NaOH/Et 3N-promoted stereoselective one-pot synthesis of α-Diazo Oxime Ethers via Diazo transfer reaction

Article abstract of DOI:10.1080/00397911.2015.1085575

For the first time, we have observed a combined effect of two bases NaOH/Et3N to promote the diazo transfer reaction of β-oximino esters. This unusual synergistic effect has been employed to obtain α-diazo oxime ethers directly from β-keto esters by one-p

Full text of DOI:10.1080/00397911.2015.1085575

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NaOH/Et3N–Promoted Stereoselective One-Pot
Synthesis of α-Diazo Oxime Ethers via Diazo Transfer
Reaction
Bharath Kumar Kurubaa, Nusrathulla Shariffa, Samuel Vasanthkumara & Lourdusamy
Emmanuvela
a School of Science and Humanities, Department of Chemistry, Karunya University,
Coimbatore, Tamil Nadu, India
Accepted author version posted online: 01 Sep 2015.
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To cite this article: Bharath Kumar Kuruba, Nusrathulla Shariff, Samuel Vasanthkumar & Lourdusamy Emmanuvel
(2015): NaOH/Et3N–Promoted Stereoselective One-Pot Synthesis of α-Diazo Oxime Ethers via Diazo Transfer Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1085575
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NaOH/Et3N–Promoted Stereoselective One-Pot Synthesis of α-Diazo Oxime Ethers
via Diazo Transfer Reaction
Bharath Kumar Kuruba1, Nusrathulla Shariff1, Samuel Vasanthkumar1, Lourdusamy
Emmanuvel1
1School of Science and Humanities, Department of Chemistry, Karunya University,
Coimbatore, Tamil nadu, India
Corresponding address: Dr. L. Emmanuvel, Assistant professor, Department of
Chemistry, Karunya University, Coimbatore – 641 114 E-mail:
emmanuvel@karunya.edu
Abstract
For the first time, we have observed a combined effect of two bases NaOH/Et3N to
promote the diazo transfer reaction of β-oximino esters. This unusual synergistic effect
has been employed to obtain α-diazo oxime ethers directly from β-keto esters by one-pot
process. This method is simple, cost effective and the reagents are readily available.
KEYWORDS: α-diazo imines, diazo transfer reaction, one-pot process, synergistic
effect.
Diazo compounds have a long history of useful applications in the organic synthesis.1
They are versatile intermediates and undergo a variety of organic transformations
including insertion, rearrangement, cycloaddition, etc.2 After the first synthesis of ethyl
diazoacetate via diazotization of glycine, several attempts had been made to achieve this
1

useful functional group.3 Among them, dehydrogenation or oxygenation of hydrazones,4
decomposition of organic azide in the presence of phosphine,5 etc. are a few to be
acknowledged. The major breakthrough came with the discovery of diazo transfer
reaction by Regitz,6 which make use of sulfonyl azides as the nitrogen source and gave
promising results with the active methylene compounds. Hitherto, the diazo transfer
reaction is identified as the simplest protocol that makes use of easy to handle reagents,
involves simple work up and purification. Chemical modification of ethyl diazoacetate
via aldol type reaction,7 Pd-catalyzed reaction,8 etc., have also helped to get diversity in
diazo compounds.
Even though several methods are available for α-diazo ketones, its nitrogen analogs i.e.,
α-diazo oxime ethers, have rarely been studied. Shimon Shatzmiller et al. carried out
diazo transfer reaction of acetophenone oxime ether using n-BuLi at -78 oC.9 Recently,
we have developed10 a methodology for the stereoselective synthesis of α-diazo imines
via diazo transfer reaction using 4-nitrobenzenesulfonyl azide and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as base at -20 oC (condition 1, Scheme 1). Even
though, both the geometrical isomers of the oxime ethers were employed for the reaction,
cis diazo imine was obtained exclusively. The limitation of this method includes use of
expensive, non-readily available reagents and requirement of very low temperature. In
this communication, we report a modified one-pot procedure for the synthesis of diazo
imines from β-keto ester via diazo transfer reaction, which makes use of the synergistic
effect between NaOH/Et3N.
2

