Focused Update on the Prins Reaction and the Prins Cyclization

Current Organic Chemistry, 2012, 16, 1277-1312

1277

Focused Update on the Prins Reaction and the Prins Cyclization Isidro M. Pastor* and Miguel Yus* Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain Abstract: The Prins reaction and the Prins cyclization have stood out as important synthetic strategies, and here the latest advances in this topic are reviewed. Different mineral acids, Lewis acids, organic acids and supported acidic materials have been employed as promoters for this type of transformation, the reaction with paraformaldehyde being the most considered one. Without any doubt, the Prins cyclization forming oxygenated heterocycles is one of the most common tranformations, and many studies have been reported on this topic. The acid-promoted Prins cyclization of an oxocarbenium ion generated in situ from suitable starting materials in order to produce the corresponding tetrahydropyrans have been extensively studied and employed in the total synthesis of a wide number of natural products. Additionally, the Prins cyclization have been employed in the synthesis of five, seven, eight and nine membered rings. The aza version of this reaction has been also considered, the analogous aza-cyclization allowing the synthesis of piperidine derivatives, which are widely distributed in natural products.

Keywords: Prins reaction, Prins cyclization, Acid catalysis, Oxocarbenium ion, Carbon-carbon bond formation. 1. INTRODUCTION

H

O

Carbon–carbon bond forming reactions are among the most important transformations in synthetic organic chemistry. They are important in the production of many man-made chemicals such as pharmaceuticals and plastics. Among them, Prins reaction is of paramount importance generating new carbon–carbon bonds by the acid-catalyzed condensation of aldehydes with alkenes. However, it is necessary to exert an accurate control of the experimental conditions, since several types of products can formally be formed, and therefore mixtures are often obtained. Thus, the outcome of the reaction depends on the substrate structure and the reaction conditions, resulting in a variety of products, such as 1,3-diols, 1,3dioxanes or unsaturated alcohols (Scheme 1). The so-called Prins cyclization, where an unsaturated alcohol and an aldehyde reacted to form a heterocyclic compound, can be considered as a really interesting transformation from a synthetic point of view. Indeed, this type of Prins transformation has been considered in many syntheses of compounds with significant value. After our previous contribution to this attractive transformation [1], the continuous growth of publications referred to this reaction in the last five years, prompted us to consider in this review an update of the previously reported one, covering the literature from 2006 to 2010.

R1

H+

O

R1

H

H R2

H

R3

O

R1

H

R3

R2

R1CHO

Nucleophile - H+

R1 R3

OH O

R3

OH

O R1

R1

R3

H

R1 R2

H

Y R2

R2 1,3-dioxane

allylic alcohol

functionalized alcohol [1,3-diol for Y = OH]

Scheme 1.

2. PRINS REACTION 2.1. Catalysis by a Lewis or an Organic Acid The Prins reaction of the alkylidene morpholinone 1 with formaldehyde in the presence of a mineral acid (e.g. sulfuric acid) provided the corresponding spirodioxane derivative 2 as a single diastereomer (Scheme 2). Compound 2 has been employed in the preparation of different nine-membered oxacycles [2].

N

Ph

N

Ph HCHO (aq.) O

O

H2SO4, dioxane

O

O

O O

1

2

Scheme 2. *Address correspondence to these authors at the Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain; Tel: (+34) 965 903548; Fax: (+34) 965903549; E-mail: [email protected]; [email protected]

15-8/12 $58.00+.00

Other Brønsted acids have been tested as catalysts for the Prins reaction. Indeed, the use of triflic acid allowed the coupling of dif© 2012 Bentham Science Publishers

1278 Current Organic Chemistry, 2012, Vol. 16, No. 10

Pastor and Yus

O R1 R1

O

O

H2SO4, (CH2O)n OEt

R1

AcOH, 70 ˚C

R1

3: R1 = H 4: R1 = Et 5: R1 = Ph 6: R1-R1 = (CH2)4

O

a) NaOH (40% solution), reflux b) H2SO4

R1

OAc

7: R1 = H (80%) 8: R1 = Et (79%) 9: R1 = Ph (74%) 10: R1-R1 = (CH2)4 (80%)

O OH R1

11: R1 = H (43%) 12: R1 = Et (76%) 13: R1 = Ph (66%) 14: R1-R1 = (CH2)4 (74%)

Scheme 3.

O Me3SiO

OMe

a) TiCl4 (150 mol%), CH2Cl2, -78 ˚C

R1

+ R1

MeO

b) H2O

H

OMe

16: R1 = Me (95%) 17: R1 = n-Pr (93%) 18: R1 = n-C5H11 (99%) 19: R1 = n-C6H13 (95%) 20: R1 = Me3Si (94%)

15

Scheme 4. 2+

R1 P P R1

[SbF6-]2

R1 Pt

NCC6F5 NCC6F5

R1

21: R1 = 4-MeC6H4

ferent styrene derivatives with an aqueous solution of formaldehyde. The corresponding 1,3-dioxanes were obtained employing 10 mol% of triflic acid. Unluckily, linear alkenes failed under this reaction conditions in order to form the final products [3]. Acetic acid has been also shown activity as catalyst for this reaction, so the alkenyl ester derivatives 3-6 were treated with paraformaldehyde in the presence of acetic acid giving the expected Prins reaction, although the hydroxyl group formed underwent intramolecular esterification producing the corresponding caprolactones 7-10 (Scheme 3) [4]. The consecutive aqueous basic and acidic treatment of lactones 7-10 yielded the corresponding hydroxyethyl -lactones 1114. An interesting advance on this reaction has been the use of molecular iodine as Lewis acid catalyst. The Prins reaction between styrene derivatives and paraformaldehyde in the presence of I2 yielded the corresponding 1,3-dioxane derivatives with good isolated yields (82-92%) [5]. The reaction needs very mild conditions employing one equivalent of the I2. Additionally, the reaction has also been successful employing aliphatic aldehydes (acetaldehyde, propanal and cyclohexanecarbaldehyde) and simple alkenes (1octene and 1-dodecene), albeit the reaction time was longer and the isolated yield lower. A Prins type reaction has been described between 1-(1cyclohexenyl)-1-cyclopropanol trimethylsilyl ether 15 and different aldehyde acetals employing titanium tetrachloride as Lewis acid catalyst. The spirolactones 16-20 have been obtained in good yields

(93-99%) and with good diastereoselectivity (Scheme 4). The reaction has been also successful employing other acetals (derived from aliphatic, aromatic aldehydes and alkynals), although the diastereoselectivity of the process was very poor [6]. A catalytic asymmetric Prins reaction has been described employing the BINAP-Pt complex 21. Thus, the reaction of 2prenylphenol 22 and the glyoxylate ester 23, in the presence of the catalyst 21, gave the carbenium intermediate 24, which was subsequently trapped by the hydroxyl group forming the diastereomeric mixture of isochromane derivatives 25 and 26 (1:1), although with high level of enantioselectivity in both cases (96% and 94% ee, respectively; Scheme 5) [7]. A hafnium complex, having bis(perfluorooctanesulfonyl)imide moieties, has been reported as an excellent active and recyclable catalyst for the Prins reaction of -methyl styrene with aldehydes under fluorous biphase system (FBS) conditions. Thus, the complex Hf[N(SO2C8F17)2]4 in a very low catalyst loading produced the corresponding 1,3-dioxane derivatives 27 and 28 (Scheme 6) [8]. The catalyst is selectively soluble in lower fluorous phase and can be then recovered simply by phase separation, and recycled (up to 17 times) without significant loss of activity. Regarding other reaction conditions, different ionic liquids with acidic properties have been considered as a reaction media, with the aim that they can also act as catalysts for Prins reactions [9]. The hydrophobic ammonium salts 29 and 30, which are easily obtained from trioctylamine and 1,3-propane- or 1,4-butanesultone, have been employed as catalysts for the Prins reaction of different styrene derivatives with formaldehyde giving the corresponding 1,3dioxane products 39-44 (Scheme 7) [10]. In this protocol, the catalyst can be recovered and reused without losing activity. Having in mind this type of catalysts, other similar Brønsted acidic ionic liquids, such as 31-38 [11], have been also tested as catalysts for the Prins reaction of styrene and formaldehyde with excellent conversions and chemoselectivities, the corresponding 1,3-dioxane derivative being the only product formed. Additionally, the coating of Brønsted acid silica materials with hydrophobic ionic liquids gave

Focused Update on the Prins Reaction and the Prins Cyclization

Current Organic Chemistry, 2012, Vol. 16, No. 10 1279

CO2But OH O

OBut

H

O

+

22

OH

H

21 (10 mol%)

OH

toluene, 23 ˚C

23

24

CO2But O

H

CO2But

OH

O

H

OH

+

25

26

Scheme 5. R1 O

O

Hf[N(SO2C8F17)2]4 (0.5 mol%), (CH2O)n or CH3CHO

R1

(CH2Cl)2/GALVEN SV 235 (1:1) 27: R1 = H (87%) 28: R1 = Me (80%) Scheme 6.

NTf2 (n-C8H17)3N

n

SO3H

HSO4 Me3N

29: n = 1 30: n = 2

H2PO4 Me3N

SO3H

N

R3

SO3H

HSO4

N

SO3H

SO3H

N

37

R2

n

33: n = 1 34: n = 2

HSO4 n

HSO4 Et3N

31: n = 1 32: n = 2

35: n = 1 36: n = 2

R1

n

SO3H

38

O

O

30 (10 mol%) HCHO (200 mol%), H2O

R2 R3 R1 39: R1 = R2 = R3 = H (95%) 40: R1 = Me, R2 = R3 = H (93%) 41: R1 = Cl, R2 = R3 = H (81%) 42: R1 = OMe, R2 = R3 = H (94%) 43: R1 = H, R2 = Me, R3 = H (74%) 44: R1 = H, R2 = R3 = Me (54%)

Scheme 7.

heterogeneous catalysts which have been also employed satisfactorily in the Prins reaction of different styrene derivatives with aqueous formaldehyde producing 1,3-dioxanes in high yields (89-96%) [12]. The development of different solid-supported acids has been reported in relation with the Prins reaction. Thus, silica-supported p-toluenesulfonic acid has been found to be an efficient catalyst for the reaction of different alkenes (styrene, -methylstyrene, p-

chlorostyrene, p-methoxystyrene and 1-octene) with formaldehyde producing the corresponding 1,3-dioxanes with good yields (7096%) [13]. The reaction was performed under microwave irradiation in the absence of solvent [14], so very short reaction time (1-7 min.) was needed. Another solid acid catalyst has been prepared by the combination of MoO3 and silica gel. The catalytic system has shown to be effective in the Prins reaction of styrene and 1-alkenes with paraformaldehyde giving the corresponding 1,3-dioxanes with


Pastor and Yus

Cl

OH

a) BF3, Bu4NCl, (AcO)2CH2, CH2Cl2, -78 to 23 ˚C R1

R1

b) H2O

45: R1 = H (79%) 46: R1 = 4-Cl (84%) 47: R1 = 3-Cl (62%) 48: R1 = 2-Cl (44%) 49: R1 = 4-Me (71%) 50: R1 = 2-Me (41%) 51: R1 = 3-MeO (36%) Scheme 8.

CO2Me CO2Me

NH2

MeO2C

H

MeO2C

NH

MeO2C HCl (10 mol%), CH2O (350 mol%)

R1

+ CO2Me

MeOH, 23 ˚C

N

O

R1

R1

52: R1 = H (70%) 53: R1 = 4-F (80%) 54: R1 = 4-Cl (82%) 55: R1 = 3-Cl (80%) 56: R1 = 4-Me (74%) 57: R1 = 4-MeO (75%)

Scheme 9.

good conversions (72-90%) [15]. Finally, mesoporous SBA-15 silica has been functionalized with sulfonic acid moieties anchored to the surface, showing high thermal and hydrothermal stability. The SBA-15-SO3H material was tested in the Prins reaction of styrene with formaldehyde, giving excellent selectivity and conversion. Furthermore, the material could be recycled, at least four times, without losing activity [16]. Methylene diacetate, which can be obtained in a stock solution of tetrabutylammonium acetate in dichloromethane, has been reported to act as formadehyde equivalent in the Prins reaction with styrenes. Thus, styrenes in the presence of boron trifluoride reacted with this stock solution of (AcO)2CH2/Bu4NCl producing the 3chloro-3-phenylpropanol derivatives 45-51 (Scheme 8) [17]. Other alkenes (cyclohexene and methylcyclohexene) produced the corresponding chloroalkanols, although in very low yield. A Brønsted acid, such as chlorhydric acid, catalyzed the reaction between an aniline derivative and dimethyl acetylenedicarboxylate leading to the corresponding product of hydroamination, which gave a Prins reaction with formaldehyde present in the reaction media. Finally, the amino alcohol generated closed up to the oxazines 52-57 (Scheme 9) [18]. Nopol (58) is an important bicyclic primary alcohol extensively employed by the agrochemical industry in producing pesticides, and also used in the preparation of various household products including fragrances. It is easily prepared from -pinene and paraformaldehyde via a Prins reaction (Scheme 10), different heterogeneous catalysts being prepared for this transformation. Thus, a series of iron-zinc solid acid catalysts has been prepared and tested in the preparation of nopol via Prins reactions [19]. In addition, heterogeneous catalysts based on MCM-41 and modified with tin, zinc and aluminium have been also prepared for this reaction, showing good selectivity and activity in all cases [20]. A tin-based catalyst, such

as mesoporous Sn-SBA-15 molecular sieve material, has been also prepared to catalyze the synthesis of nopol [21]. OH

(CH2O)n catalyst 58 Scheme 10.

