Triazole-based monophosphine ligands for palladium-catalyzed cross-coupling reactions of aryl chlorides

Article abstract of DOI:10.1021/jo060321e

A variety of triazole-based monophosphines (ClickPhos) have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes. Their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides. Ligand 7i, which has a 2,6-dimethoxybenzene moiety, provided good results in Suzuki-Miyaura reaction to form hindered biaryls. A CAChe model for the Pd/7i complex shows that the likelihood of a Pd-arene interaction might be a rationale for its high catalytic reactivity.

Full text of DOI:10.1021/jo060321e

Triazole-Based Monophosphine Ligands for Palladium-Catalyzed
Cross-Coupling Reactions of Aryl Chlorides
Qian Dai, Wenzhong Gao, Duan Liu, Lea M. Kapes, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
ReceiVed February 15, 2006
A variety of triazole-based monophosphines (ClickPhos) have been prepared via efficient 1,3-dipolar
cycloaddition of readily available azides and acetylenes. Their palladium complexes provided excellent
yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides.
Ligand 7i, which has a 2,6-dimethoxybenzene moiety, provided good results in Suzuki-Miyaura reaction
to form hindered biaryls. A CAChe model for the Pd/7i complex shows that the likelihood of a Pd-
arene interaction might be a rationale for its high catalytic reactivity.
Introduction
however, poor yields were obtained for the reaction of primary
amines with aryl halides.4 A second generation of chelating
bisphosphine ligands (1, 2) was introduced to solve this problem,
but these ligands were not effective for the reaction of
unactivated aryl chlorides.5 In the late 1990s, Buchwald and
co-workers reported a series of monophosphine ligands 3 which
are very effective for the room-temperature amination reactions.6
More recently, Beller and co-workers reported the synthesis of
ligand 4 for the coupling of sterically hindered amines7 and
Transition metal catalyzed cross-coupling reactions to form
C-C, C-N, C-O, and C-S bonds are among the most
powerful organometallic transformations in organic chemistry.1
For instance, Pd-catalyzed amination of aryl halides is a principle
method for the synthesis of aniline derivatives.2 Employing
readily available aryl chlorides in this transformation has been
a recent focus. Since the initial findings reported by Kosugi,3
numerous ligands have been developed for this type of
transformation (Figure 1). P(o-tolyl)3 was originally used;
(4) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (b)
Guram, A. S.; Rennel, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl.
1995, 34, 1348. (c) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 7901.
(5) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217. (c) Marcoux, J. F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem.
1997, 62, 1568.
(6) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
1999, 38, 2413. (c) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (d) Charles, M. D.; Schultz,
P.; Buchwald, S. L. Org. Lett. 2005, 7, 3965.
(1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985. (b) Collman, J. P., Hegedus, L. S., Norton, J. R.,
Finke, R. G., Eds. Principles and Applications of Organotransition Metal
Chemistry; University Science: Mill Valley, CA, 1987. (c) Diederich, F.,
Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 1998. (d) Diederich, F., de Meijere, A., Eds. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
2004.
(2) (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366
and references therein. (b) Miura, M. Angew. Chem., Int. Ed. 2004, 43,
2201. (c) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
(3) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
(7) Ehrentraut, A.; Zarf, A.; Beller, M. J. Mol. Catal. 2002, 182, 515.
10.1021/jo060321e CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/13/2006
3928
J. Org. Chem. 2006, 71, 3928-3934

Palladium-Catalyzed Cross-Coupling Reactions of Aryl Chlorides
FIGURE 1. Examples of ligands for Pd-catalyzed amination reactions.
ligand 5 with excellent reactivity for a wide variety of
It has been well recognized that ligands employed in these
processes have significant impact on the outcome of the
reactions. Therefore, designing ligands with appropriate natures
and great diversity is crucial for dealing with the challenging
substrates in this area. Our previous work on the Pd-catalyzed
Suzuki-Miyaura coupling reaction has demonstrated that the
triazole monophosphines, ClickPhos, are excellent ligands for
this transformation with turnovers of up to 9300.16 These ligands
can be obtained by a Grignard reagent mediated 1,3-dipolar
addition to form a triazole compound, followed by deprotonation
and reaction with different phosphine chlorides. Herein, we wish
to report a more detailed study on ligand preparation and their
applications to the amination reactions of unactivated aryl
chlorides and Suzuki-Miyaura coupling reactions of a variety
of substrates, including ortho-substituted aryl chlorides to form
hindered biaryls.
