Copper-catalyzed electrophilic amination of alkenylzirconocenes with O-benzoylhydroxylamines: An efficient method for synthesis of enamines

Article abstract of DOI:10.1021/ol302004t

Copper-catalyzed electrophilic amination of alkenylzirconocenes is accomplished under mild reaction conditions. The reaction tolerates a wide range of functional groups and can be used to prepare some hindered enamines.

Full text of DOI:10.1021/ol302004t

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4750–4753
Copper-Catalyzed Electrophilic Amination
of Alkenylzirconocenes with
O‑Benzoylhydroxylamines: An Efficient
Method for Synthesis of Enamines
Xiaoyu Yan,† Chao Chen,*,† Yiqing Zhou,† and Chanjuan Xi*,†,‡
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua University, Beijing 100084, China, and
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China
cjxi@tsinghua.edu.cn; chenchao01@mails.tsinghua.edu.cn
Received July 19, 2012
ABSTRACT
Copper-catalyzed electrophilic amination of alkenylzirconocenes is accomplished under mild reaction conditions. The reaction tolerates a wide
range of functional groups and can be used to prepare some hindered enamines.
Enamines are versatile functional groups capable of
partaking in a variety of important transformations in-
cluding regioselective alkylations and acylations, cycload-
ditions, and a range of heterocycle forming processes.1
Recently, enamines have received more attention since
they can be asymmetrically hydrogenated into chiral
amines2 or hydroborated into NꢀB frustrated Lewis
pairs.3 The traditional approach for the synthesis of en-
amines is the condensation of a secondary amine with
a carbonyl compound under mineral or Lewis acid
catalysis.4 While this approach is fairly general, it presents
several limitations, such as harsh reaction conditions and
low functional group tolerance. Furthermore, no real
control of regiochemistry and stereochemistry have been
achieved. Alternative methods for the synthesis of enam-
inesare hydroaminations of alkynes5 and methylenation of
amides.6 Although significant contributions have been made,
this method exhibits poor performance for dialkylamine
and internal alkynes.7 On the other hand, in recent years,
(5) (a) Barluenga, J.; Aznar, F.; Liz, R.; Rodes, R. J. Chem. Soc.,
Perkin Trans. 1 1980, 2732. (b) Bytschkov, I.; Doye, S. Eur. J. Org.
Chem. 2003, 935. (c) Shimada, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12670. (d) Tillack, A.; Garcıa Castro, I.; Hartung, C. G.;
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Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541. (e) Shaffer, A. R.;
Schmidt, J. A. R. Organometallics 2008, 27, 1259. (f) Kumaran, E.;
Leong, W. K. Organometallics 2012, 31, 1068. (g) Fukumoto, Y.; Asai,
H.; Shimizu, M.; Chatani, N. J. Am. Chem. Soc. 2007, 129, 13792. (h)
Zeng, X.; Frey, G. D.; Kousar, S.; Bertrand, G. Chem.;Eur. J. 2009, 15,
3056.
(6) Petasis, N. A.; Lu, S. -P. Tetrahedron Lett. 1995, 36, 2393.
(7) (a) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L.
J. Am. Chem. Soc. 2009, 131, 18246. (b) Hesp, K. D.;Stradiotto, M. J. Am.
Chem. Soc. 2010, 132, 18026.
† Tsinghua University.
‡ Nankai University.
(1) (a) Whitesell, J. K. In Comprehensive Organic Synthesis, Ed. Trost,
B. M.; Fleming, I. Pergamon, Oxford, UK, 1991. (b) Enamines: Synthesis,
Structure and Reactions, 2nd ed.; Ed. Cook, A. G.; Dekker, New York, 1988.
(c) The Chemistry of Enamines, Part I; Ed. Rappoport, Z. Wiley, New York,
1994, pp 523ꢀ636. (d) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99,
1069. (e) Mukherjee, S.; Yang, J. W.; Hoffman, S.; List, B. Chem. Rev.
2007, 107, 5471.
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Chem. Soc. 2006, 128, 11774. (b) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.;
Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366.
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(8) Pd-catalyzed formation of enamines: (a) Barluenga, J.; Fernandez,
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M. A.; Aznar, F.; Valdes, C. Chem. Commun. 2002, 2362. (b) Barluenga, J.;
Fernandez, M. A.; Aznar, F.; Valdes, C. Chem.;Eur. J. 2004, 10, 494. (c)
Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun.
2004, 1400. (d) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43, 9085.
(e) Reddy, C. R. V.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2005, 7, 4427.
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r
10.1021/ol302004t
Published on Web 09/06/2012
2012 American Chemical Society

