Lewis base organocatalyzed enantioselective hydrosilylation of 1,4-benzoxazines

Article abstract of DOI:10.1055/s-0031-1290405

A chiral Lewis base organocatalyzed enantioselective hydrosilylation of 1,4-benzoxazines is presented. The reactions afforded various enantioenriched 3-substituted dihydro-2H-1,4-benzoxazines with high yields (up to 98%) in moderate enantioselectivities (up to 87% ee).

Full text of DOI:10.1055/s-0031-1290405

LETTER
▌1797
letter
Lewis Base Organocatalyzed Enantioselective Hydrosilylation of
1,4-Benzoxazines
Enantioselective Hydrosilylation of 1,4-Benzoxazines
Yan Jiang,a,b Li-Xin Liu,a,b Wei-Cheng Yuan,a Xiao-Mei Zhang*a
a
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese
Academy of Sciences, Chengdu 610041, P. R. of China
b
Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Fax +86(28)85257883; E-mail: xmzhang@cioc.ac.cn
Received: 02.04.2012; Accepted after revision: 06.05.2012
1,4-benzoxazine, however, the reaction gave only 25%
ee.5f
Abstract: A chiral Lewis base organocatalyzed enantioselective
hydrosilylation of 1,4-benzoxazines is presented. The reactions
afforded various enantioenriched 3-substituted dihydro-2H-1,4-
benzoxazines with high yields (up to 98%) in moderate enantiose-
lectivities (up to 87% ee).
Trichlorosilane is an inexpensive and versatile reducing
agent and, recently, many efficient chiral Lewis bases6
have been developed to promote the enantioselective hy-
drosilylation of C=N double bonds with this reagent.5f,7,8
This mild and economical organocatalytic methodology
has become a new approach to the synthesis of chiral
nitrogen-containing compounds. During our continuing
research on asymmetric Lewis base catalyzed hydrosi-
lylation of C=N double bonds,8m–s we have been trying to
expand the substrate scope to prepare a wide variety of
valuable chiral nitrogen-containing compounds in high
yields and high enantioselectivities. Herein, we describe
the chiral Lewis base catalyzed hydrosilylation of 1,4-
benzoxazines through which various enantioenriched 3-
substituted dihydro-2H-1,4-benzoxazines were synthe-
sized with good yields and moderate enantioselectivities.
Key words: asymmetric catalysis, enantioselectivity, heterocycles,
hydrosilylation, imines
3-Substituted dihydro-2H-1,4-benzoxazines represent the
structural motif of various naturally occurring substances
possessing important biological and pharmacological
properties.1 They are also important chiral intermediates
for the synthesis of many pharmaceutical compounds. The
most famous example is levofloxacin, which is an effec-
tive antibacterial drug that contains the structure motif of
3-substituted dihydro-2H-1,4-benzoxazines.1b,c There-
fore, many efficient methodologies for the preparation of
these compounds have been developed.2–5 Besides the
synthesis of the racemates,2 preparation of enantioen-
riched 3-substituted dihydro-2H-1,4-benzoxazines has
predominantly focused on kinetic resolution3 and stoi-
chiometric synthesis.4 Until now, only a few asymmetric
catalytic versions have been reported.5 Kanai et al. em-
ployed Ir/BPPM/BiI3 to catalyze the asymmetric hydroge-
nation of a cyclic imine to generate a key intermediate for
levofloxacin in 90% ee.5a Zhou et al. reported Rh/(R,R)-
Me-Duphos complex catalyzed asymmetric hydrogena-
tion of exocyclic enamides to give 3-substituted dihydro-
2H-1,4-benzoxazines in up to 98.6% ee.5b Rueping et al.
employed chiral phosphoric acids to promote enantio-
selective transfer hydrogenation of 1,4-benzoxazines with
excellent enantioseletivities.5c,d Recently, Zhou et al.
demonstrated that dihydrophenanthridine (DHPD) could
be successfully employed as an easily regenerated
NAD(P)H model for biomimetic asymmetric hydrogena-
tion of cyclic C=N double bonds, in which 1,4-benzoxa-
zines underwent the reaction to provide 3-substituted
dihydro-2H-1,4-benzoxazines in high yields and with
good ee values.5e Malkov et al. employed a chiral Lewis
base to promote the enantioselective hydrosilylation of an
First, several chiral Lewis base organocatalysts 1a–h
(Figure 1) were tested in the hydrosilylation of 1,4-benz-
oxazine 2a in chloroform at 0 °C for 12 hours (Table 1).
Ephedrine derived catalysts 1a8s and cyclic catalyst 1b8n
exhibited very poor enantioselection in the reaction (Ta-
ble 1, entries 1 and 2). A higher enantiomeric excess was
observed with proline derived catalyst 1c8i (Table 1, entry
3). To our delight, catalysts 1d–g8r bearing bulky groups
at C4 of the pyrrolidine ring resulted in clear increases in
the ee values (Table 1, entries 4–7); O-pivaloyl catalyst 1g
Me
H
N
N
N
N
O
O
O
HO
Ph
O
1a
R
O2N
1b
N
N
Ar
Ar
O
HO
1c R = H, Ar = Ph
1d R = OTMS, Ar = Ph
1e R = OTBS, Ar = Ph
1f R = OBz, Ar = Ph
1g R = OPiv, Ar = Ph
1h R = OPiv, Ar = p-MeC6H4
SYNLETT 2012, 23, 1797–1800
Advanced online publication: 21.06.2012
DOI: 10.1055/s-0031-1290405; Art ID: ST-2012-W0296-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 1 Chiral Lewis base organocatalysts evaluated in this study

