Dichloromethane activation. Direct methylenation of ketones and aldehydes with CH2Cl2 promoted by Mg/TiCl4/THF

Article abstract of DOI:10.1021/ol0478887

(Chemical Equation Presented) This Mg-TiCl₄-promoted CH ₂-transfer reaction of CH₂Cl₂ represents an extremely simple, practical, and efficient methylenation of a variety of ketones and aldehydes, especially in enolizable or sterically hindered ketones such as 2,2-dimethylcyclohexanone, camphor, and fenchone.

Full text of DOI:10.1021/ol0478887

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4961-4963
Dichloromethane Activation. Direct
Methylenation of Ketones and
Aldehydes with CH2Cl2 Promoted by
Mg/TiCl4/THF
Tu-Hsin Yan,* Chia-Chung Tsai, Ching-Ting Chien, Chia-Ching Cho, and
Pei-Chen Huang
Department of Chemistry, National Chung-Hsing UniVersity,
Taichung 400, Taiwan, Republic of China
thyan@mail.nchu.edu.tw
Received October 12, 2004
ABSTRACT
This Mg−TiCl4-promoted CH2-transfer reaction of CH2Cl2 represents an extremely simple, practical, and efficient methylenation of a variety of
ketones and aldehydes, especially in enolizable or sterically hindered ketones such as 2,2-dimethylcyclohexanone, camphor, and fenchone.
The interest in the methylenation of carbonyl compounds,
which developed strongly after the discovery of the Wittig
reagents, continues to generate many exciting diverse meth-
ylenation reagents. Among such reagents, titanium methylene
complexes (Tebbe-type reagents) such as Tebbe’s reagent,1a
Grubbs’ titanacyclobutane,1b CH2I2- or CH2Br2-TiCl4-zinc
(cat. lead) reagent,2 and dimethyltitanocene3 have proven to
be extraordinarily useful. To our knowledge, no metal-
induced methylenations, wherein CH2Cl2 (DCM) serves as
a CH2 partner, have been recorded. The significant limitation
on the broad utility of CH2Cl2 often arises from its extreme
stability, and this makes it a very common solvent in organic
reactions. Effecting the insertion into the unactivated C-Cl
bond may require highly reactive bimetallic species. In this
paper, we wish to record the critical role electron-pair-donor
additives play in determining the efficiency of Mg-TiCl4
in C-Cl bond activation and the first examples of the
equivalent of a CH2 transfer reaction of CH2Cl2 mediated
by Mg-TiCl4. Considering DCM’s inertness in either Mg-
(Hg),4 Li,5 or low-valent titanium-promoted addition reac-
tions, such an observation opens up fundamental questions
of the importance of bimetallic complexes (intermetallics)
like [TiMgClx] for olefination of carbonyl compounds.
The methylenation of adamantanone 1a with CH2Cl2 was
chosen to test the feasibility of the process. When 1a and
CH2Cl2 are treated with magnesium powder (4 equiv) and
TiCl4 (1 equiv) at room temperature or reflux, nothing
happens. Remarkably, simply adding THF (2 mL) to the
original system at 0 °C led to methylenation to give
methyleneadamantane 2a in 56% yield with starting material
remaining (Table 1, entry 1). Increasing the amount of TiCl4
(1) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611. (b) Pine, S. H.; Zahier, R.; Evans, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 1980, 102, 3270.
(2) (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1978, 19, 2417. (b) Lombardo, L. Org. Synth. 1987, 65, 81. (c) Hibino, J.;
Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 26, 5581. (d)
Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59,
2668
(4) (a) Bertini, F.; Grasselli, P.; Zubiani, G.; Cainelli, G. Tetrahedron
1970, 26, 1281. (b) van de Heisteeg, B. J. J.; Schat, G.; Akkerman, O. S.;
Bickelhaupt, F. J. Organomet. Chem. 1985, 308, 1.
(5) Barluenga, J.; Fernandez-Simon, J. L.; Concellon, J. M.; Yus, M. J.
Chem. Soc., Chem. Commun. 1986, 1665.
(3) Petasis, N. A.; Bzoweej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
10.1021/ol0478887 CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/03/2004

