Versatile One-Pot Synthesis of Polysubstituted Cyclopent-2-enimines from α,β-Unsaturated Amides: Imino-Nazarov Reaction

Article abstract of DOI:10.1002/anie.201805641

The imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imines was realized. To this aim, a one-pot procedure involving reductive alkenyliminylation of α,β-unsaturated secondary amides with potassium organotrifluoroborates, followed by acid-catalyzed imino-Nazarov cyclization of the polysubstituted pentan-1,4-diene-3-imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high-yielding protocol efficiently affords polysubstituted pentan-1,4-diene-3-imines, cyclopentenimines, and α-amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan-1,4-diene-3-imines was studied by means of density-functional theory calculations. Results suggested that the electron-donating group facilitates the imino-Nazarov cyclization process.

Full text of DOI:10.1002/anie.201805641

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Accepted Article
Title: A Versatile One-Pot Synthesis of Polysubstituted Cyclopent-2-
enimines from α,β-Unsaturated Amides via Imino-Nazarov
Reaction
Authors: Ting Fan, Ao Wang, Jia-Qi Li, Jian-Liang Ye, Xiao Zheng, and
Pei-Qiang Huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805641
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10.1002/anie.201805641
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A Versatile One-Pot Synthesis of Polysubstituted Cyclopent-2-
enimines from ,-Unsaturated Amides via Imino-Nazarov
Reaction
Ting Fan,[a] Ao Wang,[a] Jia-Qi Li,[a] Jian-Liang Ye,*[a] Xiao Zheng*[a] and Pei-Qiang Huang*[a,b]
Abstract: The imino-Nazarov cyclization of polysubstituted pentan-
1,4-diene-3-imines is realized. To this aim, a one-pot procedure
involving reductive alkenyliminylation of ,-unsaturated secondary
amides with potassium organotrifluoroborates followed by acid-
catalyzed imino-Nazarov cyclization of the polysubstituted pentan-
1,4-diene-3-imine intermediates is studied systematically. This mild,
operationally simple, flexible, and high-yielding protocol efficiently
and Ulmer predicted that this process is disfavored because of
the higher stability of the pentadienyl cation I compared to the
cyclopentenyl cation II (Figure 2, a).[7] Nevertheless, in 2001,
Tius et al. reported the first imino-Nazarov cyclization via
acidifying lithioallenylimine III.[8] Subsequent to this pioneering
work, the following have been reported: a gold(I)-catalyzed [4 +
1] cyclization of internal alkynes and imines,[9] a chiral vicinal
diamine-catalyzed cyclization of -ketoenones,[8b] a gold(I)-
affords
polysubstituted
pentan-1,4-diene-3-imines,
cyclopentenimines, and -amino cyclopentenones, which are useful
scaffolds in organic synthesis. The substituent effect at the C-2
position of polysubstituted pentan-1,4-diene-3-imines was studied by
means of density functional theory calculations. The results
suggested that the electron-donating group facilitates the imino-
Nazarov cyclization process.
catalyzed annulation of -aryl-substituted allenamides,[10]
a
silver-assisted cyclization of vinyl cyclopropylamines,[11] and a
Lewis acid-catalyzed cyclization cascade of a 2,4-dienal with
secondary aniline[12]. It was assumed that these reactions pass
through the 4-electrocyclizations of postulated intermediates
IIIVIII, respectively (Figure 2b).
Polysubstituted cyclopentylamines are structural skeletons found
in many natural products and pharmacologically active
molecules,
such
as
cytotoxic
flavagline
analogs,[1]
immunosuppressive marine alkaloid palau’amine,[2] and the
novel influenza antiviral drug peramivir[3] (Figure 1). Thus, there
is ongoing interest in developing flexible and efficient protocols
for accessing this structure, and many methods have been
reported.[4]
Figure 1. Polysubstituted cyclopentylamine-containing natural products and
drugs.
The Nazarov (cyclization) reaction is a powerful method for
the construction of cyclopentenones.[5] The aza analog of a
Nazarov reaction, if it could be accessed, would provide a
convenient route to polysubstituted cyclopentylamines.[6]
However, in 1997, on the basis of ab initio calculations, Smith
[a]
T. Fan, A. Wang, J.-Q. Li, Dr. J.-L. Ye, Dr. X. Zheng and Prof. Dr.
P.-Q. Huang
Department of Chemistry, Fujian Provincial Key Laboratory of
Chemical Biology, iChEM (Collaborative Innovation Center of
Chemistry for Energy Materials), College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R.
China
Figure 2. Postulated intermediates of imino-Nazarov reactions and our
proposed work.
