Mechanistic Investigation of Castagnoli-Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones

Article abstract of DOI:10.1021/acs.joc.1c01163

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the thr

Full text of DOI:10.1021/acs.joc.1c01163

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Article
Mechanistic Investigation of Castagnoli−Cushman Multicomponent
Reactions Leading to a Three-Component Synthesis of
Dihydroisoquinolones
Sara Y. Howard, Michael J. Di Maso, Kristin Shimabukuro, Noah P. Burlow, Darlene Q. Tan,
James C. Fettinger, Thomas C. Malig, Jason E. Hein, and Jared T. Shaw*
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ABSTRACT: The mechanisms for the three- and four-component
variants of the Castagnoli−Cushman reaction (CCR) have been
investigated. A series of crossover experiments were conducted to
probe the structure and reactivity of known amide-acid
intermediates for the three- and four-component variants of the
CCR (3CR and 4CR, respectively). Control experiments paired
with in situ reaction monitoring with infrared spectroscopy for the
4CR align with a mechanism in which amide-acids derived from
maleic anhydride can reversibly form free amine and cyclic
anhydride. Although this equilibrium is unfavorable, the aldehyde
present can trap the primary amine through imine formation and
react with the enol form of the anhydride through a Mannich-like
mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous
mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes
for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of
more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit
this novel mechanism.
INTRODUCTION
■
The Castagnoli−Cushman reaction (CCR) and its related
three- and four-component reactions are powerful methods for
the facile synthesis of densely substituted lactam products.1,2
Lactams are commonly found in the core of natural products
and other biologically relevant compounds, several of which
have been synthesized using the CCR.3−6 The CCR was first
discovered in 1969, when N-benzylidene methylamine and
succinic anhydride were combined under refluxing conditions
to form γ-lactam 3.7 This reaction typically proceeds with high
diastereoselectivity for the thermodynamically favored trans
diastereomer; however, the mechanism for its formation has
been disputed for some time.8,9
Lactam formation in the CCR can follow one of two
mechanistic pathways. First, it was hypothesized that the
reaction proceeds through an iminolysis pathway, forming N-
acyl iminium ion 4 through acylation of the imine nitrogen
(Figure 1). Subsequent intramolecular Mannich addition
through carboxylic acid enolate 4b leads to 3. Alternatively,
in analogy to the Perkin reaction, the CCR could proceed
through Mannich addition of anhydride enolate 5, followed by
N-acylation to form lactam 3. Earlier studies by Cushman
focused on the electronic and steric influences of the CCR with
homophthalic anhydride and led to the acceptance of the
Figure 1. Initial discovery of the Castagnoli−Cushman reaction and
proposed reaction pathways.
Received: May 18, 2021
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former mechanistic pathway.8 Reactions with less reactive N-
aryl and N-sulfonyl imines can be accelerated with hydrogen
bonding10 and basic catalysts,11,12 respectively.
was suitable on both counts. After this discovery, a series of
control experiments led to the observation that preformation
of the imine or anhydride was unnecessary: simply mixing all
four of the components and heating gave the lactam product in
similar yield and diastereoselectivity. At the time of discovery,
we assumed that the mechanism proceeded via the same
zwitterionic intermediate originally proposed by Cushman
(Figure 3). Specifically, we discovered that the imine,
The CCR also forms the basis of a three-component
reaction (3CR) of homophthalic anhydride, amines, and
aldehydes with Lewis acid catalysts and additives.13−23 In
one case, a diacid is used as an anhydride precursor.24 Similar
zwitterionic intermediates were proposed for the 3CR of
homophthalic anhydride with amines and aldehydes, wherein
the amine attacks homophthalic anhydride to form amide-acid
11, followed by condensation with aldehyde 9 and successive
Mannich addition (Figure 2A).15 Although these ions (12) are
Figure 3. 17a and 17b have been isolated as intermediates in the 4CR
and lead to a single regioisomer and diastereomer of lactam 15.
anhydride, and thiol led to the room-temperature formation
of a mixture of amide-acid regioisomers. Heating this mixture
with aldehyde led to a single regioisomer and diastereomer of
the product. This led us to propose that the amide nitrogen
was condensing with the aldehyde to form N-acyl iminium ion
17, analogous to the proposed 3CR mechanism (Figure 3).
The previous work on the 4CR has described the scope and
utility of the 4CR, including the expansion to a variety of
amines, aldehydes, and chiral thiols,26 as well as applications to
the synthesis of a complex natural product.4,27−30 Although
there are other possible nucleophiles capable of conjugate
addition, most are insufficiently nucleophilic or undergo
competitive reaction with the aldehyde. As a result, the 4CR
has remained limited to thiol reaction partners.
Later studies of cyano-succinic anhydride with imines
revealed a Mannich-like mechanism was operative (Scheme
1). In the case of cyano-succinic anhydrides, computational
studies suggest that a rapid enol−keto tautomerization of the
anhydride enabled a reaction with the imine through a
Zimmerman−Traxler-like six-membered ring transition state
(Scheme 1). Additionally, carboxylic acid enolate 4 was
computed to be unrealistically high in energy for the CCR.9
The Mannich-like mechanism for the reactions of cyano-
succinic anhydride and imines served as a basis for explaining
the previous reactions of Castagnoli and Cushman, as well as
the original thiophenylsuccinic anhydride reaction and the
ensuing reactions of cyano-glutaric anhydrides.18,31 Further-
more, this mechanistic picture is consistent with an earlier
proposal made by Connon for the reactions of carbonyl
Figure 2. (A) Three-component variant and proposed mechanism.
(B) Observed amide-acid intermediate in the three-component
variant of the Castagnoli−Cushman reaction.
commonly invoked as intermediates, there is little precedent
for their formation by the condensation of N-substituted
amides with aldehydes. This proposed mechanism was
supported by the isolation of what was thought to be
regioisomer 11a.15 However, a later study found that the
isolated amide-acid intermediate was actually 11c (Figure
2B).24 It was suggested that a 3CR in which amine, aldehyde,
and homophthalic anhydride are simultaneously combined
without additives was not possible, as amide-acid 11c would be
unproductive for lactam formation. These opposing results
made it unclear how the 3CR proceeds to the lactam product if
amide-acid 11a is not formed.
