SYNOPSIS

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SYNOPSIS

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SYNOPSIS

Thesis entitled “Toward the Synthesis of 2,3-Dihydroxytrinervitanes and Development of New Methodologies” has been divided into three chapters.  Chapter I: It deals with Antibiotic Molecules in medicinal practice, Isolation, Structure Determination and Biological Activity of Trinervitanes Skeletons and related compound.  Chapter II: It deals Studies Directed towards the Synthesis of 2, 3-dihydroxytrinervitanes.  Chapter III: This chapter describes the development of new methodologies using IBX and based on Prins-cyclization. . 

Section A: This section describes introduction on IBX, its applications in organic synthesis and IBX mediated facile conversion of 1,3 diols to 1,2 diketones by oxidative cleavage of C-C bond.



Section B: This section describes introduction of Prins-cyclization, its applications in organic synthesis and two methodology based on Prins-cyclization. › B.1 Synthesis of 4-Chlorotetrahydropyrans via Prins- cyclization › B.2 Gallium chloride catalyzed three component coupling of naphthol, alkyne and aldehyde: a novel synthesis of 1,3-diaryl-3H-benzo[f] chromenes via Prinscyclization .

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Chapter I Antibiotics and Clinically Used Antibiotic: Antibiotic, the term came from Greek αντί-anti, "against" + βιοτικός-biotikos, "fit for life" was coined by Selman Waksman in 1942 to describe any substance produced by a micro-organism that is antagonistic to the growth of other micro-organisms in high dilution. This original definition excluded naturally occurring substances, such as gastric juice and hydrogen peroxide (they kill micro-organisms but are not produced by micro-organisms), and also excluded synthetic compounds such as the sulphonamides (which are antimicrobial agents). In modern usage, the term "antibiotic" is more loosely used to refer to any chemotherapeutic agent or antimicrobial agent with activity against micro-organisms such as bacteria, fungi or protozoa.

Isolation, Structure Determination and Biological Activity of Trinervitanes Skeletons

13

Chapter II Studies Directed towards the Synthesis of 2, 3-dihydroxytrinervitanes We carried out quantum chemical calculations as our requirement of the cis-(α, α) –H and –CH3 of five member and six member ring fusion, for that we have taken the –OSiEt3 below the plan i.e., α–OSiEt3 (Figure 1). and calculated the relative energies when the –OSiEt3 is below the plane for the Pr-2 and Pr-4, calculations were done at AM1, PM3, MNDO and B3LYP/6-31G(d) level of theory.The relative energy difference is given were given in table 1.

Pr-2 (α, α) -OSiEt3 down

Pr-4 (β, β) – OSiEt3 down

-1765.9314611 (0.0) kJ/ mol

-1765.926501 (5.14) kJ/ mol Figure 1

Table 1: Total energies and the relative energies (kJ/mol) at AM1, PM3, MNDO and B3LYP/6-31G (d) level of theory. Structure

AM1

RE

PR-2 (α, α)

-0.3426766

0.0

PR-4 (β, β)

-0.33568337

18.3

PM3 -0.3438687 -0.3351724

RE

MNDO

RE

B3LY/6-31G(d)

RE

0.0

-0.296908

0.0

-1765.9314611

0.0

22.8

-0.2912121

15.0

-1765.926501

5.14

After detailed theoretical calculation, we designed a retrosynthetic approach which is show below (Scheme 1): 14

The T2 can be synthesised by [4+2] intramolecular Diels-Alder cycloaddition (IMDA) from 3. α,β- unsaturated synthon 3 can be prepared by Julia-Kocienski olefination of sulfone 4 and aldehyde 5. The sulfone 4 can be synthesized from 9 by Sharpless epoxidation followed by Yadav’s protocol and formylation of the alkyne which has been described before. Homoalkyl aldehyde 5 can be prepared from 1, 6 hexane diol using Evan’s auxiliary.