1798
Y. Jiang et al.
LETTER
Table 1 Asymmetric Hydrosilylation of Benzoxazine 4aa
delivered the best result (Table 1, entry 7). However, an
attempt to further enhance the ee value by enlarging the
size of the aryl groups in the catalyst was not successful
(Table 1, entry 8). Thus, catalyst 1g was determined to be
the optimal catalyst in this study. Subsequent screening of
the solvents revealed that tetrahydrofuran (THF) was the
most favorable solvent in the reaction (Table 1, entry 13).
Increasing the catalyst loading from 10 to 15 mol% did
not improve the enantioselection (Table 1, entry 16).
Lowering the catalyst loading to 5 mol% led to a slight re-
duction in the ee value (Table 1, entry 17). When the re-
action was conducted at –10 °C, the ee value also dropped
slightly (Table 1, entry 18). When the temperature was
raised to 25 °C, the ee value dropped significantly (Table
1, entry 19). Hence, we found it very difficult to realize
good enantioselectivity in this reaction. It was supposed
that there may be a background reaction taking place; in
order to test this theory, reactions were performed in the
absence of the catalyst and in various solvents. When the
reaction was conducted in THF, 77% of the product was
obtained after 12 hours (Table 1, entry 20). Prolonging the
reaction time to 24 hours resulted in complete conversion
of the substrate (Table 1, entry 21). The background reac-
tion was also observed to take place in toluene (Table 1,
entry 22). However, no background reaction was detected
when the reaction was performed in chloroform (Table 1,
entry 22). It was not clear why the asymmetric reaction in
chloroform did not give a better ee value than in THF and
toluene.
O
O
1
HSiCl3
12 h
Ph
N
H
Ph
N
2a
3a
Entry
Catalyst
Temp (°C) Solvent
Yield (%)b ee (%)c
1
2
1a
0
0
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
DCE
99
98
58
93
90
97
99
97
94
93
80
98
98
93
93
91
93
93
83
77
98
91
0
16
5
1b
3
1c
0
30
35
46
50
64
64
58
53
65
64
66
64
50
64
62
64
56
–
4
1d
0
5
1e
0
6
1f
0
7
1g
0
8
1h
0
9
1g
0
10
11
12
13
14
15
16
17
18
19
20
21f
22f
23f
1g
0
1g
0
toluene
o-xylene
THF
1g
0
1g
0
1g
0
PhOMe
EtOAc
THF
1g
0
With the optimized conditions in hand, we explored the
scope of the chiral Lewis base organocatalyzed hydrosi-
lylation of 3-substituted 1,4-benzoxazines 2a–m (Table
2).9,10 Generally, 3-phenyl- and 3-para-substituted phenyl
substrates (Table 2, entries 1–7) exhibited better enantio-
selectivities than 3-meta- and 3-ortho-substituted phenyl
substrates (Table 2, entries 8–11). The electronic nature of
the substituents affected the outcome to some extent. Sub-
strates bearing strong electron-withdrawing substituents
in the phenyl groups resulted in products with higher ee
values (Table 2, entries 2 and 6), whereas substrate 2k,
bearing two electron-donating substituents in the phenyl
group, gave the product with only 18% ee (Table 2, entry
11). Finally, 3-heteroaryl substrates were also employed
in this transformation. To our surprise, 3-(furan-2-yl)-2H-
benzo[b][1,4]oxazine (2l) provided a remarkably high ee
value of 87% (Table 2, entry 12). However 3-(thiophen-2-
yl)-2H-benzo[b][1,4]oxazine (2m) exhibited only moder-
ate enantioselectivity (Table 2, entry 13).
1gd
1ge
1g
0
0
THF
–10
25
0
THF
1g
THF
none
none
none
none
THF
0
THF
–
0
toluene
CHCl3
–
0
–
a Reaction conditions (0.25 mmol scale): catalyst (10 mol%), HSiCl3
(2.0 equiv), solvent (2.0 mL).
b Isolated yield based on 1,4-benzoxazine.
c The ee values were determined using chiral HPLC.
d 15 mol% of the catalyst was used in the reaction.
e 5 mol% of the catalyst was used in the reaction.
f The reactions were conducted for 24 hours.
In conclusion, we have developed an enantioselective hy-
drosilylation of 1,4-benzoxazines promoted by chiral
Lewis base organocatalysts. This transformation enables
the straightforward and mild synthesis of various chiral 3-
substituted dihydro-2H-benzoxazines with good yields
and moderate enantioselectivities.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (20972155) and National Basic Research
Program of China (973 Program) (2010CB833301).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2012, 23, 1797–1800
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Hydrosilylation of 1,4-Benzoxazines
1799
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Table 2 Asymmetric Reduction of Benzoxazine 4 with Trichloro-
silane Catalyzed by 1ga
O
O
1g (10 mol%), 0 °C
HSiCl3, THF
12 h
N
Ar
N
H
Ar
2a–m
3a–m
Entry
2
Ar
Yield (%)b ee (%)c
1
2
3
4
5
6d
7
8
9
2a
2b
2c
2d
2e
2f
Ph
98
93
88
89
95
91
97
98
98
86
94
90
93
66 (S)
75 (S)
71 (S)
70 (S)
70 (S)
76 (S)
68 (S)
63 (S)
55 (S)
31 (S)
18 (S)
87 (S)
62 (S)
p-FC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
p-BnOC6H4
m-ClC6H4
m-BrC6H4
o-ClC6H4
m,p-(MeO)2C6H3
2-furanyl
2-thienyl
2g
2h
2i
10
2j
11d
12
2k
2l
13
2m
a Reaction conditions (0.25 mmol scale): catalyst 1g (10 mol%),
HSiCl3 (2.0 equiv), THF (2.0 mL), 0 °C, 12 h.
b Isolated yield based on 1,4-benzoxazine.
c The ee values were determined using chiral HPLC; The absolute
configurations of the products were determined as S by comparison of
the optical rotations and the orders of retention times in the HPLC
with the literature data.5c,e
d THF (3 mL) was used in the reaction.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1797–1800

