nature catalysis

Article https://doi.org/10.1038/s41929-022-00883-3

Energy transfer-enabled unsymmetrical

diamination using bifunctional
nitrogen-radical precursors

Received: 8 April 2022 Guangying Tan, Mowpriya Das, Roman Kleinmans, Felix Katzenburg ,
Constantin Daniliuc & Frank Glorius
Accepted: 20 October 2022

Published online: 8 December 2022

Vicinal diamines, especially unsymmetrical ones, are among the most
Check for updates common structural motifs in biologically active molecules, natural products
and pharmaceuticals. While the catalytic diamination of carbon–carbon
double bonds provides rapid access to diamines, these reactions are often
limited to installation of undifferentiated amino functionalities through
transition metals or hypervalent iodine reagent catalysis. Herein we disclose
a metal-free, photosensitized dearomative unsymmetrical diamination
of various electron-rich (hetero)arenes with bifunctional diamination
reagents, producing a series of previously inaccessible vicinal diamines
with excellent regio- and diastereoselectivity. A class of bifunctional
nitrogen-radical precursors was developed to simultaneously generate
two N-centred radicals with different reactivity via an energy transfer
process. In addition, the protocol was also found suitable for a wide range
of alkenes. Notably, the formed vicinal diamines bear two differentiated
amino functionalities, and either imine or amide units could readily and
orthogonally be converted to unprotected amines, thereby facilitating
selective downstream transformations.

Vicinal diamines are the central structural motifs of a wide variety
of biologically active molecules, natural products and pharma-
ceuticals (Fig. 1a)1–3. Moreover, these diamine frameworks are also
frequently employed as organocatalysts and privileged ligands for
transition-metal catalysis4. Among various synthetic approaches to
vicinal diamines, the catalytic diamination/diazidation of carbon–car-
bon double bonds is generally regarded as one of the most efficient
and straightforward methods and has been of great interest to those
working in synthetic chemistry5,6. Despite major achievements made in
the past few decades7–41, some fundamental issues remain to be solved
in this field. First, the majority of these methods require transition
metals or hypervalent iodine reagents as catalysts9–19,23–25,28,33–41. In addi-
tion, the utilization of stoichiometric amounts of metal reagents (for
example, osmium or cobalt)7,8, chemical oxidants11,15,22,23,27,28,33,34,37,38
or azide reagents14–16,18–20,26,28,40,41 leads to issues on cost, the environ-
ment and safety. Second, the established protocols are often limited
to symmetrical diamination7–23,26–28, namely installation of two undif-
ferentiated amino functionalities across alkenes. From the synthetic
perspective, unsymmetrical diamination is a more attractive but
challenging task29 due to the lack of suitable amination reagents and
potential regio- and diastereoselectivity issues. Although some elegant
unsymmetrical alkene diaminations have been realized30–41, methods
to access a diamine precursor that could readily and orthogonally be
converted into synthetically relevant unsymmetrical diamine products
remain highly desirable.
In recent years, particularly with the advent of visible light photo-
catalysis42–46, N-centred radicals have received considerable attention
from the synthetic community because these powerful species offer
great opportunities for the construction of C–N bonds with many
complementary aspects of both ionic and transition-metal-based
methods in terms of retrosynthetic bond disconnection and reaction
selectivity47–52. To date various nitrogen-radical precursors have been

Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Münster, Germany. e-mail: glorius@uni-muenster.de

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1120

Article https://doi.org/10.1038/s41929-022-00883-3

a H2 N H O
NHMe Me
O CO2Et N
N H O
Me
Ph2HC N Et HN
N H
N OH N H
Et O NH2 N N
N H H
NHAc N N O O
Me
Me
NHMe Ph
O

Asimadoline Tamiflu Psychotrimine Kapakahine F

The majority of vicinal diamine-containing, biologically active molecules bear unsymmetrical amino functionalities

b
Precursors for single N-centred radical Precursors for two N-centred radicals

Established Unknown
N LG N N LG N N N

This study Two differentiated

Single N-centered radical
N-centred radicals

Installation of only one single amino functionality Simultaneous installation of two differentiated amino functionalities

c O

Ph S NCPh2
Me Me
H Thioxanthone (5.0 mol%)
R N O
O N Ph + NHCOR
X Blue LEDs (λmax = 405 nm) X
O O
X = NR, O, S Vicinal diamines
Diamination reagents (Hetero)arenes

EnT Ph

N Ph
Ph

RCONH + N Ph NHCOR
X
Transient Persistent
electrophilic ambiphilic

Metal and additive free Exclusive diastereo- and regioselectivity Differentiated amino groups Orthogonal deprotection

Fig. 1 | Development of nitrogen-radical precursors. a, Selected examples of vicinal diamine-containing, biologically active molecules, drugs and natural products.
b, The development of nitrogen-radical precursors. LG, leaving group. c, This study: photochemical dearomative unsymmetrical diamination.

