One-Pot Synthesis of Enantioenriched β-Amino Secondary Amides via an Enantioselective [4+2] Cycloaddition Reaction of Vinyl Azides with N-Acyl Imines Catalyzed by a Chiral Br?nsted Acid

Article abstract of DOI:10.1002/chem.202002049

A catalytic enantioselective synthesis of β-amino secondary amides was achieved using vinyl azides as the enamine-type nucleophile and chiral N-Tf phosphoramide as the chiral Br?nsted acid catalyst through a five-step sequential transformation in one pot.

Full text of DOI:10.1002/chem.202002049

Accepted Article
Accepted Article
Title: One-Pot Synthesis of Enantioenriched β-Amino Secondary
Amides via Enantioselective [4+2] Cycloaddition Reaction of Vinyl
Azides with N-Acyl Imines Catalyzed by Chiral Brønsted Acid
Authors: Taishi Nakanishi, Jun Kikuchi, Atsushi Kaga, Shunsuke
Chiba, and Masahiro Terada
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202002049
Link to VoR: https://doi.org/10.1002/chem.202002049
01/2020

10.1002/chem.202002049
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One-Pot Synthesis of Enantioenriched β-Amino Secondary
Amides via Enantioselective [4+2] Cycloaddition Reaction of Vinyl
Azides with N-Acyl Imines Catalyzed by Chiral Brønsted Acid
Taishi Nakanishi,[a] Jun Kikuchi,[a] Atsushi Kaga,[b] Shunsuke Chiba,[b] Masahiro Terada*[a]
[a]
T. Nakanishi, Dr. J. Kikuchi, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science,
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@tohoku.ac.jp
[b]
Dr. A. Kaga, Prof. Dr. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University
Singapore 637371 (Singapore)
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
catalytic enantioselective synthesis of β-amino
the catalytic enantioselective synthesis of amides through the C-
C
bond formation.[10] However, the scope of the amide
functionality is strictly limited to a tertiary amide that has no
hydrogens attached to the amide nitrogen atom because of the
involvement of an amide enolate as the reactive intermediate.[6b]
Vinyl azides have been recently utilized as an enamine-type
nucleophile[11] and also reported as the synthetic equivalent to the
corresponding enols of secondary amides (Figure 1a),[12] the
secondary amides was achieved using vinyl azides as the enamine-
type nucleophile and chiral N-Tf phosphoramide as the chiral
Brønsted acid catalyst through a five-step sequential transformation
in one pot. The established sequential transformation involves an
enantioselective [4+2] cycloaddition reaction of vinyl azides with N-
acyl imines as the key stereo-determining step that is efficiently
accelerated by a chiral N-Tf phosphoramide catalyst in a highly
enantioselective manner in most cases. Further generation of the
iminodiazonium ion intermediate through ring opening of the
cycloaddition product and subsequent skeletal rearrangement
involving Schmidt-type 1,2-aryl group migration followed by
recyclization of the resulting nitrilium ion were also initiated by the
same acid catalyst. Final acid hydrolysis of the recyclized products in
the same pot gave rise to enantioenriched β-amino amides through
C-C bond formation at the α-position of the secondary amides.
The amide moiety is ubiquitous in nature as it is present in such
molecules as peptides and proteins, and widely embedded in a
variety of synthetic molecules, including pharmaceuticals,
agrochemicals, and relevant molecules.[1] Consequently, much
attention has been devoted to the development of efficient
syntheses of amide-containing molecules not only in atom- and
step-economical manners but also in enantioenriched forms.[2]
Among the efficient methods reported to date, carbon-carbon (C-
C) bond formation at the α-position of the amide moiety, namely,
the addition of an amide enolate to an electrophile, is a powerful
procedure for the construction of a range of enantioenriched
amide derivatives. However, in general, the methods require a
stoichiometric amount of a strong base or the corresponding pre-
formed silyl enol ether because of the low acidity (pKa = 35 in
DMSO)[3] at the α-position of the amide moiety.[4,5] Hence, the
catalytic enantioselective formation of an amide derivative
through the C-C bond formation at the α-position of the amide has
been a challenging topic.[6] These intrinsic issues have been
surmounted as a result of a recent advance in well-designed chiral
catalytic systems, including the combination of a transition metal
complex and an organobase co-catalyst,[7] an alkaline metal salt
derived superbase,[8] and an organosuperbase having
iminophosphorane units.[9] These efficient methods have enabled
Figure 1. Utilization of vinyl azide as a secondary amide enolate equivalent.