The lactam-forming four-component reaction (4CR),
developed in our group in 2007, emerged from initial reaction
explorations of succinic anhydrides and imines.25 Cushman
used phenylsuccinic anhydride in refluxing chloroform as part
of his mechanistic study of the CCR.8 Initially, we sought to
replace the phenyl ring with a group that would both facilitate
the reaction and serve as a functional handle for subsequent
transformations; it was found that thioaryl succinic anhydride
B
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room temperature for 24 h. This product was consistent with
the regioisomer (11b) isolated and observed by Krasavin in the
development of the 3CR of homophthalic diacid, aldehydes,
and amines, as well as other similar reports.24,33,34 A crossover
experiment was performed to probe the reaction mechanism of
the 3CR. When amide-acid 26a was isolated and treated with
p-Cl-benzylamine in refluxing toluene for 6 h, a mixture of
amide-acids 26a and 26b was observed by LCMS (Figure 4B).
Next, amide-acid 26a was isolated, combined with benzalde-
hyde, and heated in toluene, resulting in product 27a in >95:5
dr and 82% yield (Figure 4C). Additionally, mixing
homophthalic anhydride, benzylamine, and benzaldehyde in
refluxing toluene yielded lactam 27a in 84% yield and >95:5 dr
for the trans diastereomer. To the best of our knowledge, this
is the first instance of a three-component CCR with
homophthalic anhydride, amines, and aldehydes without the
necessity of a Lewis acid leading to dihydroisoquinolone
products 27.
Interested in expanding the scope of this three-component
reaction of homophthalic anhydride, amines, and aldehydes,
we screened a variety of dehydrating agents. Interestingly, the
reaction proceeds comparably regardless of the dehydrating
agent used and can proceed in the absence of a dehydrating
agent, as well.35 When the reaction was run for 6 h, a mixture
of cis and trans diastereomers was observed. Presumably, the
kinetic cis diastereomer is formed first, and under reaction
conditions, it can epimerize to the trans diastereomer over
time. Following screening, a series of substrates were
synthesized using this three-component method. The reaction
tolerates a variety of amine components, including primary and
secondary aliphatic amines as well as benzyl and aryl amines.
Both aromatic and aliphatic aldehyde-derived imines also
provided tetrahydroisoquinolone products in good yields and
excellent diastereoselectivity for the trans diastereomer (Figure
5).
Scheme 1. Mannich-like Mechanism Computed for Cyano-
succinic Anhydride
compounds to form lactones.32 However, while this mecha-
nism explains the reactions of thiosuccinic anhydrides with
preformed imines, it does not explain how amide-acids 17a and
17b proceed to the lactam product. Herein, we report detailed
synthetic experiments and kinetic investigations that culminate
in a novel mechanism for the 3CR and 4CR. This work upends
our previous decade-old proposal and opens the door for the
design of new multicomponent reactions based on the
reactivity that is described.
RESULTS AND DISCUSSION
■
Initial studies began by probing the mechanism of the 3CR. A
series of experiments were conducted to understand the
structure and reactivity of the amide-acid intermediate formed
in this reaction. First, when homophthalic anhydride was
heated in the presence of benzylamine for 1 h, a single amide-
acid intermediate 26 was observed, the structure of which was
determined by X-ray crystallography (Figure 4A). The same
product was observed when the reaction was performed at
Similar crossover experiments were performed for the 4CR
(Figure 6). Several experimental observations were important
in deciphering the mechanism. (1) At room temperature, the
mixture of maleic anhydride, benzylamine, p-tolSH, and
benzaldehyde led to the quantitative production of a 1:1
mixture of amide-acid regioisomers 17a and 17b. (2) Heating
this mixture under anhydrous refluxing toluene conditions led
to the formation of a single regioisomer of product, γ-lactam
15a. (3) Additionally, 17a and 17b were also observed when
17b was prepared, separated from 17a, and refluxed
independently; also, when benzaldehyde was added to 17b
and proceeded to partial conversion, a mixture of 17a and 17b
was produced along with lactam 15a. Two final experiments
were informative. When isolated, 17b was heated in the
presence of a second thiophenol (p-methoxythiophenol), 17a
and 17b were observed as expected, while the products of thiol
exchange (35a and 35b) were negligible as determined by
NMR and LCMS.35 When this same experiment was
performed in the presence of a second amine (p-Cl-
benzylamine), 17a and 17b were observed in addition to
exchange products 34a and 34b.
Further investigation of the relative rates of the potential first
steps leading to 17a and 17b using infrared spectroscopy in situ
(React-IR) to monitor reaction progress was informative
(Scheme 2). First, acylation of benzylamine with maleic
anhydride proceeds instantaneously at ambient temperature in
THF with a half-life (t1/2) of <1 min. Second, the conjugate
addition of p-tolSH to maleic anhydride showed no back-
Figure 4. (A) Reaction of homophthalic anhydride and benzylamine
leads to a single regioisomer of amide-acid 26. (B) Crossover
experiment with 26a and p-chlorobenzylamine leads to a mixture of
amide-acids. (C) Heating 26a with benzaldehyde and Na2SO4 leads
to a single diastereomer of the CCR product.
