New, general, and practical preparation of methyl ketones via the direct coupling of amides with CH2CI2 promoted by TiCI 4/Mg

Article abstract of DOI:10.1021/ol8004326

The direct coupling of a variety of amides with CH₂CI ₂ or CD₂CI₂ promoted by TiCI₄/Mg/THF provides an extremely simple, practical, selective, and efficient approach for the construction of methyl ketones. The efficiency and practicability of this chemistry is illustrated by the very simple synthesis of deuterated methyl ketones.

Full text of DOI:10.1021/ol8004326

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1927-1930
New, General, and Practical Preparation
of Methyl Ketones via the Direct
Coupling of Amides with CH2Cl2
Promoted by TiCl4/Mg
Kuo-Wei Lin, Chi-Hui Tsai, I.-Lin Hsieh, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing UniVersity, Taichung 400, Taiwan,
Republic of China
thyan@mail.nchu.edu.tw
Received February 25, 2008
ABSTRACT
The direct coupling of a variety of amides with CH2Cl2 or CD2Cl2 promoted by TiCl4/Mg/THF provides an extremely simple, practical, selective,
and efficient approach for the construction of methyl ketones. The efficiency and practicability of this chemistry is illustrated by the very
simple synthesis of deuterated methyl ketones.
The importance of methyl ketones as building blocks for
further structural elaboration and the ease of access to
carboxylic acid derivatives make the conversion of the latter
into the former a useful transformation.1 Interest in the direct
elaboration of carboxylic acid derivatives into methyl ketones
continues to generate many exciting organometallic com-
plexes such as Me3Al/MeNHCH2CH2NHMe,2 MeLi,3
MeMgBr,4a MeMgBr/(Me2NCH2CH2)2O,4b R3SnCH2Li,5 and
Me2CuLi.6 However, the direct acylation of methyl-metal
reagents is often complicated by accompanying overaddition,
leading to the formation of tertiary alcohols, and suffers from
one or more experimental drawbacks such as use of
expensive or potentially unstable reagents, delicate reaction
conditions, and complicated procedures. In searching for a
new and practical strategy based upon the concept of simple
carbonyl-methylenation,7,8 we turned our attention to the
methylenation of amides since the resultant enamines would
be expected to react with water quite readily to give methyl
ketones (Scheme 1). Our development of a CH2Cl2-
TiCl4-Mg system for carbonyl-methylenation led to our
consideration of such a system for this process.8 Effecting
such methylenations by use of a highly nucleophilic meth-
ylene equivalent derived from the CH2Cl2-TiCl4-Mg
system may have the advantage of (1) enhancing synthetic
(1) For the acylation of organometallic reagents with carboxylic acid
derivatives to form ketones, see:
(2) (a) O’Neill, B. T. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991; Vol. 1,
pp 397-458. (b) Chung, E.-A.; Cho, C.-W.; Ahn, K. H. J. Org. Chem.
1998, 63, 7590.
(6) (a) Posner, G. H.; Whitten, C. E.; McFarland, P. E. J. Am. Chem.
Soc. 1972, 94, 5106. (b) Fex, T.; Froborg, J.; Magnusson, G.; Thoren, S. J.
(3) (a) Rubottom, G. M.; Kim, C.-W. J. Org. Chem. 1983, 48, 1550.
(b) Cooke, M. P., Jr. J. Org. Chem. 1986, 51, 951. (c) Evans, D. A.; DiMare,
M. J. Am. Chem. Soc. 1986, 108, 2476.
Org. Chem. 1976, 41, 3518
(7) (a) Pine, S. H.; Zahier, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270. (b) Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.;
Gallego, C. H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212
(8) (a) Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang, P.-C.
.
(4) (a) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett
1997, 1414. (b) Wang, X.-J.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy,
D.; Senanayake, C. H. Org. Lett. 2005, 7, 5593.
.
(5) Sato, T.; Matsuoka, H.; Igarashi, T.; Minomura, M.; Murayama, E.
J. Org. Chem. 1988, 53, 1207.
Org. Lett. 2004, 6, 4961. (b) Yan, T.-H.; Chien, C.-T.; Tsai, C.-C.; Lin,
K.-W.; Wu, Y.-H. Org. Lett. 2004, 6, 4965
.
10.1021/ol8004326 CCC: $40.75
Published on Web 04/12/2008
2008 American Chemical Society