E-mail: pqhuang@xmu.edu.cn
Prof. Dr. P.-Q. Huang
State Key Laboratory of Elemento-Organic Chemistry
Nankai University, Tianjin, 300071, P. R. China
To clarify the contradiction between the theoretical
prediction and experimental results, there is an urgent need to
study the imino-Nazarov cyclization of polysubstituted pentan-
1,4-diene-3-imines 3 (Figure 2c). Surprisingly, this cyclization
reaction has never yet been reported. This may be partly
[b]
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
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10.1002/anie.201805641
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because polysubstituted pentan-1,4-diene-3-imines 3 are not
readily available. Indeed, very few methods have been
reported for their preparation.[13–16] Thus, based on the
development of a simple and versatile method for the synthesis
The easy access to polysubstituted pentan-1,4-diene-3-
imines 3 and cyclopentenimines 4 provided us with a rare
opportunity to investigate the substituent effect of substrates in
the imino-Nazarov cyclization reaction. Firstly, the one-pot
of polysubstituted pentan-1,4-diene-3-imines
unsaturated secondary amides 1, we herein report a metal-free
one-pot transformation of amides to polysubstituted
cyclopentenimines via tandem reductive
3
from ,-
1
cascade
phenylacrylamides with potassium trans-styryltrifluoroborate 2a
were studied. N-2,6-Dimethylphenyl 2-methyl-3-
annulations
of
N-substituted
2-methyl-3-
4
a
alkenyliminylationimino-Nazarov cyclization sequence (Figure 2,
c), together with a mechanism deciphering 4-electrocyclization
of polysubstituted pentan-1,4-diene-3-imines 3.
phenylacrylamide 1a gave the best results (see the Supporting
Information, Table S2). We next investigated the influence of
various -R2-substituents on N-2,6-dimethylphenyl ,-
unsaturated sec-amides 1ai (Table 1). Various R2-substituents
exhibited significant influence on the yield of one-pot cascade
annulations. When the R2-substituent was a strong electron-
donating group, such as a methoxyl or ethoxyl group, the
desired cyclopentenimine 4b or 4c was generated in excellent
yield within about 1 h at rt (Table 1, entries 2 and 3). In contrast,
for -phenyloxyl, -(o-substituted)phenyl, and -phenyl-,-
unsaturated sec-amides 1dg, the reactions with potassium
trans-styryltrifluoroborate 2a must be carried out at rt for about 1
h, followed by one-pot solvent exchange, and then refluxed in
toluene for about 1 h to afford 4dg in moderate to good yields.
(Table 1, entries 4–7). Notably, pentan-1,4-diene-3-imine 3h[20]
was obtained from -cyano-,-unsaturated sec-amide 1h in
moderate yield at 20C, but a complex mixture formed at a
higher temperature (Table 1, entry 8). Moreover, the reaction of
-unsubstituted ,-unsaturated sec-amide 1i afforded 3i in
nearly quantitative yield under general conditions, yet no imino-
Nazarov product was observed under either heating or acid-
catalyzed conditions (Table 1, entry 9).
We first focused on establishing an easy access to
polysubstituted pentan-1,4-diene-3-imines 3. For this purpose,
the coupling reaction of secondary amides with alkenes was
used to yield ,-unsaturated ketimines.[17] This is one of the
methods we recently developed in our laboratory for the direct
transformation of secondary amides.[18] To develop a general
and flexible entrance to polysubstituted pentan-1,4-diene-3-
imines 3, the use of readily available potassium
organotrifluoroborates
2
as alternative nucleophiles[19] was
investigated. Thus, we have established not only a protocol for
the synthesis of polysubstituted pentan-1,4-diene-3-imines 3, but
also the one-pot synthesis of polysubstituted cyclopent-2-
enimines 4 from ,-unsaturated amides 1 and potassium
organotrifluoroborates
2 (see the Supporting Information,
Scheme S1). Furthermore, the intermediacy of 3 in the one-pot
synthesis of 4 from 1 was also confirmed (see the Supporting
Information, Table S1).
Table 1: Effect of -substituted groups R2 of sec-amides 1a1i.
Table 2: Effect of -substituted groups R3 of sec-amides 1js.
