The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

Article abstract of DOI:10.3762/bjoc.13.275

The synthesis of various 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones was realized following a simple three-step process. The protocol utilized the photodecarboxylative addition of readily available carboxylates to N-(bromoalkyl)phthalimides as a versatile and efficient key step. The initially obtained hydroxyphthalimidines were readily converted to the desired N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones via acid-catalyzed dehydration and subsequent nucleophilic substitution with the corresponding secondary amines. The procedure was successfully applied to the synthesis of known local anesthetics (AL-12, AL-12B and AL-5) in their neutral forms.

Full text of DOI:10.3762/bjoc.13.275

The photodecarboxylative addition of carboxylates to
phthalimides as a key-step in the synthesis of biologically
active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones
Ommid Anamimoghadam1, Saira Mumtaz1, Anke Nietsch2, Gaetano Saya1,
Cherie A. Motti3, Jun Wang1, Peter C. Junk1, Ashfaq Mahmood Qureshi4
and Michael Oelgemöller*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2833–2841.
1James Cook University, College of Science and Engineering,
Townsville, Queensland 4811, Australia, 2Dublin City University,
School of Chemical Sciences, Dublin 9, Ireland, 3Australian Institute
of Marine Science, Townsville, Queensland, Australia and
4Bahauddin Zakariya University, Institute of Chemical Sciences,
Multan, Pakistan
doi:10.3762/bjoc.13.275
Received: 13 November 2017
Accepted: 15 December 2017
Published: 20 December 2017
Associate Editor: C. Stephenson
Email:
Michael Oelgemöller* - michael.oelgemoeller@jcu.edu.au
© 2017 Anamimoghadam et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
anesthetics; arylmethylenedihydroisoindolinones; photochemistry;
photodecarboxylation; phthalimide
Abstract
The synthesis of various 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones was realized following a simple three-step process.
The protocol utilized the photodecarboxylative addition of readily available carboxylates to N-(bromoalkyl)phthalimides as a versa-
tile and efficient key step. The initially obtained hydroxyphthalimidines were readily converted to the desired N-diaminoalkylated
3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones via acid-catalyzed dehydration and subsequent nucleophilic substitution with
the corresponding secondary amines. The procedure was successfully applied to the synthesis of known local anesthetics (AL-12,
AL-12B and AL-5) in their neutral forms.
Introduction
Phthalimides and their related 3-alkyl- and 3-arylmethylene- common local anesthetics such as procaine, xylocaine/lidocaine
2,3-dihydro-1H-isoindolin-1-ones play an important role in me- and tetracaine [8]. Their molecular structures contain the three
dicinal chemistry due to their biological activities for a wide key elements of all local anesthetics: (a) a lipophilic aromatic
range of therapeutic applications [1-7]. AL-12, AL-12B and ring, (b) an amide (or ester) linker, and (c) a terminal tertiary
AL-5 (Figure 1), for example, were described as highly active amine [9]. The original synthesis of these bioactive compounds
local anesthetics distinctly exceeding the efficiencies of involved a Perkin condensation followed by an amination reac-
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tion. An alternative pathway to AL-12B has been described by The retrosynthetic analysis is depicted in Scheme 1. The initial
Couture and co-workers and incorporated an intramolecular step comprises the photodecarboxylative addition of phenyl-
Horner–Wadsworth–Emmons reaction as a crucial step [10]. acetate to commercially available N-(bromoalkyl)phthalimides,
yielding the corresponding benzylated hydroxyphthalimidine
Due to their diverse biological activities, a variety of synthetic derivatives as key intermediates. Subsequent acid-catalyzed
pathways to 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones dehydration [41], followed by amination [42] furnishes the
has been developed over the past two decades [10-22]. The desired target compounds. The amino group is introduced in the
photodecarboxylative addition of phenylacetates to phthal- final step as it would otherwise interfere with the desired photo-
imides represents a mild alternative entrance to these target reaction. In fact, amines are very potent electron donors and are
molecules [23-31]. The reaction utilizes phenylacetate salts as easily oxidized by the excited phthalimide chromophore [43-
readily available alkylation agents [32,33]. Selected transfor- 46].
mations have been furthermore realized on large multigram
scales [25,34,35] and in continuous-flow mode [36-40]. The Results and Discussion
photodecarboxylation procedure was subsequently applied to Initial irradiation experiments were conducted with N-(2-
the synthesis of 2-dialkylaminoalkyl-3-arylmethylene-2,3- bromoethyl)phthalimide (1a) and potassium phenylacetate (2a)
dihydro-1H-isoindolin-1-ones.
as a model system (Scheme 2 and Table 1). The salt 2a, gener-
Figure 1: Molecular structures of AL-12, AL-12B and AL-5.
