An Amine Group Transfer Reaction Driven by Aromaticity

Article abstract of DOI:10.1021/acs.orglett.8b02967

A stereoselective domino inverse electron-demand Diels-Alder/amine group transfer reaction catalyzed by a bidentate Lewis acid provides 1-amino-1,2-dihydronaphthalenes, a core structure in many bioactive compounds. A concerted mechanism is proposed based on experimental studies as well as DFT computations demonstrating a new general reactivity scheme. The broad scope of the reaction was evaluated by variation of all three starting compounds, phthalazines, aldehydes, and amines. Scalability was demonstrated by a gram scale reaction without diminished yield.

Full text of DOI:10.1021/acs.orglett.8b02967

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
An Amine Group Transfer Reaction Driven by Aromaticity
†
‡
†
,†
†
‡
Sebastian Ahles, Silas Gotz, Luca Schweighauser, Mirko Brodsky, Simon N. Kessler,
̈
Andreas H. Heindl,† and Hermann A. Wegner*
†
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
‡
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
*
S Supporting Information
ABSTRACT: A stereoselective domino inverse electron-
demand Diels−Alder/amine group transfer reaction catalyzed
by a bidentate Lewis acid provides 1-amino-1,2-dihydronaph-
thalenes, a core structure in many bioactive compounds. A
concerted mechanism is proposed based on experimental
studies as well as DFT computations demonstrating a new
general reactivity scheme. The broad scope of the reaction was
evaluated by variation of all three starting compounds,
phthalazines, aldehydes, and amines. Scalability was demon-
strated by a gram scale reaction without diminished yield.
electivity control in chemical transformations demands
detailed knowledge of reaction pathways. The smart
Scheme 1. IEDDA-Domino Reactions of Phthalazines 1
Catalyzed by a Bidentate Lewis Acid
S
utilization of concerted mechanisms allows the buildup of
chemical bonds in a highly predictive way, controlling
1
,2
constitution and stereochemistry. Pericyclic reactions are
the prime example in this context. While cycloadditions,
sigmatropic rearrangements, and electrocyclizations are con-
tent of the standard chemical curriculum, concerted group
3
,4
transfer reactions represent a unique feature in reactivity.
Recently, transition metal catalyzed group transfer reactions
5
−7
have gained increased attention.
The incorporation of such
transformations within domino processes allows chemists to
dramatically increase molecular complexity in one operational
8
−11
step.
In particular, the generation of highly reactive
intermediates can enable unusual domino transformations. As
an example of the latter we reported an example of a higher
order Claisen rearrangement, the first [3,9] sigmatropic
12
rearrangement (Scheme 1). Key for the realization of such
a transformation was accessing an o-quinodimethane inter-
mediate 3 via an inverse electron demand Diels−Alder reaction
2
8
The high reactivity of o-quinodimethane 3 generated by
this reaction also proved to be a disadvantage in some cases.
For example, only moderate yields were achieved for a
protocol to synthesize substituted naphthalenes from enamines
(
IEDDA reaction) of phthalazine derivatives 1 catalyzed by a
13
bidentate Lewis acid (BDLA) 2. Compared to IEDDA
reactions with aromatics containing a higher number of
14−20
29
nitrogen atoms (e.g., 1,2,4-triazines or 1,2,4,5-tetrazines),
generated in situ from aldehydes and amines. During our
this kind of reaction with phthalazines 1 has only been scarcely
analysis of various minor side products, we identified the
formation of 1-amino-1,2-dihydronaphthalenes 4, a suitable
precursor for the synthesis of 1-aminotetralins. Such structures
represent a core motif used in various bioactive compounds,
exploited, probably due to the harsh conditions normally
2
1−24
required.
Besides the [3,9] sigmatropic rearrangement,
the intermediary o-quinodimethane 3 not only was involved in
30,31
25,26
especially in antidepressants.
The most utilized strategy to
the synthesis of substituted naphthalenes by elimination
but also took part in a second Diels−Alder (DA) reaction
leading to highly complex alkaloid-type structures (Scheme
Received: September 17, 2018
2
7
1
).
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
access substituted analogues includes different variations of
incomplete conversion (Scheme 2, 4f). We reasoned that the
in situ generated conjugated enamine is much less reactive in
the initial IEDDA reaction compared to nonconjugated ones.
