Nitrene-mediated intermolecular N–N coupling for efficient synthesis of hydrazides

Article abstract of DOI:10.1038/s41557-021-00650-0

N–N linkages are found in many natural compounds and endow fascinating structural and functional properties. In comparison to the myriad methods for the construction of C–N bonds, chemistry for N–N coupling, especially in an intermolecular fashion, remains underdeveloped. Here, we report a nitrene-mediated intermolecular N–N coupling of dioxazolones and arylamines under iridium or iron catalysis. These reactions offer a simple and efficient method for the synthesis of various hydrazides from readily available carboxylic acid and amine precursors. Although the Ir-catalysed conditions usually give higher N–N coupling yield than the Fe-catalysed conditions, the reactions of sterically more demanding dioxazolones derived from α-substituted carboxylic acids work much better under the Fe-catalysed conditions. Mechanistic studies revealed that the nitrogen atom of Ir acyl nitrene intermediates has strong electrophilicity and can undergo nucleophilic attack with arylamines with the assistance of Cl···HN hydrogen bonding to form the N–N bond with high efficiency and chemoselectivity. [Figure not available: see fulltext.].

Full text of DOI:10.1038/s41557-021-00650-0

Articles
https://doi.org/10.1038/s41557-021-00650-0
Nitrene-mediated intermolecular N–N coupling
for efficient synthesis of hydrazides
Hao Wangꢀ ꢀ1, Hoimin Jungꢀ ꢀ2,3, Fangfang Songꢀ ꢀ1, Shiyang Zhuꢀ ꢀ1, Ziqian Baiꢀ ꢀ1, Danye Chenꢀ ꢀ1,
1
ꢀ✉
Gang Heꢀ ꢀ1, Sukbok Changꢀ ꢀ2,3 and Gong Chenꢀ ꢀ
ꢀ✉
N–N linkages are found in many natural compounds and endow fascinating structural and functional properties. In comparison
to the myriad methods for the construction of C–N bonds, chemistry for N–N coupling, especially in an intermolecular fashion,
remains underdeveloped. Here, we report a nitrene-mediated intermolecular N–N coupling of dioxazolones and arylamines
under iridium or iron catalysis. These reactions offer a simple and efficient method for the synthesis of various hydrazides from
readily available carboxylic acid and amine precursors. Although the Ir-catalysed conditions usually give higher N–N coupling
yield than the Fe-catalysed conditions, the reactions of sterically more demanding dioxazolones derived from α-substituted
carboxylic acids work much better under the Fe-catalysed conditions. Mechanistic studies revealed that the nitrogen atom of Ir
acyl nitrene intermediates has strong electrophilicity and can undergo nucleophilic attack with arylamines with the assistance
of Cl···HN hydrogen bonding to form the N–N bond with high efficiency and chemoselectivity.
itrogen is an indispensable heteroatom in the structural and has also achieved an Ir-catalysed intramolecular C(sp3)–H amida-
functional design of organic molecules1,2. In addition to tion reaction of 3-alkyl dioxazolones for the synthesis of γ-lactams
N
N–C bonds, various N-heteroatom bonds, including N–N via an outer-sphere C–H insertion pathway. The use of a suitable
bonds3,4, are widely found in natural and synthetic compounds electron-donating ligand was found to be critical to suppress the
(Fig. 1a). The existing methods for constructing N–N-containing competing Curtius rearrangement of Ir acyl nitrenes, which pro-
scaffolds are mainly based on modification of N–N or N=N precur- ceeds through a relatively low energy barrier26. Here, we report a
sors such as hydrazine and diazo compounds (Fig. 1b)5–8. However, set of intermolecular N–N couplings between dioxazolones and
direct N–N coupling might provide a more convergent synthesis arylamines under the catalysis of iridium or iron (Fig. 1d). These
strategy, allowing greater retrosynthetic flexibility. In part due to reactions offer a simple and efficient method for the synthesis of
the high electronegativity of nitrogen, N–N coupling remains chal- various N-aryl, alkyl hydrazides from readily available precursors
lenging, especially in relation to intermolecular connections9–19
.
under mild conditions. Computational studies reveal the electro-
Methods for intermolecular N–N coupling via seemingly straight- philic nature of the proposed Ir acyl nitrene intermediates, which
forward nucleophilic substitution with amines are scarce, and most induce a nucleophilic attack of amines, eventually leading to N–N
existing procedures suffer from narrow substrate scope9. N–N cou- coupling.
pling reactions proceeding through aminyl intermediates under
electrochemical or metal catalysis have recently emerged, but they Results and discussion
are limited to the synthesis of N–N linked bicarbazoles and tetra-aryl Reaction discovery. We have previously reported that iridium com-
substituted hydrazines10,11. Reactions via transfer of nitrene inter- plex Cp*IrL7Cl, featuring a Phth-protected α-amino N-quinolyl
mediates to tertiary amines under rhodium or silver catalysis have carboxamide ligand (Phth, phthaloyl; Table 1) catalyses an intra-
also been reported17–20. However, these reactions are limited to the molecular C(sp3)–H amidation of 3-alkyl dioxazolones in high
formation of N-sulfonyl protected zwitterionic aminimide products. yield and enantioselectivity36. Encouraged by these studies, we set
Nucleophilic attack on electron-deficient nitrenes by amines out to modify the reaction system to engage nitrene intermediates
could potentially provide a viable strategy for intermolecular N–N in reactions with amines. As shown in Table 1, we were pleased to
coupling. However, the relatively complex reaction conditions find that a reaction of 3-phenylpropyl-dioxazolone 1 (1.5equiv.)
