Diastereo-and enantioselective synthesis of oxazine and oxazolidine derivatives with a chiral quaternary carbon center under multifunctional catalysis

Article abstract of DOI:10.1021/ol102643a

An easy one-pot, multistep cascade reaction which could afford a series of substituted benzo[d]pyrido[2,1-b]oxazolidine and [1,3]oxazine derivatives in a highly enantio-(up to 98% ee) and diastereoselective (4:1 to >20:1 dr) manner with generally good to excellent yields (up to 99%) has been developed. This well designed strategy could be applied to a wide scope of substrates under mild conditions with simple operations.

Full text of DOI:10.1021/ol102643a

ORGANIC
LETTERS
2011
Vol. 13, No. 4
564–567
Diastereo- and Enantioselective Synthesis
of Oxazine and Oxazolidine Derivatives
with a Chiral Quaternary Carbon Center
under Multifunctional Catalysis
Zhichao Jin, Xiao Wang, Huicai Huang, Xinmiao Liang, and Jinxing Ye*
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
Education, School of Pharmacy, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
yejx@ecust.edu.cn
Received November 8, 2010
ABSTRACT
An easy one-pot, multistep cascade reaction which could afford a series of substituted benzo[d]pyrido[2,1-b]oxazolidine and [1,3]oxazine
derivatives in a highly enantio- (up to 98% ee) and diastereoselective (4:1 to >20:1 dr) manner with generally good to excellent yields (up to 99%)
has been developed. This well designed strategy could be applied to a wide scope of substrates under mild conditions with simple operations.
Nitrogen-containing multiple cycles have been consid-
ered as one of the most important fragments for drug
discovery, and their synthesis has attracted more atten-
tion.1 Among those compounds, the construction of oxa-
zines and oxazolidines containing both a nitrogen and an
oxygen atom is representative of some of the interesting
endeavors. Various methodologies have been developed
with the purpose of preparing these molecules efficiently.2
For example, an efficient one-pot gold-catalyzed cascade
reaction was developed to synthesize a series of pyrrolo/
pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido [2,1-a]-
quinazolinones.3 Eycken et al. reported the preparation of
different pyridopyridazines and quinolines through a sol-
vent-free procedure.4 However, both of the studies did not
involve asymmetric induction. Therefore, the preparation
of this type of chiral heterocyclic compound, especially with
a chiral quaternary carbon center, has remained a challen-
ging task in organic synthesis.
(1) For some selected examples and reviews, see: (a) McReynolds,
M. D.; Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239.
(b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
(c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (d) Zeni, G.;
Larock, R. C. Chem. Rev. 2004, 104, 2285. (e) Yet, L. Chem. Rev. 2000,
100, 2963. (f) Clement, N. D.; Cavell, K. J. Angew. Chem., Int. Ed. 2004,
43, 3845. (g) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(h) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (i) Evano,
G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. (j) Jakopin,
Z.; Dolenc, M. S. Curr. Med. Chem. 2010, 17, 651.
Recently, the organocatalytic cascade reaction emerged
as one of the most efficient strategies for the construction of
cyclic compounds.5,6 Scientists have also succeeded in the
(3) Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang, H.; Liu,
H. J. Org. Chem. 2010, 75, 3274.
(4) Kaval, N.; Halasz-Dajka, B.; Vo-Thanh, G.; Dehaen, W.;
ꢀ
Van der Eycken, J.; Matyus, P.; Loupy, A.; Van der Eycken, E.
(2) (a) Doemling, A.; Ugi, I. K. Tetrahedron 1993, 49, 9495.
(b) Vorbrueggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353.
Tetrahedron 2005, 61, 9052.
€
(c) Zhao, D.; Jonhansson, M.; Backvall, J. Eur. J. Org. Chem. 2007,
(5) For recent reviews of organocatalysis, see: (a) Westermann, B.;
Ayaz, M.; Berkel, S. Angew. Chem., Int. Ed. 2010, 40, 846. (b) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (c) Bertelsen, S.;
Jøgensen, A. Chem. Soc. Rev. 2009, 38, 2178.
26, 4431. (d) Mitchell, M. A.; Benicewicz, B. C. Synthesis 1994, 7, 675.
(e) Meng, Q.; Liu, Q.; Li, J.; Xing, R.; Shen, X.; Zhou, B. Synlett 2009,
20, 3283.
r
10.1021/ol102643a
Published on Web 01/14/2011
2011 American Chemical Society

