Methylenation of carbonyl compounds by means of Nysted reagent

Article abstract of DOI:10.1055/s-1998-36073

Nysted reagent [cyclo-dibromodi-μ-methylene(μ-tetrahydrofuran)trizinc], a commercially available gem-dimetallic compound, reacted with aldehydes affording methylenated products in the presence of BF₃?OEt₂, whereas methylenation of ketones proceeded in the presence of BF₃OEt₂ and TiCl₂.

Full text of DOI:10.1055/s-1998-36073

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Methylenation of Carbonyl Compounds by Means of Nysted Reagent
Seijiro Matsubara,* Masakazu Sugihara, and Kiitiro Utimoto
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida, Sakyo, Kyoto 606-8501, Japan
Received 3 December 1997
Abstract:
tetrahydrofuran)trizinc],
compound, reacted with aldehydes affording methylenated products in
the presence of BF •OEt , whereas methylenation of ketones proceeded
Nysted
reagent
[cyclo-dibromodi-µ-methylene(µ-
a
commercially available gem-dimetallic
3
2
in the presence of BF •OEt and TiCl .
3
2
2
Alkylidenation of carbonyl compounds is still an important reaction in
organic synthesis. Various useful reagents have been devised, namely,
1
phosphonium ylids, alkylphosphonate anions, transition metal-carbene
2
3,4
complexes, Tebbe complex and related compounds,
and gem-
5
dimetallic compounds. In addition to these reagents, combinations of
gem-dihaloalkanes and low-valent metal salts have been used in the
6,7
alkylidenation of aldehydes, ketones, and esters, although reactive
species generated by the above reagent systems have not been
8
completely clarified. Commercially available Nysted reagent 1, that
possesses two gem-dimetallic subunits in one molecule, is assumed to
have high potential for methylenation of carbonyl compounds and some
successful application to methylenation of ketones under TiCl -
4
9
mediated conditions have been reported recently. However, the
Scheme 1
reactivity of Nysted reagent itself and the role of TiCl still remained to
4
be clarified. We intended to disclose reactivity of Nysted reagent to
methylenation of aldehydes and ketones and found that the reagent is
suitable for chemoselective methylenation of aldehydes using
BF •OEt -mediated conditions and that ketones can be methylenated
Various aldehydes were methylenated under above reaction conditions
in moderate to excellent yields as shown in Table 2. An aldehyde having
a stereogenic center at the α-position afforded the corresponding
methylenated product with complete retention of configuration (entries
3
2
using TiCl , TiCl or a combination of TiCl and BF •OEt as
4
3
2
3
2
11
mediators.
3 and 4). High chemoselectivity was observed (entries 5 and 6) in the
reaction with a keto aldehyde; aldehyde was methylenated exclusively.
Figure 1
As commercial Nysted reagent is a white suspension in THF containing
20 wt% of 1 and shows low solubility in ether, THF, and other aprotic
solvents, it is difficult to determine the purity and content of 1 in the
suspension. Concentration of 1 in commercial white suspension was
determined by transformation of 1 to CH I by the action of excess I .
2 2
2
GC and NMR analyses of CH I revealed that the concentration of 1 in
2 2
10
suspension is 21-22 wt%.
Methylenation of aldehydes was examined first. A treatment of
dodecanal 2 with Nysted reagent gave methylenated product 3 in 68%
yield along with 9% of recovery of the aldehyde. Use of excess Nysted
reagent 1 did not improve the yield. In both cases, an aldol dimer of the
aldehydes was detected from the reaction mixture in a considerable
amount. To suppress aldol reaction and to perform methylenation in
high conversion, several Lewis acids were examined as mediators.
Addition of 10 mol% of a Lewis acid to Nysted reagent (1.0 mmol)
Methylenation of ketones with Nysted reagent was examined. Since no
methylenated product 3b was obtained from 2b by BF •OEt catalyzed
3
2
reaction, TiCl -mediated reaction afforded methylenated product in fair
4
improved the yield of methylenated product; BF •OEt showed a
3
2
to good yields, depending upon the ratio of Nysted reagent : 2b : TiCl .
4
prominent effect and the methylenated product was obtained in 83%
yield (SnCl , 75%; Me SnCl, 72%; SnCl , 74%). The reaction
More than 1.5 eq of Nysted reagent was needed to obtain olefin 3b in
4
3
2
good to excellent yields. Methylenation under TiCl -mediated
3
conditions were optimized by varying the amount of BF •OEt ; results
3
2
conditions proceeded and the reaction using excess 1 afforded
methylenated product in excellent yield. Results are shown in Table 3.
are shown in Table 1.