Scheme 1. CH2Cl2 Activation Promoted by MgTi-Bimetallic
Table 1. Effect of Various EPD Additives on the
Methylenation of Adamantanone 1a
Complexes
yieldb (%)
EPD
additive
methoda conv
TiCl4/Mg (%)
run
1
2a 2-adamantanol
Having established the feasibility of the methylenation,
its generality with respect to the structure of the ketones was
established. Reaction of tert-butylcyclohexanone 1b with
CH2Cl2 using method A gave a 81% yield of the methyl-
enation product 2b (Table 2, entry 1). The aromatic ketone
1c also gave satisfactory results with CH2Cl2-Mg-TiCl4
complex. Thus, using a 4:8 TiCl4-Mg ratio, a 70% yield of
2c was obtained (entry 2). Due to the nonbasic conditions,
enolizable ketones also proved to be a satisfactory trap. Thus,
either 2-indanone or â-tetralone reacted effeciently with CH2-
Cl2-derived methylenation reagent to give the desired meth-
ylenation products 2d (84%) and 2e (79%), respectively
(entries 3 and 4).11 To further demonstrate the scope of this
methylene-forming methodology, the utility of this protocol
was examined in the methylenation of sterically demanding
ketones. Thus, reacting 2,6-dimethylcyclohexanone 1f with
CH2Cl2-Mg-TiCl4 complex using method A produced the
methylenecyclohexane 2f in 85% isolated yield (Table 2,
entry 5). Interestingly, using method B led to a slightly
increased yield of 87%. A dramatic illustration is the
comparison between Tebbe-Grubbs reagents and CH2Cl2-
Mg-TiCl4 complex wherein the former fails to effect
methylenation of 2,2-dimethylcyclohexanone1g12 but the
latter gives 2,2-dimethylmethylenecyclohexane 2g in 83%
isolated yield. Surprisingly, increasing the degree of steric
hindrance at the carbonyl group does not impede methyl-
enation. Thus, methylenation with camphor under the
standard conditions with CH2Cl2-Mg-TiCl4 gave a 61%
yield of 2h (entry 7). Notably, performing the same reaction
using method B but increasing the amount of TiCl4 increased
the yield to 74%. This methylenation reagent is also suitable
for the methylenation of a variety of camphor derivatives
bearing the carboxylic functional groups, which often
interferes with methylenation of ketones (vide infra). More
dramatically, in contrast to Tebbe-Grubbs reagents,12 the CH2-
Cl2-Mg-TiCl4 complex reacted efficiently even with the
extremely hindered fenchone, containing a carbonyl group
adjacent to two quaternary carbon atoms, to give the desired
alkene 2i in a remarkable 90% yield (Table 2, entry 8).
Considering that the previous methylenation of unreactive
fenchone, which is unaffected by methylenetriphenylphos-
phorane itself at temperatures up to 50 °C, involves activation
of methylenetriphenylphosphorane by reaction with tert-
butyllithium,13 this convenient procedure represents an
attractive alternative.
THF
A (1:4)
A (2:8)
B (2:8)
A (2:8)
B (2:8)
A (2:8)
B (2:8)
A or B
(2:8)
69
100
95
100
95
56
86
76
54
41
22
12
∼6
∼6
12
28
32
28
0
2
3
4
5
DME
pyridine
Et2O
58
55
0-38 0-30
NEt3, CH3CN,
1,4-dioxane,
furan, TMEDA
A or B
(2:8)
0
-
a Method A: To a solution of 2 mmol of TiCl4 and 8 mmol of magnesium
powder in 2 mL of CH2Cl2 at 0 °C was added a solution of admantanone
(1 mmol) in 3-4 mL of CH2Cl2 and 2 mL of EPD additive. Method B: A
solution of EPD additive (2 mL), CH2Cl2 (2 mL), TiCl4 (2 mmol), and Mg
(8 mmol) was stirred at 0 °C for 20 min prior to the addition of carbonyl
compound. b Isolated yield.
and Mg led to complete consumption of starting material
within 1 h. Thus, addition of a THF-CH2Cl2 solution of 2a
(1 equiv) to a mixture of TiCl4 (2 equiv) and magnesium
powder (8 equiv) in CH2Cl2 at 0 °C gave the desired
methyleneadamantane 2a (86% isolated yield, method A)
in addition to a trace of the reduction product readily
identified as adamantanol by its spectroscopic properties. On
the other hand, stirring the THF-CH2Cl2 solution of TiCl4-
Mg at 0 °C for 20 min (method B) prior to the addition of
adamantanone gave a slightly diminished yield of 76%. Other
electron-pair-donor (EPD) additives including DME and
pyridine gave unsatisfactory results (entries 2-3). Switching
the additive to ether, NEt3, acetonitrile, 1,4-dioxane, furan,
or TMEDA also proved undesirable (entries 4 and 5). THF
appears to be a good choice as an additive to effect
methylenation of CH2Cl2 to the carbonyl group of 1a. The
complexation of TiCl4 with THF molecules through het-
eroatoms seems to assist in the initial metals insertion
reactions. The reaction is best envisioned as involving
interception of a presumed (THF)n-TiCl4 complex by the
magnesium powder to give active bimetallic[Ti-Mg-Clx-
(THF)n]6 complex followed by methylene coordinated to both
the titanium and magnesium to generate a presumed [Ti-
CH2-Mg-Clx-(THF)n] complex (Scheme 1).7-10
(6) Aleandri, L. E.; Bogdanovic, B.; Gaidies, A.; Jones S. Liao, D. J.;
Michalowicz, A.; Roziere, J.; Schott, A. J. Organomet. Chem. 1993, 459,
87.
(7) To explore what role, if any, the low-valent titanium reagents played
in facilitating methylenation reagent formation, we have examined a variety
of low-valent titanium compounds such as TiCl3, Ti (II) species,8 Ti(I)
species,9 and Ti(0).9a,10 However, these reagents do not effect coupling with
CH2Cl2 in the presence of THF.
(8) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S. J. Org. Chem.
1976, 41, 260.
(9) (a) Dams, R.; Malinowski, M.; Westdorp, I.; Geise, H. J. J. Org.
Chem. 1982, 47, 248. (b) Lenoir, D. Synthesis 1989, 885.
(10) McMurry, J. E.; Fleming, M. P. J. Org. Chem. 1976, 41, 896.
(11) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281.
(12) Clawson, L.; Buchwald, S. L.; Grubbs, R. H. Tetrahedron Lett. 1984,
25, 5733.
(13) Corey, E. J.; Kang, J.; Kyler, K. Tetrahedron Lett. 1985, 26, 555.
4962
Org. Lett., Vol. 6, No. 26, 2004

