N?N Bond Formation Using an Iodonitrene as an Umpolung of Ammonia: Straightforward and Chemoselective Synthesis of Hydrazinium Salts

Article abstract of DOI:10.1002/adsc.202001047

The formation of hydrazinium salts by N?N bond formation has typically involved the use of hazardous and difficult to handle reagents. Here, mild and operationally simple conditions for the synthesis of hydrazinium salts are reported. Electrophilic nitrogen transfer to the nitrogen atom of tertiary amines is achieved using iodosylbenzene as oxidant and ammonium carbamate as the N-source. The resulting process is highly chemoselective and tolerant to other functional groups. A wide scope is reported, including examples with bioactive molecules. Insights on the structure of hydrazinium salts were provided by X-ray analysis. (Figure presented.).

Full text of DOI:10.1002/adsc.202001047

Title: N–N Bond Formation using an Iodonitrene as an Umpolung of
Ammonia: Straightforward and Chemoselective Synthesis of
Hydrazinium Salts
Authors: Arianna Tota, Marco Colella, Claudia Carlucci, Andrea
Aramini, Guy Clarkson, Leonardo Degennaro, James Bull,
and Renzo Luisi
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001047
Link to VoR: https://doi.org/10.1002/adsc.202001047

10.1002/adsc.202001047
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
N–N Bond Formation Using an Iodonitrene as an Umpolung of
Ammonia: Straightforward and Chemoselective Synthesis of
Hydrazinium Salts
Arianna Tota,a Marco Colella,a Claudia Carlucci,a Andrea Aramini, b Guy Clarkson,c
Leonardo Degennaro,a James A. Bull,d,* Renzo Luisia,*
a Department of Pharmacy – Drug Sciences, University of Bari “A. Moro” Via E. Orabona 4 - 70125 Bari, Italy.
E-mail: renzo.luisi@uniba.it
b Department of Discovery, Dompꢀ Farmaceutici S.p.A., Via Campo di Pile, L’Aquila 67100, Italy.
cDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
d Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood
Lane, London W12 0BZ, UK.
E-mail: j.bull@imperial.ac.uk
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
However, hydrazine must be carefully handled due to
its intrinsic toxic and explosive nature. Given the
relevance of such functional groups in medicinal
chemistry, synthetic methods to circumvent the use of
hydrazine and low molecular weight hydrazine
derivatives can provide improved and safer synthetic
sequences.
Abstract. The formation of hydrazinium salts by N-N bond
formation has typically involved the use of hazardous and
difficult to handle reagents. Here, mild and operationally simple
conditions for the synthesis of hydrazinium salts are reported.
Electrophilic nitrogen transfer to the nitrogen atom of tertiary
amines is achieved using iodosylbenzene as oxidant and
ammonium carbamate as the N-source. The resulting process is
highly chemoselective and tolerant to other functional groups.
A wide scope is reported, including examples with bioactive
molecules. Insights on the structure of hydrazinium salts were
provided by X-ray analysis.
Keywords: Hydrazinium Salts; Electrophilic Nitrogen;
Nitrene; Hypervalent Iodine; Amines
The N-N bond, typical of hydrazine derivatives,
represents a structural motif of interest in drug
discovery and modern synthesis. In fact, the
heteroatom-heteroatom linkages (X-X, where X = N,
O, S and P) are intriguing structural motifs of
pharmacologically active molecules.[1] Examples of
pharmaceutically relevant molecules bearing N-N
bonds in hydrazine or hydrazinium motifs are collected
in Figure 1. Hydrazinium salts have been studied for
their antibacterial antispasmodic,[2] pain relief
modulator,[3] and antihistaminic activities, and as
precursors of alkylhydrazines, amines, and alkenes.[4,5]
The incorporation of the N-N moiety commonly
relies on the use of hydrazine as a primary feedstock.
Figure 1. Biological relevant molecules including the N-N
motif.