the Pd- or Cu-catalyzed formation of enamines from
electrophilic alkenyl halides and nucleophilic secondary
amines is a hallmark reaction in this field.8,9 This coupling
with dialkylamine is often inefficient; in particular, the
amination with secondary acyclic alkylamines or hindered
amines is rarely reported. An umpolung strategy, reaction of
an electrophilic nitrogen source with a nucleophilic orga-
nometallic reagent,10,11 would provide a complementary
method for the construction of a CꢀN bond under mild
conditions. Although electrophilic amination of arylme-
tallic and alkylmetallic reagents has been reported,12 the
electrophilic amination of alkenylmetallic reagents has
been rarely reported.10b,c As part of an ongoing program
in our laboratory to systematically study zirconocene
chemistry, we herein describe a copper-catalyzed amina-
tion of alkenylzirconocenes with O-benzoylhydroxyla-
mines to afford a wide range of enamines (Scheme 1) in
a reverse coupling mode under mild conditions.
available materials via (i) hydrozirconation of alkynes with
the Schwartz’s reagent,14 (ii) zirconacycle-mediated carbo-
zirconation of alkynes,15 or (iii) oxidative addition of
alkenyl halides to Cp2Zr(II).16 Reactions of alkenylzirco-
nocenes with O-benzoylhydroxylamines could provide a
general route to various enamines. Herein, we report de-
tails of the synthesis of enamines via the reaction of
alkenylzirconocenes with O-benzoylhydroxylamines.
Scheme 2. Amination of 1a with 2a
A typical procedure is as follows. To a solution of
alkenylzirconocene 1a, which was produced by alcoholysis
of the corresponding zirconacyclopentene prepared from
3-hexyne and Cp2ZrEt2,15a were added CuCl (10 mol %)
and 4-benzoyloxymorpholine 2a. Enamine 3aa was formed
exclusively after the reaction was stirred at rt for 2 h
(Scheme 2). After simple extraction workup, enamine 3aa
was isolated in 83% yield with about 95% purity deter-
mined by GC analysis. This isolation process is elegant since
most enamines are sensitive to air and unsuitable for
common column chromatography. In the absence of CuCl,
the enamine 3aa was only detected in a trace amount.
The reactions with 4-benzoyloxymorpholine-derived
electrophile 2a could be performed with a number of
alkenylzirconocene species, including alkyl, aryl, alkenyl,
and alkynyl substituents. The representative results are
summarized in Table 1. Alkenylzirconocenes 1aꢀ1m, which
were prepared by alcoholysis of in situ prepared zircona-
cyclopentenes,17 were treated with 4-benzoyloxymorpho-
line 2a in the presence of 10 mol % of CuCl, and the
corresponding enamine 3aaꢀ3ma was formed in 78% to
91% isolated yields (entries 1ꢀ13). In all the cases above,
the reaction afforded only one single isomer. To confirm
the structure of the product, yellow single crystals of 3da
suitable for X-ray diffraction analysis were obtained by
recrystallization in n-hexane. The structure of 3da clearly
shows that two phenyl groups were located in cis-form to
each other (see Supporting Information), which was con-
sistent with the parent alkenylzirconocene 1d. It means
that the double bond configuration was retained during
Scheme 1. Cu-Catalyzed Amination of Alkenylzirconocenes
with Hydroxylamines
Alkenylzirconocenes are useful intermediates in organic
synthesis,13 since they can be easily prepared from
(9) Cu-catalyzed formation of enamines: Wang, Y.; Liao, Q.; Xi, C.
Org. Lett. 2010, 12, 2951.
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Angew. Chem. 1978, 90, 733. (c) Zhang, Z.; Yu., Y.; Libebeskind, L. S.
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Org. Lett., Vol. 14, No. 18, 2012
4751