1
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properties of which are completely different from those of tertiary
amides because the secondary amides serve not only as a
hydrogen bond acceptor site but also as a donor site. Generally,
vinyl azide would function as the enamine-type nucleophile and
undergo the reaction with a cationic electrophile (El+) that is
generated by an acid catalyst through the elimination of a leaving
group (OH in Figure 1a), affording an iminodiazonium
intermediate having resonance structures A and A’. Subsequent
Schmidt-type 1,2-migration of intermediate A’ would generate
nitrilium ion B with elimination of dinitrogen (N2),[13] and the
subsequent hydrolysis of nitrilium ion B by the eliminated water
molecule would furnish the corresponding secondary amide.
Over the past decades, chiral Brønsted acid catalysts have
drawn much attention as one of the privileged organocatalysts[14]
and a diverse range of enantioselective reactions have been
accomplished using them.[15,16] In our continuous efforts to expand
the scope of enantioselective reactions using a chiral Brønsted
acid catalyst, we envisioned the use of vinyl azides as an
enamine-type nucleophile for the synthesis of enantioenriched β-
amino secondary amides. We designed a five-step sequential
transformation involving a [4+2] cycloaddition reaction of vinyl
azides 1 with N-acyl imines 2 as the key enantio-determining
step.[17,18] Our proposed reaction scheme is shown in Figure 1b.
The first step of the [4+2] cycloaddition would be initiated by a
chiral phosphoric acid or its derivative as the chiral Brønsted acid
catalyst[16] to afford cycloaddition product 3 in an enantioselective
fashion. Further treatment of cycloaddition product 3 in the
presence of an acid catalyst would result in the partial formation
of iminodiazonium ion C because the resonance stabilization by
the azide functionality would be anticipated in generated cation
C.[19] Although cation C would instantaneously reproduce 3 via
intramolecular cyclization using the oxygen atom of the N-acyl
moiety under equilibrium conditions,[20] we expected that
cycloaddition product 3 could be used as the resting state of
positively charged intermediate C. Subsequently, generated C
would undergo the Schmidt-type 1,2-migration to afford nitrilium
ion D with elimination of dinitrogen, and subsequent recyclization
of the N-acyl oxygen atom at the nitrilium carbon atom of D would
give rise to N-(1,3-oxazinylidene)amine derivative 4. Further acid
hydrolysis of recyclized product 4 would provide β-amino
secondary amide 5 in an enantioenriched form. Based on this
reaction design, we successfully established an efficient one-pot
procedure[21] for the synthesis of enantioenriched secondary
amides through the five-step sequential transformation utilizing
the enantioselective [4+2] cycloaddition as the key stereo-
determining step. We report herein the details of our investigation.
To ascertain the viability of the designed sequential process,
we began the investigation with the first key reaction, namely, the
enantioselective [4+2] cycloaddition reaction of vinyl azide 1a
having a 2-naphthyl moiety with N-benzoyl imine 2a under the
influence of chiral Brønsted acid (R)-6 or (R)-7. Initially, the
reaction of 1a (1.2 eq.) with 2a was performed in the presence of
chiral phosphoric acid (R)-6a or (R)-6b[16] and molecular sieves
4A (MS 4A) in dichloromethane at 0 °C for 24 h (Table 1, entries
1 and 2). As expected, cycloaddition product 3aa was formed
albeit in low yield along with a trace amount of recyclized product
4aa. Fairly good anti-diastereoselectivities and moderate
enantioselectivities were observed in 3aa in both cases and minor
Table 1. Optimization of reaction conditions.[a]
Yield[b] (%)
Ee[e] (%) for
Entry
Catalyst
T (°C)
Solvent
anti-3aa/syn-3aa[d]
anti-3aa/syn-3aa
3aa
7
4aa[c]
(~2)
(~2)
(~5)
(~5)
(10)
(<1)
(<1)
(<1)
(<1)
8[c]
1
2
(R)-6a
(R)-6b
(R)-7a
(R)-7b
(R)-7a
(R)-7a
(R)-7a
(R)-7a
(R)-7a
0
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
(38)
(32)
(<1)
(<1)
(8)
86/14
90/10
78/22
81/19
89/11
89/11
22/78
89/11
31/69
11/40
58/61
52/31
20/62
81/81
90/90
64/38
90/90
86/96
24
50
68
63
81
72
95
95
3
0
4
0
5
0
6
-30
-60
-30
-30
(<1)
(<1)
(<1)
(<1)
7
8[f]
9[f,g]
[a] Unless otherwise noted, all reactions were carried out using 0.005 mmol of (R)-6 or (R)-7 (5 mol%), 0.12 mmol of 1a (1.2 eq.), 0.1 mmol of 2a (1.0 eq.), and MS
4A (50 mg) in the indicated solvent (1.0 mL). [b] Isolated yield, NMR yield in parenthesis using 1,1,2,2-tetrabromoethane as the internal standard. [c] 4aa and 8
were obtained as an E/Z mixture. [d] Determined by 1H NMR analysis of the crude materials. [e] Determined by chiral stationary phase HPLC analysis. [f] 0.1 mmol
of 1a (1.0 eq.) and 0.15 mmol of 2a (1.5 eq.) were used. [g] For 1 h.
