Diazirines as potent electrophilic Nitrogen sources: Application to the synthesis of Pyrazoles

Article abstract of DOI:10.1021/ol403495e

Even after more than 50 years since its discovery, the electrophilic potential of diazirines was never truly exploited. This longstanding limitation has been resolved. N-Monosubstituted diaziridines and hydrazones are obtained by nucleophilic additions. They release, under hydrolysis conditions, the corresponding monosubstituted hydrazines. The latter were converted to pyrazoles in high yields. The adamantanone can be recovered in 80-100% yields. This work demonstrates the potential of diazirines as electrophilic nitrogen sources with recoverable protecting groups.

Full text of DOI:10.1021/ol403495e

Letter
pubs.acs.org/OrgLett
Diazirines as Potent Electrophilic Nitrogen Sources: Application to
the Synthesis of Pyrazoles
Yoann Schneider, Julie Prevost, Maelle Gobin, and Claude Y. Legault*
́
̈
́ ́
University of Sherbrooke, Department of Chemistry, 2500 boul. de l’Universite, Sherbrooke, Quebec J1K 2R1, Canada
S
* Supporting Information
ABSTRACT: Even after more than 50 years since its discovery, the
electrophilic potential of diazirines was never truly exploited. This
longstanding limitation has been resolved. N-Monosubstituted
diaziridines and hydrazones are obtained by nucleophilic additions.
They release, under hydrolysis conditions, the corresponding
monosubstituted hydrazines. The latter were converted to pyrazoles
in high yields. The adamantanone can be recovered in 80−100% yields. This work demonstrates the potential of diazirines as
electrophilic nitrogen sources with recoverable protecting groups.
he hydrazine functional group and its derivatives are a
very important family of compounds and have found
scope, as numerous nucleophiles (RM) are accessible. The
nitrogen atoms will usually require electron-withdrawing
protecting groups to lower the NN LUMO and replace
acidic protons on the nitrogen atoms. An elegant example of
this approach was recently reported by Moody et al. using di-
tert-butylazodicarboxylates for the synthesis of indoles and
other heterocycles.10 The substituted hydrazine is released by
removal of both N-protecting groups. Amination of anilines is
also a possible avenue.11
The electrophilic character of diazirines has also been
recognized,12 in particular for the synthesis of N-substituted
diaziridines.13 However, their potential as general electrophilic
nitrogen sources, in which the resulting diaziridine moiety is
hydrolyzed to release the hydrazine group, has never been truly
exploited.14 This could be explained by side reactions during
the diaziridine hydrolysis process. They would be particularly
useful, as the protecting group (i.e., carbonyl compound) could
be easily recovered (Scheme 2). With this in mind, we
T
numerous applications in chemistry. They are for example used
as precursors for a variety of heterocycles. Monosubstituted
hydrazines are particularly useful for the synthesis of indoles1
and pyrazoles.2 Their synthesis can be a challenge due to the
similar reactivity of the two nitrogen atoms. In some cases, it is
possible to monofunctionalize hydrazine (N2H4) through
nucleophilic substitution or reductive amination,3 but this
often leads to the oversubstitution of the hydrazine. The
reduction of diazonium salts with sodium sulfite4 or tin(II)
chloride5 is a common strategy, although limited to the
preparation of N-aryl substituted hydrazines (Scheme 1a).
Scheme 1. Strategies To Access Monosubstituted Hydrazines
Scheme 2. Concept of Hydrazine Formation from Diazirine
Compounds
considered that a simple solution to this longstanding limitation
would be to use a nonenolizable carbonyl precursor, stable
under hydrolysis conditions. Herein we report the proof of
concept and application of this strategy to use the potential of
diazirines as general electrophilic nitrogen sources.
The diazirines illustrated in Figure 1, made from non-
enolizable carbonyl compounds, were considered. The
Transition-metal-catalyzed C−N coupling reactions of monop-
rotected hydrazines (Scheme 1b) and hydrazones (Scheme 1c)
using palladium6 or copper7 as catalysts were developed. Very
recently Stradiotto et al. reported the selective monocoupling of
aryl chlorides and tosylates with free hydrazine.8 Alternatively,
monosubstituted hydrazines can be obtained by the reaction of
a nucleophilic reagent with an electrophilic nitrogen moiety, in
particular a NN system with a low lying LUMO (Scheme
1d).9 This approach has the advantage of a wider N-substituent
Received: December 3, 2013
Published: December 30, 2013
© 2013 American Chemical Society
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Organic Letters
Letter
crude product is clean, it could not be purified due to the low
stability of 7 on silica gel. Addition of phenyl lithium at −78 °C
did result in the expected diaziridine 8 cleanly. The lower
isolated yield is due to isomerization to the corresponding
hydrazone and degradation during flash chromatography.