In addition, the elevated temperature led to the formation of
the elimination product, the naphthalene. To demonstrate the
scalability of this transformation, the reaction of phthalazine
(1a) with 3-phenylpropionaldehyde (6c) and pyrrolidine (7a)
(Scheme 2, 4c) was carried out on gram scale without
diminished yield (2.21 g, 95%).
selective metal catalyzed ring opening of either oxabenzo-
32−36
norbornadiene or azabenzonorbornadienes.
Alternatively,
amino-1,2-dihydronaphthalenes can be prepared by metathesis
3
7
reaction, [4 + 2] cycloaddition reaction of isochromenylium
3
8
tetrafluoroborates, via an organocatalytic domino nitro-
alkane-Michael/aldol condensation reaction, Pt-catalyzed
39
40
[
1,5]-sigmatropic hydrogen shift, or via dearomatization.
In nearly all of these examples, the elaborate starting materials
involve a multistep synthesis.
Variation of the amine 7 showed that cyclic ones 7a−c gave
the highest yields (Scheme 3). This observation can be
Initially observed as a side product we were able to isolate
product 4 in high yields when electron-deficient phthalazines 1
were used [e.g., 5,8-difluorophthalazine (1b)]. Increasing the
amount of amine 7 led to 1-amino-1,2-dihydronaphthalenes 4
even with electron-neutral phthalazine (1a) (see Supporting
Information (SI) for comparison). With the optimized
conditions, we explored the use of other Lewis acids. Although
BDLA 2 is easily accessible, other strong and commercially
available monodentate Lewis acids [BF , B(C F ) ] were
Scheme 3. Scope of Amines in the Domino IEDDA Amine
a
Group Transfer Reaction
3
6 5 3
41,42
assayed (see SI).
Similar to our previous studies on the
bidentate Lewis acid catalyzed IEDDA reaction of diazines,
only BDLA 2 was active and, more importantly, stable enough
43,44
under the reaction conditions.
To explore the scope of this transformation we started with
the screening of various aldehydes 6. Excellent yields were
achieved for different alkyl substitution patterns (Scheme 2,
Scheme 2. Scope of Aldehydes in the Domino IEDDA
a
Amine Group Transfer Reaction
a
Reaction conditions: Phthalazine (1a) (250 μmol, 1.00 equiv),
BDLA 2 (12.8 μmol, 5.1 mol %); amine 7 (500 μmol, 2.00 equiv), 3-
phenylpropionaldehyde (6c) (375 μmol, 1.50 equiv), THF (1.00 mL,
b
0
.25 M). Isolated as single diastereomers. Isolated as a mixture of
two diastereomers. The ratio was determined by NMR spectroscopy.
reasoned by steric effects. Still, acylic amine 7d gave the
desired product in moderate yield. Amino alkyne 7e and
primary amine 7f only generated 1-amino-1,2-dihydro-
naphthalene 4k/4m, when an electron-deficient phthalazine
1
was used [e.g., 5,8-difluorophthalazine (1b)] (Scheme 3).
We attributed this finding to the decreased electron density of
the fluorophthalazine compensating for the lower nucleophil-
icity of primary amines or amino alkynes, respectively.
Differently substituted phthalazines 1 gave the desired
product in very good yields, even for the more electron-rich
methyl substituted one 1e (Scheme 4). Nonsymmetric
substituted diazines (1c−e) generated a mixture of constitu-
tional isomers (Scheme 4, 4n−4p). In the case of 6-
methoxyphthalazine (1f) only one constitutional isomer, 1,2-
dihydronaphthalene 4q, was isolated in low yield (36%,
Scheme 4), even though complete consumption of phthalazine
a
Reaction conditions: Phthalazine (1a) (250 μmol, 1.00 equiv),
BDLA 2 (12.8 μmol, 5.1 mol %); pyrrolidine (7a) (500 μmol, 2.00
equiv), aldehyde 6 (375 μmol, 1.50 equiv), THF (1.00 mL, 0.25 M).
Isolated as single diastereomers. Isolated as a mixture of two
diastereomers and corresponding enantiomers. The ratio was
determined by NMR spectroscopy.
b
1
4
4
a−4c) even in the presence of a tertiary alcohol (Scheme 2,
d). Silyl ether protected alcohol 4e could only be isolated in a
1f was observed (by H NMR spectroscopic analysis of the
crude reaction product). Therefore, we assume that only one
constitutional isomer of the generated intermediate 3q
underwent the final group transfer reaction efficiently, while
the other isomer decomposed in an unknown side reaction.
