Pd-catalyzed α-arylation of nitriles and esters and γ-arylation of unsaturated nitriles with TMPZnCl?LiCl

Article abstract of DOI:10.1021/ol200194y

Using TMPZnCl?LiCl as a kinetically highly active base, nitriles and esters undergo a Pd-catalyzed α-arylation under mild conditions. Remarkably, in the case of α,β- or β,γ-unsaturated nitriles, a regioselective γ-arylation or a γ-alkenylation is observed.

Full text of DOI:10.1021/ol200194y

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1690–1693
Pd-Catalyzed r-Arylation of Nitriles and
Esters and γ-Arylation of Unsaturated
Nitriles with TMPZnCl LiCl
†
3
†
†
ꢀ
Stephanie Duez, Sebastian Bernhardt, Johannes Heppekausen,
Fraser F. Fleming,*,‡ and Paul Knochel*,†
€
Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377,
Mu€nchen, Germany, and Department of Chemistry and Biochemistry, Duquesne
University, 600 Forbes Avenue, Mellon Hall, Pittsburgh, Pennsylvania 15282,
United States
paul.knochel@cup.uni-muenchen.de; flemingf@duq.edu
Received January 21, 2011
ABSTRACT
Using TMPZnCl LiCl as a kinetically highly active base, nitriles and esters undergo a Pd-catalyzed R-arylation under mild conditions. Remarkably,
3
in the case of R,β- or β,γ-unsaturated nitriles, a regioselective γ-arylation or a γ-alkenylation is observed.
The Pd-catalyzed arylation of carbonyl derivatives and
related functional groups has significantly extended the
scope of enolate chemistry.1 Several bases have been used
to generate R-metalated nitriles and carbonyl derivatives.
These metal enolates produce, after reductive elimination
of an intermediate arylpalladium(II), various R-arylated
carbonyl compounds.2-5 Hagadorn has reported the use
of TMP2Zn to deprotonate amides and esters. He
†
€
Ludwig-Maximilians-Universitat.
‡ Duquesne University.
(1) (a) Johansson, C.; Colacot, T. Angew. Chem., Int. Ed. 2010, 49,
676. (b) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953.
(c) Bellina, F.; Rossi, R. Chem. Rev. 2009, 110, 1082.
(2) Mulvey, R.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew.
Chem., Int. Ed. 2007, 46, 3802.
(5) For examples with metalated nitriles, see: (a) Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330. (b) You, J.; Verkade,
J. G. J. Org. Chem. 2003, 68, 8003. (c) Wu, L.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 15824. (d) You, J.; Verkade, J. G. Angew. Chem.,
Int. Ed. 2003, 42, 5051.
(3) For examples with ketone, malonate, and amide enolates, see:
(a) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489. (b) Colacot, T. J.
Org. Lett. 2004, 6, 3731. (c) Ackermann, L.; Born, R. Angew. Chem., Int.
Ed. 2005, 44, 2444. (d) Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born,
R.; Althammer, A. Angew. Chem., Int. Ed. 2006, 45, 7627. (e) Sakamoto,
T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1998, 36,
1664. (f) Cristau, H. J.; Vogel, R.; Taillefer, M.; Gradas, A. Tetrahedron
Lett. 2000, 41, 8457. (g) De Filippis, A.; Pardo, D. G.; Cossy, J.
Tetrahedron 2004, 60, 9757. (h) Su, W.; Raders, S.; Verkade, J. G.; Liao,
X.; Hartwig, J. F. Angew. Chem., Int. Ed. 2006, 45, 5852. (i) Hama, T.;
Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976.
(4) For examples with ester enolates, see: (a) Bentz, E.; Moloney,
M. G.; Westaway, S. M. Tetrahedron Lett. 2004, 45, 7395. (b) Culkin,
D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c) Hama, T.;
Hartwig, J. F. Org. Lett. 2008, 10, 1549. (d) Hama, T.; Hartwig, J. F.
Org. Lett. 2008, 10, 1545. (e) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 11176. (f) Jorgensen, M.; Lee, S.; Liu,
X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557.
(g) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(h) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773. (i) Liu, X.;
Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
(6) (a) Hlavinka, M. L.; Hagadorn, J. R. Tetrahedron Lett. 2006, 47,
5049. (b) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26,
4105.
(7) Huang, D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 5757.
ꢀ
(8) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.; Kefalidis, C. E.; Clot,
E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261.
(9) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Wunderlich, S.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 7685. (c) Wunderlich, S.; Knochel, P. Org. Lett. 2008,
10, 4705. (d) Wunderlich, S.; Knochel, P. Chem. Commun. 2008, 6387.
(e) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (f) Mosrin, M.;
Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun. 2009, 5615.
(g) Rohbogner, C. J.; Wirth, S.; Knochel, P. Org. Lett. 2010, 12, 1984.
(h) Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J. Org. Chem.
2010, 75, 4686. (i) Wunderlich, S.; Knochel, P. Angew. Chem., Int. Ed.
2009, 48, 1501. (j) Wunderlich, S.; Kienle, M.; Knochel, P. Angew.
Chem., Int. Ed. 2009, 48, 7256. (k) Wunderlich, S.; Knochel, P. Chem.;
Eur. J. 2010, 16, 3304. (l) Wunderlich, S.; Knochel, P. Angew. Chem., Int.
Ed. 2009, 48, 9717. (m) Jeganmohan, M.; Knochel, P. Angew. Chem., Int.
Ed. 2010, 49, 8520.
r
10.1021/ol200194y
Published on Web 03/02/2011
2011 American Chemical Society