2
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syn-3aa exhibited higher enantioselectivity than major anti-3aa.
However, a significant amount of vinyl azide derivative 8, which
was produced by deprotonation at the methylene carbon of the
iminodiazonium intermediate, was also formed as an undesirable
byproduct. The low chemical yield presumably arose from the low
acidity of catalyst 6 and hence, the conjugate base of catalyst 6
having relatively high basicity would function as the deprotonating
agent of the cationic iminodiazonium intermediate. Therefore,
more acidic N-Tf phosphoramide catalysts (R)-7a and (R)-7b
were employed for further investigation (Table 1, entries 3–
9).[22,23] Using either (R)-7a or (R)-7b, the formation of undesirable
8 was completely suppressed, the yield of 3aa was markedly
improved, and the yield of 4aa was slightly enhanced (Table 1,
entries 3 and 4). When (R)-7a was used, major anti-3aa was
obtained in higher enantioselectivity than minor syn-3aa (Table 1,
entry 3). Hence, the reaction solvent and temperature were further
examined using (R)-7a. The use of toluene instead of
dichloromethane markedly improved the enantioselectivity of 3aa
and maintained the high anti-diastereoselectivity (Table 1, entry
5). Although a small amount of 4aa and undesirable 8 were
generated at 0 °C, reducing the reaction temperature to -30 °C
resulted in the exclusive formation of 3aa and an increase in
enantioselectivity of both anti- and syn-diastereomers with the
same 90% ee (Table 1, entry 6). However, further decrease of the
reaction temperature to -60 °C led to a marked decrease in
enantioselectivity and syn-3aa was formed as the major
diastereomer (Table 1, entry 7). At -30 °C, the chemical yield was
improved by changing the equivalent of 2a to 1.5 eq. (Table 1,
entries 8 and 9). More interestingly, the reaction time substantially
influenced the stereochemical outcome: a prolonged reaction
resulted in a dramatic change of the diastereoselectivity from syn-
3aa to anti-3aa and the enantioselectivities changed from 86%
ee/96% ee (for 1 h) to 90% ee/90% ee (for 24 h). These results
clearly suggest that epimerization at the 6-position of 3aa
proceeds through C-O bond cleavage, namely, equilibrium
between 3aa and iminodiazonium intermediate C (see Figure 1b),
under the reaction conditions.[24] Considering the resonance
Scheme 1. One-pot synthesis of enantioenriched secondary amide.
evaluate the formation of recyclized product 4aa, the generated
4aa was directly hydrolyzed to β-amino secondary amide 5aa by
adding 1N HCl aqueous solution to the reaction mixture without
isolating 4aa because 4aa was an E/Z mixture. Initially, the
proposed four-step sequence was performed using 5 mol% of (R)-
7a at 40 °C (Table 2). The progress of the recyclization step from
3aa to 4aa was monitored by TLC. Although 3aa was not
completely consumed even by prolonged reaction for 26 h, acid
hydrolysis of the reaction mixture afforded desired (S)-5aa[26] with
high enantioselectivity that is consistent with the averaged
enantioselectivities of initial anti- and syn-3aa (Table 2, entry 1).
Elevating the temperature to 100 °C did not markedly improve the
yield of 5aa (Table 2, entry 2),[27] whereas increasing the catalyst
loading to 10 mol% efficiently promoted the four-step sequence,
affording 5aa in an acceptable yield without any loss of
enantioselectivity (Table 2, entry 3).
