P(i-BuNCH2CH2)3N: An efficient ligand for the direct α-arylation of nitriles with aryl bromides

Article abstract of DOI:10.1021/jo034779h

A new catalyst system for the synthesis of α-aryl-substituted nitriles is reported. The bicyclic triaminophosphine P(i-BuNCH ₂CH₂)₃N (1b) serves as an efficient and versatile ligand for the palladium-catalyzed direct α-arylation of nitriles with aryl bromides. Using ligand 1b, ethyl cyanoacetate and primary as well as secondary nitriles are efficiently coupled with a wide variety of aryl bromides possessing electron-rich, electron-poor, electron-neutral, and sterically hindered groups.

Full text of DOI:10.1021/jo034779h

P (i-Bu NCH2CH2)3N: An Efficien t Liga n d for th e Dir ect r-Ar yla tion
of Nitr iles w ith Ar yl Br om id es
J ingsong You and J ohn G. Verkade*
Department of Chemistry, Gilman Hall, Iowa State University, Ames, Iowa 50011
jverkade@iastate.edu
Received J une 6, 2003
A new catalyst system for the synthesis of R-aryl-substituted nitriles is reported. The bicyclic
triaminophosphine P(i-BuNCH2CH2)3N (1b) serves as an efficient and versatile ligand for the
palladium-catalyzed direct R-arylation of nitriles with aryl bromides. Using ligand 1b, ethyl
cyanoacetate and primary as well as secondary nitriles are efficiently coupled with a wide variety
of aryl bromides possessing electron-rich, electron-poor, electron-neutral, and sterically hindered
groups.
R-Aryl-substituted nitriles are very important building
blocks for synthesizing pyridines, carboxylic acids, pri-
mary amines, bicyclic amidines, lactones, aldehydes and
esters.1 Such nitriles are also valuable for constructing
biologically active compounds such as verapamil and
related compounds containing a tertiary benzylic nitrile
which act as slow-acting calcium channel antagonists.2
Usually, such compounds are synthesized by displace-
ment of an activated benzylic alcohol or halide with
cyanide, followed by R-alkylation. In sharp contrast to
R-alkylation of nitriles with alkyl halides, however, direct
R-arylation of nitriles appears to be quite difficult to
accomplish, and consequently, chemistry related to this
transformation is much less developed. It has been
reported for uncatalyzed R-arylations of nitriles that the
corresponding anions of diphenylacetonitrile, phenylac-
etonitrile, and ethyl cyanoacetate can couple with aryl
fluorides possessing another electron-withdrawing group.3
Interestingly, Caron and co-workers recently achieved
uncatalyzed coupling of nitrile anions with aryl fluorides
lacking an additional electron-withdrawing group.4 How-
ever, limitations were encountered with the structures
of the nitriles that underwent addition. For example, the
anion of ethyl cyanoacetate was unreactive, primary
nitriles did not undergo substitution, and reactions using
either phenyl acetonitrile or isovaleronitrile with 2-fluo-
roanisole led to decomposition.4
Palladium-catalyzed R-arylations of enolates and other
stabilized carbanions have undergone significant devel-
opment in recent years.5 Although alkyl nitriles are less
acidic than ketones, a cyano group is more electron-
withdrawing than an acyl group.6 In principle, the anion
of a nitrile in the presence of a transition metal catalyst
could couple with an aryl halide, but only a few reports
of such reactions have appeared. For example, arylations
of cyanoacetates, which are considerably more acidic than
* Corresponding author. Phone: (515) 294-5023. Fax: (515) 294-
0105.
(3) (a) Loupy, A.; Philippon, N.; Pigeon, P.; Sansoulet, J .; Galons,
H. Synth. Commun. 1990, 20, 2855-2864. (b) Sommer, M. B.; Begtrup,
M.; Bogeso, K. P. J . Org. Chem. 1990, 55, 4817-4821. (c) Zhang, X.-
M.; Yang, D.-L.; Liu, Y.-C. J . Org. Chem. 1993, 58, 224-227. (d)
Makosza, M.; Podraza, R.; Kwast, A. J . Org. Chem. 1994, 59, 6796-
6799. (e) Plevey, R. G.; Sampson, P. J . Chem. Soc., Perkin Trans. 1
1987, 2129-2136.
