One-Pot Synthesis of Diazirines and 15N2-Diazirines from Ketones, Aldehydes and Derivatives: Development and Mechanistic Insight

Article abstract of DOI:10.1002/adsc.202100679

Broad scope one-pot diazirine synthesis strategies have been developed using two different oxidants depending on the nature of the starting material. In all cases, an inexpensive commercial solution of ammonia (NH₃) in methanol (MeOH) was emplo

Full text of DOI:10.1002/adsc.202100679

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100679
One-Pot Synthesis of Diazirines and 15N2-Diazirines from Ketones,
Aldehydes and Derivatives: Development and Mechanistic Insight
Quentin Ibert,+a Madeleine Cauwel,+b Thomas Glachet,a Tony Tite,b
Patricia Le Nahenec-Martel,b Jean-François Lohier,a Pierre-Yves Renard,b
Xavier Franck,b,* Vincent Reboul,a,* and Cyrille Sabotb,*
a
Normandie Univ, ENSICAEN, UNICAEN, CNRS, LCMT
6 Boulevard du Maréchal Juin, 14050 Caen Cedex
E-mail: vincent.reboul@ensicaen.fr
Normandie Univ, CNRS, UNIROUEN, INSA Rouen, COBRA
b
76000, Rouen, France
E-mail: xavier.franck@insa-rouen.fr; cyrille.sabot@univ-rouen.fr
+
Quentin Ibert and Madeleine Cauwel contributed equally to this article.
Manuscript received: June 3, 2021; Revised manuscript received: July 15, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100679
Abstract: Broad scope one-pot diazirine synthesis strategies have been developed using two different oxidants
depending on the nature of the starting material. In all cases, an inexpensive commercial solution of ammonia
(NH3) in methanol (MeOH) was employed, avoiding the difficult use of liquid ammonia. With aliphatic
ketones, t-butyl hypochlorite (t-BuOCl) was found to be the best oxidant whereas it is preferable to use
phenyliodine diacetate (PIDA) with aromatic ketones, aldehydes and imines. The nature of the imine-
15
15
protecting group is essential and only t-butyl imine allowed the synthesis of N2-diazirine with complete N
incorporation, emphasizing a key trans-imination step in the reaction mechanism. These methods are
operationally simple, and tolerant to most functional groups, providing diazirines with yields ranging from 20
to 99%.
Keywords: ammonia; t-BuOCl; PIDA; diaziridine; diazirine
Introduction
as in medicinal chemistry for identifying protein-
protein interactions and biological targets of small-
The three-membered heterocyclic ring 3H-diazirine molecule ligands.[7] Photoaffinity labeling relies on the
(diazirine) is one of the rare chemical scaffolds able to installation of discrete and biocompatible chemical
generate a highly reactive species under an external functions into proteins of interest or pharmacophores,
stimulus such as light, heat,[1] or ultrasound.[2] This which are then capable of generating highly reactive
particular reactivity has been exploited in cross- species upon UV light activation, able to insert into a
coupling reactions with aryl halides[3] or boronic variety of XÀ H bonds (X=C, N, O, or S) of
acids,[4] and for the generation of sulfur ylides which biomolecular targets. In this context, diazirine as a
are useful intermediates in synthetic chemistry.[5] carbene precursor, is one of the most popular photo-
Recently, Lopchuk and co-workers elegantly demon- reactive functions mainly due to its small size,
strated that diazirines could serve as effective electro- remarkable biochemical stability and convenient cross-
philic nitrogen transfer reagents in the decarboxylative linking reactivity that is triggered in the range of 350–
amination of redox-active esters.[6] On the other hand, 380 nm.[8] More recently, diazirines have also been
diazirine occupies a privileged position in photoaffinity used for surface functionalization including carbon
labeling of biomolecules, which has received a nanotubes, fullerenes or graphenes through a [1+2]
considerable attention in chemical biology for provid- cycloaddition reaction of carbenes with C=C bonds, in
ing new insights into biological mechanisms, as well order to tune or improve the material properties.[9]
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Remarkably, use of diazirines has emerged as a imines. In both conditions, these oxidants enable
superior cross-linking strategy for the modification of successive NÀ N and N=N bond formation.
