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Indian Journal of Chemistry Vol. 53B, August 2014, pp 1115-1121

Selectivities in acylation of primary and secondary amine with diacylaminoquinazolinones and diacylanilines Abdullah G Al-Sehemi*a,b,c, Reem S Abdul-Aziz Al-Amria & Ahmad Irfana a

Department of Chemistry, Faculty of Science, King Khalid University, Abha 61413, P.O. Box 9004, Saudi Arabia

b

Unit of Science and Technology, Faculty of Science, King Khalid University, Abha 61413, P.O. Box 9004, Saudi Arabia

c

Center of Excellence for Advanced Materials Research, King Khalid University, Abha 61413, P.O. Box 9004, Saudi Arabia E-mail: [email protected] Received 31 December 2012; accepted (revised) 11 June 2014

The diacylaminoquinazolinones are highly selective acylating agents for primary amines in the presence of secondary amines. The chemoselective N-acetylation reagents have been investigated using 2-substituted N,Ndiacylaminoquinazolinones (DAQs) and 2-substitued-N-diacylanilines (DAAs). Determination of the selectivity ratios have been made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. The control experiments in which pairs of amines compete for acetyl chloride show some selectivity but not comparable with that of DAQs and DAAs selectivity. When the DAQs, DAAs and acetyl chloride react with mixtures of pyrrolidine and piperidine, they give amides in the corresponding ratios. The DAQs 1 and 2 react entirely with diethylamine without any competitive reaction with diphenylamine. The high level of chemoselectivity has also been observed when the 1 and 2 react exclusively with the ethanolamine without any competitive reaction with diethanolamine. Moreover, 1 and 2 react with succinimide without any competitive reaction with phthalimide. Keywords: Chemoselectivity, acylation, diacylaminoquinazolinones, diacylanilines

The 4(3H)-quinazolinones and their derivatives1-3 are found in a number of biologically active compounds. Several quinazoline derivatives have been reported for their antibacterial, antifungal, anti-Human Immunodeficiency Virus (HIV)4, anti-inflammatory4, anticonvulsant5, antidepressant6, hypolipidemic7, antiulcer8, analgesic9 or immunotropic activities10. The formation of an amide bond between amine and carboxylic acid derivative is one of the most studied reactions in organic chemistry. However, the selective acylation of one amino group in the presence of others in an amine or a polyamine remains difficult11. Statistically, with equal moles of diamine and acylating agent, it is possible to obtain the desired mono-acylated product in 50% yield, which is acceptable in most cases12. Unfortunately, these statistically predicted results are not easy to be achieved. For example, when a polyamine such as 1,4diaminobutane, 2,2’-(ethylenedioxy) bis (ethylamine), piperazine, 1,2-cyclohexane diamine, or diethylenetriamine is reacted with a carboxylic acid anhydride or chloride in organic solvents, even with more than 1 equiv polyamine, di-acylated product is formed predominantly or exclusively. Sayre and co-workers attributed this phenomenon to the inefficient mixing of reactants during the addition of acylating agent to the diamine12.

More specifically, when a drop of acylating agent contacts the solution of the diamine, the acylation reaction is so fast that before additional diamines reach the reaction site, the mono-acylated products continue to react with the locally excess acylating agent, and therefore di-acylated product predominates. Wang’s group treated diamines with 2 equiv BuLi and reacted the resulting di-anions with 1 equiv acylating agents to give mono-acylated products13. The same group also achieved mono-acylation using 9-BBN to protect one of the two amino groups followed by acylation14. Christensen’s group used alkyl phenyl carbonates for selective acylation of polyamines15. Other reported methods include performing the reaction under acidic conditions16, using metal cations to protect one of the two amino groups and using special acylating agents11. Simple mix and react procedures were available for mono-acylation of diamines with short spacer between the two amino groups such as piperazine and ethylenediamine17. Unfortunately, the methods were not applicable to diamines with long spacers due to the similarity of the two pKas of the diamines and limited reduction of the reactivity of the second amino group upon acylation of the first amino group12. The protocol developed by Krapcho and Kuell for selective protection of some

