An efficient oxidative cross-coupling reaction between C-H and N-H Bonds; A transition-metal-free protocol at room temperature

Article abstract of DOI:10.1055/s-0033-1339447

A transition-metal-free oxidative coupling of allylic C-H and heterocyclic/aromatic N-H bonds was performed under mild conditions. Promoted by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), up to 99% yield could be achieved. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339447

LETTER
▌2009
lAettner Efficient Oxidative Cross-Coupling Reaction between C–H and N–H
Bonds; A Transition-Metal-Free Protocol at Room Temperature
Cross-Coupling between C–H and C–N Bonds
Yinuo Wu,a Fuk Yee Kwong,a Pengfei Li,*a,b Albert S. C. Chan*c
a
State Key Laboratory for Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hong Kong
b
Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong, P. R. of China
Fax +86(755)86245672; E-mail: flyli1980@gmail.com
c
Institute of Creativity, Faculty of Science, Hong Kong Baptist University, Hong Kong
E-mail: ascchan@hkbu.edu.hk
Received: 20.05.2013; Accepted after revision: 18.06.2013
pounds,10 such as Naftifine (antifungal medicine),11 and
Flunarizine (Ca channel blocker).12 Moreover, these
amines are versatile intermediates for a myriad of synthet-
ic applications.13 Traditional routes used to access allylic
amines often involve Pd-catalyzed allylic substitution
(Tsuji–Trost reaction) using allylic acetate as the coupling
partner (Scheme 1).14 The allylic acetate is always from
the corresponding allyl alcohol. Given the synthetic po-
tential of the Tsuji–Trost-type reaction, an exploration of
non-prefunctionalized coupling partners that could be ap-
plicable for this reaction is much warranted (Scheme 1).
Abstract: A transition-metal-free oxidative coupling of allylic C–
H and heterocyclic/aromatic N–H bonds was performed under mild
conditions. Promoted by 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), up to 99% yield could be achieved.
Key words: metal-free, cross-coupling, oxidative coupling, amina-
tion, C–H activation
The realm of transition-metal-catalyzed cross-coupling
reactions has traditionally required prefunctionalized sub-
strates, either of the electrophilic or nucleophilic partner,
for both reactivity and selectivity.1 Recent revolutionary
advancements have focused on the atom-economy issue
in the cross-coupling repertoire.2 Direct C–H bond func-
tionalization, either assisted or catalyzed by transition
metals, is a modern direction that is being used to fulfill
the spirit of waste minimization.3 Indeed, it would be
highly desirable if a C–H cross-coupling process could be
performed in a transition-metal-free environment. In
2010, transition-metal-free coupling reactions between
aryl halides (electrophiles) and non-activated arenes (nu-
cleophiles) were independently disclosed by Hayashi/Shi-
rakawa,4 Lei/Kwong,5 Shi6 and others.7,8 In addition to
traditional cross-coupling reactions, oxidative couplings
have also received considerable attention.9
Table 1 Initial Screening of the Oxidative C–H/N–H Couplinga
H
N
oxidant
N
N
N
solvent
r.t., 5 h
Ph
Ph
H
Ph
Ph
1
2
3
Entry
Oxidant (equiv)
Solvent
Yield (%)b
1
2
I2 (1.0)
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
dioxane
toluene
THF
0
30
DDQ (1.0)
BQ (1.0)
3
0
4
PhI(OAc)2 (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.2)
DDQ (1.4)
DDQ (1.4)
0
5
25
previous work
present work
6
63
R3
R4
R3
R4
N
H
N
H
7
61
R3
R4
Pd
base
metal-free
N
8
53
R1
R2
oxidant
r.t.
OAc (H)
R2
H
9
Et2O
35
R1
R1
R2
10c
11c
12d
dioxane
dioxane
dioxane
90
Scheme 1 Traditional palladium-catalyzed protocol for accessing
allylic amines and the proposed new exploration
99
>99 (93)
a Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol) and oxidant (as in-
dicated, with respect to 1), solvent (3 mL), r.t., under air, 5 h. See the
Supporting Information for detailed optimization.
b GC yield; isolated yield in parentheses.
