A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines

Article abstract of DOI:10.1039/c6ob01556e

A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines has been successfully realized with 2.5 mol% of B(C₆F₅)₃ as a catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in 93-99% yields. Up to 42% ee was also achieved for the asymmetric hydrogenation with the use of a chiral diene and HB(C₆F₅)₂.

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DOI: 10.1039/C6OB01556E
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A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines
Simin Wei,a,b Xiangqing Fenga,b and Haifeng Dua,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
extended the substrate scope to hydrazones.9 Despite
these advances, to the best of our knowledge, cyclic
imines have seldom been employed for the FLPs-catalyzed
hydrogenations, especially for the asymmetric reactions,
which will produce highly desirable nitrogen-containing
heterocycles.
A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines
has been successfully realized with 2.5 mol % of B(C6F5)3 as
catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in
93-99% yields. Up to 42% ee was also achieved for the asymmetric
hydrogenation with the use of chiral diene and HB(C6F5)2.
Since the seminal discovery of frustrated Lewis pairs (FLPs)
for their reversible activation of H2 and application in the
catalytic hydrogenation of imines,1 the lately emerging
chemistry of FLPs has witnessed an extremely rapid
growth in the past decade.2 A broad range of unsaturated
compounds have proven to be effective substrates for the
FLPs-catalyzed metal-free hydrogenations.2 In particular, in
recent several years, some significant advances have been
made for the asymmetric hydrogenations with chiral FLP
catalysts.3,4 Imines derived from aldehydes or ketones
with various amines were one type of most often studied
substrates in this field, and numerous FLPs were efficient
for their transformations.5 Moreover, some imine
analogues were also investigated for the hydrogenations.
For example, in 2011, Stephan and co-workers reported a
B(C6F5)3-catalyzed metal-free hydrogenation of ethane-
1,2-diimines.6 Recently, our group described a highly cis-
selective hydrogenation of vicinal diimines.7 In 2014,
3,4-Dihydro-2H-1,4-benzoxazines are important moieties
widely present in biologically and medicinally active
compounds such as Obscurinervidine, Niblinine, and
Levofloxacin.10 The hydrogenation of 2H-1,4-benzoxazines
provides a powerful and straightforward approach for
their synthesis. Great progress has been made for the
transition-metal catalyzed hydrogenations and the
organocatalytic asymmetric transfer hydrogenations.11,12
However, the metal-free catalytic hydrogenation of the 3-
substituted 2H-1,4-benzoxazines using H2 has rarely been
reported.
As part of our general interest in the metal-free FLP
catalysis, we have developed an in situ borane generation
strategy by the hydroboration of commercially available
alkenes, chiral dienes, and chiral diynes with Piers’ borane,
which were highly effective for the stereoselective and/or
enantioselective hydrogenations of imines, aromatic
nitrogen-containing heterocycles, and silyl enol ethers.13-15
In searching for novel substrates for the FLP catalysis, we
devoted our efforts on the hydrogenation of 2H-1,4
benzoxazines. Herein, we wish to report our preliminary
results on this subject.
Oestreich and Mohr reported
a B(C6F5)3-catalyzed
hydrogenation of oxime ethers without cleavage of the N-
O bond.8 Very recently, the same group successfully
A metal free hydrogenation of 1,4-benzoxazines 1a using
B(C6F5)316 (10 mol %) under H2 (10 bar) in toluene at room
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temperature was conducted initially. As shown in Scheme
1, this reaction went smoothly to give the desired product
desired products 1l-n can be obtained inVi9ew9A%rticlye iOenllidne.
Interestingly, 3,4-disubstituted 1,4-benzoxazines 1o and
DOI: 10.1039/C6OB01556E
2a in
a quantitative conversion. Various reaction
1p were effective substrates to give the corresponding cis
products 2o and 2p as single isomers (Scheme 3). The
structure of 2o was determined by the X-ray diffraction
(Figure 1). However, 2,3-dimethyl 2H-1,4-benzoxazine 1q
was an inert substrate for this transformation, which
might be attributed to the relatively less bulky steric
hindrance.
conditions were next optimized. 5 mol % of B(C6F5)3 was
effective enough for this reaction (Table 1, entry 1).
