Utility of neodymium diiodide as a reductant in ketone coupling reactions

Article abstract of DOI:10.1021/ol030033u

Matrix presented The viability of Ndl₂ as a one-electron reducing agent in organic synthesis has been examined by studying coupling reactions between alkyl chlorides and ketones and aldehydes.

Full text of DOI:10.1021/ol030033u

ORGANIC
LETTERS
2
003
Utility of Neodymium Diiodide as a
Reductant in Ketone Coupling Reactions
Vol. 5, No. 12
2
041-2042
William J. Evans,* Penny S. Workman, and Nathan T. Allen
Department of Chemistry, UniVersity of California-IrVine,
IrVine, California 92697-2025
weVans@uci.edu
Received March 3, 2003
ABSTRACT
2
The viability of NdI as a one-electron reducing agent in organic synthesis has been examined by studying coupling reactions between alkyl
chlorides and ketones and aldehydes.
8
For many years, samarium diiodide has been a standard one-
electron reductant in organic synthesis.1-4 It is broadly useful,
and its reduction potential can be enhanced by addition of
hexamethylphosphoramide (HMPA). Recently, there have
been rapid advances in the availability of more powerful
divalent lanthanide reducing agents useful for organic
accomplish useful organic transformations. Hence, even
though it initially appeared that Tm(II) and Dy(II) were too
strongly reducing to exhibit useful synthetic reductive
chemistry in solution, these systems have proven to be
5
7
,8
viable.
The existence of Nd(II), an even more reducing divalent
lanthanide, as a soluble molecular species was recently
established by Bochkarev et al. It was uncertain if Nd(II),
which has a Ln(III)/Ln(II) reduction potential vs NHE of
-2.6 V compared to Sm (-1.55 V), Tm (-2.3 V), and Dy
(-2.5 V), would be viable as a synthetic reagent. We report
2
can be used as a lanthanide reducing agent in
organic synthesis. In addition to being more reducing, NdI
may offer some special advantages over the other divalent
lanthanide halide reagents. It is cheaper and has a larger radial
size, which can be important in optimizing lanthanide
reaction chemistry.
synthesis. The 1997 discovery of the first molecular complex
6
10
of Tm(II) prompted the development of TmI
2
as an
/HMPA
alternative for the commonly used SmI
2
(THF)
x
5
combination. This Tm(II) reagent can effect more difficult
reductions than Sm(II)/HMPA and avoids the carcinogenicity
of HMPA. For example, it allows ketone-alkyl halide
couplings to be accomplished with chlorides even at low
9
here that NdI
2
7
temperatures.
8
The isolation of the first molecular complex of Dy(II)
9
provided an even more powerful reductant that can also
2
NdI can be generated in 40 g (100 mmol) quantities by
(
(
(
(
1) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573.
1
1
2) Molander, G. A. Chem. ReV. 1992, 92, 29.
3) Krief, A.; Laval, A. M. Chem. ReV. 1999, 99, 745.
4) Molander, G. A.; Harris, C. R. In Encyclopedia of Reagents for
direct reaction of metal and iodine at 600 °C. This solid
can be stored for months at room temperature in the absence
of solvent. Solutions are stable under an argon atmosphere12
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 6,
p 4428.
(
5) (a) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
(8) Evans, W. J.; Allen, N. T.; Ziller, J. W. J. Am. Chem. Soc. 2000,
122, 11749.
2
7, 5763. (b) Flowers, R. A.; Shabangi, M. Tetrahedron Lett. 1997, 38,
1
137.
(9) Morss, L. R. Chem. ReV. 1976, 76, 827.
(6) Bochkarev, M. N.; Fedushkin, I. L.; Fagin, A. A.; Petrovskaya, T.
(10) Bochkarev, M. N.; Fedushkin, I. L.; Dechert, S.; Fagin, A. A.;
Schumann, H. Angew. Chem., Int. Ed. 2001, 40, 3176.
(11) Evans, W. J.; Allen, N. T.; Workman, P. S.; Meyer, J. C. Inorg.
Chem. 2003, 42, 3097.
V.; Ziller, J. W.; Broomhall-Dillard, R. N. R.; Evans, W. J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 133.
(7) Evans, W. J.; Allen, N. T. J. Am Chem. Soc. 2000, 122, 2118.
1
0.1021/ol030033u CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003