developed, and the radicals thus formed can be broadly divided into
four classes on the basis of N-hybridization and substituents, including
ambiphilic iminyl radicals, electrophilic amidyl radicals, nucleophilic
aminyl radicals and their protonated analogues, and electrophilic
aminium radicals52. Despite continuous progress in research, to the
best of our knowledge all reported nitrogen-radical precursors are
designed for the production of single N-centred radicals, and so they
have been developed only for the installation of single or undifferenti-
ated amino functionalities (Fig. 1b, left). To realize the more challenging
unsymmetrical diamination, we reasoned whether we could design a
bifunctional reagent that is, in principle, amenable to the simultaneous
generation of two N-centred radicals at an equal rate but with differ-
ent reactivity (Fig. 1b, right). If successful, the regioselective stepwise
addition of two differentiated N-centred radicals across carbon–car-
bon double bonds might provide direct access to the unsymmetrical
vicinal diamines.
Herein we report a class of oxime ester-based, bifunctional
nitrogen-radical precursors utilized for the simultaneous generation of
ambiphilic iminyl and electrophilic amidyl radicals via an energy trans-
fer (EnT) strategy53–55, thereby providing a rapid and versatile protocol
for unsymmetrical diamination of various electron-rich (hetero)arenes
and alkenes (Fig. 1c). Noteworthy features of this method include the
following. (1) This mild diamination reaction was performed with
an inexpensive and commercially available thioxanthone as organic
photosensitizer, without the requirement for any transition metals and
additives, and is thus of high practicability. (2) This protocol exhibits
remarkable compatibility in regard to dearomative diamination of a
variety of (hetero)arenes, and is of exclusive diastereo- and regiose-
lectivity on account of the different reactivities of iminyl and amidyl
radicals. (3) Most notably, the formed vicinal diamines bear two dif-
ferentiated amino functionalities and either imine or amide groups
could readily and orthogonally be converted into unprotected amines,
thereby facilitating downstream transformation. Taken as a whole, the
current protocol offers a promising solution towards the key limita-
tions of catalytic diamination.
Results
Reaction development
Considering that iminyl and amidyl radicals are both types of widely
explored N-centred radicals showing ambiphilic and electrophilic
properties52, respectively, our investigation commenced with
the development of iminyl- and amidyl-containing bifunctional

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1121

Article https://doi.org/10.1038/s41929-022-00883-3

a
N O

Thioxanthone (5.0 mol%)

+ N N N
N Acetone (0.1 M), RT, 12 h N
S
Boc Blue LEDs (λmax = 405 nm) Boc
H1 S1–S12 1–8 Thioxanthone

Me Me Ph Me Me Ph Me Me Ph Me Me Ph Me Me Ph
H H H H
PhthN O Ph N O Ph N O PhO N O BnO N O
O N Ph S O N Ph O N Ph O N Ph O N Ph
O O
O O O O O O O O
S1 S2 S3 S4 S5

ET = 64.7 kcal mol–1 ET = 49.5 kcal mol–1 ET = 47.5 kcal mol–1 ET = 46.9 kcal mol–1 ET = 49.4 kcal mol–1

NCPh2 NCPh2 NCPh2 NCPh2 NCPh2

NPhth NHSO2Ph NHCOPh NHCO2Ph NHCO2Bn

N N N N N
Boc Boc Boc Boc Boc

1, 25%, >95:5 d.r. 2, 29%, >95:5 d.r. 3, 53%, 77:23 r.r., >95:5 d.r. 4, 47%, 87:13 r.r.; >95:5 d.r. 5, 25%, >95:5 d.r.

NCPh2 NCPh2
Me Me Ph Me Me Ph Me Me
H H H
N O C6F5 O N O N O
Teoc O N Ph NHTeoc O N Ph NHCO2CH2C6F5 Troc O NPhth
N N
O O O O
Boc Boc

S6 6, 57%, >95:5 d.r. S7 7, 43%, >95:5 d.r. S11, N.R.

ET = 46.8 kcal mol–1 ET = 49.8 kcal mol–1 ET = 64.4 kcal mol–1

NCPh2
Me Me Ph Me Ph Ph Me Me
H H H H
N O N O N O MeO N O
Troc O N Ph Troc O N Ph Troc O N Ph NHTroc O NPhth
N
O O O O O
Boc
S8, 72%, >95:5 d.r. S9, 39%, >95:5 d.r. S10, 33%, >95:5 d.r. 8 S12, N.R.
ET = 49.4 kcal mol–1 ET = 46.8 kcal mol–1 ET = 47.3 kcal mol–1 ET = 64.5 kcal mol–1

b c
High c
Entry Variation from Yield of 8 Entry Variation from Yield of 8 –100%
standard conditions standard conditions Low c
Big scale –75%
–50%
1 Without thioxanthone N.R. 6 THF instead of acetone 38% –25%
High I 0% Low H2O
2 Without light N.R. 7 4CzlPN instead of thioxanthone N.R. +25%
+50%

3 Thioxanthone (1.0 mol %) 46% 8 Mes-Acr-Me instead of thioxanthone N.R.

Low I Low O2

4 EtOAc instead of acetone 62% 9 [Ru(bpy)3](PF6)2 instead of thioxanthone N.R.

High T High O2
5 CH2Cl2 instead of acetone 48% 10 [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) 67%
instead of thioxanthone Low T

Fig. 2 | Reaction development. a, Screening of bifunctional nitrogen-radical
precursors. Reaction conditions: H1 (0.4 mmol), S1–S12 (0.2 mmol) and
thioxanthone (5.0 mol%) in acetone (0.1 M), irradiation with 18 W blue LEDs
(λmax = 405 nm) under Ar at room temperature (RT) for 12 h. Isolated yields are
shown. The d.r. values were determined by 1H NMR analysis. Triplet energies
were calculated at the CAM-B3LYP/def2-TZVPP level of theory after geometry
optimization at the CAM-B3LYP/def2-SVP level of theory, applying a CPCM
continuum solvation model for acetone. b, Impact of other reaction parameters.
c, Assessment of condition-based sensitivity. Deviation from standard reaction
conditions is illustrated as a black outline in a colour-coded radar diagram. The
diagram provides an intuitive readout of the general sensitivity of the reaction
based on the shape of the black line—namely, an almost round shape around the
0% deviation line indicating low sensitivity; any line deflecting from that to the
red zone indicates high sensitivity. CPCM, conductor-like polarizable continuum
model; N.R., no reaction; ET, triplet energy; T, temperature; I, light intensity;
c, concentration; Teoc, 2-(trimethylsilyl)ethoxycarbonyl. S1–S12: numbering of
bifunctional nitrogen-radical precursors.