substrates.8a,b
Pd-catalyzed Suzuki-Miyaura coupling reaction is one of
the most attractive methods for the preparation of biaryl
compounds due to the advantages of the wide functional group
tolerance and the use of stable and nontoxic organoborane
reagents.9 Some of the recent progresses in this reaction have
been focused on the use of aryl chlorides as coupling partners
in view of their low cost and readily available diversity.10
A
number of reports have shown that Pd complexes derived from
sterically hindered and electron-rich phosphines are effective
catalysts for this transformation.11 Some of the notable examples
include the use of bulky trialkylphosphines (i.e., PtBu3) by Fu,12
dialkylbiphenylphosphines (i.e., 3) by Buchwald,6a-c,13 and
dialkyl heteroaromatic phosphines (i.e., 5) by Beller.8a,c Other
strategies such as using sterically hindered N-heterocyclic
carbenes (NHCs) as ligands,14 and palladacycles as the pre-
catalysts,15 also provide efficient catalytic systems.
Results and Discussion
Although various new ligands have been reported, rapid
assembling of structurally diverse ligand systems via efficient
synthetic methods is still important for the development of
effective catalysts for the widespread applications of coupling
reactions. Recently, Sharpless and co-workers have reported
elegant chemistry for the formations of 1,4- and 1,5-disubstituted
triazole compounds. The unique properties such as modularity,
wide reaction scope, mild reaction conditions, high yields, and
regioselectivity make these reactions excellent examples of click
chemistry.17 Following the general procedure reported by
Sharpless,17c a straightforward two-step synthesis of ClickPhos
has been developed (Scheme 1). 1,5-Disubstituted triazoles
6a-e were obtained in good yields from phenyl azide18a and
various aryl acetylenes, which can be easily prepared from
(8) (a) Zapf, A.; Jackstell, R.; Rataboul, F.; Reirmeier, T.; Monsees, A.;
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Ed. 2000, 39, 4153. (b) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser,
H.-U. Angew. Chem., Int. Ed. 2002, 41, 3668. (c) Stambuli, J. P.; Kuwano,
R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41, 4746. (d) Kataoka, N.;
Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
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J. Org. Chem, Vol. 71, No. 10, 2006 3929

Dai et al.
TABLE 1. Screening Ligands and Reaction Conditions for
Amination of Aryl Chloridesa
TABLE 2. Pd/ClickPhos-Catalyzed Amination of Aryl Chloride
with Various Aminesa
entry
1
Pd (mol %)
ligand (mol %)
base
T (°C) yieldb (%)
1% Pd(OAc)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
1% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
0.5% Pd(dba)2
7c (2)
7c (2)
7c (2)
7c (2)
7c (2)
7c (1)
7c (1)
7b (1)
7d (1)
7e (1)
7f (1)
7g (1)
7h (1)
7i (1)
7j (1)
KOtBu
80
80
87
92
94
94
88
92
91
90
91
85
95
93
93
90
88
KOtBu
2
3
4
5
6
7
8
9
10
11
12
13
14
KOtBu
110
110
80
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
110
110
110
110
110
110
110
110
110
110
a 1 mmol of aryl chloride 8, 1.2 mmol of arylamine 9, 1.2 mmol of
base, 0.5-1 mol % of Pd, 1-2 mol % of ligand 7, 3 mL of toluene, 24 h.
1
b Isolated yield. Purity was confirmed by H NMR.
SCHEME 1. Synthesis of ClickPhos 7a-j
Corey-Fuchs reaction of commercial available aldehydes.18b
Treatment of 6a-e with LDA followed by addition of various
chlorophosphines furnished ligands 7a-j in good to excellent
yields.
a 1 mmol of aryl chloride 8, 1.2 mmol of arylamine 9, 1.2 mmol of
NaOtBu, 0.5 mol % of Pd(dba)2, 1 mol % of ligand 7g, 3 mL of toluene,
20 h, 110 °C. b Isolated yield. Purity was confirmed by 1H NMR. c KOtBu
was used instead of NaOtBu. d 5 equiv of amine was used.
To evaluate the effectiveness of ClickPhos in the Pd-catalyzed
amination of unactivated aryl chlorides, we first tested the
reaction between 4-chlorotoluene (8a) and aniline (9a) with
ligand 7c, which gave excellent results in the Suzuki-Miyaura
reaction (Table 1, entries 1-6). The reactions were performed
with 0.5-1 mol % of Pd(OAc)2 or Pd(dba)2. Pd(dba)2 afforded
a slightly better yield than Pd(OAc)2 (Table 1, entries 1-3).
