Triazole-based monophosphines for Suzuki-Miyaura coupling and amination reactions of aryl chlorides

Article abstract of DOI:10.1021/ol051844w

(Chemical Equation Presented) A new class of triazole-based monophosphine 1 (ClickPhos) has been prepared via efficient 1,3-dipolar cycloadditions of readily available azides and acetylenes. Palladium complexes derived from these ligands provide highly active catalysts for Suzuki-Miyaura coupling and amination reactions of aryl chlorides.

Full text of DOI:10.1021/ol051844w

ORGANIC
LETTERS
2
005
Vol. 7, No. 22
907-4910
Triazole-Based Monophosphines for
Suzuki Miyaura Coupling and Amination
4
−
Reactions of Aryl Chlorides
Duan Liu, Wenzhong Gao, Qian Dai, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received August 2, 2005
ABSTRACT
A new class of triazole-based monophosphine 1 (ClickPhos) has been prepared via efficient 1,3-dipolar cycloadditions of readily available
azides and acetylenes. Palladium complexes derived from these ligands provide highly active catalysts for Suzuki
−Miyaura coupling and
amination reactions of aryl chlorides.
Transition metal catalyzed cross-coupling reactions have
become an extremely versatile tool in organic synthesis for
the connection of two fragments via the formation of a
1
carbon-carbon bond or carbon-heteroatom bond. It has
been well recognized that ligands employed in these pro-
cesses have significant impact on the outcome of the
2
reactions. Therefore, designing ligands with appropriate
natures and great diversity is crucial for dealing with the
challenging substrates in this area. Herein, we wish to report
a concise synthesis of a novel class of triazole-based
monophosphine 1 (Figure 1), which is a highly efficient
ligand for Pd-catalyzed Suzuki-Miyaura coupling (up to
Figure 1. Examples of effective ligands for Suzuki-Miyaura
coupling of aryl chlorides.
9
,300 TON) and amination reactions of unactivated aryl
biaryl compounds because of the advantages of the wide
functional group tolerance and the use of stable and nontoxic
organoborane reagents. Some of the recent progress in this
chlorides.
3
The Pd-catalyzed Suzuki-Miyaura coupling reaction is
one of the most attractive methods for the preparation of
(
3) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
(
1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2. (c) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. (b) Chemler, S. R.; Trauner, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544. (d) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11. (e) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (f) Kotha, S.; Lahiri,
K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (f) Suzuki, A. In Modern
Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; pp 53-
106. (g) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
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.
(
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,
201.
2
1
0.1021/ol051844w CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/24/2005

