Application of a New Bicyclic Triaminophosphine Ligand in Pd-Catalyzed Buchwald-Hartwig Amination Reactions of Aryl Chlorides, Bromides, and Iodides

Article abstract of DOI:10.1021/jo034994y

The new bicyclic triaminophosphine ligand P(i-BuNCH₂) ₃CMe (3) has been synthesized in three steps from commercially available materials and its efficacy in palladium-catalyzed reactions of aryl halides with an array of amines has been demonstrated. Electron-poor, electron-neutral, and electron-rich aryl bromides, chlorides, and iodides participated in the process. The reactions encompassed aromatic amines (primary or secondary) and secondary amines (cyclic or acyclic). It has also been shown that the weak base Cs₂CO₃ can be employed with ligand 3, allowing a variety of functionalized substrates (e.g., those containing esters and nitro groups) to be utilized in our amination protocols. This ligand provides a remarkably general, efficient, and mild palladium catalyst for aryl iodide amination. Although 3 is slightly air and moisture sensitive, easy procedures can be adopted that avoid the need of a glovebox. Comparisons of the efficacy of 3 in these reactions with that of the proazaphosphatrane P(i-BuNCH₂CH₂)₃N (2) reveal that in addition to the opportunity for transannulation in 2 (but not in 3), other significant stereoelectronic contrasts exist between these two ligands which help account for differences in the activities of the Pd/2 and Pd/3 catalytic systems.

Full text of DOI:10.1021/jo034994y

Ap p lica tion of a New Bicyclic Tr ia m in op h osp h in e Liga n d in
P d -Ca ta lyzed Bu ch w a ld -Ha r tw ig Am in a tion Rea ction s of Ar yl
Ch lor id es, Br om id es, a n d Iod id es
Sameer Urgaonkar, J u-Hua Xu, and J ohn G. Verkade*
Department of Chemistry, Gilman Hall, Iowa State University, Ames, Iowa 50011-3111
jverkade@iastate.edu
Received J uly 10, 2003
The new bicyclic triaminophosphine ligand P(i-BuNCH2)3CMe (3) has been synthesized in three
steps from commercially available materials and its efficacy in palladium-catalyzed reactions of
aryl halides with an array of amines has been demonstrated. Electron-poor, electron-neutral, and
electron-rich aryl bromides, chlorides, and iodides participated in the process. The reactions
encompassed aromatic amines (primary or secondary) and secondary amines (cyclic or acyclic). It
has also been shown that the weak base Cs2CO3 can be employed with ligand 3, allowing a variety
of functionalized substrates (e.g., those containing esters and nitro groups) to be utilized in our
amination protocols. This ligand provides a remarkably general, efficient, and mild palladium
catalyst for aryl iodide amination. Although 3 is slightly air and moisture sensitive, easy procedures
can be adopted that avoid the need of a glovebox. Comparisons of the efficacy of 3 in these reactions
with that of the proazaphosphatrane P(i-BuNCH2CH2)3N (2) reveal that in addition to the
opportunity for transannulation in 2 (but not in 3), other significant stereoelectronic contrasts exist
between these two ligands which help account for differences in the activities of the Pd/2 and Pd/3
catalytic systems.
In tr od u ction
ready availability of starting materials from a myriad of
commercial sources, and relatively mild reaction condi-
tions. Palladium-catalyzed cross-coupling of aryl halides
and amines to generate arylamines was first studied by
Migita8 and was subsequently developed by Buchwald
and Hartwig.1 The pioneering work of these investigators
led to remarkable advances in our understanding of
fundamental aspects of these reactions.9 One such aspect
is the proper choice of ligand that can stabilize catalyti-
cally active Pd(0) complexes. Lloyd-J ones recently noted,
“Often unpredictably, the choice of ligand in Pd-catalyzed
reactions can make surprisingly little difference or can
open up new avenues”.10
The synthesis of arylamines from amines and aryl
halides (or halide equivalents such as tosylates and
triflates) using palladium methodology is of considerable
importance in the literature,1 primarily because aryl-
amines possess a diverse range of potential applications
in the pharmaceutical,2 dye,3 agricultural,4 and polymer5
industries. Arylamines have also been demonstrated to
be useful as ligands for transition metals.6
The palladium-catalyzed process for the synthesis of
arylamines has several advantages over commonly em-
ployed approaches such as nucleophilic aromatic substi-
tution, Ullmann coupling,7 reductive amination, and
nitration followed by reduction. Advantages include
better functional group compatibility, a one-step reaction,
The variety of effective ligands that have been intro-
duced for Pd-catalyzed amination reactions can be clas-
sified in terms of the three generations over which they
have evolved. First generation catalyst systems included
monodentate phosphines [e.g., P(o-tol)3]11 while chelating
(1) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (b) Hartwig, J . F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, Germany, 2000. (c) Yang, B. H.; Buchwald,
S. L. J . Organomet. Chem. 1999, 576, 125. (d) Wolfe, J . P.; Wagaw, S.;
Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (e)
Hartwig, J . F. Acc. Chem. Res. 1998, 31, 805. (f) Hartwig, J . F. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2046.
