Decarboxylative Amination: Diazirines as Single and Double Electrophilic Nitrogen Transfer Reagents

Article abstract of DOI:10.1021/jacs.0c09403

The ubiquity of nitrogen-containing small molecules in medicine necessitates the continued search for improved methods for C-N bond formation. Electrophilic amination often requires a disparate toolkit of reagents whose selection depends on the specific structure and functionality of the substrate to be aminated. Further, many of these reagents are challenging to handle, engage in undesired side reactions, and function only within a narrow scope. Here we report the use of diazirines as practical reagents for the decarboxylative amination of simple and complex redox-active esters. The diaziridines thus produced are readily diversifiable to amines, hydrazines, and nitrogen-containing heterocycles in one step. The reaction has also been applied in fluorous phase synthesis with a perfluorinated diazirine.

Full text of DOI:10.1021/jacs.0c09403

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Article
Decarboxylative Amination: Diazirines as Single and Double
Electrophilic Nitrogen Transfer Reagents
Preeti P. Chandrachud, Lukasz Wojtas, and Justin M. Lopchuk*
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ABSTRACT: The ubiquity of nitrogen-containing small molecules in
medicine necessitates the continued search for improved methods for C−N
bond formation. Electrophilic amination often requires a disparate toolkit of
reagents whose selection depends on the specific structure and functionality of
the substrate to be aminated. Further, many of these reagents are challenging
to handle, engage in undesired side reactions, and function only within a
narrow scope. Here we report the use of diazirines as practical reagents for the
decarboxylative amination of simple and complex redox-active esters. The
diaziridines thus produced are readily diversifiable to amines, hydrazines, and
nitrogen-containing heterocycles in one step. The reaction has also been
applied in fluorous phase synthesis with a perfluorinated diazirine.
for oxaziridines 2 are regularly reported; they are able to
transfer either their nitrogen or oxygen depending on the
reagent structure and reaction conditions.2 Both oxaziridi-
niums and diaziridiniums 3 have been more recently developed
as practical reagents.3 Like oxaziridines, they may be used for
either oxidation or amination. Diazirines 4, which are
extensively used as carbene sources in chemical biology,4 are
notably lacking among this series of heterocycles with respect
to heteroatom transfer. While scattered reports exist in the
literature that demonstrate the ability for diazirines to act as
electrophilic sources of nitrogen,5 it is apparent that none
leverage the full potential of these reagents. Given the gap in
synthetic methodologies capable of selectively delivering either
amines or hydrazines from a single reagent, we investigated
diazirines as a potential scaffold for single or double
electrophilic nitrogen transfer.
INTRODUCTION
■
The selective transfer of heteroatoms is a powerful tool in
organic synthesis that allows for the rapid conversion of
inexpensive commercial feedstocks to high-value scaffolds for
use in medicine, agrochemistry, chemical biology, and
materials science.1 One general class of heteroatom transfer
reagents with broad utility are three-membered strained
heterocycles (Figure 1A). Dioxiranes 1 are often used for
C−H oxidations to afford site selectivity that is difficult or
impossible to match with other methods.1b New applications
As partially evidenced by their widespread utility in synthetic
organic chemistry, chemical biology, and proteomics,6
diazirines are simple to prepare and their synthesis can be
conducted on a relatively large scale that lends itself well to
reagent development (Figure 1B). In principle, the mono-
functionalization of diazirine 6 with a carboxylic acid
equivalent would afford diaziridine 5. This structure, while
generally stable and isolable, can be converted to amines,
hydrazines, and a variety of nitrogen-containing heterocycles. If
Received: September 1, 2020
Figure 1. Synthetic methods for strain-release-driven heteroatom
transfer: (A) Heteroatom transfer via three-membered heterocyclic
reagents; (B) Conceptual use of diaziridines as a “diversity-enabling
disconnection” in the synthesis of amines, hydrazines, and nitrogen-
containing heterocycles.