C
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Scheme 2. Relative Rates of the Addition of Benzylamine
and p-tolSH to Maleic Anhydride
a
Time to reach 50% conversion.
the final formation of the lactam 4CR product. Further control
experiments, including the investigation of natural abundance
kinetic isotope effects, failed to produce any insight into the
final critical steps of this 4CR.16
On the basis of these results, we hypothesize that the
mechanisms of the 3CR and 4CR both proceed through the
initial formation of amide-acids 26 and 17, respectively, which
are in equilibrium with the anhydride (7 and 19) and amine 8
(Figure 7A,B). In this scenario, a carboxylic acid would serve as
a nucleophile capable of breaking an amide bond, which was
consistent with the exchange reactions described above. Similar
reactions have also been described in the literature.36−38 The
mechanistic picture that emerged for the 3CR involves the
attack of the amine on the phenylacetyl carbonyl of
homophthalic anhydride to provide amide-acid 26, which is
in equilibrium with homophthalic anhydride 7 and amine 8
(Figure 7A). In the presence of aldehyde, the amine can
condense to form imine, which can then proceed through
Mannich addition to provide cis product 10. Under refluxing
Figure 5. Substrate scope of the 3CR leading to dihydroisoquinolone
products 27.
ground rate. Consistent with the conditions for the reaction on
a preparative scale, this reaction proceeded (t1/2 = 55 min) at
room temperature once a catalytic quantity of triethylamine
was added. The kinetic profile of the reaction of 16a with p-
tolSH was found to be more complex than those of the
previous reactions, and the t1/2 was not determined. However,
it was found that stirring the reaction mixture at room
temperature results in 50% conversion to a mixture of amide-
acids 17a and 17b in 10 min. Taken together, these
experiments support the idea that 17a and 17b are
intermediates to a reaction with benzaldehyde that leads to
Figure 6. Lactam-forming 4CR proceeds via isomeric amide-acids 17a and 17b (top left). Isolated 17b equilibrates with regioisomer 17a under
refluxing conditions and in the presence of benzaldehyde proceeds to the product (top right). Isolated 17b undergoes regioisomerization and amide
scrambling when heated in the presence of 8b (bottom).
D
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the 3CR will enable the development of novel multicomponent
reactions using anhydrides and anhydride derivatives with
reactivity similar to that of homophthalic anhydride.
EXPERIMENTAL PROCEDURES
■
Materials and Instrumentation. Unless otherwise specified, all
commercially available reagents were used as received. All reactions
using dried solvents were carried out under an atmosphere of argon in
oven-dried glassware with magnetic stirring. Dry solvent was
dispensed from a solvent purification system that passes solvent
1
through two columns of dry neutral alumina. H NMR spectra and
proton-decoupled 13C NMR spectra were recorded on a 400 or 800
1
MHz Bruker or 600 MHz Varian NMR spectrometer. H chemical
shifts (δ) are reported in parts per million relative to TMS (s, δ 0).
Multiplicities are given as s (singlet), d (doublet), t (triplet), q
(quartet), p (pentet), h (hextet), and m (multiplet). Complex
splitting will be described by a combination of these abbreviations,
i.e., dd (doublet of doublets). 13C NMR chemical shifts are reported
relative to CDCl3 (t, δ 77.4) unless otherwise noted. High-resolution
mass spectra were recorded on either positive or negative ESI mode.
Melting points were recorded on an EZ-melting apparatus and were
uncorrected. Infrared spectra were recorded on a Mettler Toldedo
ReactIR 700 (serial number B929971514) with a liquid N2 MCT
detector fitted with a DiComp probe (serial number B939349478).
The system was filled with liquid N2 and allowed to cool for 1 h
before being used. Chromatographic purifications were performed by
flash chromatography with silica gel (Fisher, 40−63 μm) packed in
glass columns or by use of a Teledyne Isco Combi-Flash. The eluting
solvent for the purification of each compound was determined by
thin-layer chromatography (TLC) on glass plates coated with silica
gel 60 F254 and visualized by ultraviolet light.
Note that for the three-component reaction, the reaction mixture
must be heated to at least 110 °C to fully epimerize from the cis to
trans diastereomer. Use of aluminum beads resulted in poor
diastereoselectivity, whereas silicone oil baths led to excellent
diastereoselectivity.
Figure 7. (A) Proposed mechanism of the three-component CCR.
(B) Proposed mechanism of the four-component CCR.
Synthesis of Amide-Acids for Crossover Experiments. 2-[2-
(Benzylamino)-2-oxoethyl]benzoic Acid (26a). To a flame-dried
round-bottom flask was added homophthalic anhydride (0.81 g, 5.0
mmol), and the mixture was dissolved in CH2Cl2 (10.0 mL, 0.5 M).
Benzylamine (0.54 mL, 5.0 mmol) was added, and the reaction
mixture was stirred at rt for 24 h. The reaction mixture was
concentrated in vacuo and characterized without further purification
to provide 26a (1.3 g, 96%), a single regioisomer, as an off-white
conditions, the cis lactam epimerizes to trans isomer 27 over 24
h. Furthermore, the 4CR is consistent with a similar
mechanism of rapid formation of amide-acid regioisomers 17
(Figure 7B), followed by equilibration of the regioisomer
amide-acids with their corresponding anhydride 19. Although
this process is unfavorable, it is driven forward by the
subsequent rapid formation of the imine. Once the imine is
formed, it can react with the anhydride through a Mannich-like
mechanism in a Zimmerman−Traxler transition state 37 to
form γ-lactam 15.
In summary, we have provided experimental evidence for the
proposed mechanism of the 3CR and 4CR of the Castagnoli−
Cushman reaction. These reactions proceed through analogous
amide-acid intermediates that are formed through initial
nucleophilic attack of the amine on the anhydride. This half-
amide is in equilibrium with the anhydride and amine, which,
in the presence of aldehyde, can condense to form imine and
proceed through the classic CCR. This mechanistic inves-
tigation led to the development of new reaction conditions for
the 3CR and allowed for the synthesis of a small series of
dihydroisoquinolone products derived from alkyl and aryl
amines and aldehydes. The multicomponent variants of the
CCR have been shown to proceed with substrate tolerances,
yields, and reactivities comparable to those of their classic
CCR counterparts. The utility of multicomponent CCRs rests
in the ability to achieve γ- and δ-lactams in a one-pot single-
reaction format. Our new understanding of the mechanism of
1
crystalline solid: mp range 135.3−140.3 °C; H NMR (400 MHz,
DMSO-d6) δ 12.87 (s, 1H), 8.38 (t, J = 6.0 Hz, 1H), 7.83 (dd, J = 7.7,
1.5 Hz, 1H), 7.48 (td, J = 7.5, 1.5 Hz, 1H), 7.38−7.17 (m, 7H), 4.27
(d, J = 5.9 Hz, 2H), 3.92 (s, 2H); 13C{1H} NMR (101 MHz, DMSO-
d6) δ 170.1, 168.6, 139.6, 137.0, 131.9, 131.5, 131.2, 130.2, 128.2,
127.1, 126.7 (two carbons), 42.2, 40.5; IR 2961.0 (broad), 2153.4,
1716.5, 1619.0, 1552.3 cm−1; AMM (ESI-TOF) m/z calcd for
−
C16H14NO3 [M − H]− 268.0979, found 268.0981.