nitrogen-radical precursors. As shown in Fig. 2a, various oxime tert-butyl 1H-indole-1-carboxylate H1 as a N-centred radical accep-
ester-based nitrogen-radical precursors were synthesized and their tor. We hypothesized that these precursors could undergo N–O bond
reactivities examined under visible-light-sensitized conditions using fragmentation through photosensitization to their triplet excited

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1122

Article
state via EnT catalysis, resulting in iminyl and amidyl radicals along
with the release of CO2 and aldehyde/ketone. Indeed, the desired
dearomative diamination reactions of H1 with a series of bifunctional
nitrogen-radical precursors S1–S10 were observed in the presence of
the inexpensive and commercially available thioxanthone as photo-
sensitizer (5.0 mol%), after irradiation for 12 h with blue light-emitting
diodes (LEDs; 18 W, λmax = 405 nm) in acetone. To our pleasant surprise,
the desired vicinal diamine, product 8, was obtained at 72% isolated
yield with excellent regio- and diastereoselectivity when employing
2,2,2-trichloroethoxycarbonyl (Troc)-protected bifunctional reagent
S8. Reasonably, the monomethyl or α-unsubstituted Troc-protected
bifunctional reagents S9 and S10 gave a reduced yield of product 8,
probably because of the fact that α-substituents may have increased
the rate of the radical decarboxylation step56,57. After replacement of
the benzophenone iminyl with a phthalimidyl unit (S11 and S12) the
transformation was shut down completely, suggesting that the benzo-
phenone iminyl radical with a relatively long lifespan had played a criti-
cal role in dearomative diamination58. To understand the reactivities
of these bifunctional reagents, their triplet energies were determined
by density functional theory (DFT) calculations, ranging from 46.8 to
64.7 kcal mol−1 (Fig. 2 and Supplementary Table 4). Meanwhile, the
triplet energy of thioxanthone was calculated as 61.8 kcal mol−1 using
the same computational method, with a solvation model for acetone as
applied for the bifunctional reagents. Accordingly, EnT from thioxan-
thone to S2–S10 is thermodynamically feasible. In contrast, EnT to S1,
S11 and S12 is endergonic, thus leading to either reduced efficiency or
missing reactivity. To further explore the lack of reactivity of S11 and
S12, the spin-density distributions of triplet states were determined
(Supplementary Fig. 14). For both species, spin density is predomi-
nantly localized on the phthalimide functionalities and it is expected
that a high energy barrier must overcome to enable homolytic N–O
bond breakage. In addition, the reaction of H1 with S8 was analysed
by gas chromatography–mass spectrometry to elucidate the composi-
tion of reaction mixtures (Supplementary Fig. 3). S8 was completely
consumed, given its high reactivity in generating a pair of N-centred
iminyl and amidyl radicals under standard reaction conditions. The
protonation of both N-centred iminyl and amidyl radicals, as well as
the homocoupling reaction of persistent N-centred iminyl radical,
were the main side reactions observed in the reaction. Meanwhile, a
small amount of 1H-indole was also observed in the reaction mixtures,
resulting from the deterioration of H1. Subsequently, the impact of
other reaction parameters was also investigated (Fig. 2b). As expected,
this transformation did not proceed in the absence of either thioxan-
thone or blue light (Fig. 2b, entries 1 and 2). Satisfactorily, product 8
could be obtained at 48% yield following reduction of the loading of
thioxanthone to 1.0 mol% (Fig. 2b, entry 3). The reaction appeared
to be less sensitive to the solvents, because replacement of acetone
with EtOAc, CH2Cl2 or THF as solvent still furnished 8 at moderate to
good yields (Fig. 2b, entries 4–6). Moreover, different photocatalysts
were screened and the [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) complex also
proved to be a suitable catalyst for this dearomative diamination with-
out diminution of the outcome. Furthermore, screening of the ratio of
H1 and S8 was conducted under standard conditions (Supplementary
Table 2). Either reducing the dosage of H1 or switching the stoichiom-
etry of H1 and S8 led to diminished yields of 8 (Supplementary Table 2,
entries 1–5), probably because of the deterioration of H1 in the reaction.
Finally, a conditions-based sensitivity screening suggested that this
protocol was less sensitive towards the concentration of substrates,
moisture and scale-up, suffering only from slightly diminished yields
at high oxygen concentration or low light intensity (Supplementary
Table 3 and Supplementary Fig. 5)59.
Mechanistic investigations
To gain some insights into this dearomative diamination, a series of
mechanistic studies were performed. First, the reaction of H1 and
Nature Catalysis | Volume 5 | December 2022 | 1120–1130
https://doi.org/10.1038/s41929-022-00883-3
S8 was completely inhibited by the addition of 2.0 equivalent of
2,2,6,6-tetramethylpiperidinooxy (TEMPO) as a radical scavenger;
TEMPO-adduct 9 and radical–radical cross-coupled product 10 were
detected by high-resolution mass spectroscopy, and products 11–13
were observed as the major byproducts by gas chromatography–mass
spectrometry (Supplementary Figs. 9 and 10). These results clearly
hinted at the radical nature of the reaction and also demonstrated the
generation of iminyl and amidyl radicals (Fig. 3a). Second, the reaction
of S8 with A38 under standard conditions formed cyclic product 14 at
22% yield, further suggesting the involvement of two N-centred radicals
(Fig. 3b). Subsequently, product 8 was obtained at 36% yield when the
reaction mixture of S8 and H1 was irradiated with a higher-energy light
source (λmax = 365 nm) in the absence of any photocatalyst, indicating
that single-electron transfer events are unlikely in this transformation
(Fig. 3c). Then, ultraviolet-visible (UV-vis) absorption spectroscopy of
all reactants and their mixtures was measured, with thioxanthone found
to be the only absorbing species in the reaction near the irradiation
wavelength (λmax = 405 nm) (Fig. 3d). Moreover, Stern–Volmer analysis
demonstrated that the luminescence emission of thioxanthone was
quenched efficiently by S8 rather than by H1, implying that an interac-
tion between thioxanthone and S8 might exist in the reaction medium
(Fig. 3e). To understand the nature of this interaction, comparison of
certain photocatalysts with varying properties was conducted (Fig. 3f).
As a result, yields of product 8 correlate to the triplet state energy of
photocatalysts while they are unrelated to redox properties44,60. These
results implied that an EnT process is likely to have been operational
in the reaction. Furthermore, cyclic voltammetry measurement was
conducted. As shown in Fig. 3g, no obvious oxidation peak of S8 and H1
was observed before +1.4 V versus saturated calomel electrode (SCE),
which suggests that these two compounds could not be oxidized by the
excited state *thioxanthone (half-wave potential, E1/2[PC]*/[PC]− = +1.18 V
versus SCE, where PC represents photocatalyst). Similarly, no obvi-
ous reduction peak of S8 and H1 was observed before −1.5 V versus
SCE, which means that these two compounds could not be reduced
by *thioxanthone (E1/2[PC]+/[PC]* = −1.11 V versus SCE). Therefore, the ther-
modynamic feasibility of a single-electron transfer (SET) reduction of
S8 by the excited thioxanthone was also excluded by means of cyclic
voltammetry (Fig. 3g).
Taking the above results together, a plausible mechanism is pro-
posed as outlined in Fig. 3h. The reaction starts with an interaction
between S8 and the excited thioxanthone through a photo-induced
EnT process to generate the excited S8*. The triplet energy of S8 is
computed to be 49.4 kcal mol−1, which is sufficient to undergo tri-
plet–triplet EnT with an excited thioxanthone (ET = 65.5 kcal mol−1).
Then, S8* undergoes N–O bond fragmentation to form a transient
amidyl radical and a persistent iminyl radical (species 15 and 16) along
with the release of CO2 and acetone. Based on the persistent radical
effect61,62, the electrophilic amidyl radical 15 is captured by H1 at the
C2 position to produce transient C-centred radical 17, followed by a
radical–radical coupling process with the ambiphilic iminyl radical
16 from the opposite, sterically accessible side to produce the desired
trans-diamine 8. We speculated that the observed regioselectivity
of this reaction might have been driven mainly by the stability and
electronic property—as well as the steric hindrance—of the generated
C-centred radical after the addition of the N-centred amidyl radical
to H1. The addition to H1 at the C2 position generated a stabilized
benzyl radical (17), while the addition at the C3 position would yield a
highly nucleophilic α-aminoalkyl radical (18). Although C3 is relatively
more nucleophilic than C2, the polar match of ambiphilic N-centred
iminyl radical with stabilized benzyl radical (17) might be higher than
that with highly nucleophilic α-aminoalkyl radical (18). Moreover,
the steric hindrance of the generated C-centred radical undoubtedly
played a key role in regiocontrol. Clearly, radical 17 was less sterically
hindered than radical 18, facilitating the radical–radical cross-coupling
of C-centred radical with N-centred iminyl radical to furnish the desired
1123
Article https://doi.org/10.1038/s41929-022-00883-3