314
LETTERS
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12
Recently we observed that TiCl
is an active mediator in TiCl -
4
2
mediated reaction of bis(iodozincio)methane with ketones yielding
methylenated products, where TiCl and TiCl were reduced to TiCl by
4
3
2
gem-dimetallic reagent. Analogously, TiCl -mediated reaction of 1 with
2
ketones afforded methylenated products in excellent yields. Results
were summarized in Table 4. The best yield of our results was shown in
entry 3; a methylenation of 1.0 mmol of 2-tridecanone was proceeded in
96% yield in the presence of 2.0 mmol of TiCl and 0.1 mmol of
2
BF •OEt .
3
2
Various ketones were methylenated with Nysted reagent. Results were
summarized in Table 5. The Nysted reagent system is superior to Wittig
reagent especially in the case of easily enolizable carbonyl compounds.
Cyclopentanone derivative (entry 5) and tetralone derivatives (entry 3,4)
were methylenated with Nysted reagent under the reaction conditions
described above. An optically active ketone possessing a stereogenic
center at the α-position 2l was converted into the methylenated product
3l without epimerization.
Scheme 2
Since methylenation of a keto aldehyde proceeded chemoselectively on
aldehyde under BF -catalyzed conditions (entries 5,6 in Table 2), both
3
aldehyde and ketone were methylenated by TiCl -mediated conditions.
2
Scheme 3
Typical Procedure for Methylenation
Under Ar atmosphere, 2.3 g of Nysted reagent (20 wt.% suspension in
THF, 1.0 mmol), purchased from Aldrich, was weighed and 3 ml of
THF was added at 0 °C. Before weighing, the bottle of Nysted reagent
was shaken well. A solution of BF •OEt (0.14 g, 0.1 mmol) in THF (2
3
2
ml) was added and the resulting mixture was stirred at 0 °C for 5 min. A
THF solution of benzaldehyde (0.11 g, 1.0 mmol) was added at 0 °C,
and the mixture was stirred for 2 h at 18 °C. The resulting mixture was
poured into aq 1 M HCl and extracted with hexane. The combined
organic layers were dried over Na SO , and concentrated. The styrene
2
4
was obtained in 96% yield. In the case of titanium mediated reactions in
Table 3-5, a suspension of TiCl or TiCl (as indicated in Table) in THF
3
2
was added into a mixture of Nysted reagent and BF •OEt in THF, just
3
2
before an addition of carbonyl compounds. In the case of TiCl , neat
4
TiCl
was added into a THF suspension of Nysted reagent without
4
just before an addition of carbonyl
BF •OEt as shown in Table 3,
3
2
Figure 2
compounds
.

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315
Acknowledgement: This work is supported by the Ministry of
Education, Science and Culture (Grant in Aid, #09231223, #09238221)
(6) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.,
1978, 2417; Hibino, J.-I.; Okazoe, T.; Takai, K.; Nozaki, H. ibid.,
1986, 26, 5579 and 5581; Lombardo, Org. Synth. 1987, 65, 81.
(7) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem.,
1987, 52, 4410; Takai, K.; Kataoka, Y.; Miyai, J.; Okazoe, T.;
Oshima, K.; Utimoto, K. Org. Synth. 1996, 73,73.
References and Notes
(1) Maercker, A. Org. React.. 1965, 14, 270; Maryanoff, B. E.; Reits,
A. B. Chem. Rev., 1989, 89, 863.
(8) The Nysted reagent (L. N. Nysted, US Patent 3 865 848, 1975;
Chem. Abstr. 1975, 83, 10406q) is commercially available from
Aldrich Co. Preparation of the Nysted reagent uses zinc-lead
couple or zinc activated with hydrochloric acid.
(2) Schrock, R. R.; Depue, R. T.; Feldman, J.; Yap, K. B.; Yang, D.
C.; Davis, W. M.; Park, L.; Dimare, M.; Schofield, M.; Anhaus,
J.; Walborsky, E.; Evitt, E.; Kruger, C.; Betz, P. Organometallics,
1990, 9, 2262.
(9) Tochtermann,W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E-M.,
Peters, K.; von Schnering, H. G. Tetrahedron, 1995, 51, 1623 ;
Gleiter, R.; Herb, T.; Hofmann, J. Synlett, 1996, 987.
(3) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.,
1978, 100, 3611; Clawson, L.; Buchwald, S. L.; Grubbs, R. H.
Tetrahedron Lett., 1984, 25, 5733.
(10) The data also indicated that commercial Nysted reagent keeps
original concentration.
(4) Petasis, N. A.; Browej, E. I. J. Am. Chem. Soc., 1990, 112, 6392;
Petasis, N. A.; Browej, E. I. J. Org. Chem., 1992, 57, 1327;
Petasis, N. A.; Staszewski, J. P.; Fu, D. K. Tetrahedron Lett.,
1995, 36, 3619.
(11) Purity was determined by glc using chiral column; Chrompack,
CP-Chiralsil-DexCB, 25 m x 0.25 mm.
(12) Narula, S. P.; Sharma, H. K. Inorg. Syn., 1985, 24, 181.
(5) Marek, I. ; Normant, J. F. Chem. Rev., 1996, 96,3241.