Unusual Reactions of the 1,3-Dithiane Derivative of the Garner Aldehyde and Related Compounds

Abstract

Treatment of the 1,3-dithiane derivative of the Garner aldehyde with alkyl halides in the presence of n-butyllithium resulted in a ring-opening reaction to give differentially substituted propane-1,3-dithioethers, instead of the expected 2,2-dialkylated 1,3-dithiane products. The corresponding 1,3-dithiolane derivative also reacted in a similar manner. Such ring-opening reactions of dithiane or dithiolane derivatives are rare. A detailed study of this unusual reaction was carried out and a possible mechanism is proposed.

Garner’s aldehyde (1) and a number of related derivatives have been widely used in the synthesis of various natural and unnatural products. Aldehyde 1 has quite often been used as an efficient chiral starting material for the synthesis of a number of amino acids and carbohydrate derivatives.[1] In connection with our efforts to develop new methods for the synthesis of unnatural amino acids,[2] we postulated that the use of the 1,3-dithiane derivative of 1, as an umpolung equivalent of the aldehyde function, could be a suitable starting material. Although the chemistry of the Garner aldehyde (1) has been widely studied and applied, its 1,3-dithiane derivative has not been reported. We believed that the use of such a derivative could add a new dimension to the chemistry of this versatile synthetic precursor. To our surprise, the 1,3-dithiane derivative 2 synthesized from 1 reacted quite differently to other dithianes and in a completely unpredictable manner. Our observations and the results of related studies toward understanding this rather unusual reactivity are reported here.

The 1,3-dithiane derivative of the Garner aldehyde was synthesized by treatment of 1 with propane-1,3-dithiol (BF₃·OEt₂, CH₂Cl₂, –20 °C). The reaction conditions resulted in the opening of the oxazolidine ring, yielding an amino alcohol derivative 3, which was recyclized with 2,2-dimethoxypropane (p-TsOH, benzene, 80 °C) to provide 2 (Scheme [1]).

As an initial reaction, we attempted to couple 1,3-dithiane 2 with benzyl bromide, after generating the corresponding anion using n-butyllithium (1.5 equiv, THF, –20 °C), and expected to obtain the 2,2-disubstituted 1,3-dithiane derivative 4 (Scheme [2]). The reaction proceeded cleanly and only a single product could be isolated; however, the NMR spectra of the product did not match what was expected for 4 and looked very simple, unlike those of many dithiane derivatives. A careful spectroscopic analysis of the product indicated that the dithiane ring had been cleaved under the reaction conditions. The product formed was an unsymmetrical propane-1,3-dithioether, namely 5a (Figure [1]). The ¹H and ¹³C NMR spectra confirmed the presence of a double bond in the compound. The individual peaks in ¹H NMR spectrum were correlated with the ¹³C peaks using heteronuclear correlation spectroscopy and the configuration of the double bond was determined from NOE experiments.

In order to further confirm the structure of the product formed in this reaction, the oxazolidine ring of 5a was opened and the Boc group was removed by treatment with trifluoroacetic acid (50% in MeOH). As expected, the ketone derivative 6 was isolated, in 91% yield (Scheme [3]), confirming the structure of 5a as that shown in Figure [1].

The formation of 5a as the only isolable product was surprising, and we could not isolate even traces of the expected product 4. Products similar to 5a, formed via opening of the dithiane ring, have very rarely been observed. The only other report of such a reaction was in the case of a dithian-2-yl derivative of diethyl malonate, which underwent a ring-opening reaction on treatment with sodium hydride and iodomethane.[3] It has also been shown that S-alkylation of dithianes can be exploited to achieve ring opening of dithianes.[4] However, since then, cleavage of the dithiane ring as a side reaction during umpolung reactions has not been reported. This prompted us to study this reaction further to comprehend our observation of this unusual reactivity. We performed the reaction of 1,3-dithiane 2 with three other alkyl halides, and the results are listed in Table [1]. All of the alkyl halides studied reacted with 2 in the same way as benzyl bromide, and the yields were generally good. Alkyl iodides and bromides reacted in the same manner, and varying the temperature of the reaction did not have any effect on the nature of the product formed (see entries 4 and 5).

