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Synthesis 2022; 54(21): 4827-4833
DOI: 10.1055/a-1894-9073
paper

Organic Base-Mediated Carboxylation of (Hetero)aromatic Compounds Using Supercritical Carbon Dioxide (scCO2)

Lloyd C. Chetty 
a   Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, 4001, South Africa
,
Hendrik G. Kruger 
a   Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, 4001, South Africa
,
Per I. Arvidsson 
a   Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, 4001, South Africa
b   Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
,
Tricia Naicker 
a   Catalysis and Peptide Research Unit, University of KwaZulu Natal, Durban, 4001, South Africa
,
Thavendran Govender  ∗
c   Department of Chemistry, University of Zululand, Private Bag X1001, KwaDlangezwa 3886, South Africa
› Author Affiliations

The South African National Research Foundation grant numbers 137961, 145774, 120419.
› Further Information
 
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Abstract

A straightforward site-selective method for the direct carboxylation of resorcinols (3-hydroxyphenol derivatives), phenols, and indoles is reported. The products were obtained in moderate to high yields using supercritical carbon dioxide as an electrophile and solvent under basic conditions. This method offers solvent and metal free conditions without the cumbersome exclusion of air or water with convenient purification.


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Key words

supercritical carbon dioxide - Kolbe–Schmitt - C–H carboxylation - metal free - solvent free

Direct functionalisation of C–H bonds represents a powerful transformation in organic synthesis. It allows for the efficient and economical synthesis of known and unknown compounds.[1] The direct C–H carboxylation of (hetero)aromatic compounds avoids pre-functionalisation and provides the fewest synthetic steps with the highest atom economy.[2] This methodology is of particular importance to the pharmaceutical industry as (hetero)aromatic carboxylic acids are important intermediates in the synthesis of numerous biological molecules (Figure [1]).[3] (Hetero)aromatic carboxylic acids are also promising feedstock chemicals, which may be used to populate libraries of complex small molecules.[4] Unsurprisingly, the global market for carboxylic acids is expected to increase yearly by 5% to 2023, reaching approximately $20 billion.[5]

Zoom Image
Figure 1 Examples of useful bioactive molecules prepared from (hetero)aromatic carboxylic acids[3`] [b] [c]

CO2 utilisation is of academic and industrial interest since CO2 is a desirable carbon feedstock,[6] due to its abundance, low cost, and nontoxicity.[7]

The Kolbe–Schmitt synthesis is one of the most significant and recognised examples of a direct C–H carboxylation of aromatic compounds.[8] The Kolbe–Schmitt synthesis is one of the few industrially relevant reactions utilising CO2. [9] Established in 1860 by H. Kolbe,[10] enhanced in 1885 by R. Schmitt,[11] and simplified in 1893 by S. Marasse,[12] the Kolbe–Schmitt synthesis is a standard method utilised in the production of aromatic hydroxycarboxylic acids.[13] However, this process still possesses significant disadvantages, such as the time-consuming preparation and isolation of highly hygroscopic phenoxides (Scheme [1], A).[14]

Zoom Image
Scheme 1 Previous and current approaches for the direct C–H carboxylation of (hetero)aromatic compounds

Unfortunately, current methods for the direct C–H carboxylation still possess disadvantages such as the use of solvents, metals, moisture-sensitive conditions, and prolonged reaction times (Scheme [1], B).[14] [15] In recent years, supercritical carbon dioxide (scCO2, Tc = 31 °C, Pc = 73.8 bar) has been utilised as a cheaper, environmentally friendly alternative to conventional organic solvents,[16] which are often flammable, harmful, and volatile.[17]

In an effort to improve reaction efficiency and reduce waste,[18] we sought to incorporate the ideals of green chemistry such as reducing solvent use and applying more efficient purification techniques.[19] Therefore, we utilised scCO2 as a reactant and reaction medium. Herein, we report a solvent and metal free organic base-mediated Kolbe–Schmitt type reaction of (hetero)aromatic compounds that does not require rigorous exclusion of air or water (Scheme [1], C).

