Straightforward conversion of arene carboxylic acids into aryl nitriles by palladium-catalyzed decarboxylative cyanation reaction

Article abstract of DOI:10.1055/s-0030-1258526

A one-pot procedure to convert aromatic carboxylic acids into aromatic nitriles is described. The methodology is based on a palladium(II)-catalyzed decarboxylative cyanation reaction using cyanohydrins as soluble cyanide sources. The described reaction worked on a panel of substrates and is additionally of particular interest for the straightforward preparation of ¹³C- or ¹⁴C-labeled compounds.

Full text of DOI:10.1055/s-0030-1258526

LETTER
2083
Straightforward Conversion of Arene Carboxylic Acids into Aryl Nitriles by
Palladium-Catalyzed Decarboxylative Cyanation Reaction
Conversion of
A
re
a
ne Carboxy
h
lic Acids int
io ArylnNitriles a Ouchaou, Dominique Georgin, Frédéric Taran*
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette 91191, France
Fax +33(1)69087991; E-mail: frederic.taran@cea.fr
Received 16 June 2010
HX, CO2
Abstract: A one-pot procedure to convert aromatic carboxylic ac-
CN
ids into aromatic nitriles is described. The methodology is based on
ArPdX
ox.
ArCN
ArCOOH
a palladium(II)-catalyzed decarboxylative cyanation reaction using
cyanohydrins as soluble cyanide sources. The described reaction
worked on a panel of substrates and is additionally of particular in-
terest for the straightforward preparation of 13C- or 14C-labeled
compounds.
PdX2
Pd(0)
Scheme 1 Proposed route to aryl nitriles from arene carboxylic acids
Key words: palladium, cyanation, arene carboxylic acids, cyano-
hydrin, decarboxylation
To investigate this reaction, we first looked at the influ-
ence of several parameters likely to influence the decar-
boxylation process. 2,4-Dimethoxy benzoic acid (1a) was
used as reference for the optimization of the reaction con-
ditions (Scheme 2). Mixing this substrate with one equiv-
alent of KCN in the conditions previously described by
Myers and co-workers for Heck olefination5a (PdOTf2 +
Ag2CO3) provided the hoped aryl nitrile 2a with 38%
yield (Table 1, entry 1), therefore encouraging us to im-
prove the procedure. A large number of combinations of
palladium sources [PdOAc2, Pd(acac)2, PdCl2, PdO and
PdSO4], palladium ligands (phosphines and N–N biden-
tate ligands) as well as bases (K2CO3, Cs2CO3, and
CuCO3) were thus screened but without great improve-
ment of the yield (data not shown). In accordance with
previous findings,5a the system DMSO/O2 from air was
found to play a central role in the catalytic process. The
use of other co-solvent or other oxidants led to dramatical-
ly reduced yields. These findings led us to suggest that the
increase of the reaction efficiency would involve im-
provements of the cyanation rather than the decarboxyla-
tion step. The use of crown ether (Table 1, entry 2) or
soluble cyanide salt (Table 1, entry 5) induced also strong
decrease of the yields.
Aryl nitriles are not only versatile intermediates in syn-
thetic organic chemistry but are also of considerable in-
dustrial importance as integral parts of dyes, herbicides,
natural products, agrochemicals, and pharmaceuticals.1
One of the most popular methods for the preparation of
aryl nitriles is the palladium-catalyzed cyanation of aryl
halides.2 Many efforts have been accomplished to im-
prove the robustness of this chemical transformation and
to apply it on aryl chlorides that are industrially the most
attractive starting materials among the aryl halides.3 How-
ever, from both economically and sustainability aspects,
arene carboxylic acids are even more advantageous start-
ing materials.4 In addition, they are easy to store, simple
to handle, and commercially accessible in a large structur-
al variety. For these reasons the use of carboxylic acids as
substrates in transition-metal-catalyzed coupling reaction
is currently in expansion.4 Decarboxylative coupling reac-
tions in particular have emerged as powerful alternatives
for C–C bond formation, thus providing new efficient
methods for Heck-5 or Suzuki-type6 reactions as well as
oxidative arylations,7 redox-neutral couplings,8 and
allylations9 for example.