While the acid-catalyzed diaziridine−hydrazone isomeriza-
tion is known,12a,17 it is not reported for N-metalated
diaziridines (Scheme 5). To determine if the in situ
Figure 1. Potential diazirine candidates from nonenolizable aldehyde
and ketone compounds.
diazirines from aromatic aldehydes and ketones (1 and 2) could
suffer from light-induced isomerization to the corresponding
diazo compounds,12 resulting in a diminished reagent shelf life.
The synthesis of diazirine 3, derived from pivalaldehyde, proved
to be low yielding. We turned to 4, derived from
adamantanone. Conformational restriction prevents its enoliza-
tion. This compound has been widely used as a carbene
precursor.15
Scheme 5. Diaziridine−hydrazone Rearrangement of N-
Metalated Species
Compound 4 is rapidly obtained in two steps from
adamantanone. Diaziridine 5 is made using a literature
procedure.16 Diaziridine oxidation usually involves transition
metals (e.g., Ag2O, CrO3).12b Sodium hypochlorite was
evaluated as a low cost oxidant.
Gratifyingly, a biphasic reaction using bleach afforded the
desired diazirine 4 in 99% yield within 30 min, with no need for
further purification (Scheme 3). Diazirine 4 is a white
rearrangement was related to temperature, control experiments
were carried out. Reaction with PhLi at 0 °C for 2 h did not
result in the isomerization. Reaction of PhMgBr at −40 °C for
2 h did result in addition to the diazirine (86% conversion), and
a mixture of 7 and 8 (14:86) was isolated. The isomerization
process is thus slowed at lower temperature but mainly affected
by the metal counterion. This metal-dependent isomerization
will prove particularly interesting in further studies to
selectively functionalize the metalated intermediates.
Scheme 3. Bleach-Mediated Oxidation of 5 to 4
Since pure monosubstituted hydrazines can be difficult to
isolate and manipulate, we devised to evaluate direct
deprotection condensation procedures. We elected to test the
concept with 1,3-diketones to isolate pyrazoles. They are an
important class of molecules in the pharmaceutical industry.
Indeed, they are found in numerous drug compounds with
multiple biological activities (e.g., antiviral, antitumor, anti-
depressant).18 The transfer reactions were tested with pure 719
and 8, using acetylacetone (9). Gratifyingly, the desired
pyrazole 10a was obtained with excellent yields in both cases
(Scheme 6), and the adamantanone was recovered in >80%
yield.
hydrophobic solid, facilitating its storage and use. It can be
isolated or kept in solution, to prevent its manipulation on a
large scale. To ensure a suitable anhydrous solution, the latter
can be rigorously dried under reflux over CaH2 for 24 h. The
resulting solution shows absolutely no loss or degradation of
the diazirine, demonstrating stability under these conditions.
With 4 in hand, initial addition reactions were made to ensure
acceptable reactivity despite the increased steric hindrance
around the diazirine moiety from the adamantyl group. The
results are illustrated in Scheme 4.
Scheme 6. Initial Hydrazine Transfer Attempts
Alkyl and aryl Grignard reagents add cleanly and rapidly
within 2 h at 0 °C (Scheme 4a and b). The N-ethyl diaziridine
6 is obtained in quantitative yield following purification by flash
chromatography. In contrast, addition of PhMgBr did not lead
to the N-phenyl diaziridine, but hydrazone 7. Although the
Scheme 4. Initial Additions Attempts on Diazirine 4
While the optimized conditions involve the use of p-TsOH as
the acid to promote the hydrazine transfer, it can be replaced by
other strong acids to lessen the reaction waste products.19
The addition process is very clean, and to simplify the
methodology and prevent degradation of the diaziridine or
hydrazone intermediate, we elected to directly use the crude
addition product for the transfer reaction. The conditions of
addition/transfer were optimized, and the results are
summarized in Table 1. As described in Scheme 4c, the
isolated yield of the N-phenyl diaziridine 8 was due to
purification issues. In fact, when crude 8 is used for the transfer
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Organic Letters
Letter
Table 1. Preparation of Pyrazoles 10 by Addition/Transfer
Procedure from Diazirine 4
Scheme 7. Multigram Scale Example
a
b
entry
R′
M
product
yield (%)
1
Ph
Li
10a
10a
10b
10c
10d
10e
10f
95
67
83
82
2
Ph
MgBr
Li
reagent in the laboratory. This compound has the added
advantage that the diazirine precursor (i.e., ketone) can easily
be recovered in the reaction process, reducing its overall
environmental impact. Additionally, the variety of accessible
nucleophiles makes it a great complement to transition-metal-
catalyzed C−N coupling methods. The examples described
herein have focused on the synthesis of numerous pyrazoles
compounds. The potential of diazirines in methodologies to
access polysubstituted hydrazines, as well as yield simple
amination products, is currently investigated and will be
reported in due course.
