Metal-free cross-dehydrogenative C–N coupling of azoles with xanthenes and related activated arylmethylenes

Article abstract of DOI:10.1080/00397911.2019.1615097

A metal-free C(sp³)–H/N–H cross-coupling of azoles with xanthenes and related activated arylmethylenes is presented. Both the use of azoles and the activation pattern of C(sp³)–H sources are essential for this transformation. In the

Full text of DOI:10.1080/00397911.2019.1615097

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Metal-free cross-dehydrogenative C–N coupling
of azoles with xanthenes and related activated
arylmethylenes
Yanni Li, Yanping Li, Yuan Li, Chunlin Chen, Fengyuan Ying, Ying Dong &
Deqiang Liang
To cite this article: Yanni Li, Yanping Li, Yuan Li, Chunlin Chen, Fengyuan Ying, Ying
Dong & Deqiang Liang (2019): Metal-free cross-dehydrogenative C–N coupling of azoles
with xanthenes and related activated arylmethylenes, Synthetic Communications, DOI:
10.1080/00397911.2019.1615097
To link to this article: https://doi.org/10.1080/00397911.2019.1615097
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1615097
Metal-free cross-dehydrogenative C–N coupling of azoles
with xanthenes and related activated arylmethylenes
Yanni Lia, Yanping Lia, Yuan Lia, Chunlin Chena, Fengyuan Yinga, Ying Dongb, and
Deqiang Lianga,c
b
aDepartment of Chemistry, Kunming University, Kunming, China; College of Chemistry, Chemical
c
Engineering and Materials Science, Shandong Normal University, Jinan, China; Yunnan Engineering
Technology Research Center for Plastic Films, Kunming, China
ABSTRACT
ARTICLE HISTORY
A metal-free C(sp3)–H/N–H cross-coupling of azoles with xanthenes
and related activated arylmethylenes is presented. Both the use of
azoles and the activation pattern of C(sp3)–H sources are essential
for this transformation. In the presence of 2.0 equiv of benzoyl per-
oxide (BPO), methylenes bearing a heteroatom-bridged bisaryl group
reacted with various azolic N–H sources to afford C–N bond forming
products in usually excellent or quantitative yields, and the diphenyl-
methane and methylenes coactivated by a phenyl group and an
adjacent heteroatom are less reactive. Mechanistic investigations
suggest that a radical/radical cross-coupling pathway might be
involved.
Received 14 January 2019
KEYWORDS
Amination; C–N coupling;
cross-dehydrogenative cou-
pling; radical reaction
GRAPHICAL ABSTRACT
N
H
H
N
BPO (2.0 equiv)
DCE, 80 ºC
N
N
+
N
N
O
O
metal-free
C(sp3)-H/N-H cross-coupling
up to 97% yields
Introduction
Nitrogen-containing motifs are ubiquitous in natural and synthetic bioactive products,[1]
and the construction of C–N bonds is of fundamental interest in organic synthesis.[2–4]
Over the past decades, great progress has been made in the field of transition metal-cat-
alyzed C–H amination reaction,[4] and advantages of this strategy include atom- and
step-economy and the elimination of substrate prefunctionlization. The toxicity of heavy
metal residues, however, is concerned.[5] On the other hand, whereas a plethora of
methodologies for C(sp2)–H amination have been developed, direct amination of
C(sp3)–H bonds remains more rudimentary due to their high bond energy and
low acidity.[2–4]
CONTACT Deqiang Liang
liangdq695@nenu.edu.cn
Department of Chemistry, Kunming University, Kunming,
650214, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
Y. LI ET AL.
The xanthen-9-amine motif is frequently encountered in alkaloids and synthetic bio-
active compounds,[6] and finding increasing applications in organic synthesis.[7] Despite
the above advances in C–N bond formation, xanthen-9-amines were traditionally syn-
thesized through nucleophilic substitution of halogenated xanthenes, which suffers from
substrate prefunctionalization and toxic wastes (Scheme 1a).[6b,8] Alternatively, C–H
amination of xanthenes with nitrenes could afford xanthen-9-amines, wherein a noble
and/or elaborated transition-metal complex and a nitrene precursor are required
(Scheme 1b).[9] The cross-dehydrogenative coupling (CDC) reaction has recently
emerged as a powerful and ideal tool for the formation of C–C and C–heteroatom
bonds,[10] and in 2018, Zeng and coworkers reported an electrochemical C(sp3)–H/N–H
cross-coupling of xanthenes with N-alkoxyamides using ferrocene as a redox mediator
(Scheme 1c).[11] This is a remarkable progress, yet specialized electrochemical appara-
tuses, expensive electrodes, and excess electrolyte were necessary. A complementary
CDC protocol using traditional chemistry is still highly desirable. In connection with
our continuous efforts in radical chemistry[12] and the synthesis of bioactive mole-
cules,[13] herein we report a metal-free cross-dehydrogenative C–N coupling of
(a) Nucleophilic substitution of halogenated xanthenes
R1 R2
Cl
N
R1R2NH
O
O
prefunctionalized substrates
toxic wastes
(b) C-H amination of xanthenes with nitrenes
R1 R2
H
N
Rh, Ru, Fe, etc.
nitrene precursors
O
O
noble and/or elaborated transition-metal complexes
nitrene precursors
(c) Electrochemical CDC between xanthenes and N-alkoxyamides
O
(+) C | C (-), 5 mA/cm2
H
O
OMe
N
Fc (0.5 equiv), Na2CO3 (1.0 equiv)
Tol
OMe
+
Tol
N
LiClO4 (0.1 M)
CH3CN/CH2Cl2 (2:1, v/v)
undivided cell
H
O
O
specialized electrochemical apparatuses
excess electrolyte, additive and redox mediator
(d) This work: CDC reaction of azoles with xanthenes and beyond
N
H
H
N
BPO (2.0 equiv)
DCE, 80 ºC
N
N
+
N
N
O
O
metal-free
simple conditions
C(sp3)-H/N-H cross-coupling
up to 97% yields
Scheme 1. Synthesis of xanthen-9-amines.