Inspired by these findings, we decided to investigate the
decarboxylative cyanation of arene carboxylic acids
(Scheme 1). Such reaction would provide a direct access
to aryl nitriles starting from readily available reactants and
would be of potential interest compared to traditional
methods for the conversion of aromatic acids into aromat-
ic nitriles that usually required several steps10 or forcing
conditions.11
CO2
OMe
CN
OMe
CO2H
Pd(OTf)2,
Ag2CO3
+
XCN
MeO
MeO
DMF–DMSO
air, 100 °C, 3 h
2a
1a
Scheme 2 Model reaction under investigation
These observations reflect deactivation of the catalyst by
an excess of dissolved cyanide ions in the reaction mix-
ture.12 Several attempts to improve the procedure by using
reported efficient systems for palladium-catalyzed cyana-
tion of aryl halides, addition of NiBr2,13 CuI,14 or replace-
SYNLETT 2010, No. 14, pp 2083–2086
x
x
.x
x
.2
0
1
0
ment of KCN by CuCN15 or Zn(CN)2 were all
16
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258526; Art ID: G18110ST
© Georg Thieme Verlag Stuttgart · New York

2084
K. Ouchaou et al.
LETTER
Table 1 Optimization of the Model Reactiona
CO2
+
Entry
Cyanide source
KCN
Yield of 2a (%)b
O
Pd(OTf)2,
Ag2CO3
1
2
38
9
OH
CN
ArCOOH
+
ArCN
KCN + 18C6
KCN + NiBr2
KCN + CuI
Bu4N+CN–
CuCN
DMF–DMSO
air, 100 °C, 1 h
1
2
OMe
CN
3
18
47
3
OMe
CN
OMe
CN
4
MeO
5
OMe
2b 91%
6
45
27
11
10
16
47
2a 93%
2c 80%
OMe
Cl
7
AgCN
CN
NO2
O2N
CN
CN
MeO
MeO
8
Zn(CN)2
9
Hg(CN)2
Cl
2f 17%
2d 51%
2e 7%
10
11
K4Fe(CN)6
CN
CN
OMe
OH
CN
CN
O
2g 14%
2h 96%
2i 80%
addition on 1 min
12
13
14
98
26
5
OH
CN
O
NC
OMe
CN
CN
N
S
addition on 5 min
OH
OMe
2j 79%
CN
2k 54%
2l 11%
addition on 30 min
OMe
OMe
CN
OH
CN
MeO
MeO
CN
addition on 2 h
Br
2n 29%
a Reaction conditions: 1a (0.5 mmol, 1 equiv), cyanide source (1
equiv), Pd(OTf)2 (0.2 equiv), Ag2CO3 (3 equiv), DMF–DMSO (95:5,
5 mL).
2m 66%
Scheme 3 Synthesis of aryl nitriles 2 through decarboxylative cya-
nation of arene carboxylic acids 1 (isolated yields)
b GC yields (internal standard protocol).
ple, reaction conducted with p-anisic acid provided the
attempted 4-methoxybenzonitrile in only 5% yield where
2,4-dimethoxy benzoic acid (1a) reacted almost quantita-
tively. Electron-rich arene carboxylic acids as well as cer-
tain heterocyclic acids were globally efficient substrates.
Protonolysis of the aryl palladium intermediate leading to
decarboxylated products was the major side reaction that
was observed. This pathway was prevalent with substrates
bearing electron-withdrawing groups. It should be noticed
that the reaction seems amenable with substrates bearing
halogen atoms; product 2n is, for example, produced
without formation of byproduct from bromide transfor-
mation.
unsatisfactory (Table 1, entries 3, 4, 6, and 8). Finally, the
reaction was successfully improved by the use of cyclo-
hexanone cyanohydrin as liquid cyanide source. This re-
agent has the advantage to allow the control of the dosage
of cyanide ions by continuous addition through a syringe
pump therefore limiting the destruction of the palladium
catalyst by cyanide ions. A highly efficient procedure for
the palladium-catalyzed cyanation of aryl halides based
on this idea was previously described.17 Interestingly, the
palladium-catalyzed decarboxylative cyanation reaction
proceeded in high yield when the cyanohydrin was added
during the first 5 minutes of reaction (Table 1, entry 12).
