Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal Diazirines and 15N2-Diazirines and Their Application as Hyperpolarized Markers

Article abstract of DOI:10.1021/jacs.9b07035

A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDA-mediated transformation occurs via three consecutive reactions and involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it is operationally simple, and it can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that this transformation could be applied to dipeptides without racemization. Furthermore, ¹⁴N₂ and ¹⁵N₂ isotopomers can be obtained, emphasizing a key trans-imination step when using ¹⁵NH₃. In addition, we report the first experimental observation of ¹⁴N/¹⁵N isotopomers directly creating an asymmetric carbon. Finally, the ¹⁵N₂-diazirine from l-tyrosine was hyperpolarized by a parahydrogen-based method (SABRE-SHEATH), demonstrating the products' utility as hyperpolarized molecular tag.

Full text of DOI:10.1021/jacs.9b07035

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Article
Iodonitrene in Action: Direct Transformation of Amino Acids into Terminal
15
2
Diazirines and N-Diazirines and their Application as Hyperpolarized Markers
Thomas Glachet, Hamid MARZAG, Nathalie Saraiva Rosa, Johannes F. P. Colell,
GUANNAN ZHANG, Warren S. Warren, Xavier Franck, Thomas Theis, and Vincent Reboul
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Aug 2019
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Iodonitrene in Action: Direct Transformation of Amino Acids into
Terminal Diazirines and N2-Diazirines and their Application as
Hyperpolarized Markers
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Thomas Glachet,a Hamid Marzag,a Nathalie Saraiva Rosa,a Johannes F. P. Colell,b Guannan Zhang,b
Warren S. Warren,b Xavier Franck,c Thomas Theisb,d* and Vincent Reboula*
a Normandie Univ, ENSICAEN, UNICAEN, CNRS, LCMT, 14000 Caen, France
b Duke University, Department of Chemistry, 124 Science Drive, Durham, NC27708, USA
c Normandie Univ, CNRS, UNIROUEN, INSA Rouen, COBRA, 76000 Rouen, France
d North Carolina State University, Department of Chemistry, 2620 Yarbrough Drive Raleigh, NC 27695 , USA
ABSTRACT: A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using
phenyliodonium diacetate (PIDA) and ammonia. This PIDA mediated transformation occurs via three consecutive reactions and
involves an iodonitrene intermediate. This method is tolerant to most functional groups found on the lateral chain of amino acids, it
is operationally simple, and can be scaled up to provide multigram quantities of diazirine. Interestingly, we also demonstrated that
this transformation could be applied to dipeptides without racemization. Furthermore, 14N2 and 15N2 isotopomers can be obtained,
emphasizing a key trans-imination step when using 15NH3. In addition, we report the first experimental observation of 14N/15N
isotopomers directly creating an asymmetric carbon. Finally, the 15N2-diazirine from L-tyrosine was hyperpolarized by a
parahydrogen-based method (SABRE-SHEATH), demonstrating the products utility as hyperpolarized molecular tag.
from sulfoxides, using PIDA and ammonia.9 In this reaction,
two short-lived electrophilic intermediates were suggested: the
INTRODUCTION
Since the early 2010’s, transition metal-catalyzed nitrene
transfer reactions1 to C=C, C-H and R–S–R group have become
well established methods for the preparation of aziridines,2
amines3 or sulfilimines4 respectively (Figure 1). In addition to
common reactions, recent studies have emerged and extended
the scope of the synthetic nitrene chemistry.5 These
methodologies typically require iminoiodinane N-protected
nitrene species, easily generated from PIDA (phenyliodonium
diacetate) or PhIO.
iminoiodinane PhI=NH and the iodonitrene PhI(OAc)N.
Simultaneously, during our mechanistic investigation of the
NH-sulfoximination of sulfide using the same reagents, we
proposed the formation of the nitrene species due to the
observation of its fast dimerization into N2.10 In order to expand
the reactivity and synthetic applications of nitrene species, we
envisioned their use for the synthesis of terminal 3H-diazirines.
