Direct organocatalytic asymmetric mannich addition of 3-substituted-2H-1,4- benzoxazines: Access to tetrasubstituted carbon stereocenters

Article abstract of DOI:10.1002/adsc.201300654

3-Substituted-2H-1,4-benzoxazines undergo a highly enantioselective direct Mannich reaction with acetone in the presence of an L-proline catalyst at room temperature. The corresponding N-heterocycles with α-tetrasubstituted carbon stereocenters were obtai

Full text of DOI:10.1002/adsc.201300654

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DOI: 10.1002/adsc.201300654
Direct Organocatalytic Asymmetric Mannich Addition of
3-Substituted-2H-1,4-Benzoxazines: Access to Tetrasubstituted
Carbon Stereocenters
You-Qing Wang,a,* Yongna Zhang,b Kun Pan,a Junxiong You,a and Jin Zhaoa
a
Provincial Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, Henan 475004,
Peopleꢀs Republic of China
Fax : (+86)-378-286-4665; e-mail: wyouqing@hotmail.com or wyouqing@foxmail.com
Basic Experiment Teaching Center, Henan University, Kaifeng, Henan 475004, Peopleꢀs Republic of China
b
Received: July 25, 2013; Revised: September 9, 2013; Published online: November 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300654.
Abstract: 3-Substituted-2H-1,4-benzoxazines under-
go a highly enantioselective direct Mannich reac-
tion with acetone in the presence of an l-proline
catalyst at room temperature. The corresponding
N-heterocycles with a-tetrasubstituted carbon ste-
reocenters were obtained in good yields (48–92%)
and excellent enantioselectivity (up to >99% ee).
Furthermore, a novel modification involving the
diastereoselective reduction of the Mannich adduct
was carried out leading to the formation of a 1,3-
amino alcohol with a chiral tetrasubstituted carbon
stereocenter in high yield.
of aldimines produced in situ from aldehydes and
amines.[4] Over the last decade, the organocatalytic
direct asymmetric Mannich reaction involving un-
modified carbonyl compounds as nucleophile sources
has become an area of active interest.[4] Excellent re-
sults with a variety of aldimines or their equivalents
have been reported thereby.[4,5] Obviously, the Man-
nich adducts will be very important b-aminocarbonyl
compounds bearing tetrasubstituted carbon stereocen-
ters while ketimines were employed as electrophilic
acceptors. However, unlike aldimines, a few successful
examples have been appeared describing the catalytic
asymmetric Mannich reaction of ketimines. In 2003,
Jørgensenꢀs group reported the first highly enantiose-
lective Mannich reaction of a-ketimino esters anch-
ored to the aryloxy formyl groups on the nitrogen
atom with various silylketene acetals in the presence
of a Zn Lewis acid catalyst, thus providing a direct
access to optically active tetrasubstituted a-amino
acid derivatives.[6a] Subsequently, the same activated
Keywords: asymmetric catalysis; Mannich reaction;
nitrogen heterocycles; organocatalysis; tetrasubsti-
tuted carbon stereocenters
Catalytic enantioselective nucleophilic 1,2-additions ketimines were also employed for the organocatalytic
to imines is one of the most efficient synthetic tools enantioselective Mannich reaction of unmodified al-
for obtaining
a
wide range of optically active dehydes.[6b] The proline-catalyzed asymmetric Man-
amines.[1] The asymmetric addition to ketimines lead- nich reaction of aryl trifluoromethyl ketimines was re-
ing to the formation of chiral amines bearing an a-tet- ported by Vovk et al.,[7a] and while only one example
rasubstituted carbon stereocenter has rarely been ex- of an aryl trifluoromethyl ketimine was described by
plored compared to the corresponding aldimines, due Nakamura and co-workers.[7b] A diamine-Brønsted
to their lower electrophilicity and issues related to acid-catalyzed asymmetric Mannich reaction of the
steroselectivity.[1,2] Therefore, the search for a catalytic cyclic trifluoromethyl N-acylketimine was described,
enantioselective addition to ketimines[2] continues in which a trifluoromethyldihydroquinazoline with
with the goal of increasing the diversity of possible a tetrasubstituted carbon stereocenter was formed.[8]
substrates and reaction types.