BnO

BnO

H

TESO

H

H

OH

TESO

H

OH

OH

OH 2, 3 dihydroxy trinervitanes

OH T1

T2

OTES O

BnO

CHO

O

H

N

N

OTBDPS

O S

CHO 5

4

Ph

3

OBn

OMEM +

N N

OTBDPS HO

Bn

OMEM 6 N

O OH TBDPSO

O

O TBDPSO

OBn O

10

Cl 8

7

1, 6 hexanediol

TBDPSO

OH 9

Geraniol

Scheme 1

15

Synthesis of sulfone (4): The synthesis of sulfone fragment 4 was commenced with geraniol (Scheme 2). Hydroxyl groups of geraniol was protected as TBDPS (tert-butyl diphenylsilane) ether using imidazole and TBDPS-Cl in dry CH2Cl2 yielding 11 in 95%. Compound 11 was converted to epoxide 12 by mCPBA (77% in water) as addition in chloroform in 85% yield. The epoxide 12 was treated with periodic acid in THF-diethyl ether to yield the aldehyde 13. which was directly subjected to Wittig olefination with stable ylide carboethoxymethylenetriphenyl-phosphorane to produce trans α,β-unsaturated ester 14 in 87% yield over two steps. The chemoselective reduction of the ester group of compound 14 using DIBAL-H (20% in Hexane) as reducing agent furnished allyl alcohol 9 in 89% yield. a OH

OTBDPS

b

11 H

c O

d

OTBDPS

OTBDPS

O

12

13 e OTBDPS

EtO2C

HO

14

OTBDPS 9

Scheme 2 Reagents and conditions: a) TBDPS-Cl, Imdidazole, CH2Cl2, 0 oC to r.t; b) m-CPBA, CH3Cl, 0 oC; c) H5IO6, Ether, THF, 0 oC to r.t; d) Ph3PCHCO2Et, CH2Cl2, 4 steps 60%; e) DIBAL-H, Ether, –78 oC.

Compound 9 on Sharpless asymmetric epoxidation using L(+)DIPT, Ti(OiPr)4 and TBHP in CH2Cl2 gave epoxy alcohol 15 in 87% yield (94% ee) (Scheme 3). Chlorination of hydroxyl group of 15 with TPP and catalytic amount of NaHCO3 in dry CCl4 at reflux temperature afforded the epoxy chloro compound 8 in 90% yields.

16

O a 9

O b

TBDPSO

OH

TBDPSO

Cl

15

8

OH c

OTBDPS d

TBDPSO

e

TBDPSO 16

7 OTBDPS

OTBDPS f

TBDPSO

TBDPSO

OH

OMEM 18

17

Scheme 3 Reagents and conditions: a) L(–)DIPT, Ti(OiPr)4, TBHP, CH2Cl2, –30 oC, 87%; b) TPP, NaHCO3, CCl4, 90%; c) LiNH2,–78 oC, 80%; d) TBDPS-Cl, imidazole, CH2Cl2, 92%; e) n-BuLi, THF, –78 oC-rt, CH2O, 0 oC- rt, 85%; f) ) MEM-Cl, DIEPA, CH2Cl2, 0 oC- rt, 87%.

Reductive ring opening of epoxychloride 8 to secondary propargylic alcohol 7 was achieved using the methodology developed by us, Li/liq.NH3 and catalytic amount of ferric nitrate at –78 oC. This stereogenic center can set the platform for introducing chiral centers. The secondary hydroxyl group has been protected as TBDPS ether using TBDPS-Cl and imidazole in dry DMF yielding 16 in 92%. The formylation of propargylic system was achieved by n-BuLi in dry THF followed by addition of paraformaldehyde to get the product 17 in 85% yield. The primary hydroxyl group of 17 has been protected with MEM ether using iPr2EtN and MEM-Cl in dry DCM yielded 18 in 87%. Now primary TBDPS of compound 18 was deprotected, using catalytic mount of CSA in MeOH and CH2Cl2 sovent system in 1:1 ratio yielding 6 (Scheme 3). The allylic alcohol 6 was converted to the sulfide 19 by 1-phenyl-1H-tetrazole-5-thiol (1.2 eq.), Ph3P, DEAD, in dry THF at 0 oC to r. t. in good yield. The sulfide 19 was treated with catalytic amount of ammonium molybdate (NH4)2MoO4, in H2O2, in ethanol at 0 oC to room temperature for 20 hours to get the sulfone 4 for the Julia-Kocienski olefination.

