Pd Catalysis in Cyanide-Free Synthesis of Nitriles from Haloarenes via Isoxazolines

Article abstract of DOI:10.1021/acs.orglett.6b03103

A method to obtain aryl nitriles from the corresponding halides by Pd catalysis, in the absence of any cyanide source, is reported. The reaction of an aryl halide, ethyl nitroacetate, and an olefin readily delivers an aromatic nitrile. A variety of aryl iodides/bromides have been converted into the corresponding cyanoarenes in fair to excellent yields. The reaction likely involves the following steps: (a) Pd-catalyzed α-arylation of ethyl nitroacetate; (b) nitrile oxide formation; (c) [3 + 2]-cycloaddition with an olefin to provide an isoxazoline; (d) isoxazoline cleavage to benzonitrile formation.

Full text of DOI:10.1021/acs.orglett.6b03103

Letter
pubs.acs.org/OrgLett
Pd Catalysis in Cyanide-Free Synthesis of Nitriles from Haloarenes via
Isoxazolines
Giovanni Maestri,†,‡ Tatiana Caneque,‡ Nicola Della Ca’,† Etienne Derat,§ Marta Catellani,*,†
̃
Gian Paolo Chiusoli,†,∥ and Max Malacria*,‡,§
†Dipartimento di Chimica and CIRCC, Universita
‡Institut de Chimie des Substances Naturelles, ICSN-CNRS UPR 2301, Gif/Yvette Cedex 91198, France
§Institut Parisien de Chimie Molec
ulaire, UPMC Universite Paris 06, IPCM-UMR 8232, Paris 75005 Cedex, France
̀
di Parma, Parco Area delle Scienze, 17/A, 43124 Parma, Italy
́
́
S
* Supporting Information
ABSTRACT: A method to obtain aryl nitriles from the
corresponding halides by Pd catalysis, in the absence of any
cyanide source, is reported. The reaction of an aryl halide,
ethyl nitroacetate, and an olefin readily delivers an aromatic
nitrile. A variety of aryl iodides/bromides have been converted
into the corresponding cyanoarenes in fair to excellent yields.
The reaction likely involves the following steps: (a) Pd-
catalyzed α-arylation of ethyl nitroacetate; (b) nitrile oxide
formation; (c) [3 + 2]-cycloaddition with an olefin to provide
an isoxazoline; (d) isoxazoline cleavage to benzonitrile formation.
ryl nitriles are recurrent scaffolds found in both natural
Scheme 1. Catalytic Synthesis of Aryl Nitriles
A
and synthetic compounds that are extensively used in the
pharmaceutical, agrochemical, and materials industries.1 The
nitrile group is also a versatile motif that can be easily converted
into a broad range of useful functionalities.1c
Transition-metal-catalyzed cyanations usually involve Pd, Cu,
and Ni catalysts in combination with inorganic cyanides (e.g.,
NaCN or KCN) or organic reagents such as acetone
cyanohydrin and Me3SiCN.2 These synthetically relevant
reactions have long been plagued by catalyst deactivation due
to the formation of stable metal−cyanide complexes.3 During
the past decade, these limitations were partially overcome both
by catalyst design and the use of poorly soluble inorganic
cyanides such as Zn(CN)2 and K4Fe(CN)6.5 Moreover, to
4
Scheme 2. Unexpected Formation of Nitriles 2a and 2′a
avoid the use of hazardous reagents, new methodologies have
been developed to form the cyano group in situ via tailor-made
redox processes employing dimethylformamide,6 sodium
azide,7 formamide/phosphorus oxychloride,8 or dimethylmalo-
nonitrile.9
We report herein a complementary approach exploiting Pd
catalysis. The method likely involves sequential Pd-catalyzed α-
arylation of ethyl nitroacetate, temperature- and based-induced
formation of the corresponding nitrile oxide, [3 + 2]-
cycloaddition with an olefin to provide an isoxazoline, and
ring cleavage and fragmentation to the desired nitrile under the
basic reaction conditions (Scheme 1). This Pd-catalyzed, one-
pot synthesis of aryl nitriles from the corresponding aryl halides
and nitroacetates in the presence of an activated olefin such as
dimethyl maleate has, to the best of our knowledge, not been
previously observed.10
nitroacetates11 by biarylpalladium complexes via Pd/norbor-
nene catalysis.12 We were surprised to find that the reaction of
1-iodonaphthalene 1a with ethyl nitroacetate13 in the presence
of norbornene and Pd(OAc)2 as catalyst and K2CO3 and PhOK
We came across this unique transformation (Scheme 2)
serendipitously during our studies aimed at the α-arylation of
Received: October 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
as bases12d in DMF at 120 °C gave nitriles 2a and 2′a14 in ca.