2.2. Prins Reaction in Natural Product Synthesis A Prins reaction has been employed during the total synthesis of cyathin A3 (62) and cyathin B2 (63). Thus, the vinyl cyclopropanol derivative 59 reacted with the acetal 60 in the presence of TiCl4 producing the spirocyclobutanone 61 in 78% yield as a mixture of isomers (ratio 10:3; Scheme 11) [22]. Similar cyclization has been employed in the preparation of compounds 64 and 65, which have been employed in the synthesis of lepadiformines A and C (Scheme 12) [23]. 3. AZA PRINS REACTION The use of imine derivatives instead of carbonyl compounds opens the possibility of performing an aza version of the Prins reaction. Thus, the use of the reagent combination TiI4/I2 has been reported as an efficient procedure for the aza Prins reaction of olefins and acetylenes producing the corresponding iodoamine derivatives 66-73 in good yields (Scheme 13) [24]. The use of iodine has been observed to be crucial for the success of these processes. The possible mechanism involves the reaction between TiI4 and I2 in order to generate 74, which can activate the nitrogen of the imine, thus provoking the subsequent iodoethylation and protonation (Scheme 14).



O

TMSO a) TiCl4 (260 mol%), 2,6-lutidine (80 mol%), Me3SiOTf (100 mol%), CH2Cl2, -78 ˚C

OMe +

Br

MeO

b) NaHCO3 (saturated solution)

Br

H

OMe

60 59

61

O

O OH CHO

H

H

OH

62

63

Scheme 11.

Me3SiO

O

TiCl4, CH2Cl2

+ R1

H

R1

OH

O

N3

N3

H

0 or -40 ˚C

64: R1 = n-C6H13 (30%) 65: R1 = n-C4H9 (22%)

15 Scheme 12.

N

Ts R1

+

EtO2C

R1

I R1

66: R1 = Ph (75%, syn/anti: 59/41) 67: R1 = 1-naphthyl (58%, syn/anti: 59/41) 68: R1 = 2-furyl (42%, syn/anti: 61/39) 69: R1 = 2-thienyl (44%, syn/anti: 62/38) Ts NH I

Ts +

NH

EtO2C


N EtO2C

Ts a) TiI4 (250 mol%), I2 (300 mol%), CH2Cl2, 25 ˚C

a) TiI4 (250 mol%), I2 (300 mol%), CH2Cl2, 25 ˚C

R1

EtO2C


70: R1 = Ph (76%, Z/E: 65/35) 71: R1 = 4-MeOC6H4 (64%, Z/E: 58/42) 72: R1 = 4-MeC6H4 (65%, Z/E: 71/29) 73: R1 = 4-ClC6H4 (84%, Z/E: 77/23) Scheme 13.

TiI4

+

TiI3 · I3

I2

74 N

Ts Ts

TiI3 · I3

TiI3 N

Ts I

H2O

NH

I

EtO2C R1 Scheme 14.

EtO2C

R1

EtO2C

R1


Pastor and Yus

R1 R1

O

R2

O

R2

76 R1 R2

O

R1 75

R1

O

O R2

R1

O

or

R2 R2

77

Scheme 15.

Ph Ph O

Ph

SnCl4 (110 mol%) H

H

Br H

O

2-(HO)C6H4CHO, CH2Cl2, 23 ˚C

SnBr4 (110 mol%), Me3SiBr (110 mol%) O

2-(NO2)C6H4CHO, CH2Cl2, -78 ˚C

OH

NO2

79 (88%)

78 (83%)

Scheme 16. Ph

O

R2 Me3SiOTf (300 mol%) R1

R2CHO, CH2Cl2, -78 to 23 ˚C

TfO R1

R1

OH Ph

Ph

O

R2

Me3SiOTf (300 mol%) R1

R2CHO, Et2O, -78 to 23 ˚C O

80

R2

86: = Me, = Ph (68%) 87: R1 = Me, R2 = 4-(NO2)C6H4 (77%) 88: R1 = R2 = Me (68%) 89: R1 = Me, R2 = i-Pr (60%) 90: R1 = Me, R2 = n-C5H11 (65%) 91: R1 = Ph, R2 = 4-(NO2)C6H4 (64%)

R1

81: = Me, R2 = Ph (38%) 1 82: R = Me, R2 = 4-(NO2)C6H4 (41%) 83: R1 = R2 = Me (30%) 84: R1 = Me, R2 = i-Pr (18%) 85: R1 = Ph, R2 = 4-(NO2)C6H4 (35%)

Scheme 17.

4. PRINS CYCLIZATIONS 4.1. Formation of Five Membered Rings In the intermolecular the Prins cyclization, the substrates first react producing usually a ,-unsaturated oxonium intermediate 75, which can undergo 6- or 5-membered ring closure depending on the relative energies of the corresponding transition states, that are related to the stability of the carbenium ions 76 and 77 (Scheme 15). Different tetrahydrofuran derivatives have been prepared by reaction of (E)-4-phenylbut-3-en-1-ol with alkylic and arylic aldehydes in the presence of SnBr4 and trimethylsilyl bromide. In all cases, among the different possible diastereomers, one has been obtained as the major component (>60%) in the reaction mixture. The ratio of diastereomers depends on the electrophile employed, so the compound 78 has been the only isolated product starting from 2-nitrobenzaldehyde (Scheme 16) [25]. For salicylaldehyde and in the absence of an external nucleophile the hydroxyl group trapped the corresponding carbocation forming the furo[3,2c]benzopyran 79 (Scheme 16).

The Prins-type cyclization of a homopropargylic alcohol 80 with different aldehydes in the presence of trimethylsilyl triflate gave the 5-exocyclic products 81-85 (Scheme 17). Analogous cyclization has been observed but with the formation of the corresponding exocyclic vinyl triflate products 86-91, just by changing the solvent from diethyl ether to dichloromethane (Scheme 17) [26]. Moreover, a Prins-type cyclization has been also observed between 1-phenyl-5-(trimethylsilyl)pent-3-yn-1-ol (80 with R1 = CH2SiMe3) and different aldehydes, producing cis-2,5-disubstituted 3-allenyltetrahydrofurans [27]. The Prins cyclization of different alkynyl diethyl acetals has been achieved employing iron halides as catalysts, so five-membered carbo- and heterocycles 92-101 have been obtained under very mild reaction conditions as depicted in Scheme 18 [28]. Later on, the catalytic version of the reaction has been reported, employing FeCl3·6H2O in substoichiometric amount (5-20 mol%) and acetyl chloride as an external source of chloride, to obtain the corresponding products having a chlorovinyl moiety [29].



X R1 Y

R1

FeCl3 or FeBr3 (100 mol%)

OEt

Y CH2Cl2, 0 ˚C

OEt

OEt R1

92: = Ph, Y = O, X = Cl (77%) 93: R1 = Ph, Y = O, X = Br (73%) 94: R1 = 4-MeC6H4, Y = O, X = Cl (78%) 95: R1 = 4-ClC6H4, Y = O, X = Cl (91%) 96: R1 = 3-MeOC6H4, Y = O, X = Cl (75%) 97: R1 = Me, Y = NTs, X = Cl (77%) 98: R1 = Ph, Y = NTs, X = Cl (78%) 99: R1 = Ph, Y = NTs, X = Br (90%) 100: R1 = Ph, Y = C(CO2Et)2, X = Cl (71%) 101: R1 = Ph, Y = C(CO2Et)2, X = Br (75%) Scheme 18.

MeO OMe SnCl4 (50 mol%) OTIPS

MeO

MeO H

CHO

H

+

CHO

CH2Cl2, 0 ˚C n

n

n

102-104 (n = 1-3)

105: n = 1 (69%, 1:3.4 cis/trans) 106: n = 2 (75%, 1:1 cis/trans) 107: n = 3 (71%, 1.2:1 cis/trans)

Scheme 19.

The Prins–pinacol reaction of different alkylidenecycloalkane derivatives (102-104) has been performed in the presence of SnCl4 as catalyst affording the 1-(cyclopentyl)cycloalkanecarbaldehydes 105-107 as a mixture of isomers (Scheme 19) [30]. The titanium chloride catalyzed Prins reaction and subsequent pinacol rearrangement has been employed for the desymmetrization of cyclohexa-1,4-dienes 108-111 yielding the corresponding isobenzofuran carbaldehyde derivatives with moderate yields (Scheme 20) [31]. In addition, the use of triflic acid has been found to be effective for this desymmetrization reaction, generally giving higher yields than with titanium chloride [32].

R1 O

OH O

R1 OH

n

n

R1 O

H R1

H

O

TiCl4 (250 mol%)

O

CH2Cl2, -78 ˚C

R2

R1

OH n

O

Me3SiOTf (300 mol%) O

R1CHO, CH2Cl2, -78 ˚C n

112-113

H 108: R1 = 2-BrC6H4, R2 = Me 109: R1 = 2-BrC6H4, R2 = i-Bu 110: R1 = R2 = Me 111: R1 = Me, R2 = i-Bu

OH

O

114: n = 1, R1 = Ph (93%) 115: n = 1, R1 = 4-(NO2)C6H4 (96%) 116: n = 1, R1 = 4-ClC6H4 (95%) 117: n = 1, R1 = n-C5H11 (98%) 118: n = 1, R1 = i-Pr (96%) 119: n = 2, R1 = Ph (80%) 120: n = 2, R1 = 4-(NO2)C6H4 (88%) 121: n = 2, R1 = 4-ClC6H4 (83%) 122: n = 2, R1 = n-C5H11 (82%) 123: n = 2, R1 = i-Pr (85%)

R2

(20-44%)

Scheme 20.

The stereoselective synthesis of the 2-oxaspiro[4.4]nonane and [4.5]decane structural motifs, which are present in a number of natural products, has been performed by a Prins–pinacol annulation of olefinic diols and carbonylic compounds. Methylene diols 112 and 113 reacted with various aldehydes forming the corresponding oxocarbenium intermediates, which underwent a Prins cyclization followed by a pinacol rearrangement to afford the 3-substituted 2oxaspiro compounds 114-123 (Scheme 21) [33]. The reaction has been also effective employing ketones as electrophiles, with the

Scheme 21.

formation of the corresponding 2-oxaspirobicycles. More recently, the stereoselective cyclization of different 2-(5,5-dimethoxypentyl)1-substituted cyclopentanols, promoted by iron trichloride, to give the corresponding spiro[4.5]decanes 124-129 has been reported; the


Pastor and Yus

R1

R1

O

O Me

Me

H2O HO

OMe

R1

R1 OMe

FeCl3 (100 mol%) OMe CH2Cl2, 0 ˚C

124: R1 = PhCC (65%) 125: R1 = 4-MeC6H4CC (54%) 126: R1 = 2-MeC6H4CC (47%) 127: R1 = 2-(CF3)C6H4CC (58%) 128: R1 = n-C6H13 (58%) 129: R1 = Ph (64%) Scheme 22.

R2 R1 OMe OMe

OSiPri3

OSiPri3

MeO TiBr4 (200 mol%)

+ R2

R3

CH2Cl2, -78 ˚C

R1

Br

H R3

130: R1 = R2 = Me, R3 = Et (90%) 131: R1 = R2 = R3 = Et (91%) 132: R1-R2 = (CH2)3, R3 = Et (86%) 133: R1 = R2 = Me, R3 = CH2OBn (81%) Scheme 23.

R1

O

R2 Prins

R1 Prins

R1

Nu

Nu-

oxonia-Cope rearrangement

O

R2

O

R1

O

R2

134

R2

Scheme 24.

reaction proceeding via the possible mechanism depicted in Scheme 22 [34]. The synthesis of cyclopentyl derivatives 130-133 has been achieved in good yield and diastereoselectivity via a tandem Mukaiyama-Aldol–Prins (MAP) reaction (Scheme 23) [35]. This sequence of reactions provides an interesting synthetic strategy to create a highly functionalized five-membered ring system with the generation of up to five new stereogenic centers. The asymmetric version of the process has been evaluated starting from an optically pure cyclic acetal. By means of the same protocol but starting from but-3-enal acetal (R3 = H), the cyclization underwent via a 6-endo process (vide infra). 4.2. Formation of Six-Membered Rings The Prins cyclization is an interesting and powerful synthetic strategy for the construction of six-membered heterocyclic derivatives. The Prins cyclization (or carbonyl ene) of allyl (3-

oxopropyl)tosylamines produced piperidine derivatives [36]. More studies have been dedicated to the acid-promoted Prins-type cyclization of an oxocarbenium ion generated in situ, for the synthesis of tetrahydropyrans, this methodology having been employed in a stereoselective manner for the synthesis of a number of natural products. However, the mechanism of Prins cyclizations is not simple [1], due to the participation of the oxonia-Cope rearrangement and the allyl transfer processes under certain reaction conditions. The proposed mechanism for the Prins cyclization and oxonia-Cope rearrangements involves the cation 134, on the basis of DFT calculations (Scheme 24) [37]. More recently, a study to evidence the participation of this cationic intermediate has been carried out [38]. As a consequence of these intermediates, there is an inherent problem of racemization [1,39]. The Prins reaction catalyzed by heteropolyacids has been already studied [1,40]. Indeed, phosphomolybdic acid (PMA, H3PMo12O40) has been succesfully employed as catalyst in the Prins



OH OH

H3PMo12O40 (40 mol%)

R3

R1COR2, H2O, 23 ˚C

R1 R2

R3

O

135: R1 = Ph, R2 = R3 = H (92%) 136: R1 = 4-ClC6H4, R2 = R3 = H (90%) 137: R1 = 4-MeC6H4, R2 = R3 = H (89%) 138: R1 = 4-MeOC6H4, R2 = R3 = H (82%) 139: R1 = 4-(NO2)C6H4, R2 = R3 = H (80%) 140: R1 = Et, R2 = R3 = H (92%) 141: R1 = c-C6H11, R2 = R3 = H (90%) 142: R1-R2 = (CH2)5, R3 = H (88%) 143: R1 = n-C5H11, R2 = H, R3 = n-C5H11 (90%) 144: R1 = 2,4-Cl2C6H3, R2 = H, R3 = c-C6H11 (86%) Scheme 25. R1 HO

R1 O3ReSiPh3 (5 mol%)

O Ph

R1CHO,

OH

TfOH (10 mol%), R1CHO

Ph

CH2Cl2, 23 ˚C

150: R1= Ph (82%) 151: R1 = 4-MeOC6H4 (88%, 97% ee) 152: R1 = 2-MeOC6H4 (84%) 153: R1 = 4-(CF3)C6H4 (73%) 154: R1 = (E)-CH=CHCH2CH2CH3 (83%) 155: R1 = (E)-CH=CHPh (70%)

AcO

O Ph

AcOH (1000 mol%), 40 ˚C

146: R1 = Ph (77%, >99% ee) 147: R1 = CH2CH2Ph (79%, >99% ee) 148: R1 = n-C5H11 (63%, >99% ee) 149: R1 = (E)-CH=CHPh (74%, >99% ee)

145

Scheme 26.

