Ring-opening reactions of 2-imidazolines and their applications

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Ring-opening reactions of 2-imidazolines and their applications Alexander Sapegin, Mikhail Krasavin∗ Saint Petersburg State University, Saint Petersburg, Russian Federation ∗ Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Reductive opening of 2-imidazoline rings 3. Oxidative opening of 2-imidazoline rings 4. Hydrolytic opening of 2-imidazoline rings 5. Opening of 2-imidazoline rings by a nitrogen nucleophile 6. Opening of 2-imidazoline rings by a carbon nucleophile 7. Thermal opening of 2-imidazoline rings 8. Other methods of 2-imidazoline ring opening 9. Concluding remarks Acknowledgment References Further reading

1 2 18 19 34 41 47 50 52 52 52 56

Abstract Scaffold-generating and scaffold-morphing tranformations exploiting the chemical instability of the 2-imidazoline moiety under reductive, oxidation, hydrolytic, thermal conditions as well as toward the addition of C- and N-nucleophiles are reviewed. Keywords: 2-Imidazoline, Ring opening, Hydrolytic conditions, Reducing conditions, Oxidation, Nitrogen nucleophile, Carbon nucleophile, Thermal ring opening, Electrophilicity

1. Introduction 2-Imidazolines are nonflat, nonaromatic five-membered heterocycles which have found prominence in medicinal chemistry (2015EJMC525), particularly, as ligands of imidazoline receptors (1996ARPT511). 2-Imidazolines Advances in Heterocyclic Chemistry ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2019.10.004

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2019 Elsevier Inc. All rights reserved.

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have been actively exploited in such areas of chemistry as homogeneous catalysis (2009ASC489) and development of surfactants (2007JOLS211). However, the 2-imidazoline ring can be viewed as a useful synthon in organic synthesis, due to its nonaromaticity, lower chemical stability and tendency toward ring opening following nucleophilic addition at C2. Opening of a 2-imidazoline ring (as such or alkylated at N3 to increase its electrophilicity) can be performed selectively which can lead to polysubstituted derivatives containing a 1,2-ethylenediamine backbone (Scheme 1).

Scheme 1 Ring-opening reactions of 2-imidazolines.

This chapter aims to review the currently available literature reports involving opening of a 2-imidazoline ring. The latter will be systematized according to the nature of the chemical event triggering the subsequent ring opening.

2. Reductive opening of 2-imidazoline rings Examples involving reductive opening of a 2-imidazoline ring unsubstituted at the nitrogen atom are rather scarce in the literature. Horner and Hod investigated electrochemical reduction of 2-phenyl-2-imidazoline (2) (1977LA2036). On passing electrical current through a solution of 2 and Me4N+ Cl
in ethanol–acetic acid mixture at pH 5–6, a small amount of 2-phenylimidazolidine (3) was isolated. Upon prolonged electrochemical reduction, the latter gave N-benzylethane-1,2-diamine (4). Alkaline saponification of the reaction mixture also produced benzil 6, presumably formed via the dimeric product 5 (Scheme 2).

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Scheme 2 Processes occurring on electrochemical reduction of 2.

An innovative method to obtain racemic (1R,2R/1S,2S)-1,2diphenylethane-1,2-diamine (12), which involves formation and subsequent opening of a 2-imidazoline ring, was reported by Mastryukov (2002IZV2142). Starting from benzaldehyde (7) and ammonia, hydrobenzamide 8 was initially obtained. Heating the latter in dimethyl sulfoxide (DMSO) with a catalytic quantity of NaOH produced the delocalized anion 9 which, in turn, cyclized at 130°C to give the thermodynamically more stable diaza allylic anion 10. Reaction workup gave (4R,5R/4S,5S)-2,4,5-triphenyl-1Himidazoline 11 in 90% overall yield. Reduction of the latter with Al amalgam gave the racemic product (12) in 83% yield (70% combined yield from 7). Reducing imidazoline 11 with LiAlH4 in tetrahydrofuran (THF) or LiH(i-Bu)2 (DIBAL) in xylene gave the N-benzylated product, (1R,2R/ 1S,2S)-N1-benzyl-1,2-diphenylethane-1,2-diamine (13), in 37% yield (Scheme 3) (2003ARKIVOC133).

Scheme 3 Condensation of benzaldehyde (7) with ammonia followed by reduction.

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A two-step protocol for the conversion of carboxylic acids 14a–n into the respective aldehydes 17a–n, which involves the formation and subsequent opening of a 2-imidazoline ring, was reported by Shi and Gu (1997SC2701). Imidazolines 16a–n were obtained by heating 14a–n in ethylene-1,2-diamine 15 and then reduced by dissolving Na metal reduction in ethanol (Scheme 4).

Scheme 4 Reduction of carboxylic acids to aldehydes via 2-imidazolines.

The method is applicable to the reduction of both aromatic and aliphatic carboxylic acids and provides good overall yields (Table 1). Salerno and co-workers exemplified the reduction of 2-alkyl and 2-vinyl imidazolines 19a–p, obtained by cyclodehydration of N-acyl-N0 arylethylene-1,2-diamines 18a–p with trimethylsilyl polyphosphate (PPSE) under microwave irradiation (2012SC2083, 2004S851). Imidazolines 19a–p were reduced with sodium cyanoborohydride in ethanol to give N-aryl-N0 -alkyl ethylene-1,2-diamine derivatives 20a–p (Scheme 5).

Table 1 Yields of aldehydes 17a–n obtained according to Scheme 4 Product R Yield (%) Product R

Yield (%)

17a

Me

70

17h

4-ClC6H4

63

17b

n-C9H19

79

17i

4-MeOC6H4

62

17c

n-C11H23

78

17j

2-O2NC6H4

49

17d

n-C15H31

76

17k

3,4-(MeO)2C6H3

54

17e

Ph

66

17l

CH3CH(OH)

75

17f

Bn

70

17m

PhCH(OH)

72

17g

4-O2NC6H4 69

17n

(Z)-CH3(CH2)7CH ¼ CH 72 (CH2)7

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Ring-opening reactions of 2-imidazolines and their applications

The net result of this transformation is the reduction of the carbonyl group in amide 18 which can, in principle, be achieved by direct reduction. However, the use of the mild reducing agent (NaBH3CN) as opposed to difficult-to-workup aluminum hydride reductants and the good-toexcellent overall yields achieved in this two-step transformation (Table 2) are the main attractive features of this new cyclodehydration–reduction protocol.

Scheme 5 Reduction of monoamides 18 via 2-imidazolines 19.

Chida and co-workers developed a facile access to 4-acetoxymethyl imidazolines 22 via the use of the hypervalent iodine reagent PhI(OAc)2 and the 1,10-phenanthroline/Cu(OAc)2 catalytic system (2012OL5342). Several imidazolines 22a–f obtained using this protocol were reduced with aluminum hydride generated in situ from AlCl3 and LiAlH4. The resulting 2,3-diaminopropan-1-ols 23a–f were obtained in satisfactory 58%–63% yield (Scheme 6).

Table 2 Yields of N-aryl-N0 -alkyl ethylene-1,2-diamine derivatives 20a–p Yield Product R Ar (%) Product R Ar

Yield (%)

20a

Me

4-ClC6H4

67

20i

tert-Bu 4-O2NC6H4 74

20b

Et

4-ClC6H4

72

20j

H

Ph

76

20c

i-Pr

4-ClC6H4

69

20k

H

4-MeC6H4

83

20d

tert-Bu

4-ClC6H4

74

20l

H

2-MeC6H4

78

20e

Bn

4-ClC6H4

70

20m

H

mesityl

81

20f

4-ClC6H4CH2 4-ClC6H4

73

28n

H

4-MeOC6H4 80

20g

PhCH¼ CH

4-ClC6H4

67

28o

H

4-ClC6H4

20h

i-Pr

4-O2NC6H4 75

20p

H

4-O2NC6H4 79

77

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Scheme 6 Cyclization and reduction of allylic amidines 21.

The Chida group has also developed a convenient protocol to convert acyclic amidines 24 into 1,2-diphenyl imidazolines 25 also employing PhI(OAc)2 in the presence of Cu(OAc)2 catalyst (2013OL212). Reductive opening of the imidazolines 25 with AlH3 (also generated in situ as described above) gives polysubstituted ethylene-1,2-diamines 26a–e in excellent yield (Scheme 7).

Scheme 7 Cyclization and reduction of alkyl amidines 24.