For this study, resorcinols (3-hydroxyphenol derivatives) were chosen to investigate the Kolbe–Schmitt reaction in scCO2. The traditional Kolbe–Schmitt synthesis of resorcinol requires high-pressure CO2 and is performed batch-wise with prolonged reaction times.[13] In recent years, several studies have been conducted to eliminate the drawbacks of the Kolbe–Schmitt reaction on resorcinol, such as the use of microwave-assisted reactions,[9] ionic liquids,[9] [13] ultrasonication,[20] and biocatalysis.[21] Unfortunately, these methods produce poor yields or atom economy and possess a limited substrate scope. Recently, Yamada et al. reported the first organic base-mediated Kolbe–Schmitt synthesis from resorcinols.[22] However, this protocol used anhydrous conditions utilising acetonitrile and the relatively expensive superbase 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) at 30 °C using 20 bars of CO2.

We sought to develop a more economical, greener method for the direct C–H carboxylation of resorcinol using neat scCO2. Initially, the carboxylation was performed under neat scCO2 conditions with DBU, and the corresponding salicylic acid was obtained with a 65% conversion of resorcinol (Table [1], entry 1). Thereafter, the application of the more economical organic bases such as N,N-diisopropylethylamine (DIPEA) and triethylamine (TEA) were performed (entries 2, 3). To our delight, the reaction worked with TEA. However, a higher reaction temperature was necessary (entry 3, 62% conversion). A higher TEA equivalence was shown to increase the conversion to 83% (entry 4). The addition of acetonitrile as a co-solvent had a detrimental effect, decreasing the conversion to 8% (entry 5). Finally, the effects of temperature and pressure were investigated. Increasing the pressure to 100 bars positively affected the conversion (entries 6, 7; 82 and 63%, respectively). This result contrasts the flow synthesis of resorcinol reported by Stark et al., where the use of supercritical pressures did not significantly increase the conversion.[23] However, increasing the temperature further, decreased the conversion to 70%, most likely due to promoting the decarboxylation reaction (entry 8).[13] The complete optimisation can be found in the accompanying ESI (Table S1).

Table 1 Optimisation of Reaction Conditions for the Carboxylation of Resorcinola

Entry

Base (equiv)

Temp (°C)

Pressure (bar)

Conversion (%)b

1c

DBU (3)

 55

100

65

2d

DIPEA (3)

 55

 88

43

3

TEA (3)

100

100

62

4

TEA (5)

100

100

83

5e

TEA (5)

100

100

 8

6

TEA (5)

100

 80

82

7

TEA (5)

100

 20

63

8

TEA (5)

120

100

70

a Reaction conditions: 1a (0.91 mmol), base, dry ice as the CO2 source, stirred in a high-pressure vessel for 2 h.

b Conversion of resorcinol was determined by LC-MS analysis of the reaction mixture.

c Stirred in a high-pressure vessel for 4 h.

d stirred in a high-pressure vessel for 24 h.

e Acetonitrile as a solvent.

Inspired by these results, we next set out to perform the carboxylation on phenols (Table [2]). Unfortunately, the economical TEA could not promote the carboxylation of this substrate (Table [2], entry 1); similarly, DIPEA did not significantly promote the reaction (entry 2). The carboxylation of phenol proceeded well in the presence of DBU (entry 3, 59%). Interestingly decreasing the equivalence of DBU led to an increase in conversion (entry 4, 53%).

Table 2 Optimisation of Reaction Conditions for the Carboxylation of Phenolsa

Entry

Base (equiv)

Temp (°C)

Pressure (bar)

Conversion (%)b

1c

TEA (5)

100

100

nr

2c

DIPEA (5)

120

100

10

3c

DBU (3)

100

100

59

4c

DBU (5)

100

100

53

5

DBU (3)

120

100

77

6

DBU (3)

120

 60

63

7

DBU (3)

120

 20

46

8d

DBU (3)

140

  1

 4

a Reaction conditions: 3a (1.06 mmol), base, dry ice as the CO2 source, stirred in a high-pressure vessel for 15 h.

b Conversion of phenol was determined by LC-MS analysis of the reaction mixture; nr: no reaction.

c Stirred in a high-pressure vessel for 24 h.

d Stirred in a Schlenk tube for 24 h.