The relative configuration of the substituents was correlated
to the proximity of the substituents in accordance with the
moderate yield (Scheme 2, 4e), probably due to cleavage of
the silyl group under Lewis acidic conditions. When phenyl-
acetaldehyde (6f) was used, no formation of product was
observed at 60 °C. Even heating the reaction mixture to 100
°
C (solvent was changed to 1,4-dioxane) showed only
B
DOI: 10.1021/acs.orglett.8b02967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Scope of Dienes in the Domino IEDDA Amine
Group Transfer Reaction
Scheme 5. Proposed Mechanism for Domino IEDDA Amine
Group Transfer Reaction
a
a
Reaction conditions: Phthalazine 1 (250 μmol, 1.00 equiv), BDLA 2
(
12.8 μmol, 5.1 mol %); pyrrolidine (7a) (500 μmol, 2.00 equiv), 3-
phenylpropionaldehyde (5) (375 μmol, 1.50 equiv), THF (1.00 mL,
.25 M). Isolated as single diastereomers. The ratio of constitutional
0
isomers was determined by NMR spectroscopy.
computed structures by NOESY NMR measurements (see SI
for details). The results correspond unambiguously to the
trans-configuration in the final product. In accordance to our
previous reported domino IEDDA-DA reaction, we concluded
that the reactive intermediate 3, generated after nitrogen
27
expulsion, also adopts a trans-configuration.
As the reaction outcome is positively influenced by an excess
of amine, we propose that the generated o-quinodimethane 3 is
attacked by a second amine 7. The attack is directed and
supported by the amine group within the intermediate 3. Such
an attack can occur simultaneously with the expulsion (Scheme
5
, pathway A) or in a stepwise manner resulting in the
formation of zwitterionic intermediate 9 (Scheme 5, pathway
B). In the latter case, a proton transfer from one nitrogen to
the other follows, leading to the elimination of the protonated
amine and generation of the product 4. The driving force of
this reaction is clearly the generation of the aromatic system.
To support the mechanistic proposal, structures were
optimized at the B3LYP/6-311++G** level of theory and
energies were computed at DLPNO-CCSD(T)/def2-TZVPPD
using the IEFPCM solvent model for THF. They were carried
out on the example of the reaction of phthalazine (1a) with 3-
methylbutyraldehyde (6a) and pyrrolidine (7a) (Scheme
Figure 1. Relative Gibbs energy profile for the reaction from
intermediate 3a to product 4a. Structures were optimized at the
B3LYP/6-311++G** level of theory, and energies were computed at
DLPNO-CCSD(T)/def2-TZVPPD using the IEFPCM solvent model
for THF.
53
4
5−50
2
).
Starting from the o-quinodimethane intermediate 3a,
the remaining reaction path was computed (Figure 1). While
the zwitterionic intermediate 9a was clearly established, it
converts without barrier to the following transition state TS2a,
leading to product 4a. This outcome indicates an “enforced”
In summary, we demonstrate efficient access to 1-amino-1,2-
dihydronaphthalenes 4 through a diastereoselective domino
IEDDA-group transfer reaction in one step. The reaction can
be carried out on gram scale and shows a broad substrate scope
of secondary amines as well as aldehydes. In the case of the
diazine, electron-neutral to electron-poor phthalazines are
necessary for good yields. The generality of combining
bidentate Lewis acid catalysis for the generation of highly
51
concerted mechanism (pathway A). An alternative higher
order N[1,9] sigmatropic shift, in analogy to a N[1,3]
sigmatropic shift, reported by Xu and co-worker, and the
higher order Claisen rearrangement reported by us can be
5
2
ruled out. The fact that product formation is dependent on
amine concentration and a higher activation energy was
computed for this pathway precludes it (see SI for details).
C
DOI: 10.1021/acs.orglett.8b02967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactive o-quinodimethane intermediates with the driving force
of aromaticity promises fruitful application for future reaction
design.
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7
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Experimental details, analytical data, NMR spectra,
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(PDF)
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AUTHOR INFORMATION
Corresponding Author
E-mail: hermann.a.wegner@org.chemie.uni-giessen.de.
Donsbach, C.; Wegner, H. A. Org. Lett. 2016, 18, 1330−1333.
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ORCID
Andreas H. Heindl: 0000-0002-5403-2177
Hermann A. Wegner: 0000-0001-7260-6018
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1
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MS-support, respectively, Urs Gellrich and Andre
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help with the TOC image.
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K. Eckharrdt
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