Formal [4 + 2] Cycloadditions of Anhydrides and α,β-Unsaturated N-Tosyl Ketimines

Article abstract of DOI:10.1021/acs.orglett.8b04091

A method for the diastereoselective synthesis of highly substituted β-enamino ketones from anhydrides and ketone-derived imines is reported. Cyclic, enolizable anhydrides undergo a base-promoted conjugate addition reaction with α,β-unsaturated N-tosyl ket

Full text of DOI:10.1021/acs.orglett.8b04091

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Formal [4 + 2] Cycloadditions of Anhydrides and α,β-Unsaturated
N‑Tosyl Ketimines
Noah P. Burlow, Sara Y. Howard, Carla M. Saunders, James C. Fettinger, Dean J. Tantillo,
and Jared T. Shaw*
Department of Chemistry, University of California, One Shields Ave, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: A method for the diastereoselective synthesis of
highly substituted β-enamino ketones from anhydrides and
ketone-derived imines is reported. Cyclic, enolizable anhydrides
undergo a base-promoted conjugate addition reaction with α,β-
unsaturated N-tosyl ketimines, followed by an intramolecular
acylation to give formal [4 + 2] cycloaddition products. The
carboxylic acid-containing products are formed with modest
selectivity for the cis-diastereomer and can be fully epimerized to
the trans-diastereomer upon esterification.
yclic anhydrides are useful dipolar synthons for the
or 1.2 equiv of anhydride (entries 2 and 3). Switching the base
Csynthesis of complex organic molecules through formal to 1 equiv of i-Pr2NEt resulted in a reversal of selectivity to the
cycloaddition reactions.1 The most widely studied reaction
cis isomer (entry 12), and performing the reaction in CH2Cl2
provided a dr of 94:6 (entry 14). Attempts at using
substoichiometric quantities of i-Pr2NEt resulted in lower
conversion (entry 15). We attribute the reduced reactivity in
this case to the acidity of the N-tosyl vinylogous amide proton,
which results in a catalyst inhibition by protonation.
involves the addition to imines to form lactams, recently
referred to as the Castagnoli−Cushman reaction (Figure 1).1b
Although most previous studies of this reaction employed N-
alkyl imines, the reaction of N-sulfonyl imines was recently
shown to proceed by base mediation2 and rendered
asymmetric using organocatalysts.3 Although N-aryl imines
are less commonly used, they exhibit excellent reactivity in a
recently reported catalytic reaction.3b In parallel, Tamura has
demonstrated that homophthalic anhydride undergoes base-
mediated addition to alkynes to form, after decarboxylation,
highly substituted naphthalenes.4 Early studies included
limited examples of addition to alkenes to form substituted
tetralins,4,5 and more recently, Connon developed an
asymmetric variant of this process.6 We initiated a study of
α,β-unsaturated ketimines, which have the potential to exhibit
merged “Tamura-like” and “Cushman-like” reactivity. Herein,
we report the first reactions of cyclic anhydrides in reactions
with electron-deficient unsaturated imines,7 which proceed in
high diastereoselectivity and, for the first time, exhibit
“Tamura-like” reactivity to form 5-membered ring products.
For our initial investigation of this reaction, we used the
readily enolizable homophthalic anhydride and methoxy-
substituted chalcone imine 1c (Table 1). Chalcone-derived
imines were chosen for their ease of synthesis and
diversification. Our favored conditions for the base-catalyzed
anhydride−Mannich reaction (AMR), 1 equiv of TMG in
acetonitrile, provided the desired product in full conversion
but with virtually no diastereoselectivity (entry 1).8 Similar
results were observed with 20 mol % of TMG with either 1.0
Acid 3c was converted to the corresponding methyl ester for
ease of purification. Upon treatment with TMS-diazomethane,
the diastereomer ratio of the resulting ester shifted to varying
degrees and with the addition of DBU seemed to invert
completely. As such, we suspected that the configuration of the
initially formed acid was cis, and as a result of base-mediated
epimerization of the stereogenic center α to the carboxyl
group, the configuration of the ester was trans. To support our
hypothesis, the ester 4c was hydrolyzed back to the acid using
LiOH (Figure 2). We hoped to obtain an X-ray crystal
structure by converting the carboxylic acid to a benzyl amide.
After examining several conditions for amide coupling, those of
Knapp and co-workers resulted in the formation of a less polar
product lacking the expected amide protons.9 X-ray crystallog-
raphy revealed that the nitrile had been formed, presumably
through a von Braun-like mechanism proceeding through
cleavage of the PMB amide.10 Additionally, this structure
showed the relative stereochemistry of nitrile 5 to be trans.
Given the similarity in coupling constants between ester 4c and
nitrile 5, we conclude that both compounds have a trans
configuration between the adjacent stereogenic centers.11
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04091
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Conversion of 4c to nitrile 5; X-ray crystal structure of
nitrile 5.
Figure 1. Imine−anhydride formal [4 + 2] cycloadditions.
