Highly active palladium catalysts supported by bulky proazaphosphatrane ligands for stille cross-coupling: Coupling of aryl and vinyl chlorides, room temperature coupling of aryl bromides, coupling of aryl triflates, and synthesis of sterically hindered biaryls

Article abstract of DOI:10.1021/ja0450096

A family of proazaphosphatrane ligands [P(RNCH₂CH ₂)₂N(R′NCH₂CH₂): R = R′ = i-Bu, 1; R = Bz, R′ = 1-Bu, 3; R = R′ = Bz, 4] for palladium-catalyzed Stille reactions of aryl chlorides is described. Catalysts derived from ligands 1 and 4 efficiently catalyze the coupling of electronically diverse aryl chlorides with an array of organotin reagents. The catalyst system based on the ligand 3 is active for the synthesis of sterically hindered biaryls (di-, tri-, and tetra-ortho substituted). The use of ligand 4 allows room-temperature coupling of aryl bromides and it also permits aryl inflates and vinyl chlorides to participate in Stille coupling.

Full text of DOI:10.1021/ja0450096

Published on Web 11/24/2004
Highly Active Palladium Catalysts Supported by Bulky
Proazaphosphatrane Ligands for Stille Cross-Coupling:
Coupling of Aryl and Vinyl Chlorides, Room Temperature
Coupling of Aryl Bromides, Coupling of Aryl Triflates, and
Synthesis of Sterically Hindered Biaryls
Weiping Su, Sameer Urgaonkar, Patrick A. McLaughlin, and John G. Verkade*
Contribution from the Department of Chemistry, Gilman Hall, Iowa State UniVersity,
Ames, Iowa 50011
Received August 18, 2004; E-mail: jverkade@iastate.edu
Abstract: A family of proazaphosphatrane ligands [P(RNCH2CH2)2N(R′NCH2CH2): R ) R′ ) i-Bu, 1; R )
Bz, R′ ) i-Bu, 3; R ) R′ ) Bz, 4] for palladium-catalyzed Stille reactions of aryl chlorides is described.
Catalysts derived from ligands 1 and 4 efficiently catalyze the coupling of electronically diverse aryl chlorides
with an array of organotin reagents. The catalyst system based on the ligand 3 is active for the synthesis
of sterically hindered biaryls (di-, tri-, and tetra-ortho substituted). The use of ligand 4 allows room-
temperature coupling of aryl bromides and it also permits aryl triflates and vinyl chlorides to participate in
Stille coupling.
Introduction
handicapped by the need to use aryl bromides or iodides as the
reaction partner. Surprisingly, unlike the case with other Pd-
The coupling of two sp2-centered carbons remains an
important goal as well as a challenge for synthetic organic
chemists. Among various strategies, transition-metal-catalyzed
processes, especially those catalyzed by palladium, have made
significant contributions to this field.1 The palladium-catalyzed
Stille cross-coupling2 of aryl halides (or halide equivalents) with
organotin reagents is an important C-C bond forming reaction
that has found wide application in natural product synthesis,3
carbohydrate chemistry,4 and biological research,5 which in part
stems from the ready availability of organotin reagents, their
air- and moisture-stability and the excellent functional group
tolerance of this approach. Until recently, this method was
catalyzed processes (e.g., Suzuki,6 Heck,7 and Buchwald-
Hartwig amination8 reactions), wherein a myriad of catalyst
systems allow coupling of economically attractive but notori-
ously unreactive aryl chlorides, the same is not true for the Stille
coupling of aryl chlorides.9 Here, the low reactivity of aryl
chlorides has generally been attributed to its reluctance to
participate in oxidative addition, the first step of the catalytic
cycle. However, significant progress has been achieved recently.
For example, Fu,10 in his pioneering studies, disclosed a
palladium-catalyst, based on sterically demanding electron-rich
P(t-Bu)3 as the supporting ligand, for the Stille cross-coupling
(6) For leading references to Suzuki couplings of aryl chlorides, see (a) Old,
D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722;
(b) Littke, A. F.; Fu, G. C. Angew Chem., Int. Ed. Engl. 1998, 37, 3387.
(c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(d) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001, 1540. (e) Li, G.
Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (f) Herrmann, W. A.; Reisinger,
C.-P.; Spiegler, M. J. Organomet. Chem. 1998, 557, 93. (g) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804. (h)
Urgaonkar, S. Nagarajan, M. Verkade, J. G. Tetrahedron Lett. 2002, 43,
8921.
(7) For leading references to Heck reactions of aryl chlorides, see (a) Littke,
A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b) Selvakumar, K.;
Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (c) Schnyder, A.; Aemmer,
T.; Indolese, A. F.; Pittelkow, U.; Studer, M. AdV. Synth. Catal. 2002, 344,
495. (d) Proeckl, S. S.; Kleist, W.; Gruber, M. A.; Koehler, K. Angew.
Chem., Int. Ed. 2004, 43, 1881.
(1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985. (b) Tsuji, J. Palladium Reagents and Catalysts:
InnoVations in Organic Synthesis; Wiley & Sons: New York, 1995. (c)
Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, Chapter 4.
(2) For reviews of the Stille reaction, see: (a) Stille, J. K. Pure Appl. Chem.
1985, 57, 1771. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508. (c) Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic Synthesis;
Butterwoth: London, 1987. (d) Farina, V.; Krishnamurthy, V.; Scott, W.
J. Org. React. 1997, 50, 1. (e) Hassa, J.; Svignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (f) Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 4176.
(3) For recent applications of the Stille reaction in natural product synthesis,
see (a) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupali,
P.; Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443. (b) Kadota, I.; Takamura,
H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 46. (c) Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003,
68, 2968. (d) Boger, D. L.; Ichikawa, S.; Jing, H. J. Am. Chem. Soc. 2000,
122, 12169. (e) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells, K.
M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett.
2000, 2, 1081.
(8) For leading references to Buchwald-Hartwig amination reactions of aryl
chlorides, see: (a) Wolfe, J. P.; Tomori, J.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158. (b) Hartwig, J. F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (c) Huang, J.; Grasa, G. A.; Nolan, S. P. Org. Lett. 1999,
1, 1307. (d) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 2367. (e) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg,
W. H.; Guram, A. S.; Petersen, J. L. Organometallics 1999, 18, 1840. (f)
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (g)
Reddy, N. P.; Tanaka, M.; Tetrahedron Lett. 1997, 38, 4807. (h) Urgaonkar,
S.; Nagarajan, M.; Verkade, J. G. Org. Lett. 2003, 5, 815.
(4) Kuribayashi, T.; Gohya, S.; Mizuno, Y.; Satoh, S. J. Carbohyd. Chem.
1999, 18, 383.
(5) Nicolaou, K. C.; King, N. P.; Finlay, M. R. V.; He, Y.; Roschangar, F.;
Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic, S.; Hepworth, D.
Bioorg. Med. Chem. 1999, 7, 665.
(9) For Pd-catalyzed Stille reactions of activated aryl chlorides, see, Kosugi,
M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301
9
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Su et al.
of aryl chlorides. This method, although general, employs a
highly air-sensitive and pyrophoric ligand that requires special
handling. Although air-stable Pd[P(t-Bu)3]2 was recommended
as an alternative to Pd2(dba)3/P(t-Bu)3 for these reactions, its
high cost is a deterrent to its widespread use. On the other hand,
the air-stable [(t-Bu)3PH]BF4,11 which is now commercially
available,12 can serve as a replacement for P(t-Bu)3 via its
deprotonation by base to release the free ligand in situ. Nolan13
reported a Pd/N-heterocyclic carbene system for the Stille
reaction of aryl chlorides. However, this protocol provided good
yields only for activated aryl chlorides. Unactivated and
deactivated aryl chlorides afforded only poor to moderate yields.