17

OTBDPS

OTBDPS a

18

N

b

HO

N

OMEM

O N

N

S OMEM

N Ph

6

c

N

19

OTBDPS

O S

OMEM

N N Ph

4

Scheme 4 Reagents and conditions: a) CSA, MeOH: CH2Cl2 (1:1), 12h, 77%; b) DEAD, TPP, Tetrazol, THF, 80%; c) (NH4)2MoO4, H2O2, EtOH. 0 oC to r.t, 65%.

Synthesis of homo alkyl aldehyde (5): One of the two hydroxyl groups of 1,6- hexane diol was protected as its mono benzyl ether using 60% NaH (1.5 eq.) and BnBr (1 eq.) in the presence of a catalytic amount of TBAI in dry THF at room temperature to furnish 20 in 76% yield (Scheme 4). Then primary hydroxyl group in 20 was converted to the carboxyl acid group to give 21 by the oxidation with catalytic amount of TEMPO and 2.5 equivalents of BAIB in 2:1 ratio of CH3CN/H2O. This was then coupled with Evan’s auxiliary. N-Acylation of the chiral (S)-oxazolidin-2-one using the mixed anhydride conditions furnished 22 in 85% yields over two steps. Diastereoselective alkylation of the Na-enolate of 22 with NaHMDS at –78 oC followed by the addition of MeI afforded 10 in 80% yield. Reductive cleavage of the chiral auxiliary in compound 10 was achieved by using LiBH4 and catalytic amount of H2O in THF at

0 oC to give alcohol 23 as the only isomer in

86% yield which was subjected to oxidition using Swern conditions in CH2Cl2 to afford an aldehyde,

which

was

directly

subjected

to

Wittig

olefination with

stable

ylide

carboethoxymethylenetriphenyl-phosphorane to produce trans α,β-unsaturated ester 24 in 83% yield over two steps. The α,β-unsaturated ester 24 underwent diastereoselective reduction using NaBH4, NiCl2.6H2O in methanol for 10 mins (Scheme 4) at 0 oC to provide the saturated ester, introduced to LiAlH4 reduction in dry THF at 0 oC for 1 hour to get the alcohol 25. The conversion was tried using LiBH4 in THF but it took more than 2 days for 80% conversion from 24 to 25. For Julia-Kocienski olefination the alcohol 25 was oxidized to aldehyde by using IBX 18

(iodoxybenzoic acid) in minimum amount of dry DMSO and THF solvent system at ambient temperature to afford the aldehyde 5.

a

b

HO

1, 6 Hexanediol

HO O

20 Bn c

Bn e N

O

OBn O

O

O

OBn O

10

22 h, i

f, g

HO

21

d

N

O

OBn

OBn

OBn

OH EtO2C

23 j

OBn

OBn 25

24

OBn O

5

H

Scheme 5 Reagents and conditions: a) BnBr, NaH, THF, 0 oC to r.t, 90%; b) BAIB, TEMPO, CH2Cl2:H2O, (2:1), 88%; c) Piv-Cl, Et3N, LiCl, (S)-Oxazolidinone, –20 oC, 83%; d) NaHMDS, MeI, –78 oC, 80%; e) LiBH4, MeOH (1drop H2O), 86%; f) (COCl)2, DMSO, Et3N, CH2Cl2, –78 oC, 90%; g) Ph3PCHCO2Et, CH2Cl2, 91%; h) NaBH4, NiCl2.6H2O, MeOH; i) LiAlH4, THF, 0 oC, 2 steps 85%; j) IBX, DMSO, THF, 87%.

