α-Amidation of cyclic ethers catalyzed by simple copper salt and a mild and efficient preparation method for α,ω-amino alcohols

Article abstract of DOI:10.1021/ol070537i

Copper(II) trifluoromethanesulfonate catalyzed the amidation of cyclic ethers with iminoiodanes under mild conditions (CH₂Cl₂, 40°C) with good yields (up to 86% based on 97% conversion) and selectivity (only α-amino products were fou

Full text of DOI:10.1021/ol070537i

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2277-2280
r
-Amidation of Cyclic Ethers Catalyzed
by Simple Copper Salt and a Mild and
Efficient Preparation Method for
r,P-Amino Alcohols
Ling He,†,‡ Jing Yu,‡ Ji Zhang,† and Xiao-Qi Yu*,†
Department of Chemistry, Key Laboratory of Green Chemistry and
Technology (Ministry of Education), Sichuan UniVersity, Chengdu, 610064,
People’s Republic of China, and Key Laboratory of Drug-Targeting of Education
Ministry of China, West China School of Pharmacy, Sichuan UniVersity, Chengdu,
610041, People’s Republic of China
xqyu@tfol.com
Received March 2, 2007
ABSTRACT
Copper(II) trifluoromethanesulfonate catalyzed the amidation of cyclic ethers with iminoiodanes under mild conditions (CH2Cl2, 40
good yields (up to 86% based on 97% conversion) and selectivity (only -amino products were found). Subsequently, the tosylamidated
-amino alcohols.
°C) with
r
products could undergo a reductive ring-opening reaction to give
r,P
Nitrene insertion into C-H bonds catalyzed by transition
metal complexes is an attractive methodology for the
construction of C-N bonds and many interesting organic
molecules.1-5 Such reactions could play a key role in the
preparation of many natural products and pharmacologically
active compounds.6
Although a series of studies on catalyzed inter- or
intramolecular amidation reactions of saturated C-H bonds
by ruthenium prophyrin have demonstrated that the method
could effectively promote the formation of carbon-nitrogen
bonds in alkanes and alkyl aromatics, the amidation reactions
of cyclic ethers are sparse in the literature.7 Recently, Albone
and co-workers found that copper(I) chloride could activate
the amidation reaction of ethers with chloramine-T as the
nitrene source to give the desire product with moderate
yields.8 In this paper, we report the intermolecular amidation
of saturated C-H bonds of cyclic ethers catalyzed by simple
copper salts using TsNH2/PhI(OAc)2 or PhIdNTs as the
† Key Laboratory of Green Chemistry and Technology.
‡ Key Laboratory of Drug-Targeting of Education Ministry of China.
(1) (a) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Che, C.-M. J. Org. Chem.
2004, 69, 3610-3619. (b) He, L.; Chan, P. W. H.; Tsui, W.-M.; Yu, W.-
Y.; Che, C.-M. Org. Lett. 2004, 6, 2405-2408. (c) Au, S.-M.; Huang, J.-
S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J. Am. Chem. Soc. 1999, 121,
9120. (d) Zhou, X.-G.; Yu, X.-Q.; Huang, J.-S.; Che, C.-M. Chem. Commun.
1999, 2377. (e) Liang, J.-L.; Yu, X.-Q.; Che, C.-M. Chem. Commun. 2002,
124. (f) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M.
Angew. Chem., Int. Ed. 2002, 41, 3465.
(6) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b) Reymond, J. L.;
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Marcaccini, S.; Pepino, R.; Torroba, T. J. Org. Chem. 1996, 61, 2202. (d)
Marcotte, F. A.; Rombouts, F. J. R.; Lubell, W. D. J. Org. Chem. 2003,
68, 6984. (e) Cunha, S.; Rodrigues, M. T.; Silva, C. C.; Napolitano, H. B.;
Vencato, I.; Lariucci, C. Tetrahedron, 2005, 61, 10536. (f) Sanchez, A.;
Nunez, A.; Builla, J. A.; Burgos, C. Tetrahedron, 2004, 60, 11843.
(7) Fructos, M. R.; Swiatoslaw Trofimenko; Diaz-Requejo, M. M.; Perez,
P. J. J. Am. Chem. Soc. 2006, 128, 11784-11791.
(2) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
(3) (a) Breslow, R.; Gellman, S. H. Chem. Commun. 1982, 1400. (b)
Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728. (c) Yang,
J.; Weinberg, R.; Breslow, R. Chem. Commun. 2000, 531.
(4) (a) Espino, C. G.; Du, Bois, J. Angew. Chem., Int. Ed. 2001, 40,
598. (b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du, Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935.
(5) (a) D’az-Requejo, M. M.; Belderra’n, T. R.; Nicasio, M. C.;
Trofimenko, S.; Pe’rez, P. J. J. Am. Chem. Soc. 2003, 125, 12078. (b)
Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003, 5, 4113.
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J. L. Org. Biomol. Chem. 2005, 3, 107-111.
10.1021/ol070537i CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/11/2007

