A new entry to 1,5-keto esters and their 4,4-dideuterio derivatives via methylene chloride as methylene dianion equivalents

Article abstract of DOI:10.1021/jo800732s

(Chemical Equation Presented) This TiCl₄-Mg promoted multicomponent coupling of various amides with CH₂Cl₂ and methyl acrylate represents an extremely simple and practical synthesis of 1,5-keto esters. The efficiency of this chemistry is illustrated by the very simple preparation of unusual 4,4-dideuterio- 1,5-keto esters.

Full text of DOI:10.1021/jo800732s

SCHEME 1. Retrosynthesis of 1,5-Keto Esters
A New Entry to 1,5-Keto Esters and Their
4,4-Dideuterio Derivatives via Methylene
Chloride as “Methylene Dianion” Equivalents
Kuo-Wei Lin, Cheng-Yih Chen, Wei-Fan Chen, and
Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing UniVersity,
Taichung 400, Taiwan, Republic of China
thyan@mail.nchu.edu.tw
ReceiVed April 2, 2008
TABLE 1. Reaction Conditions for a Multicomponent Coupling of
Amide 1a with CH2Cl2 and Methyl Acrylate
rxn. temp
(°C)
time
(h)
TiCl4/Mga
(equiv)
NEt3
(equiv)
yield (%)
entry
of 2ab
1
2
3
4
5
6
7
0
25
0
25
0
3
12
3
3
3
1.5/8
1.5/8
1.5/8
1.5/8
1.5/8
2.0/8
6/35c
0
0
3
3
6
∼15
∼15
75
74
74
This TiCl4-Mg promoted multicomponent coupling of
various amides with CH2Cl2 and methyl acrylate represents
an extremely simple and practical synthesis of 1,5-keto esters.
The efficiency of this chemistry is illustrated by the very
simple preparation of unusual 4,4-dideuterio-1,5-keto esters.
0
0
3
3
3
10
71
73
a The reaction was performed on a 1-mmol scale with 2 mL of THF
and 2-3 equiv of methyl acrylate. b Isolated yield. c 5-mmol scale.
The importance of 1,5-keto esters in and of themselves and
as building blocks for further structural elaboration make their
availability important. Michael addition of electron-rich alkenes
such as metal enolates,1 enamines,2 trimethylsily enol ethers/
TiCl4,3 and stannyl ketone enolates/Bu4NBr4 to R,ꢀ-unsaturated
carbonyls constitutes one of the most useful methods for
construction of 1,5-dicarbonyl compounds under mild condi-
tions. The major shortcoming of this transformation lies in the
preparation or isolation of the ketone- or ester-derived nucleo-
philic species. In searching for new strategies based upon the
concept of multicomponent addition, we turned our attention
to the one-pot joining reaction of amides, CH2Cl2, and methyl
acrylate promoted by TiCl4-Mg bimetallic species, wherein the
titanium-methylene complex5,6 serves as a synthetic equivalent
to methylene dianion as illustrated in Scheme 1. The indication
that such a one-pot joining process may occur came as a result
of our probing the mechanism of the amide-cyclopropanation
promoted by the titanium-methylene complex derived from the
TiCl4-Mg-CH2Cl2 system,6a wherein the intermediate enamine
generated in situ can undergo subsequent coupling with methyl
acrylate. Herein we wish to record protocols whereby such a
novel multicomponent coupling promoted by TiCl4-Mg can
be directed to form either 1,5-keto esters or unusual deuterated
keto esters.
The multicomponent coupling of a simple morpholine amide
1a with CH2Cl2 and methyl acrylate was chosen to test the
feasibility of the process (Table 1). Exposing 1a to magnesium
powder (8 equiv, ca. 50 mesh) and TiCl4 (1.5 equiv) in CH2Cl2/
(1) (a) ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
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to methyl acrylate at low temperature, see: Qiu, Z.-M.; Burton, D. J. J. Org.
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(5) For some recent references for titanium-methylene complexes, see: (a)
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(6) (a) Lin, K.-W.; Yan, S.; Hsieh, I.-L.; Yan, T.-H. Org. Lett. 2006, 8, 2265.
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10.1021/jo800732s CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4759–4761 4759