Scheme 1. Direct NH Transfer Reactions via Nitrene Species
Figure 1. Common Metal-Catalyzed Nitrene Transfer
Reactions
Great improvements were recently described by Ess, Kürti
and Falck groups, using homogeneous catalysis with rhodium
based Dubois’s catalyst, with the direct stereospecific synthesis
of NH-aziridines6 using O-(2,4-dinitrophenyl)-hydroxylamine
(DPH) via a triplet state of the nitrene,7 and the primary
amination reaction of arenes (Scheme 1a).8 At the same time,
Luisi and Bull reported the first electrophilic metal-free NH
transfer (Scheme 1b) during the synthesis of NH-sulfoximines
Diazirines, three-membered rings containing two nitrogen
atoms and one carbon atom, were first identified as
photoaffinity labeling groups by Knowles in the 1970’s,11 and
remain widely used in chemical biology.12 Indeed, upon UV-
irradiation (360 nm), diazirines generate carbenes, which form
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covalent bonds with the nearest target protein via C–C, C–H or Scheme 3. Targeted and Side Reactions During the
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O–H insertion.13 A few years later, Richards introduced a
trifluoromethyl group in aromatic series to further stabilize the
carbene.14 Interestingly, the reactivity of halodiazirines15 was
widely studied because they are easily prepared from nitriles
using Graham’s method.16 In recent years, new practical
applications for diazirines were disclosed; they were used as
carbon radical traps in amination processes,17 as carbene
sources for the formation of sulfur ylides,18 as electrophilic
nitrogen sources in the synthesis of pyrazoles,19 and as reagents
in the Pd-catalyzed cross-coupling reactions with aryl halides,20
or even in oxidative cross-coupling reactions with aryl boronic
acid.21 Another recent promising application for substituted
diazirines is the use of 15N2-diazirines in hyperpolarization,
which enhances NMR signals by >10,000-fold. In this context,
diazirines generate detectable signals that last for more than an
hour.22
Decarboxylation Step.
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Finally, its subsequent oxidation, with the release of
iodobenzene and acetic acid, should lead to the expected
diazirine.32 With this hypothesis in mind, we chose L-histidine
(1a) as the model substrate (Table 1). First, we tested conditions
used for the sulfoximination of sulfide,10 namely 2 equiv. of
PIDA and 1.5 equiv. of ammonium carbamate (AC), in
methanol at rt, with the addition of an extra equiv. of PIDA in
order to perform the decarboxylation reaction. However, with
these conditions (entry 1), only traces of expected diazirine 2a
were detected by 1H NMR of the crude product and histidine 1a
was recovered. In contrast, increasing the amount of AC (17.5
equiv) or switching to ammonia (entries 2-3), allowed for the
isolation of diazirine 2a in 29% yield for both cases despite low
conversion (<40%). In those cases (and all other entries), small
amounts of nitrile 3a were also formed.33 The yield of 2a was
significantly increased (86%) by conducting the reaction at 0 °C
(entry 4) and similar yield was obtained when trifluoroethanol
was added (entry 5).34
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To date, the main obstacle for widespread utilization of
diazirines is the lack of simple and efficient synthetic methods
to prepare them. Indeed, their syntheses usually require at least
3 to 4 steps,23 generally using liquid ammmonia (at –78°C) with
moderate reaction yields. For aliphatic diazirines, conventional
methodologies involve treatment of carbonyl derivatives with
NH3, subsequent reaction with hydroxylamine-O-sulfonic acid
(HOSA) to form the corresponding diaziridines, and, finally,
their oxidation into diazirines (Scheme 2).24 Unfortunately, the
synthesis of terminal diazirines remains underexploited
compared to their substituted counterparts.25 For
trifluoromethylaryl diazirine synthesis, an additional step is
needed to form the O-sulfonyl oxime. Recently, some
improvements were made using resin-bound sulfonyl oximes,26
or t-BuOK as a dehydrogenating agent in a one-pot reaction.27
Table 1. Optimization of Reaction Conditions with Histidine as
the Model Substrate
Scheme 2. Typical Synthesis of Diazirines from Carbonylated
Compounds
Entry
equiv
PIDA,
additive
ACa or
NH3
(equiv)
°C 2a/3a Isolated
b
(%)c
yield of
2a
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6
3
3
3
3
AC (1.5)
rt
0
rt
0
0
0
-
tracese
AC (17.5)
NH3 (24.5)
NH3 (24.5)
80/20 29e
92/8
98/2
96/4
98/2
29e
In this study, we focused on the synthesis of terminal
diazirines from unprotected amino acids via three consecutive
one-pot reactions mediated by PIDA (Scheme 1c):
1) decarboxylation of the amino acid into the corresponding
imine; 2) insertion of the iodonitrene to form a diaziridine; 3)
its oxidation into the desired diazirine. The details for this new
one-pot and metal-free reaction are reported herein.