required for the generation of nitrene or nitrenoid intermediates, and N-methylaniline 2 (1equiv.) in the presence of 2mol% of
and the existence of multiple competing reaction pathways for the Cp*IrL7Cl gave the N–N coupling hydrazide product 3 in excellent
reactive nitrene intermediates, may have hampered efforts to har- yield (93%) at room temperature for 12h (entry 2). By comparison,
ness these reactivities for intermolecular couplings19,21,22. Recently, only ring-opening condensation product O-hydroxamic carbamate
1,4,2-dioxazol-5-ones, which can be prepared readily from car- 4 was obtained in the absence of catalyst (entry 3)48. Interestingly, a
boxylic acids in two steps, have reemerged as attractive precursors reaction using 1mol% of commercially available [Cp*IrCl2]2 cata-
for metal acyl nitrenes upon CO2 extrusion under mild conditions lyst also proceeded cleanly at room temperature to give 3 in 94%
(Fig. 1c)23–42. Studies from Chang24–27 and others39–47 have shown that isolated yield (entry 1). Varying the concentration of 1 and 2 led
these reagents participate in directed intermolecular C–H amida- to a notable impact on the reaction profile. As shown in entry 5, a
tion reactions under various metal-catalysed conditions through neat reaction of 1 and 2 was completed within 20min. By contrast,
an inner-sphere C–N reductive elimination mechanism. Chang lowering the concentration of 2 from 4.0M to 0.2M led to a reduced
1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, China. 2Department of Chemistry,
Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. 3Center for Catalytic Hydrocarbon Functionalizations, Institute
✉
for Basic Science (IBS), Daejeon, Republic of Korea. e-mail: sbchang@kaist.ac.kr; gongchen@nankai.edu.cn
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a
b
O
N
H
OMe
OH
P
R4
N
N
R2
H2N
HN
O
O
N
C
HN
Me
R3
Well-explored
H
N
O
O
HO
or
O
O
O
O
N
R1
N
N
H
R4
FR-900137
N
N
R2
R4
N
H
Cl
NH
R2
N
O
N
N
H
Divergent, inflexible
HO
Cl
R3
OMe
HO2C
O
O
OH
Ph
N
N
H
N
H
N
Kutzneride 1
OMe
N
O
Underexplored
N
N
N
MeO
N
H
N
H
O
Nitrene
Amine
Aminyl
Reyataz (antiretroviral drug)
Convergent, flexible
c
d
Curtius
rearrangement
O
C
R
N
R
M
N
Intramolecular
C-H insertion
R'
Ar
H
Cl
N
N
O
H
O
R
O
Directed
intermolecular
C–H amidation
O
R'
N
R'
N
M
M-nitrenoid as electrophile
L
N
O
+
O
O
N
R
N
H
Ar
[Cp*IrCl2]2 (1 mol%), CHCl3, r.t.
or FeCl2•4H2O (5 mol%), DCE, r.t.
L
X
H
Ar
R
R
Hydrazide
C
O
NH
M =
Ir, Rh, Co, Ru
Intermolecular
Nuc addition ?
Nuc
R
N
H
Fig. 1 | Occurrence and synthesis of N–N-containing compounds. a, N–N linkage in selected natural products and drugs. b, General strategies for hydrazine
synthesis. Although the methods based on modification of various N–N or N=N precursors have been well established, direct N–N coupling of two N
partners is underdeveloped and could potentially provide a more convergent and flexible synthesis strategy. c, The mechanistic challenges with controlling
the intermolecular reactivity of metal acyl nitrenes. d, Intermolecular N–N coupling of dioxazolone and amine under the catalysis of Ir or Fe (this work). The
advantages of this work are the mild conditions, high efficiency and broad scope. Mechanistic studies suggest the electrophilic N atoms of Ir acyl nitrene
intermediates undergo nucleophilic attack with arylamines, with the assistance of Cl···HN hydrogen bonding, to form the N–N bond.
yield of 3 (68%), along with the formation of 31% of urea 6 (entry 6). chloride complexes were found to catalyse the N–N coupling reac-
This side product 6 is probably formed by the addition reaction of 2 tion in satisfactory yields (entries 14–19)49–53. FeCl2 is slightly better
with isocyanate 5, which is generated via a Curtius-type rearrange- than FeCl3, and FeCl2·4H2O is slightly better than anhydrous FeCl2.
ment of the putative nitrenoid intermediate. Notably, no γ-lactam Reaction of 1 with 5mol% of FeCl2·4H2O in DCE at room tempera-
7 was observed, which would arrive via intramolecular C(sp3)–H ture gave 3 in 74% isolated yield (entry 16). In comparison with
amidation at the γ-benzylic position. Non-coordinating haloge- the best Ir-catalysed conditions, Fe-catalysed reactions were slightly
nated hydrocarbon solvents gave the best results. Although slower less selective and formed several unidentified by-products in trace
conversion was observed at 0°C (entry 11), a reaction at high tem- amounts in addition to compounds 4 and 6. In comparison to
perature gave slightly more side products (Supplementary Table 1). FeCl2, FeBr2 gave considerably lower reactivity (~40% of 3), whereas
When dioxazolone 1 was subjected to the same conditions but in the Fe(OAc)2, FeSO4 and FeF2 gave the desired N–N coupling product
absence of 2, isocyanate by-product 5 was formed predominantly in in only negligible amounts (Supplementary Table 1).