reaction has been focused on the use of aryl chlorides as
coupling partners in view of their low cost and readily
available diversity. A number of reports have shown that
elegant chemistry for the formation of 1,4- and 1,5-
disubstituted triazole compounds via 1,3-dipolar cycloaddi-
tions of organoazides and acetylenes. The unique properties
4
11
Pd complexes derived from sterically hindered and electron-
rich phosphines are effective catalysts for this transforma-
such as modularity, wide reaction scope, mild reaction
conditions, high yields, and regioselectivity make these
reactions excellent examples of click chemistry. We
5
12
tion. Some of the notable examples include the use of bulky
t
6
trialkylphosphines (i.e., P( Bu)
3
, 2) by Fu, dialkyl biphe-
envisioned that triazole-based monophosphines, i.e., 1 (Figure
1), might be a promising and attractive ligand family for
coupling reactions because of the facile synthesis of the
triazole moiety and the ease of individual tuning of the
7
nylphosphines (i.e., 3) by Buchwald, and dialkyl heteroaro-
matic phosphines (i.e., 4) by Beller. Other strategies such
8
as using sterically hindered N-heterocyclic carbenes (NHCs)
9
10
1
2
3
as ligands and palladacycles as the precatalysts also
provide efficient catalytic systems.
substituents, i.e., R , R , and R .
On the basis of the efficient formation of 1,5-disubstituted
triazoles, a straightforward two-step synthesis of the several
ligands 1a-e (ClickPhos) has been developed (Scheme 1).
Although many ligands have been reported, rapid assembly
of structurally diverse ligand systems via efficient synthetic
methods is still important for the development of effective
catalysts for the widespread applications of coupling reac-
tions. Recently, Sharpless and co-workers have reported
Scheme 1. Synthesis of ClickPhos 1a-e
(
4) For a review on Pd-catalyzed couplings of aryl chlorides, see: Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
5) For some recent examples of Suzuki-Miyaura coupling using aryl
(
chlorides, see: (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int.
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.
(e) Li, G. Y. J. Org. Chem. 2002, 67, 3643. (f) Hu, Q.; Lu, Y.; Tang, Z.;
Yu, H. J. Am. Chem. Soc. 2003, 125, 2856. (g) Altenhoff, G.; Goddard, R.;
Lehmann, C. W.; Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690. (h)
Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025. (i) Roca, F. X.;
Richards, C. J. J. Org. Chem. 2003, 68, 2592. (j) O¨ zdemir, I.; Alici, B.;
G u¨ rb u¨ z, N.; C¸ etinkaya, E.; C¸ etinkaya, B. J. Mol. Catal. A 2004, 37. (k)
Tewari, A.; Hein, M.; Zapf, A. Beller, M. Synthesis 2004, 925. (l) an der
Heiden, M.; Plenio, H. Chem. Eur. J. 2004, 10, 1789. (m) Colacot, T. J.;
Shea, H. A. Org. Lett. 2004, 6, 3731. (n) Arvela, R. K.; Leadbeater, N. E.;
Sangi, M. S.; Williams, V. A.; Granados, P.; Singer, R. D. J. Org. Chem.
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005, 70, 161. (o) Zapf, A.; Beller, M. Chem. Commun. 2005, 431. (p)
Lemo, J.; Heuze, K.; Astruc, D. Org. Lett. 2005, 7, 2253.
6) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (c)
Netherton, M. R.; Dai, C.; Neusch u¨ tz, K.; Fu, G. C. J. Am. Chem. Soc.
001, 123, 10099. (d) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu,
Following the general procedure reported by Sharpless,11b
1
,5-disubstituted triazoles 6a-c were obtained from phenyl
(
(
azide and various aryl acetylenes in good yields by quenching
the in situ generated 4-halomagnesium triazole intermediates