INDIAN J. CHEM., SEC B, AUGUST 2014

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diamines using Boc2O under high dilution and slow addition conditions in 1,4-dioxane is quite simple to follow and good yields of desired product can be obtained18. Recently, Pringle reported a new monoacylation method using ionic immobilization of diamines to sulfonic acid-functionalized silica gel. The method worked well for mono-acylation of piperazine and homopiperazine, but failed to give useful yields for other polyamines19. In the present study, the aim is to investigate the chemoselective N-acetylation reagents, using 2-substituted N,N-diacylaminoquinazolinones (DAQs) and 2-substitued-N-diacylanilines (DAAs). Results and Discussions When DAQs 1 and 2 reacted with mixtures of pyrrolidine and piperidine (1 eq. each, Scheme Ι), they gave the ratios of the corresponding amides 7 and 11. Unexpectedly, the chemoselectivity increases as the substituent R on the side chain decreases in size from Et → Pri. This increase may be related to the greater preference for a defined conformation around the C-C bond in the (Q)-2-substituent in DAQs 1 than N R

N N

,

N H

O

N H

N

O

N

Et N

O

N

O

N H

11

Et

Et

N

+ Ph

N

O

Ph

R1

15

OH

O

R2

N

16

OH

N N

O

NH2

,

O, O N O H

OH

+

HN

O

O

N

N H

O

7 R2 =CH3

R2

,

O

N H

N H

Cl

N

8

17

18 Br ,

O N –O

N+ O

6

O O

N H

N H

N O

+ R

9 R= CH4-NO2-4 10 R=CH4-Br-4 Scheme Ι

N R

O

13 R= CH4-NO2-4 14 R=CH4-Br-4

N O O

20 +

N R2 O

11 R2 =CH3 12 R2 =CH2 Cl +

N O

7

HO

O

N O

O

+O

O R2

8 R2 =CH2Cl

HO

OH

HN

O N O O

19

N H O

N

O N H

,

Et , Ph N Ph H

O

R

R N O N O O

O

7

N R

N

+

O

O

in DAQ 2. When 1 and 2 reacted with mixtures of diethylamine and diphenylamine (1 eq. each) they gave the ratios of the corresponding amides 15 and 16. Both of DAQs 1 and 2 are acylating agents; and both react with diethylamine and diphenylamine to give high levels of chemoselectivity, which react exclusively with the diethylamine without any competitive reaction with diphenylamine. When 1 and 2 reacted with mixtures of ethanolamine and diethanolamine (1 eq. each) they gave the ratios of the corresponding amides 17 and 18. Both of DAQs 1 and 2 are acylating agents; and both react with ethanolamine and diethanolamine to give high levels of chemoselectivity, which react exclusively with the ethanolamine without any competitive reaction with diethanolamine. When 1 and 2 reacted with mixtures of succinimide and phthalimide (1 eq. each) they gave the ratios of the corresponding amides 19 and 20 are shown in Table Ι. Determination of these ratios was made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. Both of DAQs 1 and 2 are acylating agents; and both react with succinimide to

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AL-SEHEMI et al.: SELECTIVITIES IN ACYLATION OF PRIMARY AND SECONDARY AMINE

Table Ι — Chemoselectivity in reactions of DAQs with different mixturesa-d at RT DAQs

R

Corresponding amides

Ratio

7 and 11a DAQ 1 DAQ 2

Et Pri

15 : 1 10 : 1 15 and 16 b

DAQ 1 DAQ 2

Et Pri

DAQ 1 DAQ 2

Et Pri

99 : 1 99 : 1 17 and 18c 99:1 99:1

19 and 20d DAQ 1 Et 99:1 DAQ 2 Pri 99:1 a Nacetylated-pyrrolidine and N-acetylated-piperidine; b N-acetylated-diethylamine and N-acetylated-diphenylamine; c N-acetylated-ethanolamine and N-acetylated-diethanolamine; d N-acetylated-succinimide and N-acetylated-phthalimide

