Fe(III)-Catalyzed Aerobic Intramolecular N-N Coupling of Aliphatic Azides with Amines

Article abstract of DOI:10.1021/acs.orglett.9b01396

An Fe(III)-catalyzed intramolecular N-N coupling of aliphatic azidoamines that forms diverse five- and six-membered semisaturated diazoheterocycles using air as an oxidant is reported, providing an alternative to hydrazine-based methods. Mechanistic studies suggest that a N-radical induced intramolecular homolytic substitution (S_H2) is involved in ring closure. The power of this N-N bond-forming method is also demonstrated by using it as the final step in a total synthesis of (-)-newbouldine.

Full text of DOI:10.1021/acs.orglett.9b01396

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Fe(III)-Catalyzed Aerobic Intramolecular N−N Coupling of Aliphatic
Azides with Amines
Yue Zhang,†,∥ Dongyu Duan,†,∥ Ying Zhong,†,∥ Xin-Ai Guo,† Jiawei Guo,† Jing Gou,§ Ziwei Gao,*,†
and Binxun Yu*,†,‡
†Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry & Chemical Engineering,
Shaanxi Normal University, Xi’an 710062, China
‡Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Science,
Shaanxi Normal University, Xi’an 710062, China
§Shaanxi Key Laboratory for Advanced Energy Devices, Shaanxi Normal University, Xi’an 710062, China
S
* Supporting Information
ABSTRACT: An Fe(III)-catalyzed intramolecular N−N
coupling of aliphatic azidoamines that forms diverse five-
and six-membered semisaturated diazoheterocycles using air
as an oxidant is reported, providing an alternative to
hydrazine-based methods. Mechanistic studies suggest that a
N-radical induced intramolecular homolytic substitution
(SH2) is involved in ring closure. The power of this N−N
bond-forming method is also demonstrated by using it as the final step in a total synthesis of (−)-newbouldine.
emisaturated heterocycles containing nitrogen−nitrogen
S
(N−N) bonds, such as 2-pyrazolines and tetrahydropyr-
idazines, are ubiquitous in natural products and pharmacolog-
ically active agents.1,2 N−N bonds are most often incorporated
from hydrazine.2c,3 An attractive alternativeintramolecular
N−N bond formationhas generally been limited to the
formation of aromatic five-membered heterocycles.5−12 Here-
in, we describe the first catalytic synthesis of semisaturated
five- and six-membered diazo-containing rings from aliphatic
azidoamine adducts, employing an Fe(III)-catalyzed intra-
molecular N−N coupling using air as the oxidant.
Compared to the direct construction of C−C bonds, there
are relatively few examples of transition metal-catalyzed or
metal-free N−N bond formation,4 despite the appeal of such a
strategy as an atom-economical and straightforward way to
prepare diazo compounds. Most intramolecular N−N bond
formation methods are limited to the synthesis of aromatic
five-membered diazo heterocycles using stabilized aryl or vinyl
nitrogen-centered reactive intermediates (e.g., nitrenes, N-
radicals, and nitrenium) which are trapped by imines or amides
(Figure 1a). For example, copper has been used to build up
N−N bonds for the synthesis of aromatic five-membered
diazo-heterocycles from benzaldimine substrates.5 Such hetero-
cycles have also been prepared via N−N formation by
oxidative cyclization of an acylnitrenium intermediate from
amides with hypervalent iodine.6 Other achievements include
reductive N−N cyclization of ortho-nitrobenzaldimines
through a phosphine oxide intermediate with organophospho-
rus7 or a hydroxylamine intermediate with Sn(II)8 or Ru(III)/
visible light.9 While thermolysis and photolysis of aryl azides to
give nitrene intermediates can also form N−N bonds, they
suffer from either harsh reaction conditions or a long reaction
Figure 1. N−N bond formation using aliphatic azidoamines to
synthesize semisaturated diazoheterocycles.
