Ketone coupling with alkyl iodides, bromides, and chlorides using thulium diiodide: A more powerful version of SmI2(THF)(x)/HMPA

Full text of DOI:10.1021/ja992951m

2118
J. Am. Chem. Soc. 2000, 122, 2118-2119
Ketone Coupling with Alkyl Iodides, Bromides, and
Chlorides Using Thulium Diiodide: A More
Powerful Version of SmI2(THF)x/HMPA
Scheme 1. The Reaction of 2-Phenethyl Halides with
-tert-Butylcyclohexanone
4
William J. Evans* and Nathan T. Allen
Department of Chemistry, UniVersity of California
IrVine, California 92697-2025
To determine if TmI
it had utility as an alternative for SmI
2
(DME) 14
x
was viable as a reagent and if
(THF) /HMPA, we have
2
x
ReceiVed August 16, 1999
examined its reactivity in the coupling of 4-tert-butylcyclohex-
anone with alkyl halides, Scheme 1. This reaction was used as
an assay, since it has been thoroughly studied with samarium
1
Since Kagan’s seminal studies in 1977, samarium diiodide
has become a popular reducing agent in organic synthesis.2 It is
,3
15,16
17
diiodide.
Reactions were carried out in accordance with the
used under a variety of conditions to accomplish a wide range of
16
samarium Grignard procedure introduced by Curran in which
transformations. In many cases, reactivity is enhanced by adding
2
equiv of the lanthanide reagent are added to the alkyl halide
and the ketone is added subsequently. Reactions using SmI
THF) /HMPA were conducted to ensure that Sm/Tm comparisons
could be made under one uniform set of conditions.
As shown in Table 1, SmI (THF) /HMPA gives yields and
4
hexamethylphosphoramide (HMPA) to SmI
2
(THF)
x
. Unfortu-
2
-
nately, this most effective and popular additive is highly
(
x
5
6
carcinogenic and alternatives are highly desirable. Several other
methods for increasing SmI reactivity have been reported and
include the addition of transition metal salts or samarium metal,
2
2
x
7
8
selectivities for the reaction of phenethyl iodide with 4-tert-
butylcyclohexanone under our conditions which are consistent
9
10
photolysis, and the design of intramolecular reactions.
Recently, in collaboration with the Bochkarev group, we
reported the synthesis and structure of the first molecular Tm(II)
with the literature (entry 1). TmI
results (entry 2), but without any HMPA present. In contrast, SmI
THF) without HMPA is reported to reduce iodides only after
extended reaction times in refluxing THF.
After establishing that HMPA-free TmI
equivalent to SmI (THF) /HMPA, less reactive halides were
examined. In our control reactions with 2-phenethyl bromide
entry 3), SmI (THF) /HMPA required 15 min to change color
2 x
(DME) in DME matched these
2
-
1
1
complex, TmI
2 3
(DME) . This complex was found to be structur-
(
x
12
ally analogous to samarium diiodide in DME, but it is much
2a
1
3
more reactive since 4f Tm(II) has a much greater reduction
2
x
(DME) was at least
6
13
potential than 4f Sm(II). Preliminary studies indicated that this
3d
2
x
compound was so reactive12 that it was uncertain if it would be
2 x
useful as a reagent like SmI (THF) in organic transformations.
(
2
x
from the deep purple of Sm(II) to an orange-yellow characteristic
of Sm(III). After the addition of 4-tert-butylcyclohexanone, a 65%
conversion to 1 and 2 in a 77:23 ratio was found. In contrast,
when 2-phenethyl bromide was added to TmI (DME) (entry 4),
2 x
the color changed immediately from the emerald green Tm(II)
solution to bright yellow. A white/gray precipitate formed
(
1) Namy, J. L.; Girard, P.; Kagan, H. B. New J. Chem. 1977, 1, 5-7.
2) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
(
2
693-2698. (b) Namy, J. L.; Girard, P.; Kagan, H. B.; Caro, P. E. New J.