The successful formation of enantioenriched 5aa from
cycloaddition product 3aa prompted us to accomplish a five-step
sequential transformation that starts from enantioselective [4+2]
cycloaddition ends with acid hydrolysis in one pot. As shown in
Scheme 1, the initial enantioselective [4+2] cycloaddition reaction
of 1a with 2a (1.5 eq.) was performed using (R)-7a in accordance
with the optimized procedure (Table 1, entry 9) and then the
reaction mixture was heated to 100 °C (Table 2, entry 3).
Subsequent acid hydrolysis in the same pot gave rise to β-amino
secondary amide 5aa in good yield with the same
enantioselectivity as that of the individual enantioselective
cycloaddition.
With the optimal one-pot procedure in hand, the generality of
the present sequential reaction was demonstrated by exploring
several combinations of vinyl azides 1 and N-benzoyl imines 2
(Figure 2). As shown in the top portion of Figure 2, the sequential
reaction of a series of vinyl azides 1 having different electronic
properties of the aryl group with imine 2a proceeded smoothly to
afford enantioenriched amides 5 in acceptable yields,[28] although
the enantioselectivities were highly dependent on the electronic
nature of the aryl ring of 1. The introduction of an electron-
donating group to the aryl ring, particularly, at the ortho- and para-
positions, led to a significant decrease in enantioselectivity. It is
considered that the electronically enriched aryl ring, which would
stabilize the positively charged species generated in the transient
structure, could influence the [4+2] cycloaddition reaction
pathway. Thus, the reaction tends to proceed via a stepwise
pathway presumably because of the resonance stabilization of
the positively charged species not only by the azide functionality
but also by the electronically enriched aryl ring. Further screening
for the substrates was performed using vinyl azide 1a and a series
of imines 2. As shown in the bottom portion of Figure 2, the
electronic nature of the aryl ring of imine 2 markedly influenced
the yields and the enantioselectivities of amides 5. Imine 2b
having a strong electron donor, namely, a 4-methoxyphenyl group,
underwent the cycloaddition reaction and the formation of
cyclized product 3ab was confirmed by 1H NMR measurement.[29]
However, desired amide product 5ab was not formed at all after
the following sequential transformation. Thus, the decomposition
of intermediate 3ab and/or 4ab was observed when the reaction
mixture was heated at 100 °C presumably because of the C-N
bond cleavage at C4-position of 3ab and 4ab. In contrast, the
introduction of a weak electron-donating group, such as 2c (R2 =
4-tolyl) and 2d (R2 = 4-fluorophenyl), led to the formation of
stabilization of cationic intermediate
C
by the azide
functionality,[25] we anticipated that elevating the temperature
would lead to efficient generation of iminodiazonium intermediate
C under the influence of acid catalyst (R)-7a, and the subsequent
Schmidt-type migration of C and recyclization of nitrilium ion D
would afford N-(1,3-oxazinylidene)amine derivative 4aa.
Based on the above considerations, isolated 3aa was treated
with optimized catalyst (R)-7a under elevated temperatures. To
Table 2. Transformation of 3aa into secondary amide 5aa under the influence
of (R)-7a.[a]
Entry (R)-7a (mol%)
T (°C)
Time (h)
Yield[b] (%)
Ee[c] (%)
90
40
1
2
3
5
5
26
2
45
56
100
100
90
10
2
74
90
[a] Unless otherwise noted, all reactions were carried out using (R)-7a, 0.05
mmol of 3aa, and MS 4A (25 mg) in toluene (0.5 mL). [b] Isolated yield. [c]
Determined by chiral stationary phase HPLC analysis.
3
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10.1002/chem.202002049
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This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Hybrid Catalysis for Enabling
Molecular Synthesis on Demand” from MEXT, Japan (No.
JP17H06447).
Keywords: β-amino amide • vinyl azide • Brønsted acid •
enantioselective • [4+2] cycloaddition
[1]
[2]
For a review, see: G. Arthur, C. M. Breneman, J. F. Liebman, The Amide
Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and
Material Science, 12; John Willey & Sons Inc.: New York, 2000.
For selected reviews on amide syntheses, see: a) E. Valeur, M. Bradley,
Chem. Soc. Rev. 2009, 38, 606–631; b) V. R. Pattabiraman, J. W. Bode,
Nature, 2011, 480, 471–479; c) C. L. A. Allen, J. M. J. Williams, Chem.