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it is considered in a retrosynthetic manner, the use of
diaziridine intermediates represents a “diversity-enabling
disconnection”, since diaziridine 5 may be thought of as
both a masked amine and a masked hydrazine.
adduct. Thus, several significant challenges needed to be
addressed in order to develop a practical diazirine-based
amination: (i) replacement of the photolabile and thermally
labile thiohydroxamate ester 11 with a more bench stable
radical precursor, (ii) avoidance of either uncontrolled
photochemical conditions or excessive heating that would be
expected to convert the diazirine to its corresponding carbene,
(iii) reduction of the amounts of diazirine required from
approximately 20 equiv (in Barton’s chemistry) to 3 equiv or
less, and most importantly, (iv) avoidance of imine formation
and retention of both nitrogen atoms in the form of a
diaziridine intermediate.
Herein we report the discovery, development, and
application of diazirines as practical electrophilic amination
reagents for the synthesis of amines, hydrazines, and nitrogen-
containing heterocycles. The use of a perfluorinated diazirine
allows entry into fluorous phase chemistry, which both
simplifies purification and affords access to the high-
throughput synthesis of large nitrogen-rich compound libraries
critical to drug discovery. This work lays the foundation for a
new class of strain-driven reagents that can be used to rapidly
forge C−N bonds on simple and complex scaffolds alike.
Toward this end, N-(acyloxy)phthalimides (e.g., 14),
commonly referred to as redox-active esters (RAEs), were
employed as a precursor for the alkyl radicals.7 RAEs have
exploded in popularity in recent years, finding numerous
applications in carbon−carbon and carbon−heteroatom bond
formation.8 Among the many advantages of RAEs are their
simple and rapid preparation from ubiquitous carboxylic acids,
ease of purification, and high bench stability.9 Furthermore,
they may be converted to the corresponding alkyl radicals
under either transition-metal-catalyzed or photochemical
conditions.7 Despite their obvious advantages, the use of
RAEs in C−N bond formation has been limited to several
recent reports.10 Each of these reactions require a tandem
photoredox/copper catalyst system to form the C−N bond,
and all approaches are restricted to the addition of one
nitrogen, via a phthalimide,10a primary amine,10c or imine.10d
Exploration of the decarboxylative amination began with
nickel-catalyzed conditions employing the piperidine-derived
RAE 14 with diazirine 6 (Figure 2C). Diazirine 6 was
conveniently prepared in a high-yielding, four-step sequence
on a decagram scale (Figure S1).11 While no amination
product was observed with NiCl2-glyme/18 (entry 1), a 50%
yield of diaziridine 15 was obtained with NiCl2·6H2O/18.
Importantly, no trace of imine 16 was observed in the reaction
mixture. In an attempt to improve the yields, the catalyst was
changed to Fe(acac)3 and the reaction screened with
phosphine ligands (17 and 19−21), varying amounts of Zn/
TMSCl, and a chlorinated RAE (TCNHPI) (entries 3−9).
While the highest yield (76%) was observed with dppBz (17),
dppb (21) was found to be an inexpensive alternative with only
a slight decrease in yield. In cases where the RAE was prone to
hydrolysis under the reaction conditions, FeCl3·6H2O was
found to increase stability and lead to an improved yield of the
diaziridine (entry 6). Critically, the use of diazenes 22 and 23,
perhaps the most commonly used electrophilic amination
reagents for the synthesis of hydrazines,12 in place of diazirine
6 did not afford any corresponding amination products
(entries 10 and 11). Instead, only reduction of the diazenes
was observed under various conditions (Table S17). Finally,
contrary to all expectations, similar yields could be obtained
without running the reaction under strict precautions, such as
an inert atmosphere, anhydrous conditions, or complete
elimination of ambient light (76%, entry 12).