Different bases have also been tested; both KOtBu and NaOtBu
gave similar results. When the reaction temperature was
increased from 80 to 110 °C, better yields were obtained. In
general, ligands bearing di-tert-butylphosphino substituents are
more efficient than those having dicyclohexylphosphino groups.
Catalysts generated from other ligands 7b, 7d, 7e, 7h, and 7i
provided results comparable to those of 7c, while 7f and 7j gave
slightly lower yields (Table 1, entries 7-10 and 12-14).
ClickPhos 7g was found to be the ligand of choice, giving the
highest yield of product 10a (95%, Table 1, entry 11). These
results demonstrated that delicate tuning of the electronic and
steric properties of the ligands by changing different substituent
groups on the triazole ring can enhance the reaction yield.
On the basis of the optimized reaction conditions, the coupling
reactions between several aryl chlorides and a variety of primary
and secondary amines were carried out to explore the scope of
the Pd(dba)2/7g catalytic system (Table 2). In most cases, the
corresponding anilines were obtained in good to excellent yields
(>90%) with a low catalyst loading (0.5 mol % of Pd). For an
electron-rich amine 9b, a better result was obtained when a
stronger base, KOtBu, was used instead of NaOtBu (Table 2,
entry 2). In the case of an aliphatic primary amine (Table 2,
entry 8), a large excess of n-butylamine (5 equiv) had to be
(17) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (c) Krasinski, A.;
Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237. (d) Feldman, A.
K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897. (e) Himo, F.; Lovell,
T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin,
V. V. J. Am. Chem. Soc. 2005, 127, 210.
(18) (a) Zhu, W.; Ma, D. Chem. Commun. 2004, 7, 888. (b) Gilbert, A.
M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607.
3930 J. Org. Chem., Vol. 71, No. 10, 2006

Palladium-Catalyzed Cross-Coupling Reactions of Aryl Chlorides
TABLE 3. Screening of Ligands and Reaction Conditionsa
TABLE 4. Pd-Catalyzed Suzuki-Miyaura Coupling of Aryl
Chloridesa
entry
ligand
base
yieldb (%)
entry
aryl chloride
boronic acid
yieldb (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7c
7c
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KF
<5
70
94
88
91
20
91
79
86
57
1
2
3
4
5
6
7
8
9
10
11
12
13
14
R1 ) p-Me, 8a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) H, 11a
R2 ) p-Me, 11b
R2 ) H, 11a
R2 ) p-Me, 11b
89 (12a)
92 (12b)
98 (12c)
86 (12d)
99 (12e)
93 (12f)
96 (12g)
94 (12g)
91 (12h)
89 (12i)
90 (12j)
92 (12k)
99 (12l)
99 (12a)
R1 ) o-Me, 8b
R1 ) 2,5-di-Me, 8c
R1 ) p-OMe, 8d
R1 ) p-COMe, 8e
R1 ) p-COMe, 8e
R1 ) p-NO2, 8f
R1 ) p-CO2Me, 8g
R1 ) p-CF3, 8h
R1 ) p-COMe, 8i
R1 ) o-CN, 8j
10
CsF
a 1 mmol of 4-chlorotoluene 8a, 1.5 mmol of phenylboronic acid 11a, 2
mmol of base, 1 mol % of Pd(dba)2, 2 mol % of ligand 7, 3 mL of toluene,
R1 ) o-CN, 8j
12 h, 80 °C. b Isolated yield. Purity was confirmed by H NMR.
1
R1 ) 2-pyridinyl, 8k
R1 ) H, 8l
a 1 mmol of aryl chloride 8, 1.5 mmol of arylboronic acid 11, 2 mmol
of K3PO4, 0.1 mol % of Pd(dba)2, 0.20 mol % of ligand 7c, 3 mL of toluene,
used to suppress the disubstituted products. Ortho substituents
on the aryl chlorides can be tolerated as well, leading to the
corresponding hindered coupling products in high yields (Table
2, entries 9-12). These results demonstrate the broad substrate
scope and high catalytic efficiency of the Pd(dba)2/7g system
for the amination reactions of aryl chlorides, which are
comparable or better than those reported to date with other
catalytic systems.8b,19
1
12 h, 100 °C. b Isolated yield. Purity was confirmed by H NMR.
nearly quantitative yield (Table 4, entry 13). For more chal-
lenging electronically unactivated and deactivated aryl chlorides,
the corresponding biaryl products were obtained in good to
excellent yields (Table 4, entries 1-4). Ortho substituents on
the aryl chlorides can be tolerated as well, leading to the
corresponding hindered coupling products in high yields (Table
4, entries 2, 3, and 10-12). Reactions using aryl boronic acid
11b were also performed, and the yields were as good as those
of 11a (Table 4, entries 12 and 14). Furthermore, when applying
very low catalyst loading (0.01 mol % of catalyst), aryl chloride
8d also coupled with phenylboronic acid (11a) efficiently, giving
the product 12d in 93% yield (Table 4, entry 6, 9300 TON).