Soc. Rev. 2011, 40, 3405–3415; d) R. Marcia de Figueiredo, J.-S. Suppo,
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V. Vijayakumar, Org. Chem. Front. 2019, 6, 2570–2599; f) T. N. Reddy,
A. Breatriz, V. J. Rao, D. P. D. Lima, Chem. Asian. J. 2019, 14, 344–388;
g) M. R. Petchey, G. Grogan, Adv. Synth. Catal. 2019, 361, 3895–3914.
[3]
[4]
Based
on
the
Bordwell
pKa
Table,
see:
http://www.chem.wisc.edu/areas/reich/pkatable/index.htm
For reactions using a stoichiometric amount of a strong base, see: a) D.
A. Oare, M. A. Henderson, M. A. Sanner, C. H. Heathcock, J. Org. Chem.
1990, 55, 132–157; b) R. B. Lettan II, T. E. Reynolds, C. V. Galliford, K.
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II, C. V. Galliford, C. C. Woodward, K. A. Scheidt, J. Am. Chem. Soc.
2009, 131, 8805–8814.
[5]
For enantioselective reactions using amide silyl enol ethers, see: a) S. E.
Denmark, J. R. Heemstra, Jr., J. Am. Chem. Soc. 2006, 128, 1038–1039;
b) S. E. Denmark, J. R. Heemstra, Jr., J. Org. Chem. 2007, 72, 5668–
5688; c) V. B. Gondi, K. Hagihara, V. H. Rawal, Angew. Chem. Int. Ed.
2009, 48, 776–779; d) V. B. Gondi, K. Hagihara, V. H. Rawal, Chem.
Commun. 2010, 46, 904–906; e) M. Frias, R. Mas-Balleste, S. Arias, C.
Alvarado, J. Aleman, J. Am. Chem. Soc. 2017, 139, 672−679; f) M. Frias,
A. C. Carrasco, A. Fraile, J. Aleman, Chem. Eur. J. 2018, 24,3117–3121.
a) S. Saito, T. Tsubogo, S. Kobayashi, Chem. Commun. 2007, 1236–
1237; b) S. Saito, S. Kobayashi, J. Am. Chem. Soc. 2006, 128, 8704–
8705; c) S. Kobayashi, H. Kiyohara, M. Yamaguchi, J. Am. Chem. Soc.
2011, 133, 708–711.
Figure 2. Scope of substrates 1 and 2.
[6]
[7]
amides 5ac and 5ad in moderate yields with good
enantioselectivities. An imine having an aryl ring with an electron-
withdrawing group, such as 2e (R2 = 4-bromophenyl) and 2f (R2
= 4-trifluoromethylphenyl), facilitated the sequential reaction in
fairly good yields albeit with marked decreases in the
enantioselectivities.[30] Steric congestion also influenced the
sequential reaction. Imine 2h having a 1-naphthyl substituent
afforded amide 5ah in only a trace amount, whereas imine 2g
For selected examples of the combination of transition metal complex
and organobase co-catalyst system, see: a) L. Yin, L, Brewitz, N.
Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2014, 136, 17958–17961; b)
K. Weidner, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed. 2014, 53,
6150–6154; c) K. Weidner, Z. Sun, N. Kumagai, M. Shibasaki, Angew.
Chem. Int. Ed. 2015, 54, 6236–6240; d) L. Brewitz, F. A. Arteaga, L. Yin,
K. Alagiri, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2015, 137,
15929–15939; e) A. Saito, N. Kumagai, M. Shibasaki, Angew. Chem. Int.
Ed. 2017, 56, 5551–5555; f) B. Sun, P. V. Balaji, N. Kumagai, M.
Shibasaki. J. Am. Chem. Soc. 2017, 139, 8295–8301; g) H.-J. Zhang, C.-
Y. Shi, F. Zhong, L. Yin, J. Am. Chem. Soc. 2017, 139, 2196–2199; h) X.
Huo, R. He, J. Fu, J. Zhang, G. Yang, W. Zhang, J. Am. Chem. Soc.
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Soc. 2018, 140, 1239–1242; j) B. Sun, R. Pluta, N. Kumagai, M.
Shibasaki, Org. Lett. 2018, 20, 526–529; k) R. Pluta, N. Kumagai, M.
Shibasaki, Angew. Chem. Int. Ed. 2019, 58, 2459–2463.
having
a less sterically congested 2-naphthyl substituent
underwent the sequential reaction to produce amide 5ag in good
yield with high enantioselectivity.