performed Pd-catalyzed cross-couplings using Pd2dba3
and tBu3P as catalytic system.6 The choice of the appro-
priate base, the palladium catalyst, and the reaction con-
ditions is essential for obtaining high yields. Recently,
Hartwig reported silyl ketene acetals as enolate equivalents
in a new Pd-catalyzed γ-arylation of R,β-unsaturated
esters.7 In an alternative approach, Baudoin developed a
direct β-arylation of carbonyl compounds through an R-
metalation-elimination-addition sequence.8
Table 1. R-Arylation of Benzylic Nitriles with TMPZnCl LiCl
3
We developed a range of LiCl-solubilized TMP-bases9
(TMP = 2,2,6,6-tetramethylpiperidyl) which directly gen-
erate functionalized organometallics ideally suited for
transition metal coupling. The bases are monomeric in
solution, bear a sterically hindered TMP-moiety coordi-
nated to LiCl, and display an exceptionally high kinetic
basicity. Contrary to less hindered amines such as iPr2NH
or (Me3Si)2NH, TMPH does not slow down Pd-catalyzed
Negishi cross-couplings.10 These bases are excellent for
deprotonating various functionalized aromatics and het-
eroaromatics. We envisioned using some of these TMP-
bases to generate metal enolates directly to improve sub-
sequent transition metal couplings. Herein, we report the
entry
2
3
4 yield (%)a
1
2
3
4
5
2a, R1 = CO2Et
2a, R1 = CO2Et
2b, R1 = CN
2c, R1 = OMe
2c, R1 = OMe
3a, R2 = CO2Et
3c, R2 = OMe
3a, R2 = CO2Et
3a, R2 = CO2Et
3b, R2 = CN
4a (83)
4b (89)b
4c (80)
4d (79)
4e (85)
a Yield of isolated analytically pure product. b 2.0 equiv of
TMPZnCl LiCl was used.
3
use of TMPZnCl LiCl8e-h (1) for the Pd-catalyzed R-
3
arylation of nitriles and esters as well as a new γ-arylation
Table 2. R-Arylation of Aliphatic Nitriles with TMPZnCl LiCl
3
and γ-alkenylation of unsaturated nitriles.
Exploratory optimizations revealed a delicate depen-
dence on the nature of the base, palladium source, and
ligand for sequential deprotonation-arylations. Opti-
mally, treating a benzylic nitrile such as 2a with
TMPZnCl LiCl (1: 1.5 equiv, THF, 25 °C, 10 min)
3
followed by the addition of Pd(OAc)2 (2 mol %), SPhos
ligand11 (4 mol %), and ethyl 4-bromobenzoate (3a: 0.8
equiv, 50 °C, 4 h) produces the mono-R-arylated product
4a as the sole product in 83% yield (Table 1, entry 1). This
procedure proved to be general and is applicable to
benzylic nitriles bearing either an electron-withdrawing
group (2a,b) or an electron-donating group (2c). Conse-
quently, the reaction with various aryl bromides (3a-c)
affords the arylated nitriles 4a-e in 79-89% yield
(Table 1).
A competitive bis-arylation of aliphatic nitriles may
complicate the reaction outcome. Verkade has shown the
utility of a bicyclic proazaphosphatrane for selectively
performing the mono-arylation of metalated nitriles.5d
Hartwig developed a more general approach using tri-
methylsilylalkylnitriles in the presence of ZnF2 for avoid-
a Yield of isolated analytically pure product. b The reaction time for
this example was 26 h.
ing bis-arylation.5c Interestingly, by using TMPZnCl LiCl
3
(3d) is well tolerated (Table 2, entry 1). This selective
mono-arylation occurs with various functionalized aryl
and heteroaryl bromides (3a-e) furnishing the arylated
nitriles (4g-j) in 64-89% yield (Table 2, entries 2-5). As
expected, the prototypical cyclic nitrile, cyclohexanecar-
bonitrile (2e), reacts under the same conditions (Pd(OAc)2
(2 mol %), SPhos (4 mol %)) with the aryl bromides 3b,c
(0.8 equiv, 50 °C, 3 h) to afford nitriles (4k,l) efficiently in
73-92% isolated yield (Table 2, entries 6 and 7). In
contrast to previous nitrile arylations,5a-d the use of
as a base, the primary aliphatic nitrile valeronitrile (2d)
undergoes a selective mono-arylation with 4-bromoaniline
(3d: 0.8 equiv, THF, 50 °C, 2 h) and Pd(OAc)2 (2 mol %),
SPhos (4 mol %) yielding the aniline derivative (4f) in 74%
yield. Remarkably, a free NH2- group in the aryl bromide
(10) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.;
Knochel, P. Org. Lett. 2008, 10, 2765.
(11) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685. (c) Altman, R. A.; Buchwald, S. L. Nat. Protoc. 2007, 2, 3115.
(d) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
TMPZnCl LiCl (1) allows cross-coupling under milder
conditions (50 °C) and with shorter reaction times. Also,
3
Org. Lett., Vol. 13, No. 7, 2011
1691