Increasing the reaction temperature positivity affected the conversion and reaction time (Table [2], entry 5, 77%). Decreasing the pressure negatively affected the conversion (entries 6–8; 46 and 63%, respectively). The effects of pressure agree with previous reports where supercritical pressures were beneficial.[23] [24] The less reactive phenols required longer reaction times and higher reaction temperatures. The complete optimisation can be found in the accompanying ESI (Table S2).

Having established the optimal protocol for the reaction, we then explored the electronic properties of both resorcinol and phenol substrates to synthesise the corresponding salicylic acid derivatives (Table [3]). The corresponding salicylic acid derivatives were conveniently isolated in high purity using solvent extraction. The carboxylation of resorcinols showed good yields for electron-donating and withdrawing groups (2a–d). Complete selectivity for the 2,4-dihydroxybenzoic acid derivatives was achieved with C2-substituted and C6-substituted resorcinols. The carboxylation of C5-substituted 5-methylresorcinol produced 2,6-dihydroxy-4-methylbenzoic acid (2e) exclusively in 53% yield. A higher temperature and reaction time was required (120 °C, 12 h). The lower yield could be due decarboxylation occurring at the higher temperature. This is an interesting result as Yamada et al.[22] obtained 2,4-dihydroxy-6-methylbenzoic acid from 5-methylresorcinol, with the C2 position of 5-methylresorcinol being the most reactive. We hypothesise that 2,4-dihydroxy-6-methylbenzoic acid is not thermodynamically stable under these reaction conditions and decarboxylation proceeded. The carboxylation of 5-methylresorcinol has been reported to produce 2,6-dihydroxy-4-methylbenzoic acid utilising potassium bicarbonate under similar higher temperatures.[25]

Table 3 Substrate Scope for the Carboxylation of Aromatic Compounds

Resorcinola

2a, 76%

2b, 84%

2c, 78%

2d, 78%

2e, 53%b

Phenolc

4a, 50%

4b, 62%

4c, 51%

4d, 36%

4e, 66%

4f, 32%

a Reaction conditions: 1a (0.91 mmol), TEA (5 equiv), 100 bar, stirred in a high-pressure vessel for 2 h at 100 °C.

b TEA (5 equiv), 100 bar, stirred in a high-pressure vessel for 12 h at 120 °C.

c Reaction conditions: 3a (1.06 mmol), DBU (3 equiv), 100 bar, stirred in a high-pressure vessel for 15 h at 120 °C.

The high reaction temperature might also play a pivotal role in the selectivity of the reaction for C2-substituted and C6-substituted resorcinols and contribute to the low yield of 2e as 2,6-dihydroxybenzoic acid is reported to undergo decarboxylation above 80 °C.[26]

The carboxylation of phenols tolerated electron-donating and -withdrawing groups, albeit in moderate to low yields (4a–f). In contrast to previous studies where a mixture of ortho/para-isomers were obtained, this protocol selectively produced the para-substituted acid.[15a] [23] [24] The attempted carboxylation of p-cresol resulted in no product formation. A mixture of 2-amino-4-hydroxybenzoic acid and a by-product was obtained when 3-aminophenol was used as a substrate. LC-MS analysis revealed the by-product had a second addition of CO2. Considering the selectivity of the method, it is possible that a carbamate formation occurred between the primary amine and CO2, which further reacted with carboxylic acid group.

The selectivity of the Kolbe–Schmitt reaction has been reported to be affected by temperature, pressure, and the type of alkali metal used.[8] [27] Mechanistically, we believe that the steric bulk of DBU prevents ortho-carboxylation. Additionally, DBU-mediated carboxylation mitigates the use of highly hygroscopic alkaline metal phenoxides allowing the reaction to be performed in a one-pot process with wet CO2. Despite the moderate to low yields obtained, para-carboxylated substituted phenols are important motifs and intermediates in medicinal applications.[28] To the best of our knowledge, this is the first para-selective organic base mediated Kolbe–Schmitt reaction.

