Dichloromethane as an unusual methylene equivalent. A new entry of highly nucleophilic and selective titanium-methylene complexes for ester methylenation

Article abstract of DOI:10.1021/ol047887e

(Chemical Equation Presented) The successful application of CH ₂Cl₂-Mg-TiCl₄-system mediated methylenation of various esters such as tert-butyl ester and 2,5-cyclohexadiene-1-carboxylate highlights the extraordinary reactivity, selectivity, and the nonbasic nature of this new methylene-carbenoid, which serves as a practical reagent applicable to large-scale synthesis.

Full text of DOI:10.1021/ol047887e

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4965-4967
Dichloromethane as an Unusual
Methylene Equivalent. A New Entry of
Highly Nucleophilic and Selective
Titanium−Methylene Complexes for
Ester Methylenation
Tu-Hsin Yan,* Ching-Ting Chien, Chia-Chung Tsai, Kuo-Wei Lin, and
Yen-Hsien Wu
Department of Chemistry, National Chung-Hsing UniVersity,
Taichung 400, Taiwan, Republic of China
thyan@mail.nchu.edu.tw
Received October 12, 2004
ABSTRACT
The successful application of CH2Cl2−Mg−TiCl4-system mediated methylenation of various esters such as tert-butyl ester and 2,5-cyclohexadiene-
1-carboxylate highlights the extraordinary reactivity, selectivity, and the nonbasic nature of this new methylene−carbenoid, which serves as
a practical reagent applicable to large-scale synthesis.
Tebbe-type carbene complexes such as Cp2TiCl2-AlMe3,1
Cp2TiMe2,2 and TiCl2-CH2(ZnI)2-TMEDA3 have been
reported to effect methylenation of esters. However, their
generation suffers from one or more experimental drawbacks,
such as use of expensive or potentially unstable reagents,
delicate reaction conditions, and complicated procedures.
Therefore, the search for a new entry of titanium methylene
complexes, which are highly nucleophilic and available in
bulk at a low price, continues to stimulate much thought from
a synthetic point of view.4 Both CH2Br2- and CH2I2-Zn
(cat. lead)-TiCl4 systems have participated in normal
methylenation of ketones or aldehydes; however, these
processes do not generally extend to esters even in the
presence of TMEDA.3,4a,b,5 The reasons stem from the low
nucleophilic nature of the systems. Believing an inorganic
Grignard reagent6 might be more reactive than a titanium-
zinc bimetallic species, we turned to Mg-TiCl4 bimetallic
complex (intermetallic) promoted methylene-transfer process.
Earlier work in our laboratories established that methylena-
tion of sterically hindered ketones such as 2,2-dimethylcy-
(4) For some examples of alkylidenation of ester carbonyl groups, see:
(a) Clift, S. M.; Schwartz, J. J. Am. Chem. Soc. 1984, 106, 8300. (b) Okazoe,
T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1987, 52, 4410. (c)
Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59,
2668. For some examples of ester-methylenation using the Takai protocol,
see: Cox, J. M.; Rainier, J. D. Org. Lett. 2001, 2919. Postema, M. H. D.;
Piper, J. L. Org. Lett. 2003, 1721. (d) Takeda, T.; Sasaki, R.; Fujiwara, T.
J. Org. Chem. 1998, 63, 7286.
(5) For some other examples of ketone methylenation promoted by metals
such as Mo and B, see: (a) Kauffmann, T.; Ennen, B.; Sander, J.;
Wieschollek, R. Angew. Chem., Int. Ed. Engl. 1983, 22, 244. (b) Pelter,
A.; Singaram, B.; Wilson, J. W. Tetrahedron Lett. 1983, 24, 635.
(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. (c) Cannizzo, L. F.; Grubs, R. H. J.
Org. Chem. 1985, 50, 2316. (d) Pine, S. H.; Petti, R. J.; Geib, G. D.; Cruz,
S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50,
1212.
(2) Petasis, N. A.; Bzoweej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(3) Matsubara, S.; Ukai, K.; Mizuno, T.; Utimoto, K. Chem. Lett. 1999,