CDCl3 (97% yield, 3h). By comparison, the same treatment in hexa-
fluoroisopropanol (HFIP) gave 7% of lactam 7 and 60% of a carba- Substrate scope. We next examined the scope of amine reac-
mate side product, which is formed by the nucleophilic addition of tants in the coupling with 3-methyl-dioxazolone 8 under two sets
HFIP to isocyanate 5. This result suggests that N–N coupling of 1 of optimized conditions A and B using 1mol% [Cp*IrCl2]2 and
with amine can easily outcompete both the Curtius rearrangement 5mol% FeCl2·4H2O catalyst, respectively (Table 2). In most cases,
and the intramolecular C–H amidation processes under Ir catalysis. Ir-catalysed conditions gave higher yields of hydrazides than the
Use of 1,2-dicholorethane (DCE) solvent gave slightly lower yield Fe-catalysed conditions. As shown by the series of compounds 9
(93%, entry 9). Addition of tetramethylpiperidine 1-oxyl (TEMPO) and 10, N-monosubstituted aniline derivatives gave good to excel-
had little impact on the reaction (entry 13).
lent product yields under both conditions. The structure of 10c
A quick survey of commonly used late-transition metal com- was confirmed by X-ray crystallographic analysis. Substrates bear-
plexes revealed that [Ru(p-cymene)Cl2]2 catalyst also gave N–N ing electron-withdrawing groups on the aniline ring gave slightly
coupling product 3 in 53% yield along with 20% of urea by-product decreased reactivity (for example, 10a versus 10e). Reaction of ani-
6 under the same conditions (Supplementary Table 1). Screening line did not give the desired hydrazide product 11 under either set
of common complexes of Co, Pd, Rh, Ni, Cu, Au and Pt did not of conditions, and mainly formed the corresponding O-hydroxamic
reveal any effective catalysts, with most promoting the formation carbamate by-product. As exemplified by 18, secondary alkyl-
of O-hydroxamic carbamate 4. Surprisingly, simple iron (ii or iii) amines also failed to give hydrazide products. As shown by 19–24,
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Table 1 | Optimization of the N–N coupling reaction of 1 and 2
O
O
Cl
Cl
Ph
N
O
N
H
Ph
O
[Cp*IrCl2]2
Ir
Ir
Ph
N
Cl
3
Cl
[Cp*IrCl2]2 (1 mol%)
1 (1.5 equiv.)
O
CDCl3, N2, r.t., 12 h; [2] = 4 M
Standard Ir-catalysed conditions
Ph
N
+
Ph
O
O
N
C
3
N
Ph
3
O
O
H
O
N
4
5
N
H
Ph
Cp*IrL7Cl
(L7: Phth-Tle-AQ)
Ir
H
N
Cl
H
N
N
2 (1 equiv.)
Ph
Ph
NPhth
tBu
N
Ph
3
6
7
O
entry
1
Change from the standard ir-catalysed conditions
Standard Ir-catalysed conditions
[Cp*IrCl2]2 (1ꢀmol%) to Cp*IrL7Cl (2ꢀmol%)
No [Cp*IrCl2]2; room temperature
No [Cp*IrCl2]2; 85ꢀ°C
yield of 3/4/6 (%)a
96 (94b)/<2/<2
93/<2/<2
0/56/0
2
3
4
0/54/33
5
Neat condition; 20ꢀmin
93/<2/<2
68/0/31
6
[2]: 4.0ꢀM to 0.2ꢀM
7
[1] (1.1ꢀequiv.)
92/<2/<2
97/<2/<2
<2/96/<2
93/<2/<2
76/<2/<2
95/<2/<2
94/<2/<2
57/<2/<2
68/<2/<2
76 (74b)/<2/<2
57/<2/<2
49/<2/<2
67/<2/<2
45/<2/<2
8
[Cp*IrCl2]2 (5ꢀmol%), 1ꢀh
9
HFIP as solvent
10
11
DCE as solvent
0ꢀ°C
12
13
14
15
16
17
18
19
20
Air atmosphere
Addition of TEMPO (3ꢀequiv.)