a
Me
Me Ph Ph
NCPh2 Troc
Me Me Ph Standard conditions N
H O NH NH N
+ N O Me Me N N
N NHTroc TrocNH2
Troc O N Ph N
TEMPO (2.0 equiv.) NHTroc Ph Ph
Boc O Ph Ph Ph Ph
Boc N
Boc 11 12 13
H1 (2.0 equiv.) S8 (1.0 equiv.) 8, Trace 9 10
Detected by HRMS Detected by HRMS Major byproducts

b c
NCPh2
Me Me Ph Me Me Ph N H1
H A38 Ph2CN NHTroc
H
N O N O Boc NHTroc
Troc O N Ph EtO2C CO2Et Troc O N Ph N
O EtO2C CO2Et O Acetone (0.1 M), RT, 24 h
Boc
Standard conditions UV lamp (λ max = 365 nm)
S8 14, 22%, >95:5 d.r. S8 8, 36%, >95:5 d.r.

d e g
1.20 250
[PC]
MeCN
H1 1.16 200
1.0 S8 in MeCN
S8
H1 in MeCN
[PC] + H1

Current (µA)
1.12 150
[PC] + S8
Intensity

S8
[PC] + H1 + S8
I0/I

1.08 H1 100
0.5

1.04
50
E1/2 = 1.47 V
1.00
0 0

300 350 400 450 0 2 4 6 8 10 12 3.0 2.5 2.0 1.5 1.0 0.5 0
Wavelength (nm) Concentration (mM) Potential (V versus SCE)

f
NCPh2
Me Me Ph 0
H [PC]
N O
+ Troc O N Ph NHTroc –10
N Acetone, hν N
O
Current (µA)

