Enantioselective tandem reaction of chromone-derived Morita-Baylis-Hillman carbonates with benzylamines catalyzed by a trifunctional organocatalyst: The synthesis of chiral 3-aminomethylene-flavanones

Article abstract of DOI:10.1039/c3cc41011k

An enantioselective tandem reaction of chromones-derived MBH carbonates (1) with benzylamines (2) catalyzed by a trifunctional organocatalyst, cinchonidine-amide-thiourea, has been developed in moderate to good yields (50-87%) and enantioselectivities (up to 89% ee). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41011k

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Enantioselective tandem reaction of chromone-derived
Morita–Baylis–Hillman carbonates with benzylamines
catalyzed by a trifunctional organocatalyst: the
synthesis of chiral 3-aminomethylene-flavanones†
Cite this: Chem. Commun., 2013,
49, 3697
Received 6th February 2013,
Accepted 11th March 2013
Neng-jun Zhong,ab Li Liu,*a Dong Wanga and Yong-Jun Chen*a
DOI: 10.1039/c3cc41011k
www.rsc.org/chemcomm
An enantioselective tandem reaction of chromones-derived MBH
carbonates (1) with benzylamines (2) catalyzed by a trifunctional
organocatalyst, cinchonidine–amide–thiourea, has been developed
in moderate to good yields (50–87%) and enantioselectivities
(up to 89% ee).
The structural moiety of benzodihydropyranone (chromanone) is
a common heterocyclic framework existing in numerous natural
compounds and pharmaceutical molecules.1 Among these com-
pounds, flavanone (2-phenyl-benzodihydropyran-4-one) and its
derivatives show excellent biological activities such as being
nonsteroidal, aromatase inhibition and exhibiting antimicrobial
Scheme 1 The reaction of chromone-derived MBH adducts with amines.
effects.2 Several 3-aminomethylene-flavanones with biological been developed extensively.3 Correspondingly, the synthesis of the
activities are shown in Fig. 1. To search a novel compound with chiral flavanones has also gained great progress.4
biological and pharmaceutical activities, it is desirable and neces-
Very recently, we reported In(III)-catalyzed reactions of
sary to enhance the diversity of flavanones. In the last decades, chromone-derived Morita–Baylis–Hillman (MBH) adducts with
synthetic methods to construct the flavanone structural unit have amines via tandem allylic amination/ring-opening/oxa-Michael
addition reactions in a one pot process, affording the products,
3-aminomethylene-flavanones (Scheme 1).5 It was noteworthy
that only one chiral center at the C2-position was newly formed
in the course of the tandem reactions. The configuration of the
chiral center depends on the stereochemistry of the intra-
molecular oxa-Michael addition to a,b-unsaturated imine. In
order to access chiral flavanone derivatives by this one-pot
synthetic protocol a chiral In(III)-catalyst was employed in the
same tandem reaction. When (R,R)-Ph-BOX/In(OTf)3 was used
as a chiral Lewis acid catalyst, the desired product was obtained
in a yield of 72%, but as a racemic mixture, unfortunately.
Fig. 1 3-Aminomethylene-flavanone.
In view of the process of the tandem reaction, a multifunctional
catalyst, which could activate the MBH adduct in the allylamina-
tion, as well as the generated intermediate bearing phenol unit
and a,b-unsaturated imine moieties, and provide excellent stereo-
chemical control in the subsequent asymmetric intramolecular
oxa-Michael addition, was required. Probably, the use of the
organocatalyst with bifunctions could meet the multiple demands.6
Moreover, recently, the organocatalytic tandem reaction has
emerged as a powerful tool in organic synthesis.7 For asymmetric
oxa-Michael addition, which offered a powerful and efficient tool
a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy
of Sciences, Beijing 100190, China. E-mail: lliu@iccas.ac.cn;
Fax: +86 10 6255 4449; Tel: +86 10 6255 4614
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and chiral chromatographic analysis for all new
compounds. CCDC 915036. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc41011k
c
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cinchonidine-derived thiourea catalyst 4 (20 mol%) was carried
out in toluene for 60 h at 40 1C to afford the product 3a in a yield
of 30% with enantioselectivity of 32% ee (Fig. 2 and Table 1,
entry 1). When 2a was changed to 2b (Ar = 1-naphthyl), the yield of
the product 3b increased to 72%, but the ee value was only 34%
(entry 2). For the catalyst 4, the yield and enantioselectivity of the
reaction of 1b (R = Boc) with 2b only had a marginal improvement
(entry 3). Next, the pseudoenantiomer of 4, cinchonine-derived
thiourea 5, was employed as a catalyst in the reaction of 1b with
2b, giving the product with the opposite ee value of À23%
(entry 4). When quinine-derived thiourea catalyst 6 was employed
the results obtained with entry 5 are similar to that from the
catalyst 4. Obviously, although simple cinchona alkaloid-based
thiourea could catalyze the tandem reaction, it was not applicable
to the asymmetric intramolecular oxa-Michael addition of the
generated intermediate bearing the a,b-unsaturated imine unit.