Table 1. Reaction Optimization for Chalcone-Derived α,β-
Unsaturated N-Tosyl Imine 1c
a
a
entry
base (equiv)
2 (equiv)
solvent
dr
conv (%)
1
2
3
4
5
6
7
8
TMG (1.0)
TMG (0.2)
TMG (0.2)
TMG (1.0)
TMG (1.0)
TMG (1.0)
TMG (1.0)
TMG (1.0)
TMG (1.0)
TMG (1.0)
TMG (1.0)
i-Pr2NEt (1.0)
i-Pr2NEt (1.0)
i-Pr2NEt (1.0)
i-Pr2NEt (0.2)
i-Pr2NEt (1.2)
i-Pr2NEt (1.0)
1.0
1.0
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
EtOAc
toluene
DMF
n-hexane
1,4-dioxane
acetone
CH3CN
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
57:43
54:46
51:49
29:71
21:79
23:77
26:74
31:69
N/A
29:71
45:55
79:21
64:36
94:6
100
82
85
97
91
95
94
82
0
90
79
93
58
81
20
89
97
9
10
11
12
13
14
15
16
17
Figure 3. α,β-Unsaturated N-tosyl imine scope of the aza-Tamura
reaction.
>95:5
79:21
93:7
with electron-donating groups giving an improved dr for the
cis-diastereomer. Alternatively, electron-withdrawing groups
resulted in an erosion of dr, which can be explained by a
faster rate of epimerization to the trans-diastereomer under the
reaction conditions. Enolizable imines (1h) and (1i) were
tolerated under the reaction conditions as well (Figure 3).
Methyl-substituted homophthalic anhydride and phenyl
succinic anhydride also give formal cycloaddition products
(Figure 4). The relative stereochemistries of 4i and 7 were
a
1
Determined by the H NMR spectrum of the unpurified reaction
mixture.
Chalcone imines with a variety of substituents provided
formal cycloaddition products in high yield (Figure 3). The
electronics of the aryl ring adjacent to the imine had a
noticeable effect on the diastereoselectivity of the reaction,
B
DOI: 10.1021/acs.orglett.8b04091
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Organic Letters
Letter
Enamino ketones have been shown to undergo condensation
reactions; however, we found the carbonyl of our β-enamino
cyclohexanone substrate to be inert to these conditions.15
Scheme 2. Derivatization of Aza-Tamura Products 4c and 9
Figure 4. Expanded scope of the aza-Tamura reaction.
assigned by computational NMR.11,12 Product 9 was converted
to the corresponding nitrile, which provided an X-ray crystal
structure for the stereochemical assignment of 9 and 11.11
We hypothesize that the mechanism for this reaction
involves conjugate addition of the anhydride enolate to the
imine, followed by an intramolecular acylation (Scheme 1).
In summary, we have developed a base-promoted reaction
between α,β-unsaturated N-tosyl ketimines and cyclic,
enolizable anhydrides. Although the reaction can be run
catalytically with TMG, the use of stoichiometric Hunig’s base
̈
Scheme 1. Mechanistic Hypothesis
provides higher yield and diastereomer ratio. Conversion to
the methyl ester allows for full epimerization to the trans-
diastereomer by subsequent treatment with DBU. The
resulting β-enamino ketone products can be detosylated and
derivatized with a variety of acylating reagents.
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.8b04091.
Experimental procedures, computational NMR data, X-
ray crystallographic data, 1H and 13C NMR spectra
(PDF)
Accession Codes
CCDC 1887468 and 1887611 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or 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.
The ambident enamine anion resulting from conjugate
addition can undergo N-acylation to form a δ-lactam (15) or
C-acylation followed by tautomerization to form a β-enamino
cyclohexanone (3a−k).
We have observed the N-acylation product of type 15 in 1H
NMR studies as a transient, kinetically favored intermediate
that converts to the β-enamino ketone over the course of the
reaction. The structure of this intermediate was assigned on
the basis of comparison of 1H NMR signals with similar
molecules that have been previously synthesized by Smith and
co-workers.13 Product 15 was formed exclusively when the
reaction was run overnight at −20 °C in THF using TMG as
the base, albeit in low conversion. Resubjection to reaction
conditions at room temperature gave full conversion to 3c.
The N-Ts products can be cleanly detosylated by dissolution
in neat sulfuric acid.14 As exemplified with 4c, the resulting β-
enamino ketone (17) can then be acylated with various acid
chlorides and reagents of similar reactivity (Scheme 2). β-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jtshaw@ucdavis.edu.
ORCID
Carla M. Saunders: 0000-0001-6699-2848
James C. Fettinger: 0000-0002-6428-4909
Dean J. Tantillo: 0000-0002-2992-8844
Jared T. Shaw: 0000-0001-5190-493X
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.8b04091
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1764309-0, CHE-1414298). N.P.B. acknowledges addi-
tional support in the form of an administrative supplement
from the NSF (CHE-1764309-0) and a Bradford Borge
fellowship from UC Davis. This work used the Extreme
Science and Engineering Discovery Environment (XSEDE)
with the award TG-CHE180098 supported by National
Science Foundation grant number ACI-1548562. D.J.T.
acknowledges computational support from the National
Science Foundation (CHE-030089 [XSEDE]).
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DOI: 10.1021/acs.orglett.8b04091
Org. Lett. XXXX, XXX, XXX−XXX