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SYNTHETIC COMMUNICATIONSV
3
xanthenes as well as related activated arylmethylenes using azoles as N–H sources,
which provides a direct and straightforward access to xanthen-9-amines and beyond
with high efficiency and under simple conditions (Scheme 1d).
Results and discussion
Our studies started with the C(sp3)–H/N–H cross-coupling of xanthene 1a and benzo-
triazole 2a (Table 1). In the presence of 10 mol% of CuBr and 2.0 equiv of benzoyl per-
oxide (BPO), 1a reacted with 2a in 1,2-dichloroethane (DCE) at 80 ꢀC to afford
xanthen-9-azole 3a in a high yield (entry 1). A copper catalyst is not necessary, and
product 3a was formed in 89% yield in the absence of it (entry 2). While anhydrous
tert-butyl hydroperoxide (TBHP, entry 3) is less active than BPO, the use of dicumyl
peroxide (DCP, entry 4), di-tert-butyl peroxide (DTBP, entry 5) or tert-Butyl peroxy-
benzoate (TBPB, entry 6) as the oxidant proved fruitless. Using K2S2O8 (entry 7) or
Oxone (entry 8), coupling product 3a was yielded in only poor yields. Other solvents
were evaluated in comparison with DCE. Whereas cross-couplings carried out in tetra-
hydrofuran (THF, entry 13) or dimethylsulfoxide (DMSO, entry 15) were incomplete,
diminished yields, ranging from 50-83%, were obtained using CH2Cl2 (entry 9), toluene
Table 1. Screening of reaction conditionsa.
N
H
O
H
N
N
N
conditions
+
N
N
O
O
O
1a
2a
3a
4
Entry
Catalyst
Oxidant (equiv)
Solvent
Temperature (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
CuBr
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
BPO (2.0)
BPO (2.0)
TBHPb (2.0)
DCP (2.0)
DTBP (2.0)
TBPB (2.0)
K2S2O8 (2.0)
Oxone (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (2.0)
BPO (1.5)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
toluene
CH3CN
CH3NO2
THF
DMF
DMSO
EtOH
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
80
80
73
89
75 (21)c
6 (91)c
trace (96)c
trace (94)c
46 (44)c
22 (71)c
74
9
10
11
12
13
14
15
16
17d
18e
19e
65
79
78
53 (16)c
50
61 (11)c
83
38 (55)c
96
DCE
DCE
91
aReaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst (0.05 mmol), oxidant (1.0 mmol), solvent (5 mL), 80 ꢀC, in a
sealed tube, 6 h.
b5.0–6.0 mol/L in decane.
cRecovery of 2a.
dThe reaction time was prolonged to 12 h.
e1.5 equiv of 1a was used.