An asymmetric Mannich addition of five-membered
The Mannich-type reaction[3] is an example in or- C-acylketimines was successfully carried out to afford
ganic synthesis of an addition to C=N intermediates the corresponding products catalyzed by proline with
by a variety of nucleophiles such as enolized carbonyl moderate to excellent region- and enantioselectivi-
compounds, resulting in new C C bond formation ad- ties.[9] Recently, the ketimines activated by two differ-
jacent to the nitrogen atom. In 2000, List reported the ent ester groups were used in highly enantioselective
first proline-catalyzed asymmetric Mannich reaction Mannich reactions of aldehydes with secondary amine
À
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Table 1. Optimization of the conditions for the Mannich reaction of imine 1a and acetone.[a]
Entry
Catalyst
Solvent
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
l-proline
l-proline
l-proline
l-proline
l-proline
l-prolinamide
l-proline methyl ester
C-1
C-2
C-3
C-4
C-5
l-valine
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline
DMSO
DMF
–
–
–
–
–
–
–
–
–
–
–
–
75
58
9
21
32
28
78
34
NR
78
NR
NR
trace
73
75
25
76
79
97
95
94
95
27
85
75
97
N/A
87
N/A
N/A
N/A
97
95
97
86
96
CH3CN
acetone
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11
12
13
14
15
16
17
18
19
20
21[e]
22[f]
–
3ꢂ MS[d]
4ꢂ MS[d]
5ꢂ MS[d]
50 mol% CH3CO2H
1.0 equiv. H2O
5.0 equiv. H2O
10.0 equiv. H2O
55.5 equiv. H2O
–
77
72
NR
37
96
97
-
31
[a]
Unless otherwise specified, all reactions were carried out at room temperature with imine 1a (0.1 mmol), acetone
(1.0 mmol), and catalysts (0.03 mmol, 30 mol%) in the solvent (0.2 mL) for 5 days.
Isolated yield.
Determined by HPLC using a chiral column.
20.0 mg molecular sieves were added.
0.1 mL DMSO and 0.1 mL H2O were used.
In an oil bath at 508C.
[b]
[c]
[d]
[e]
[f]
organocatalysts.[10] More recently, activated oxindole zines and acetone to afford N-heterocycles with tetra-
imines (isatin imines) were used as Mannich acceptors substituted carbon stereocenters.
to construct 3-aminooxindole derivatives with excel-
Based on our previous research on the phosphine-
lent enantioselectivity.[11] However, all the aforemen- catalyzed [3+2]cycloaddition of allenoate and cyclic
tioned ketimines are activated by incorporating elec- imines to afford the sulfamidate N-heterocycles,[14] we
tron-withdrawing groups (carbonyl or trifluorometh- continue to explore the Mannich addition of cyclic
yl). Therefore, unactivated ketimines still remain as imines. However, the use of cyclic imines as acceptors
unexplored substrates for the direct catalytic enantio- in the Mannich reaction has rarely been studied while
selective Mannich reaction.[12] Moreover, the develop- much attention has been given to the corresponding
ment of an efficient Mannich reaction of unactivated acyclic imines.[6,8–10,15–16] Moreover, the cyclic imines
imines is still challenging and is in great demand as would be more efficient alternative acceptors com-
interest in the asymmetric synthesis of chiral mole- pared to the acyclic imines because the induced ring-
cules continues to grow.[13] Herein, we disclose the strain increases the reactivity towards nucleophiles,
highly enantioselective organocatalytic direct Man- and also rotational freedom is minimized by blocking
nich reactions between 3-substituted-2H-1,4-benzoxa- E/Z isomerization of C=N bond.