5% and 30% yield, respectively, in place of the expected arylated
and biarylated ethyl nitroacetates.11
To our further surprise, when a control experiment was
carried out in the absence of norbornene no traces of 2a and
2′a were detected by GC (Table 1, entry 1). The negative
upon formation of Pd black. Compound 2a did not form in the
absence of a Pd salt, the nitro derivative, or the olefin.
With these conditions in hand, we evaluated the scope of the
reaction by employing differently substituted aryl halides as
summarized in Table 2.
Good results were obtained with 1-iodo- and 1-bromonaph-
thalene (88 and 71%) (Table 2, entries 1 and 2), while an
electron-donating methoxy substituent proved to be detrimen-
tal (42%) (Table 2, entry 3). Aryl halides bearing alkyl groups,
whether in ortho, meta, or para positions, were usually well
tolerated (56−81%) (Table 2, entries 4−7). The presence of
electron-withdrawing groups had a positive effect and provided
excellent yields with iodides and good yields with bromides
(Table 2, entries 8−16). Interestingly, the reaction proved to
tolerate the presence of the chloride substituent (Table 2,
entries 8−11), useful for further functionalization. The formal
cyanation of 3- and 4-bromopyridine occurred smoothly,
delivering the 3- and 4-cyanopyridine in 80 and 72% yield,
respectively (Table 2, entries 17 and 18).
a
Table 1. Screening of Additives and Reaction Conditions
b
c
time
(h)
PPh3
(mol %)
conv 1a
(%)
yield 2a
(%)
entry
olefin
1
2
3
5
100
100
d
cyclohexene
20
24
5
e
methyl
cinnamate
55
We were intrigued by the unexpected formation of aryl
nitriles under these conditions, and thus, we carried out
experimental studies to gain insights into the mechanism of this
sequential reaction. Although research is still underway to
define the precise pathway, a possible rationale for the observed
reactivity is shown in Scheme 3 for benzonitrile formation.
The aryl halide oxidatively adds to Pd(0) to afford
arylpalladium(II) complex I. Activation of ethyl nitroacetate
delivers II, which on reductive elimination, liberates the
arylated nitroacetate 3 and Pd(0). The basic medium and
thermal activation favor the formation of phenyl nitrile oxide
4,15 which can undergo a [3 + 2]-cycloaddition with the olefin
to afford the isoxazoline 5.16 Likely through a deprotonation
step by the bases present in the reaction medium, species 6 is
formed, which eventually delivers benzonitrile 2o and the enol
of ketosuccinate 7 by C−C and N−O bond cleavage. Although
the isoxazoline 5 has not been detected, its formation from
benzonitrile oxide 4 and dimethyl maleate16 and its subsequent
fragmentation to benzonitrile have been previously reported.17
To provide evidence supporting the proposed reaction
pathway, isoxazoline 5 was synthesized to ascertain how the
species present in the reaction mixture could affect the
benzonitrile formation (Table 3). When Pd(OAc)2, PPh3 and
bases were not used, compound 5 was almost completely
recovered after 3 h or longer at 120 °C (Table 3, entry 1). In
the presence of both K2CO3 and PhOK as the bases, or an
equimolar amount of PhOK alone, benzonitrile was obtained in
20 and 32% yield, respectively (Table 3, entries 2 and 3). While
a comparable result was achieved in the presence of Pd(OAc)2
(25% yield) (Table 3, entry 4), we were pleased to find that the
addition of 20 mol % of PPh3 promoted the transformation of
isoxazoline 5 to benzonitrile in 78% yield (Table 3, entry 5).
We then carried out the same reaction in the absence of
Pd(OAc)2 and obtained compound 2o in a similar yield (75%)
(Table 3, entry 6). Increasing the amount of PPh3 up to 80 mol
% gave 2o in 89% yield (Table 3, entry 7). However, when the
reaction was carried out in the presence of PPh3 alone, only
traces of benzonitrile were detected even after 24 h at 120 °C
(Table 3, entry 8).