synthesis of fused heterocyclic compounds employing this
metal-free strategy.7-9 However, compared with the glori-
ous achievements in the cascade reactions employing
proline-derived catalysts, the cascade methodology of R,β-
unsaturated ketones catalyzed by primary amine cata-
lysts still represents a great challenge for chemists.10
We have been interested in the activation of R,β-unsatu-
rated ketones and achieved great success in the asymmetric
Michael additions of different nucleophiles to R,β-unsatu-
rated ketones under multifunctional catalysis.11 We have
also made great efforts in the exploitation of cascade
reactions from which complex compounds could be af-
forded in a highly stereoselective manner and a simple one-
pot operation. In this letter, we report a one-pot cascade
procedure for the synthesis of a series of enantio- and di-
astereoenriched oxazine and oxazolidine derivatives based
on the rational design of bifunctional nucleophiles and the
activation of vinyl ketones. Notably, a chiral quaternary
carbon center with satisfactory selectivities has been con-
structed in the final annulation step by using a simple
Brønsted acid.
Table 1. Screening of the Reaction Conditions for the First Step
of the Tandem Reactiona
The rationally designed nucleophilic reagent 1a was
selected as the Michael donor to participate in the cascade
reaction with 4-phenylbut-3-en-2-one 2a under several
different conditions to form the desired oxazolidine deriva-
tive 3a. Based on the former studies8,9 we assumed that the
enantiopurity of the final product would be dominantly
determined by the first step of the cascade procedure.
Thus the reaction conditions for the Michael addition were
first investigated to optimize the enantioselectivity of the
cascade reaction (Table 1). Poor enantioselectivity was
obtained using the diamine catalysts 5 and 6 (entries 1 to
2). Moderate stereoselectivity could be acquired using the
famous catalyst 9-amino (9-deoxy) epiquinine 7 (entry 3).
When the thiourea motif was imported, great improvement
entry
cat.
solvent
CH2Cl2
t (h)b
conv %c
ee %d
dre
1
5
48
48
89
51
30
35
-51
85
--
4:1
4:1
4:1
4:1
--
2
6
CH2Cl2
3
7
CH2Cl2
48
80
4
8a
8b
9
CH2Cl2
48
70
5
CH2Cl2
48
0
6
CH2Cl2
24
>95
>95
>95
>95
>95
>95
>95
64
86
77
91
89
91
92
94
95
94
94
4:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
9:1k
7
9
Toluene
24
8
9
1,4-dioxane
THF
24
9
9
24
10
11
12
13
14
15
9f
9g
9g
9g
9g
9g
1,4-dioxane
1,4-dioxane
1,4-dioxaneh
1,4-dioxanei
1,4-dioxanej
1,4-dioxanek
24
24
72
144
144
72
50
>95
(6) For some very recent examples, see: (a) Jiang, K.; Jia; Yin, Z. X.;
Wu, L.; Chen, Y. Org. Lett. 2010, 12, 2766. (b) Tan, B.; Zhu, D.; Zhang,
L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem.;Eur. J. 2010, 16, 3842.
(c) Li, J.; Zhou, S.; Han, B.; Wu, L.; Chen, Y. Chem. Commun. 2010, 46,
2665. (d) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027. (e) Enders, D.; Wang, C.; Mukanova, M.; Greb, A. Chem.
Commun. 2010, 46, 2447.
(7) For some selected recent examples of organocatalytic cascade
reactions, see: (a) Zhu, D.; Lu, M.; Dai, L.; Zhong, G. Angew. Chem.,
Int. Ed. 2009, 48, 6089. (b) Tan, B.; Shi, Z.; Chua, P. J.; Li, Y.; Zhong, G.
Angew. Chem., Int. Ed. 2009, 48, 758. (c) Jiang, H.; Elsner, P.; Jensen,
K. L.; Falcicchio, A.; Marcos, V.; Jøgensen, K. A. Angew. Chem., Int.
Ed. 2009, 48, 6844. (d) Cai, Q.; Zhao, Z.; You, S.-L. Angew. Chem., Int.
Ed. 2009, 48, 7428. (e) Wang, Y.; Yu, D.; Liu, Y.; Wei, H.; Luo, Y.;
Dixon, D. J.; Xu, P. Chem.;Eur. J. 2010, 16, 3922.
a Unless otherwise noticed, all reactions were carried out using 1.0
equiv of 1a (0.10 mmol), 1.5 equiv of 2a, 0.1 equiv of catalyst, 0.2 mL of
solvent, and 1.5 equiv of HBr in water (40%). b t represented the reaction
time of the first step of the tandem reaction. c The conversion of the
Michael addition which was determined by 1H NMR on the crude
reaction mixture after the certain time given. d Enantiomeric excess of 3a,
determined by chiral HPLC. e Determined by 1H NMR on the crude
reaction mixture 12 h after adding 1.5 equiv of HBr aq into the isolated
intermediate (0.25 M). f 5.0 mol % catalyst was used. g 2.0 mol % catalyst
was used. h The Michael addition was carried out at 0.2 M using 0.5 mL
i
of 1,4-dioxane. The Michael addition was carried out at 0.1 M using
1.0 mL of 1,4-dioxane. j The Michael addition was carried out at 0.067 M
using 1.5 mL of 1,4-dioxane. k The annulation step was carried out at
0.067 M using 6 mL of CH2Cl2 under 0 °C.
ꢀ
(8) (a) Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787.
ꢀ
(b) Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352, 499.
(9) Wu, X.; Dai, X.; Nie, L.; Fang, H.; Chen, J.; Ren, Z.; Cao, W.;
in the ee value was implemented using catalyst 8a, with70%
conversion within 48 h (entry 4). However, no reaction
occurred when the primary amine was protected (entry 5).
Finally, when the multifunctional catalyst 9 was employed
both the reaction rate and ee value were acceptable (entry 6).
After the screening of different solvents, 1,4-dioxane ap-
peared to be the most suitable reaction media for the
Michael addition (entry 8).12 Further optimizations of the
Zhao, G. Chem. Commun. 2010, 46, 2733.
(10) (a) Wu, L.-Y.; Bencivenni, G.; Mancinelli, M.; Mazzanti, A.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7196.
(b) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli,
F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009,
48, 7200.
(11) (a) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008,
3302. (b) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J.
Org. Lett. 2009, 11, 753. (c) Wen, S.; Li, P.; Wu, H.; Yu, F.; Liang, X.;
Ye, J. Chem. Commun. 2010, 46, 4806. (d) Zhou, Y.; Li, X.; Li, W.; Wu,
W.; Liang, X.; Ye, J. Synlett 2010, 15, 2357. (e) Huang, H.; Yu, F.; Jin,
Z.; Li, W.; Wu, W.; Liang, X.; Ye, J. Chem. Commun. 2010, 46, 5957.
(f) Yang, J.; Li, W.; Jin, Z.; Liang, X.; Ye, J. Org. Lett. 2010, 12, 5218.
(12) For more details, see Supporting Information.
Org. Lett., Vol. 13, No. 4, 2011
565

