Influence of N-Substitution in 3-Alkyl-3-hydroxyisoindolin-1-ones on the Stereoselectivity of Br?nsted Acid-Catalyzed Synthesis of 3-Methyleneisoindolin-1-ones

Article abstract of DOI:10.1002/ejoc.202100400

A comprehensive study on the influence of N-substitution on the stereoselective outcome of the synthesis of 3-methyleneisoindolin-1-ones from 3-alkyl-3-hydroxyisoindolin-1-ones is reported. The study was performed on an array of structurally diverse 3-alkyl-3-hydroxyisoindolin-1-ones with tunable sizes of N-substituents. In a methanesulfonic acid-catalyzed reaction, substrates without N-substituent (N?H) afforded exclusively the Z-isomer, while an increase in their size was followed by the formation of a stereoisomeric mixture with the E-isomer as the major component.

Full text of DOI:10.1002/ejoc.202100400

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Influence of N-Substitution in 3-Alkyl-3-hydroxyisoindolin-
1-ones on the Stereoselectivity of Brønsted Acid-Catalyzed
Synthesis of 3-Methyleneisoindolin-1-ones
Nikola Topolovčan,*[a] Filip Duplić,[a] and Matija Gredičak[a]
A comprehensive study on the influence of N-substitution on
the stereoselective outcome of the synthesis of 3-meth-
yleneisoindolin-1-ones from 3-alkyl-3-hydroxyisoindolin-1-ones
is reported. The study was performed on an array of structurally
diverse 3-alkyl-3-hydroxyisoindolin-1-ones with tunable sizes of
N-substituents. In a methanesulfonic acid-catalyzed reaction,
substrates without N-substituent (NÀ H) afforded exclusively the
Z-isomer, while an increase in their size was followed by the
formation of a stereoisomeric mixture with the E-isomer as the
major component.
Introduction
Synthesis of 3-methyleneisoindolin-1-ones – ubiquitous com-
pounds found in a broad range of natural products and
structurally related pharmaceuticals[1] – has experienced a
substantial rise over the years. Consequent advancement in this
field has led to numerous creative approaches to these valuable
structural motifs (Scheme 1). Strategies utilizing transition-metal
complexes are attractive because of their wide functional-group
tolerance, effectiveness, and versatility. In this regard, Pd-
catalyzed hetero-annulations dominate other accessible meth-
ods for the synthesis of these useful heterocycles.[2] In addition,
methodologies based on Co,[3] Cu,[4] Ni,[5] Rh,[6] Ru,[7] and Ag[8]
catalysis are equally attractive as they provide alternative
options for the design of specific synthetic routes comprising 3-
methyleneisoindolin-1-ones as intermediates.
Although their metal-free counterparts are not as nearly
represented in the literature, several methodologies have
emerged in the past decade. Zhou and Lu reported reaction
between alkynes and N-hydroxyphthalamides where the stereo-
chemical outcome depended on the employed reaction con-
ditions – E isomer was preferably obtained in a reaction with
potassium carbonate, and Z product in a reaction mediated by
tributylphosphine.[9] In 2018, Mehta et al developed synthesis of
E-enamides by a P4-tBu catalyzed intramolecular cyclization of 2-
alkyne benzamides.[10] By developing the Horner reaction
between α-aminophosphonates and aryl aldehydes, Ordóñez et
Scheme 1. Stereoselective syntheses of isoindolinone-derived enamides.
al obtained preferably
E
stereoisomer of the product.[11]
Although these are elegant examples for the construction of 3-
methyleneisoindolin-1-ones, main drawbacks of majority of the
reported methodologies are sometimes tedious prefunctionali-
zations of starting materials – resulting in the increased step-
count, use of expensive reagents and complicated experimental
techniques – and regioselectivity issues in cyclization reactions,
where the competition between 5-exo-dig and 6-endo-dig
cyclization leads to two structurally different compounds.[14]
The presence of an exocyclic double bond renders 3-
methyleneisoindolin-1-ones useful substrates in further func-
tionalization, such as annulation with propargylic alcohols,[12]
intramolecular arylation,[13] and oxidative CÀ H amination.[14]
Moreover, several isoindolin-1-one alkaloids exhibiting pain-
[a] Dr. N. Topolovčan, F. Duplić, Dr. M. Gredičak
Division of Organic Chemistry and Biochemistry
Ruđer Bošković Institute
Bijenička cesta 54, 10000 Zagreb, Croatia
E-mail: ntopolov@irb.hr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100400
Part of the “Organocatalysis” Special Collection.