Boc Boc –20

MeCN
H1 S8 8
S8 in MeCN
–30
+ – H1 in MeCN
Entry Photocatalyst ET (kcal mol–1) E1/2 [PC] /[PC]* (V) E1/2[PC]*/[PC] (V) Yield of 8 (%)
–40
1 Thioxanthone 65.5 –1.11 +1.18 72
–50
2 [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) 61.8 –0.89 +1.21 67

3 fac-Ir(ppy)3 58.1 –1.73 +0.31 ND 0 –0.5 –1.0 –1.5 –2.0 –2.5

Potential (V versus SCE)
4 [Ir(ppy)2(dtbbpy)](PF6) 49.2 –0.96 +0.66 43

5 [Ru(bpy)3](PF6)2 46.5 –0.81 +0.77 ND

h
O
* CO2 + N
Me Me Ph [PC] [PC]* Me Me Ph Me Me Ph
H H Boc
N O N O H1
Troc O N Ph Troc O N Ph TrocNH + N Ph
O O Fragmentation Radical addition
EnT catalysis
S8 S8* 15 16
ET = 49.4 kcal mol–1
Ph
N NHTroc
Ph NCPh2

N Radical–radical cross-coupling
versus Ph NHTroc
NHTroc N
Boc N
N
Ph Boc
17 Boc 18 8

Stabilized benzyl radical and less sterically hindered Highly nucleophilic a-aminoalkyl radical and more sterically hindered

Fig. 3 | Mechanistic investigations. a, TEMPO trapping experiment. dF(CF3)ppy, 2-(2,4-difluorophenyl)−5-(trifluoromethyl)pyridine; dtbbpy,

b, Radical probe experiment. c, Direct excitation. d, UV-vis absorption 4,4′-di-tert-butyl-2,2′-bipyridine; ppy, 2-phenylpyridine; bpy, 2,2’-bipyridine.
spectrum. e, Stern–Volmer quenching studies. f, Comparison of different HRMS, high-resolution mass spectrometry; I0, luminescence intensity without
photocatalysts for 8. g, Cyclic voltammetry. h, Proposed mechanism. the quencher; I, intensity in the presence of the quencher; ND, not detected.

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1124

Article https://doi.org/10.1038/s41929-022-00883-3

NCPh2
Me Me Ph Thioxanthone (5.0 mol%) O
H Acetone (0.1 M), RT, 12 h
R + N O R NHTroc + + CO2
Troc O N Ph Blue LEDs (λ max = 405 nm) Me Me
X X
X = NR, O or S O
(Hetero)arenes S8
a
NCPh2 NCPh2 NCPh2 NCPh2

NHTroc NHTroc NHTroc NHTroc

N N N N N
Boc OMe t
Bu O S Ph
O O O
8, 72%, >95:5 d.r. 19, 51%, >95:5 d.r. 20, 68%, >95:5 d.r. 21, 52%, >95:5 d.r.

NCPh2 NCPh2 NCPh2 NCPh2 NCPh2

Me MeO BnO
NHTroc NHTroc NHTroc NHTroc NHTroc
N Me N N N N

Ph Boc Boc Boc Boc

O
22, 43%, >95:5 d.r. 23, 70%, >95:5 d.r. 24, 74%, >95:5 d.r. 25, 68%, >95:5 d.r. Me 26, 59%, >95:5 d.r.
Me
Boc Me O
NCPh2 NCPh2 NCPh2 NCPh2 NCPh2
O F Br Me B
O
NHTroc NHTroc NHTroc NHTroc NHTroc
N N Cl N N N
Boc Boc Boc Boc Boc
27, 52%, >95:5 d.r. 28, 66%, >95:5 d.r. 29, 70%, >95:5 d.r. 30, 63%, >95:5 d.r. 31, 62%, >95:5 d.r.
O O
NCPh2 NCPh2 NCPh2 NCPh2 NCPh2
NC Bn
H N N
NHTroc NHTroc H NHTroc NHTroc NHTroc
N N N N N N
Boc Boc Boc Boc Boc
32, 50%, >95:5 d.r. 33, 59%, >95:5 d.r. 34, 42%, >95:5 d.r. 35, 70%, >95:5 d.r. 36, 65%, >95:5 d.r.
MeO2C
NHCO2Bn
Ph2CN Ph2CN Ph2CN Ph2CN Ph2CN
CO2Me NHBoc
Me CO2Et
NHTroc NHTroc NHTroc NHTroc NHTroc
N N N N N
Boc Boc Boc Boc Boc
37, 44%, >95:5 d.r. 38, 56%, >95:5 d.r. 39, 65%, >95:5 d.r. 40, 56%, >95:5 d.r. 41, 30%, 50:50 d.r.
NCPh2 NCPh2 H from Z-Trp-OMe
Me Br O O
Limitations
NHTroc NHTroc H H NHTroc Me
N N H
H Me NHTroc
O N N
O O N
Me Me Me Me Me H
O H27 Me Ph
42, 48%, 77:23 d.r. 43, 40%, 79:21 d.r.
No reaction 44, 16% 45, 15%
from gemfibrozil derivative from dehydrocholic acid derivative
b
NCPh2 Ph2CN Ph2CN Ph2CN Ph2CN
Me Me Me Cl Me
O
NHTroc NHTroc NHTroc NHTroc NHTroc
O O O O Me O
Cl Me N
46, 61%, >95:5 d.r. 47, 55%, >95:5 d.r. 48, 58%, >95:5 d.r. 49, 65%, >95:5 d.r. 50, 62%, >95:5 d.r.
CN Me
O