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The only example of catalytic hydrogenation of a 2-imidazoline moiety is described by Kuwano (2011JA7312). tert-Butyl (S)-4-methyl-2phenylimidazoline-1-carboxylate (27) was reduced by H2 gas over 10% Pd/C, which gave tert-butyl (S)-(2-aminopropyl)carbamate (28). The latter was not isolated but rather protected with a second Boc group to give di-tertbutyl propane-1,2-diyl(S)-dicarbamate (29) in 92% overall yield (Scheme 8).

Scheme 8 Reductive opening of 2-imidazoline 27 followed by Boc-protection.

Alkylation (quaternization) of a 2-imidazoline moiety at the nitrogen atom (to give the respective imidazolinium cations) increases the electrophilicity of 2-imidazolines at the amidine carbon atom (C2). This allows for reducing the resulting N,N0 -disubstituted imidazolinium salts with mild reductants. Anderson and Jones compared the behavior of imidazoline 30 and its quaternized derivative 33 under various reducing conditions (Scheme 9) (1986JCS(P1)1995). As had been anticipated, imidazolinium salt 33 reacted with much milder reducing agents (such as NaBH4, KBH4, Bu4NBH4) and gave a good yield of nearly equimolar mixture of ethylene-1,2-diamine derivatives 35 and 36 (the authors failed to perform unequivocal regiochemical assignment). Notably, the reduction proceeded so rapidly that the putative imidazolidine intermediate 34 was not detected in the reaction mixture.

Scheme 9 Reductive and alkylative manipulation of 2-imidazoline 30.

At the same time, the less reactive, nonquaternized imidazoline 30 underwent reduction with the strong reductant LiAlH4 in diethyl ether. The authors were curious to follow the course of this reduction at different

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Table 3 Reduction of 30 with LiAlH4 in diethyl ether at various temperatures Components of the reaction mixture (%) T (oC)

Reaction time (h)

30

31

32


78

3

100

—

—


40

3

100

—

—


20

1.5

100

—

—


20

2

90

8

2


20

2.5

85

10

5


20

3

80

10

10


10

0.5

95

5

—


10

1

85

10

5


10

1.5

80

10

10


10

2

40

10

50


10

2.5

30

10

60


10

3

25

10

65

25

3

—

10

90

temperatures (Table 3) and showed that at lower temperatures, it was possible to detect imidazolidine 31 in the reaction mixture. The maximum yield of the ethylene-1,2-diamine end-product 32 was achieved at 25°C over 3 h. It was possible to perform the reduction 30➔32 with sodium borohydride; however, the reaction took a significantly longer time (72 h, EtOH, 25°C) to complete. At the same time, imidazoline 30 was completely resistant to action of such reductants as LiBH4 (THF, 25°C) or NaBH3CN (MeOH, 25°C or aq. THF, pH 3, 25°C). Salerno and co-workers (1992JHC1725) obtained more insight into the regiospecificity of the reductive 2-imidazoline opening when they studied the reduction of quaternized imidazolines 37a–m with various reducing agents. Using an equimolar amount of LiAlH4 in refluxing THF, imidazolidines 38a–m were obtained in good yields. With reductants such as NaBH4, KBH4 or NaBH3CN in ethanolic solution at room temperature, imidazolidine 38a–m were also obtained; however, the rate of their subsequent conversion into ethylene-1,2-diamine end-products was dependent of their structure. Imidazolidines 38a–e,g gradually formed linear reduction products 39a–e,g with full conversion achieved in 36 h. In contrast, imidazolidines 38k,

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m were not isolated at all due to their overly rapid conversion into ring-opening products 39k,m. Reduction of imidazolinium salt 37l was also rapid and gave, surprisingly, a mixture of ethylene-1,2-diamines 39l and 40l (Scheme 10).

Scheme 10 Reduction and alternative modes of opening of imidazolinium salts 37.

Such a behavior of differently substituted imidazolinium salts 37 in the reduction reactions has been rationalized by the following mechanistic interpretation. The contribution of the alternative reductive opening pathways A and B, it is argued, will depend on the relative stabilization of resonance hybrids 41(42)A and 41(42)B, respectively (Scheme 11).

Scheme 11 Mechanistic interpretation of imidazolinium 37 reduction with borohydride.

Reduction and subsequent hydrolytic opening of a 2-imidazoline ring (or its more electrophilic, imidazolinium version) can generate an aldehyde. Thus, a 2-imidazoline ring can be viewed as a masked aldehyde (at C2). This notion was realized in the formal total synthesis of naturally occurring alkaloid (
)-mesembrine (46) reported by a French team of researchers (1998TL8979). Imidazoline 43 was bis-methylated with MeI in the presence of BaO in a sealed tube at 130°C and the resulting imidazolinium salt

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44 was subjected to mild reduction and acidic hydrolysis to produce the key aldehyde synthon 45 for the synthesis of (
)-mesembrine (46) (Scheme 12).

Mesembrine

Scheme 12 Application of imidazolinium reduction in the synthesis of (
)-mesembrine.

Similar unmasking of an aldehyde was employed (1998JOC8107) in the conversion of imidazoline 47 to the imidazolinium iodide 48 and then to (S)-6-(benzyloxy)-2-methyl-2-phenylhexanal 49, the key intermediate en route to (S)-2-methyl-2-phenylcyclohexan-1-one (50) (Scheme 13).

Scheme 13 Application of imidazolinium reduction in the synthesis of enantiopure ketone 50.

In the last two examples, the ethylene-1,2-diamine portion of the 2-imidazoline core becomes “disposable,” i.e., the aldehyde portion derived from C2 of the 2-imidazoline and the substituent at it is the target. In contrast, a more elaborate ethylene-1,2-diamine portion (in combination with a “disposable” aldehyde) can also be obtained via reductive ring opening of 2-imidazolines. Similarly to examples from the Chida group presented in

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Schemes 6 and 7 (vide supra), in 2015, the same group reported (2016OBC5481) the formation of imidazoline 52 from acyclic amidine 51 (on action of a hypervalent iodine reagent) followed by its alkylation (to give 53), reduction and acidic hydrolysis of imidazoldines 54. As a result, the fluoroalkyl-substituted ethylene-1,2-diamines 55a–p (which are likely impossible to obtain otherwise) were synthesized in very good yields over three steps (Scheme 14).

Scheme 14 Reduction of imidazolinium in the synthesis of fluoroalkyl ethylene-1,2diamines.

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N-Acyl and N-sulfonyl 2-imidazolinium salts display different reactivities in reduction reactions, as was shown by the Netherlands team (1983T3971). They noticed that the N-acetyl imidazolinium salt 56a is easily reduced with sodium borohydride to give an isolable imidazolidine 57a which can, in turn, be hydrolyzed to benzaldehyde (58). In contrast, the N-tosyl derivative 56b was promptly reduced all the way to N-benzyl ethylene-1,2-diamine 61b (obtained in 74% yield). The authors attributed these differences to the more preferable formation of the boron complex 60. Interestingly, using transfer hydrogenation with two equivalents of the so-called Hantzsch ester (3,5diethoxycarbonyl-2,6-dimethyl-l,4-dihydropyridine), 56a could be forcereduced to give 61a in 50% yield (Scheme 15).

Scheme 15 Regiospecific reduction of imidazolinium salts.

A similar reduction of N-sulfonyl imidazolines 62 via the formation of an imidazolinium salt 63 was reported by a Chinese team (2000SC3307, 2002SC1447). The regiospecific character of this transformation leading to the ring-opened tertiary amines 64a–e in excellent yields is notable (Scheme 16).

Scheme 16 Reduction of N-sulfonyl imidazolinium salts.

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Particularly interesting is the outcome of the reductive imidazoline ring opening in condensed bicyclic systems described for the first time in 1981 (1981JA4186). In this work, lactams 65a–b were elaborated into bicyclic fused imidazolines 67a–b by reaction with triethyloxonium tetrafluoroborate and aziridine (66). Subsequent treatment with DIBAL-H in hexane led to the reduction of the C]N bond and the formation of intermediate imidazolidine-aluminum species 68. However, further reduction, somewhat surprisingly, led to the regiospecific rupture of the central CdN bond to give ring-expanded aluminum diamide species 69 and, upon aqueous workup, medium-sized-to-macrocyclic diamines 70a–c obtained in excellent yields from 67 (Scheme 17).

Scheme 17 Reductive ring expansion of bicyclic imidazolines 67.