86
3, TFE (10) NH3 (24.5)
84
20e
PIDA·BF3
in-situ (3),
CH2Cl2
PIFAe (3)
NH3 (24.5)
d
7
NH3 (24.5)
NH3 (24.5)
NH3 (24.5)
NH3 (28)
0
0
0
0
0
0
0
-
tracese
75
8
4
2
3
3
3
3
97/3
98/2
97/3
96/4
97/3
RESULTS AND DISCUSSION
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Hypervalent iodine reagents are known to allow for oxidative
decarboxylation of -amino acids28 resulting in an imine
intermediate that in some cases, leads to the formation of nitrile
(Scheme 3).29
10
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13
68
NH3 (21)
96
NH3 (17.5)
NH3 (10.5)
98
The successful formation of diazirine depends on the
(supposedly very fast) insertion reaction of the iodonitrene
(formed from the reaction of PIDA and ammonia)9,10 on this
imine30 leading to the corresponding diaziridine intermediate.31
85/15 84
a Ammonium carbamate. b 7 M solution in methanol. c Estimated
1
d
e
by H NMR on the crude. CH2Cl2 was used instead of MeOH.
PIFA [phenyliodonium bis(trifluoroacetate)] was used instead of
PIDA. e Incomplete conversion
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Table 2. Scope of the Diazirination Reactiona,b
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b
c
a The name of the starting amino-acid was indicated above the corresponding diazirine. Isolated yield. Highly volatile compound. d
Sublime
However, the utilization of a PIDA·BF3 complex35 (entry 6)
reduced the yield dramatically down to 20%. In addition, no
reaction occurred when PIFA [phenyliodonium
bis(trifluoroacetate)] was used instead of PIDA (entry 7). The
amount of PIDA (entries 8-9) and NH3 (entries 10-13) were then
optimized and an excellent 98% yield was obtained using 3
equiv. of PIDA with 17.5 equiv. of NH3 (entry 12).
indole heterocycle (Trp), carboxylic acid (Asp, Glu) or hydroxy
group (Ser, Thr), and thus precluded accurate yield
quantification. Consequently, we point out that diazirination
enhances the volatility of the synthesized compounds and the
troublesome functional groups were protected with
conventional protecting groups (Boc, Bn, silyl ether, ester or
secondary amide) and the corresponding diazirines could then
be obtained in moderate to excellent yields (38-98%).
Regarding primary amide (Asn, Gln), sublimation of the
diazirines prevented accurate yield quantification, but X-ray
structures (diazirines 2k and 2l) could be obtained.
Surprisingly, for L-glutamine, the crystal structure showed that
the isolated compound was the corresponding urea 2k resulting
from a Hofmann-like rearrangement40 which was not observed
with L-asparagine. Notably, the use of theanine (N-ethyl-L-
glutamine) prevented this rearrangement and led to the desired
diazirine 2j with 48% yield. L-citrulline, an amino acid bearing
a urea functional group, was readily converted into diazirine 2m
with 90% yield. Not surprisingly, these reaction conditions
were not compatible with sulfurated amino acids (Cys,41 Met42)
due to possible side reactions with PIDA. Thus, the thiol group
With these conditions in hand, the scope of this reaction was
evaluated using natural and unnatural amino acids (Table 2).
Amino acids with hydrophobic side chains (Ala, Val, Ile, Leu,
Phe) were not used as starting material due to the high volatility
of aliphatic diazirine,36 a rarely mentioned property. With
L-tyrosine,37 KOH (2 equiv) is added to the reaction mixture in
order to ensure solubility38 and the reaction furnished the
expected diazirine 2b in quantitative yield. Hence, the
scalability of this reaction was demonstrated by conducting the
reaction with 1b on a gram scale (5.5 mmol) to afford 2b in an
80% yield. Surprisingly, problems resulting from the volatile
nature of the diazirine group39 were also observed with
numerous amino acids bearing functional groups such as free
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was transformed into the corresponding tritylsulfide and
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extrusion. In methanol, the excited state of the diazirine leads to
the carbene generation which is subsequently trapped by the
solvent. In addition, when the photolysis of diazirine 2b was
performed in dichloromethane (20 mM) in presence of
methanol (2 – 300 equiv.), various mixture of methylether 4 and
styrene derivative were obtained (from 0/100 to 20/80),
showing that carbene generation and subsequent trapping of the
carbene is possible but less effective with terminal diazirines
than with trifluoromethylated diazirines. Then, in order to
facilitate the synthesis of potential PAL probes, the resulting
diazirines should be easily derivatized into more complex
molecules. Thus, the phenol group of the tyrosine derivative 2b
was transformed into carboxylic acid 6 in two steps with
quantitative yield (Scheme 4, bottom).