Scheme 1
.
Synthesis of Methyl Ketones via Direct
Table 2. Results and Conditions of the Coupling of Various
Amine-Derived Cinnamamides with TiCl4-Mg-CH2Cl2
efficiency by not requiring expensive or potentially unstable
reagents and (2) extending the preparation to deuterated
methyl ketones via Ti-Mg-promoted CD2-transfer reactions
of CD2Cl2. We wish to report that such a TiCl4/Mg-promoted
coupling process may provide a new, general, and practical
approach for the construction of methyl ketones, R,R-
dideuteriomethyl ketones, and R,R,R-trideuteriomethyl ketones.
Table 1. Reaction Conditions for Elaboration of
Morpholine-Derived Amide 1a into Methyl Ketone 2a
entry reaction temp (°C) TiCl4/Mga (equiv) yield (%) of 2ab
a The reaction was performed on a 1 mmol scale. b Isolated yield.
1
2
3
4
5
6
7
0
25
0
0
0
1/4
1/4
1/8
15
14
75
80
82
85
83
2). Methylenation onto the pyrrolidine amide 1b was equally
effective (entry 1). Using the piperidine-derived amide 1c
also gave satisfactory results with CH2Cl2-Mg-TiCl4-THF
(entry 2). Switching from the heterocyclic amine-derived
amide to the acyclic amine-derived analogue 1d or 1e led to
equally gratifying results (entries 3 and 4) with formation
of methyl ketone 2a. In the case of sterically more bulky
amides 1f and 1g, applying the standard reaction conditions
led to coupling adduct 2a in less than 20% yield. Interest-
ingly, increasing the amount of THF dramatically improved
the methyl ketone formation, leading to smooth coupling to
give the desired ketone 2a in good yields (Table 2, entries
5 and 6).
Extension of these observations to other amides confirms
their generality. Variation of acyl structure was briefly
explored. Elaboration of the less reactive aromatic amide 3
into methyl ketone was equally effective (Table 3, entry 1).
Under the above conditions, Mg-TiCl4-promoted coupling
of 3 with CH2Cl2 gave acetophenone3a,10a in 71% yield. More
delightfully, this highly nucleophilic system also reacted
efficiently with either sterically demanding amide 4 or cyclic
amide 5. Thus, when 3:12 CH2Cl2/THF was used, either 4
or 5 reacted efficiently with CH2Cl2-Mg-TiCl4 to afford
the desired cyclohexyl methyl ketone4a,10b (75% yield) and
aminoheptanone 5a10c (82% yield), respectively (entries 2
and 3). To further demonstrate the scope of this methyl
ketone-forming methodology, the utility of this protocol was
2/8
1.2/8
1.5/8
0
0
5/30c
a The reaction was performed on a 1 mmol scale using 2 mL of THF.
b Isolated yield. c 5 mmol scale.
The reaction of a simple morpholine amide 1a with CH2Cl2
was chosen to test the feasibility of the process (Table 1).
After treatment of 1a with CH2Cl2, magnesium powder (4
equiv) and TiCl4 (1 equiv) at 0 °C for 1 h followed by
quenching with aqueous K2CO3, the desired methyl ketone
2a9 was indeed produced but only in less than 15%
completion after 1 h (entry 1), with starting material
remaining. Running the reaction at 25 °C failed to improve
the conversion (entry 2). As shown in Table 1, increasing
the amount of Mg and TiCl4 dramatically improved the
methyl ketone formation; the yield varying from 75% to 85%
(entries 3-6). More gratifyingly, the reaction directly scales
up; thus, 2a was obtained in 83% yield on a 5-mmol scale
using a 5 equiv of TiCl4 and 30 equiv of Mg (entry 7).
Adopting as a standard protocol exposure of a mixture of
1a (1 equiv) and THF in CH2Cl2 to Mg (8 equiv) and TiCl4
(1.5 equiv) in CH2Cl2 at 0 °C followed by treatment with
aqueous K2CO3 produced an 85% isolated yield of the
desired adduct 2a.
With conditions established to give excellent yield, we
explored the effect of the alkyl groups on nitrogen (Table
(10) (a) Grill, J. M.; Ogle, J. W.; Miller, S. A. J. Org. Chem. 2006, 71,
9291. (b) Pelter, A.; Smith, K; Elgendy,Said, M. A.; Rowlands, M
Tetrahedron 1993, 49, 7104. (c) Honda, T.; Ishikawa, F. J. Chem. Soc.,
Chem. Commun. 1999, 1065.
(9) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935.
1928
Org. Lett., Vol. 10, No. 10, 2008

