Br?nsted Acid-Initiated Formal [1,3]-Rearrangement Dictated by β-Substituted Ene-Aldimines

Article abstract of DOI:10.1021/acs.orglett.9b01533

The rearrangement of ene-aldimines is a useful reaction for affording homoallylic amines. Despite their utilities in synthetic chemistry, the rearrangement for accessing homoallylic amines substituted at the 2-position remains elusive. In this study, the

Full text of DOI:10.1021/acs.orglett.9b01533

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Acid-Initiated Formal [1,3]-Rearrangement Dictated by
β‑Substituted Ene-Aldimines
Chanantida Jongwohan,†,‡ Yasushi Honda,§ Toshiyasu Suzuki,†,‡ Takeshi Fujinami,†
Kiyohiro Adachi,†,∥ and Norie Momiyama*,†,‡
†Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
‡SOKENDAI, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8787, Japan
§West Japan Office, HPC Systems Inc., 646 Nijohanjikicho, Shimogyo-ku, Kyoto 600-8412, Japan
∥Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 111-8656,
Japan
S
* Supporting Information
ABSTRACT: The rearrangement of ene-aldimines is a useful reaction for
affording homoallylic amines. Despite their utilities in synthetic chemistry, the
rearrangement for accessing homoallylic amines substituted at the 2-position
remains elusive. In this study, the Brønsted acid-initiated formal [1,3]-
rearrangement of ene-aldimines was developed to synthesize 2,4,4-substituted
homoallylic amines that were otherwise inaccessible previously. Our study
reveals an intermolecular pathway in which the rearrangement proceeds via a
protonation-mediated 2-azaallenium cation.
ubstituted homoallylic amines are important structural
motifs because the carbon−carbon double bonds of the
Scheme 2. Discovery and Development of Formal [1,3]-
Rearrangement of Ene-Aldimines
S
allyl groups are readily converted into potentially important
nitrogen-containing molecules.1 First reported by Geissman in
1950,2 the 2-azonia-[3,3]-sigmatropic rearrangement (cationic
2-aza-Cope rearrangement) of ene-imines has received
significant attention, and a number of irreversible rearrange-
ments has been developed (Scheme 1) since then.3 On the
Scheme 1. Reported 2-Azonia-[3,3]-Sigmatropic
Rearrangement of Ene-Imines
basis of these precedents, 2-azonia-[3,3]-sigmatropic rearrange-
ments have recently been recognized as a useful route to afford
1,4- and 1,4,4-substituted homoallylic amines.4 In marked
contrast, the synthesis of homoallylic amines containing
substituents at the 2-position but not the 1-position has not
been realized so far, and thus, these structural motifs are
missing in this well-explored field. Herein, we report the
discovery of a Brønsted acid-initiated formal [1,3]-rearrange-
ment reaction of ene-aldimines and demonstrate its use in the
synthesis of 2,4,4-substituted homoallylic amines (Scheme 2).
Received: May 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01533
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Table 1. Brønsted Acid-Initiated Formal [1,3]-
a
Rearrangement of Ene-Aldimines
b
temperature
time
(h)
catalyst loading
(mol %)
yield
entry
4
(°C)
(%)
1
2
3
4
5
6
7
(E)-4a
(E)-4a
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
(E)-4b
40
40
60
60
60
80
80
100
120
150
150
150
150
150
150
150
20
20
20
20
20
20
20
1
1
1
2
3
<1
24
26
79
41
81
74
72
87
89
92
92
92
91
89
10
30
30
30
10
30
10
10
10
10
10
5
c
8
9
c
c
10
11
12
13
14
15
16
c
c
c
3
4
12
1
3
2
1
c
c
c
a
Reactions were performed with ene-aldimine substrates in the
b
presence of ( )-CSA in 1,2-dichloroethane. Determined by 1H
NMR using dibromomethane. Microwave reactor was used.
c
Our initial design for the synthesis of substituted homoallylic
amine was based on Couty’s report (Scheme 1b).4a We
considered the Brønsted acid-catalyzed 2-azonia-[3,3]-sigma-
tropic rearrangement of the β-disubstituted ene-aldimines,
which irreversibly rearrange to formyl iminium cations with
less nucleophilic internal double bonds. Initial attempts to
react the ene-aldimine 1a did not result in the desired [3,3]-
rearrangement product 2a. Surprisingly, the corresponding
formal [1,3]-rearrangement product 3a was solely obtained in
a good yield instead (Scheme 2a). To the best of our
knowledge, this is the first report of Brønsted acid-initiated
formal [1,3]-rearrangement of ene-imines. To explore its
potential applications, we decided to use this reaction for
synthesizing 2,4,4-substituted homoallylic amines by further
introducing substituents at the terminal olefin (Scheme 2b).