Few approaches are available for the synthesis of
hydrazinium salts, the most common being alkylation
of alkylhydrazines by reaction with alkyl halides,
sulfates or sulfonates (Scheme 1, a).[6] An alternative
approach involves the direct amination of tertiary
amines with electrophilic nitrogen sources (Scheme 1,
b).[7-10] The transfer of the amino group to form
hydrazinium salts has been achieved using, 1) the in
1
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10.1002/adsc.202001047
Advanced Synthesis & Catalysis
situ generation of chloramine from ammonia and
chlorine, which poses problems related to the use of
toxic molecular chlorine; 2) the use of the explosive O-
(mesitylsulfonyl)hydroxylamine (MSH) as the
aminating agent; 3) the use of the corrosive and
harmful hydroxylamine-O-sulfonic acid.
Scheme 1. Available approaches to hydrazinium salts.
As the amination of tertiary amines represents a
strategy to avoid the use of hydrazine we envisaged
applying safer amination reagents, generating
umpolung ammonia using hypervalent iodine reagents.
Here we report a new simple approach for the direct
preparation of hydrazinium salts from tertiary amines
using an electrophilic iodonitrene.
In 2016 we reported that an electrophilic N-
species, as iodonitrene [PhIN]+ (or iminoiodinane
PhINH),[11] was generated by reacting a hypervalent
iodine reagent (PhI(OAc)2 or PhIO), with ammonium
carbamate as a simple source of ammonia (Scheme
2).[12] This electrophilic N-species is able to react with
sulfur compounds providing several iminated
derivatives such as sulfoximines,[12,13] sulfonimidates
and sulfonamides,[14] and sulfonimidamides[15]
(Scheme 2). Reboul reported recently an elegant
synthesis of 1,2-diazirine starting from -aminoacids,
using a combination of PhI(OAc)2 and an excess of
NH3.[16] Diaziridine A resulting from the addition of an
iodonitrene to an imine (Scheme 2), was proposed as
an intermediate.
Scheme 2. Use of iodonitrene as source of electrophilic
nitrogen.
to detect the expected hydrazinium salt 2a’ in 88%
yield. However, isolation of a pure hydrazinium salt
was complicated by the excess acetic acid derived from
the oxidant. For this reason, PhIO[17] was selected as
suitable hypervalent iodine reagent for this reaction.
Importantly, the addition of 4-methylbenzenesulfonic
acid (TsOH) to the reaction rendered the tosic acid-
hydrazinium salt an easily separable solid. The
optimized conditions used PhIO (2.5 equiv),
NH2COONH4 (2 equiv) and TsOH (1 equiv) in
acetonitrile at 0.5 M concentration (Table 1, entry 1).
Under these conditions, hydrazinium salt 2a could be
obtained almost quantitatively as a flowing powder
after 3 h reaction time.
Other N-sources, ammonium carbamate,
ammonium carbonate ((NH4)2CO3), ammonium
acetate (NH4OAc), and aqueous ammonia were also
suitable providing very good yields of hydrazinium salt
2a (Table 1, entries 2-4). The use of methanolic
ammonia was unsuccessful returning only unreacted
starting material (Table 1, entry 5). Furthermore,
several solvents were successful using 2.5 equiv of
PhIO and 2 equiv of NH4COONH2. High yields
(>90%) were obtained with i-PrOH, CH2Cl2, DMF and
toluene (entries 7-10). In contrast, the use of MeOH
returned a modest 53% yield of 2a (entry 6), while
CPME was unsuitable (entry 12). Interestingly, this
reaction can be run in water obtaining 67% yield of the
We started our investigation using N-
ethylpiperidine 1a as model substrate; the results of the
optimization study are collected in Table 1. First, we
tested conditions successfully employed with sulfides
and sulfoxides,[12,13a] using PhI(OAc)2 (2.5 equiv) as
the oxidant, and ammonium carbamate (2.0 equiv) as
nitrogen source in MeOH. To our delight we were able
2
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10.1002/adsc.202001047
Advanced Synthesis & Catalysis
salt 2a (Table 1, entry 11). Slightly lower yields were With the optimal conditions in hand, we investigated
obtained reducing the reaction time and lowering the the scope of this method using various tertiary amines
amount of the oxidant and N-source (Table 1, entries (Scheme 3). Pleasingly, the reaction could be applied
16-17). As control reactions, two experiments were run to different cyclic amines derived from piperidine,
in absence of the oxidant or the N-source (Table 1, morpholine, pyrrolidine and azepane, furnishing the
entries 18-19) returning only unreacted starting corresponding hydrazinium salts 2a-j in good to
material.
