Novel trans-spanned palladium complexes as efficient catalysts in mild and amine-free cyanation of aryl bromides under air

Article abstract of DOI:10.1021/ol0601038

The use of a novel trans-spanned palladium complex as an efficient and selective catalyst in the cyanation of aryl halides is described. The suggested reaction conditions are mild, exhibit good scope of substrates, and circumvent the need for an inert atmosphere and amine co-ligands.

Full text of DOI:10.1021/ol0601038

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1189-1191
Novel Trans-Spanned Palladium
Complexes as Efficient Catalysts in Mild
and Amine-Free Cyanation of Aryl
Bromides under Air
Olga Grossman and Dmitri Gelman*
Department of Organic Chemistry, The Hebrew UniVersity of Jerusalem,
Jerusalem 91904, Israel
dgelman@chem.ch.huji.ac.il
Received January 13, 2006
ABSTRACT
The use of a novel trans-spanned palladium complex as an efficient and selective catalyst in the cyanation of aryl halides is described. The
suggested reaction conditions are mild, exhibit good scope of substrates, and circumvent the need for an inert atmosphere and amine co-
ligands.
Substituted benzonitriles are very common structural motifs
in a variety of natural products, pharmaceuticals, dyes, and
agrochemicals.1 In addition, nitriles are valuable precursors
in organic synthesis because they can be easily converted
into an array of functional groups.2
In general, benzonitriles can be prepared via classical
reaction of aryl halides with a stoichiometric amount of copper
cyanide (Rosenmund-von Braun reaction). However, this
method requires very harsh reaction conditions and laborious
isolation of products.3 Since the discovery of transition metal-
catalyzed cross-coupling reactions, a great deal of interest
has been devoted to the development of a practical catalytic
version of this trans-formation.4 Recently, a number of suc-
cessful palladium- and nickel-catalyzed protocols were re-
ported disclosing several important factors that govern the
overall efficiency of the process. For example, an exposure
of a palladium catalyst to high concentrations of cyanide ions
significantly inhibits the catalytic cycle, apparently due to
the formation of inactive palladium cyanide species which
cannot be easily reduced to catalytically active Pd(0) com-
pounds.5 This problem, namely, the problem of a slow cya-
nide delivery, can be successfully solved by a careful choice
of solvents and cyanide sources. Thus, the use of KCN,
CuCN, or Zn(CN)2 in nonpolar solvents such as toluene or
xylene was found beneficial in palladium-catalyzed trans-
formations.6 The recently suggested employment of the
masked cyanides such as TMS-CN or acetone cyanohydrin
to control the dosage of the inhibiting species appears as an
even more elegant overcoming of this drawback.7
(1) (a) Liu, K. C.; Howe, R. K. J. Org. Chem. 1983, 48, 4590. (b)
Robertson, D. W.; Beedle, E. E.; Swartzendruber, J. K.; Jones, N. D.; Elzey,
T. K.; Kauffman, R. F. L.; Wilson, H.; Hayes, J. S. J. Med. Chem. 1986,
29, 635. (c) Harris, T. M.; Harris, C. M.; Oster, T. A.; Brown, L. E., Jr.;
Lee, J. Y. C. J. Am. Chem. Soc. 1988, 110, 6180. (d) Knight, V. K.; Berman,
M. H.; Ha¨ggblom, M. M. EnViron. Toxicol. Chem. 2003, 22, 540.
(2) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience
Publishers: London, UK, 1970. (b) Larock, R. C. ComprehensiVe Organic
Transformations; Wiley-VCH: New York, 1988.
Further improvements such as the use of TMEDA,
DABCO, or MDP as cocatalysts have been introduced. As
(4) (a) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003,
3513. (b) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 2890.
(5) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Ohno, A.; Oka, S.; Hayama,
N. Bull. Chem. Soc. Jpn. 1976, 49, 3177.
(3) (a) Ellis, G. A.; Romney-Alexander, T. M. Chem. ReV. 1987, 87,
779. (b) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron
Lett. 1999, 40, 8193.
10.1021/ol0601038 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/22/2006