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Direct Organocatalytic Asymmetric Mannich Addition of 3-Substituted-2H-1,4-Benzoxazines
In an initial experiment, the reaction of 3-phenyl- forded the normal 1,2-addition Mannich product with
2H-1,4-benzoxazine 1a[17] and acetone was carried out significantly decreased enantioselectivity (entry 10).[19]
at room temperature using l-proline as a catalyst in
To further explore the scope of imines, the effect of
dry DMSO. The progress of the reaction was moni- a variety of substituents at different positions on the
tored by TLC. One major new spot was observed benzo-fused ring was investigated. As shown in
along with a small amount unreacted imine 1a. The Scheme 1, the corresponding Mannich products 4 with
desired Mannich addition product could be isolated in tetrasubstituted carbon stereocenters were obtained
75% yield with 97% ee in five days (Table 1, entry 1). in 48–88% yields and excellent enantioselectivities
The effect of different solvents was investigated (en- (87 to >99% ee). This indicates that the para-sub-
tries 1–5). The best result considering reactivity and stituents on the oxygen atom of the 2H-1,4-benzoxa-
enantioselectivity was obtained in DMSO. Different zine backbone exhibit some influence on the enantio-
chiral amino acids and their derivatives were em- selectivity, resulting in reduced enantioselectivities for
ployed as the organocatalysts to test the efficiency of Cl and F substituents (4c and 4d). It seems that the
this reaction (entries 1, 6–13). Cyclic amino acids para-substituents on the nitrogen atom of 2H-1,4-ben-
proved to be more effective in enhancing the reactivi- zoxazine backbone exhibit a major influence only on
ty and enantioselectivity. Only five-membered proline the yield (4e and 4f).[20]
and four-membered azetidine gave good yields. The
The typical transformation of Mannich product 2a
effect of additives was also studied (entries 14–21). In- was carried out, and the results are illustrated in
terestingly, in contrast to Ohsawaꢀs report[15a] on the Scheme 2. The carbonyl group of 2a was smoothly re-
Mannich reaction of cyclic aldimines, water had no duced to a hydroxy group using NaBH4, as the reduc-
apparent effect on this reaction (entries 18 and 20). ing reagent, in THF leading to the formation of 1,3-
However, the reaction failed in the presence of excess amino alcohol 5. The single diastereoselective product
water because of the insolubility of imine 1a in the re-
action mixture (entry 21). Moreover, the yield and
enantioselectivity decreased significantly when the
Table 3. Scope of the Mannich reaction.[a]
temperature was increased to 508C (entry 22).
The course of the Mannich reaction with respect to
the conversion and enantioselectivity was studied
with time (Table 2). Aliquots from the reaction mix-
ture were analyzed by HPLC at several intervals. The
maximum conversion reached in about two days using
proline (10 mol%) as the catalyst. A further increase
in time and catalyst loadings[18] did not improve the
yield. The enantioselectivity slightly gradually de-
creased with time.
Next, the scope of the reaction was explored with
respect to the substrate having different substituents
(R of 1) attached to the electrophilic carbon, as listed
in Table 3. Under the optimized reaction conditions,
the Mannich adducts 2 with a variety of aryl substitu-
ents at different positions on the aromatic ring, could
be readily obtained with excellent enantioselectivity
except for 4-methyl-substituted imine 1f (entry 5), for
which a slightly lower ee of 86% was obtained. Nota-
bly, the high 98% ee and 70% yield were also ob-
served for imine 1j containing a naphthyl group
(entry 9). 4-Chlorostyryl substituted imine 1k[17b] af-
Entry R of 1
Time
[h]
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
9
4-FC6H4 (1b)
48
72
72
72
48
72
60
72
72
82
91
78
56
71
92
94
78
70
>99
>99
98
97
86
4-NO2C6H4 (1c)
4-ClC6H4 (1d)
4-PhC6H4 (1e)
4-MeC6H4 (1f)
3-ClC6H4 (1g)
3-BrC6H4 (1h)
3,4-Cl2C6H3 (1i)
2-naphthyl (1j)
98
>99
>99
98
10
72
61
61
[a]
Reaction conditions: imine
1
(0.2 mmol), acetone
(2.0 mmol), proline (0.02 mmol, 10 mol%), and dry
DMSO (0.4 mL).