Scheme 1: Retrosynthetic analysis of AL-12, AL-12B and AL-5 (in their neutral forms) and their derivatives.
Scheme 2: Optimization study using phenylacetate 2a.
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Table 1: Impact of the reaction medium on the photodecarboxylative addition.
Entry
Co-solvent
T [°C]
Time [h]
Yield [%]
1a
2a
3
water
30
20
20
4
4
3
45b (3a)
49b (3a)
87 (3a)
water
pH 7 buffer
aCompound 4 formed as byproduct (25–30%). bIsolated yield after column chromatography.
ated from the corresponding phenylacetic acid and potassium the desired benzylated products 3a–q were obtained as color-
carbonate, was used in excess amounts to suppress competing less crystalline solids in good to excellent yields of 63–95%
‘simple’ decarboxylation (-CO2− ↔ -H exchange) reactions to (Table 2, entries 1–17). In many cases, the photoproducts 3
the corresponding toluene derivatives [25].
simply precipitated during irradiation or after removal of the
co-solvent acetone and could be isolated by filtration. In all
Following the established protocol and utilizing a 1:1 acetone/ other cases, the desired products 3 were obtained after extrac-
water mixture as reaction medium [27,30], irradiations with tion and subsequent column chromatography. All compounds 3
UVB light (300 ± 30 nm) for 4 hours under nitrogen purging in showed a characteristic pair of doublets between 3 and 4 ppm
Pyrex flasks (cutoff: <300 nm [47]) furnished the desired addi- with a large geminal 2J coupling of 12–16 Hz for the benzylic
tion product 3a in yields of 45 and 49% (Table 1, entries 1 and
2). The pH raised from approx. 7.5 at the beginning to about
Table 2: Experimental results for photodecarboxylative additions.
11.5 at the end of each irradiation experiment. In both cases, the
Entry
n
R
Time [h] Yield 3 [%]
tetracyclic oxazolidine compound 4, originating from intramo-
lecular nucleophilic substitution, was obtained as a byproduct in
25–30%. Noteworthy, compound 4 is formed as the only prod-
uct when 1a is treated with organometallic reagents [48-50].
When the photoreaction was repeated in a 1:1 mixture of ace-
tone and pH 7 buffer at 20 °C [28], the formation of 4 was
prevented and the desired benzylated hydroxyphthalimidine 3a
precipitated during irradiation for 3 hours. Subsequently, 3a
was obtained in an excellent yield of 87% by simple filtration
and washing (Table 1, entry 3). The pH increased from about
7.8 at the start to ca. 8.7 at the end of the irradiation. Tempera-
ture control was crucial as thermal conversion of 3a into 4 was
found to occur above 40 °C. Compound 1a could be converted
quantitatively to the oxazolidine derivative 4 by treatment with
either sodium carbonate or potassium tert-butoxide in aceto-
nitrile.