4
Y. LI ET AL.
(entry 10), CH3CN (entry 11), CH3NO2 (entry 12), N,N-dimethylformamide (DMF,
entry 14), or ethanol (entry 16). Lowering the reaction temperature to 50 ꢀC led to a
poor yield of xanthen-9-azole 3a (entry 17). Much to our satisfaction, 3a was furnished
in a nearly quantitative yield by using 1.5 equiv of xanthene 1a (entry 18), while an
excellent yield was still achieved with a reduced loading of BPO (entry 19). In most
cases, xanthen-9-one 4 was formed.
Under optimized conditions, the C–N bond forming reaction was further explored
(Table 2). It was found that the electronic nature of the substituents on the azolic ben-
zyl ring plays a poor role in the reaction kinetics. With 5-chloro benzotriazole 2b as the
N–H source, poor N1/N3 selectivity was observed probably due to spin delocalization,
and 5- or 6-chloro-substituted triazole products 3b and 3b0 were delivered in 45% and
36% yields, respectively (entry 2). 5,6-Dimethyl benzotriazole 2c (entry 3), 5-phenyl
tetrazole 2d (entry 4), 1,2,4-triazole 2e (entry 5), pyrazole 2f (entry 6), ethyl pyrazole-4-
carboxylate 2g (entry 7), 5-chloro isatin 2h (entry 8), and 3-acetyl indole 2i (entry 9)
are all suitable N–H coupling partners, and they reacted with xanthene 1a to give corre-
sponding xanthen-9-amines 3c–i in high to quantitative yields. Corresponding C–N
bond forming products 3j–l were delivered in only poor to moderate yields from aceta-
mide 2j (entry 10), benzamide 2k (entry 11), or N-methylbenzamide 2l (entry 12),
probably due to insufficiently stabilized N-radicals. 2-Acetylxanthene 1b (entry 13) and
2-benzoylxanthene 1c (entry 14) are less reactive than xanthene 1a, and their reactions
with benzotriazole 2a led to xanthen-9-azoles 3m,n in high yields. Thioxanthenes 1d–f
could be alternative C(sp3)–H coupling partners. Whereas thioxanthene 1d reacted with
benzotriazole 2a (entry 15) or 5,6-dimethyl benzotriazole 2c (entry 16) to afford C–N
coupling products 3o,p in 97% and 90% yields, respectively, thioxanthen-9-azole 3q
derived from 1,2,4-triazole 2e was produced in a good yield (entry 17). 2-Isopropyl
thioxanthene 1e (entry 18) and 2-chloro thioxanthene 1f (entry 19) are competent
C(sp3)-H sources as well, and corresponding xanthen-9-azoles 3r,s derived from 2a
were furnished in 90% and 92% yields, respectively. The remote activating heteroatom
is essential, and diphenylmethane 1g without such a group reacted with benzotriazole
2a (entry 20) or 5-phenyl tetrazole 2d (entry 21) to give benzhydryl azoles 3t,u in only
50% and 5% yields, respectively. The substantially lower yield of 3u might reflect the
fact that 5-phenyl tetrazole 2d is far less active, although 2a and 2d reacted with xan-
thene 1a with comparable ease, probably owing to the leveling effect associated with the
remarkable reactivity of 1a (entries 1 and 4). Isochromane 1h (entry 22) and protected
1,2,3,4-tetrahydroisoquinoline 1i (entry 23), which possess a methylene moiety coacti-
vated by a phenyl group and an adjacent heteroatom, are less reactive than xanthene 1a
as well, and related coupling products 3v,w were produced in 70–74% yields. The use of
the methylene compound 1j bearing an aryl, a remote methoxy and an adjacent benzoy-
loxy group furnished in 30% yield bisazole 3x, which might arise from the further sub-
stitution by 2a of the initial C–N coupling product (entry 24). The extraordinary
performance of xanthenes and thioxanthenes as C(sp3)–H sources might be attributed
to the activation of the heteroatom-bridged bisaryl group, and the use of other diacti-
vated methylenes, such as 2-phenylacetophenone, ethyl benzoylacetate, 1,3-benzodioxole,
and 1,3-dithiane, failed to give desired C–N bond forming products (Fig. 1).