2-{2-[(4-Chlorobenzyl)amino]-2-oxoethyl}benzoic Acid (26b). To
a flame-dried round-bottom flask was added homophthalic anhydride
(0.081 g, 0.5 mmol), and the mixture was dissolved in toluene (1.0
mL, 0.5 M). p-Chlorobenzylamine (0.060 mL, 0.5 mmol) was added,
and the reaction mixture was stirred for 30 min. The reaction mixture
was concentrated in vacuo and characterized without further
purification to afford 26b, a single regioisomer, as a white crystalline
solid (0.134 g, 96%): mp range 172.7−173.9 °C; 1H NMR (400
MHz, DMSO-d6) δ 8.40 (t, J = 6.1 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H),
7.48 (t, J = 7.5 Hz, 1H), 7.42−7.23 (m, 6H), 4.25 (d, J = 6.0 Hz, 2H),
3.92 (s, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 170.4, 168.7,
138.8, 137.0, 132.1, 131.7, 131.3, 131.2, 130.3, 129.1, 128.2, 126.9,
−
41.7, 40.7; AMM (ESI-TOF) m/z calcd for C16H13ClNO3 [M −
H]− 302.0589, found 302.0594.
Synthesis of S1 and S2. To a flame-dried round-bottom flask were
added 3-(p-tolylthio)dihydrofuran-2,5-dione (1.55 g, 7 mmol) and p-
chlorobenzylamine (0.851 mL, 7 mmol), and the mixture was
E
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1
dissolved in acetone (70 mL, 0.1 M). After 10 min, K2CO3 (0.967 mg,
7 mmol), KI (1.162 g, 7 mmol), and p-methoxybenzyl chloride (1.03
mL, 7 mmol) were added, and the reaction mixture was stirred
overnight. The crude reaction mixture was concentrated in vacuo,
dissolved in EtOAc and H2O, extracted with EtOAc (3 × 20 mL), and
dried over Na2SO4. Purification by gradient flash column chromatog-
raphy (20−100% EtOAc/hexanes) afforded regioisomer S1 as an off-
white amorphous solid (0.393 g, 12%) and S2 (0.080 g, 3%) as an off-
white amorphous solid.
4-Methoxybenzyl 4-[(4-Chlorobenzyl)amino]-4-oxo-3-(p-
tolylthio)butanoate (S1). The structure of S1 was assigned on the
basis of the comparison of J coupling values:25 1H NMR (400 MHz,
CDCl3) δ 7.27 (dd, J = 8.4, 6.4 Hz, 4H), 7.23−7.18 (m, 2H), 7.14−
7.02 (m, 4H), 6.94−6.82 (m, 2H), 6.66 (s, 1H), 5.15−4.94 (m, 2H),
4.46−4.28 (m, 2H), 3.95 (dd, J = 7.5, 6.3 Hz, 1H), 3.80 (s, 3H), 3.12
(dd, J = 16.9, 7.5 Hz, 1H), 2.78 (dd, J = 16.9, 6.3 Hz, 1H), 2.32 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 169.9, 159.7, 138.8,
136.4, 133.3, 133.1, 130.2, 130.1, 129.1, 128.8, 128.5, 127.7, 114.0,
66.7, 55.3, 48.3, 43.3, 36.7, 21.1; AMM (ESI-TOF) m/z calcd for
C26H26ClNO4SNa+ [M + Na]+ 506.1163, found 506.1182.
4-Methoxybenzyl 4-[(4-Chlorobenzyl)amino]-4-oxo-2-(p-
tolylthio)butanoate (S2). The structure of S2 was assigned on the
basis of the comparison of J coupling values:25 1H NMR (400 MHz,
CDCl3) δ 7.30−7.09 (m, 8H), 7.02 (d, J = 7.9 Hz, 2H), 6.90−6.80
(m, 2H), 6.12 (t, J = 5.8 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 4.95 (d, J
= 11.9 Hz, 1H), 4.39−4.23 (m, 2H), 4.07 (dd, J = 9.3, 5.8 Hz, 1H),
3.79 (s, 3H), 2.73 (dd, J = 15.1, 9.3 Hz, 1H), 2.58 (dd, J = 15.2, 5.8
Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.5,
169.5, 159.6, 139.0, 136.6, 134.5, 133.2, 130.1, 129.8, 129.0, 128.7,
127.9, 127.5, 113.8, 66.9, 55.3, 46.3, 42.8, 38.2, 21.2; AMM (ESI-
TOF) m/z calcd for C26H26ClNO4SNa+ [M + Na]+ 506.1163, found
506.1173.
mg, 56%) as an off-white amorphous solid: H NMR (400 MHz,
CDCl3) δ 8.22 (dd, J = 8.0, 1.4 Hz, 1H), 7.58 (td, J = 7.5, 1.4 Hz,
1H), 7.48−7.41 (m, 3H), 7.32−7.26 (m, 3H), 7.26−7.22 (m, 1H),
5.19 (s, 2H), 4.07 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
169.9, 164.9, 137.1, 134.1, 133.7, 129.3, 129.0, 128.4, 127.8, 127.5,
+
127.1, 125.4, 43.3, 36.5; AMM (ESI-TOF) m/z calcd for C16H14NO2
[M + H]+ 252.1019, found 252.1024.
Liquid Chromatography-Mass Spectrometry Experiments.
