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Synthesis 2023; 55(21): 3610-3616
DOI: 10.1055/a-2114-5426
special topic
C–H Bond Functionalization of Heterocycles

Sustainable Ru(II)-Catalyzed ortho-C(sp2)–H Hydroxyalkylation of Phthalazinones Using Ethyl Glyoxalate: Access to α,α′-Arylcarboxy sec-Alcohols

Alagumalai Ramkumar
,
Thirumanavelan Gandhi∗

Fundings from DST-SERB, India (CRG/2021/001143) and the VIT, Vellore­ (Seed Grant/SG20210167) are gratefully acknowledged.
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Abstract

An operationally simple and expeditious protocol for Ru(II)-catalyzed ortho-C(sp2)–H hydroxyalkylation of phthalazinones using commercially available ethyl glyoxalate in 2-Me-THF is reported. This greener approach involves the imine nitrogen on the phthalazinones as a directing group to effect the regioselective hydroxyalkylation. Ample examples of biologically relevant hydroxyalkylated phthalazinones were prepared, and relevant controlled studies were performed to decipher the reaction mechanism.


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Key words

ethyl glyoxalate - ruthenium - phthalazinones - 2-Me-THF - hydroxyalkylation

Transition-metal-catalyzed C–H bond functionalization in conjunction with directing group assistance is considered a paradigm shift in organic synthesis as it is a concise and very efficient process.[1] In this regard, Ru(II) catalyzed C(sp2)–H activation and functionalization were found to be in an uptrend owing to its efficiency and economic viewpoint. Ru(II) catalysts react with aromatics possessing directing group to form the corresponding cyclometalated species with ease, and notably, they are compatible with commonly employed oxidants, and feasible in air and water medium.[2] Besides, this reliable process curtails the large waste generation and cuts short the synthetic steps, and promotes C–H bond activation and functionalization regioselectively.[3] This prevailing strategy enables the construction of a wide range of heterocycles, which shows interesting biological, photo-, and electrochemical applications.[4]

Zoom Image
Figure 1 Representative examples of biologically active compounds possessing hydroxylmethyl group

Manipulating the phthalazinones by transition metal catalysis helps to forge new C–C bonds in the phthalazinones, which will expand its applicability in pharmaceuticals and advanced materials.[5] The inclusion of alcohol onto heterocycles augments its biological activity and turns those derivatives more interesting (Figure [1]).[6] Conventionally, alcohols are prepared by the nucleophilic addition of organometallic reagents to the carbonyl compounds. As a downside, organohalides and their organometallic form used (Grignard reagent)[7] are corrosive and air- and moisture-sensitive, respectively. To counter and make this addition practical, synthetic chemists applied the transition-metal-catalyzed strategy for the addition of C(sp2)–H bonds to aldehydes to generate alcohols.[8] [9] [10] [11] [12] Ackermann,[13] Li,[14] and Kim[15] independently reported Mn, Co, and Rh-catalyzed directing-assisted selective C2 C(sp2)–H bond functionalization of indoles with aldehydes, respectively. Kim had further extended to indolines where C-7 functionalized examples were observed by ruthenium catalysis. Later in 2020, Kim reported the Ru(II)-catalyzed C–H hydroxyalkylation of 2-phenyl-2,3-dihydrophthalazine-1,4-dione[16] and 2-aryl­quinazolinones with aldehydes.[17] In the same year, Hajra synthesized α-branched alcohols of 2-arylindazoles using ethyl glyoxalate in the presence of a catalytic amount of Rh(III) (Scheme [1]).[18] Although, the above-mentioned reports highlighted the directing group-assisted C–H hydroxyalkylation of various heterocycles, utilization of 2-phenylphthalazin-1(2H)-one (phthalazinones) is not shown in the literature. Herein, we report environmentally friendly Ru(II)-catalyzed ortho-C(sp2)–H hydroxyalkylation of phthalazinones using ethyl glyoxalate in 2-methyltetrahydrofuran (2-Me-THF). At the outset, we chose 2-phenylphthalazin-1(2H)-one (1a) as a model substrate and ethyl glyoxalate (2a) as a substituted hydroxymethylating agent.