(2) Beland, F. A.; Kadlubar, F. F. Handbook of Experimental
Pharmacology, Carcinogenesis and Mutagenesis; Grove, Springer,
Verlag: Heidelberg, Germany, 1990.
(3) Waring, D. R.; Hallas, G. The Chemistry and Application of Dyes;
Plenum: New York, 1990.
(4) CRC Handbook of Pesticides; Milne, G. W. A., Ed.; CRC Press:
Boca Raton, FL, 1994.
(5) (a) Mukundan, T. Macromol. Mater. Eng. 2002, 287, 442. (b)
Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J . R. Handbook of
Conducting Polymers, 2nd ed.; Marcel Dekker: New York, 1997.
(6) (a) Westmoreland, I.; Munslow, I. J .; O’Shaughnessy, P. N.; Scott,
P. Organometallics 2003, 22, 2972. (b) Greco, G. E.; Popa, A. I.; Schrock,
R. R. Organometallics 1998, 17, 5591.
(7) For recent work on copper-catalyzed Ullmann coupling, see: (a)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (b) Kwong, F.
Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (c) Gujadhur,
R.; Venkataraman, D.; Kintigh, J . T. Tetrahedron Lett. 2001, 42, 4791.
(8) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
(9) For mechanistic studies, see: (a) Singh, U. K.; Strieter, E. R.;
Blackmond, D. G.; Buchwald, S. L. J . Am. Chem. Soc. 2002, 124, 14104.
(b) Stambuli, J . P.; Buhl, M.; Hartwig, J . F. J . Am. Chem. Soc. 2002,
124, 9346. (c) Alcazar-Roman, L. M.; Hartwig, J . F. J . Am. Chem. Soc.
2001, 123, 12905. (d) Alcazar-Roman, L. M.; Hartwig, J . F.; Rheingold,
A. L.; Liable-Sands, L. M.; Guzei, I. A. J . Am. Chem. Soc. 2000, 122,
4618 and references therein.
(10) Lloyd-J ones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
(11) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1996, 61, 1133.
(b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1348.
10.1021/jo034994y CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/27/2003
8416
J . Org. Chem. 2003, 68, 8416-8423

Pd-Catalyzed Buchwald-Hartwig Amination Reactions
bidentate phosphines such as BINAP12 or DPPF13 com-
prise second generation catalyst systems that greatly
improved the scope of amination reactions. Further
improvements came with the advent of electron-rich
sterically hindered third generation phosphines such as
SCHEME 1
P(t-Bu)3 and o-(biphenyl)P(t-Bu)2.15 Nonphosphine
14
ligands, such as N-heterocyclic carbenes (saturated as
well as unsaturated), can also be considered to belong to
this generation.16 Third generation catalysts permitted
the use of otherwise notoriously unreactive but cheaper
aryl chlorides as substrates in amination reactions.
In recent years our explorations of the chemistry of
proazaphosphatranes of type 1, first synthesized in our
laboratories, have shown them to be exceedingly potent
catalysts, promoters, and strong nonionic stoichiometric
bases that facilitate a variety of useful organic transfor-
mations.17 More recently, we discovered that commer-
cially available 2 is a highly active ligand in Suzuki18 and
Buchwald-Hartwig amination reactions of aryl halides,
including those of aryl chlorides.19,20
plane is perpendicular to and contains the 3-fold axis at
its center.21,22
In view of the efficiency of ligand 2 in Buchwald-
Hartwig amination reactions,19,20 its bicyclic nature
prompted us to speculate whether ligand 3 could also be
employed in these transformations, since the two ligands
are structurally quite similar. The three PN nitrogens
in proazaphosphatranes such as 2 have virtually planar
geometries and those in 3 can be assumed to have the
same property. Because 3 is a liquid (see below) that did
not crystallize well at low temperature, the determination
of its molecular structure by X-ray means was precluded.
Such a study reported by us for the oxide analogue OP-
(MeNCH2)3CMe revealed nearly perfect C3v symmetry
with a sum of the angles around the nitrogens of 357°.23
As in this derivative of 3, the three PN nitrogens in 3
are also capable of providing electron density to the
phosphorus, thereby electronically enriching the Pd(0)-
Ln complex for oxidative addition with aryl halides. In
addition, the bulky isobutyl groups in 3 would facilitate
reductive elimination. Importantly, however, ligand 3
(unlike 2) lacks the possibility for basicity enhancement
through transannulation. Thus utilization of 3 as a ligand
could potentially provide insight regarding the impor-
tance of transannulation in the activity of 2. In this
article, we describe the synthesis of the new ligand 3,
which though structurally similar to 2, has quite different
stereoelectronic properties. Here we also present the
utility of 3 in Pd-catalyzed Buchwald-Hartwig amination
reactions of aryl chlorides, bromides, and iodides and we
provide a rationale for differences in the activity of the
Pd/3 and Pd/2 systems.
We believed that the unusually high activity of 2 in
Suzuki and Buchwald-Hartwig amination reactions was
due primarily to (a) the electron-donating capability of
the three planar PN3 nitrogens, (b) a desirable degree of
bulk provided by the isobutyl groups, and (c) potential
transannulation from the bridgehead nitrogen’s lone pair
to phosphorus.18 Thus in contrast, acyclic triaminophos-
phines [e.g., P(NMe2)3 or P(Ni-Bu2)3] were shown to be
very ineffective ligands in amination reactions partly
because the phosphorus in these triaminophosphines is
not sufficiently electron-rich owing to a departure of the
conformation of these molecules from a C3v arrangement
of the P(NC2)3 moiety in which the unhybridized lone pair
orbital on each nitrogen lies tangential to a circle whose
(12) (a) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144.
