MHz, C6D6) δ 148.41, 143.24, 136.12, 135.51, 129.86, 123.26,
123.12, 109.49; MS (EI) 235 (M+), 206, 128, 77, 51. Anal. Calcd
for C16H13NO: C, 81.70; H, 5.53; N, 5.96. Found: C, 81.48; H,
5.68; N, 5.85.
2-(Diph en ylam in o)th ioph en e (Table 1, en tr y 7). Method
A of the above general procedure was followed with 2-bro-
mothiophene (408 mg, 244 µL, 2.5 mmol), 1.0 equiv of diphen-
ylamine (432 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265 mg,
2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at 100 °C, the
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 370 mg (63%) of 2-(diphenylamino)thiophene as a white
solid: 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J ) 5.6 Hz, 2H),
7.17 (d, J ) 8.4 Hz, 2H), 7.05 (d, J ) 7.7 Hz, 4H), 6.94 (m,
3H), 6.81 (dd, J ) 3.7, 5.6 Hz, 1H), 6.65 (m, 1H); 13C{1H} NMR
(126 MHz, CDCl3) δ 151.85, 148.40, 129.50, 126.26, 123.15,
122.71, 121.92, 121.21; MS (EI) 251 (M+), 173, 147, 115, 77,
51. Anal. Calcd for C16H13NS: C, 76.49; H, 5.18; N, 5.58; S,
12.75. Found: C, 76.58; H, 5.38; N, 5.58; S, 12.77.
120.1, 116.4, 100.9, 90.7, 50.6, 49.2. Anal. Calcd for C14H16
-
N2S: C, 68.81; H, 6.60; N, 11.46. Found: C, 68.63; H, 6.56; N,
11.19.
3-(N-Meth yl-N-p h en yla m in o)th ion a p h th en e66 (Ta ble 1,
en tr y 12). Method B of the above general procedure was
followed with 3-bromothionaphthene (213 mg, 1.0 mmol), 1.0
equiv of N-methylaniline (108 µL, 1.0 mmol), 1.1 equiv of
NaOtBu (106 mg, 1.1 mmol), 5 mol % of Pd(dba)2, and 5 mol
% of tri-tert-butylphosphine in 2 mL of toluene. After 20 h at
room temperature in a drybox, the mixture was adsorbed onto
neutral alumina and eluted with 2% ethyl acetate in hexanes
to give 206 mg (86%) of 3-(N-methyl-N-phenylamino)thio-
naphthene as an oil: 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J
) 8.2 Hz, 1H), 7.40 (d, J ) 8.2 Hz, 2H), 7.32 (dt, J ) 7.6, 1.5
Hz, 1H), 7.20 (m, 3H), 7.11 (s, 1H), 6.81 (t, J ) 7.3 Hz, 1H),
6.76 (dd, J ) 8.5, 1.0 Hz, 2H), 3.38 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 149.1, 141.9, 139.0, 135.2, 128.9, 124.6, 123.9,
123.2, 122.4, 118.8, 117.7, 115.5, 40.7.
3-(Diph en ylam in o)th ioph en e (Table 1, en tr y 8). Method
A of the above general procedure was followed with 3-bro-
mothiophene (408 mg, 234 µL, 2.5 mmol), 1.0 equiv of diphen-
ylamine (432 mg, 2.5 mmol), 1.1 equiv of NaOtBu (265 mg,
2.8 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 5 mL of toluene. After 16 h at 100 °C, the
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
2-(N-Meth yl-N-p h en yla m in o)th iop h en e (Ta ble 1, en tr y
13). Method B of the above general procedure was followed
(65) Scheithauer, S.; Hartmann, H.; Mayer, R. Z. Chem. 1968, 8,
181.
(66) Zyl, G. V.; J ongh, D. C. D.; Heasley, V. L.; Dyke, J . W. V. J .
Org. Chem. 1961, 26, 4946.
2870 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
with 2-chlorothiophene (118 mg, 1.0 mmol), 1.0 equiv of
N-methylaniline (108 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106
mg, 1.1 mmol), 5 mol % of Pd(dba)2, and 5 mol % of tri-tert-
butylphosphine in 1 mL of xylene. After 24 h at 120 °C, the
mixture was adsorbed onto neutral alumina and eluted with
2% ethyl acetate in hexanes to give 97.8 mg (52%) of 2-(N-
methyl-N-phenylamino)thiophene as an oil.
3-(N-Meth yl-N-p h en yla m in o)th iop h en e (Ta ble 1, en tr y
14). Method B of the above general procedure was followed
with 3-chlorothiophene (118 mg, 1.0 mmol), 1.0 equiv of
N-methylaniline (108 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106
mg, 1.1 mmol), 5 mol % of Pd(dba)2, and 5 mol % of tri-tert-
butylphosphine in 1 mL of xylene. After 24 h at 120 °C, the
mixture was adsorbed onto neutral alumina and eluted with
2% ethyl acetate in hexanes to give 90.5 mg (48%) of 3-(N-
methyl-N-phenylamino)thiophene as an oil.
