Ethyl Lithiodiazoacetate: Extremely Unstable Intermediate Handled Efficiently in Flow

Article abstract of DOI:10.1002/chem.201602133

Ethyl diazoacetate (EDA) is one of the most prominent diazo reagents. It is frequently used in metal–carbene-type reactions. However, EDA can also be used as a nucleophile under base catalysis. Whilst the addition of EDA to aldehydes can be performed using organic bases, the addition of EDA to other carbonyl electrophiles requires the use of organometallics such as lithium diisopropylamide (LDA). The generated ethyl lithiodiazoacetate is highly reactive and decomposes rapidly, even at low temperatures. Herein, we report a continuous flow protocol that overcomes the problems associated with the instantaneous decomposition of ethyl lithiodiazoacetate. The addition of ethyl lithiodiazoacetate to ketones provides direct access to tertiary diazoalcohols in good yields.

Full text of DOI:10.1002/chem.201602133

A Journal of
Accepted Article
Title: Ethyl lithiodiazoacetate: Extremely unstable intermediate handled efficiently in
flow
Authors: Simon Mu¨ller; Tobias Hokamp; Svenja Ehrmann; Paul Hellier; Thomas
Wirth
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To be cited as: Chem. Eur. J. 10.1002/chem.201602133
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COMMUNICATION
Ethyl lithiodiazoacetate: Extremely unstable intermediate handled
efficiently in flow
Simon T. R. Müller[a], Tobias Hokamp[a], Svenja Ehrmann[a], Paul Hellier[b] and Thomas Wirth*[a]
Abstract: Ethyl diazoacetate (EDA) is one of the most prominent
diazo reagents. It is frequently used in metal carbene type reactions.
However, EDA can also be used as a nucleophile under base
catalysis. Whilst the addition of EDA to aldehydes can be performed
using organic bases, the addition of EDA to other carbonyl
electrophiles requires the use of organometallics such as LDA. The
generated ethyl lithiodiazoacetate is highly reactive and decomposes
rapidly even at low temperatures. Herein, we report a continuous
flow protocol that overcomes the problems associated with the
instantaneous decomposition of ethyl lithiodiazoacetate. The
addition of ethyl lithiodiazoacetate to ketones provides direct access
to tertiary diazoalcohols in good yields.
organometallics was necessary. We herein describe the first
combination of a diazo compound with organometallics in
continuous flow chemistry.
Figure 1. Ethyl diazoacetate 1 and ethyl lithiodiazoacetate 2.
The reaction of EDA 1 with LDA generates highly reactive ethyl
lithiodiazoacetate 2. Ethyl lithiodiazoacetate 2 is very unstable,
Diazo compounds are among the most versatile classes of
reagents in synthetic chemistry.[1] One of the most prominent
members of this group of reagents is ethyl diazoacetate (EDA)
1.[ 2 ] Ethyl diazoacetate is easily obtained by the reaction of
glycine ethyl ester hydrochloride with sodium nitrite and sulfuric
acid. The disadvantage of diazo compounds in general and ethyl
diazoacetate in particular is their thermal profile.[ 3 ] Diazo
compounds are energetic compounds which can react highly
exothermally. This prevents their large-scale use under standard
batch reaction conditions. Similar to other hazardous reagents,
continuous flow technology can provide a solution to this
problem.[ 4 ] The small quantities of dangerous compounds
generated within the flow reactors combined with the high
surface-to-volume ratio of these devices make flow chemistry a
and
decomposes
at
temperature
above
−50
°C
instantaneously[10] into a brown gel insoluble in most organic
solvents. The generation of ethyl lithiodiazoacetate[11] at very low
temperatures and its addition to ketones has been known in
synthetic chemistry for some time.[12] Also additions to lactones
and thiolactones[13] or chromanones[14] have been investigated
previously.
Batch experiments using 2 proved very unreliable, giving low
yields and being difficult to repeat. The unstable nature of 2 also
proved a major challenge in developing an efficient continuous
flow protocol for the use of 2. A very careful temperature control
over the entire continuous flow set-up was absolutely mandatory
to circumvent clogging of the microreactor. If any of the reactor
tubes were placed outside the cooling bath, the system clogged
immediately. Even the collection vial had to be dispersed in the
dry ice/acetone cooling bath to ensure that no blockages
occurred (Scheme 1). The efficient exclusion of air and water
was achieved by drying the system according to a protocol of
Ley et al. and keeping it under an argon atmosphere.[15] In this
set-up, LDA was generated in a first reactor (R1) at room
temperature within one minute and then cooled to −78 °C (C1).
A stream of ethyl diazoacetate 1 in dry THF was cooled down in
coil C2 and combined with the cooled LDA solution. The
lithiation occurred at –78 ºC within 0.2 min in reactor R2, the
ethyl lithiodiazoacetate 2 was then immediately trapped by a
precooled (in coil C3) solution of the electrophile in the reactor
R3. The formation of ethyl lithiodiazoacetate 2 within 0.2 min
was confirmed by subsequent trapping with benzaldehyde as
very reactive electrophile at –78 ºC. A reaction time of 1.2 min
led to 79% conversion. Also a colour change to dark orange
indicated a successful generation of 2. Due to its instability no
kinetic or calorimetric data could be obtained. Next studies were
performed using acetophenone 3 which reacts also efficiently
with the in situ generated ethyl lithiodiazoacetate 2 (Table 1).
Due to the instability of 2, all optimisations had to be performed
by establishing the conversion and yield of product 4 by varying
the equivalents of EDA 1 and LDA (Table 1, entries 1-4). An
5
]
great enabling tool for the use of diazo compounds.[
Consequently, some excellent protocols for the use of diazo
compounds in flow synthesis have been reported in recent
years.[6] Among those protocols are several methods for the
continuous flow preparation and use of EDA.[7] We[8] and Kim et
9
]
al.[
independently developed multi-step continuous flow
protocols for the generation of EDA and the subsequent
nucleophilic addition to aldehydes using DBU as base. Although
many different aldehydes were used as electrophiles
successfully, the reactions are limited to aldehydes as carbonyl
electrophiles. To expand the use of EDA as nucleophile to
reactions with ketones or lactones in flow, the use of
[a]
[b]
Dr. S. T. R. Müller, T. Hokamp, S. Ehrmann, Prof. Dr. T. Wirth
School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-mail: wirth@cf.ac.uk
Homepage: http://blogs.cardiff.ac.uk/wirth/
Dr. P. Hellier
Pierre Fabre Médicament
Parc Industriel de la Chartreuse
81106 Castres CEDEX (France)
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201602133
COMMUNICATION
attempt to increase the temperature slightly to −72 °C did not
improve the yield of the reaction product 4 any further (Table 1,
entry 5). The yield of 4 obtained in the optimized flow process
(62%) is higher than in the batch protocol reported previously
(50%).[16]
(Table 2, entries 8-9). Unfortunately, the optimized reaction
conditions were still not capable in furnishing substantial
amounts of diazoester 22 when γ-butyrolactone 21 is used as
electrophile (Table 2, entry 10) due to a mixture of side-products
that were formed aside of 22.
O
O
Table 2. Substrate scope of ethyl lithiodiazoacetate addition to carbonyl
compounds
OEt
N2
1
3
Entry
1
Electrophile
Product
Yield [%]
62
1 M in THF
1 M in THF
C2
0.25 mL
2.6 min
C3
0.25 mL
2.6 min
n-BuLi
4
3
5
R2
R1
1.25 M in n-hexane
C1
H
N
0.03 ml
0.2 min
0.25 mL
1.3 min
0.16 mL
22 °C
0.8 min
R3
12.4 ml
31 min
2
3
4
5
6
7
70
66
60
71
53
40
6
1 M in THF
benzoic acid quench
in THF
–78 ºC
8
7
O
HO
OEt
N2
4
10
9
Scheme 1. Continuous flow lithiation of ethyl diazoacetate 1.
12
11
Table 1. Optimisation of the formation and use of ethyl lithiodiazoacetate 2
in reaction with acetophenone 3
14
13
Conversion 4 [%][a]
EDA 1
[equiv.]
Entry
LDA [equiv.]
T [°C]
(Yield 4 [%])
46 (28)
71 (58)
80 (62)
84 (62)
79
16
15
1
2
3
4
5
0.9
1.3
1.3
1.3
1.3
1
−78
−78
−78
−78
−72
1
8
65
1.25
1.5
1.5
17
18
9
48
12
19
20
[a] Conversion determined by 1H NMR.
10
21
22
With the optimised reaction conditions in hand (Table 1,
entry 4), the scope of ketones for the addition of ethyl
lithiodiazoacetate
2 was investigated. Substitution on the
After screening various substrates as shown in Table 2, the
ring expansion of compound 18 using rhodium catalysis in flow
was investigated. Such ring-homologation reactions using diazo
alcohols have already been investigated in batch and similar
catalysts are being applied to the flow reaction.[16, 17 ] Diazo
alcohol 18 can be rapidly decomposed to give the seven-
membered ring system of product 23 in excellent yields in a
short reaction time using rhodium acetate as catalyst (Scheme
aromatic moiety of the acetophenone is well tolerated and the
reaction products (Table 2, entries 2-4) are obtained in good
yields. However, pyridine as aromatic substituent gave the
product 6b in slightly reduced yield (53%, Table 2, entry 6) while
the highest yield (71%) was obtained with 2,2,2-trifluoroaceto-
phenone (Table 2, entry 5). Aliphatic ketones also produced the
diazoalcohols 18 and 20 under the same reaction conditions