1
2 (1a)
2 (1a)
2 (1a)
2 (1a)
2 (1a)
2 (1a)
2 (1a)
2 (1a)
2 (1a)
3 (1b)
3 (1b)
3 (1b)
3 (1b)
3 (1b)
3 (1b)
3 (1b)
3 (1b)
2 (1a)
1 (1c)
H (2a)
3
3
3
3
3
3
3
3
2
3
3
3
3
3
3
3
3
6
4
87 (3a)
83 (3b)
79 (3c)
63 (3d)
85 (3e)
88 (3f)
66 (3g)
71 (3h)
77 (3i)
95 (3j)
75 (3k)
80 (3l)
73 (3m)
76 (3n)
89 (3o)
91 (3p)
73 (3q)
26 (3a)b
37 (5)
2
4-F (2b)
4-Cl (2c)
4-Br (2d)
4-MeO (2e)
4-Me (2f)
3-Me (2g)
2-Me (2h)
4-AcO (2i)
H (2a)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18a
19
4-F (2b)
4-Cl (2c)
4-Br (2d)
4-MeO (2e)
4-Me (2f)
3-Me (2g)
2-Me (2h)
H (2a)
Mixtures of N-(bromoalkyl)phthalimides 1 and phenylacetates 2
in acetone/pH 7 buffer were subsequently irradiated with UVB
light for 2–4 hours (Scheme 3 and Table 2). With the N-(2-
bromoethyl)- and N-(3-bromopropyl)phthalimides 1a and 1b,
H (2a)
aExposure to sunlight in a solar float. b47% conversion of 1a.
Scheme 3: Photodecarboxylative additions to N-(bromoalkyl)phthalimides.
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Beilstein J. Org. Chem. 2017, 13, 2833–2841.
methylene group (-CH2Ar) in their 1H NMR spectra and a imide 1c and phenylacetate (2a) in acetone/water. Subse-
singlet at 90 ± 3 ppm for the newly formed tertiary alcohol quently, compound 5 was independently prepared by photode-
(C–OH) in their 13C NMR spectra, respectively. Small amounts carboxylative benzylation of 6 for 4 h in 91% yield.
(<10%) of non-volatile toluene derivatives were occasionally
detected in the crude products by 1H NMR spectroscopic analy- Sulfuric acid-catalyzed dehydrations of the benzylated hydroxy-
sis but no attempts were made to isolate these compounds. The phthalimidines 3a–q in dichloromethane at room temperature
reaction was additionally studied with natural sunlight [51,52]. resulted in the corresponding olefins 7a–q in good to excellent
Solutions of 1a and 2a were exposed to direct sunlight in a solar yields of 66–95% (Scheme 5 and Table 3). The simple reaction
float developed by Liu and co-workers [53,54]. After 6 hours of protocol enabled parallel operations in a Radleys Carousel 6
illumination, the reaction had reached a conversion of 47% and Plus Reaction Station™. In line with DFT calculations by Kise
3a was subsequently isolated by column chromatography in et al. [12] and independently by Li and Janesko [21], the ther-
26% yield (Table 2, entry 18).
modynamically favored E-isomer was obtained as the main or
sole product. The high E-selectivity was furthermore confirmed
The structures of the photoaddition products 3a and 3b were un- by 1H NMR analyses. The olefinic protons of the minor
ambiguously confirmed by X-ray crystallography (Figure 2). In Z-isomers are shifted downfield by approx. 0.25 ppm due to the
the solid state, molecules of both compounds undergo hydro- shielding effect of the adjacent isoindolin-1-one ring [31,41]. A
gen bonding between the newly formed hydroxy group and the similar but deshielding effect was found for the N-bromoalkyl
intact carbonyl group, resulting in a one-dimensional network protons and the arylmethylene group. No such shifts were ob-
(see Supporting Information File 1).
served for the corresponding major E-isomers.
Notably, irradiation of N-(bromomethyl)phthalimide (1c) in the The structure of the dehydration product (E)-7a was further-
presence of phenylacetate (2a) did not furnish the desired addi- more confirmed by X-ray crystallographic analysis (Figure 3).
tion product, but the benzylated ester 5 in 37% yield instead Remarkably, the phenyl group of the arylmethylene unit is posi-
(Scheme 4). The electron-withdrawing character of the phthal- tioned almost perpendicular to the isoindolinone ring. Com-
imide group favored thermal nucleophilic substitution between pound (E)-7a forms dimers through CH–π interactions between
1c and phenylacetate (2a) to phthalimide 6. Ester 6 was indeed the phenyl ring and the olefinic =CH group (see Supporting
obtained in 37% yield by gently heating a mixture of phthal- Information File 1).
Figure 2: Crystal structures of photoaddition products 3a (left) and 3b (right).
Scheme 4: Formation of 5 by photodecarboxylative additions.
