Efficient and Clean Nickel Catalyzed α-Allylation Reaction of Nitriles

Article abstract of DOI:10.1002/adsc.202001338

A clean method has been developed for the α-allylation of phenyl and alpha alkyl phenyl acetonitrile with allylic alcohols. The reaction is catalyzed by nickel complexes in situ generated from a combination of Ni(cod)₂ and the dppf ligand and performed at 80 °C in methanol as reaction solvent.Accordingly to this simple and base-free protocol that only yields water as a side-product, many allylic nitriles were synthetized with good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202001338

UPDATES
DOI: 10.1002/adsc.202001338
Efficient and Clean Nickel Catalyzed α-Allylation Reaction of
Nitriles
Bouchaib Mouhsine,a, b Abdallah Karim,b Clément Dumont,c Isabelle Suisse,a and
Mathieu Sauthiera,*
a
Univ. Lille, CNRS, Centrale Lille, ENSCL,
and
Univ. Artois, UMR 8181-UCCS Unité de Catalyse et Chimie du Solide, F-59000 Lille, (France)
E-mail: mathieu.sauthier@univ-lille.fr
Équipe de Chimie de Coordination et de Catalyse Département de Chimie Faculté des Sciences Semlalia, Université Cadi
b
Ayyad, BP 2390, Marrakech (Morocco)
ICAM, Site de Lille, 6 rue Auber, 59016 Lille Cedex (France).
c
Manuscript received: October 29, 2020; Revised manuscript received: January 20, 2021;
Version of record online: Februar 8, 2021
Dedicated to P.H. Dixneuf for his outstanding contribution to organometallic chemistry and catalysis
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001338
first stand, it is noteworthy that most of the commonly
used allylation reagents are synthesized from allylic
Abstract: A clean method has been developed for
the α-allylation of phenyl and alpha alkyl phenyl
alcohols. The direct use of allylic alcohols in allylation
acetonitrile with allylic alcohols. The reaction is
reactions is more straightforward and consistent with a
catalyzed by nickel complexes in situ generated
step economy. It is also noteworthy that their use
from a combination of Ni(cod)2 and the dppf ligand
generates only water as byproduct. In such case, this is
°
and performed at 80 C in methanol as reaction
solvent.
related to the fact that the hydroxyl group acts as a
base toward the nucleophile. On the point of view of
Accordingly to this simple and base-free protocol
the accessibility, allyl alcohol is industrially produced
that only yields water as a side-product, many
allylic nitriles were synthetized with good yields.
from propene oxydation[3] and potentially accessible
form vegetal feedstock like glycerol.[4] The main
limitation with the use of allylic alcohols is related to
the low reactivity of this reagent as the hydroxyl group
Keywords: allylation; nickel; nitrile; allylic alcohol
is recognised as a weak leaving group. To activate
allylic alcohols, catalytic amounts of transition metals
are generally needed.[5] We reported very simple
protocols of Ni-catalyzed allylic alkylation with allylic
alcohol for the transformation of nucleophiles such as
Introduction
amides,[6] ketoesters and diketones,[7] malonates,[8]
Allylic alkylation reactions remain one of the most aldehydes[9] and ketones.[10] Beyond the use of more
powerful tools for the formation of homo (CÀ C ) and precious metals such as palladium,[11] iridium,[12]
hetero (CÀ O, CÀ N, CÀ S) bonds.[1] The introduction of ruthenium,[13] platinum[14] and rhodium,[15] the use of
the allylic moiety is particularly attractive as it allows nickel has opened up interesting prospects. This metal
subsequent chemical transformations based on the is abundant and inexpensive and it is noteworthy that
C=C bond reactivity.[2] Commonly used allylation nickel based catalysts prevent the addition of bases or
reagents bear good leaving groups like acetate, other additives.[16] The highly efficient α-allylation of
carbonate or halide. Such reagents are however limited carbonyl compounds obtained with nickel-based
to the low atom economy related with their use that catalysts[7–10] opens the question of the reactivity of
often results in the production of large amounts of side nitriles (Scheme 1).
products such as salts. In comparison to other reagents,
Nitriles are industrially used as precursors to many
allylic alcohols could be advantageously used. At a other functional groups such as carboxylic acids,
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Table 1. Optimization of the nickel catalyzed allylation of
phenylacetonitrile with allyl alcohol.[a]
°
Entry L T ( C) Solvent
Nb eq Yield (%)[b]
2a
3a
4a
1
2
3
4
5
6
7
8
L1 80
L2 80
L3 80
L4 80
L4 100
L4 120
L4 80
L4 80
L4 80
L4 80
L4 80
L4 80
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Toluene
neat
MeOH+10% NaOH 2
MeOH+ 2% PTSA
MeOH
MeOH
MeOH
2
2
2
2
2
2
2
2
16
34
0
40
Scheme 1. The nickel-catalyzed α-allylation of nitriles with
allyl alcohol.