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Scheme 1 a) Transition-metal-catalyzed C–H hydroxyalkylation of heterocycles using ethyl glyoxalate, b) Ru(II)-catalyzed ortho-C(sp2)–H hydroxyalkylation of phthalazinones using ethyl glyoxalate.

At first, 5 mol% of [RuCl2(p-cymene)]2 and an additive combination of AgSbF6 (10 mol%) and NaOAc (50 mol%) in DCE at 120 °C was attempted. After 16 hours, hydroxyalkylated product 3a was isolated in 60% yield (Table [1], entry 1). When the additive was changed to NH4OAc or KOAc in place of NaOAc, a reduction in yield of 3a about 23% and 22%, respectively, was observed. Screening of various solvents like 2-Me-THF, MeCN, TFE, THF, 1,4-dioxane, DMF, toluene, DMSO, and H2O was carried out (entries 4–12). Among these, 2-Me-THF (entry 4) was found to be the best for this transformation (yield: 75%). To study the effect of silver salt, AgOTf, AgOAc, AgO, and Ag2CO3 were tried (entries 13–16). In the absence of silver salt and NaOAc, the yield of the reaction is 34% and 0%, respectively (entries 17, 18).

Table 1 Optimization of Reaction Conditionsa

Entry

Catalyst

Additive

Solvent

Yield (%)

 1

Ru(II)

AgSbF6

NaOAc

DCE

60

 2

Ru(II)

AgSbF6

NH4OAc

DCE

23

 3

Ru(II)

AgSbF6

KOAc

DCE

22

 4

Ru(II)

AgSbF6

NaOAc

2-MeTHF

75

 5

Ru(II)

AgSbF6

NaOAc

MeCN

15

 6

Ru(II)

AgSbF6

NaOAc

TFE

33

 7

Ru(II)

AgSbF6

NaOAc

THF

55

 8

Ru(II)

AgSbF6

NaOAc

1,4-dioxane

trace

 9

Ru(II)

AgSbF6

NaOAc

DMF

trace

10

Ru(II)

AgSbF6

NaOAc

toluene

trace

11

Ru(II)

AgSbF6

NaOAc

DMSO

 0

12

Ru(II)

AgSbF6

NaOAc

H2O

 0

13

Ru(II)

AgOTf

NaOAc

2-Me-THF

70

14

Ru(II)

AgOAc

NaOAc

2-Me-THF

20

15

Ru(II)

AgO

NaOAc

2-Me-THF

 0

16

Ru(II)

Ag2CO3

NaOAc

2-Me-THF

 0

17

Ru(II)

–

NaOAc

2-Me-THF

34

18

Ru(II)

AgSbF6

–

2-Me-THF

 0

19

–

AgSbF6

NaOAc

2-Me-THF

 0

20

Ru(II)

AgSbF6

NaOAc

2-Me-THF

30b

21

Ru(II)

AgSbF6

NaOAc

2-Me-THF

45c

22

Ru(II)

AgSbF6

NaOAc

2-Me-THF

76d

23

Ru(II)

AgSbF6

NaOAc

2-Me-THF

50e

24

Rh(III)

AgSbF6

NaOAc

2-Me-THF

 0

a Unless otherwise mentioned, all the reactions were carried out with 1a (0.45 mmol), 2a (2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF at 120 °C for 16 h. Ru(II) = [RuCl2­(p-cymene)]2, Rh(III) = [RhCp*Cl2]2.

b Amount of 2a used: 0.9 mmol.

c Amount of 2a used: 1.8 mmol.

d Amount of 2a used: 3.6 mmol.

e Under N2 atmosphere.