The same authors (1981JA4186) describe an intriguing example of a double reductive 2-imidazoline ring expansion in substrates 71a–b leading to 16- and 22-membered macrocyclic tetramines 72a–b, respectively (Scheme 18).

Scheme 18 Double reductive imidazoline ring expansion.

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The latter example, undoubtedly, inspired another example of a double reductive 2-imidazoline ring expansion in 2,3,5,6,8,9-hexahydrodiimidazo [1,2-a:20 ,10 -c]pyrazine (74). The latter was obtained in respectable 69% yield via condensation of tetraethylenetetramine with dithiooxalamide 73, the overall process represents a remarkable “stitching” of the terminal nitrogen atoms in 73 together, leading to the 12-membered tetramine 75 (Scheme 19).

Scheme 19 Double reductive ring expansion of tricyclic bis-imidazoline 74.

The formation and reductive opening of the 2-imidazoline ring in another type of bicyclic systems (77) obtained, in turn, by CuCl-promoted [3 + 2]-cyclization of amidines 76 in an oxygen atmosphere, was described by Chida (2012JA3679). Because of the specific topology of the bicyclic amidines 76 (in contrast to 67, vide supra), the subsequent reduction with LiAlH4/AlCl3 duo (generating AlH3 in situ) did not lead to ring expansion but rather to the usual loss of the “disposable” benzaldehyde and the valuable (benzylamino)methyl-substituted amines 78a–f were obtained in good to excellent yields (Scheme 20).

Scheme 20 “Zip-in/zip-out” approach to converting amidine 76 to pyrrolidine 78.

Jones and Smallridge studied the reductive opening of scaffolds 79 fused to a quinoline or isoquinoline moiety (1990JCS(P1)385), used as substrates as such or in their N-methylated (81) form, leading to products containing

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secondary (80) or tertiary (82) amine side-chains, respectively (Scheme 21). Interestingly (though not unexpectedly), isoquinoline-fused 2-imidazolines (Table 4, Entries 1–3) are more resistant to reduction compared to quinoline-fused counterparts (Table 4, Entries 4–5). Of course, more electrophilic imidazolinium salts (Table 4, Entries 6–8) are markedly easier to reduce (Table 5, Entries 7–8).

Scheme 21 Reductive manipulation of (iso)quinolone-fused imidazolines 79. Table 4 Comparative reactivity of selected substrates 79 and 81 in the reduction reactions Entry Substrate Reduction conditions Yield (%)

1

LiAlH4 THF, reflux, 0.5 h

86

2

LiAlH4 Et2O, reflux, 1 h

57

3

NaBH4 DMSO/Py, RT, 12 h

80

4

LiAlH4 Et2O, reflux, 2 h

58

5

NaBH4 EtOH, reflux, 5 day

92

6

NaBH4 EtOH, RT, 12 h

40

7

NaBH4 DMSO/Py, RT, 0.5 h

75

8

NaBH4 EtOH, RT, 1 h

60

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Table 5 The outcome of various conditions for the reduction of imidazolines 89 Entry R1 R2 Reduction conditions Yield 90 (%) Yield 91 (%)

1

Et

H

NaBH4, EtOH,
20°C

23

4

2

Et

H

B2H4, THF, 0°C, 2 h

0

97

3

Et

H

(a) BF3 ∙ Et2O; (b) B2H4, THF, 0°C, 2 h 82

0

4

Et

H

Pt, 1 atm H2, EtOH, 20°C

0

96

5

Me H

Pt, 1 atm H2, EtOH, 20°C

0

94

6

Ph H

Pt, 1 atm H2, EtOH, 20°C

0

98

7

Me Me Pt, 1 atm H2, EtOH, 20°C

0

98

Quaternization of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (83) on reaction with methyl iodide or benzyl bromide (1977JHC603) gives the salts 84a and 84b, respectively. The latter are reduced by sodium borohydride in ethanol. However, in this case, reductive ring opening leads to regiospecific rupture of the CdN bond with the formation of thiazolidine products 85a–b and not ring-expanded products 86 (Scheme 22).

Scheme 22 Reductive manipulation of imidazoline-thiazolidine hybrids.

An interesting example illustrating the use of reductive imidazoline ring opening was described by Hirst and co-workers (1989TL5365, 2003ARKIVOC133). Starting from 2-(4-oxoalkyl)-2-imidazolines 89, synthesized, via the Michael addition of enamine 87 to α,β-unsaturated ketones 88, a mixture of piperidine 90 and tetrahydropyridine 91 can be obtained on reduction (Scheme 23). The ratio 90:91 was shown to strongly depend on the specific reduction conditions employed as illustrated by the results summarized in Table 5.

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Scheme 23 Scaffold morphing: from imidazolines to tetrahydropyridines and piperidines.

Mechanistically, the above transformation probably proceeds via the initial formation of intermediate 92 leading to intramolecular activation of the imidazoline nucleus toward reduction to 93. Dehydration of the latter leads to the formation of iminium ion 94 which undergoes a second reduction to give imidazolidine 95. The latter can be presented as existing in equilibrium with the ring-opened form 96 which can undergo deprotonation to give 91, or reduction yielding 90 (Scheme 24).

Scheme 24 Mechanistic interpretation of the piperidine and tetrahydropyridine formation.

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3. Oxidative opening of 2-imidazoline rings In contrast to the abundant body of examples in the literature illustrating the practical utility of the reductive 2-imidazoline ring opening, there are only two examples reported to-date, demonstrating the said transformation triggered by the action of an oxidant on a 2-imidazoline ring. Troisi and co-workers studied oxidation of various C]N bonds by 3-chloroperbenzoic acid (m-CPBA). Among a wealth of examples described (2013S53), oxidation of 1-(2-methyl-4,5-dihydro-1H-imidazol-1-yl) ethan-1-one 97 is particularly relevant to the scope of this review. As the result of addition of m-CPBA to a 0°C solution of 97, nitroso compound 100 was isolated and shown to promptly dimerize forming 101. The transformation is thought to involve the formation of oxaziridine 98 which undergoes the second oxidation to 99 before opening up to give 100 (Scheme 25).

Scheme 25 m-CPBA-triggered imidazoline ring opening.

The second example of an oxidative 2-imidazoline ring opening was described by Zhang and co-workers (2005TL2087) who attempted to aromatize the 2-imidazoline ring in benzodiazepine 102 with MnO2 in refluxing toluene, to obtain the respective imidazole. However, this attempt only led to oxidative ring opening and the formation of carboxamide 103 in moderate yield (Scheme 26).

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Scheme 26 Imidazoline ring opening triggered by manganese dioxide.

4. Hydrolytic opening of 2-imidazoline rings The proneness of the 2-imidazoline ring to hydrolysis is perhaps the most widely utilized transformation involving the opening of this cyclic amidine ring and, often, the formation of a new heterocyclic system. The 2-imidazoline ring can by effectively hydrolyzed in basic, acidic or neutral medium. 2-Alkyl and 2-aryl imidazolines unsubstituted at the nitrogen atom undergo hydrolysis on boiling in neutral aqueous ethanol over 12–24 h (1951HCA1, 1983HCA542, 2000TL8431, 2012IZV50, 2013CEJ16550, 2019OL2156, 2019OL2688) or in the same solution made alkaline with NaOH (1970BCJ2167, 2006TA2935, 2012EJO2118, 2015RSCA68179). This transformation is frequently employed (2019OL2156, 2019OL2688, 2013CEJ16550, 2012EJO2118, 2006TA2935) for monoacylation of optically active amines 104 (with intermediacy of 2-imidazoline 105) to obtain monoacyl derivatives 106 required for various enantioselective catalysis applications (Scheme 27).

Scheme 27 Imidazoline ring closure-ring opening en route to monoacyl ethylene-1,2diamines.

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2-Alkoxy-substituted imidazolines 107 are more resistant to hydrolysis and generally require more forcing conditions—refluxing in aqueous HCl (1989TL1679) or in water in the presence of Ba(OH)2 (1983JA4106, 1985JA2931)—to achieve the complete conversion to ethylene-1,2diamines 108, typically obtained in high (72%–99%) yield (Scheme 28).

Scheme 28 Acidic or basic imidazoline hydrolysis.