Isolated yield.
[b]
[c]
Determined by HPLC using a chiral column.
Table 2. Mannich reaction of imine 1a with acetone.[a]
Time [h]
3
6
12
48
72
120
Conv.[b] [%]
12
27
50
72
69
68
ee [%]
98.7
98.4
98.0
97.4
97.1
96.5
[a]
Reaction conditions: imine 1a (0.2 mmol), acetone (2.0 mmol), l-proline (0.02 mmol, 10 mol%), and DMSO (0.4 mL) at
room temperature.
Calculated by HPLC analysis in 254 nm for the aliquots.
[b]
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Scheme 1. Effect of a variety of substituents at different positions on the benzo-fused ring.
In conclusion, we have described the highly enan-
tioselective direct Mannich addition to 3-substituted-
2H-1,4-benzoxazines using l-proline as the organoca-
talyst. This also represents the first demonstration of
a catalytic asymmetric Mannich reaction to synthesize
3,4-dihydro-2H-1,4-benzoxazines, N-heterocycles with
tetrasubstituted carbon stereocenters. Further studies
Scheme 2. Transformation of product 2a.
5 was easily isolated in 91% yield by column chroma- on the reactions of ketimines with other nucleophiles
tography on silica gel, without any decrease in the op- are in progress.[22] The ring opening reactions of the
tical purity as determined by HPLC analysis. Both the 3,4-dihydro-2H-1,4-benzoxazines to the corresponding
newly formed carbon stereocenters, one attached to chiral amines with a-tetrasubstituted carbon stereo-
a hydroxy group and the other in an adjacent tetra- centers will also be investigated.
substituted carbon stereocenter, had the S-configura-
tion.
The relative and absolute configurations of com-
Experimental Section
pound 5 were established by an X-ray diffraction
study of its O-4-chlorobenzoyl ester 6 (Figure 1).[21]
Typical Procedure for the Mannich Reaction
The stereochemistry of the adduct 2a was assigned as
To the mixture of ketimine (0.2 mmol) and l-proline
being of the S-configuration. The absolute configura-
(10 mol%, 0.02 mmol) in DMSO (0.4 mL) was added ace-
tions of the other Mannich adducts were assigned by
tone (2 mmol) by a micro syringe. This reaction mixture was
analogy (Table 3 and Scheme 1). This indicates that
stirred at room temperature for the stated reaction time.
the cyclic ketimine is attacked on the re-face by the
carbon nucleophile of an active enamine obtained
from acetone in this Mannich addition.
Direct purification of the reaction mixture by chromatogra-
phy on a silica gel column (petroleum ether/EtOAc: 20/1 to
10/1) gave the desired Mannich adducts. The enantiomeric
Figure 1. X-ray structure of O-4-chlorobenzoyl derivative 6.
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Direct Organocatalytic Asymmetric Mannich Addition of 3-Substituted-2H-1,4-Benzoxazines
excess was determined by HPLC. Racemic Mannich adducts
were obtained under catalysis with racemic proline.
[10] T. Kano, S. Song, Y. Kubota, K. Maruoka, Angew.
Chem. 2012, 124, 1217–1220; Angew. Chem. Int. Ed.
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[11] a) X. Chen, H. Chen, X. Ji, H. Jiang, Z.-J. Yao, H. Liu,
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Liu, X.-C. Li, L.-Z. Zhong, Y.-G. Peng, J. Org. Chem.
2012, 77, 3589–3594.
Work-Up for HPLC Analysis (Table 2)
An aliquot (1–2 drops) of the reaction mixture was filtered
through a small silica gel column (petroleum ether/EtOAc:
4/1). After evaporation of the solvents, the residue was re-
dissolved in isopropyl alcohol and subjected to HPLC analy-
sis.
[12] Asymmetric Mannich reactions of ketimines with tran-
sition metal catalysts, see: a) Y. Suto, M. Kanai, M. Shi-
basaki, J. Am. Chem. Soc. 2007, 129, 500–501; b) R.