DEVELOPMENT AND SCOPE
■
The initial investigation of diazirines as amination reagents was
inspired by the work of Krespan and Barton, both of whom
found that diazirines could react with alkyl radicals to form
imines. Diazirine 7, upon heating to 165 °C with an excess of
cyclohexane (8), afforded a modest amount of imine 9 in
addition to the typical carbene insertion product 10 (Figure
2A).5a A more detailed study was later reported by Barton,
Figure 2. Inspiration and development of the diazirine-based
decarboxylative amination: (A) Krespan’s reaction of diazirine 7
with cyclohexane (8); (B) Barton’s reaction of diazirine 6 with
thiohydroxamate ester 11; (C) Optimization of the reaction of
diazirine 6 with redox-active ester 14. All yields refer to isolated
compounds.
With the optimized conditions in hand, the scope of the
amination was explored with a wide variety of primary,
secondary, and tertiary carboxylic acids (Figure 3). The
required RAEs 25 were prepared in generally high yields by
treatment of the carboxylic acids 24 with N-hydroxyphthali-
mide in the presence of N,N′-diisopropylcarbodiimide (DIC)
and 4-(dimethylamino)pyridine (DMAP) in multigram
quantities.9 The decarboxylative amination was successful
where his eponymous thiohydroxamate ester 11 was found to
react with diazirine 6 to afford a mixture of imine 12 and
sulfide 13 (Figure 2B).5b,c Unless a large excess of diazirine 6
was used (20 equiv), sulfide 13 was found to be the major
product along with low yields of imine 12. Notably, these
precedents lacked both practicality and what we viewed as the
critical ability to retain both nitrogen atoms in the initial
B
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Figure 3. Scope of the decarboxylative amination of redox-active esters with diazirines. Reaction conditions: redox-active ester (25, 0.1 mmol, 1.0
equiv), diazirine (6 or 26, 1.5 equiv unless otherwise noted), Fe(acac)3 (20 mol %), dppBz (25 mol %), zinc (3 equiv), TMSCl (3 equiv), DMF
(0.3 mL), 60 °C, 16 h. All yields refer to isolated compounds. Legend: (a) 2.5 equiv of diazirine was used; (b) 3 equiv of diazirine was used.
with either cyclic or acyclic hydrocarbons and heterocycles
such as tetrahydrofuran (31, 48), piperidine (15, 38, 39, 41,
61), tetrahydropyran (40, 55), tetrahydrothiopyran (46),
indoline (52), and oxetane (62). The observed functional
group tolerance was quite broad: difluoro (29, 43) and
trifluoromethyl groups (42), carbamates (38, 39), alcohols
(44, 58, 65), ketones (45), sulfones (46), ethers (58, 63),
esters, (49, 53, 59), enones (54, 65), olefins (56, 58, 66), and
lactones (58) were all tolerated. Highly sterically hindered
bonds were formed with relative ease, as shown in the menthol
derivative 37 and numerous tertiary systems (60−66). The
reaction was also useful for preparing orthogonally protected
C
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mixed aminals such as indoline (52) and glutamic acid (53).
The late-stage functionalization of complex natural products
and pharmaceuticals was achieved with progesterone (54),
mycophenolic acid (58), gemfibrozil (63), glycerrhetinic acid
(65), and abietic acid (66). The reaction was demonstrated
both on a gram scale and via a one-pot RAE formation/
decarboxylative amination sequence in the preparation of
piperidine 15 in 70% and 58% yields, respectively (Figures S21
and S27).
The reaction of primary RAEs with diazirine 6 proved to be
challenging. Despite extensive attempts at optimization,
including the use of large excesses of diazirine 6, low yields
or no reaction was observed with most substrates. To
circumvent this problem, perfluorinated diazirine 26 was
synthesized (Figure S13) and tested under the standard
reaction conditions. Gratifyingly, moderate to high yields were
obtained for a variety of structurally distinct substrates (55−
59). Like other transition-metal-catalyzed reactions of redox-
active esters, this transformation is presumed to proceed via a
radical mechanism, which is supported through trapping
experiments with TEMPO (Figure S35).