Shorter or longer times of addition lead to lower yields of
aryl nitrile 2a and increased formation of dimethoxy ben-
zene as byproduct.
We contemplated that a possible application of this chem-
istry would be found in the synthesis of 13C- or 14C-labeled
compounds. Indeed, carboxylic acids might be converted
into labeled nitriles using 13C- or 14C-labeled cyanohy-
drines (easily prepared from readily available labeled cy-
anide salts), then labeled nitriles might be hydrolyzed into
labeled carboxylic acids. The global process, resulting in
carbon isotope exchange of the carboxylic acid function,
is of particular interest for labeling synthesis. Preliminary
investigations conducted in our laboratory proved that this
To explore the scope and limitation of the reaction, we
then carried out a series of decarboxylative cyanation
reactions using the optimized conditions (Scheme 3).
Similarly to the limitations observed for the Heck-type
olefination of arene carboxylates,5a the decarboxylative
cyanation reaction proceeded well on a variety of sub-
strates including at least one ortho substituent. For exam-
Synlett 2010, No. 14, 2083–2086 © Thieme Stuttgart · New York

LETTER
Conversion of Arene Carboxylic Acids into Aryl Nitriles
2085
1)
2)
Pd(OTf)2,
13CO2H
CO2H
Ag2CO3,
DMF–DMSO
air, 100 °C, 1 h
OH
13CN
+
KOH–H2O
80 °C, 12 h
1h
3h
72% yield
98% IE
Scheme 4 Preparation of 13C-labeled 9-anthracenecarboxylic acid (isolated yield); IE = isotopic enrichment (determined by MS)
Cherney, R. J.; Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9,
1711.
(4) Gooßen, L. J.; Rodriguez, N.; Gooßen, K. Angew. Chem. Int.
Ed. 2008, 47, 2.
process is highly suitable for the synthesis of labeled are-
ne carboxylic acids: reaction of 9-anthracenecarboxylic
acid (1h) with 13C-labeled cyclohexanone cyanohydrin,
obtained as previously described,18 afforded its labeled
homologue 3h in good yield and high isotopic enrichment
(IE, Scheme 4).
(5) For recent examples, see: (a) Myers, A. G.; Tanaka, D.;
Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250.
(b) Hu, P.; Kan, J.; Su, W.; Hong, M. Org. Lett. 2009, 11,
2341. (c) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(6) For recent examples, see: (a) Baudoin, O. Angew. Chem.
Int. Ed. 2007, 46, 2. (b) Gooßen, L. J.; Rodriguez, N.;
Lange, P. P.; Linder, C. Angew. Chem. Int. Ed. 2009, 48, 1.
(c) Becht, J.-M.; Catala, C.; Le Drian, C.; Wagner, A. Org.
Lett. 2007, 9, 1781. (d) Gooßen, L. J.; Zimmermann, B.;
Knauber, T. Angew. Chem. Int. Ed. 2008, 47, 7103.
(7) (a) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree,
R. H. Chem. Commun. 2008, 6312. (b) Wang, C.; Piel, I.;
Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(8) (a) Gooßen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313,
662. (b) Gooßen, L. J.; Rodriguez, N.; Melzer, B.; Linder,
C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129,
4824. (c) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.;
Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945. (d) Shang,
R.; Fu, Y.; Li, J. B.; Zhang, S. L.; Guo, Q. X.; Liu, L. J. Am.
Chem. Soc. 2009, 131, 5738. (e) Shang, R.; Fu, Y.; Wang,
Y.; Xu, Q.; Yu, H. Z.; Liu, L. Angew. Chem. Int. Ed. 2009,
48, 9350.