Ir cat. to FeCl2 (5ꢀmol%)
Ir cat. to FeCl2·4H2O (5ꢀmol%)
Ir cat. to FeCl2·4H2O (5ꢀmol%); DCE as solvent
Ir cat. to FeCl3 (5ꢀmol%); DCE as solvent
Ir cat. to FeCl3·6H2O (5ꢀmol%); DCE as solvent
Ir cat. to FeCl2·4H2O (5ꢀmol%); DCE as solvent; air
Ir cat. to FeBr2 (5ꢀmol%); DCE as solvent
aAll screening reactions were carried out in a 4-ml glass vial on a scale of 0.2ꢀmmol, and yields were based on 1H NMR analysis of the reaction mixture with an internal standard. A purity of >99.99% was
used for all Fe catalysts. bIsolated yield. See Supplementary Table 1 for more screening results.
arylamines bearing six or seven-membered ortho-fused aliphatic our cis-3-aminocyclohexanecarboxylic acid substrate only gave
rings worked well. Functional groups such as allyl (9e), cyano (10f, the urea by-product under Ir-catalysed conditions, the desired
15), carbamate (Boc, 16), ketone (22), ether (23) and cyclopropyl N–N coupling product 36 could be obtained in 90% yield with Fe
(17) groups were well tolerated. The coupling procedure was scaled catalysis. A broad range of functional groups including alkyl bro-
to give 1g of 19 in 92% yield. As shown with 25–28, reactions of mide (38), alkenyl (39, 40, 46), alkynyl (41, 42), alkyl chloride
N-phenyl derivatives of α-amino acids glycine, alanine, phenyl- (44, 45), amide (36, 43) and unprotected indole (47) were well toler-
alanine and glycylproline dipeptide worked well. Overall, the high ated. Product 39 bearing a terminal olefin was formed in 87% yield
reaction efficiency was not deteriorated by steric congestion around along with a small amount of di-aminated γ-lactam by-product
the arylamine substrates.
(Supplementary compound 39-by). Erucic acid-derived product
N–N coupling reactions of various dioxazolones and second- 40 bearing an internal alkene was obtained in near quantitative
ary arylamines were next examined. C3-substituted dioxazolones yield. A similar reactivity pattern was also observed with alkynyl
were readily prepared from the corresponding carboxylic acids in substrates (41, 42). On the other hand, benzoic acid-derived dioxa-
good yield via a two-step sequence26. As shown by the compound zolone gave the corresponding hydrazide product 32 in low yield.
series 29 and 30, dioxazolones bearing various C3-alkyl groups Hydrazides featuring various mixed acyl and amine moieties can
worked well. As exemplified by 33–36, reactions of sterically more also be obtained in high yield (45–48). Although the reactions of
demanding dioxazolones derived from α-substituted carbox- dioxazolones derived from N-Phth-protected α-amino acids were
ylic acids proceeded in poor to moderate yield under Ir-catalysed unsuccessful under either condition (for example, 49), dioxazolones
conditions. Interestingly, the yields of these hydrazides increased derived from β- and γ-amino-acid precursors worked well under
considerably under Fe-catalysed conditions. For example, while Ir- and Fe-catalysed conditions (for example, 50 and 51). In addition,
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CO2Et
CO2Et
(1.5 equiv.)
CO2Et
O
H
N
Ac
c
[Cp*RhCl2]2 (5 mol%)
Cu(OAc)2 (1 equiv.)
O
N
N
N
8
O
N
HCl (1 M)/EtOH
N
MeCN, 110 °C
36 h, 61%
Reflux, 59%
55
a
O
[Cp*IrCl2]2 (0.5 mol% )
96% (1 g)
HN
57
58
N
Br
b
Ac
H2N
(2 equiv.)
CuI (5 mol%)
N
24
N
ZnCl2 (2 equiv.)
N
N
aq. HCl (12 M)/EtOH (1:5),
60 °C, 6 h, 92%
Toluene, 90 °C, 2 h
Two steps, one pot
40%
DMEDA (10 mol%)
K2CO3 (1 equiv.)
d
56
toluene, 110 °C, 24 h
59
60
Fig. 2 | Formation and selected transformation of hydrazide 24. a, Gram-scale synthesis of 24. b, Deprotection of the N-acetyl group to form 56. c, The
hydrazide group of 24 directs a Rh-catalysed ortho C–H functionalization to furnish a complex N–N-containing tricyclic scaffold 58. d, The hydrazide group
of 24 is alkenylated and then rearranged into a tetracylic indole scaffold 60.
a
b
O
O
CDCl3, r.t., 12 h
No metal
O
N
O
+
N
N
H
Ph
O
H
Ph
N
N
O
H
Ph
O
8
2
61, 70%
O
2
(D/H)
(1 equiv.)
(1 equiv.)
(+30% of 2, 0% of 9a)
KH/KD: ~1.0
N
N
H
N
O
vs
+
O
[Cp*IrCl2]2 (1 mol%)
CHCl3, N2,
N
62
(1 equiv.)
61
O
N
O
r.t., 30 min
D
Ph
N
N
8
N
N
9a
(1.5 equiv.)
2-d
(1 equiv.)