N-Alkyl or N-aryl-substituted imidazolines 109 not condensed to other rings can undergo efficient hydrolysis with ethanolic NaOH at room temperature (1964JHC188, 1980FSA57, 1981TL261, 1981JHC933, 1986JCS (P1)205, 2004IZV767, 2005JPC(B)22674, 2015CEL403), on passing through a SiO2 column (2010S3934) or in an aqueous acidic medium at room temperature (1983JHC1585). The resulting N-acyl-N0 -alkyl(aryl) derivatives 111 are formed regiospecifically and no products 110 have been obtained so far. Total hydrolysis under more forcing conditions produces ethylene-1,2-diamines 112 and carboxylic acids 113 (Scheme 29). The kinetic parameters of hydrolysis of imidazolines 109 under various conditions have been studied for N-alkyl (1964JHC188) and N-aryl (1981JHC933, 1983JHC1585) derivatives.

Scheme 29 Hydrolytic imidazoline ring opening is regiospecific.

Some illustrative examples of derivatives 111 obtained by the hydrolysis of a 2-imidazoline ring are provided in Fig. 1. Alkaline hydrolysis of quaternized 2,3-diaryl-substituted imidazolines 114 has been studied in detail (1975JCS(P1)894, 1978JCS(P2)545, 1987JHC1717, 1997JHC709). Addition of a hydroxy-anion at the

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Fig. 1 Examples of acyl ethylene-1,2-diamines obtained by hydrolytic imidazoline ring opening.

amidinium carbon atom produces the hydroxyl derivatives 115 which undergo elimination (via intermediates 116) of the aminoalkyl side chain to give derivatives 117. The latter were shown to rearrange into the isomeric compounds 118 (Scheme 30).

Scheme 30 Mechanism of imidazoline hydrolysis.

2-Benzyl-1-nitrosoimidazoline (119a) was hydrolyzed in acetic medium to give a complex mixture of products containing two principal components—N-(2-hydroxyethyl)-2-phenylacetamide (120) and 2-aminoethyl 2-phenylacetate 121 (2008CRT308). In contrast, alkaline hydrolysis of N-(1-nitro-4,5-dihydro-1H-imidazol-2-yl)methanesulfonamide (119b) gave N-(2-aminoethyl)nitramide (122) as the main product (Scheme 31) (1964JOC1047).

Scheme 31 N-Nitroso and nitro imidazolines: hydrolysis.

N-Sulfonyl (2001AGE4277, 2009TL3042, 2010HCA233, 2011S1771, 2012TA1010, 2015JA9816, 2008CBDD71, 2003OBC2919, 2003OL3313) and N-acyl (2006ASC911, 1992RTC59, 1994IZV472, 2006TA2935)

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Fig. 2 Examples of N-acyl and N-sulfonyl ethylene-1,2-diamine derivatives obtained by imidazoline hydrolysis.

2-imidazolines 122 are easily hydrolyzed in aqueous HCl (with an organic solvent additive to aid in dissolution). Similarly, such hydrolysis has been reported in the presence of silica (2012TA1010, 2015HCA1351) as well as in neutral water at room temperature (1994IZV472). This allowed access to the specifically substituted ethylene-1,2-diamine derivatives 123–124 in rather good yields (Scheme 32). Some illustrative examples of the latter are shown in Fig. 2.

Scheme 32 Hydrolytic opening of N-acyl and N-sulfonyl imidazolines.

Quaternized 2-methyl-1-sulfonyl imidazolines 125 are hydrolyzed with NaOH in aqueous ethanol at room temperature (1999HH406, 2000SC3307). The reaction is complete in 2 h and provides good yields (Table 6) of the ethylene-1,2-diamine derivatives 126 (Scheme 33).

Table 6 Yields of ethylene-1,2-diamine derivatives 126 Product 126a 126b 126c 126d

Ar

Ph

Yield (%) 94

126e

126f

4-MeC6H4 4-MeOC6H4 4-O2NC6H4 3-O2NC6H4 4-ClC6H4 96

96

98

98

87

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Scheme 33 Basic hydrolysis of N-sulfonyl imidazolinium salts.

N-Carbomethoxy-N0 methyl-2-oxyimidazolinium tetrafluoroborates 127a–c have been conveniently hydrolyzed in either neutral or alkaline aqueous solution to give N-(methylamino)ethyl imides 128a–c in good to excellent yields (Scheme 34) (1980JA3928).

Scheme 34 Hydrolysis of 1-methoxycarbonyl-2-alkoxy imidazolines.

Hydrolytic opening of a 2-imidazoline ring can be triggered by N-acylation of NH-imidazolines. For example, attempted acylation of the bifunctional substrate 129 with excess 4-nitrobenzoyl chloride (130) using the Schotten–Baumann method led to bis-acylation and subsequent 2-imidazoline ring opening that produced the linear product 131 in good yield (Scheme 35) (1994IZV472).

Scheme 35 Benzoylation-triggered hydrolytic imidazoline ring opening.

Similar, acylation-triggered ring-opening reaction occurred with substrate 132 in refluxing acetic anhydride, leading to the unsymmetrically bis-acylated product 133 (Scheme 36) (1986CSJ931).

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Scheme 36 Acetylation-triggered imidazoline ring opening.

An interesting scaffold transformation of 1,2-dimethyl-1H-imidazoline 134 upon heating with excess aroyl chlorides 135 in the presence of triethylamine has been reported (2010S141). It involves not only acylation-driven hydrolytic opening (most likely by adventitious water) but also incorporation of two more aroyl groups, presumably via Claisen condensation and acylation of the enol form of the initial condensation product (Scheme 37). The interesting linear products 136a–j are obtained in moderate to good yields (Table 7).

Scheme 37 Imidazoline ring opening with triple aroylation.

Imidazoline ring opening can be triggered by intramolecular N-acylation. For example, imidazoline 137, containing various carboxylic acid side chains, rearranges in refluxing aqueous HCl to give 3-(2aminoethyl)thiazolidine-2,4-dione 139 (1956JOC193, 1964JOC1715, 2006CHE221). The formation of the latter is thought to involve the formation of bicyclic N-acyl intermediate 138 and its subsequent hydrolytic opening (Scheme 38). Table 7 Yields of compounds 136a–j Product Ar Yield (%)

Product

Ar

Yield (%)

136a

Ph

74

136f

2-MeC6H4

60

136b

4-MeOC6H4

63

136g

2-FC6H4

36

136c

4-MeC6H4

65

136h

3-ClC6H4

52

136d

4-ClC6H4

70

136i

3-MeC6H4

60

136e

4-FC6H4

56

136j

3-MeOC6H4

55

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Ring-opening reactions of 2-imidazolines and their applications

Scheme 38 Intramolecular acylation-triggered imidazoline ring opening.

Hydrolytic imidazoline ring opening generating a 2-aminoethyl side chain has been described by Temple and co-workers for tricyclic purine derivatives 140a–b (1980JMC1188). The resulting 2-aminoethyl derivatives 141a–b are obtained in rather low yield (Scheme 39).

Scheme 39 Imidazoline in tricyclic system.

The tricyclic imidazolines 143a–f, synthesized from N-cyaniminoesters 142a–f, undergo an interesting recyclization on heating in alkaline or acidic aqueous medium to give 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones 145a–f in good yield (Table 8) (2012JOC2649). The reaction presumably proceeds via expulsion of the 2-aminoethyl side chain (in 144a–f) followed by intramolecular nucleophilic aromatic substitution of ammonia (Scheme 40). Table 8 Yields of compounds 145a–f Product R1 R2

Yield (%)

145a

H

H

72

145b

H

Cl

68

145c

OMe

OMe

53

–OCH2O–

145d

64

145e

Br

H

61

145f

H

Br

63

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Scheme 40 Imidazoline ring opening followed by intramolecular nucleophilic substitution.

Viewing a fused imidazoline as a masked N-(2-aminoethyl)lactam helped envision the preparation of the impurity 147 in the plant-scale synthesis of a highly selective α1-adrenoceptor antagonist DL-028A (146) (Scheme 41) (2002OPRD273).

Scheme 41 Synthesis of selective α1-adrenoceptor antagonist DL-028A.

4,6-Dichloroquinazoline (148) is conveniently converted to chloro-3(2-(ethylamino)ethyl)quinazolin-4(3H)-one (151) via a reaction sequence involving the formation and hydrolytic ring opening of the quaternized tricyclic imidazoline intermediate 150 (Scheme 42) (1954JOC699).

Scheme 42 Installment of a side chain via imidazolinium salt hydrolysis.