Julia-Kocienski olefination: The sulfone 28 and aldehyde 29 was mixed and cooled at –78 oC, and 0.5M KHMDS was added to get the Julia-Kocienski olefination product in 65% yield (Scheme 6). Rf value of product and aldehyde was same even after three time runing in 20% of EtOAc in hexane. Then both the MEM and TBDPS ether were deprotected to get pure compound 26. The alkynediol 26 underwent Red-Al reduction using in diethyl ether for 30 min at room temperature to provide the allyl alcohol 27. The allyl alcohol 27 protected with triethylsilyl ether with TES-Cl and imidazole in dry CH2Cl2 at 0 oC to room temperature for overnight to provide diprotected compound, which on treatment with 1eq. of TBAF at 0 oC for 1 mins to get 28. For 19

intramolecular Diels-Alder cyclization, the alcohol 28 was oxidized to aldehyde 3 by using IBX oxidation, ensuring that secondary TES did not deprotect, IBX oxidation at ambient temperature afforded the aldehyde 3.

O N

OTBDPS

O

N

S

OBn

OMEM +

N N 4

Ph

O 5

H

a, b

OH

BnO OH

26 c

OH OH

BnO 27 OTES

d, e

OH

BnO 28 f

OTES O

BnO H

3

Scheme 6 Reagents and conditions: a) KHMDS, THF, –78 oC; b) 2N HCL, MeOH, 2 steps 60%; c) Red-Al, Ether, 85%; d) TES-Cl, Imdidazole, 92%; e) TBAF, 0 oC, 2 min, 75%; f) IBX, DMSO, THF, 1eq. NaHCO3, 82%.

Intramolecular Diels-Alder cyclization: The aldehyde 3 on heating at 180 oC in toluene with catalytic amount of BHT for 1day in a sealed tube under went intramolecular Diels-Alder cyclization to afford T2, the five and six member ring of trinervitanes skeleton (Scheme 7). BnO TESO

TESO Toluene, 0.1 eq. BHT,

CHO OBn

H H CHO H H

180 oC sealed tube, 20h. 70%

3

20

CH3 T2

Scheme 7 For cis five and six membered intramolecular Diels-Alder cyclization [2+4] half chair boat conformation is favorable, in which case intermediate 27a facing only C-3 H and C-7 CH3 steric hindrance that also is five carbon-carbon bond away where as intermediate 27b facing strong steric hindrance between C-3 H, C-4 H, C-7 CH3 and C-10 H (Figure 2). H Et3SiO 5

11

10 7

1

4

CH3 H

12

Cis-fusion

H3C H T2

H

H

Et3SiO

11 12

6

2

7 8

9

H

CHO H (CH2)4OBn

exo [2+4]

10

5 3

H

3a

H

H

Et3SiO

(CH2)4OBn

endo [2+4]

(CH2)4OBn

O

2

3

H3C H

H

Et3SiO

9

8

6

CHO

H

4

(CH2)4OBn

Cis-fusion H

O 1

H3C

3b

H

31

Figure 2

For further conformation we reduced the aldehyde T2 (Scheme 7) to alcohol 32.

BnO TESO T2

OH H

H H

NaBH4, MeOH, 0 oC. H

80% H 3C 32

Scheme 7

21

Further confirmed by NOESY interactions between the HA, HB and HC protons in 32 (Figure 3) gave full support in favor of the desired isomer which was also supported by quantum chemical calculations (Figure 1). Si HA

O

HC

H

HB

H3C

H

OH

H

H

H

H

OBn

H

H

H

H

H

H

H H

H

H

H

H H H

H H

H

32

Figure 3: NOESY interaction between the protons the HA, HB and HC.

In conclusion, we contructed stereoselective synthesis of the five and six member ring framework of the diterpene 2,3 dihydroxytrinervitanes with 19 carbon skeletons, where we used intramolecular Diels-Alder approach to contruct the core five and six member ring. We have executed highly stereoselective Julia-Kocienski olefination for the construction of the conjugated E-alkene , Sharpless epoxydation and Yadav’s protocol and Evan’s asymmetric alkylation to construct the chiral allyl aldehyde. The approach is thus feasible, simple and hopefully can be applied for first total synthesis of 2, 3 dihydroxytrinervitanes.