non-functionalized alkane polymers.[10] Recently, a
promising application was developed in hyperpolariza-
Results and Discussion
tion using 15N2-diazirines, which enhances NMR
signals by >10000-fold for more than an hour.[11]
A commercially available and easily storable solution
Despite the importance of the diazirine function, of 7 N NH3 in MeOH was selected as the ammonia
synthetic routes are particularly time-consuming with source in all these studies in order to circumvent the
low efficiency, and based on multi-step tedious use of condensed ammonia at low temperature.
protocols, with the isolation, and sometimes purifica-
We first focused on the diazirine synthesis from
tion of instable intermediates which are difficult to aliphatic ketones and the ketoamide 1a was selected as
obtain in pure forms or poorly compatible with fragile a functionalized model substrate. Different oxidants
functional groups.[12]
were explored and results are summarized in Table 1.
We first started with PIDA (4.5 equiv.) which was
Although the one-pot synthesis of terminal diazir-
ines from α-amino acids in the presence of phenyl- successfully used by our group for the synthesis of
iodine diacetate [PIDA, PhI(OAc)2] was recently diazirines from α-amino acids;[13] however, it led to the
reported by our group (Scheme 1a),[13] most of the formation of the expected diazirine 2a in only 11%
diazirines are usually prepared from corresponding isolated yield (Table 1, Entry 1). With metal oxidants
ketones through the formation of diaziridine intermedi- such as silver(I) oxide (Ag2O), or manganese(IV)
ates (Scheme 1b), requiring a two-step protocol, and oxide (MnO2)[20] that were already reported to oxidize
multiple temperature modifications:[14] ketones are diaziridines into diazirines, ketoamide 1a did not react
treated with liquid ammonia at very low temperature and was recovered unchanged (entries 2 and 3). A
°
(À 78 C) to form imine intermediates, which then similar observation was made with the use of t-BuOK
undergo the nucleophilic addition of hydroxylamine- under air, which has recently been reported as an
O-sulfonic acid (HOSA, NH2OSO3H) to enable intra- effective strategy for the dehydrogenation of the
molecular cyclization and furnish corresponding diazir- NHÀ NH bond in particular for diazirine synthesis
idines.
(Entry 4).[19a] Under similar conditions, t-BuOCl en-
They can subsequently be oxidized into diazirines abled the formation of 2a in a promising 32% isolated
with a range of reagents including transition metals yield, along with 41% of the intermediate diaziridine
such as freshly prepared silver (I) oxide,[15] (entry 5). This important result reveals that t-BuOCl is
dichromate,[16] or low-cost oxidants such as sodium or able to perform both oxidation steps, forming NÀ N
t-butyl hypochlorite (t-BuOCl),[17] iodine in the pres- then N=N bond, in one-pot. Following this preliminary
ence of trimethylamine, or Hunig’s base.[18]
Very recently, a one-pot strategy was reported,
based on the successive use of HOSA in liquid
ammonia, and potassium t-butoxide (t-BuOK) under
air in order to complete the two oxidation steps.[19]
This procedure can however be difficult to implement,
in particular due to the use of a large amount of liquid
ammonia.
Herein, we describe two, straightforward, one-pot
and liquid ammonia-free, access to the diazirine
function. t-BuOCl was found to be the best oxidant
with aliphatic ketones whereas, PIDA was found to be
more effective with aromatic ketones, aldehydes and
Table 1. Optimization of the reaction conditions.