OH R2

N3

a) TFA (1000 mol%), R1CHO, NaN3 (200 mol%), CH2Cl2, 23 ˚C b) NaHCO3 (saturated solution)

R1 R1

R2

O R2

156: = Ph, = H (89%) 157: R1 = 4-MeC6H4, R2 = H (90%) 158: R1 = 4-BrC6H4, R2 = H (91%) 159: R1 = 4-(NO2)C6H4, R2 = H (80%) 160: R1 = CH2CH2Ph, R2 = H (83%) 161: R1 = n-C9H19, R2 = H (90%) 162: R1 = c-C6H11, R2 = H (91%) 163: R1 = Ph, R2 = Ph (85%) 164: R1 = 4-ClC6H4, R2 = 4-ClC6H4 (84%) 165: R1 = c-C6H11, R2 = c-C6H11 (91%) 166: R1 = n-C5H11, R2 = n-C5H11 (92%) Scheme 27.

cyclization of different carbonyl compounds with homoallylic alcohols in water, giving the corresponding tetrahydropyran-4-ol derivatives 135-144 as a single diastereomer (Scheme 25) [41]. Another solid acid material, cellulose-SO3H, has been effectively employed in the preparation of 4-hydroxytetrahydropyran derivatives. The catalytic system can be easily recycled without losing activity, making this method very simple, and economically viable for large scale synthesis [42]. The use of a catalytic amount of triflic acid in acetic acid has been shown to be an effective catalyst for the Prins cyclization of the homoallylic alcohol (E,R)-145 with different aldehydes producing the expected 4-acetoxy tetrahydropyrans 146-149 (Scheme 26), the products being isolated with more than 99% of enantiopurity [43]. Additionally, other Lewis acids have been also effective as

catalysts for this process, albeit the final products were isolated with slight lower yields. Starting from the diastereomer (Z,S)-145 the corresponding diastereoisomeric tetrahydropyrans have been obtained with the same level of enantiopurity. The same chiral starting homoallylic alcohol (E,R)-145 has been also coupled with different aldehydes in the presence of rhenium(VII) compounds (O3ReSiPh3, Re2O7 and perrhenic acid), the corresponding 4hydroxytetra-hydropyran derivatives 150-155 being in this case isolated with good yields and enantioselectivities (Scheme 26) [44]. The combination of trifluoroacetic acid and sodium azide has allowed the preparation of 4-azidotetrahydropyrans via a Prins cyclization followed by azidation. This methodology provided a direct access to the 2,4-di- and 2,4,6-trisubstituted tetrahydropyran derivatives 156-166, as depicted in the Scheme 27. Neither the use of


OH

Pastor and Yus

R2 MsOH (150 mol%),

R3CHO O

CH2Cl2, 23 ˚C R1

R2

R1

R1

O

R2 R3

167: R1 = Ph, R2 = H 168: R1 = 4-ClC6H4, R2 = H 169: R1 = 4-FC6H4, R2 = H 170: R1 = 4-MeC6H4, R2 = H 171: R1 = 4-MeOC6H4, R2 = H 172: R1 = H, R2 = Ph

R3 MsO173 R2

R1 OMs

R1 R3

+

OMs

R2 R3

O

O

[R3CHO = PhCHO, 4-MeC6H4CHO, 4-ClC6H4CHO, MeCHO, PhCH2CH2CHO] Scheme 28.

Ph

O OH

Sc(OTf)3 (5 mol%)

Ph

O

H

CHO CH2Cl2, -78 to 23 ˚C

H

H

Ph

H

Ph

H O H H

OH H

Ph

H

O

HO-

O + H

H

H

OH

(9:1) Scheme 29.

acetic acid nor Lewis acids [metal halides, such as InCl3, InBr3, BiCl3, ZrCl4, and metal triflates, such as Sc(OTf)3, In(OTf)3, Bi(OTf)3] in combination with NaN3 produced the expected final products [45]. Trifluoroacetic acid has been also an effective catalyst in the three-component coupling of an arylic aldehyde, but-3en-1-ol and an arylic thiol, the corresponding 2-aryl-4-arylthiotetrahydropyrans being isolated with satisfactory yields (76-90%). The formation of 4-azido tetrahydropyran derivatives has been also achieved by means of a phosphomolybdic acid catalyzed reaction, the products being isolated with yields ranging from 80 to 91% [46]. In the presence of other organic acids, such as MsOH (or TsOH), 2-(arylmethylene)cyclopropylcarbinols 167-172 reacted with an aldehyde forming the corresponding oxonium ion, which underwent intramolecular Prins cyclization giving the cationic intermediate 173 (Scheme 28) [47]. The intermediate 173 was afterward trapped by the mesilate (or tosylate) ion yielding a mixture of two isomers with different geometry in the double bond independently of the starting material. The bicyclic intermediate 173 could be trapped by other nucleophile when the reaction of the 2(arylmethylene)cyclopropylcarbinols was performed in the presence of the scandium catalyst Sc(OSO2C8F17)3 with different aldehyde acetals [48]. The reaction of methylenecyclopropane derivatives with aldehydes in the presence of a Lewis acid has been also reported, involving processes related to the Prins reaction [49]. In the presence of a Lewis acid, (R)-citronellal is known to undergo intermolecular carbonyl-ene reaction to produce a mixture of

diastereomeric products. The diastereoselectivity generally depends on the reaction conditions including the nature of the Lewis acid employed, isopulegol being the favored diastereomer. The use of a catalytic amount of Sc(OTf)3 has been useful to promote the ene reaction of citronellal to isopulegol, and the subsequent Prins reaction of the resulting homoallylic alcohol with a variety of aldehydes, with good yields (85-90%) [50]. The plausible mechanism is depicted in Scheme 29. Having in mind that heterogeneous acid catalysts are interesting from an environmental point of view in the preparation of bulk and fine chemicals [51], a mesoporous silicate material incorporating zirconium has been tested in the Prins cyclization of citronellal to give isopulegol with excellent conversion and selectivity (>99%) [52]. Moreover, a synergic effect between Brønsted acid sites and Lewis acid sites, of a mesoporous material having zirconium and aluminium incorporated, has been studied [53]. Molecular iodine has been employed as catalyst in different transformations, due to its Lewis acidic nature. Regarding Prins cyclizations, the formation of 4-iodotetrahydropyran derivatives 174-182 by coupling of different homoallylic alcohols and aldehydes has been achieved under very mild conditions in the presence of iodine (Scheme 30) [54]. The methodology worked smoothly in the preparation of sugar-based furo[3,2-b]pyrans, such as compounds 184-190, from the D-glucose secondary alcohol derivative 183 (Scheme 31) [55]. Molecular iodine catalyzed the coupling reaction between different alkynols and aldehydes to the corresponding 4-iododihydropyrans 191-196 (Scheme 32) [56]. Fur-



I OH R3

R2

R3

a) I2 (100 mol%), R1CHO, CH2Cl2, 23 ˚C b) H2O

R1

R2

O

174: R1 = Ph, R2 = R3 = H (89%) 175: R1 = 4-BrC6H4, R2 = R3 = H (87%) 176: R1 = n-C5H11, R2 = R3 = H (90%) 177: R1 = i-Bu, R2 = Me, R3 = n-Bu (88%) 178: R1 = n-C9H19, R2 = Me, R3 = n-Bu (91%) 179: R1 = c-C6H11, R2 = Me, R3 = n-Bu (92%) 180: R1 = 4-MeOC6H4, R2 = Me, R3 = n-C6H13 (85%) 181: R1 = i-Pr, R2 = Me, R3 = n-C6H13 (85%) 182: R1 = n-C5H11, R2 = Me, R3 = n-C6H13 (90%) Scheme 30.

I O

O O O

HO

a) I2 (100 mol%), R1CHO, CH2Cl2, 23 ˚C

O R1

b) H2O

O O

183

184: R1 = Ph (74%) 185: R1 = 4-ClC6H4 (76%) 186: R1 = 2-HOC6H4 (76%) 187: R1 = 4-MeOC6H4 (74%) 188: R1 = PhCH2CH2 (76%) 189: R1 = n-Pr (76%) 190: R1 = i-Pr (75%)

Scheme 31.

I SiMe3 HO

b) H2O

R2

SiMe3

a) I2 (100 mol%), R1CHO, CH2Cl2, 23 ˚C R2

O

R1

191: R1 = n-C5H11, R2 = Me (80%) 192: R1 = i-Bu, R2 = Me (85%) 193: R1 = c-C6H11, R2 = Me (90%) 194: R1 = Bn, R2 = Me (72%) 195: R1 = c-C6H11, R2 = CH2OBn (90%) 196: R1 = Bn, R2 = CH2OBn (72%) Scheme 32.

OH

O a) I2 (5 mol%), R1COR2, CH2Cl2, 23 ˚C

R2 R1

b) H2O 197: R1 = R2 = H (54%) 198: R1 = Me, R2 = H (78%) 199: R1 = Ph, R2 = H (77%) 200: R1 = 4-(NO2)C6H4, R2 = H (68%) 201: R1-R2 = (CH2)4 (77%) 202: R1-R2 = (CH2)5 (74%) Scheme 33.

thermore, the iodine-catalyzed Prins cyclization has been employed in the preparation of hexahydrobenzo[f]isochromenes 197-202 (Scheme 33) [57].

Other iodine salts, such as LiI, KI and NaI, failed to produce the expected 4-iodotetrahydropyrans, albeit the cerium chloride-lithium iodide combination has been also revealed as an interesting catalyst


Pastor and Yus

I OH R3

CeCl3·7H2O (100 mol%)/LiI (150 mol%) R1COR2, (CH2Cl)2, 80 ˚C

R4

R1 R2

R3 R4

O

203: R1 = c-C6H11, R2 = R3 = R4 = H (91%) 204: R1 = Ph, R2 = R3 = R4 = H (90%) 205: R1 = 4-BrC6H4, R2 = R3 = R4 = H (88%) 206: R1 = i-Bu, R2 = R3 = R4 = H (92%) 207: R1 = i-Pr, R2 = R3 = R4 = H (89%) 208: R1 = n-C6H13, R2 = R3 = R4 = H (90%) 209: R1 = R2 = Me, R3 = R4 = H (85%) 210: R1-R2 = (CH2)5, R3 = R4 = H (90%) 211: R1 = 4-ClC6H4, R2 = H, R3 = n-C5H11, R4 = H (91%) 212: R1 = i-Bu, R2 = H, R3 = n-C5H11, R4 = H (90%) 213: R1 = n-C5H11, R2 = H, R3 = n-C5H11, R4 = H (92%) 214: R1 = Ph, R2 = H, R3-R4 = (CH2)5 (85%) Scheme 34.