Chem. 1981, 5, 479-484. (c) Kagan, H. B.; Namy, J. L. In Handbook on the
Physics and Chemistry of Rare Earths; Gschneidner, K. A., Jr., Eyring, L.,
Eds.; Elsevier: Amsterdam, 1984; Vol. 6, Chapter 50.
(
3) For reviews see: (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42,
6
573-6614. (b) Soderquist, J. A. Aldrichim. Acta 1991, 24, 15-23. (c)
Molander, G. A. Chem. ReV. 1992, 92, 29-68. (d) Krief, A.; Laval, A. M.
Chem. ReV. 1999, 99, 745-777. (e) Molander, G. A.; Harris, C. R. In
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 6, pp 4428-4432.
(15) Fukuzawa, S. M.; Mutoh, K.; Tsuchimoto, T.; Hiyama, T. J. Org.
Chem. 1996, 61, 5400-5405.
(16) Curran, D. P.; Totleben, M. J. J. Am. Chem. Soc. 1992, 114, 6050.
2 x
(17) (a) The procedures for reactions using isolated TmI (DME) and for
(
4) (a) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986,
complexometric analysis of the stock solutions are given in the Supporting
Information. (b) Procedure using TmI (DME) generated in situ. To a Schlenk
flask containing Tm powder (0.80 g, 4.7 mmol) and 90 mL of dry, oxygen-
free DME was added iodine (1.20 g, 4.7 mmol) under a N purge to generate
5
7, 4437 (b) Flowers, R. A.; Shabangi, M. Tetrahedron Lett. 1997, 38, 1137.
5) Vogel, E. W.; Van Zeeland, A. A.; Raaymakers-Jansen Verplanke, C.
A.; Zijlstra, J. A. Mutation Res. 1985, 150, 241-260.
6) (a) Curran, D. P.; Hasegawa, E. J. Org. Chem. 1993, 58, 5008-5010.
b) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485. (c)
2
x
(
2
(
a dark brown-red solution. The solution was heated to reflux with rapid stirring.
After about 2 h the solution changed to white. Shortly thereafter (10 min) the
color changed to emerald green. Heating continued until white insoluble
materials were replaced by dark green product. After about 1 h, no more white
(
Kagan, H. B.; Namy, J.-L. In Lanthanides: Chemistry and Use in Organic
Synthesis; Kobayashi, S., Ed.; Springer: Berlin, 1999; pp 156-198.
(
7) Machrouhi, F.; Hamann, B.; Namy, J.-L.; Kagan, H. B. Synlett 1996,
precipitate was observable and dark green TmI
precipitate from the saturated solution. An aliquot of the saturated solution
2 x
(DME) was present as a
7
, 633.
8) Ogawa, A.; Nanke, T.; Takami, N.; Sumino, Y.; Ryu, I.; Sonoda, N.
Chem. Lett. 1994, 379-380.
9) (a) Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.; Hirao,
1
7a
(
[0.05 M (determined by complexometric titration ), 10 mL, 5 mmol] was
then added via syringe to a solution of 0.25 mmol of the organic halide in ca.
5 mL of DME in a septum-covered flask under nitrogen. Once an orange-
yellow solution was formed, 0.25 mmol of the ketone was injected through
the septum resulting in a clear solution with a white precipitate. The reaction
(
T. J. Am. Chem. Soc. 1997, 119, 2745-2746. (b) Ogawa, A.; Ohya, S.; Hirao,
T. Chem. Lett. 1997, 3, 275-276.
(
10) (a) Molander, G. A.; Sono, M. Tetrahedron 1998, 54, 9289-9302.
was then quenched with an aqueous solution saturated with NH
4
Cl and
(
b) Molander, G. A.; Harris, C. R. J. Org. Chem. 1998, 63, 4374-4380. (c)
extracted with ether/pentane (1:1). The organic extracts were washed with
Molander, G. A.; Alonso-Alija, C. J. Org. Chem. 1998, 63, 4366-4373. (d)
H
2
O (2 × 5 mL) and dried over MgSO
4
. The crude product was analyzed by
Molander, G. A.; Machrouhi, F. J. Org. Chem. 1999, 64, 4119-4123.