Ph
H
[Cp*IrCl2]2 (1 mol%)
CDCl3, N2,
[Cp*IrCl2]2 (1 mol%)
H
CDCl3, N2,
r.t., 12 h
9a, 32%
(+66% of 61)
10a, 45%
(+9% of 9a)
r.t., 12 h
c
O
Intramolecular
C–H insertion
HN
γ
R
R
R
R
VIII
IrL
IrL
O
O
N
IrL
O
H
N
O
N
IrL
O
N
O
R'
N
R
–CO2
ArR'NH II
O
N
N
H
N
Ar
O
R
R
N
H
Ar
Ar
IrL
Ir
Ar
R'
O
N
R'
N
R'
H
R'
Ar
N
Ar
N–H cleavage
R
Major pathway
Ir
III
I
V
Reductive
elimination
Nucleophilic
attack
ArR'NH
II
Curtius
Ir
Transfer of nitrene to amine
O
R'
N
O
Minor
pathway
II
O
C
O
R
R
N
H
Ar
N
H
N
R'
N
O
IV
VI
VII
Fig. 3 | mechanistic studies with control experiments. a, Formation and reaction of O-hydroxamic carbamate intermediate 61. Reaction of 61 probably
provides a minor pathway due to the relatively slow formation of 9a, coupled with the low reactivity of 61. b, KIE experiments indicate that cleavage of
the N–H bond is not the rate-limiting step. c, Envisaged pathways of a metal acyl nitrenoid with amine. Decarboxylation of i gives metal acyl nitrenoid
iii. iii could react with amine to form hydrazide V via N–N reductive elimination, nucleophilic attack of amine or insertion to the N–H bond of amine.
Condensation of ii and i can slowly form intermediate iV. Cleavage of the N–O bond of iV provides a minor pathway for the formation of iii.
trimeric pseudopeptides 53 and 54 were obtained in excellent yield. precursor for various subsequent transformations to furnish com-
Overall, this hydrazide synthesis procedure offers a new way to link plex structures. For example, Rh-catalysed hydrazide-directed
amido and aryl amino groups, complementing the commonly used ortho C(sp2)–H functionalization of 24 with ethyl acrylate using
amide linkage approach.
Zhang and Kim’s protocol gave 2,3-dihydroindazoles 5754,55, which
As shown in Fig. 2, reaction of 1,2,3,4-tetrahydrobenzazepine was readily converted to indazole 58. Following Liang’s protocol
55 with dioxazolone 8 using 0.5 mol% of [Cp*IrCl2]2 gave 24 in for Fischer indole synthesis, tetracyclic indole compound 60 was
96% yield on a gram scale. Acidic hydrolysis of the N-acyl group obtained in 40% overall yield from 24 in two steps56.
of 24 cleanly gave hydrazine 56. This two-step operation provides
an efficient and practical method to install an amino group at the Mechanistic study. The mechanism of this N–N coupling reac-
nitrogen atom of arylamines. Hydrazide 24 can serve as a versatile tion under the Ir-catalysed conditions was probed by both control
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a
b
z
Cl
y
O
Cl
ClA
N
x
Ir
∆G
(calc.)
Ir
Me
Ir
Cl
Ir
Ir
+
Cl
Cl
S
Cp*–=
Cl
Cl
ClB
[Ir]-3
(singlet)
[Ir]2
+
[Ir]
[Ir]-S
Substrate (S)
1 × 10–3
6 × 10–4
2 × 10–4
LUMO
–2 × 10–4
–6 × 10–4
–1 × 10–3
ClB-Ir-N(π*)
O
O
[Ir]
[Ir]
[Ir]
N
O
N
NH2
Ph
H
Tol
HOMO-5
ClB-Ir-N(nb)
[Ir]-1
(2.8)
)
[Ir]-2
(1.6)
[Ir]-TolNH2
(–1.8)
2.708 Å
Blue for
∆G
electrophilicity
on N
(kcal mol–1
X-ray of [Ir]-TolNH2
LUMO
HOMO-15
Fukui function analysis
ClB-Ir-N
Ph
c
O
∆G
(kcal mol–1
)
Cl
N
Me
Ph
Cl
Ir
O
Ir
N
H
H
Cl
N
O
Cl
Ir
Cl
N
N
Nuc attack
assisted by C=O--HN
Cl
Me
Me
Cl--H mediated
complex
[Ir]-4'-TS
[Ir]-3-TS
8.1
11.5
O
[Ir]-4
6.8
O
Me
Ir
Cl
Cl
N
N
Me
N
H
Ph
[Ir]-4-TS
9a
7.1
[Ir]-4'
2.1
[Ir]-3
0.0
–6.3
[Ir]-5'
–20.5
[Ir]
Me
Cl
[Ir]-5
–21.3
O
Ir
N
O
Cl
2.44
Cl
N
Me
H
Ir
Cl
N
2.28
Ph
N
[Ir]-5-isocy
Nuc attack
assisted by Cl--HN
H
–43.1
Ph
[Ir]-4-TS
Product extrusion
Curtius rearrangement (disfavoured)
Hydrogen-bond-mediated nucleophilic attack (more favoured)
Fig. 4 | Computational studies of the reaction mechanism. a, Binding of substrates to [ir] (for details see Supplementary Fig. 18). b, Optimized structure of
[ir]-3 and its key frontier molecular orbital (FMO), electronic structure and Fukui function analysis (Supplementary Figs. 16 and 17). nb, non-bonding orbital.