Table 1 Reaction of 1,3-Dithiane 2 with Alkyl Halides

Entry	RX	Temp (°C)	5	Yielda (%)
1	PhCH2Br	–20	5a	52
2	H2C=CHCH2Br	–20	5b	47
3	i-PrBr	–20	5c	50
4	MeI	–20	5d	54
5	MeI	–78	5d	51

^a Isolated yield.

We attempted the reaction of 1,3-dithiane 2 with other electrophiles, such as 4-nitrobenzaldehyde and ethyl acrylate. These compounds did not react with 2 to give any isolable products; however, unreacted 2 could not be isolated from the reaction mixture. After the addition of n-butyllithium, the 1,3-dithiane 2 disappeared completely by TLC, indicating that it decomposes in the absence of an alkyl halide to react with. In order to confirm this observation and also to understand the exact nature of the deprotonation of 2 with n-butyllithium, we tried to quench the anion with D₂O and CD₃OD. When one or more equivalents of n-butyllithium were used and the reaction was quenched with deuterated solvents, we could not isolate any amount of deuterated 2. TLC showed complete disappearance of the starting material and formation of a mixture of polar products, none of which could be isolated and characterized. When the reaction was carried out with 0.5 equivalents of n-butyllithium and the reaction mixture was quenched with D₂O, almost half of compound 2 could be recovered; however, an NMR analysis of 2 isolated from the reaction mixture did not indicate the presence of deuterium. The experiment suggests that deprotonation of 1,3-dithiane 2 leads to its decomposition, unless a very reactive electrophile such as an alkyl halide is present.

It is known that protons in the α-position to a N-Boc group are reasonably acidic.[5] Hence, it is justified to assume that in compound 2 the C–H adjacent to the N-Boc group is more acidic than the 2-H in the 1,3-dithiane, and thus deprotonated upon treatment with n-butyllithium. We propose the following mechanism for the unusual reaction of 2 with alkyl halides in the light of these assumptions (Scheme [4]). It is most likely that the cleavage of the 1,3-dithiane ring happens only as a result of the formation of the sulfonium ion A. If a sulfide anion was formed prior to the reaction of the sulfur atom with benzyl bromide, the same anion could have reacted with ethyl acrylate, but it does not. Any stable anionic species formed as an intermediate in the above reaction could have given an isolable product on treatment with D₂O. The absence of any isolable deuterated product even after repeated attempts indicates the possible formation of A which, when not possible in the absence of an alkyl halide, results in complete decomposition of the anion formed.

If the C–H adjacent to the N-Boc group was rendered less acidic, the reaction of 2 could have proceeded as expected. To substantiate this argument, we prepared the O-benzyl derivative 7 of the amino alcohol 3, and treated it with allyl bromide in the presence of excess n-butyllithium. The reaction yielded the 2-allyl-1,3-dithiane derivative 8, albeit in moderate yield (Scheme [5]). The reaction may have proceeded with deprotonation of the NHBoc group, thereby reducing the acidity of the adjacent C–H.[6] Excess n-butyllithium deprotonates the 1,3-dithiane at the 2-position, generating the dithianyl anion B, which reacts with allyl bromide to give derivative 8, as expected.

The reaction of dithianes with a base is quite different to that of the corresponding dithiolanes. Dithiolanyl anions are known to dissociate into dithiocarboxylates and ethylene.[7] We assumed that if a dithiolane equivalent of 2 could be prepared, its reaction with n-butyllithium would confirm the position of initial deprotonation. If the deprotonation occurs at the 2-position of the dithiolane the product would be a dithiocarboxylate derivative, whereas deprotonation of the C–H adjacent to the N-Boc group would result in a product similar to 5. The 1,3-dithiolane derivative 9 was prepared from the Garner aldehyde (1) using a procedure similar to that used for the preparation of 1,3-dithiane 2. When 9 was treated with benzyl bromide and n-butyllithium, the dithioether 10 was obtained (Scheme [6]), confirming the proposed mechanism for the reaction of 2.