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5
Table 2. Cross-dehydrogenative C–N coupling between azoles and activated arylmethylenesa.
Y4 Y3
H
H
N
N
N
Y2
BPO (2.0 equiv)
+
N
Y4
Y2
Y3
DCE, 80 ºC
Y1
Y1
1
2
3
Activated
Yield
(%)
Entry
1
1
arylmethanes 1
2
Azoles 2
3
Products 3
N
N
N
N
N
1a
2a
2b
2c
3a
96
45
N
H
O
O
Cl
N
N
N
3b
Cl
N
O
N
2
1a
N
H
O
N
N
Cl
N
3b'
3c
36
92
O
N
N
N
N
N
3
1a
N
H
O
O
O
N
N
N
N
N
Ph
N
N
N
4
5
6
1a
1a
1a
2d
2e
2f
3d
3e
3f
94
97
N
H
Ph
O
N
N
N
N
N
O
H
O
N
N
N
95
N
H
O
O
(continued)

6
Y. LI ET AL.
O
EtO
O
N
EtO
7
1a
2g
3g
96
N
N
O
N
H
O
Cl
O
O
Cl
O
N
8
9
1a
1a
2h
2i
3h
3i
85
71
O
O
O
N
H
O
Ac
O
N
N
H
O
Ac
Bz
NH
O
10 1a
11 1a
2j
3j
36
66
NH2
O
O
O
NH
O
2k
3k
Ph
NH2
O
N
Bz
Bz
N
12 1a
2l
3l
44
82
H
O
O
N
N
N
Ac
Bz
N
N
N
N
13 1b
2a
3m
N
H
Ac
Bz
O
O
O
N
N
N
N
14 1c
2a
2a
3n
3o
86
97
N
H
O
N
N
N
N
15 1d
N
H
S
S
(continued)

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7
N
N
N
N
N
16 1d
17 1d
18 1e
2c
2e
2a
3p
3q
3r
90
N
H
S
S
S
N
N
N
N
N
61
N
H
S
N
N
N
i-Pr
N
N
90
N
H
i-Pr
S
S
N
N
N
Cl
N
N
N
19
1f
2a
3s
92
Cl
N
H
S
S
N
N
N
20 1g
21 1g
2a
2d
3t
50
5
Ph
Ph
Ph
Ph
N
N
H
Ph
Ph
N
N
N
N
N
N
Ph
3u
N
N
H
Ph
Ph
Ph
N
N
N
O
N
N
N
N
22 1h
2a
2a
2a
3v
3w
3x
70
74
30
N
H
O
N
N
N
COPh
N
N
23
24
1i
1j
N
H
COPh
N
N
N
N
O
N
N
H
MeO
Ph
O
N
anisyl
N
N
aReaction conditions: 1 (0.75 mmol), 2a (0.5 mmol), BPO (1.0 mmol), DCE (5 mL), 80 ꢀC, in a sealed tube, 6 h.