Predictably, the reaction did not progress in the absence of [RuCl2(p-cymene)]2 (Table [1], entry 19). Increasing the equivalence of ethyl glyoxylate did not improve the yield of 3 (entries 20–22). When the reaction was carried out under an N2 atmosphere, a drop in yield was observed (entry 23). Finally, when Rh(III) was used in place of Ru(II), the reaction did not progress. Thus, the optimized conditions involve 0.45 mmol of 1a, 2.69 mmol 2a, 5 mol% of [RuCl2(p-cymene)]2, 10 mol% of AgSbF6, and 50 mol% NaOAc in 2 mL of 2-Me-THF for 16 hours at 120 °C. Based on the usage of ruthenium salt, 2-Me-THF, and NaOAc in our reactions, the methodology is considered green and sustainable. 2-Me-THF is produced from renewable resources like corncobs and bagasse, and it shows interesting features like easy separation and recovery, access to higher reaction temperature, and less solvent loss during the reaction reflux. Ruthenium precursors are very economical compared to Rh, Pd, Ir, and Pt; and NaOAc is a cheaper additive.[19]

With optimized conditions in hand, the scope of phthalazinones was studied as summarized in Scheme [2]. The electron-donating group on the phthalazinones (4-Me, 3,4-Me, 3-Me, 4-Me,3-Cl, and 4-MeO) underwent hydroxyalkylation smoothly to give the corresponding products 3b, 3c, 3d, 3e, and 3f in 54%, 47%, 51%, 40%, and 54% yield, respectively.

Zoom Image
Scheme 2 Reaction of phthalazinones with ethyl glyoxylate. Reagents and conditions: Unless otherwise mentioned, all the reactions were carried out with 1 (0.45 mmol), 2a (2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF at 120 °C for 16 h.

Likewise, the electron-withdrawing group on the phthalazinones 4-OCF3, 3,5-F2, 3,5-Cl2, and 3,4-Cl2, 3-Cl, 4-Cl, and 3-Br reacted well with 2 to give 3g, 3h, 3i, 3j, 3k, 3l, and 3m in the range of 44–60% yield. Interestingly, 3b was crystallographically characterized.[20] Unfortunately, other substituted phthalazinones like 3-NO2 1n, 2-Me 1o, 2-F 1p, and 2-Cl 1q did not furnish the desired product. Besides, a simplified form of phthalazinone, 6-methyl-2-phenylpyridazin-3(2H)-one (1r), too did not take part in the reaction. Out of curiosity, aldehydes like 4-nitrobenzaldehyde (2b), 2-phenylacetaldehyde (2c), cinnamaldehyde (2d), formaldehyde (2e), n-butyl aldehyde (2f), and isobutyl aldehyde (2g) were tried under the optimized reaction conditions and found to be reluctant. Similarly, ethyl trifluoropyruvate (2h), a ketone derivative did not participate in the reaction (Scheme [3]).

Zoom Image
Scheme 3 Screening of aldehydes. Reagents and conditions: Unless otherwise mentioned, all the reactions were carried out with 1a (0.45 mmol), 2b–h (2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF at 120 °C for 16 h.

Furthermore, to elucidate reaction mechanism, we carried out several mechanistic studies (Scheme [4]). First, a reaction of phthalazinone (1a) devoid of a coupling partner 2a was carried out in D2O in standard conditions. It was observed that the C2 and C6 positions of the N-phenyl ring in 1a were deuterated ~90% to give 1a-D2 , which indicates the reversible C–H bond cleavage (Scheme [4a]). Second, we reacted 1a-D2 with ethyl glyoxalate (2a) under standard conditions, and no deuterium incorporation was observed in the final compound 3a (Scheme [4b]). Next, to pinpoint whether the amide oxygen or nitrogen was the directing group, we reacted substrate 4 with 2a under optimized conditions, surprisingly, the reaction did not progress, which infers that the nitrogen is the directing group (Scheme [4c]). Next, we performed KIE experiment, and it is found out to be 1.02. This infers that C–H insertion is not rate-determining and delivering intermediate via a concerted metalation-deprotonation (Scheme [4d]). Gram-scale synthesis was performed without notable erosion in the yield of 3a 66% (Scheme [4e]).