While excellent results have been achieved between the
coupling of a wide range of aryl chlorides with several boronic
acids, coupling between ortho-substituted aryl chlorides and
ortho-substituted boronic acids, forming highly hindered biaryls,
are considerably more challenging reactions. The steric hin-
drance prevents an effective oxidative addition of aryl chlorides
to palladium centers. Recently, Buchwald reported a highly
active ligand with a 2,6-dimethoxybenzene moiety for this type
of reaction,13b which prompted us to diversify ClickPhos for
Suzuki-Miyaura coupling of more hindered substrates.
Reaction between 2-chloro-p-xylene (8c) and 2-methylphen-
ylboronic acid (11c) was first tested with ligands 7c-j (Table
5). In most cases, moderate to good yields were obtained with
the exception that ligand 7d only gave 17% yield (Table 5, entry
2). A general trend is that ligands bearing a di-tert-butylphos-
phino group (7c, 7e, 7g, and 7i) give much higher yields than
their dicyclohexylphospino analogues (7d, 7f, 7h, and 7j).
Ligand 7i, which has a 2,6-dimethoxybenzene moiety on the
triazole ring, provided the best yield of biaryl 12d (96%, Table
5, entry 7).
The high activities of the Pd/ClickPhos catalysts in the
amination reactions led us to further explore their applications
to Suzuki-Miyaura coupling reactions of aryl chlorides. The
reaction between 4-chlorotoluene (8a) and phenylboronic acid
(11a) was first tested with ligands 7a-h (Table 3, entries 1-8).
The reactions were performed in the presence of the catalysts
derived from 1 mol % of Pd(dba)2 and 2 mol % of ligands.
While a very low yield (<5%) of the coupling product was
observed with diphenylphosphine ligand 7a, good to excellent
yields were achieved with dialkylphosphine ligands 7b and 7c
(70% and 94%, respectively). These results are consistent with
the general trend of the ligand efficiency observed in coupling
reactions with other structurally related ligand sets. In general,
sterically hindered and electron-rich ligands are more efficient
for coupling reactions. Catalysts generated from another two
ligands 7e and 7g, having di-tert-butylphosphino substituents,
also provided the coupling product in yields comparable to that
of 7c (Table 3, entries 5 and 7). Ligand 7d affored similar results
to its analogue 7e, while 7f,h gave much lower coupling yields
(Table 1, entries 4, 6, and 8). Using the best ligand 7c, various
bases, such as K3PO4, KF, and CsF, were examined. K3PO4
was found to be the base of choice for the Pd/7c catalytic system
(Table 3, entries 3, 9, and 10).
On the basis of the optimized reaction conditions, the coupling
reactions between a range of aryl chlorides and several aryl
boronic acids were carried out to explore the general effective-
ness of the Pd/7c catalytic system (Table 4). Excellent yields
were obtained with 0.1 mol % of the catalyst in the reactions
between various electron-deficient aryl chlorides and phenyl-
boronic acid (Table 4, entries 5-12). A heteroaromatic chloride
8k coupled with phenylboronic acid providing product 12l in
Using ligands 7c, 7i, and 7j, several hindered disubstituted
aryl chlorides were employed in the Pd-catalyzed Suzuki-
Miyaura reaction with boronic acids (Table 6). For 2-chloro-
p-xylene (8c), ligand 7c gave results comparable to those
achieved by 7i (Table 6, entries 1-4). However, for more
hindered substrate 2-chloro-m-xylene (8m), the coupling with
2-methoxyboronic acid (11d) proceeded to give biaryl 12o in
(19) For most recent examples of Pd-catalyzed amination reactions of
aryl chlorides, see: (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J.
F. Angew. Chem., Int. Ed. 2005, 44, 1371. (b) Stambuli, J. P.; Incavito, C.
D.; Buehl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 1184.
J. Org. Chem, Vol. 71, No. 10, 2006 3931

Dai et al.