DIVERSIFICATION TO AMINES, HYDRAZINES,
AND HETEROCYCLES
■
The utility and diversity of applications of the diazirine-based
decarboxylative amination lies in the underexplored versatility
of diaziridines (Figure 4−6). By a judicious choice of the
reaction conditions, the diaziridine can be selectively hydro-
lyzed, leaving either one or both nitrogen atoms on the
substrate (Figure 4A).5d,13 Thus, the diaziridines serve as
“masked” amines or hydrazines and obviate the need for the
troublesome purification of the highly polar free amines or
hydrazines. Treatment of piperidine derivative 15 with MsOH
in ethanol effects a hydrolysis reaction to afford hydrazine 67
in 92% yield. Upon purification as the mesylate salt, the yield
of the hydrazine drops to 55%, highlighting the utility of the
diaziridine approach, which avoids the isolation step. Instead, if
the acid is coupled with a nucleophilic counterion (e.g.,
iodide), the hydrolysis occurs with concomitant N−N bond
cleavage to afford amine 69. We have demonstrated 14 such
transformations (69a−n) on different substrates to form the
corresponding aliphatic amines in excellent yields for most
cases (Figure 4B). For more sensitive functionalities (e.g.,
69g,h,k,l,n), a combination of LiCl/TMSCl may be used to
convert the diaziridine to the amine. In each of the cases,
ketone 68 can be recovered and recycled into the diazirine
reagent synthesis, boosting efficiency and atom economy. If
desired, the amine synthesis can be combined with the
decarboxylative amination in one pot; the addition of LiCl into
the initial reaction mixture affords amine 69f in 63% isolated
yield (Figure 4C).
Figure 4. Diversification and one-pot heterocycle synthesis with
diaziridines: (A) Selective conversion of diaziridines to amines or
hydrazines with recovery of ketone 68; (B) Aliphatic amines
synthesized from the corresponding diaziridines; (C) One-pot
synthesis of amines from diazirines and redox-active esters. Isolated
yields are reported. Legend: (a) Yield determined by NMR; (b)
isolated yield. (c) HI/MeCN, r.t.; (d) HCl/I2, EtOH, r.t., 16 h; (e)
NaI/HCl, EtOH, r.t., 16 h; (f) LiCl/TMSCl, EtOH, 60 °C, 16 h.
carbonyl derivatives. In this manner, pyrazole 75 was obtained
in 95% yield from 1,3-diketone 78 in the presence of p-
TsOH.5d Pyridazinone 76 and triazole 77 were obtained in a
similar fashion from aldehyde 79 and formamide 80 in 64%
and 58% yields, respectively.17
With both the diversification reactions and heterocycle-
forming protocols in hand, our attention was turned to
realizing improved synthetic routes to several commonly
employed building blocks in medicinal chemistry: amines 69k,l
and pyrazoles 84 and 87 (Figure 6). These fragments have
been used in the synthesis of numerous pharmaceutical
candidates (88−95; Figure 6A,B gray insets) spanning
therapeutic areas from oncology to the treatment of
coagulation disorders.18 Keto diaziridine 45 was converted to
amine 69k in 92% yield, a compound previously prepared via a
sequence of protection, oxidation, and deprotection. The same
diazidirine intermediate 45 was also converted to pyrazole 84
in 64% yield. This one-pot sequence involves in situ generation
of the hydrazine and subsequent reaction with the dialdehyde
obtained from 1,1,3,3-tetraethoxypropane. To the best of our
knowledge, the hydrazine derived from 45 is unknown in the
literature and helps manifest a new route to pyrazole 84.
