Asymmetric catalyzed intramolecular aza-Michael reaction mediated by quinine-derived primary amines

Article abstract of DOI:10.1016/j.cclet.2017.04.017

An intramolecular organocatalytic enantioselective aza-Michael reaction of carbamates, sulfonamides and acetamides to α,β-unsaturated ketones was developed. This process is promoted by 9-amino-9-deoxy-epi-quinine and diphenyl hydrogen phosphate to afford

Full text of DOI:10.1016/j.cclet.2017.04.017

Accepted Manuscript
Title: Asymmetric catalyzed intramolecular aza-Michael
reaction mediated by quinine-derived primary amines
Authors: Xian-Dong Zhai, Zhong-Duo Yang, Zhi Luo,
Hong-Tao Xu
PII:
S1001-8417(17)30146-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.04.017
CCLET 4053
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Chinese Chemical Letters
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Accepted date:
13-1-2017
7-4-2017
17-4-2017
Please cite this article as: Xian-Dong Zhai, Zhong-Duo Yang, Zhi
Luo, Hong-Tao Xu, Asymmetric catalyzed intramolecular aza-Michael
reaction mediated by quinine-derived primary amines, Chinese Chemical
Lettershttp://dx.doi.org/10.1016/j.cclet.2017.04.017
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Original article
Asymmetric catalyzed intramolecular aza-Michael reaction mediated by quinine-derived primary amines
Xian-Dong Zhai a, Zhong-Duo Yang a,*, Zhi Luo b, Hong-Tao Xu b
a School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
 Corresponding author.
E-mail address: yangzhongduo@126.com (Z.-D. Yang)
Graphical Abstract
An intramolecular organocatalytic enantioselective aza-Michael reaction of carbamates, sulfonamides and acetamides
to α,β-unsaturated ketones has been developed with excellent enantioselectivity and very good yield.
ABSTRACT
An intramolecular organocatalytic enantioselective aza-Michael reaction of carbamates, sulfonamides and acetamides to
α,β-unsaturated ketones was developed. This process is promoted by 9-amino-9-deoxy-epi-quinine and diphenyl
hydrogen phosphate to afford a straightforward and expeditious synthesis of several synthetically useful five- and
six-membered heterocycles with excellent enantioselectivity (92%-97.5% ee) and very good yields (up to 99%).
Keywords:
Asymmetric catalysis
Intramolecular aza-Michael reaction
Primary amine
Five- and six-membered heterocycles
Pyrrolidine and piperidine
Enantioselective organocatalytic
1. Introduction
The field of organocatalysis [1] has expanded in recent years, since the discovery of the proline-catalyzed aldol reaction [2].
During this period, an overwhelming number of novel, highly efficient organocatalysts have been reported in the literature. In
particular, chiral secondary amines are extremely powerful reagents that have dominated the field of amino catalysis [3]. However, in
spite of the tremendous success of the use of secondary amines in the asymmetric functionalization of aldehydes, only minor progress
has been achieved in the corresponding transformations of ketones, because of the inherent difficulties in generating congested
covalent intermediates between chiral secondary amines and ketones. Primary amine catalysis offers the unique possibility of
participating in processes between sterically demanding partners [4] and chiral primary amines have also been demonstrated to be
effective catalysts in a wide range of enantioselective organic reactions [5], especially for the activation of challenging substrates,
such as α,α-disubstituted aldehydes [6] and ketones [7].
β-Amino carbonyl derivatives bearing heterocyclic nitrogen atoms have become attractive targets in organic and medicinal
chemistry, as they are versatile synthetic intermediates that can be used in the preparation of a wide variety of heterocycles [8].
Among the β-amino carbonyl molecules, pyrrolidine and piperidine moieties are extremely valuable scaffolds due to their widespread
occurrence in diverse biologically active natural products and pharmaceutical agents [9], as well as their utility as chiral auxiliaries
and chiral ligands in asymmetric catalysis [10]. The aza-Michael reaction is the most direct method for selectively creating a

carbon–nitrogen bond at the β-position of an activated olefin. Despite the importance of this methodology, organocatalytic
enantioselective aza-Michael reactions remained undeveloped until very recently [11] and can thus be considered to be challenging
Moreover, most of the present work has focused on intermolecular aza-Michael reactions and only a few reports involving
enantioselective organocatalytic intramolecular reactions have been published, especially for α,β-unsaturated ketones.
