Copper-catalyzed C-P bond construction via direct coupling of secondary phosphines and phosphites with aryl and vinyl halides

Article abstract of DOI:10.1021/ol0346640

(Matrix presented) A general method for the coupling of aryl and vinyl halides with diaryl and dialkyl phosphines, as well as with dibutyl phosphite, is reported. This highly efficient transformation is realized through the use of copper(I) iodide as a catalyst, N,N′-dimethylethylenediamine as a ligand, and Cs₂CO₃ as a base. A variety of sterically hindered and/or functionalized substrates were found to react under these reaction conditions to provide products in good to excellent yields.

Full text of DOI:10.1021/ol0346640

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2315-2318
Copper-Catalyzed C−P Bond
Construction via Direct Coupling of
Secondary Phosphines and Phosphites
with Aryl and Vinyl Halides
Dmitri Gelman, Lei Jiang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts, 02139
sbuchwal@mit.edu
Received April 18, 2003
ABSTRACT
A general method for the coupling of aryl and vinyl halides with diaryl and dialkyl phosphines, as well as with dibutyl phosphite, is reported.
This highly efficient transformation is realized through the use of copper(I) iodide as a catalyst, N,N′-dimethylethylenediamine as a ligand, and
Cs2CO as a base. A variety of sterically hindered and/or functionalized substrates were found to react under these reaction conditions to
3
provide products in good to excellent yields.
The formation of carbon-heteroatom bonds by transition-
metal-catalyzed cross-coupling methodology has been the
subject of intensive investigation in recent years.1 Although
the majority of efforts have been focused on the formation
of carbon-nitrogen,2 -oxygen,3 and -sulfur bonds,4 limited
protocols for direct coupling of aryl halides with secondary
phosphines have been published.5 Recent reinvestigation of
Ullmann-type chemistry showed that many of the above-
mentioned cross-coupling processes may be performed using
a catalytic quantity of a copper complex.6 However, examples
of copper-mediated carbon-phosphorus bond formation are
rare.7 In this communication, we wish to report a general
(1) For reviews, see: (a) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New
York, 2002; p 1051. (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131.
(5) (a) Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel,
T.; Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem. 2002,
645, 14. (b) Stadler, A.; Kappe, C. O. Org. Lett. 2002, 4, 3541. (c) Kraatz,
H.-B.; Pletsch, A. Tetrahedron: Asymmetry 2000, 11, 1617. (d) Bergbreiter,
D. E.; Liu, Y.-S.; Furyk, S.; Case, B. L. Tetrahedron Lett. 1998, 39, 8799.
(e) Machnitzki, P.; Nickel, T.; Stelzer, O.; Landgrafe, C. Eur. J. Inorg.
Chem. 1998, 1029. (f) Herd, O.; Hessler, A.; Hingst, M.; Trepper, M.;
Stelzer, O. J. Organomet. Chem. 1996, 522, 69. (g) Cai, D.; Payack, J. F.;
Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem.
1994, 59, 7180.
(6) Selected recent publications: (a) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (b) Kwong, F. Y.; Buchwald,
S. L. Org. Lett. 2002, 4, 3517. (c) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (d) Ma, D.; Xia, C.
Org. Lett. 2001, 3, 2583. After this manuscript was submitted, a paper
describing the Cu-catalyzed coupling of diphenylphosphine and aryl iodides
appeared on the web: (e) Van Allen, D.; Venkataraman, D. J. Org. Chem.
Published ASAP May 2, 2003.
(2) For example: (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (b) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2002, 41, 4746. (c) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig,
J. F. J. Org. Chem. 2002, 67, 5553. (d) Kogan, V.; Aizenshtat, Z.; Popovitz-
Biro, R.; Neumann, R. Org. Lett. 2002, 4, 3529. (e) Wolfe, J. P.; Tomori,
H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(3) (a) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 10770. (c) Shelby, Q.; Kataoka, N.;
Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 10718. (d) Palucki,
M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. (e)
Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(4) For a review, see: (a) Kondo, T.; Mitsudo, T. Chem. ReV. 2000,
100, 3205. For copper-catalyzed C-S bond formation, see: (b) Kwong, F.
Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (c) Bates, C. G.; Gujadhur,
R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
(7) Ogawa, T.; Usuki, N.; Ono, N. J. Chem. Soc., Perkin Trans. 1 1998,
2953.
10.1021/ol0346640 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/23/2003