O

OH R3

HN

R4

O

R3

a) CeCl3·7H2O (10 mol%), AcCl (150 mol%), R1COR2, R4CN, 23 ˚C b) H2O

R1 R2

215: R1 = 4-BrC6H4, R2 = R3 = H, R4 = Me (90%) 216: R1 = 4-BrC6H4, R2 = R3 = H, R4 = Ph (89%) 217: R1 = 4-BrC6H4, R2 = R3 = H, R4 = Bn (86%) 218: R1 = 4-BrC6H4, R2 = R3 = H, R4 = n-Pr (82%) 219: R1 = 4-(NO2)C6H4, R2 = R3 = H, R4 = Me (80%) 220: R1 = 4-MeC6H4, R2 = R3 = H, R4 = Me (91%) 221: R1 = 3,4,5-(MeO)3C6H2, R2 = R3 = H, R4 = Me (85%) 222: R1-R2 = (CH2)5, R3 = H, R4 = Me (88%) 223: R1 = 4-BrC6H4, R2 = H, R3 = Ph, R4 = Me (90%) 224: R1 = Ph, R2 = H, R3 = Ph, R4 = Me (92%) 225: R1 = 4-BrC6H4, R2 = H, R3 = c-C6H11, R4 = Me (91%) 226: R1 = 4-MeC6H4, R2 = H, R3 = c-C6H11, R4 = Me (94%) Scheme 35.

for Prins cyclizations. Thus, efficient Prins cyclization has been achieved in the reaction of different allylic alcohols (3-buten-1-ol, 1-nonen-4-ol and 1-allyl-1-cyclohexanol) with several aldehydes and ketones, in the presence of the CeCl3·7H2O/LiI combination under neutral conditions, producing the highly functionalized tetrahydropyran derivatives 203-214 (Scheme 34) [58]. Under these reaction conditions, only the 4-iodo derivatives have been detected, but in the absence of LiI, the corresponding 4-chloro-tetrahydropyrans have been obtained. Moreover, the combination of trimethylsilyl chloride and NaI has been reported to be an active catalyst for the Prins cyclization of homoallylic and homopropargylic alcohol with ketones producing the corresponding 4-iodo heterocyclic systems with good isolated yields (52-98%) [59]. Additionally, cerium chloride has been also reported to be effective in a tandem Prins–Ritter [60] type cyclization, performing the reaction between a homoallylic alcohol and a carbonyl compound in the presence of a nitrile and acetyl chloride. This simple and practical procedure produced highly substituted 4-amido tetrahydropyrans, such as 215226, with high yields and complete cis-selectivity (Scheme 35) [61]. The use of phosphomolybdic acid as catalyst has been also reported to be effective for this Prins–Ritter sequence of reaction,

the final 4-amidotetrahydropyrans being obtained in good isolated yields (80-92%) [62]. The reaction of aldehydes with allyltrimethylsilane, in the presence of a Lewis acid, produced first the formation of a homoallylic alcohol which subsequently can be reacted with another equivalent of aldehyde via a Prins cyclization. To finish the reaction, the carbenium intermediate can react with any nucleophile present in the reaction media, thus an arylation reaction took place when performing the reaction in an aromatic solvent. Different homo-2,6disubstituted 4-aryltetrahydropyrans have been prepared in good yields (50-99%), by means of this Hosomi-Sakurai–Prins–FriedelCrafts protocol, using boron trifluoride as catalyst [63]. In addition, the reaction of a carbonyl compound and a homoallylic alcohol, in the presence of BF3·OEt2, in an aromatic solvent underwent Prins cyclization, followed by a Friedel-Crafts reaction of the carbenium formed and an aromatic ring. Heterocyclic compounds 227-238 have been prepared via this multicomponent Prins–Friedel-Crafts reaction sequence (Scheme 36) [64]. As expected, other aromatic compounds with electron-donating groups, such as toluene and anisole, reacted faster than benzene, and the final Friedel-Crafts process gave a mixture of regioisomers.



Ph OH

BF3·OEt2 (120 mol%), R1COR2

R3

benzene, 0 or 40 ˚C

R1 R2

R3

O

227: R1 = Ph, R2 = R3 = H (75%) 228: R1 = 4-ClC6H4, R2 = R3 = H (88%) 229: R1 = 4-MeC6H4, R2 = R3 = H (70%) 230: R1 = 4-MeOC6H4, R2 = R3 = H (65%) 231: R1 = 4-(CF3)C6H4, R2 = R3 = H (93%) 232: R1 = 4-(NO2)C6H4, R2 = R3 = H (90%) 233: R1 = 3-(NO2)C6H4, R2 = R3 = H (90%) 234: R1 = c-C6H11, R2 = R3 = H (80%) 235: R1 = n-C6H13, R2 = R3 = H (85%) 236: R1 = Ph, R2 = H, R3 = 4-(NO2)C6H4 (75%) 237: R1 = n-C6H13, R2 = H, R3 = 4-(NO2)C6H4 (90%) 238: R1-R2 = (CH2)5, R3 = H (56%) Scheme 36.

R1

OAc O

O R2

239: R1 = c-C6H11; R2 = t-Bu 240: R1 = c-C6H11; R2 = n-Pr 241: R1 = CH2CH2Ph; R2 = t-Bu 242: R1 = CH2CH2Ph; R2 = n-Pr

Interestingly, another multicomponent reaction, which involves a Hosomi-Sakurai–Prins–Ritter sequence, has been reported for the preparation of 4-amidotetrahydropyrans. In this case the reaction has been performed in acetonitrile, which is needed for the final Ritter reaction, and in the presence of bismuth triflate [65], or boron trifluoride as catalysts [66]. Employing two electrophiles being different in terms of reactivity is possible the preparation of nonsymmetrically 2,6-disubstituted 4-amido-tetrahydropyrans. Having this in mind, the two acetal moieties in 4-acetoxy-1,3-dioxanes 239242 are sufficiently differentiated in terms of their ionization rates. Therefore, dioxanes 239-242 have been reacted with an allyl silane via a Sakurai reaction producing an intermediate that underwent

Prins cyclization, and the final cabenium ion formed has been trapped with a nitrile as nucleophile [67]. Similarly, after the coupling of a homoallylic alcohol and an aldehyde in the presence of boron trifluoride, the corresponding carbenium ion formed has been also reacted with an in situ formed copper acetylide giving the tetrahydropyran derivative 243 in 76% yield (Scheme 37) [68]. In addition, other aromatic and aliphatic aldehydes have been employed under these reaction conditions yielding the corresponding 4-phenacyl tetrahydropyrans in good yields (71-83%). Regarding other Lewis acid catalysts, titanium chloride has been employed in the cyclization of compounds 244 and 245 to the corresponding spiroethers 246 and 247, respectively, with high diastereoselectivities (Scheme 38) [69]. Additionally, this catalyst has been also effective in the cyclization of different ,-enones giving the corresponding chlorocyclohexanols 248-250 as a mixture of diastereomers, the cis-isomer being normally the major adduct (Scheme 39) [70]. The trans-isomer, referred to the hydroxy and chloride moieties, has been obtained as the major one (ratio ca. 1:4 cis/trans) when employing (Z)-4,4-dimethylhex-6-en-2-one as starting material. Moreover, the reaction has been applied to allyl pulegone derivatives ending up in the formation of a bicyclic system, an interesting influence of the Lewis acid on the diastereoselectivity of Ph

O +

+

O

BF3·OEt2/CuCl (10 mol%) Ph

O

CH2Cl2, 23 ˚C

H

Ph

HO

Ph

243 (76%) Scheme 37.

R2 R1

Pri

O

Ph

OH O

244: R1 = i-Pr, R2 = H 245: R1-R2 = (CH2)4 Scheme 38.

R2

NMe S

TiCl4 (100 mol%) CH2Cl2, -78 ˚C

R1

O

NMe S

Ph Cl

Pri

O

246: R1 = i-Pr, R2 = H (70%, >98% de) 247: R1-R2 = (CH2)4 (68%, >98% de)


Pastor and Yus

O

OH

OH

TiCl4 (100 mol%) R1 R1

CH2Cl2, -78 ˚C

R2

R1

Cl

R1

+

R1

R2

R2

R1

Cl

248: R1 = R2 = H (52%, cis/trans ca. 9:1) 249: R1 = Me, R2 = H (57%, cis/trans ca. 6:1) 250: R1 = R2 = Me (52%, cis/trans ca. 12:1) Scheme 39.

X O

Catalyst (100 mol%)

X

OH

OH +

CH2Cl2, T

H

H

TiCl4, 78 ˚C: X = Cl (70%, cis/trans ca. 10:1) TiBr4, 78 ˚C: X = Br (76%, cis/trans ca. 15:1) TiI4, 0 ˚C: X = I (43%, cis/trans ca. 1:50) BCl3, 0 ˚C: X = Cl (75%, cis/trans ca. 25:1) BBr3, 0 ˚C: X = Br (62%, cis/trans ca. 10:1) InCl3, 25 ˚C: X = Cl (56%, cis/trans ca. 1:50) ZrCl4, 0 ˚C: X = Cl (63%, cis/trans ca. 1:50)

251

[cis/trans ratio referred to the X and OH moieties] Scheme 40.

PhO CHO

OH

O a) Hf(OTf)4 (5 mol%), CH3CN, 23 ˚C OH

+

H

b) NaHCO3 (saturated solution) 252

OH

OPh

253 (94%)

Scheme 41.

the cyclization of 251 being observed (Scheme 40). In addition, the preparation of the bicyclic system 253 has been achieved employing hafnium triflate as catalyst for the coupling of the diol 252 with 4-phenoxybenzaldehyde (Scheme 41). Under the optimal reaction conditions various substituted benzaldehydes and heteroaromatic carbaldehydes gave the corresponding bicyclic systems, except for the case of pyridine aldehyde derivatives, for which it has been necessary the protection of one of the hydroxyl groups in 252 in order to get turnover in the catalytic reaction. Ionic liquids having hydrogen fluoride in their structure present both the acidic protons for catalyzing the Prins reaction and the fluoride ions for acting as nucleophiles. Consequently, a variety of aldehydes have been coupled with homoallylic alcohols in the presence of the ionic liquid Et4NF·5HF, that has been chosen after testing different HF salts, such as Et3N·3HF, Et3N·4HF, Et3N·5HF and Et4NF·5HF. The corresponding 2,4,6-trisubstituted tetrahydropyrans 254-260 have been produced with almost quantitative yields in all cases (Scheme 42) [71]. The products could be isolated by simple extraction and the residual ionic liquid has been then reused more than five times keeping the yields above 90% in all cycles. Furthermore, this methodology has been employed with substrates 261 and 262 (having an acetal and a homoallylic alcohol moiety), so the formation of 4-fluorinated tetrahydropyran-containing polymers was observed [72]. Also, titanium tetrafluoride has been employed as catalyst and as fluorinating agent for the synthesis of 4-

fluorotetrahydropyran derivatives via a Prins cyclization. Homoallylic alcohols have been coupled with different aromatic and aliphatic aldehydes affording the corresponding 2,4-disubstituted of 2,4,6-trisubstituted tetrahydropyrans with good yields (e.g. compounds 254 and 255 were isolated in 82 and 84% yield respectively) [73]. Similarly, tetrafluoroboric acid etherate (HBF4·OEt2) [74] and trifluoroborane etherate (BF3·OEt2) [75] have been reported as efficient catalysts in the Prins cyclization with the incorporation of a fluorine atom when they have been used in stoichiometric amount. F OH R2

Et4NF·5HF R1CHO, 23 ˚C

R2

O

R1

254: R1 = Ph, R2 = H (>99%) 255: R1 = 4-MeC6H4, R2 = H (96%) 256: R1 = 4-(NO2)C6H4, R2 = H (>99%) 257: R1 = n-C7H15, R2 = H (>99%) 258: R1 = c-C6H11, R2 = H (93%) 259: R1 = R2 = n-C7H15 (>99%) 260: R1 = R2 = Ph (98%) Scheme 42.


R1


R1

EtO

Cl OH

InCl3 (100 mol%)

OH EtO

R1CHO,

F R1

CH2Cl2, reflux

R1

O

Scheme 44.

Indium metal is able to mediate the allylation of carbonyl compounds with allyl iodides, producing the corresponding homoallylic alcohols. After that, the indium iodide generated during this process can act as a Lewis acid in order to catalyze a Prins cyclization between the new formed homoallylic alcohol and a new carbonylic compound. Thus, an efficient one-pot synthesis of cis-2,6disubstituted tetrahydropyrans has been performed using indium metal and starting from allyl iodides 274 and 275. The first allylation reaction has been carried out in a mixture of water/THF at room temperature, and after concentration in vacuo (to remove THF) the second aldehyde has been added producing the Prins cyclization in a mixture of water/isopropanol. Finally, the corresponding tetrahydropyran derivatives 276-284 have been isolated (Scheme 45) [82]. The chiral methyl ricinoleate 285 reacted with different aldehydes in the presence of alumnium chloride yielding the expected tetrahydropyran derivatives 286-288 with a chlorine substituent at the C4 (Scheme 46) [83]. The reaction with these aldehydes proceeded with high level of diastereoselectivity, and the correspondBr

Ph

a) InBr3 (100 mol%), Me3SiBr (120 mol%), R1CHO, CH2Cl2, 0 ˚C

OH Br

Br Ph


O

R1

263: R1 = Ph (77%) 264: R1 = CH2CH2Ph (90%) 265: R1 = n-C8H17 (82%) 266: R1 = CHEt2 (90%) 267: R1 = c-C6H11 (92%) Scheme 43.

R4 R3

a) In(s) (100 mol%), R1CHO, H2O/THF (1:1), 23 ˚C b) concentration in vacuo

X I

c) R2CHO, H2O/i-PrOH (1:1), 23 ˚C

R1

O

R2

R3 R4

274: X = SiMe3, R3 = R4 = H 275: X = H, R3-R4 = (CH2)3

Scheme 45.

