Copper(i)/TF-BiphamPhos catalyzed asymmetric nitroso Diels-Alder reaction

Article abstract of DOI:10.1039/c6cc09587a

A highly efficient enantioselective nitroso Diels-Alder reaction of 6-methyl-2-nitroso pyridine with various 1,3-dienes was successfully developed using a Cu(i)/(S)-TF-BiphamPhos complex as the catalyst. For most of the cyclic dienes, synthetically important heterocyclic 3,6-dihydro-1,2-oxazines were obtained in high yields with excellent regio-, diastereo- and enantioselectivities. Acyclic 2-silyloxy-1,3-diene also worked well in the reaction.

Full text of DOI:10.1039/c6cc09587a

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Copper(I)/TF-Biphamphos Catalyzed Asymmetric Nitroso Diels-
Alders Reaction
Jun Li,a Hai-Yan Tao,a Chun-Jiang Wang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient enantioselective Nitroso Diels-Alder reactions of biphenyl]-2,2'-diamine) based on the rigid biphenyl
6-methyl-2-nitroso pyridine with various 1,3-dienes were framework, which exhibited excellent asymmetric induction in
successfully developed with Cu(I)/(S)-TF-BiphamPhos complex as the azomethine ylide-involved Cu(I) or Ag(I)-catalyzed
the catalyst. For most of the cyclic dienes, the synthetically asymmetric 1,3-dipolar cycloaddition,6 Michael addition7 and
important heterocyclic 3,6-dihydro-1,2-oxazines were obtained in Mannich reaction.8 Considering the structural similarity
high
yields
with
excellent
regio-,
diastereo-
and between the metalated azomethine ylide and 2-
enantioselectivities. Acyclic 2-silyloxy-1,3-diene also worked well nitrosopyridine (Scheme 1), we envisioned the combination of
in the reaction.
copper or silver salts with chiral TF-BiphamPhos could realize
the challenging asymmetric Nitroso Diels-Alder reaction in
highly stereoselective control. To further expanding the
application of our catalyst system in asymmetric catalysis,
Asymmetric transition metal catalyzed reaction has become
one of the most efficient tools for obtaining enantiopure
compounds, and numerous of novel metal-chiral ligand
complexes have been exploited for different asymmetric
transformations.1 The challenge in this field is matching the
correct catalyst with the appropriate reaction to pursue high
level of stereoselectivity and efficiency.2 Nitroso Diels-Alder
(NDA) reaction has attracted great attention due to the
extensively utilization in natural product synthesis since it was
discovered by Wichterle in 1947.3 However, the instability of
the nitroso compounds and extremely facile background
reaction make the asymmetric approach become very difficult.
To the best of our knowledge, few of the efficient catalyst
systems for asymmetric metal catalyzed Nitroso Diels-Alder
reaction has been discovered to date. The ground-breaking
discovery came from Yamamoto’s group, who reported a
Cu(I)/Segphos-catalyzed highly efficient asymmetric NDA
reaction of 2-nitrosopyridines with cyclic and acyclic dienes.4
By introducing the additional cooperating site on the nitroso
compound, 2-nitrosopyridine chelated to the copper metal
center give a more stable and rigid complex which could
suppress the dimerization of materials and enhance the
stereoselective control. Base on this strategy, Studer and co-
workers developed another catalysis system using
Cu(I)/Walphos-CF3 complex as the catalyst in the same
reaction and obtained high enantioselectivity and
diastereoselectivity.5 Recently, our research group developed a
serial of axially chiral N,P-ligands TF-BiphamPhos (N2-
(diphenylphosphanyl)-4,4',6,6'-tetrakis(tri-fluoromethyl)-[1,1'-
herein, we report
a
Cu(I)/TF-BiphamPhos-catalyzed
asymmetric Nitroso Diels-Alder reaction of 6-methyl-2-nitroso
pyridine with various 1,3-cyclic dienes, affording the
synthetically important 3,6-dihydro-1,2-oxazines in high yields
with
exclusive
regioselectivities
and
diastereoselectivities and high enantioselectivities.
excellent
Scheme 1. Structural Similarity between Metalated Azomethine Ylide and
2-Nitroso Pyridine
R
*LM
O
N
*LM
O
N
N
O
Initially, 1,3-cyclohexadiene 1a and 6-methyl 2-nitiroso-
pyridine 2a were selected as model substrates. The reaction
was examined in the presence of catalytic amount of
Cu(MeCN)4BF4 and various chiral (S)-TF-BiphamPhos (L1-L5
)
o
using dichloromethane as the solvent at -80 C and gradually
warmed to -50 oC in 5 h. All of the reactions went to
completion with high yields and exclusive diastereoselectivities
(Table 1, entries 1-5). The simplest ligand L1 exhibited no
enantioselectivity (Table 1, entry 1), and varying the groups on
the nitrogen or phosphorous atom of the ligands delivered
unsatisfactory enantioselectivities. To our delight, ligand L5
bearing two bromine atoms in the 3,3’-position of the biphenyl
aCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan
430072, China. E-mail: cjwang@whu.edu.cn Fax: 86-27-68754067
bState Key Laboratory of Oganometallic Chemistry, Shanghai Institute of
Oganic Chemistry, Shanghai, 230012, China
backbone
provided
quantitative