At the outset of our study, we prepared the benchmark
substrates (E)-4 starting from aromatic aldehydes and (E)-2,2-
dimethylpent-3-en-1-amine. (E)-4 was treated with ( )-10-
camphorsulfonic acid (CSA) in 1,2-dichloroethane (Table 1).
At 40 °C, the reaction did not proceed in the absence of a
Brønsted acid (entry 1). In contrast, with 30 mol % of
( )-CSA, the reactions of (E)-4a and (E)-4b gave rise to the
respective desired formal [1,3]-rearranged ene-aldimines 5a
and 5b without any [3,3]-rearranged products (entries 2 and
3).5 These results demonstrated that Brønsted acid plays a key
role in initiating the formal [1,3]-rearrangement. Furthermore,
we found that (E)-4b with 2-hydroxyl group6 is more
advantageous in the point of handling: unlike 4a and 5a, 4b
and 5b do not easily decompose on TLC or with moisture.
Fortunately, (E)-4b proved to have similar reactivity to that of
(E)-4a derived from benzaldehyde, albeit with low con-
versions. Further optimization of the reaction conditions
Figure 1. Substrate scope of Brønsted acid-initiated formal [1,3]-
rearrangement. Reactions were performed with ene-aldimine substrate
in the presence of ( )-CSA in 1,2-dichloroethane under microwave
heating. Yields were determined by 1H NMR using dibromomethane.
In (E)-4b, (E)-4c, (E)-4d, (E)-4e, (E)- and (Z)-4h, and (E)- and
(Z)-4i, 2 mol % of ( )-CSA was used. In (Z)-4b, (E)-4f, (E)-4g, (Z)-
4j, (Z)-4k, and (Z)-4m, 10 mol % of ( )-CSA was used. In (Z)-4l
and (Z)-4n, 2 mol % of ( )-CSA was used for the left results; 10 mol
% of ( )-CSA was used for the right results.
successfully gave the formal [1,3]-rearrangement product 5b in
high yields (entries 6−11). The optimal reaction temperature
(150 °C) was possible in a microwave reactor. This reaction
could proceed in 1,2-dichloroethane and acetonitrile in the
presence of various Brønsted acids, including acetic acid,
phosphoric acids, sulfonic acids, and trifluoroacetic acid
(Supporting Information, pages S5 and S6). However,
( )-CSA was found to be the best catalyst in terms of yields
and handling, and under the optimized conditions, its loading
was lowered to 1 mol % without deteriorating the yield (entry
15). Furthermore, in the absence of ( )-CSA, the [1,3]-
rearrangement product was obtained in only 10% yield, in
which 90% of (E)-4b remained (entry 16), indicating that
Brønsted acid is required even for the thermally induced
reaction in a microwave reactor.
With the optimal reaction conditions in hand, we turned our
attention to the substrate scope (Figure 1). The use of (E)-4c,
4d, and 4e with dialkyl substituents R2 at the β-position gave
the corresponding products 5c, 5d, and 5e in high yields in the
B
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Scheme 3. Transformation of Ene-Aldimine Products
Scheme 4. Crossover Experiments
Scheme 5. Asymmetric Formal [1,3]-Rearrangement of
(R,E)- and (R,Z)-9
Figure 2. DFT calculations for conformational stabilities of (a) ene-
aldimine substrates with β-substitution R1, (b) protonated ene-
aldimine substrate R1-H+, and (c) concerted chair transition state in
2-azonia-[3,3]-sigmatropic rearrangement. Optimized geometries and
Gibbs free energies (ΔG, kcal mol−1, in parentheses) were calculated
at the SMD(DCE)/M06-2X-D3/6-311+G(d,p) level at 333 K.
cyclohexyl proceeded smoothly, and the corresponding formal
[1,3]-rearrangement product 5h was obtained in good yield
under 2 mol % catalyst loading. Phenyl-substituted (E)-4i also
afforded 5i with excellent yield. In addition to (E)-4, (Z)-4
could also be used, although 10 mol % ( )-CSA was necessary
in some cases. For example, (Z)-4b, (Z)-4h, and (Z)-4i were
successfully converted to 5b, 5h, and 5i in high yields,
respectively. Furthermore, (Z)-4 with terminal substituent R3
such as ethyl and isopropyl (4j−4n) gave the corresponding
products 5j−5n in moderate to good yields. Importantly,
presence of 2 mol % ( )-CSA. Although the reactions of
cyclobutyl-substituted (E)-4f and cyclopentyl-substituted (E)-
4g led to moderate yields of 5f and 5g, that of (E)-4h with
C
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Figure 3. Proposed mechanism for the generation of 2-azaallenium cation and intramolecular reaction. REA indicates reactant ene-aldimine and
PRO indicates [1,3]-rearrangement product.
among a variety of substrates, the cyclohexyl and phenyl
groups of 4 achieved better reactivities than other β-
substituents, and these reactions gave the products 5h and 5i
in good yields at only 60 °C with 10 mol % catalyst loading
(Supporting Information, page S6).