TABLE 5. Screening Ligands and Reaction Conditionsa
TABLE 6. Pd-Catalyzed Suzuki-Miyaura Coupling of Hindered
Aryl Chloridesa
entry
ligand
yieldb (%)
1
2
3
4
5
6
7
8
7c, Ar ) Ph, R ) tBu
89
17
70
45
94
63
96
5x
7d, Ar ) 1-Np, R ) Cy
7e, Ar ) 1-Np, R ) tBu
7f, Ar ) 2-MeO-Ph, R ) Cy
7g, Ar ) 2-MeO-Ph, R ) tBu
7h, 2-NMe2-Ph, R ) tBu
7i, Ar ) 2,6-dimethoxy-Ph, R ) tBu
7j, Ar ) 2,6-dimethoxy-Ph, R ) Cy
a 1 mmol of 8c, 1.5 mmol of 11c, 2 mmol of K3PO4, 0.1 mol % of
Pd(dba)2, 0.2 mol % of ligand 7, 3 mL of toluene, 12 h, 80 °C. b Isolated
1
yield. Purity was confirmed by H NMR.
FIGURE 2. MM2 calculations of Pd/7i complex based on the CAChe
program.
only 12% yield even with 1 mol % of the catalyst derived from
7c. In constrast, using the catalyst derived from 7i, the yield
was greatly increased to 72% (Table 6, entry 6). Ligand 7j was
also effective for this reaction, affording a moderate yield of
57% (Table 6, entry 7). The electronic property of boronic acids
also played an important role in this type of reaction. When a
less electron rich boronic acid 11c was used, higher yields were
generally achieved (Table 6, entry 8-10). Ligand 7i was again
found to the most efficient ligand, giving 90% yield of biaryl
12p (Table 6, entry 9). Compared to ligand 7j, the higher
catalytic efficiency observed with ligand 7i is likely because
the bulky di-tert-butyl groups can better facilitate the reductive
elimination to form the product.6c
a 1 mmol of 8, 1.5 mmol of 11, 2 mmol of K3PO4, 0.1 mol % of Pd(dba)2,
0.2 mol % of ligand 7, 3 mL of toluene, 12 h, 80 °C. b Isolated yield. Purity
was confirmed by 1H NMR. c 1 mol % of Pd(dba)2 and 2 mol % of ligand
were used. d The reaction was carried out at 120 °C.
Conclusions
In conclusion, we have developed a new series of mono-
phosphines 7 (ClickPhos) bearing a triazole heterocycle in the
backbone. These ligands are readily accessible and could be
easily diversified via efficient 1,3-dipolar cycloadditions of
various azides and acetylenes. With Pd complex derived from
ligand 7g, up to 98% yield was achieved in the amination
reactions of aryl chlorides. Pd/7c complex provided highly active
catalyst for Suzuki-Miyaura coupling of aryl chlorides with
excellent yields and TONs. Among the ClickPhos series, ligand
7i, which has a 2,6-dimethoxybenzene moiety on the triazole
ring, was particularly effective in the Pd-catalyzed Suzuki-
To further understand the special activity of ligand 7i, a
CAChe model of Pd/7i complex based on the MM2 calculation
was obtained. The key feature of the complex structure is the
orientation of the arene group on the 5-position of the triazole
ring. The distance between the palladium and the sp2-carbon
on the 2,6-dimethoxybenzene moiety (as indicated by the arrow
in Figure 2) is around 2.245 Å based on the MM2 calculation,
which is appreciably shorter than the sum of the van der Waals
radii for Pd and C, 3.33 Å (Pd ) 1.63 Å, C ) 1.70 Å). This
points to the likelihood of a metal-arene interaction, which
might stabilize the palladium complex in the catalytic cycle and
therefore enhance the catalyst reactivity. Similar observations
have previously been reported by Buchwald13d and Fink.20
(20) Reid, S. M.; Boyle, R. C.; Mague, J. T.; Fink, M. J. J. Am. Chem.
Soc. 2003, 125, 7816.
3932 J. Org. Chem., Vol. 71, No. 10, 2006

Palladium-Catalyzed Cross-Coupling Reactions of Aryl Chlorides
10.3, 14.3 Hz); 31P NMR (CD2Cl2, 145 MHz) δ 3.63; HRMS
(ESI+) calcd for C26H31N3P (MH+) 416.2256, found 416.2252.
