Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization

Journal Pre-proofs Digest paper Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization Oleksandr O. Grygorenko PII: DOI: Reference:

S0040-4039(20)30062-9 https://doi.org/10.1016/j.tetlet.2020.151645 TETL 151645

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Tetrahedron Letters

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Please cite this article as: Grygorenko, O.O., Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151645

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Graphical Abstract

Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization Oleksandr O. Grygorenko*

1

Tetrahedron Letters journal homepage: www.elsevier.com

Synthesis of saturated nitrogen heterocycles by Strecker reaction – nucleophilic cyclization Oleksandr O. Grygorenkoa,b* Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine Taras Shevchenko National University of Kyiv, Volodymyrska Street, 60, Kyiv 01601, Ukraine

a b

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

Approaches to -cyanopyrrolidines, -piperidines, and -azepanes, as well as their bi- and polycyclic analogues are surveyed, which are based on Strecker reaction – intramolecular nucleophilic cyclization. The reactions are categorized according to the nature of the internal electrophile participating in the cyclization step, i.e. carboxylic acid or its derivative, carbonyl compound, or alkylating agent. Special attention is paid to one-pot tandem Strecker reaction – SN2-type nucleophilic cyclization (STRINC), or “cyanide-induced dynamic intramolecular cyclization”, which is an efficient and convenient approach to various mono- and bicyclic amino nitriles and -amino acids.

Keywords: Amino nitriles Strecker reaction Bicyclic compounds Nitrogen heterocycles

The Strecker reaction, i.e. reaction of a carbonyl compound, ammonia or amine, and a cyanide source leading to -amino nitriles is a classical synthetic method widely used for the preparation of natural products or their analogues (first of all, amino acids) and many other compounds of practical significance.1–3 While the classical version of this powerful method provides acyclic -amino nitriles, there are several variations which result in the formation of saturated heterocyclic rings (Scheme 1). One of such approaches (A) relies on the use of amino carbonyl compounds or their synthetic equivalents;4–6 these methodologies are beyond the scope of this paper. Another strategy (B) involves tandem Strecker reaction and cyclization of the resulting -amino nitrile upon nucleophilic attack of the amino group at the internal electrophile, typically originating from the carbonyl component. The part of the electrophile can be performed by alkylating agent, aldehyde or ketone, as well as carboxylic acid or its derivative; the cyclization can result in the formation of five-, six-, or seven-membered heteroaliphatic ring. Such heterocyclizations are the subject of this digest. In fact, the title synthetic methodology is rather old: as early as in 1889, Kühling reported that ethyl levullinate (1) reacted with ammonia and hydrogen cyanide to give the pyrrolidone derivative 2 (Scheme 2).7 Later, the method was applied to a number of aliphatic and aromatic primary amines.8–10 The method could be extended to benzo-fused analogues. Thus, Baum and Staveski reported a two-step reaction sequence commencing from methyl 2-formylbenzoate (3) and leading to 2aryl-3-cyanophthalimidines 4 (Scheme 3).11 Later, several one

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step three-component versions of the method involving catalysis with Zn(OTf)2 or In(OTf)3 and then – TFA additive,12 Sc(OTf)3,13 sulfamic acid (H2NSO3H),14 lignin,15 and mesoporous silica OSU-616 were described in the literature (Scheme 4). A variation of the method involving o-formylbenzoic acid as the biselectrophile was also reported.17,18 (A)

R1 1

R

2

N

R H



[CN ]

+

NC

O

N R2

(B)

R1

R1 NH2

+

2

[E]

R



+

[CN ]

NC

O

N R2

Scheme 1. Strecker reactions leading to saturated nitrogen heterocycles (schematic representations) O OEt 1

NH3, EtOH HCN

O

O

N H 2

CN

Scheme 2. CO2Me ArNH 2 3

CHO

3992%

Scheme 3.

Corresponding author. Tel.: +38-044-239-33-15; fax: +38-044-502-48-32; e-mail: [email protected]

O

CO2Me

HCN

N

1454%

Ar

N Ar 4

CN

Tetrahedron Letters

2 CO2Me

R2NH2, TMSCN

1

1

R N R2 acidic catalyst (see the text) 4 CN 7197% R2 = mostly aryl; Bn, allyl

R

3

Such reaction was used for synthesis of polyhydroxylated piperidines 18 (Scheme 10).26,27 An alternative approach to compounds of this type included two-step reaction sequence involving tandem Strecker reaction – nucleophilic cyclization and reductive amination.28,29

O

CHO

Scheme 4.