Another example of 2-aminoethyl side chain expulsion was reported for hydrolytic transformation of bicyclic s-triazine derivative 152 (2016HEC281). The best yield of 153 was obtained using HBr rather than HCl as the protic acid (Scheme 43).

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Scheme 43 2-Aminoethyl side chain expulsion.

Table 9 Yield of 1-[2-(pyridin-2-ylamino)ethyl]-1H-pyridin-2-ones 157a–c Product 157a 157b 157c

R1

H

H

Me

2

H

Cl

Cl

86

80

82

R

Yield (%)

Another, rather clever scaffold evolution involving a strategic formation of the puridoimidazolinium bromides 155, via regiospecific bis-alkylation of bispyridinamines 154 followed by hydrolytic ring opening, leads to the high-yielding (Table 9) formation of the medicinally important pyridines 157a–c (Scheme 44) (2002JOC2382).

Scheme 44 Synthesis 1-[2-(pyridin-2-ylamino)ethyl]-1H-pyridin-2-ones 157a–c.

An example involving formation of an elaborate tricyclic imidazoline 175 (via N-bromosuccinimide (NBS)-mediated condensation of aldehyde 173 with the ethylene-1,2-diamine 174) followed by quaternization and hydrolytic ring opening of 176 to give target compound 177 bearing a 2-aminoethyl side chain has been described by Fujioka and co-workers (Scheme 45) (2006CHC832).

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Scheme 45 NBS-triggered cyclization and imidazoline ring opening.

However, the addition of a hydroxide ion at the imidazoline (or imidazolinium) carbon atom does not always lead to ring opening with the expulsion of a 2-aminoethyl side chain. Provided there is sufficient thermodynamic driving force, the imidazoline ring can be opened with the rupture of an alternative CdN bond. This leads, in the case of fused imidazolines, to ring expansion of the ring system formerly fused to the imidazoline (or quaternized imidazoline) nucleus. One of the earliest examples of such a ring opening triggered by the hydration of a quaternized imidazoline nucleus was described by Ishikawa and co-workers in 1980 (1980CPB2587). Cyclization of the 2-hydroxyethyl side chain in 158 onto the nearby guanidine nitrogen atom produces intermediate 159 containing a 2-aminoimidazolinium moiety. Hydration of the latter tetracyclic intermediate in aqueous methanol in the presence of Dowex 2x8 (hydroxide type) resin produced the ring-expanded, tricyclic product 160 (Scheme 46).

Scheme 46 Central ring opening of a tetracyclic system.

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A very similar hydrolysis-triggered ring enlargement was described (1998ACSA1247) for the tricyclic amidinium salt 162a–b obtained, in turn, by Hoffmann-type fragmentation of octahydro-2a,4a,6a,8a-tetraazapentaleno[1,6-cd]pentalene (161). Exposure of 162a–b to alkaline aqueous solution at room temperature produced bicyclic medium-sized heterocycles 163a–b in excellent yield (Scheme 47).

Scheme 47 Medium-sized ring synthesis.

A similar strategy was applied to the remarkable case (2002JOC4081, 2008BMC2455) of converting linear tetramine 164 to tetracyclic salt 165 containing both an imidazolidine and imidazolinium moieties. Once the latter was hydrated in refluxing alkaline aqueous solution, 1,4,7,10tetraazacyclododecane (168) was obtained in excellent yield. This transformation presumably involves ring expansion in the “hydrated imidazoline” intermediate 166 to give 167 followed by further alkaline hydrolysis (hence the forcing conditions) leading to the loss of a glyoxylic acid unit and the formation of 168 (Scheme 48).

Scheme 48 “Zip-in/zip-out” approach to medium-sized cyclic tetramines.

Relief of ring strain in the cycle fused with a 2-imidazoline motif can provide sufficient driving force for hydrolysis-triggered ring expansion (2005T1531). Attempts to separate, by chromatography on silica gel,

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Table 10 Yields of compounds cis-170a–d and trans-171a–d Compound Ar Yield cis-170 (%)

Yield trans-171 (%)

a

4-ClC6H4

26

23

b

4-BrC6H4

25

24

c

3,5-(MeO)2C6H3

25

23

d

4-O2NC6H4

20

17

mixtures of cis-170 and trans-170 obtained, in turn, via intramolecular Staudinger [2 + 2]-cycloaddition reaction of ketamine-imines 169 led to obtaining ring-expanded trans-171 while cis-170 remained intact (Scheme 49). The isolated yields of the four examples reported are shown in Table 10.

Scheme 49 Bicyclic imidazoline ring expansion.

Hydrolytic transformation of cis-170 required using stronger acid; however, it still proceeded under fairly mild conditions (room temperature) over 12 h (Scheme 50). Along with the anticipated ring-expanded products cis171, the product of an alternative CdN bond rupture 172 containing an intact β-lactam ring and 2-aminoethyl side chain was also obtained (Table 11). Such a difference in the stability of cis-170 and trans-170 can be attributed to the differences in the β-lactam ring strain.

Scheme 50 Alternative ways of imidazoline ring opening.

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Table 11 Yields of compounds cis-171 and 172 Compound Ar Yield cis-171 (%)

Yield 172 (%)

a

4-ClC6H4

42

20

b

4-BrC6H4

50

22

c

3,5-(MeO)2C6H3

59

16

The ring-expanded and the 2-aminoethyl side chain-containing products are, in principle, interconvertible. Therefore, the tendency for a hydrated 2-imidazoline to undergo ring-expansion, rather than 2-aminoethyl side chain expulsion, can be increased by suppressing the reverse process of N➔N0 acyl migration in the ring-expanded product. This notion is very well illustrated by the hydrolytic transformation or two bicyclic compounds 178a–b in which the 2-imidazoline nucleus is fused to a seven- and eight-membered cycle, respectively (1981HCA399). While 178a only gave 179a, i.e. the product of 2-aminoethyl side chain expulsion, its homologue 178b only gave a trace of 179b and the major product was the ring-expanded (11-membered) lactam 180b (Scheme 51).

Scheme 51 Side chain expulsion vs ring expansion.

Entropic reasons could be the crux of the matter in the ring expansion of 13-membered N-(2-aminoethyl) lactam 181 (2014EJMC286) which involves its cyclodehydration (driven by azeotropic removal of water) to give fused imidazoline 182. On exposure to KOH in aqueous acetone, the latter gives only the n + 3 ring expansion product 183 and not the product of 2-aminoethyl side chain expansion 181 (Scheme 52).

Scheme 52 Side chain insertion via imidazoline ring closure/ring opening.

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A series of works by these authors describes an approach inspired by the above examples illustrating hydrolytic ring opening of a bicyclic 2-imidazoline leading to an n + 3 ring expansion of the cycle fused to it. This approach is termed Hydrated Imidazoline Ring Expansion or HIRE (2017OBC2906, 2018JOC9707, 2019TL20). The HIRE approach has been mostly exemplified in tetracyclic systems where the imidazoline is integrated with a heteroatom-containing diareneazepine scaffold (Scheme 53). Such oxygen- and sulfur-containing heterocyclic systems 186 are synthesized by a facile, base-promoted condensation of 2-phenylimidazoline derivatives 184 with bis-electrophilic (hetero)aromatic substrates 185. The imidazoline moiety in 186 turned out to be rather resistant to basic or acidic hydrolysis. Therefore, the authors quaternized this core by N-alkylation in order to activate it toward the “hydration.” Imidazolinefused [1.4]oxazepines 186 (X ¼ O) did not allow for a significant diversity of alkyl groups as these core were only alkylated by dimethyl or diethyl sulfate. The resulting imidazolinium salts 187 (X ¼ O) can be directly treated with a solution of potassium carbonate in aqueous acetonitrile, which leads to the anticipated expansion of the [1.4]oxazepine ring. Some examples of the resulting [1,4,7]oxadiazecin-9(6H)-ones 188 are presented in Fig. 3 (2017OBC2906).

Scheme 53 Hydrated imidazoline ring expansion (HIRE).

The nitrogen atom in the imidazoline-fused [1.4]thiazepines 186 (X ¼ S) turns out to be more nucleophilic compared to its [1.4]oxazepines counterpart 186 (X ¼ O) and this permits introduction of a wider variety of alkyl

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Fig. 3 Medium-sized rings as products of the HIRE process: [1,4,7]oxadiazecin-9(6H)ones.