summarized in Table 2. As expected, esters, amides, acids,
and sulfonyl group were completely unaffected. The latter
is particularly noteworthy since rapid reduction of sulfones
to sulfides at low temperatures had been noted with titanium-
(II) reagent previously.14 The broad scope of this methyl-
enation is illustrated by the tolerance of ketal (entry 14).
Aldehydes, which are particularly prone to reduction to give
alcohols, can also lead to good chemoselectivity by changing
the amount of Mg-TiCl4. Thus, in the reaction of hydro-
cinnamaldehyde with CH2Cl2 using 4 equiv of TiCl4 and 8
equiv of Mg, alcohol formation was suppressed and a 8:1
ratio of methylenation vs reduction products was isolated in
71% yield (entry 15). For the methylenation of piperonal,
use of 5 equiv of TiCl4 and 10 equiv of Mg proves most
satisfactory, giving an 83% yield of a 10:1 ratio of methyl-
enedioxystyrene to piperonol (entry 16). In each aldehyde-
methylenation, about 5% of the minor pinacol coupling
product formed under these conditions.
Table 2. Methylenation via Activation of CH2Cl2
The ability to elaborate CH2Cl2 into an unusual titanium
methylene complex via Mg-Ti bimetallic complex (inter-
metallic) promoted oxidative addition of the unactivated
C-Cl bond should prove to be a particularly valuable
strategy. This Mg-TiCl4-promoted CH2-transfer reaction of
CH2Cl2 represents an extremely simple, practical, and
efficient methylenation of a variety of ketones and aldehydes,
especially in the case of enolizable or sterically hindered
ketones. These observations suggest that there may be a
wealth of intermetallic species-promoted reactions of CH2-
Cl2 yet to unfold and that the THF-TiCl4 complex appears
to be just tight enough to accelerate reaction with Mg leading
to highly active [TiMgClx(THF)n] intermetallic species.15
While further mechanistic work is clearly required, the
efficiency of this chemistry opens an opportunity of utilizing
this strategy for other members of this class such as
dichlorides and trichlorides.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for generous support.
Supporting Information Available: Experimental pro-
cedures and spectra data for 2d-e,g,i-o. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. b Plus 8% dimerization product derived from ketone.
c Plus <5% reduction product derived from ketone. d Plus ∼8% reduction
product derived from ketone. e Reduction product (8%) and 4-phenyl-2-
butanol (22%) were produced as byproducts.
OL0478887
(14) Akgun, E.; Mahmood, K.; Mathis, C. A. J. Chem. Soc., Chem.
Commun. 1994, 761.
(15) For [Ti(MgCl)2(THF)n]-catalyzed cleavage of ethers, see: (a)
Bartmann, E. J. Organomet, Chem. 1985, 284, 149. (b) Kadam, S. M.;
Nayak, S. K.; Banerji, A. Tetrahedron Lett. 1992, 33, 5129.
The chemoselectivity was explored with sulfonyl ketone
(entry 9) and a series of keto carboxylates (entries 9-13) as
Org. Lett., Vol. 6, No. 26, 2004
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