The phthalimidine ring system was also formed in the attempted Bucherer – Bergs reaction with benzophenone derivative 8 (Scheme 5).19 CO2Me

(NH4)2CO3, KCN

Ph

MeOH, 100110 oC

NH

+

NH

NC Ph

8 O

Ph NH2

O

Scheme 5.

Homologous tetrahydroisoquinoline derivatives 9 were formed in the Zn(OTf)2- or In(OTf)2-catalyzed tandem Strecker reaction – lactamization of aldehydo esters 10 (Scheme 6).12 Isosteric tetrahydroisoxazolo[3,4-c]pyridine derivative 11 formed upon spontaneous cyclization of amino nitrile 12, in turn obtained by the Strecker reaction of aldehyde 13 (Scheme 7).20 O

2 CO2Me R NH2, TMSCN

R1 10

R1

N 2 Zn(OTf)2 or In(OTf)3 R then TFA 9 CN 5572% R2 = aryl, Bn, allyl etc.

CHO

OH

1

OH

R

HO

OH

O

O

KCN, citric acid 2. ZnBr2

KCN 37%

CO2Et 13

O N

O

NH2 CO2Et 12

NH

N

O 11

H CN

CO2Me

67% 14a : 14b = 7:3

O

H CN

NH + H O 14a

H

COOEt NaCN, NH4OAc 87%

HX

NH H O 14b

R R 19

NH2

+

Cl

N NC H 15

Ph

1. KCN, citric acid N NC OH 2. EtOH, reflux 52% 17 Ph

R

CN

NH3, MeOH 2183%

CN

R

N n

21

Another important finding was disclosed by Stevens and coworkers in 2002.37 They described synthesis of 2,4-methanopyrrolidine derivatives 22 from 3-(chloromethyl)cyclobutanone (23) via reaction of imines 24 and ACH (Scheme 12). A reversible formation of amino nitrile intermediates 25 was proposed, and their equilibrium could be shifted towards cis isomer 25a with its subsequent cyclization – the so-called “cyanide-induced dynamic intramolecular cyclization”. Amino nitrile 22 (R = Bn) was used to synthesize a naturally occurring non-proteinogenic amino acid, 2,4-methanoproline (26). O

O

23

Strecker reaction – nucleophilic cyclization with dicarbonyl compounds (i.e. dialdehydes, aldehydoketones, diketones, or their synthetic equivalents) typically included subsequent intramolecular nucleophilic addition step resulting in one-pot closure of two rings. For example, citric acid-promoted reaction of 2,5dimethoxytetrahydrofuran (16), (R)-phenylglycinol, and cyanide led to bicyclic oxazolidine 17 (Scheme 9).25 O

R1 18b

R2

m

n

RNH2 TiCl4

Scheme 8.

O 16

CN

Scheme 11.

The methodology was also used for the preparation of saturated bicyclic lactams 1421 and 1522,23 (Scheme 8), as well as their benzo-fused analogues.24 aq NH3, NaCN

N

O

X = O or NH (20), R = H or Me, n = 1 or 2, m = 13

Scheme 7.

O

+

R1 18a

Cl

CN

CN

CN

OH

Although examples described above had considerable impact on the synthesis of saturated nitrogen heterocycles, the most important version of the methodology discussed in this digest included Strecker reaction followed by nucleophilic cyclization of SN2 type. Significant development of this reaction sequence was made by the author’s group, as well as by Stevens and coworkers. A prerequisite of these studies were works by Oka and co-workers, who described the first examples of one-pot tandem Strecker reaction – SN2-type nucleophilic cyclization (STRINC) including reaction of ,-dichloroketones 19 with acetone cyanohydrine (ACH) or amino nitrile 20 and ammonia leading to the formation of bicyclic -amino nitriles 21 (Scheme 11).30,31 Later, this transformation was used in the synthesis of a number of biologically active pyrrolizidine derivatives.32–36 Cl

NH4Br

N

HO

Scheme 10.

m

Scheme 9.

O

O

O

OH OH

R2

R2

Scheme 6.

O

OH HO

O

O

O N

NH2

1.

O

5074% N NC 22 R

(from 23)

R

N Cl

24 HO MeOH reflux, 5 d



OOC

CN

RHN

RHN

NC

NC

Cl 25a

26

N + H2

Cl 25b

Scheme 12.