Table 3. TiCl4-Mg-CH2Cl2 System for Elaboration of Various
Amides into Methyl Ketones
Scheme 2
.
Conversion of Amides into Deuterated Methyl
Ketone
group in 11, effecting selective elaboration of the less
electrophilic carbamoyl group into acetyl group (entry 9).
Thus, exposing morpholine amide 11 to 1.5 equiv of TiCl4
and 8 equiv of Mg produced the keto ester 11a12 in 82%
isolated yield.
The widespread utility of deuterium-labeled compounds
in research13,14 make their easy availability by synthesis
important. To further demonstrate the synthetic utility of this
protocol, a synthesis of deuterated methyl ketones 2b,c was
carried out (Scheme 2).
Scheme 3. Synthesis of Dideuteriomethyl and Trideuteriomethyl
Ketones via Coupling of Amides with CD2Cl2
a Coupling reaction was performed on a 1 mmol scale using 1.5 mmol
of TiCl4 and 8 mmol of Mg. b Isolated yield. c Coupling reaction was
performed with 0.5 mmol of substrate.
examined in the elaboration of chiral diamide 6 into diketone.
Reacting tartaric acid-derived diamide
6
with
CH2Cl2-Mg-TiCl4 complex proceeded smoothly, resulting
in a 81% yield of the desired diketone6a11 without danger
of racemizations (entry 4).
The chemoselectivity was explored with a series of amides
as summarized in Table 3, entries 5-9. As expected, acetal,
sulfide, alkene, and alkyne have no effect (entries 5-8). A
particularly interesting example illustrating the chemoselec-
tivity of this process is the coupling of dicarbonyl compound
11 with CH2Cl2. Surprisingly, CH2Cl2-Mg-TiCl4 system
can discriminate between carbamoyl and tert-butoxycarbonyl
Performing the Ti-Mg-promoted CD2-transfer reaction of
CD2Cl2 in toluene to maintain homogeneity allowed the use
of 3 equiv of CD2Cl2. Thus, direct coupling of amide 1a
with CD2Cl2 at 0 °C followed by the normal hydrolysis with
(13) For reviews, see:(a) Junk, T.; Catallo, W. J. Chem. Soc. ReV. 1997,
26, 401. (b) Elander, N.; Jones, J. R.; Lu, S.-Y.; Stone-Elander, S.; Koike,
Y Chem. Soc. ReV. 2000, 29, 239.
(14) (a) Lienhard, G. E.; Wang, T.-C J. Am. Chem. Soc. 1969, 91, 1146.
(b) Furuta, T.; Takahashi, H.; Kasuya, Y J. Am. Chem. Soc. 1990, 112,
3633. (c) Gardner, K. H.; Kay, L. E. J. Am. Chem. Soc. 1997, 119, 7599.
(11) Prasad, K.; Chandrakumar, A. Synthesis 2006, 2159
.
(12) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912
.
Org. Lett., Vol. 10, No. 10, 2008
1929

H2O produced a 75% yield of a mixture of R,R-dideuterio
ketone,2b monodeuterio ketone, and 2a in a 91.2:8.3:0.5 ratio
as determined by 1H NMR spectroscopy. Similarly, quench-
ing the coupling adducts with D2O afforded a 74% yield of
a >93:7 ratio of R,R,R-trideuterio ketone 2c to R,R-dideuterio
ketone 2b. Scheme 3 provides further examples of the
selective elaboration of amides 4 and 11 into dideuteriom-
ethyl ketones and trideuteriomethyl ketones.
This TiCl4/Mg-promoted coupling of amides with CH2Cl2
or CD2Cl2 represents an extremely practical, and general
approach for the construction of methyl ketones.15 Not only
is this titanium methylene complex highly nucleophilic, but
it also seems highly selective and might become a practical
methylenation reagent applicable to large-scale synthesis. The
efficiency and practicability of this chemistry is illustrated
by the very simple synthesis of deuterated methyl ketone.
The novel nucleophilicity involved suggested several intrigu-
ing directions which are currently under active investigation.
(15) The following procedure for the synthesis of 4-phenyl-2-butanone
2a is illustrative. To a 0 °C suspension consisting of Mg (192 mg, 8 mmol)
and TiCl4 (1.5 mmol, 1 M in CH2Cl2, 1.5 mL) in CH2Cl2 (4 mL) was added
over a 2 min period a solution of amide 1a (219 mg, 1 mmol) in CH2Cl2
(5 mL) and THF (2 mL). After being stirred for 1 min at 0 °C, the resulting
green-black mixture was stirred for an additional 1 h at 0 °C. Saturated
potassium carbonate solution (10 mL) was added, and the mixture was
diluted with CH2Cl2 (25 mL). The organic layer was separated, dried,
evaporated, and purified by flash chromatography on silica gel (elution with
1:15 ethyl acetate-hexane) to give 2a (126 mg, 85% yield) as a colorless
oil. See the Supporting Information for characterization. In the case of
aromatic amide 3, treatment under the above conditions gives the desired
acetophenone 3a as well as the intermediate enamine (olefinic signals at δ
4.31 and 4.17). For 3, a standard operating procedure which involved adding
H2O or potassium carbonate solution to the green-black mixture followed
by stirring at 0-25 °C for 2-3 h was adopted.
Acknowledgment. We thank the National Science Council
of the Republic of China for generous support.
Supporting Information Available: Experimental pro-
1
cedures and spectral data, including copies of H and 13C
NMR spectra for 2b,c, 4b,c, and 11b,c. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 10, No. 10, 2008