NCPh2 Ph2CN Ph2CN N NCPh2

OAc CO2Me Ph2CN N Me
NHTroc NHTroc NHTroc NHTroc NHTroc
O O O O O
51, 49%, >95:5 d.r. 52, 51%, >95:5 d.r. 53, 47%, >95:5 d.r. 54, 53%, >95:5 d.r. 55, 66%, >95:5 d.r.
c d
CO2Et NCPh2 NCPh2
NCPh2 Br NCPh2 NHTroc
Ph2CN
NHTroc NHTroc
S S
NHTroc
S NHTroc
56, 32%, >95:5 d.r. 57, 30%, >95:5 d.r. 58, 45%, >95:5 d.r. 59, 40%, >95:5 d.r. 60, 43%, >95:5 d.r.

Fig. 4 | Dearomative unsymmetrical diamination of (hetero)arenes. Reaction conditions: (hetero)arenes H1–H44 (0.4 mmol), S8 (0.2 mmol) and thioxanthone
(5.0 mol%) in acetone (0.1 M), irradiation with 18 W blue LEDs (λmax = 405 nm) under Ar at room temperature for 12 h. Isolated yields are shown. The d.r. values were
determined by 1H NMR analysis. H1–H44: numbering of (hetero)arenes.

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1125

Article https://doi.org/10.1038/s41929-022-00883-3

R1 Ph NCPh2 O
Me Me
H Thioxanthone (5.0 mol%) R1
+ N O NHTroc + + CO2
R2 Troc O N Ph Acetone (0.1 M), RT, 12 h R2 Me Me
R3 O R3
Blue LEDs (λ max = 405 nm)
Alkenes S8

NCPh2 NCPh2 62, R = tBu, 73% NCPh2

NHTroc NHTroc 63, R = NHBoc, 64% NHTroc

64, R = Cl, 76% N

R
61, 75% 65, R = Br, 72% 66, 57%

NCPh2 NCPh2 NCPh2 NCPh2 NCPh2

S NHTroc NHTroc NHTroc NHTroc NC NHTroc
Me Ph
N Me
Me I O
Me
67, 57% 68, 62% 69, 78% 70, 63%, >95:5 d.r. 71, 46%, >95:5 d.r.

Me
NCPh2 NCPh2 NCPh2 NCPh2 NCPh2 NCPh2
Ph N
NHTroc NHTroc NHTroc NHTroc NHTroc NHTroc
OH B
Ph O N O
Me 4 O
O
O O
72, 32%, >95:5 d.r. 73, 58%, 57:43 d.r. 74, 75% 75, 71% 76, 63% 77, 35%

NCPh2 NCPh2 O NCPh2 NCPh2 NCPh2

R NHTroc Boc NHTroc NHTroc EtO NHTroc Me NHTroc
N N N P
H H EtO
78, R = CHO, 54% Me O O

79, R = Boc, 48% 80, 43%, 50:50 d.r. 81, 55% 82, 38% 83, 61%

O NCPh2 O NHTroc NCPh2 NCPh2

MeO Me NHTroc NCPh2 NC NHTroc NHTroc
MeO + MeO
O
84, 50:50 d.r. Me 85, 50:50 d.r. Me OH
86, 48% 87, 42%

84 + 85, 36%, 53:47 r.r.

O
O NCPh2 NCPh2 O NCPh2 O NCPh2
NHTroc N NHTroc NHTroc PhthN NHTroc
N S O O
O 7
O
NPhth
O
88, 44% 89, 40% 90, 36%, 50:50 d.r. 91, 39%
Complex alkenes
NCPh2
Me
Me NHTroc
NCPh2 Me NCPh2 Me NCPh2
Me O
NHTroc NHTroc NHTroc
Me O
Me Me O
Me
Me O O O
Me Me
O
92, 47%, 55:45 d.r. 93, 42%, 66:34 d.r. 94, 68%, 50:50 d.r. Me Me
from carvone from nootkatone from camphanic acid derivative 95, 66%, 50:50 d.r.

Me from D-gamma-tocopherol
Me
O
O NCPh2 Me O NCPh2 Me NCPh2
H
NHTroc NHTroc NHTroc
O O O Me H O O
Me Me Me Me Me
Me N
Me S H H
O O O O
96, 48% 97, 39% 98, 40%, 50:50 d.r.
H
from gemfibrozil derivative from probenecid derivative from dehydrocholic acid derivative

Fig. 5 | Unsymmetrical diamination of alkenes. Reaction conditions: alkenes A1–A38 (0.4 mmol), S8 (0.2 mmol) and thioxanthone (5.0 mol%) in acetone (0.1 M),
irradiation with 18 W blue LEDs (λmax = 405 nm) under Ar at room temperature for 12 h. Isolated yields are shown. The d.r. values were determined by 1H NMR analysis.
A1–A38: numbering of alkenes.