time, which limits substrate diversity.10 Iron- or copper-
catalyzed cyclizations of ortho-azido benzaldimines can afford
aromatic 2H-indazoles via planar reactive intermediates.5a,11,12
The aforementioned established N−N bond-forming
methods are incapable of building up semisaturated diazo-
heterocycles. To overcome this, we envisioned tethering
aliphatic azides and amines to achieve intramolecular N−N
Received: April 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01396
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coupling to generate five- or six-membered rings. Although
aliphatic azides cannot be the proper and stable entrance to the
generation of nitrenes due to lack of stabilization through
vicinal conjugation,13−15 they have been used as alkyl radical
acceptors leading to aminyl radicals,16 affording 5-exo and 6-
exo C−N cyclization products (Figure 1b). Considering that
secondary alkyl amines can convert into a N-centered radical
through successively removing one electron and one proton
under proper oxidative conditions with transition metals or
added oxidants,17 we proposed that a N-centered radical
stemming from an amine precursor could attack an azide and
achieve N−N formation. However, the single-electron transfer
(SET) to an amine is usually followed by generation of an
imine,18 which poisons transition metals. We envisioned
skirting the above problems through in situ formation of a
cyclometal intermediate (Figure 1c). This coordination could
serve to stabilize an N-centered radical, thereby suppressing
the oxidation of amines into imines.
To validate the catalytic system for in situ metal complex
formation and N−N cyclization, we initially investigated the
reaction of benzyl protected linear γ-azidoamine 1a in the
presence of various transition metal catalysts (Table 1). First,
we evaluated catalysts widely utilized for the generation of
metal nitrenes from aryl azides. No N−N cyclization product
was observed in the presence of Rh2(OAc)4, Rh2(O2CCF3)4,
or CoTPP at 100 °C in sealed tubes for 2 h (entries 1, 2, and
3). Cu(OAc)2 and CuI also failed to form the desired N−N
bond (entries 5 and 6). To our delight, 1a underwent a desired
N−N cyclization in the presence of 20 mol % Fe(TPP)Cl(III)
(entry 4) that was accompanied by a conversion of the C−N3
single bond into a C−N double bond to afford 2H-pyrazoline
product 2a in 11% yield. Further study identified iron(III) salts
as superior agents for the formation of the desired N−N
cyclization products, including FeCl3, FeBr3, Fe(acac)3, and
Fe(OTf)3, among which 20 mol % of Fe(acac)3 gave 28% yield
in refluxing THF under an air atmosphere (entry 15). To our
surprise, a lower loading of FeCl3 (5.0 mol %) in the presence
of air as an oxidant at 100 °C in a sealed tube led to a 75%
yield (entry 11). A nearly identical yield was obtained with 1
atm of O2 (entry 13). Reactions using dichloroethane or
toluene induced lower yields. Alternative oxidants, such as
Cu(OAc)2 or PhI(OAc)2 (entries 16 and 17), as well as
various N- or P-containing ligands were ineffective (entry 18).
Using our optimized conditions, the scope of the intra-
molecular N−N bond formation of aminoazides was evaluated.
As shown in Scheme 1, a variety of alkyl and aryl amines were
found to be amenable to five-membered ring formation. 3-
Azidobenzylamines with various arene substituents were
efficiently converted into pyrazolines (2a−2g) in moderate
yields, and benzyl group cleavage was not observed. The acetal
group of 2g was also stable under the reaction conditions. In
Scheme 1. Scope of Fe(III)-Catalyzed N−N Cyclization for
a
Construction of Five-Membered Diazoheterocycles
Table 1. Selected Optimization Data on Iron-Catalyzed N−
N Cyclization
temp (°C)/time (min)/ yield
a
b
entry
catalyst (equiv)
solvent
DCE
atmosphere
(%)
1
2
3
4
5
6
Rh2(OAc)4 (0.2)
Rh2(CF3CO2)4 (0.2) DCE
CoTPP (0.2)
Fe(TPP)Cl (0.2)
Cu(OAc)2 (0.2)
100/120/argon
100/120/argon
100/120/argon
100/120/argon
100/120/argon
100/120/argon
n.d.
n.d.
n.d.