1800
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LETTER
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(0.025 mmol) in anhydrous THF (2 mL) at 0 °C. The mixture
was stirred at the same temperature for 12 h, then quenched
with sat. aq NaHCO3 and extracted with EtOAc. The
combined extract was washed with brine and dried over
anhydrous Na2SO4 and the solvents were evaporated.
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(10) 3-(Furan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine
(3l): Yield: 90%; light-yellow oil; 87% ee. 1H NMR (300
MHz, CDCl3): δ = 7.39 (d, J = 0.9 Hz, 1 H), 6.84–6.78 (m,
2 H), 6.72–6.65 (m, 2 H), 6.36 (dd, J = 1.8, 3.2 Hz, 1 H),
6.30 (d, J = 3.2 Hz, 1 H), 4.63–4.62 (m, 1 H), 4.43–4.38 (m,
1 H), 4.23 (dd, J = 7.0, 10.6 Hz, 1 H), 4.10 (br s, 1 H). 13
NMR (75 MHz, CDCl3): δ = 152.5, 143.4, 142.2, 132.6,
C
121.5, 119.2, 116.6, 115.6, 110.4, 106.7, 67.8, 48.3. HPLC
(OD-H column; n-hexane–2-propanol, 80:20; flow rate = 1.0
mL/min): tR = 8.08 (minor), 9.12 (major) min; [α]D20 +32.6
(c = 0.4, CHCl3). HRMS (ESI): m/z [M + H]+ calcd. for
C12H11NO2 + H+: 202.0863; found: 202.0865.
(9) Enantioselective Hydrosilylation of Benzoxazine;
General Procedure: Trichlorosilane (51 μL, 0.5 mmol, 2.0
equiv) dissolved in THF (0.15 mL) was added to a stirred
solution of 1,4-benzoxazine 2 (0.25 mmol) and catalyst
Synlett 2012, 23, 1797–1800
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