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afforded moderate 38% yield upon diazirination (2q). In
addition, S-benzyl-L-cysteine and L-methionine were converted
into their sulfoxide analogs to avoid sulfoximination reaction10
and the corresponding diazirines 2r and 2s were then obtained
in 71% and 79% yields, respectively. Interestingly, diazirine 2t
bearing a sulfoximine function can also be obtained in
quantitative yield from methionine sulfoxide simply by
doubling the amount of reactants. The free amino group of L-
lysine and the guanidine function of L-arginine showed to be
incompatible with the reaction conditions and gave complex
mixtures where no specific compound could be identified.
However, protected N-acetyl- or N-Cbz-lysine furnished
diazirines 2v and 2w in high yields. Next, to broaden the
synthetic interest of this method, we investigated the
diazirination of non-classical dipeptides resulting from peptide
couplings of the lateral chain of L-glutamic acid, L-aspartic acid
and L-lysine. Diazirines 2g and 2h were isolated with modest
43% and 21% yield, respectively, due to their relatively high
volatility compared to compound 2i (derived from -aspartame)
which was obtained with a 66% yield. Then, L-lysine was
coupled with N-Cbz-amino acids (glycine, L-alanine and L-
valine) and afforded corresponding peptides 2x, 2y and 2z upon
diazirination with moderate to high yields (41-91%). In
particular, X-ray structure of 2x was obtained and a racemic
version of diazirine 2y confirmed that this reaction proceeds
without racemization (see SI). In addition, because the diazirine
of L-phenylalanine is volatile, we used 4-iodo-L-phenylalanine
instead, which led to diazirine 2u in 78% yield. This was easily
derivatized further into diazirine 5 with quantitative yield using
a Suzuki-Miyaura cross coupling reaction (Scheme 4).43
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Next, to provide insight into the reaction mechanism, we
examined the diazirination using 15NH3 generated from 15NH4Cl
as the most economical source of 15NH3 upon treatment with
CH3ONa (Figure 2a).47 We first synthesized 15N2-diazirine 8b
from 15N-tyrosine, with quantitative yield and complete
incorporation of 15N (Figure 2b).48 In 1H NMR, the signal of the
diazirine proton was characteristic due to a supplementary 2JN-H
coupling: a triplet of triplet is observed for 8b compared to the
triplet of diazirine 2b (Figure 2c). Surprisingly, when the
reaction was performed with unlabeled tyrosine, 15N2-diazirine
was obtained with an unexpected 87% of 15N incorporation
(Figure 2d).
Figure 2. Preparation of 15NH3 and Subsequent Reactions
Next, considering that substituted diazirines are primarily
used for photoaffinity labelling (PAL) via the generation of a
carbene species, it was essential to verify their generation with
terminal diazirines.
Scheme 4. Carbene Generation and Derivatization of 2b and 2u
Moreover, when 15N-tyrosine was treated by NH3, only
unlabeled diazirine 2b was isolated (Figure 2e). These results
prompted us to reconsider the proposed reaction mechanism
(Scheme 5).
Indeed, 15N2-diazirine 8b can only result from the
intermediate 15N-imine A. This latter species could either be
formed through direct trans-imination49 or via the
corresponding aldehyde obtained after hydrolysis of unlabeled
imine with water formed during the generation of the
iodonitrene.9 However, when the reaction was conducted in an
NMR tube in CD3OD and monitored over time, no aldehyde
signal could be observed.50 Next, the key diaziridine D could
Hence, diazirine 2b was irradiated for 2 hours at 360 nm in a
quartz tube under Argon in presence of methanol (20 mM) to
afford the corresponding methylether 4 adduct isolated with
70% yield (Scheme 4, top).44 When the reaction was performed
in dichloromethane without methanol, the corresponding
styrene derivative 4’ was formed in 52% yield.45 This
compound originates from the rearrangement in the excited
state (RIES) first described by Platz.46 Indeed, like the
dialkyldiazirines or alkylphenyldiazirines, the photolysis of the
terminal diazirine 2b promotes the diazirine to the S1 excited
state which undergoes a [1,2]-H shift in concert with nitrogen
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either be formed after insertion of the 15N-iodonitrene into
imine A, or through the formation of intermediate C.