4
5
6
7
8
9
dimethyl maleate
dimethyl maleate
dimethyl maleate
dimethyl maleate
stilbene
24
24
22
24
40
47
55
90
37
74
81
88
30
48
5
10
20
20
20
95
100
95
dimethyl
fumarate
60
10
fumaronitrile
24
24
24
20
20
20
5
70
f
11
dimethyl maleate
dimethyl maleate
55
87
g
12
100
a
Reaction conditions: 1-iodonaphthalene (0.4 mmol, 1 equiv), ethyl
nitroacetate (5 equiv), olefin (2.5 equiv), Pd(OAc)2 (2.5 mol %, 0.002
M), K2CO3 (3 equiv), PhOK (0.3 equiv) in DMF (4 mL) under N2 or
Ar at 120 °C. By GC. By H NMR. 55% yield of Heck product.
17% yield of Heck product. Nitromethane in place of ethyl
nitroacetate. Benzoylnitromethane in place of ethyl nitroacetate.
b
c
d
1
e
f
g
result clearly indicated the involvement of norbornene not only
in the biaryl construction12 but also in the transformation of the
CH2NO2 group into a CN. The requirement of an olefin for the
formation of the nitrile group was readily confirmed by addition
of cyclohexene to the reaction mixture (Table 1, entry 2),
which gave a small but significant amount of naphthonitrile (2a,
ca. 5% yield) together with 55% of the arylated olefin (Heck
product). The addition of an activated alkene such as methyl
cinnamate afforded 2a in 55% yield and 17% of the
corresponding Heck product (Table 1, entry 3). Switching to
dimethyl maleate, a disubstituted olefin that does not readily
undergo a Heck reaction proved beneficial to the selectivity of
the reaction and delivered 37% of 2a at 55% conversion (Table
1, entry 4). The addition of 5 mol % of PPh3 boosted the
conversion and yield to 90% and 74%, respectively (Table 1,
entry 5). Further increasing the amount of PPh3 up to 20 mol
% gave 2a in good to excellent yield (81 and 88%, respectively)
(Table 1, entries 6 and 7). Under these conditions, other
electron-poor disubstituted olefins performed much worse
(Table 1, entries 8−10). The nitroacetate can be replaced by
nitromethane, although at the expense of yield (55%) (Table 1,
entry 11), while another commercially available nitromethylene
derivative (benzoylnitromethane) has a comparable efficiency
(87%) (Table 1, entry 12). Lower yields were observed upon
reducing the amount of the nitro derivative, the olefin, or one
of the two bases. In all cases, conversion of the halide stopped
Thus, the fragmentation of isoxazoline 5 to benzonitrile is
strongly promoted by the inorganic bases in combination with
PPh3; the latter, however, does not show any substantial activity
in the absence of the bases.
B
DOI: 10.1021/acs.orglett.6b03103
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Letter
Table 2. Catalytic Access to Aryl Nitriles*
Scheme 3. Proposed Reaction Mechanism
Table 3. Effect of Pd(OAc)2, PPh3, and Bases on Yield of
a
2o
b
Pd(OAc)2
(mol %)
PPh3
(mol %)
K2CO3
(equiv)
PhOK
(equiv)
2o, yield
(%)
entry
1
2
3
4
5
6
7
8
c
2
0.3
1
20
32
25
78
75
89
2.5
2.5
2
2
2
2
0.3
0.3
0.3
0.3
20
20
80
80
c
traces
a
Reaction conditions: isoxazoline 5 (0.21 mmol, 1 equiv) in DMF (4
b
c
mL) under N2 at 120 °C for 3 h. GC yield. The GC conversion of
isoxazoline 5 after 3 and 24 h at 120 °C was less than 5%.
Moreover, efforts to identify the expected aliphatic
coproducts proved fruitless, likely owing to the thermal
instability of ketosuccinates. We reasoned that synthesizing an
isoxazoline bearing a suitable tether would intramolecularly trap
the coproduct and thus corroborate our rationale. The
candidate of choice appeared to be polycyclic isoxazoline 8
(Scheme 4) despite its propensity to readily deliver oxime 10
Scheme 4. Ring Opening of Isoxazoline 8
even at room temperature in basic medium.18 The expected
arylnitrile 9 features a stable, tethered phenol fragment isolobal
to the unstable and elusive ketosuccinate, and its formation
would further substantiate our proposal.