Fig. 4 Medium-sized rings as products of the HIRE process: [1,4,7]thiadiazecines.

groups by direct alkylation. The resulting imidazolinium salts 187 (X ¼ S) are directly transformed into ring-expanded [1,4,7]thiadiazecines 189 using the same HIRE protocol. Examples of the medium-sized cyclic compounds 189 thus obtained are shown in Fig. 4 (2018JOC9707).

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Imidazoline-fused [1.4]diazepine 191 was obtained from the antiviral drug nevirapine (190) in three simple steps involving imidoyl chloride synthesis, condensation with β-aminoethanol and cyclodehydration. The quaternization of the imidazoline nucleus followed by the HIRE step (mild alkaline hydration of 192) led to the formation of medium-sized rings, i.e., 1,4,7-triazecines 193a–d (Scheme 54).

Scheme 54 Ring expansion of the drug Nevirapine.

5. Opening of 2-imidazoline rings by a nitrogen nucleophile McKay and co-workers studied reactions of nitroso and nitro derivatives of 2-imidazolines (1950JA3659, 1951JOC1395). In particular, they investigated the behavior of 1-nitroso-2-nitramino-2-imidazoline 194 in the reaction with primary amines 195 (Scheme 55). Conducted in aqueous ethanol at 30°C, this reaction gave a mixture of N-substituted 2-nitramino-2-imidazolines 199 and 1,2-disubstituted 3-nitroguanidines 200. The reaction is thought to involve successive nucleophilic addition of two molecules of amine 195 at the guanidine carbon atom of 194, leading to the formation of postulated intermediates 196, 197 and 198 followed by either ring closure of the latter intermediate (to give 199) or its trapping by the second molecule of 195 leading to the formation of 200.

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Scheme 55 Addition of a nucleophile to 1-nitroso-2-nitramino-2-imidazoline 194.

An interesting result was obtained by Mujumdar and co-workers (2013TL3336) when they tried to reduce the nitro group in 2-(4,5dihydro-1H-imidazol-1-yl)-3-nitropyridines (203) obtained, in turn, via Pd-catalyzed Buchwald-Hartwig-type arylation of N-unsubstituted imidazolines 201 with 2-chloro-3-nitropyridine (202). Reduction under the Bechamp conditions (Fe in aqueous ethanol at reflux) gave, instead of the expected nitro group reduction products 204, 2-(3H-imidazo[4,5-b] pyridin-3-yl)ethan-1-amines 205 (Scheme 56).

Scheme 56 Unexpected formation of 2-(3H-imidazo[4,5-b]pyridin-3-yl)ethan-1amines 205.

The authors explained such an unusual outcome of this reaction by the formation of the expected 3-aminopyridines 204 first, followed by intramolecular addition of the amino group at the amidine carbon atom of the imidazoline ring to give 206 and aromatization of the latter via 2-aminoethyl side chain expulsion (Scheme 57).

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Scheme 57 General synthesis of 2-(3H-imidazo[4,5-b]pyridin-3-yl)ethan-1-amines 205.

This facile entry into 2-(3H-imidazo[4,5-b]pyridin-3-yl)ethan-1-amines 205 was employed by the same team of authors in the synthesis of 2-(2-(2bromophenyl)-3H-imidazo[4,5-b]pyridin-3-yl)ethan-1-amines 208 (via the Bechamp reduction of compounds 207) with subsequent intramolecular Buchwald–Hartwig arylation of the 2-aminoethyl side chain in 208 leading to the hitherto unknown heterocyclic system 209 (Scheme 58).

Scheme 58 Novel tetracyclic scaffold.

Another example of formal involvement of a nucleophilic nitrogen atom in the opening of a 2-imidazoline ring (most likely, however, proceeding via hydrolytic ring opening followed by recyclization) was observed (1982JPC1026) on attempted hydrolysis of hydrazone 210 in aqueous HCl. Instead of the expected N-aminoimidazoline product (211), tetrahydro-1,2,4-triazine 212 was obtained in modest yield (Scheme 59).

Scheme 59 Formation of tetrahydro-1,2,4-triazine 212.

2-Imidazolines can be recyclized to form new dinitrogen heterocycles on simple reflux with excess diamines (1983JCS(P1)2197, 1989JCS(P1)155). For example, ethylene-1,2-diamines can be “swapped” to propylene-1,3diamine (to give tetrahydropyridines 214), substituted ethylene-1,2-diamines (to give substituted 2-imidazolines 215) and even phenylene-1,2-diamine—to produce benzimidazoles 126 (Scheme 60).

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Scheme 60 Transamination of imidazolines.

The “exchange” of diamine component in cyclic amidines, i.e., 2-imidazolines 213, is thought to proceed via the addition of the new amine, e.g., propylene-1,3-diamine (taken in excess to drive the reversible process forward) to give 217, formation of ring opened intermediates 218 and 219 (most likely, existing in equilibrium) and cyclization with the elimination of ethylene-1,2-diamine (Scheme 61).

Scheme 61 Mechanism of imidazoline transamination.

The nucleophilic addition step (i.e., the formation of intermediate 217) is likely the rate-limiting step, considering the sensitivity of the reaction yield to the electrophilicity of the amidine carbon atom in question (Table 12). Imidazoline quaternization, expectedly, makes the ring more prone to nucleophilic attack and such compounds (e.g., 220) react more readily with ethylene-1,2-diamine (to give, in this illustrative case, 221 and 222) or hydroxylamine (to give ring-opened product 223) (Scheme 62) (1997JHC709).

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Table 12 Yields of heterocycles 214–216 obtained via recyclization of 213 with various diamines Product R R0 Yield (%) Product R R0 Yield (%)

214a

n-C17H35

— 90

215a

Me

H, Me

82

214b

9-cis-C17H33

— 92

215b

Ph

H, Me

61

214c

9-trans-C17H33 — 94

215c

n-C17H35 H, Me

97

214d

n-C15H31

— 95

216a

Me

H

75

214e

n-C13H27

— 95

216b

Me

Me

81

214f

n-C11H23

— 95

216c

Ph

H

20

214g

n-C9H19

— 97

216d

n-C17H35 H

70

214h

Me

— 98

216e

n-C17H35 Me

63

214i

Ph

— 85

216f

Me

Me, Me 86

Scheme 62 Addition of various nucleophiles to imidazolinium salt 220.

Primary aliphatic (but not aromatic or secondary aliphatic) amines can open the ring in imidazolinium salts 224, via the series of intermediates 225–227 (likely existing in equilibrium with each other) to lead to regiospecific formation of linear amidines 228—and not 229 (Scheme 63) (1997JHC709). Properly activated imidazolines (e.g., N-sulfonylimidazolinium salts 230) can recyclize not only with diamines but also with other reagents bearing two nucleophilic centers. For instance, reacting 230 with phenyl-1,2-diamine, o-aminophenol and o-aminothiophenol (231; X ¼ NH2, OH, SH) displaces the ethylene-1,2-diamine derivatives 233 and leads to the formation of new aromatic heterocyclic systems 232 (Scheme 64) (2014COS911, 2000H433) in generally good or excellent yields (Table 13).

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Scheme 63 Addition of primary amines ro imidazolinium salts.

Scheme 64 Transamination with aromatic bis-nucleophilic amines.

Table 13 Yields of compounds 232 Yield Product Ar R X (%)

Product Ar

R

X

Yield (%)

232a

Ph cyclo-C6H11 S

68

232i

Ph

232b

Ph cyclo-C6H11 O

61

232j

4-MeC6H4 sec-Bu

O

232c

Ph cyclo-C6H11 NH 70

232k

4-MeC6H4 sec-Bu

NH 79

232d

Ph Ph

O

232l

Ph

i-Pr

O

232e

Ph Ph

NH 59

232m

Ph

i-Pr

NH 61

232f

Ph 4-MeC6H4 O

54

232n

Ph

Pr

O

232g

Ph 4-MeC6H4 NH 56

232o

Ph

Pr

NH 72

232h

Ph n-C7H15

232p

Ph

Et

O

O

91

61

n-C7H15 NH 66 72

54

60

67

N-Sulfonylimidazolinium salts 234 can also react with aromatic and aliphatic amines 235 yielding, via the formation of tetrahedral intermediates 236, linear (sulfonylamino)ethyl amidines 237 (Scheme 65) in good to excellent yields (Table 14) (2000SC3307, 2002SC1129).

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Scheme 65 Formation of acyclic amidines via addition of primary amines.