Three-Component Amide-Exchange Experiment. To a flame-dried
microwave vial were added 26a (0.135 g, 0.5 mmol) and p-
cholorobenzylamine (0.036 mL, 0.5 mmol), and the mixture was
dissolved in toluene (4.5 mL, 0.5 M) and heated to reflux. After 6 h,
the reaction mixture was cooled to room temperature and
concentrated in vacuo. The mixture was analyzed using liquid
chromatography-mass spectrometry, which gave masses correspond-
ing to amides 26a and 26b.
Imide-Exchange Experiment. To a flame-dried microwave vial was
added S3 (0.055 g, 0.22 mmol). S3 was dissolved in toluene (1.0 mL,
0.22 M), then p-cholorobenzylamine (0.027 mL, 0.22 mmol) added,
and the reaction mixture heated to reflux. After 24 h, the reaction
mixture was cooled to room temperature and concentrated in vacuo.
The mixture was analyzed using liquid chromatography-mass
spectrometry, which gave masses corresponding to only S3 and p-
chlorobenzylamine.
Four-Component Amide-Exchange Experiment. To a flame-dried
microwave vial were added 17b (0.100 g, 0.30 mmol) and p-
cholorobenzylamine (0.036 mL, 0.30 mmol), and the mixture was
dissolved in toluene (4.5 mL, 0.066 M) and heated to reflux. After 17
h, the reaction mixture was cooled to room temperature and
concentrated in vacuo. The reaction mixture was cooled to room
temperature and concentrated in vacuo. The mixture was analyzed
using liquid chromatography-mass spectrometry, which gave masses
corresponding to amides 17a, 17b, 34a, and 34b.
Four-Component Thiol-Exchange Experiment. To a flame-dried
microwave vial were added 17b (0.100 g, 0.30 mmol) and p-
methoxythiophenol (0.036 mL, 0.30 mmol), and the mixture was
dissolved in toluene (4.5 mL, 0.066 M) and heated to reflux. After 17
h, the reaction mixture was cooled to room temperature and
concentrated in vacuo. The mixture was analyzed using liquid
chromatography-mass spectrometry, which gave masses correspond-
ing to 17a, 17b, and negligible quantities of 35a and 35b.
4-[(4-Chlorobenzyl)amino]-4-oxo-2-(p-tolylthio)butanoic Acid
(34a). To a flame-dried round-bottom flask was added S2 (0.050 g,
0.103 mmol), and the mixture was dissolved in dichloromethane
(5.15 mL, 0.02 M). TFA (0.052 mL, 0.2M) was added, and the
reaction mixture was stirred overnight. The reaction mixture was
concentrated in vacuo. Hexanes (10 mL) were added, followed by
diethyl ether (10 mL), and a white solid precipitated. The solid was
filtered and used without further purification (0.023 g, 62%): mp
1
range 130.1−131.9 °C; H NMR (400 MHz, MeOD) δ 7.41−7.36
(m, 2H), 7.32−7.23 (m, 4H), 7.15 (d, J = 7.9 Hz, 2H), 4.32 (d, J =
3.2 Hz, 2H), 3.99 (dd, J = 8.8, 6.6 Hz, 1H), 2.79 (dd, J = 15.4, 8.8 Hz,
1H), 2.63 (dd, J = 15.4, 6.6 Hz, 1H), 2.33 (s, 3H); 13C{1H} NMR
(101 MHz, CD3OD) δ 174.7, 172.4, 140.1, 138.8, 135.3, 133.9, 130.8,
130.1, 130.1, 129.5, 47.9, 43.3, 39.0, 21.2; AMM (ESI-TOF) m/z
calcd for C18H17ClNO3S− [M − H]− 362.0623, found 362.0626.
4-[(4-Chlorobenzyl)amino]-4-oxo-3-(p-tolylthio)butanoic Acid
(34b). To a flame-dried round-bottom flask was added S1 (0.384 g,
0.8 mmol), and the mixture was dissolved in dichloromethane (40.0
mL, 0.02 M). TFA (4.0 mL, 0.2M) was added, and the reaction
mixture was stirred overnight. The reaction mixture was concentrated
in vacuo. Hexanes (15 mL) were added, followed by diethyl ether (15
mL), and a white solid precipitated. The solid was filtered and used
General Procedure for the Synthesis of Dihydroisoquino-
lones (27). Homophthalic anhydride (81.0 mg, 0.5 mmol) and
Na2SO4 (1 equiv) were added to a flame-dried microwave vial under
argon and dissolved in toluene (1.0 mL, 0.5 M). Aldehyde (0.5 mmol,
1 equiv) and amine (0.5 mmol, 1 equiv) were added sequentially, and
the vial was sealed shut. The vial was then placed in a silicone oil bath
and heated to 110 °C. After 24 h, the reaction mixture was
concentrated in vacuo. The crude reaction mixture was purified using
gradient flash column chromatography (EtOAc/hexanes).
trans-2-Benzyl-1-oxo-3-phenyl-1,2,3,4-tetrahydroisoquinoline-4-
carboxylic Acid (27a). The title compound was prepared according
to the general three-component reaction procedure. The crude
reaction mixture was purified by gradient flash column chromatog-
raphy (40−100% EtOAc in hexanes) to afford 27a (0.150 g, 84%), a
single diastereomer, as a white solid. 27a was also prepared on a 1
mmol scale. In this experiment, 27a was purified by sequential
trituration from hexanes and then ether to afford (0.285 g, 80%) a
single diastereomer as a white solid. Finally, 27a was also prepared in
two steps from 26a. 26a (0.134 g, 0.5 mmol) and Na2SO4 (0.071 g,
0.5 mmol) were added to a flame-dried microwave vial under argon
and dissolved in toluene. Benzaldehyde (0.051 mL, 0.5 mmol) was
added to the reaction mixture, and the vial was sealed shut. The vial
was then placed in a silicone oil bath and heated to 110 °C. After 24
h, the reaction mixture was concentrated in vacuo. The crude reaction
mixture was purified using gradient flash column chromatography
(40−100% EtOAc in hexanes) to afford 27a (0.146 g, 82%), a single
1
without further purification (0.243 g, 83%): mp 123.9−126.6 °C; H
NMR (600 MHz, DMSO-d6) δ 8.69 (t, J = 6.1 Hz, 1H), 7.34 (d, J =
8.1 Hz, 2H), 7.30 (d, J = 7.7 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.14
(d, J = 7.8 Hz, 2H), 4.24 (qd, J = 15.5, 6.0 Hz, 2H), 3.97 (dd, J = 9.5,
5.3 Hz, 1H), 2.76 (dd, J = 16.7, 9.5 Hz, 1H), 2.29 (s, 3H), 1.09 (t, J =
7.0 Hz, 2H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.3, 170.3,
138.7, 138.3, 133.8, 131.7, 130.1, 129.4, 129.1, 128.5, 46.5, 42.0, 37.0,
21.1; AMM (ESI-TOF) m/z calcd for C18H17ClNO3S− [M − H]−
362.0623, found 362.0628.