Entry Conditions[a]
Isolated
yield
1
2
3
4
5
6
7
PIDA
Ag2O
MnO2
t-BuOK, under air
t-BuOCl
11
0
0
0
32
46
41
°
t-BuOCl, 35 C
a) t-BuOCl (3 equiv.), 4 h
b) t-BuOCl (1.5 equiv.), 0.5 h
a) t-BuOCl (3 equiv.), 4 h
b) N2 degas., then t-BuOCl (1.5 equiv.),
0.5 h
8
72 (68)[b]
[a] Unless specified, all reactions were carried out in a 7 N NH3
solution in MeOH (~10 equiv.) with corresponding oxidant
(4.5 equiv.) at room temperature for 4 h.
[b] 5-fold scale-up reaction (3.4 mmol), 5 min degassing.
Scheme 1. Routes to diazirine systems.
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screening, the use of t-BuOCl as the only oxidant was ylic acid (67%, 2d), hydroxyl (41%, 2e), carbamate
further investigated. Warming the reaction mixture to (76%, 2g), and azide (58%, 2h). The presence of
°
35 C improved the efficiency of the diazirine forma- electron-deficient (CF3) and electron-rich group (OMe)
tion, which was isolated in 46% yield. Likewise, a on the phenyl ring system were well tolerated, as only
sequential addition of t-BuOCl, afforded 2a in 41% 4% of separable 3-chlorinated phenyl diazirine 2k-Cl
yield (Entry 7). As the presence of residual ammonia was observed with the benzyl ketone 1k (see Support-
in the medium may consume t-BuOCl and thus ing Information). Whilst the 1,3-disubstituted ketone
compete with the diaziridine oxidation, the excess of 1l afforded the corresponding diazirine in reasonable
ammonia was removed by nitrogen bubbling for 54% yield, the dibenzyl ketone 1m furnished the
20 min before adding the second batch of t-BuOCl diazirine in a low 25% yield, presumably due to the
(1.5 equiv.), which then significantly improved the predominance of the enol form stabilized by the phenyl
yield to 72% (Entry 8). A 5-fold scale up reaction ring systems. In contrast, cyclic 1,3-disubstituted
(3.4 mmol) was carried out leading to the formation of ketones 1n and 1o provided the corresponding
2a in 68% yield. The degassing time reduced to 5 min diazirines 2n and 2o in high 93% and 94% yields,
proved sufficient to remove residual ammonia as no respectively. In addition, the diketone 1p provided the
diaziridine was observed in the crude reaction mixture. bis-diazirine 2p in good 66% yield, with the use of
With the optimized reaction conditions in hand, the twice the amount of oxidant and solvent. Besides, the
scope of the reaction was next examined with different 3-phenylpropionaldehyde 1q formed the mono sub-
ketones. Results obtained are reported in Table 2. A stituted diazirine 2q in a low 20% yield, partly due to
series of aliphatic methyl ketones were transformed its low boiling point. However, aromatic ketones and
into their corresponding diazirines in good yields. aldehydes constitute a limitation of this methodology,
Experimental conditions were tolerant to a variety of as the oxidation of 1r and 3a did not form any
functional groups including amide (72%, 2a), carbox- detectable diazirines. Bifunctional diazirine 2s and 2t,
bearing an alkyne group, were obtained in satisfying
55% and 42% yield, respectively, which could be used
as
photoactivable
platforms
for
biological
Table 2. Scope of the one-pot liquid ammonia-free synthesis of
alkyl diazirines 2.
applications.[21]
Next, we focused on the synthesis of aromatic
diazirines from aldehydes which have been signifi-
cantly less studied,[22] as well as their reactivity.[23]
While this class of diazirines cannot be prepared from
α-amino acids (with a combination of PIDA and
ammonia) as we previously reported, we were inspired
by its mechanism of formation that also involves an
imine as an intermediate. In addition, the low yield
obtained for aliphatic ketone 2a in the presence of
PIDA (Table 1, entry 1) prompted us to optimize the
conditions for aromatic starting materials.