Zoom Image
Scheme 4 Mechanistic investigation

Based on the controlled studies and literature reports, a plausible mechanism is shown in Scheme [5]. The reaction of [RuCl2(p-cymene)]2 with AgSbF6 and NaOAc generates first the active cationic Ru(II) catalyst A. Then phthalazinone (1a) undergoes C–H metalation with A to generate five-membered ruthenacycle B. Next, the incoming ethyl glyoxalate (2a) coordinates to complex B to afford a new intermediate C. The irreversible insertion of 2 to the Ru–C bond of intermediate C generates the seven-membered ruthenacycle D. Subsequent protonation of intermediate D provides the hydroxylmethylated product 3a with the regeneration of the active Ru(II) catalyst.[21]

Zoom Image
Scheme 5 Plausible mechanism

In summary, we have shown the greener Ru(II)-catalyzed ortho-C(sp2)–H hydroxyalkylation of phthalazinones using commercially available ethyl glyoxalate to access α,α′-arylcarboxy sec-alcohols. This methodology paves the way to prepare sufficient examples of biologically relevant hydroxyalkylated phthalazinones. Various controlled studies were performed to understand the mechanistic pathway of the reaction.


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α,α′-Arylcarboxy sec-Alcohols 3; General Procedure

An oven-dried vial equipped with a stir bar was charged with the corresponding phthalazinone 1 (0.45 mmol), ethyl glyoxylate (2a; 2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF: The mixture was placed in a preheated oil bath at 120 °C and stirred for 16 h. After the mentioned time, the reaction mixture was cooled to rt, diluted with DCM and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (100–200 mesh) using hexane/EtOAc as the eluent.


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Ethyl 2-Hydroxy-2-(2-(1-oxophthalazin-2(1H)-yl)phenyl)acetate (3a)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 109 mg (75%); 966 mg (66%); off-white colored solid; mp 98–100 °C.

1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 7.8 Hz, 1 H), 8.25 (s, 1 H), 7.84–7.75 (m, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.54–7.52 (m, 1 H), 7.43 (t, J = 8.8 Hz, 2 H), 7.39–7.31 (m, 1 H), 5.14 (d, J = 6.68 Hz, 1 H), 4.10 (d, J = 6.72 Hz, 1 H), 4.01–3.38 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.3, 160.3, 139.8, 139.8, 139.0, 135.5, 133.9, 132.3, 129.6, 129.5, 128.5, 128.1, 127.3, 126.4, 70.7, 61.7, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C18H16N2O4Na: 347.1002; found: 347.1005.


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Ethyl 2-Hydroxy-2-(5-methyl-2-(1-oxophthalazin-2(1H)-yl)phenyl)acetate (3b)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 82 mg (54%); off-white colored solid; mp 100–102 °C.

1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 7.48 Hz, 1 H), 8.23 (s, 1 H), 7.79–7.72 (m, 2 H), 7.70 (d, J = 7.36 Hz, 1 H), 7.32 (s, 1 H), 7.19 (t, J = 12.16 Hz, 2 H), 5.07 (s, 1 H), 4.01 (s, 1 H), 3.98–3.87 (m, 2 H), 2.33 (s, 1 H), 0.99 (t, J = 6.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.3, 160.4, 139.6, 139.0, 137.2, 135.1, 133.8, 132.3, 130.4, 130.2, 129.5, 128.2, 128.2, 127.2, 126.4, 70.6, 61.6, 21.2, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O4Na: 361.1159; found: 361.1168.


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Ethyl 2-(2,3-Dimethyl-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3c)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 74 mg (47%); off-white colored solid; mp 138–140 °C.