[a] General method: To a DCM solution (0.05 M) of amide (1.0 equiv) and
RBF3K (2.0 equiv) was added 2-F-Pyr. (0.6 equiv) and Tf2O (1.1 equiv),
successively, at 0C. After stirring in DCM at 0C for several minutes, the
reaction mixture was stirred in DCM at rt for 0.5–3 h. Then DCM was removed
in vacuo, toluene was added. The reaction mixture was stirred at 110C for
0.5–1 h. [b] Protocol 1: To a DCM solution (0.05 M) of amide (1.0 equiv) and
RBF3K (2.0 equiv) was added 2-F-Pyr. (0.6 equiv) and Tf2O (1.1 equiv),
successively, at 0C. After stirring in DCM at 0C for several minutes, the
reaction mixture was stirred in DCM at rt for 0.5–3 h. [c] Isolated yield. [d]
Protocol 2: To a DCM solution (0.05 M) of amide (1.0 equiv) and RBF3K (2.0
equiv) was added 2-F-Pyr. (0.6 equiv) and Tf2O (1.1 equiv) successively at
20C. The reaction mixture was stirred at 20C for 3 h. [e] The structure and
stereochemistry of 4a were confirmed by single crystal X-ray diffraction
analysis.[20] [f] E/Z ratio of enimine 3h was determined by 1H NMR analysis.
[a] Protocol 1. [b] General method. [c] Isolated yield. [d] E/Z ratio of
enimine was determined by 1H NMR analysis. [e] Protocol 2.
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10.1002/anie.201805641
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Then a wide array of -R2- and -R3-substituted N-2,6-
dimethylphenyl ,-unsaturated sec-amides 1js were
investigated. As shown in Table 2, when -R2 is a methoxyl
group, the reactions of -aryl-,-unsaturated sec-amides 1-jl
afforded desired cyclopentenimines in good to excellent yields.
The reaction of electron-rich -aryl amide 1j gave a higher yield
than reactions of electron-deficient -aryl amides 1k and 1-l
(Table 2, entries 1–3). When -R2 is a methyl group, the reaction
of -unsubstituted ,-unsaturated sec-amide 1m gave
cyclopentenimine 4m in 90% yield. The reactions of -methyl
and -ethyl ,-unsaturated sec-amides 1n and 1o produced the
desired cyclopentenimines 4n and 4o in moderate yields, along
with complex mixtures (Table 2, entries 5 and 6). The observed
attenuated yields in the case of entries 5 (-methyl) and 6 (-
ethyl) deserves comments. According to our observation, for all
the amide substrates, the reductive olefination reactions
proceeded smoothly to give the corresponding enimines 3 in
excellent yields. The difference in yield comes from the second
step, namely, the imino-Nazarov cyclization. Among several
possible factors that may affect the yield, the stability of the
products under the reaction conditions appears to play an
important role. In fact, while other products were formed cleanly,
the formation of 4o and in particular 4n was accompanied with
many un-identified by-products. Moreover, a prolonged reaction
resulted in a decrease in yield. The product stability may be in
related with the kinetic acidity of the proton at -alkyl
substituents. Possessing the most acidic proton, -Me derivative
4n is easier to form a more nucleophilic dienamine tautomer,
and thus causes side reactions, which results in the lowest yield.
The reaction of cyclohexenyl sec-amide 1p also provided the
imino-Nazarov product 4p in 86% yield, while reactions of 3,4-
dihydro-2H-pyran-6-yl, 2-furyl, and phenyl carboxamides 1qs
only afforded substituted enimines 3qs. The failure for the
former is due to the lability of enimine 3q which was stable only
at 20 C under the acidic reaction conditions (Table 2, entry 8).
The lability of enimine 3q could be attributed to the high
reactivity arisen from its resonance structure: 2,3-
dihydropyrylium. On the other hand, 3r and 3s are too stable to
undergo the desired imino-Nazarov cyclization reaction (Table 2,
entries 9 and 10).
Scheme 1. Other organotrifluoroborates suitable for this one-pot reaction.
To rationalize the crucial substituent effect shown in Table 1-
2 and Scheme 1, density functional theory (DFT) calculations on
the selected 3-amino pentadienyl cations I (Figure 3a), IX-a, IX-b,
and IX-c (Figure 3b) were conducted. Figure 3a shows that our
DFT calculated free energies are essentially consistent with
those of Smith and Ulmer obtained by ab initio calculation.[7] In
the case of polysubstituted pentan-1,4-diene-3-imines, the
disrotatory transition state (TSD) barriers are higher than those of
the corresponding conrotatory TSC. The results are in line with
polysubstituted pentan-1,4-diene-3-imine 3 undergoing a 4-
electrocyclization process; and demonstrated that an electron-
rich substituent (such as methoxyl) at the -position of 3-imino-
pentadienyl cation IX can lower the activation energy of the
2
transition state TSC and stabilize the 3 cyclopentenyl cation X,
thus facilitating the imino-Nazarov cyclization. Both our
experimental and DFT calculation results are consistent with the
substituent effects observed in normal Nazarov reactions.[21]
Furthermore, the one-pot cascade annulations of ,-
unsaturated
sec-amide
1b
with
potassium
2-
arylvinyltrifluoroborates 2b and 2c were investigated (Scheme 1).