Yazaki, T. Nitabaru, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2008, 130, 14477–14479; c) Y. Du, L.-W.
Xu, Y. Shimizu, K. Oisaki, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2008, 130, 16146–16147; d) L. C. Wie-
land, E. M. Vieira, M. L. Snapper, A. H. Hoveyda, J.
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Acknowledgements
This project is financially supported by the National Natural
Science Foundation of China (No. 21002022), Chinese Minis-
try of Education (the Scientific Research Foundation for the
Returned Overseas Chinese Scholars), and the postdoctoral
science foundation supports of Henan province in China. We
thank Professor Yong-Gui Zhou (DICP, CAS, China) for
a gift of imines 1.
[13] E. Gꢃmez-Bengoa, J. Jimꢅnez, I. Lapuerta, A. Mielgo,
M. Oiarbide, I. Otazo, I. Velilla, S. Vera, C. Palomo,
Chem. Sci. 2012, 3, 2949–2957.
[14] Y.-Q. Wang, Y. Zhang, H. Dong, J. Zhang, J. Zhao,
Eur. J. Org. Chem. 2013, 3764–3770.
[15] For asymmetric direct Mannich reactions of cyclic aldi-
mines and ketones catalyzed by proline, see: a) T. Itoh,
M. Yokoya, K. Miyauchi, K. Nagata, A. Ohsawa, Org.
Lett. 2003, 5, 4301–4304; b) B. T. Hahn, R. Frçhlich, K.
Harms, F. Glorius, Angew. Chem. 2008, 120, 10134–
10137; Angew. Chem. Int. Ed. 2008, 47, 9985–9988;
c) K. Schulz, L. Ratjen, J. Martens, Tetrahedron 2011,
67, 546–553; d) M. R. Monaco, P. Renzi, D. M. S. Schie-
troma, M. Bella, Org. Lett. 2011, 13, 4546–4549; e) D.-J.
Cheng, S.-K. Tian, Adv. Synth. Catal. 2013, 355, 1715–
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[16] For related reactions of cyclic aldimines and methyl
vinyl ketones, see: a) T. Itoh, M. Yokoya, K. Miyauchi,
K. Nagata, A. Ohsawa, Org. Lett. 2006, 8, 1533–1535;
b) K. Nagata, H. Ishikawa, A. Tanaka, M. Miyazaki, T.
Kanemitsu, T. Itoh, Heterocycles 2010, 81, 1791–1798;
c) M. P. Lalonde, M. A. McGowan, N. S. Rajapaksa,
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E. N. Jacobsen, Org. Lett. 2013, 15, 706–709.
[17] The cyclic ketimines, 2H-1,4-benzoxazines, were used
as the substrates of a catalytic asymmetric reduction,
see: a) M. Rueping, A. P. Antonchick, T. Theissmann,
Angew. Chem. 2006, 118, 6903–6907; Angew. Chem. Int.
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[18] Similar results (65% conversion in 24 h, 70% conver-
sion in 48 h) were also observed in the presence of
30 mol% proline.
[19] The ketimines containing other saturated alkyl substitu-
ents (such as, R=Me, t-Bu) were unstable, and decom-
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tion.
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You-Qing Wang et al.
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[20] The Mannich reaction was also conducted between 3-
phenyl-1,2-dihydroquinoxaline and acetone under the
optimized reaction conditions, but no desired Mannich
product was observed after two days and major product
was 2-phenylquinoxaline. See the Supporting Informa-
tion for details.
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[22] Other ketones such as 2-butanone and cyclohexanone
were also tested, however, much lower reactivities were
observed.
[21] The compound 6 was obtained on the treatment of al-
cohol 5 and 4-chlorobenzoyl chloride in pyridine, and
a single crystal could be grown from its solution in di-
chloromethane and hexane. See the Supporting Infor-
mation for more experimental details. CCDC 951533
contains the supplementary crystallographic data for
this paper (compound 6). These data can be obtained
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