yield
and
high
enantioselectivity (96% ee) (Table 1, entry 5). Switching the
metal salts to Cu(II) or Ag(I) lower the enantioselectivity (Table
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1, entries 6 and 7), while variation of the counter anion seems methyl group adjacent to cooperative nitrogen atom were
have no effect on the reactivity and enantioselectivity (Table 1, proven to be crucial for this asymmetric catalytic reaction.
entry 8). Further solvent effects study found that best
To gain further insight into the catalytic efficiency and
enantioselectivity was achieved with ethyl acetate and stereoselectivity control of the catalyst system, a series of
dichloromethane as the solvent, but less satisfactory results cyclic dienes were explored under the optimized experimental
were obtained with toluene and THF (Table 1, entries 9-11). condition, and the results are shown in Table 2. Notably, the
Subsequently, 2-nitiroso N-containing heterocycles 2b-2e were regioselectivity of the nitroso Diels-Alder reaction is an
synthesized according to the literature9,4a to investigate the ineluctable challenge when it comes to unsymmetrical cyclic
influences of the steric and electronic properties of aryl nitroso 1,3-dienes.10 To our delight, unsymmetrical 2-substituted 1,3-
compounds on the stereoselectivity control. It was found that cyclohexadiene 1b-1d were tested in this catalytic system, and
removing the methyl group of pyridine or replacing the the corresponding cyclic products 3b-3d were achieved in high
pyridine moiety with pyrimidine or pyridazine moiety resulted yields and excellent enantioselectivities with exclusive
in low enantioselectivities (Table 1, entries 12-15). The steric regioselectivities (Table 2, entries 1-3). Perfect regioselectivity
effect of
and good enantioselectivity were also achieved in the NDA
reaction of 2,4-disubstituted 1,3-cyclohexadiene 1e (Table 2,
entry 4). N-Cbz protected aza-spirodiene 1f was also proven to
be a suitable substrate in the NDA reaction, affording the
2 | J. Name., 2012, 00, 1-3
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cycloadduct 3f in 96% yield and 90% ee (Table 2, entry 5).11
In summary, with Cu(I)/(S)-TF-Biphamphos complex as the
Five-membered cyclic diene 1,3-Cyclopentadiene 1g was also a catalyst we have successfully developed an efficient
viable diene, and the corresponding cycloadduct 3g was asymmetric nitroso Diels-Alder cycloaddition reaction of 6-
obtained in good yield with high diastereo-/enantioselectivity methyl 2-nitrosopyridine and various cyclic and acyclic 1,3-
(Table 2, entry 6). Larger cyclic dienes, such as 1,3- dienes, leading to the cycloadducts in high yields and
Cycloheptadiene 1h and cis,cis-1,3-cyclooctadiene 1i, were enantioselectivities in most cases. Further studies to
next evaluated in the NDA reaction with the nitroso compound investigate the mechanistic details and stereochemistry of this
2a under the optimized reaction condition, and the reaction reaction are currently underway in our laboratory.
proceeded smoothly affording the desired cycloadducts 3h and
3i in high yields and excellent diastereoselectivities, albeit with
moderate enantioselectivities, which probably resulted from
the steric hindrances induced by the ring strains (Table 2,
entries 7 and 8).
Acknowledgements
This work was supported by NSFC (21372180, 21525207), Large-scale
Encouraged by the results achieved with cyclic dienes, we
further investigated acyclic diene in our catalytic system.
Under the optimized reaction conditions, readily available 2-
silyloxy-1,3-dienes 1j was employed as an acyclic diene. The
NDA reaction proceeded very well, delivering the
corresponding cycloadduct 3j in high yield (93%) with excellent
stereoselectivity (> 20:1 dr and 96% ee) (Scheme 2). The
absolute configuration of the cycloadducts were determined
by comparison the optical rotation and the NMR spectroscopy
with the literature results.4,12
Instrument and Equipment Sharing Founding of Wuhan University, and
the Fundamental Research Funds for the Central Universities. The
Program of Introducing Talents of Discipline to Universities of China
(111 Program) is also appreciated.
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Based on the stereoselectivity of this Cu(I)/TF-BiphamPhos
catalyzed NDA reaction and our previous research work,13
a
possible transition state was proposed in Figure 2. The chiral
(S)-TF-BiphamPhos and nitrosopyridine chelated to copper
metal center giving rise to an active tetrahedral complex. The
methyl group on the 6-position of 2-nitiroso-pyridine maybe
contribute to the stabilization of the metal complex. The steric
congestion in the backside of nitrosopyridine caused by the
bulky PPh2 group of the chiral ligand forces the diene approach
from the front side of the dienophile, which led to the
observed cycloadducts with (1R,4S)-configuration in high
diastereo- and enantioselectivity.
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