give high levels of chemoselectivity, which react exclusively with the succinimide without any competitive reaction with phthalimide. The selective monoacylation of amino groups in the presence of other functional groups has great practical utility. N-Acylation is sometimes carried out using acyl transfer reagents developed by devising an appropriate leaving group. Several reagents have been developed for the above purpose. However, some of the reagents available are unsatisfactory in terms of their usefulness and selectivities. Thus, satisfactory alternatives are required which are ortho-(or 2-) subsumed diacylaniline. When the DAAs 3, 4, and 5 reacted with mixtures of pyrrolidine and piperidine (1 eq. each), they gave the ratios of the corresponding amides 7, 8 and 11, 12 as shown in Table ΙI. Determination of these ratios was made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. The 4-bromo-N-(2-methoxyphenyl)-N-(4-nitrobenzoyl)benzamide 6 reacted with mixtures of pyrrolidine and piperidine (1 eq. each) and gave the ratios of the corresponding amides 9, 10 and 13, 14 presented in Table ΙI. Determination of these ratios was made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. Both pyrrolidine and piperidine react preferentially with the para-nitrobenzoyl group, without any competitive reaction with the para-bromobenzoyl group. Preferential reaction at the para-nitrobenzoyl carbonyl of DAA 6 is not unexpected based on the DFT calculation discussed later in this paper. As

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Table ΙI — Chemoselectivity in reactions of DAAs and acetyl chloride at room temperature R1

R2

a

Ratio of

DAA 3 Me CH2Cl 18.5 : 1 DAA 4 Me Me 4.4 : 1 DAA 5 OCH3 Me 4.1 : 1 DAA 6 1 : 2.3 Acetyl chloride 1 : 2.5 a N-acetylated-pyrrolidine and N-acetylated-piperidine

nitro-group is more electron-withdrawing than bromo which has a greater partial positive charge on its carbonyl carbon and is thus more susceptible to nucleophilic attack. The structure of p-nitrobenzoyl amide has been shown in supporting information with partial charges assigned to the ring system. The nitro group is located at para position to the amide moiety and thus the electron density is reduced adjacent to the carbonyl functionality. An electron-withdrawing group attached to an amide would increase the positive charge on the carbonyl carbon. The reaction of acetyl chloride 21 with mixtures of pyrrolidine and piperidine (1 eq. each) gave the ratios of the corresponding amides 7 and 11 as shown in Table ΙI. Determination of these ratios was made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. The control experiments in which pairs of amines competed for acetyl chloride (1 equiv.) showed some selectivity, but nothing comparable with that of DAQs and DAA selectivity. The basic mechanism involves nucleophilic attack by the amine on a carbonyl carbon of the imide moiety in the DAQs. There are two possibilities for the rate-determining step (RDS) of the reaction. In the first the RDS is irreversible attack on the carbonyl carbon of the acyl group and any chemoselectivity in the reaction is brought about in this step involving formation of the tetrahedral intermediate (a). In the alternative TS# attack on the carbonyl group is reversible. In this case, chemoselectivity would arise only where breakdown of the tetrahedral intermediate (a') to the products occurred. Hence the factors affecting chemoselectivity might be different from controlling chemoselection. Experimental Section General procedure (I) for the (competitive) acylation of amines with diacylaminoquinazolinones (DAQs) and N-diacylaniline (DAAs) The DAQs or DAAs (1 mol eq.) were dissolved in dichloromethane (1cm3/100 mg) then the amine

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(2 mol eq.) or mixture of two amines (one eq. each) in dichloromethane (1 cm3/ 100 mg) was added. The solution stirred at RT from 1-24 hr. Further dichloromethane (~ 5 cm3/ 100 mg) was added with hydrochloric acid (2 M; 2 cm3/ 100 mg) to separate unreacted amine. The organic layer was separated, washed with water, dried and the solvent removed under reduced pressure. Deuterochloroform was used for direct NMR spectroscopic examination of the reaction mixture. Competitive reactions of pyrrolidine and piperidine with N-acetyl-N-(2-ethyl-4-oxo-4H-quinazolin-3-yl)acetamide, 1. General procedure (I) was followed using DAQ 1 (0.1 g, 0.366 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedpyrrolidine and-piperidine to be ~ 15:1 respectively by comparison with the signals at δ 1.35-1.55 and 1.7-1.9 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with N-acetyl-N-(2-isopropyl-4-oxo-4H-quinazolin3-yl)-acetamide, 2. General procedure (I) was followed using DAQ 2 (0.1 g, 0.348 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedpyrrolidine and –piperidine to be ~10:1 respectively by comparison with the signals at δ 1.35-1.55 and 1.71.9 with those in the spectra of authentic samples. Competitive reactions of diethylamine and diphenylamine with DAQ, 1. General procedure (I) was followed using DAQ 1 (0.1 g, 0.366 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-diethylamine and-diphenylamine to be ~99:1 respectively by comparison with the signals at δ 0.09-1.01 with those in the spectra of authentic samples. Competitive reactions of diethylamine and diphenylamine with DAQ, 2. General procedure (I) was followed using DAQ 2 (0.1 g, 0.348 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylateddiethylamine and-diphenylamine to be ~99:1 respectively by comparison with the signals at δ 0.09-1.01 with those in the spectra of authentic samples. Competitive reactions of ethanolamine and diethanolamine with DAQ, 1. General procedure (I) was followed using DAQ 1 (0.1 g, 0.366 mmol) in

dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedethanolamine and-diethanolamine to be ~99:1 respectively by comparison with the signals at δ 3.653.7 with those in the spectra of authentic samples. Competitive reactions of ethanolamine and diethanolamine with DAQ, 2. General procedure (I) was followed using DAQ 2 (0.1 g, 0.348 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedethanolamine and-diethanolamine to be ~99:1 respectively by comparison with the signals at δ 3.65-3.7 with those in the spectra of authentic samples. Competitive reactions of succinimide and phthalimide with DAQs, 1. General procedure (I) was followed using DAQ 1 (0.1 g, 0.366 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-succinimide and-phthalimide to be ~99:1 respectively by comparison with the signals at δ 7.9-8 with those in the spectra of authentic samples. Competitive reactions of succinimide and phthalimide with DAQ, 2. General procedure (I) was followed using DAQ 2 (0.1 g, 0.348 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedsuccinimide and –phthalimide to be ~99:1 respectively by comparison with the signals at δ 7.9-8 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with 2-Chloro-N-(2-chloro-acetyl)-N-o-tolyl-acetamide, 3. General procedure (I) was followed using DAA 3 (0.1 g, 0.384 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-pyrrolidine and-piperidine to be ~18.5:1 respectively by comparison with the signals at δ 1.45 and 1.9 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with N-Acetyl-N-o-tolyl-acetamide, 4. General procedure (I) was followed using DAA 4 (0.1 g, 0.523 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-pyrrolidine andpiperidine to be ~4.4:1 respectively by comparison


with the signals at δ 1.35-1.55 and 1.7-1.9 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with N-acetyl-N-(2-methoxyphenyl)acetamide, 5. General procedure (I) was followed using DAA 5 (0.1 g, 0.483 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-pyrrolidine and-piperidine to be ~4.1:1 respectively by comparison with the signals at δ 1.35-1.55 and 1.7-1.9 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with N-(4-nitrobenzamide)-N-(2-Methoxy-phenyl)4-bromo-benzamide, 6. General procedure (I) was followed using DAA 6 (0.1 g, 0.219 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylatedpyrrolidine and-piperidine to be ~1: 2.3 respectively by comparison with the signals at δ 1.34 and 3.03 with those in the spectra of authentic samples. Competitive reactions of pyrrolidine and piperidine with acetyl chloride (control experiment). General procedure (I) was followed using acetyl chloride (0.1 g, 1.264 mmol) in dichloromethane (0.5 cm3) and the solution was stirred for 24 hr at RT. A 1H NMR spectrum (500 MHz) of the resulting solution showed the ratio of the N-acetylated-pyrrolidine and-piperidine to be ~1:2.5 respectively by comparison with the signals at δ 1.00-1.25 and 1.4-1.6 with those in the spectra of authentic samples. General procedure (ΙI) for N-acylation of amines (preparation of authentic samples) To a stirred solution of the amine (2 g) in dichloromethane was added pyridine (1.2 eq.) followed by dropwise addition of the acid chloride (1.2 eq.). After 1 hr, further dichloromethane (10 ml) was added, the solution then washed successively with saturated aqueous sodium hydrogen carbonate, hydrochloric acid (2 M), water, then dried and the solvent removed under reduced pressure to give the amide. The complete synthesis route, FTIR, NMR spectra of 1-7 can be found in Ref 20. N-Acetylpyrrolidine, 7. The general procedure (ΙI) for the N-acylation of amines was followed using pyrrolidine (2 g, 28 mmol), pyridine (3.3 g, 42 mmol) and acetyl chloride (3.3 g, 42 mmol). After work-up, N-acetylpyrrolidine was obtained as a pale yellow oil (2.7 g, 84%), b.p. 105-107°C; 1H NMR (CDCl3 500 MHz): δ 1.7-1.95 (4H, m, 2 × CH2), 1.97 (3H, s,

