Copper-catalyzed tandem nucleophilic ring-opening/intramolecular oxidative amidation of N-tosylaziridines and hydrazones under aerobic conditions

Article abstract of DOI:10.1021/ol902376w

[Chemical Equation Presented] A novel and efficient copper-catalyzed tandem reaction of N-tosylaziridines and hydrazones under aerobic conditions to afford the functionalized tetrahydrotriazines is described. The process involves a nucleophilic ring-openi

Full text of DOI:10.1021/ol902376w

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5678-5681
Copper-Catalyzed Tandem Nucleophilic
Ring-Opening/Intramolecular Oxidative
Amidation of N-Tosylaziridines and
Hydrazones under Aerobic Conditions
Deng Hong,† Xufeng Lin,*,† Yuanxun Zhu,† Ming Lei,† and Yanguang Wang*,†,‡
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic
of China, and State Key Laboratory of Applied Organic Chemistry, Lanzhou
UniVersity, Lanzhou 730000, People’s Republic of China
lxfok@zju.edu.cn; orgwyg@zju.edu.cn
Received October 15, 2009
ABSTRACT
A novel and efficient copper-catalyzed tandem reaction of N-tosylaziridines and hydrazones under aerobic conditions to afford the functionalized
tetrahydrotriazines is described. The process involves a nucleophilic ring-opening and an intramolecular oxidative amidation.
Carbon-nitrogen bond formation is one of the most useful
and fundamental reactions in both academic and industrial
chemistry, due to the high prevalent subunits of nitrogen-
containing heterocycles in a variety of biologically active
natural products and pharmaceuticals.1 Of course, the major-
ity of methods for installation of an amine functionality
involve reaction of a nitrogen-based nucleophile with an
electrophilic carbon center. With the emergence of the
concepts of atom economy2 and green chemistry,3 new
methods to introduce C-N functionality by direct C-H
activation are both important and highly desirable because
of its conciseness and atom economy. Although there were
a lot of excellent results about C-N bond formation through
C-H activation,4 examples of the reactions under copper-
catalyzed aerobic conditions are rare.5
In the past decades, much attention has been attracted to
tandem reactions because tandem reaction is a powerful
synthetic method for the construction of complex chemical
frameworks from readily available materials.6 This strategy
allows the formation of two or more bonds in a one-pot
reaction without the isolation of intermediates and greatly
(4) For selected recent reports on catalytic intramolecular C-H ami-
nations, see: (a) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed.
2005, 44, 3518–3520. (b) Wasa, M.; Yu, J. Q. J. Am. Chem. Soc. 2008,
130, 14058–14059. (c) Brasche, G.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 1932–1934. (d) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi,
T. Org. Lett. 2008, 10, 5147–5150. (e) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048–9049. (f) Lebel, H.; Huard, K.; Lectard,
S. J. Am. Chem. Soc. 2005, 127, 14198–14199. For selected recent reports
on catalytic intermolecular C-H aminations, see: (g) Hamada, T.; Ye, X.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833–834. (h) Chen, X.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6791–6792.
(i) Li, Z.; Capretto, D.; Rahaman, R.; He, C. Angew. Chem., Int. Ed. 2007,
46, 5184–5186. (j) Reed, S.; White, M. C. J. Am. Chem. Soc. 2008, 130,
3316–3317. (k) Kalita, B.; Nicholas, K. M. Tetrahedron Lett. 2005, 46,
1451–1454. (l) Aburel, P. S.; Zhuang, W.; Hazell, R. G.; Jorgensen, K. A.
Org. Biomol. Chem. 2005, 3, 2344–2347.
† Zhejiang University.
‡ Lanzhou University.
(1) For reviews on carbon-nitrogen bond formation reactions, see: (a)
Trost, B. M.; Vranken, D. L. Chem. ReV. 1996, 96, 395–422. (b) Johannsen,
M.; Jorgensen, K. A. Chem. ReV. 1998, 98, 1689–1708. (c) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905–2919. (d) Bolm, C.; Legros, J.; Paih, J. L.;
Zani, L. Chem. ReV. 2004, 104, 6217–6254. (e) Du Bois, J.; Tomooka,
C. S.; Hong, J.; Carreira, E. M. Acc. Chem. Res. 1997, 30, 364–372.
(2) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705. (b) Trost, B. M.
Angew. Chem., Int. Ed. 1995, 34, 259–281. (c) Trost, B. M. Science 1991,
254, 1471–1477.
(3) Winterton, N. Green Chem. 2001, 3, G73.
10.1021/ol902376w  2009 American Chemical Society
Published on Web 11/19/2009