Based on the above observations, a similar reactivity profile could be anticipated for the 1,3-dithiane and 1,3-dithiolane derivatives of N-protected prolinals. We synthesized the 1,3-dithiolane 11 and 1,3-dithiane 12 derivatives of Boc-prolinal following the procedure used for the synthesis of derivatives 9 and 2. When the 1,3-dithiolane derivative 11 was treated with n-butyllithium (1.5 equiv) and benzyl bromide (1 equiv), the only isolable product was the dithio derivative 13, in low yield. On performing the reaction with 2.5 equivalents of n-butyllithium and 2 equivalents of benzyl bromide, product 13 could be isolated in 62% yield (Scheme [7]). The formation of 13 gives a new insight into these reactions. The 2-H in the 1,3-dithiolane is the first proton to be removed in this reaction, which results in the elimination of ethylene and formation of the benzyl dithiocarboxylate derivative C; however, the proton adjacent to the N-Boc group becomes more acidic after the formation of derivative C, and is deprotonated. The formation of thioenolate D from C results in a subsequent reaction with one more equivalent of benzyl bromide, giving the product 13 (Scheme [7]). This is a clear indication that the acidity of the 2-alkyl-2-dithiolanyl proton, and possibly that of 2-alkyl-2-dithianyl protons, lies between the acidity of the C–H adjacent to the N-Boc group in 9 and that of the adjacent C–H in 11. Unfortunately, the reaction of the corresponding 1,3-dithiane 12 with n-butyllithium and benzyl bromide was quite complex and we could not isolate any products from the reaction, even after repeated efforts at different temperatures (Scheme [8]).

In conclusion, our studies clearly suggest that dithianes and dithiolanes react in an unusual manner if an acidic β-hydrogen is present in the molecule. Ideally, a base-­induced reaction, such as those with dithianes, should not have any other acidic protons in the substrate. However, a clear definition of how much acidity could be accommodated in such a reaction is not trivial. Our studies shed more light on defining such a limit for reactions involving dithianes and dithiolanes, and also provide a very curious reactivity profile for compounds with an acidic β-hydrogen. The ring-opening reaction is facilitated if the β-carbon is sterically hindered, as in the case of the Garner aldehyde or prolinal derivatives. From our studies, it is safe to say that the acidity of the 2-CH of 2-alkyl-1,3-dithianes and -dithiolanes is between that of the 2-CH of a N-Boc-protected pyrrolidine and the 4-CH of a N-Boc-protected oxazolidine.

All the chemicals were purchased from commercial sources and were used without further purification. ¹H and ¹³C NMR spectra were recorded either on a 400 MHz (100 MHz for ¹³C) or on a 500 MHz (125 MHz for ¹³C) JEOL-Lambda NMR spectrometer at 25 °C. The ¹H NMR signals are referenced to TMS (δ = 0.00 ppm) and the ¹³C NMR peaks are referenced to the residual CHCl₃ signal (δ = 77.0 ppm). The chemical shifts are reported in parts per million and coupling constants in Hz. The multiplicities are assigned as s (singlet), d (doublet), t (triplet), qu (quintet), br s (broad singlet), dd (double doublet) and m (multiplet). High-resolution mass spectra were obtained using a Waters Q/Tof Premier micromass HAB 213 spectrometer with an ESI source. IR spectra were recorded on a Bruker Vector 22 FTIR instrument and melting points were recorded on a DBK Automatic Programmable digital instrument. Column chromatography was performed using 100–200 mesh silica gel, and appropriate mixtures of petroleum ether (PE) and EtOAc were used as eluent.

