SECTION D)

CHAPTER II

PART II

Results and Discussion

In the Chapter II of the Part II in the Section A, Section B and Section C, we have shown that bromonium ion can be applied for dethioacetalization reaction. We have also developed first time catalytic synthetic protocol for deprotection of dithioacetals by involving bromonium ion by employing peroxovaanadium oxidation of bromide ion to the bromonum ion. Although this procedure is quite effective as compared to the other methods, still we were interested whether some other method can be devised by using a combination of other reagents. The usual standard procedure for cleavage of dithioacetals is by involving mainly a suitable electrophile, which is captured by soft nucleophile sulfur atom followed by hydrolysis with water. Then, we realize whether the electrophilic species such as NO⁺ can be employed for regeneration of carbonyl compounds from the corresponding protected compounds or not as we are working mainly to develop a new synthetic methodology. After going through the literature, we have noticed that sodium nitrite in combination with trifluoroacetic acid,¹⁰³ isoamyl nitrite¹¹⁸ and a mixture of nitrogen oxides¹¹⁹ have been used for deprotection of dithioacetals to the carbonyl compounds. However, these procedures have some drawback such as incompatibility with other protecting group like TBS ethers due to large excess of trifluoroacetic acid, drastic reaction conditions and longer reaction times,¹¹⁸ and provide low yield for enolizable ketone.¹¹⁹In this chapter, we would like to discuss that sodium nitrite in combination with acetyl chloride is a useful reagent system for cleavage of dithioacetals under a mild reaction conditions as depicted in scheme 70.

R1= alkyl / aryl / sugar residue; R2= H / alkyl / aryl;

R3= Et, - (CH2)2-, -(CH2)3-

Scheme 70

C R₁

R₂

SR₃

SR₃

C R₁

R₂

O NaNO₂/ CH₃COCl / H₂O

0^oC-rt, CH₂Cl₂

As per our requirement, we prepared various acyclic and cyclic dithioacetals by employing our method or followed by other method. When the compound 109 was treated with 2 equivalent amount of NaNO2-CH3COCl (1:1) mixture at 0-5^oC, it was smoothly converted to the product 205 in good yield. The product was identified by comparison of IR and ¹H NMR with the authentic sample spectra. Similarly, the compound 111 was transformed to the compound 207 in good yields by following identical procedure without acetylation of the hydroxyl group. Likewise, various acyclic and cyclic dithioacetals 107-188 (Table 7) were cleaved chemoselectively to the parent carbonyl compounds (205-193) under identical conditions without affecting other protecting groups. Moreover, by using our protocols diethyldithioacetals of carbohydrate compounds such as 135 and 214 can be transformed easily into the corresponding open chain aldehydic sugars 194 and 220, respectively.

Table 7. Cleavage of Various Dithioacetals Using NaNO2-CH3COCl / H2O in CH2Cl2

Substrate Substra te No.

Time in min

Product^a Product No.

Yield^b (%)

AcO

S S

109 225 ^{AcO CHO} 205 85

HO

S S

114 15 HO CHO 207 90^c

BnO

S S

107 45 BnO CHO 206 97

TBSO

S S

105 70 TBSO CHO 209 85

OTBS

S

S 133 45

OTBS CHO

204 94

MeO

SEt SEt

101 90 MeO CHO 65 98

MeO

S S

66 30 MeO CHO 65 95

MeO

S S

34 45 MeO CHO 65 90

MeO

S S

OMe

103 45 ^{MeO CHO}

OMe

190 97

MeO MeO MeO

SEt SEt

184 45 ^{MeO CHO}

MeO MeO

189 96

MeO MeO MeO

S S

38 90 ^{MeO CHO}

MeO MeO

189 96

SEt SEt

111 60

CHO

162 95

S S

112 45

CHO

162 96

MeO

S S Br

221 45 ^{MeO CHO}

Br

222 80

CH(SEt)₂ 210

30 ^CHO

151

95

O

S S

106 40 ^{O CHO} 216 97

CH₃(CH₂)₁₀CH(SEt)₂ 187 70 ^CH3(CH₂)₁₀CHO 192 82

SEt EtS

186 70

O

85 90

SEt EtS

211 45

O

215 87

S S 136 45

O

215 90

SEt

SEt 188 45

O

193 78

AcO CH(SEt)₂ OAc

OAc OAc

135 45 _AcO ^CHO

OAc OAc

OAc

194 75

AcO CH(SEt)₂ OAc

OAc OAc

214 60 _AcO ^CHO

OAc OAc

OAc

220 72

aProducts have been characterized by co-IR with the authentic compounds, ¹H NMR and elemental analyses of the samples.^bIsolated yields.

cAfter addition of the substrate, water was added after 2 min. instead of 5 min.

The starting dithoacteals 133 and its hydrolyzed 204 products were characterized by recording IR,¹H NMR as shown in the figures 39-41.

The formation of the parent carbonyl compounds from their corresponding dithiacetals can be rationalized as follows. Sodium nitrite reacts with acetyl chloride to form acetyl nitrite, which ultimately generates a highly reactive species NO⁺ ion. Then the reactive species NO⁺reacts with sulfur atom to form a complex¹¹⁸, which is finally hydrolyzed by water to provide the carbonyl compound, as represented by scheme 71.

