Cu(OAc)2/TFA-promoted formal [3 + 3] cycloaddition/oxidation of enamines and enones for synthesis of multisubstituted aromatic amines

Article abstract of DOI:10.1021/ol3014733

New strategies for the oxidative cycloaddition of enones with enamines are developed. These cycloaddition reactions directly afford substituted aromatic amines, which are important in organic chemistry, in moderate to good yield. Cu(OAc)₂/TFA is shown to be essential to achieve high reaction efficiency.

Full text of DOI:10.1021/ol3014733

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3506–3509
Cu(OAc)2/TFA-Promoted Formal [3 þ 3]
Cycloaddition/Oxidation of Enamines and
Enones for Synthesis of Multisubstituted
Aromatic Amines
Liang Li, Mi-Na Zhao, Zhi-Hui Ren, Jian-Li Li, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, Department of Chemistry & Materials Science, Northwest University,
Xi’an 710069, P. R. China
guanzhh@nwu.edu.cn
Received May 29, 2012
ABSTRACT
New strategies for the oxidative cycloaddition of enones with enamines are developed. These cycloaddition reactions directly afford substituted
aromatic amines, which are important in organic chemistry, in moderate to good yield. Cu(OAc)2/TFA is shown to be essential to achieve high
reaction efficiency.
[3 þ 3] Cycloaddition reactions are useful for the synth-
esis of six-membered cyclic compounds1,2 and have been
widely used in natural product synthesis.3 However, this
strategy is mainly limited to the synthesis of heterocycles4
such as pyrans,5 piperidine,6 and pyridines.7 The direct
formation of multisubstituted arenes via formal [3 þ 3]
cycloaddition has rarely been reported. Although some
methods tosynthesize arene derivatives are available,8ꢀ10
a
(1) (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
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r
10.1021/ol3014733
Published on Web 06/22/2012
2012 American Chemical Society

