Monoalkylation of acetonitrile by primary alcohols catalyzed by iridium complexes

Article abstract of DOI:10.1021/ol2015972

The monoalkylation of acetonitrile by primary alcohols was achieved in a one-pot sequence in the presence of iridium catalysts. A diversity of nitriles has been obtained from aryl- and alkyl-methanols in excellent yield.

Full text of DOI:10.1021/ol2015972

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4084–4087
Monoalkylation of Acetonitrile by
Primary Alcohols Catalyzed by
Iridium Complexes
Bruno Anxionnat,† Domingo Gomez Pardo,† Gino Ricci,‡ and Janine Cossy*,†
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231-Paris Cedex 05, France, and Sanofi-Aventis, Process Development,
ꢀ
45 chemin de Meteline, BP 15, 04201-Sisteron Cedex, France
janine.cossy@espci.fr
Received June 14, 2011
ABSTRACT
The monoalkylation of acetonitrile by primary alcohols was achieved in a one-pot sequence in the presence of iridium catalysts. A diversity of
nitriles has been obtained from aryl- and alkyl-methanols in excellent yield.
Nitriles are useful compounds as they can be trans-
formed easily to amides, carboxylic acids, aldehydes,
ketones, amines, etc. The monoalkylation of acetonitrile
represents a challenge since the formation of the bis-
alkylated nitrile is often observed.1 This alkylation is
generally performed by generating the anion using a sub-
stoichiometric amount of base followed by the addition
of an alkyl halide.2 The other procedure is the use of
cyanomethylcopper (generated by treatment of acetoni-
trile with n-BuLi, followed by the addition of CuI) which
reacts according to an SN02 process with an allyl bromide
to produce the monoallylated acetonitrile.3 All the known
methods to achieve the monoalkylation of acetonitrile
were realized by using alkyl halides which are toxic.
Alternatively, it has been demonstrated that [Ir]- and
[Ru]-complexes can serve as efficient catalysts for hydro-
gen transfer from alcohols to aldehydes,4 and this process
has been used to realize the alkylation of activated nitriles5
and esters.6 In this case, the alkylating reagent is an alcohol
which is less toxic and more easily accessible than an alkyl
halide. Furthermore, the only byproduct of the reaction is
water.
† ESPCI ParisTech.
‡ Sanofi-Aventis.
(1) (a) Berlan, J.; Delmas, H.; Duee, I.; Duche, J. L.; Vuiglio, L.
ꢀ
Synth. Commun. 1994, 24, 1253–1260. (b) For a review of nitrile
alkylations, see: Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Organic
Reactions, Vol. 31; John Wiley & Sons, Inc.: 1984; pp 1ꢀ364.
(2) (a) Taber, D. F.; Kong, S. J. Org. Chem. 1997, 62, 8575–8576. (b)
Shrestha-Dawadi, P. B.; Lugtenburg, J. Eur. J. Org. Chem. 2003, 4654–
4663. (c) Crich, D.; Xu, H.; Kenig, F. J. Org. Chem. 2006, 71, 5016–5019.
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Nickerson, K. W.; Dussault, P. H. Bioorg. Med. Chem. 2008, 16, 1842–
1848.
Here, we report that nonactivated nitriles, such as aceto-
nitrile, can be monoalkylated in good to excellent yields
by utilizing primary alcohols and iridium complexes. In
order to optimize the monoalkylation of acetonitrile 1 by
(3) Corey, E. J.; Kuwajima, I. Tetrahedron Lett. 1972, 6, 487–489.
(4) For examples, see: (a) Sakaguchi, S.; Yamaga, T.; Ishii, Y. J. Org.
Chem. 2001, 6, 4710–4712. (b) Taguchi, K.; Nakagawa, H.; Hirabayashi,
T.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2004, 126, 72–73. (c) Fujita,
K.; Asai, C.; Yamaguchi, T.; Hanasaka, F.; Yamaguchi, R. Org. Lett.
2005, 7, 4017–4019. (d) Matsu-ura, T.; Sakaguchi, S.; Obora, Y.; Ishii,
Y. J. Org. Chem. 2006, 71, 8306–8308. (e) Burling, S.; Paine, B. M.;
Nama, D.; Brown, V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.;
Whittlesey, M. K.; Williams, J. M. J. J. Am. Chem. Soc. 2007, 129, 1987–
1995. (f) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007,
9, 73–75. (g) Maeda, K.; Obora, Y.; Sakaguchi, S.; Ishii, Y. Bull. Chem.
Soc. Jpn. 2008, 81, 689–696. (h) Aramoto, H.; Obora, Y.; Ishii, Y. J. Org.
Chem. 2009, 74, 628–633. (i) Kawahara, R.; Fujita, K.; Yamaguchi, R.
J. Am. Chem. Soc. 2010, 132, 15018–15111.
(5) (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai,
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Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
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2537.
r
10.1021/ol2015972
Published on Web 07/06/2011
2011 American Chemical Society