Chapter III, Section A 1,2-diketones have received a great attention because of their wide application in organic synthesis. Hypervalent iodine reagents have attracted increasing interest as oxidants in organic synthesis due to their mild, selective and environmentally benign nature. Among various hypervalent iodine reagents, o-iodoxybenzoic acid (IBX) is a versatile oxidizing agent because of its high efficiency, easy availability, mild reaction condition and its stability to moisture and air. In recent years, IBX has been used as versatile reagents in mediating a wide array of

22

transformations with far-reaching synthetic applicability. However, there are no reports on the use of IBX for the conversion of 1,3-diol to 1,2-ketones. We have reported for the first time, the direct conversion of 1,3-diols to 1,2-diketones by an oxidative cleavage of C-C bond by using 3.5 eq. IBX in DMSO at ambient temperature (Scheme 8).

OH

O

3.5 eq. IBX OH

R1

DMSO, THF, r.t.

R2

R1 O

R2 1

2

R1= alkyl, aryl R2= methyl, alkyl

Scheme 8

In efforts toward the synthesis of biologically active molecule (+) membrenone-C, (Figure 5) we attempted the selective oxidation of the primary alcohol in 1, 3-diol systems. Following the furan scheme we can get the compound A (scheme 25), followed by LAH reduction and protection deportations we can have the starting material 1b and 1c.

O

O O

O

(+)-Membrenone -C

Figure 5

We found that 1b and 1c with an excess of IBX, the 1,3-diol systems underwent oxidative cleavage to afford 1,2-diketones. Theoretically we should get B, but in situ decarbonylation of B gives the compound C (Scheme 9). For other oxidation system like PCC and swern oxidation we could not able to isolate any product or could not recover starting material. Encouraged by the result obtained by the oxidation of 1b to 2b, several other 1,3-diol systems with aliphatic and aromatic substituents were oxidized with 3.5 eq. of IBX to yield the respective 1,2-diketones in good yields within appreciable amounts of time. 23

O

O

LAH, THF

O OBn A

0 0C - rt, 4 hrs.

OH

OH

O

OBn OH

O

OBn OTBDPS

TBDPSO O

O

OH

OH

OH

OBn OH 1b

1c

A :Reaction conditions : 1).IBX(2 eq.) / DMSO, THF 2) (COCl)2 ,DMSO, Et3N, -780C

H

3) PCC, DCM,rt. O

O

O

O

O

B O

O

O

C O 1b

3.5 eq. IBX

TBDPSO

DMSO, THF, r.t.

OBn O 2b

Scheme 9

Noticeably, there were no considerable effect on the yield of products for simple aliphatic system or sterically hindered different type of hydroxy protecting groups present in 1,3-diols (entry a-d, Table 1) and aromatic systems (entry e-j, Table 1). Interestingly cyclic 1,3-diol 1k afforded unsaturated diketone 2k in 70% yield (entry k, Table 1). 2-Alkyl substituted 1,3-diol such as other than methyl under same reaction condition such as 2-pentyl-1,3-butanediol gave compound 2a, less than 30% yield. We have carried out the reaction using less equivalent of IBX with respect to 2methyloctan-1,3-diol (1a). Thus, treatment of compound 1a with 1 eq. of IBX gave a mixture of products 2a, 3 and 4 in a ratio of 55: 15: 30 in 35% yield after recovery of 60% starting diol (1a). 24

We were surprised to note that there was no hydroxy aldehyde in the mixture of the products formed. The products 2a, 3 and 4 were separated and further oxidized individually with 1 eq. of IBX. Thus, compound 3 was treated with 1 eq. of IBX to result in keto aldehyde 4 with diketone 2a. The keto aldehyde when further oxidized with 1 eq. of IBX resulted in only single product the diketone 2a. This experiment clearly revealed that 3 eq. of IBX will exclusively afford the 1,3-diol system to 1,2-diketone (Scheme 10).

OH

O

1 eq IBX OH

C5 H9

DMSO, THF, r.t.