In elegant work, Choudary reported a layered double-hydroxide-
supported nanopalladium catalyst for the Stille reaction of aryl
chlorides, including electron-rich examples which operate under
mild conditions (50 °C).14 However, the generality of the process
remains to be determined. Stille reaction of aryl chlorides in
water utilizing palladium-phosphinous acid complexes was
described by Wolf.15 This methodology required quite elevated
temperatures (135-140 °C); important functional groups such
as esters and aldehydes were not compatible under the conditions
employed; and more significantly, no examples involving
electron-rich aryl chlorides were reported. More recently,
Baldwin found that the PdCl2/P(t-Bu)3 catalyst system, in
combination with CuI and CsF using DMF as the solvent,
facilitates Stille coupling of aryl chlorides at 100 °C.16 But again,
the reaction is effective with electron-deficient aryl chlorides
(except for one example reported) and less effective with
electron-rich systems (one example reported). Consequently,
catalyst systems with a higher degree of stability and activity
that can accomplish Stille coupling of electronically diverse aryl
chlorides are highly desired.
amination,18 Suzuki,6h and R-arylation19 reactions. Very recently,
we reported in a communication that Pd/1 also serves as a
general catalyst for the Stille coupling of aryl chlorides.20 In
this paper, we fully describe our studies of Stille coupling of
aryl chlorides as well as of room-temperature coupling of aryl
bromides.
Results and Discussion
At the outset, we performed experiments to examine the
influence of varying the substituents on PN3 nitrogens on catalyst
activity. We discovered that palladium catalysts supported by
ligands 2-4, bearing benzyl as well as a combination of iso-
butyl and benzyl groups on PN3 nitrogens, generate more active
catalysts for the coupling of 4-chlorotoluene with tributylphe-
nyltin than the one supported by ligand 1, with ligand 4
functioning as the most effective of all. Activation of the less
nucleophilic tin reagent was achieved by the addition of 2.2
equiv of CsF.21
Proazaphosphatranes,17 first synthesized in our laboratories,
are unusually electron-rich compounds compared with their
acyclic counterparts [e.g., P(NMe2)3] because: (a) the three PN3
nitrogens in these rigid bicyclic triaminophosphines are quite
planar,18 thus contributing their electron-density to phosphorus
thereby making it more electron-rich and (b) transannulation
from the bridgehead nitrogen’s lone pair to phosphorus could
also potentially enhance its basicity. Not surprisingly, acyclic
triaminophosphines lack both of these electron-richness en-
hancement features. It should be noted that the catalytic activity
of proazaphosphatranes can be further augmented by the
introduction of suitable groups on PN3 nitrogens.
The scope of the palladium-catalyzed Stille reaction of aryl
chlorides was explored by using 1.5 mol % of Pd2(dba)3 and 6
mol % of commercially available ligand 1 (two ligands per
palladium) in reactions conducted at 100-110 °C. A selection
of pertinent results from our previous communication20 plus one
new example (entry 11) are collected in Table 1. The reaction
has a broad scope, tolerating a variety of functional groups (NO2,
CN, CO2Me, CHO, COPh, and OMe) and substrate steric
hindrance. Chloropyridines can also be successfully coupled.
Stille Cross-Coupling Using the Pd2(dba)3/4 Catalyst
System: Activated Aryl Chlorides. We were pleased to
discover that with 4 as the ligand, the reaction temperature could
be decreased to 60 °C without compromising reaction yields in
Stille coupling of activated aryl chlorides (Table 2). We also
found that the use of a 1:1 (or 1:1.2) ratio of Pd:4 generated a
more active catalyst than a 1:2 ratio. In the presence of CsF as
an activator of the organotin reagent, the Pd2(dba)3/4 catalyst
system catalyzed the Stille reactions of a wide array of activated
aryl chlorides, encompassing functional groups such as ester
(entries 1 and 7), nitro (entry 2), aldehyde (entry 3), ketone
(entry 4), cyano (entry 5), and trifluoromethyl (entry 6), with
tributylphenyltin at 60 °C in dioxane. All these reactions
afforded excellent yields of the corresponding biaryls.
Previous work in our laboratories has established that a
bicyclic proazaphosphatrane17 bearing iso-butyl groups on the
PN3 nitrogens (1) is a highly effective ligand for several Pd-
catalyzed cross-coupling reactions, including Buchwald-Hartwig
(10) (a) Littke, A. F.; Fu, G. C. Angew Chem., Int. Ed. Engl. 1999, 38, 2411.
(b) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343.
(11) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(12) Available from Strem Chemicals.
(13) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119.
(14) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar,
B. J. Am. Chem. Soc. 2002, 124, 14127.
(15) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7551.
(16) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004, 43,
1132.