Table 14 Yields of compounds 237a–r Product Ar

R

Yield (%) Product Ar

R

Yield (%)

237a

4-ClC6H4

4-MeC6H4

98

237j

4-MeOC6H4 4-MeOC6H4 75

237b

4-ClC6H4

4-MeOC6H4 78

237k

4-MeOC6H4 Bn

60

237c

4-ClC6H4

Bn

65

237l

4-MeOC6H4 Ph

90

237d

4-ClC6H4

Ph

95

237m

4-MeOC6H4 4-ClC6H4

88

237e

4-ClC6H4

4-ClC6H4

90

237n

4-O2NC6H4 4-MeC6H4

77

237f

4-MeC6H4

4-MeC6H4

82

237o

4-O2NC6H4 4-MeOC6H4 90

237g

4-MeC6H4

4-MeOC6H4 84

237p

4-O2NC6H4 Bn

97

237h

4-MeC6H4

Bn

78

237q

3-O2NC6H4 4-MeC6H4

93

237i

4-MeOC6H4 4-MeC6H4

80

237r

3-O2NC6H4 4-MeOC6H4 93

Tetracyclic flavinium compound 238 containing a quaternized imidazolinium moiety underwent regiospecific addition of aliphatic amines, as confirmed by NMR spectroscopy monitoring of the reaction (2001TL4523). The initial adducts 239, however undergo slow rearrangement into the spirocyclic hydantoins 240 (Scheme 66).

Scheme 66 Rearrangement triggered by the addition of a primary amine.

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Another example demonstrating the exclusive electrophilicity of the imidazolinium moiety is provided by the reactions of tricyclic salts 141 with primary aliphatic amines, in the presence of N,N-diisopropylethylamine (DIPEA), in methanol. The initial adduct 242 undergoes protonation (to give 243) and elimination of aminoalkyl side chain to give compounds 244 (Scheme 67) (2006S2031).

Scheme 67 Ring opening triggered by the addition of a primary amine.

6. Opening of 2-imidazoline rings by a carbon nucleophile Early studies by Anderson and co-workers reported in 1982 showed that 2-imidazolines themselves are resistant to the action of Grignard reagents and butyllithium (1982JCS(CC)282). However, quaternized imidazolines 245 reacted quite well with Grignard reagents and, even more readily, with butyllithium leading initially to the formation of imidazolidines 246 and, after acidic aqueous workup, to ketones 247 and ethylene-1,2-diamines 248 (Scheme 68, Table 15).

Scheme 68 Ketone synthesis.

The outcome of the Grignard reagent addition to 245 appeared to depend on the nature of the carbanionic portion. While primary alkyl Grignard regents gave very good yields of the ketones 247, secondary alkyl (i-Pr) and aryl (Ph) groups added more sluggishly. Surprisingly, t-BuMgBr gave excellent yields of the respective ketones (Table 16).

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Table 15 Yields of ketones 247 Product R1 R2

R3

M

Yield (%)

247a

Bn

n-C9H19

Me

MgBr

85

247b

Bn

n-C9H19

n-C4H9

MgBr

70

247c

Bn

n-C9H19

Me

MgBr

55

247d

Bn

n-C9H19

n-C4H9

MgBr

64

247e

Bn

(n-C8H17)CHMe

Me

MgBr

83

247f

Bn

(n-C8H17)CHMe

n-C4H9

MgBr

56

247b

Bn

n-C9H19

n-C4H9

Li

80

247f

Bn

(n-C8H17)CHMe

n-C4H9

Li

68

Table 16 Grignard reagent variations in the 245➔247 transformation 245 R 3M

R1 5 Ph, R2 5 Ph

R1 5 4-O2NC6H4, R2 5 Ph

R1 5 4-ClC6H4, R2 5 Ph

R1 5 4-ClC6H4, R2 5 Ph

MeMgI

91%

83%

81%

85%

PhMgBr

6%

10%

10%

6%

EtMgBr

93%

72%

—

—

PrMgBr

94%

58%

—

—

i-PrMgBr

56%

51%

—

—

t-BuMgBr

87%

43%

—

—

i-BuMgBr

22%

19%

—

—

C6H11MgBr

52%

20%

—

—

Bis-Grignard reagents such as 250 can add to the imidiazolinium salt 249 as was reported by Bai and co-workers (2001SL544). The resulting 1,14-diketone 251 is obtained in good yield (Scheme 69).

Scheme 69 Acetyl equivalents.

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Carbanions generated from malononitrile and nitromethane in the presence of sodium hydride have been reported to efficiently add to the imidazolinium salt 220 to give rise to the enamine adducts 252 and 253, respectively (Scheme 70) (2000JHC1329).

Scheme 70 Malononitrile and nitromethane addition.

Under virtually identical conditions, the stabilized carbanions generated from malononitrile and nitromethane add to imidazolinium salt 254 bearing an arylsulfonyl group at the imidazoline nitrogen atom (2002SC2979). Enamines 255a–e are isolated in good to excellent yields (with rough correlation with electron-withdrawing or -donating character of the R substituent). The nitromethane adduct 256 (also obtained in excellent yield) has been employed as an acetyl nitromethane equivalent and condensed with tryptamine to give the carboline 257 (Scheme 71).

Scheme 71 Malononitrile and nitromethane addition to N-sulfonyl imidazolinium salt.

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An intriguing scaffold interconversion involving addition of nitromethanederived carbanion to imidazolinium 259 (obtained, in turn by cyclodehydration of N-acetyl 2-alkylthioimidazoline 258) was described by Kohn and Davis (1977JOC72). Nitromethane adduct 260 fragmented to expel the 2-(acetylamino)ethyl side chain; this transformation resulted in the formation of 2-nitromethylene thiazoline 261 (Scheme 72).

Scheme 72 Addition of nitromethane to imidazothiazolium salt.

Even less predictable morphing of the initial imidazolinium compounds 262 was described by Khan and Sandstram (1991JOC1902). Addition of thiolate generated with mild base treatment from 262 at dimethyl acetylenedicarboxylate (DMAD) generated putative betaines 263 which undergo intramolecular addition of the C-nucleophilic at the imidazolinium carbon atom resulting in first the tricyclic compounds 264 and then, after acidic workup, 2-aminoethyl side chain expulsion and the formation of end products 265 (Scheme 73).

Scheme 73 Scaffold rearrangement on action of DMAD.

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The productivity of C-nucleophile addition at the imidazolinium carbon atom and the opportunity to premeditate subsequent scaffold-transforming events must have inspired Jones and co-workers to develop and report a nonobvious outcome of condensing, under basic conditions in THF, imidazolines 266 and bromoketones 267 (2001TL3951, 2006OBC3155). The strong alkylating agents 267 first quaternized the imidazoline and created an “electron sink” for α-deprotonation, resulting in betaines 268. The latter underwent cascade cyclization involving intramolecular conjugate addition at the acrylate terminus and addition of the α-carbanion at the amidinium carbon atom leading to the formation of 269. The fragile imidazolidines 269 can expel the 2-aminoethyl side chain (in 270) which readily recyclize onto the nearby cyclohexanone moiety giving enamines 271. The latter are likely to tautomerize and restore pyrrole aromaticity, eventually leading to the isolable pyrrolo[1,2,3-de]quinoxalines 272 (Scheme 74) in moderate overall yields (Table 17).

Scheme 74 Tricyclic pyrrole synthesis.

Stahle and co-workers described an interesting transformation of imidazoline receptor agonist clonidine (273) involving regiospecific alkylation of the guanidine moiety with 3-chloropropyl ketone 274 to give 275 (1980CB2841). Heating the latter in hexamethylphosphoramide (HMPT) gave an intriguing skeletal morphing into 278, apparently involving a nucleophilic aromatic substitution of chlorine step. The same product was obtained on condensing 273 with either 3-acetyldihydrofuran-2(3H)-one (276) or methyl 2-methyl-4,5-dihydrofuran-3-carboxylate (277) (Scheme 75).

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Table 17 Yields of pyrrolo[1,2,3-de]quinoxalines 272 Product R1 R2 R3

Yield (%)

272a

H

H

Me

31

272b

H

H

Et

30

272c

H

H

t-Bu

33

272d

H

Ph

Me

33

272e

H

Ph

Et

31

272f

H

Ph

t-Bu

34

272g

Ph

H

Me

30

272h

Ph

H

Et

30

Scheme 75 Chlonidine transformations.

