Organic Letters
Letter
Scheme 1. Radical Cyclization via 1,n-Hydrogen Atom
Transfer
Table 1. Control Experiments and Effects Reaction
a
Parameters
b
entry
variation from the standard conditions
yield (%)
c
d
1
2
3
4
5
6
7
8
9
10
11
12
13
none
without Cu(OAc)2
toluene instead of 1,2-DCE
1,4-dioxane instead of 1,2-DCE
Cu(OTFA)2 instead of Cu(OAc)2
CuO instead of Cu(OAc)2
CuCl instead of Cu(OAc)2
Ag2O instead of Ag2CO3
AgNO3 instead of Ag2CO3
TEMPO instead of Ag2CO3
120 °C instead of 135 °C
10 mol % Cu(OAc)2 instead of 20 mol % Cu(OAc)2
100 mol % Ag2CO3 instead of 150 mol % Ag2CO3
90 (75 )
nd
nd
81
nd
14
9
61
nd
nd
59
91
52
b
b
a
Reaction conditions: 1 (0.1 mmol), Cu(OAc)2 (20 mol %), and
Ag2CO3 (1.5 equiv) in 1,2-DCE (2.0 mL) at 135 °C for 25 h under
b
c
air. GC yield; nd = not detected. Isolated yield, the ratio of the
d
diastereomer is 1.3:1. 1 mmol scale, 48 h.
as the catalyst, Ag2CO3 as the oxidant were essential for the
catalytic cycle. Reducing the catalyst loading of Cu(OAc)2 to
10 mol % only gave a slight decrease of the yield of 2a at 91%
yield (entry 12, Table 1). However, while using 1 equiv of
Ag2CO3 as the oxidant, the yield of this reaction diminished
sharply (entry 13, Table 1). Meanwhile, lowering the reaction
temperature to 120 °C decreased the yield evidently, possibly
due to the high bond dissociation energy of N−H bond in
secondary amine (entry 11, Table 1).
intramolecular arylation, giving the corresponding azacycle
followed by a deprotonation. Accordingly, a relatively stable
carbocation at the benzylic position may play a key role in
realizing such cyclization for the construction of nitrogen-
containing heterocycles.
Herein, we report a copper-catalyzed intramolecular
amination via the cross coupling of C(sp3)−H and N−H
bonds of the secondary amine, which offers an efficient
solution to construction of a range of nitrogen-containing
heterocycles. The key to this reaction is the second oxidation
of in situ generated benzylic radical to carbocation for facile
intramolecular amination. Besides the well-established five-
membered ring that can be synthesized via a traditional HLF-
route, in our system, we can also achieve the equally important
four- and six-membered azacycles via a 1,n-HAT process
(Scheme 1b).
Initially, we commenced the intramolecular amination with
secondary benzylamine 1a as the model substrate in the
presence of Cu(OAc)2 (20 mol %) as the catalyst. After careful
substrate 1a could afford the desired product 2a with 90%
yield by using Cu(OAc)2 (20 mol %) as catalyst, Ag2CO3 (1.5
equiv) as oxidant and 1,2-dichloroethane (1,2-DCE, 2.0 mL)
as solvent at 135 °C for 25 h (entry 1, Table 1). Not
surprisingly, 2a could not be obtained in the absence of copper
salt (entry 2, Table 1). We found that the investigation of
copper source indicated that Cu(OAc)2 played key roles as the
catalyst in this radical cyclization, while almost none of the
desired product was obtained using Cu(OTFA)2 or CuCl as
the catalyst instead of Cu(OAc)2 (entries 5−7, Table 1).
Moreover, the replacement of Ag2CO3 with other silver salts or
other oxidants afforded poor results to even no reactivity, while
only Ag2O could give a moderate yield at 61% (entries 8−10,
Table 1). All of these results further confirmed that Cu(OAc)2
With the optimal conditions in hand, we sought to test the
scope of this intramolecular amination and found a variety of
nitrogen-containing heterocycles were obtainable (Scheme 2).
With respect to the substituent effect on the phenyl ring of
anilines (R1), the results for pyrrolidine synthesis (m = 1)
indicated that both electron-donating and -withdrawing groups
were well tolerated in this catalytic reaction. As for the para-
substituents, including alkyl (2b−d), phenyl (2e), methoxy
(2f), and halogen (2g−h), the corresponding pyrrolidines
could be smoothly obtained with moderate to excellent yields.
Generally, meta-substituents, such as methyl (2i), chloro (2j),
and trifluoromethyl (2k), on the aniline were compatible with
this cyclization reaction in good yield. Notably, the o-methyl
group on the phenyl rings was also properly tolerated in this
transformation with good yield (2l). Furthermore, by replacing
the phenyl ring on the aniline to naphthyl ring, the reaction
proceeded effectively with relatively lower yield (2m,n). The
substituent effect on the phenyl ring linked to α-position of
nitrogen atom was next investigated, which also revealed that
various substituted groups were well compatible for this
reaction (2o−q). Of note is that changing the phenyl
substituent to an alkyl substituent had little impact to the
reactivity of this reaction, providing the cyclization product
(2r) with good yield. To our delight, besides the benzylic
C(sp3)−H bond, the allylic C(sp3)−H bond could be
aminated successfully in good yield with pyrrolidine as the
422
Org. Lett. 2021, 23, 421−426