Previously this compound was prepared from dione 82
To further demonstrate the practical utility of the
decarboxylative amination, the amine and hydrazine synthesis
was then applied to a series of one-pot or telescoped syntheses
of various medicinally relevant heterocycles (Figure 5). To
leverage the one-pot heterocycle synthesis via in situ
generation of the amine, N-tosylpiperidine diaziridine 15 was
treated with HI in MeCN, followed by addition of the carbonyl
or dibromide reagents to afford imidazole 70,14 pyrrole 71,15
and aziridine 72,16 in good yields.
Alternatively, to prepare heterocycles via the in situ
generated hydrazines, N-tosylpiperidine diaziridine 15 was
treated with either p-TsOH or MsOH followed by various
D
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Figure 5. One-pot and telescoped syntheses of pharmaceutically relevant heterocycles from diaziridines.
Figure 6. Synthetic applications of diaziridines to pharmaceutically relevant building blocks: (A) Diversification of ketone-containing diaziridine 45
compared to literature methods (inset: pharmaceutical candidates whose synthetic routes required amine 69k and pyrazole 84); (B) Diversification
of hydroxy-containing diaziridine 44 compared to literature methods (inset: pharmaceutical candidates whose synthetic routes required amine 69l
and pyrazole 87).
through a sequence of monoketalization, reduction of the
carbonyl, tosylation, SN2 displacement with pyrazole, and
deprotection, which affords the desired compound in 20%
yield over five steps. Furthermore, similar building blocks were
obtained through hydroxy diaziridine 44. In this case, amine
69l was isolated in 95% yield and pyrazole 87 in 50% yield
from diaziridine 44. Pyrazole 87 was made from ketone 85
through a lengthy sequence of protection, hydrazone
formation, simultaneous reduction of the hydrazone and
hydrogenolysis of the benzyl protecting group, deprotection,
and ring formation of the pyrazole (16% over five steps). In
summary, this application highlights the diversification
potential of diaziridines to amines, hydrazines, and nitrogen-
containing heterocycles, the utility of diaziridines as masked
amines and hydrazines, and in some cases, more concise
synthetic route alternatives made possible by the use of this
method.
APPLICATIONS TO FLUOROUS PHASE
CHEMISTRY
■
Fluorous phase synthesis comprises a family of techniques that
were developed to simplify the separation and purification of
solution-phase reaction mixtures on the basis of fluorine
content.19 Light fluorous phase chemistry requires a
perfluorinated “tag” (typically C6F13 or C8F17) to be attached
either to the substrate (often via a protecting group) or the
reagent/catalyst.20 After a given reaction, the perfluorinated
molecules are easily separated from the nonperfluorinated
E
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components via fluorous solid-phase extraction (F-SPE) or
other fluorous chromatographic methods. One of the main
challenges in the successful use of fluorous phase synthesis is
identifying a suitable site in the substrate or reagents to install
the perfluorinated tag that avoids negatively affecting the
reactivity.19b Since the trifluoromethyl group was already
successfully embedded in diazirine 6, we postulated that the
switch to the perfluoro group would maintain reactivity and
possibly enhance it. Furthermore, the inherent advantage in
using the perfluorinated tag on the diazirine is that it allows for
simplified purification in both stages of the amination:
synthesis of the diaziridine and conversion to the correspond-
ing amine, hydrazine, or heterocycles.
Under the standard reaction conditions, perfluorinated
diazirine 26 was found to react smoothly with piperidine-
derived RAE 14. Upon completion of the reaction, the entire
crude mixture was applied to the F-SPE cartridge and washed
with a single aliquot of aqueous methanol (nonfluorous phase),
which eluted all nonfluorous compounds and impurities such
as N-hydroxyphthalimide and the catalyst/ligand system. A
second wash with anhydrous methanol (fluorous phase)
afforded pure perfluorinated diaziridine 96 in 88% yield
(Figure 7A). Perfluorinated diaziridine 96 was readily
diazirine was shown to enable the use of fluorous phase
chemistry in both steps of the amination, which allows for the
high-throughput preparation of nitrogen-rich compound
libraries without the need for chromatography. Given the
diversity of high-value scaffolds readily accessible through the
use of diazirines, these amination reagents are expected to be
incorporated by practitioners across research areas in both
industrial and academic laboratories. The use of diazirines in
reactions beyond the decarboxylative amination is well
underway and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09403.