1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 8.48 Hz, 1 H), 8.24 (s, 1 H), 7.82–7.75 (m, 2 H), 7.71 (d, J = 6.88 Hz, 1 H), 7.27 (s, 1 H), 7.08 (s, 1 H), 5.04 (s, 1 H), 3.99–3.84 (m, 2 H), 2.24 (s, 1 H), 2.21 (s, 1 H), 1.00 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.5, 160.5, 139.0, 138.6, 138.4, 137.2, 133.8, 132.3, 130.8, 129.5, 129.4 128.0, 127.2, 127.2 126.4, 70.5, 61.6, 19.5, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C20H20N2O4Na: 375.1315; found: 375.1331.


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Ethyl 2-Hydroxy-2-(2-methyl-6-(1-oxophthalazin-2(1H)-yl)phenyl)acetate (3d)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 77 mg (51%); off-white colored solid; mp 100–102 °C.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 7.76 Hz, 1 H), 8.24 (s, 1 H), 7.84–7.74 (m, 2 H), 7.72 (d, J = 7.68 Hz, 1 H), 7.41 (d, J = 7.92 Hz, 1 H), 7.24 (d, J = 7.92 Hz, 1 H), 7.13 (s, 1 H), 5.07 (s, 1 H), 4.00–3.86 (m, 2 H), 2.33 (s, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.4, 160.4, 140.0, 139.5, 139.0, 133.9, 132.6, 132.3, 130.4, 129.6, 129.6, 128.9, 128.1, 127.3, 126.3, 70.5, 61.6, 21.0, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O4Na: 361.1159; found: 361.1168.


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Ethyl 2-(2-Chloro-3-methyl-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3e)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 90 mg (40%); off-white colored solid; mp 138–140 °C.

1H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 7.76 Hz, 1 H), 8.23 (s, 1 H), 7.84–7.75 (m, 2 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.40 (s, 1 H), 7.33 (s, 1 H), 7.13 (s, 1 H), 5.07 (s, 1 H), 4.01–3.86 (m, 2 H), 2.33 (s, 3 H), 1.00 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.1, 160.2, 139.2, 138.1, 137.7, 135.0, 134.0, 133.9, 132.4, 131.6, 129.5, 129.0, 128.0, 127.3, 126.4, 70.0, 61.9, 19.8, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C19H17ClN2O4Na: 395.0769; found: 395.0778.


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Ethyl 2-Hydroxy-2-(5-methoxy-2-(1-oxophthalazin-2(1H)-yl)phenyl)acetate (3f)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 86 mg (54%); off-white colored solid; mp 120–122 °C.

1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 6.88 Hz, 1 H), 8.23 (s, 1 H), 7.80–7.74 (m, 2 H), 7.71 (d, J = 7.64 Hz, 1 H), 7.22 (dd, J = 8.6 Hz, 1 H), 7.04 (d, J = 2.72 Hz, 1 H), 6.93 (d, J = 8.68 Hz, 1 H), 5.07 (s, 1 H), 4.17–4.14 (m, 1 H), 3.99–3.86 (m, 2 H), 3.77 (t, J = 3.6 Hz, 3 H), 0.99 (t, J = 6.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 172.1, 160.5, 160.0, 139.0, 136.7, 133.8, 132.5, 132.3, 129.5, 128.0, 127.2, 126.4, 115.2, 114.2, 70.5, 61.7, 55.6, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C19H18N2O5Na: 377.1108; found: 377.1121.


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Ethyl 2-Hydroxy-2-(2-(1-oxophthalazin-2(1H)-yl)-5-(trifluoromethoxy)phenyl)acetate (3g)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 110 mg (60%); off-white colored solid; mp 110–112 °C.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 7.8 Hz, 1 H), 8.25 (s, 1 H), 7.86–7.76 (m, 2 H), 7.73 (d, J = 7.37 Hz, 1 H), 7.42–7.76 (m, 2 H), 7.28–7.25 (m, 2 H), 5.17 (s, 1 H), 4.01–3.89 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.7, 160.0, 149.3, 139.3, 138.0, 137.7, 134.1, 132.5, 130.2, 129.5, 128.0, 127.3, 126.5, 121.7, 121.6, 119.1, 69.9, 62.2, 13.7.

