Synthesis of α-diazo-β-hydroxy esters using nanocrystalline MgO

Article abstract of DOI:10.1016/j.tetlet.2007.06.141

Nanocrystalline magnesium oxide (NAP-MgO) has been found to be an effective heterogeneous, solid base catalyst for the direct aldol type reaction of ethyl diazoacetate and various aldehydes to afford the corresponding α-diazo-β-hydroxy esters in excellent yields with high selectivity under mild conditions.

Full text of DOI:10.1016/j.tetlet.2007.06.141

Tetrahedron Letters 48 (2007) 6121–6123
Synthesis of a-diazo-b-hydroxy esters using nanocrystalline MgO
M. Lakshmi Kantam,* L. Chakrapani and T. Ramani
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 7 May 2007; revised 19 June 2007; accepted 27 June 2007
Available online 4 July 2007
Abstract—Nanocrystalline magnesium oxide (NAP-MgO) has been found to be an effective heterogeneous, solid base catalyst for
the direct aldol type reaction of ethyl diazoacetate and various aldehydes to afford the corresponding a-diazo-b-hydroxy esters in
excellent yields with high selectivity under mild conditions.
Ó 2007 Published by Elsevier Ltd.
Constructions of carbon–carbon bonds are important
reactions that find numerous applications in synthetic
organic chemistry. a-Diazo carbonyl compounds are
valuable intermediates for the synthesis of amino alco-
hols and amino acids.1 Moreover, the carbene species
generated from a-diazo carbonyl compounds are widely
used in molecular insertion reactions to form new C–C
and/or C–heteroatom bonds.2 Despite their tendency
to interconvert into the corresponding b-keto carbonyl
compounds, they are useful synthetic intermediates for
many natural products.3 These versatile a-diazo car-
bonyl compounds are generally prepared by the azido
transfer reaction of carbonyl compounds. This can be
usually achieved by reaction with a strong base, such
as butyllithium, lithium diisopropylamide (LDA),
sodium hydride or potassium hydroxide, 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) and quaternary ammonium
hydroxide under controlled conditions.4 However, some
of these methods involve the use of very strong bases or
expensive reagents and afford low yields of products.
Moreover, the use of strong bases may not be compati-
ble with certain functional groups in the substrates.
Therefore, the development of alternative catalysts for
the synthesis of b-hydroxy-a-diazo carbonyl compounds
is highly desirable.
induced by heterogeneous catalysts over homogeneous
processes in view of the ease of handling, simple work-
up and regenerability. We herein report the use of nano-
crystalline magnesium oxide (NAP-MgO) for the synthe-
sis of b-hydroxy-a-diazo-b-hydroxy esters in excellent
yields with high selectivity under mild conditions
(Scheme 1). Recently, our group developed single-site
NAP-MgO for the synthesis of chiral epoxy ketones, chi-
ral nitro alcohols and Michael adducts, chiral b-hydroxy
carbonyl compounds, flavanones and a,b-unsaturated
esters and nitriles.5
Various magnesium oxide crystals [commercial MgO,
CM-MgO (30 m2/g); conventionally prepared MgO,
NA-MgO (252 m2/g); aero gel prepared NAP-MgO
(590 m2/g)] were initially screened in the reaction of 4-
chlorobenzaldehyde and ethyl diazoacetate at room
temperature. NAP-MgO was found to be more active
when compared to the other crystalline forms of MgO
(Table 1).
In the process of optimization of the reaction condi-
tions, we explored the use of different solvents. From
Table 2, it is evident that DMSO was the best solvent
in terms of product yield. Only low yields of products
were isolated in the nonpolar solvents DCM and tolu-
ene, while moderate yields of products were isolated in
MeCN, THF and MeOH.
Although high selectivity for the desired products was
achieved, there were many drawbacks under homoge-
neous conditions including catalyst recovery and waste
disposal problems. Industry favours catalytic processes
OH
O
CO Et
2
NAP-MgO
CO Et
+
2
R
R
H
Keywords: NAP-MgO; a-Diazo-b-hydroxy esters; Aldol type reaction;
Heterogeneous; Solid base.
DMSO, rt
N
2
N
2
*
Corresponding author. Tel./fax: +91 40 27160921; e-mail:
mlakshmi@iict.res.in
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.06.141

