Hydrogen-Bond-Guided Reaction of Cyclohexadienone-aldehydes with Amines: Synthesis of an Aminal Group Containing a Fused Tetracyclic Framework

Article abstract of DOI:10.1021/acs.orglett.0c02284

A modular approach has been developed for an efficient synthesis of an aminal group containing a new tetracyclic framework. The strategy has been devised based on selective hydrogen-bond-guided aza-Michael addition of heteroaromatic amines to cyclohexadie

Full text of DOI:10.1021/acs.orglett.0c02284

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Letter
Hydrogen-Bond-Guided Reaction of Cyclohexadienone-aldehydes
with Amines: Synthesis of an Aminal Group Containing a Fused
Tetracyclic Framework
Anil Chauhan, Raj Kumar Patel, Mary Grellier,* and Ravindra Kumar*
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ABSTRACT: A modular approach has been developed for an efficient synthesis of an aminal group containing a new tetracyclic
framework. The strategy has been devised based on selective hydrogen-bond-guided aza-Michael addition of heteroaromatic amines
to cyclohexadienone-aldehydes. The reaction is highly atom economic and practical and involves stereoselective construction of four
new C−N bonds and four rings. The synthetic utility of the tetracyclic product was explored. The role of a H-bond was explained
with the help of experimental and density functional theory (DFT) computation studies.
he sp3-rich molecular complexity of the natural products
reactivity. A domino reaction often provides a modular
Thas always been an inspiration for the development of a
approach to complex molecular architectures, which can be
envisioned from the design of suitable starting materials having
multiple reactive points.3 Suitably substituted symmetrical
cyclohexadienones, which are readily available through
oxidation of phenols, are an ideal substrate in this regard.4−7
A catalytic desymmetrization strategy has been widely explored
with the suitably substituted (alkene/alkyne) symmetrical
cyclohexadienones to afford bicyclic5 and tricyclic6 frame-
works. Cyclohexadienone tethered with an aldehyde 1 could
also be a multifunctional synthon to generate molecular
complexity; however, it was remarkably less explored.7 Al-Tel
et al. have elegantly investigated the reactivity of symmetrical
aldehyde 1 with various amines, in which aniline was reported
to give a desymmetrized bicyclic diamine product 2 through
usual aza-Michael reaction on dienone-imine (I, Scheme 1).7b
Given the importance of H-bonding that often dictates the
reactivity profile, nitrogen-containing heteroaromatic amines
were sought to be explored. It was envisioned that nitrogen in
an aromatic ring may impart H-bonding that may switch the
reactivity of amine toward symmetrical cyclohexadienone-
aldehyde 1 (II, Scheme 1). Herein, we report H-bond-guided
selective synthesis of an aminal group containing symmetrical
newer strategy for target-oriented and diversity-oriented
organic synthesis.1 Although the ring-fused aminal (N−C−
N) system is frequently found in naturally occurring alkaloids
(Scheme 1),2 the stereoselective and step-economical synthesis
of this core is quite challenging due to its inherent chemical
Scheme 1. Ring-Fused Aminal (N−C−N) Group
Containing Natural Products and Stereoselective Reaction
of Cyclohexadienone-aldehyde with Aromatic Amines
Received: July 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02284
© XXXX American Chemical Society
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and unsymmetrical fused tetracyclic scaffolds 3 for the first
time (Scheme 1).
The reaction scope of cyclohexadienone-aldehyde 1 was
further investigated with 2-aminothiazoles (Scheme 3). 2-
The modular reaction of cyclohexadienone-aldehyde 1a with
2-aminopyridine gave a mixture of 3a and 4a in 71% and 5%
yields, respectively, as a single diastereomer for each in
methanol at room temperature (Scheme 2). The correspond-
a
Scheme 3. Reaction of 1 with 2-Aminothiazoles
a
Scheme 2. Reaction of 1a with 2-Aminopyridine
a
Conditions: 1 (0.5 mmol), thiazole (2.2 equiv), solvent (2 mL).
b
Isolated yields are mentioned. Gram-scale synthesis was conducted
(1.17 g, 71% yield). Yields are over two steps.
c
Aminobenzothiazole (5a) gave a solely hemiaminal product 6a
in methanol at 65 °C (Scheme 3). Change of solvent to
acetonitrile gave tetracyclic products (7a−d; 62−81% yields)
with no formation of bicyclic byproducts 9 (like 4) (Scheme
3). The inherent reactivity of the hemiaminal intermediate (6)
was subsequently exploited with 2-aminothiazole and 2-
aminopyridine in the presence of p-TSA, giving unsymmetrical
tetracyclic products (8a and 8b in 67% and 54% yields,
respectively; Scheme 3), whereas bicyclic products (9a−d)
were obtained at room temperature in the absence of any
amine (Scheme 3).