(17) For recent reviews, see (a) Verkade, J. G. Top. Curr. Chem. 2002, 233, 1.
(b) Kisanga, P. B.; Verkade, J. G. Tetrahedron 2003, 59, 7819. (c) Verkade,
J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37, 3.
(18) (a) Urgaonkar, S. Nagarajan, M.; Verkade, J. G. J. Org. Chem. 2003, 68,
452. (b) Urgaonkar, S.; Verkade, J. G. AdV. Synth. Catal. 2004, 346, 611.
Also see ref 8h. (c) Urgaonkar, S.; Verkade, J. G. Tetrahedron 2004, in
press.
(19) (a) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051. (b)
You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003.
(20) Su, W.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2004, 6, 1421.
(21) From the screening of various additives to activate the tin reagent, we found
that CsF can be replaced by Me4NF. Other fluoride sources such as KF
and ZnF2 were much less effective. Amines such as Cy2NMe (an additive
successfully used by Wolf15) gave only a moderate yield.
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A R T I C L E S
Table 2. Stille Cross-Coupling of Activated Aryl Chlorides
Table 1. Stille Cross-Coupling of Aryl Chlorides Catalyzed by
Pd2(dba)3/1
Catalyzed by Pd2(dba)3/4
a Isolated yields (average of two runs).
Table 3. Stille Cross-Coupling of Unactivated, Deactivated and
Hetero Aryl Chlorides Catalyzed by Pd2(dba)3/4
b
a Isolated yields (average of two runs). The reaction temperature was
100 °C. c The reaction temperature was 110 °C. d The ratio was determined
1
by H NMR spectroscopy.
Encouraged by the results obtained using ligand 4 with 1:1
ratio of L to Pd, we reexamined the activity of a palladium
catalyst based on ligand 1 using a 1:1 ratio of L to Pd in the
Stille process. For activated aryl chlorides, we found that the
use of 1 as the ligand gave results comparable to those obtained
when ligand 4 was employed. For example, the reaction of
4-chlorobenzonitrile with phenyltributyltin at 60 °C provided
the coupling product in 96% yield using Pd2(dba)3/1.
Stille Cross-Coupling Using the Pd2(dba)3/4 Catalyst
System: Unactivated, Deactivated, and Hetero Aryl Chlo-
rides. The Pd2(dba)3/4 catalyst system was also found to be
effective for the cross-coupling of unactivated and deactivated
aryl chlorides with tributylphenyltin at 110 °C (Table 3). For
example, the reaction of 4-chloroanisole (entry 1), 2-chloro-p-
xylene (entry 2), and 5-chloro-1,3-benzodioxole (entry 3) with
tributylphenyltin all proceeded in high yield at 110 °C using 3
mol % of Pd and 3.5 mol % of 4 (Pd:4 ) 1:1.2). Examples in
a Isolated yields (average of two runs). b 6 mol % of 1 was used.
entries 4-6 demonstrate the viability of heteroaryl chlorides in
Stille coupling. Interestingly, the reaction of activated 2-chlo-
ropyridine provided only a moderate yield (64%) of product
compared with deactivated 3-chloropyridine (97%). It should
be noted that several research groups have experienced problems
in palladium-catalyzed Heck reactions of 2-halopyridines,
presumably owing to formation of an unreactive pyridyl-bridged
palladium dimer during the course of reaction.22 Nevertheless,
(22) Nakatsu, K.; Kinoshita, K.; Kanda, H.; Isobe, K.; Nakamura, Y.; Kawaguchi,
S. Chem. Lett. 1980, 913. See also: ref 7a.
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Table 4. Stille Cross-Coupling of 4-Chloroanisole with Various
Organotin Reagents Catalyzed by Pd2(dba)3/4
Table 5. Synthesis of Sterically Hindered Biaryls via Stille
Cross-Coupling Catalyzed by Pd2(dba)3/3
b
a Isolated yields (average of two runs). The ratio was determined by
1H NMR spectroscopy.
the reaction of 2-chloropyridine occurred in 85% yield with 1
as the ligand when the ratio of Pd to ligand was increased to
1:2 (see Table 1, entry 5). Overall, catalysts based on 1 using
a 1:1.2 ratio of L to Pd gave inferior yields for deactivated and
unactivated aryl chlorides compared with the catalyst based on
4.