enhances synthetic efficiency. Aziridines are widely used
building blocks in organic synthesis,7 and many excellent
examples about nucleophilic ring-opening reaction of aziri-
dines have been reported.8 As a part of our continuing
program on development of tandem reactions of aziridines,9
we herein report an efficient and general approach to
tetrahydrotriazines via the copper-catalyzed tandem reaction
of N-tosylaziridines with hydrazones.
Table 1. Optimization of Reaction Conditionsa
An exhaustive study of the reaction conditions for the
synthesis of 3a from phenylaziridine 1a with hydrazone 2a
was conducted (Table 1). A screening of the catalysts showed
that 0.1 equiv of Cu(OTf)2 was the most efficient catalyst
for this transformation (Table 1, entries 3-9).
yieldb (%)
entry
catalyst
temp (°C)
solvent
t (h)
3a
3aa
1
2
3
4
5
6
7
8
9
AgOTf
80
80
80
80
80
50
RT
60
80
80
80
80
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
10
10
10
4
10
10
24
15
10
15
15
15
0
0
0
58
50c
35
0
65
60
57
0
Yb(OTf)3
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
When the copper loading was reduced to 5 mol %, a low
yield of 3a was obtained. Interestingly, when other catalysts,
such as AgOTf, Yb(OTf)3, and Sc(OTf)3 were used, only a
simple nucleophilic ring-opening reaction occurred, and
ꢀ-hydrazinylamine 3aa was isolated in moderate yield and
product 3a was not observed (Table 1, entries 1-3). Other
metal salts, such as CuI, CuBr2, and FeCl3, could not catalyze
this reaction (Table 1, entries 10-12). Solvent also highly
affected this reaction and toluene was the most suitable
solvent, whereas both THF and 1,2-dichloroethane (DCE)
provided mainly the product 3aa (Table 1, entries 8 and 9).
Further screening of the catalytic reaction conditions revealed
that the reaction products largely depended on the reaction
temperature. When the reaction was conducted under aerobic
conditions at room temperature for 24 h, only the product
3aa was isolated in 60% yield (Table 1, entry 7). It was
noteworthy that 3aa could also be converted into 3a in 83%
yield via Cu(OTf)2-catalyzed intramolecular C-H amination
0
26
60
53
49
5
5
DCE
10
11
12
toluene
toluene
toluene
NR
NR
NR
CuBr2
FeCl3
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst (0.1 mmol),
and solvent (8 mL). b Yield of the isolated product. c Catalyst (0.05 mmol).
Scheme 1. Synthesis of 3a from 3aa
(5) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607–1610. (b) Tsang, W. C. P.; Munday, R.; Brasche, G.; Zheng,
N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603–7610. (c) Wang, D.;
Mei, T.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 17676–17677. (d) Hamada,
T.; Ye, X.; Stahl, A. S. J. Am. Chem. Soc. 2008, 130, 833–835. (e) Stahl,
S. S. Science 2005, 309, 1824–1826. (f) Wu, L.; Qiu, S.; Liu, G. Org. Lett.
2009, 11, 2707–2710. (g) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43,
3400–3420. (h) Tsang, W.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560–14561.
reaction under 1 atm of air at 80 °C for 4 h (Scheme 1).
However, no reaction occurred for 3aa under air-free
conditions. These reults indicated that the ꢀ-hydrazinylamine
3aa is the key intermediate to tetrahydrotriazine 3a. Thus,
the most suitable reaction conditions for the formation of
3a were established, and optimal conditions featured 10 mol
% Cu(OTf)2, toluene, 80 °C, and 1 atm of air as oxidant
(Table 1, entry 4).
Since hydrazones are readily available, then, we extended
the substrate scope to various hydrazones 2 using the
optimized reaction conditions (Table 2). As shown in Table
2, a wide range of hydrazones could react with 1a and
resulted in tetrahydrotriazines 3 in moderate to good yields
(50-76%). The reaction tolerated substrates 2 with both
electron-donating and electron-withdrawing aryl substituents
under the present reaction conditions (Table 2, entries 1-7
and 12-15). Furthermore, the structure of compound 3f was
unambiguously confirmed by single-crystal X-ray analysis
(Figure 1). Phenylallyl hydrazone 2j and naphthyl hydrazone
2k were also transformed into tetrahydrotriazines 3j and 3k
in 74% and 57% yields, respectively (Table 2, entries 10
and 11). We were happy to observe that the alkyl-substituted
hydrazones 2h, 2i, and 2p also reacted well under the
standard conditions (Table 2, entries 8-9 and 16).
(6) (a) Meijere, A. D.; Zezschwitz, P. V.; Bra¨se, S. Acc. Chem. Res.
2005, 38, 413–422. (b) Hussain, M. M.; Walsh, P. J. Acc. Chem. Res. 2008,
41, 883–893. (c) Sun, X. L.; Tang, Y. Acc. Chem. Res. 2008, 41, 937–948.
(d) Wasike, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV.
2005, 105, 1001–1020. (e) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Rabbe,
G. Nature 2006, 441, 861–863. (f) Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (g) Pinto,
A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291–3295. (h)
Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054–3061. (i) Chapman,
C. J.; Frost, C. G. Synthesis 2007, 1–21. (j) Trost, B. M.; Gutierrez, A. C.;
Livingston, R. C. Org. Lett. 2009, 11, 2539–2542. (k) Trost, B. M.; Frontier,
A. J. J. Am. Chem. Soc. 2000, 122, 11727–11728. (l) Trost, B. M. J. Am.
Chem. Soc. 1992, 114, 791–792. (m) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3168–3210. (n) Ramon, D. J.; Yus, M. Angew. Chem.,
Int. Ed. 2005, 44, 1602–1634.
(7) (a) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006,
39, 194–206. (b) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247–258.
(8) (a) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599–619. (b) Savoia,
D.; Alvaro, G.; Fabio, R. D.; Gualandi, A. J. Org. Chem. 2007, 72, 3859.
(c) Wang, L.; Liu, Q.; Sheng, D.; Li, X.; Han, X.; Xiao, W.; Zhou, Y. Org.
Lett. 2009, 11, 1119–1122. (d) Han, H.; Base, I.; Yoo, E. J.; Lee, J.; Do,
Y.; Chang, S. Org. Lett. 2004, 6, 4109–4112. (e) Hou, X.; Fan, R.; Dai,
L. X. J. Org. Chem. 2002, 67, 5295–5300. (f) Sureshkumar, D.; Koutha,
S. M.; Chandrasekaran, S. J. Am. Chem. Soc. 2005, 127, 12760–12761.
(9) (a) Wang, S. Y.; Zhu, Y. X.; Wang, Y. G.; Lu, P. Org. Lett. 2009,
11, 2615–2618. (b) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2008, 10,
13–16. (c) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2007, 9, 5023–
5025.
Org. Lett., Vol. 11, No. 24, 2009
5679