Table 2. Cu(OAc)2/TFA-Promoted Formal [3 þ 3] Cycloaddition/
Scheme 1. ConstructionofArylamines by Formal[3þ 3] Strategy
Oxidation with Different Enaminesa
yield
entry
substrate
product
(%)b
1
2
2a (R1 = Bn; R2 = H; R3 = OMe)
2b (R1 = Cy; R2 = H; R3 = OMe)
2c (R1 = i-Pr; R2 = H; R3 = OMe)
2d (R1 = Et; R2 = H; R3 = OMe)
2e (R1 = Me; R2 = H; R3 = OMe)
2f (R1 = Ph; R2 = H; R3 = OMe)
2g (R1 = H; R2 = H; R3 = OMe)
2h (R1 = Et; R2 = Et; R3 = OMe)
2i (R1 = Cy; R2 = H; R3 = OEt)
2j (R1 = Cy; R2 = H; R3 = Me)
3aa
3ab
3ac
3ad
3ae
3af
56
67
63
43
42
24
0
3
4
5
6
Table 1. Optimization of [3 þ 3] Cycloaddition/Oxidation
Reaction Conditionsa
7
3ag
3ah
3ai
8
0
9
66
56
10
3aj
a Reactions were carried out using Cu(OAc)2 (1.0 equiv), TFA (1.0
equiv), 1a (0.3 mmol), and 2aꢀ2j (0.36 mmol) in toluene (3 mL) at reflux
(in a 140 °C oil bath) under air, 4ꢀ7 h. b Isolated yields.
t
yieldb
(%)
and vinyl moiety of enamines makes it powerful for azahe-
terocycles synthesis, such as Hantzsch dihydropyridine
(pyridine) synthesis and Nenitzescu indole synthesis.14 There
are a few examples of formal [3 þ 3] cycloadditions of
enamines and enones for the construction of cyclohexenes.15,16
Although the reactions are still limited in substrate scope
and low yields, a regioselective reaction on an allylic sp3
CꢀH bond of enamines was achieved. We hypothesized
that an oxidative [3 þ 3] cycloaddition of prevalent
enones and enamines may be used to construct multi-
substituted aromatic amines directly (Scheme 1). In this
communication, we report a novel cycloaddition reaction
of enones and enamines to synthesize substituted aro-
matic amines.
entry
oxidant
acid
solvent
(h)
1
AcOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
CH3OH
CH3OH
toluene
DMF
10
10
5
trace (23)
trace (42)
17 (40)
13 (10)
18 (0)
2
3
4
5
5
CuSO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5
6
CuCl2
5
10 (0)
7
CuO
5
21 (0)
8
Oxone
7
11 (0)
9
(t-BuO)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5
10 (0)
10
11c
12d
13d,e
5
27 (0)
5
36 (0)
5
56 (0)
5
45 (0)
a Reactionswerecarriedoutusing oxidant(1.0equiv), acid (50mol%),
1a (0.3 mmol), and 2a (0.36 mmol) in toluene (3 mL) at 120 °C under air.
b The numbers in parentheses are the isolated yields of 4. c TFA
(1.0 equiv). d The reaction was refluxed in a 140 °C oil bath. e The reaction
was carried out under Ar.
Our investigation commenced with the cycloaddition/
oxidation of benzylidene acetone 1a and methyl 3-
(benzylamino)but-2-enoate 2a (Table 1). To our delight,
when the reaction was performed under acidic conditions
in CH3OH at reflux (oil bath, 120 °C), cyclohexadiene 4
was isolated as a major product (Table 1, entries 1ꢀ2). The
structure of 4 prompted us to optimize the reaction condi-
tions. Screening of various parameters revealed that to-
luene and TFA were the most efficient solvent and acid,
respectively, for this transformation although the main
product was not what we desired (Table 1, entries 1ꢀ4). A
series of oxidants were then screened, and it was found that
Cu(OAc)2 was the best oxidant for the selective formation
of aromatic amine 3aa (Table 1, entries 5ꢀ10; see the
Enamines are powerful building blocks in organic synth-
esis. They are widely used in nucleophilic addition reac-
tions for stereoselective construction of CꢀN12 and CꢀC13
bonds. Additionally, the high reactivityof the amino group
(12) (a) Drouet, F.; Lalli, C.; Liu, H.; Masson, G.; Zhu, J. Org. Lett.
2011, 13, 3388. (b) Chang, L.; Kuang, Y.; Qin, B.; Zhou, X.; Liu, X.; Lin,
L.; Feng, X. Org. Lett. 2010, 12, 2214.
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Soc. 2011, 133, 11430. (b) Wang, Q.-S.; Xie, J.-H.; Li, W.; Zhu, S.-F.;
Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2011, 13, 3388. (c) Guo, C.; Song,
J.; Huang, J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong, L.-Z. Angew. Chem.,
Int. Ed. 2012, 51, 1046.
(15) (a) Rimoli, M. G.; Avallone, L.; Zanarone, S.; Abignente, E.;
Mangoni, A. J. Heterocycl. Chem. 2002, 39, 1117. (b) Abdallah-El
Ayoubi, S.; Toupet, L.; Texier-Boullet, F.; Hamelin, J. Synthesis 1999,
1112. (c) Jacobs, J.; Kesteleyn, B.; De Kimpe, N. Tetrahedron 2008, 64,
7545.
€
ꢀ
(14) (a) Kurti, L.; Czako, B. In Strategic Applications of Named
Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA,
2005; pp 194ꢀ195. (b) Kucklaender, U. Tetrahedron 1972, 28, 5251.
(c) Patrick, J. B.; Saunders, E. K. Tetrahedron Lett. 1979, 20, 4009.
(d) Guan, Z.-H.; Li, L.; Ren, Z.-H.; Li, J. L.; Zhao, M.-N. Green Chem.
2011, 13, 1664.
(16) (a) Movassaghi, M.; Chen, B. Angew. Chem., Int. Ed. 2007, 46,
ꢀ
565. (b) Sridharan, V.; Menendez, J. C. Org. Lett. 2008, 10, 4303.
Org. Lett., Vol. 14, No. 13, 2012
3507