(1) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J .; You,
J .; Holzgrabe, U.; Heller, E.; Oehme, G. J . Org. Chem. 2002, 67, 4414-
4422. (b) Leader, H.; Smejkal, R. M.; Payne, C. S.; Padilla, F. N.; Doctor,
B. P.; Gordon, R. K.; Chiang, P. K. J . Med. Chem. 1989, 32, 1522-
1528. (c)Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankey, C. J .; Roark,
W. H.; Picard, J . A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.;
Krause, B. R. J . Med. Chem. 1993, 36, 3300-3307. (d) Convery, M.
A.; Davis, A. P.; Dunne, C. J .; MacKinnon, J . W. Tetrahedron Lett.
1995, 36, 4279-4282. (e) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli,
D. Tetrahedron 1990, 46, 7139-7150. (f) Pascal, C.; Dubois, J .;
Gue´nard, D.; Tchertanov, L.; Thoret, S.; Gue´ritte, F. Tetrahedron 1998,
54, 14737-14756. (g) Bush, E. J .; J ones, D. W. J . Chem. Soc., Perkin
Trans. 1 1997, 3531-3536.
(2) (a) Bromidge, S. M.; Brown, F.; Cassidy, F.; Clark, M. S. G.;
Dabbs, S.; Hawkins, J .; Loudon, J . M.; Orlek, B. S.; Riley, G. J . Bioorg.
Med. Chem. Lett. 1992, 2, 791-796. (b) Dei, S.; Romanelli, M. N.;
Scapecchi, S.; Teodori, E.; Chiarini, A.; Gualtieri, F. J . Med. Chem.
1991, 34, 2219-2225. (c) Mitani, K.; Sakurai, S.; Suzuki, T.; Morikawa,
E.; Kato, H.; Ito, Y.; Fujita, T. Chem. Pharm. Bull. 1988, 36, 4121-
4135. (d) Theodore, L. J .; Nelson, W. L. J . Org. Chem. 1987, 52, 1309-
1315. (e) Christensen, S. B.; Guider, A.; Forster, C. J .; Gleason, J . G.;
Bender, P. E.; Karpinski, J . M.; DeWolf, W. E., J r.; Barnette, M. S.;
Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.;
Bochnowicz, S.; Osborn, R. R.; Manning, C. D.; Grous, M.; Hillegas, L.
M.; O’Leary Bartus, J .; Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R.
C.; Torphy, T. J . J . Med. Chem. 1998, 41, 821-835.
(4) Caron, S.; Vazquez, E.; Wojcik, J . M. J . Am. Chem. Soc. 2000,
122, 712-713.
(5) (a) Lloyd-J ones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953-
956. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-
4211. (c) Lee, S.; Beare, N. A.; Hartwig, J . F. J . Am. Chem. Soc. 2001,
123, 8410-8411. (d) Ehrentraut, A.; Zapf, A.; Beller, M. Adv. Synth.
Catal. 2002, 344, 209-217. (e) Moradi, W. A.; Buchwald, S. L. J . Am.
Chem. Soc. 2001, 123, 7996-8002. (f) Hamada, T.; Chieffi, A.; Åhman,
J .; Buchwald, S. L. J . Am. Chem. Soc. 2002, 124, 1261-1268. (g) Fox,
J . M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J . Am. Chem. Soc. 2000,
122, 1360-1370. (h) J ørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J . P.;
Hartwig, J . F. J . Am. Chem. Soc. 2002, 124, 12557-12565. (i) Palucki,
M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 11108-11109. (j)
Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053-
4056. (k) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2002, 43, 101-104. (l) Culkin, D. A.; Hartwig, J . F.