Table 2. Copper-Catalyzed Tandem Reaction of 1a and
Hydrazones 2a
Table 3. Copper-Catalyzed Tandem Reaction of 1 and
Hydrazone 2ca
.
entry
R
t (h)
product
yieldb (%)
entry
R1/R2
t (h)
product
yieldb (%)
1
2
3
4
5
Ph (1a)
8
4
4
4
4
3c
3q
3r
3s
3t
60
65
75
50
80
4-ClC6H4 (1b)
4-CH3C6H4 (1c)
C6H5CH2 (1d)
H (1e)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-CH3C6H4/Ph (2a)
4-CH3OC6H4/Ph (2b)
Ph/Ph (2c)
4-BrC6H4/Ph (2d)
4-NO2C6H4/Ph (2e)
3-NO2C6H4/Ph(2f)
2-ClC6H4/Ph (2g)
i-Pr/Ph (2h)
4
20
8
8
20
4
4
1
1
30
20
20
48
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
58
50
60
63
70
68
69
73
76
74
57
55
70
72
67
61
a Reaction conditions: 1 (1 mmol), 2c (1 mmol), Cu(OTf)2 (0.1 mmol),
and toluene (8 mL). b Yield of the isolated product.
n-C9H19/Ph (2i)
C6H5CHdCH/Ph (2j)
2-naphthyl/Ph (2k)
Ph/4-CH3OC6H4 (2l)
Ph/4-CH3C6H4 (2m)
Ph/4-NO2C6H4 (2n)
Ph/4-ClC6H4 (2o)
Ph/C6H5CH2 (2p)
Scheme 2. Possible Mechanism for the Formation of 3
6
4
a Reaction conditions: 1a (1 mmol), 2 (1 mmol), Cu(OTf)2 (0.1 mmol),
and toluene (8 mL). b Yield of the isolated product.
reaction pathways were possible to convert linear adduct 3aa
to final product 3a: (1) copper-catalyzed direct oxidative
amidation (pathway A)4g,5a and (2) nucleophilic addition of
tosylamide to hydrazone followed by copper-mediated
oxidation of the resulting hexahydrotriazines (pathway B).
However, 3aa could not be converted into 3a or the
nonoxidative cyclization product 5 in the presence of
Cu(OTf)2 under air-free conditions. We also treated 3aa with
NaH, but 5 was not observed and all of 3aa was recovered.
These results suggest that 5 is not an intermediate. Therefore,
pathway A is a possible route to 3a.
Figure 1. Crystal structure of compound 3f.
Further investigations into the scope of various N-
tosylaziridines 1 were then carried out with hydrazone 2c
under the same reaction conditions as above, and representa-
tive results are listed in Table 3. The desired products 3c
and 3q-t were obtained in moderate to good yields
(50-80%). Significantly, 1-tosylaziridine (1e) also worked
well to afford the corresponding product 3t as a single
product in 80% yield under the present reaction conditions
(Table 3, entry 5).
We proposed a possible mechanism for this tandem
reaction as shown in Scheme 2. The first step is most likely
the copper-catalyzed regioselective nucleophilic ring-opening
reaction of N-tosylaziridines and hydrazones, which leads
to a ꢀ-hydrazinylamine-type intermediate 3aa. Two possible
1,2,4-Triazine and its derivatives are a well-known class
of heterocycles, most of them having biological activities.10
They are also useful synthetic intermediates.11 Consequently,
a number of synthetic approaches have been set up for
(10) (a) Carling, R. W.; Russell, M. G. N.; Moore, K. W.; Mitchinson,
A.; Guiblin, A.; Smith, A.; Wafford, K. A.; Marshall, G.; Atack, J. R.;
Street, L. J. Bioorg. Med. Chem. Lett. 2006, 16, 3550–3554. (b) Fink, B. E.;
Vite, G. D.; Mastalerz, H.; Kadow, J. F.; Kim, S.-H.; Leavitt, K. J.; Du,
K.; Crews, D.; Mitt, T.; Wong, T. W.; Hunt, J. T.; Vyas, D. M.; Tokarski,
J. S. Bioorg. Med. Chem. Lett. 2005, 15, 4774–4779. (c) Hay, M. P.; Hicks,
K. O.; Pchalek, K.; Lee, H. H.; Blaser, A.; Pruijn, F. B.; Anderson, R. F.;
Shinde, S. S.; Wilson, W. R.; Denny, W. A. J. Med. Chem. 2008, 51, 6853–
6865. (d) El-Sayed Ali, T. Eur. J. Med. Chem. 2009, 44, 4385–4392.
(11) (a) Shi, B. L.; Lewis, W.; Campbell, I. B.; Moody, C. J. Org. Lett.
2009, 11, 3686–3688. (b) Catozzi, N.; Wasnaire, P.; Taylor, R. J. K.
Tetrahedron 2008, 49, 2865–2868.
5680
Org. Lett., Vol. 11, No. 24, 2009