Table 4 Optimisation of Reaction Conditions for the Carboxylation of Indolea

Entry

Base (equiv)

Temp (°C)

Pressure (bar)

Conversion (%)b

1c

TEA (5)

120

100

nr

2d

DIPEA (5)

120

100

nr

3

DBU (5)

100

100

99

4

DBU (5)

100

 20

99

5

DBU (3)

100

 20

93

6

DBU (5)

 80

 20

81

7

DBU (5)

100

 10

37

8e

DBU (5)

100

  1

 8

a Reaction conditions: 5a (0.85 mmol), base, dry ice as the CO2 source, stirred in a high-pressure vessel for 2 h.

b Conversion of indole was determined by LC-MS analysis of the reaction mixture; nr: no reaction.

c Stirred in a high-pressure vessel for 6 h.

d Stirred in a high-pressure vessel for 17 h.

e Stirred in a Schlenk tube for 24 h.

Encouraged by the preceding results, we decided to pursue the carboxylation of indoles. Initial attempts using TEA and DIPEA proved unsuccessful (Table [4], entries 1, 2). The carboxylation proceeded readily in the presence of DBU (entry 3, 99%). The carboxylation was shown to occur in quantitative yields even at subcritical pressures (entry 4, 99%). Decreasing the equivalence of DBU or temperature had detrimental effects on the conversion (entries 5, 6; 93 and 81%, respectively). This is in accordance with previous reports where a high equivalence of base was necessary to prevent decarboxylation from occurring.[15b] [29] Attempts to further decrease the pressure negatively affected the conversion (entries 7, 8; 37 and 8% respectively).

The carboxylation of indole was performed in quantitative yield (6a), while electron-withdrawing groups at the 5-position led to a slight decrease in yields (6b,c) (Table [5]). The carboxylation was selective for the 3-position, as previously reported.[15b] [c] [29] When 4-acetoxyindole was used as a substrate a mixture of 4-acetoxyindole-3-carboxylic acid and by-products were obtained.

Table 5 Substrate Scope for the Carboxylation of Heteroaromatic Compoundsa

6a, 99%

6b, 76%

6c, 88%

a Reaction conditions: 5a (0.91 mmol), DBU (5 equiv), 20 bar, stirred in a high-pressure vessel for 2 h at 100 °C.

Kobayashi et al. reported the direct carboxylation of indoles under atmospheric CO2 utilising LiO t Bu as a base. While high yielding, this procedure is moisture sensitive and possesses prolonged reactions times (24 h).[15b] Alternatively, Hattori et al. reported the Lewis acid mediated direct carboxylation of indoles under 30 bars of CO2. Although moderate yields were obtained at room temperature for 1-substituted indoles, low yields were obtained with free (NH) indoles.[15c] Our method represents a high yielding, greener, solvent, and metal free approach with straightforward purification.

(Hetero)aromatic carboxylic acids are valuable intermediates in synthesising various biologically active molecules.[30] Therefore, substrates generated from this protocol were coupled with various amines using coupling reagents under microwave conditions to produce synthetically useful precursors of bioactive molecules (Figure [2]). Resorcinol based compound 7a is an intermediate to potential Hsp90 inhibitors.[3c] Indole based compound 7b is a precursor of a vasopressin 1a antagonist for the potential treatment of autism.[3b]

Zoom Image
Figure 2 Precursors for bioactive molecules[3`] [b] [c]

In conclusion, we have developed a practical and efficient protocol for the direct carboxylation of resorcinols, phenols, and indoles in moderate to high yields with scCO2 as an electrophile and solvent. The carboxylation was site-selective, and the product was obtained as a single isomer. We hypothesise that the reaction proceeds via the previously reported Kolbe–Schmitt type reaction mechanism, that is, under basic conditions involving the nucleophilic addition of phenolate or indoles and CO2.[8] [22]

This method represents a greener and operationally simplistic approach over existing direct carboxylation methodologies. Specifically, the solvent and metal free conditions avoids tedious exclusion of air or water during reaction and offers a straightforward purification through a simple solvent extraction. Additionally, this protocol can be used to generate valuable (hetero)aromatic carboxylic acids which are intermediates in various biologically active molecules. Further applications of this method are presently under active investigation in our laboratory.

Reagents and solvents were purchased from Sigma Aldrich and Merck and unless otherwise noted used without further purification. All solvents were reagent grade or better. Deuterated solvents were used as received. Dry ice was made from with tech grade-wet CO2 (90%). TLC was performed using Merck Kieselgel 60 F254 plates. Synthetic steps were characterised using LC-MS (Shimadzu 2020 UFLC-MS, Japan). Preparatory supercritical fluid chromatography was performed on a Sepiatec Prep SFC basic 30 (Germany). NMR data were recorded using a Bruker Avance III 400 MHz at rt. The NMR chemical shifts (δ) are reported in parts per million (ppm) relative to the residual solvent peak (1H NMR δ = 7.26 for CDCl3, δ = 2.50 for DMSO-d 6; 13C NMR δ = 77.0 for CDCl3, δ = 39.52 for DMSO-d 6).


