Copper-catalyzed domino halide exchange-cyanation of aryl bromides

Article abstract of DOI:10.1021/ja0299708

An efficient copper-catalyzed domino halogen exchange-cyanation procedure for aryl bromides was developed utilizing 10 mol % CuI, 20 mol % KI, 1.0 equiv of the inexpensive N,N′-dimethylethylenediamine as ligand, and 1.2 equiv of NaCN in toluene at 110 °C. The new method represents a significant improvement over the traditional Rosenmund-von Braun reaction: the reaction conditions are much milder, and the use of stoichiometric amounts of copper(I) cyanide and polar solvents is avoided; therefore the isolation and purification of the aromatic nitrile products is greatly simplified. In addition, the new method exhibits excellent functional group compatibility comparable to that of the analogous Pd-catalyzed cyanation methodology. Copyright

Full text of DOI:10.1021/ja0299708

Published on Web 02/15/2003
Copper-Catalyzed Domino Halide Exchange-Cyanation of Aryl Bromides
Jacopo Zanon, Artis Klapars, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received December 31, 2002 ; E-mail: sbuchwal@mit.edu
Reaction of copper(I) cyanide with aryl halides, also known as
1
the Rosenmund-von Braun reaction, is an important method for
2
the preparation of aromatic nitriles. Unfortunately, several problems
limit the generality of this classic method; for example, the
cyanation of aryl bromides requires extreme reaction conditions
(150-280 °C) which may not be compatible with sensitive
substrates. This is a serious limitation because aryl bromides are
more available and less expensive than the corresponding aryl
iodides. In addition, the stoichiometric amount of copper(I) cyanide
which is utilized in the reaction may complicate the separation of
the nitrile products from the copper halide salts produced in the
3
reaction. When used on the industrial scale, the stoichiometric
amounts of the copper salts also present a significant waste disposal
4
5
problem. More recently, palladium- and nickel-catalyzed aryl
cyanation methods have been developed as milder alternatives to
the classic Rosenmund-von Braun reaction. Although many
successful applications of the palladium-catalyzed aryl cyanation
reaction have been documented, the method suffers from poor
reliability. A notable improvement was presented in the report by
Anderson and co-workers at Lilly who found that the addition of
CuI (10 mol %) to the reaction greatly improved the efficiency of
Figure 1. Copper-catalyzed cyanation of 5-bromo-m-xylene. Performed
with 10 mol % CuI, 1.0 equiv of ligand 1, 20 mol % KI, 1.2 equiv of
NaCN, and toluene as solvent at 110 °C.
of NaCN in toluene at 110 °C was identified as a highly efficient
system for the conversion of aryl bromides into aromatic nitriles
6
this transformation. Still, their procedure necessitated the use of
11
via concurrent halogen exchange.
3 4
relatively high quantities of the expensive Pd(Ph P) (5 mol %).
Presumably, this is required to compensate for catalyst deactivation
during the cyanation reaction.7
The success of the halide exchange-cyanation reaction largely
relies on matching the relative rates of the two steps in the domino
reaction sequence (eq 1). This is achieved by proper choice of the
iodide salt, the cyanide salt, and the solvent, thus ensuring optimal
concentrations of the iodide and cyanide salts in the solution. Using
the combination of KI, NaCN, and toluene, we find that about
5-10% of the aryl iodide (according to GC analysis) is present
throughout the reaction, the concentration of aryl iodide decreasing
only toward the end of the cyanation reaction (Figure 1). This result
indicates that the rate of halide exchange is comparable to or
exceeds the rate of the cyanation of the resulting aryl iodide. If
polar solvents, such as DMF or sulfolane, that dissolve sodium
cyanide relatively well, are used instead of toluene, very low
conversion (<5%) of the aryl bromide is observed. Apparently,
high concentration of the dissolved cyanide in the reaction mixture
strongly inhibits both the halide exchange and the aryl cyanation
reaction. A similar effect has been noted before in both palladium-
and copper-catalyzed aryl cyanation reactions.12
The copper-catalyzed halide exchange-cyanation reaction toler-
ates a wide range of functional groups including strongly electron-
donating substituents (Table 1, entries 2 and 7), potentially C-H
acidic groups (entry 6), as well as free N-H and O-H groups
(entries 5, 8, and 9). Although the cyanation reaction is slower with
ortho-substituted aryl bromides, high yields of the aromatic nitriles
can still be obtained at a slightly higher reaction temperature (130
°C; entries 4, 7, and 9). As shown in Table 2, various heteroaryl
Recently, we reported that 1,2-diamine ligands accelerate copper-
catalyzed reactions of aryl halides with such diverse nucleophiles
as amides, nitrogen heterocycles, and iodide ion.8 Our initial
attempts at using the cyanide ion as the nucleophile in analogous
procedures indicated that diamine ligand 1 was very beneficial for
the copper-catalyzed cyanation of aryl iodides. Thus, the cyanation
of 5-iodo-m-xylene proceeded to >99% conversion after 24 h at
9
0 °C, comparable results being obtained with either CuI, CuBr,
9
or CuCN as precatalysts (10 mol %). Surprisingly, the cyanation