25+11[d] 35
25
60
25+5[d] 60
26+10[d]
5
aldehydes, ketones, and amines.[17] They are also
available in many natural products and medicinal
compounds.[18] In order to perform the alpha-allylation
of this family of compounds, palladium-based catalysts
have been commonly used. As examples, the direct
coupling of allylic alcohols with weakly acidic
pronucleophiles has been efficiently performed using
catalytic Pd(PPh3)4 via activation of C-OH bonds with
CO2.[19] Allylic alcohols were also used as allylic
reagents during the palladium catalyzed deacylative
allylation of ketone enolates, α-arylcyanoacetones and
α-arylcyanoacetic esters.[20] Other metals were likewise
used as rhodium in the enantioselective metal-cata-
lyzed allylic alkylation of nitriles with allyl benzoate[21]
or iridium during allylation of cyanoacetates with allyl
carbonate.[22]
24+34[d] 28
24+33[d] 28
9
5
2
80
0
10
11
12
2
1
3
1
2
3
30
20
36
30
0
14
70
40
70
>99
13[c] L4 80
14[c] L4 80
15[c] L4 80
MeOH
MeOH
[a] Conditions: 1a (1.8 mmol), Ni(cod)2: 1 mol%, Ldiphosphine/Ni=
2, L(monophosphine)/Ni=4, 17 h, in a sealed Schlenk tube.
[b] Determined by GC.
[c] 1.5 mol % of catalyst.
[d] Hydrolysis to the corresponding amide.
Herein, we wish to report the first nickel catalyzed
α-allylation of nitriles with allyl alcohol performed
under neutral conditions (Scheme 1).
Results and Discussion
The optimization of the reaction parameters was
carried out with phenylacetonitrile 1a and allyl alcohol
2a (Table 1). The reaction led to the mono 3a and the
bis-allylated 4a compounds (Scheme 2). Ni(cod)2
associated with phosphorus ligands was used as Scheme 2. Allylation of phenylacetonitrile 1a and ligands used
in the initial study.
catalyst precursor. The first experiments were per-
°
formed in MeOH as solvent at 80 C for 17 h. The
triphenylphosphine (PPh3) ligand L1 gave only 16%
yield into the monoallylnitrile 3a although 2 equiv- was increased to 100 C and 120 C (Entries 5 and 6).
alents of allyl alcohol were used (Entry 1). The use of However, a higher temperature did not lead to better
diphosphines gave better results such bis results but favored the hydrolysis of 3a. Moreover the
°
°
°
(diphenylphosphino)-1,1’-binaphtyle (BINAP L2) with increase of the temperature up to 120 C resulted to a
a global yield of 74% (34% monoallylated product 3a lower catalytic efficiency probably due to a catalyst
and 40% of bisallylated product 4a) (Entry 2). The use decomposition at that temperature (Entry 6). As
of 1,2-bis[(diphenylphosphino)methyl]benzene L3 observed in previous studies that involved ketones and
(dppmb) gave similar results with a mixture of mono aldehydes as nucleophile,[14,15] the use of aprotic
(36%) and bis-allylated (35%) products. It is note- solvents such as toluene (Entry 7) or solvent-free
worthy that 3a was partially hydrolyzed in the conditions (Entry 8) led to reduced yields along with a
corresponding amide (11%) that has been isolated and larger part of hydrolysis. A remarkable yield of 80% in
1
fully characterized by H and 13C NMR whereas no 4a was expectedly observed with sodium hydroxide as
product of hydrolysis of 4a was never observed additive (Entry 9). The addition of a base probably
(Entry 3). Significantly better yields were obtained favorably increased the concentration of the deproto-
with the ferrocenyl ligand L4 (dppf) that led to 25% of nated nucleophile. On the other hand, it is thus not
3a and 60% yield of 4a (Entry 4). In order to improve surprising that poor results were obtained in the
the conversion of the nitrile, the reaction temperature presence of a strong acid such as PTSA (Entry 10).
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Finally, we varied the amount of the allyl alcohol 2a.