During our study on diazo compounds,11 we found that the diazo transfer reaction of
imines also proceeds with readily available 4-toluenesulfonyl azide (TsN3) when a
mixture of bases, i.e., NaOH/Et3N was employed. Accordingly, oxime ether 1b reacts
with TsN3 in the presence of NaOH/Et3N in CH3CN to give diazo compound 2b at
ambient conditions (condition 2, Scheme 1).
It is noteworthy to observe that the reaction proceeds at room temperature with higher
reaction rate in the presence of NaOH/Et3N to give comparable yield of the compound
2b. But, the reaction failed to give the desired product when NaOH or Et3N was
employed as the only base (Entry 1 & 2, Table 1). Hence, the use of two bases is
mandatory and the need for two bases is not well understood. For the first time we have
come across such a peculiar observation with diazo transfer reaction. To our
understanding, Et3N surrounds the metal cations (A & B) formed in the presence of metal
hydroxide and fine-tune its nucleophilicity to attack the TsN3 to give the diazo
compounds. When NaOH is employed as the base, such increase in nucleophilicity is not
possible whereas, Et3N due to its poor basicity is not able to generate the anion (Fig. 1).
We also tried this reaction with combination of different bases, of which one is strong
inorganic base and the other is organic amine. For instance, KOH/Et3N, K2CO3/Et3N,
NaOH/DMAP, NaOH/DIPEA, NaOH/pyridine, were screened and the results are given
in the Table 1. Both NaOH and KOH gave comparable yields of the diazo compound
while K2CO3 failed to give the product. Among the amines, Hunig’s base, pyridine,
diisopropyl amine gave moderate yield after three hours and the reaction rate was found
3

to be considerably slow. Among the solvents, acetonitrile gave the better yield while
THF, dioxane, diethyl ether and halogenated solvents gave moderate to poor yields.
There was not much increase in the yield of the diazo compounds when the reaction was
carried out at 0 oC.
In order to understand the scope of the reaction, we screened a few active methylene
oxime ethers and the results are given in the Table 2. The oxime ethers were prepared
from the corresponding keto esters by reacting with methoxylamine hydrochloride in
pyridine as solvent and were used without purification after work up. Even though both
cis and trans oxime ethers were employed only cis diazo oxime ethers were obtained in
consistence to our earlier method. All the yields obtained are comparable with our earlier
method.
Since the oxime ethers are prepared in pyridine as solvent and diazo transfer reaction
proceeds smoothly in NaOH/ Pyridine condition (Entry 6, Table 1), we attempted to
synthesize α-diazo oxime ethers directly from β-keto esters by one-pot process.
Accordingly, β-keto esters 3 were converted to the corresponding oxime ethers 4 by
reacting with methoxylamine hydrochloride in the presence of pyridine for 3 h.
Subsequent addition of NaOH and TsN3 to the reaction mixture facilitated the diazo
transfer reaction with in situ generated oxime ethers to give α-diazo oxime ethers 5
(Scheme 2). Even though the reaction rate was comparatively slow, good yields were
obtained after 24 h. In consistence with our earlier observation, only cis isomer was
obtained with comparable yields. Interestingly, 1,3-diones such as, 1,3-pentadione,
4

cyclohexadione, dimedone were successfully subjected to this reaction to obtain
corresponding α-diazo mono oxime ethers in good yields ( Entry c, d, and f Table 3).
In conclusion, we have developed a simple and cost effective protocol for the synthesis of
diazo oxime ethers via diazo transfer reaction using NaOH/Et3N mixture as base. The
reaction is carried out at ambient conditions and is fast enough to reach completion in 30
minutes. We have also developed a one-pot process for the synthesis of α-diazo oxime
ethers from β-keto esters. Further, this methodology could be extended for non-active
methylene compounds and the need for the two bases can be studied.
EXPERIMENTAL
All reagents and solvents were obtained from Merck and Aldrich is used without any
purification. 1H- and 13C- NMR spectra were recorded on Bruker FT- 500 or 400 using
tetramethyl silane (TMS) as an internal standard. The IR spectra were recorded on
Shimadzu FTIR spectrophotometer (in KBr).The compounds were purified by column
chromatography using silica gel (100-200 mesh) and pet ether:ethyl acetate. TLC was
performed using silica gel 60 F254 precoated on aluminium sheets, obtained from Merck.
Visualization of spots on TLC plate was done with uv light (254 nm).
TYPICAL PROCEDURE
Procedure For One-Pot Synthesis Of Α-Diazo Oxime Ethers
To a solution of β-keto ester (1 eq.) in pyridine at room temperature was added
methoxylamine hydrochloride (1.1 eq.) in one portion and the reaction mixture was
5