alcohols, benzyl alcohol 2 was chosen as the alkylating
agent and different conditions were tested (Table 1). At
first, acetonitrile 1 (10 equiv) and benzyl alcohol 2
(1 equiv) were treated with Cs2CO3 (0.2 equiv) in the
presence of [IrCp*Cl2]2 (2 mol %) for 16 h at 150 or
180 °C (Table 1, entries 1 and 2). Under these conditions,
it was observed that the reaction was slow, the conver-
sion of 2 was incomplete (35% to 80%), and the yield
in 3a was moderate (30% to 71%). It was noticed
that, under similar conditions, the replacement of
[IrCp*Cl2]2 by the less expensive catalyst [IrcodCl]2
led to similar results (Table 1, entries 3 and 4). It is worth
noting that a complete conversion of 2 was observed after
3 days and, under these conditions, the isolated yield in 3a
was 89% and no polyalkylation of acetonitrile was ob-
served. In order to accelerate the metal-catalyzed reaction,
microwave irradiation was performed.5c,7 With 2ꢀ5
mol % of catalyst, at 180 °C after 9 h, the conversion of
2was not complete (75ꢀ88%) and the yield in 3a was modest
(Table 1, entries 5 and 6). When [IrcodCl]2 was added in
two portions with an interval of 30 min, the conversion of 2
was increased to 90% (Table 1, entry 7) and the yield in 3a
was increased to 70% (Table 1, entry 8) even with 2 ꢁ 1
mol % ofcatalyst. The bestyield of 3awas obtainedwhen1
and 2 werepreheated inthe presence of Cs2CO3 (0.2 equiv),
and after 20 min, 1 mol % of [IrcodCl]2 was added. Then, the
reaction mixture was again heated under microwave irra-
diation, and 20 min later, 1 mol % of [IrcodCl]2 was added
and the reaction mixture was heated for an additional
20 min. Under these latter conditions, the conversion of 2
was complete and 3a was isolated in 90% yield (Table 1,
entry 9).8
Table 2. Generalization to Substituted Benzylic Alcohols
Table 1. Optimization of the Monoalkylation of Acetonitrile by
Benzyl Alcohol
cat. [Ir]
τc
of 2a
yield
entry
1
(x mol %)
temp
t
in 3a
[IrCp*Cl2]2
(2 mol %)
150 °C
16 h
35%
80%
79%
100%
30%a
71%a
61%a
89%b
2
3
4
5
6
7
8
9c
[IrCp*Cl2]2
(2 mol %)
180 °C
180 °C
180 °C
16 h
16 h
3 d
[IrcodCl]2
(2 mol %)
[IrcodCl]2
(2 mol %)
[IrcodCl]2
(2 mol %)
180 °C
MW
1 h
9 h
60%
75%
50%
88%
90%
ꢀ
48%b
ꢀ
[IrcodCl]2
(5 mol %)
180 °C
MW
1 h
9 h
55%b
73%b
[IrcodCl]2
(2 ꢁ 2.5 mol %)
[IrcodCl]2
(2 ꢁ 1 mol %)
[IrcodCl]2
(2 ꢁ 1 mol %)
180 °C
MW
2 ꢁ 30 min
180 °C
MW
2 ꢁ 30 min
2 ꢁ 20 min
90%
70%b
90%b
180 °C
MW
100%
a Determined by GC/MS. b Isolated yield. c 1 and 2 were preheated
with Cs2CO3 at 180 °C during 20 min.
a 3 mol % were necessary to perform a complete conversion of 2.
b Isolated yields.
Org. Lett., Vol. 13, No. 15, 2011
4085