8
Y. LI ET AL.
O
O
O
O
O
S
Ph
Ph
Ph
OEt
S
Figure 1. Diactivated methylenes failing to undergo CDC with benzotriazole 2a.
(a) Radical trapping experiments
N
N
N
N
N
N
a1)
1a
N
N
N
TEMPO or BHT (2 equiv)
standard conditions
+
2a
+
t-Bu
t-Bu
t-Bu
t-Bu
O
OH
, 36%
OH
3a
5
5'
, 5%
, 0%
O
TEMPO or BHT (2 equiv)
standard conditions
TEMPO: 90%
BHT: 31%
a2) 1a
O
4
PhCOO
OCOPh
PhCOO
[O]
O
A
O
B
a3)
O
O
O
O
2c
+
Ph
OEt
OCOPh
6, 28%
standard conditions
Ph
OEt
1.5 equiv
Nu
(b) Electrophile trapping experiments
O
O
1a
(1.5 equiv)
NuH
+
standard conditions
O
O
not detected
Cl
4, 71-95%
N
N
N
Nu = MeOH, HOAc,
N
OH
NH2
OH
O
(c) Proposed mechanism
N
N
BPO
PhCOO
N
3a
2a
A
C
Scheme 2. Mechanistic investigations.
To probe the reaction mechanism, radical trapping experiments were performed
(Scheme 2a). Upon addition of 2 equiv of either 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) or butylated hydroxytoluene (BHT) as the radical scavenger, the model
reaction under otherwise standard conditions was suppressed (Scheme 2a1).

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9
Moreover, benzotriazol-1-BHT adduct 5 was formed in 36% yield in the BHT
experiment, along with regioisomeric benzotriazol-2-BHT adduct 5’ in 5% yield.
Interestingly, N2-coupling product was not observed in the above cross-couplings.
These results suggest that azolic N-radicals might be involved in the title reaction.
On the other hand, exposure of xanthene 1a to 2 equiv of TEMPO or BHT under
otherwise standard conditions furnished xanthen-9-one 4 as the only product in 90%
and 31% yields, respectively (Scheme 2a2). Though xanthen-9-TEMPO/BHT adduct
was not detected, according to the abundant literature, xanthenic radical A does be
involved in the oxidation of xanthene 1a leading to xanthen-9-one 4.[14] In addition,
such oxidation could be catalyzed by TEMPO[15] or N-hydroxyphthalimide
(NHPI),[16] thus it might be reasonable that xanthenic radical A has never been
trapped by TEMPO or BHT. Upon hydrogen atom transfer from C(sp3)–H bond of
1a to benzoate radical, A is generated, and its coupling with another benzoate rad-
ical produces xanthen-9-yl benzoate B, which is subsequently oxidized to afford
xanthen-9-one 4. Benzoate-benzoylacetate adduct 6 was furnished in 28% yield in
the reaction of ethyl benzoylacetate and 5,6-dimethyl benzotriazole 2c, confirming
the involvement of the benzoate radical[17] (Scheme 2a3).
Then, electrophile trapping experiments were conducted (Scheme 2b). Xanthene 1a
was exposed to several nucleophiles under standard conditions, and the nucleophiles
include MeOH, HOAc, NHPI, 1-hydroxybenzotriazole (HOBt), and 4-chloroaniline.
While cross-coupling did not proceed, again, xanthen-9-one 4 was the only product,
suggesting that xanthen-9-azole products 3 might not be delivered from xanthen-9-yl
benzoate B or xanthen-9-ylium since an acid catalyst is not involved in our protocol.[18]
Though we could not completely rule out this polar possibility, a pathway of radical/
radical cross-coupling is more likely.
On the basis of the above observations, a plausible mechanism is proposed (Scheme
2c). At the beginning, thermal decomposition of BPO releases the benzoate radical,
hydrogen abstraction by which from benzotriazole 2a affords benzotriazolic radical C.
Subsequent cross-coupling of C with xanthenic radical A derived from 1a affords
xanthen-9-azole product 3a.
Conclusions
In conclusion, we report a metal-free cross-dehydrogenative C-N coupling of azoles
with xanthenes and related activated arylmethylenes. Both the use of azoles and the acti-
vation pattern of C(sp3)–H sources are essential for this transformation. Methylenes
bearing a heteroatom-bridged bisaryl group reacted with various azolic N–H sources to
afford C–N coupling products in usually excellent or quantitative yields, whereas the
diphenylmethane and methylenes coactivated by a phenyl group and an adjacent heter-
oatom are less reactive. Mechanistic investigations suggest that a radical/radical cross-
coupling pathway might be involved.
Experimental
Chemicals were all purchased from commercial sources and used without treatment.
Reactions were monitored by Thin Layer Chromatography (TLC) using silica gel F254