825.
10.1021/ol047887e CCC: $27.50
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clohexanone and fenchone was possible with the CH2Cl2-
Mg-TiCl4-THF system.7 We envisioned the feasibility of
a direct coupling of esters with CH2Cl2 promoted by Mg-
Ti-intermetallic. In this paper, we report the critical role
that the amount of magnesium relative to titanium chloride
plays in enhancing the activity of titanium methylene
complexes and the success of this goal which resulted in a
practical and selective approach to vinyl ethers.
Table 2. Methylenation of Esters with CH2Cl2/TiCl4/Mg/THF
Initial studies centered on a simple methyl ester 1a (Table
1). When 1a and CH2Cl2 were treated with magnesium
Table 1. Reaction Conditions for Methylenation of Ester 1a
isolated yield (%)
reaction
temp (°C)
TiCl4/Mg
(equiv)
entry
1a
2a
1
2
3
4
5
6
7
8
0-25
25
0-25
25
0-25
25
25
1:4
1:4
1:6
1:6
1:8
1:8
2:6
2:8
91
78
84
65
63
15
51
0
∼9
22
16
35
37
85
49
94
25
powder (4 equiv) and TiCl4 (1 equiv) at 0-25 °C, 2a was
indeed produced but only in less than 10% conversion after
1 h (entry 1).
As the data in Table 1 show, performing the reaction at
25 °C showed more conversion of 1a to 2a (entries 1-2,
3-4, and 5-6). Most revealing was the effect of the amount
of Mg relative to titanium chloride on this process. Increasing
the amount of Mg dramatically improved the vinyl ether
formation, the yield varying from 22% to 85% (entries 2
and6). Adopting as a standard ptotocol exposure of a mixture
of 1a (1 equiv) and THF in CH2Cl2 to Mg (8 equiv) and
TiCl4 (2 equiv) in CH2Cl2 at 25 °C, followed by treatment
with aqueous K2CO3, produced a 94% isolated yield of the
desired vinyl ether 2a (entry 8). The methyl keto ester 1b
gave an analogous result. Use of a 2:8 TiCl4/Mg ratio effects
complete methylenation of both ketone and ester carbonyl
groups as illustrated in entry 2 wherein the olefin 2b was
obtained in 92% yield (Table 2, entry 1). Variation of alkoxy
size was briefly explored. Methylenation onto the ethyl ester
1c was equally effective (entry 2). Notably, the isopropyl
substrate 1d also gave satisfactory results with CH2Cl2-Mg-
TiCl4-THF (entry 3). Switching the ester from alkyl to
a Isolated yield. b Plus ∼45% olefin isomerization products derived from
2f. c Yield obtained by performing reaction in toluene/THF. d Plus ∼20%
hydrolysis product derived from 2h. e 10 mmol scale. f Plus recovered
starting ester 1o (40%) and 4-phenyl-2-butanone (10%) derived from
hydrolysis of 2o.
phenyl had little effect (entry 4). The methylenation product
2e was obtained in 90% yield. Methylenation with dihydro-
coumarin 1f (entry 5) under the standard conditions gave a
40% yield of methylenechroman 2f in addition to two internal
alkenes derived from isomerization of 1f.8 Using a 1:1
toluene/THF mixture as solvent, isomerization of exo-
methylene vinyl ether 2f was suppressed and 2f was isolated
(6) For some examples of novel inorganic Grignard reagents, see: (a)
Aleandri, L. E.; Bogdanovic, B.; Gaidies, A.; Jones S. Liao, D. J.;
Michalowicz, A.; Roziere, J.; Schott, A. J. Organomet. Chem. 1993, 459,
87. (b) Kornowski, A.; Giersig, M.; Vogel, R.; Chemseddine, A.; Weller,
H. AdV. Matter. 1993, 5, 634. (c) Dams, R.; Malinowski, M.; Westdorp, I.;
Geise, H. J. J. Org. Chem. 1982, 47, 248. (d) Sobota, P.; Jezowska-
Trzebiatowska, B. Coord. Chem. ReV. 1978, 26, 71.
(8) In the case of benzyl formate as substrate, the desired benzyl viny
ether was found to be admixed with significant amounts (>75%) of benzyl
alcohol derived from viny ether hydrolysis.
(7) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C. Org.
Lett. 2004, 6, 4961.
4966
Org. Lett., Vol. 6, No. 26, 2004