c, Energy diagram of the reaction pathway featuring a Cl–H bonding-assisted nucleophilic attack of arylamine to [ir]-3 (red line, Curtius rearrangement
pathway; blue line, Cl···NH-assisted SN2 pathway; grey line, CO···NH-assisted SN2 pathway) (Gaussian16-A03, M06-D3(0)/6-311+G**-SDD(Ir)
(SMD-CHCl3)//B3LYP-D3(BJ)/6-31G*-LANL2DZ(Ir)(gas), kcalꢀmol−1). See Supplementary Figs. 23 and 24 for the computed pathways via concerted N–H
insertion and hydrogen atom abstraction/radical rebound, inner-sphere N–N reductive elimination mechanisms.
experiments and density functional theory (DFT) calculations. As with low reactivity of 61. Furthermore, the reaction of 61 with
shown in Fig. 3a, N-methylaniline 2 reacts slowly with dioxazo- N-methyl-p-toluidine 62 gave a mixture of 9a and 10a under the
lone 8 in the absence of any catalyst at room temperature, giving standard Ir-catalysed conditions. The observation that formation of
O-hydroxamic carbamate 61 in 70% yield in 12h. Subjecting 61 10a bearing the more electron-rich arylamine was favoured indi-
to the standard Ir-catalysed N–N coupling conditions gave partial cates that the arylamine group is most likely liberated from the
conversion, leading to hydrazide 9a in 32% yield. In situ infrared metal centre after N–O cleavage of 61 and CO2 extrusion. Reactions
analysis of the reaction of 8 and 2 under the standard Ir-catalysed of dioxazolone 8 with N-methylaniline 2 or its deuterated deriva-
conditions showed that a trace amount of 61 (<3%) was gener- tive 2-d showed a kinetic isotope effect (KIE) value of 1.0 under the
ated at an early stage and quickly disappeared as the reaction pro- Ir-catalysed conditions (Fig. 3b). As outlined in Fig. 3c, Ir nitrenoid
ceeded (Supplementary Figs. 10–12). These experiments indicate intermediates with a general description of III (L for ligand)
that the reaction via intermediate 61 is probably a minor pathway would be responsible for this intermolecular N–N coupling with
due to the relatively slow formation of hydrazide product coupled arylamine. Oxidative coupling of the Ir catalyst with dioxazolone
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Table 2 | Scope of dioxazolones and amine reagents
[A] : [Cp*IrCl2]2 (1 mol%)
CHCl3, N2, r.t., 12 ha
O
O
O
R'
N
R'
N
1. NH2OH
Ar
O
R
CO2H
CO2
vs
+
+
R
N
R'
O
R
N
H
Ar
or [B] : FeCl2•4H2O (5 mol%)
DCE, N2, r.t., 12 ha
2. CDI
H
Ar
N
R
Standard conditions
(1.5 equiv.)
(1 equiv.)
Reaction with 8
10a (R = 4-Me), 93% [A]; 79% [B]
10b (R = 4-F), 93% [A]; 81% [B]
10c (R = 4-Cl), 93% [A]; 79% [B]
10d (R = 4-CF3), >95% [A]
O
R
O
9a (R = Me), >95% [A]; 79% [B]
9b (R = Et), >95% [A]; 82% [B]
9c (R = Bn), >95% [A]; 84% [B]
9d (R = iPr), 91% [A]
NHAc
N
O
HN
N
O
R
10e (R = 4-NO2), 75% [A]
N
2
4
10f (R = 4-CN), 74% [A]
9e (R = allyl), 92% [A]
3
8
10g (R = 3-Cl), 74% [A]
9f (R = Ph), 69% [A]
10h (R = 3-CF3), 99% [A]
X-ray of 10c
NHAc
NH
NHAc
N
F
NHAc
N
NHAc
N
NHAc
N
NHAc
N
NHAc
N
NHAc
N
Ph
N
Boc
CN
11, NDb [A]
18, NDb [A] or [B]
12, 83% [A]; 85% [B]
13, >95% [A]
NHAc
14, >95% [A]
15, >95% [A]
16, >95% [A]; 78% [B]
17, 90% [A]; 58% [B]
NHAc
N
NHAc
N
NHAc
N
NHAc
N
NHAc
N
NHAc
NHAc
N
N
CO2Et
N
CO2Me
Ph
Ph
NC
O
O
19, >95% [A];
92% [A, 1 g]
20, 82% [A]; 75% [B]c
21, 55% [A]
22, 54% [A]
23, 81% [A]; 62% [B]c
24, >95% [A]
25, >95% [A]; 62% [B]c 26, >95% [A]; 76% [B]c
Mixed dioxazolones and amines:
NHAc
N
NHAc
N
CO2Me
30a (R = cyclobutyl), >95% [A]; 81% [B]
30b (R = cyclopentyl), >95% [A]; 78% [B]
O
O
29a (R = butyl), >95% [A]; 70% [B]
29b (R = pentyl), >95% [A]; 69% [B]
29c (R = stearyl), 91% [A]; 51% [B]
CO2Me
Ph
Ph
N
R
N
O
N
30c (R = cyclohexyl), >95% [A]; 79% [B]
R
N
H
Ph
N
Ph
30d (R = cycloheptyl), >95%a[A]; 82% [B]
O
H
Ph
28, 89% [A]; 85% [B]c
27, >95% [A]; 78% [B]c
O
O
O
O
O
N
N
PhthN
N
N
N
N