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Article https://doi.org/10.1038/s41929-022-00883-3

a
NH2 NCPh2 NCPh2
HCl (1 N), MeOH, r.t., 2 h TBAF, THF, r.t., 3 h
NHTroc NHTroc NH2
N N N
t
Bu tBu tBu
O O O

99, 92% 20 (10 mmol scale, 56%) 100, 78%

b c

NH2 NCPh2 NCPh2 NCPh2 NH3 Cl

HCl (1 N), MeOH TBAF, THF HCl (6 N)
NHTroc NHTroc NH2 NHTroc HO NHTroc
r.t., 2 h r.t., 3 h 100 oC, 12 h
N
O

101, 95% 61 102, 83% 76 103, 90%

d
NCPh2
Ph R Ph
Me Me DIAD, PPh3, THF Me Me R
H Standard conditions
N O N O + N
Troc O N Ph Troc O N Ph N N
EtOH or CD3OD Troc
O O Boc Boc
0 oC to r.t., 12 h
S8 S13, R = Et, 98% H1 104, R = Et, 57%, 56:44 d.r.
S14, R = CD3, 96% 105, R = CD3, 50%, 52:48 d.r.

Fig. 6 | Synthetic applications. a, Orthogonal deprotection of 20. b, Orthogonal deprotection of 61. c, Transformation of 76. d, Derivativation of S8. TBAF,
tetra-n-butylammonium fluoride; DIAD, diisopropyl azodicarboxylate.

diamine product. Notably, while 17 is a nucleophilic and relatively
stabilized benzyl radical, the radical–radical cross-coupling of 17 with
the electrophilic amidyl radical 15 was not observed in the reaction
(Supplementary Fig. 4).
Reaction scope
After investigation of the reaction mechanism, the scope of this dearo-
mative diamination was systematically investigated using bifunctional
reagent S8 as N-centred radical source under optimized reaction condi-
tions. As shown in Fig. 4, a range of representative electron-rich (hetero)
arenes, such as indoles, benzofurans, benzothiophenes, phenanthrene
and anthracene, smoothly underwent this protocol to form a variety of
unsymmetrical diamines at moderate to good yields. Indoles with differ-
ent N-protection groups, such as tert-butoxycarbonyl (Boc), methoxy-
carbonyl, pivaloyl, sulfonyl or benzoyl, reacted with S8 at satisfactory
yields (Fig. 4a, 8, 19–22), and the structure of product 21 was further
confirmed by X-ray crystallography. Various N-Boc-protected indoles
bearing either electron-donating or -withdrawing substituents on the
aromatic ring or C3 position were highly compatible with this reac-
tion (Fig. 4a, 23–40). Especially sensitive functional groups, such as
chloro, bromo, acyloxy, ester, amide, cyano, formyl—and even boronic
ester—were well tolerated under the optimized conditions. To further
test the compatibility of this method in more structurally complex
contexts, several complicated indole-containing, biologically active
compounds—such as Boc-protected Z-Trp-OMe and indoles embedded
in gemfibrozil or dehydrocholic acid—were tested, affording the corre-
sponding diamines at moderate yield (41–43). Unprotected indoles and
N-alkyl or N-aryl indoles were, however, unsuitable for this protocol. For
instance, the reaction of 1H-indole H27 with S8 did not yield any desired
diamine product; neither did the reactions of S8 with 1-methyl-1H-indole
H28 or 3-methyl-1-phenyl-1H-indole H29. Instead, the C–H amidation
products 44 and 45, resulting from rearomatization after the addition
of N-centred amidyl radical to indoles, were obtained at yields of 16 and
15%, respectively. These results suggested that the electron-withdrawing
group at the indole N atom is indispensable for dearomative diamina-
tion. We speculated that the electron-withdrawing group at the indole
N atom might decrease the nucleophilicity of C-centred benzyl radical,
thereby improving the polar match with ambiphilic N-centred iminyl
radical. This ultimately facilitated the smooth passage of the reaction
toward the desired dearomative diamination rather than the rearo-
mative C–H amidation. In addition, the protocol could be extended
smoothly to various benzofurans (Fig. 4b, 46–55), as well as to benzo-
thiophenes (Fig. 4c, 56–58). Surprisingly, conjugated arenes—such as
phenanthrene and anthracene, despite having lower reactivity—were
also found suitable for this transformation, forming the products at
acceptable yields (Fig. 4d, 59, 60). Most notably, high diastereoselec-
tivity was obtained within these diamination reactions because the
stepwise addition of amidyl and iminyl radicals across carbon–carbon
bonds proceeded from the opposite, sterically accessible side, produc-
ing a series of cyclic trans-diamines.
The applicability of this method towards alkene substrates was
also examined. As summarized in Fig. 5, a wide range of alkenes, rang-
ing from styrenes, cyclic alkenes, enynes, electron-poor or -rich alk-
enes and even to unactivated alkenes, was included in the reaction
(61–98), delivering the corresponding unsymmetrical diamines at
moderate to good yields and with excellent regioselectivity. It is of
note that acyclic 1,2-disubstituted alkenes were also suitable for this
reaction. For example, (E)-prop-1-en-1-ylbenzene and (E)-tert-butyl
prop-1-en-1-ylcarbamate smoothly underwent the reaction, yielding
the corresponding products 73 (57:43 diastereomeric ratio (d.r.))
and 80 (50:50 d.r.) at yields of 58 and 43%, respectively. Moreover,
(E)-methyl hex-3-enoate reacted with S8 to give an inseparable dias-
tereoisomeric (50:50 d.r.) and regioisomeric (53:47 regioisomeric
ratio (r.r.)) mixture (84 and 85) at 36% total yield. Finally, the synthetic
application of this protocol was further highlighted by the reaction of
S8 with complex alkenes (92–98), including natural alkene-containing
products such as carvone (92) and nootkatone (93), as well as those
derived from camphanic acid (94), d-gamma-tocopherol (95), gemfi-
brozil (96), probenecid acid (97) and dehydrocholic acid (98).
Subsequently, to highlight the synthetic utility of this method, a
10 mmol-scale reaction of H3 with S8 was performed under standard
reaction conditions yielding product 20 at 56% yield (Fig. 6a). Moreover,
both imine and amide units on compound 20 were orthogonally depro-
tected under mild conditions to yield the corresponding unprotected
amines (99 and 100)63, thereby facilitating downstream transformation.
Similarly, orthogonal deprotections of product 61 were conducted