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CH3CO) and 3.35(4 H, struct. m, 2 × CH2N), 1.89-2.0 (4 H, m, 2 × CH2), 2.1 (3 H, s, CH3CO) and 3.42 (4 H, struct. m, 2 × CH2N); lit. 1H NMR (300 MHz, CDCl3): δ 1.86-2.0 (m, 4H), 2.06 (s, 3H) and 3.45 (dd, J 7.1, 16.0, 4 H). 2-Chloro-1-(pyrrolidin-1-yl) ethanone, 8. The general procedure (ΙI) for the N-acylation of amines was followed using pyrrolidine (2 g, 28.1 mmol), pyridine (3.67 g, 34 mmol) and chloroacetyl chloride (3.81 g, 34 mmol). After work-up, 2-chloro-1(pyrrolidin-1-yl) ethanone was obtained as a pale brown liquid (2 g, 54%), b.p. 201-204°C; 1H NMR (CDCl3 500 MHz): δ 1.77-1.90 (4H, m, 2 × CH2), 3.30-3.46 (4H, m, 2 × CH2) and 4.28 (2H, S, CH2-Cl); 13 C NMR (CDCl3, 125 MHz): δ 23.5 and 23.6 (2 × CH2), 40.1and 40.5 (2 × CH2), 45.98 (CH2-Cl) and 162.60 (C=O). (4-Nitrophenyl)(pyrrolidin-1-yl)methanone, 9. The general procedure (ΙI) for the N-acylation of amines was followed using pyrrolidine (2 g, 28.1 mmol), pyridine (2.67 g, 33.7 mmol) and 4-nitrobenzoyl chloride (6.26 g, 33.7 mmol). After work-up, (4-nitrophenyl)(pyrrolidin-1-yl)methanone was obtained as light yellow shiny crystals (5.3 g, 86%), m.p. 63-65°C; 1 H NMR (CDCl3 500 MHz): δ 1.88-1.98 (4H, m, 2 × CH2), 3.34-3.63 (4H, m, 2 × CH2), 7.65 [2H, m, 2 × CH (Ar)], 8.2 [2H, m, 2 × CH (Ar)]; 13C NMR (CDCl3, 125 MHz): δ 24.3 and 26.3 (2× CH), 46.4 and 49.4 (2× CH2), 123.4,123.6, 127.9 and 128.3 [4 × CH (Ar)], 143.1 and 148.4 (CCO and C-NO2) and 167.3 (CO); IR: 1710 (C=O), 1690 (C=O), 1493 (N-O), 1351 cm-1 (N=O). (4-Bromophenyl)(pyrrolidin-1-yl)methanone, 10. The general procedure (IΙ) for the N-acylation of amines was followed using pyrrolidine (2 g, 28.1 mmol), pyridine (2.67 g, 33.7 mmol) and 4-nitrobenzoyl chloride (6.26 g, 33.7 mmol). After work-up, (4-nitrophenyl)(pyrrolidin-1-yl) methanone was obtained as light yellow shiny crystals (5.3 g, 86%), m.p. 188-192°C; 1H NMR (CDCl3 500 MHz): δ 1.2-1.98 (4H, br m, 2 × CH2), 3.1, 4.0 (4H, br m, 2 × CH2), 7.26-7.31 [2H, m, 2 × CH (Ar)] and 7.52-7.57 [2H, m, 2× CH (Ar)]. N-Acetylpiperidine, 11. The general procedure (IΙ) for the N-acylation of amines was followed using piperidine (2 g, 23.5 mmol), pyridine (2.8 g, 35.3 mmol) and acetyl chloride (2.8 g, 35.7 mmol). After work-up, N-acetylpiperidine was obtained as pale yellow oil (2.5 g, 83%), b.p. 226°C; 1H NMR (CDCl3, 500 MHz): δ 1.3-1.65 (6H, br m, CH2), 1.99 (3H, s,