Reducing the number of allyl alcohol equivalents to 1
did not promote the monosubstitution in respect to the
disubstitution but only contributed to reduce the over-
all conversion of 1a (Entry 11). By increasing the
number of equivalents up to 3, a comparable con-
version of 1a was observed (90%) with yields in 3a
and 4a of 20% and 70% respectively (Entry 12).
Nevertheless, the yield in 4a remained limited to 70%
with 2 equivalents of allylic alcohol (Entry 14). In
order to achieve a full conversion of the starting
material and a very high selectivity in 4a, a combina-
tion of higher catalyst loading up to 1.5 mol% and 3
equivalents of allyl alcohol proved to be necessary
(Entry 15).
Table 2. Reaction scope of the nickel catalyzed direct allyla-
tion of the alpha-aromatic acetonitriles with allyl alcohol.[a]
Using the optimized conditions, we then examined
the possibility to perform this reaction with alpha-
monosubstituted acetonitriles bearing aromatic rings
(Table 2). After isolation of the product, phenylaceto-
nitrile 1a led to 87% of 4a yield (Entry 1, Table 2).
The presence of a methoxy group on the ortho position
oriented the synthesis toward the sole formation of the
monoallylated derivative 3b with a yield of 51%
(Entry 2). Good yields into the bisallylated product
were observed with 3,4-dimethoxyphenylacetonitrile
1c and 3,4,5-trimethoxyphenylacetonitrile 1d, 70 and
62% respectively (Entries 3 and 4). These results
showed that the presence of methoxy groups on the
meta and para positions of the aromatic ring did not
bring significant steric hindrance. 2-cyanophenylaceto-
nitrile 1e and 2-fluorophenyl acetonitrile 1f were
efficiently diallylated and the compounds 4e and 4f
were thus isolated with 62% and 60% yields respec-
tively (Entries 5–6).
Very similar results were obtained with the fluori-
nated phenylacetonitrile 1g (Entry 7). The 3-meth-
ylphenylacetonitrile 1h and 4-biphenyl acetonitrile 1i
were converted in derivatives 4h and 4i with yields of
60% and 65% respectively (Entries 8–9). A very good
yield was observed with naphthylacetonitrile 1j (89%
yield; Entry 10) while 7-methoxy-2-naphthylacetoni-
trile 1k gave only the monoallylated product 3k with
an isolated yield of 57% (Entry 11). The higher steric
hindrance due to the presence of the methoxy group
likely impeded further substitution on the carbon atom.
Using the same conditions, the scope of the nitriles
was extended to α,α-disubstituted acetonitriles. In that
case, only monoallylation could be performed. It is
noteworthy that in all cases reported in Table 3,
complete conversions of the starting materials were
observed. High isolated yields were obtained with
diphenylacetonitrile 5a and methyl-2-naphthylacetoni-
trile 5b of 94% and 85% respectively (Entries 1 and
2). A slight decrease of yield with substrates bearing
an electrodonor group was observed after isolation: α-
methylphenylacetonitrile 5c, α-ethylphenyl acetonitrile
5d and 1,2,3,4-tetrahydronaphthalene-1-carbonitrile 5e
[a] Reaction conditions: 1a–k (1.8 mmol), 2a (5.4 mmol), Ni
(cod)2 (0.027 mmol), dppf (0.054 mmol), MeOH (0.5 mL),
°
17 h, T=80 C in a sealed Schlenk tube.
[b] Isolated yield after silica gel chromatography.
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Table 3. Reaction scope of the nickel catalyzed direct allyla-
Table 4. Scope of the Ni-catalyzed allylation of diphenyl
tion of the α,α disubstituted acetonitriles with allyl alcohol.[a]
acetonitrile 5a with various allylic alcohols.[a]
[a] Reaction conditions: 5a–f (1.8 mmol), 2a (5.4 mmol), Ni
(cod)2 (0.027 mmol), dppf (0.054 mmol), MeOH (0.5 mL),
[a] Reaction conditions: 5a (1.8 mmol), 7a–d (5.4 mmol), Ni
(cod)2 (0.027 mmol), dppf (0.054 mmol), MeOH (0.5 mL),
°
17 h, T=80 C in a sealed Schlenk tube.
°
17 h, T=80 C in a sealed Schlenk tube.
[b] Isolated yield after silica gel chromatography.
[b] Isolated yield after silica gel chromatography.
[c] 2 mol% of Ni(dppf)2.
were converted with yields of 73%, 65% and 61%
respectively (Entries 3, 4 and 5). The 4-benzoyl-α-
methylbenzeneacetonitrile 5f was isolated with an nitrile. The fact that this alcohol is more substituted
excellent yield of 91% (Entry 6). disfavors the oxidative addition to a low valent Ni(0)
We further investigated different allylic alcohols intermediate.
with diphenylacetonitrile 5a as substrate (Table 4).