R1

268: R1 = Bn (74%) 269: R1 = n-C5H11 (69%) 270: R1 = c-C6H11 (80%) 271: R1 = Et2CH (68%) 272: R1 = Ph2CH (57%) 273: R1 = Ph (39%)

261: R1 = H 262: R1 = F

Indium salts [76] have been already considered as efficient catalysts for the Prins cyclization. Thus, indium trichloride mediated the Prins cyclization of homoallylic alcohols and aldehydes has been reported, giving the expected heterocycles with good yields and high selectivities [77]. The combination of In(OTf)3 and Me3SiCl has been also effective as catalyst in the formation of 4chloro tetrahydropyrans [78]. Moreover, indium tribromide has been recently employed in the stereoselective Prins cyclization of (Z)- and (E)-6-bromo-1-phenyl-5-hexen-3-ol with several aldehydes. The (E)-isomer has been selectively cyclized to the 2,3,4,6tetrasubstituted tetrahydropyrans 263-267 under very mild conditions employing TMSBr as the bromine source (Scheme 43) [79]. The corresponding all cis-tetrasubstituted tetrahydropyrans have been obtained with the same yields when the (Z)-isomer was used. Taking into account this concept, allyl bromide reacted with carbonyl compounds, in the presence of SnBr2 and a quarternary imidazolium salt, in a one-pot tandem Barbier reaction–Prins cyclization, producing the corresponding 2,6-disubstituted-4-bromo tetrahydropyrans in good yields (54-85%) [80]. Indium trichloride has been also reported to promote efficiently the Prins cyclization of 2fluorobut-3-en-1-ol with various aldehydes, this methodology allowing the preparation of fluorinated tetrahydropyrans 268-273 in good yields as a single diastereoisomer, except for aromatic aldehydes (Scheme 44) [81].

F

276: R1 = R2 = Ph, R3 = R4 = H (76%) 277: R1 = R2 = n-C5H11, R3 = R4 = H (83%) 278: R1 = n-C5H11, R2 = Ph, R3 = R4 = H (75%) 279: R1 = n-C5H11, R2 = 4-ClC6H4, R3 = R4 = H (68%) 280: R1 = i-Pr, R2 = Ph, R3 = R4 = H (79%) 281: R1 = i-Pr, R2 = 4-ClC6H4, R3 = R4 = H (65%) 282: R1 = i-Pr, R2 = n-C5H11, R3 = R4 = H (68%) 283: R1 = n-C5H11, R2 = Ph, R3-R4 = (CH2)3 (51%) 284: R1 = i-Pr, R2 = 4-MeOC6H4, R3-R4 = (CH2)3 (55%)


Pastor and Yus

OH montmorillonite KSF/O

AlCl3 (50 mol%)

R1

n-C6H13CHO, CH2Cl2, reflux

R3CHO, CH2Cl2, 23 ˚C

R2

285 [R1 = n-C6H13, R2 = (CH2)7CO2Me] OH

Cl (CH2)7CO2Me

H3C(H2C)5

O

(CH2)7CO2Me

(CH2)5CH3

H3C(H2C)5

O

R3

286: R3 = n-C6H13 (76%) 287: R3 = i-Pr (70%) 288: R3 = Ph (73%)

289 (61%) Scheme 46. Br DDQ (105 mol%), SnBr4 (100 mol%) R2

O

R1

4 Å MS, CH2Cl2, 23 ˚C

R2

O

R1

290: R1 = Me, R2 = Ph (70%) 291: R1 = c-C6H11, R2 = 4-MeC6H4 (85%) 292: R1 = c-C6H11, R2 = 3-MeC6H4 (80%) 293: R1 = Me, R2 = 4-MeOC6H4 (89%) 294: R1 = (CH2)2Ph, R2 = 4-MeOC6H4 (75%) 295: R1 = (CH2)3OSiMe2But, R2 = 4-MeOC6H4 (68%) 296: R1 = (CH2)3OAc, R2 = CH=CMe2 (91%) 297: R1 = (CH2)3OAc, R2 = CH=CH2 (70%) 298: R1 = (CH2)3OAc, R2 = CMe=CH2 (80%)

Scheme 47.

MeOTiBr4

MeOTiBr4 OMe Ph

OMe 299

OMe

TiBr4 (400 mol%), CH2Cl2 DBMP (150 mol%), -78 ˚C

O

Ph

OMe

301 O

Ph

Ph 300

Ph

302 Br OMe Ph

O

Ph

303 [67%, dr (Br) 92:8, dr (OMe) 55:45]

Scheme 48.

ing all-cis isomer was obtained with a ratio higher than 85:15. The ratio was lower, and the major diastereomer was different, when employing pivaldehyde. Similarly, the corresponding tetrahydropyran 289 has been obtained when performing the reaction betweeen 285 and heptanal catalyzed by montmorillonite KSF/O, although the selectivity was significantly lower with this catalyst. Benzyl homoallyl ethers were treated with dichloro-dicyanoquinone (DDQ) producing the oxidation to the corresponding oxonium intermediate, which in the presence of SnBr4 underwent Prins cyclization to give the corresponding 2,4,6-trisubstituted tetrahydropyrans 290-295 (Scheme 47) [84]. Allyl homoallyl ethers behaved the same under these reaction conditions generating the corresponding compounds 296-298. Furthermore, the reaction pro-

ceeded with high sterochemical fidelity, so the tetrahydropyran was obtained with the same level of enantiopurity than the optically active starting material employed. The Mukaiyama aldol–Prins (MAP) reaction is an alternative tandem process, in which an oxocarbenium ion (generated from the Mukaiyama aldol addition of a homoallylic vinyl ether to an aldehyde) has been shown to undergo an intramolecular Prins cyclization, the reaction being also performed employing acetals instead of aldehydes. Thus, initial coordination of Lewis acid (i.e. TiBr4) to the acetal 299 provided the oxocarbenium ion 300, which underwent Mukaiyama aldol addition with the vinyl ether 301 producing the intermediate 302, and finally this system collapsed to the Prins cyclization product 303 (Scheme 48) [85]. Various acetals and or-



Br OSiPri3 O

O

TiBr4 (200 mol%)

+ R2

Br

Pri3SiO

CH2Cl2, -78 ˚C

R1

R2

R1

+

O

304

Pri3SiO

R2

R1

O

OH

OH

305: R1 = R2 = Me (80%, trans/cis 65/35) 306: R1-R2 = (CH2)5 (90%, trans/cis 62/38) 307: R1 = R2 = Et (89%, trans/cis 57/43) [trans/cis ratio referred to the Br and OSiPri3 moieties] Scheme 49.

OMe MeO SnCl4 (50 mol%) OTIPS

MeO

MeO H

CHO

H

+

n

R1 n

R1

CHO

CH2Cl2 (or MeNO2), 0 ˚C R1

n

R1

R1

R1

308: n = 2, R1 = H (82%, 1.5:1 cis/trans) 309: n = 3, R1 = H (68%, 2.4:1 cis/trans) 310: n = 1, R1 = Me (84%, 1.4:1 cis/trans) Scheme 50.

S

O

S MeO

CHO

O

O

SnCl4 (50 mol%) CH2Cl2, 0 ˚C

O

O

S S

H

O

OTBS 311

312 (72%)

Scheme 51.

thoesters have been employed as coupling partners of the vinyl ether, the expected products from a MAP cyclization (or a double MAP cyclization in the case of the orthoesters) being isolated with yields ranging from 52 to 71%. The reaction of the optically pure cyclic acetal 304 with different silyl enol ether derivatives in the presence of titanium bromide proceeded via a Mukaiyama aldol– Prins cascade reaction generating the highly functionalized cyclohexane derivatives 305-307 (Scheme 49) [86]. Both diastereomers formed during the reaction were obtained with a high level of enantioselectivity (>99:1). As previously commented in the preparation of five-membered rings, different alkylidenecycloalkenes underwent Prins cyclization–pinacol transformation producing the cyclohexane derivatives 308-310 as a mixture of isomers (Scheme 50) [30]. The process has been more efficient when gem-dimethyl groups were present in the cyclohexyl ether precursor. The construction of a tricyclic system, such as 312, has been described by a stereospecific Prins–pinacol tandem reaction starting from an unsaturated -dithianyl acetal, such as 311 (Scheme 51) [87]. Bycyclic systems were prepared by an intramolecular nucleophile-terminated Prins cyclization. The reaction of hydroxy-

alkenoate 313 with various aldehydes in the presence of trimehtylsilyl triflate produced the bicyclic systems 314-319 with the formation of three stereogenic centers (Scheme 52) [88]. Thus, the carbenium ion intermediate, after the Prins cyclization, was trapped by intramolecular reaction with the ester moiety. Additionally, the use of a cyclic ketone allowed the synthesis of the spirocyclic compounds, such as 320 (Scheme 52). Similarly, (Z)-hex-3-ene-1,6-diol gave a Prins cyclization with a series of aldehydes followed by an intramolecular reaction of the other hydroxy group with the carbenium ion, producing the corresponding furo[3,2-c]pyran derivatives 321-326, with complete cis-selectivity (Scheme 53) [89]. As expected, the use of the corresponding (E)-diol produced the transfused bicycles. Furthermore, starting from the (E)- and (Z)-N-tosyl6-hydroxyhex-3-en-1-amide the corresponding pyrano[4,3b]pyrrole derivatives have been prepared via a Prins cyclization terminated by the amide moiety [90]. Dihydropyran derivatives can also be prepared via a Prins cyclization. Regarding to this topic, the anologous alkyne Prins cyclization has been reported starting from the corresponding homopropargylic alcohols and different aldehydes in the presence of a Lewis acid catalyst. Thus, iron(III) halides [91] have been succes-


Pastor and Yus

R2 CO2Me HO

Me3SiOTf (100 mol%)

R1 H O

O

O

R1COR2, CH2Cl2, -10 to 23 ˚C 313

H 314: R1 = Ph, R2 = H (81%) 315: R1 = 4-(NO2)C6H4, R2 = H (71%) 316: R1 = 4-MeOC6H4, R2 = H (93%) 317: R1 = CH2CH2Ph, R2 = H (73%) 318: R1 = Et, R2 = H (72%) 319: R1 = CH=CH2, R2 = H (84%) 320: R1- R2 = (CH2)4 (63%)

Scheme 52.

H TsOH (10 mol%)

HO HO

O

O

R1COR2, (CH2Cl)2, reflux

R2 H

R1

321: R1 = Ph, R2 = H (54%) 322: R1 = 4-BrC6H4, R2 = H (72%) 323: R1 = 2-thienyl, R2 = H (71%) 324: R1 = c-C6H11, R2 = H (62%) 325: R1 = Et, R2 = H (45%) 326: R1- R2 = (CH2)5 (57%) Scheme 53.

R1

O

R1 BF3·OEt2 (60 mol%) benzene, 23 to 40 ˚C

O

Fe(acac)3 (7 mol%), Me3SiX (150 mol%) HO


Ph R1

= Ph (45%) 331: 332: R1 = 4-(NO2)C6H4 (61%) 333: R1 = 4-ClC6H4 (54%) 334: R1 = 3-BrC6H4 (64%) 335: R1 = n-Pr (95%) 336: R1 = n-C15H31 (81%) 337: R1 = c-C6H11 (95%) 338: R1 = i-Bu (75%)

X R1

327: = i-Bu, X = Cl (90%) 328: R1 = i-Bu, X = Br (85%) 329: R1 = (CH2)2CH=CH2, X = Cl (30%) 330: R1 = (CH2)3OAc, X = Cl (90%)

Scheme 54.

fully tested as catalysts for the Prins cyclization [1] of homopropargylic alcohols and aldehydes, both aromatic and aliphatic, producing the corresponding 4-halo-dihydropyran derivatives [92]. The reaction required stoichiometric amounts of iron halide in order to complete the transformation of the reactants, a halogenated solvent being the best choice to perform the reaction. Different authors pointed out that a mixture of dihydropyrans bearing different halogen atoms could be obtained if the halogen of the iron salt and of the solvent are different. Based on some calculations at the “ab initio” level on the interaction of iron salt and the solvent, an association between both generated a complex in solution, from which any halogen can be transferred to the vinylic carbocation [93]. More recently, a catalytic version of this process has been described using a substoichiometric amount of Fe(acac)3 and trimethylsilyl halide (as a source of the nucleophile), so different 4-chloro- and 4bromodihydropyrans 327-330 have been prepared (Scheme 54) [94]. Furthermore, homopropargylic alcohols reacted with aldehydes in an aromatic solvent, and in the presence of boron trifluoride etherate, producing 4-arylhydropyrans 331-338 via a

Prins Friedel-Crafts sequence reaction (Scheme 54). A mixture of regioisomers is obtained when employing toluene or anisole as solvent. The Prins-type cyclization of 1-phenylhex-4-yn-1-ol with a series of aldehydes led to the formation of the corresponding pyranylidene derivatives 339-343 (Scheme 55) [95]. The corresponding vinylidene tetrahydropyrans, such as 344-346, were obtained when performing the reaction with a propargylsilane derivative (Scheme 55) [96]. Another synthetic approach to form dihydropyrans is the use of an elimination-terminated Prins cyclization. The vinylstannanes 347-349 reacted with various aldehydes in the presence of trimethylsilyl triflate at low temperature in diethyl ether to afford the corresponding dihydropyrans 350-360 (Scheme 56) [97]. Additionally, an optically enriched (91% ee) starting stannane (S)-348 produced the expected 2,6-disubstituted dihydropyrans with comparable level of enantioselectivity as the starting material. Similarly, symmetric 2,6-disubstituted dihydropyrans 362-365 have been prepared by


Ph


R2

R1

O

Ph

Me3SiOTf (200 mol%)

Me3SiOTf (300 mol%)

R1CHO, Et2O, -78 ˚C

•

R1

O

R1CHO, CH2Cl2, -78 to 23 ˚C

OH

OTf

Ph R1

R2

R1

344: = Ph, = SiMe3 (92%) 345: R1 = 4-BrC6H4, R2 = SiMe3 (87%) 346: R1 = CH2CH2Ph, R2 = SiMe3 (84%)

R2

339: = Ph, = H (79%) 340: R1 = 4-(NO2)C6H4, R2 = H (82%) 341: R1 = Me, R2 = H (76%) 342: R1 = i-Pr, R2 = H (75%) 343: R1 = n-C5H11, R2 = H (76%)

Scheme 55.

