One-step conversion of alcohols into nitriles with simultaneous two-carbon chain elongation. (Cyanomethyl)trimethylphosphonium iodide as a reagent with a dual mode of action

Article abstract of DOI:10.1021/jo025731r

Treatment of alcohols with an excess of (cyanomethyl)trimethylphosphonium iodide leads, after aqueous hydrolysis, to the clean formation of nitriles with two more carbon atoms than present in the original alcohol. Benzylic, allylic, and aliphatic alcohols without β-branching (RCH₂- CH₂OH) have been converted to nitriles with success. The required phosphonium iodide is simple to prepare and can be stored for a long time at room temperature.

Full text of DOI:10.1021/jo025731r

On e-Step Con ver sion of Alcoh ols in to
Nitr iles w ith Sim u lta n eou s Tw o-Ca r bon
Ch a in Elon ga tion .
SCHEME 1. P ossible Mech a n ism for th e
P h osp h on iu m Sa lt-Med ia ted F or m a tion of Nitr iles
8
fr om Alcoh ols 2
(
Cya n om eth yl)tr im eth ylp h osp h on iu m
Iod id e a s a Rea gen t w ith a Du a l Mod e of
Action
Florencio Zaragoza
Novo Nordisk A/ S, Novo Nordisk Park,
DK-2760 M a˚ løv, Denmark
flo@novonordisk.com
Received March 19, 2002
Abstr a ct: Treatment of alcohols with an excess of (cya-
nomethyl)trimethylphosphonium iodide leads, after aqueous
hydrolysis, to the clean formation of nitriles with two more
carbon atoms than present in the original alcohol. Benzylic,
allylic, and aliphatic alcohols without â-branching (RCH2-
CH2OH) have been converted to nitriles with success. The
required phosphonium iodide is simple to prepare and can
be stored for a long time at room temperature.
TABLE 1. P h osp h on iu m Iod id e-Med ia ted Con ver sion of
Alcoh ols in to Nitr ilesa
We recently reported the use of (cyanomethyl)trialkyl-
phosphonium iodides as mediators of the intermolecular
1
2
alkylation of amines and thiols with aliphatic alcohols.
These reactions presumably proceed via initial conversion
of the alcohol into an alkyl iodide, which then alkylates
the amine or the thiol. Because only water-soluble and
volatile byproducts are formed, these reactions yield
crude products of high purity, and are therefore well
suited for parallel solution-phase chemistry.
While investigating the reactions of alcohols with an
excess of (cyanomethyl)trimethylphosphonium iodide in
the absence of additional nucleophiles, with the aim of
preparing alkyl iodides and thereby substantiate our
mechanistic proposal, the formation of C-alkylated (cya-
nomethyl)phosphonium salts 7 was observed (Scheme 1).3
These phosphonium salts were unstable toward aqueous
base, and when water was added to the reaction mixture
and heating was continued, these phosphonium salts
underwent dealkylation to yield nitriles 8. A possible
mechanism for this reaction is sketched in Scheme 1.
This new reaction turned out to be applicable to
benzylic, allylic, and aliphatic alcohols without â-branch-
a
A mixture of phosphonium salt 1 (2.5-3.0 equiv), alcohol 2
-
1
(
(
(
1.0 equiv, 0.5 mol L ), propionitrile, and diisopropylethylamine
DIPEA, 3.0-3.5 equiv) was stirred at 97 °C for 20-26 h. Water
6 equiv) was then added, and stirring at 97 °C was continued for
1-16 h. Reaction times (alkylation/hydrolysis). c Yields of puri-
fied products. Products 8a , 8d , 8f, and 8g were purified by bulb-
to-bulb distillation; products 8b, 8c, and 8e were purified by
column chromatography.
b
2 2
ing (RCH CH OH, Table 1). It represents a practical
alternative to known, multistep procedures, in which the
alcohol first has to be converted into an alkyl halide or
sulfonate, which is then treated with lithiated acetoni-
4
,
5
6
High concentrations of reactants and long reaction
times (24-48 h) were generally required to attain good
yields. Because the conversion of alcohols into iodides
with reagent 1 is complete in less than 1 h under the
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(
1) Zaragoza, F.; Stephensen, H. J . Org. Chem. 2001, 66, 2518-
2
521.
(
(
2) Zaragoza, F Tetrahedron 2001, 57, 5451-5454.
3) The alkylated phosphonium salts 7 were isolated by aqueous
1
currently used conditions, the long reaction times are
1
probably required because of the slow C-alkylation of the
workup under acidic conditions and identified by HPLC-MS and
H
3
NMR. The title reaction can be monitored by hydrolysis of small
samples with aqueous hydrochloric acid (1 M), extraction with ethyl
acetate, concentration of the organic layer, and determination of the
ratio 5/7 by 1H NMR.
cyanomethylphosphorane 6. When the alkylation and
the hydrolysis were complete, a simple aqueous extrac-
(
4) J ansen, F. J . H. M.; Lugtenburg, J . Eur. J . Org. Chem. 2000,
(5) Inaba, S.; Rieke, R. D. Synthesis 1984, 842-844.
(6) Hunter, D. A.; Perry, R. A. Synthesis 1977, 37-39.
8
29-836.
1
0.1021/jo025731r CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002
J . Org. Chem. 2002, 67, 4963-4964
4963