Allylic amines are important structural motifs in various
biologically active and pharmaceutically useful com-
SYNLETT 21709013, 2415, 2009–2013
Advanced online publication: 08.08.2013
c 2 (0.12 mmol) was used.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
d 2 (0.12 mmol) was used and the reaction was performed in dioxane
(1.0 mL) for 2 h.
DOI: 10.1055/s-0033-1339447; Art ID: ST-2013-W0465-L
© Georg Thieme Verlag Stuttgart · New York

2010
Y. Wu et al.
LETTER
The metal-catalyzed amination of C–H bonds to form new yields (3b). Imidazole was found to be a feasible coupling
C–N bonds is a current challenge.15 Despite notable prog- partner (3c).20 Indazole, carbazole and indoline were ap-
ress that has been made, it would clearly be attractive if plicable to generate the corresponding products in good
these reactions could be carried out in a transition-metal- yields (3d, 3e and 3f), whereas a more sterically hindered
free manner.16,17 Very recently, Bao reported the metal- coupling partner gave a more moderate yield (3g).
free cross-coupling of 1,3-diarylpropenes with anilines
In addition to heterocycles, we also examined aniline type
and amides.18 Herein, we report our further development
substrates 5 (Scheme 3).21 Coupling partners having a
on the metal-free oxidative coupling between allylic C–H
bromo group were found to be applicable (5c, 5d and 5e),
and heterocyclic/aromatic N–H bonds. Notably, 1,3-diar-
with the bromo moiety remaining intact during the course
ylpropenes can react with N-heterocycles smoothly at a
of the reaction. This serves as a complement to current Pd-
room temperature and up to 99% yield can be achieved.
catalyzed coupling protocols, which are often incompati-
We initially tested the prototypical oxidative coupling us- ble with bromo substituents. Nitro and cyano groups were
ing 1,3-diphenylpropene and pyrazole as benchmark sub- also tolerated under these reaction conditions (5f, 5g and
strates (Table 1).19 A series of commonly available 5i), and sterically hindered anilines provided moderate
oxidizing agents were examined for their use in generat- product yields (5k and 5n). Interestingly, the alkynyl ani-
ing the desired allylic amine product. In short, DDQ was line was also found to be a feasible substrate (5o).
found to be the most effective oxidant for this reaction
(entries 1–4), and dioxane and toluene were the solvents
of choice (entries 5–9). Upon investigating the stoichiom-
etry of the oxidant, 1.2–2.0 equivalent of DDQ were
The scope of the reaction with 1,3-diarylpropenes was
also investigated (Scheme 4). Product 6 was obtained in
90% yield, and sterically congested 1,3-di(2-methoxyphe-
nyl)propene 7 provided moderate yield (55%). However,
found to provide excellent yields (entries 6 and 10–12).
the use of 1-[(E)-but-1-enyl]benzene as substrate only led
With the optimized reaction conditions in hand, we next to he formation of a trace amount of product.
examined the scope of the reaction with respect to hetero-
cycles used for the oxidative C–N bond formation
(Scheme 2). Substituted pyrazoles provided good product
The functionalization of a C–H bond by an NH2 group is
highly attractive. We therefore attempted to prepare (E)-
Het
H
Het
DDQ
+
N
Ph
Ph
dioxane
r.t., 2 h
N
H
Ph
Ph
1
2a–g
3a–g
Me
N
N
N
N
N
N
Me
3a: 93%
3b: 82%
3c: 96%
N
N
N
3d: 74% a
3e: 90%a
N
N
3f: 76%a
3g: 52%a
Scheme 2 Scope of the oxidative coupling between heterocyclic N–H and allylic C–H bonds. Reagents and conditions: 1 (0.1 mmol), 2a–g
(0.12 mmol), DDQ (0.14 mmol), dioxane (1.0 mL), r.t., under air, 2 h. Isolated yields of 3a–g are reported. a The reactions were conducted for
5 h.