Table 1. Reductive Coupling of Cyclohexanone with Alkyl
Table 2. Reductive Coupling of 2-Hexanone with Alkyl
Chlorides Using NdI
2
in THF
Chlorides Using NdI
2
in THF
alkyl chloride
% yield (GC, based on unreacted ketone)
alkyl chloride
% yield (GC, based on unreacted ketone)
n-butyl chloride
97
99
0
n-butyl chloride
sec-butyl chloride
tert-butyl chloride
phenethyl chloride
allyl chloride
100
77
0
81
82
sec-butyl chloride
tert-butyl chloride
phenethyl chloride
81
for several hours at -15 °C but decompose over a period of
minutes at room temperature. Hence, NdI must be used
quickly once it is put in solution and reactions must be
performed at subambient temperatures.
primary and secondary chlorides proceeds in good yield. No
reaction occurs, however, when a tertiary chloride is used.
Similar results were obtained using the noncyclic ketone,
2
2
-hexanone, as shown in Table 2.
NdI coupling of an alkyl halide with an aldehyde substrate
2 2
Although NdI is more reactive than the other LnI
2
reagents, its high reactivity actually leads to a simpler
experimental protocol. Since the reagent is best stored as a
solid and solutions are used immediately, the problem of
solutions changing concentration over time is avoided. A
standardized solution, typically 0.05 M at -15 °C, can be
produced and transferred via a syringe to a flask containing
the substrate to be reduced.13 The reactions are run at low
temperatures and are often complete upon mixing.
was also examined. The coupling of 1-chlorobutane with
valeraldehyde gave the coupled alcohol, 5-nonanol in 93%
yield (eq 2).
The first set of transformations examined with NdI
2 x
(THF)
were ketone coupling reactions with alkyl halides, since the
1
4,15
NdI
2
in THF has also been found to reduce naphthalene.
with naphthalene forms an
2
results could be directly compared with those for SmI ,
7
8
Reaction of 2.2 equiv of NdI
2
TmI
2
, and DyI
2
. Addition of 1-chlorobutane to a solution
intense blue solution, which after hydrolysis yields dihy-
dronaphthalene (eq 3), i.e., it has Birch reduction-type
reactivity.
of NdI
2
(THF) at -15 °C immediately dissipated the purple
x
color to form a light green intermediate. After reaction with
cyclohexanone, a 97% (GC) yield of the coupled product,
1-butylcyclohexanol, was obtained following aqueous work-
up (eq 1). Other chlorides may also be reduced in a similar
In conclusion, these preliminary results show that NdI
not too reactive to be useful as a reductant in organic
synthesis. Hence, NdI can join TmI and DyI in bridging
the gap in available reductants with reduction potentials
between those of SmI /HMPA and alkali metal/liquid am-
monia Birch reductants. It is anticipated that NdI
2
is
manner, as shown in Table 1. It was found that reaction of
2
2
2
(
12) We have found that the presence of dinitrogen substantially reduces
the stability of solutions, even at -30 °C.
13) General Method for Using NdI2(THF)x. A septum-capped flask
2
2
will
has
(
was charged with black NdI2 (1.0 g, 2.5 mmol) and a stir bar under argon.
The flask was placed in a -15 °C 2-propanol/ice bath. Precooled THF (45
mL, -15 °C) was added via cannula, immediately producing a purple
solution. The solution was stirred for 45 min. An aliquot of the saturated
solution was removed and its concentration determined to be 0.05 M by
develop into a broadly useful reagent, just as SmI
developed over the past 20 years.
2
1-4
Acknowledgment. We thank the National Science Foun-
dation for support for this research.
7
complexometric titration. An aliquot (24.0 mL, 1.2 mmol) was added via
syringe to a septum-covered flask under argon at -15 °C. Subsequently,
the organic halide (0.55 mmol) was added via syringe. Once a green solution
was formed, the ketone (0.50 mmol) was added via syringe, resulting in a
light blue solution. The reaction was then quenched with a saturated solution
of NH4Cl and extracted with ether or pentanes. The organic extract was
washed with H2O (2 × 10 mL) and dried over MgSO4. The solvent was
removed in vacuo to yield the coupled product.
OL030033U
(14) Fukuzawa, S. N.; Mutoh, K.; Tsuchimoto, T.; Hiyama, T. J. Org.
Chem. 1996, 61, 5400.
(15) Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114, 6050.
2042
Org. Lett., Vol. 5, No. 12, 2003