Table 1. Initial Optimization Experiments
no.
conditions
KCN, toluene, TMEDA
CuCN, DMF, TMEDA
Zn(CN)2, DMF, TMEDA
K4Fe(CN)6, DMF, K3PO4, TMEDA, 85 °C
K3Fe(CN)6, DMF, K3PO4, TMEDA, 85 °C
K4Fe(CN)6, DMF, K3PO4, no TMEDA, 85 °C
K4Fe(CN)6, DMF, K3PO4, no TMEDA, air, 85 °C
GCY,a,b
8
%
1
2
3
4
5
6
7
36 (71)
23 (63)
44 (84)
41 (81)
Figure 1. 1,8-Bis(diisopropylphosphino)triptycene.
a GC-based yield after 6 h at 85 °C. b Yield in parentheses indicates the
GCY after 24 h at 85 °C.
was claimed, the amines serve as co-ligands to allow an
additional stabilization of the palladium catalysts.8
Finally, the employment of nontoxic cyanide sources such
as potassium hexacyanoferrate9 makes the palladium-
catalyzed cyanation of aryl halides an attractive laboratory
method.
It is worth noting that despite the diversity of the reported
protocols the general reaction conditions remain rather harsh
(120-140 °C). As was suggested, the high reaction temper-
ature needed stems from either a slow oxidative addition (due
to cyanide interfering)6-8 or a transmetalation step (when
ferrocyanides are used).9
employed. Second, the wide bite of the ligand may also assist
the reductive elimination11 of the resulting benzonitrile from
the palladium center. Indeed, several theoretical and experi-
mental studies indicate that this step might also be prob-
lematic.12
Thus, our initial experiments comprised attempts to
accomplish the reaction between 1-bromonaphthalene and
different cyanide sources at 85 °C in the presence of 1 mol
% of PdCl2(L1) (Table 1).
Recently, we reported the synthesis and characterization
of a new class of strongly bent trans-spanning diphosphine
ligands based on the triptycene scaffold that exhibited unique
coordination chemistry and promising catalytic activity in
cross-coupling reactions (Figure 1 (left)).10 Inter alia, we
found that the palladium geometry in PdCl2(L1) (Figure 1
(right)) is strongly distorted from the expected square planar
geometry toward a rare butterfly-like environment (P-Pd-P
and Cl-Pd-Cl angles are 154.871(17)° and 174.90(2)°,
respectively). In principle, this arrangement around the
catalytic site might be particularly beneficial in the described
transformation. First, we assumed that the unique bent
structure of the ligand may provide an effective protection
of the transition metal center from the premature contact with
inhibiting cyanide ions thus enhancing the reactivity of the
catalyst at milder temperatures. One can expect that the effect
would be more pronounced if bulky cyanide carriers are
Upon examination of various solvent/base/cyanide com-
binations we found that the reaction indeed proceeds under
mild heating when either K4Fe(CN)6 or K3Fe(CN)6 in DMF
are used (entries 4 and 5, Table 1). This is especially
remarkable because previous reports claimed that the cyanide
transfer from K4Fe(CN)6 is difficult below 120 °C.9 Interest-
ingly, unlike previously reported procedures, our catalyst
does not require the co-assistance of amine ligands (TMEDA,
DBU, etc.). In contrast, their effect on the reaction was
somewhat deleterious (entry 4 vs entry 6, Table 1).
Furthermore, we found that our catalytic system is
perfectly stable to air and the reaction can be performed
without rigorous exclusion of oxygen. Only slightly reduced
yields were observed when air- and nitrogen-filled reactions
were run side by side (entry 6 vs entry 7, Table 1).
Noteworthily, cheap and readily accessible DMF can be
used as the solvent to perform the desired reaction: normally,
notable decomposition of DMF under the harsh and basic
reaction conditions takes place prompting researchers to
employ less convenient N-methylpyrrolidone (NMP) or N,N-
dimethylacetamide (DMAC) which may complicate the
isolation of products.9c
(6) (a) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik,
B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887. (b) Okano,
T.; Kiji, J.; Toyooka, Y. Chem. Lett. 1998, 425. (c) Maligres, P. E.; Waters,
M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40, 8193. (d) Sakamoto,
T.; Ohsawa, K. J. Chem. Soc., Perkin Trans. 1 1999, 2323. (e) Jin, F.;
Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271. (f) Veauthier, J. M.;
Carlson, C. N.; Collis, G. E.; Kiplinger, J. L.; John, K. D. Synthesis 2005,
2683.
(7) (a) Cassar, L.; Ferrara, S.; Foa, M. AdV. Chem. Ser. 1974, 132, 252.
(b) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003,
42, 1661. (c) Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.;
Beller M. J. Organomet. Chem. 2003, 684, 50.
(8) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.;
Weiss, S.; Beller M. Eur. J. Org. Chem. 2003, 9, 1828.
(9) (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
(b) Schareina, T.; Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689,
4567. (c) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70,
1508.
Further experiments, which aimed at the discovery of the
optimum reaction conditions, revealed that 0.5-1 mol % of
(11) (a) Gillie, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4933. (b)
Kohara, T.; Yamamoto, T.; Yamamoto, A. J. Organomet. Chem. 1980, 192,
265. (c) Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta 1994, 220, 249. (d)
Marcone, J. E.; Moloy, K. G. J . Am. Chem. Soc. 1998, 120, 8527. (e)
Stockland, R. A., Jr.; Levine, A. M.; Giovine, M. T.; Guzei, I. A.; Cannistra,
J. C. Organometallics 2004, 23, 647.
(12) (a) Backvall, J.-E.; Bjorkman, E. E.; Petterson, L.; Siegbahn, P. J.
Am. Chem. Soc. 1985, 107, 7265. (b) Goldberg, K. I.; Yan, J.; Breitung, E.
M. J. Am. Chem. Soc. 1995, 117, 6889. (c) Huang, J.; Haar, C. M.; Nolan,
S. P.; Marcone, J. E.; Moloy, K. G. Organometallics 1999, 18, 297.
(10) Grossman, O.; Azerraf, C.; Gelman, D. Organometallics 2006, 25,
375.
1190
Org. Lett., Vol. 8, No. 6, 2006