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Carboxylation of Resorcinols; 2,4-Dihydroxybenzoic Acid (2a); Typical Procedure

A mixture of resorcinol (1a; 100 mg, 0.91 mmol), TEA (5 equiv), and dry ice (CO2) was added into a 10 mL microwave reaction tube and placed into a high-pressure reaction vessel (Parr instrument company, USA). The high-pressure reaction vessel was then placed in a preheated oil bath. The temperature was maintained by an external temperature probe connected to a digital hot plate. Pressure was monitored by a pressure gauged attached to the reaction vessel. Upon completion, the mixture was acidified with aq 2 M HCl and extracted with EtOAc. The combined EtOAc layers were washed with 5% aq NaHCO3 to extract product from any unreacted starting material. Thereafter, the combined aqueous layers were acidified with aq 2 M HCl and extracted with EtOAc. The resultant organic layers were combined and dried (anhyd MgSO4), and the solvent was evaporated under reduced pressure to provide pure 2,4-dihydroxybenzoic acid (2a);[22] white solid; yield: 76%.

1H NMR (400 MHz, DMSO-d 6): δ = 11.45 (br s, 1 H), 10.35 (br s, 1 H), 7.61 (d, 1 H), 6.34 (dd, 1 H), 6.26 (d, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 172.0, 164.1, 163.4, 130.8, 131.9, 108.0, 104.3, 102.3.


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2,4-Dihydroxy-3-methylbenzoic Acid (2b)[22]

White solid; yield: 84%.

1H NMR (400 MHz, DMSO-d 6): δ = 13.27 (br s, 1 H), 11.73 (br s, 1 H), 10.22 (br s, 1 H), 7.49 (d, 1 H), 6.41 (d, 1 H), 1.97 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 172.5, 161.6, 161.4, 128.4, 110.1, 106.9, 103.9, 7.8.


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5-Chloro-2,4-dihydroxybenzoic Acid (2c)[31]

White solid; yield: 78%.

1H NMR (400 MHz, DMSO-d 6): δ = 11.21 (br s, 1 H), 7.67 (s, 1 H), 6.48 (s, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 171.0, 161.6, 159.3, 130.9, 111.2, 105.4, 103.6.


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3-Bromo-2,4-dihydroxybenzoic Acid (2d)[22]

White solid; yield: 78%.

1H NMR (400 MHz, DMSO-d 6): δ = 12.26 (br s, 1 H), 11.21 (br s, 1 H), 7.64 (d, 1 H), 6.55 (d, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 171.9, 160.7, 160.2, 130.2, 107.5, 105.2, 97.2.


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2,6-Dihydroxy-4-methylbenzoic Acid (2e)[25b]

White solid; yield: 53%.

1H NMR (400 MHz, DMSO-d 6): δ = 9.96 (br s, 3 H), 6.20 (s, 2 H), 2.17 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 172.3, 160.6, 146.0, 107.8, 99.1, 21.5.


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Carboxylation of Phenols; 4-Hydroxybenzoic Acid (4a); Typical Procedure

A mixture of phenol (3a; 100 mg, 1.06 mmol), DBU (3 equiv), and dry ice (CO2) was added into a 10 mL microwave reaction tube and placed into a high-pressure reaction vessel (Parr instrument company, USA). Upon completion, the mixture was acidified with aq 2 M HCl and extracted with EtOAc. The combined ethyl acetate layers were washed with 5% aq NaHCO3. Thereafter, the combined aqueous layers were acidified with aq 2 M HCl and extracted with EtOAc. The resultant organic layers were combined, dried (anhyd MgSO4), and the solvent was evaporated under reduced pressure to provide pure 4-hydroxybenzoic acid (4a);[32] white solid; yield: 50%.

1H NMR (400 MHz, DMSO-d 6): δ = 12.41 (br s, 1 H), 10.21 (s, 1 H) 7.79 (d, 2 H), 6.82 (d, 2 H).