(9) (a) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129,
14860. (b) Fields, W. H.; Khan, A. K.; Sabat, M.; Chruma,
J. J. Org. Lett. 2008, 10, 5131. (c) Pi, S. F.; Tang, B. X.; Li,
J. H.; Liu, Y. L.; Liang, Y. Org. Lett. 2009, 11, 2309.
(10) (a) Bueler, C. A.; Pearson, D. E. Survey of Organic
Synthesis; Wiley Interscience: New York, 1970, 951.
(b) Vorbrüggen, H. Tetrahedron Lett. 1968, 13, 1631.
(11) (a) Miller, C. S. Org. Synth., Coll. Vol. III 1955, 646.
(b) Lücke, J.; Winkler, R. E. Chimia 1971, 25, 94.
(c) Hulkenberg, A.; Troost, J. J. Tetrahedron Lett. 1982, 23,
1505.
In summary, we have shown that palladium(II)-catalyzed
decarboxylation of arene carboxylic acids can be effi-
ciently exploited to cyanation reaction. This methodology
is the first example of direct conversion of carboxylic ac-
ids into the corresponding nitriles. The reaction might be
carried out on a panel of substrates19 and is well adapted
to labeled compounds synthesis.20 Some limitations of the
process occurred during this study. Protonolysis of the
aryl palladium intermediate, especially those obtained
from electron-poor aromatic carboxylic acids or sub-
strates lacking ortho substituents, was the main competi-
tive pathway of the process. High palladium loading is
furthermore necessary to the reaction mainly due to Pd
black formation during the process. However, although
the procedure is perfectible, it is of particular interest in
the field of labeled synthesis. The procedure was easily
used in our laboratory for 14C-labeled compound synthe-
sis (e.g., 9-anthracene-14C-carboxylic acid was prepared
in 61% yield from its cold analogue).
Acknowledgment
We thank D. Buisson for experimental assistance with MS and
LC/MS measurements.
References and Notes
(12) (a) Sekiya, A.; Ishikawa, N. Chem. Lett. 1975, 277.
(b) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.;
Sans, J.; Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9, 1828.
(13) Sakakibara, Y.; Sasaki, K.; Okuda, F.; Hokimoto, A.; Ueda,
T.; Sakai, M.; Takagi, K. Bull. Chem. Soc. Jpn. 2004, 77,
1013.
(14) Allentoff, A. J.; Markus, B.; Duelfer, T.; Wu, A.; Jones, L.;
Ciszewska, G.; Ray, T. J. Labelled Compd. Radiopharm.
2000, 43, 1075.
(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances: Syntheses, Patents,
Application, 4th ed.; Thieme: Stuttgart, 2001.
(2) See, for example: (a) Sundermeir, M.; Zapf, A.; Beller, M.
Eur. J. Inorg. Chem. 2003, 3513. (b) Anderson, B. A.; Bell,
E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepsiec, J. P.
J. Org. Chem. 1998, 63, 8224. (c) Maligres, P. E.; Waters,
M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40,
8193. (d) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000,
41, 3271.
(15) Ellis, G. P.; Rommey-Alexander, T. M. Chem. Rev. 1987,
87, 779.
(3) (a) Herrman, W. A.; Broßmer, C.; Öfele, K.; Priermeier, T.;
Beller, M.; Fisher, H. Angew. Chem., Int. Ed. Engl. 1995, 34,
1844. (b) Beller, M.; Fisher, H.; Herrman, W. A.; Broßmer,
C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848. (c) Zapf,
A.; Beller, M. Chem. Eur. J. 2001, 7, 2908.
(16) (a) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41,
3271. (b) Ramnauth, J.; Bhardwaj, N.; Renton, P.; Rakhit,
S.; Maddaford, S. P. Synlett 2003, 2237.
(17) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem. Int. Ed.
2003, 42, 1661.
(d) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.;
Sans, J.; Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9, 1828.
(e) Littke, A.; Soumeillant, M.; Kaltenbach, R. F. III.;
(18) Carr, G.; Whittaker, D. J. Chem. Soc., Perkin Trans. 2 1989,
359.