11
n.d.
n.d.
DCE
THF
DCE
DCE
CuI (0.2), TMEDA
(0.2)
7
8
9
10
11
12
13
14
15
16
FeBr2 (0.2)
FeCl3 (0.2)
FeCl3 (0.2)
FeBr3 (0.2)
FeCl3 (0.05)
FeCl3 (0.05)
FeCl3 (0.05)
Fe(acac)3 (0.2)
Fe(OTf)3 (0.2)
THF
THF
THF
THF
THF
PhMe
THF
THF
THF
THF
100/120/argon
rt/24 h/argon
reflux/30/argon
reflux/30/argon
100/30/air
100/120/air
100/30/O2
100/30/air
trace
12
14
10
75
20
76
28
22
n.d.
100/30/air
100/120/argon
FeCl3 (0.2),
PhI(OAc)2 (0.5)
17
18
FeCl3 (0.2),
THF
THF
100/120/argon
100/120/argon
n.d.
n.d.
Cu(OAc)2 (0.5)
FeCl3 (0.2),
4,4′-bipyr (0.2)
a
a
Conditions: 1a (0.2 mmol), solvent (0.125 M), sealed tube (25 mL).
Isolated yield of 2a after purification by flash column chromatog-
Conditions: 1 (0.5 mmol), FeCl3 (0.025 mmol), air (1 atm), THF
b
(4 mL), 100 °C in sealed tube (100 mL), 0.5 h; isolated yields are
raphy. DCE, 1,2-dichloroethane; TPP, tetraphenylporphyrin; n.d., not
detected.
reported with flash column chromatography (average of two runs).
b
Reaction time was prolonged to 1 h.
B
DOI: 10.1021/acs.orglett.9b01396
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Letter
addition, aliphatic amine adducts also cyclized in good yield
(2h−2k). In comparison, 2j and 2k converted minimally,
which may be a result of steric hindrance about the amine due
to the alkyl side chains. Furthermore, substrates bearing
electron-donating or electron-withdrawing N-aryl groups were
smoothly converted into the desired products (2l−2o) in
higher yields than either aliphatic or benzylic amines.
Scheme 2. Scope of Fe(III)-Catalyzed N−N Cyclization for
a
Construction of Six-Membered Diazoheterocycles
We next investigated the scope of the reaction using γ-
azidoamine substrates bearing substituents within their alkyl
linkers (as shown in Scheme 1). First, we focused on γ-azido
benzylamines varying in their β- or γ-substituent and found
methyl, ethyl, propyl, and phenyl groups to be well tolerated
(2q, 2r, 2s, 2w, and 2x). Among these examples, benzylic
secondary azides (as in 1s and 1t), which are typically Lewis
acid sensitive, proved to be robust. The transformation even
worked for more sterically hindered sec- and tert-butyl groups,
affording the corresponding products 2y and 2z in moderate
yields. Additionally, 1,3-benzoxazine 1u and piperidine 1v
afforded [6,6,5]- and [6,5]-fused products 2u and 2v in 75%
and 66% yields. For tryptamine derivatives, cyclization onto
the aliphatic amines afforded tetracyclic products 2aa and 2ab,
again in good yields. X-ray diffraction analysis confirmed the
structure of 2aa. Critically, in all cases, the new five-membered
rings resisted dehydrogenation to unsaturated heterocycles.