3-(Mor p h olin o)th iop h en e65 (Ta ble 1, en tr y 15). Method
B of the above general procedure was followed with 3-chlo-
rothiophene (119 mg, 1.0 mmol), morpholine (87.2 µL, 1.0
mmol), 1.1 equiv of NaOtBu (106 mg, 1.1 mmol), 5 mol % of
Pd(dba)2, and 5 mol % of tri-tert-butylphosphine in 1 mL of
xylene. After 30 h at 120 °C, the mixture was adsorbed onto
neutral alumina and eluted with 20% ethyl acetate in hexanes
to give 72.4 mg (43%) of 3-(morpholino)thiophene as a solid.
2-(N-Meth yl-N-p h en yla m in o)-5-m eth ylfu r a n (Ta ble 2,
en tr y 1). Method A of the above general procedure was
followed with 2-bromo-5-methylfuran (161 mg, 101 µL, 1.0
mmol), 1.0 equiv of N-methylaniline (107 mg, 1.0 mmol), 1.1
equiv of NaOtBu (106 mg, 1.1 mmol), 2 mol % of Pd(dba)2, and
2 mol % of tri-tert-butylphosphine in 2 mL of toluene. After
16 h at room temperature, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 56 mg (30%) of 2-(N-
methyl-N-phenylamino)-5-methylfuran as a colorless oil: 1H
NMR (400 MHz, C6D6) δ 7.15 (m, 2H), 6.76 (m, 3H), 5.87 (m,
1H), 5.70 (d, J ) 3.0 Hz, 1H), 3.17 (s, 3H), 2.18 (s, 3H); 13C-
{1H} NMR (101 MHz, CDCl3) δ 152.92, 148.34, 147.64, 129.31,
119.69, 115.13, 106.71, 100.13, 39.45, 14.17; MS (EI) 187 (M+),
172, 144, 77, 51. Anal. Calcd for C12H13NO: C, 76.96; H, 7.00;
N, 7.48. Found: C, 76.73; H, 6.88; N, 7.72.
2-(Dip h en yla m in o)-5-m eth ylfu r a n (Ta ble 2, en tr y 2).
Method A of the above general procedure was followed with
5-methyl-2-bromofuran (81 mg, 51 µL, 0.5 mmol), 1.0 equiv of
diphenylamine (85 mg, 0.5 mmol), 1.1 equiv of NaOtBu (53
mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 1 mL of toluene. After 16 h at 100 °C, the
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 102 mg (82%) of 2-(diphenylamino)-5-methylfuran as
a white solid: 1H NMR (400 MHz, C6D6) δ 7.15 (m, 4H), 7.05
(m, 4H), 6.83 (t, J ) 7.3 Hz, 2H), 5.79 (d, J ) 3.1 Hz, 1H),
5.75 (m, 1H), 1.91 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ
151.74, 148.70, 147.30, 129.86, 123.37, 122.41, 107.56, 103.51,
13.99; MS (EI) 249 (M+), 206, 172, 103, 77, 51. Anal. Calcd for
C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C, 81.76; H, 6.21;
N, 5.54.
2-(N-Meth yl-N-ph en ylam in o)-5-m eth ylth ioph en e (Table
2, en t r y 3). Method A of the above general procedure was
followed with 2-bromo-5-methylthiophene (177 mg, 111 µL, 1.0
mmol), 1.0 equiv of N-methylaniline (107 mg, 1.0 mmol), 1.1
equiv of NaOtBu (106 mg, 1.1 mmol), 2 mol % of Pd(dba)2, and
2 mol % of tri-tert-butylphosphine in 2 mL of toluene. After
16 h at room temperature, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 106 mg (52%) of 2-(N-
methyl-N-phenylamino)-5-methylthiophene as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J ) 7.3, 8.8 Hz, 2H),
6.81 (m, 2H), 6.76 (t, J ) 7.3 Hz, 1H), 6.47 (m, 1H), 6.43 (d, J
) 3.6 Hz, 1H), 3.21 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 150.90, 149.82, 135.55, 129.25, 123.55, 121.13,
119.47, 115.48, 42.19, 16.34; MS (EI) 203 (M+), 188, 173, 155,
77, 51. Anal. Calcd for C12H13NS: C, 70.90; H, 6.45; N, 6.89;
S, 15.58. Found: C, 71.14; H, 6.57; N, 6.90; S, 15.58.