O

C 5H 9

O

O

3

C5 H9

OH

O

DMSO, THF, r.t.

3

O

C5H9

H O

4

2a O

O

C 5H 9 4

O

1 eq IBX C 5H 9

OH

C5H9 2a O

1a

H

O

2 eq IBX C 5H 9

C 5H 9

OH DMSO, THF, r.t.

3 O C5 H9

H

2a O

1 eq IBX O

DMSO, THF, r.t.

4

O

C 5H 9 2a

O

Scheme 10

Plausible Reaction Mechanism A plausible mechanism is shown in (Scheme 11). The keto-aldehyde 4 would undergo tautomerism to form the keto-enol intermediate 5, which would form a spirocyclic intermediate 6 with 2-iodoxybenzoic acid most likely through nucleophilic attack; simultaneous ring cleavage gives the 1,2- diketone, and on workup fromic acid and iodosobenzoic acid were formed.

25

O

OH R

R

OH

O

O H

24

OH

R

H

R

OH

OH

28O

27

O

H

O O

O

R = alkyl, aryl

O

O H O O I O

workup

O

O H

O

H O

R

+

O

R O

O

I

H

O R

OH OH

O

I O

O

25

O O 29

IO +

OH

I

I

HCOOH

COOH

Scheme 11 In conclusion, we have developed a mild and efficient protocol for the conversion of 1,3-diols to 1,2-diketones using inexpensive and environmentally benign oxidant IBX and the protocol is very useful to get 1,2-diketones in presence of acid and base sensitive protecting group (entry bd, Table 1). In addition to its simplicity and efficiency, this method provides high yields of 1,2diketones with high selectively.

26

Table 1 1,2-Diketones synthesized from 1,3-diols by using IBX Entry Substrate (1) Producta (2) O

OH a

Time (h)

Yield (%)b

3.5

75

2.5

78

2.5

75

2.5

76

2.8

84

3.0

81

3.0

81

2.8

80

3.0

83

3.0

78

3.0

70c

OH O

b

O

TBDPSO

TBDPSO OBn OH OH

OBn O O

c O

O

OH OH

O

O

O

O d

OBn OBn OH OH

OBn OBn O O

OH OH e

O OH OH

O

f Cl

O

Cl O

OH OH

O

g OPh

OPh OH OH

O

h O 2N

O

O 2N OH OH

i

F

O O

F

O

OH OH j

O

MeO

MeO

O

OH OH

O

k

a Reaction

conditions: 1,3- diol (1mmol), iodoxybenzoic acid (3.5 mmol). b Isolated yield. 4.0 mmol of IBX was used. c

27

Chapter III, Section B B.1: Synthesis of 4-Chlorotetrahydropyrans via Prins- cyclization. We wish to report a mild and efficient version of Prins-cylization for the rapid synthesis of halogenated tetrahydropyrans. Accordingly, treatment of benzaldehyde 1 with 3-buten-1-ol 2 in presence of 20 mol% of niobium chloride afforded 4-chloro-2-phenyltetrahydro-2H-pyran 3a in 92% yield (Scheme 12). Cl O Ph

20 mol% NbCl5 H

+

r.t., 10-30 min

HO 1

2

Ph

345 21 6 O 3a

Scheme 12

The stereochemistry of 3a was assigned on the basis of coupling constants of the hydrogens at C-2 and C-4 positions. The coupling constants of the benzylic hydrogens 2-Hc (δ 4.30, J = 11.3 Hz) ppm as well as the hydrogen on the carbon bearing the halide group 4-Hc (δ 4.18, J = 4.5 and 11.3 Hz) ppm in the 1H NMR spectrum showed a structure consistent with the phenyl group and the halide group being in the cis-configuration and equatorial position as shown in Fig. 1. The signal at δ 4.30 (2-Hc) ppm of 3a showed nOe correlation with the signal at δ 4.18 (4-Hc) ppm. H