The coupling of chlorothiophenes is challenging in palladium-
based methodologies because of the strong affinity of sulfur
for Pd, resulting in catalyst poisoning. Gratifyingly, we found
that the Pd2(dba)3/1 catalyst system effects Stille coupling of
3-chlorothiophene in respectable yield (Table 3, entry 6). For
this substrate, the catalyst based on ligand 4 was less effective.
To our knowledge, this represents the first example of Stille
coupling of chlorothiophenes.
Stille Cross-Coupling Using the Pd2(dba)3/4 Catalyst
System: Variation of Organotin Reagents. The scope of the
Pd2(dba)3/4/CsF catalyst system was further expanded to include
a diverse set of organotin reagents, in which deactivated
4-chloroanisole was chosen as the coupling partner (Table 4).
Functionalities on organotin reagents that were successfully
coupled using this methodology included vinyl (entries 1 and
2), allyl (entry 3), aryl (Table 3, entry 1), and heteroaryl groups
(entries 4 and 5 in Table 4). The results obtained in the latter
entries are particularly significant, since very few examples of
Stille reactions of aryl chlorides with heteroaryl tin reagents
are known. To the best of our knowledge, this is the first time
that cross-coupling of an aryl chloride with organotin reagents
possessing thiophene and furan moieties has been successfully
carried out.
b
a Isolated yields (average of two runs). 3 mol % of Pd2(dba)3 and 7
mol % of 3 were used.
related Suzuki-Miyaura cross-coupling reactions for synthesizing
tri- and tetra-ortho substituted biaryls,23 their efficient production
via the Stille reaction has not been rewarding so far except for
the catalyst system [Pd(P(t-Bu)3)2] reported by Fu.10b As a
logical extension of our efforts, the synthesis of sterically
hindered biaryls via Stille coupling was then examined using
proazaphosphatranes as ligands. Disappointingly, the reaction
of 2-chloro-m-xylene with 2,4,6-trimethylphenyl(tributyl)tin
provided only a trace amount of tetra-ortho substituted biaryl
when 1 was employed as the ligand. However, ligands 2 and 4
afforded a 27% and 61% yield of the desired biaryl, respectively.
Subsequently, much to our delight, we found that the introduc-
tion of ligand 3 allowed such cross-coupling to occur in high
yield (81%, Table 5, entry 4). The ability of the catalyst system
Pd2(dba)3/3 to produce sterically hindered biaryls was then
explored (Table 5). As seen from this table, the reaction tolerates
not only one or two ortho-substituents on the aryl halide, but it
also tolerates the same steric hindrance on the aryl tin reagent.
Synthesis of Sterically Hindered Biaryls Using the Pd2-
(dba)3/3 Catalyst System. An important criterion used to judge
the performance of a catalyst system in Pd-catalyzed cross-
coupling processes is its ability to generate sterically hindered
biaryls. Although great progress has been achieved in closely
(23) (a) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc. 2003, 125,
16194. (b) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew.
Chem., Int. Ed. 2003, 42, 3690. (c) Yin, J.; Rainka, M. P.; Zhang, X.-X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162. (d) Walker, S. D.;
Barder, T. E.; Martineli, J. R.; Bulchwald, S. L. Angew. Chem., Int. Ed.
2004, 43, 1871.
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A R T I C L E S
Table 6. Room Temperature Stille Cross-Coupling of Aryl
Bromides Catalyzed by Pd2(dba)3/4
Stille couplings, THF was found to be the most effective solvent.
The results described in Table 6 demonstrate that Pd2(dba)3/4/
CsF enables coupling of electronically and sterically diverse
aryl bromides with a broad spectrum of tin reagents at room
temperature. Thus, electron-neutral 4-tert-butylbromobenzene
(Table 6, entries 1-4), ortho-substituted and electron-rich
4-bromo-3-methylanisole (entries 5-7), and even very electron-
rich 4-N,N-dimethylaminobromobenzene coupled in excellent
yields (entries 9 and 10) at room temperature. However, Stille
reactions of substrates containing the thiophene moiety were
very slow at room temperature, and mild heating (50 °C) was
required for the reactions to proceed to completion (entries 8,
11, 12, and 13). This result may be ascribed to a tendency of
the thiophenic sulfur to bind to palladium, thus reducing its
activity and/or retarding transmetalation.