2-(Dip h en yla m in o)-5-m eth ylth iop h en e (Ta ble 2, en tr y
4). Method A of the above general procedure was followed with
5-methyl-2-bromothiophene (89 mg, 55 µL, 0.5 mmol), 1.0
equiv of diphenylamine (85 mg, 0.5 mmol), 1.1 equiv of NaOt-
Bu (53 mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of
tri-tert-butylphosphine in 1 mL of toluene. After 16 h at 100
°C, the mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 101 mg (76%) of 2-(diphenylamino)-5-methylthiophene
as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.17 (m, 4H),
7.04 (m, 4H), 6.92 (t, J ) 8.1 Hz, 2H), 6.47 (m, 2H), 2.35 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.69, 148.34, 136.36,
129.44, 123.88, 123.00, 122.83, 122.31, 16.37; MS (EI) 265 (M+),
97, 77, 51. Anal. Calcd for C17H15NS: C, 76.94; H, 5.70; N,
5.28. Found: C, 76.93; H, 5.51; N, 5.21.
2-(N-Meth yl-N-ph en ylam in o)-3-m eth ylth ioph en e (Table
2, en t r y 5). Method A of the above general procedure was
followed with 2-bromo-3-methylthiophene (177 mg, 108 µL, 1.0
mmol), 1.0 equiv of N-methylaniline (107 mg, 1.0 mmol), 1.1
equiv of NaOtBu (106 mg, 1.1 mmol), 2 mol % of Pd(dba)2,
and 2 mol % of tri-tert-butylphosphine in 2 mL of toluene. After
16 h at room temperature, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 12 mg (6%) of 2-(N-
methyl-N-phenylamino)-3-methylthiophene as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J ) 7.3 Hz, 8.8 Hz,
2H), 7.09 (d, J ) 5.7 Hz, 1H), 6.84 (d, J ) 5.7 Hz, 1H), 6.81 (t,
J ) 7.3 Hz, 1H), 6.71 (m, 2H), 3.29 (s, 3H), 2.04 (s, 3H); 13C-
{1H} NMR (CDCl3, 101 MHz) δ 147.93, 127.90, 127.36, 126.85,
124.79, 120.48, 116.94, 112.26, 39.36, 11.85; MS (EI) 203 (M+),
188, 173, 154, 77, 51. The low yield of this reaction prevented
our obtaining samples that were analytically pure.
2-(Dip h en yla m in o)-3-m eth ylth iop h en e (Ta ble 2, en tr y
6). Method A of the above general procedure was followed with
3-methyl-2-bromothiophene (89 mg, 54 µL, 0.5 mmol), 1.0
equiv of diphenylamine (85 mg, 0.5 mmol), 1.1 equiv of NaOt-
Bu (53 mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of
tri-tert-butylphosphine in 1 mL of toluene. After 16 h at 100
°C, the mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 66 mg (50%) of 2-(diphenylamino)-3-methylthiophene
as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.17 (m, 4H),
6.98 (m, 5H), 6.90 (t, J ) 7.3 Hz, 2H), 6.42 (d, J ) 5.6 Hz,
1H), 1.88 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.54,
144.03, 133.07, 129.42, 129.12, 122.49, 122.18, 121.63, 13.51;
MS (EI) 265 (M+), 186, 173, 77, 51. Anal. Calcd for C17H15NS:
C, 76.94; H, 5.70; N, 5.28. Found: C, 76.66; H, 5.74; N, 4.99.
3-(N-Meth yl-N-ph en ylam in o)-4-m eth ylth ioph en e (Table
2, en t r y 7). Method A of the above general procedure was
followed with 3-bromo-4-methylthiophene (177 mg, 112 µL, 1.0
mmol), 1.0 equiv of N-methylaniline (107 mg, 1.0 mmol), 1.1
equiv of NaOtBu (106 mg, 1.1 mmol), 2 mol % of Pd(dba)2, and
2 mol % of tri-tert-butylphosphine in 2 mL of toluene. After
16 h at room temperature, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The
crude product was adsorbed onto neutral alumina and eluted
with 5% diethyl ether in hexanes to give 112 mg (55%) of 3-(N-
methyl-N-phenylamino)-4-methylthiophene as a colorless oil:
1H NMR (500 MHz, CDCl3) δ 7.20 (m, 2H), 6.99 (m, 2H), 6.71
(m, 1H), 6.66 (m, 1H), 6.64 (m, 1H), 3.26 (s, 3H’), 1.96 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.73, 147.32, 136.16,
129.34, 121.63, 118.50, 118.13, 114.34, 40.49, 14.17; MS (EI)
203 (M+), 203, 188, 170, 77, 51.