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CH3CO) and 3.2-3.50 (4H, br m, 2 × CH2); 13C NMR (CDCl3, 125 MHz): δ 25.2 (CH3CO), 25.6, 26.3, 26.5, and 28.9 (4×CH2), 42.9 and 47.6 (2×CH2) and 168.7 (CO). 2-Chloro-1-piperidin-1-yl-ethanone, 12. The general procedure (ΙI) for the N-acylation of amines was followed using piperidine (2 g, 23.5 mmol), pyridine (2.8 g, 35.3 mmol) and chloroacetyl chloride (3.98 g, 35.24 mmol). After work-up, 2-Chloro-1piperidin-1-yl-ethanone was obtained as a clear pale yellow liquid (3.1 g, 82%), b.p. 180-182°C; 1H NMR (CDCl3 500 MHz): δ 1.3-2.0 (6H, br m, CH2), 3.453.60 (4H, br m, CH) and 4.31 (2H, s, CH2ClCO); 13C NMR (CDCl3, 125 MHz): δ 24.1, 25.0 and 25.8 (3 × CH2), 41.5 (CH2Cl), 47.1 and 47.2 (2 × CH2) and 164.1 (CO). 4-(Nitrophenyl)(piperidin-1-yl)methanone, 13. The general procedure (ΙI) for the N-acylation of amines was followed using piperidine (2 g, 23.5 mmol), pyridine (2.23 g, 28.2 mmol) and 4-nitrobenzoyl chloride (5.23 g, 28.2 mmol). After work-up, (4-nitrophenyl) (piperidin-1-yl) methanone was obtained as Yellowish white crystals (4.3 g, 78%), m.p. 106-108°C; 1H NMR (CDCl3 500 MHz): δ 1.40-1.63 (6H, br m, 3 × CH2), 3.0-3.63 (4H, m, 2 × CH2) and 7.45-7.49 (4H, m, 4 × CH); 13C NMR (CDCl3, 125 MHz): δ 24.14, 26.38 (3 × CH2), 43.04, 48.52 (2 × CH2) 123.24-124.01(2 × CH), 127.52-128.08 (2× CH), 130.77 (C-C=O), 142.74, 148.03 (C-NO2), 167.46, 167.72 (C=O). (4-Bromophenyl)(piperidin-1-yl) methanone, 14. The general procedure (ΙI) for the N-acylation of amines was followed using pyrrolidine (2 g, 23.5 mmol), pyridine (2.23 g, 28.2 mmol) and 4-bromobenzoyl chloride (6.19g, 28.2 mmol). After work-up, 4-bromophenyl)(piperidin-1-yl) methanone was obtained as white flakes (5.3 g, 86%), m. p. 79-85°C; 1H NMR (CDCl3 500 MHz): δ 1.68, 1.69 (6H, m, 3 × CH2), 3.39, 3.61 (4H, m, 2 × CH2), 7.27, 7.29 (2H, m, 2 × CH), 7.53, 7.55 (2H, m, 2 × CH) ); 13C NMR (CDCl 3, 125 MHz): δ 24.36, 24.51, 24.62, 25.86 (3× CH2), 43.28, 48.66 (2 × CH2) 123.65 (2× CH), 128.34-129.50 (2 × CH), 131.38-131.94 (C-C=O), 135.23(C-Br), 169.28 (C=O). N,N-Diethylacetamide, 15. The general procedure (ΙI) for the N-acylation of amines was followed using diethylamine (3.73 g, 50 mmol) and acetyl chloride (2 g, 25 mmol). After work-up, N,N-diethylacetamide was obtained as clear colorless liquid (3.7 g, 76%), b.p. 179°C; 1H NMR (CDCl3 500 MHz): δ 1.01, 1.06, 1.08 (6H, t, 2×CH3), 1.94, 1.98 (3H,s, CH3) and 3.18, 3.21, 3.26 (4H, q, × CH2N); 13C NMR (CDCl3, 125