1,3-Dithiane Derivatives of the Garner Aldehyde and Boc-Prolinal

A soln of the Garner aldehyde (1; 1.145 g, 5 mmol) or Boc-prolinal (0.995 g, 5 mmol) in CH₂Cl₂ was cooled to –20 °C, and propane-1,3-dithiol (0.500 mL, 0.540 g, 5 mmol) was added under nitrogen. The solution was stirred at –20 °C and BF₃·OEt₂ (0.001 mL) was added. The reaction mixture was allowed to attain r.t. (30 °C) and the stirring was continued until complete disappearance of the starting material (by TLC). The reaction was quenched by adding H₂O (10 mL) and the mixture was diluted with CH₂Cl₂ (50 mL) and then transferred into a separating funnel. The organic layer was separated and washed with a 10% soln of KOH (15 mL) and with brine (15 mL), dried over anhyd Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography. Although the expected 1,3-dithiane derivative 12 was obtained from Boc-prolinal, the product obtained from the Garner aldehyde was the amino alcohol derivative 3, which was cyclized to provide the 1,3-dithiane derivative 2 in a subsequent step.

The amino alcohol derivative 3 (0.837 g, 3 mmol) was suspended in benzene (10 mL), and 2,2-dimethoxypropane (0.734 mL, 0.624 g, 6 mmol) and p-TsOH (0.010 g, 0.06 mmol) were added. The reaction mixture was refluxed for 2.5 h, quenched with sat. Na₂CO₃ soln (10 mL) and extracted with Et₂O (2 × 30 mL). The crude solution was dried over anhyd Na₂SO₄ and concentrated, and the 1,3-dithiane 2 was purified by column chromatography.

N-Boc-Protected 2-Amino-2-(1,3-dithian-2-yl)ethanol (3)

Yield: 976 mg (70%); oily liquid; R_f  = 0.45 (PE–EtOAc, 7:3).

IR (thin film): 3418, 1694 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 5.18–5.22 (m, 1 H), 4.29 (d, J = 5.0 Hz, 1 H), 3.99 (br s, 1 H), 3.91 (dd, J = 11.2, 3.7 Hz, 1 H), 3.74 (dd, J = 11.5, 4.6 Hz, 1 H), 2.79–2.93 (m, 4 H), 1.86–2.07 (m, 2 H), 1.43 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 156.0, 80.0, 63.0, 54.9, 48.6, 29.6, 28.3, 25.7.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₁H₂₁NO₃S₂: 302.0861; found: 302.0754.

N-Boc-Protected 4-(1,3-Dithian-2-yl)-2,2-dimethyloxazolidine (2)

Yield: 918 mg (96%); white crystalline solid; mp 71–73 °C; R_f  = 0.50 (PE–EtOAc, 15:1).

IR (KBr): 1698 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 4.45–4.49 (m, 1 H), 4.12–4.19 (m, 2 H), 3.88–3.91 (m, 1 H), 2.72–2.85 (m, 4 H), 1.79–2.05 (m, 2 H), 1.41–1.57 (m, 15 H).

¹³C NMR (125 MHz, CDCl₃): δ (mixture of rotamers) = 152.7, 151.8, 94.7, 94.1, 80.6, 80.4, 65.2, 65.0, 60.3, 60.1, 51.3, 49.1, 30.4, 30.1, 28.6, 28.5, 26.1, 25.9, 24.3.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₄H₂₅NO₃S₂: 342.1174; found: 342.1171.

N-Boc-Protected 2-(1,3-Dithian-2-yl)pyrrolidine (12)

Yield: 1.29 g (89%); solid; mp 66–68 °C; R_f  = 0.50 (PE–EtOAc, 97:3).

IR (KBr): 1684 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ (mixture of rotamers) = 4.79 (br s), 4.60 (br s), 4.07 (br s), 3.98 (br s), 3.70 (br s), 3.49 (br s), 3.22–3.27 (m), 2.74–2.89 (m), 2.57–2.61 (m), 2.06–2.08 (br s), 1.92–1.93 (br s), 1.42–1.45 (m).