Synlett 2013, 24, 2009–2013
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling between C–H and C–N Bonds
2011
1,3-diphenylprop-2-en-1-amine using our methodology attractiveness of the metal-free environment and the fa-
(Scheme 5).22 To our delight, the desired product could be vorable reaction conditions (room temperature, 2–5 h), we
obtained in moderate to good yield.
believe that this method should find widespread use in
convergent cross-coupling type organic synthesis. Appli-
cation of this methodology in micro-channel reactors is
under way.
In summary, we have demonstrated a transition-metal-
free oxidative coupling of allylic C–H and aromatic/het-
erocyclic N–H bonds. This protocol provides rapid access
to a variety of allylic amines. No inorganic insoluble base
is required. This homogeneous DDQ-promoted system
exhibits good functional group tolerance, in which bromo,
nitrile, nitro, sulfanyl and alkynyl groups remain intact
during the course of reaction. Notably, the free allylic
amine can be obtained by using this protocol. Given the
Acknowledgment
We thank the Research Grants Council of Hong Kong (GRF: PolyU
5001/08P).
R
R
H
DDQ
+
HN
dioxane
r.t., 5 h
Ph
Ph
NH2
Ph
Ph
1
4a–o
5a–o
F
Br
HN
HN
HN
5a: 72%
5b: 80%
5c: 62%
NO2
Br
Br
HN
HN
Br
HN
NO2
5d: 74%
5e: 80%
5f: 88%
CF3
CN
CN
HN
HN
CF3
HN
CF3
5g: 82%
5h: 70%
5i: 79%
F
PhO
OPh
HN
CF3
HN
HN
5j: 72%
5k: 66%
5l: 79%
Me
SCF3
HN
HN
HN
Me
5m: 70%
5n: 42%
5o: 53%
Scheme 3 Scope of the oxidative coupling between aniline N–H and allylic C–H bonds. Reagents and conditions: 1 (0.1 mmol), 4a–o (0.12
mmol) , DDQ (0.14 mmol), dioxane (1.0 mL), r.t., under air, 5 h. Isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2009–2013

2012
Y. Wu et al.
LETTER
(7) For a pioneering study by Itami and co-workers on metal-
free cross-coupling of electron-deficient heterocyclic
substrates, see: (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.;
Itami, K. Org. Lett. 2008, 10, 4673. (b) For peroxide-
mediated metal-free oxidative C–H/C–H cross-coupling of
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333.
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Chem. Int. Ed. 2011, 50, 4671. (f) Rueping, M.;
H
DDQ
N
R
N
N
+
N
dioxane
r.t., 5 h
Ar
R
H
Ar
N
N
N
OMe
N
OMe
Me
Me
6: 90%
7: 55%
N
N
Me
Leiendecker, M.; Das, A.; Poisson, T.; Bui, L. Chem.
Commun. 2011, 47, 10629. (g) Yong, G. P.; She, W. L.;
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8: trace
Scheme 4 Scope of the reaction with substituted 1,3-diarylpropenes
NH2
O
H
DDQ
+
t-Bu
Ph
Ph
O
NH2
dioxane
air
r.t., 5 h
Ph
Ph
61%
(E)-1,3-diphenylprop-2-en-1-amine
Scheme 5 Preparation of (E)-1,3-diphenylprop-2-en-1-amine by
oxidative C–H/N–H coupling
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
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Synlett 2013, 24, 2009–2013
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling between C–H and C–N Bonds
2013
(16) For an intramolecular oxidative C–H amination under metal-
free conditions, see: Antonchick, A. P.; Samanta, R.;
Kulikov, K.; Lategahn, J. Angew. Chem. Int. Ed. 2011, 50,
8605.
(17) For metal-free iodine(III)-promoted direct intermolecular
C–H amination reactions of acetylenes, see: Souto, J. A.;
Becker, P.; Iglesias, Á.; Muñiz, K. J. Am. Chem. Soc. 2012,
134, 15505.