■
sı
General information, experimental details, stability
studies, graphical procedures, and analytical data (1H,
13C, and 19F NMR and MS) for all new compounds
(PDF)
Crystallographic data for 36 (CIF)
Crystallographic data for 46 (CIF)
Crystallographic data for 53 (CIF)
Crystallographic data for 57 (CIF)
Crystallographic data for 62 (CIF)
Crystallographic data for 96 (CIF)
Crystallographic data for 70 (CIF)
Crystallographic data for S57 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Justin M. Lopchuk − Drug Discovery Department, H. Lee
Moffitt Cancer Center and Research Institute, Tampa,
Florida 33612, United States; Department of Chemistry and
Department of Oncologic Sciences, College of Medicine,
University of South Florida, Tampa, Florida 33620, United
States; orcid.org/0000-0002-6910-6132;
Email: justin.lopchuk@moffitt.org
Figure 7. Application of the decarboxylative amination of redox-active
esters with diazirines to fluorous phase synthesis: (A) Chromatog-
raphy-free F-SPE synthesis and purification of the diaziridine
intermediate 96; (B) Chromatography-free F-SPE synthesis and
purification of the amine 69f with concomitant recovery of ketone 97.
Authors
Preeti P. Chandrachud − Drug Discovery Department, H. Lee
Moffitt Cancer Center and Research Institute, Tampa,
Florida 33612, United States
Lukasz Wojtas − Department of Chemistry, University of
South Florida, Tampa, Florida 33620, United States
converted to amine 69f as previously described. Purification
under F-SPE conditions furnished amine 69f in 82% yield in
the nonfluorous phase wash, while ketone 97 was recovered in
87% yield in the fluorous phase wash (Figure 7B). The use of
perfluorinated diazirine 26 and its high-yielding and high-
purity conversion to amine 69f with F-SPE demonstrates a
proof of concept for the use of diazirine-based aminations in
high-throughput library synthesis.21
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09403
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Harshani Lawrence for assistance with NMR
experiments and Chuan Shan and Gaurav Verma for assistance
with DSC and X-ray crystallography. We gratefully acknowl-
edge the Donors of the American Chemical Society Petroleum
Research Fund (59537-DNI1) and the National Science
Foundation (CHE-1903144) for support of this research.
This work has also been supported in part by the Chemical
Biology Core Facility at the H. Lee Moffitt Cancer Center &
Research Institute, an NCI designated Comprehensive Cancer
Center (P30-CA076292). X-ray crystallographic data are
available free of charge from the Cambridge Crystallographic
CONCLUSIONS
■
We have demonstrated that diazirines can serve as single and
double electrophilic nitrogen transfer reagents in the
decarboxylative amination of redox-active esters. The initial
reaction affords diaziridines, which are selectively converted in
one-pot/telescoped reactions to amines, hydrazines, and
various nitrogen-containing heterocycles. The method is
suitable for primary, secondary, and tertiary substrates and
exhibits a broad functional group tolerance. A perfluorinated
F
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Generate Protected Amines: An Alternative to the Curtius Rearrange-
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Cabrera, P. J.; Lee, M.; Sanford, M. S. N -Acyloxyphthalimides as
Nitrogen Radical Precursors in the Visible Light Photocatalyzed
Room Temperature C−H Amination of Arenes and Heteroarenes. J.
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redox-active Esters with Benzophenone Imines: Tandem Photoredox
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decomposition of 1559 and 802 J/g, respectively. Caution should
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(12) (a) Kosmrlj, J.; Kocevar, M.; Polanc, S. Diazenes as Powerful
and Versatile Tools in Organic Synthesis. Synlett 2009, 2009, 2217−
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