OH

R2

a) Me3SiOTf (200 mol%), R2CHO, Et2O, -78 ˚C

R1

R1

O


SnBu3 347: R1 = H 348: R1 = Ph, 349: R1 = n-C6H13

350: R1 = H, R2 = Ph (92%) 351: R1 = H, R2 = CH2CH2Ph (86%) 352: R1 = R2 = Ph (94%) 353: R1 = Ph, R2 = 4-BrC6H4 (80%) 354: R1 = Ph, R2 = CH2CH2Ph (76%) 355: R1 = Ph, R2 = c-C6H11 (72%) 356: R1 = Ph, R2 = n-C6H13 (87%) 357: R1 = n-C6H13, R2 = Ph (91%) 358: R1 = n-C6H13, R2 = 4-BrC6H4 (86%) 359: R1 = n-C6H13, R2 = CH2CH2Ph (83%) 360: R1 = n-C6H13, R2 = c-C6H11 (69%)

Scheme 56.

R1

a) InCl3 (150 mol%), R1CHO, CH3CN, 60 ºC

Me3Si SnBu 3

O

R1

b) NaHCO3 (saturated solution) 362: R1 = n-C6H13 (63%) 363: R1 = c-C6H11 (70%) 364: R1 = n-C7H15 (82%) 365: R1 = CH2CH2Ph (47%)

361 (E/Z, 95:5)

Scheme 57.

OSiEt3 BiBr3 (5 mol%), R2CHO

R1

R2

O

R1

R2

O

R1

+ SiMe3

CH2Cl2, 23 ˚C

366: R1 = H 367: R1 = n-C5H11 368: R1 = Ph

369: R1 = H, R2 = Ph (74%) 370: R1 = n-C5H11, R2 = Ph (70%, cis/trans >99:1) 371: R1 = n-C5H11, R2 = 4-(CF3)C6H4 (74%, cis/trans 73:1) 372: R1 = n-C5H11, R2 = 4-MeOC6H4 (58%, cis/trans 3:1) 373: R1 = n-C5H11, R2 = i-Pr (88%, cis/trans >99:1) 374: R1 = R2 = Ph (55%, cis/trans 5:1) 375: R1 = Ph, R2 = 4-(CF3)C6H4 (82%, cis/trans >99:1) 376: R1 = Ph, R2 = 4-MeOC6H4 (47%, cis/trans 3:1) 377: R1 = Ph, R2 = Bn (94%, cis/trans 35:1)

Scheme 58.

coupling of compound 361 with two molecules of an aldehyde in the presence of indium trichloride (Scheme 57) [98]. Moreover, a polymer supporting the reagent 361 has been prepared and used in the Prins cyclization with similar efficiency as the soluble 361, the supported reagent being regenerated and reused several times without losing activity. Similarly, the reaction of -(triethylsilyloxy) vinyltrimethylsilanes 366-368 with a variety of aldehydes, in the

presence of bismuth bromide, has been succesfully employed in the preparation of 2,6-disubstituted dihydropyrans 369-377, their diastereoselectivities being significantly affected by the aldehyde employed (Scheme 58) [99]. Efficient BF3·OEt2 promoted Prins cyclization for the preparation of 4-fluorinated dihydropyrans has been reported. Thus, the allenic alcohol 378 and various aldehydes have been cyclized in the


Pastor and Yus

R1

SiMe3

CO2Pri

BF3·OEt2 (300 mol%)

CO2Pri

•

O

SiMe3


OH

F 379: R1 = Ph (51%) 380: R1 = 4-ClC6H4 (53%) 381: R1 = c-C6H11 (85%) 382: R1 = n-C8H17 (82%) 383: R1 = i-Bu (80%) 384: R1 = t-Bu (77%) 385: R1 = CH2CH2Ph (78%)

378

Scheme 59.

MeO OMe OH O

+

OPh

N H 386

387

OPh

O

Me3SiOTf (100 mol%)

O CH2Cl2, -40 to 23 ˚C

N H 388 (78%, dr 13:1, >99% ee)

Scheme 60.

presence of an excess of trifluoroborane, giving the expected heterocyclic compounds 379-385 with good yields and high transselectivities (Scheme 59) [100]. Likewise, the corresponding 4bromo dihydropyrans were prepared employing In(OTf)3/Me3SiBr as catalytic system [101]. The reaction of homoallylic alcohols with isatin ketal derivatives in the presence of trimethylsilyl triflate has allowed the preparation of oxindoles. Thus, the isatin dimethylketal 386 underwent a Prins cyclization with the homoallylic alcohol 387 yielding the indol derivative 388 with good yield and enantioselectivity (Scheme 60) [102]. The synthesis of analogous spirooxindole oxepenes has been achieved employing the corresponding bishomoallylic alcohols. Other isatin derivatives, such as 389-394 reacted with 1,1-diphenylethylene in the presence of titanium chloride, and the addition occurred to the carbonyl moiety in the 3position, the carbenium formed being then trapped by one of the phenyl substituents, forming indene-spiro-oxindoles [103]. O R1 O N R2 R1

R2

389: = =H 390: R1 = Cl, R2 = H 391: R1 = Br, R2 = H 392: R1 = Me, R2 = H 393: R1 = H, R2 = Me 394: R1 = H, R2 = Et

The formation of macrocycles by dimerization via a double Prins reaction has been also reported. The use of silylilated 2[(trimethylsilyl)methyl]prop-2-en-1-ol 395 in combination with an aldehyde produced the corresponding oxonium intermediate 396, but the subsequent intramolecular cyclization was not observed (the 5-endo-trig cyclization is kinetically disfavored according to Baldwin’s rules). Instead of this cyclization, another molecule of

395 reacted with 396 producing a new intermediate 397 which formed the oxonium ion 398, which finally cyclized to give the corresponding 1,6-dioxecanes 399-404 (Scheme 61) [104]. Similarly, the allenylmethyl silane 405 was treated under the same reaction conditions forming the expected tetramethylene-1,6-dioxecanes 406-411 (Scheme 62). Recently, noble metals complexes derived from gold and platinum, have been reported to catalyze the exo-cycloisomerization of alkynols of type 412 to give cyclic systems of type 413, which in the presence of a metal complex produced the oxonium intermediate that participate in a Prins cyclization with an allylic moiety present in the structure (Scheme 63). Finally, the carbenium ion generated after the cyclization was trapped by the methanol employed as solvent. Thus, Pt(II), Pt(IV) and Au(III) complexes [PtCl2(cod), PtCl4 and AuCl3] catalyzed effectively the diastreroselective synthesis of different bicyclic systems 414-424 with good yields, through a tandem cycloisomerization–Prins cyclization sequence [105]. Interestingly, other nucleophiles have been employed in order to trap the carbenium ion after the Prins cyclization, such as other alcohols (EtOH, n-PrOH, BnOH), carboxylic acids (MeCO2H, EtCO2H), acetonitrile (Ritter-type reaction), halides (employing CH2Cl2, CH2Br2). Additionally, the reaction with an aromatic compound (4-chloroanisole, 1,4-dimethoxybenzene and 1,3,5trimethoxybenzene), in the presence of AuCl(PPh3)/AgOTf as catalyst, gave the cycloisomerization/Prins cyclization of the allyl alkynol and then a Friedel-Crafts reaction with the aromatic compound [105b]. On the contrary, a gold(I) catalyst is able to catalyze cyclization of enynes forming an alkenyl metal intermediate, which then underwent Prins cyclization when employing certain starting materials, such as 425-427. Finally, the corresponding tricycles 428-430 have been obtained together with the rearranged ketones 431-433 (Scheme 64) [106]. 4.3. Seven-, Eight- and Nine-Membered Ring Formation The preparation of seven membered rings has been achieved from 2-allylphenols and different carbonylic compounds. The reactions with ketones have been performed in the presence of alumin-



HO Me3Si

O 397

R1

R1

O Me3Si

Me3Si

R1

O

O 398

396

O

a) Me3SiOTf (100 mol%), R1CHO, THF, -78 ˚C Me3Si

R1

R1

OH b) NaHCO3 (saturated solution) 399: 400: 401: 402: 403: 404:

395

R1 R1 R1 R1 R1 R1

O R1 = Ph (72%) = 4-MeOC6H4 (40%) = 3-MeOC6H4 (70%) = 4-MeC6H4 (52%) = 4-FC6H4 (71%) = 2-thienyl (45%)

Scheme 61.

• Me3Si

O

a) Me3SiOTf (100 mol%), R1CHO, THF, -78 ˚C OH


R1

R1

O

406: R1 = Ph (73%) 407: R1 = 4-MeOC6H4 (55%) 408: R1 = 3-MeOC6H4 (83%) 409: R1 = 4-MeC6H4 (75%) 410: R1 = 4-FC6H4 (85%) 411: R1 = 2-thienyl (50%)

405

Scheme 62. R2 R2

LnM

O

H

X

R1

R1

X

R1 O

O

R2

LnM

413

MeOH LnM

R2

OH

R1

R2

LnM

R2

X R1 412

R2

MeO PtCl4 (2 mol%), MeOH, 65 ˚C

OH

Scheme 63.

X

R1 O

X

O

X

R1 414: R1 = allyl, R2 = H, X = CH2 (95%) 415: R1 = allyl, R2 = H, X = O (95%) 416: R1 = allyl, R2 = H, X = NPh (89%) 417: R1 = allyl, R2 = H, X = NTs (93%) 418: R1 = allyl, R2 = H, X = NC6H4(4-OMe) (90%) 419: R1 = R2 = H, X = CH2 (88%) 420: R1 = Me, R2 = H, X = CH2 (94%) 421: R1 = i-Pr, R2 = H, X = CH2 (92%) 422: R1 = Et, R2 = Ph, X = CH2 (81%) 423: R1 = allyl, R2 = Me, X = O (89%) 424: R1 = allyl, R2 = Ph, X = O (87%)


[Au]

Pastor and Yus

[Au]

R1 Prins

MeO2C

MeO2C

O

MeO2C

[Au]

R1 MeO2C

O

MeO2C

MeO2C

R1

O

H

H

R1 [Au] O MeO2C MeO2C H

R1 O MeO2C MeO2C

R1

AuCl (3 mol%)

MeO2C

MeOH, 23 ˚C

MeO2C

O

R1 O +

MeO2C

H 425: R1 = H 426: R1 = Me 427: R1 = i-Pr

MeO2C

428: R1 = H (58%) 429: R1 = Me (79%) 430: R1 = i-Pr (84%)

431: R1 = H (18%) 432: R1 = Me (10%) 433: R1 = i-Pr (12%)

Scheme 64. Cl R1

R1

AlCl3 (150 mol%) OH

R2COR3, CH2Cl2, -10 to 0 ˚C

O

R3 R2 434: R1 = H, R2 = R3 = Et (70%) 435: R1 = H, R2-R3 = (CH2)5 (72%) 436: R1 = Me, R2 = R3 = Et (73%) 437: R1 = Me, R2-R3 = (CH2)4 (72%) 438: R1 = MeO, R2-R3 = (CH2)4 (74%) 439: R1 = MeO, R2-R3 = (CH2)11 (75%)

Scheme 65.

R1

R2 OH

SiMe3

Me3SiOTf (200 mol%) R1CHO, Et2O, -78 ˚C

R2

O •

440: R1 = R2 = Ph (95%) 441: R1 = 4-(NO2)C6H4, R2 = Ph (75%) 442: R1 = CH2CH2Ph, R2 = Ph (89%) 443: R1 = Ph, R2 = Et (92%) 444: R1 = 4-(NO2)C6H4, R2 = Et (75%) 445: R1 = 4-MeOC6H4, R2 = Et (90%) 446: R1 = 2-furyl, R2 = Et (81%) Scheme 66.

ium chloride as Lewis acid catalyst, and the corresponding benzoxepins 434-439 were prepared (Scheme 65) [107]. In contrast to ketones, the reaction with aldehydes produced the corresponding benzoxepins with moderate yields and as a mixture of syn/anti diastereomers. The formation of oxepanes 440-446 having a 3-vinylidene substituent has been achieved starting from propargylsilanes via a Lewis-catalyzed Prins cyclization (Scheme 66) [96].