(b) Wolfe, J . P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359. (c)
Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118,
7215.
(13) Driver, M. S.; Hartwig, J . F. J . Am. Chem. Soc. 1996, 118, 7217.
(14) (a) Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575. (b)
Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39,
617.
(15) (a) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413. (b) Wolfe,
J . P.; Tomori, J .; Sadighi, J . P.; Yin, J .; Buchwald, S. L. J . Org. Chem.
2000, 65, 1158. (c) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413.
(16) (a) Viciu, M. S.; Kissling, R. M.; Stevens, E. D.; Nolan, S. P.
Org. Lett. 2002, 4, 2229. (b) Grasa, G. A.; Viciu, M. S.; Huang, J .; Nolan,
S. P. J . Org. Chem. 2001, 66, 7729. (c) Stauffer, S. R.; Lee, S.; Stambuli,
J . P.; Hauck, S. I.; Hartwig, J . F. Org. Lett. 2000, 2, 1423. (d) Huang,
J .; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307.
(17) For a recent review, see: Verkade, J . G. Top. Curr. Chem. 2002,
233, 1.
Resu lts a n d Discu ssion
Syn th esis of Liga n d 3. This ligand was synthesized
from triamine 4 as summarized in Scheme 1. Although
commercially available,24 4 can be easily prepared in
three high-yield steps from cheaper and commercially
available 1,1,1-tris(hydroxymethyl)ethane.25 Treatment
(21) (a) Molloy, K. G.; Petersen, J . L. J . Am. Chem. Soc. 1995, 117,
7696. (b) Xi, S. K.; Schmidt, H.; Lensink, C.; Kim, S.; Wintergrass, D.;
Daniels, L. M.; J acobson, R. A.; Verkade, J . G. Inorg. Chem. 1990, 29,
2214. (c) Socol, S. M.; J acobson, R. A.; Verkade, J . G. Inorg. Chem.
1984, 23, 88. (d) Romming, C.; Songstad, J . Acta Chem. Scand., Ser. A
1980, 34, 365. (e) Romming, C.; Songstad, J . Acta Chem. Scand., Ser.
A 1979, 33, 187.
(22) For a discussion of the electronic structure of tris(dialkylamino)-
phosphines, see: Cowley, A. H.; Lattman, M.; Stricklen, P. M.; Verkade,
J . G. Inorg. Chem. 1982, 21, 543.
(18) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. Tetrahedron Lett.
2002, 43, 8921.
(19) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. J . Org. Chem.
2003, 68, 452.
(23) Clardy, J . C.; Kolpa, R. L.; Verkade, J . G. Phosphorus 1974, 4,
133.
(24) Available from Fluka.
(20) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. Org. Lett. 2003,
5, 815.
(25) Fleischer, E. B.; Gebala, A. E.; Levey, A.; Tasker, P. A. J . Org.
Chem. 1971, 36, 3042.
J . Org. Chem, Vol. 68, No. 22, 2003 8417

Urgaonkar et al.
TABLE 1. P d /3-Ca ta yzed Am in a tion of Ar yl a n d
SCHEME 2
Heter oa r yl Br om id esa
of triamine 4 with isobutyryl chloride followed by LiAlH4
reduction resulted in the formation of triisobutyl-
substituted amine 5 in 81% yield in two steps. Ring
closure of 5 to 3 was achieved by heating the former in
the presence of P(NMe2)3 at 175 °C for 48 h to afford 3
as a colorless liquid in 85% yield and in 69% overall yield
from 4. Ligand 3 was unambiguously characterized by
1H, 13C, and 31P NMR spectroscopy as well as elemental
analysis (see Experimental Section). Remarkably, 31P
NMR spectroscopic monitoring of 3, kept in the air for
40 h, revealed that about 90% of 3 remained unchanged.
Interestingly, P(t-Bu)3, a highly effective ligand for a wide
variety of Pd-catalyzed cross-coupling reactions,26 includ-
ing amination reactions, has been shown to be destroyed
in air within 2 h.15b Although 3 showed a high degree of
air and moisture stability, we recommend that it be
stored under argon.
Ca ta lytic Activity of 3 in Ar yl Br om id e Am in a tion
R ea ct ion s. Our initial test of the efficacy of 3 in Pd-
catalyzed amination reactions involved aryl bromides
with NaO-t-Bu as the base. We were intrigued to discover
that conditions developed for the amination reactions
that employed 2 as the ligand27 also worked for ligand 3.
The general reaction conditions for the coupling reaction
are described in Scheme 2 and results are provided in
Table 1.