As we previously reported for the allylation of
High yields were obtained with the allylic linear ketones,[10] diallylether 9a could also be involved in
alcohols such as crotyl alcohol 7a and octa-2,7-dien-1- that reaction. As example with 2,2-diphenylacetonitrile
ol 7b, 85% and 80% respectively (Entries 1 and 2). A 5a, a good isolated yield of 80% was then obtained by
very similar result was obtained with 2-methyl-2- using 1 equivalent of diallylether 9a (Scheme 3).
propen-1-ol 7c as a branched alcohol (Entry 3).
The diallylated nitriles can be further used in other
Cinnamyl alcohol (Entry 4) could also be converted in transformations that involve either the allylic or the
the allylated derivative 8d with 62% isolated yield. nitrile moieties. The reduction of the nitrile in the
The linear allylic structure was selectively obtained corresponding primary amine was accomplished with
and the branched isomer was not observed. However, lithium aluminum hydride in ether leading to the amine
the reaction with a more substituted alcohol such as 3- 11a. The ruthenium catalyzed ring closing metathesis
methyl-2-buten-1-ol 7e did not give the allylated was also performed in high yield in refluxing toluene
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Acknowledgements
We acknowledge the Ministère de l’Enseignement supérieur, de
la Recherche et de l’Innovation, the Institut Universitaire de
France and the CNRS for their financial support. We also would
like to thank Céline Delabre for her technical support (GC
analysis of the crudes).
Scheme 3. The nickel-catalyzed α-allylation of α,α-diphenyla-
cetonitrile with diallyether.
References
[1] a) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96,
395–422; b) G. Consiglio, R. M. Waymouth, Chem. Rev.
1989, 89, 257–276; c) B. M. Trost, Acc. Chem. Res.
1996, 29, 355–364; d) B. M. Trost, Chem. Pharm. Bull.
2002, 50, 1–14; e) T. Graening, H. G. Schmalz, Angew.
Chem. Int. Ed. 2003, 42, 2580–2584; f) B. M. Trost,
M. L. Crawley, Chem. Rev. 2003, 103, 2921–2944;
g) B. M. Trost, J. Org. Chem. 2004, 69, 5813–5837;
h) B. M. Trost, M. R. Machacek, A. Aponick, Acc.
Chem. Res. 2006, 39, 747–760.
to form the cyclopentene ring along with the release of
ethylene (Scheme 4).
Conclusion
In conclusion, we have developed an efficient and very
clean nickel-catalyzed process for the direct allylic
alkylation of α-substituted nitriles with allyl alcohol.
The reaction was carried out under neutral conditions
giving only water as side product. A large variety of
allylic nitriles were synthesized and different allylic
alcohols were also investigated. Similar results were
observed with diallylether in place of allyl alcohol.
The thus obtained allylated derivatives can be further
chemically modified through nitrile reduction or olefin
metathesis reactions to generate a primary amine or a
cyclopentene ring respectively. We believed that this
methodology is relevant to straightforwardly produce
new allyl compounds and derivatives.
[2] M. L. Randall, M. L. Snapper, J. Mol. Catal. Chem.,
1998, 133, 29–40; N. W. Cant, W. Keith Hall, J. Catal.
1972, 27, 70–78.
[3] G. I. Panov, E. V. Starokon, M. V. Parfenov, B. Wei, V. I.
Sobolev, L. V. Pirutko, ACS Catal. 2018, 8, 1173–1177.
[4] a) E. Arceo, J. A. Ellman, R. G. Bergman, J. Am. Chem.
Soc. 2010, 132, 11408–11409; b) M. Shiramizu, F. D.
Toste, Angew. Chem. Int. Ed. 2012, 51, 8082–8086; c) I.
Ahmad, G. Chapman, K. M. Nicholas, Organometallics,
2011, 30, 2810–2818; d) S. Raju, M. E. Moret, R. J. M.
Klein Gebbink, ACS Catal. 2015, 5, 281–300.
[5] For reviews of palladium-catalyzed allylation of nucleo-
philes by directly using allylic alcohols, see a) Y.
Tamaru, Eur. J. Org. Chem. 2005, 2647–2656; b) M.
Kimura, J. Synth. Org. Chem. Jpn. 2012, 70, 216–226;
c) B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc.
Rev. 2012, 41, 4467–4483.
[6] M. S. Azizi, Y. Edder, A. Karim, M. Sauthier, Eur. J.