2-(N′-Meth yl-N′-p h en yla m in o)-N-m eth ylin d ole (Ta ble
2, en t r y 8). Method A of the above general procedure was
J . Org. Chem, Vol. 68, No. 7, 2003 2871

Hooper et al.
followed with 2-bromo-N-methylindole (210 mg, 1.0 mmol), 1.0
equiv of N-methylaniline (107 mg, 1.0 mmol), 1.1 equiv of
NaOtBu (106 mg, 1.1 mmol), 2 mol % of Pd(dba)2, and 2 mol
% of tri-tert-butylphosphine in 2 mL of toluene. After 16 h at
room temperature, the mixture was poured into pentane (15
mL), filtered, and concentrated in vacuo. The crude product
was adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 185 mg (78%) of 2-(N-methyl-N-
phenylamino)-N-methylindole as a white solid: 1H NMR (400
MHz, C6D6) δ 7.51 (d, J ) 7.8 Hz, 1H), 7.21 (d, J ) 8.1 Hz,
1H), 7.14 (m, 3H), 7.05 (m, 1H), 6.76 (m, 1H), 6.62 (d, J ) 8.8
Hz, 2H), 6.20 (s, 1H), 3.38 (s, 3H), 3.30 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3) δ 149.15, 144.04, 134.97, 129.35, 127.39,
121.42, 120.52, 119.88, 119.24, 114.73, 109.45, 94.69, 40.78,
29.11; MS (EI) 236 (M+), 221, 118, 77, 51. Anal. Calcd for
C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found: C, 81.31; H,
6.85; N, 11.69.
2-(N′,N′-Dip h en yla m in o)-N-m eth ylin d ole (Ta ble 2, en -
tr y 9). Method A of the above general procedure was followed
with 2-bromo-N-methylindole (105 mg, 0.5 mmol), 1.0 equiv
of diphenylamine (85 mg, 0.5 mmol), 1.1 equiv of NaOtBu (53
mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 1 mL of toluene. After 16 h at 100 °C, the
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 121 mg (81%) of 2-(N′,N′-diphenylamino)-N-methylin-
dole as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J
) 7.8 Hz, 1H), 7.21-7.13 (m, 5H), 7.03 (t, J ) 8.0 Hz, 2H),
6.97 (d, J ) 7.7 Hz, 4H), 6.92 (t, J ) 7.3 Hz, 2H), 6.16 (s, 1H),
3.37 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.17, 142.46,
135.22, 129.56, 127.85, 122.95, 121.96, 121.61, 120.69, 120.13,
109.58, 97.35, 29.61; MS (EI) 298 (M+), 282, 221, 206, 131,
91, 77, 51. Anal. Calcd for C21H18N2: C, 84.53; H, 6.08; N, 9.39.
Found: C, 84.36; H, 6.08; N, 9.33.
3-(N′-Meth yl-N′-p h en yla m in o)-N-m eth ylin d ole (Ta ble
2, en tr y 10). Method A of the above general procedure was
followed with 3-bromo-N-methylindole (105 mg, 0.5 mmol), 1.0
equiv of N-methylaniline (54 mg, 0.5 mmol), 1.1 equiv of NaOt-
Bu (53 mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of
tri-tert-butylphosphine in 1 mL of toluene. After 16 h at room
temperature, the mixture was poured into pentane (15 mL),
filtered, and concentrated in vacuo. The crude product was
adsorbed onto neutral alumina and eluted with 5% diethyl
ether in hexanes to give 97 mg (82%) of 3-(N-methyl-N-
phenylamino)-N-methylindole as a white solid: 1H NMR (400
MHz, C6D6) δ 7.26 (m, 2H), 7.16 (m, 1H), 7.08 (t, J ) 8.4 Hz,
2H), 6.97 (t, J ) 7.3 Hz, 1H), 6.91 (s, 1H), 6.69 (d, J ) 8.1 Hz,
2H), 6.63 (t, J ) 7.2 Hz, 1H), 3.71 (s, 3H), 3.28 (s, 3H); 13C-
{1H} NMR (126 MHz, CDCl3) δ 150.52, 136.28, 129.16, 125.01,
124.96, 124.82, 122.34, 119.60, 119.41, 117.30, 113.80, 109.78,
41.36, 33.17; MS (EI) 236 (M+), 221, 206, 118, 91, 77, 51. Anal.
Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found: C,
81.06; H, 6.71; N, 11.63.