The reaction sequences shown in Schemes 11 and 12 became the foundation for our further study on synthesis of 2,4-methanoproline homologues.38,39 Initial attempts to extend the method shown in Scheme 12 to 3-(chloromethyl)cyclohexanone (26) were unfruitful: the target bicyclic amino nitriles 27 were obtained in less than 1% yield. The problem was solved after serendipitous discovery that refluxing a mixture of 26, -phenylethylamine and ACH in MeOH led to the desired products 27a,b

3 O

NH2

+

HO

+

CN

Cl

Ph

MeOH

N H 28

Ph

CN 27b, 40%

CN 27a, 40%

26

CN

N

+

N

reflux, 30 h

Ph

Ph

Scheme 13. O

O

B; BH+Cl

O

B; BH+Cl

Cl BH+Cl; B 32

33

N Ph CN 31

28; ACH Ph N

28; ACH

ACH; 28

28; ACH

Ph

ACH

Cl (S)-29

ACH; 28

HO

ACH

BH+Cl; B

N

Cl N

O

Ph HN

ACH; 28

CN

CN Ph 30b, formed from (R)-29

+ Ph

Cl B; BH+Cl +



BH Cl ; B Cl

N

Ph BH+Cl; B +

N

ACH

Ph



CN

+

HN

O

CN

HCl

+

ACH

B; BH Cl

CN Ph 30a

Cl

Cl

N

Scheme 14 (B – any base present in the reaction mixture, ACH – acetone cyanohydrine. Apart from (S)-29, (R)-29 and the corresponding intermediates are also present).

in 80% overall yield (Scheme 13). Expectedly, amino nitrile 28 was formed from the starting reagents, and it served as a slowlyreleasing source of both amine and cyanide, which ensured high efficiency of the method. Attempts to extend the substrate scope for the described reaction resulted in even more interesting discoveries.38,40 As in the case of 26, cyclobutanone derivative 23 reacted smoothly with benzylamine and ACH in MeOH and gave bicyclic amino nitrile 22 in 70% yield. Nevertheless, cyclopentanone derivative 29, -phenylethylamine and ACH did not give the target bicyclic products 30 under the same conditions. When the solvent was changed to MeCN, a mixture of aminonitriles 30a (8% yield), 30b (8% yield), and 31 (24% yield) was obtained. To rationalize this result, a complex equilibrium was proposed including formation of cyclopropane derivative 32 (Scheme 14). Indeed, 4chlorohexanone (33) also gave mixture of 30a, 30b, and 31 under analogous conditions. Moreover, reaction of 32, -phenylethylamine, its hydrochloride, and ACH gave comparable mixture of the products; similar results were also obtained for some other cyclopropyl-substituted ketones. Further study of the reaction scope showed that there is some optimal reactivity of the carbonyl group in the substrate required to achieve high yield of the products (Figure 1).40 Thus, mixtures of diastereomeric 2-cyanopyrrolidines 34 and 35 were obtained in 66% and 15% yields, respectively, by reaction of 28 and -halocarbonyl compounds 36 and 37 (Scheme 15). No reaction occurred with aromatic ketone 38, and only traces of the products 39 were obtained from fluorinated derivative 40.

O

CN

+ Ph R 36, X = Cl, R = H 37, X = Cl, R = Me 38, X = Cl, R = 4-FC6H4 40, X = Br, R = CF3 X

MeCN

N H 28

CN R

N

Ph 34, R = H, 66% 35, R = Me, 15% 39, R = CF3, 1%

Scheme 15.

Reaction of 28 and aromatic aldehyde 41 was accompanied by formation of unstable isoindole 42, which was trapped with Narylmaledimide to give cycloadduct 43 (Scheme 16).40 Unusual side products were also isolated upon reaction of benzylamine, ACH and pyrrolidine-derived -bromoketone 44 (Scheme 17). Depending on the solvent used, the target bicyclic diaminonitrile 45 (up to 33% yield), piperidine derivative 46 (in MeOH), and pyrrole 47 (in MeCN) could be obtained (see the original paper for more details and mechanistic considerations).41 O

N

N Ar

Br Ph

28

O

N

MeCN 41

Ph

O

40%

N 43

42

O

O

Ar

Scheme 16. O

Br N Boc 44

rac BnNH2 Boc HO

CN

N

NC 45

N Bn

CN

N Bn

NHBn +

+ O

N Boc 46

BocHN 47

Scheme 17.

Figure 1. Total yields of 2-cyanopyrrolidines obtained by STRINC rection of -halocarbonyl compounds (the substrates are given in order of increasing reactivity of their carbonyl group towards nucleophiles).