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Table 1. Screening of reaction conditions.a
alleviating properties contain either Z- or E-configured stilbe-
noid unit. Hence, the stereoselective synthesis of such com-
pounds is highly desirable, as it would allow an access to
intermediates in syntheses leading to biologically active sub-
stances possessing this structural motif with defined C=C
double bond stereochemistry that reflects on the chemical
behavior.
Entry
Cat.
Solvent
Time [h]
Z-2a[%]
E-2a[%]
As a part of our ongoing research,[15] we became interested
on how the size of the N-substituent reflects on the stereo-
chemistry around the exocyclic double bond in the organo-
catalytic dehydration of 3-alkyl-3-hydroxyisoindolin-1-ones.
While addition of organometallic reagents to phthalimide
followed by an acidic quench yielding the corresponding 3-
methyleneisoindolin-1-ones is already described, to the best of
our knowledge, a detailed investigation of the stereochemical
outcome of this type of reaction is not reported.
We hypothesized that the formation of the two possible
stereoisomers might be mainly affected by the size of the N-
substituent (Scheme 2). When N-substituent is non-existent or
small enough, we anticipate preferable formation of Z isomer
because of the less steric hindrance between the C-3 and N-
substituents. On the other hand, with a more sterically
demanding N-substituent, the stereochemical outcome is
expected to be inverted; the R group will be steered away from
it, affording a E stereoisomer as the major product. Easy access
to various N-aryl 3-alkyl-3-hydroxyisoindolin-1-ones allows tun-
ing the steric effect imposed by the N-substituent. Moreover, by
allocating the functional groups around the N-aryl substituent,
the extent of the proposed effect can be tested as well.
1
2
3
4
5
6
7
8
AcOH
TFA
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
toluene
48
2
1
86
92
86
91
88
36
82
86
92
91
81
70
81
95d
81
89
58
89e
91f
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
p-TsOH
MsOH
PhCO2H
DPPb
0.25
168
20
20
24
24
24
90
90
90
24
1
PPAc
BF3xOEt2
SnCl2x2H2O
Pd(OAC)2
ZnCl2
FeCl3
AlCl3
MsOH
MsOH
MsOH
MsOH
MsOH
MsOH
9
10
11
12
13
14
15
16
17
18
19
cyclohexane
dichloroethane
acetonitrile
acetonitrile
1
1
1
1.5
[a] Reactions were carried out on a 0.2 mmol scale. Stereochemistry
around double bond determined by NOESY experiments. [b] Diphenyl
phosphate. [c] Phenyl phosphinic acid. [d] 25 C. [e] MsOH (5 mol%). [f]
°
MsOH (1 mol%).
yield after 48 hours (entry 1). The reaction catalyzed with
trifluoroacetic acid proceeded in a similar fashion, yielding the
product in just slightly better isolated yield, but in substantially
shorter time (92%, 2 hours, entry 2). The reaction with p-
toluenesulfonic acid afforded 2a in 86% yield within 1 hour
(entry 3), while even faster reaction kinetics were observed
when the catalytic amount of methanesulfonic acid (MsOH) was
employed, yielding the product after merely 15 minutes
(entry 4).
On the other hand, benzoic acid, diphenyl phosphate, and
phenyl phosphinic acid were inferior compared to MsOH, both
in reaction time, and in efficiency (entries 5–7). Since Lewis
acids, such as BF3 ×Et2O, Ca(NTf)2, Cu(OTf)2, and Sc(NTf2)4, are
also capable of initiating dehydration of 3-hydroxyisoindolin-1-
ones,[17] we screened several representatives of this type of
activators as well. The reaction with BF3 ×Et2O under the same
reaction conditions resulted in 2a in 86% isolated yield after
24 hours (entry 8). A similar trend was observed in dehydration
catalyzed by SnCl2 and Pd(OAc)2, which resulted in the
formation of 2a in almost identical yield (entries 9 and 10).
Other Lewis acids, ZnCl2, FeCl3, and AlCl3 were equally effective,
but in all three cases the reaction was completed after 96 hours
(entries 11–13).