2-Benzylisoquinoline-1,3(2H,4H)-dione (S3). To a flame-dried
round-bottom flask was added homophthalic anhydride (0.81 mg, 0.5
mmol), and the mixture was dissolved in toluene (1.0 mL).
Benzylamine (0.0054 mL, 5.0 mmol) was added, and the reaction
mixture was stirred at reflux for 24 h. The reaction mixture was then
cooled and concentrated in vacuo. Purification by gradient flash
column chromatography (20−100% EtOAc/hexanes) gave S3 (69.8
1
diastereomer, as a white solid: mp 220.2−224.3 °C; H NMR (600
MHz, CDCl3) δ 8.29 (dd, J = 7.6, 1.6 Hz, 1H), 7.46 (dtd, J = 25.4,
7.5, 1.4 Hz, 2H), 7.26−7.21 (m, 5H), 7.18−7.12 (m, 3H), 7.11−7.06
F
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Article
(m, 1H), 7.06−7.02 (m, 2H), 5.66 (d, J = 14.5 Hz, 1H), 5.11 (s, 1H),
3.87 (s, 1H), 3.70 (d, J = 14.6 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 175.1, 163.8, 138.2, 136.5, 132.3, 131.3, 129.3, 129.1, 128.9
(two carbons), 128.8, 128.4, 128.3, 128.1, 127.6, 126.3, 60.1, 50.9,
159.3, 159.0, 132.2, 131.6, 130.3, 130.2, 129.3, 129.1, 128.8, 128.7,
128.3, 127.5, 114.2, 113.7, 59.5, 55.3, 55.2, 51.2, 48.3; AMM (ESI-
−
TOF) m/z calcd for C25H22NO5 [M − H]− 416.1503, found
416.1506.
−
49.0; AMM (ESI-TOF) m/z calcd for C23H18NO3 [M − H]−
trans-2-(4-Chlorobenzyl)-3-(4-methoxyphenyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acid (27g). The title com-
pound was prepared according to the general three-component
reaction procedure. The crude reaction mixture was purified by
gradient flash column chromatography (EtOAc in hexanes) to afford
27g (0.200 g, 95%), a single diastereomer, as a white solid: mp range
247.3−249.3 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (dd, J = 7.2,
2.0 Hz, 1H), 7.49−7.37 (m, 2H), 7.30 (d, J = 2.3 Hz, 4H), 7.23−7.17
(m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.22 (d, J
= 15.1 Hz, 1H), 5.18 (s, 1H), 4.03 (s, 1H), 3.84 (d, J = 15.0 Hz, 1H),
3.66 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 172.1, 163.5,
158.7, 136.5, 133.9, 132.1, 131.8, 130.8, 130.0, 129.7, 128.9, 128.2,
128.0, 127.3, 127.0, 114.1, 60.8, 55.1, 51.0, 48.6; IR 2949.0, 2831.6,
356.1292, found 356.1293.
trans-2-Benzyl-3-(4-methoxyphenyl)-1-oxo-1,2,3,4-tetrahydroi-
soquinoline-4-carboxylic Acid (27b). The title compound was
prepared according to the general three-component reaction
procedure. The crude reaction mixture was purified by gradient
flash column chromatography (20−100% EtOAc inhexanes) to afford
27b (0.142 g, 89%), a single diastereomer, as a yellow solid: mp
1
102.4−105.3 °C; H NMR (600 MHz, CDCl3) δ 8.28 (dd, J = 7.5,
1.6 Hz, 1H), 7.46 (dtd, J = 20.9, 7.5, 1.4 Hz, 2H), 7.23 (dd, J = 6.9,
2.7 Hz, 2H), 7.13 (dd, J = 5.3, 1.9 Hz, 3H), 7.09 (d, J = 7.3 Hz, 1H),
6.95 (d, J = 8.6 Hz, 2H), 6.76−6.74 (m, 2H), 5.64 (d, J = 14.7 Hz,
1H), 5.04 (s, 1H), 3.83 (s, 1H), 3.74 (s, 3H), 3.68 (d, J = 14.6 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.3, 163.8, 159.5, 136.7,
132.4, 131.6, 130.3, 129.5, 129.3, 129.0, 128.9, 128.5, 128.5, 127.7,
127.7, 114.4, 59.8, 55.4, 51.2, 49.0; AMM (ESI-TOF) m/z calcd for
−
1697.8, 1641.5 cm−1; AMM (ESI-TOF) m/z calcd for C24H19ClNO4
[M − H]− 420.1008, found 420.1011.
trans-1-Oxo-3-phenyl-2-propyl-1,2,3,4-tetrahydroisoquinoline-
4-carboxylic Acid (27h). Homophthalic anhydride (162.0 mg, 1.0
mmol) and Na2SO4 (142.0 mg, 1 mmol) were added to a flame-dried
microwave vial under argon and dissolved in toluene (2.0 mL, 0.5 M).