Ph

Cl H (δ, 4.18, J = 4.5, 11.3 Hz) H

O

H (δ, 4.30, J = 11.3 Hz)

nOe

Figure 6: Important nOe’s of product 3a

In a similar manner, various substituted benzaldehydes such as o-chloro-, m-phenoxy-, p-cyano-, p-fluoro-, and p-nitro-derivatives reacted efficiently with 3-buten-1-ol to afford the corresponding 4-chloropyrans (entries b-f, Table 1). Furthermore, aliphatic aldehydes such as npropanal, phenyl ethanal and n-hexanal also afforded the similar adducts under the reaction 28

conditions (entries h, i and j, Table 1). The reactions are clean and the products were obtained in excellent yields with high diastereoselectivity. Like niobium(V) chloride, gallium tribromides (35 mol%) and gallium triiodide (35 mol%) gave the corresponding bromo- and iodo-adducts respectively, under similar conditions (entries g, k and l, Table 1, Scheme 13). X O R

35 mol% GaX3 H

+ r.t., 10-25 min

HO 1

2

O

R

3 X = Br, I

Scheme 13 In all cases, the reactions proceeded rapidly at room temperature with high efficiency. In the absence of catalyst, no reaction was observed between homoallyl alcohol and aldehyde. As solvent, dichloromethane appeared to give the best results. + NbCl4 O R

NbCl5 H

+

Cl

O HO

- HCl

R

Cl

(+)

O

- [NbOCl4] -

R

O

R

O

Scheme 14 Among various Lewis acids such as InCl3, InBr3, InI3, CeCl3.7H2O-NaI and BiCl3 tested, niobium(V) chloride and gallium tribromide or triiodide were found to be the most effective catalysts for this conversion. The formation of the products may be explained by hemi-acetal formation and subsequent Prins-type cyclization (Scheme 14). Various functional groups, e.g. halogens, methoxy, phenoxy and nitro subtituents were well tolerated under these reaction conditions. The nature of the substituents on the aromatic ring shows some effect on this conversion. It should be noted that simple aromatic and moderately activated aldehydes like chloro, fluoro and meta-phenoxy benzaldehydes gave better yields of products compared to the strongly activated or deactivated ones. Finally, we attempted the coupling of aldehydes with allyl alcohol (2-propen-1-ol) in presence of niobium(V) chloride and gallium(III) halides. No reactions were observed under the reaction condition. The scope and generality of this process is illustrated with respect to various aldehydes and the results are presented in Table

29

Table 1: synthesis of 4-halotetrahydropyran derivatives Entry

Aldehyde

3-buten-1-ol

Catalyst

Producta

Time (min)

Yield (%)b

Cl a

CHO

OH

20 mol% NbCl5

10

92

12

95

15

90

O Cl

Cl CHO

b

"

Cl 20 mol% NbCl5

O Cl

c

"

d

PhO

CHO

CHO

"

20 mol% NbCl5

PhO

O

20 mol% NbCl5

10

93

15

89

12

91

10

89

O

NC NC

Cl CHO e

"

20 mol% NbCl5

O

F F

Cl

CHO f

"

20 mol% NbCl5

O2N

O O2N I

g

"

Br

CHO

35 mol% GaI3

Br

O

Cl h

"

CHO

20 mol% NbCl5

O

25

78

20

82

30

80

15

87

25

82

Cl i)

"

Ph

CHO

20 mol% NbCl5

Ph

O Cl

j

"

CHO

20 mol% NbCl5 O Br

k

"

CHO

35 mol% GaBr3

O I

l

"

CHO

35 mol% GaI3 O

30 aAll

1.

products were characterized by IR, NMR and mass spectroscopy. and unoptimized yields

bIsolated

Chapter III, Section B B.2: Gallium chloride catalyzed three component coupling of naphthol, alkyne and aldehyde: a novel synthesis of 1,3-diaryl-3H-benzo[f] chromenes via Prins- cyclization. We developed a novel and efficient protocol for the alkenylation and alkylation of naphthols and phenols with aryl acetylenes and vinyl arenes using a catalytic amount of gallium(III) chloride. Initially, we attempted the hydroarylation of phenyl acetylene (2), with βnaphthol (1) in the presence of 10 mol% of gallium(III) chloride. The reaction proceeded smoothly in refluxing toluene to afford 1-(1-phenylvinyl)-2-naphthol 3a in 80% yield (Scheme 16).