As part of our continuing interest in the development of a general and highly selective methodology for an intramolecular
aza-Michael reaction (IMAMR), herein we described an operationally simple, very high enantioselective organocatalytic IMAMR for
carbamates bearing an α,β-unsaturated ketone using chiral primary amines and a weak organic acid as co-catalyst. The application of
this methodology for the synthesis of several enantiomeric five- and six-membered heterocycles was also conducted. Starting
carbamates, sulfonamides and acetamides bearing conjugated ketones 1 were easily obtained in moderate to high yields through a
cross-metathesis reaction of the corresponding unsaturated N-protected amines with vinyl ketones in the presence of
second-generation Hoveyda-Grubbs catalyst.
2. Results and discussion
In order to find the optimum conditions and catalysts for the enantioselective IMAMR, the model reaction was performed with
catalyst I (Fig. 1) and various organic acids as co-catalyst in CHCl3 for 40 h at room temperature (Table 1, entries 1-5). The results
indicated that low yields were achieved when weak acids, such as CH3COOH, 2-F-C6H4COOH and 2-NO2-C6H4COOH, were used
(Table 1, entries 1-3). A significant improvement in yield (90%) and ee (75%) was achieved when the reaction was performed in the
presence of trifluoroacetic acid, and a higher yield (95%) and ee value (89%) of 2a was observed when the slightly weaker acid, DPP
(diphenyl hydrogen phosphate), was used (Table 1, entries 4-5). Further screening showed that toluene was a suitable solvent (Table
1, entry 7). Interestingly, in contrast to a previous report [12], the use of a chiral co-catalyst, such as (S)-IV, (R)-V and (R)-VI (Fig.
1), had a negative effect on both the enantioselectivity and yield of the reactions (Table 1, entries 10-12). Furthermore, increasing the
co-catalyst loading from 15 mol% to 30 mol% resulted in a slight decrease in yield (96%) and ee (94%) (Table 1, entry 14). When a
lower temperature was used, however, there was no improvement in the final ee (81%) and yield (65%) (Table 1, entry 13). Under the
same condition, no improvement in the ee and yield was observed when catalysts II and III were used (Table 1, entries 15 and 16).
Meanwhile, the yield of 2a was decreased when the loading of catalyst I was reduced (Table 1, entries 17 and 18).
With the optimized conditions in hand, to further explore the influence of protecting groups on the enantioselectivity and yield of
the IMAMR (Table 2), substrates 1b-1e, bearing carbamates, sulfonamides, or acetamides as nitrogen-protecting groups, were
investigated. Excellent asymmetric induction and yield were observed when Cbz, Boc and Ts were used as protecting groups (Table 2,
entries 1-3). Even when substrate 1e, which has very weak nucleophilicity of the acetyl amide [12d], was tested, the IMAMR still
provided the desired product 2e with excellent yield (95%) and ee (93%). Unlike previous reports [13], our current methodology
suggested that placing a heteroatom in the α-position relative to the nitrogen-centered nucleophile (α-effect) to enhance
nucleophilicity was unnecessary. More importantly, this method allowed a highly enantioselective assembly of a stereogenic
nitrogen-containing carbon center in the functionalized 2-substituted piperidines, providing an efficient synthetic method for many
biologically active 2-substituted piperidine alkaloids [14].
Our attention was then turned to other substrates containing different heteroatoms within the alkyl chain, since the corresponding
products could be potentially valuable in medicinal chemistry. Table 3 shows that under the same conditions, reaction of substrates
1f-1i, which contain oxygen, and sulfur in the alkyl chain, led to the corresponding five- or six-membered heterocycles in yields
ranging from 55% to 97% and with excellent ee (92%-97%) (Table 3).
.
Finally, the absolute configuration of the newly created stereocenter was determined to be R by comparing the [α]2D5 values and
NMR data of compound 2a-2c with those described in the literatures [15-17] and identical stereochemical development was assumed
for 2d-2i.
3. Conclusion
In conclusion, we have developed a highly efficient and enantioselective organocatalytic IMAMR of carbamates bearing an
α,β-unsaturated ketone using 9-amino-9-deoxy-epi-quinine and DPP as co-catalysts. Importantly, a series of synthetically useful
2-substituted five- and six-membered heterocycles could be directly produced in a highly enantioselective fashion (92%-97.5% ee). It
is worth noting that in the IMARMR described herein, no α-effect was necessary to enhance the nucleophilicity of the nitrogen and
the process took place with very high yield and excellent ee values even if acetamide was used as a nitrogen-protecting group.