Table 3. Cu(OAc)2/TFA-Promoted Formal [3 þ 3] Cycloaddition/
Oxidation of Various Enones with Enamine 2ba
Scheme 3. Proposed Mechanism of Cu(OAc)2/TFA-Promoted
Formal [3 þ 3] Cycloaddition/Oxidation
entry
substrate
product yield (%)b
1
1a (R1 = H; R2 = Me; R3 = H)
3ab
3bb
3cb
3db
3eb
3fb
3gb
3hb
3ib
3jb
5k
67
66
63
68
56
63
67
68
60
65
33
36
29
37
28
63
62
73
76
63
34
2
1b (R1 = 4-Cl; R2 = Me; R3 = H)
1c (R1 = 2-Cl; R2 = Me; R3 = H)
1d (R1 = 2,4-Cl; R2 = Me; R3 = H)
1e (R1 = 4-F; R2 = Me; R3 = H))
1f (R1 = 4-Br; R2=Me; R3 = H)
1g (R1 = 4-NO2; R2 = Me; R3 = H)
1h (R1 = 3-NO2; R2 = Me; R3 = H)
1i (R1 = 4-Me; R2 = Me; R3 = H)
1j (R1 = 3-Me; R2 = Me; R3 = H)
1k (R1 = 4-Me2N; R2 = Me; R3 = H)
1l (R1 = 2-MeO; R2 = Me; R3 = H)
3
4
5
6
7
8
9
10
11
12
3 lb
5l
13
1m (R1 = 4-MeO; R2 = Me; R3 = H)
3mb
5m
14
15
16
17
18
19
1n (R1 = H; R2 = Et; R3 = H)
3nb
3ob
3pb
3qb
3rb
3sb
1o (R1 = H; R2 = Ph; R3 = H)
1p (R1 = H; R2 = Me; R3 = CO2Me)
1p (R1 = H; R2 = Me; R3 = CO2Et)
1r (R1 = H; R2 = Me; R3 = COCH3)
1s (R1 = H; R2 = H; R3 = H)
a Reactions were carried out with Cu(OAc)2 (1.0 equiv), TFA
(1.0 equiv), 1aꢀ1s (0.3 mmol), and 2a (0.36 mmol) in toluene (3 mL)
at reflux (in a 140 °C oil bath) under air, 4ꢀ7 h. b Isolated yields.
Scheme 2
Supporting Information for the X-ray structure of 3aa).
Furthermore, by optimizing the ratio of Cu(OAc)2 and
TFA, it was found that the reaction proceeded most
effectively in Cu(OAc)2 (1.0 equiv) and TFA (1.0 equiv)
(Table 1, entry 11). The vigorous reflux was important for
the reaction. A 140 °C oil bath was required tofacilitate the
reaction (Table 1, entry 12). Additionally, the product 3aa
was obtained in 45% yield when the reaction was per-
formed under an argon atmosphere (Table 1, entry 13).
This result indicated that the oxygen play a role for the
reaction.
N-Substituted enamines with different aliphatic or aryl
groups exhibited different reactivity. The degree of reac-
tivity follows the sequence cyclohexyl > isopropyl >
benzyl > ethyl > methyl > phenyl (Table 2, entries 1ꢀ6).
Enamines with NH2 or NEt2 substituents (2g and 2h,
respectively) were unreactive (Table 2, entries 7 and 8). In
addition, enaminone 2j showed similar reactivity to enam-
inoester 2i; both gave the desired amines 3ai and 3aj,
respectively, in good yield (Table 2, entries 9ꢀ10).
With the optimal parameters for this formal [3 þ 3]
cycloaddition/oxidation process established, its applica-
bility to different enamines was investigated (Table 2).
3508
Org. Lett., Vol. 14, No. 13, 2012