nitrene source. Moreover, the tosylamidated product could
be reduced with sodium borohydride to form ω-amino
alcohols, which are important compounds in organic syn-
thesis, especially for use as potential drugs, and prepare some
biologically active compounds.9,10
Table 1. Intermolecular Amidation Catalyzed by Various
Metal Complexes
The intermolecular C-N bond formation reactions medi-
ated by copper(II) trifluoromethanesulfonate provide a
convenient access to N-substituted amino cyclic ethers. When
using tetrahydrofuran (THF) as substrate, and with substrate:
PhI(OAc)2:p-toluenesulfonamide in the molecular ratio of
1:3:1, the product R-tosylamino tetrahydrofuran was obtained
with 86% yield (Scheme 1). The reaction possibly occurred
% yielda
entry
nitrene Source
Catalyst
(conversionb)
1
2
3
4
5
6
7
8
9
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
TsNH2/PhI(OAc)2
PhI)NTs
Cu(tfac)2
CuI
trace (-)
0 (0)
21 (36)
trace (-)
trace (-)
trace (-)
53 (57.8)
trace (-)
68 (65)
Cu(CF3SO3)2
Ru(TTP)(CO)
Co(TTP)(CO)
Cu(TTP)(CO)
Rh2Ac4
Scheme 1
Mn(TTP)Cl
Rh2Ac4
10
PhI)NTs
Cu(CF3SO3)2
33 (42)
a Isolated yield based on the amount of ether consumed. b Substrate
conversion determined by GC analysis.
via an intermolecular nitrogen atom transfer from copper
imido complexes to saturated R C-H of the cyclic ether
(Scheme 2). The structure of the product was confirmed by
1H NMR, 13C NMR, and high-resolution MS.
amidation reaction, and the results are listed in Table 2.
Increasing the loading of Cu(II) triflate led to the increase
of substrate conversion and product yield (entries 1-4).
Excess PhI(OAc)2 was found to be favorable for the product
yield. When using 1.5 equiv of PhI(OAc)2, the conversion
was 65% (entry 4). The conversion was dramatically
increased to 97% (entry 7) by adding PhI(OAc)2 to 3 equiv.
Temperature also affected the reaction. At lower temperature,
longer reaction time was needed to achieve similar yield
(entry 6). A further increase of temperature (65 °C) led to
the decrease of reaction yield (entries 9 and 10). Otherwise,
the bases, such as Al2O3, were found to be helpful for the
amidation reactions.
Scheme 2
Table 2. Optimization of Reaction Conditionsa
At the beginning of this work, in order to evaluate the
catalytic efficiency of various metal complexes, the reaction
of cyclic ether with TsNH2/PhI(OAc)2 or PhIdNTs was
studied by using a variety of catalysts with dichloromethane
as solvent. The results were shown in Table 1. It was found
that only Cu(II) triflate and rhodium(II) acetate could be used
as catalyst for the amidation of THF (entries 3, 7, 9, and
10).
Other metal complexes, such as CuI, Cu(II) trifluoro-
acetate, and several metal porphyrin complexes, displayed
poor catalytic activity. As a result, we used Cu(II) triflate
for the subsequent studies.
temp
mol ratio of
catalyst loading
(mol %)
% yieldb
entry (°C) TsNH2/PhI(OAc)2
(conversionc)
1
2
3
4
5
6
7
8
9e
10e
40
40
40
40
25
25
40
40
65
65
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:3.0
1:3.0
1:3.0
1:1.5
1:3.0
0
2
5
10
10
10
10
5
0
∼20 (36)
70 (59)
88 (65)
85 (68)
86 (95)d
86 (97)
84 (57)
30 (70)
32
We also studied the effects of temperature, catalyst
loading, and the amount of PhI(OAc)2 on the intermolecular
10
10
a Mole ratio of THF:catalyst:TsNH2 was 1:0.1:1. b Isolated yield based
on the amount of ether consumed. c Substrate conversion determined by
GC analysis. d Reaction time was 10 h. e Reactions were performed in
ClCH2CH2Cl.
(9) (a) Gibson, S. E.; Lecci, C.; White, A. J. P. Synlett 2006, 2929-
2934. (b) Wu, X.-F.; Li, X.-H.; McConville, M.; Saidi, O.; Xiao, J.-L. J.
Mol. Catal. A: Chem. 2006, 247, 153-158.
(10) Selambarom, J.; Monge, S.; Carre, F.; Roque, J. P.; Pavia, A. A.
Tetrahedron 2002, 58, 9559-9566.
2278
Org. Lett., Vol. 9, No. 12, 2007