For the majority of substrates, 0.5 mol % of Pd was
sufficient to achieve high yields of arylamines, and most
of these reactions were completed in less than 20 h. No
attempts were made to optimize reaction times. Electron-
poor, electron-neutral, and electron-rich aryl bromides,
including bromopyridines, were readily aminated with
the Pd(OAc)2/3 catalyst system. Primary anilines with
ortho substituents and secondary anilines were efficiently
coupled at 80 °C. As was the case with the Pd(OAc)2/2
catalyst system, amination reactions of highly sterically
hindered substrates with Pd(OAc)2/3 also proceeded
exceedingly well (entry 13, Table 1).19 Hydrodehaloge-
nation side products were detectable in most cases by
TLC. The Pd(OAc)2/3 catalyst system was also effective
for the arylation of cyclic secondary amines (entries 2, 6,
7, and 14, Table 1). Di-n-butylamine (a member of a
normally difficult class of substrates) was also cleanly
coupled, giving the desired product in very good to
acceptable yields. For this class of amines, 2 mol % of Pd
was needed (entries 3, 8, and 15, Table 1). This result
contrasts that observed when ligand 2 was employed,
namely, that reactions of acyclic secondary amines
proceeded in only moderate yields (57-70%) and required
5 mol % of Pd.19 Unfortunately, long-chain (n-hexylamine)
or branched primary aliphatic amines (cyclohexylamine)
did not react cleanly under our conditions.
a
Conditions: 1.0 equiv of aryl bromide, 1.2 equiv of amine, 1.5
equiv of NaO-t-Bu, cat. Pd(OAc)2, cat. ligand 3 (2 L/Pd), 3 mL of
toluene, 80 °C, 15-20 h. Reaction times have not been optimized.
Isolated yields. c Reaction was performed at 100 °C. Pd2(dba)3
b
d
used in place of Pd(OAc)2.
Although primary anilines without an ortho substitu-
ent reacted poorly with the 3/Pd catalyst system at 80
°C, a reaction temperature of 100 °C allowed efficient
coupling of this class of anilines. For example, the
reaction of 4-bromoanisole with p-toluidine proceeded to
completion with 2 mol % of Pd(OAc)2 and 4 mol % of 3 at
(26) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(27) Reactions were also performed with the trimethyl and triiso-
propyl analogues of ligand 2. For the reaction shown in Table 1, entry
6, the trimethyl analogue provided less than 20% yield whereas
triisopropyl analogue yielded 62% of the coupled product with 2 mol
% of Pd in both cases.
8418 J . Org. Chem., Vol. 68, No. 22, 2003

Pd-Catalyzed Buchwald-Hartwig Amination Reactions
TABLE 2. P d (OAc)2/3-Ca ta lyzed Am in a tion of
F u n ction a lized Ar yl Br om id esa
TABLE 3. P d /3-Ca ta lyzed Am in a tion of Ar yl Ch lor id esa
a
Conditions: 1.0 equiv of aryl bromide, 1.2 equiv of amine, 1.5
equiv of Cs2CO3, 1.0 mol % of Pd(OAc)2, 2.0 mol % of ligand 3 (2
L/Pd), 3 mL of toluene, 80 °C, 15-20 h. Reaction times have not
b
d
been optimized. Isolated yields. c R ) CO2Me. Reaction was
performed at 100 °C.
100 °C, affording the desired product in 77% yield (entry
11, Table 1). Similarly, 4-tert-butylbromobenzene coupled
with p-anisidine to give a 78% yield of product (entry 5,
Table 1).
Although the above protocol is reasonably useful, it
involves the use of NaO-t-Bu as the base, thus rendering
the conditions ineffective for aryl halides containing base-
sensitive functional groups. After surveying a range of
bases, we were pleased to find that the weaker base Cs2-
CO3 could also be employed in the presence of the Pd/3
catalyst system, and examples of amination reactions
demonstrating the use of this base are reported in Table
2. In most cases these reactions proceeded successfully
at 80 °C with 1 mol % of Pd(OAc)2 and 2 mol % of 3. It is
worth noting that by contrast, alkylphosphine catalysts
[biphenyl- or ferrocenyl-based, or P(t-Bu)3] generally
require heating to 100 °C for the amination of function-
alized aryl bromides.14a,15b,28
Ca ta lytic Activity of 3 in Ar yl Ch lor id e Am in a -
tion Rea ction s. The utilization of aryl chlorides in Pd-
catalyzed cross-coupling reactions is important from a
commercial as well as an academic standpoint. Conse-
quently, a significant proportion of recent papers on
amination reactions have focused on the use of aryl
chlorides as substrates. The results of our investigations
of such couplings using the Pd/3 catalyst system are
summarized in Table 3. We found that a higher catalyst
loading (4 mol % of Pd) and a reaction temperature of
110 °C were needed to drive the reactions to completion.
In a control experiment, the reaction of activated 4-chlo-
ronitrobenzene with morpholine in toluene at 110 °C gave
no desired product in the presence of Cs2CO3. A similar
a
Conditions: 1.0 equiv of aryl chloride, 1.2 equiv of amine, 1.5
equiv of NaO-t-Bu, 2.0 mol % of Pd2(dba)3, 8.0 mol % of ligand 3
(2 L/Pd), 3 mL of toluene, 110 °C, 24 h. Reaction times have not
been optimized. Isolated yields. c Cs2CO3 used in place of NaO-
b
(28) Kataoka, N.; Shelby, Q.; Stambuli, J . P.; Hartwig, J . F. J . Org.