J . Am. Chem. Soc. 2001, 123, 5816-5817. (m) Churruca, F.; SanMartin,
R.; Tellitu, I.; Dominguez, E. Org. Lett. 2002, 4, 1591-1594. (n) Kashin,
A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R. Tetrahedron Lett. 2002,
43, 2539-2542.
(6) Culkin, D.; Hartwig, J . F. Acc. Chem. Res. 2003, 36, 234-245.
10.1021/jo034779h CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003
J . Org. Chem. 2003, 68, 8003-8007
8003

You and Verkade
TABLE 1. Ca ta lytic r-Ar yla tion of Eth yl Cya n oa ceta te
alkyl nitriles, were reported in 1993 to occur in moderate
yields using catalytic amounts of copper, although the
reaction was limited to aryl iodides.7 Very recently, cross-
coupling products of aryl bromides or chlorides with
cyanoacetates were achieved in good yields under mild
conditions in the presence of a palladium/P(t-Bu)3 or
(Ph5C5)Fe(C5H4)P(t-Bu)2 catalyst system.8 For alkyl
nitriles, the Miura group reported in 1998 that the
palladium-catalyzed R-arylation of phenylacetonitrile
gave a moderate product yield at high temperature, even
though the electronic properties of phenylacetonitrile are
similar to those of ketones (which couple easily with aryl
halides). Unfortunately, other alkyl nitriles that were
tried did not take part in this reaction.9 Very recently,
Hartwig and co-workers reported that BINAP or P(t-Bu)3-
ligated palladium was effective for the monoarylation of
secondary alkyl nitriles and for the diarylation of aceto-
nitrile (as well as other unhindered primary nitriles) with
aryl bromides giving moderate to good yields.10
Although a variety of triaminophosphines [e.g. P(NR2)3]
are well-known, there have been no reports of the use of
such ligands in Pd-catalyzed R-arylations of stabilized
carbanions. This may be partly due to the diminished
electron-donating capability of acyclic triaminophos-
phines compared with trialkylphosphines, as was ratio-
nalized recently by Woollins et al. on structural grounds.11
Bicyclic proazaphosphatranes of type 1 (of which 1a -c
w ith Br om oben zen ea
proazaphosphatrane
(mmol)
temp yieldb
palladium (mmol) (° C) (%)
entry
1
2
3
4
5
6
7
8
9
Pd2(dba)3 (0.02)
90
90
70
90
38
none
98
95
94
75
44
52
72
1b (0.08)
1b (0.08)
1b (0.08)
1b (0.08)
1b (0.04)
1a (0.08)
1c (0.08)
1d (0.08)
Pd2(dba)3 (0.02)
Pd(OAc)2 (0.04)
{Pd(allyl)Cl]2 (0.02) 90
Pd2(dba)3 (0.02)
Pd2(dba)3 (0.02)
Pd2(dba)3 (0.02)
Pd2(dba)3 (0.02)
70
70
70
70
70
10
P(NMe2)3 (0.08) Pd2(dba)3 (0.02)
43
a
Reaction conditions: 1.0 mmol of aryl bromide, 1.1 mmol of
ethyl cyanoacetate, 2.0 mmol of KO-t-Bu in the presence or absence
of triaminophosphine/palladium in 2.0 mL of toluene at 70-90 °C
under Ar atmosphere for 5 h. b Isolated yields (average of two runs)
based on aryl bromide.
Very recently, we reported that the bicyclic P(i-BuNCH2-
CH2)3N (1b) serves as an effective ligand for palladium-
catalyzed Suzuki cross-coupling16 and for aminations of
a wide array of aryl chlorides, bromides, and iodides.17
Herein we show that 1b is also an excellent ligand in
the palladium-catalyzed direct R-arylation of nitriles with
aryl bromides.
Resu lts a n d Discu ssion
Our initial exploration of reaction conditions for the
palladium-catalyzed R-arylations of nitriles focused on
the coupling of ethyl cyanoacetate with bromobenzene.