N
H
Ph
N
Ph
N
H
Ph
Ph
N
H
Ph
Ph
N
H
Ph
Ph
N
H
Ph
H
BocN
31, >95% [A]; 74% [B]
32, 29%c [A]; messy [B]
33, 56% [A]; 91% [B]
34, 34% [A]; 93% [B]
35, 59% [A]; 84% [B]
36, NDe [A]; 90% [B]
O
O
O
O
O
N
Ph
N
Br
N
N
N
H
Ph
N
9
N
H
Ph
N
H
Ph
N
N
H
Ph
N
H
7
37, 71% [A]; 51% [B]
38, >95% [A]
39, 87% [A]; 76% [B]
40, >95% [A]
from erucic acid
41, 59% [A]; 62% [B]
Cl
Cl
Ph
O
NPhth
O
O
O
N
NH
Ph
O
N
N
N
N
N
N
N
N
H
Ph
H
Ph
H
H
Cl
42, >95% [A]
43, >95% [A]; 55% [B]
44, 67% [A]
45, 62% [A]
46, 65% [A]
from chlorambucil
O
Ph
HN
O
O
O
O
PhthN
N
N
H
Ph
N
Ph
N
N
N
N
H
PhthN
N
H
Ph
H
49, NDd [A] or [B]
47, 93% [A]
48, 74% [A]
50, 95% [A]; 69% [B]
O
Ph
N
O
O
Ph
N
CO2Me
O
Ph
N
O
CO2Me
O
PhthN
CO2Me
PhthN
N
H
N
PhthN
N
H
PhthN
N
N
N
N
H
Ph
H
51, >96% [A]; 68% [B]
52, 95% [A]; 95% [B]
53, 92% [A]; 87% [B]
54, 95% [A]; 91% [B]
from Lyrica
aIsolated yield on a scale of 0.4ꢀmmol. bRing-opening carbamate by-product was formed as the main product. cSubstantial amount of urea by-product (>40%) was formed. dMostly urea by-product formed.
CDI, 1,1′-carbonyldiimidazole; eND, not detected.
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I via N–O bond cleavage57 with concomitant CO2 extrusion pro- nucleophilic attacks (Supplementary Fig. 24). A radical-mediated
vides the main pathway to generate the key intermediate III, which pathway featuring hydrogen atom abstraction/radical rebound via
then engages with arylamine II to form the N–N coupling product. an open-shell singlet state of [Ir-3] proceeds with an energy barrier
We propose some plausible pathways of the corresponding Ir acyl of 11.5kcalmol−1, which is still higher than the nucleophilic attack
nitrenoid transfer to arylamine reactant, as shown in Fig. 3c.
pathway (Supplementary Fig. 23). Control experiments includ-
DFT calculations of a model reaction of dioxazolone 8 and ing the addition of TEMPO (entry 13, Table 1) and radical clock
arylamine 2 using [Cp*IrCl2]2 catalyst were conducted to examine experiments (7 and 39) also suggest a non-radical pathway. Overall,
the mechanisms of the N–N coupling reaction (Fig. 4). Upon dis- nucleophilic attack of arylamines assisted by the Cl···HN bond pro-
sociation of the dimeric iridium precursor into a monomeric spe- vides the most plausible pathway for the present Ir-catalysed N–N
cies [Ir], both dioxazolone 8 and amine 2 can coordinate to the Ir coupling system, and the decarboxylation of dioxazolone is the
metal centre of [Ir], forming [Ir]-1 and [Ir]-2, respectively, with rate-limiting step. Preliminary DFT calculations suggest that a simi-
little change in free energy (Fig. 4a; Supplementary Fig. 18 provides lar Cl···HN bond-assisted nucleophilic attack of the acyl-nitrenoid
detailed calculations starting from [Cp*IrCl2]2). By comparison, the intermediate by arylamine could be operative for the Fe-catalysed
complexation of a primary arylamine such as p-toluidine with [Ir] system. However, the Fe-catalysed reaction pathways could be
is more favoured, as it readily forms a stable complex [Ir]-TolNH2 much more complicated and further studies will be needed to draw
by mixing with [Cp*IrCl2]2 in CHCl3. The structure of [Ir]-TolNH2 a more detailed mechanistic description60–63
was confirmed by X-ray crystallography analysis and the relatively
.
short distance between N–H and a chloride ligand (2.71Å) implies Conclusion
the existence of a Cl···H bonding interaction. The strong complex- In summary, we have developed a new strategy for constructing the
ation of primary arylamines or alkylamines with Ir catalyst would N–N bond via unprecedented nitrene-mediated pathways under Ir- or
be responsible for the suppression of their N–N coupling (11 and Fe-catalysed conditions. These reactions offer an efficient and practi-
18; Table 2).