stirred for 3 h. Sodium hydroxide (2 eq.) and 4-toluenesulfonyl azide (1.1 eq.) were then
added to the same reaction mixture and stirred for 24 h. After the completion of the
reaction as indicated by the TLC, the mixture was washed with water, brine, and
extracted with ethyl acetate and dried over anhydrous Na2SO4. The organic layer was
concentrated under reduced pressure to get crude product which was purified by column
chromatography using pet ether:ethyl acetate (19:1) to obtain pure α-diazo oxime ethers.
(Z)-Ethyl 2-diazo-3-(methoxyimino) butyrate: (5a & 2c) Yield: 65% (Yield: 0.240
gm); IR (cm-1) 2125, 1708, 1470, 1373, 1320; 1H NMR (500 MHz, CDCl3) δ 4.20 (q, 2H,
J = 14.0 & 7.0 Hz), 3.84 (s, 3H), 1.60 (s, 3H), 1.3 (t, 3H, J = 7.0 Hz); 13C NMR (125
MHz, CDCl3) δ 163.0, 146.1, 61.7, 61.1, 52.1, 19.2, 14.3; MS (EI) m/z [M+H]+: Calcd
for C7H11N3O3: 185.1805, Found: 185.1825.
FUNDING
The authors thank DST/ SERB, New Delhi, India and Karunya University, Coimbatore,
for Fast Track financial support and the SEED MONEY Research Grant respectively to
carry out this research work.
SUPPLEMENTAL MATERIAL
Full experimental detail, and 1H and 13C NMR spectra for this article can be accessed on
the publisher’s website.
ACKNOWLEDGMENTS
6

The authors also thank the administration and the management of Karunya University for
their constant support and encouragement.
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9

Table 1 Screening of base and solvent for the diazo transfer reactiona
OMe
OMe
N
4-MePhSO2N3
27 oC
N
N2
Ph
Ph
CO2Et
CO2Et
Entry Base
Solvent
Time (min) Yieldb
1
2
NaOH
CH3CN
CH3CN
180
180
No reaction
Et3N
No reaction
3
NaOH/ Et3N
KOH/ Et3N
CH3CN
CH3CN
30
91
4
30
88
5
NaOH/ iPr2NEt CH3CN
NaOH/ Pyridine CH3CN
NaOH/ iPr2NH CH3CN
NaOH/ DMAP CH3CN
180
180
180
180
180
62
6
65 (89)c
52
7
8
45
9
K2CO3/ Et3N
NaOH/ Et3N
NaOH/ Et3N
NaOH/ Et3N
NaOH/ Et3N
CH3CN
-
10
11
12
13
1,4-dioxane 180
30
THF
180
180
180
25
Et2O
10
CHCl3
Traced
aoxime ether (2 mmol), tosyl azide (2 mmol), mixture of base (Inorganic/organic, 2
mmol/2 mmol), solvent (6 mL), RT. byield corresponds to the isolated yield by column
chromatography. cYield after 24 h. dobserved by HPLC.
10

Table 2 Synthesis of α-diazo oxime ethers using TsN3 and NaOH/Et3Na
Entry Reactantb (1)
Product (2)
Yieldc Reference
A
77
10
10
B
89
C
D
65
68
-
-
E
75
-
aoxime ether (2 mmol), tosyl azide (2 mmol), NaOH/Et3N (2 mmol/ 6 mmol), CH3CN (6
mL), 30 min, 27 oC.
c
bcis trans ratio has been given in the parenthesis. Yield corresponds to the isolated yield
by column chromatography.
11

Table 3 Synthesis of α-diazo mono oxime ethers using TsN3 and NaOH/Et3Na
Entry R1
R2
OEt
Yieldb Reference
a
CH3
65
75
70
66
-
B
C
D
E
F
PhCH2CH2- OEt
-CH2-CH2-CH2-
-CH2-C(CH3)2–CH2-
-
-
-
CH3
PhCH2O- 68
-
CH3
CH3
63
65
80
70
77
-
G
CH3
OMe
OMe
10
10
10
10
H
I
4-NO2Ph
CH C-CH2 OMe
PhCH2CH2- OMe
J
aNH2OMe (2.2 mmol), pyridine (6 ml), 3 h then tosyl azide (2 mmol), NaOH (2 mmol),
24 h, 27 oC.
bYield corresponds to the isolated yield by column chromatography.
12

Scheme 1.
13

Scheme 2. One-pot synthesis of α-diazo oxime ethers
14

Figure 1.
15