For this model reaction, three palladium sources were
employed at 4 mol % loading in the presence of 1b as a
ligand (Table 1). Although Pd2(dba)3, Pd(OAc)2, and
[Pd(allyl)Cl]2 were all effective precatalysts, Pd2(dba)3
gave a higher activity (entries 3-5). No reaction was
observed in the absence of Pd2(dba)3 (entry 2), and the
yield was only 38% with Pd2(dba)3 in the absence of
ligand 1b (entry 1). After screening a variety of bases
(e.g., Na3PO4, K3PO4, Na2CO3, Cs2CO3, NaH, NaN-
(SiMe3)2, KO-t-Bu, and NaO-t-Bu), we found that KO-t-
Bu gave the best results. Reactions with weaker bases,
such as Na3PO4, K3PO4, Na2CO3, and Cs2CO3, provided
only poor conversions after 15 h. Toluene and dioxane
were the most effective solvents in the presence of KO-
t-Bu. In an effort to obtain an optimum palladium:ligand
ratio, we found that a 1:2 Pd/L ratio gave faster reaction
rates and better product yields, while a 1:1 ratio provided
only a 75% yield (compare entries 3 and 6).
are commercially available12) were first synthesized in
our laboratories and they have proven to be versatile,
nonionic, very strong, stoichiometric bases and potent
catalysts for a variety of useful transformations over the
past 10 years.13 These transformations appear to be quite
dependent upon the proven or speculated occurrence of
transannulation of the bridgehead nitrogen’s lone pair
to the phosphorus, which enhances the basicity of these
phosphines and the stability of the reaction intermediates
they form. In addition, the fairly rigid but strain-free
bicyclic (approximately C3v) framework of these bases
serves to augment the lone pair electron density at
phosphorus.14,15 The electronic and steric properties of
these molecules are easily finely tuned by introducing
an appropriate organic substituent at each of the PN3
nitrogens.
(14) For discussions of the electronic structure of tris(alkylamino)-
phosphines, see: (a) Cowley, A. H.; Lattman, M.; Stricklen, P. M.;
Verkade, J . G. Inorg. Chem. 1982, 21, 543-549. (b) Molloy, K. G.;
Petersen, J . L. J . Am. Chem. Soc. 1995, 117, 7696-7710. (c) Xi, S. K.;
Schmidt, H.; Lensink, C.; Kim, S.; Wintergrass, D.; Daniels, L. M.;
J acobson, R. A.; Verkade, J . G. Inorg. Chem. 1990, 29, 2214-2220. (d)
Socol, S. M.; J acobson, R. A.; Verkade, J . G. Inorg. Chem. 1984, 23,
88-94. (e) Romming, C.; Songstad, J . Acta Chem. Scand., Ser. A. 1980,
34, 365-373. (f) Romming, C.; Songstad, J . Acta Chem. Scand., Ser.
A. 1979, 33, 187-197.
(15) Wroblewski, A. E.; Pinkas, J .; Verkade, J . G. Main Group Chem.
1995, 1, 69-79. An X-ray structural study of 1c showed that the
bonding environment around the PN3 nitrogen is rather planar, the
sum of angles being 354.9°, 356.6°, and 357.5°.
(16) Urganonkar, S.; Nagarajan, M.; Verkade, J . G. Tetrahedron
Lett. 2002, 43, 8921-8924.
(17) (a) Urganonkar, S.; Nagarajan, M.; Verkade, J . G. J . Org. Chem.
2003, 68, 452-459. (b) Urganonkar, S.; Nagarajan, M.; Verkade, J . G.
Org. Lett. 2003, 5, 815-818.
(7) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J . Org. Chem.
1993, 58, 7606-7607.
(8) (a) Stauffer, S. R.; Beare, N. A.; Stambuli, J . P.; Hartwig, J . F.
J . Am. Chem. Soc. 2001, 123, 4641-4642. (b) Beare, N. A.; Hartwig,
J . F. J . Org. Chem. 2002, 67, 541-555.
(9) Sataoh, T.; Inoh, J ., Kawamura, Y.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. J pn. 1998, 71, 2239-22467.
