Pyrrolidine-catalyzed condensation of ethyl diazoacetate to aldehydes in water

Article abstract of DOI:10.1080/00397911003794517

A simple and convenient protocol for the synthesis of-diazo carbonyl compounds from the condensation of ethyl diazoacetate to aldehydes in water was developed using pyrrolidine as a catalyst. Copyright

Full text of DOI:10.1080/00397911003794517

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Pyrrolidine-Catalyzed Condensation
of Ethyl Diazoacetate to Aldehydes in
Water
a
a
a
M. Lakshmi Kantam , L. Chakrapani , T. Ramani & K. Rajender
a
Reddy
a
Inorganic and Physical Chemistry Division, Indian Institute of
Chemical Technology , Hyderabad, India
Published online: 17 May 2010.
To cite this article: M. Lakshmi Kantam , L. Chakrapani , T. Ramani & K. Rajender Reddy (2010)
Pyrrolidine-Catalyzed Condensation of Ethyl Diazoacetate to Aldehydes in Water, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:12, 1724-1729, DOI: 10.1080/00397911003794517
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Synthetic Communications , 40: 1724–1729, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003794517
PYRROLIDINE-CATALYZED CONDENSATION OF ETHYL
DIAZOACETATE TO ALDEHYDES IN WATER
M. Lakshmi Kantam, L. Chakrapani, T. Ramani, and
K. Rajender Reddy
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
A simple and convenient protocol for the synthesis of a-diazo carbonyl compounds from the
condensation of ethyl diazoacetate to aldehydes in water was developed using pyrrolidine as
a catalyst.
Keywords: Aldol-type reaction; a-diazo carbonyl compounds; ethyl diazoacetate; pyrrolidine; water
INTRODUCTION
a-Diazo carbonyl compounds are valuable intermediates for the synthesis of
amino alcohols and amino acids. Moreover, the carbene species generated from
[1]
a-diazo carbonyl compounds are widely used in molecular insertion reactions to
form a new carbon–carbon (C-C) and=or C-heteroatom bond. Despite their
[
2]
[
3]
tendency to convert into corresponding b-keto carbonyl compounds, they are
[
4]
useful synthetic intermediates for many natural products. These versatile a-diazo
carbonyl compounds are generally prepared by the azido transfer reaction of
carbonyl compounds. This can be usually achieved by treatment 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 quartenary ammonium
[5]
hydroxde under controlled conditions. However, some of these methods involve
the use of strong bases or expensive reagents and have poor yields of products.
Moreover, the use of strong bases may not be compatible with functional groups
in the substrates.
Catalytic transformations involving small organic molecules, known as
[
6]
organocatalysis, has attracted much interest in recent years. These catalysts are
environmentally more benign, as they do not involve metals. Though a number of
these reactions have been performed in organic solvents, use of aqueous media is
much more attractive because of environmental considerations. A number of organic
reactions are now efficiently performed in water and display, in some cases, impress-
[
7]
ive rate accelerations, selectivity, new reactivity, and excellent yields. Despite the
Received August 14, 2007.
Address correspondence to M. Lakshmi Kantam, Inorganic and Physical Chemistry Division,
Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: mlakshmi@iict.res.in
1
724

CONDENSATION OF ETHYL DIAZOACETATE TO ALDEHYDES
1725
Scheme 1. Condensation of ethyl diazoacetate to aldehydes.
considerable progress made, the number of organocatalyzed reactions in pure
water remains scarce, and there is a clear demand for new, direct, and efficient
applications.
Pyrrolidine is a mild, readily available, and inexpensive organobase. Recently,
the use of pyrrolidine and the pyrrolidine-derived organo catalysts was shown to be
[
8]
much more efficient for C-C bond-forming reactions. Barbas and coworkers have
shown that simple pyrrolidine can be utilized as an efficient catalyst for multicompo-
[
8]
nent reactions.
catalyzed direct cross-aldol reaction of aromatic=heterocyclic aldehydes and ketones
Recently, Chimni and Mahajan have reported pyrrolidine-
[9]
in water for the first time.
We have exploited further the advantage of
pyrrolidine-catalyzed addition of ethyl diazoacetate (EDA) to various aromatic
and heterocyclic aldehydes to yield diazo esters exclusively without any side products
(Scheme 1).
RESULTS AND DISCUSSION
Optimization of the reaction conditions was performed with 4-chlorobenzalde-
hyde. Initially, we examined the effects of various solvents. It was found that the nat-
ure of the solvent had a significant effect on the reaction. No formation of aldol-type
product was observed when the reaction was conducted in nonpolar solvents, such as
Et O, CH Cl , and PhCH (Table 1, entries 1–3), or even in the polar solvents, such
2
2
2
3
as MeOH and MeCN (Table 1, entries 4 and 5). Surprisingly, the rate of the reaction
was accelerated in the presence of water, and very good conversions were observed
when the reactions were carried out with a 1:1 mixture of MeOH=H O, MeCN=H O,
2
2
and tetrahydrofuran (THF)=H O (Table 1, entries 8–10). These results clearly
2
indicate that water plays an important role in the activity of the catalyst. Later,
we performed the reaction in pure water, in which greater yields were obtained in
shorter reaction times (Table 1, entry 11).
Later, we examined the effect of various cyclic secondary amines, such as
piperidine, morpholine, and proline for the present reaction. The results revealed
that pyrrolidine was the most efficient catalyst, giving the products in greater yield,
as shown in Table 2.
Under the optimized conditions, we performed the reaction of ethyl diazoace-
tate with a variety of structurally divergent aldehydes possessing a wide range of
functional groups, and the results are summarized in Table 3. The aromatic
aldehydes, having an electron-withdrawing substituent, gave the corresponding
b-hydroxy-a-diazo carbonyl compounds in good yields (Table 3, entries 1–10),