Chem. 2002, 67, 5553.
d
t-Bu. Pd(OAc)2 used in place of Pd2(dba)3.
J . Org. Chem, Vol. 68, No. 22, 2003 8419

Urgaonkar et al.
TABLE 4. P d (OAc)2/3-Ca ta lyzed Am in a tion of Ar yl
experiment conducted with 4 mol % of Pd(OAc)2 without
any added ligand resulted in the formation of only a trace
amount of product after 36 h. Among the solvents tested
(toluene, THF, dioxane, and DME) toluene was found to
be the most effective. Either Pd(OAc)2 or Pd2(dba)3 can
be used as the palladium(0) precursor. As expected, the
best yields were obtained with aryl chlorides possessing
electron-withdrawing groups, but electron-neutral and
electron-rich aryl chlorides provided good to moderate
yields of desired product. Cyclic secondary amines,
secondary anilines, primary anilines, and diphenylamine
participated well in our amination process. In contrast
to aryl chloride aminations involving ligand 3, those with
ligand 2 can be performed at a lower temperature
(80 °C) providing good to excellent yields with electroni-
cally diverse systems.20
Iod id esa
Ca ta lytic Activity of 3 in Ar yl Iod id e Am in a tion
Rea ction s. Although more reactive, aryl iodides usually
provide lower yields than their bromide counterparts in
such reactions. Catalyst systems that have been de-
scribed in the literature involve toxic additives such as
18-crown-6,29 higher catalyst loading (up to 5 mol %),13
lack of generality,16b and the use of the strong base (NaO-
t-Bu).
Recently, Buchwald’s group has reported an efficient
procedure for the coupling of aryl iodides with amines
using biphenyl-based phosphine ligands and Xantphos,
a chelating bisphosphine.30 Although their procedure was
effective when NaO-t-Bu was the base, reactions involv-
ing Cs2CO3 had several disadvantages. First, higher
temperatures were required to achieve good yields (100
or 120 °C). Second, cosolvents (Et3N or t-BuOH) were
needed for rate enhancements. Third, secondary acyclic
amines and diarylamines were problematic. The single
case of a reaction involving an acyclic secondary amine
that was described utilized electronically favored 4-io-
dobenzophenone as a substrate and that reaction re-
quired 5 mol % of Pd loading. Since the appearance of
that report, we described a Pd catalyst system utilizing
ligand 2 for the amination of aryl iodides,19 which though
attractive, utilized the strong base (NaO-t-Bu) that limits
substrate scope. Thus a catalyst system that can achieve
a higher degree of versatility for aryl iodide aminations
would be desirable.
a
Conditions: 1.0 equiv of aryl iodide, 1.2 equiv of amine, 1.5
equiv of Cs2CO3, cat. Pd(OAc)2, cat. ligand 3 (2 L/Pd) 3 mL of
toluene, 80 °C, 15-20 h. Reaction times have not been optimized.
Isolated yields. c R ) CO2Et. Reaction was performed at 100
b
d
By an extension of our amination experiments that
gave promising results with aryl bromides and chlorides,
we found that the Pd(OAc)2/3 catalyst system, in combi-
nation with Cs2CO3 as the base, allowed a variety of aryl
iodides to couple successfully with amines at 80 °C (20-
40 °C lower than the literature reports).
°C.
reactions of aryl iodides with primary anilines lacking
an ortho substituent required the use of a somewhat
higher reaction temperature (entries 10 and 15, Table
4). Reactions of an acyclic secondary amine with aryl
iodides also occurred at 80 °C (entries 4, 8, and 13, Table
4). Reactions of diphenylamine also proceeded smoothly
at 100 °C with the Pd/3 catalyst system when Cs2CO3
was employed (entries 5 and 14, Table 4). As with aryl
bromides, reactions of aryl iodides with primary aliphatic
amines gave poor results when Cs2CO3 or NaO-t-Bu was
employed as the base. Notwithstanding this limitation,
it appears that the Pd/3 catalyst system utilizing Cs2-
CO3 as the base is the most efficient, general, and mild
catalytic combination reported to date for the amination
of aryl iodides.
Exceptions to this approach were reactions in which a
primary aniline lacking an ortho substituent was used
as a coupling partner. For unfunctionalized substrates,
NaO-t-Bu was also able to function as the base. For
activated aryl iodides, and for one example of a deacti-
vated aryl iodide, 0.5 mol % of Pd led to excellent yields
of diarylamines (entries 1, 2, 3, and 11, Table 4). The use
of 2 mol % of Pd allowed the reaction of unactivated and
deactivated aryl iodides to occur in good yields (entries
6, 7, 11, and 12, Table 4). As observed with aryl bromides,
(29) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 6066.
(30) Ali, M. H.; Buchwald, S. L. J . Org. Chem. 2001, 66, 2560.