TABLE 2. Multicomponent Coupling of Amides with CH2Cl2 and
Methyl Acrylatea,b,c
SCHEME 2. Multicomponent Coupling of Amides with
CH2Cl2 and Methyl Acrylate
THF at 0 °C for 3 h followed by adding methyl acrylate (2-3
equiv) did indeed produce the desired coupling adduct 2a7 but
only in less than 15% yield (entry 1), with the remainder largely
being methyl ketone derived from methylenation of amide 1a.
Performing the reaction at 25 °C for 12 h failed to improve the
yield (entry 2). Remarkably, simply adding a small amount of
NEt3 (∼3 equiv) to the original system at 0 °C led to smooth
coupling to give a 75% yield of the desired keto ester 2a (entry
3).2b,c Running the reaction at room temperature or increasing
the amount of NEt3 or TiCl4 did not prove beneficial (entries
4-6). Notably, the reaction directly scales up (entry 7); thus,
adduct 2a was obtained in 73% yield on a 5-mmol scale with
use of 6 equiv of TiCl4, 35 equiv of Mg, and 12 equiv of methyl
acrylate.
The reaction is best envisioned as involving interception of
the enamine 3 formed via an amide-methylenation by a
presumed electrophilic titanium-acrylate complex 4 to give an
alkylated iminium ion 5 (Scheme 2). In contrast to the thermal
conjugate-addition of enamine with acrylate, which requires high
temperature (refluxing in ethanol, dioxane, acetonitrile, or
DMF),2a this TiCl4-Mg-promoted mild coupling represents an
attractive alternative.
With conditions established to give high yields, we explored
the effect of amide structure (Table 2). Applying the standard
reaction condition to sterically more bulky cyclohexanecarbo-
nylmorpholine 1b or cyclic amide 1c led to coupling adduct in
only ∼20% yield. Interestingly, increasing the amount of THF
dramatically enhances the multicomponent coupling. Thus, using
a 3:12 CH2Cl2:THF mixture as solvent led to equally gratifying
results with formation of keto ester 2b8 (72%) and 2c (60%)
(entries 1 and 2). Changing the amide to aromatic amide 1d
also led to smooth coupling to afford the desired keto ester 2d9a
(entry 3).
The reaction exhibits good chemoselectivity. As expected,
acetal, sulfide, alkene, and alkyne have no effect (entries
4-7). Remarkably, the CH2Cl2-Mg-TiCl4 system can also
discriminate between carbamoyl and the tert-butoxycarbonyl
group in a dicarbonyl compound, effecting selective elabora-
tion of the less sterically hindered amide into 1,5-keto ester.
Thus, exposing carbamoylester 1i to 1.5 equiv of TiCl4 and
a Reactions were run on a 1-mmol scale with 2 mL of THF and 2-3
equiv of methyl acrylate in CH2Cl2 (5 mL)/THF (2 mL) at 0-25 °C
unless noted otherwise. b Isolated yield. c Reactions were run in CH2Cl2
(3 mL)/THF (12 mL).
8 equiv of Mg produced the keto ester 2i in 68% isolated
yield (entry 8).10
This TiCl4-Mg-promoted multicomponent coupling opens
a convenient entry into the deuterium-labeled compounds,
which serve as a major avenue to probing the course of the
reaction.11,12 To further demonstrate the efficiency and
practicability of this chemistry, a very simple synthesis of
(9) (a) Jo, E.-A.; Jun, C.-H. Eur. J. Org. Chem. 2006, 11, 2504. (b) Compound
2f was previously prepared by a different route: Paul, M.; Nakanishi, K. J. Org.
Chem. 1992, 57, 1047–1051.
(7) Miyasaka, T.; Monobe, H.; Noguchi, S. Chem. Lett. 1986, 449.
(8) Babudri, F.; Finadanese, V.; Marchese, G.; Punzi, A. Tetrahedron 1996,
52, 13513.
(10) All new compounds have been satisfactorily characterized spectroscopi-
cally.
4760 J. Org. Chem. Vol. 73, No. 12, 2008