¹³C NMR (125 MHz, CDCl₃): δ (mixture of rotamers) = 154.7, 154.2, 79.9, 79.6, 61.3, 60.2, 53.8, 52.1, 47.6, 47.1, 33.5, 33.4, 31.4, 30.7, 30.1, 28.6, 27.7, 27.4, 26.4, 24.5, 24.4, 23.8, 23.5, 23.3.

HRMS (ESI): m/z [M + H⁺] calcd for C₁₃H₂₃NO₂S₂: 290.1248; found: 290.1248.

1,3-Dithiolane Derivatives of the Garner Aldehyde and Boc-Prolinal

The 1,3-dithiolane derivatives 9 and 11 of the Garner aldehyde and Boc-prolinal, respectively, were prepared using a similar procedure to that used for the 1,3-dithiane derivatives.

N-Boc-Protected 4-(1,3-Dithiolan-2-yl)-2,2-dimethyloxazolidine (9)

Yield: 960 mg (63%); white crystalline solid; mp 70–72 °C; R_f  = 0.50 (PE–EtOAc, 15:1).

IR (KBr): 1703 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ (mixture of rotamers) = 5.07, 4.92 (1 H), 4.20, 4.06 (1 H), 3.96–4.00 (m, 2 H), 3.19–3.25 (m, 4 H), 1.45–1.61 (m, 15 H).

¹³C NMR (125 MHz, CDCl₃): δ (mixture of rotamers) = 152.9, 152.0, 95.3, 94.7, 80.6, 80.4, 65.7, 65.3, 61.1, 60.9, 55.7, 55.2, 38.9, 38.9, 38.7, 38.5, 28.5, 28.4.

HRMS (ESI): m/z [M + H⁺] calcd for C₁₃H₂₃NO₃S₂: 306.1198; found: 306.1194.

N-Boc-Protected 2-(1,3-Dithiolan-2-yl)pyrrolidine (11)

Yield: 963 mg (70%); gummy solid; R_f  = 0.50 (PE–EtOAc, 97:3).

IR (KBr): 1686 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 4.08 (s, 1 H), 3.51 (s, 1 H), 3.29–3.34 (m, 2 H), 3.16–3.23 (m, 4 H), 1.72–2.03 (m, 4 H), 1.46 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 154.6, 79.8, 61.7, 56.3, 47.6, 38.9, 38.8, 29.8, 28.6.

HRMS (ESI): m/z [M + H⁺] calcd for C₁₂H₂₁NO₂S₂: 276.1092; found: 276.1095.

Reaction of 1,3-Dithianes and 1,3-Dithiolanes with Alkyl ­Halides; General Procedure

The 1,3-dithiane or 1,3-dithiolane (1 mmol) was dissolved in THF (10 mL) under nitrogen atmosphere; the solution was cooled to –20 °C and 1.6 M n-BuLi in hexane (0.950 mL, 1.5 mmol) was added dropwise. The mixture was stirred for 30 min, then a soln of the alkyl halide (1 mmol) in THF (3 mL) was added dropwise over a period of 10 min. The stirring was continued for 30 min, then the reaction mixture was brought to r.t. and quenched with sat. NH₄Cl soln (3 mL). The solution was partitioned between H₂O (30 mL) and EtOAc (30 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (30 mL). The organic layers were combined, dried over anhyd Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography.

N-Boc-Protected (E)-4-((3-(Benzylthio)propylthio)methylene)-2,2-dimethyloxazolidine (5a)

Yield: 213 mg (52%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1705 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.23–7.30 (m, 5 H), 6.18 (s, 1 H), 4.58 (d, J = 2.0 Hz, 2 H), 3.69 (s, 2 H), 2.63 (t, J = 7.2 Hz, 2 H), 2.50 (t, J = 7.2 Hz, 2 H), 1.84 (qu, J = 7.2 Hz, 2 H), 1.56 (s, 6 H), 1.52 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 150.7, 138.5, 138.1, 128.9, 128.6, 127.1, 98.1, 96.4, 81.9, 77.5, 77.1, 76.9, 66.9, 36.3, 33.9, 30.0, 29.2, 28.4, 25.6.