128.8, 128.5, 128.4, 127.6, 127.0, 126.9, 126.1, 122.3,
121.9, 121.8, 120.4, 117.9, 69.3. IR: 3059, 3028, 1627, 1513,
1495, 1451, 1390, 1152, 1134, 967, 756, 695 cm–1 .
(21) Analytical data of product 5a: 1H NMR (400 MHz, CDCl3):
δ = 7.45 (d, J = 8.8 Hz, 2 H), 7.39–7.36 (m, 4 H), 7.32–7.29
(m, 3 H), 7.25–7.22 (m, 1 H), 7.17–7.13 (m, 2 H), 6.72 (t,
J = 7.4 Hz, 1 H), 6.66–6.62 (m, 3 H), 6.41 (dd, J = 6.2,
15.8 Hz, 1 H), 5.10 (d, J = 6.0 Hz, 1 H), 4.13 (br s, 1 H). 13
NMR (100 MHz, CDCl3): δ = 147.4, 142.2, 136.8, 131.2,
130.9, 129.3, 129.0, 128.7, 127.8, 127.7, 127.4, 126.7,
C
(18) Wang, Z.-M.; Mo, H.-J.; Cheng, D.-P.; Bao, W.-L. Org.
Biomol. Chem. 2012, 10, 4249.
(19) Analytical data of product 3a: 1H NMR (400 MHz, CDCl3):
δ = 7.61 (d, J = 1.6 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.41–
7.23 (m, 10 H), 6.73 (dd, J = 7.0, 15.8 Hz, 1 H), 6.45 (d,
J = 16.0 Hz, 1 H), 6.32 (t, J = 2.0 Hz, 1 H), 6.20 (d,
J = 7.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 139.8,
139.6, 136.2, 133.9, 128.9, 128.74, 128.67, 128.29, 128.27,
127.54, 127.48, 126.9, 105.8, 67.7. IR: 3060, 3028, 1508,
1495, 1450, 1395, 1280, 1088, 1046, 748, 695 cm–1. HRMS:
m/z [M+Na]+ calcd for C18H16N2Na: 283.1211; found:
283.1198.
117.9, 113.8, 60.8. IR: 3407, 3055, 3025, 1601, 1502, 1449,
1314, 1261, 968, 747, 692 cm–1. HRMS: m/z [M – H]+ calcd
for C21H18N: 284.1439; found: 284.1426.
(22) Analytical data of (E)-1,3-diphenylprop-2-en-1-amine: 1H
NMR (400 MHz, CDCl3): δ = 7.46–7.36 (m, 6 H), 7.33–7.28
(m, 3 H), 7.25–7.21 (m, 1 H), 6.61 (dd, J = 3.8, 15.8 Hz,
1 H), 6.41–6.30 (m, 1 H), 5.11 (t, J = 7.6 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 141.4, 141.3, 136.8, 131.7, 131.5,
130.6, 130.5, 128.7, 127.9, 127.8, 127.2, 126.8, 79.4, 79.3.
(23) Unless otherwise noted, the reaction was carried out as
following: To a solution of 1, 4-dioxane (1.0 mL) was added
1,3-diphenylpropenes 1 (0.1 mmol), nitrogen-based
nucleophile 2 or 4 (0.12 mmol) and oxidant (0.14 mmol).
The reaction mixture was stirred at r.t. for 2–5 h and then the
solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel to yield the
desired product.
(20) Analytical data of product 3c: 1H NMR (400 MHz, CDCl3):
δ = 8.01 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.66 (d,
J = 8.4 Hz, 1 H), 7.45 (d, J = 6.8 Hz, 2 H), 7.41–7.38 (m,
2 H), 7.37–7.34 (m, 2 H), 7.33–7.30 (m, 3 H), 7.12 (dd,
J = 3.0, 8.2 Hz, 1 H), 6.88 (dd, J = 7.0, 15.8 Hz, 1 H), 6.56
(d, J = 16.4 Hz, 1 H), 6.52 (d, J = 6.8 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 149.0, 139.0, 136.0, 134.6, 129.0,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2009–2013

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