Furthermore, the formal[3 þ 3] cycloaddition/oxidation
reaction proceeded smoothly with a series of enones 1aꢀ1s
and enamine 2b (Table 3). Benzalacetones with either
electron-donating or -withdrawing groups on the phenyl
groups reacted efficiently to give the corresponding aryla-
mines in good yields (Table 3, entries 1ꢀ10). Overall, this
transformation displays high functional group tolerance.
It is worth noting that reaction with o-MeO- or p-MeO-
substituted substrates not only gave the corresponding
products 3lb and 3mb in 36 and 37% yield, respectively,
but also afforded aryl-shift byproducts 5l and 5m in 29 and
28% yield, respectively (Table 3, entries 12ꢀ13; see the
Supporting Information for the X-ray structure of 5m).
Only aryl-shift product 5k was observed when 1k was used
as the substrate (Table 3, entry 11). When (E)-1-phenyl-
pent-1-en-3-one 1n and (E)-chalcone 1o were employed as
substrates, the corresponding arylamines 3nb and 3ob,
respectively, were obtained in good yield (Table 3, entries
14ꢀl5). In addition, enones bearing an electron-withdraw-
ing group at R-C, such as an ester and carbonyl moiety,
also gave good results (Table 3, entries 16ꢀ18). Cinnamal-
dehyde 1s was also converted into the corresponding
arylamine 3sb in 34% yield along with a mixture of
byproducts (Table 3, entry 19).
tained in 64 and 66% yield, respectively, as shown in
Scheme 2.
A possible mechanism for the formal [3 þ 3] cycloaddi-
tion/oxidation process is outlined in Scheme 3. The reac-
tion commences with a Michael addition of enamine 2 to
enone 1 yielding A, which undergoes an intramolecular
cyclization reaction to form intermediate B. Subsequent
dehydration andtautomerizationgivesintermediateC that
is then oxidized by Cu2þ to form intermediates D and E.
After elimination of a proton, D and E produce the
energetically favored arylamine product 3.17 Alternatively,
aryl migration of intermediate E followed by proton
elimination would give product 5.18 Electron-rich arenes
promote aryl migration,19 which is consistent with the
above results (Table 3, entries 11ꢀ13).
In conclusion, we have developed a novel Cu(OAc)2/
TFA-promoted formal [3 þ 3] cycloaddition oxidation
reaction for direct synthesis of multisubstituted aromatic
amines. This novel method tolerates a wide range of
functional groups and is a reliable procedure for rapid
elaboration of readily available enamines and enones into
a variety of substituted aromatic amines under mild con-
ditions. Further scope and mechanistic studies of this
reaction are underway in our laboratory.
To expand the applicability of the present method, the
reaction of enones 1t and 1u with enamine 2b was per-
formed in the presence of Cu(OAc)2 and TFA. The
corresponding arylamine products 3tb and 3ub were ob-
Acknowledgment. We thank the National Natural
Science Foundation of China (NSFC-21002077, 20972124)
and Fund of New Scientific Stars of Shanxi Province
(2012KJXX-26) for financial support.
(17) Hull, J. F.; Balcells, D.; Sauer, E. L. O.; Raynaud, C.; Brudvig,
G. W.; Crabtree, R. H.; Eisenstein, O. J. Am. Chem. Soc. 2010, 132, 7605.
(18) (a) Sakamoto, M.; Takahashi, M.; Moriizumi, S.; Yamaguchi,
K.; Fujita, T.; Watanabe, S. J. Am. Chem. Soc. 1996, 118, 8138. (b) Jiang,
N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989. (c) Garcıa-Garcıa, P.;
Supporting Information Available. Experimental pro-
cedures, spectral data for all products, and X-ray data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Martınez, A.; Sanjuan, A. M.; Fernandez-Rodrıguez, M. A.; Sanz, R.
Org. Lett. 2011, 13, 4970.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3509