10
Y. LI ET AL.
plates. Products were purified by column chromatography over 300–400 mesh silica gel
1
under a positive pressure of air. H NMR, 13C NMR, and DEPT spectra were recorded
at 25 ꢀC on a Bruker AscendTM 400 spectrometer using tetramethyl silane (TMS) as an
internal standard. High-resolution mass spectra (HRMS) were obtained using a Bruker
microTOF II Focus spectrometer (ESI).
General procedure (taking the synthesis of 3a as an example)
A 35-mL Schlenk tube, equipped with a magnetic stirring bar, was charged with 9H-
xanthene 1a (137 mg, 0.75 mmol), 1H-benzo[d][1,2,3]triazole 2a (60 mg, 0.5 mmol), and
BPO (242 mg, 1.0 mmol), followed by the addition of DCE (5.0 mL). The mixture was
stirred at 80 ꢀC for 6 h; then it was quenched with saturated aqueous Na2S2O3 (2.0 mL,
to react with the residual oxidant), saturated aqueous K2CO3 (2.0 mL), and water
(20.0 mL), and extracted with CH2Cl2 (20.0 mL) three times. The residue obtained after
evaporation of the solvent was purified by column chromatography on silica gel (petrol-
eum ether/ethyl acetate ¼ 12:1, v/v) to afford 1-(9H-xanthen-9-yl)-1H-benzo[d][1,2,3]-
triazole 3a as a colorless crystal (144 mg, 96% yield): m.p. 194–195 ꢀC. 1H NMR
(400 MHz, CDCl3) d ¼ 6.84 (ddd, J ¼ 1.0, 0.9, 8.3 Hz, 1 H), 7.01–7.05 (m, 2 H), 7.15
(ddd, J ¼ 1.0, 7.0, 8.1 Hz, 1 H), 7.20–7.24 (m, 3 H), 7.28 (dd, J ¼ 1.2, 8.3 Hz, 2 H),
7.35–7.39 (m, 2 H), 7.62 (s, 1 H), 8.00 (ddd, J ¼ 1.0, 1.0, 8.3 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) d ¼ 151.03, 146.98, 130.98, 130.49, 129.38, 127.37, 124.05, 123.94,
120.04, 117.06, 116.86, 110.15, 55.39; HRMS (ESI-TOF) Calcd for C19H14N3Oþ
([M þ H]þ) 300.1131. Found 300.1130.
Funding
We gratefully acknowledge the financial support from the National Natural Science Foundation
of China (21702083), the General Projects of Yunnan Education Department (2017ZZX093), the
Program for Innovative Research Team (in Science and Technology) in Universities of Yunnan
Province, and the Yunnan Ten Thousand Talent Program for Young Top-Notch Talents.
ORCID
Deqiang Liang
http://orcid.org/0000-0003-0482-0527
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