4-Dicyclohexylphosphanyl-1-phenyl-5-(2-methoxyphenyl)-1H-
[1,2,3]triazole (7f). This compound was prepared from triazole
compound 6c and PCy2Cl following the general procedure as a
white solid (64% yield): 1H NMR (360 MHz, CD2Cl2) δ 7.36-
7.42 (m, 6H), 7.30 (dd, J ) 1.3, 7.5 Hz, 1H), 7.05-7.09 (m, 1H),
6.89 (d, J ) 8.4 Hz, 1H), 3.47 (s, 3H), 2.10-2.33 (m, 2H), 1.61-
2.05 (m, 10H), 0.98-1.52 (m, 10H); 13C NMR (90 MHz, CD2Cl2)
δ 157.2, 141.8 (d, J ) 27.4 Hz), 141.5 (d, J ) 15.3 Hz), 137.6,
132.4, 131.1, 128.8, 128.4, 123.8, 120.3, 117.1, 111.1, 55.0, 33.0
(d, J ) 42.4 Hz), 30.3, 29.4 (d, J ) 30.8 Hz), 27.2 (d, J ) 19.5
Hz), 27.1, 26.6; 31P NMR (145 MHz, CD2Cl2) δ -27.99; HRMS
(ESI+) calcd. for C27H35N3OP (MH+) 448.2518, found 448.2510.
4-Di-tert-butylphosphanyl-1-phenyl-5-(2-methoxyphenyl)-1H-
[1,2,3]triazole (7g). This compound was prepared from triazole
compound 6c and PtBu2Cl following the general procedure as a
white solid (76% yield): 1H NMR (CD2Cl2, 360 MHz) δ 7.47-
7.32 (m, 7H), 7.09 (t, J ) 7.2 Hz, 1H), 6.90 (d, J ) 8.2 Hz, 1H),
3.48 (s, 3H), 1.41 (d, J ) 11.8 Hz, 9H), 1.24 (d, J ) 11.8 Hz, 9H);
13C NMR (CDCl3, 90 MHz) δ 157.3, 142.5 (d, J ) 9.3 Hz), 142.2
(d, J ) 24.5 Hz), 137.6, 132.6 (d, J ) 2.6 Hz), 131.1, 128.8, 128.5,
123.9, 120.3, 117.4, 111.0, 54.9, 32.5 (dd, J ) 10.3, 17.0 Hz), 30.2
(dd, J ) 14.1, 44.1 Hz); 31P NMR (CD2Cl2, 145 MHz) δ 3.47;
HRMS (ESI+) calcd for C23H31N3OP (MH+) 396.2205, found
396.2202.
Miyaura coupling to form hindered biaryl compounds (up to
96% yield). A CAChe model for the Pd/7i complex shows that
the likelihood of a Pd-arene interaction might be a rationale
for the its high catalytic reactivity.
Experimental Section
General Procedure for the Preparation of ClickPhos 7a-j.
4-Di-tert-butylphosphanyl-1,5-diphenyl-1H-[1,2,3]triazole (7c).
To a solution of 1,5-diphenyl-1H-[1,2,3]triazole (6a) (0.520 g, 2.35
mmol) in THF (20 mL) was added LDA (2.35 mmol) at 0 °C. The
reaction mixture was stirred at 0 °C for 1.5 h followed by addition
of PtBu2Cl (0.446 mL, 2.35 mmol). The resulting mixture was
slowly warmed to rt and stirred overnight. TLC showed the reaction
was essentially complete after 16 h. The solvent was removed under
vacuum. A degassed mixture of brine/H2O (1:1) was added, and
the resulting mixture was extracted with degassed ether (15 mL ×
3). The combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel under nitrogen (hexanes/ether,
80:20) to afford 7c as a sticky solid (0.78 g, 91%): 1H NMR (CD2-
Cl2, 360 MHz) δ 7.41-7.23 (m, 10H), 1.27 (d, J ) 12.1 Hz, 18H);
13C NMR (CDCl3, 90 MHz) δ 145.2 (d, J ) 39.0 Hz), 142.2 (d,
J ) 27.9 Hz), 137.2, 131.1 (d, J ) 2.5 Hz), 129.4, 129.3, 129.0,
128.6, 128.5, 125.2, 33.1 (d, J ) 17.0 Hz), 30.6 (d, J ) 14.4 Hz);
31P NMR (CD2Cl2, 145 MHz) δ 3.51; HRMS (ESI+) calcd for
C22H29N3P (MH+) 366.2084, found 366.2099.
4-Diphenylphosphanyl-1,5-diphenyl-1H-[1,2,3]triazole (7a).
This compound was prepared from triazole compound 6a and PPh2-
Cl following the general procedure as a white solid (90% yield):
1H NMR (CDCl3, 360 MHz) δ 7.73-7.69 (m, 4H), 7.44-7.36 (m,
14H), 7.26 (d, J ) 7.3 Hz, 2H); 13C NMR (CDCl3, 90 MHz) δ
143.3 (d, J ) 39.5 Hz), 141.1 (d, J ) 14.2 Hz), 136.40, 136.38 (d,
J ) 15.4 Hz), 133.8, 133.5, 130.1 (d, J ) 3.5 Hz), 129.2, 129.0,
128.8, 128.6, 128.35, 128.28, 128.2, 126.5, 124.8; 31P NMR (CDCl3,
145 MHz) δ -35.85; HRMS (ESI+) calcd for C26H21N3P (MH+)
406.1475, found 406.1473.