The method could also extended for the preparation of fused -cyanopyrrolidines 48 and 49,42,43 as well as various bicyclic cyanopiperidine derivatives 50–5343,44 (Scheme 18). A modified procedure for the STRINC reaction was proposed by Stevens and co-workers, which included heating of the starting materials in the presence of Et3N (2 eq) in MeOH at 100–

Tetrahedron Letters

4

110 C. This method was used to obtain improved yields of a series N-alkyl-substituted bicyclic -amino nitriles, including derivatives of 7-azabicyclo[2.2.1]heptane 54,45–48 2-azabicyclo[2.2.2]octane 55,49 and 2-azabicyclo[3.1.1]heptane 56.50 For example, to obtain derivatives 54, 4-sulfonyloxycyclohexanones 57 reacted with ACH and various primary amines under the conditions mentioned above (Scheme 19). O

MeCN

CN

+

Ph

N H 28

60% H

O

Cl

CN HO 5564%

O

NC N

Cl

NC N

62

NC

N Bn 49, n = 1 50, n = 2

O

CN HO 36% OTs

CHO

Bn N 52

N Boc 64

CN

HO OTs

CN 69%

Bn N 53

O

CN

HO

MeOH 100110 oC XO 57, X = Ms or Ts 3997%

CN

CO2Me

65

R N

CN 55

NC 54

57

1. NaHSO3

NC R

N

CN

NBn

99%

63

MeO2C H 2 CHO R CH2CH2NH2 MeO OTs KCN, MgSO4 R1O 87% H

CN N

R2

R2

Scheme 24.

Finally, Strecker reaction of polyfunctional aldehyde 67 followed by intramolecular aziridine ring opening was used for the preparation of azasugars (Scheme 25).57 O BocN

NHBoc

BnO

OBn OBn OBn 67

1. BnNH2, then TMSCN 2. DIPEA

BnO BnO

NBn CN

Acknowledgments

58

Reaction of binaphthyl-derived -bromoaldehyde 60 with allylamine and NaBF4 and then – NaCN was the first example of using the STRINC-type sequence to construct a seven-membered ring (Scheme 21).52 CN

Br 2. NaCN, >95%

N Boc

CN

DBU BocN

Scheme 25.

Scheme 20.

O 1. AllylNH2, NaBF4, 65%

NHBn

MeO2C CO2Allyl MeO2C CO2Allyl H BnO R2CH2CH2NH2 BnO CN CHO KCN, MgSO OBs N 4 8190% H 66

N R CN 56

With some - and -functionalized aldehydes, more classical conditions for the Strecker reaction – SN2-type intramolecular nucleophilic cyclization involving the use of KCN, NaCN or TMSCN as the cyanide source were found to be fruitful. Thus, de Kimpe and co-workers described a three-step one-pot reaction sequence for transformation of aldehyde 57 into 2cyanopyrrolidines 58 including reaction with NaHSO3, primary amine, and KCN, although the yields of the product were modest (13–36%) (Scheme 20).51

Cl 2. RNH2 3. KCN 1336%

TsO

(EtO)2P(O)CN 95%

MeO

Scheme 19.

O

BnNH2

R1O

R N

N 2 R 61 CN R2 = aryl, Bn, allyl etc.

Scheme 23.

Scheme 18. RNH2, Et3N

R1

Reaction of -functionalized aldehydes 65 and 66 with primary amines was one of the steps in the synthesis of alcaloids reserpine,55 venenatine and alstovenine56 (Scheme 24).

BnNH2

N CN CN Bn 42% 51

Zn(OTf)2 or In(OTf)3 7092%

Diazabicyclo[2.2.1] heptane derivative 63 was obtained from 4-hydroxyproline-derived aldehyde 64 in two steps including Strecker reaction with (EtO)2P(O)CN and BnNH2 and then – DBU-promoted cyclization (Scheme 23).54 TsO

Ph 48b

n

CHO

R2NH2, TMSCN

Scheme 22.

BnNH2

BnNH2 HO

+

Ph 48a

O

BnNH2 n

H

H

Br

Br R1

The work was funded by Enamine Ltd and Ministry of Education and Science of Ukraine (grant No. 19BF037-03). The author thanks Prof. Andrey A. Tolmachev for his encouragement and support.

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7 Highlights 

Strecker reaction – cyclization is reviewed.



Historically, the title reaction sequence was first applied to aldehydo- and ketoesters.



The most important version of the methodology includes Strecker reaction followed by SN2-type cyclization (STRINC).



The method is efficient for the preparation of various mono- and bicyclic -amino nitriles and -amino acids.

intramolecular

nucleophilic