The stronger hydrogen bond interaction between the catalyst and
the intermediate at multi points was desired. On the other hand,
for the thiourea-type organocatalyst derived from chiral diamine 7,
poor asymmetric induction (7% ee) was observed (entry 6). As
suggested by Zhu and Lu,12 trifunctional catalysts containing
primary amino acid units were more favorable for the asymmetric
conjugate addition than the bifunctional thiourea catalyst. The
trifunctional catalyst interacted with both electro- and nucleo-
philes simultaneously through the formation of a multiple hydro-
gen bond in a cooperative manner. According to the method
described in ref. 12, various trifunctional catalysts, cinchonidine–
amide–thioureas (8a–d and 9), were prepared and employed in the
reaction of 1b with 2b. The results in Table 1 (entries 7–13)
indicate that the amide unit played an important role in govern-
ing the enantioselectivity of the tandem reaction. To our delight,
when the trifunctional catalyst 8b was used, the enantioselectivity
of the product 3b was increased to 77% ee, but the yield was only
42% (entry 7). It was found that the close system was turbid
during the reaction time. When the reaction tube was not sealed,
exposed to air, the system became very clear and the yield was
increased to 71% (entry 8). Upon changing the ratio of 1b/2b to
2 : 1, the ee value increases slightly up to 79% (entry 9). The results
on solvent effect (in ESI†) revealed that toluene was the best choice.
The best results (75% yield and 82% ee) were obtained by the use of
the catalyst 8d (20 mol%) under the conditions: in an open tube
with toluene at 40 1C for 60 h (entry 12).
Fig. 2 Organocatalysts for screening.
for the synthesis of chiral heterocycles and natural products,8 its
organocatalytic version has attracted considerable attention. The
Michael acceptor such as a,b-unsaturated carbonyl compounds
were activated by organoamine catalysts, diarylprolinolsilyl ether
mostly, through iminium ion activation mode.9 Some oxa-
Michael addition reactions, including intramolecular conjugate
addition of a phenol to an unsaturated ketone,10a the hydroxyla-
tion of nitroalkenes10b and intramolecular conjugate addition
with borononate,10c could be catalyzed by cinchona alkaloid-
based thiourea through hydrogen bond activation mode,11 pro-
viding good to high enantioselectivities.10 However, to the best of
our knowledge, it has not been reported that a,b-unsaturated
imine as a Michael acceptor was activated by the hydrogen bond
interaction in the asymmetric oxa-Michael addition reaction.
Herein we describe the enantioselective tandem reaction of
chromone-derived MBH carbonates with benzylamines cata-
lyzed by chinconidine–amide–thiourea for the synthesis of
chiral 3-aminomethylene-flavanones in moderate to good yields
with good enantioselectivities.
Initially, the reaction of chromone-derived MBH acetate 1a
(R
= Ac) with benzylamine 2a in the presence of the
Table 1 The reaction of MBH carbonates (1a and b) with amines (2a and b)a
Entry
MBH carbonate
Amine
Catalystb
Yieldc (%)
eed (%)
Under the optimized reaction conditions, the substrate scope of
MBH carbonates and benzylamines was examined (Table 2).
The MBH carbonates, the substituent (R2) with either an electron-
withdrawing (1c–f) or electron-donating group (1h) at the ortho
position of the phenyl ring can react smoothly with 2b in moderate
to excellent yields with good enantioselectivities (entries 2–5 and 7).
Notably, the high enantioselectivities (89% and 80% ee) were
obtained when R2 was o-biphenyl (1g) or p-biphenyl (1i) (entries 6
and 8), which are important structural units present in a number of
natural and artificial compounds with bioactivity. Moreover,
the MBH carbonates 1j (R1 = F) and 1k (R1 = CH3) also gave products
3j and 3k, respectively, in good yields and enantioselectivities
(entries 10 and 11). If the R2 group was changed from phenyl (1b)
to 1-naphthyl (1l) the yield of the product was increased to 87% and
1
2
3
4
5
6
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
4
4
4
5
6
7
8b
8b
8b
8a
8c
8d
9
30
72
74
70
72
42
42
71
75
81
72
75
63
32
34
36
–23
36
–7
77
77
79
43
7
8e
9e,f
10e,f
11e,f
12e,f
13e,f
79
82
–58
a
Reaction conditions: 1a, 1b (0.1 mmol), 2a, 2b (0.2 mmol), solvent
b
c
d
(1 mL), 40 1C. Catalyst loading: 20 mol%. Isolated yield. Determined
by chiral HPLC analysis. Open system. 1b (0.2 mmol), 2b (0.1 mmol).