GaCl3

OH

Toluene, reflux 1

2

3

Scheme 16 We reported a novel protocol for the one-pot synthesis of 1,3-diaryl-3Hbenzo[f]chromenes by means of a coupling of naphthol, alkyne and aldehyde using a catalytic amount of GaCl3. Accordingly, we first attempted a three component coupling (3CC) of 2naphthol (1) with phenyl acetylene (2) and benzaldehyde (4) using 10 mol% GaCl3 in toluene. The reaction proceeded at 110

o

C in toluene and the desired product, 1,3-phenyl-3H-

benzo[f]chromene 5a, was obtained in 75% yield (Scheme 17).

OH

CHO

GaCl3

O

Toluene, reflux 1

2

4

5

Scheme 17 31

This result provided incentive to extend this process for various substrates. Interestingly, a wide variety of aldehydes such as cyclohexanecarboxaldehyde, 1-octanal, 4-methoxybenzaldehyde, 2-bromobenzaldehyde, cinnamaldehyde and citral underwent smooth coupling with 2-naphthol and phenyl acetylene under identical conditions (entries c-h, Table 1). Other alkynes such as 1-ethynyl-4-methylbenzene and 1-octyne also underwent coupling with naphthol and benzaldehyde to give the corresponding chromene derivatives in good yields (entries b, l and i, Table 1). Besides β-naphthol, α-naphthol and p-cresol also participated in the 3CC reaction (entries j-m, Table 1). The products were fully characterized by NMR, IR and mass spectroscopy. In the absence of catalyst, no reaction was observed even after long reaction time (12 h) under reflux conditions. Toluene appeared as a solvent of choice for the best conversions. The effects of various metal halides such as FeCl3, BiCl3, InCl3, ZnCl2, CeCl3.7H2O and metal triflates like In(OTf)3, Bi(OTf)3, Sc(OTf)3, Yb(OTf)3 were screened for this conversion. Of these, GaCl3 was found to be the most effective in terms of conversion. This is because of high alkynophilicity of gallium. However, Brønsted acids such as montmorillonite K10, heteropoly acid and ion-exchange resins failed to produce the desired product. In the absence of aldehyde, only 1-(1-phenylvinyl)naphthalen-2-ol was obtained exclusively. It reveals that the reaction proceeds via arylation of alkyne followed by a subsequent cyclization with aldehyde would give the desired chromene (Scheme 18). Ga Ga(III)

Ph

H

.. OH

O Protodemetallation

+

+ O Ga(III)

H Ph

H H

H

OGa(III)

Ph

OH ..

Ph O Ph

Scheme 18 32

.. O

Ph

The scope of this method is illustrated with respect to various aldehydes and alkynes and the results are presented in Table 1.6 Table 1: Gallium(III) chloride-catalyzed three component coupling of naphthol, alkyne and aldehyde Entry

Naphthol/Phenol

Alkyne

Producta

Aldehyde

OH

OH

b

Yield(%)b

Ph

Ph

CHO

a

Time (h)

O

CHO

Ph

2.0

75

2.0

72

2.5

75

2.5

70

2.5

69

3.0

76

2.0

68

2.0

70

3.0

68

2.0

72

2.0

72

2.0

70

4.0

65

O

OH

c

CHO O

CHO

OH

d

O CHO OH

e

OMe MeO O

OH

f

Br CHO O

CHO

OH

g

Br

Ph O OH

h

CHO O

OH

i

CHO

Ph O

OH

Ph

CHO

j

O

OH

Ph

Br CHO

k

O

Br

Ph OH

O

CHO

l

Ph

OH m

CHO CH3

a

Products were characterized by NMR, IR and mass spectroscopy. Yield refers to pure products after column chromatography.

b

33

O