Taking diazo transfer to water: α-diazo carbonyl compounds from in situ generated mesyl azide

Article abstract of DOI:10.1016/j.mencom.2020.05.037

Mesyl azide generated in situ in aqueous medium converted a range of active methylene substrates into the corresponding diazo compounds in good yields and high purity with no need for chromatographic purification. The products thus obtained are suitable for the subsequent Rh^II-catalyzed O–H insertions with no need for chromatography in the interim.

Full text of DOI:10.1016/j.mencom.2020.05.037

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 372–373
Taking diazo transfer to water: a-diazo carbonyl compounds
from in situ generated mesyl azide
Robert M. Shevalev, Petr A. Zhmurov, Dmitry V. Dar’in and Mikhail Krasavin*
Institute of Chemistry, St. Petersburg State University, 199034 St. Petersburg, Russian Federation.
E-mail: m.krasavin@spbu.ru
DOI: 10.1016/j.mencom.2020.05.037
i, MsCl (1.1 equiv.), NaN3 (1.2 equiv.)
K2CO3 (0.6 equiv.), H2O, 20 °C, 30 min
Mesyl azide generated in situ in aqueous medium converted
a range of active methylene substrates into the corresponding
diazo compounds in good yields and high purity with no need
for chromatographic purification. The products thus
obtained are suitable for the subsequent RhII-catalyzed O–H
insertions with no need for chromatography in the interim.
EWG1
EWG2
EWG1
EWG2
13 examples
41–83%, >95% purity
(no chromatography)
N2
ii, K2CO3 (1.0 equiv.), 3 h
Keywords: diazo transfer, sulfonyl azides, in situ generation, mesyl azide, active methylene compounds, aqueous medium.
Over the last few decades, diazo carbonyl compounds have been
extensively studied for their wide range of chemical
transformations.1–4 The range of insertion reactions which can
be triggered by diazo compounds decomposition into the carbene
species with the loss of a nitrogen molecule is quite
breathtaking.1,4 Numerous diazo compounds can be prepared via
the transfer of diazo function to sufficiently CH-acidic substrates
(the process dubbed the Regitz diazo transfer5). Despite the
practical simplicity of this method, one can be deterred from its
frequent use because of the need to initially prepare and handle
the potentially explosive6 sulfonyl azide reagents such as tosyl
azide, the most commonly employed reagent in diazo transfer
reactions.4 In principle, the hazards associated with diazo
transfer reagents can be almost entirely avoided by preparing
them in situ, as exemplified by Hoveyda,8 by the flow reactor
diazo transfer synthesis described by Maguire and Collins.9,10
The recently described ‘sulfonyl-azide-free’ (SAFE) diazo
transfer11–14 relying on the in situ generation of the active reagent
from m-carboxybenzenesulfonyl chloride and sodium azide in
aqueous medium seems promising. The general green character
of this transformation and the high purity of the crude products
obtained by this method prompted us to investigate if the same
approach, i.e. the in situ preparation of a sulfonyl azide in
aqueous medium, could be applied to any of the conventional
diazo transfer reagents.
We reasoned that mesyl azide which is less lipophilic
compared to tosyl azide (cLogP are 0.39 and 2.37, respectively)
would be a good choice of a sulfonyl azide reagent suitable for
realization of our strategy. Similarly, methanesulfonamide (the
by-product of diazo transfer) will be more likely to remain in the
aqueous phase (cLogP is –0.90) upon completion of diazo
transfer, compared to its p-toluenesulfonamide counterpart
(cLogP is 1.08).† After preliminary experimentation with ethyl
acetoacetate 1a as a model substrate, it was established that
along with the full conversion, the optimum yield (78%) and
purity (>95%) of the obtained ethyl 2-diazoacetoacetate 2a
(Scheme 1) were achieved with the use of 1.1 equiv. of MsCl,
1.2 equiv. of NaN3 and 0.6 equiv. of K2CO3. The unreacted MsN3
EWG1
EWG1
EWG2
N
–
EWG1
EWG2
iii
N2
N
N
1a–i
NaN3
EWG2
2a–i
MeSO2N3
MeSO2Cl
– MsNH2
ii
i
Ms
a EWG1 = C(O)Me, EWG2 = CO2Et, 78%
b EWG1 = EWG2 = C(O)Me, 77%
Y
c EWG1 = EWG2 = CO2Me, 54%
X
O
X
Y
X
i, ii, iii
X
d EWG1 = C(O)But, EWG2 = CN, 41%
O
e EWG1 = 3-pyridylcarbonyl, EWG2 = CO2Et, 70%
f EWG1 = 2-thienylcarbonyl, EWG2 = CO2Et, 71%
g EWG1 = C(O)Ph, EWG2 = C(O)Me, 83%
h EWG1 = 4-ClC6H4C(O), EWG2 = CO2Me, 80%