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Beilstein J. Org. Chem. 2017, 13, 2833–2841.
Scheme 5: Acid-catalyzed dehydration of 3a–q.
Table 3: Experimental results for acid-catalyzed dehydrations.
Entry
n
R
E/Z ratioa
Yield 7 [%]
1
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
H
9:1
91 (7a)
85 (7b)
88 (7c)
83 (7d)
90 (7e)
94 (7f)
83 (7g)
90 (7h)
66 (7i)
83 (7j)
91 (7k)
90 (7l)
84 (7m)
95 (7n)
92 (7o)
92 (7p)
83 (7q)
2
4-F
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
8:1
3
4-Cl
4
4-Br
4-MeO
4-Me
3-Me
2-Me
4-AcO
H
5
6
7
8
9
10
11
12
13
14
15
16
17
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
4-F
Figure 3: Crystal structure of (E)-7a. Side view and front view.
4-Cl
4-Br
4-MeO
4-Me
3-Me
2-Me
presence of the respective secondary amine, K2CO3 and KI in
DMF (Scheme 6 and Table 4). Subsequent work-up and isola-
tion by column chromatography furnished the desired 2-dialkyl-
aminoalkyl-3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones
8a–y in moderate yields of 49–61% (Table 4), among these the
biologically active AL-12 (8e), AL-12A (8i) and AL-5 (8w) in
their neutral forms. Interestingly, the Z-isomer of 8a–y was
aDetermined by 1H NMR analysis.
The final amination step was achieved following a modified formed as the sole product in almost all cases as confirmed by
procedure by Marzabadi and co-workers [42]. Catalytic 1H NMR analyses and by comparison with literature data
amounts of potassium iodide were added for in situ halogen (Table 4, entries 1–25) [10]. Subsequent investigations revealed
exchange. The dehydrated products 7a–q were heated in the that E-to-Z isomerization was caused during acidic work-up or
Scheme 6: Amination of dehydrated products 7a–q.
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Beilstein J. Org. Chem. 2017, 13, 2833–2841.
purification. When products 8a and 8j were isolated by extrac-
tion under neutral conditions, the high E-selectivity of the dehy-
dration step was retained. After column chromatographic purifi-
cation on silica gel, partial isomerization to the Z-isomers was
again observed (Table 4, entries 26 and 27).
Table 4: Experimental results for amination reactions.
Entry
n
R
R’
E/Z ratioa
Yield 8
[%]
1 (7a)
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
2
2
2
2
2
3
3
3
2
3
H
C2H5
C2H5
C2H5
C2H5
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>1:10
>10:1b/1:1c
>10:1b/10:7c
55 (8a)
55 (8b)
53 (8c)
51 (8d)
50 (8e)
57 (8f)
51 (8g)
58 (8h)
57 (8i)
53 (8j)
57 (8k)
60 (8l)
59 (8m)
55 (8n)
58 (8o)
61 (8p)
49 (8q)
58 (8r)
57 (8s)
55 (8t)
49 (8u)
60 (8v)
58 (8w)
55 (8x)
53 (8y)
65 (8a)
72 (8j)
2 (7b)
4-F
4-Cl
4-Br
The solid state structure of the amination product (Z)-8a was
furthermore established by X-ray crystal structure analysis
(Figure 4). The phenyl group of the arylmethylene unit is posi-
tioned almost perpendicular to the isoindolinone ring on top of
one of the N-ethyl groups of the side chain.
3 (7c)
4 (7d)
5 (7e)
4-MeO C2H5
6 (7f)
4-Me
3-Me
2-Me
4-AcO
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
7 (7g)
8 (7h)
9 (7i)
10 (7j)
11 (7k)
12 (7l)
13 (7m)
14 (7n)
15 (7o)
16 (7p)
17 (7q)
18 (7a)
19 (7b)
20 (7c)
21 (7e)
22 (7f)
23 (7j)
24 (7k)
25 (7q)
26 (7a)
27 (7j)
4-F
4-Cl
4-Br
4-MeO C2H5
4-Me
3-Me
2-Me
H
C2H5
C2H5
C2H5
CH3
4-F
CH3
Figure 4: Crystal structure of (Z)-8a. Side view and front view.