Org. Chem. 2016, 22, 3796–3803.
[7] R. Blieck, M. S. Azizi, A. Mifleur, M. Roger, C. Persyn,
M. Sauthier, H. Bonin, Eur. J. Org. Chem. 2016, 6,
1194–1198.
Experimental Section
α-Allylation of phenylacetonitrile 1a with allyl alcohol 2a: In a
Schlenk tube were placed first the catalytic precursor Ni(cod)2
(1.5 mol %), then the ligand (3 mol %), the nitrile (1.8 mmol,
1 equiv.). Under nitrogen, freshly distilled and degassed allyl
alcohol (3 eq.) or diallyl ether (1 eq.) were then added.
Degassed MeOH (0.5 mL) was added under nitrogen and the
°
reaction mixture was stirred at 80 C for 18 h. The reaction
mixture was then concentrated under reduced pressure and the
product was purified by silica gel column chromatography with
petroleum ether/ethyl acetate (90/10) as eluent.
[8] H. Bricout, J. F. Carpentier, A. Mortreux, J. Mol. Catal.
A 1998, 136, 243–251.
[9] Y. Bernhard, B. Thomson, V. Freely, M. Sauthier, Angew.
Chem. Int. Ed. 2017, 56, 7460–7464.
[10] B. Mouhsine, A. Karim, C. Dumont, M. Sauthier, Green
Chem. 2020, 22, 950–955.
[11] a) J. Muzart, Tetrahedron 2005, 61, 4179–4212; b) F.
Ozawa, H. Okamoto, S. Kawagishi, S. Yamamoto, T.
Minami, M. Yoshifuji, J. Am. Chem. Soc. 2002, 124,
10968–11096.
[12] a) S. Krautwald, M. A. Schafroth, D. Sarlah, E. M.
Carreira, J. Am. Chem. Soc. 2014, 136, 3020–3023; b) S.
Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira,
Science 2013, 340, 1065–1068.
[13] D. Wang, C. J. Chen, J. X. Haberman, C. J. Li, Tetrahe-
dron 1998, 54, 5129–5142.
Scheme 4. Transformations of diallylnitrile 4a.
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[14] a) H. Bricout, J. F. Carpentier, A. Mortreux, Tetrahedron
Lett. 1996, 37, 6105–6108; b) E. Alvarez, T. Cuvigny,
1456; e) X. Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev,
W. Zhang, Angew. Chem. Int. Ed. 2014, 53, 6776–6780.
M. Julia, J. Organomet. Chem. 1988, 339, 199–212; [17] R. C. Larock, Comprehensive Organic Transformations,
c) Y. Kita, H. Sakaguchi, Y. Hoshimoto, D. Nakauchi, Y. 3rd ed; Wiley & Sons: Hoboken, NJ, 2018, 3821–3830.
Nakahara, J. F. Carpentier, S. Ogoshi, K. Mashima, [18] a) F. F. Fleming, Nat. Prod. Rep. 1999, 16, 597–60;
Chem. Eur. J. 2015, 21, 14571–14578.
[15] T. B. Wright, P. A. Evans, J. Am. Chem. Soc., 2016, 137,
6156–6159.
b) F. F. Fleming, L. Yao, P. C. Ravikumar, L. Funk, B. C.
Shook, J. Med. Chem. 2010, 53, 7902–7917.
[19] S. B. Lang, T. M. Locascio, J. A. Tunge, Org. Lett. 2014,
16, 4308–4311.
[16] a) M. Kimura, Y. Horino, R. Mukai, S. Tanaka, Y.
Tamaru, J. Am. Chem. Soc. 2001, 123, 10401–10402; [20] A. J. Grenning, J. A. Tunge, J. Am. Chem. Soc. 2011,
b) M. Kimura, M. Shimizu, K. Shibata, M. Tazoe, Y. 133, 14785–14794.
Tamaru, Angew. Chem. Int. Ed. 2003, 42, 3392–3395; [21] B. W. H. Turnbull, P. A. Evans, J. Am. Chem. Soc. 2015,
Angew. Chem. 2003, 115, 3514–3517; c) G. Jiang, B. 137, 6156–6159.
List, Adv. Synth. Catal. 2011, 353, 1667–1670; d) I. [22] A. Matsunami, K. Takizawa, S. Sugano, Y. Yano, H.
Usui, S. Schmidt, B. Breit, Org. Lett. 2009, 11, 1453–
Sato, R. Takeuchi, J. Org. Chem. 2018, 83, 12239–
12246.
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