We then tested the one-pot reaction with p-nitro-
benzaldehyde 3a as model substrate (Table 3), which
under the previous t-BuOCl conditions, did not provide
the expected diazirine 4a (Table 2).[24] Once again, we
used commercially available 7 N NH3 in MeOH as the
source of ammonia.
After optimization (see supporting information),[25]
the best result was obtained using conditions that are
similar to the diaziridination reaction of α-amino acids,
namely, PIDA (3 equiv.) and NH3 (17.5 equiv.) in
°
MeOH at 0 C for 2 h. Indeed, we were delighted to
observe the formation of the expected diazirine 4a in a
moderate isolated yield of 47% (entry 1) along with
the
corresponding
nitrile
and
unidentified
byproducts.[26] This result is quite remarkable as
aldehydes are known to lead to the corresponding
nitriles in almost quantitative yield under similar
oxidative conditions.[27] X-ray cristallography of single
crystal of 4a (obtained by slow evaporation of CH2Cl2
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Table 3. Choice of conditions and imine protecting group. X-
Ray of 4a.
Table 4. Scope of diazirine synthesis from aldehydes 3, N-
tosyl imines 9 and N-t-butyl imines 5.[a]
[a] The corresponding nitrile was also isolated.
solution) confirmed the formation of the terminal
diazirine.
Since the reaction of diazirination from α-amino
acids has previously been shown to involve a key
trans-imination step, we also decided to use other
easily accesible starting material, such as aldimines
bearing various protecting groups (Table 3, entries 2–
8): alkyl (5a, 6a, 8a), phenyl (7a), tosyl (9a), silyl
(10a) or hydroxyl (11a). The unprotected imine
(R1=NH) cannot be employed due to its instability.
Among them, the N-t-butyl (5a) and N-tosyl aldimines
[a] Isolated yields.
[b] The corresponding nitrile was obtained.
[c] Volatile compound.
[d] Not isolated, conversion based on 19F NMR analysis of the
crude material.
(9a) afforded the diazirine 4a in higher yields (80% sulfur atom is considered as an electron-donating
and 99%, respectively) than others. With these con- group, the nitrile was not observed in this case,
ditions in hand, the scope of this reaction was probably because the sulfur atom can participate to the
evaluated using N-tosyl and N-t-butyl aldimines (9 and diazirine formation by assistance (a putative mecha-
5) obtained from various aromatic aldehydes (Table 4). nism in proposed in Figure S91).
In addition, these results were also compared with the
Interestingly para-cyano diazirine 4b and meta-
direct conversion of benzaldehydes 3 to the diazirine cyano diazirine 4k were also prepared from di-N-t-
(Table 4).
First, with benzaldehydes (3a–g) or tBu-imines
butyl imine 5j and 5k (Scheme 2) in 60 and 31%
(5a–g) bearing-electron withdrawing groups (NO2,
CN, CO2Et), the corresponding diazirines were isolated
in excellent yields, especially from N-tosyl imines.
According to 1H NMR of the crude product, the
formation of diazirine 4e with a CF3 group was
complete (the corresponding nitrile was not observed)
but unfortunately, this compound is highly volatile as
already observed with some diazirines generated from
ketones or α-amino acids.
Diazirine 4h, bearing a sulfide substituent, was
obtained in moderate yield due to concurrent formation
of corresponding sulfoximine (12%).[28] Eventhough
Scheme 2. Synthesis of diazirines 4b and 4k from 5j and 5k.
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yield, respectively. This reaction proceeds sequentially confirming the presence of a trans-imination step
but the second diazirination reaction does not take (Scheme 4).[30] 15N2-diazirine 15N2-2d also was synthe-
place considering that first formed diazirine ring is not tized in a single step from levulinic acid 1d, in 24%
an electron-withdrawing group; conversion of the yield, with almost quantitative incorporation of both
second imine to nitrile is then observed. With 15N atoms.
benzaldehydes or imines bearing electron-donating
As 15N2-diazirine can be hyperpolarized by a para-
groups (ether, halogen), the corresponding diazirines hydrogen-based method (SABRE-SHEATH) and con-
were not obtained, and only the corresponding nitriles sequently used as hyperpolarized molecular tag,[11] the
were isolated. Unfortunately, imines of heterocycles scope of reaction was studied, from N-tosyl imine
(indole, pyridine) were found to be not suitable derivatives as they were found to be a good compro-
substrates for the diazirination reaction and corre- mise in terms of chemical yield and 15N incorporation
sponding nitriles were isolated in quantitative yields.