Further reducing the catalyst loading to 2.5 mol % gave a
slight lower conversion (Table 1, entry 2). But no reaction
occurred at room temperature or 50 °C with 1 mol % of
catalyst (Table 1, entry 3). Raising the temperature to
50 °C, a complete conversion of 1,4-benzoxazine 1a was
obtained with only 2.5 mol % of B(C6F5)3 (Table 1, entry
4). The reaction under H2 (10 bar) gave product 2a in
85% conversion (Table 1, entry 6). Solvents were found
to influence this reaction largely, and toluene was an
optimal solvent (Table 1, entries 4, 7-11).
O
O
B(C6F5)3 (2.5 mol %)
R
R
H2 (20 bar), toluene
50 ºC, 6 h
N
H
Ar
N
Ar
1a-n
2a-n
O
O
O
F
R'
N
H
N
H
N
H
R'
B(C6F5)3
(10 mol %)
O
O
2g: 98% yield
2a: R' = H, 93% yield
2b: R' = OMe, 99% yield
2c: R' = Ph, 98% yield
2d: R' = OMe, 98% yield
2e: R' = F, 93% yield
2f: R' = Cl, 95% yield
H2 (20 bar)
toluene, 12 h
Ph
N
Ph
N
H
2a
1a
O
O
O
>99% conv.
Cl
Scheme 1 Metal-free hydrogenation of 1,4-benzoxazine 1a.
Table 1 Optimization of reaction conditions a
N
H
N
H
N
H
Cl
2h: 96% yield
2i: 90% yield
2j: 99% yield
Entry B(C6F5)3 Solvent
Temp (°C) Time (h) Conv (%)b
(mol %)
O
O
1
2
5.0
2.5
1.0
2.5
1.0
2.5
2.5
2.5
2.5
2.5
2.5
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
C6H5F
25
25
25
50
50
50
50
50
50
50
50
6
24
24
6
>99
84
NRc
>99
NRc
85
2l: R' = Cl, 99% yield
2m: R' = Br, 99% yield
2n: R' = Me, 99% yield
S
N
H
R'
N
H
3
2k: 99% yield
4
Scheme 2 Metal-free hydrogenation of 1,4-benzoxazines.
5
6d
24
6
O
R
O
R
B(C6F5)3 (5 mol %)
7
6
92
H2 (20 bar), toluene
rt,12 h
N
H
R'
N
R'
8
C6H5Cl
CH2Cl2
THF
6
90
9
6
83
1o-q
2o-p
10
11
6
5
Hexane
6
78
O
Me
Me
O
Me
Ph
O
Ph
Ph
a
All the reactions were carried out with 1,4-benzoxazine 1a (0.10 mmol) in
N
H
N
H
N
H
b
solvent (1.0 mL) under H2 (20 bar) unless otherwise noted. The conversion
was determined by crude 1H NMR. c No reaction. c H2 (10 bar).
2q: 0% yield
2p: 98% yield
2o: 99% yield
Scheme 3 Metal-free hydrogenation of 3,4-disubstituted 1,4-benzoxazines.
The substrate scope was subsequently investigated by
subjecting a variety of 1,4-benzoxazines 1a-n into the
metal-free hydrogenations. As shown in Scheme 2, all
these reactions proceeded efficiently to furnish 3,4-
dihydro-2H-1,4-benzoxazines 2a-n in 93-99% yields.
Electron-withdrawing and donating substituents at the
para- and meta-positions of phenyl groups were well
tolerant. Naphthyl and thienyl substituted 2H-1,4-
benzoxazines 1i-k were also suitable substrates for this
reactions. When employing 1,4-benzoxazines 1i-n with
substituents at the 6-positions as substrates, the
Figure 1 X-ray structure of compound 2o.
With these results in hand, we moved on our attention to
the asymmetric reactions, and a variety of chiral dienes
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3a-i were evaluated for the asymmetric hydrogenation of
1,4-benzoxazine 1a at room temperature. As shown in
Scheme 4, all these reactions went with high reactivities,
but gave disappointing ee’s. Chiral diene 3i bearing bulky
substituents at 3,3’-positions gave a slightly higher ee.
After a simple optimization, CH2Cl2 was a better solvent.
1,4-Benzoxazines 1a-f were then subjected to this
asymmetric hydrogenation, and products 2a-f were
obtained in 90-97% yields with 30-42% ee’s (Scheme 5).