GC. Isolation of the products by flash chromatography gave a white crystalline
6
(
11) Bochkarev, M. N.; Fedushkin, I. L.; Fagin, A. A.; Petrovskaya, T.
product whose spectra were consistent with the literature values.1 (c) Procedure
V.; Ziller, J. W.; Broomhall-Dillard, R. N. R.; Evans, W. J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 133-135.
2 x
using TmI (THF) generated in situ in THF. To a Schlenk flask containing
Tm powder (1.0 g, 5.9 mmol) and 50 mL of dry, oxygen-free THF was added
(1.4 g, 5.5 mmol) under a N purge to generate a dark brown-red solution.
(
12) Evans, W. J.; Broomhall-Dillard, R. N. R.; Ziller, J. W. Polyhedron
I
2
2
1
998, 17, 3361-3370.
13) Estimated Ln(III)/(II) reduction potentials vs NHE for Tm and Sm
are -2.3 and -1.5 V, respectively: Morss, L. R. Chem. ReV. 1976, 76, 827.
The solution was heated to reflux with rapid stirring. After about 20 min the
solution changed to white. Shortly thereafter (10 min) the color changed to
emerald green. Heating continued until white insoluble materials were replaced
by dark green product. After about 1 h, no more white precipitate was
(
1
1
(
14) TmI
and x ) 2 as a powder. Cf. SmI
a powder. See: Evans, W. J.; Gummersheimer, T. S.; Ziller, J. W. J. Am.
Chem. Soc. 1995, 117, 8999. TmI (DME) can be produced by reduction of
a suspension of TmI (DME) (2.5 g, 3.4 mmol) in 50 mL of oxygen-free, dry
2 x
(DME) has x ) 3 when obtained as single crystals from DME
12
2
(THF)
x
: x ) 5 as single crystals, x ) 2 as
observable and dark green TmI
2 x
(THF) was present as a precipitate from the
saturated solution. An aliquot of the saturated solution [0.1 M (determined
1
7a
2
2
by complexometric titration ), 5 mL, 5 mmol] was then added via syringe
to a solution of 0.25 mmol of the organic halide in ca. 5 mL of THF in a
septum-covered flask under nitrogen. Once an orange-yellow solution was
formed, 0.25 mmol of the ketone was injected through the septum resulting
in a clear solution with a white precipitate. The reaction was then quenched
as described in (b).
3
2
DME with Tm powder (0.65 g, 3.86 mmol). The reaction is heated to reflux
under nitrogen for 40 min and filtered to remove unreacted Tm metal. Removal
of the solvent under vacuum leads to quantitative conversion to TmI
3.07 g, 5.1 mmol) as an emerald green powder.
2 2
(DME)
(
1
0.1021/ja992951m CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/23/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2119
Table 2. Additional TmI Reactivity: Other Substrates, Low
Table 1. Comparison of Reactivity of TmI
2
(DME)
x
and
2
2
SmI (THF)
x
/HMPA at 25 °C
2 x
Temperature Reactions, and TmI (THF) Reactions in THF
a
Time elapsed until color change from characteristic Ln(II) to
Ln(III); in each case the Ln(III) color changed immediately to white
b
upon addition of the ketone. Determined by GC/MS based on
unreacted ketone. Isomer ratio was determined by GC/MS. d Isolated
c
yields were obtained for entries 2 (97%), 4 (97%), and 6 (95%).
Scheme 2. The Reaction of Methyl Iodide and n-Butyl
Halides with 4-tert-Butylcyclohexanone (RX ) MeI, n-BuI,
n-BuBr, n-BuCl)
a-c
See Table 1. d Barbier conditions.
concurrently which is consistent with the formation of TmI
addition of the ketone, a 92% conversion to 1 and 2 in a 79:21
ratio was observed.
The difference between the Tm and Sm diiodide reagents was
even more pronounced with 2-phenethyl chloride. When SmI
3
. After
of the ketone and the alkyl halide gave significantly lower yields
of coupled products and generated 4-tert-butylcyclohexanol, due
to reduction of the ketone. This is consistent with the expected
high reactivity of Tm(II) compared to Sm(II) with ketones.