These optimized reaction conditions (Table 1, entry 9)
proved to be quite general as the yields in 3 (Table 2)
were good when different benzylic alcohols were
used (up to 86%). The alkylation of acetonitrile 1 can
be performed with benzylic alcohols substituted by
electron-donating groups (2bꢀ2e). However, the subs-
titution of the aromatic ring of the benzylic alcohols
by electron-withdrawing groups (2f and 2g) did not
afford the desired alkylated nitriles (3f and 3g).
Substitution of the aromatic ring of 2 by a fluorine
atom (2hꢀ2j) or by a chloride atom (2kꢀ2m) led to
3hꢀ3m in good yield; in contrast, compounds 3
were not observed when a bromide or an iodide was
present on the aromatic ring of the benzylic alcohols 2
(2n and 2o).9
the alkylation of acetonitrile by 4 produced the corre-
sponding nitriles 5 in good yields (Table 3).
It was also possible to use nonactivated primary
alcohols such as 6 as they allowed the monoalkylation
of acetonitrile. Thus, although preheating was still re-
quired, [IrcodCl]2 (3 mol %) was added at once and the
reaction mixture was heated at 180 °C for 12 h under
microwave irradiation. When acetonitrile was heated with
octanol 6a, the corresponding nitrile 7a was isolated in
60% yield. Nitriles 7bꢀ7d were synthesized in good yields
(52ꢀ80%) by utilizing the corresponding alkyl alcohols
6bꢀ6d, and diol 6e was converted to the bis-nitrile 7e in
74% yield. This reaction is very sensitive to steric hin-
drance as γ-substituted alcohol 6f was transformed to the
corresponding nitrile in poor yield and 6g led to a complex
mixture of nonidentified compounds (Table 4, entries 6
and 7).
Table 3. Alkylation by Heteroaryl-methanols
Table 4. Alkylation of Acetonitrile by Aliphatic
Alcohols
a 3 mol % were necessary to perform a complete conversion of 4.
b Isolated yields.
Heteroaryl-methanols such as 4 can be involved in
the alkylation of acetonitrile. The results are reported in
Table 3. Pyridine, furan, and thiophene were tolerated as
(7) (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717–727. (b) Hayes, B. L. Aldrichimica Acta 2004, 37, 66–77.
(c) Nicks, F.; Borguet, Y.; Delfosse, S.; Bicchielli, D.; Delaude, L.;
Sauvage, X.; Demonceau, A. Aust. J. Chem. 2009, 62, 184–207.
(d) Appukkuttan, P.; van der Eycken, E. Eur. J. Org. 2008, 1133–
1155. (e) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127–1139.
(f) Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P. G. Org. Lett.
2009, 11, 3586–3589. (g) Irfan, M.; Fuchs, M.; Glasnov, T. N.; Kappe,
C. O. Chem.;Eur. J. 2009, 15, 11608–11618. (h) Johnstone, M. D.;
Lowe, A. J.; Henderson, L. C.; Pfeffer, F. M. Tetrahedron Lett. 2010,
51, 5889–5891.
a Isolated yields.
The reaction may be explained by the mechanism re-
ported in Scheme 1 inspired by previously published
mechanisms.5 At first, it seems important to generate a
cesium alcoholate (B from A) to get good yields in the
(8) The reaction can be performed without microwave irradiation;
however by using this later, the reaction was accelerated.
(9) The cleavage of the CꢀBr and CꢀI bonds was observed.
(10) The necessity of the presence of both alcohol and Cs2CO3 in the
first step has been studied.
4086
Org. Lett., Vol. 13, No. 15, 2011

intermediate C which goes through a β-elimination
to produce aldehyde D which undergoes a base-cata-
lyzed aldol condensation with acetonitrile to form
R,β-unsaturated nitrile E. This latter reacts with the
Ir-hydride to give F, and the iridium complex is
then regenerated. More detailed mechanistic studies
are presently performed and will be reported in due
time.
Scheme 1. Proposed Mechanism
Acknowledgment. B.A. thanks Sanofi-Aventis for a
grant, and Sanofi-Aventis is gratefully acknowledged for
financial support. Dr. K. Rossen (Sanofi-Aventis) is
acknowledged for his comments
Supporting Information Available. Experimental pro-
cedure and characterization data and NMR spectra of
compounds 3, 5, and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
monoalkylated acetonitrile.10 The alcoholate B can then
react with the iridium complex to produce an iridium
Org. Lett., Vol. 13, No. 15, 2011
4087