19F NMR (376 MHz, CDCl3): δ = –57.76.

HRMS (ESI): m/z [M + Na]+ calcd for C19H15F3N2O5Na: 409.1017; found: 408.9998.


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Ethyl 2-(2,4-Difluoro-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3h)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 79 mg (49%); off-white colored solid; mp 130–132 °C.

1H NMR (400 MHz, CDCl3): δ = 8.40 (s,1 H), 8.24 (s, 1 H), 7.85–7.71 (m, 2 H), 6.94 (d, J = 8.6 Hz, 2 H), 5.25 (s, 1 H), 3.95–3.92 (m, 2 H), 1.05 (t, J = 3.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.6, 160.3, 142.2, 142.0, 142.1, 142,0, 139.7, 134.3, 132.7, 129.4, 127.7, 127.4, 126.6, 121.0, 121.0, 120.8, 112.5, 112.4, 112.2, 112.2, 105.4, 105.2, 104.9, 64.9, 64.9, 61.9, 13.8.

19F NMR (376 MHz, CDCl3): δ = –107.7, –110.6.

HRMS (ESI): m/z [M + Na]+ calcd for C18H14F2N2O2Na: 383.0814; found: 383.0830.


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Ethyl 2-(2,4-Dichloro-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3i)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 88 mg (50%); off-white colored solid; mp 153–155 °C.

1H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 7.76 Hz, 1 H), 8.22 (s, 1 H), 7.87–7.77 (m, 2 H), 7.73–7.71 (m, 1 H), 7.52 (d, J = 2.12 Hz, 1 H), 7.26 (d, J = 2.12 Hz, 1 H), 5.46 (d, J = 6.08 Hz, 1 H), 4.19–3.87 (d, J = 3.68 Hz, 1 H), 3.97–3.82 (m, 2 H), 1.05 (t, J = 7.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.9, 171.6, 142.0, 139.8, 136.7, 135.2, 134.4, 132.8, 132.8, 130.7, 129.4, 128.0, 127.6, 127.3, 126.7, 68.4, 62.0, 13.8.

HRMS (ESI): m/z [M + Na]+ calcd for C18H14Cl2N2O2Na: 415.0223; found: 415.0232.


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Ethyl 2-(2,3-Dichloro-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3j)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 83 mg (47%); off-white colored solid; mp 110–112 °C.

1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 7.76 Hz, 1 H), 8.24 (s, 1 H), 7.86–7.76 (m, 2 H), 7.73 (d, J = 7.68 Hz, 1 H), 7.66 (s, 1 H), 7.46 (s, 1 H), 5.12 (s, 1 H), 4.01–3.87 (m, 2 H), 0.99 (t, J = 7.12 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.1, 159.9, 139.5, 138.6, 135.6, 134.2, 133.6, 133.2, 132.6, 130.8, 130.5, 129.5, 127.9, 127.3, 126.6, 69.5, 62.3, 13.7.

HRMS (ESI): m/z [M + Na]+ calcd for C18H14Cl2N2O2Na: 415.0223; found: 415.0232.


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Ethyl 2-(2-Chloro-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3k)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 73 mg (44%); green liquid.

1H NMR (400 MHz, CDCl3): δ = 8.42 (dd, J = 7.84 Hz, 1 H), 8.24 (s, 1 H), 7.85–7.75 (m, 2 H), 7.72 (dd, J = 7.84 Hz, 1 H), 7.70 (dd, J = 8.44 Hz, 1 H),7.75 (dd, J = 8.44 Hz, 1 H), 7.19 (d, J = 7.84 Hz, 1 H), 5.14 (s, 1 H), 3.99–3.87 (m, 2 H), 1.01 (m, 3 H), 1.01 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.9, 160.0, 140.6, 139.4, 134.8, 134.1, 132.5, 132.5, 131.6, 130.7, 129.5, 127.9, 127.2, 126.5, 122.7, 69.9, 61.9, 14.0.