8420 J . Org. Chem., Vol. 68, No. 22, 2003

Pd-Catalyzed Buchwald-Hartwig Amination Reactions
Sa lien t F ea tu r es of a Con ven ien t Rea ction P r o-
t ocol. Although ligand 3 is slightly moisture and air-
sensitive, easy procedures can be adopted that avoid the
need for a glovebox. A stock solution of 3 was prepared
in toluene, and the appropriate amount was collected
with a syringe. NaO-t-Bu and Cs2CO3 were stored inside
the glovebox and were moved (in small amounts) to the
outside just before use. Thus, for all the reactions
presented in this paper, aryl halide (if solid), amine (if
solid), base, and palladium acetate were weighed in air
in a Schlenk flask. The flask was then evacuated and
purged with argon three times. Ligand 3 was then added
via syringe and also aryl halides and amines (if liquids).
It was determined that the order of addition of reagents
was not important.
Although the structures of 1135 and 1236 have been
obtained by crystallographic means, the standard devia-
tions for the metrics of interest in 11 are too large (3° to
4°) to make a useful comparison for our purposes. For
crystallographic metric differences to be significant, we
believe they should be outside 3 × esd values. As expected
from the foregoing discussion, the NPN [103.7(2)°] and
PNN [113.6(3)°] bond angles in 12 are similar to their
counterparts in 7.37
Ster eoelectr on ic Com p a r ison s of Liga n d s 2 a n d
3. The difference in reactivity between 2 and 3 in
palladium-catalyzed aryl halide aminations can be at-
tributed to the presence of interesting contrasts in their
stereoelectronic properties. Because of the greater con-
straint in the bicyclic smaller cage framework of 3
relative to 2, steric protection of the phosphorus in the
former by the isobutyl groups may well be diminished
substantially. This suggestion is supported by the PNCexo
bond angle of 119.1(2)° in 631 and 126.3(2)° in 7.23 We
It thus appears that any opening of the NPN bond
angle in 2 or 3 upon coordination to the palladium(II)
center in the oxidative addition intermediate would result
mainly in widening of the PNCexo angle by perhaps
comparable amounts in each ligand, thereby reducing
steric hindrance to coordination. The smaller steric
encumbrance of the phosphorus in 3 compared with that
in 2 (stemming from the larger PNCexo angle in the
former) would enhance the donor capability of the
phosphorus of 3, thereby favoring the oxidative addition
step. The greater constraint in 3 also confers on it a more
rigid C3v symmetry that maximizes electron donation
from each PN3 nitrogen lone pair to the phosphorus,38
whereas in 2, conformational inversion around the mo-
lecular axis between extreme C3 conformations mitigates
such electron donation. Thus in the absence of transan-
nulation in 2, 3 can be assumed to be the more basic
ligand based on its larger PNCexo angle and its confor-
mational rigidity.
The idea that the basicity of ligand 3 is greater than
that of untransannulated 2, but less than that of trans-
annulated 2 can be used to rationalize observed differ-
ences in the activities of these ligands in palladium-
assisted aminations of aryl halides. In the case of aryl
bromides and iodides, the scope of such reactions sup-
ported by the Pd/3 system appears at first glance to be
quite similar to that facilitated by the Pd/2 system.
However, the scope is actually greater for the Pd/3 system
because substrates bearing base-sensitive substituents
are much better tolerated. As with aryl bromides and
iodides, the Pd/3 system is also effective in catalyzing
aminations of aryl chlorides possessing base-sensitive
substituents. This advantage can be rationalized on the
basis of the more weakly basic nature of 3 compared with
2 if transannulation of 2 in the oxidative addition
intermediate of these aryl halides (Figure 1) is occurring
believe that a similar difference in PNCexo bond angles
exists between the trivalent phosphorus ligands 2 and
3, although structural data are available only for 8,32
which is an analogue of 2. Thus the average of the PNCexo
bond angles in 8 [115.11(11)°] represents a ca. 4° decrease
from that in 6 owing to narrowing of the NPN bond angle
in 8, while the PNCcage angle remains quite constant in
both compounds. A similar decrease in PNCexo angle from
7 to 3 can be expected for the same reason. Support for
the suggestion that the PNCcage angle remains quite
constant upon oxidation (or coordination) of the phos-
phorus emanates from a comparison of the structural
metrics of 933 and 1034 in which opening of the OPO bond
angle from 10 to 9 does not greatly affect the POC angle.
(34) Milbrath, D. S.; Springer, J . P.; Clardy, J . C.; Verkade, J . G. J .
Am. Chem. Soc. 1976, 98, 5493.
(35) Vandoorne, W.; Hunt, G. W.; Perry, R. W.; Cordes, A. W. Inorg.
Chem. 1971, 10, 2591.
(36) Gilje, J . W.; Seff, K. Inorg. Chem. 1972, 11, 1643.
(37) However, the PNC angle in 12 [116.9(2)°] is considerably
smaller than this angle in 7, which may be associated with the
observation that the nitrogens in 12 are not planar. See ref 35.
(38) (a) Clarke, M. L.; Cole-Hamilton, D. J .; Slawin, A. M. Z.;
Woollins, J . D. Chem. Commun. 2000, 2065. (b) Clarke, M. L.; Cole-
Hamilton, D. J .; Woollins, J . D. J . Chem. Soc., Dalton Trans. 2001,
2721.
(31) Tang, J .-S.; Mohan, T.; Verkade, J . G. J . Org. Chem. 1994, 59,
4931.
(32) Wroblewski, A. E.; Pinkas, J .; Verkade, J . G. Main Group Chem.
1995, 1, 69.