In conclusion, we have developed a catalytic enantioselective
synthesis of chiral amides that is characterized by a five-step
sequential transformation in one pot using chiral N-Tf
phosphoramide as the chiral Brønsted acid catalyst. The method
provides enantioenriched β-amino secondary amides through the
C-C bond formation at the α-position of the amide using vinyl
azides as the enamine-type nucleophile. The established
sequential transformation involves an enantioselective [4+2]
cycloaddition reaction of vinyl azides with N-acyl imines as the
key stereo-determining step and the chiral N-Tf phosphoramide
efficiently accelerates not only the cycloaddition process in a
highly enantioselective manner in most cases but also further
skeletal rearrangement and recyclization processes involving
cationic intermediates in the same pot. Further studies of the
development of other enantioselective reactions using vinyl
azides as the enamine-type nucleophile will be conducted in due
course.
[8]
[9]
For alkaline metal salt derived superbase system, see: a) H. Suzuki, I.
Sato, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc. 2015, 137, 4336–
4339; b) A. Kondoh, S. Ishikawa, M. Terada, J. Am. Chem. Soc. 2020,
142, 3724–3728.
For organosuperbase having iminophosphorane unit system, see: A.
Kondoh, M. Oishi, H. Tezuka, M. Terada, Angew. Chem. Int. Ed. 2020,
132, 2–7.
[10] For reviews, see: a) N. Kumagai, M. Shibasaki, Chem. Eur. J. 2016, 22,
15192–15200; b) Y. Yamashita, S. Kobayashi, Chem. Eur. J. 2018, 24,
10–17.
[11] For the use of vinyl azides as an amide enolate equivalent, see: a) F.-L.
Zhang, Y.-F. Wang, G. H. Lonca, X. Zhu, S. Chiba, Angew. Chem. Int.
Acknowledgements
4
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Chemistry - A European Journal
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Ed. 2014, 53, 4390–4394; b) F.-L. Zhang, X. Zhu, S. Chiba, Org. Lett.
2015, 17, 3138–3141; c) C. Lin, Y. Chen, B. Huang, Y. Liu, S. Cui, J. Org.
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84, 15865–15876.
[24] Epimerization at the 6-position of 3aa was confirmed under the same
reaction conditions using syn-3aa as the major diastereomer. See
Supporting Information for details.
[25] When a [4+2] cycloaddition product having a methyl substituent, instead
of the azide, at the 6-position was subjected to similar reaction conditions
using a chiral phosphoric acid catalyst, no epimerization was observed
at the 6-position. See Ref. [17a].
[12] For reviews on synthetic application of vinyl azides, see: a) B. Hu, S. G.
Dimagno, Org. Biomol. Chem. 2015, 13, 3844–3855; b) H. Hayashi, A.
Kaga, S. Chiba, J. Org. Chem. 2017, 82, 11981–11989; c) J. Fu, G.
Zanoni, E. A. Anderson, X. Bi, Chem. Soc. Rev. 2017, 46, 7208–7228.
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[26] The absolute configuration of enantioenriched 5aa was assigned to be
(S)-isomer by analogy of the stereochemical determination of 5ba. The
absolute stereochemistry of 5ba was determined by derivatization of the
stereochemically known compound into 5ba. See Supporting Information
for details.
[27] The results of screening for reaction conditions are summarized in
Supporting Information (Table S5).
[28] Aliphatic substituted vinyl azide, R1 = (CH2)2Ph, was also used in the
present reaction, however the initial cycloaddition reaction did not
proceed efficiently. The cycloaddition product was formed in low yield,
less than 15%, even at elevated reaction temperature to 0 °C.
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Supporting Information.
[30] Further optimization of the reaction conditions by changing the reaction
temperature was unsuccessful. See Supporting Information.
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[23] The results of screening for a series of catalysts are summarized in
Supporting Information (Table S1).
5
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10.1002/chem.202002049
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Entry for the Table of Contents
A catalytic enantioselective synthesis of β-amino secondary
amides was achieved using vinyl azides and chiral N-Tf
phosphoramide as the chiral Brønsted acid catalyst through a
five-step sequential transformation in one pot. The established
sequential transformation involves an enantioselective [4+2]
cycloaddition reaction of vinyl azides with N-acyl imines as the
key stereo-determining step that is accelerated by a chiral N-Tf
phosphoramide.
6
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