Even sterically hindered biaryls could be synthesized at room
temperature using ligand 3 (eqs 1 and 2). Equation 2, which
depicts the first successful synthesis of a tri-ortho-substituted
biaryl through a Stille reaction of an aryl bromide at room-
temperature, is particularly interesting.
Another challenging coupling of electron-rich 4-bromoanisole
with electron-deficient 4-(tributylstannyl)nitrobenzene was also
accomplished at room-temperature in good yield (eq 3).
Interestingly, the reaction proceeded quite sluggishly using our
standard conditions [Pd2(dba)3/4/THF or Pd2(dba)3/4/dioxane].
However, by employing the conditions developed by Baldwin16
[except that in the present study ligand 4 was employed whereas
Baldwin used P(t-Bu)3], the desired coupling product was
obtained in 76% isolated yield. It should also be noted that in
this case, the addition of CuI to the reaction mixture significantly
improved the yield because in its absence, only a trace amount
of the desired coupled product was obtained. Similar enhance-
ment of a Stille process using a combination of CuI and CsF
was observed by Baldwin.16
a Isolated yields (average of two runs). b The reaction temperature was
50 °C.
Excellent yields were obtained in all cases. Even very sterically
hindered 2,4,6-triisopropyl bromobenzene can be coupled. For
example, the reaction of 2,4,6-triisopropyl bromobenzene with
o-tolyltributyltin gave an 88% isolated product yield (Table 5,
entry 9). To our knowledge, this represents the first example
of the synthesis via a Stille reaction of a tri-ortho-substituted
biaryl bearing ortho groups larger than a methyl group.
Stille Cross-Coupling of Aryl Bromides at Room Tem-
perature Using the Pd2(dba)3/4 Catalyst System. We next
turned our attention to Stille reactions of aryl bromides. There
are numerous reports on Stille reactions of aryl bromides at
elevated temperatures,24 but only one general catalyst system
[Pd2(dba)3/P(t-Bu)3] has been described for room-temperature
reactions.10b Initially, we performed room-temperature Stille
experiments were using 1 as the ligand. We found that although
Pd2(dba)3/1/CsF catalyzes the room-temperature coupling of
4-tert-butylbromobenzene and 4-bromo-3-methylanisole with
vinyl(tributyl)tin in 91% and 82% yields, respectively, reactions
did not proceed to completion in THF even after 21 h. We were
pleased to observe, however, that the use of 4 as the ligand
leads to a significantly more active catalyst, allowing the reaction
to proceed to completion in 10-16 h. For room-temperature
We also briefly examined the efficacy of aryl triflates as
substrates in Stille reactions catalyzed by proazaphosphatrane
ligands. We found that aryl triflates are also viable substrates
(24) For recent examples, see: Alonso, D. A.; Njera, C.; Pacheco, M. C. Org.
Lett. 2000, 2, 1823. See also: refs 13 and 15.
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and again the use of ligand 4 provided the best results (eq 4).
The reaction did not proceed to completion with the use of
ligand 1 even after 36 h, whereas the use of ligands 2, 3, and
4 led to completion within that time.
Competition Experiments for the Order of Reactivity. To
determine the order of reactivity of aryl halides and triflates in
Stille cross-couplings catalyzed by Pd2(dba)3/4, two competition
experiments were conducted as shown in eqs 5 and 6. Not
surprisingly, it was established that the product obtained was
derived almost exclusively from the aryl bromide (eq 5), whereas
the competition experiment between aryl chloride and triflate
performed at 90 °C revealed that the aryl triflate reacted in
preference to the aryl chloride (eq 6). From these two experi-
ments, it can be concluded that the order of reactivity under
our conditions follows the traditional order: aryl bromide >
aryl triflate > aryl chloride.2 It is worthy of note that this
observed reactivity is quite different from the one reported by
Fu’s group for Stille coupling using P(t-Bu)3 as a ligand, which
follows the unexpected order: aryl bromide > aryl chloride >
aryl triflate.10b
Table 7. Stille Cross-Coupling of Vinyl Chlorides Catalyzed by
Pd2(dba)3/4
Stille Cross-Coupling of Vinyl Chlorides Using the Pd2-
(dba)3/4 Catalyst System. Another challenging Stille reaction
involves the use of unactivated vinyl chlorides and not
unexpectedly, only one catalyst system (Pd/P(t-Bu)3)10b,25 has
thus far been reported for the Stille coupling of such substrates.