Benzaldehyde (0.102 mL, 1.0 mmol) and propylamine (0.082 mL, 1.0
mmol) were added sequentially, and the vial was sealed shut. The vial
was then placed in a silicone oil bath and heated to 115 °C. After 24
h, the reaction mixture was concentrated in vacuo. The crude reaction
mixture was purified using gradient flash column chromatography
(20−100% EtOAc in hexanes) to afford 27h (0.185 g, 60%), a single
diastereomer, as a white amorphous solid: 1H NMR (400 MHz,
CDCl3) δ 8.21−8.08 (m, 1H), 7.40 (td, J = 6.9, 4.0 Hz, 2H), 7.22 (d,
J = 6.4 Hz, 3H), 7.15−7.08 (m, 1H), 7.08−7.02 (m, 2H), 5.29 (s,
1H), 4.09−3.97 (m, 1H), 3.94 (s, 1H), 2.82 (ddd, J = 14.0, 8.8, 5.8
Hz, 1H), 1.62 (dp, J = 14.6, 7.1 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 174.5, 164.2, 138.6, 132.1,
−
C24H20NO4 [M − H]− 386.1398, found 386.1400.
trans-3-(4-Bromophenyl)-2-(4-methoxyphenyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acid (27c). The title compound
was prepared according to the general three-component reaction
procedure. The crude reaction mixture was purified first by trituration
with hexanes, followed by gradient flash column chromatography
(20−100% EtOAc in hexanes) to afford 27c (0.192, 85%), a single
diastereomer, as an off-white solid. 1H NMR data match the reported
literature spectrum:24 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J =
7.5 Hz, 1H), 7.44 (d, J = 7.8 Hz, 4H), 7.25 (d, J = 8.7 Hz, 3H), 7.16
(d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.62 (s, 1H), 4.19 (s,
1H), 3.74 (s, 3H).
trans-2-Benzyl-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroiso-
quinoline-4-carboxylic Acid (27d). The title compound was prepared
according to the general three-component reaction procedure. The
crude reaction mixture was purified by gradient flash column
chromatography (20−100% EtOAc in hexanes) to afford 27d
(0.167 g, 88%), a single diastereomer, as an off-white amorphous
solid: 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 7.4, 1.8 Hz, 1H),
7.54−7.37 (m, 4H), 7.23−7.16 (m, 2H), 7.16−7.02 (m, 6H), 5.43 (d,
J = 14.5 Hz, 1H), 5.18 (s, 1H), 3.96 (d, J = 14.5 Hz, 1H), 3.81 (d, J =
1.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 174.3, 163.6,
143.7, 135.9, 132.7, 132.7, 130.7, 129.2, 129.2, 129.1, 128.9, 128.6,
128.4, 127.9, 127.1, 118.1, 112.2, 60.1, 50.7, 49.6; AMM (ESI-TOF)
131.7, 131.7, 129.4, 129.0, 128.8, 128.5, 128.0, 126.2, 61.1, 51.2, 48.7,
+
20.8, 11.3; AMM (ESI-TOF) m/z calcd for C19H20NO3 [M + H]+
310.1438, found 310.1437.
trans-2-Isopropyl-1-oxo-3-phenyl-1,2,3,4-tetrahydroisoquino-
line-4-carboxylic Acid (27i). Homophthalic anhydride (162.0 mg, 1.0
mmol) and Na2SO4 (142.0 mg, 1 mmol) were added to a flame-dried
microwave vial under argon and dissolved in toluene (2.0 mL, 0.5 M).
Benzaldehyde (0.102 mL, 1.0 mmol) and isopropylamine (0.082 mL,
1.0 mmol) were added sequentially, and the vial was sealed shut. The
vial was then placed in a silicone oil bath and heated to 115 °C. After
24 h, the reaction mixture was concentrated in vacuo. The crude
reaction mixture was purified using gradient flash column
chromatography (20−100% EtOAc in hexanes) to afford 27i (0.261
g, 84%), a single diastereomer, as a white amorphous solid: 1H NMR
(400 MHz, CDCl3) δ 8.16 (dd, J = 7.5, 1.6 Hz, 1H), 7.43−7.31 (m,
2H), 7.18 (s, 3H), 7.05 (ddd, J = 12.8, 7.5, 2.0 Hz, 3H), 5.34 (d, J =
1.6 Hz, 1H), 4.98 (hept, J = 7.0 Hz, 1H), 3.88 (d, J = 1.6 Hz, 1H),
1.21 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 174.6, 164.1, 140.4, 132.1, 131.5, 130.1, 129.1,
128.6, 128.6, 128.0, 127.6, 126.2, 56.6, 52.2, 46.4, 20.3, 20.0; AMM
−
m/z calcd for C24H17N2O3 [M − H]− 381.1245, found 381.1246.
trans-2-(4-Methoxyphenyl)-1-oxo-3-phenyl-1,2,3,4-tetrahydroi-
soquinoline-4-carboxylic Acid (27e). The title compound was
prepared according to the general three-component reaction
procedure. The crude reaction mixture was purified by gradient
flash column chromatography (20−100% EtOAc in hexanes) to afford
27e (0.144 g, 77%), a single diastereomer, as a brown amorphous
solid: 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.20 (dd, J = 5.8,
3.4 Hz, 1H), 7.41 (dd, J = 5.7, 3.3 Hz, 2H), 7.21−7.14 (m, 6H),
7.13−7.08 (m, 2H), 6.78−6.71 (m, 2H), 5.52 (d, J = 1.4 Hz, 1H),
3.96 (d, J = 1.5 Hz, 1H), 3.70 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 174.3, 164.3, 158.5, 139.0, 134.9, 132.7, 132.6, 129.6, 129.3,
128.9, 128.7, 128.5, 128.2, 128.1, 126.6, 114.4, 65.3, 55.4, 51.7; AMM
+
(ESI-TOF) m/z calcd for C19H20NO3 [M + H]+ 310.1438, found
310.1438.
−
(ESI-TOF) m/z calcd for C23H18NO4 [M − H]− 372.1241, found
trans-2-Benzyl-3-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquino-
line-4-carboxylic Acid (27j). Homophthalic anhydride (162.0 mg, 1.0
mmol) and Na2SO4 (142.0 mg, 1 mmol) were added to a flame-dried
microwave vial under argon and dissolved in toluene (2.0 mL, 0.5 M).