4. Experimental

All solvents and reagents were used as purchased and received from Aldrich without any further purification. Mass spectra and
1
high-resolution mass spectra were measured on a Finnigan MAT-95 mass spectrometer. H NMR and 13C NMR spectra were
determined on Bruker AM-400 instrument using tetramethylsilane as an internal reference. Data are presented as follows: chemical
shift, multiplicity, coupling constant in hertz (Hz). The signals of the 13C NMR were assigned using DEPT experiments and on the
basis of previously published data. The enantiomeric excess (ee) was measured by HPLC (chiralcel OD-H, n-hexane/i-PrOH= 97/3,
flow rate 1.5 mL/min). Silica gel 60H (200-300 mesh) manufactured by Qingdao Haiyang Chemical Group Co., China) was used for
general chromatography.
General procedure for the organocatalytic IMAMR reaction at room temperature: The chiral primary amine I (0.015 mmol) was
added to a solution of DPP (0.015 mmol) in toluene (0.6 mL) and the mixture was stirred for 15 min at room temperature. Then
substrate 1 (0.1 mol) was added. When TLC indicated there was no remaining starting substrate 1, the solvent was removed and the
residue was purified by flash column chromatography on silica gel (n-hexane:AcOEt= 7:1), affording the aza-Michael adducts 2a-i.
1H NMR and 13C NMR spectra for all compounds are available in Supporting information and typical spectral data of some
compounds are listed below.
Benzyl 2-(2-oxopropyl)pyrrolidine-1-carboxylate (2a): Yield: 98%. [α]2D5 +35.5 (c 0.15, CHCl3). ee 95%. H NMR (CDCl3, 400
1
MHz): δ 7.34 (m, 5H), 5.12 (s, 2H), 4.22 (m, 1H), 3.42 (m, 2H), 3.24-2.84 (m, 1H), 2.42 (dd, 1H, J = 16.4, 9.6 Hz), 2.22-2.00 (m,
4H), 1.90-1.78 (m, 2H), 1.70-1.60 (m, 1H); Major: 13C NMR (CDCl3, 100 MHz): δ 207.2, 154.6, 136.8, 128.4, 128.4, 127.9, 127.9,
127.8, 66.5, 53.9, 47.5, 46.3, 30.8, 30.3, 23.6; Minor: 13C NMR (CDCl3, 100 MHz): δ 207.2, 154.6, 137.6, 128.4, 128.4, 127.9, 127.9,
127.8, 66.8, 53.2, 48.5, 46.6, 31.6, 30.3, 22.8; HRMS (EI) calcd. for C15H19NO3 (M+): 261.1365, found 261.1369.
Benzyl 2-(2-oxopropyl)piperidine-1-carboxylate (2b): Yield: 99%. [α]2D5 +14.0 (c 0.13, CHCl3). ee 97.5%. 1H NMR (CDCl3, 400
MHz): δ 7.34 (m, 5H), 5.11 (d, 2H, J = 3.2 Hz), 4.80 (m, 1H), 4.03 (m, 1H), 2.85 (t, 1H, J = 12.2 Hz), 2.68 (m, 2H), 2.13 (s, 3H), 1.52
(m, 6H); 13C NMR (CDCl3, 100 MHz): δ 206.7, 155.2, 136.7, 128.4, 128.4, 127.9, 127.8, 127.8, 67.0, 47.4, 44.2, 39.7, 30.0, 28.2,
25.1, 18.7; HRMS (EI) calcd. for C16H21NO3 (M+): 275.1521, found 275.1526.
tert-Butyl 2-(2-oxopropyl)piperidine-1-carboxylate (2c): Yield: 97%. [α]2D5 +7.3 (c 0.1, CHCl3). ee 92%. H NMR (CDCl3, 400
1
MHz): δ 4.72 (brs, 1H), 3.97 (m, 1H), 2.77 (t, J = 12.4 Hz, 1H), 2.64 (dd, J = 7.1, 2.8 Hz, 2H), 2.18 (s, 3 H), 1.70-1.45 (m, 5H), 1.43
(s, 9H), 1.43-1.40 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 207.1, 154.7, 79.6, 47.2, 44.3, 39.3, 30.0, 28.3, 28.3, 28.3, 25.2, 18.8;
HRMS (EI) calcd. for C13H23NO3 (M+): 241.1678, found 241.1672.