Results and Discussion
As there is a lack of information on the catalytic dehydration of
3-alkyl-3-hydroxyisoindolin-1-ones,[16] at the outset, an extensive
screening of reaction conditions with respect to type of catalyst,
catalyst loading, temperature, and solvent was performed
(Table 1). We started our investigations by employing 3-ethyl-3-
hydroxyisoindolin-1-one 1a as a model substrate. Initially, the
reaction conditions included acetic acid as a catalyst in
°
acetonitrile at 80 C. The corresponding product meth-
yleneisoindolin-1-one Z-2a (Z/E >20:1) was afforded in 86%
After identifying MsOH as the best catalyst for the trans-
formation (with respect to yield and reaction time), we turned
our attention to investigating the influence of temperature,
solvent and catalyst loading. By performing the reaction at
°
25 C, the full conversion of the starting 3-ethyl-3-hydroxyisoin-
dolin-1-one 1a was observed after 24 hours (entry 14). Reac-
Scheme 2. Possible stereoisomers formed in an acid catalyzed dehydration
of 3-alkyl-3-hydroxyisoindolin-1-ones.
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Table 2. Substrate scope.a
tions in toluene and cyclohexane proceeded smoothly affording
the enamide Z-2a in 81% and 89% isolated yield after 1 hour,
respectively (entries 15 and 16). On the other hand, the reaction
was not that effective when it was performed in dichloroethane
(58%, 1 hour, entry 17). Finally, decreasing the catalyst loading
to 5 mol% and 1 mol%, respectively, did not have a significant
impact on the reaction outcome with respect to effectiveness,
but the reaction time was again longer in comparison to the
reaction catalyzed with 10 mol% of MsOH (entries 18 and 19).
These results represent useful input for cost effectiveness
analysis if the reaction would be run on an industrial scale.
Within the frame of screened conditions, the best results were
obtained in the reaction catalyzed by MsOH (10 mol%) in
°
acetonitrile at 80 C.
Next, we turned our attention to investigate substrate scope
and limitations (Table 2). Same as the reaction with 1a,
reactions with 1b and 1c bearing 3-benzyl and 3-butyl
substituents afforded Z-2b and Z-2c, respectively, while the
formation of the opposite stereoisomers was not detected. Also,
dehydration of 1d proceeded smoothly, affording only Z-2d,
thus indicating that the size of the 3-alkyl substituent does not
impose impact on the stereochemical outcome of the reaction.
The reaction of 1e comprising of the N-methyl moiety afforded
an inseparable mixture of two stereoisomers, E-2e and Z-2e, in
a 7:1 ratio with a combined isolated yield of 96%. The N-benzyl
substitution in 1f had almost the same effect on the stereo-
chemical outcome, where
a stereoisomeric mixture was
afforded with E-2f as the major component (E/Z 8:1). Interest-
ingly, reactions with 1g and 1h bearing more sterically
demanding MeO and Me groups afforded 2g and 2h, both as
mixture of stereoisomers in E/Z ratio 5:1. Contrary to expect-
ations, ratio was even lower comparing to ratio of products
obtained in reaction with unsubstituted benzyl group in 1f. A
similar trend was also observed in the reaction with N-phenyl
substituted starting alcohol 1i, but in this case a ratio between
E-2i and Z-2i dropped to 2:1. Dehydration of 1j, possessing an
ortho-substituted N-phenyl ring, resulted in a mixture of E-2j
and Z-2j (ratio 2:1) in 96% combined isolated yield. Although a
stronger influence of the steric hindrance imposed by the
hydroxyl group was anticipated, the isomeric ratio did not
change compared to the unsubstituted N-phenyl ring. Comple-
mentary, the stereoisomeric ratio did not change in dehydra-
tions of 1k, 1l, and 1m, bearing meta substituted phenyl ring,
and in all cases the formation E isomer was predominant.
Two stereoisomers were also obtained in the reaction with
alcohol 1n possessing N-naphthyl group, again in 2:1 ratio. The
presence of para-Br and para-OMe substituents in 1o and 1p,
again did not enforce any significant effect on the double bond
stereochemistry. In these cases, a mixture of the corresponding
enamides was formed in a 3:1 ratio.
[a] Reactions were carried out on a 0.2 mmol scale. E/Z ratio determined
by 1H NMR.
and the reaction of 1f provided a mixture of two stereoisomers
with predominant formation of the E-2f, we investigated
whether Z-2f could be prepared by a simple N-alkylation of Z-
2a. Indeed, the reaction between Z-2a and benzyl bromide
mediated by sodium hydride provided targeted product Z-2f in
92% isolated yield (Scheme 3).
Obtained results provide a spring-board for further mod-
ification and implementation of the formed enamides into
synthesis of compounds with higher molecular complexity and
defined stereochemistry. Therefore, we were interested in
whether it would be possible to obtain only one stereoisomer
simply by changing the order of the synthetic steps. Since the
reaction of 1a yielded product 2a exclusively as the Z isomer,
Scheme 3. Approach to the stereoisomer Z-2f.