Not surprisingly, isoxazoline 8 in DMF in the presence of
K2CO3 quantitatively delivered compound 10 in 1 h at room
*
Reaction conditions: 1 (0.4 mmol, 1 equiv), ethyl nitroacetate (5
equiv), dimethyl maleate (2.5 equiv), Pd(OAc)2 (2.5 mol %, 0.002 M),
PPh3 (20 mol %), K2CO3 (3 equiv), PhOK (0.3 equiv) in DMF (4
mL) under N2 or Ar at 120 °C for 24 h. Isolated yields based on the
a
average of two runs.
C
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Letter
(b) Dobbs, K. D.; Marshall, W. J.; Grushin, V. V. J. Am. Chem. Soc.
2007, 129, 30.
temperature. We were delighted, however, to observe formation
of nitrile 9 in 14% yield upon addition of a catalytic amount of
Pd(dba)2 (2.5 mol %) and PPh3 (5 mol %).
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C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790.
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12898.
In conclusion, we have developed a catalytic method to
obtain aryl nitriles from the corresponding halides in the
absence of any cyanide source. Aryl nitriles are formed in fair to
excellent yields, making this formal cyanation a viable synthetic
method complementary to existing cyanide-free alternatives.
The reaction proceeds through a sequential process that
consists of four consecutive transformations. Under the
adopted conditions, each transformation spontaneously occurs
with high efficiency, eventually delivering the stable target
molecule. Notably, dimethyl maleate enables the construction
of isoxazolines suitable for fragmentation to benzonitriles
without interfering with the Pd cycle. Further detailed
mechanistic studies and synthetic applications of this reaction
are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03103.
(12) (a) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Acc.
Chem. Res. 2016, 49, 1389. (b) Catellani, M.; Motti, E.; Della Ca’, N.
Acc. Chem. Res. 2008, 41, 1512. (c) Chiusoli, G. P.; Catellani, M.;
Costa, M.; Motti, E.; Della Ca’, N.; Maestri, G. Coord. Chem. Rev.
2010, 254, 456. (d) For Pd/norbornene catalysis in arene and ketone
C−H bond functionalization, see: G. Maestri, G.; Della Ca’, N.;
Catellani, M. Chem. Commun. 2009, 4892. (e) Maestri, G.; Motti, E.;
Della Ca’, N.; Malacria, M.; Derat, E.; Catellani, M. J. Am. Chem. Soc.
2011, 133, 8574. (f) Martins, A.; Mariampillai, B.; Lautens, M. Top.
Curr. Chem. 2009, 292, 1. (g) Ye, J.; Lautens, M. Nat. Chem. 2015, 7,
863.
Detailed experimental procedures and spectra of all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: marta.catellani@unipr.it.
*E-mail: max.malacria@upmc.fr.
ORCID
Giovanni Maestri: 0000-0002-0244-8605
Etienne Derat: 0000-0002-8637-2707
Marta Catellani: 0000-0002-6145-0211
Max Malacria: 0000-0002-3563-3508
(13) Ethyl nitroacetate is an energetic material and should be
handled carefully and stored away from strong oxidants and bases.
(14) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am. Chem. Soc.
2007, 129, 15372.
(15) (a) Quilico, A.; Stagno D’Alcontres, G.; Grunanger, P. Nature
̈
Notes
1950, 166, 226. (b) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc.
1960, 82, 5339.
The authors declare no competing financial interest.
∥Deceased February 2, 2013.
(16) Trogu, E.; De Sarlo, F.; Machetti, F. Chem. - Eur. J. 2009, 15,
7940. The formation of nitrile oxide (4) was confirmed by employing
benzoylnitromethane (Table 1, entry 12) and recovering the desired
aryl nitrile and an almost equimolar amount of benzoic acid.
(17) (a) Golebiewski, W. M.; Gucma, M. J. Heterocyclic Chem. 2006,
43, 509. (b) Baranski, A.; Shvekhgeimer, G. Polym. J. Chem. 1982, 56,
459. (c) Koroleva, E. V.; Bondar, N. F.; Katok, Y. M.; Chekanov, N. A.;
Chernikhova, T. V. Chem. Heterocycl. Compd. 2007, 43, 362.
ACKNOWLEDGMENTS
We thank MIUR, UNIPR, CNRS, and UPMC for funding.
■
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DOI: 10.1021/acs.orglett.6b03103
Org. Lett. XXXX, XXX, XXX−XXX