excellent yields. The pure salts could be obtained by
removing iodobenzene under high vacuum followed
by precipitation and filtration (see Supplementary
material). In the case of 2b, the structure was
Table 1. Optimization study.
unambiguously
assigned
by
X-ray
crystal
diffraction.[18] Acyclic trialkyl amines were also
suitable substrates, transformed to the corresponding
hydrazinium salts 2k-o in good to excellent yields.
Other open-chain benzylic amines furnished salts 2p-r,
and 2u with very good yields (>80%). The
tetrahydroisoquinoline scaffold was also successfully
employed leading to hydrazinium derivatives 2s, 2t
with high yields. An aromatic amine was also tested
with success in this N-transfer process, obtaining
derivative 2v with 88% yield. As reported in Scheme
2, the investigation of the scope of the reaction
revealed functional group tolerance for this process. In
fact, the presence of an hydroxyl group was tolerated
as in the case of 2g and 2k, as well as the presence of
carboxylic ester functionality or a triple bond as for 2u
and 2v. Primary and secondary amines and other
nitrogen containing compounds such as sulfonamides
were unreactive under these conditions, while the use
of imines led to the corresponding benzonitrile.[19]
PhIO
Ti
me
(h)
3
Solvent
Yield
(%)[b]
Entry (equiv N- source (equiv)
)
[a]
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
0.5
0
NH2COONH4 (2)
MeCN
MeCN
MeCN
MeCN
MeCN
99
88
98
98
0
2
AcONH4 (2)
3
3
3
3
3
3
3
3
3
3
3
2
1
3
(NH4)2CO3 (2)
NH3 (aq) (2)
4
5
NH3 (MeOH) (2)
6
NH2COONH4 (2) MeOH
NH2COONH4 (2) iPrOH
53
98
94
98
93
67
24
99
88
87
89
25
0
7
8
NH2COONH4 (2) toluene
NH2COONH4 (2) CH2Cl2
9
10
11
12
13
14
15
16
17
18
19
NH2COONH4 (2)
NH2COONH4 (2)
NH2COONH4 (2)
NH2COONH4 (2)
NH2COONH4 (2)
NH2COONH4 (2)
NH2COONH4 (1)
NH2COONH4 (2)
NH2COONH4 (2)
none
DMF
H2O
CPME
MeCN
MeCN
MeCN 0.5
MeCN
MeCN
MeCN
MeCN
3
3
3
3
2.5
0
[a]Solvents: dimethylformamide (DMF), cyclopentylmethylether
(CPME). [b]Determined by 1H NMR analysis of the crude reaction
mixture using 1,3,5-trimethoxybenzene as internal standard.
3
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10.1002/adsc.202001047
Advanced Synthesis & Catalysis
Scheme 3. Scope for the hydrazinium salts.
chemoselectivity, installing the amino group on the
nitrogen atom of the quinuclidine and tropane moiety
of 2ab and 2ac respectively. A single diastereoisomer
for both hydrazinium products was observed (Scheme
5, 2ab, 2ac).
Interestingly, the use of a 15N-labelled N-source
allowed for a selective introduction of a labelled amino
group. Using 4 equiv of 15N.ammonium acetate, 4
equiv of PhIO and 1 equiv of TsOH in MeCN,
furnished the 15N-labelled hydrazinium salt 2aa with a
95% yield (Scheme 4).