the catalyst derived from Pd(OAc)2 and 0.75-1.5 mol % of
L1 can effect the successful transformation of 1-bromonaph-
thalene into 1-cyanonaphthalene when 0.3 equiv of the
nontoxic K4Fe(CN)6 and 1.5 equiv of K3PO4 were used per
each equivalent of the aryl halide. Reduction of the starting
aryl bromide was the only side reaction (up to 2%).
Since it was previously suggested that K4Fe(CN)6 can
stabilize palladium catalysts under ligand-free conditions,9b,c
an experiment in the absence of L1 was carried out to ensure
the catalytic effect of Pd(OAc)2/L1. Only 26% conversion
of the starting material was obtained under the latter reaction
conditions in this case.
Table 2. Pd(OAc)2/L1-Catalyzed Cyanation of Aryl Halides
under Air
These results prompted us to study the scope and the
possible limitations of the new catalytic systems. The results
of this study are tabulated in Table 2.
Very efficient transformation of electron deficient (entry
1) and electron neutral (entries 2-8) aryl bromides was
observed under mild reaction conditions and air atmosphere.
In all these cases, the reaction reached full conversion to
the desired cyanoarene after ca. 24 h. Moderately electron-
rich heterocycles and polysubstituted aryl bromides exhibited
satisfactory reactivity as well (entries 9 and 10, respectively).
We also found that 0.5 mol % of the catalyst derived from
Pd(OAc)2/L1 is enough to drive the reaction to completion
(entry 6), though slightly higher reaction temperature (90
°C) and a longer reaction time were required. Electron-rich
aryl bromides (entry 11) were generally less reactive and
led to incomplete reaction under the suggested reaction
conditions.
Remarkably, our catalyst was quite insensitive to the steric
hindrance of substrates and very good to excellent yields of
ortho-substituted benzonitriles were obtained with 2-bromo-
toluene, 1-bromonaphthalene, and 9-bromoanthracene (en-
tries 2, 3, and 7).
Inspired by these results, we attempted to extend the
suggested method to less reactive but less costly aryl
chlorides.8,13 Unfortunately, the reactivity of our catalyst was
insufficient to drive the reaction to completion even under
higher reaction temperature and prolonged reaction time
(entry 12, Table 2).
To conclude, we demonstrated that 1,8-bis(diisopropylphos-
phino)triptycene (L1) is an efficient ligand for the mild pal-
ladium-catalyzed cyanation of aryl bromides. In addition, a
simple and efficient protocol for the above-mentioned reac-
tion has been developed that circumvents the use of amine
co-ligands, nitrogen atmosphere, and troublesome solvents.
Finally, the strong dependence of the reaction efficiency on
the steric properties of the ligand was observed. The most
important ramification of this finding is that the steric proper-
ties of the ligand can lead to enhanced protection against
premature contact between a catalyst and an inhibiting re-
agent, and consequently, to more effective catalysis. There-
fore, steric factors should not be neglected when more effi-
cient catalysts for this and related transformation are sought.
a Reaction conditions: 1 equiv of aryl bromide (1 mmol), 0.3 equiv of
K4Fe(CN)6, 2 equiv of K3PO4, 1 mol % of Pd(OAc)2, 1.5 mol % of L1, 3
mL of DMF, 85 °C, 24 h. b Reaction temperature of 90 °C was required to
reach full conversion. c GC-based conversion. d Isolated yield of at least
95% pure material (average of two runs). e Conversion obtained with 0.5
mol % of the catalyst after 36 h at 90 °C. f GC yield is reported. g Full
conversion was not reached even after 48 h (120 °C).
In-depth studies on the ligand influence on this transfor-
mation, as well as attempts to activate industrially favorable
aryl chlorides, are underway.
Acknowledgment. We acknowledge Grant No. 034.9043
601 for financial support.
Supporting Information Available: General procedure
and spectral data for the compounds listed in Table 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) (a) Jin, F.; Confalone, P. N.Tetrahedron Lett. 2000, 41, 3271. (b)
Sundermeier, M.; Zapf, A.; Beller M.; Sans, J. Tetrahedron Lett. 2001, 42,
6707.
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