To get further insights into the reaction mechanism, density
functional theory (DFT) calculation was conducted (Figures
2). Benzaldehyde-derived ene-aldimine with dimethyl group
R1 (Ar = Ph; R, R = Me, Me; R′ = H) was used as a model
substrate because the 2-OH on the aryl group of the
benzylidene unit does not significantly affect the progress of
the reaction (Table 1, entries 2 and 3). In fact, the reaction of
ene-aldimine (Ar = 2-OHC6H4; R, R = Me, Me; R′ = H) was
conducted under conditions the same as those in Scheme 2a.
The [1,3]-rearrangement product was obtained in 82% yield.
The DFT calculations indicate six conformers, demonstrating
that R1(1b) is the most conformationally favorable structure
(Figure 2a). Importantly, although R1 is readily protonated by
( )-CSA in 1,2-dichloroethane (Supporting Information,
pages S75−S80), R1-H+(1a) is a more favorable conformation
compared with R1-H+(1b) (Figure 2b). In fact, in contrast to
α-disubstituted ene-aldimines, R1-H+(1b) is predicted to be
thermodynamically unfavorable for 2-azonia-[3,3]-sigmatropic
rearrangement (Figure 2c). We speculated that the differences
in the energetically stable conformers under protonation affect
the formation of the rearrangement products.
The product 5 of our rearrangement reaction is an important
synthetic intermediate that can, for example, be transformed
into the previously inaccessible free 2,4,4-homoallylic amines
(Scheme 3). To demonstrate the synthetic utilities of such
compounds, we first subjected ene-aldimines 5h, 5i, and 5l to
hydrolysis with hydroxyamine hydrochloride,3a and the free
primary amines 6h, 6i, and 6l were obtained in good yields
(Scheme 3a). Additionally, protection of 6i with p-nosyl
chloride to form the p-nosylate 7h, followed by intramolecular
hydroamination with substoichiometric amounts of triflic acid,
afforded the spiropyrrolidine 8h (Scheme 3b).7 Moreover, by
the treatment with (Boc)2O, the free primary homoallylic
amine 6i was transformed with an excellent yield into the tert-
butoxycarbonyl (Boc) protected amine 7i, which is a useful
intermediate for β-amino acid synthesis (Scheme 3c).8
We conducted a series of experiments to gain mechanistic
insight into our Brønsted acid-initiated [1,3]-rearrangement of
ene-aldimines (Schemes 4 and 5). We designed and prepared a
deuterated crossover substrate d2-(E)-4i and a chiral substrate
9. Under the reaction conditions, the substrates d2-(E)-4i and
(Z)-4j yielded four products: two normal rearranged products
d2-5i and 5j and two crossover products d2-5j and 5i in a ratio
of ca. 1:1:1:1 (Scheme 4a). When the mixture of d2-5i and 5j
was treated with 10 mol % of ( )-CSA, we could no longer
observe d2-5j and 5i (Scheme 4b). These results indicated that
the fragmentation of d2-(E)-4i and (Z)-4j occurred via C(α)−
C(β) bond cleavage during the rearrangement process.
Furthermore, the asymmetric rearrangement of (R)-9 with
E- or Z-olefin was examined under both normal and microwave
heating (Scheme 5). The reaction of (R,E)-9 generated the
rearrangement product (R,E)-10 in a high yield with an
excellent enantioselectivity. On the other hand, the reaction of
(R,Z)-9 gave the rearrangement product (S,E)-10 in low yield.
We determined the absolute configurations of the substrates
and products at the protection step by single crystal X-ray
diffraction, comparison of derivatives, and crystal sponge
method (Supporting Information, pages S66−S74.). These
results of the crossover and chirality transfer experiments
indicated that this formal [1,3]-rearrangement proceeds
completely through an intermolecular pathway.
Although the details of the reaction pathway are still under
investigation, we propose a 2-azaallenium9-mediated chain
reaction mechanism for the chirality transfer based on the
experimental and computational studies, which suggest the
involvement of two nucleophilic sites of the ene-aldimine,
namely imino nitrogen and allylic carbon (Figure 3). In the
fragmentation step, nitrogen on the ene-aldimine reactant is
protonated, as evident from the conformational stability of the
ene-aldimine substrates, followed by the protonation of the
allyl group. The product formation begins with the
nucleophilic attack by either imino nitrogen (Path A) or
allylic carbon (Path B).