Next, we evaluated whether six-membered-ring formation
could be achieved by using δ-azidoamine substrates (Scheme
2). We began by optimizing reactions of δ-azidoamines
containing either aryl or benzyl amines and found that FeBr3
in dioxane at 110 °C efficiently catalyzed intramolecular N−N
bond formation to afford the corresponding tetrahydro-
pyridazines (4a−4h, 4k, 4n, and 4o). To the best of our
knowledge, this intramolecular N−N formation approach for
construction of the six-membered heterocycles using azides is
unprecedented. Heterocycle-substituted azidoamines, includ-
ing those bearing thiophene, furan, and benzofuran hetero-
cycles, were also smoothly converted to products 4i, 4j, and
4p, despite their sensitivity to Lewis acids. Cinnamylamine-
derived product 4q was synthesized in 69% yield; the
conjugated olefin did not interrupt the cyclization. Similarly,
several fused cyclic products, particularly 4l, 4m, 4r, and 4s,
were constructed in synthetically useful yields from the
heterocyclic precursors. Single-crystal X-ray diffraction con-
firmed the polycyclic structure of 4r.
a
Conditions: 3 (0.5 mmol) and FeBr3 (0.025 mmol) in air (1 atm),
and dioxane (4 mL) at 110 °C in a sealed tube (100 mL) for 0.5 h.
Isolated yields of products purified by flash column chromatography
are reported (average of two runs).
Scheme 3. Control Experiments
Our subsequent efforts focused on the elucidation of reactive
intermediates to aid our interpretation of the mechanism
(Scheme 3). Neither the protected product (5) nor H2 were
detected by GC under an argon atmosphere with 50 mol %
FeCl3; the major product obtained was pyrazoline 2a (eq 1).
This suggests that no iron hydride species is generated, and the
reaction does not proceed through a cyclic hydrazine in the
absence of O2 as the oxidant. Next, after reduction of 2a with
NaBH3CN, the resulting saturated tetrahydropyrazole 6 was
oxidized at room temperature by either the FeCl3/air system or
air only (eq 2). The latter afforded pyrazoline 2a in relatively
low yield compared to the reaction in the presence of FeCl3,
indicating that (1) oxidative H-abstraction to produce imines
under the optimized reaction conditions is favored by the
synergistic effects of FeCl3 and O2 and (2) the high reaction
temperature must be more crucial for the N−N coupling step
than oxidation to the imine. Next, we were curious if the
reaction proceeds by an initial single-electron transfer from the
amine to Fe(III).18a,19 When 1a was subjected to modified
reaction conditions (20 mol % FeCl3 and subsequent 50 mol %
DMPO (5,5-dimethyl-1-pyrroline-N-oxide)), the radical trap-
ping products 16 and 17 were observed with an ESI high-
C
DOI: 10.1021/acs.orglett.9b01396
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Letter
resolution mass spectrum (eq 3). Furthermore, electron
paramagnetic resonance (EPR) experiments of 1a as substrate
were performed. Strong radical signals were observed with an
average g value of 2.00609 after addition of DMPO, implying
that FeCl3 reacts with substrate to produce N-centered
radicals. Taken together, these experiments indicate that the
ring-closure step could proceed by an intramolecular
homolytic substitution (SH2) from an N-centered radical to
the azide to form N−N bond.
addition/oxidative H-abstraction cascade process (Scheme
4). The formation of imine might be caused by a more reactive
Scheme 4. Further Transformations of Pyrazolines via
Formal C−H Functionalizations
To further unravel the mechanism, a DFT calculation
investigation into the Fe(III)-catalyzed N−N coupling of 1a as
the model reaction was carried out (see the Supporting
Information for details). Combining with the control experi-
ments, a possible reaction mechanism was proposed in Figure
2. Starting from the γ-azidoamine 1a, the six-membered
secondary amino species bonded to a metal center that is more
easily oxidized by air. We also utilized TMSCN to cyanidate
pyrazoline in the presence of Lewis acid TiCl4.20 When treated
with N-chlorosuccinimide, 4-chloropyrazoline 11 was synthe-
sized via a chloronium ion induced oxidation.