4.4. Prins Cyclization in Synthesis The Prins cyclization, which is an old reaction (more than half century), has recently revealed as a very powerful and versatile procedure for the diastereoselective preparation of functionalized THP scaffolds [108]. The Prins cyclization reaction has been shown to be a very useful procedure for the construction of oxygencontaining heterocyclic units that appear in many bioactive compounds [109]. Additionally, Prins cyclization has been employed in



employed in the preparation of different polyketide derivatives [118]. Two different Prins cyclization processes have been described during the stereoselective synthesis of (+)-cryptocarya diacetate 455 (Scheme 67). The alcohol derivative 451 reacted with crotonaldehyde in the presence of trifluoroacetic acid obtaining the tetrahydropyran compound 452 with high levels of stereoselectivity. A new Prins cyclization with crotonaldehyde was performed, after transforming compound 452 into the diol 453, under the same reaction conditions, obtaining the THP derivative 454 with good diastereoselectivity [119]. Under the same reaction conditions a Prins cyclization has been reported during the stereoselective synthesis of crocacin C (459), in which the homoallylic alcohol 456 and the aldehyde 457 were treated in the presence of trifluoroacetic acid producing the compound 458 with a good control of the stereochemistry (Scheme 68) [120]. Trifluoroacetic acid has been also employed in the intramolecular cyclization of compound 460 to the alcohol 461 (as an diastereoisomer mixture 3:1), which is an intermediate in the total synthesis of (+)-exiguolide 462 (Scheme 69) [121]. Following the same strategy, other natural products bearing a -pyrone moiety have been succesfully prepared, as in the synthesis of tarchonanthuslactone [122], obolactone [123], (+)-strictifolione [124], (–)-pironetin [125], a pheromone of the giant white butterfly Idea leuconoe [126], and in the synthesis of an antifungal isolated from Ravensara crassifolia [127]. Additionally, the protocol has been employed in the preparation of other natural occurring products having a macrolactone scaffold, as the synthesis of cryptofolione [128], xestodecalactone C [129], decarestrictine-J [130], herbarumin III [131], (–)-colletol [132], some bryostatin analogs [133], and the preparation of the antifungal antibiotics PF1163A and PF1163B [134]. Other natural products, such as basiliskamides A and B [135], aculeatin A and B [136], (+)-pseudohygroline [137], (–)-tetrahydrolipstatin [138], and epi-sporostatin [129], have been also prepared using a Prins cyclization key step. Compound 463 was treated in acidic media inducing the intramolecular Prins reaction, and subsquently the resulting carbenium intermediate was captured by the hydroxyl moiety present in the starting material yielding the bicyclic system 464 (Scheme 70) [139]. This double cyclization has been employed as the key step for the synthesis of the bicyclic [2.2.1]-core of natural products, such as (+)-chabranol 465. The formation of a polycyclic com-

the preparation of different dihydro- and tetrahydropyran derivatives with several substituents in order to study their activity profile against human solid tumor cell lines of diverse origin [110]. Trifluoracetic acid has been employed as catalyst in the Prins cyclization producing different tetrahydropyran derivatives [111], which are part of a variety of natural products. Thus, the core of the diospongin A (447) has been prepared by a Prins cyclization using TFA [112]. The stereoselective synthesis of simplactone B (448) has been also achieved using a Prins cyclization catalyzed by TFA as a key step [113]. Recently, a boron trifluoride mediated Prins cyclization has been employed for the preparation of both the lactone 449 and its corresponding cis-isomer, allowing the elucidation of the correct structure of the active principle from the extract of barks of Vitex cymosa [114]. During the total synthesis of goniothalesdiol A, the cis-2,6-dihydropyran derivative 450 has been constructed via a silyl-Prins reaction [115]. OH

OH O

Ph

Ph

O

O

O

447

448

OH O O

O

MeO

449

O

Ph

450

The development of synthetic methodologies for the preparation of polyketide-derived natural products contain syn or anti-1,3diol unit is important, specially with a stereoselective control of the process [116]. Related to this, the Prins cyclization has been successfully employed for the stereochemical control in the synthesis of polyketide precursors containing anti-1,3-diol units with a variety of alkyl branches and functional groups [117]. Indeed, a variety of tetrahydropyran moieties obtained after a Prins cyclization, employing trifluoroacetic acid as catalyst, have been subsequently OH a) CH3CH=CHCHO, TFA, CH2Cl2, 23 ˚C OH 451

b) K2CO3, MeOH

a) Na, NH3(l), THF, -33 ˚C b) O3, Ph3P, CH2Cl2, -78 ˚C

OH

OH

c) CH3PPh3I, t-BuOK, THF, 0 ˚C

O 452 (70%, >97% de)

453 a) CH3CH=CHCHO, TFA, CH2Cl2, 23 ˚C b) K2CO3, MeOH

OH OH OAc

OAc

O O

455 Scheme 67.

O

454 (55%, >95% de)


Pastor and Yus

OH Me OHC

OBn

+ OH

a) TFA, CH2Cl2, 23 ˚C

HO

O

b) K2CO3, MeOH

Me

OBn Me

OH 458 (55%)

457

456

Me

Me

Ph

O OMe

OMe

Me

NH2

459 Scheme 68.

BnO

BnO

MeO2C

MeO2C a) TFA, CH2Cl2, 23 ˚C O

O

b) K2CO3, MeOH

O

O

HO 460

461 (81%)

MeO2C O O O

O

MeO2C 462 Scheme 69.

pound has been also achieved in the preparation of compound 468, which structure is related to (–)-patchoulol. Thus, an equimolecular mixture of compound 466 and p-toluenesulfonic acid was heated in benzene affording the product 467 via a Prins cyclization (Scheme 71) [140]. The Prins cyclization has been also reported as a key step in the preparation of the core of calyxin structures, such as (–)blepharocalyxin D (471), what allowed the revision of the reported structures of related natural products [141]. Thus, the alkenol 469 reacted with p-anisaldehyde in the presence of a triethylsilyl triflate/trimethylsilyl acetate/acetic acid mixture, and the corresponding adduct 470 was isolated in 60% yield (Scheme 72) [142]. The Prins-type macrocyclization has emerged as a powerful synthetic methodology for the preparation of polyketide natural products [143]. Symmetric macrocycles can be prepared by a Prins dimerization, thus compound 472 was treated with a mixture of

Et3SiOTf/Me3SiOAc producing a double Prins cyclization ending up with the formation of the macrocycle 473 (Scheme 73) [144]. A model for the synthesis of clavosolide A has been demonstrated by means of this powerful methodology for the preparation of macrocyclic dimers [144]. Additionally, the synthesis of the macrocyclic metabolite (–)-clavosolide D (480) was achieved by the formation of tetrahydropyran derivatives 478 and 479 via a Prins cyclization. The alcohols 474 and 475 were treated with methyl propiolate, in the presence of a catalytic amount of quinuclidine, giving the enol ether intermediates 476 and 477, which were treated with TFA producing then, after hydrolysis, the corresponding compounds 478 and 479 with moderate yields (Scheme 74) [145]. Both tetrahydropyran derivatives were afterwards modified in their side chains and finally coupled to form (–)-clavosolide D. Similarly, the intramolecular cyclization of intermediates 481 or 482 produced the corresponding bicyclic macrolactone 483 (Scheme 75). This com-



HO HO TBSOTf (150 mol%), CH2Cl2

O

collidine (200 mol%), 0 ˚C

O

H 463

464 (64%)

O

HO

O 465 Scheme 70.

O

H

O

H

TsOH (100 mol%)

OH O

benzene, reflux

O

HO 467 (59%)

466

468

Scheme 71.

MeO

OMe

MeO OH

O

Et3SiOTf (400 mol%), 4-MeOC6H4CHO OAc

Me3SiOAc (100 mol%), AcOH, 23 ˚C H OAc

OAc 469

OAc OAc

470 (60%)

HO

OH O

OH H

HO

O

H

471 Scheme 72.

pound 483 has been used in the total synthesis of (+)-neopeltolide 484 [146]. Later on the same Prins cyclization forming a bicyclic macrolactone has been employed in the preparation of the toxin polycavernoside A [147]. One more Prins cyclization forming a macrocycle has been employed as a key step during the preparation of the kendomycin skeleton 485 (Scheme 76) [148].

The coupling reaction between vinylsilane 486 and acetal 487 mediated by indium trichloride produced the dihydropyran 488 with 72% yield and a 77:23 relation of both possible cis/trans isomers (Scheme 77) [149]. The heterocyclic compound 488 was employed, as a mixture of both isomers, in the preparation of the bisspiroacetal moiety 489, which is a fragment of the shellfish toxins, spirolides B and D.


Pastor and Yus

H O O

OH a) Et3SiOTf (2000 mol%), AcOH, Me3SiOAc (3000 mol%), 23 ˚C

O

O O

O AcO

b) K2CO3, MeOH MeO

OAc O

O H

OMe 472

473 (43%)

Scheme 73.

BnO

BnO HCCCO2Me

OH

O

CO2Me

quinuclidine (cat.) R1

R1

474: R1 = H 475: R1 = Me

476: R1 = H 477: R1 = Me

a) TFA, CH2Cl2, 23 ˚C b) K2CO3, MeOH

OMe MeO

BnO OMe O

O

CO2Me

O R1

O H

OH

H

O

R1

478: = H (65%) 479: R1 = Me (53%)

O O

O

H

H

O O

MeO

O

OMe OMe 480

Scheme 74.

The Prins cyclization of the homoallylic alcohol 490 with the aldehyde 491 in the presence of iron(III) chloride produced the corresponding 4-chlorotetrahydropyran 492, the all-cis-isomer being the major product (Scheme 78). This cyclic compound 492 was then employed in the synthesis of the C1–C13 subunit of spirastrel-

lolides A and B [150]. Compounds 493 and 494 have been respectively prepared, by means of a boron trifluoride mediated Prins cyclization, during the synthesis of the fragment C16–C29 of the sorangicin A [151] and a novel diarylheptanoid extracted from Zingiber officinale [152].



OMe

OMe O EtO

O

O

O

a) Et3SiOTf (2000 mol%), AcOH, Me3SiOAc (3000 mol%), 23 ˚C

TBSO

O

O

a) Et3SiOTf (2000 mol%), AcOH, Me3SiOAc (3000 mol%), 23 ˚C

O

b) K2CO3, MeOH

OEt

OMe

OPMB

b) K2CO3, MeOH

OMe

OH 481

482

483 47% from 481 66% from 482 OMe O

O O OMe HN O O

O O

N 484

Scheme 75.

a) BF3·OEt2 (300 mol%), CH2Cl2, AcOH (1500 mol%), 0 ˚C

O H

OH

O O

b) KOH, EtOH, 80 ˚C HO

O PhO2SO

HO

OMe

485 OMe (33%) Scheme 76.

OH

Br O +

SiMe3

OBn

Br

CH2Cl2, 23 ˚C

487

486

O

+ OBn 488 (72%) [ 77 : 23 ]

BnO

O

O O

MeO O 489 Scheme 77.

Br

InCl3 O

OH

OMe

O OBn


Pastor and Yus

OH

OHC

OH

OBn O

+

OBn

O

FeCl3 (100 mol%)

O CH2Cl2, 0 to 20 ˚C

BnO 490

OH

BnO

Cl 492 (62%)

491

Scheme 78.

OBn O

OAc

O

O O

AcO

OAc OMe

493

494 Cl

O

OH

TiCl4 (100 mol%)

OH +

OTBS

495

CH2Cl2, -70 to -20 ˚C 496

OH

Cl O O

MeO

O 497 (63%)

O MeO

OH

O

498

Scheme 79.

The hemiacetal (R)-4-hydroxypentanal 495, which can be easily obtained by reduction of (R)--valerolactone, was coupled with the homoallylic alcohol 496 in the presence of titanium chloride giving the Prins adduct 497 with 63% yield (Scheme 79) [153]. Afterward, compound 497 has been employed in the synthesis of (+)spirolaxine methyl ether 498. A Mukaiyama aldol Prins cyclization process has been employed in the preparation of the tetrahydropyran moieties of the polyketide SCH 351448. Thus, the enol ether 499 and the aldehyde 500 were subjected to a TiBr4 promoted MAP reaction in the presence of 2,6-di-tert-butyl-4-methylpyridine (DBMP) at low temperature, the resultant adduct 501 being isolated in 76% yield as a mixture of isomers. The bromide at the C4 in THP ring was then removed for the preparation of the compound 502, which is a fragment of the natural product (Scheme 80) [154]. Previously, the preparation of the tetrahydropyran ring in SCH 351448 was reported by an indium catalyzed Prins cyclization [155]. In addition, the total synthesis of leucascandrolide A was achieved via generation of the molecule core by means of a titanium bromide mediated MAP reaction protocol [156].

5. AZA PRINS CYCLIZATIONS The piperidine ring is widely distributed in natural products (e.g. in alkaloids) [157], and is an important scaffold for drug discovery, being the core of many pharmaceutically appealing compounds [158]. The preparation of this heterocyclic system can be approached employing an aza version of the Prins cyclization, using Lewis acids. An interesting protocol involves the use of iron(III) halides, thus iron salts mediated the formation of a ,-unsaturated iminium intermediate, from the corresponding homoallylic amine and aldehyde, which underwent cyclization under the reaction conditions. Compounds 503-512 have been prepared by means of this methodology (Scheme 81) [159]. Additionally, the use of a combination of FeCl3 with an imidazolium salt in benzotrifluoride (BTF) has been employed in the preparation of 4-chloro piperidine derivatives (e.g. 504 in 92% yield and trans/cis >99:1 ratio, and 507 in 93% and trans/cis 89:11 ratio) [160]. The catalytic version of this process has been also performed by using Fe(acac)3 and trimethylsilyl halides as nucleophile source [93,94]. Other protecting groups on the nitrogen have minor effect, both on the yield and the selectivity, so the use of a nosyl group gave better diastereoselectivities



O

Br O

O OBn

O +

O TiBr4 (100 mol%)

OHC

OH

DBMP, CH2Cl2, -78 ˚C

O

OBn 499

501

500

a) Bu3SnH, AIBN b) SEMCl, i-Pr2EtN O Me3Si

O O

O O OBn

502 (55%) Scheme 80.