(10) Culkin, D. A.; Hartwig, J . F. J . Am. Chem. Soc. 2002, 124,
9330-9331.
(11) (a) Clarke, M. L.; Cole-Hamilton, D. J .; Slawin, A. M. Z.;
Woollins, J . D. Chem. Commun. 2000, 2065-2066. (b) Clarke, M. L.;
Cole-Hamilton, D. J .; Woollins, J . D. J . Chem. Soc., Dalton Trans. 2001,
2721-2723.
(12) Aldrich and Fluka for 1a , 1b, 1c; Strem for 1b.
(13) (a) Verkade, J . G. Top. Curr. Chem. 2003, 233, 1-44 and
references therein. (b) Kisanga, P. B.; Verkade, J . G. Tetrahedron, in
press.
8004 J . Org. Chem., Vol. 68, No. 21, 2003

P(i-BuNCH2CH2)3N: A Ligand for Direct R-Arylation
TABLE 2. r-Ar yla tion of Eth yl Cya n oa ceta te w ith Ar yl Br om id es Ca ta lyzed by P (i-Bu NCH2CH2)3N (1b)a
a
Reaction conditions: 1.0 mmol of aryl bromide, 1.1 mmol of ethyl cyanoacetate, 2.0 mmol of KO-t-Bu, 0.02 mmol of Pd2(dba)3, and
b
0.08 mmol of 1b in 2.0 mL of toluene at 90 °C under Ar atmosphere for 5 h. Isolated yields (average of two runs) based on aryl
bromide. c 0.01 mmol of Pd2(dba)3 and 0.04 mmol of 1b. 0.005 mmol of Pd2(dba)3 and 0.02 mmol of 1b. e Dioxane as a solvent. f 70 °C.
d
g
In the presence of strong base, the substrate decomposed.
While 1a as a ligand was disappointing, providing only
a 44% product yield in the reaction in Table 1 (entry 7),
the more bulky 1b delighted us with a 98% yield (entry
3), whereas 1c was not as efficient (entry 8). As described
earlier by us, the latter result could arise from the fact
that 1c does not provide sufficient bulk, since the methyl
groups on the i-Pr substituents are probably turned
outward and away from the phosphorus lone pair when
it coordinates to the Pd, a conformation that is also
present in the solid-state structures of 1c as well as in
its protonated form.15,17 While a similar conformation of
the isobutyl groups could occur in ligand 1b, the greater
flexibility of these substituents and the larger cone angle
they can sweep out as they rotate around the C-N bonds
in 1b effectively increases their steric requirements over
that of an isopropyl group, thus conferring on this ligand
a unique balance of steric and electronic inductive
influences that optimize the activity of the 1b/Pd catalyst
system. Interestingly, the further increase in nitrogen
substituent cone angles provided in ligand 1d was not
beneficial (entry 9).
generated in situ from 2 mol % Pd2(dba)3 and 8 mol %1b.
Under these conditions, a broad range of aryl bromides,
including electron-rich, electron-poor, electron-neutral,
sterically hindered, and heteroaryl bromides, were
smoothly coupled. Electron-poor substrates such as those
in entries 12-14 of Table 2 led to very high yields, except
for 4-bromonitrobenzene, which did not afford the desired
product, although conversion of starting material was
complete (entry 15). Deactivated aryl bromides afforded
the expected coupling products in excellent yields. Thus,
the reaction of p-methyoxybromobenzene with ethyl
cyanoacetate gave a 94% yield of product (Table 2, entry
10). Substrates with an ortho or pseudo-ortho substituent
also reacted to afford excellent product yields (entries 4
and 7-9). Our protocol was equally effective for aryl
bromides possessing substituents at other positions
(entries 4 and 5). The reaction of p-(dialkylamino)-
bromobenzene gave a 95% product yield (entry 11). The
arylation of ethyl cyanoacetate with p-dibromobenzene
afforded exclusively the para-coupled aromatic product
in excellent yield (entry 17) and no monocoupled aromatic
product was observed, even when a 1:1.1 ratio of p-
dibromobenzene to ethyl cyanoacetate was employed.