5 with aqueous NH Cl solution. Treatment of 6 with LDA
4
2
G. C. J. Am. Chem. Soc. 2002, 124, 13662. (e) Kirshhoff, J. H.; Dai, C.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945. (f) Zhou, J.; Fu, G. C. J.
Am. Chem. Soc. 2004, 126, 1340.
followed by addition of various chlorophosphines furnished
ligands 1a-e in good to excellent yields. It is worthy of
note that the ligand synthesis could be shortened into a one-
pot operation with comparable crude yield of the desired
product by directly quenching the intermediate 5 with a
chlorophosphine. The isolation of triazole 6 prior to instal-
lation of the phosphino substituents is solely because of the
ease of purification of the final phosphine ligands. Although
only five members of ClickPhos are presented herein, the
powerful connectivity of Sharpless click chemistry should
allow us to rapidly make a wide variety of ClickPhos
derivatives using readily available azides and acetylenes.
To evaluate the effectiveness of ClickPhos in the Pd-
catalyzed Suzuki--iyaura coupling, we first tested the
reaction between 4-chlorotoluene (7a) and phenylboronic
acid (8a) with ligands 1a-e (Table 1, entries 1-5). The
(
7) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1
1
998, 120, 9722. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
999, 38, 2413. (c) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J. Am. Chem. Soc. 1999, 121, 9550. (d) Wolfe, J. P.; Tomori, H.; Sadighi,
J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (e) Yin, J.;
Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
1
24, 1162. (f) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649. (g)
Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871. (h) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(
8) (a) Zapf, A.; Jackstell, R.; Rataboul, F.; Reirmeier, T.; Monsees, A.;
Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun.
004, 38. (b) Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier,
T.; Monsees, A.; Beller, M. AdV. Synth. Catal. 2004, 346, 1742.
9) (a) Gst o¨ ttmayr, C. W. K.; B o¨ hm, V. P. W.; Herdtweck, E.; Grosche,
2
(
M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1363. (b) Grasa,
G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
Organometallics 2002, 21, 2866. (c) Viciu, M. S.; Germaneau, R. F.;
Navarro-Fernandez, O.; Stevens, E. D.; Nolan, S. P. Organometallics 2002,
2
1, 5470. (d) Navarro, O.; Kelly, R. A. III; Nolan, S. P. J. Am. Chem. Soc.
2
003, 125, 16194. (e) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J.
Org. Chem. 2004, 69, 3173. (f) Lebel, H.; Janes, M. K.; Charette, A. B.;
Nolan, S. P. J. Am. Chem. Soc. 2004, 126, 5046.
(11) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Krasinski, A.; Fokin, V. V.;
Sharpless, K. B. Org. Lett. 2004, 6, 1237. (c) Feldman, A. K.; Colasson,
B.; Fokin, V. V. Org. Lett. 2004, 6, 3897. (d) Himo, F.; Lovell, T.; Hilgraf,
R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J.
Am. Chem. Soc. 2005, 127, 210.
(10) (a) Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Angew. Chem.,
Int. Ed. 2002, 41, 4120. (b) Bedford, R. B.; Hazelwood, S. L.; Limmert,
M. E. Chem. Commun. 2002, 2610. (c) Bedford, R. B.; Hazelwood, S. L.;
Limmert, M. E.; Albisson, D. A.; Draper, S. M.; Scully, P. N.; Coles, S. J.;
Hursthouse, M. B. Chem. Eur. J. 2003, 9, 3216. (d) Bedford, R. B.; Blake,
M. E.; Butts, C. P.; Holder, D. Chem. Commun. 2003, 466. (e) Bedford, R.
B.; Hazelwood, S. L.; Limmert, M. E. Organometallics 2003, 22, 1364.
(12) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
4908
Org. Lett., Vol. 7, No. 22, 2005