reaction; instead, O-benzoylhydroxylamine acted as an
oxidant and 1,3-diene was isolated.18,19 In other words,
the reaction is not convenient for the preparation of
mono- and disubstituted enamines.
Table 1. Scope of Electrophilic Amination of Various Alkenyl-
zirconocenesa
Scheme 3. Reduction of Enamine to Amines by NaB(OAc)3H
The enamines could be reduced to amines. Here, as
examples, the enamines 3aa and 3fa were directly reduced
with NaB(OAc)3H/HOAc to isolate 4aa and 4fa in 92%
and 84% yield, respectively (Scheme 3). This result indir-
ectly indicates efficiency in the synthesis of amines and the
purity of the parent enamines.
To establish the full scope of the amination reaction
of alkenylzirconocenes, we further explored a range of
O-benzoylhydroxylamines (Figure 1). O-Benzoylhydroxyl-
amine 2b derived from piperidine was used in the reaction to
afford the corresponding enamines (Scheme 4, 3bb and
3eb). O-Benzoylhydroxylamines 2cꢀ2e derived from com-
mon acyclic amines or hydroxylamines, such as diethyl-
hydroxylamine, N-methylbutan-1-amine, and N-methyl-
cyclohexanamine, were also used in the reaction to give the
corresponding enamines (3bc, 3ec, 3fd, and 3fe). Further-
more, O-benzoyl-N,N-diallylhydroxylamine 2f was em-
ployed in the reaction to give the corresponding enamine
3bf. Both cyclic and acyclic O-benzoylhydroxylamines
afforded the corresponding products in excellent yield.
Hindered enamines are usually difficult to prepare by
traditional methods. When O-benzoyl-N,N-diisopropyl-
hydroxylamine 2g was employed, the reaction did not
occur at rt. When the reaction mixture was heated to 50 °C
for 2 h, enamines 3bg and 3eg were obtained in excellent
yields. When 1-benzoyloxy-2,2,6,6-tetramethylpiperidine
a Reaction conditions: alkenylzirconocene 1 (0.5 mmol) prepared in
situ in 3 mL of THF solution, 4-benzoyloxymorpholine 2a (0.55 mmol),
CuCl (0.05 mmol), N2, rt, 2 h. b Isolated yield based on alkyne.
the amination. This is important for a well-defined pre-
paration of multisubstituted enamines. It is also note-
worthy that products 3eaꢀ3ka, dependent upon three
different substituents in the enamines, were successfully
obtained (entries 5ꢀ11). Notably, products 3ja and 3ka
are E/Z isomers prepared by the different configuration
of alkenylzirconocenes (entries 10ꢀ11). When alkenylzir-
conocenes 1n and 1o, which were prepared by reaction
of the zirconacyclopentenes with diallyl ether,15c,d were
employed, skipped dienamines 3na and 3oa were formed
in 83% and 81% yield, respectively (entries 14ꢀ15). In
addition, dienylzirconocene complex 1p generated by the
alcoholysis of the corresponding zirconacyclopentadiene15e
can also be used as a nucleophile to afford dienamine 3pa
(entry 16), which is a particularly interesting type of electron-
rich diene for [4 þ 2] cycloaddition reactions.17 All the
aminations of alkenylzirconocenes were accomplished in
less than 2 h at rt. Hydrozirconation of alkynes with
Schwartz’s reagent could afford mono- and disubstituted
chloroalkenylzirconocenes,14 which were expected to re-
act with O-benzoylhydroxylamine to afford mono- and
disubstituted enamines in the presence of CuCl. How-
ever, the expected enamines were not observed in such a
(18) (a) Knochel, P; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2390. (b) Lipshutz, B. H.; Ellsworth, E. J. Am. Chem.
Soc. 1990, 112, 7440. (c) Takahashi, T.; Kotora, M.; Kasai, K.; Suzuki,
N. Tetrahedron Lett. 1994, 35, 5685.
(19) LiCl was often used to activate chloroalkenylzirconocenes in the
presence of CuCl;18 however LiCl was not effective in this reaction. When
t-BuOLi was added, the reaction proceeded to afford enamine in 30%
NMR yield. 1,4-Diphenyl-1,3-diene was observed as another product.
(20) Leading references: (a) Takahashi, T.; Kotora, M.; Kasai, K.;
Suzuki, N.; Nakajima, K. Organometallics 1994, 13, 4184. (b) Takahashi,
T.; Hara, R.; Nishihara, Y.; Kotora, M. J. Am. Chem. Soc. 1996,
118, 5154. (c) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.; Nakajima,
K.; Kotora, M. J. Am. Chem. Soc. 1998, 120, 1672. (d) Takahashi, T.;
Sun, W.-H.; Liu, Y.; Nakajima, K.; Kotora, M. Organometallics 1998,
17, 3841. (e) Kotora, M.; Xi, C.; Takahashi, T. Tetrahedron Lett. 1998,
39, 4321. (f) Xi, C.; Kotora, M.; Nakajima, K.; Takahashi, T. J. Org.
Chem. 2000, 65, 945. (g) Chen, C.; Xi, C.; Jiang, Y.; Hong, X. J. Am.
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4752
Org. Lett., Vol. 14, No. 18, 2012