13C NMR (100 MHz, DMSO-d 6): δ = 167.2, 161.6, 131.6, 121.4, 115.2.


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3-Bromo-4-hydroxybenzoic Acid (4b)[33]

White solid; yield: 62%.

1H NMR (400 MHz, DMSO-d 6): δ = 12.74 (br s, 1 H), 11.13 (s, 1 H), 7.99 (d, 1 H), 7.77 (dd, 1 H), 7.02 (d, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 168.0, 158.2, 134.2, 130.5, 123.0, 116.0, 109.0.


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2-(Dimethylamino)-4-hydroxybenzoic Acid (4c)[28a]

Red solid; yield: 51%.

1H NMR (400 MHz, DMSO-d 6): δ = 7.54 (d, 1 H), 6.27 (dd, 1 H), 6.06 (d, 1 H), 3.00 (s, 6 H).

13C NMR (100 MHz, DMSO-d 6): δ = 172.1, 163.0, 155.3, 131.1, 104.0, 100.3, 97.2, 39.6.


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4-Hydroxy-2-methylbenzoic Acid (4d)[34]

White solid; yield: 36%.

1H NMR (400 MHz, DMSO-d 6): δ = 10.03 (s, 1 H), 7.74 (d, 1 H), 6.62–6.64 (m, 2 H), 2.46 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 168.1, 160.5, 142.3, 133.1, 120.5, 118.1, 112.6, 21.9.


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4-Hydroxy-3-methylbenzoic Acid (4e)[35]

White solid; yield: 66%.

1H NMR (400 MHz, DMSO-d 6): δ = 10.12 (s, 1 H), 7.62–7.69 (m, 2 H), 6.84 (d, 1 H), 2.15 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 167.4, 159.8, 132.2, 129.0, 123.9, 121.1, 114.3, 15.9.


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4-Hydroxy-2,5-dimethylbenzoic Acid (4f)[36]

White solid; yield: 32%.

1H NMR (400 MHz, DMSO-d 6): δ = 9.91 (s, 1 H), 7.64 (s, 1 H), 6.64 (s, 1 H), 2.42 (s, 3 H), 2.09 (s, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 168.2, 158.6, 139.4, 133.7, 121.1, 120.0, 117.3, 22.0, 15.3.


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Carboxylation of Indoles; 1H-Indole-3-carboxylic Acid (6a); Typical Procedure

A mixture of indole (5a; 100 mg, 0.85 mmol), DBU (5 equiv), and dry ice (CO2) was added into a 10 mL microwave reaction tube and placed into a high-pressure reaction vessel (Parr instrument company, USA). Upon completion, the mixture was acidified with aq 2 M HCl and extracted with EtOAc. The combined ethyl acetate layers were washed with 5% aq NaHCO3. Thereafter, the combined aqueous layers were acidified with aq 2 M HCl and extracted with EtOAc. The resultant organic layers were combined, dried (anhyd MgSO4), and the solvent was evaporated under reduced pressure to provide pure 1H-indole-3-carboxylic acid (6a);[15d] white solid; yield: 99%.

1H NMR (400 MHz, DMSO-d 6): δ = 11.79 (br s, 1 H), 7.99–8.01 (m, 2 H), 7.45–7.47 (m, 1 H), 7.13–7.20 (m, 2 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.9, 136.4, 132.2, 126.0, 122.1, 120.9, 120.6, 112.2, 107.4.


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5-Bromo-1H-indole-3-carboxylic Acid (6b)[37]

Brown solid; yield: 76%.

1H NMR (400 MHz, DMSO-d 6): δ = 12.13 (br s, 1 H), 12.00 (br s, 1 H), 8.14 (d, 1 H), 8.06 (d, 1 H), 7.44 (d, 1 H), 7.31 (d, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.6, 135.2, 133.6, 127.8, 124.8, 122.7, 114.3, 113.9, 107.1.


#

5-Nitro-1H-indole-3-carboxylic Acid (6c)[38]

Light yellow solid; yield: 88%.