We are grateful for the financial support by the
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National Natural Science FounDdOaIt:i1o0n.1039/oCf6OBC01h5i5n6aE
(21222207, 21572231, and 21521002).
Notes and references
1
(a) G. C. Welch, R. R. San Juan, J. D. Masuda and D. W. Stephan,
Science, 2006, 314, 1124; (b) P. A. Chase, G. C. Welch, T. Jurca
and D. W. Stephan, Angew. Chem., Int. Ed., 2007, 46, 8050.
For leading reviews, see: (a) A. L. Kenward and W. E. Piers,
Angew. Chem., Int. Ed., 2008, 47, 38; (b) D. W. Stephan and G.
Erker, Angew. Chem., Int. Ed., 2010, 49, 46; (c) T. Soós, Pure
Appl. Chem., 2011, 83, 667; (d) J. Paradies, Angew. Chem., Int.
Ed., 2014, 53, 3552; (e) D. W. Stephan and G. Erker, Angew.
Chem., Int. Ed., 2015, 54, 6400; (f) D. W. Stephan, J. Am. Chem.
Soc., 2015, 137, 10018; (g) D. W. Stephan, Acc. Chem. Res.,
2015, 48, 306.
2
chiral diene 3 (2.5 mol %)
HB(C6F5)2 (5 mol %)
O
O
N
H2 (20 bar), toluene
rt, 12 h
N
H
Ph
Ph
2a
1a
3
4
For leading reviews, see: (a) Y. Liu and H. Du, Acta Chim. Sinica,
2014, 72, 771; (b) X. Feng and H. Du, Tetrahedron Lett., 2014,
55, 6959; (c) L. Shi and Y.–G. Zhou, ChemCatChem, 2015, 7, 54.
For selected examples, see: (a) D. Chen and J. Klankermayer,
Chem. Commun., 2008, 2130; (b) D. Chen, Y. Wang and J.
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M. Leskelä, I. Pápai and T. Repo, J. Am. Chem. Soc., 2015, 137,
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For selected examples, see: (a) P. Spies, S. Schwendemann, S.
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R
3a: R = 4-Ph (87% conv., 15% ee)
3b: R = 4-tBu (>99% conv., 19% ee)
3c: R = 4-OMe (>99% conv., 29% ee)
3e: R = 3-Me (>99% conv., 30% ee)
3f: R = 3,5-tBu2 (>99% conv., 13% ee)
3g: R = 3,5-(CF3)2 (>99% conv., 28% ee)
3h: R = 2,4,6-Me3 (>99% conv., -14% ee)
3i: R = 3,5-(3,5-tBu2C6H3)2 (>99% conv., 31% ee)
R
Scheme 4 Evaluation of chiral dienes for asymmetric hydrogenation.
chiral diene 3i (2.5 mol %)
HB(C6F5)2 (5 mol %)
O
O
N
H2 (20 bar), CH2Cl2
rt, 12 h
N
H
Ar
Ar
5
1a-f
2a-f
O
O
R
N
H
N
H
R
2d: R = OMe, 92% yield, 33% ee
2e: R = F, 92% yield, 31% ee
2f: R = Cl, 97% yield, 30% ee
2a: R = H, 95% yield, 33% ee
2b: R = OMe, 90% yield, 40% ee
2c: R = Ph, 90% yield, 42% ee
Scheme 5 Metal-free asymmetric hydrogenation of 1,4-benzoxazines.
6
D. W. Stephan, S. Greenberg, T. W. Graham, P. Chase, J. J. Hastie,
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Conclusions
In summary, a frustrated Lewis pair catalyzed metal-free
hydrogenation of 1,4-benzoxazines has been successfully
realized with 2.5 mol % of B(C6F5)3 under a mild condition
to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in
93-99% yields. For 3,4-disubstitued 1,4-benzoxazines, cis-
products were obtained as single isomers. Using chiral
borane catalysts generated in situ by the hydroboration of
chiral dienes with HB(C6F5)2, a preliminary attempt for the
asymmetric hydrogenation gave 30-42% ee’s. Further
efforts on searching for more effective chiral FLPs for the
asymmetric hydrogenations are underway in our
laboratory.
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