Table 1. Copper-Catalyzed Phosphination of Aryl and Vinyl Halides
a Conditions A: R-I (1 mmol), R2PH (1.1 mmol), CuI (5 mol %), Cs2CO3 (2 mmol) in toluene at 110 °C. Conditions B: R-X (1 mmol), R2PH (1 mmol),
CuI (5 mol %), ligand (35 mol %), Cs2CO3 (2 mmol) in toluene at 110 °C. Conditions C: R-X (1 mmol), R2PH (0.9 mmol), CuI (5 mol %), ligand (35 mol
%), Cs2CO3 (2 mmol) in toluene at 110 °C. Conditions D: R-X (1 mmol), R2PH (1.1 mmol), CuI (5 mol %), ligand (20 mol %), Cs2CO3 (2 mmol) in toluene
at 110 °C. b Isolated yield (average of two runs). c All dialkylarylphosphines were isolated as borane complexes to aid in isolation. d 1.5 equiv of base was
used.
protocol for copper-catalyzed synthesis of tertiary phosphines
and phosphonates from aryl or vinyl halides and secondary
phosphines or phosphites. Both classes of products are of
great importance in organic synthesis: tertiary phosphines
are widely used as ligands for transition-metal-catalyzed
reactions, and alkenylphosphonates are common precursors
for preparation of biologically active molecules,8 flame
retardants,9 and polymer additives.10
aimed at the discovery of the optimum reaction conditions,
revealed that 5 mol % of CuI can effect the transformation
of 1-iodonaphthalene to 1-diphenylphosphinonaphthalene.
This reaction was performed using 1.1 equiv of diphen-
ylphosphine and 2 equiv of Cs2CO3 as a base with 1 equiv
of the aryl iodide in toluene at 110 °C (Table 1, entry 1).
Reduction of the starting aryl iodide was the only side
reaction (up to 7%). Applying these conditions to cross-
coupling reactions between a variety of aryl halides and
different phosphines immediately revealed several problems.
For instance, the reaction was sensitive to the steric bulk of
the aryl iodide when dialkylphosphines were used as coupling
partners; this was reflected in the formation of a large amount
of the reduced arene.11 In addition, aryl bromides did not
react under these reaction conditions. Furthermore, using a
1:1 ratio of phosphine/aryl iodide, the reaction did not go to
completion. The use of excess phosphines to obtain complete
1-Iodonaphthalene and diphenylphosphine were selected
as prototypical reaction partners for ligand-free copper-
catalyzed coupling reactions. Initial examination, which was
(8) (a) Raboisson, P.; Baurand, A.; Cazenave, J.-P.; Gachet, C.; Schultz,
D.; Spiess, B.; Bourguigon, J.-J. J. Org. Chem. 2002, 67, 8063. (b) Holstein,
S. A.; Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl, R. J. Bioorg. Med.
Chem. 1998, 6, 687. (c) Lazrek, H. B.; Rochdi, A.; Khaider, H.; Barascut,
J. L.; Imbach, J. L.; Balzarini, J.; Witvrouw, M.; Pannecouque, C.; De
Clercq, E. Tetrahedron 1998, 54, 3807. (d) Smith, P. W.; Chamiec, A. J.;
Cobley, K. N.; Duncan, K.; Howes, P. D.; Whittington, A. R.; Wood, M.
R. J. Antibiot. Tokyo 1995, 48, 73.
(9) Welch, C. M.; Gonzales, E. J.; Guthrie, J. D. J. Org. Chem. 1961,
26, 3270.
(10) Jin, J. I. U.S. Patent 74-496233; Chem. Abstr. 1979, 90, 153010m.
(11) Up to 70% of conversion to the reduced products were found in all
reactions using ortho-substituted aryl iodides.
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Org. Lett., Vol. 5, No. 13, 2003