MHz): δ 13.94, 14.07, 14.25 (2× CH3), 20.66, 20.89, 21.25 (CH3), 39.87-43.17 (2× CH2), 170.06 (CH3CO). N,N-diphenylacetamide, 16. The general procedure (ΙI) for the N-acylation of amines was followed using diphenylamine (2 g, 11 mmol) pyridine (1.39 g, 17 mmol) and acetyl chloride (1.39 g, 17 mmol). After work-up, N,N-diphenylacetamide was obtained as nearly colorless crystals (1.97 g, 78%), m.p. 99-101°C; 1 H NMR (CDCl3 500 MHz): δ 2.02-2.19 (3H, s, COCH3), 7.11-7.35 (10H, m, Ar–H); 13C NMR (CDCl3, 125 MHz): δ 23.88 (CH3), 117.75 (2 × CH), 126.45129.74 (8 × CH ), 142.73, 143.39 (2 × C-N), 170.51 (COCH3). N-Acetylethanolamine, 17. The general procedure (ΙI) for the N-acylation of amines was followed using ethanolamine (2 g, 32 mmol) and acetyl chloride (3.78 g, 48 mmol). After work-up, N-acetylethanolamine was obtained as pale yellow viscous liquid (2.49 g, 73%), b.p. 151-153°C; 1H NMR (CDCl3 500 MHz): δ 3.22 (1H, OH) 3.24, 3.25 (3H, s, CH3), 3.33, 3.34, 3.35 (2H, d, CH2-N), 3.86-4.02 (2H, t, CH2-O), 7.35, 7.39 (1H, s, NH). N-Acetyldiethanolamine, 18. The general procedure (IΙ) for the N-acylation of amines was followed using diethanolamine (2 g, 19 mmol) and acetyl chloride (3.24 g, 28 mmol). After work-up, N-acetyldiethanolamine was obtained as yellow viscous liquid (1.76 g, 62%), b.p. 139-144°C; 1H NMR (CDCl3 500 MHz): δ 2.032.15 (3H, s, CH3), 3.47-3.61 (4H, t, 2× CH2-N), 4.19-4.23 (4H, s, 2 × CH2-O); 13C NMR (CDCl3, 125 MHz): δ 20.76-22.02 (CH3), 45.33-49.63 (2× CH2-N), 50.3862.23 (2 × CH2-O), 170.8, 171.25 (COCH3). Acetyl Succinimide, 19. The general procedure (ΙI) for the N-acylation of amines was followed using pyrrolidine-2,5-dione (succinimide) (2 g, 20 mmol) pyridine (2.39 g, 30 mmol) and acetyl chloride (2.38 g, 30 mmol). After work-up, 1-acetyl-pyrrolidine-2,5dione(N-acetyl succinimide) was obtained as brown liquid (1.89 g, 66%), b.p. 220-225°C; 1H NMR(CDCl3 500 MHz): δ 2,38 (3 H, s, CH3), 2.59, 2.67 (4H, 2 × CH2); 13 C NMR (CDCl3, 125 MHz): δ 21.09-22.95 (CH3), 31.82-36.98 (2 × CH2), 166.52 (C=O), 173.65-174.79 (2 C=O). N-Acetylphthalimide, 20. The general procedure (ΙI) for the N-acylation of amines was followed using isoindole-1,3-dione (phthalimide) (2 g, 13 mmol) pyridine (1.6 g, 20 mmol) and acetyl chloride (1.6 g, 20 mmol). After work-up, 2-acetyl-isoindole-1,3-dione (N-acetyl phthalimide) was obtained as yellow crystals (1.56 g, 60%), m.p. 128-130°C; 1H NMR (CDCl3 500 MHz): δ 2,66 (3 H, s, CH3CO), 7.84-7.86 [2 H, m, 2 × CH