It may be noted that cyanoacetate esters did not couple
with aryl bromides possessing electron-withdrawing
groups such as esters, ketones, and nitriles in the
After optimization of the reaction conditions, we in-
vestigated various aryl bromides that could be coupled
with ethyl cyanoacetate (Table 2). The best results were
obtained between 70 and 90 °C in toluene using KO-t-
Bu as a base in the presence of a catalyst system
J . Org. Chem, Vol. 68, No. 21, 2003 8005

You and Verkade
TABLE 3. Ca ta lytic r-Ar yla tion of Nitr iles w ith Ar yl Br om id esa
a
Reaction conditions: 1.0 mmol of aryl bromide, 1.2 mmol of nitrile, 1.4 mmol of NaN(SiMe3)2, 0.01-0.04 mmol of Pd(OAc)2 and 0.02-
b
0.08 mmol of 1b in 2.0 mL of toluene at 70-100 °C under Ar atmosphere. Isolated yields (average of two runs) based on aryl bromide.
c CH3CN: 2.0 mmol. 1.05 mmol of NaN(SiMe3)2. e Dioxane as a solvent.
d
presence of the Pd/(Ph5C5)-Fe(C5H4)P(t-Bu)2 or Pd/P(t-
Bu)3 catalyst systems.8b Moreover, pyridyl halides were
unreactive with ethyl cyanoacetate, and coupling of very
hindered aryl halides such as bromomesitylene with ethyl
cyanoacetate also did not take place.8b By contrast, our
catalytic system allows for a broad scope of substrates,
and it functions very well for aryl bromides of the
aforementioned types. Thus, the arylation of ethyl cy-
anoacetate with 2-bromopyridine, methyl 4-bromoben-
zoate, 4-bromobenzonitrile, and 2-bromomesitylene gave
the desired products in 94%, 93%, 98%, and 88% yields
(Table 2; entries 16, 14, 13, and 8, respectively).
Although not investigated in detail, the R-arylation of
ethyl cyanoacetate also proceeded with substantially
lower catalyst loadings than with the 2 mol % Pd2(dba)3
used under our standard conditions. As shown in entries
2 and 3 of Table 2, the reaction of ethyl cyanoacetate with
bromobenzene at 70 °C still gave a high yield with 2 mol
% or even with 1 mol % of the palladium precursor.
In contrast to our results obtained with KO-t-Bu as a
base in the R-arylation of ethyl cyanoacetate, NaN-
(SiMe3)2 was the most effective base for the arylation of
alkyl nitriles. Reactions involving KO-t-Bu failed to go
to completion, even after extended periods of heating.
Moreover, Pd(OAc)2 proved to be more effective in the
R-arylation of ethyl cyanoacetate than Pd2(dba)3. As
shown in Table 3, secondary nitriles were effectively
coupled to afford monoarylation products with aryl
bromides possessing electron-rich, electron-poor, electron-
neutral, and sterically hindered groups in high yields,
even with palladium loadings as low as 1.0 mol %. For
example, cross-coupling of isobutyronitrile with bro-
mobenzene, 1-bromo-4-tert-butylbenzene, 2-bromotolu-
ene, and 4-bromobenzonitrile gave the corresponding
tertiary R-arylnitriles in 2-5 h in 95%, 92%, 89%, and
98% yield, respectively (entries 1-4). The reaction of
isobutyronitrile with electron-rich 4-bromoanisole needed
a somewhat longer reaction time to obtain a good yield
8006 J . Org. Chem., Vol. 68, No. 21, 2003

P(i-BuNCH2CH2)3N: A Ligand for Direct R-Arylation
(entry 5). The 1b/Pd(OAc)2 catalyst system was also
effective for primary nitriles, although these reactions
required higher catalyst loadings. Thus, the coupling of
primary nitriles, such as benzyl nitrile and n-butyroni-
trile, with bromobenzene gave the corresponding monoary-
lated product as the major one in 93% and 85% yields,
(entries 6 and 9, respectively). The monoarylated product
of n-butyronitrile was easily coupled with a second
equivalent of bromobenzene to form the corresponding
diarylated product (entry 10). Interestingly, diarylation
of acetonitrile occurred preferentially over monoarylation
(entry 7), and monoarylated product was not observed,
even in the presence of 2.0 equiv of CH3CN, presumably
because the monoarylated species is readily deprotonated
and is sufficiently unhindered to bind to palladium
during the reaction pathway (entry 8). Apparently,
arylation of acetonitrile beyond the disubstituted stage
is prevented by steric hindrance of the deprotonated
disubstituted species to coordination to palladium. In-
terestingly, the reaction of PhSO2CH2CN with bromoben-
zene conducted in dioxane gave a higher product yield
than in toluene, possibly because the poor solubility of
the sodium salt of (phenylsulfonyl)acetate in toluene, as
was suggested by precipitate formation observed when
NaN(SiMe3)2 was added (entry 11).