HRMS (ESI): m/z [M + Na⁺] calcd for C₂₁H₃₁NO₃S₂: 432.1643; found: 432.1645.

N-Boc-Protected (E)-4-((3-(Allylthio)propylthio)methylene)-2,2-dimethyloxazolidine (5b)

Yield: 169 mg (47%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1706 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 6.17 (s, 1 H), 5.71–5.79 (m, 1 H), 5.05–5.09 (m, 2 H), 4.57–4.58 (m, 2 H), 3.09 (d, J = 7.1 Hz, 2 H), 2.64 (t, J = 7.1 Hz, 2 H), 2.51 (t, J = 7.0 Hz, 2 H), 1.83 (qu, J = 7.3 Hz, 2 H), 1.56 (s, 6 H), 1.49 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 150.7, 138.1, 134.4, 117.1, 98.1, 96.4, 81.9, 66.9, 34.8, 33.9, 29.3, 29.2, 28.4, 25.5.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₇H₂₉NO₃S₂: 382.1487; found: 382.1489.

N-Boc-Protected (E)-4-((3-(Isopropylthio)propylthio)methylene)-2,2-dimethyloxazolidine (5c)

Yield: 181 mg (50%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1701 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 6.16 (s, 1 H), 4.57 (d, J = 2.0 Hz, 2 H), 2.86–2.87 (m, 1 H), 2.65 (t, J = 6.9 Hz, 2 H), 2.58 (t, J = 6.9 Hz, 2 H), 1.83–1.86 (m, 2 H), 1.53 (s, 6 H), 1.46 (s, 9 H), 1.23 (s, 3 H), 1.21 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 150.7, 138.0, 128.7, 98.1, 96.5, 81.9, 66.9, 34.9, 34.1, 29.8, 29.2, 28.3, 25.7, 23.5.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₇H₃₁NO₃S₂: 384.1643; found: 384.1647.

N-Boc-Protected (E)-2,2-Dimethyl-4-((3-(methylthio)propylthio)methylene)oxazolidine (5d)

Yield: 170 mg (51%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1706 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 6.14 (s, 1 H), 4.55 (d, J = 2.2 Hz, 2 H), 2.67 (t, J = 7.1 Hz, 2 H), 2.57 (t, J = 7.1 Hz, 2 H), 2.03 (s, 3 H), 1.85–1.89 (m, 2 H), 1.55 (s, 6 H), 1.51 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 150.7, 138.1, 128.7, 98.1, 96.4, 81.9, 66.9, 33.8, 32.8, 28.2, 25.5, 15.5.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₅H₂₇NO₃S₂: 356.1330; found: 356.1331.

O-Benzyl-N-Boc-Protected 2-(2-Allyl-1,3-dithian-2-yl)-2-aminoethanol (8)

n-BuLi (3 equiv) was used for this reaction.

Yield: 155 mg (38%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 3065, 1714 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.18–7.27 (m, 5 H), 5.91–6.01 (m, 1 H), 4.99–5.08 (m, 2 H), 4.41–4.52 (m, 2 H), 3.81 (m, 2 H), 3.07 (m, 1 H), 2.84 (m, 1 H), 2.57–2.66 (m, 4 H), 1.78–1.92 (m, 2 H), 1.38 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.0, 138.1, 133.4, 128.4, 127.7, 127.7, 118.5, 79.6, 73.1, 69.5, 56.4, 53.5, 41.3, 28.5, 26.5, 26.2, 24.7.

HRMS (ESI): m/z [M + H⁺] calcd for C₂₁H₃₁NO₃S₂: 410.1824; found: 410.1811.