Both electron-rich and electron-deficient aryl conjugated
vinyltrifluoroborates reacted well in DCM at rt to give the desired
cyclopentenimines 4t and 4u in good yields (yields were lower
than 4b from 2a, Table 1). In addition, the one-pot cascade
annulation of ,-unsaturated sec-amide 1b with potassium
allyltrifluoroborate 2d afforded cyclopentenimine 4v in 72% yield
after a one-pot solvent exchange and heating in toluene at 70 C
for about 1 h. Notably, the reaction of amide 1p with potassium
allyltrifluoroborate 2d afforded cyclopentenimine 4w in 52% yield.
This means a -aryl group on polysubstituted pentan-1,4-diene-
3-imine is not critical for this imino-Nazarov cyclization.
Figure 3. a) The DFT calculated free energies and Smith and Ulmer’s ab initio
calculated energies (in parentheses) for the 3-amino pentadienyl cation I; b)
The DFT calculated free energies for acid-promoted imino-Nazarov cyclization
of some pentan-1,4-diene-3-imines. All energies are reported in Kcal/mol.
Finally, to obtain further insight into this reaction, preliminary
investigations were carried out into the chiral BINOL-derived
phosphoric acid-catalyzed imino-Nazarov cyclization of pentan-
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10.1002/anie.201805641
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COMMUNICATION
1,4-diene-3-imines 3b and 3v (Scheme 2). [22] Interestingly, by
using Cat. 1, racemic -amino cyclopentenones 5a and 5b were
Keywords: imino-Nazarov reaction • cyclization • potassium
organotrifluoroborates • pentan-1,4-diene-3-imines • one-pot
reaction
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obtained as a single diastereomer in 74% and 30% yields,
respectively. Notably, the bulkier Cat. 2-catalyzed imino-
Nazarov cyclization of 3b also yielded 5a as
a single
diastereomer in 76% yield but with 24% ee. Because
cyclopentenimines 4b and 4v were not observed during these
reactions, we speculated that the -amino cyclopentenones
2
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that of trans-5b was established via the NOESY technique (see
Supporting Information for details).
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one-pot
cascade
reductive
alkenyliminylationimino-Nazarov cyclization was established
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secondary amides with potassium organotrifluoroborates. This
expeditious protocol features easy operation, broad substrate
scope, a high-yielding synthesis of polysubstituted pentan-1,4-
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and an acid-promoted
cascade
4-
electrocyclization, hence providing flexible and efficient access
to a series of polysubstituted cyclopentenimines. Of particular
significance was that a study of substituent effect of substrates
and DFT calculations revealed that an electron-donating
substituent at the C-2 position of pentan-1,4-diene-3-imine can
promote the imino-Nazarov cyclization and stabilize the
cyclopentenyl cation. The possibility of enantioselective
organocatalytic imino-Nazarov cyclization also emerged.
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Acknowledgements
The authors are grateful for financial support from the National
Key R&D Program of China (grant No. 2017YFA0207302), the
NSF of China (21332007, 21472153, 21472157 and 21672175),
the Natural Science Foundation of Fujian Province of China
(2017J01021), the Fundamental Research Funds for the Central
Universities (No. 20720140538), and the Program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT) of Ministry of Education, China. We also
thank Mr. Jin-Cheng Liao for the preparation of chiral BINOL
phosphoric acids during his graduate period in our group.
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Crystallographic Data Centre (CCDC) as 1823654 (4a) and 1840268
(5a),
and
can
be
obtained
free
of
charge
from
www.ccdc.cam.ac.uk/structures. The predominant s-trans/trans (AA)
conformation of major isomers of polysubstituted pentan-1,4-diene-3-
imines (such as 3h) and their cations IX was confirmed by single-crystal
X-ray diffraction analysis of 3e (CCDC 1823653) and DFT calculations
(see Supporting Information for details).
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10.1002/anie.201805641
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
An imino-Nazarov cyclization of
Ting Fan, Ao Wang, Jia-Qi Li, Jian-Liang
Ye,* Xiao Zheng* and Pei-Qiang
Huang,*
polysubstituted pentan-1,4-diene-3-
imines 3 to prepare polysubstituted
cyclopentenimines 4 is established,
which features a one-pot reductive
alkenyliminylation of ,-unsaturated
secondary amides 1 with potassium
organotrifluoroboratesacid-catalyzed
4-electrocyclization of enimines 3.
Page No. – Page No.
A Versatile One-Pot Synthesis of
Polysubstituted Cyclopent-2-
enimines from ,-Unsaturated
Amides via Imino-Nazarov Reaction
This article is protected by copyright. All rights reserved.