3-(N′,N′-Dip h en yla m in o)-N-m eth ylin d ole (Ta ble 2, en -
tr y 11). Method A of the above general procedure was followed
with 3-bromo-N-methylindole (105 mg, 0.5 mmol), 1.0 equiv
of diphenylamine (85 mg, 0.5 mmol), 1.1 equiv of NaOtBu (53
mg, 0.6 mmol), 2 mol % of Pd(dba)2, and 2 mol % of tri-tert-
butylphosphine in 1 mL of toluene. After 16 h at 100 °C, the
mixture was poured into pentane (15 mL), filtered, and
concentrated in vacuo. The crude product was adsorbed onto
neutral alumina and eluted with 5% diethyl ether in hexanes
to give 97 mg (65%) of 3-(N′,N′-diphenylamino)-N-methylindole
as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J )
8.1 Hz, 1H), 7.25-7.18 (m, 6H), 7.12 (d, J ) 6.9 Hz, 4H), 7.01
(t, J ) 5.6 Hz, 1H), 6.98 (s, 1H), 6.92 (t, J ) 5.8 Hz, 2H), 3.78
(s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.63, 136.37,
129.28, 125.97, 125.07, 123.31, 122.39, 121.70, 121.61, 119.82,
119.62, 109.76, 33.26; MS (EI) 298 (M+), 283, 221, 180, 152,
77, 51. Anal. Calcd for C21H18N2: C, 84.53; H, 6.08; N, 9.39.
Found: C, 84.28; H, 6.20; N, 9.15.
2-(Mor p h olin o)th ia zole67 (Ta ble 3, en tr y 1). Method B
of the above general procedure was followed with 2-bromothia-
zole (166 mg, 1.0 mmol), 4.0 equiv of morpholine (349 µL, 4.0
mmol), 1.1 equiv of K3PO4 (234 mg, 1.1 mmol), 5 mol % of Pd-
(O2CCF3)2, and 5 mol % of tri-tert-butylphosphine in 1 mL of
toluene. After 20 h at 80 °C, the mixture was adsorbed onto
neutral alumina and eluted with 20% ethyl acetate in hexanes
to give 117 mg (68%) of 2-(morpholino)thiazole as a solid: 1H
NMR (400 MHz, CDCl3) δ 7.21 (d, J ) 3.4 Hz, 1H), 6.60 (d, J
) 3.8 Hz, 1H), 3.81 (dt, J ) 4.8, 1.2 Hz, 4H), 3.46 (dt, J ) 4.9,
1.1 Hz, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 139.6,
107.7, 66.2, 48.7.
2-(Dibu tyla m in o)th ia zole (Ta ble 3, en tr y 2). Method B
of the above general procedure was followed with 2-bromothia-
zole (164.9 mg, 1.01 mmol), 4.0 equiv of dibuthylamine (674.1
µL, 4.00 mmol), 1.1 equiv of K3PO4 (234 mg, 1.1 mmol), 5 mol
% of Pd(O2CCF3)2, and 5 mol % of tri-tert-butylphosphine in 1
mL of xylene. After 16 h at 150 °C, the mixture was adsorbed
onto neutral alumina and eluted with 5% ethyl acetate in
hexanes to give 149 mg (70%) of 2-(dibutylamino)thiazole as
an oil: 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J ) 3.5 Hz, 1H),
6.42 (d, J ) 3.9 Hz, 1H), 3.41 (t, J ) 7.6 Hz, 4H), 1.63 (quintet,
J ) 7.7 Hz, 4H), 1.36 (sextet, J ) 7.5 Hz, 4H), 0.95 (t, J ) 7.4
Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 139.5, 105.1,
51.4, 29.4, 20.2, 13.9. Anal. Calcd for C11H20N2S: C, 62.22; H,
9.49; N, 13.19. Found: C, 62.17; H, 9.43; N, 13.20.
2-(N-Meth yl-N-p h en yla m in o)th ia zole68 (Ta ble 3, en tr y
3). Method B of the above general procedure was followed with
2-bromothiazole (164 mg, 1.0 mmol), 3.0 equiv of N-methyl-
aniline (325 µL, 3.00 mmol), 1.1 equiv of NaOtBu (106 mg, 1.1
mmol), 5 mol % of Pd(OAc)2, and 5 mol % ferrocenyldi-tert-
butylphosphine (17.4 mg, 0.05 mmol) in 1 mL of xylene. After
24 h at 120 °C, the mixture was adsorbed onto neutral alumina
and eluted with 5% ethyl acetate in hexanes to give 91.8 mg
(48%) of 2-(N-methyl-N-phenylamino)thiazole as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.40 (m, 4H), 7.24 (m, 2H), 6.47
(d, J ) 3.8 Hz, 1H), 3.53 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 170.6, 146.4, 139.3, 129.6, 126.2, 124.8, 107.4, 40.3.
2-(Mor p h olin o)b en zot h ia zole69 (Ta b le 3, en t r y 4).