Scheme 1. R-Arylation of Ethyl Esters
Scheme 2. γ-Arylation of Unsaturated Nitriles (7a or 9) with an
Aryl Bromide (3c)
Table 3. γ-Arylation of Unsaturated Nitriles
sensitive ester and nitrile substituents are tolerated in the
aryl bromides.
Prior palladium-catalyzed arylations of primary esters
often required the sterically protected tert-butyl esters.4d-j
Under our new conditions using TMPZnCl LiCl (1),
3
arylations are readily performed with ethyl esters. Thus,
the reaction of ethyl butyrate (5a: 1.0 equiv) with
TMPZnCl LiCl (1: 1.5 equiv, THF, 25 °C, 10 min)
3
followed by the addition of Pd(OAc)2 (2 mol %), SPhos
(4 mol %), and 4-bromoanisole 3c (0.8 equiv, 25 °C, 1 h)
provides the polyfunctional arylated ester (6a) in 96%
isolated yield (Scheme 1). The presence of an ethyl ester
in the aryl bromide is also tolerated, providing that the
reaction is performed at 50 °C with 2 equiv of ethyl
butyrate (5a). With these modifications, the expected
arylated ethyl ester (6b) is isolated in 80% yield.12 Simi-
larly, the secondary ester ethyl isobutyrate (5b) undergoes
the expected cross-coupling at 50 °C giving the R-arylated
ethyl ester (6c) in quantitative yield (Scheme 1).
γ-Arylation reactions of R,β-unsaturated carbonyl com-
pounds have been well-studied for unsaturated ketone or
aldehydes.13 Only recently have γ-arylations been exam-
ined with unsaturated esters.6 Using TMPZnCl LiCl (1),
3
we have performed the first arylations of R,β- and β,γ-
unsaturated nitriles and observe an exceptionally regiose-
lective γ-arylation. Thus, the reaction of cyclohexene-1-
a Yield of isolated analytically pure product. b The double bond is
conjugated with the aromatic ring. c 2.0 equiv of nitrile was used. d 2.5
equiv of nitrile was added over 60 min to the reaction mixture.
carbonitrile (7a: 1.0 equiv) with TMPZnCl LiCl (1: 2.0
3
(9) led under the same conditions to 8a in 80% yield. This
somewhat lower yield was attributed to the self-condensa-
tion reaction of 9.14 This side reaction could be avoided by
equiv, THF, 25 °C, 10 min) followed by the addition of
4-bromoanisole (3c: 0.8 equiv) and the usual catalytic
system at 50 °C for 1 h furnishes regioselectively the γ-
arylated cyclohexene carbonitrile (8a) in 95% yield
(Scheme 2). Performing the arylation reaction with the
isomericβ,γ-unsaturated nitrile cyclohexene-2-carbonitrile
adding the base TMPZnCl LiCl (1) to a mixture of the
3
nitrile 9, the aryl bromide 3c, and the Pd-catalytic system at
25 °C and stirring the reaction mixture at 50 °C for 1 h.
Under these optimized conditions, the γ-arylated nitrile 8a
is obtained in 94% yield (Scheme 2).
(12) Performing the arylation reaction at 25 °C results in extensive
addition reactions of the intermediate zinc enolate to the ester function
of 3a. Conducting the reaction at 50 °C with 2 equiv of 5a leads to the
best results. This may be explained by a higher catalyst activity at this
temperature.
(13) (a) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1998, 39, 6203. (b) Varseev, G. N.; Maier, M. E. Org. Lett. 2005, 7,
The arylation of alkenenitriles is similarly effective for a
range of aryl bromides bearing various functional groups
(Table 3, CO2Et, Cl, F: 3f-h) giving the γ-arylated R,β-
unsaturated nitriles 8b-d in 69-74% yield (Table 3,
3881. (c) Martın, R.; Buchwald, S. Angew. Chem., Int. Ed. 2007, 46, 7236.
´
(d) Hyde, A.; Buchwald, S. Angew. Chem., Int. Ed. 2008, 47, 177.
(e) Hyde, A. M.; Buchwald, S. L. Org. Lett. 2009, 11, 2663.
(14) Cargill, R. L.; Bushey, D. F.; Good, J. J. J. Org. Chem. 1979, 44,
300.
1692
Org. Lett., Vol. 13, No. 7, 2011