6122
M. L. Kantam et al. / Tetrahedron Letters 48 (2007) 6121–6123
Table 1. Aldol type reaction 4-chlorobenzaldehyde and ethyl diazoac-
etate (EDA) with different crystallites of MgOa
Table 4. Direct aldol type reaction of heterocyclic aldehydes and ethyl
diazoacetate using NAP-MgOa
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
Entry
Substrate (R)
Time (h)
Yieldb (%)
1
2
3
NAP-MgO
CP-MgO
CM-MgO
DMSO
DMSO
DMSO
1
1
1
92
56
25
1
2
3
4
5
4-Pyridyl
3-Pyridyl
2-Pyridyl
2-Furfuryl
2-Thiophenyl
1
1
1
6
6
96
96
98
61
63
a Catalyst (50 mg), aldehyde (0.5 mmol), EDA (0.55 mmol), DMSO
(2 mL), rt.
b Isolated yield.
a NAP-MgO (50 mg), aldehyde (0.5 mmol), EDA (0.55 mmol), DMSO
(2 mL), rt.
b Isolated yield.
Table 2. Screening of solvents in the reaction of 4-chlorobenzaldehyde
and ethyl diazoacetate using NAP-MgO at room temperaturea
products albeit in longer reaction times. 2-Naphtha-
ldehyde and alicyclic cyclohexane carboxaldehyde affor-
ded excellent yields of a-diazo-b-hydroxy esters in short
reaction times (Table 3, entries 13 and 14). Excellent
yields were also obtained in the reactions of N-hetero-
cyclic aldehydes (Table 4, entries 1–3).
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
DMSO
DMF
NMP
MeOH
THF
MeCN
DCM
Toluene
1
1
1
12
1
12
12
12
92
76
59
54
57
38
17
37
After completion of the reaction (monitored by TLC),
the reaction mixture was centrifuged to separate the cat-
alyst and washed several times with ethyl acetate, ether
and air-dried. The recovered catalyst was recycled three
times without loss of activity after activation at 250 °C
for 1 h under a flow of nitrogen.
a NAP-MgO (50 mg), aldehyde (0.5 mmol), EDA (0.55 mmol), solvent
(2 mL).
b Isolated yield.
In conclusion, we have shown that NAP-MgO is a
highly active, reusable catalyst for the synthesis of b-
hydroxy-a-diazo carbonyl compounds. Thus nanocrys-
talline MgO with its definite shape, size and accessible
OH groups, and higher density of Mg+ at the edges/cor-
ners shows high activity in the synthesis of b-hydroxy-a-
diazo carbonyl compounds.
A variety of different aromatic aldehydes, containing
electron-withdrawing or donating groups and hetero-
cyclic aldehydes, were subjected to this reaction and
the results are summarized in Tables 3 and 4.6 As
expected the rate of reaction was high for the aldehydes
possessing electron-withdrawing groups compared with
the aldehydes bearing electron-donating groups. Excel-
lent yields were obtained with aromatic aldehydes bear-
ing an electron-withdrawing group at the para position
(Table 3, entries 2–4) and high yields were afforded with
ortho- and meta-substituted aromatic aldehydes (Table
3, entries 7–9). Aromatic aldehydes bearing electron-
donating groups afforded high yields of the desired
Acknowledgements
We wish to thank the CSIR for financial support under
the Task Force Project CMM-0005. L.C. thanks the
CSIR, India, and T.R. thanks the UGC for providing
a senior research fellowship.
Table 3. Direct aldol type reaction of various aldehydes and ethyl
diazoacetate using NAP-MgOa
Entry
Substrate (R)
Time (h)
Yieldb (%)
References and notes
1
2
3
4
5
C6H5
4-Cl–C6H4
4-CN–C6H4
4-CF3–C6H4
4-F-C6H4
2
1
1
0.5
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98, 93c
98
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3-NO2–C6H4
4-Br–C6H4
4-OMe–C6H4
4-CH3–CcH4
2-Naphthyl
Cyclohexyl
6-Bromo piperonyl
6
3
91
80
a NAP-MgO (50 mg), aldehyde (0.5 mmol), EDA (0.55 mmol), DMSO
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4. (a) Schollkopf, U.; Frasnelli, H.; Hoppe, D. Angew. Chem.,
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c Yield after third cycle.

M. L. Kantam et al. / Tetrahedron Letters 48 (2007) 6121–6123
6123
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itored by TLC. After completion of the reaction, the
catalyst was separated by centrifuging the reaction mixture
and the supernatant solution was quenched with saturated
ammonium chloride solution and extracted with ethyl
acetate. The organic layer was dried over anhydrous
Na2SO4 and concentrated to afford the crude product.
Column chromatography of the crude on silica gel (60–120
mesh) using a mixture of ethyl acetate and hexane in
varying proportions as eluent, gave the corresponding b-
hydroxy-a-diazo ester. All the products (except for that in
Table 3, entry 15) are known compounds, which were
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1
identified by IR, H NMR and mass spectroscopic data.4
Spectroscopic and analytical data of the new compound
(Table 3, entry 15): Yellow oil. Yield: 0.137 g (80%), 1H
NMR (300 MHz, CDCl3) d 7.19 (1H, s), 6.97 (1H, s), 5.99
(1H, s), 5.91–5.92 (d, J = 3.0 Hz, 1H), 4.26 (q, J = 7.5 Hz,
2H), 3.8 (1H, br s), 1.3 (t, J = 7.5 Hz, 3H); 13C NMR
(50.3 MHz, CDCl3) d 14.64, 61.47, 68.83, 102.18, 107.92,
112.24, 112.98, 131.40, 147.94, 148.37, 166.64; IR (neat):
3427, 2980, 2902, 2096, 1671 cmÀ1; Mass (ESI): m/z 364
(M+Na)+; HRMS (ESI-MS): exact mass calcd for
C12H11N2O5 NaBr, 364.9749; found, 364.9743.
6. A typical procedure: To a dried 25 mL round-bottomed
flask charged with NAP-MgO (50 mg) was added DMSO
(2 mL) followed by aldehyde (0.5 mmol) and EDA
(0.55 mmol) at room temperature. The reaction was mon-