Method B of the above general procedure was followed with
2-chlorobenzothiazole (171 mg, 1.0 mmol), 1.0 equiv of mor-
pholine (87.2 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106 mg, 1.1
mmol), 5 mol % of Pd(O2CCF3)2, and 5 mol % of tri-tert-
butylphosphine in 1 mL of toluene. After 16 h at room
temperature, the mixture was adsorbed onto neutral alumina
and eluted with 20% ethyl acetate in hexanes to give 155 mg
(70%) of 2-(morpholino)benzothiazole as a white solid: 1H
NMR (400 MHz, CDCl3) δ 7.61 (d, J ) 7.8 Hz, 1H), 7.57 (d, J
) 7.6 Hz, 1H), 7.30 (dt, J ) 7.7, 1.1 Hz, 1H), 7.09 (dt, J ) 7.6,
0.9 Hz, 1H), 3.81 (t, J ) 4.9 Hz, 4H), 3.60 (t, J ) 4.9 Hz, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 152.4, 130.5, 126.0,
121.6, 120.7, 119.2, 66.1, 48.4.
2-(4-Meth ylp ip er a zin o)ben zoth ia zole (Ta ble 3, en tr y
5). Method B of the above general procedure was followed with
2-chlorobenzothiazole (173 mg, 1.0 mmol), 1.0 equiv of 4-me-
thylpiperazine (116 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106
mg, 1.1 mmol), 5 mol % of Pd(O2CCF3)2, and 5 mol % of tri-
tert-butylphosphine in 1 mL of toluene. After 16 h at room
temperature, the mixture was adsorbed onto neutral alumina
and eluted with 80% ethyl acetate in hexanes to give 162 mg
(68%) of 2-(4-methylpiperazino)benzothiazole as a solid: 1H
NMR (400 MHz, CDCl3) δ 7.59 (d, J ) 7.7 Hz, 1H), 7.55 (d, J
) 7.7 Hz, 1H), 7.29 (dt, J ) 7.7, 1.3 Hz, 1H), 7.07 (dt, J ) 7.6,
1.0 Hz, 1H), 3.65 (t, J ) 5.3 Hz, 4H), 2.53 (t, J ) 5.3 Hz, 4H),
2.34 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 152.7,
130.8, 126.0, 121.4, 120.7, 119.1, 54.3, 48.3, 46.2. Anal. Calcd
(67) Noack, A.; Schroder, A.; Hartmann, H. Angew. Chem., Int. Ed.
2001, 40, 3008-3011.
(68) Maeda, R. S. African 1980, 32.
(69) Khalaf, A. I.; Alvarez, R. G.; Suckling, C. J .; Waigh, R. D.
Tetrahedron 2000, 56, 8567-8571.
2872 J . Org. Chem., Vol. 68, No. 7, 2003

Amination of Five-Membered Heterocyclic Halides
for C12H15N3S: C, 61.77; H, 6.48; N, 18.01. Found: C, 61.55;
H, 6.43; N, 17.84.
benzoxazole as a solid: 1H NMR (400 MHz, CDCl3) δ 7.37 (dd,
J ) 7.9, 0.9 Hz, 1H), 7.26 (dd, J ) 8.0, 0.5 Hz, 1H), 7.17 (dt,
J ) 7.6, 1.1 Hz, 1H), 7.03 (dt, J ) 7.7, 1.2 Hz, 1H), 3.81 (t, J
) 4.9 Hz, 4H), 3.68 (t, J ) 4.9 Hz, 4H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.1, 148.8, 142.9, 124.1, 120.9, 116.5, 108.8,
66.2, 45.7. Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N,
13.72. Found: C, 64.52; H, 5.90; N, 13.51.
2-(Dib u t yla m in o)b en zot h ia zole70 (Ta b le 3, en t r y 6).
Method B of the above general procedure was followed with
2-chlorobenzothiazole (169 mg, 1.0 mmol), 1.0 equiv of dibu-
tylamine (169 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106 mg,
1.1 mmol), 5 mol % of Pd(O2CCF3)2, and 5 mol % of tri-tert-
butylphosphine in 1 mL of toluene. After 16 h at 50 °C, the
mixture was adsorbed onto neutral alumina and eluted with
2% ethyl acetate in hexanes to give 203 mg (78%) of 2-(dibu-
tylamino)benzothiazole as an oil: 1H NMR (400 MHz, CDCl3)
δ 7.55 (d, J ) 7.3 Hz, 1H), 7.51 (d, J ) 7.9 Hz, 1H), 7.26 (dt,
J ) 7.7, 1.2 Hz, 1H), 7.01 (dt, J ) 7.6, 1.1 Hz, 1H), 3.49 (t, J
) 7.6 Hz, 4H), 1.68 (quintet, J ) 7.6 Hz, 4H), 1.40 (sextet, J
) 7.6 Hz, 4H), 0.97 (t, J ) 7.5 Hz, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 167.8, 153.2, 130.6, 125.6, 120.5, 120.3, 118.4,
50.9, 29.5, 20.0, 13.8.