Isobutyraldehyde (0.091, 1.0 mmol) and benzylamine (0.109 mL, 1.0
mmol) were added sequentially, and the vial was sealed shut. The vial
was then placed in a silicone oil bath and heated to 115 °C. After 24
h, the reaction mixture was concentrated in vacuo. The crude reaction
mixture was purified using gradient flash column chromatography
(20−100% EtOAc in hexanes) to afford 27j (0.243 g, 75%), a single
diastereomer, as a yellow amorphous solid: 1H NMR (400 MHz,
CDCl3) δ 8.15 (dd, J = 7.4, 1.7 Hz, 1H), 7.53−7.40 (m, 2H), 7.27 (s,
1H), 7.25 (s, 1H), 7.19 (dd, J = 7.2, 1.6 Hz, 1H), 7.11 (t, J = 7.3 Hz,
372.1241.
trans-2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic Acid (27f). The title compound
was prepared according to the general three-component reaction
procedure. The crude reaction mixture was purified by gradient flash
column chromatography (EtOAc in hexanes) to afford 27f (0.158 g,
1
76%), a single diastereomer, as a yellow amorphous solid: H NMR
(400 MHz, CDCl3) δ 8.27−8.21 (m, 1H), 7.43 (qt, J = 7.4, 3.6 Hz,
2H), 7.22−7.13 (m, 2H), 7.08 (dd, J = 6.9, 1.8 Hz, 1H), 6.99−6.91
(m, 2H), 6.79−6.66 (m, 4H), 5.57 (d, J = 14.4 Hz, 1H), 5.10−5.01
(m, 1H), 3.82 (d, J = 1.5 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.63 (d,
J = 14.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 175.5, 163.7,
G
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Article
2H), 7.05 (t, J = 7.2 Hz, 1H), 5.54 (d, J = 14.5 Hz, 1H), 3.96 (d, J =
14.5 Hz, 1H), 3.75 (s, 1H), 3.71 (dd, J = 7.0, 1.3 Hz, 1H), 1.91 (h, J =
6.8 Hz, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (101 MHz, MeOD) δ 174.9, 166.0, 138.5, 136.8,
133.5, 130.4, 130.1, 129.5, 129.4, 129.1, 128.5, 128.5, 65.6, 52.1, 45.9,
accessed with poor CCR substrates wherein Mannich addition
is comparably high in energy.
ACKNOWLEDGMENTS
■
+
32.9, 20.2, 19.2; AMM (ESI-TOF) m/z calcd for C20H22NO3 [M +
This work was supported by the National Science Foundation
(NSF, CHE-1764309-0 and CHE-1414298). Financial support
for this work was also provided by the University of British
Columbia, the Canadian Foundation for Innovation (CFI-
35883), and the Natural Sciences and Engineering Research
Council of Canada (RCPIN-2016-04613 and CRDPJ 530118-
18). The authors also acknowledge support from the NSF
(CHE-0840444) for a dual-source X-ray diffractometer. N.P.B.
and M.J.D.M. acknowledge the Bradford Borge fellowship from
the University of California, Davis. Student support was
provided by an NSERC CGSD scholarship (T.C.M.). S.Y.H.
thanks the Olson lab for the use of their LCMS instrument.
Finally, the authors thank Paul Cheong for helpful discussions.
H]+ 324.1594, found 324.1595.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01163.
■
sı
Experimental procedures, characterization details, in-
1
cluding H and 13C NMR spectra, and LCMS traces
(PDF)
Accession Codes
CCDC 2075126−2075127 contain the supplementary crys-
tallographic 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.
REFERENCES
■
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AUTHOR INFORMATION
Corresponding Author
■
Jared T. Shaw − Department of Chemistry, University of
California, Davis, California 95616, United States;
orcid.org/0000-0001-5190-493X; Email: jtshaw@
ucdavis.edu
Authors
Sara Y. Howard − Department of Chemistry, University of
California, Davis, California 95616, United States;
orcid.org/0000-0001-9481-1928
Michael J. Di Maso − Department of Chemistry, University of
California, Davis, California 95616, United States;
orcid.org/0000-0003-1262-6126
Kristin Shimabukuro − Department of Chemistry, University
of California, Davis, California 95616, United States
Noah P. Burlow − Department of Chemistry, University of
California, Davis, California 95616, United States
Darlene Q. Tan − Department of Chemistry, University of
California, Davis, California 95616, United States
James C. Fettinger − Department of Chemistry, University of
California, Davis, California 95616, United States;
orcid.org/0000-0002-6428-4909
Thomas C. Malig − Department of Chemistry, University of
British Columbia, Vancouver, BC, Canada V6T 1Z1
Jason E. Hein − Department of Chemistry, University of
British Columbia, Vancouver, BC, Canada V6T 1Z1
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01163
Notes
(11) Laws, S. W.; Moore, L. C.; Di Maso, M. J.; Nguyen, Q. N. N.;
Tantillo, D. J.; Shaw, J. T. Diastereoselective Base-Catalyzed Formal
[4 + 2] Cycloadditions of N-Sulfonyl Imines and Cyclic Anhydrides.
Org. Lett. 2017, 19 (10), 2466−2469.
(12) Cronin, S. A.; Gutierrez Collar, A.; Gundala, S.; Cornaggia, C.;
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The authors declare no competing financial interest.
It should be noted that N,O-acetal byproducts of the CCR,
which are thought to proceed through carboxylate attack on
the iminium ion of 4, have been isolated.5,39,40 N,O-Acetal
byproducts have been found to form instantaneously in the
case of cyclopentane-fused maleic anhydride, and over the
course of 3 days with indolenines, leading exclusively to the
aforementioned byproducts with no evidence of the CCR
product.5,40 It is likely that zwitterionic intermediate 4 can be
H
https://doi.org/10.1021/acs.joc.1c01163
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The Journal of Organic Chemistry
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