4-Di-tert-butylphosphanyl-1-phenyl-5-(2-N,N-dimethylphenyl)-
1H-[1,2,3]triazole (7h). This compound was prepared from triazole
compound 6d and PtBu2Cl following the general procedure as a
1
white solid (69% yield). H NMR (360 MHz, CD2Cl2) δ 7.53 (d,
J ) 7.6 Hz, 1H), 7.35-7.40 (m, 4H), 7.26-7.29 (m, 2H), 7.05-
7.10 (m, 1H), 6.88 (d, J ) 8.2 Hz, 1H), 2.16 (s, 6H), 1.38 (d, J )
11.8 Hz, 9H), 1.30 (d, J ) 12.1 Hz, 9H); 13C NMR (90 MHz,
CD2Cl2) δ 151.8, 143.9 (d, J ) 38.2 Hz), 141.5 (d, J ) 28.6 Hz),
138.2, 133.5 (d, J ) 5.0 Hz), 130.4, 128.6, 128.1, 122.8, 120.7,
120.1, 118.8, 41.8, 33.1 (dd, J ) 17.1, 22.3 Hz), 30.6 (dd, J ) 8.7,
14.4 Hz); 31P NMR (145 MHz, CD2Cl2) δ 2.72; HRMS (ESI+)
calcd for C24H34N4P (MH+) 409.2521, found 409.2537.
4-Dicyclohexylphosphanyl-1,5-diphenyl-1H-[1,2,3]triazole (7b).
This compound was prepared from triazole compound 6a and PCy2-
Cl following the general procedure as a white solid (93% yield):
1H NMR (CD2Cl2, 360 MHz) δ 7.41-7.23 (m, 10H), 2.28-2.21
(m, 2H), 1.87-1.67 (m, 10H), 1.38-1.09 (m, 10H); 13C NMR
(CDCl3, 90 MHz) δ 144.7 (d, J ) 34.8 Hz), 141.2 (d, J ) 24.6
Hz), 137.2, 130.9 (d, J ) 2.9 Hz), 129.4, 129.3, 129.1, 128.6, 128.0,
125.3, 33.5 (d, J ) 8.4 Hz), 30.8 (d, J ) 16.3 Hz), 29.8 (d, J ) 7.5
Hz), 27.5 (d, J ) 18.5 Hz), 27.4 (d, J ) 1.6 Hz), 26.8; 31P NMR
(CD2Cl2, 145 MHz) δ -27.76; HRMS (ESI+) calcd for C26H33N3P
(MH+) 418.2419, found 418.2412.
4-Dicyclohexylphosphanyl-1-phenyl-5-(1-naphthyl)-1H-[1,2,3]-
triazole(7d). This compound was prepared from triazole compound
6b and PCy2Cl following the general procedure as a white solid
(81% yield): 1H NMR (300 MHz, CD2Cl2) δ 7.93 (dd, J ) 8.3,
18.7 Hz, 2H), 7.24-7.53 (m, 10H), 2.36 (t, J ) 11.3 Hz, 1H),
2.09 (t, J ) 11.2 Hz, 1H), 1.52-1.98 (m, 10H), 0.97-1.48 (m,
10H); 13C NMR (75 MHz, CD2Cl2) δ 143.5 (d, J ) 27.4 Hz), 143.2,
143.0, 137.2, 133.7, 132.4, 130.3, 129.3, 128.9, 128.8, 127.1, 126.7,
125.9, 125.5, 125.3, 124.2, 33.6 (d, J ) 9.2 Hz), 30.9 (d, J ) 16.3
Hz), 30.0 (d, J ) 8.8 Hz), 27.4 (d, J ) 10.3 Hz), 27.2 (d, J ) 3.7
Hz), 26.8; 31P NMR (145 MHz, CD2Cl2) δ -28.31; HRMS (ESI+)
calcd for C30H35N3P (MH+) 468.2569, found 468.2571.