Scheme 3. Stereo- and Regioselective (E) and (Z) γ-Alkenyla-
tion of the Unsaturated Nitrile 9
Scheme 4. Stereo- and Regioselective (E) and (Z) γ-Alkenyla-
tion of the Unsaturated Nitrile 7a
of 1-iodocyclohex-1-ene 11b and cyclohex-2-enecarboni-
trile (9) giving the diene nitrile 12c in 64% yield (Scheme 3).
In the case of the R,β-unsaturated nitrile (7b), the
configuration of both double bonds is controlled, furnish-
ing after the reaction with E- or Z-11a the (Z,Z) and (Z,E)
skipped dienes (Z,Z)-12b and (Z,E)-12b with high diaster-
eoselectivity (>99% (Z,Z) or (Z,E)) (Scheme 4).
In summary, we have reported a practical Pd-catalyzed
arylation of zincated nitriles and ester enolates with di-
verse, functionalized aryl bromides. Highly regioselective
γ-arylation or γ-alkenylation of R,β- or β,γ-unsaturated
nitriles faithfully translate the vinyl iodide and unsaturated
nitrile stereochemistry into a variety of γ-substituted un-
saturated nitriles.
entries 1-3). Interestingly, in the case of 4- bromobenzo-
nitrile (3b), the γ-arylation occurs with concomitant mi-
gration of the double bond into conjugation with the
aromatic ring, furnishing the allylic nitrile 8e in 67% yield
(Table 3, entry 4). Cross-coupling of cyclohexene-1-carbo-
nitrile 7a with the unprotected 5-bromoindole (3i) leads to
the functionalized indole (8f) in 60% yield (Table 3, entry
5). The open-chain 2-phenyl-substituted R,β-unsaturated
nitrile (Z)-2-phenylpent-2-enenitrile (7b) reacts similarly
under the same conditions. Coupling 7b with various aryl
bromides (3b,c, 3j-l) provides the γ-arylated Z-unsatu-
rated nitriles 10a-e in 55-76% yield, maintaining the
olefin stereochemistry (Table 3, entries 6-10).
In contrast to enolate arylations, the corresponding
alkenylation is particularly rare6,15 and is unknown for
nitriles. The alkenylation of unsaturated nitriles 7b and 9
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the European Research Council (ERC), and the
Deutsche Forschungsgemeinschaft (DFG) for financial
support. Prof. F. Fleming thanks the Center of Advanced
was readily achieved with TMPZnCl LiCl (1) with com-
3
plete γ-regioselectivity. Thus, the reaction of the β,γ-
unsaturated nitrile 9 (1.0 equiv) with either (E)- or (Z)-1-
iodohex-1-ene ((E)- or (Z)-11a) affords the corresponding
unsaturated nitriles (E)-12a and (Z)-12a in 85-88% yield
with perfect retention of the double bond stereochemistry
(Scheme 3). Increasing the steric demand in the alkenyl
iodide is similarly effective with the Pd-catalyzed reaction
€
€
Studies, Ludwig Maximilians-Universitat Munchen
(CAS) for a visiting professor fellowship. We also thank
BASF AG (Ludwigshafen) and Chemetall GmbH
(Frankfurt) for the generous gift of chemicals.
Supporting Information Available. Experimental pro-
cedures and full characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Negishi, E.-I.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G.
Aldrichim. Acta 2005, 38, 71. (b) Watanabe, S.-i.; Ikeda, T.; Kataoka,
T.; Tanabe, G.; Muraoka, O. Org. Lett. 2003, 5, 565.
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