NaNO₂+ CH₃COCl

CH₃CO-ONO + CH₃COCl NOCl + (CH₃CO)₂O 2 CH₃COOH H₂O

CH₃CO-ONO + NaCl

R₁ SR₃ R₂

SR₃

R₁ SR₃ R₂

SR₃

NO R₁

SR₃ R₂

OH R₁

SR₃ R₂

OH

NO

R₁ R₂

O

NO⁺ -R₃SNO

H₂O

NO⁺

-R₃SNO

I II III IV

V Scheme 71

In conclusion, we have demonstrated mild and easy to handle procedure for deprotection of dithioacetals to the parent carbonyl compounds by using a mixture of sodium nitrite and acetyl chloride, which is a useful addition to the existing procedures. In addition, this methodology is compatible with the presence of a large number of other protecting groups such as acetyl, benzyl, benzoyl, TBS ether, allyl and also provide good yield for enolizable ketones.

CHAPTER II

PART II (SECTION D)

NEW SYNTHETIC PROCEDURE FOR REGENERATION OF CARBONYL COMPOUNDS FROM THEIR CORRESPONDING DITHIOACETALS USING A COMBINATION OF SODIUM NITRITE AND ACETYL CHLORIDE

EXPERIMENTALS

Experimental

The characterization data of all dithioacetals and their corresponding carbonyl compounds are mentioned in the previous Chapter I and Chapter II in the experimental section except the dithioacetal derivative 221 and its corresponding aldehyde 222.

2-[3-Bromo-4-methoxyphenyl]-1,3-dithiane (221):

Nature: White solid Yield: 87%

Rf: 0.75 (Hexane/AcOEt = 9.5: 0.5) IR (KBr): cm^-12945, 2889, 2832, 1598, 1485, 1408, 1270, 1050, 1009, 901, 768

1H NMR (400 MHz, CDCl3):  1.91 (m, 1H, -SCH2CHCH2S-), 2.16 (m, 1H, - SCH2CHCH2S-), 2.9(m, 2H, -SCH2-), 3.03 (m, H, -SCH2-), 3.88 (s, 3H, -OCH3), 5.08 (s, 1H, ArCH-), 6.85 (d, 1H, J = 8.56 Hz, ArH), 7.38 (dd, 1H, J = 1.96 Hz, J = 8.04 Hz, ArH), 7.67 (d, 1H, J = 2.2 Hz, ArH)

13C NMR (100 MHz, CDCl3):  24.95, 32.05 (2C), 49.94, 56.29, 111.65, 111.83, 127.93, 132.71, 155.84, 158.98

Elemental Analysis Calculated Found

C11H13BrOS2 C 43.28 C 43.36

305.25 H 4.29 H 4.34

S 21.01 S 21.09

A typical procedure for deprotection of Dithioacetals

The reaction mixture of NaNO2(0.138 g, 2 mmol) and AcCl (142L, 2 mmol) in CH2Cl2

(3 ml) was stirred for 10 min at 0-5 C. Then, the substrate (1 mmol) in CH2Cl2 (2 ml) was added into the above reaction mixture at the same temperature. After stirring for 5 min, water (1 ml) was added into it and the reaction mixture was brought to room temperature. The reaction was completed in short time as shown in the Table 7. Finally,

MeO Br

S S

the reaction mixture was neutralized with NaHCO3 and extracted with CH2Cl2 (2 15 ml). The organic layer was washed with water (2  20 ml) and dried over Na2SO4. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel to obtain the desired compounds.

3-Bromo-4-methoxybenzaldehyde (222):

Nature: White solid Yield: 80%

Melting point: 52C [Lit. 51-54C]

1H NMR (400 MHz, CDCl3):4.00 (s, 3H, -OCH3), 7.01 (d, 1H, J = 8.4 Hz, ArH), 7.82 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz, ArH), 8.08 (d, 1H, J = 2.0 Hz, ArH), 9.80 (s, 1H, -CHO)

Elemental Analysis Calculated Found

C8H7BrO2 C 48.27 C 48.35

199.05 H 3.54 H 3.59

CHO MeO

Br

Figure 27:¹H NMR Spectrum of diethyldithioacetal of 4-Nitrobenzaldehyde (400 MHz, CDCl3) (132)

O₂N

SEt SEt

Figure 28:¹³C NMR Spectrum of diethyldithioacetal of 4-Nitrobenzaldehyde (100 MHz, CDCl3) (132)

O₂N

SEt SEt

Figure 29:¹H NMR Spectrum of diethyldithioacetal of Cyclododecanone (400 MHz, CDCl3) (188)

SEt SEt

Figure 30:¹³C NMR Spectrum of diethyldithioacetal of Cyclododecanone (100MHz, CDCl3) (188)

SEt SEt

Figure 31:¹H NMR Spectrum of Diethyldithioacetal of tetraacetate Arabinose (400 MHz, CDCl3) (135)

AcO CH(SEt)₂ OAc

OAc

OAc

Figure 32:¹³C NMR Spectrum of Diethyldithioacetal of tetraacetate Arabinose (100 MHz, CDCl3) (135)

AcO CH(SEt)₂ OAc

OAc

OAc

Figure 33:¹H NMR Spectrum of 4-Nitrobenzaldehyde (400MHz, CDCl3) (191)

CHO O₂N