Scheme 5. Proposed 15N2-Diazirination Mechanism from
incorporation is in the range of 42-91%.52 Interestingly, in the
case of mono-15N-labeled diazirine, the presence of both 14N
and 15N induced the formation of an asymmetric carbon. Hence,
for compounds bearing a chiral center (8p, 8r, 8s and 8t),
diastereoisomers are formed and could be observed in 15N NMR
(see SI). To the best of our knowledge, this is the first
experimental observation of chiral 14N/15N isotopomer where
the induced stereogenic center is created directly.53
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Unlabeled Amino Acids
Lastly, we wondered if the resulting terminal diazirines could
be used in hyperpolarization. Indeed, substituted diazirines may
have a new role as hypersensitive NMR and MRI tags. The
hyperpolarization technique enhances traditional NMR and
MRI signals by up to five orders of magnitude, however a major
obstacle is the fast decay of hyperpolarization after injection
into an animal or patient (typically signal vanish in less than one
minute). Substituted 15N2 diazirines have been found to
overcome this problem with their ability to store
hyperpolarization for up-to one hour. In fact, the
hyperpolarization can be stored, either as quantum-
mechanically protected 15N2 singlet states or simply as 15N
magnetization. In every case, the decay time constant T1 (for
magnetization) or TS (for singlet states) is much larger than
typical NMR decay time constants in small organic molecules.
An important issue is that T1 and TS may be shortened in
terminal diazirines because of dipole-dipole interaction with
close, neighboring hydrogen spins. The original study avoided
this issue by using deuterated substituted 15N2-diazirine.22 Here,
we investigated the first hyperpolarization of a terminal 15N2-
diazirine 8b, the L-tyrosine derivative, using the SABRE-
SHEATH method (Figure 3).22,24b,54
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Indeed, this second pathway cannot be ruled out since the
formation of intermediate B could be possible via nucleophilic
addition of 15NH3,51 followed by cyclization into diaziridine C.
Finally, 15N2-diazirine could be obtained after subsequent
oxidation. So, while our results shed light on important aspects
of the reaction mechanism, further studies are warranted to
elucidate the exact details of trans-imination and
diaziridination.
Figure 3. Hyperpolarized 15N-NMR Experiments of 8b. A)
Hyperpolarized 15N NMR spectrum observed at 443.4 ppm (37
MHz, CD3OD) and J-coupling analysis. B) Hyperpolarization
decay time (T1) measurement at 0.3 mT.
Table 3. Synthesis of 15N2-Diazirines from Unlabeled Amino
Acidsa,b
a
The name of the starting amino-acid is indicated above the
b
c
corresponding diazirine. Isolated yield. Estimated by HRMS.
d Estimated by 15N NMR.
Finally, the scope of the reaction was evaluated for unlabeled
amino acids leading to 8 non-volatile 15N2-diazirines (Table 3).
The yields for 15N2-diazirines 8 are comparable to the unlabeled
diazirines, except for 8a and 8r which are lower. 15N
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A sample of 18.6 mM of 8b in methanol-d4, also containing
for terminal 15N2-diazirine as molecular tags. In addition,
biocompatibility assays were conducted and showed no specific
cytotoxicity for a representative panel of the diazirine
compounds, allowing us to move forward to in vitro or in vivo
hyperpolarization experiments in the near future. Lastly, further
investigations that aim to expand the synthetic usefulness of
iodonitrene species are currently in progress in our laboratory.
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0.125 mM [Ir(COD)(IMes)Cl] as hyperpolarization catalyst and
0.5 mM pyridine as auxiliary ligand, was exposed to 1.5 min of
bubbling with parahydrogen at a magnetic field of 0.4 µT. After
transfer of the solution into an 8.45 T NMR spectrometer, we
were delighted to observe a signal enhancement of 3300 fold
corresponding to a polarization of 0.92 %, indicating that the
hydrogen atom of the terminal diazirine does not cause
excessive relaxation and does not prevent hyperpolarization.