Mechanistically, the unusual conversion 275➔278 was rationalized as follows (1980CB2841). The protonated enol form of the aliphatic ketone side chain 279 undergoes intramolecular addition at the guanidine carbon atom to give spirocyclic imidazolidine 280. The latter is set for an intramolecular nucleophilic aromatic substitution step to give 281. The latter, in its protonated form (282), eliminates the 2-aminoethyl side chain (a common transformation in 2-imidazoline chemistry) to give 283. Considering the proximity of the nucleophilic primary amine and the methyl ketone group, it is natural to expect these two moieties to form an imine thus delivering end product 278 (Scheme 76).

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Scheme 76 Mechanism of chlonidine transformation.

7. Thermal opening of 2-imidazoline rings The tetrasubstituted imidazolines 286 (obtained via condensation of chloroamidines 285 with 1,2-diaminoethylenes 284) have been shown by Citerio and co-workers (1978TL2175) to undergo an interesting rearrangement, when heated in xylene at reflux, to give 2,4-diaryl-5,6diaminopyrimidines 288 in excellent yield. The reaction is thought to proceed with the regiospecific rupture of a CdN bond to initially give intermediates 287; the latter then undergo cyclodehydration to form the pyrimidines 288 (Scheme 77).

Scheme 77 Transformation of imidazoline to pyrimidine.

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These authors proceeded to investigate more closely how would the reaction outcome depend on the structure of periphery motifs (R1, R2 and X) in the series of substrates 289 (1980JCS(P1)722). 2-Alkylsubstituted bis-morpholine imidazolines (R1 ¼ Me) gave a separable mixture of regioisomers 292 an 293. N-Alkoxycarbonyl imidazolines (R2 ¼ OR) gave 4-hydroxypyrimidines 291. For 2-aryl, N-aroyl imidazolines (R1 and R2 ¼ Ar), the reaction outcome was, surprisingly dependent on the amine periphery and gave opposite regiochemistry (290 and 294) for morpholine- and piperidine-substituted imidazoline substrates 289, respectively (Scheme 78). The yields of products obtained in each case investigated varied greatly from modest to excellent (Table 18).

Scheme 78 Various directions of imidazoline 289 evolution.

The formation of regioisomers in the case of 2-alkyl imidazolines 289 (R1 ¼ Me) was rationalized by the possible existence of two competing pathways for the evolution of the initial intermediate 295 formed after the thermal rupture of the CdN bond in the imidazoline cycle. The expected direct cyclization pathway A (proceeding via tautomer 296 to give the expected regioisomer 297) was argued to be more likely (in this case compared to R1 ¼ Ar) to compete with pathway B involving a [1,3]sigmatropic shift to produce 298, leading to recyclization of the latter into regioisomer 299 (Scheme 79).

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Ring-opening reactions of 2-imidazolines and their applications

Table 18 Yields of compounds 291–294 Yield X (%) Product R1 Product R1 R2

R2

X

4-FC6H4 O

Yield (%)

290a

Ph Ph

O 65

292b

Me

20

290b

Ph 4-MeC6H4 O 65

293b

4-FC6H4 Me

290c

Ph 4-FC6H4

O 75

292c

Me

290d

Ph 4-BrC6H4 O 80

293c

4-BrC6H4 Me

290e

Ph 4-ClC6H4 O 75

292d

Me

291

Ph —

O 30

293d

4-ClC6H4 Me

O

292a

Me Ph

O 30

294a

4-BrC6H4 Ph

CH2 85

293a

Ph Me

O 40

294b

4-ClC6H4 Ph

CH2 80

O

20

4-BrC6H4 O

80

O

4-ClC6H4 O

80

Scheme 79 Alternative pathways for amidine 295 evolution.

Fig. 5 Resonance stabilization of amidine 300.

Prevalence of pathway A for piperidine-substituted substrates 289 was rationalized by the better stabilization of the initial intermediate’s resonance hybrid [300$ 301] (Fig. 5), compared to the case involving morpholinesubstituted substrates 289 (X ¼ O).

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8. Other methods of 2-imidazoline ring opening Miscellaneous approaches to triggering the opening of a 2-imidazoline ring include nitrosation of the imidazoline 302 with NaNO2 in glacial acetic acid, reported by Loeppky and Cui (1998TL1845). In 3 h at 0°C, a mixture of bis- and mono-nitrosation products 303 and 304 is formed in nearly quantitative combined yield (by 1H NMR). However, on warming to room temperature, this mixture is transformed into the acetoxy-substituted product 305 (Scheme 80).

Scheme 80 Nitrosation-triggered imidazoline ring opening.

An unusual method for imidazoline activation toward hydrolytic opening has been reported by Bessonov and co-workers (2005IZV206). The ring opening is achieved only for the cis-configured triarylimidazolines 306 on treatment with aldehydes 307 in 1,4-dioxane in the presence of catalytic amounts of acetic acid, providing facile access to the Schiff bases 308 (Scheme 81) in good to excellent yields (Table 19). Notably, trans-configured imidazolines did not undergo this transformation at all.

Scheme 81 Condensation with aldehydes.

The hydrochloride salt 310 obtained by oxidative cyclization of the dithione 309 was ring-opened with ethanolic or methanolic alkaline solution to give linear products 311a–b in good yields (Scheme 82) (1986S751). To the best of our knowledge, this is the only example of nonhydroxide anion adding at the imidazoline ring’s amidine carbon and triggering ring opening.

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Table 19 Yields of N-aroyl-N0 -alkylidene ethylene-1,2-diamines 308 Product Ar R Yield (%)

308a

Ph

Ph

98

308b

4-MeOC6H4

4-MeOC6H4

76

308c

3-O2NC6H4

3-O2NC6H4

80

308d

Ph

4-BrC6H4

87

308e

Ph

4-MeOC6H4

91

308f

Ph

4-HOC6H4

76

308g

4-MeOC6H4

Ph

87

308h

4-t-BuC6H4

3-O2NC6H4

76

Scheme 82 Disulfide opening.

Finally, the Parke-Davis team reported (1996JOC6060) two interesting transformations of 2-(4,5-dihydro-1H-imidazol-2-yl)benzenethiol 312. Treatment of the latter with methyl chloroacetate (313) in refluxing methanol gave benzothiophene 314 while the reaction with bromoketone 315 at higher temperature (reflux in 2-ethoxyethanol) gave diazepine 316 (Scheme 83). The formation of both probably involves intramolecular addition of the enolates at the amidine carbon causing imidazoline ring opening (followed by intramolecular imine formation in the latter case; however, no mechanistic detail was provided).

Scheme 83 Benzothiophene synthesis by Parke-Davis.

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9. Concluding remarks The instability of 2-imidazolines, nonaromatic, amidine-type dinitrogen heterocycles, under various conditions can be viewed as a powerful synthetic tool to generate novel scaffolds. Under reductive conditions, 2-imidazolines can be viewed as synthetic equivalents of both ethylene-1, 2-diamines and carboxylic acids. Under reductive conditions, ethylene1,2-diamines are more typically obtained. A typical result of the 2-imidazoline ring opening under hydrolytic conditions (the most widely exploited type of reactions involving imidazolines) is the elimination of a 2-aminoethyl side chain with subsequent recyclization onto nearby electrophilic moieties in some cases. However, the initial hydration of the 2-imidazoline moiety can lead to alternative ring opening involving CdN bond rupture which, in fused systems, can lead to elegant ring expansion. Besides reduction, oxidation and hydrolysis, imidazolines (often activated by N-alkylation to form more electrophilic imidazolinium salt) can react with N- and C-nucleophiles, the latter transformation often leading to rather intriguing scaffold evolution.

Acknowledgment This work was supported by the Russian Foundation for Basic Research (Project Grant 18-03-01081).

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Alexander Sapegin and Mikhail Krasavin

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2013CEJ16550 2013OL212 2013S53 2013TL3336 2014COS911 2014EJMC286 2015CEL403 2015EJMC525 2015HCA1351 2015JA9816 2015RSCA68179 2016HEC281 2016OBC5481 2017OBC2906 2018JOC9707 2019TL20 2019OL2156 2019OL2688

Further reading 1990CJC333 1996JOC5186 2014SL2323

X. Chi-Zhong, Z. Pei-Wen, and D. Jing-Fan, Chin. J. Chem., 8, 333 (1990). G.R. Weisman and D.P. Reed, J. Org. Chem., 61, 5186 (1996). M. Krasavin, P. Mujumdar, M. Korsakov, and M. Dorogov, Synlett, 25, 2323 (2014).