Since TmI
temperature, its viability at reduced temperature was examined.
In these reactions, TmI (DME) was added as a DME solution
2 x
(DME) exhibited such high reactivity at room
2
-
(
THF) /HMPA (entry 5) was employed, little color change was
x
observed, even after 18 h at 25 °C. After addition of the ketone,
2
x
by syringe using a saturated stock solution generated in situ from
Tm and I2.1 Phenethyl iodide reacted smoothly with cyclohex-
anone at -22 °C in 10 min to form phenethylcyclohexanol in
96% yield (entry f). Phenethyl bromide reacts at 0 °C in 20 min
(entry g), while reaction at -22 °C gave a 94% yield in 60 min
(entry h). Phenethyl chloride reacted at 0 °C to give a 90% yield
after 1 h (entry j). This variation of reaction time as a function of
temperature could be used to control regiochemistry in sequenced
reactions.10
no product was formed. This is consistent with literature reports
7b
that unactivated chlorides18 are not very reactive with samarium
diiodide unless some type of enhancement is employed, e.g. the
7
addition of catalytic amounts of NiX
2
, reaction in the presence
8
of samarium metal at 67 °C for 20 h, photolysis for 3-9 h at
9
10
2
5-40 °C, or an intramolecular reaction. However, TmI
2
-
(
DME) in DME (entry 6) reacted to give a yellow solution in 3
x
min, which after addition of the ketone resulted in a 79:21 ratio
of 1 and 2 in 88% yield.
Encouraged by these results, we examined the possibility of
Since THF is typically used for SmI
effects can be influential in SmI (THF)
with 2-phenethyl iodide was carried out in THF with TmI
entry 7). The results showed comparable yields and identical
selectivities to reactions conducted in DME (entry 2). However,
the reaction of SmI (THF) /HMPA in DME gave ethylbenzene
2
reactions and since solvent
6a
accomplishing this TmI
may be desirable to avoid DME in some situations. As shown in
(THF) generated conveniently in situ in THF
2
reactivity exclusively in THF, since it
2
x
reductions, the reaction
(DME)
2
x
entries k-m, TmI
2
x
(
1
7c
as a stock solution on a Schlenk line from Tm and I
excellent results as well.
2
gave
2
x
On the basis of these results, TmI
effective replacement for SmI (THF)
avoided, when the SmI (THF) /HMPA system is too weak a
2
has the potential to be an
as the only product by GC (entry 8). This is consistent the report
2
x
when HMPA is to be
of Molander that DME is an unacceptable solvent for organosa-
marium reactions.19
2
x
reductant to accomplish a reaction, when subambient reaction
temperatures are desirable, and when reactions faster than those
Reactions of TmI
investigated, Scheme 2 (Table 2). The reaction of MeI with 2
equiv of TmI (DME) in DME led to 99% conversion to products
2 x
(DME) with other alkyl halides were also
7
8
9
achievable via MX
2
and samarium addition and photolysis are
may limit its functional
2
x
needed. The higher reactivity of TmI
2
with a ratio of axial 3 to equatorial 4 of 64:36 (entry a). The
reaction of n-butyl iodide (entry b) gave a 99% conversion with
an axial 5:equatorial 6 ratio of 74:26. 5 and 6 can also be obtained
from n-butyl bromide and chloride in yields of 96% and 97%,
respectively (entries c and d). The product ratios are the same as
for the n-butyl iodide reaction. Reactions using the Barbier
group tolerance in some applications, but it is possible that this
can be overcome by developing the appropriate protocols.
Acknowledgment. We thank the National Science Foundation for
support for this research.
procedure (entry e) in which TmI
2
(DME)
x
is added to a mixture
Supporting Information Available: Experimental procedures (PDF).
These materials are available free of charge via the Internet at
http://pubs.acs.org.
(
18) Huang, Z. Z.; Jin, H. W.; Duan, D. H.; Huang, X. J. Chem. Res. (S)
999, 564-565.
19) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132-3139.
1
(
JA992951M