HBr produced a 4:1 diastereomeric ratio in the final step.12
With an efficient and diastereoselective annulation reaction
was in hand, we next investigated a catalytic one-pot
process without separation of the intermediates. After a
series of examinations, the dr value could be increased to
more than 9:1 when diluting the reaction mixture into 0.03 M
under 0 °C with CH2Cl2 as the solvent (entry 15).
Table 2. Scope of the Tandem Reactiona
With the best reaction conditions for both steps of the
one-pot cascade process in hand, the scope of the asym-
metric process was next examined using nucleophilic re-
agents 1a and vinyl ketones 2 (Table 2). Data showed that
this well developed strategy could be applied to a large
variety of vinyl ketones involving both aromatic and
aliphatic substituents. Most of the desired oxazine deriva-
tive products could be afforded in excellent yields with
excellent enantio- and diastereoselectivities using only
2.0 mol % of catalyst 9. Substrate generality under the
present reaction conditions was broad, covering aryl and
linear enones. Examination of substituent effects revealed
that substituted moieties did not strongly affect enantios-
electivity but slightly affected the reaction rates and the dr
values of the final products.
t1
t2 yield
ee
entry R1
R2
(d)b (d)c (%)d product (%)e drf
1
2
3
4
5
6
7
8
9
Me Ph
Me 2-FPh
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
88
85
76
95
96
89
95
91
93
88
82
77
99
78
89
89
87
82
82
64
82
83
91
97
96
3a
3b
3c
3d
3e
3f
93
97
95
95
95
92
90
93
9:1
9:1
8:1
14:1
7:1
8:1
8:1
8:1
2
Me 4-FPh
9g
3
Me 2-ClPh
Me 3-ClPh
Me 4-ClPh
Me 3-BrPh
Me 4-BrPh
Me 2-MeOPh
4
3
3
3g
3h
3i
5
2
97 >20:1
10 Me 3-MeOPh
11 Me 4-MeOPh
9g
9g
9g
7
3j
87
95
92
90
90
94
90
85
95
93
96
90
84
95
98
90
7:1
11:1
10:1
11:1
11:1
14:1
19:1
10:1
4:1
3k
3l
12 Me 2-MePh
13 Me 3-MePh
14 Me 4-MePh
15 Me 2,3-(MeO)2Ph
16 Me 2,4-(MeO)2Ph
17 Me 2-naphthyl
18 Me 2-furanyl
19 Me 2-thiophenyl
20 Me 2-NO2Ph
21 Me 3-NO2Ph
22 Me 4-NO2Ph
23 Me n-Pr
3m
3n
3o
3p
3q
3r
3s
3t
9g
3
Scheme 1. Example of the Cascade Reaction of 1a with Cyclic
Enone
3
6
5h
9g
8h
5
6:1
7:1
3u
3v
3w
3x
3y
5:1
6
4:1
5h
2h
5h
15:1
16:1
8:1
24 Me i-Bu
25 Et Me
a Unless otherwise noticed, all reactions were carried out using 1.0
equiv of 1a (0.20 mmol), 1.5 equiv of 2, 0.02 equiv of 9, 1.0 mL of 1,4-
dioxane, 6 mL of CH2Cl2, and 2.0 equiv of HBr in water (40%). b The time
needed for the first step of Michael addition, which is determined by TLC
of the disappearance of the nucleophilic reagent 1. c The time needed for
the annulation step of the tandem reaction. d Isolated yield of the product
mixture of both diastereoisomers. e Enantiomeric excess of the major
diastereoisomer, which was determined by chiral HPLC. f Determined
by 1H NMR on the product mixture. g Without full conversion of 1. h 10 mol
% of 9 was employed.
Table 3. Cascade Reactions of 1b with Different Vinyl Ketonesa
catalyst loading and the reaction concentration could
afford the oxazolidine product with up to 95% ee and only
2% of catalyst loading (entry 13).
concn temp
t
yield
ee
entry
solvent
(M)b
(°C)c (d)d (%)e
4
(%)f drg
As the optimized reaction conditions for the Michael
addition had been acquired, we next exploited the diastereo-
selectivities of the cascade procedure, which were deter-
mined completely by the annulation step initiated by a
strong acid. The effects of different solvents were first
surveyed by adding aqueous HBr into the isolated Michael
product under the same concentration as that for the first
step, which is summarized in the last column of Table 1
(entries 6-15). From these data we could see that CH2Cl2
and CHCl3 showed a sharp distinction from other solvents
and afforded the highest diastereomeric ratios of the final
products. Then different acidic additives were screened to
find the most suitable acid for the annulation step. Aqueous
1
2
3
4
5
dioxane
0.5
0.1
0.1
0.1
0.1
rt
0
2
9
9
9
9
nd
45
53
54
41
4a
4a
4b
4c
4d
65
83
80
73
82
10:1
10:1
9:1
mixtureh
mixtureh
mixtureh
mixtureh
0
0
6:1
0
7:1
a Unless otherwise noticed, all reactions were carried out using 1.0
equiv of 1b (0.20 mmol), 1.5 equiv of 2, 0.1 equiv of 9 for the first step and
6 mL of CH2Cl2, 2.0 equiv of HBr in water (40%) for the annulation step.
b The concentration of the reaction mixture for the first step was based on
1b. c The reaction temperature for the first step of the tandem reaction.
d The reaction time for the first step. e Isolated yield of both diastereomers.
f Enantiomeric excess of the major diastereoisomer, which was determined
by chiral HPLC. g Determined by 1H NMR in the product mixture. h The
mixture of dioxane/THF = 9/1.
566
Org. Lett., Vol. 13, No. 4, 2011