X HN

X

Ts FeX3 (150 mol%) R1CHO, CH2Cl2, 23 ˚C

+ N Ts

R1

N

R1

Ts

R1

503: = H, X = Cl (91%) 504: R1 = n-C7H15, X = Cl (88%, trans/cis 97:3) 505: R1 = c-C6H11, X = Cl (68%, trans/cis 98:2) 506: R1 = i-Bu, X = Cl (82%, trans/cis 99:1) 507: R1 = Ph, X = Cl (46%, trans/cis 90:10) 508: R1 = H, X =Br (91%) 509: R1 = n-C7H15, X = Br (82%, trans/cis 98:2) 510: R1 = c-C6H11, X = Br (82%, trans/cis 98:2) 511: R1 = i-Bu, X = Br (96%, trans/cis 97:3) 512: R1 = Ph, X = Br (82%, trans/cis 92:8) Scheme 81.

with a slight decrease of the yields of compounds 513-515 (Scheme 82). On the contrary, N-mesylamines produced the final products 516-518 with higher yields but lower stereoselectivities (Scheme 82) [161]. Similarly, the procotol can be applied to the corresponding homopropargyl amines (tosyl, nosyl and mesyl derivatives) for the formation of the corresponding tetrahydropyridines with satisfactory yields (from 63 to 96%) [159,161]. Moreover, an efficient bismuth chloride mediated stereoselective synthesis of trans-2alkyl-4-chloropiperidine derivatives has been achieved coupling Ntosyl- and N-mesylbut-3-en-ylamines with different monosubstituted epoxides. Thus, the bismuth salts produced the isomerization of the epoxide to the aldehyde and then promoted the aza-Prins cyclization [162]. The reaction of aldehydes with other homoallylic amines, such as 519-523, has been studied employing indium trichloride. Depending on the starting amine and the aldehyde dif-

ferent products of cyclization have been observed, resulting in some cases a mixture of them [163]. The formation of 4-iodopiperidine derivatives has been achieved employing trimethylsilyl iodide to promote the reaction between homoallyl(tosyl)amine and different aldehydes. The corresponding 2-alkyl-4-iodopiperidines were isolated with good yields (80-88%) and diastereoselectivities (94:6 to 97:3 for the trans/cis ratio) [164]. The aromatic aldehydes gave no conversion under these reaction conditions. Moreover, the use of a catalytic amount of gallium(III) iodide in combination with a stoichiometric amount of molecular iodine allowed the preparation of the corresponding 4iodopiperidine derivatives with similar levels of activity and diastereoselectivity, both aliphatic and aromatic aldehydes being actives under these reaction conditions [165]. Furthermore, fluorinated piperidines have been also prepared via a Prins cyclization,


Pastor and Yus

X HN

X

R2 FeX3 or Fe(acac)3 (10-15 mol%) +

Me3SiX (100 mol%), R1CHO, CH2Cl2, 23 ˚C

R1

N

N

R2

R1

R2

513: R1 = i-Bu, R2 = Ns, X = Cl (FeCl3/Me3SiCl, 80%, trans/cis >99:1) [Fe(acac)3/Me3SiCl, 88%, trans/cis >99:1] 514: R1 = i-Bu, R2 = Ns, X = Br (FeBr3/Me3SiBr, 70%, trans/cis >99:1) [Fe(acac)3/Me3SiBr, 84%, trans/cis >99:1] 515: R1 = Ph, R2 = Ns, X = Cl (FeCl3/Me3SiCl, 74%, trans/cis 85:15) [Fe(acac)3/Me3SiCl, 67%, trans/cis 90:10] 516: R1 = i-Bu, R2 = Ms, X = Cl (FeCl3/Me3SiCl, 99%, trans/cis 90:10) [Fe(acac)3/Me3SiCl, 99%, trans/cis 88:12] 517: R1 = i-Bu, R2 = Ms, X = Br (FeBr3/Me3SiBr, 99%, trans/cis 85:15) [Fe(acac)3/Me3SiBr, 90%, trans/cis 87:13] 518: R1 = Ph, R2 = Ms, X = Cl (FeCl3/Me3SiCl, 76%, trans/cis 85:15) [Fe(acac)3/Me3SiCl, 58%, trans/cis 85:15] Scheme 82.

N H

R1

Ts N H

519: R1 = Me 520: R1 = Et

OH

Ts HN

PMA (10 mol%)

521

R1CHO, CH2Cl2, reflux

N Ts

N H

Ts N H

522

thus the reaction of various aldehydes and homoallylic amines, in the presence of Et4NF·5HF, allowed the synthesis of fluorinated piperidines 524-529 (Scheme 83) [71]. The amine moiety needed to be protected as tosylamide or carbamate in order to obtain the reaction to work properly. 4-Fluoro-piperidines have been obtained as a mixture of diasteromers, the cis-isomer being the major one in all cases. Moreover, a solution of tetrafluoroboric acid etherate complex in dichlomethane has been proved to be useful for the preparation of 4-fluoro piperidine derivatives by means of an aza-Prins cyclization [166]. The use of different solid acid catalysts (montmorillonite K10 clay, SBA-15, ion-exchange resins and heteropoly acids) has been used for the aza-Prins cyclization, heteropoly acids being superior in terms of conversions. Indeed, phosphomolybdic acid

R1

Ts

(H3PMo12O40) has been employed for catalyzing the reaction between different aldehydes and N-tosylbut-3-en-1-amine. Consequently, the corresponding 2-aryl- and 2-alkyl-4-hydroxypiperidine derivatives 530-537 were obtained in good isolated yields and diastereoselectivities, in favor of the trans-isomer (Scheme 84) [167]. As commented previously for the normal Prins cyclization, the aza-Prins cyclization–Friedel-Crafts sequence reaction can be performed employing boron trifluoride in an aromatic solvent. As a result, compounds 538-542 have been obtained when the reaction was performed in benzene, obtaining the trans-isomer exclusively F

F

Et4NF·5HF + N R2

R1

N

R1

R2

524: R1 = n-C7H15, R2 = Ts (>99%, cis/trans 88:12) 525: R1 = c-C6H11, R2 = Ts (>99%, cis/trans 92:8) 526: R1 = Ph, R2 = Ts (17%, cis/trans 82:18) 527: R1 = n-C7H15, R2 = CO2Me (92%, cis/trans 93:7) 528: R1 = c-C6H11, R2 = CO2Me (97%, cis/trans 95:5) 529: R1 = Ph, R2 = CO2Me (29%, cis/trans 97:3) Scheme 83.

N

Scheme 84.

R2

R1CHO, 23 ˚C

+ R1

530: R1 = Me (79%, trans/cis 97:3) 531: R1 = i-Pr (81%, trans/cis 96:4) 532: R1 = c-C6H11 (87%, trans/cis 98:2) 533: R1 = Ph (90%, trans/cis 97:3) 534: R1 = 4-BrC6H4 (87%, trans/cis 94:6) 535: R1 = 3-ClC6H4 (91%, trans/cis 95:5) 536: R1 = 4-MeC6H4 (89%, trans/cis 95:5) 537: R1 = 4-MeOC6H4 (86%, trans/cis 96:4)

Ts

523

HN

OH

Ts



(Scheme 85) [168]. Additionally, other aromatic solvents have been tested, obtaining the final piperidine systems as a mixture of regioisomers from the Friedel-Crafts alkylation reaction.

Ts N

NHTs H

Ph NHTs

R1CHO, (CH2Cl)2, 80 ˚C

BF3·OEt2 (120 mol%) R1CHO, benzene, 0 to 23 ˚C

N Ts

545: R1 = (E)-CH=CHPh (78%) 546: R1 = i-Bu (70%) 547: R1 = c-C6H11 (73%)

N Ts

538: R1 = Ph (80%) 539: R1 = n-Pr (85%) 540: R1 = n-C5H11 (86%) 541: R1 = i-Bu (86%) 542: R1 = c-C6H11 (90%)

Scheme 87. MeO2C

NH

CO2Me

NHTs

H

N

TFA, (CH2O)n (100 mol%)

Scheme 85.

An aza-Prins–pinacol transformation has been described for the preparation of the key 7-azabicyclo[2.2.1]heptane system present in the structure of (±)-epibatidine and (±)-epiboxidine. Thus, compound 543, as a mixture of diastereoisomers, upon treatment with tin chloride rearranged to give the bicyclic system 544 as a single isomer, having the aldehyde moiety exclusively in the exo orientation (Scheme 86) [169]. Ts

R1

TsHN R1

H

Sc(OTf)3 (10 mol%)

Ts

N

CH3CN/CHCl3, 23 ˚C

(10-20%)

Scheme 88.

Bn N

N

H

N

Me

O

N

HO N Ts 543

OMe

SnCl4

N

Cl

O

CH2Cl2, 0 ˚C

549

H

H

Ts

Cl

548

HO

R1

H

Me O

HO

TsN

H

N

H

H O

CHO 544

550: R1 = H 551: R1 = Me

552

Scheme 86.

The coupling of (E)-N,N-ditosyl-hex-3-ene-1,6-diamide with an aldehyde in the presence of scandium triflate gave the corresponding trans-fused octahydropyrrolo[3,2-c]pyridine derivatives 545547 (Scheme 87) [90], and the (Z)-isomer produced the cis-fused bicyclic system as the major isomer. The reaction occurred via an aza-Prins cyclization terminated by a nucleophilic addition of the other amide moiety to the carbenium ion. Additionally, the use of a catalytic amount of p-toluenesulfonic acid allowed the isomerization of styrene derivative epoxides to the corresponding aldehydes, which then underwent nitrogen-terminated aza-Prins cyclization [170]. A sulfonamide-terminated aza-Prins cyclization has been employed in the synthesis of the polycyclic diamine core of (+)nankakurines A and B and (±)-5-epi-nankakurine A (Scheme 88) [171]. The piperidine motifs in compounds 548-552 have been prepared via an aza-Prins reaction terminated by an intramolecular carbon–oxygen bond formation starting from 1,3-diene-containing allylic amines having a hydroxy moiety in their structure [172]. Similarly, a tandem aza-Prins cyclization and transannular etherification has been performed in the synthesis of (+)-cortistatin A

(Scheme 89) [173]. Moreover, other polycyclic scaffolds (e.g. compound 553) have been prepared from different styrene derivatives with N-phosphinylimines in the presence of lantanum triflate and trifluoroacetic acid anhydride (Scheme 90) [174]. An alkyne aza-Prins cyclization has been described starting from different alkynyl(methoxymethyl)amine derivatives, which in the presence of a gold(I) catalyst produced an iminium ion that underwent cyclization to the corresponding 4-methoxytetrahydropyridines 554-559 (Scheme 91) [175]. 6. CONCLUSIONS The Prins reaction has become one of the cornerstone reactions in synthetic organic chemistry over the last 15 years. This transformation has been employed as a key step in the total synthesis of many natural products. The Prins cyclization allows the preparation of different heterocycles by forming a carbon–carbon and a carbon– heteroatom bond in a very simple protocol. Interesting features are: (a) the control of the stereochemistry during the cyclization process; and (b) the possibility of the introduction of different substituents by nucleophilic addition to the formed carbenium ion after the Prins


Pastor and Yus

OAc

OAc

AcO

AcO ZnBr2 (150 mol%), CH3CN

Me OHC

OTBS

HO

Me Me2N

Me2NH (300 mol%), 50 ˚C

OTBS

O

H

H (65%)

Scheme 89.

O

O

Ph P N

F3C

Ph

NH

MeO La(OTf)3 (25 mol%), CH3CN

MeO

+ MeO

OMe

H

H OMe

TFAA (150 mol%), 80 ˚C

OMe 553 (83%, 5:1 dr) Scheme 90.

OMe Cbz

Cbz N

N

Au[P(C6F5)3]Cl/AgSbF6 (2-5 mol%)

R1

R1

DBMP (1.5-4 mol%), CH2Cl2, 23 ˚C

OMe

R2

R2

R3

R3

554: R1 = CH2CH2Ph, R2 = R3 = H (92%) 555: R1 = (CH2)7CH=CH2, R2 = R3 = H (87%) 556: R1 = R2 = R3 = H (94%) 557: R1-R2 = (CH2)5, R3 = H (76%) 558: R1-R3 = (CH2)3, R2 = H (91%) 559: R1-R3 = (CH2)5, R2 = H (90%)

Scheme 91.

cyclization. There are several reactions that can be combined with a Prins reaction expanding the scope of this transformation via tandem reactions. Finally, the Prins cyclization and the corresponding tandem reaction have become a key strategic process in the total synthesis of heterocyclic and carbocyclic natural products.

DBMP

=

2,6-di-tert-butyl-4-methylpyridine

DDQ

=

Dichloro-dicyanoquinone

de ee

= =

Diastereomeric excess Enantiomeric excess

e.g.

=

Exempli gratia

MAP Ms

= =

Mukaiyama aldol–Prins Mesyl (methanesulfonyl)

Ns PMA

= =

Nosyl (4-nitrobenzenosulfonyl) Phosphomolybdic acid

This work was generously supported by the Spanish Ministerio de Educación y Ciencia [CTQ2007-65218, and CONSOLIDER INGENIO 2010 (CSD2007-00006)], the Generalitat Valenciana (GRUPOS 03/135, GV05/52, GV/2007/036, GVPRE/2008/278, PROMETEO 2009/039, and FEDER) and the Universidad de Alicante.

SEMCl

=

2-(Trimethylsilyl)ethoxymethyl chloride

TBS Tf

= =

tert-Butyldimethylsilyl Trifluoromethanesulfonyl

TFA

=

Trifluoroacetic acid

TFAA TIPS

= =

Trifluoroacetic anhydride Triisopropylsilyl

LIST OF ABBREVIATIONS

Ts

=

Tosyl (4-toluenesulfonyl)

CONFLICT OF INTEREST Declared none. ACKNOWLEDGMENT

AcCl AcOH AIBN BTF Cbz

= = = = =

Acetyl chloride Acetic acid Azobisisobutyronitrile Benzotrifluoride (,,-trifluorotoluene) Benzyloxycarbonyl

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Revised: October 17, 2011

Accepted: October 18, 2011