Furthermore, we measured the signal lifetimes of magnetization
and found exponential decay time constant of T1 = (1.34 ± 0.16)
min at a magnetic field of 0.3 mT. Notice that 8b does not bear
a stereogenic center and therefore we could only measure the
decay of magnetization characterized by T1, whereas the
potentially much longer singlet-state lifetime remained
inaccessible. For this purpose, chiral diazirines 8r and 8s,
bearing a sulfoxide group (asymmetric sulfur atom), were
specifically designed and synthesized, and their unprecedented
reactivity towards singlet-order hyperpolarization will be
reported soon.55 Then, in order to evaluate the biocompatibility
of terminal diazirines for future in vitro or in vivo applications,
the cytotoxicity of a representative panel of compounds (2a, 2b,
2g, 2m, 2r, 2t and 2y) was evaluated on immortalized
human fibroblast cell lines (AG-1521). Several assays were
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The Supporting Information is available free of charge on the
ACS Publications website.
Methods, syntheses, characterizations, NMR spectra, details
of X-ray structural analysis.
CIF files for compounds 2k, 2l and 2x.
AUTHOR INFORMATION
Corresponding Author
vincent.reboul@ensicaen.fr
ttheis@ncsu.edu
conducted
[Cellular
activity
by
Impedancemetry
(xCELLigence), Cellular Confluency, MTS and Cellular
Morphology] and no cytotoxicity was observed at 5, 10 and 25
µM. In addition, our lead compounds 2b and 2r did not even
show cytotoxicity at 50 or 100 µM (see SI).
ORCID
Vincent Reboul: 0000-0002-1474-4065
Thomas Theis: 0000-0001-6779-9978
Xavier Franck: 0000-0002-5615-7504
Thomas Glachet: 0000-0002-5114-1116
CONCLUSION
In conclusion, this work reports the first direct synthesis of
terminal diazirine from unprotected amino acids. Many
functional groups present in the amino acid side chain are
tolerated, such as heteroarene, carboxylic acid, hydroxyl,
carboxyl, sulfide, sulfoxide, amide, urea and ester groups. This
procedure is operationally facile, high yielding, and provides a
rapid access to terminal diazirines, which is not straightforward
by other synthetic routes. Interestingly, we also demonstrated
that this transformation could be applied to dipeptides without
racemization. In addition, terminal 15N2-diazirines were also
prepared from unlabeled amino acids. This points out a
probable trans-imination step in the reaction mechanism and it
allowed us to report the first direct observation in 15N NMR of
the formation of an asymmetric carbon induced by 14N/15N
isotopomers. Finally, the 15N2-diazirine of L-tyrosine was
hyperpolarized using parahydrogen using the SABRE-
SHEATH method. The expected decay of hyperpolarization
due to dipole-dipole interactions between the 15N2-diazirine and
the neighboring hydrogen atom of the terminal diazirine does
not prevent hyperpolarization, promising future developments
REFERENCES
NOTES
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
The authors thank the CNRS, Normandie Université, Labex
Synorg (ANR-11-LABX-0029), the Conseil Régional de
Normandie and the European FEDER fundings for financial
support. Research reported in this publication was also supported
by the National Institute of Biomedical Imaging and
Bioengineering of the NIH under R21EB025313. We gratefully
acknowledge E. Brotin and C. Denoyelle for cytotoxicity analysis
(BioTICLA), K. Jarsalé for HRMS analysis, J.-F. Lohier for X-ray
1
analysis, H. Elsiblani and R. Legay for H and 15N NMR studies
carried out in Caen. We also thank Dr S. Perrio for helpful
discussions.
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The only other example of chiral 14N/15N isotopomer is:
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Remarkable rate enhancement of sulfoximination reaction was
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The maximal absorption wavelength of diazirine 2b was
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3-nitrobenzene as internal standard (89% conversion).
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47 Ammonium chloride (15NH4Cl) was rather employed as readily
available source of 15NH3 instead of expensive 15NH3 commercial
solution in methanol. See experimental section.
48
15N incorporation was estimated by HRMS.
Ciaccia, M.; Di Stefano, S. Mechanisms of imine exchange
49
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one-pot reaction
metal free reaction
wide scope (34 examples)
hyperpolarized tag
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