Table 1. Screening of Ligands and Reaction Conditionsa
Table 2. Pd-Catalyzed Suzuki-Miyaura Coupling of Aryl
Chloridesa
entry
ligand
base
yield (%)b
entry
aryl chloride
boronic acid
yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1c
1c
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KF
<5
70
94
88
91
86
57
1
2
1
2
3
R ) p-Me 7a
R ) p-COMe 7b
R ) p-COMe 7b
R ) p-NO2 7c
R ) p-CO2Me 7d
R ) p-CF3 7e
R ) o-COMe 7f
R ) o-CN 7 g
R ) 2-pyridinyl 7h
R ) o-Me 7i
R ) 2,5-di-Me 7j
R ) p-OMe 7k
R ) H 7l
R ) o-CN 7g
R ) 2,5-di-Me 7j
R ) 2,5-di-Me 7j
R ) H 8a
89 (9a)
99 (9b)
93 (9b)
96 (9c)
94 (9d)
91 (9e)
89 (9f)
90 (9g)
99 (9h)
92 (9i)
98 (9j)
86 (9k)
99 (9a)
92 (9l)
89 (9m)
85 (9n)
1
2
R ) H 8a
c
1
2
R ) H 8a
1
2
4
5
6
7
8
9
R ) H 8a
1
2
R ) H 8a
1
2
CsF
R ) H 8a
1
2
R ) H 8a
a
1
mmol of 4-chlorotoluene 7a, 1.5 mmol of phenylboronic acid 8a, 2
1
2
R ) H 8a
mmol of base, 1 mol % Pd(dba)2, 2 mol % ligand 1, 3 mL of toluene, 12
1
2
b
1
R ) H 8a
h, 80 °C. Isolated yield. Purity was confirmed by H NMR.
1
2
10
11
12
13
14
15
16
R ) H 8a
1
2
R ) H 8a
1
2
R ) H 8a
reactions were performed in the presence of the catalysts
derived from 1 mol % of Pd(dba) and 2 mol % of ligands.
2
Although very low yield (<5%) of the coupling product was
observed with diphenyl phosphine ligand 1a, good to
excellent yields were achieved with dialkyl phosphine ligands
1
2
R ) p-Me 8b
1
2
R ) p-Me 8b
d
d
1
2
R ) o-Me 8c
1
2
R ) o-OMe 8d
a
1
mmol of aryl chloride 7, 1.5 mmol of aryl boronic acid 8, 2 mmol of
1
b and 1c (70% and 94%, respectively). These results are
K3PO4, 0.1 mol % Pd(dba)2, 0.2 mol % ligand 1c, 3 mL of toluene, 12 h,
100 °C. b Isolated yield. Purity was confirmed by H NMR. 0.01 mol %
1
c
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 1d and 1e, having a di-
tert-butylphosphino substituent, also provided the coupling
product in yields comparable to that of 1c. Using the best
d
Pd(dba)2 and 0.02 mol % ligand 1c were used. The reaction was carried
out at 80 °C.
Pd/1c system for the Suzuki-Miyaura coupling of aryl
chlorides, which are comparable or better than those reported
to date with other catalytic systems.
ligand 1c, several bases, such as K
3
PO
4
, KF, and CsF, were
Palladium-catalyzed amination of aryl halides is a powerful
method for the synthesis of aniline derivatives. Employing
readily available aryl chlorides in this transformation has
become a recent focus, and a number of effective catalytic
systems have been developed for this purpose. Using Pd
catalytic systems based on ligands 1b and 1c, we were also
examined. K PO Was found to be the base of choice for
3
4
the Pd/1c catalytic system (Table 1, entries 3, 6, and 7).
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 effectiveness of the Pd/1c catalytic system (Table
1
3
2). Excellent yields were obtained with 0.1 mol % of the
catalyst in the reactions between various electron-deficient
aryl chlorides and phenylboronic acid (Table 2, entries 2-8).
A heteroaromatic chloride 7h coupled with phenyl boronic
acid provided product 9h in nearly quantitative yield (Table
Table 3. Pd-Catalyzed Amination of Aryl Chloridesa
2, entry 9). For more challenging electronically unactivated
and deactivated aryl chlorides, the corresponding biaryl
products were obtained in good to excellent yields (entries
1
and 10-12). ortho-Substituents on the aromatic rings can
be tolerated as well, leading to the corresponding hindered
coupling products in high yields (Table 2, entries 7, 8, 10,
11, and 14-16). Reactions using other aryl boronic acids
8b-d were also performed, and the yields were as good as
those of 8a (Table 2, entries 13-16). Furthermore, when
applying very low catalyst loading (0.01 mol % of catalyst),
aryl chloride 7b also coupled with phenylboronic acid (8a)
efficiently, giving the product 9b in 93% yield (Table 2, entry
a
1
mmol of aryl chloride 7, 1.2 mmol of arylamine 10, 1.2 mmol of
t
NaO Bu, 0.5 mol % Pd(dba)2, 1 mol % ligand 1, 3 mL of toluene, 24 h,
3, 9,300 TON). Therefore, these results demonstrate the
reflux. b Isolated yield. Purity was confirmed by H NMR.
1
broad substrate scope and high catalytic efficiency of the
Org. Lett., Vol. 7, No. 22, 2005
4909

able to obtain very good yields (91-93%) in the amination
reactions of unactivated aryl chlorides 7a and 7i with both
primary and secondary amines (Table 3). These preliminary
results indicate the potential applications of the Pd/ClickPhos
catalytic systems to a number of cross-coupling reactions.
In conclusion, we have developed a new type of mono-
phosphine 1 (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. Palladium complexes
derived from these ligands provide highly active catalysts
for Suzuki-Miyaura coupling and amination reactions of aryl
chlorides. Further ligand modifications and their applications
to various cross-coupling reactions are currently under
investigation in our lab and will be reported in due course.
(
13) (a) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.;
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Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
S. L. J. Am. Chem. Soc. 2003, 125, 6653. (h) Urgaonkar, S.; Xu, J.-H.;
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OL051844W
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Org. Lett., Vol. 7, No. 22, 2005