Nature Catalysis | Volume 5 | December 2022 | 1120–1130 1127

Article
(Fig. 6b, 101 and 102). This protocol therefore offers general access to
diamine precursors that could be selectively converted to syntheti-
cally relevant unsymmetrical diamine products. Additionally, treat-
ment of product 76 with HCl (6 N) at 100 °C for 12 h generated a valuable
1,2-diamino acid 103 (Fig. 6c). Finally, N-alkyl-substituted bifunctional
nitrogen-radical precursors S13 and S14 were readily prepared through
the Mitsunobu reaction of S8 with EtOH or CD3OD at excellent yields
(Fig. 6d)64. To our pleasant surprise, S13 and S14 smoothly underwent
this reaction, yielding the desired diamines (104 and 105) at moder-
ate yields. These findings further extend the scope of bifunctional
nitrogen-radical precursors and highlight the practicality of this method.
Conclusions
In summary, we have demonstrated photosensitized dearomative
unsymmetrical diamination of various electron-rich (hetero)arenes
that is highly regio- and diastereoselective and runs under mild and
transition-metal- and additive-free conditions. The developed bifunc-
tional nitrogen-radical precursors were elaborately designed for this
transformation to simultaneously generate two N-centred radicals with
different reactivities via an EnT process. In addition, the protocol is
also applicable to a wide range of alkenes. Notably, the formed vicinal
diamines bear two differentiated amino functionalities, and either
imine or amide units could readily and orthogonally be converted
to unprotected amines thereby facilitating downstream transforma-
tion. We believe that this method represents an operationally simple,
effective and practical route to unsymmetrical vicinal diamines in both
academic research and industry.
Methods
Representative procedure for diamination of (hetero)arenes
or alkenes
In an oven-dried 10 ml Schlenk tube equipped with a
poly­tet­ra­fluoroethylene-coated, rare-earth ‘extra power’ oval stir-
ring bar, bifunctional diamination reagent (0.2 mmol, 1.0 equiv. unless
otherwise stated), (hetero)arene or alkene (0.4 mmol, 2.0 equiv. if
solid) and thioxanthone photosensitizer (2.1 mg, 5 mol%) were charged
under air, then the vessel was evacuated and refilled with argon four
times. Dry acetone (2.0 ml, 0.1 M) and appropriate (hetero)arene or
alkene (0.4 mmol, 2.0 equiv. if liquid) were added under argon coun-
terflow. The vessel was tightly sealed and stirred under irradiation with
18 W blue LEDs (λmax = 405 nm) for 12 h, unless otherwise stated. After
irradiation, the resulting homogenous solution was transferred to a
25 ml round-bottom flask with the inclusion of CH2Cl2 (2 × 3 ml). NEt3
(approximately 0.5 ml) and SiO2 were added to this solution and vola-
tiles were removed under reduced pressure, yielding a powder that was
loaded onto a column. Purification by flash-column chromatography
on SiO2, prebasified with NEt3 using pentane/EtOAc mixtures, yielded
the corresponding diamine products.
Data availability
Materials and methods, experimental procedures, mechanistic stud-
ies, computational studies, sensitivity assessment and nuclear mag-
netic resonance (NMR) spectra are available in the Supplementary
Information. Crystallographic information data files and xyz coordi-
nates of the optimized structures are available as Supplementary files.
Crystallographic data for the structures reported in this article have
been deposited at the Cambridge Crystallographic Data Centre under
deposition nos. CCDC 2145161 (21) and 2145162 (66). Copies of crystal-
lographic data can be obtained free of charge via https://www.ccdc.
cam.ac.uk/structures/. All other data are available from the authors
upon reasonable request.
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Acknowledgements
We thank P. Bellotti, X. Yu, X. Zhang (all WWU) and H. Keum (KAIST)
for helpful assistance and discussions. Generous financial support
provided by the Alexander von Humboldt Foundation (G.T.), Fonds
der Chemischen Industrie (R.K., Kekulé Scholarship no. 106151)
and Deutsche Forschungsgemeinschaft (no. SFB 858) is gratefully
acknowledged.
Author contributions
F.G. and G.T. conceived the project. G.T. and R.K. performed the
initial screening experiments. G.T. and M.D. performed synthetic
experiments. F.K. conducted computations. C.D. analysed X-ray
structures. G.T. and F.G. supervised research and wrote the manuscript
with contributions from all authors.
Competing interests
The authors declare no competing interests.
Nature Catalysis | Volume 5 | December 2022 | 1120–1130
https://doi.org/10.1038/s41929-022-00883-3
Additional information
Supplementary information The online version
contains supplementary material available at
https://doi.org/10.1038/s41929-022-00883-3.
Correspondence and requests for materials should be addressed to
Frank Glorius.
Peer review information Nature Catalysis thanks Wujiong Xia,
Fangrui Zhong and the other, anonymous, reviewer(s) for their
contribution to the peer review of this work.
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