tion yielded crude products of high purity, as judged by
H NMR, and small amounts of colored, polar byproducts
could be easily removed by filtration through a pad of
silica or by bulb-to-bulb distillation. With secondary
alcohols the reaction did not proceed at all, and with
NMR (100 MHz, CDCl
136.8. Anal. Calcd for C H ClN (165.62): C, 65.27; H, 4.87; N,
3
) δ 19.7, 31.3, 119.1, 129.4, 130.1, 133.6,
1
9
8
8
8
.46. Found: C, 64.84; H, 4.96; N, 8.77.
-(4-Nitr op h en yl)p r op ion itr ile (8b). Yellow crystals, mp
2.5-83.5 °C (lit. 79 °C ). The H and C NMR spectra of this
3
7
1
13
7
product were identical to the reported ones. Anal. Calcd for
(176.18): C, 61.36; H, 4.58; N, 15.90. Found: C, 61.45;
2 2
â-branched alcohols (R CHCH OH) or when the alkyla-
9 8 2 2
C H N O
tion was interrupted too early, mixtures of the desired
nitriles 8 and alkyl iodides 5 were obtained.
H, 4.50; N, 15.87.
3-An th r a cen -9-ylp r op ion itr ile (8c). Orange crystals, mp
148.5-149.5 °C (lit. 143-145 °C ). H NMR (300 MHz, CDCl
δ 2.79 (t, J ) 7 Hz, 2H), 4.03 (t, J ) 7 Hz, 2H), 7.50 (m, 2H),
8
1
The results given in Table 1 indicate that the phos-
phonium salt 1 is a valuable reagent for the conversion
of alcohols into nitriles with simultaneous chain elonga-
tion by two carbon atoms. This salt thereby mediates two
types of reaction: the halogenation and the chain exten-
sion of the alcohol. Phosphonium iodide 1 is easy to
3
)
7
2
1
.58 (m, 2H), 8.04 (br d, J ) 8 Hz, 2H), 8.19 (br d, J ) 8 Hz,
H), 8.43 (s, 1H); 13C NMR (100 MHz, CDCl
) δ 18.0, 23.7, 119.2,
23.0, 125.1, 126.5, 127.4, 129.4, 129.6, 131.5. Anal. Calcd for
13N (231.30): C, 88.28; H, 5.67; N, 6.06. Found: C, 88.04;
3
17
C H
H, 5.72; N, 5.97.
1
prepare and nonhygroscopic and can be kept at room
5-Meth yl-4-h exen en itr ile (8d ). Oil, 93% pure by GC. The
1
temperature without decomposition. The reactions of this
salt with alcohols are easy to perform and significantly
less tedious than alternative, multistep protocols, and
yield crude products of high purity.
H NMR spectrum of this product was identical to the reported
one.4 C NMR (100 MHz, CDCl
13
) δ 17.7, 17.8, 24.1, 25.7, 119.7,
3
1
20.2, 135.6.
1
4
-(4-Br om op h en oxy)bu tyr on itr ile (8e). Oil. H NMR (400
MHz, CDCl
H), 4.04 (t, J ) 7 Hz, 2H), 6.78 (m, 2H), 7.39 (m, 2H); C NMR
(100 MHz, CDCl ) δ 14.6, 25.8, 66.0, 113.9, 116.7, 119.4, 132.8,
57.9; IR 2943, 2880, 2248, 1591. Anal. Calcd for C10 10BrNO
240.10): C, 50.03; H, 4.20; N, 5.83. Found: C, 50.06; H, 4.20;
N, 5.92.
-P h en ylbu tyr on itr ile (8f). Oil, 98% pure by GC. The 1H
3
) δ 2.13 (quint, J ) 7 Hz, 2H), 2.58 (t, J ) 7 Hz,
13
2
Exp er im en ta l Section
3
1
(
H
Gen er a l P r oced u r e for th e P r ep a r a tion of Nitr iles.
Octa n en itr ile (8g). To a mixture of 1-hexanol (204 mg, 2.00
1
mmol) and (cyanomethyl)trimethylphosphonium iodide (1, 1.24
4
g, 5.10 mmol) were added propionitrile (4.0 mL) and DIPEA (1.10
mL, 6.32 mmol), and the mixture was stirred at 97 °C for 24 h.
Water (0.20 mL, 11.1 mmol) was added (strong bubbling), and
stirring at 97 °C was continued for 15 h. Water (25 mL) and
concentrated hydrochloric acid (1.0 mL, 12 mmol) were added,
and the mixture was extracted with ethyl acetate (3 × 25 mL).
The combined extracts were washed once with brine, dried with
magnesium sulfate, and concentrated. The residue was purified
by bulb-to-bulb distillation (10 mbar), to yield 185 mg (74%) of
1
3
NMR (300 MHz) and C NMR (100 MHz) spectra of this product
and an authentic sample were identical.
Ack n ow led gm en t. I thank Otto Larsson, Henrik
Stephensen, and Flemming Gundertofte for technical
assistance.
J O025731R
1
the title compound as an oil, 98% pure by GC. The H NMR
1
3
(
300 MHz) and C NMR (100 MHz) spectra of this product and
(7) Strazzolini, P.; Giumanini, A. G.; Runcio, A.; Scuccato, M. J . Org.
an authentic sample were identical.
Chem. 1998, 63, 952-958.
3
-(4-Ch lor op h en yl)p r op ion itr ile (8a ). Oil. The 1H NMR
(8) Rhodes, R. A.; Boykin, D. W. Synth. Commun. 1988, 18, 681-
5
13
spectrum of this product was identical to the reported one.
C
688.
4
964 J . Org. Chem., Vol. 67, No. 14, 2002