1-(1-Tosylpiperidin-2-yl)propan-2-one (2d): Yield: 97%. [α]2D5 +23.0 (c 0.18, CHCl3). ee 95%. H NMR (CDCl3, 400 MHz): δ
1
7.70 (d, 2H, J = 8.2 Hz), 7.27 (d, 2H, J = 8.2 Hz), 4.51 (m, 1H), 3.78 (m, 1H), 2.92 (td, 1H, J = 13.6, 2.4 Hz), 2.78 (dd, 1H, J = 16.0,
9.6 Hz), 2.59 (dd, 1H, J = 16.0, 4.4 Hz), 2.41 (s, 3H), 2.12 (s, 3H), 1.55-1.25 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 206.0, 143.1,
138.0, 129.6, 129.6, 127.0, 127.0, 48.6, 43.8, 41.1, 30.2, 27.6, 24.5, 21.4, 18.3; HRMS (EI) calcd. for C15H21NO3S (M+): 295.1242,
found 295.1251.
1-(1-Acetylpiperidin-2-yl)propan-2-one (2e): Yield: 95%. [α]2D5 +44.0 (c 0.2, CHCl3). ee 93%. Major: H NMR (CDCl3, 400
1
MHz): δ 5.26 (m, 1H), 3.59 (d, 1H, J = 18.0 Hz), 3.12 (dt, 1H, J = 18.0, 3.2 Hz), 2.79 (d, 1H, J = 9.2 Hz), 2.63 (t, 1H, J =9.2 Hz),
2.20 (s, 3H), 2.04 (s, 3H), 1.75-1.30 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 207.3, 169.4, 44.7, 44.2, 42.1, 29.8, 28.1, 25.8, 21.9,
18.8; Minor: 1H NMR (CDCl3, 400 MHz): δ 4.62-4.48 (m, 2H), 2.79 (d, J = 9.2 Hz, 1H), 2.63 (t, 1H, J =9.2 Hz), 2.57-2.47 (m, 1H),
2.17 (s, 3H), 2.14 (s, 3H), 1.75-1.30 (m, 6H); 13C NMR (CDCl3, 100 MHz): δ 205.9, 169.4, 49.2, 44.1, 36.9, 30.9, 29.3, 25.3, 21.5,
19.2; HRMS (EI) calcd. for C10H17NO2 (M+): 183.1259, found 183.1266.
tert-Butyl 3-(2-oxopropyl)morpholine-4-carboxylate (2f): Yield: 97%. [α]2D5 +38.5 (c 0.15, CHCl3). ee 97%. H NMR (CDCl3,
1
400 MHz): δ 4.38 (brs, 1H), 3.85-3.67 (m, 3H), 3.56 (dd, 1H, J = 12.0, 2.0 Hz), 3.43 (td, 1H, J = 11.7, 2.4 Hz), 3.06 (brs, 2H), 2.56
(d, 1H, J = 15.3 Hz), 2.18 (s, 3H), 1.44 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 206.5, 154.3, 80.2, 68.9, 66.7, 47.2, 42.4, 39.1, 30.4,
28.2, 28.2, 28.2; HRMS (EI) calcd. for C12H21NO4 (M+): 243.1471, found 243.1472.
tert-Butyl 4-(2-oxopropyl)oxazolidine-3-carboxylate (2g): Yield: 96%. [α]2D5 +67.0 (c 0.11, CHCl3). ee 94%. H NMR (CDCl3,
1
400 MHz): δ 4.90-4.65 (m, 2H), 4.20-4.10 (m, 2H), 3.72-3.66 (m, 1H), 3.25-2.85 (m, 1H), 2.65-2.45 (m, 1H), 2.13 (s, 3H), 1.43 (s,
9H); 13C NMR (CDCl3, 100 MHz): δ 206.8, 152.5, 80.4, 78.6, 72.5, 51.4, 46.0, 30.2, 28.3, 28.2, 28.3; HRMS (EI) calcd. for
C11H19NO4 (M+): 229.1314, found 229.1323.