Synlett 2010, No. 14, 2083–2086 © Thieme Stuttgart · New York

2086
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LETTER
(19) General Procedure for the Preparation of Aryl Nitriles 2
Arene carboxylic acid (250 mg, 1 equiv), Ag2CO3 (3 equiv),
and palladium trifluoroacetate (0.2 equiv) were suspended in
DMSO–DMF (95:5, 5 mL) under air. The reaction mixture
is heated at 100 °C, then, cyclohexanone cyanohydrin
(1 equiv) diluted in DMSO–DMF (95:5, 5 mL) was added
dropwise with a syringe pump. The reaction mixture rapidly
turned black, was further heated for 1 h, then was cooled,
poured into EtOAc, and filtered. The filtrate was washed
sequentially with aq NaHCO3 (1 M), H2O and brine, then
was dried over MgSO4, filtered, and concentrated.
Chromatography of the residue on silica gel (EtOAc–
heptane) gave the desired product. Compounds 2a–l are
known compounds.
IR (NaCl): 2989, 2224, 1595, 1561, 1492, 1471, 1433, 1386,
1317, 1284, 1221, 1161, 1020, 896, 838, 780 cm–1. HRMS:
m/z calcd for [M + Na]+:263.9636; found:263.9644.
(20) Procedure for the Preparation of 3h
13C-Labeled 9-anthracenecarboxylic acid was prepared in
two steps. 13C-Labeled 9-anthracenecarbonitrile was first
prepared from 13C-labeled cyclohexanone cyanohydrin
according to the procedure described above. After
purification, the 13C-labeled nitrile was hydrolyzed under
basic conditions: 13C-labeled nitrile (1 mmol) was reacted
overnight at 80 °C with aq KOH (10 mL, 40% w/w) and abs.
EtOH (10 mL). The mixture was acidified to pH 3 (HCl
solution) and extracted by EtOAc. The organic phase was
concentrated, and the residue was purified by reversed-phase
chromatography with MeOH–H2O (70:30) to afford product
3h; mp 212–214 °C. 1H NMR (400 MHz, CDCl3): d = 8.61
(s, 1 H), 8.34 (d, 2 H, J = 8.8 Hz), 8.07 (d, 2 H, J = 8.8 Hz),
7.62 (t, 2 H, J = 7.2 Hz), 7.54 (t, 2 H, J = 7.2 Hz) ppm.
13C NMR (100 MHz, CDCl3): d = 171.38 (13CO2H), 131.23,
130.96, 129.96, 128.47, 127.68, 126.80, 125.50, 124.96
ppm. IR (KBr): 3200-2700, 2761, 2623, 1680, 1626, 1557,
1523, 1487, 1447, 1425, 1399, 1343, 1319, 1292, 1266,
1254, 1229, 1177, 1154, 1142, 1020, 992, 917, 891, 857,
847, 793, 738, 723, 639, 596, 559, 513 cm–1. HRMS: m/z
calcd for C1413CH10O2Na: 246.0578; found: 246.0581.
Compound 2m: white solid, mp 69.6 °C. 1H NMR (400
MHz, CDCl3): d = 2.47 (s, 3 H), 3.84 (s, 3 H), 3.88 (s, 3 H),
6.30 (s, 1 H), 6.38 (s, 1 H) ppm.13C NMR (100 MHz,
CDCl3): d = 20.81, 55.51, 55.90, 94.67, 95.70, 106.87,
116.05, 145.25, 163.81, 164.51 ppm. IR (NaCl): 2972, 2212,
1606, 1577, 1468, 1425, 1336, 1304, 1238, 1209, 1153,
1095, 1053, 935, 853, 830 cm–1. HRMS: m/z calcd for [M +
H]+:178.0868; found:178.0863.
Compound 2n: white solid, mp 168.8 °C. 1H NMR (400
MHz, CDCl3): d = 3.96 (s, 3 H), 3.97 (s, 3 H), 6.46 (s, 1 H),
7.68 (s, 1 H) ppm.13C NMR (100 MHz, CDCl3): d = 56.28,
56.47, 94.68, 95.68, 102.20, 116.12, 138.78, 160.41, 162.52.
Synlett 2010, No. 14, 2083–2086 © Thieme Stuttgart · New York