In summary, we discovered a new reaction of ene-aldimine
and developed a Brønsted acid-initiated formal [1,3]-
rearrangement for the synthesis of 2,4,4-homoallyl amines. A
broad substrate scope was achieved in the presence of a
catalytic amount of ( )-CSA. We propose that the reaction is
catalyzed by the 2-azaallenium cation and proceeds by the
intermolecular reaction of ene-aldimines with this cation.
Furthermore, a formal asymmetric [1,3]-rearrangement with
complete enantioselectivity was achieved for the first time.
This study will significantly advance the use of rearrangement
reactions of ene-aldimines in the synthesis of nitrogen-
containing small organic molecules. Efforts to explore the
reaction mechanism and further develop catalytic asymmetric
D
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version of this rearrangement are ongoing in our laboratory
and will be reported due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01533.
Crystallographic data (PDF)
Cartesian coordinates (PDF)
Procedure and results of rearrangement reaction of ene-
aldimines, characterization of rearrangement products,
procedure and characterization of derivatives, synthesis
and characterization of starting material, mechanistic
studies, asymmetric formal [1,3]-rearrangement, DFT
calculations, computational details, additional references
(PDF)
1H NMR spectra (PDF)
Accession Codes
(5) Substituent effect on the benzylidene unit was studied by the use
of ene-aldimines derived from 4-chloro, 4-methoxy, and 2-methoxy
benzaldehyde under conditions the same as those in entry 1, Table 1.
Neither [3,3]- nor formal [1,3]-rearrangement proceeded in the
reactions of these ene-aldimines: conversion yields were less than 10%
in all of these cases.
(6) (a) Kim, H.; Nguyen, Y.; Yen, C. P-H.; Chagal, L.; Lough, A. J.;
Kim, B. M.; Chin, J. Stereospecific Synthesis of C2 Symmetric
Diamines from the Mother Diamine by Resonance-Assisted Hydro-
gen-Bond Directed Diaza-Cope Rearrangement. J. Am. Chem. Soc.
2008, 130, 12184−12191. (b) Kim, H.; So, S. M.; Yen, C. P-H.;
Vinhato, E.; Lough, A. J.; Hong, J.-I.; Kim, H.-J.; Chin, J. Highly
Stereospecific Generation of Helical Chirality by Imprinting with
Amino Acids: A Universal Sensor for Amino Acid Enantiopurity.
Angew. Chem., Int. Ed. 2008, 47, 8657−8660. (c) So, S. M.; Mui, L.;
Kim, H.; Chin, J. Understanding the Interplay of Weak Forces in
[3,3]-Sigmatropic Rearrangement for Stereospecific Synthesis of
Diamines. Acc. Chem. Res. 2012, 45, 1345−1355.
(7) (a) Schlummer, B.; Hartwig, J. F. Brønsted Acid-Catalyzed
Intramolecular Hydroamination of Protected Alkenylamines. Syn-
thesis of Pyrrolidines and Piperidines. Org. Lett. 2002, 4, 1471−1474.
(b) Haskins, C. M.; Knight, D. W. Sulfonamides as Novel
Terminators of Cationic Cyclization. Chem. Commun. 2002, 2724−
2725.
(8) Bower, J. F.; Williams, J. M. Palladium Catalysed Asymmetric
Allylic Substitution. Routes to β-Amino Acids. Synlett 1996, 1996,
685−686.
(9) Bottger, G. M.; Frohlich, R.; Wurthwein, E. U. Electrophilic
Reactivity of a 2-Azaallenium and of a 2-Azaallylium Ion. Eur. J. Org.
Chem. 2000, 2000, 1589−1593.
CCDC 1847526−1847529 and 1884788 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: momiyama@ims.ac.jp.
ORCID
Toshiyasu Suzuki: 0000-0003-4572-2384
Norie Momiyama: 0000-0001-6659-7100
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research (C) for N.M. (KAKENHI Grant 23550114) from
the JSPS. We deeply thank Ms. Asuka Sano, Mr. Yuta
Tsukahara, and Prof. Masahiro Terada for their work and
discussion in the early stage of this study. We also sincerely
appreciate Prof. Makoto Fujita for his fruitful advice regarding
determination of the absolute configuration by crystal sponge
method. N.M. and T.F. gratefully acknowledge JST-ACCEL
for financial support. N.M. thanks the NOVARTIS Foundation
(Japan) for the Promotion of Science for financial support via
Novartis Research Grants and the Toyoaki Scholarship
Foundation. The computations were partially performed at
Research Center for Computational Science, Okazaki, Japan.
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