Moreover, this one-pot strategy could even be applied to
a cyclic vinyl ketone to afford a much more congested
multicyclic compound in a highly enantioselective manner
as a single diastereomer with a relatively unsatisfactory
yield. An example is shown in Scheme 1.
A more challenging oxazolidine derivative was selected
as the target of the cascade reaction. When using the other
nucleophilic reagent 1b, an oxazolidine derivative was
obtained with moderate stereoselectivity and yield. This
was probably attributed to the stereohindrance in the
formation of five-membered ring oxazolidine. We contin-
ued investigate optimal conditions by screening solvents
and temperature to improve the stereoselectivities in the
formationofthedesiredoxazolidineproducts. Afterseveral
screenings, those oxazolidine derivatives could be afforded
in good stereoselectivities, but in moderate yields (Table 3).
The bromide product 3h was recrystallized from CH2Cl2,
and the single crystal was subjected to X-ray analysis to
determine the absolute configuration (Figure 1).12
In summary, an efficient one-pot multistep cascade reac-
tion has been developed to afford a series of oxazine and
oxazolidine derivatives. This new process could be applied
to a wide scope of substrates in a highly enantio- and
diastereoselective manner with generally good to excellent
yields.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20902018),
the Fundamental Research Funds for the Central Univer-
sities, the Shanghai Pujiang Program (08PJ1403300), and
the Innovation Program of Shanghai Municipal Educa-
tion Commission (11ZZ56).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC
chromatograms of the products and cif file of enantiopure
3h. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. X-ray analysis of 3h.
Org. Lett., Vol. 13, No. 4, 2011
567