N-Boc-Protected (E)-4-((2-(Benzylthio)ethylthio)methylene)-2,2-dimethyloxazolidine (10)

Yield: 205 mg (52%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1714 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.25–7.30 (m, 5 H), 6.18 (s, 1 H), 4.59 (s, 2 H), 3.71–3.74 (m, 2 H), 2.68–2.71 (m, 2 H), 2.60–2.63 (m, 2 H), 1.56 (s, 6 H), 1.53 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ (mixture of rotamers) = 150.7, 139.6, 138.3, 128.9, 128.3, 127.0, 126.8, 98.3, 95.4, 82.1, 67.0, 66.5, 36.4, 36.3, 34.8, 31.4, 31.1, 28.3, 25.6.

HRMS (ESI): m/z [M + Na⁺] calcd for C₂₀H₂₉NO₃S₂: 418.1487; found: 418.1486.

N-Boc-Protected 2-(Bis(benzylthio)methylene)pyrrolidine (13)

n-BuLi (2.5 equiv) and BnBr (2 equiv) were used for this reaction.

Yield: 252 mg (62%); oily liquid; R_f  = 0.70 (PE–EtOAc, 97:3).

IR (thin film): 1701 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.17–7.33 (m, 10 H), 3.99 (s, 2 H), 3.90 (s, 2 H), 3.39 (t, J = 7.0 Hz, 2 H), 2.13 (t, J = 7.6 Hz, 2 H), 1.56 (s, 9 H), 1.39–1.45 (m, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 152.6, 151.5, 138.9, 138.8, 129.2, 128.3, 128.1, 126.6, 110.7, 81.2, 49.7, 39.1, 37.9, 32.3, 29.8, 28.5, 20.6, 14.3.

HRMS (ESI): m/z [M + H⁺] calcd for C₂₄H₂₉NO₂S₂: 428.1718; found: 428.1809.

1-(3-(Benzylthio)propylthio)-3-hydroxypropan-2-one (6)

The disulfide derivative 5a (0.410 g, 1 mmol) was dissolved in MeOH (3 mL), and TFA (3 mL) was added to this solution at 0 °C. After 30 min, the volatiles were removed under reduced pressure and the crude product was filtered through a silica gel column.

Yield: 245 mg (91%); oily liquid; R_f  = 0.40 (PE–EtOAc, 4:1).

IR (thin film): 3428, 1715 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.21–7.32 (m, 5 H), 4.44 (s, 2 H), 3.69 (s, 2 H), 3.46 (s, 1 H), 3.21 (s, 2 H), 2.57 (t, J = 7.1 Hz, 2 H), 2.47 (t, J = 7.1 Hz, 2 H), 1.78 (qu, J = 7.1 Hz, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 205.2, 138.3, 128.9, 128.6, 127.1, 66.5, 36.6, 36.3, 31.1, 29.9, 28.2.

HRMS (ESI): m/z [M + Na⁺] calcd for C₁₃H₁₈O₂S₂: 293.0646; found: 293.0647.

O-Benzyl-N-Boc-Protected 2-Amino-2-(1,3-dithian-2-yl)ethanol (7)

The amino alcohol derivative 3 (0.280 g, 1 mmol) dissolved in THF (2 mL) was added to a suspension of NaH (0.026 mg, 1 mmol) in THF (5 mL) at 0 °C. After 15 min, a soln of BnBr (0.171 mg, 0.118 mL, 1 mmol) in THF (1 mL) was added dropwise to the above solution with constant stirring, and the stirring was continued at r.t. for 16 h. The reaction was quenched with MeOH (1 mL), the volatiles were removed under reduced pressure and the residue was dissolved in Et₂O (50 mL), which was then washed with sat. NH₄Cl soln (20 mL). The ether solution was dried over anhyd Na₂SO₄ and concentrated under reduced pressure, and the benzyl derivative 7 was isolated by column chromatography.

Yield: 100 mg (27%); oily liquid; R_f  = 0.50 (PE–EtOAc, 97:3).