1726
M. L. KANTAM ET AL.
a
Table 1. Screening of solvents for the addition of EDA to 4-chloro benzaldehyde
b
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Ether
DCM
24
24
24
24
24
24
24
2
0
0
Toluene
MeCN
MeOH
THF
0
0
0
0
DME
0
MeOH=H
2
O (1:1)
O (1:1)
67
70
55
89
MeCN=H
THF=H
2
2
1
0
1
2
O (1:1)
2
1
H
2
O
2
a
All reactions were carried out with 30 mol% catalyst, aldehdye (0.5 mmol), EDA
0.55 mmol), solvent (2 mL).
(
b
Isolated yields.
whereas the aromatic aldehydes with the electron-donating substituent gave greater
yields after longer reaction times (Table 3, entry 11). In contrast, b-naphthaldehyde
and cyclohexane carboxaldehyde provided lesser yields even after longer reaction
times (Table 3, entries 12 and 13).
Later, we carried out the reactions with different heterocyclic aldehydes. The
highly water-soluble pyridine aldehydes readily condensed with EDA to provide
excellent yields in lesser reaction times. Reactions of aliphatic aldehydes and trans-
cinnamaldehyde with EDA were unsuccessful under similar reaction conditions.
Table 2. Screening of different bases for the addition of EDA to
a
4-chlorobenzaldehyde
b
Entry
Base
Time (h)
Yield (%)
1
2
3
4
pyrrolidine
piperidine
morpholine
proline
2
2
89
22
12
10
18
18
a
All reactions were carried out with 30 mol% catalyst, aldehdye (0.5 mmol), EDA
O (2 mL).
Isolated yields.
(
0.55 mmol), H
2
b

CONDENSATION OF ETHYL DIAZOACETATE TO ALDEHYDES
1727
a
Table 3. Pyrrolidine-catalyzed condensation of various aldehydes with ethyl diazoacetate
b
Entry
Substrate (R)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
4-Cl-C
4-CN-C
4-CF -C
4-F-C
3-NO -C
4-Br-C
6
H
4
2
<1
2
89
90
83
80
80
65
60
71
65
50
80
25
40
6
H
4
3
6 4
H
6
H
4
3
2
6
H
4
1
6
H
4
2
4-NO
2-NO
2
-C
-C
6
H
4
<1
<1
2
2
6
H
4
6 5
C H
1
1
1
1
0
1
2
3
6
2-Cl-C H
4
2
4-CH -C
3
6
H
4
12
12
12
2-Naphathyl
Cyclohexyl
a
All reactions were carried out with 30 mol (%) catalyst, aldehyde (0.5 mmol), EDA
0.55 mmol), H O (2 mL).
(
2
b
Isolated yields.
Table 4. Pyrrolidine-catalyzed condensation of various heterocyclic aldehydes with
a
ethyl diazoacetate
b
Entry
Substrate (R)
Time (h)
Yield (%)
1
2
3
4
5
4-Pyridyl
3-Pyridyl
2-Pyridyl
0.5
<1
6
95
83
50
75
40
2-Furfuryl
2-Thiophenyl
12
12
a
All reactions were carried out with 30 mol (%) catalyst, aldehyde (0.5 mmol),
EDA (0.55 mmol), H O (2 mL).
2
b
Isolated yields.

1728
M. L. KANTAM ET AL.
CONCLUSION
In conclusion, we have demonstrated that pyrrolidine is a highly efficient
catalyst for the aldol-type reaction of various aromatic and heterocyclic aldehydes
with EDA to give b-hydroxy-a-diazo carbonyl compounds in excellent yields in
water at room temperature.
EXPERIMENTAL
Typical Experimental Procedure for the Condensation of Ethyl
Diazoacetate to Aldehydes
Water (2 mL), followed by aldehyde (0.5 mmol) and EDA (0.55 mmol), was
added to a dried, 25-mL, round-bottomed flask charged with pyrrolidine
(
0.30 mmol, 21 mg) at room temperature. The reaction was monitored by thin-layer
chromatography (TLC). The reaction was quenched with saturated ammonium
chloride and extracted with ethyl acetate. The organic layer was dried over anhy-
drous Na SO and distilled to obtain the crude product. Coloumn chromatography
2
4
of the crude product on silical gel (60–120 mesh) using a mixture of ethyl acetate
and hexane in varying proportions as eluent gave the corresponding b-hydroxy-
a-diazo carbonyl compound. All the products are known and were determined
by comparison of their physical data and spectral data with those reported in
the literature.
ACKNOWLEDGMENTS
We thank the Council for Scientific and Industrial Research (CSIR) for
financial support under the Task Force Project CMM-0005. L. C. thanks the CSIR,
India, and T. Ramani thanks the University Grants Commission for providing a
senior research fellowship.
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