Finally, to further illustrate the utility of this method, we
were able to apply the N−N cyclization strategy process to the
synthesis of (−)-newbouldine (I), an alkaloid possessing
potent neurological effects (Scheme 5).2a,21 Grignard reaction,
Scheme 5. Total Synthesis of (−)-Newbouldine Using a Late
Stage N−N Cyclization Strategy
Figure 2. Proposed mechanistic cycle.
complex (A) can be generated by coordination of Fe to the
internal N atom of azide, releasing −18.1 kcal/mol. Then, a
concerted single electron oxidation by Fe(III) and deprotona-
tion of amine with a Cl anion give rise to a neutral N-centered
radical (B), which is 14.1 kcal/mol higher in free energy with a
barrier of 24.2 kcal/mol (via TS1). When the N-radical of B
attacks the internal N of azide, an intramolecular homolytic
substitution (SH2) occurs. It undergoes a concerted loss of N2
without any intermediate, providing C directly. This process
(via TS2) requires an energy barrier of 32.8 kcal/mol, which is
12.0 kcal/mol higher than TS3 to form E from D. However,
dissociation of Fe from B to give D is endergonic by 22.8 kcal/
mol. A combined energy comparison prefers the Fe
coordinated pathway from B to C. Fe(II) is detached and
further oxidized to Fe(III) by dioxygen. Fe(III) can coordinate
with E again to afford H, which is armed for H-abstraction.
Conversion of intermediate H to J by a second H-abstraction
to give imine via oxidation to Fe(III) was calculated to be
highly exergonic by 22.8 kcal/mol via transition state TS7
(ΔG⧧ = 2.3 kcal/mol). The intermediate J finally undergoes
dissociation of Fe(II) to afford desired product 2. Fe(III) can
be regenerated by dioxygen.
With the importance of the semisaturated diazoheterocycles
as the useful bioactive moiety and the versatile synthetic
building blocks, the N−N coupling products afford great
potential for their further derivatizations. For example, when
2a reacted with various metal-containing nucleophiles, such as
allylic zinc bromide, ethyl α-bromozincacetate, n-BuLi, and
PhMgBr, the corresponding formal C−H functionalization
products were observed after quenching of reactions under an
air atmosphere, presumably occurring via a nucleophilic
Wittig reaction, and subsequent hydroboration−oxidation
from the readily available proline precursor 12 proceeded in
high yield to construct 13;22 azidation of 13 afforded the
protected azidoamine 14 in 75% yield (dr = 1.5:1). After Boc
deprotection, our N−N cyclization was utilized to construct
the [5,5]-bicyclic framework and access (−)-newbouldine in
42% yield. The ability to synthesize diazo-heterocyclic
fragments using this method should prove useful in the
synthesis of drug candidates and natural products.
We have developed the first synthetic tool for efficient
construction of highly functionalized five- and six-membered
semisaturated diazo-heterocycles through Fe-catalyzed intra-
molecular N−N bond formation using aliphatic aminoazides. A
series of synthetic applications of the resulting pyrazoline have
been described for preparation of valuable derivatives. The
catalytic method was also showcased as a key step in the
synthesis of (−)-newbouldine. Efforts are underway to extend
this method for the construction of more complex hetero-
cycles.
D
DOI: 10.1021/acs.orglett.9b01396
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01396.
■
S
Experimental procedures, product characterization,
copies of NMR spectra, computational data, and
crystallographic data for 2aa and 4r (PDF)
Accession Codes
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(b) Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Angew. Chem., Int.
CCDC 1579248−1579249 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
Ed. 2016, 55, 9437−9440. (c) Maestre, L.; Dorel, R.; Pablo, O.;
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Escofet, I.; Sameera, W. M. C.; Alvarez, E.; Maseras, F.; Díaz-Requejo,
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yubx@snnu.edu.cn.
*E-mail: zwgao@snnu.edu.cn.
ORCID
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Binxun Yu: 0000-0001-8091-0669
Author Contributions
∥Y.Z., D.D., and Y.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported National Natural
Science Foundation of China (21772117 and 21603140), and
the Fundamental Research Funds for the Central Universities
(GK201803029 and GK201803036). We are also grateful to
Mr. Min-Zhen Wang for help NMR analysis, Dr. Hua-Min Sun
for X-ray crystallographic analysis of compound 2aa and 4r,
and Ms. Juan Fan for mass spectrometric analysis (Shaanxi
Normal University).
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