constructing this important heterocyclic system.12 An ex-
ample for the formation of tetrahydrotriazine from aziridine
and nitrilimines was reported by Tsuge and co-workers.13
Compared with the published methods, the present tandem
method is more efficient and general and should be very
attractive to medicinal chemists as well as organic synthetic
chemists.
In conclusion, we have developed a single-step approach
to tetrahydrotriazines via the Cu(II)-catalyzed tandem reac-
tion of N-tosylaziridines and hydrazones under aerobic
conditions. The process is thought to involve a copper-
catalyzed nucleophilic ring-opening reaction and a copper-
catalyzed intramolecular C-H amidation. The use of inex-
pensive Cu catalyst and air as the ideal oxidant is a significant
practical advantage. The synthetic applications of this new
methodology are under investigation.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China (No.
20872128 and Jo830413) as well as the Natural Science
Foundation of Zhejiang Province (R407106).
Supporting Information Available: Detailed experimen-
1
tal procedures, characterizaton data, copies of H and 13C
NMR spectra for all products, and a crystallographic
information file (CIF) for compound 3f. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) (a) Winternitz, P. HelV. Chim. Acta 1978, 61, 1175–1185. (b)
Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Pibiri, I.; Vivona, N.;
Giorgi, G.; Mazzanti, A.; Spinelli, D. J. Org. Chem. 2006, 71, 8106–8113.
(13) Tsuge, O.; Watanabe, H.; Kiryu, Y. Bull. Chem. Soc. Jpn. 1979,
52, 3654–3658.
OL902376W
Org. Lett., Vol. 11, No. 24, 2009
5681