(Scheme 3). Under these optimized conditions, moder-
Next, we performed the diazirination reaction using ate but useful chemical yields of 15N2-diazirines 15N2-
15NH3 generated from 15NH4Cl upon treatment with 4a–d and 15N2-4f–g were obtained (10–75% yield),
CH3ONa, in order to access a series of compounds along with 15N incorporation ranging from 49% to
suitable for hyperpolarization studies, as well as to 92% as determined by 15N NMR (Table 5).
provide insight into the reaction mechanism. Thus,
Finally, the reactivity of aromatic ketones was
diazirine 15N2-4a was synthesized from N-t-butyl investigated since these are a limitation of the previous
1
imine 5a in 60% yield (Scheme 3a). In H and 13C methodology using t-BuOCl. The NH-ketimine 12,[31]
NMR, the signals of the diazirine were characteristic stabilized by hydrogen bonding with a hydroxy group,
2
1
due to a supplementary JN-H (2.5 Hz) and JC-N was first tested. However, in the presence of PIDA/
(9.0 Hz) couplings, compared to the unlabeled diazir- NH3/MeOH, the expected diazirine was not observed,
ine. Surprisingly, complete 15N incorporation was but the benzoxazole 13 was isolated in 70% yield,[32]
observed by 15N NMR with the presence of a single due
to
a
rapid
Beckmann
rearrangement
doublet (Scheme 3a). On the other hand, when the (Scheme 5a).[33]
diazirination reaction was performed using N-tosyl
imine 9a, although a better yield was obtained (75%),
a lower 15N incorporation (73%)[29] was observed
according to 15N NMR spectra. Indeed, a second
deshielded doublet appeared with the same JN-H
coupling constant (Scheme 3b) corresponding to
mono-labeled diazirine 15N-4a (27%).
In addition, the same trend was observed when N-t-
15
butyl imine of levulinic acid 5m reacted with NH3: a
complete 15N incorporation was obtained for 15N2-2d,
Scheme 4. Synthesis of diazirine 15N2-2d of levulinic acid.
Table 5. Scope of 15N2-diazirine synthesis from N-tosyl imines
9.[a]
Scheme 3. Synthesis of diazirine 15N2-4a and 15N-4a from
imines 5a and 9a and corresponding 15N NMR spectra.
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Scheme 5. Synthesis of diazirine 2r/2v and X-ray of 2r/13.
Scheme 6. Proposed diazirination mechanisms from carbony-
lated or imines derivatives.
Consequently, N-tosyl ketimines 15 were chosen as
substrates based on the aldimine series, which were
easily prepared from N-sulfinyl imine 14 (Scheme 5b)
by oxidation with mCPBA.[34]
allows the formation of chloroketimine II. Alterna-
Surprisingly, using the same diazirination condi- tively, chloroketimine II can be formed by t-BuOCl
tions, N-sulfinyl imine 14w (R=Br) and 14x oxidation of NH-imine, obtained by addition of
(R=OMe) did not afford the corresponding diazirine ammonia on the carbonyl compound. Chloroketimine
but led to the corresponding ketones in quantitative II can then react with ammonia to led to diaziridine III
yields, while N-sulfinyl imine 14a (R=NO2) and 14b after cyclisation. After evaporation of ammonia, its
(R=CN) led to expected diazirines 2r and 2v in 67% oxidation with t-BuOCl, forms the diazirine IV
and 74%, respectively (Scheme 5b). Although the (Schema 6a).