SCHEME 3. One-Step Conversion of Amides into
4,4-Dideuterio-1,5-keto Esters
added over a 2-min period a solution of amide 1a (219 mg, 1 mmol)
in CH2Cl2 (5 mL) and THF (2 mL). After the solution was stirred
for 1 h at 0 °C, NEt3 (0.4 mL) was added and stirring continued
for 30 min.. The green-black mixture was quenched with methyl
acrylate (0.2 mL, 3 mmol) and stirred for an additional 2 h at 0-25
°C. Saturated potassium carbonate solution (10 mL) was added and
the mixture was diluted with CH2Cl2 (30 mL). The organic layer
was separated, dried, evaporated, and purified by flash chromatog-
raphy on silica gel (elution with 1:10 ethyl acetate-hexane, Rf 0.3)
to give 2a (176 mg, 75% yield) as a colorless oil: IR (neat) 3062,
2951, 1736, 1706, 1600, 1499 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.22-7.09 (m, 5 H), 3.58 (s, 3 H), 2.82 (t, J ) 7.6 Hz, 2 H),
2.65 (t, J ) 7.6 Hz, 2 H), 2.38 (t, J ) 7.2 Hz, 2 H), 2.26 (t, J )
7.2 Hz, 2 H), 1.80 (tt, J ) 7.2 Hz, J ) 7.2 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 209.1, 173.5, 141.0, 128.4, 128.3, 126.1, 51.5,
44.2, 41.7, 33.0, 29.7, 18.8; high-resolution MS (EI) m/e calcd for
C14H18O3 234.1256, found 234.1258.
General Procedure for the One-Step Conversion of Amides
into 4,4-Dideuterio-1,5-keto Esters with 6a as an Example.
Methyl 4,4-Dideuterio-5-oxo-7-phenylheptanoate, 6a. To a 0 °C
suspension consisting of Mg (192 mg, 8 mmol) and TiCl4 (1.5
mmol, 1 M in toluene, 1.5 mL) was added over a 2-min period a
solution of amide 1a (219 mg, 1 mmol) in PhCH3 (2 mL), CD2Cl2
(0.3 mL), and THF (2 mL). After the solution was stirred for 1 h
at 0 °C, NEt3 (0.4 mL) was added and stirring continued for 30
min. The green-black mixture was quenched with methyl acrylate
(0.2 mL, 3 mmol) and stirred for an additional 2 h at 0-25 °C.
Saturated potassium carbonate solution (10 mL) was added and
the mixture was diluted with CH2Cl2 (30 mL). The organic layer
was separated, dried, evaporated, and purified by flash chromatog-
raphy on silica gel (elution with 1:10 ethyl acetate-hexane, Rf 0.3)
to give 6a (158 mg, 67% yield) as a colorless oil: IR (neat) 3062,
2951, 1734, 1702, 1599, 1497 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.28-7.14 (m, 5 H), 3.64 (s, 3 H), 2.87 (t, J ) 7.6 Hz, 2 H),
2.71 (t, J ) 7.6 Hz, 2 H), 2.41 (t, J ) 7.2 Hz, ∼0.24 H), 2.29 (t,
J ) 7.2 Hz, 2 H), 1.85 (t, J ) 7.2 Hz, ∼1.95 H); 13C NMR (100
MHz, CDCl3) δ 209.1, 173.4, 140.9, 128.4, 128.2, 126.0, 51.4, 44.1,
41.3 (quintet, J ) 19.1 Hz), 32.8, 29.6, 18.6; high-resolution MS
(EI) m/e calcd for C14H16D2O3 236.1381, found 236.1384.
unusual deuterated keto esters was carried out (Scheme 3).
Thus, reacting amides 1a and 1f with CD2Cl2 under the same
conditions but replacing dichloromethane with toluene led
to smooth coupling to give the desired 4,4-dideuterioketo
1
esters 6a (67%) and 6f (61%), respectively. Analysis by H
NMR indicated that about 10% of unlabeled keto ester was
present. Notably, performing the multicomponent coupling
in toluene to maintain homogeneity allowed the use of 3 equiv
of CD2Cl2. A dramatic illustration of the utility of this
protocol was the elaboration of amide 1i into the unusual
4,4-dideuterioketo diester 6i (66%) (contaminated by less than
5% of unlabeled keto ester).
This TiCl4-Mg-promoted multicomponent coupling of vari-
ous amides with CH2Cl2 and acrylate represents an extremely
simple and practical synthesis of 1,5-keto esters. The efficiency
of this chemistry is illustrated by the very simple preparation
of unusual deuterated 1,5-keto esters.
Acknowledgment. We thank the National Science Council
of the Republic of China for generous support.
Experimental Section
Supporting Information Available: Experimental proce-
1
dures and spectral data, including copies of H and 13C NMR
General Procedure for TiCl4-Mg-Promoted Multicompo-
nent Coupling of Amides with CH2Cl2 and Methyl Acrylate
with 2a as an Example. Methyl 5-Oxo-7-phenylheptanoate, 2a.
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
spectra for 2c, 2e, 2g, 2h, 2i, 6a, 6f, and 6i. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800732S
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