To test the generality of the catalytic system, we applied
several cyclic ethers to the amidation reaction. Almost
all substrates could give their corresponding product with
good yields, and the amino groups were always added to
the R-position of the substrate (Table 3). For R-alkyl-
we could conclude that this method could provide a
convenient and efficient method for the preparation of 2-N-
substituented cyclic ether with commercially available
reagents.
R-Amino cyclic ethers can undergo a reductive ring-
opening reaction with use of sodium borohydride. The
products are R,ω-amino alcohols, which can be used as
intermediates in the synthesis of some biologically active
compounds. Thus we used the products of the intermolecular
amidation for the reductive ring-opening reactions. The
results demonstrated that a series of 2-tosylamino cyclic
ethers could readily be reduced to give the corresponding
amino alcohol products, which were shown in Table 4. All
Table 3. Intermolecular Amidation of Saturated C-H Bonds
a
Catalyzed by Cu(CF3SO3)2
Table 4. Reductive Ring-Opening Reactions of 2-Tosylamino
Cyclic Ethersa
a Reactions were performed in THF at 25 °C for 2-4 h with NaBH4 as
reducing agent. b Isolated yields. c n ) 4, 6.
ring-opening products could be obtained with excellent yields
(entries 1-5) except the crown ether derivative (entry 6).
The reason for the low yield of the reaction was due to
tosylamino-18-crown-6 contamination of the reactant. In the
amidation reaction of 18-crown-6, mono- and multi-tosyl-
amino products could be formed and they were difficult to
separate.
a Reactions were performed in CH2Cl2 at 40 °C for 4 h with a catalyst/
substrate/TsNH2/PhI(OAc)2 ratio of 0.1:1:1:3. b Isolated yield based on the
amount of ether consumed. c Substrate conversion determined by GC
annlysis. d n ) 4, 6. Reaction was performed in CH2Cl2 at 40 °C for 4 h
with a catalyst/substrate/TsNH2/PhI(OAc)2 ratio of 0.1:1:10:30.
In summary, we introduced a facile and efficient prepara-
tion method of 2-tosylamino cyclic ethers and R,$-amino
alcohols. Copper(II) triflate could catalyze the intermolecular
amidation of cyclic ethers under mild condition. The reaction
proceeded in a highly selective manner, generating exclu-
sively the R-amidation product. Subsequent reductive ring-
opening reaction by NaBH4 could give R,$-amino alcohols,
which could be important intermediates in the synthesis of
some biologically active compounds.
carbonyloxymethyl THF, two amidation products were
found, and the products with an amino group on the
cycle were found to be the major product (entries 5and 6).
For 1, 3-dioxolane and morpholine derivatives, only moderate
yields were obtained (entries 8 and 9). From these results
Org. Lett., Vol. 9, No. 12, 2007
2279

Acknowledgment. This work was financially supported
by the National Science Foundation of China (Nos. 20471038
and 20572075), Program for New Century Excellent Talents
in University and Specialized Research Fund for the Doctoral
Program of Higher Education.
Supporting Information Available: Detailed experi-
mental procedures and characterization data of central
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070537I
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