1H NMR (400 MHz, DMSO-d 6): δ = 12.44 (br s, 1 H), 8.89 (d, 1 H), 8.27 (s, 1 H), 8.08 (dd, 1 H), 7.66 (d, 1 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.2, 142.2, 139.6, 135.9, 125.4, 117.6, 117.1, 113.1, 109.6.


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Synthesis of Bioactive Precursors


#

N-Benzyl-5-chloro-2,4-dihydroxybenzamide (7a)[3c]

A mixture of 5-chloro-2,4-dihydroxybenzoic acid (2c; 100 mg, 0.53 mmol, 1 equiv), benzylamine (1.5 equiv), i-Pr2NEt (1 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 equiv), and 1-hydroxybenzotriazole monohydrate (1 equiv) in DMF was added into a 10 mL microwave reaction tube. The reaction mixture was stirred under microwave irradiation at 120 °C for 2 h in 1 h intervals. Upon completion, the mixture was dissolved in EtOAc. The organic layer was washed with aq 2 M HCl (3 ×). The resultant organic layer was dried (anhyd MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH and purified utilising prep SFC with the following parameters: injection volume = 100 μL, column = silica gel (250 × 10 mm, 300 Å) at 40 °C, mobile phase = a MeOHl modifier (10%), with tech grade-wet CO2 (90%), in 7 min, flow rate = 10 mL min–1, stacked injection program with a 1-min equilibration time, BPR setting = 150 bar, monitoring and collection at 230 nm; yellow oil; yield: 79%.

1H NMR (400 MHz, CD3OD): δ = 7.79 (s, 1 H), 7.33–7.31 (m, 4 H), 7.26–7.22 (m, 1 H), 6.45 (s, 1 H), 4.54 (s, 2 H).

13C NMR (100 MHz, CD3OD): δ = 169.9, 161.7, 158.9, 139.9, 130.0, 129.5, 128.4, 128.1, 112.9, 109.7, 105.0, 43.9.


#

(1H-Indol-3-yl)(piperidin-1-yl)methanone (7b)[39]

A mixture of 1H-indole-3-carboxylic acid (6a; 100 mg, 0.62 mmol, 1 equiv), piperidine (1.5 equiv), i-Pr2NEt (1 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 equiv), and 1-hydroxybenzotriazole monohydrate (1 equiv) in DMF was added into a 10 mL microwave reaction tube. The reaction mixture was stirred under microwave irradiation at 120 C for 1 h. Upon completion, the mixture was dissolved in EtOAc. The organic layer was washed with aq 2 M HCl (3 ×). The resultant organic layer was dried (anhyd MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in MeOH was purified utilising prep SFC with the following parameters: injection volume = 100 μL, column = silica gel (250 × 10 mm, 300 Å) at 40 °C, mobile phase = a MeOH modifier (10%), with tech grade-wet CO2 (90%), in 7 min, flow rate = 10 mL min–1, stacked injection program with a 1-min equilibration time, BPR setting = 150 bar, monitoring and collection at 230 nm; brown solid; yield: 57%.

1H NMR (400 MHz, DMSO-d 6): δ = 11.52 (br s, 1 H), 7.62–7.64 (m, 2 H), 7.43 (d, 1 H), 7.06–7.16 (m, 2 H), 3.57 (t, 4 H), 1.60–1.65 (m, 2 H), 1.49–1.54 (m, 4 H).

13C NMR (100 MHz, DMSO-d 6): δ = 165.4, 135.6, 127.4, 125.9, 121.7, 120.0, 111.9, 110.3, 25.9, 24.3.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors would like to thank the South African National Research Foundation, the Nuclear Medicine Research Infrastructure, and the College of Health Sciences, UKZN for the financial support.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1894-9073.
  • Supporting Information

Corresponding Author

Thavendran Govender
Department of Chemistry, University of Zululand
Private Bag X1001, KwaDlangezwa 3886
South Africa   

Publication History

Received: 26 May 2022

Accepted after revision: 08 July 2022

Accepted Manuscript online:
08 July 2022

Article published online:
16 August 2022

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Figure 1 Examples of useful bioactive molecules prepared from (hetero)aromatic carboxylic acids[3`] [b] [c]
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Scheme 1 Previous and current approaches for the direct C–H carboxylation of (hetero)aromatic compounds
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Figure 2 Precursors for bioactive molecules[3`] [b] [c]