(ph)], 7.95-7.96 [2H, m, 2 × CH(Ph)] ); 13C NMR (CDCl3, 125 MHz): δ 22.66 (CH3), 123.50-136.10 (6 × CH), 165.37 (CO), 168.16, 168.86 (2 × CO). Conclusions When DAQs 1 and 2 reacted with mixtures of pyrrolidine and piperidine, they gave the ratios of the corresponding amides 7 and 11. The chemoselectivity increases as the substituent R on the side chain decreases in size. The DAQs 1 and 2 react exclusively with diethylamine without any competitive reaction with diphenylamine. The DAQs 1 and 2 when reacted with mixtures of ethanolamine and diethanolamine gave high levels of chemoselectivity, which react exclusively with the ethanolamine without any competitive reaction with diethanolamine. Both of DAQs 1 and 2 react with succinimide to give high levels of chemoselectivity, which react exclusively with the succinimide without any competitive reaction with phthalimide. 2-Substitued-N-diacylanilines 3, 4, and 5 when reacted with mixtures of pyrrolidine and piperidine, gave the ratios of the corresponding amides 7, 8 and 11, 12. The 6 reacted with mixtures of pyrrolidine and piperidine and gave the ratios of the corresponding amides 9, 10 and 13, 14. Both pyrrolidine and piperidine reacts preferentially with the para-nitrobenzoyl group, without any competitive reaction with the para-bromobenzoyl group. Reaction of acetyl chloride 21 with mixtures of pyrrolidine and piperidine gave the ratios of the corresponding amides 7 and 11. Control experiments in which pairs of amines competed for acetyl chloride showed some selectivity in an opposite sense to that of chemoselectivity, but not comparable with that found when using DAQs and DAA. Molecular modeling reveals that for a secondary amine, attack on one face of the exo carbonyl group is preferred.

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Supporting information FTIR spectra and NMR spectra can be found in supporting information. Acknowledgement Reem S. Abdul-Aziz Al-Amri thanks King Abdul Aziz City of Science and Technology (KACST) for their financial support by the grant No. GSP-18-138. References 1 Panicker C Y, Varghese H T, Ambujakshan K R, Mathew S, Ganguli S, Nanda A K & Alsenoy C V, J Raman Spectrosc, 40, 2009, 1262. 2 El-Hiti G A, Spectrosc Lett, 32, 1999, 671. 3 Pendergast W, Johnson J V, Dickerson S H, Dev I K, Duch D S, Ferone R, Hall W R, Humphreys J, Kelly J M & Wilson D C, J Med Chem, 36, 1993, 2279. 4 Alagarsamy V, Giridhar R, Yadav H R, Revathi R, Rukmani K & De Clercq E, Indian J Pharm Sci, 68, 2006, 532. 5 Gupta D P, Ahmed S, Kumar A & Shankar K, Indian J Chem, 27, 1988, 1060. 6 Jatav V, Mishra P, Kashaw S & Stables J P, Eur J Med Chem, 43, 2008, 135. 7 Joshi V & Chaurasia R P, Indian J Chem, 26, 1987, 602. 8 Prouse I R, Drugs Future, 18, 1993, 475. 9 Bhandari S V, Deshmane B J, Dangare S C, Gore S T, Raparti V T, Khachane C V & Sarkate A P, Pharmacologyonline, 2, 2008, 604. 10 Azza M R, Eman E R & Fatma G E, Arch Pharm, 337, 2004, 527. 11 Bender J A, Meanwell N A & Wang T, Tetrahedron, 58, 2002, 3111. 12 Jacobson A R, Makris A N & Sayre L M J, J Org Chem, 52, 1987, 2592. 13 Wang T, Zhang Z X & Meanwell N A, J Org Chem, 64, 1999, 7661. 14 Zhang Z X, Yin Z W, Meanwell N A, Kadow J F & Wang T, Org Lett, 5, 2003, 3399. 15 Pittelkow M, Lewinsky R & Christensen J B, SynthesisStuttgart, 2002, 2195. 16 Lee D W, Ha H J & Koo L W, Synth Commun, 37, 2007, 737. 17 Hall H K, J Am Chem Soc, 78, 1956, 2570. 18 Krapcho A P & Kuell C S, Synth Commun, 20, 1990, 2559. 19 Pringle W, Tetrahedron Lett, 49, 2008, 5047. 20 Al-Sehemi A G, Al-Amri R S A & Irfan A, J Chem Soc Pak, in press, 2012.