cal procedure to access various N-aryl, alkyl hydrazide scaffolds from
Complex [Ir]-1 undergoes an irreversible decarboxylation to readily available carboxylic acid and arylamine precursors in an inter-
form a putative Ir-acyl-nitrenoid intermediate [Ir]-3 with a barrier molecular fashion. Mechanistic studies reveal a strong electrophilic
of 22.2kcalmol−1 (Supplementary Fig. 19). Because the triplet state of property of the putative key Ir-acyl-nitrenoid intermediate to induce
[Ir]-3 species is 5.4kcalmol−1 higher in energy than the singlet state, a reaction with arylamines. Computational investigations led us to
the reaction mechanism on its singlet energy surface is examined propose that this nucleophilic attack is assisted by Cl···HN bonding to
(see Supplementary Figs. 21, 23 and 24 for the corresponding reac- outcompete the Curtius rearrangement as well as the intramolecular
tion energy profiles via the triplet of [Ir]-3). The optimized struc- C–H amidation pathways, thereby giving rise to the N–N coupling
ture of [Ir]-3 adopts a pseudo-octahedral geometry where the Cp* products with high efficiency and chemoselectivity.
ligand acts as a tridentate, six-electron donor and the Ir–N bond sits
on the y axis (Fig. 4b). Atoms ClA–Ir–N–C adopt a near co-planar Online content
arrangement with a dihedral angle of 2.99°, and the ClB–Ir bond Any methods, additional references, Nature Research report-
is perpendicular to the plane. Frontier molecular orbital (FMO) ing summaries, source data, extended data, supplementary infor-
analysis based on the localized molecular orbital (LMO) using the mation, acknowledgements, peer review information; details of
Multiwfn program revealed that the lowest unoccupied molecular author contributions and competing interests; and statements of
orbit of [Ir]-3 has a Ir=N π* character where the ClB ligand plays data and code availability are available at https://doi.org/10.1038/
a notable role24,58. The involvement of ClB ligand might be attrib- s41557-021-00650-0.
uted to its orbital interaction with a d orbital of Ir. Based on this
Received: 27 November 2019; Accepted: 1 February 2021;
Published online: 22 March 2021
information, the FMO diagram of the three-centred, four-electron
bonding relationship consisting of the d orbital of Ir, the p orbital
of N and the p orbital of ClB can be drawn. The relatively large MO
coefficient on the nitrogen atom in the ClB–Ir–N(π*) orbital of
[Ir]-3 indicates that it can effectively overlap with the highest occu-
pied molecular orbital of the arylamine nucleophile, thus displaying
an electrophilic reactivity. Fukui function (f+) analysis is also con-
sistent with an electrophilic nature of the N atom in [Ir]-3. Hence, a
nucleophilic attack on the nitrenoid nitrogen by amines can lead to
formation of the N–N bond.
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NATure CHeMIsTry
Articles
Foundation (2018M640225, 2019T120179) and Laviana Pharma for the experimental
part of this work. S.C. thanks the Institute for Basic Science (IBS-R010-D1) in the
Republic of Korea for financial support.
methods
Caution. Tis N–N coupling reaction will release stoichiometric CO2 gas, so please
handle carefully when conducting it on a large scale.
Typical procedure for synthesis of hydrazides via the Ir(iii)-catalysed N–N
coupling reaction. To an oven-dried threaded glass vial (4ml) equipped with a
rod-shaped Teflon stirbar were added [Cp*IrCl2]2 (3.2mg, 0.004mmol, 1mol%),
amine reactant (0.4mmol), CHCl3 (100μl) and 3-alkyldioxazolone substrate
(0.6mmol). After sealing, the reaction mixture was stirred in a metal heating plate
at 25°C for 12h under a nitrogen atmosphere. Water (2ml) was added, and the
mixture was extracted with ethyl acetate (3×10ml). The combined organic layers
were washed with water and brine, dried over anhydrous Na2SO4 and concentrated
in vacuo. The resulting residue was purified by silica gel flash chromatography
using petroleum ethers/acetone eluent (10:1 to 3:1) to give the hydrazide product.
All products were obtained as a mixture of rotamers.
author contributions
H.W. formulated the initial ideas for this work, carried out most of the reaction
optimization and structural determination of products studies, and prepared the
Supplementary Information. F.S. helped with the development of reaction conditions and
expansion of substrate scope. S.Z., Z.B. and D.C. helped with expanding the substrate
scope. H.J. and H.W. conducted the computational studies and prepared part of the
manuscript and Supplementary Information. S.C. supervised the computational studies
and edited the manuscript. G.H. supervised experimental studies. G.C. supervised
the project, coordinated with S.C. on computational studies, and prepared most of the
manuscript.
Competing interests
Data availability
The authors declare no competing interests.
The X-ray crystallographic data for compounds 10c and [Ir]-TolNH2 have been
deposited in the Cambridge Crystallographic Data Centre with CCDC nos.
1952123 and 1956819, respectively, and can be obtained free of charge from
the CCDC via www.ccdc.cam.ac.uk/getstructures. All other data supporting
the findings of this study are available within the Article and its Supplementary
Information.
additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41557-021-00650-0.
Correspondence and requests for materials should be addressed to S.C. or G.C.
Peer review information Nature Chemistry thanks the anonymous reviewers for their
acknowledgements
contribution to the peer review of this work.
G.C. acknowledges financial support from grants NSFC-21725204, NSFC-21672105,
NSFC-21421062, NSFC-21901127 and NCC2020FH02, the China Postdoctoral Science
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