3
4-Me-C6H4
4-F-C6H4
4-Br-C6H4
4
Li
c
5
Li
86
6
3,5-(CF3)-C6H3
Li
88
89
74
67
84
7
2-Me-C6H4
Li
8
2-Et-C6H4
Li
10g
10h
10i
9
2-OMe-C6H4
Li
10
11
12
13
14
15
16
17
2-(SO2NEt2)-5-Me-C6H3
Li
d
2-(SO2NEt2)-5-Me-C6H3
Li
10j
73
n-Bu
n-Bu
Et
Li
10k
10k
10l
82
79
MgCl
MgBr
MgCl
MgBr
MgCl
c
41 (74)
49 (70)
72
ASSOCIATED CONTENT
* Supporting Information
■
c
i-Pr
Allyl
Bn
10m
10n
10o
S
Characterization and NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
100
a
All reactions with lithium reagents were performed at −78 and at 0
°C for Grignard reagents. In all cases, the adamantanone was
recovered in 80−100% yield. See Supporting Information for details
on the generation of the lithium reagents. Isolated yields. Product
was isolated as the hydrochloride salt. 1,3-Diphenyl-1,3-propanedione
was used instead of 9 for the transfer reaction, affording 10j (R = Ph).
b
c
AUTHOR INFORMATION
Corresponding Author
■
d
*E-mail: claude.legault@usherbrooke.ca.
Notes
reaction, the pyrazole is obtained in excellent yield (Table 1,
entry 1), identical to the yield from pure 8 (Scheme 5b). This
confirms the quantitative addition of PhLi on 4. In contrast, a
lower yield of 10a is obtained after addition of the phenyl
Grignard to 4 (Table 1, entry 2). Aryl lithium reagents were
thus used to explore the scope of the reaction. They were either
generated by halogen−metal exchange or directed ortho-
metalation.19
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Science and
Engineering Research Council of Canada (NSERC), the
■
́
Fonds Quebecois de Recherche − Nature et Technologies
(FQRNT), the Canada Foundation for Innovation (CFI), the
Centre in Green Chemistry and Catalysis (CGCC), and the
The method proved to be quite general: 2-substituted, 4-
substituted, and polysubstituted aryl moieties with varying
electron density afforded good yields of the pyrazole (Table 1,
entries 3 to 11). Acetylacetone can be replaced by another 1,3-
diketone (Table 1, entry 11). As stated earlier, the use of an
electrophilic nitrogen source has the advantage of a larger
substituent scope. The addition of aliphatic, allylic, and benzylic
nucleophiles is also possible on diazirine 4 (Table 1, entries 12
to 17). Both organolithium and Grignard reagents lead to very
good yields (Table 1, entries 12 and 13). Lower isolated yields
were observed for pyrazoles bearing small alkyl chains, due to
their volatility (Table 1, entries 14 and 15). In such cases,
precipitation of the pure hydrochloride salt of the pyrazole did
increase substantially the isolated yield. This proved to be
efficient when flash chromatography proved difficult (Table 1,
entry 5). Finally, the procedure is easily scalable, as described
by the example illustrated in Scheme 7. On a larger scale, the
precipitation is facilitated, leading to a very good yield of the
final pyrazole hydrochloride salt and recovered adamantanone.
In conclusion, we have demonstrated the synthetic potential
of diazirines as general electrophilic hydrazine precursors.
Diazirine 4 is stable over time, making it a desirable storable
Universite
́
de Sherbrooke.
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