(33) Nimrod, D. M.; Fitzwater, D. R.; Verkade, J . G. J . Am Chem.
Soc. 1968, 90, 2780.
J . Org. Chem, Vol. 68, No. 22, 2003 8421

Urgaonkar et al.
Exp er im en ta l Section
Syn th esis of Bicyclic Liga n d 3. Isobutyryl chloride (80.0
mmol) in 20 mL of dry CH2Cl2 was added dropwise to a
mixture of tris(2-aminomethyl)ethane 4 (20.0 mmol) and
triethylamine (80.0 mmol) in 40 mL of dry CH2Cl2 at 0 °C.
The mixture was stirred at room temperature overnight. After
the precipitate that formed was filtered, the filtrate was
concentrated on a rotary evaporator and then diluted with
water (30 mL). The product was extracted with EtOAc (3 ×
100 mL) and then the organic layers were combined and dried
(Na2SO4) and the solvent was removed under reduced pressure
to afford a slurry that was used in the next step without
further purification. The slurry (18.0 mmol, as crude product)
in 50 mL of dry THF was added dropwise to a solution of
LiAlH4 (126.0 mmol) in 200 mL of dry THF over a period of
30 min. The mixture was then refluxed for 3 days after which
it was cooled to 0 °C. Fifty milliliters of a 10% KOH solution
in water was then added and the mixture was again heated
to reflux for 4 h. The white precipitate that had formed was
filtered and washed with hot THF (3 × 100 mL) and the
filtrates were then combined. THF was removed under reduced
pressure and the crude product obtained was distilled under
vacuum to afford 5 in 81% yield from 4 as a colorless oil (bp
F IGURE 1. Outline of the catalytic cycle for Buchwald-
Hartwig amination reactions.
to some significant degree.39 The relatively poor σ-donor
ability of 3 compared with transannulated 2 in the
arylPd(II)amine(X) complex (Figure 1) allows the amine
to bind more tightly when 3 is the ligand, thus rendering
the N-H proton more acidic, consequently enabling a
relatively weak base such as Cs2CO3 to function. It should
be noted that attempts to isolate an oxidative addition
intermediate with 3 or with 2 (or sterically less hindered
analogues of the latter) have thus far failed.
The general and substantial increase in activity of the
Pd/2 system relative to the Pd/3 system in aminations
of aryl chlorides not bearing base-sensitive substituents
suggests that 2 transannulates to a greater extent in the
corresponding aryl chloride than in aryl bromide or aryl
iodide oxidative addition intermediates, owing to the
presence of a more electronegative halide on the aryl
chloride oxidative addition intermediate. This intermedi-
ate is thus stabilized by enhanced phosphorus atom
basicity17 in 2 through enhanced transannulation in this
ligand.
In summary, the new bicyclic triaminophosphine ligand
3, which was synthesized in three facile steps, generates
a very active and broadly useful Pd catalyst system for
Buchwald-Hartwig amination reactions. Couplings of an
electronically diverse array of aryl halides with amines
are realized in good to excellent yields. In addition, the
use of Cs2CO3 in the presence of ligand 3 in these
reactions permits aryl chlorides, bromides, and iodides
with base-sensitive functional groups to be aminated
efficiently. It appears that though the basicity of 3 is
greater than that of untransannulated 2 this relationship
can be reversed on coordination of these ligands in their
respective Pd(II) oxidative addition intermediates arising
from aryl halides. Although it has been shown that
significant versatility can be achieved in the amination
of aryl bromides and iodides with use of the Pd/3 catalyst
system, there are limitations to our protocol for aryl
chlorides. The latter substrates require higher catalyst
loading and a reaction temperature of 110 °C, and
primary alkylamines (normal or branched chain) do not
function well as reagents. The same is true for the Pd/2
system except that the reactions can be carried out at
80 °C.
1
78-80 °C/200 mTorr). H NMR (CDCl3) δ 0.86 (d, 21 H, J )
6.7 Hz), 1.53 (br s, 3H), 1.65 (m, 3H), 2.33 (d, 6H, J ) 6.6 Hz),
2.50 (s, 6H); 13C NMR (CDCl3) δ 20.9, 22.8, 28.3, 38.4, 58.6,
59.3. Anal. Calcd for C17H39N3: C, 71.58; H, 13.68; N, 14.74.
Found: C, 71.71; H, 13.30; N, 14.66.
Tris(2-isobutylaminomethyl)ethane
5 (8.8 mmol) and
P(NMe2)3 (9.0 mmol) were charged to a 50-mL flask under Ar.
The flask was placed in a 175 °C oil bath and the reaction
mixture was stirred for 3 days at that temperature. The crude
material obtained was distilled under vacuum to afford 3 in
85% yield (overall yield from 4, 69%) as a colorless oil (bp 80-
82 °C/200 mTorr). 1H NMR (C6D6) δ 0.58 (s, 3H), 0.88 (d, 18H,
J ) 6.6 Hz), 1.70 (m, 3H), 2.46 (d, 6H, J ) 3.1 Hz), 2.62 (m,
6H). 13C NMR (C6D6) δ 20.4, 22.6, 27.0 (d, J ) 11.0 Hz), 34.3
(d, J ) 1.6 Hz), 59.8 (d, J ) 4.0 Hz), 61.6 (d, J ) 25.0 Hz). 31P
NMR (C6D6) δ 81.6. Anal. Calcd for C17H36N3P: C, 65.17; H,
11.50; N, 13.42. Found: C, 64.27; H, 11.70; N, 13.64.