in 82% yield. The utility of allyl vinyl ethers as easy
precursors of γ,δ-unsaturated carbonyl compounds led to our
examination of 2-cyclohexenyl ester 1g (entry 6), which
participated equally well, giving the desired allyl vinyl ether
2g in 75% yield. With an eye to extending these observations
to other less reactive carboxylic esters, we explored the
methylenation of aromatic ester with CH2Cl2. Fortunately,
exposing methyl p-tert-butylbenzoate 1h (entry 7) to the CH2-
Cl2-Mg-TiCl4-THF system led to smooth methylenation
to give the desired vinyl ether 2h in 70% isolated yield.
Methylenation onto ethyl benzoate was equally effective
(entry 8). The methylenation product 2i was obtained in 85%
yield. More gratifyingly, the reaction directly scales up; thus,
ethyl vinyl ether 2j (entry 9) was obtained in 87% yield on
a 10-mmol scale using a 15 equiv of TiCl4 and 60 equiv of
Mg. Notably, decreasimg the amount of Mg led to incomplete
methylenation of 1jspresumably the collapse of titanium-
methylene complex to its precursor is competitive with its
methylene transfer to the ester carbonyl group. On the other
hand, using the 2-cyclohexenyl benzoate 1k also gave
satisfactory results (entry 10) wherein the allyl vinyl ether
2k was obtained in 78% yield. Surprisingly, applying the
standard reaction condition to sterically more bulky isopropyl
benzoate 1l led to methylenation product in only 10% yield
(entry 11). Interestingly, decreasing the amount of TiCl4 to
1.2 equiv significantly increased the yield to 66%.
A dramatic illustration of the utility of this protocol was
the methylenation of 2,5-cyclohexadiene-1-carboxylate 1m
(entry 12), which by virtue of the sensitivity of the poly-
unsaturation within a small molecular framework demands
very mild methods. Most delightfully, performing the me-
thylenation at ambient temperature led to complete consump-
tion of starting material within 2 h to give the desired vinyl
ether 2m in excellent yield. None of the olefin isomerization
product could be detected by 400 MHz 1H NMR. Changing
the ester to benzyl ester 1n or isopropyl ester 1o led to
equally gratifying result (entries 13 and 14) with formation
of vinyl ethers 2n and 2o.9 The ability to effect such a
methylenation even in the presence of an active methine
hydrogen highlights the nonbasic nature of this new titanium
methylene complex. On the other hand, steric hindrance does
play a role. Thus, tert-butyl ester 1p fails to react under the
standard conditions. Remarkably, increasing the amount of
Mg by going from 8 to 12 equiv dramatically enhances the
nucleophilicity of this new titanium methylene complex.
Thus, using a 1:12 TiCl4/Mg ratio proves most satisfactory,
giving a 50% yield of vinyl ether 2p (entry 15) with starting
material remaining (82% yield based upon recovered starting
material). It should be noted that there is an optimum equiv
of Mg above which no further improvement pertains. While
further mechanistic work is clearly required, such steric
factors may provide good chemoselectivity with diesters.
The chemoselectivity was briefly explored with a series
of esters as summarized in Table 3. As expected, exposure
Table 3. Selectivity in CH2Cl2-TiCl4-Mg System Mediated
Methylenation of Diesters at 0-25 °C
1
a Isolated yields; ratios determined by 400 MHz H NMR.
of a mixture of ethyl ester 1q and tert-butyl ester 1p to a 1
equiv of TiCl4 and 8 equiv of Mg in CH2Cl2/THF produced
exclusively the ethyl vinyl ether 2q (Table 3, entry 1). The
isopropyl substrate gave an analogous result in the presence
of tert-butyl ester, as in the methylenation of a mixture of
1d and 1p (entry 2). A particularly interesting example
illustrating the chemoselectivity of this process is the
methylenation of a mixture of aliphatic and aromatic esters
(entries 3 and 4). The preference (>12:1) for methylenation
of an aliphatic ester highlihgts the chemoselectivity of the
process.
The successful application of the Mg-TiCl4-promoted
CH2 transfer to a variety of ester carbonyl groups illustrates
the extraordinary reactivity of this new titanium methylene
complex. Not only is this CH2Cl2-Mg-TiCl4 system highly
nucleophilic but it also seems highly selective and might
become a practical methylenation reagent applicable to large-
scale synthesis. This method constitutes the first report that
CH2Cl2 can be directed to serve as a highly nucleophilic
methylene equivalent in methylenation of esters. The novel
nucleophilicity involved suggested several intriguing direc-
tions which are currently under active investigation.
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 2b,e-g,k,n,p. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) New compounds have been characterized spectroscopically.
OL047887E
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