P r ep a r a tion of [P d 2(µ-Br )2(P tBu 3)2].43,44 In a drybox, Pd-
(dba)2 (140 mg, 0.243 mmol) and PtBu3 (50 mg, 0.247 mmol)
were weighed directly into a screw capped vial. A stir bar was
added followed by 5 mL of toluene. 2-Bromothiophene (242 µL,
2.5 mmol) was added and the mixture was stirred for 30 min.
The reaction was monitored by removing an aliquot and
obtaining a 31P NMR spectrum. Upon completion of the
reaction, the mixture was concentrated in vacuo to ap-
proximately 2 mL, layered with 10 mL of ether, and placed at
-40 °C for 24 h. The supernatant was removed, and the
resulting green crystals were washed with 2 × 3 mL of pentane
and dried in vacuo to give 78 mg (83%) of [Pd2(µ-Br)2(PtBu3)2]
as dark green crystals: 1H NMR (C6D6, 400 MHz) δ 1.31
(pseudo-triplet, J HP ) 5.96 Hz, 54H). 31P{1H} NMR (162 MHz,
C6D6) δ 86.8 (s).
2-(N-Meth yl-N-p h en yla m in o)ben zoth ia zole69 (Ta ble 3,
en tr y 7). Method B of the above general procedure was
followed with 2-chlorobenzothiazole (172 mg, 1.0 mmol), 1.0
equiv of N-methylaniline (108 µL, 1.0 mmol), 1.1 equiv of
NaOtBu (106 mg, 1.1 mmol), 5 mol % of Pd(O2CCF3)2, and 5
mol % of tri-tert-butylphosphine in 1 mL of xylene. After 24 h
at 120 °C, the mixture was adsorbed onto neutral alumina and
eluted with 20% ethyl acetate in hexanes to give 163 mg (67%)
of 2-(N-methyl-N-phenylamino)benzothiazole as an oil: 1H
NMR (400 MHz, CDCl3) δ 7.62 (d, J ) 8.2 Hz, 1H), 7.45 (d, J
) 7.8 Hz, 1H), 7.39 (m, 4H), 7.28 (m, 2H), 7.03 (t, J ) 8.2 Hz,
1H), 3.59 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.1,
152.6, 145.7, 131.1, 129.9, 127.3, 125.9, 125.8, 121.7, 120.4,
119.1, 40.4.
Am in a tion Rea ction s Ca ta lyzed by th e Com bin a tion
of P d (d ba )2 a n d P tBu 3 Mon itor ed by NMR Sp ectr oscop y.
In a drybox, heteroaryl bromide (0.25 mmol), NaOtBu (26 mg,
0.275 mmol), and amine (0.25 mmol) were weighed directly
into a small vial. Benzene-d6 (0.25 mL) was added and the
resulting suspension was transferred to a screw cap NMR tube.
Pd(dba)2 (7 mg, 0.0125 mmol, 5 mol %), PtBu3 (2.5 mg, 0.0125
mmol, 5 mol %), and P(mesityl)3 (3 mg) were weighed into a
small vial. Benzene-d6 (0.25 mL) was added. After 60 min the
catalyst suspension was added to the NMR tube. The reactions
2-(Mor p h olin o)-N-m eth ylben zim id a zole71 (Ta ble 3, en -
tr y 8). Method B of the above general procedure was followed
with 2-chloro-N-methylbenzimidazole (166 mg, 1.0 mmol), 1.0
equiv of morpholine (87.2 µL, 1.0 mmol), 1.1 equiv of K3PO4
(234 mg, 1.1 mmol), 5 mol % of Pd(O2CCF3)2, and 5 mol % of
tri-tert-butylphosphine in 1 mL of xylene. After 14 h at 120
°C, the mixture was adsorbed onto neutral alumina and eluted
with 50% ethyl acetate in hexanes to give 168 mg (77%) of
2-(morpholino)-N-methylbenzimidazole as a solid: 1H NMR
(400 MHz, CDCl3) δ 7.62 (m, 1H), 7.21 (m, 3H), 3.90 (t, J )
4.6 Hz, 4H), 3.63 (s, 3H), 3.34 (t, J ) 4.6 Hz, 4H); 13C{1H}
NMR (101 MHz, CDCl3) δ 157.3, 140.7, 135.4, 121.9, 121.5,
118.0, 108.4, 66.5, 50.5, 30.5.