P d (OAc)2/3-Ca ta lyzed Am in a tion of Ar yl a n d Het-
er oa r yl Br om id es (Ta ble 1): Gen er a l P r oced u r e. An
oven-dried Schlenk flask equipped with a magnetic stirring
bar was charged with Pd(OAc)2 (x mol %, see Table 1) and
NaO-t-Bu (1.5 mmol). Amine (1.2 mmol) and aryl bromide (1.0
mmol) were also added at this time, if they were solids. The
flask was capped with a rubber septum, evacuated, and then
flushed with argon. This cycle was repeated three times.
Ligand 3 (2x mol %, see Table 1) was then added via syringe
from a stock solution. Aryl bromide (if a liquid, 1.0 mmol),
amine (if a liquid, 1.2 mmol), and toluene (3 mL) were then
successively added by syringe. The reaction mixture was
heated at the temperature indicated in Table 1 until the
starting material had been completely consumed as judged by
TLC (15-20 h). The mixture was then cooled to room tem-
perature, adsorbed onto silica gel, and then purified by column
chromatography (hexanes/ethyl acetate as eluent).
P d (OAc)2/3-Ca ta lyzed Am in a tion of F u n ction a lized
Ar yl Br om id es (Ta ble 2): Gen er a l P r oced u r e. An oven-
dried Schlenk flask equipped with a magnetic stirring bar was
charged with Pd(OAc)2 (x mol %, see Table 2) and Cs2CO3 (1.5
mmol). Amine (1.2 mmol) and aryl bromide (1.0 mmol) were
also added at this time, if they were solids. The flask was
capped with a rubber septum, evacuated, and then flushed
with argon. This cycle was repeated three times. Ligand 3 (2x
mol %, see Table 2) was then added via syringe from a stock
solution. Aryl bromide (if a liquid, 1.0 mmol), amine (if a liquid,
1.2 mmol), and toluene (3 mL) were then successively added
by syringe. The reaction mixture was heated at a temperature
indicated in Table 2 until the starting material had been
completely consumed as judged by TLC (15-20 h). The
mixture was cooled to room temperature, adsorbed onto silica
(39) The existence of variable degrees of transannulation in adducts
of proazaphosphatranes has been documented from crystallographic
data. See ref 17.
8422 J . Org. Chem., Vol. 68, No. 22, 2003

Pd-Catalyzed Buchwald-Hartwig Amination Reactions
gel, and then purified by column chromatography using a
mixture of hexanes and ethyl acetate as eluent.
added at this time if they were solids. The flask was capped
with a rubber septum, evacuated, and then flushed with argon.
This cycle was repeated three times. Ligand 3 (2x mol %, see
Table 4) was then added via syringe from a stock solution. Aryl
iodide (if a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol),
and toluene (3 mL) were then successively added by syringe.
The reaction mixture was heated at a temperature indicated
in Table 4 until the starting material had been completely
consumed as judged by TLC (15-20 h). The mixture was cooled
to room temperature, adsorbed onto silica gel, and then
purified by column chromatography (hexanes/ethyl acetate as
eluent).
P d (OAc)2- or P d 2(d ba )3/3-Ca ta lyzed Am in a tion of Ar yl
Ch lor id es (Ta ble 3): Gen er a l P r oced u r e. An oven-dried
Schlenk flask equipped with a magnetic stirring bar was
charged with Pd(OAc)2 or Pd2(dba)3 (x mol %, see Table 3) and
NaO-t-Bu (1.5 mmol) or Cs2CO3 (1.5 mmol). Amine (1.2 mmol)
and aryl chloride (1.0 mmol) were also added at this time if
they were solids. The flask was capped with a rubber septum,
evacuated, and then flushed with argon. This cycle was
repeated three times. Ligand 3 (2x mol %, see Table 3) was
then added via syringe from a stock solution. Aryl chloride (if
a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol), and toluene
(3 mL) were then successively added by syringe. The reaction
mixture was heated at 110 °C until the starting material had
been completely consumed as judged by TLC (24 h). The
mixture was cooled to room temperature, adsorbed onto silica
gel, and then purified by column chromatography (hexanes/
ethyl acetate as eluent).
Ack n ow led gm en t. The authors thank the National
Science Foundation for financial support in the form of
a grant.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all compounds, references for products in
Tables 1-4, and 31P NMR spectra for ligand 3. This material
is available free of charge via the Internet at http://pubs.acs.org.
P d(OAc)2/3-Catalyzed Am in ation of Ar yl Iodides (Table
4): Gen er al P r ocedu r e. An oven-dried Schlenk flask equipped
with a magnetic stirring bar was charged with Pd(OAc)2 (×
mol %, see Table 4) and NaO-t-Bu (1.5 mmol) or Cs2CO3 (1.5
mmol). Amine (1.2 mmol) and aryl iodide (1.0 mmol) were also
J O034994Y
J . Org. Chem, Vol. 68, No. 22, 2003 8423