Selective amination of the tertiary amino group
occurred with chloroquine, leading to hydrazinium salt
2ad in 98% yield. Similarly, no interference was
observed in the amination of benzydamine furnishing
2ae in 96% yield. Remarkably, in the cases of
ranolazine (antianginal agent) and Sigma-2 agonist
PB28,[20] bearing two tertiary N-centers, the
electrophilic nitrogen transfer takes place selectively
only at one nitrogen atom of the piperazine ring
leading to 2af and 2ag. By accurate 1H NMR analysis
it was possible to ascertain which position of the
piperazine core was aminated (see Supplementary
material). An unexpected result was obtained using
peracetylated lincomycin bearing a sulfide moiety. To
our surprise, in place of the expected sulfoximine
derivative,[21] chemoselective amination occurred at
the pyrrolidine nitrogen. The structure of the
hydrazinium salt 2ah was unambiguously assigned by
Scheme 4. Preparation of 15N-labelled hydrazinium salt.
To further test the method, and evaluate
chemoselectivity,
several
biologically
active
molecules containing multiple basic N-atoms or other
nucleophilc sites were considered as substrates
(Scheme 5). This electrophilic nitrogen transfer
occurred on quinine and atropine with high
4
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10.1002/adsc.202001047
Advanced Synthesis & Catalysis
X-ray analysis[22] showcasing the chemoselectivity of
this nitrogen transfer process.
Scheme 6. Proposed mechanism.
In summary we have developed a new approach for
the synthesis of hydrazinium salts starting from
tertiary amines, and using an electrophilic N-transfer
reaction. Compared to other available methodologies,
this provides safer and milder conditions, with a
hypervalent iodine reagent as the oxidizing species and
ammonium carbamate as the nitrogen source. This
procedure was applied to varied tertiary amines and
displayed high tolerance to various functional groups.
Examples of late-stage amination of relevant bioactive
molecules and APIs have been also demonstrated.
Further studies are ongoing in our laboratories in order
to expand the applicability of this N-transfer
methodology.
Experimental Section
General procedure for the preparation of hydrazinium
salts. Ammonium carbamate (3 mmol) and iodosylbenzene
(3.75 mmol) were added to a stirred solution of the tertiary
amine (1.5 mmol) in acetonitrile (0.5 M, 3.0 mL), at 25 °C.
p-Toluenesulfonic acid monohydrate (1.5 mmol) was added,
and the reaction mixture stirred for 2 hours. After this time,
the mixture was concentrated to remove acetonitrile.
Removal of the remaining iodobenzene under high vacuum
afforded the desired hydrazinium salt as flowing powder.
Scheme 5. Hydrazinium salts of current drugs APIs.
Based on our previous findings,[12,13] the mechanism of
the N-transfer could be rationalised as depicted in
Scheme 6. Two possible pathways could be viable,
involving either the iminoiodinane (path a) or the
iodonitrene (path b). Both generate an electrophilic N-
species to be attacked by the tertiary amine
nucleophile. The selectivity for the tertiary amine
substrates suggests significant nucleophilicity is
required. In path b, the reagent can be further oxidized
to the nitrene, with the subsequent cleavage of the N-I
bond after amination. Protonation of the transferred N-
atom, initially formed as an ylide, generates the salt
form with the tosylate counter ion.
Acknowledgements
This research was supported by the project MISE, Horizon 2020 –
PON 2014/2020 FARMIDIAB “code 338”; the University of Bari
– Fin. Ateneo Degennaro2019 and Dompè Farmaceutici. We are
grateful to Prof. Giovanni Lentini and Dr. Mauro Niso for
providing samples of APIs utilized for the preparation of
derivatives in Scheme 5.
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6
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10.1002/adsc.202001047
Advanced Synthesis & Catalysis
COMMUNICATION
N–N Bond Formation using an Iodonitrene as
an Umpolung of Ammonia: Straightforward
and Chemoselective Synthesis of Hydrazinium
Salts
Adv. Synth. Catal. Year, Volume, Page – Page
Arianna Tota, Marco Colella, Claudia
Carlucci, Andrea Aramini, Guy Clarkson,
Leonardo Degennaro, James A. Bull, Renzo
Luisi
7
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