In that report, 3 mol % of Pd(P(t-Bu)3)2 was employed as the
catalyst, and the reaction temperature was 100 °C. We observed
that the Pd2(dba)3/4 catalyst system was also effective for cross-
coupling a vinyl chloride with various tin reagents at 100 °C,
affording the corresponding coupled products in excellent yields
(Table 7).
31P NMR Studies. To gain some insights into the mecha-
nism,26 we investigated the fate of ligand 4 in Stille reactions
by 31P NMR spectroscopy. A mixture of 4 (δ 127.9) and Pd2-
(dba)3 in a 1:1 ratio at room temperature shows a phosphorus
resonance at δ 132.4. We tentatively assigned this peak to a
Pd-4 complex. We then monitored the reaction of 1-bromo-4-
tert-butylbenzene with tributylphenyltin in THF at room tem-
perature as well as the reaction of 4-chlorotoluene with
a Isolated yields (average of two runs).
tributylphenyltin in dioxane at 110 °C in the presence of ligand
4. In both cases, the same 31P chemical shift at 132.4 ppm was
observed as the only major phosphorus-containing species
(>90%). These observations suggest that perhaps the Pd-4
complex (δ 132.4) is the resting state species in the catalytic
cycle. Further work in our laboratory is underway to delineate
the palladium-species involved in these reactions.
Conclusions
Proazaphosphatrane ligands (1, 3, and 4) provide general and
effective palladium catalysts for Stille transformations. Catalysts
utilizing 1 and 4 as the supporting ligand efficiently allow
coupling of electronically diverse aryl chlorides with a wide
array of organotin reagents. Reactions of sterically hindered
substrates are most effectively catalyzed with 3 as the supporting
ligand and Stille couplings of aryl bromides are more easily
(25) Stille couplings of activated vinyl chlorides are known. See: (a) Rubin,
Y.; Knobler, C. B.; Diederich, F. J. Am. Chem. Soc. 1990, 112, 1607. (b)
Liebeskind, L. S.; Yu, M. S.; Yu, R. H.; Wang, J.; Hagen, K. S. J. Am.
Chem. Soc. 1993, 115, 9048. (c) May, P. D.; Larsen, S. D. Synlett 1997,
895.
(26) For an excellent review of the mechanisms of the Stille reaction, see:
Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
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Highly Active Palladium Catalysts
A R T I C L E S
facilitated at room-temperature with ligand 4. Vinyl chlorides
and aryl triflates are also suitable substrates.
electron density at palladium favoring oxidative addition, while
simultaneously inhibiting decomposition of the complex.
We believe that a unique balance of unusual electron-richness
and steric hindrance is a salient feature of these ligands. The
exceptional activity shown by the palladium catalyst supported
by ligand 4 may also stem from the possibility that a benzyl
group stabilizes the active palladium catalyst through the
interaction of its aromatic π-orbitals with empty d-orbitals on
palladium.27 Another possibility is that subtle stereoelectronic
effects presently unclear may operate to ligate 4 more tightly
to the Pd center compared with 1, thereby maintaining a higher
Acknowledgment. We thank the Aldrich Chemical Co. for
their generous support of this study by supplying research
samples. The National Science Foundation is gratefully ac-
knowledged for financial support of this work in the form of a
grant.
Supporting Information Available: Experimental details,
references for known compounds, complete characterization of
unknown compounds, and copies of 1H and 13C for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) Pd-arene interactions in palladium complexes have been proposed to
cotribute to their catalytic activity. See (a) Reid, S. M.; Boyle, R. C.; Mague,
J. T.; Fink, M. J. J. Am. Chem. Soc. 2003, 125, 7856. (b) Catellani, M.;
Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am.
Chem. Soc. 2002, 124, 4336. See also: refs 8a, 22c, and 22d.
JA0450096
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