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This result represents high potential of the developed
formation and its subsequent conversion to 3 under the used
reaction conditions.
Based on obtained results, we propose the following
reaction mechanism (Scheme 5). Protonation of 3-hydroxyisoin-
dolin-1-one 1 affords activated intermediate II. Then, water
method, where a set of consecutive steps can lead to a variety
of N-substituted 3-methyleneisoindolin-1-ones in terms of the
stereochemical outcome.
It is well established that the activation of the hydroxyl
group in 3-aryl 3-hydroxyisoindolin-1-ones is followed by
elimination of a water molecule via rearrangement of an
electron pair on the adjacent nitrogen atom, leading to the
formation of highly reactive and electrophilic N-acyl
ketimine.[15d,18] On the other hand, 3-alkyl substituted acylimi-
num intermediates could isomerize to the corresponding
enamides, which hampers the formation of the desired
product.[19] Thus, we investigated the competitiveness between
the formation of enamide and the addition of an external
molecule is eliminated to generate
a reactive ketimine
intermediate III. The resulting cation III undergoes elimination
in two possible ways. If there is no substituent on nitrogen, R1
group moves away from isoindolinone aromatic ring, and the
elimination in IIIa results in Z product. On the other hand, larger
substituents on nitrogen directs R1 away from it, and β-
hydrogen elimination in IIIb leads to E product.
nucleophile. The reaction between 1a and indole under Conclusion
standard reaction conditions provided exclusively product 3,
while the corresponding enamide Z-2a was not detected
(Scheme 4). Likewise, Brønsted acid catalyzed aza-Friedel-Crafts
arylation of Z-2a with indole provided product 3 in 85%
isolated yield. In a similar fashion, intramolecular cyclization of
tryptamine-containing isoindolin-1-one 1q afforded fused poly-
cycle 4 in 68% isolated yield.
Since it was previously reported that N-substitution has a
detrimental effect on the rate of ketimine formation[15e] and
taking into account differences in reaction times between the
N-substituted and NÀ H 3-alkyl-3-hydroxyisoindolin-1-ones, it is
reasonable to assume that ketimine forms during the course of
the reaction. Dehydration of 1a occurred within 15 minutes,
while in other cases it took up to 2.5 hours for the reaction to
complete. Moreover, synthesis of 3 directly from alcohol 1a was
faster compared to its synthesis from enamide 2a (1 hour vs
24 hours). This observation excludes the possibility of enamide
In conclusion, we have demonstrated that the stereochemistry
around the C=C double bond in 3-methyleneisoindolin-1-ones,
prepared by acid-catalyzed dehydration of the parent 3-alkyl-3-
hydroxyisoindolin-1-ones, is affected by the size of the N-
substituent. A variable steric hindrance imposed by the size of
the N-substituent is in direct correlation with the stereo-
chemical outcome. With a large group, a stereoisomeric mixture
is afforded with the E-isomer as the major component. On the
other hand, the absence of N-substituent leads to an exclusive
formation of the Z-isomer. Our results provide a background on
which the levels of stereoselectivity in these types of reactions
can be predicted. Finally, we have also demonstrated that the
undesired stereochemistry in 3-methyleneisoindolin-1-ones
could be circumvented by changing the order of the synthetic
steps.
Experimental Section
General procedure for enamide synthesis. To a suspension of
selected 3-alkyl-3-hydroxyisoindolin-1-one[15a] (0.20 mmol) in MeCN
°
(1.0 mL) was added MsOH (0.02 mmol) at 25 C. Reaction mixture
°
was stirred at 80 C until the full consumption of the starting
material was confirmed by TLC. Pure enamide was obtained by
flash column chromatography of the reaction mixture on silica gel.
Scheme 4. Control experiments.
Scheme 5. Proposed reaction mechanism for the formation of enamides 2.
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0.02 mmol) at 25 C. Reaction mixture was stirred for 1 hour at
°
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1
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Acknowledgements
Financial support was provided by the Croatian Science Founda-
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Keywords: Catalysis
Stereoselectivity · Steric hindrance
·
Enamides
·
N-Substitution
·
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Manuscript received: March 31, 2021
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Revised manuscript received: June 18, 2021
Accepted manuscript online: June 23, 2021
Eur. J. Org. Chem. 2021, 3920–3924
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