HRMS (ESI): m/z [M + Na]+ calcd for C18H15ClN2O4Na: 381.0613; found: 381.0620.


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Ethyl 2-(5-Chloro-2-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3l)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 85 mg (53%); off-white colored solid; mp 140–142 °C.

1H NMR (400 MHz, CDCl3): δ = 8.41 (d, J = 7.76 Hz, 1 H), 8.24 (s, 1 H), 7.83–7.75 (m, 2 H), 7.72 (d, J = 7.68 Hz, 1 H), 7.54 (s, 1 H), 7.21 (s, 1 H), 5.12 (s, 1 H), 4.00–3.87 (m, 2 H), 1.01 (t, J = 7.6 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.1, 159.9, 138.2, 138.2, 137.1, 136.2, 134.1, 133.6, 133.0, 131.4, 128.9,128.6, 128.5, 128.4, 127.0, 126.2, 125.4, 68.9, 12.7.

HRMS (ESI): m/z [M + Na]+ calcd for C18H15ClN2O4Na: 381.0613; found: 381.0620.


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Ethyl 2-(2-Bromo-6-(1-oxophthalazin-2(1H)-yl)phenyl)-2-hydroxyacetate (3m)

Purified by column chromatography on silica gel using hexane/EtOAc (70:30); yield: 81 mg (45%); off-white colored solid; mp 148–150 °C.

1H NMR (400 MHz, CDCl3): δ = 8.42 (dd, J = 7.84 Hz, 1 H), 8.25 (s, 1 H), 7.84–7.78 (m, 2 H), 7.73 (dd, J = 7.76 Hz, 1 H), 7.56 (dd, J = 7.42 Hz, 1 H), 7.50 (dd, J = 1.84 Hz, 1 H), 7.43 (d, J = 8.36 Hz, 1 H), 5.11 (s, 1 H), 4.01–3.87 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 171.9, 160.0, 140.6, 139.4, 134.8, 134.1, 132.5, 132.5, 131.6, 130.7, 129.5, 127.9, 127.2, 126.5, 122.7, 69.9, 61.9, 14.0.

HRMS (ESI): m/z [M + Na]+ calcd for C18H15BrN2O4Na: 425.0107; found: 425.0111.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank VIT-SIF for instrument facilities.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2114-5426
  • Supporting Information

Corresponding Author

Thirumanavelan Gandhi
Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology
Vellore, Tamil Nadu – 632014
India   

Publication History

Received: 31 March 2023

Accepted after revision: 21 June 2023

Accepted Manuscript online:
21 June 2023

Article published online:
07 August 2023

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Figure 1 Representative examples of biologically active compounds possessing hydroxylmethyl group
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Scheme 1 a) Transition-metal-catalyzed C–H hydroxyalkylation of heterocycles using ethyl glyoxalate, b) Ru(II)-catalyzed ortho-C(sp2)–H hydroxyalkylation of phthalazinones using ethyl glyoxalate.
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Scheme 2 Reaction of phthalazinones with ethyl glyoxylate. Reagents and conditions: Unless otherwise mentioned, all the reactions were carried out with 1 (0.45 mmol), 2a (2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF at 120 °C for 16 h.
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Scheme 3 Screening of aldehydes. Reagents and conditions: Unless otherwise mentioned, all the reactions were carried out with 1a (0.45 mmol), 2b–h (2.69 mmol), [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (10 mol%), and NaOAc (50 mol%) in 2-Me-THF at 120 °C for 16 h.
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Scheme 4 Mechanistic investigation
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Scheme 5 Plausible mechanism