Benzyl 3-(2-oxopropyl)thiomorpholine-4-carboxylate (2h): Yield: 55%. [α]2D5 +18.5 (c 0.1, CHCl3). ee 95%. H NMR (CDCl3,
1
400 MHz): δ 7.35 (m, 5H), 5.13 (s, 2H), 4.99 (brs, 1H), 4.34 (m, 1H), 3.45-2.90 (m, 3H), 2.80-2.30 (m, 4H), 2.16 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 206.1, 155.1, 136.4, 128.5, 128.5, 128.1, 127.9, 127.9, 67.5, 46.4, 43.0, 40.7, 31.1, 30.4, 27.4; HRMS (EI) calcd.
for C15H19NO3S (M+): 293.1086, found 293.1089.
(S)-Benzyl 4-(2-oxopropyl)thiazolidine-3-carboxylate (2i): Yield: 91%. [α]2D5 +14.2 (c 0.18, CHCl3). ee 92%. 1H NMR (CDCl3,
400 MHz): δ 7.45-7.28 (m, 5H), 5.13 (s, 2H), 4.70-4.45 (m, 2H), 4.33 (d, 1H, J = 9.2 Hz), 3.24 (dd, 1H, J = 12.0, 6.4 Hz), 3.03-2.70
(m, 3H), 2.18-2.02 (m, 3H); Major: 13C NMR (CDCl3, 100 MHz): δ 206.5, 153.4, 136.1, 128.5, 128.5, 128.1, 127.9, 127.9, 67.3, 56.3,
47.8, 45.9, 35.3, 30.2; Minor: 13C NMR (CDCl3, 100 MHz): δ 206.5, 153.4, 136.1, 128.5, 128.5, 128.1, 127.9, 127.9, 67.3, 55.3, 48.5,
46.7, 36.3, 30.2; HRMS (EI) calcd. for C14H17NO3S (M+): 279.0929, found 279.0936.
Acknowledgements
We greatly acknowledge financial support from the National Natural Science Foundation of China (No. 21262022).

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Fig. 1. Structures of catalysts and organic acids used in this report.
Table 1
Catalyst screening and optimization of reaction conditions.
Entry cat.(mol %) Acid (mol%)
Solvent
CHCl3
CHCl3
Temp (°C) Yield (%)
ee (%)b
n.d.
n.d.
n.d.
75
89
86
95
89
82
87
81
71
81
94
79
-72
95
1
2
3
4
5
6
7
8
9
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
I (15)
CH3COOH (15)
2-F-C6H4COOH (15)
2-NO2-C6H4COOH (15) CHCl3
25
25
25
25
25
25
25
25
25
25
25
25
-10
25
25
25
25
25
5
10
10
90
95
91
98
83
50
65
91
65
65
96
90
85
16
6
TFA (15)
DPP (15)
TFA (15)
DPP (15)
DPP (15)
DPP (15)
(S)-IV (15)
(R)-V (15)
(R)-VI (15)
DPP (15)
DPP (30)
DPP (15)
DPP (15)
DPP (15)
DPP (15)
CHCl3
CHCl3
Toluene
Toluene
THF
Acetone
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
10 I (15)
11 I (15)
12 I (15)
13 I (15)
14 I (15)
15 II (15)
16 III (15)
17 I (10)
18 I (5)
95
TFA = trifluoroacetic acid; DPP = diphenyl hydrogen phosphate. n.d. = no detected.
a In all cases, reactions were carried out in the specified solvent and time (40 h).
b Determined by means of chiral-phase HPLC analysis.
Table 2
Influence of the nitrogen-protecting group on the IMAMR.
Entry
Substrate
PG
Cbz
Boc
Ts
Product
2b
2c
2d
2e
Yield (%) ee (%)a
1
2
3
4
99
97
97
95
97.5
92
95
1b
1c
1d
1e
Ac
93
a Determined by means of chiral-phase HPLC analysis.

Table 3
Scope of the organocatalytic intramolecular aza-Michael reaction.
Entry
X
O
O
S
n
2
1
2
1
PG
Boc
Boc
Cbz
Cbz
Product Yield (%) ee (%)a
1
2
97
96
55
91
97
94
95
92
2f
2g
2h
2i
3b
4
S
a Determined by means of chiral-phase HPLC analysis.
b Reaction time = 4 days