synthesis of N-tosyl imines 15a and 15b requires an
As demonstrated by the previous experiment with
additional oxidation step, diazirines 2r and 2v were 15NH3, (Scheme 3 and Scheme 4), a trans-imination
obtained in better yields of 90% and 92%, respectively. occurs with N-t-butyl imine and would explain the
Additionally, direct transformation of acetophenone formation of 15N-imine 15N-I (Scheme 6b). This latter
into diazirine was also attempted. Satisfyingly, diazir- would be trapped by PIDA to lead to the imine V. This
ine 2r and 2v were isolated in 95 and 45% yield, step and subsequent steps must be highly favored since
respectively (Scheme 5c), but the reaction required only 15N2-diazirine 15N2-IV was obtained and not the
however a larger amount of PIDA (8 equiv.). The X- mono-labeled 15N-IV one. A similar explanation could
ray analysis of 2r was also obtained and revealed be used for N-tosyl imine since aminal VI could form
similar angles than structure of diazirine 4a but with a the same 15N-labeled imine 15N-I (path a) with
longer CÀ N bond.
concomitant tosylamine release.[35] On the other hand,
A mechanistic proposal explaining all these results the cyclisation of the aminal VI (path b) could explain
is depicted in Scheme 6. In the presence of t-BuOCl the formation of mono-labeled diaziridine 15N-III,
and ammonia, chloroamine I is formed in-situ and
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for 4 h at room temperature. Then, the excess of NH3 was
removed by N2 degassing for 20 minutes before adding the
second portion of t-butyl hypochlorite (114 μL, 1 mmol,
1.5 equiv.) in t-butanol (0.5 mL). The consumption of the
diaziridine intermediate was followed by ninhydrin testing. The
mixture was stirred for 30 minutes at room temperature, then
concentrated under reduced pressure. The crude was diluted
with a solution of saturated aq. Na2S2O3 (5 mL) and extracted
with Et2O (3×10 mL). The combined organic layers were dried
over MgSO4 and evaporated under vacuum. Finally, the crude
material was purified by flash chromatography over silica gel.
which is further oxidized with PIDA into correspond-
ing monolabeled diazirine 15N-IV.
Finally, a plausible mechanism for the formation of
diazirines from aromatic carbonyl derivatives in the
presence of ammonia and PIDA is proposed in
Scheme 6c. The nucleophilic attack of the carbonyl
derivative on PIDA would lead to the intermediate IX
which, after reaction of ammonia, would furnish the
corresponding primary imine I.[36] But, after ligand
exchange between PIDA and ammonia,[37] intermediate
VIII or iminoiodinane VII,[38] can also be formed
which reacted with aromatic aldehydes and ketones to
form iodinated imine V. A large excess of PIDA
(8 equiv.) is thereby necessary due to formation of
iodonitrene from VII[38] which dimerized into N2.[28]
General Procedure for the Synthesis of 3H-Diazir-
ines (4) from Imines (5) or (9)
(Diacetoxyiodo)benzene (1.5 mmol, 3 equiv.) was added in one
portion to a stirred solution of imine 5 or 9 (0.5 mmol, 1 equiv.)
°
in NH3 in MeOH 7 M (1.25 mL, 17.5 equiv.) at 0 C under
Conclusion
°
Argon. After 30 minutes at 0 C, the batch was allowed to reach
room temperature and was left stirred for 1 h30. After
In conclusion, this report describes a direct access to
aliphatic and aromatic diazirines in the presence of
inexpensive oxidizing agents t-BuOCl and PIDA,
respectively. Reaction conditions are distinguished by
their operational simplicity (one-pot protocol, mostly
room temperature), and the absence of freshly con-
densed ammonia. The wide scope of these approaches
(although limited to electron-poor aromatics) was
demonstrated by the synthesis of more than 30
diversely functionalized diazirines, including amide,
carboxylic acid, alcohol, thioether, and azide groups, to
cite a few. On one hand, the access to aliphatic
diazirines was illustrated by the design of a minimalist
bioconjugatable platform 2t achieved in only 4 steps,
which will find applications in proteomics. On the
other hand, this strategy also affords a straightforward
entry to 15N2-diazirines with complete 15N incorpora-
tion, with potent applications in hyperpolarized mag-
netic resonance imaging. Importantly, these labeling
1
completion (monitored by TLC and H NMR), the batch was
concentrated under reduced pressure and the crude was purified
by flash chromatography on silica gel to afford diazirine 4.