Scheme 5. Possible Reaction Pathway
Figure 1. O-Benzoylhydroxylamines employed in the reaction.
known facts, a plausible mechanism is shown in Scheme 5.
In the first step, alkenylzirconocene 1 is transmetalated
with CuCl to give alkenylcopper intermediate 5. Then
subsequent electrophilic amination12c of the alkenylcop-
per intermediate 5 with hydroxylamine affords enamine 3
with regeneration of the Cu(I) salt.
Scheme 4. Scope of Electrophilic Amination of Various
Hydroxylaminesa
In summary, we have developed an efficient method
for the preparation of enamines via copper-catalyzed
electrophilic amination of alkenylzirconocene reagents
with O-benzoylhydroxylamines. The reaction proceeds
under mild conditions in high yields with a wide range
of functional groups. The products can be efficiently
isolated from the reaction mixture by simple extraction.
The configuration of enamines is retained during this
reaction.
Acknowledgment. This work was supported by the Na-
tional Key Basic Research Program of China (973
program) (2012CB933402) and National Natural Science
Foundation of China (20972085 and 21032004). We also
thank Mr. Kun Fang in Tsinghua University for his kind
assistance in preparation of O-benzoylhydroxylamines.
a Reaction conditions: alkenylzirconocenes 1 (0.5 mmol) prepared in
situ in 3 mL of THF solution, O-benzoylhydroxylamines 2 (0.55 mmol),
CuCl (0.05 mmol), N2, rt, 2 h, the isolated yield based on alkyne.
b 50 °C, 2 h.
Supporting Information Available. Experimental pro-
cedures, full characterization including 1H NMR and 13
C
NMR data for all new compounds and X-ray crystal
structure of 3da, and X-ray data for 3da (CIF). These
materials are available free of charge via the Internet at
http://pubs.acs.org.
was used, the corresponding enamine was detected by
GC-MS in low yield.
Transmetalations of the CꢀZr bond to the CꢀCu bond
have been extensively observed.20 In combination with
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4753