conversion complicated the isolation procedure. Thus, we
sought an alternative set of reaction conditions that would
be capable of overcoming the above-listed problems.
Recently, we reported that chelating diamine ligands could
be employed to enhance the efficiency of copper-catalyzed
reactions.6,12 Therefore, we decided to test commercially
available N,N′-dimethylethylenediamine as a ligand for the
copper-catalyzed phosphination of aryl halides. To our
delight, when 35 mol % of this ligand was used in
combination with 5 mol % of CuI, a dialkylphosphine (Cy2-
PH) could be successfully coupled with 1-iodonaphthalene.
Further examination revealed that various aryl iodides reacted
with diaryl- and dialkylphosphines even when a 1:1 ratio of
aryl iodide/phosphine was used. In this case the separation
and the purification of the product were greatly simplified,
and for some runs a sample of ∼95% pure compound could
be obtained simply by filtering the crude reaction mixture
through a short pad of silica gel, followed by concentrating
the filtrate.
entries 12 and 13). We also discovered that vinyl phosphine
can be accessed from the corresponding iodide in satisfactory
yields (Table 1, entry 10) under the same conditions.
We have also found that the described copper-catalyzed
cross-coupling protocol can be extended to the preparation
of aryl and vinyl phosphonates. Despite the variety of recent-
ly published protocols, regio- and stereoselective approaches
are still lacking.7,14 We found that various aryl iodides could
be successfully coupled with dibutyl phosphite, employing
this newly developed chemistry to afford the desired aryl
phosphonates in good to excellent yields (Table 2, entries
Table 2. Copper-Catalyzed Coupling of Aryl and Vinyl
Halides with HP(O)(OBu)2
The reaction is tolerant to the steric bulk of the starting
aryl iodide. Thus, using this technique, we were able to
prepare o-diphenyl-biphenyl phosphine ligands2d,13 in good
yields (Table 1, entries 5, 8, and 17). We also found that in
some instances aryl bromides could be successfully converted
to the desired products under these new reaction conditions.
For instance, electron-poor methyl 4-bromo-benzoate could
be coupled with diphenylphosphine in 70% isolated yield
(Table 1, entry 7). Unfortunately, chemoselective phosphi-
nation of bromoiodoarenes was problematic because of the
formation of a complex mixture of mono- and disubstituted
products, as well as reduced byproducts. In this case,
applying ligand-free conditions is recommended in order to
prepare halosubstituted tertiary phosphines (Table 1, entry
4). Interestingly, these mild reaction conditions also allow
the presence of a number of functional groups (e.g., amino,
cyano, esters) as listed in Table 1 (entries 3, 7, 11, 14, and
16).
The electronic and steric properties of phosphines are
important for the success of the reaction. Diarylphosphines
are typically more reactive than their dialkyl analogues in
this process. For example, aryl bromides failed to couple
with dialkylphosphines even in the presence of ligand. It
seems that the steric demand of the phosphine rather than
of the aryl halide determines the rate and the efficiency of
the transformation. Thus, for example, no reaction was
observed with bulky t-Bu2PH. In contrast, relatively fast
reactions took place when i-Bu2PH or Cy2PH were used as
the coupling partners. In addition, an excess of dialkylphos-
phine (1.1 equiv) was required in some cases in order to
reach complete conversion (Table 1, entries 11 and 12). i-Bu2-
PH exhibited reactivity higher than that of Cy2PH and reacted
with the excess of aryl iodide, leading to comparable yields
of the tertiary phosphines (Table 1, entries 11, 14, and 17).
However, an increased amount of reduction product (up to
15%) was observed in several reactions of Cy2PH (Table 1,
a Isolated yield (average of two runs). b Reaction was conducted at 110
°C. c Reaction was conducted at 70 °C;
1-3). The coupling of vinyl iodides with dibutyl phosphite
using the same protocol proceeded even under milder
reaction conditions (Table 2, entries 7-9). Thus, a variety
of vinyl iodides as well as vinyl bromides were coupled to
phosphite in high yield. We also demonstrated that the
(12) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(13) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5334.
(14) (a) Kabalka, G. W.; Guchhait, S. K. Org. Lett. 2003, 5, 729. (b)
Quntar, A. A. A.; Srebnik, M. Org. Lett. 2001, 3, 1379. (c) Hirao, T.;
Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron Lett. 1980, 21, 3595.
Org. Lett., Vol. 5, No. 13, 2003
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reaction of vinyl halides with dibutyl phosphite proceeds
stereoselectively and with retention of the original stereo-
chemistry. For instance, only a negligible amount of the E
stereoisomer was detected when Z vinyl iodides were used
(Table 2, entries 7-9) under the suggested reaction condi-
tions. Such high stereoselectivity is of great value due to
easy access of starting materials with well-defined stereo-
chemistry.15
conditions. This method is of particular value given its
experimental simplicity, functional group compatibility, and
the low cost of the catalytic system.
Acknowledgment. We thank the NIH (GM 45906).
Pfizer, Merck, and Bristol-Myers Squibb are acknowledged
for additional unrestricted support. L.J. was supported as a
postdoctoral trainee of the National Cancer Institute (NCI
training grant CI T32CA09112).
In conclusion, we have developed a general and efficient
copper-catalyzed carbon-phosphorus bond-forming protocol
for both aromatic and vinylic halides under relatively mild
Supporting Information Available: Experimental pro-
cedure and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Urch, C. J. In ComprehensiVe Organic Functional Group Trans-
formations; Katritzky, A. S., Metz-Cohn, O., Rees, C. W., Eds.; Perga-
mon: Oxford, New York, 1995; Vol. 2, Chapter 2.16, pp 622-625 and
628-630.
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