General Procedure for the Synthesis of 3H-Diazir-
ines (4) from Aldehydes
(Diacetoxyiodo)benzene (1.5 mmol, 3 equiv.) was added in one
portion to a stirred solution of aldehyde 3 (0.5 mmol, 1 equiv.)
°
in NH3 in MeOH 7 M (1.25 mL, 17.5 equiv.) at 0 C under
°
Argon. The batch was left stirred at 0 C for 2 h00. After
1
completion (monitored by TLC and H NMR), the batch was
concentrated under reduced pressure and the crude was purified
by flash chromatography on silica gel to afford diazirine 4.
General Procedure for the Synthesis of 15N2-Diazir-
ine (15N-2or 15N-4)
(Diacetoxyiodo)benzene (3 equiv.) was added in one portion to
experiments contributed to unveil the mechanisms of a stirred solution of imine 5 or 9 (1 equiv.) in 15NH3 in MeOH
°
°
7 M (17.5 equiv.) at 0 C under argon. After 30 minutes at 0 C,
the batch was allowed to reach room temperature and was left
stirred for 1 h30. After completion (monitored by TLC and H
diazirines formation, in particular from imine precur-
sors in the presence of PIDA.
1
NMR), the batch was concentrated under reduced pressure and
the crude was purified by flash chromatography on silica gel.
Experimental Section
CCDC-2074588 (4a), CCDC 2074589 (2r) and CCDC
2074590 (13) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
Acknowledgements
This work was supported by the Region Normandie, and a PhD
financial support to MC and QI. This work has been partially
supported by University of Rouen Normandy, the Centre
National de la Recherche Scientifique (CNRS), INSA Rouen
Normandy, European Regional Development Fund (ERDF),
Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the
graduate school for research XL-Chem (ANR-18-EURE-0020
XL CHEM), and by Region Normandie.. We also thank Albert
Marcual (CNRS, Rouen) and Karine Jarsalé (Caen) for HRMS
analyses.
General Procedure A for the Synthesis of Diazirine
(2) from Aliphatic Ketones
To a solution of the corresponding ketone (0.675 mmol) in a
7 N solution of NH3 (7 mmol, 10.4 equiv.) in MeOH (1 mL) in
a dried microwave tube equipped with a rubber septum, was
carefully added a solution of t-butyl hypochlorite (229 μL,
2 mmol, 3 equiv.) in t-butanol (1 mL). The mixture was stirred
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[19] a) L. Wang, A. Ishida, Y. Hashidoko, M. Hashimoto,
Angew. Chem. Int. Ed. Engl. 2017, 56, 870–873; b) L.
Wang, Z. P. Tachrim, N. Kurokawa, F. Ohashi, Y.
Sakihama, Y. Hashidoko, M. Hashimoto, Molecules
2017, 22, 1389.
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RESEARCH ARTICLE
asc.wiley-vch.de
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© 2021 Wiley-VCH GmbH
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RESEARCH ARTICLE
One-Pot Synthesis of Diazirines and 15N2-Diazirines from
Ketones, Aldehydes and Derivatives: Development and
Mechanistic Insight
Adv. Synth. Catal. 2021, 363, 1–10
Q. Ibert, M. Cauwel, T. Glachet, T. Tite, P. Le Nahenec-
Martel, J.-F. Lohier, P.-Y. Renard, X. Franck*, V. Reboul*, C.
Sabot*