e
f
c
3698 Chem. Commun., 2013, 49, 3697--3699
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Table 2 Asymmetric organocatalytic reaction of 1b–l with 2a–g a
with benzylamines, via allylic amination/ring-opening/oxa-Michael
addition, was developed. The protocol provided an efficient and
convenient method for the synthesis of chiral 3-aminomethylene-
flavonones. The use of a trifunctional catalyst, cinchona alkaloid–
amide–thiourea, enforced the interactions between the catalyst
and the Michael acceptor through multiple hydrogen bonds,
leading to a high enantioselectivity of the intramolecular oxa-
Michael addition with a,b-unsaturated imine.
MBH carbonate
Yieldb eec
Product (%)
Entry (R1, R2)
Amine (Ar)
(%)
1
1b (H, Ph)
2b, (1-naphthyl) 3b
75
64
65
64
80
84
72
78
61
60
87
60
50
70
75
66
80
82
86
84
79
85
89
89
80
82
77
85
76
84
80
65
80
71
We thank the National Natural Science Foundation of
China, Ministry of Science and Technology (no.
2011CB808600 and 2010CB833305) and the Chinese Academy
of Sciences for the financial support.
2d
3d
4
1c (H, 2-BrPh)
1d (H, 2-ClPh)
1e (H, 2-FPh)
1f (H, 2-CF3Ph)
1g (H, 2-PhPh)
1h (H, 2-CH3Ph)
1i (H, 4-PhPh)
1j (F, Ph)
2b
2b
2b
2b
2b
2b
2b
2b
2b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
5
6
7
8
Notes and references
9
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10
11
12
13
14
15
16
17
1k (CH3, Ph)
1l (H, 1-naphthyl) 2b
1h
1h
1h
1h
1h
1h
2a (Ph)
2c (2-naphthyl)
2d (2-ClPh)
2e (2-CH3Ph)
2f (4-ClPh)
2g (4-CH3Ph)
3m
3n
3o
3p
3q
3r
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), toluene (1 mL), 8d
b
c
(20 mol%), 40 1C, open system, 60 h. Isolated yields. Determined by
chiral HPLC analysis. At 50 1C.
d
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Fig. 3 Proposed intermediate and transition state.
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the catalyst 8d proceeded smoothly, providing good yields (50–80%)
with 65–84% ee (entries 12–17).
¨
S. Brase, Chem. Soc. Rev., 2012, 41, 988.
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The molecular structure of the tandem reaction product 3c was
further confirmed by X-ray crystallographic analysis,13 by which
the absolute configuration of newly created chiral centers at the
C2 position was deduced as R and the configuration of the double
bond at the C3 position as Z. On the basis of these observations,
the intermediate and transition states of the tandem reaction
were proposed. In the first step, amines (ArCH2NH2) attack the
MBH carbonate activated by the thiourea-type catalyst (8d) 10 (a) M. M. Biddle, M. Lin and K. A. Scheidt, J. Am. Chem. Soc., 2007,
´
129, 3830; (b) P. Diner, M. Nielsen, S. Bertelsen, B. Niess and
through the formation of hydrogen bonds to generate the inter-
mediate A (Fig. 3). Then followed by an oxa-Michael addition in
which the multiple hydrogen bonds were formed between the
trifunctional catalyst and the intermediate A to realize rate-
enhancement and the optimal stereochemical control, the phenol
group attacks the double bond of the a,b-unsaturated imine
moiety in the intermediate A from the Si face of the double bond.
In conclusion, an organocatalytic enantioselective tandem reac-
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X. Han and Y. X. Lu, Adv. Synth. Catal., 2011, 353, 2971.
11 The chiral phosphoric acid-catalyzed oxa-Michael addition through
hydrogen bond activation mode, see: (a) Q. Gu, Z. Q. Rong, C. Zheng
and S. L. You, J. Am. Chem. Soc., 2010, 132, 4056; (b) Z. Feng,
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12 Q. Zhu and Y. X. Lu, Angew. Chem., Int. Ed., 2010, 49, 7753.
tion of the chromone-derived Morita–Baylis–Hillman carbonates 13 CCDC 915036.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 3697--3699 3699