4
Preparation of Ketones from Nitriles and
Phosphoranes
Our results are summarized in Table 1. Ketones 2c,
5
6
7
8
3
c, 5c, 6c, and 7c have previously been described. The
preparation of the phosphonium iodide 1a has also been
described before.9
Douglass F. Taber* and Lisi Cai
This procedure for preparing ketones appears to be
general (Table 1). Each of the condensations proceeded
effectively with only a small excess of the less expensive
component. We expect that this approach will be par-
ticularly useful when it is necessary to prepare a ketone
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
by coupling two advanced intermediates in a synthe-
sis.10,11
Received February 9, 2005
Experimental Section
Procedure from Phosphonium Iodide, Ketone 1c. [2-(2,2-
5
Dimethyl-[1,3]dioxolan-4-yl-ethyl]-triphenyl-λ -phosphonium io-
dide (1a, 9.79 g, 18.90 mmol, 1.0 equiv) was suspended in 140
mL of anhydrous THF. The reaction flask was wrapped with
aluminum foil. At ice-water temperature, 10.0 mL of 2.5 M BuLi
in hexane (25.00 mmol, 1.3 equiv) was added, producing the
orange-red solution of the phosphorane. After 20 min, 5 mL of
THF containing 3.42 g of isovaleronitrile (1b, 28.7 mmol, 1.5
equiv) was added. The reaction mixture was then maintained
at 50 °C for 8 h.
The preparation of a ketone from a phosphorane and a nitrile
is described. The workup conditions are mild, and the yields
are high. The unreacted starting materials can easily be
recovered.
After cooling to room temperature, the reaction mixture was
4
partitioned between saturated aqueous NH Cl (80 mL) and,
sequentially, CH
The organic extracts were washed with saturated aqueous NaCl
45 mL), dried (Na SO ), and concentrated. Anhydrous Et O was
Cl
2 2
(15 mL) and 25% MTBE/PE (25 mL × 3).
(
2
4
2
The ketone is the central functional group in organic
synthesis. One route to a ketone is the addition of an
organometallic reagent to the nitrile. The disadvantage
of this approach is that any unreacted organometallic
reagent is protonated on workup and so lost. We describe
an improved procedure for the addition of a phosphorane
to the nitrile. The advantage of this approach is that any
unreacted phosphonium salt can easily be recovered and
reused.
added. The resulting suspension was filtered to recover a small
amount of the starting phosphonium iodide salt (3.80 g, 61%
conversion rate). The solution residue was absorbed by silica gel
and chromatographed to yield ketone 1c (1.11 g, 6.99 mmol, 61%
f
yield from 1a) as a colorless oil (TLC R (20% MTBE/PE) ) 0.52).
-
1
1
IR (cm ) 1713, 1369, 1064; H NMR δ 4.10-3.95 (m, 2H), 3.5
(
m, 1H), 2.58-2.40 (m, 2H), 2.25 (d, J ) 7.1 Hz, 2H), 2.18-2.10
m, 1H), 1.90-1.80 (m, 1H), 1.79-1.70 (m, 2H), 1.39 (s, 3H), 1.30
(s, 3H), 0.93 (d, 3H), 0.92 (d, 3H); C NMR δ u 210.2, 108.9,
69.2, 51.9, 39.1, 27.2, d 75.1, 26.9, 25.6, 24.6, 22.6, 22.5; MS m/z
99(100), 157 (17), 156 (18), 113 (24); HRMS calcd for C11
99.1334, obsd 199.1343.
Procedure from Phosphonium Bromide, Ketone 4c.
(
1
3
1
1
19 3
H O
1
In 1967, McEwen reported that the ylide produced by
deprotonating a triphenylphosphonium iodide with BuLi
can react with a nitrile to give the corresponding ketone.
The procedure included vigorous hydrolysis with metha-
nol and HCl. Perhaps because of the harsh workup
conditions, the procedure has been little used.2 We have
found that the hydrolysis procedure specified by McEwen
is not required. Mild workup of the reaction with aqueous
ammonium chloride gives the ketone directly.
n-Decyl triphenylphosphonium bromide (2a, 1.57 g, 3.25 mmol,
1.8 equiv) and LiI (0.13 g, 0.97 mmol, 0.5 equiv) were suspended
in 40 mL of anhydrous THF. The reaction flask was wrapped
with aluminum foil. At ice-water temperature, 1.6 mL of 1.8
M BuLi in hexane was added, producing the red solution of the
phosphorane. After 20 min, 5 mL of THF containing 0.318 g of
4-phenoxybutanenitrile (4b, 1.82 mmol, 1.0 equiv) was added.
The reaction mixture was then maintained at 50 °C for 8 h.
After cooling to room temperature, the reaction mixture was
,3
Our procedure begins by suspending the phosphonium
salt in anhydrous THF. As specified by McEwen, 0.5
equiv of LiI is added if the phosphonium salt is not the
iodide. At ice-water temperature, BuLi in hexane is
added to produce the red solution of the phosphorane.
The nitrile is added, and the reaction mixture is main-
tained at 50 °C for 8 h. The reaction is then quenched
partitioned between saturated aqueous NH
CH Cl
(10 mL) and 25% MTBE/PE (25 mL × 3). The organic
extracts were washed with saturated aqueous NaCl (15 mL),
dried (Na SO ), and concentrated. The residue was chromato-
4
Cl and, sequentially,
2
2
2
4
(
4) Chang, D.-H.; Lee, D.-Y.; Hong, B.-S.; Choi, J.-H.; Jun, C.-H. J.
Am. Chem. Soc. 2004, 126, 424.
5) Morris, H. H.; St. Lawrence, C. J. J. Am. Chem. Soc. 1955, 77,
(
with aqueous NH
4
Cl. Any unreacted phosphonium salt
1692.
(
6) Osei-Twum, E. Y.; McCallion, D.; Nazran, A. S.; Panicucci, R.;
and nitrile can easily be recovered by crystallization or
column chromatography.
Risbood, P. A.; Warkentin, J. J. Org. Chem. 1984, 49, 336.
(7) Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119, 5982.
(
8) Veenstra, G. E.; Zwanenburg, B. Tetrahedron 1978, 34, 1585.
9) Taber, D. F.; Xu, M. J. Am. Chem. Soc. 2002, 124, 13121.
(
(
1) Barnhardt, R. G., Jr.; McEwen, W. E. J. Am. Chem. Soc. 1967,
(10) For such a construction, see Ghosh, A. K.; Liu, C. J. Am. Chem.
Soc. 2003, 125, 2374.
8
9, 7009.
(
2) Trabelsi, H.; Cambon, A. Synthesis 1992, 315.
3) Hamzaoui, M.; Provot, O.; Gregoire, F.; Riche, C.; Chiaroni, A.;
(11) For a recent report of ketone construction by the condensation
of Weinreb amides with phosphoranes, see: Murphy, J. A.; Com-
meureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T. A.; Hisler,
K.; Dewis, M. L.; Carling, R. Org. Lett. 2005, 7, 1427.
(
Gay, F.; Moskowitz, H.; Mayrargue, J. Tetrahedron: Asymmetry 1997,
8
, 2085.
1
0.1021/jo050266u CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/06/2005
J. Org. Chem. 2005, 70, 4887-4888
4887
Taber, Douglass F.