The practical applicability of the present reaction was
evaluated with gram-scale syntheses for 3a (1.60 g, 73%;
Scheme 2) and 8a (1.17 g, 71%; Scheme 3).8 Furthermore, the
tetracyclic structures have interesting cage-like molecular
architecture and latent functional handles, such as the carbonyl
and aminal groups, encouraged us to explore their synthetic
utility (Scheme 4). Reduction of carbonyl with NaBH4 gave
secondary alcohol 10 in 89% yield (dr = 7:1). Ketone 3a was
converted into ring-fused seven-membered lactam 12 in 55%
yield through an oxime intermediate 11,9,10 whereas an oxime
11 was synthesized in 87% yield from 3a.11 The carbon
functionality at the carbonyl carbon was introduced by
palladium-catalyzed cross-coupling reactions between the
corresponding enol-triflate (13) and various coupling partners
(Ph, H, alkyne; 14−16). The reactivity of the aminal group
was investigated under acidic conditions. The selective
cleavage of an aminal C−N bond gave a bicyclic diamine
product (17, single diastereomer, 75%) in the presence of
trifluoromethanesulfonic acid, whereas bicyclic product 4a was
obtained in 69% yield in the presence of acetic acid (Scheme
4).
a
Conditions: 1 (0.5 mmol), aminopyridine (2.2 equiv). Isolated
b
yields are mentioned. Aminopyridines (1.1 equiv each) were
c
employed. Gram-scale synthesis was conducted (1.6 g, 73% yield).
d
Ellipsoid structure of 3a is shown with 50% probability level. See
Table S1 for the optimization study.8
ing bicyclic diamine product 2a was never obtained, as
reported previously with simple aniline.7b The structure of 3a
was unequivocally established by a single-crystal X-ray,8
showing the formation of a new tetracyclic framework, having
an aminal group (Scheme 2).
The substrate scope was investigated by varying cyclo-
hexadienone-aldehydes 1 and 2-aminopyridines (Scheme 2). 4-
Methyl-, 5-methyl-, 6-methyl-, 4-ethyl-, and 4-chloro-2-amino-
pyridine gave the corresponding tetracyclic products (3b−f;
55−78% yields) with 1a. Variation in substituents at the fourth
position of 1 gave the corresponding 4-ethyl- (3g−l; 58−68%
yields), 4-phenyl- (3m−o; 52−66% yields), and 4-cyclohexyl-
(3p and 3q; 56% and 60% yields) substituted tetracyclic
products. However, polysubstituted cyclohexadienone-alde-
hydes failed to give the desired tetracyclic products (3r−t),
probably due to steric congestion. However, the corresponding
bicyclic products (4r and 4s; 60% and 55% yields, respectively)
were obtained from 2,4-dimethyl- and 3,4-dimethyl-substituted
aldehydes (Scheme 2). Unsymmetrical tetracyclic products
could also be obtained by the reaction of 1a with two different
2-aminopyridines (3u−3w; 41−55% yields, Scheme 2).
B
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On the other hand, when 4a was heated exclusively with 2-
aminopyridine in MeOH (or in the presence of CF3SO3H; eq
5), there was no reaction. It advocates that desymmetrization
of enone through the usual aza-Michael reaction would be a
less likely pathway for the synthesis of 3. The minor product 4
was also confirmed to not be formed from 3 by thermal
decomposition (eq 6, Scheme 5).
Scheme 4. Synthetic Transformations of 3a
To further support our hypothesis, density functional theory
(DFT) calculation was conducted, considering the imine and
the 2-aminopyridine as the reference system (A0).8 Both
reaction pathways leading to tetracyclic product 3a and the
bicyclic product 4a are exergonic (ΔG = −26.4 and −13.9 kcal
mol−1, respectively; Figure 1). We have selected the condensed
a
Isolated yields are mentioned.
In order to gain deeper insight into a possible reaction
mechanism and the cause of product switch (2 vs 3), a series of
controlled experiments were conducted (Scheme 5). The
Figure 1. DFT calculation E in kcal mol−1; In parentheses (), ΔG in
kcal mol−1. In blue: transition states (TS). In red dotted line: bonds
formed and/or broken at the TS. The TS4, A8, and A9 energy values
presented take into account the contribution of one additional free 2-
aminopyridine energy.
Scheme 5. Control Experiments
local nucleophilicity index (Nk) to compare the nucleophilicity
of nitrogen. The “N” index was associated with the condensed
−
local Fukui function (fk ) by the following relation Nk =
−
N*fk . The Nk values obtained with different aminopyridines
are shown in Table 1. A higher value of the Nk index is
a
Table 1. Nucleophilicity Indexes
−
entry
compound
N
fk
Nk
1
2
3
4
5
6
2-aminopyridine
3-aminopyridine
4-chloroaniline
AO
A1
A3
2.86
3.08
4.13
2.21
3.16
3.36
0.269
0.278
0.240
0.137
0.288
0.299
0.77
0.86
0.99
0.30
0.91
1.01
reaction between 1a and 4-chloroaniline in MeOH did not give
the corresponding tetracyclic product 3, and a solely bicyclic
diamine product was obtained in 45% yield (18, like 2; eq 1).