Exp er im en ta l Section
Typ ica l P r oced u r e for r-Ar yla tion of Eth yl Cya n oa c-
eta te w ith Ar yl Br om id es. A dried Schlenk flask equipped
with a magnetic stirring bar was charged with Pd2(dba)3 (0.02
mmol) and KO-t-Bu (2.0 mmol) inside a nitrogen-filled drybox.
The flask was capped with a rubber septum followed by
removal from the drybox. Toluene or dioxane (2 mL), P(i-
BuNCH2CH2)3N (1b) (0.08 mmol), and aryl bromide (1.0 mmol)
were then added successively. After stirring for 20 min at room
temperature, ethyl cyanoacetate (1.1 mmol) was added and
stirring was continued under the conditions indicated in Table
2. The mixture was then quenched by adding aqueous 1 N HCl,
followed by extraction with ethyl acetate. The organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel.
Typ ica l P r oced u r e for r-Ar yla tion of Alk yl Nitr iles
w ith Ar yl Br om id es. An oven-dried Schlenk flask equipped
with a magnetic stirring bar was charged with Pd(OAc)2 (0.01-
0.04 mmol) and NaN(SiMe3)2 (1.4 mmol) inside a nitrogen-
filled drybox. The flask was capped with a rubber septum
followed by removal from the drybox. Toluene (2 mL), P(i-
BuNCH2CH2)3N (1b) (0.02-0.08 mmol), and aryl bromide (1.0
mmol) were then added successively. After stirring for 20 min
at room temperature, an alkyl nitrile (1.2 mmol) was added.
The reaction mixture was stirred under the conditions indi-
cated in Table 3. The mixture was then quenched by adding
aqueous 1 N HCl followed by extraction with ether. The
organic phase was dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel.
Ack n ow led gm en t. The authors are grateful to the
National Science Foundation for grant support of this
research.
In summary, we have developed an efficient and
versatile catalytic system for the synthesis of R-aryl-
substituted nitriles that is of broad scope. Bicyclic 1b is
the first member of a new class of triaminophosphines
that has been demonstrated to be an advantageous ligand
in palladium-catalyzed R-arylations of stabilized carban-
ions. Particularly noteworthy are the generally better
product yields and the broader reaction scope facilitated
by our catalytic systems compared with rac-BINAP,
(Ph5C5)Fe(C5H4)P(t-Bu)2, and P(t-Bu)3. Further develop-
ment of our synthetic methodology is in progress, includ-
ing direct R-arylations of nitriles with aryl chlorides.
Note Ad d ed a fter ASAP P ostin g. The aryl bromide
structure in entry 17, Table 2, was incorrect in the
version posted September 26, 2003; the correct version
was posted September 30, 2003.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods used, characterizational NMR spectral data (1H
and 13C), and chromatography conditions for product purifica-
tion. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O034779H
J . Org. Chem, Vol. 68, No. 21, 2003 8007