4-Cl
CH3
4-MeO CH3
4-Me
H
CH3
CH3
CH3
CH3
C2H5
C2H5
The mechanism of the photodecarboxylation is well established
(Scheme 7) and involves triplet sensitization by acetone and
electron transfer between the phenylacetate and the excited
phthalimide [55-57]. Subsequent decarboxylation, radical com-
bination and protonation furnishes the observed benzylated
hydroxyphthalimidine derivatives 3a–q.
4-F
2-Me
H
H
aAfter acidic work-up. Determined by 1H NMR analysis. bCrude prod-
uct after neutral work-up. cPure product after neutral work-up followed
by column chromatography on silica gel.
The nucleophilic cyclization to the oxazolidine derivative 4
may occur at different stages of the photodecarboxylation
Scheme 7: Mechanistic scenario for the photodecarboxylative addition.
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Beilstein J. Org. Chem. 2017, 13, 2833–2841.
(Scheme 8). The phthalimide radical anion may undergo shown for other simple N-substituted benzylideneisoindolin-1-
nucleophilic cyclization prior to C–C bond formation (path A), ones [12,21]. Remarkably, acidic reaction conditions induced
as postulated by Griesbeck et al. for the photocyclization of thermal isomerization of compounds 8a–y, possibly via an
phthaloyl-L-methionine [58]. Alternatively, the alcoholate ob- acylaminium cation intermediate (Scheme 9) [60]. The change
tained after C–C bond formation may cyclize to the oxazolidine in stability may be caused by a stabilizing ionic–π interaction
(path B), as known from reactions of 1a with organometallic for the Z-isomer during isomerization [61]. A similar thermal
reagents [48-50]. When compound 1a was treated with either isomerization towards the more stable isomer induced by cata-
sodium carbonate or potassium tert-butoxide it was indeed con- lytic amounts of pyridinium p-toluenesulfonate has been
verted quantitatively to the oxazolidine derivative 4. Similarly, recently reported by Kise and co-workers [12].
the final benzylated hydroxyphthalimidine may undergo cycli-
zation instead (path C), as was found to occur at elevated tem- Conclusion
perature of >40 °C. Temperature control during the reaction, Photodecarboxylation reactions are emerging as versatile trans-
work-up and isolation was thus important to suppress this unde- formations in organic synthesis [24,33,62-65]. The photodecar-
sired transformation. The usage of pH 7 buffer as a co-solvent boxylative addition of phenylacetates to N-(bromoalkyl)phthal-
significantly improved yields and selectivity, possibly due to imides was used as a mild key step in the synthesis of 2-dialkyl-
the avoidance of extreme basic conditions found for photode- aminoalkyl-3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones,
carboxylations in acetone/water [34,59].
among these the potent local anesthetics AL-12, AL-12A and
AL-5 (in their neutral forms). The simple procedures make this
The high stereoselectivity during the formation of compounds three-step process attractive for in-series continuous flow appli-
7a–q is supported by the higher stability of the E-isomer, as cations [40,66,67].
Scheme 8: Possible scenarios for nucleophilic cyclization to 4.
Scheme 9: Possible E/Z isomerization for compounds 8a–y.
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Beilstein J. Org. Chem. 2017, 13, 2833–2841.
16.Reyes-González, M. Á.; Zamudio-Medina, Á.;
Supporting Information
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Supporting Information File 1
Experimental details, detailed spectroscopic and
crystallographic data.
17.Gogoi, A.; Guin, S.; Rout, S. K.; Majji, G.; Patel, B. K. RSC Adv. 2014,
4, 59902–59907. doi:10.1039/C4RA12782J
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[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-275-S1.pdf]
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This work was financially supported by the Australian Research
Council (ARC, DP130100794). SM thanks the Higher Educa-
tion Commission Pakistan for providing a Scholarship under the
International Research Support Initiative Program. MO thanks
Professor Emeritus Robert (Bob) S. H. Liu from the University
of Hawaii for the donation of the solar float reactor.
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Ommid Anamimoghadam - https://orcid.org/0000-0002-7350-3472
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