2-(N ′-Me t h y l-N ′-p h e n y la m in o )-N -m e t h y lb e n zim i-
d a zole72(Ta ble 3, en tr y 9). Method B of the above general
procedure was followed with 2-chloro-N-methylbenzimidazole
(166 mg, 1.0 mmol), 1.0 equiv of N-methylaniline (108 µL, 1.0
mmol), 1.1 equiv of NaOtBu (106 mg, 1.1 mmol), 5 mol % of
Pd(O2CCF3)2, and 5 mol % of tri-tert-butylphosphine in 1 mL
of xylene. After 16 h at 120 °C, the mixture was adsorbed onto
neutral alumina and eluted with 20% ethyl acetate in hexanes
to give 176 mg (75%) of 2-(N′-methyl-N′-phenylamino)-N-
methylbenzimidazole as a solid: 1H NMR (400 MHz, CDCl3) δ
7.67 (dd, J ) 6.5, 1.8 Hz, 1H), 7.30 (t, J ) 8.0 Hz, 2H), 7.20
(m, 3H), 7.05 (t, J ) 7.4 Hz, 1H), 6.94 (d, J ) 8.1 Hz, 2H),
3.56 (s, 3H), 3.23 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
154.7, 147.5, 141.4, 135.2, 129.5, 123.2, 121.7, 121.3, 120.7,
118.0, 108.4, 41.5, 30.5.
1
were monitored by obtaining H and 31P NMR spectra.
Am in a tion Rea ction s Mon itor ed by GC. In a drybox,
heteroaryl bromide (0.25 mmol), NaOtBu (26 mg, 0.275 mmol),
and amine (0.25 mmol) were weighed directly into a screw-
capped vial with a Teflon septa. Toluene (0.25 mL) was added
followed by 50 µL of a 0.5 M solution of naphthalene in toluene.
Pd(dba)2 (7 mg, 0.0125 mmol, 5 mol %) and PtBu3 (2.5 mg,
0.0125 mmol, 5 mol %) were weighed into a small vial.
Benzene-d6 (0.2 mL) was added. After 5 min the catalyst
suspension was added to the reaction mixture (t ) 0). Aliquots
of approximately 10 µL were removed from the reaction
mixture at defined times and immediately diluted with ether
(1 mL). The resulting solutions were analyzed by GC with
comparison to isolated compounds. Reactions with other
catalysts were performed in a similar procedure. Timing was
always started upon addition of the catalyst to the reaction
mixture.
Kin etic Exp er im en ts Mea su r ed by 1H NMR Sp ectr o-
scop y. Stock solutions of each reagent in benzene-d6 were
made up and stored at -35 °C: HNMePh (0.65 M, 70 µL in 1
mL of benzene-d6), NaOCEt3 (1.67 M, 315 mg in 1.5 mL),
2-bromothiophene (2.66 M, 387 µL in 1.5 mL of benzene-d6),
Pd(PtBu3)2 (0.0126 M, 6.4 mg in 1 mL of benzene-d6) and 1,3,5-
trimethoxybenzene (0.06 M, 10 mg in 1 mL of benzene-d6). A
typical reaction mixture was prepared in a screw-capped NMR
tube by mixing C6D6 stock solutions of HNMePh (20 µL),
NaOCEt3 (90 µL), 2-bromothiophene (150 µL), Pd(PtBu3)2 (100
µL), and 1,3,5-trimethoxybenzene (50 µL) with enough C6D6
to make a total volume of 0.5 mL. The amine was added
immediately prior to initiation of the data acquisition program.
Zero-order rate constants were obtained by fitting a plot of
the amine versus time to the expression y ) mx + b, where m
is the zero-order rate constant kobs. NaOtBu was added as a
solid in place of NaOCEt3 when necessary.
2-(Mor p h olin o)ben zoxa zole (Ta ble 3, en tr y 10). Method
B of the above general procedure was followed with 2-chlo-
robenzoxazole (153 mg, 1.0 mmol), 1.0 equiv of morpholine
(87.2 µL, 1.0 mmol), 1.1 equiv of NaOtBu (106 mg, 1.1 mmol),
5 mol % of Pd(O2CCF3)2, and 5 mol % of tri-tert-butylphosphine
in 1 mL of toluene. After 16 h at 80 °C, the mixture was
adsorbed onto neutral alumina and eluted with 20% ethyl
acetate in hexanes to give 106 mg (52%) of 2-(morpholino)-
Ack n ow led gm en t. We thank the NIH (GM-55382)
for support of this work and J ohnson-Matthey for a gift
of palladium. M.U. was supported by Mitsubishi Chemi-
cal Corporation.
(70) D’Amico, J . J .; Webster, S. T.; Campbell, R. H.; Twine, C. E. J .
Org. Chem. 1965, 30, 3618.
(71) Hunger, A. V.; Kebrle, J .; Rossi, A.; Hoffmann, K. Helv. Chim.
Acta 1961, 44, 1273.
(72) Musco, J .; Murphy, D. B. J . Org. Chem. 1971, 36, 3469.
J O0266339
J . Org. Chem, Vol. 68, No. 7, 2003 2873