of aryl bromides was much more sensitive to the nature of the
copper precatalyst; for example, CuI performed dramatically better
than either CuBr or CuCN.10 This result can be rationalized
assuming in situ copper-catalyzed conversion of the aryl bromide
into the more reactive aryl iodide followed by the cyanation of the
resulting aryl iodide (eq 1). In accord with this hypothesis, addition
of 20 mol % KI to the reaction mixture improved the efficiency of
the cyanation reaction. Consequently, 10 mol % CuI, 20 mol %
KI, 1.0 equiv of the inexpensive diamine ligand 1, and 1.2 equiv
2890
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J. AM. CHEM. SOC. 2003, 125, 2890-2891
10.1021/ja0299708 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 1. Copper-Catalyzed Cyanation of Aryl Bromides
Table 2. Copper-Catalyzed Cyanation of Heteroaryl Bromides
a
Isolated yields (average of two runs); >95% purity as determined by
GC and 1H NMR; all reactions proceeded to >99% conversion of aryl
bromide. b Performed for 20 h.
References
(
1) (a) Rosenmund, K. W.; Struck, E. Chem. Ber. 1919, 52, 1749. (b) Pongratz,
A. Monatsh. Chem. 1927, 48, 585. (c) von Braun, J.; Manz, G. Liebigs
Ann. Chem. 1931, 488, 111. (d) Connor, J. A.; Leeming, S. W.; Price, R.
J. Chem. Soc., Perkin Trans. 1 1990, 1127. (e) Carr, R. M.; Cable, K.
M.; Wells, G. N.; Sutherland, D. R. J. Labelled Compd. Radiopharm.
1994, 34, 887. A single example of Cu-catalyzed (5 mol % CuI) cyanation
of an aryl bromide has been reported to proceed with 55% conversion
when the reaction is carried out in an ionic liquid: (f) Wu, J. X.; Beck,
B.; Ren, R. X. Tetrahedron Lett. 2002, 43, 387.
a
Isolated yields (average of two runs); >95% purity as determined by
1
(2) For a review, see: Ellis, G. P.; Romney-Alexander, T. M. Chem. ReV.
GC and H NMR; all reactions proceeded to >99% conversion of aryl
bromide except for entry 7 (98% conversion). Performed for 20 h.
b
1987, 87, 779.
(
3) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett.
1
999, 40, 8193.
4) (a) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Chem. Lett. 1973,
71. (b) Sekiya, A.; Ishikawa, N. Chem. Lett. 1975, 277. (c) Tschaen, D.
(
4
bromides are also excellent substrates for the cyanation reaction.
Even heterocyclic substrates containing N-H groups are well
tolerated and do not suffer N-arylation (Table 2, entries 1 and 4),
presumably because of the high affinity of the cyanide nucleophile
toward the copper(I) catalyst.
M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.; King, S.;
Verhoeven, T. R. Synth. Commun. 1994, 24, 887. (d) Sundermeier, M.;
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(
5) (a) Cassar, L. J. Organomet. Chem. 1973, 54, C57. (b) Sakakibara, Y.;
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6
6, 2776. (c) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
6
895.
In summary, we have developed a copper-catalyzed domino
halogen exchange-cyanation procedure for aryl bromides. The new
method represents a significant improvement over the traditional
Rosenmund-von Braun reaction: the reaction conditions are much
milder, and the use of stoichiometric amounts of copper(I) cyanide
and polar solvents is avoided; therefore, the isolation and purifica-
tion of the nitrile products is greatly simplified. In addition, the
new method exhibits excellent functional group compatibility
comparable to that of the analogous Pd-catalyzed cyanation
methodology. We are currently exploring other possibilities for
combining concurrent copper-catalyzed transformations into domino
processes.
(6) (a) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224. See also: (b) Allentoff, A.
J.; Markus, B.; Duelfer, T.; Wu, A.; Jones, L.; Ciszewska, G.; Ray, T. J.
Labelled Compd. Radiopharm. 2000, 43, 1075.
(
7) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
8) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 7421. (c) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (d) Klapars, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 14844.
(
(9) Conversion of 5-iodo-m-xylene into 3,5-dimethylbenzonitrile (in the
absence of added KI) was performed using 10 mol % Cu precatalyst, 1.0
equiv of ligand 1, and 1.2 equiv of NaCN in toluene for 24 h at 90 °C.
All three precatalysts (CuI, CuBr, CuCN) afforded 96-98% yield (GC)
and 99.7-99.9% conversion of aryl iodide.
10) Conversion of 5-bromo-m-xylene into 3,5-dimethylbenzonitrile using 10
mol % Cu precatalyst, 1.0 equiv of ligand 1, and 1.2 equiv of NaCN in
toluene for 24 h at 110 °C provided the following yields of the nitrile
product: CuI, 82%; CuBr, 2%; CuCN, 1%.
(
Acknowledgment. We thank the National Institutes of Health
(
11) The copper-catalyzed cyanation reactions are sensitive to oxygen and
moisture. Nevertheless, glovebox techniques are not required (see Sup-
porting Information).
(GM 45906) for supporting this work. We are grateful to H.
Lundbeck A/S for additional funds.
(
12) (a) Takagi, K.; Sasaki, K.; Sakakibara, Y. Bull. Chem. Soc. Jpn. 1991,
6
4, 1118. (b) CuCN effects the cyanation 4 times faster than Na[Cu-
Supporting Information Available: Experimental procedures and
characterization data for all products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
2
(CN) ] (used in stoichiometric amounts): House, H. O.; Fischer, W. F.,
Jr. J. Org. Chem. 1969, 34, 3626.
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