4-Di-tert-butylphosphanyl-1-phenyl-5-(2,6-dimethoxyphenyl)-
1H-[1,2,3]triazole (7i). This compound was prepared from triazole
compound 6e and PtBu2Cl following the general procedure as a
1
white solid (79% yield): H NMR (360 MHz, CD2Cl2) δ 7.37-
7.42 (m, 6H), 6.58 (d, J ) 8.4 Hz, 2H), 3.63 (s, 6H), 1.28 (d, J )
12.0 Hz, 18 H); 13C NMR (90 MHz, CD2Cl2) δ 158.5, 143.0, 139.5,
137.4, 131.5, 128.7, 128.5, 124.1, 105.7, 103.3, 55.2, 32.3 (d, J )
16.2 Hz), 30.2 (d, J ) 14.4 Hz); 31P NMR (145 MHz, CD2Cl2) δ
4.73; HRMS (ESI+) calcd for C24H33N3O2P (MH+) 426.2310,
found 426.2307.
4-Dicyclohexylphosphanyl-1-phenyl-5-(2,6-dimethoxyphenyl)-
1H-[1,2,3]triazole (7j). This compound was prepared from triazole
compound 6e and PCy2Cl following the general procedure as a
1
white solid (76% yield): H NMR (360 MHz, CD2Cl2) δ 7.38-
7.42 (m, 6H), 6.59 (d, J ) 8.4 Hz, 2H), 3.65 (s, 6H), 2.16-2.22
(m, 2H), 1.69-1.77 (m, 10H), 1.13-1.39 (m, 10H); 13C NMR (90
MHz, CD2Cl2) δ 158.9, 142.6 (d, J ) 20.4 Hz), 139.0 (d, J ) 40.6
Hz), 137.7, 131.9, 129.1, 128.8, 124.2, 105.9, 103.8, 55.7, 33.2 (d,
J ) 7.8 Hz), 30.5 (d, J ) 16.3 Hz), 29.7 (d, J ) 7.9 Hz), 27.5 (d,
J ) 10.5 Hz), 27.4 (d, J ) 6.0 Hz), 26.9; 31P NMR (145 MHz,
CD2Cl2) δ -27.36; HRMS (ESI+) calcd for C28H37N3O2P (MH+)
478.2623, found 478.2599.
General Procedure for Amination of Aryl Chlorides. To a
Schlenk tube, which was flame-dried under vacuum and backfilled
with nitrogen, NaOtBu (1.2 mmol), were subsequently added toluene
(3 mL), a stock solution of ligand 7 in toluene (0.01 mmol), a stock
solution of Pd(dba)2 (0.005 mmol) in toluene, aryl chloride 8 (1.0
mmol) and amine 9 (1.2 mmol). The flask was sealed, and the
reaction mixture was heated at 110 °C with vigorous stirring for
20 h. After the mixture was cooled to rt, 15 mL of EtOAc was
added and the mixture was washed with 5 mL of brine. The organic
4-Di-tert-butylphosphanyl-1-phenyl-5-(1-naphthyl)-1H-[1,2,3]-
triazole (7e). This compound was prepared from triazole compound
6b and PtBu2Cl following the general procedure as a white solid
(75% yield): 1H NMR (CD2Cl2, 300 MHz) δ 7.98-7.88 (m, 2H),
7.55-7.21 (m, 10H), 1.34-1.24 (m, 18H); 13C NMR (CDCl3, 75
MHz) δ 144.1 (d, J ) 14.9 Hz), 143.7 (d, J ) 28.6 Hz), 137.3,
133.7, 132.4, 130.6, 130.3, 129.3, 129.0, 128.8, 127.0, 126.6, 126.1,
125.6, 125.3, 124.2, 32.9 (dd, J ) 17.0, 21.7 Hz), 30.8 (dd, J )
J. Org. Chem, Vol. 71, No. 10, 2006 3933

Dai et al.
layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash column chro-
matography on basic Al2O3.
dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel.
General Procedure for Suzuki Coupling of Aryl Chlorides.
A Schlenk tube was charged with boronic acid 11 (1.5 mmol) and
K3PO4 (2 mmol). The flask was evacuated and backfilled with
nitrogen three times. Toluene (3 mL), a stock solution of ligand 7
in toluene (0.002 mmol), a stock solution of Pd(dba)2 (0.001 mmol)
in toluene, and aryl chloride 8 (1.0 mmol) were subsequently added.
The flask was sealed, and the reaction mixture was heated at 80
°C with vigorous stirring for 12 h. After the mixture was cooled to
rt, 15 mL of EtOAc was added, and the mixture was washed with
5 mL of 1 N NaOH (aq) and 5 mL of brine. The organic layer was
Acknowledgment. This work was supported by the National
Institutes of Health.
Supporting Information Available: General experimental
methods, preparation and characterization data for triazole com-
pounds 6a-e and 1H, 13C NMR spectral data for 10a-l and 12a-
p. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060321E
3934 J. Org. Chem., Vol. 71, No. 10, 2006