Chemistry - A European Journal
10.1002/chem.201602133
COMMUNICATION
2). The silica plug is used for an efficient removal of the rhodium
catalyst.
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in CH2Cl2
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in CH2Cl2 / CH3CN
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In conclusion, we report a new, highly efficient protocol using
continuous flow technology for the in situ formation and the
direct use of ethyl lithiodiazoacetate from EDA. Difficulties with
the decomposition of ethyl lithiodiazoacetate were solved
through careful temperature control of the entire continuous flow
system. The system operated at low temperature (−78 °C) under
exclusion of air and water in an argon atmosphere. The method
gave excess to diversely substituted tertiary diazo alcohols
derived from ketones in moderate to good yields. A symmetrical
diazo alcohol was subsequently decomposed efficiently in
continuous flow conditions to give the seven-membered ketone
23 in excellent yield.
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Acknowledgements
Support from Pierre Fabre, France, and the School of Chemistry,
Cardiff University, is gratefully acknowledged. We thank the
EPSRC National Mass Spectrometry Facility, Swansea, for
mass spectrometric data. The support to TH and SE from the
Erasmus programme is gratefully acknowledged.
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Keywords: diazo compounds • flow chemistry • hazardous
intermediates • lithiation
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[17] K. Nagao, M. Chiba, S.-W. Kim, Synthesis 1983, 197-199.

Chemistry - A European Journal
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Only flow synthesis allows the rapid
generation and safe handling of ethyl
lithiodiazoacetate as an extremely
unstable, but highly versatile building
block for flexible synthesis.
S. T. R. Müller, T. Hokamp, S. Ehrmann,
P. Hellier, T. Wirth*
Page No. – Page No.
Ethyl lithiodiazoacetate: Extremely
unstable intermediate handled
efficiently in flow