i EWG1 = 4-MeC6H4SO2, EWG2 = CO2Me, 73%
O
O
N2
4a–c
3a–c
a X = O, Y = CMe2, 69%
b X = CH, Y = CMe2, 72%
c X = NMe, Y = C(O), 56%
Scheme 1 Reagents and conditions: i, MsCl (1.1–1.25 equiv.), NaN3 (1.2–1.5 equiv.), H2O, room temperature, 10 min; ii, K2CO3 (0.6 equiv.), H2O, MeCN
(when needed), room temperature, 30–60 min; iii, K2CO3 (1.0 equiv.), H2O, room temperature, 3 h.
© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 372–373
(~0.1 equiv.) was hydrolyzed over 3 h into water-soluble
In summary, we have modified the known diazo transfer
protocol so that potentially explosive mesyl azide is prepared
and used in situ. Conducting the reaction in aqueous medium
will likely reduce the environmental impact of these syntheses,
particularly on industrial scale (the volume of the organic solvent
employed for product extraction is a less critical factor, compared
to the volume of the reaction mixture, and can be substantially
limited). The high purities of diazo compounds thus obtained
make them suitable for subsequent transformations, with no
need for interim chromatographic purification.
methanesulfonamide (which remained in the water phase after
extractive workup) by adding an additional equivalent of K2CO3.
Notably, addition of 25% MeCN to the reaction mixture did not
affect the outcome of the reaction thus demonstrating the
suitability of water as the solvent of choice. This protocol was
extended to a range of other linear (1b–i) and cyclic (3a–c)
active-methylene substrates to produce the corresponding diazo
compounds 2b–i, 4a–c in generally good yields and high purity
without a need for chromatographic purification (see Scheme 1).
In some cases, reaction time for the diazo transfer step (synthesis
of 2i) or the amount of MsCl/NaN3 (synthesis of 2f–h) had to be
increased in order to achieve full conversion.
This work was supported by the Russian Foundation for Basic
Research (grant no. 19-03-00775). Petr Zhmurov is grateful to
St. Petersburg State University for the postdoctoral fellowship.
We thank the Research Centre for Magnetic Resonance, the
Center for Chemical Analysis and Materials Research of
St. Petersburg State University Research Park for obtaining the
analytical data.
The utility of this approach was successfully demonstrated by
deacylative diazo transfer to a-acetobutyrolactone 5, which gave
a-diazobutyrolactone 6 (Scheme 2).
Encouraged by these findings, we were keen to demonstrate that
the purity of the diazo compounds thus obtained would make them
suitable for the immediate use in subsequent transformations (as
was demonstrated previously for the SAFE diazo transfer
procedure11). To this end, to the dichloromethane extracts of diazo
compounds 2b and 2g (see Scheme 1), benzoic acids were added
followedbytheadditionof1mol%ofRh2(esp)2 catalyst(Scheme 3).
The reactions carried over 18 h afforded, after aqueous workup and
chromatographic purification, the anticipated O–H insertion
products 7a,b in moderate yields.
Online Supplementary Materials
Supplementary data associated with this article (experimental
procedures, analytical data and copies of 1H NMR spectra) can be
found in the online version at doi: 10.1016/j.mencom.2020.05.037.
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O
O
N2
O
i, ii, iii
O
Me
O
6, 59%
5
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Scheme 2 Reagents and conditions: i, MsCl (1.1 equiv.), NaN3 (1.2 equiv.),
H2O, room temperature, 10 min; ii, K2CO3 (0.6 equiv.), H2O, room
temperature, 60 min; iii, K2CO3 (1.0 equiv.), H2O, room temperature, 3 h.
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EWG1
EWG2
EWG1
EWG2
EWG1
EWG2
i, ii, iii
ArCO2H
iv
O
O
N2
Ar
2b,g
1b,g
7a,b
a EWG1 = EWG2 = Ac, Ar = Ph, 38%
b EWG1 = Bz, EWG2 = Ac, Ar = 4-FC6H4, 22%
Scheme 3 Reagents and conditions: i, MsCl (1.1 equiv.), NaN3 (1.2 equiv.),
H2O, room temperature, 10 min; ii, K2CO3 (0.6 equiv.), H2O, room
temperature, 30 min; iii, K2CO3 (1.0 equiv.), H2O, room temperature, 3 h;
iv, Rh2(esp)2 (1 mol%), DCM, room temperature, 18 h.
14 D. Dar’in, G. Kantin and M. Krasavin, Synthesis, 2019, 51, 4284.
†
cLogP values were calculated using Molinspiration property engine
v2018.10 at www.molinspiration.com.
Received: 13th January 2020; Com. 20/6108
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