IR (thin film): 1711 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.31–7.34 (m, 5 H), 5.04 (d, J = 8.9 Hz, 1 H), 4.52 (s, 2 H), 4.17–4.24 (m, 1 H), 3.59–3.86 (m, 2 H), 2.72–3.01 (m, 4 H), 1.88–2.06 (m, 2 H), 1.44 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 155.6, 138.0, 128.4, 127.8, 127.7, 79.7, 73.3, 69.3, 52.8, 47.9, 28.7, 25.8.

HRMS (ESI): m/z [M + H⁺] calcd for C₁₈H₂₇NO₃S₂: 370.1511; found: 370.1531.

Acknowledgment

This work was supported by the Department of Science and Technology. A.T.P. thanks the University Grants Commission and S.C. thanks the Council of Scientific and Industrial Research for senior research fellowships.

• References

• 1a Liang X, Andersch J, Bols M. J. Chem. Soc., Perkin Trans. 1 2001; 2136
• 1b Zhang X, Ni W, Van der Donk WA. J. Org. Chem. 2005; 70: 6685
  CrossrefSearch in Google Scholar
• 1c Passiniemi M, Koskinen AM. P. Org. Biomol. Chem. 2011; 9: 1774
  CrossrefPubMedSearch in Google Scholar
• 1d Chandrasekhar B, Rao JP, Rao BV, Naresh P. Tetrahedron Lett. 2011; 52: 5921
  CrossrefSearch in Google Scholar
• 1e Dubey A, Harbindu A, Kumar P. Synthesis 2011; 901
  Thieme Connect
• 2 Chacko S, Ramapanicker R. Eur. J. Org. Chem. 2012; 7120
• 3 Kruse CG, Janse AC. V, Dert V, van der Gen A. J. Org. Chem. 1979; 44: 2916
  CrossrefSearch in Google Scholar
• 4 Marshall JA, Seitz DE. J. Org. Chem. 1975; 40: 534
  CrossrefSearch in Google Scholar
• 5 Sibi MP, Rutherford D, Renhowe PA, Li B. J. Am. Chem. Soc. 1999; 121: 7509
  CrossrefSearch in Google Scholar
• 6 Examples of similar reactions can be found, see: Chen YL, Leguijt R, Redlich H, Fröhlich R. Synthesis 2006; 4212
  Thieme Connect
• 7 Wilson SR, Georgiadis GM, Khatri HN, Bartmess E. J. Am. Chem. Soc. 1980; 102: 3577
  Search in Google Scholar

• References

• 1a Liang X, Andersch J, Bols M. J. Chem. Soc., Perkin Trans. 1 2001; 2136
• 1b Zhang X, Ni W, Van der Donk WA. J. Org. Chem. 2005; 70: 6685
  CrossrefSearch in Google Scholar
• 1c Passiniemi M, Koskinen AM. P. Org. Biomol. Chem. 2011; 9: 1774
  CrossrefPubMedSearch in Google Scholar
• 1d Chandrasekhar B, Rao JP, Rao BV, Naresh P. Tetrahedron Lett. 2011; 52: 5921
  CrossrefSearch in Google Scholar
• 1e Dubey A, Harbindu A, Kumar P. Synthesis 2011; 901
  Thieme Connect
• 2 Chacko S, Ramapanicker R. Eur. J. Org. Chem. 2012; 7120
• 3 Kruse CG, Janse AC. V, Dert V, van der Gen A. J. Org. Chem. 1979; 44: 2916
  CrossrefSearch in Google Scholar
• 4 Marshall JA, Seitz DE. J. Org. Chem. 1975; 40: 534
  CrossrefSearch in Google Scholar
• 5 Sibi MP, Rutherford D, Renhowe PA, Li B. J. Am. Chem. Soc. 1999; 121: 7509
  CrossrefSearch in Google Scholar
• 6 Examples of similar reactions can be found, see: Chen YL, Leguijt R, Redlich H, Fröhlich R. Synthesis 2006; 4212
  Thieme Connect
• 7 Wilson SR, Georgiadis GM, Khatri HN, Bartmess E. J. Am. Chem. Soc. 1980; 102: 3577
  Search in Google Scholar

• Supplementary Material