The reaction of 1a with 2-aminopyridine at −78 °C in
methanol (as well as in DCM) gave 3a (30−35% yield; eq 2).
In both solvents, the corresponding bicyclic diamine product
was not obtained. These experiments suggest that neither
solvent nor temperature is the origin of the product switch. To
check the key involvement of the H-bond from neighboring
nitrogen, reactions were investigated with 3- and 4-amino-
pyridines (eqs 3 and 4). There was no formation of
corresponding tetracyclic products. It reveals that precisely
positioned neighboring aromatic nitrogen might take part in
H-bonding12 with another 2-aminopyridine to bring it closer to
being attacked on imine to form the aminal (N−C−N) bond.
a
The values rely on the nitrogen involved in the nucleophilic attack to
the enone/imine fragment (see SI for the calculation details).
equivalent to better nucleophilicity of the corresponding
nitrogen. Considering the Nk values, 4-chloroaniline is a better
nucleophile than 2-aminopyridine and 3-aminopyridine
(entries 1−3, Table 1). This first comparison is in agreement
with the synthesis of the bicyclic diamine product 18 (like 2),
as the first step could be the nucleophilic attack at the Cβ
position in cyclohexadienone (eq 1, Scheme 5). The possibility
to form the ring is unfavorable due to the low nucleophilicity
of the imine nitrogen (A0, entry 4, Table 1 and Figure 1). The
possible formation of a H-bond between imine and 2-
aminopyridine, inside the solvation cavity, is slightly ender-
C
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gonic (see Figure 1). This formation enhances the nucleophil-
icity of the 2-aminopyridine fragment (Nk values: 0.77 to 0.91;
entries 1 and 5, respectively). H-bonded preorganization of A1
followed by hydrogen transfer to the pyridine-N led to a new
intermediate A3 (see Figure 1). The activation associated with
the formation of A3 is the rate-determining step for ring
closure. The nucleophilicity of the nitrogen center involved in
the ring closure (A3) increases dramatically (Nk = 1.01, entry
6), which is in the same order of magnitude as in 4-
chloroaniline (entry 3). The ring closure could occur in a
concerted process involving the formation of the N−C bond
and hydrogen transfer (see video in the Supporting
Information). Conformation changes of the six aza-membered
rings from A5 to A6 and subsequent attack of nitrogen to the
electrophilic Cβ position on cyclohexenone led to tetracyclic
product 3a (= A7). Alternatively, the synthesis of minor
product 4a (= A9) has also been investigated by calculations
(see molecular orbital frontiers in the Supporting Informa-
tion).8 Thus, a plausible reaction mechanism has been
proposed based on a previous report12 and experimental and
DFT studies. H-bond-directed addition of 2-aminopyridine to
an imine followed by aza-Michael to cyclohexadienone gives an
aminal intermediate, which on subsequent aza-Michael
reaction leads to a tetracyclic product (Path A, Scheme 6).
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Ravindra Kumar − Division of Medicinal and Process
Chemistry, CSIR-Central Drug Research Institute, Lucknow
226031, UP, India; Academy of Scientific and Innovative
Research (AcSIR), New Delhi 110025, India; orcid.org/
0000-0003-0290-679X; Email: ravindra.kumar1@cdri.res.in
́
Mary Grellier − LCC-CNRS, Universite de Toulouse, CNRS,
UPS, Toulouse F-31077 Cedex 4, France;
Email: mary.grellier@lcc-toulouse.fr
Authors
Anil Chauhan − Division of Medicinal and Process Chemistry,
CSIR-Central Drug Research Institute, Lucknow 226031, UP,
India; Academy of Scientific and Innovative Research (AcSIR),
New Delhi 110025, India
Raj Kumar Patel − Division of Medicinal and Process
Chemistry, CSIR-Central Drug Research Institute, Lucknow
226031, UP, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02284
Scheme 6. Plausible Mechanism
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from SERB, New Delhi, grant no-CRG/
2018/002147 (GAP321) is highly acknowledged. AC and RKP
thank the CSIR and UGC, respectively, for providing a
fellowship. The authors acknowledge SAIF, CSIR-CDRI, for
providing analytical supports. We were also granted access for
this research to the HPC resources of the CALMIP
supercomputing center under the allocation 2020-[p0909],
Toulouse, France. CDRI communication number 10098.
In conclusion, a H-bond-guided stereoselective double aza-
Michael strategy has been developed for an efficient synthesis
of aminal-group-containing tetracyclic fused scaffolds. The
developed method is the mildest so far reported for such a
complex tetracyclic framework. The reaction is highly atom
economic and operationally simple. Controlled experimental
and DFT calculation studies were conducted to draw the
plausible reaction mechanism. Detailed studies of the reaction
mechanism and further exploration of desymmetrization
strategy on cyclohexadienone-aldehyde are underway in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02284.
(3) (a) Domino Reactions: Concepts for Efficient Organic Synthesis;
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