New and Efficient Route for the Synthesis of Ketone from Alkyl Halide Using α-Chloro Nitrone as Oxidizing Reagent

 

Bhaskar Chakraborty* and Prawin K. Sharma

Organic Chemistry laboratory, Sikkim Government College, Gangtok, Sikkim  737102,  India

*Corresponding Author E-mail: bhaskargtk@yahoo.com

ABSTRACT:

Consecutive S_N2 reaction of α-chloro nitrones are studied with isopropyl halides and the nitrones are found to have remarkable oxidizing properties for the conversion of isopropyl halides to ketones with high yields.  In addition, the side product obtained can serve as efficient dipolarophile in 1,3-Dipolar cycloaddition reaction to produce spiro cycloadduct in good yield. 

 

 

 

INTRODUCTION:

Conventional methods for the synthesis of ketone are well known from long time back which includes oxidation of secondary alcohols, hydration of alkynes, Friedel-Crafts acylation and the use of grignard reagents. Although plenty of modern methods are available for the synthesis of ketone from secondary alcohol^1-10 but no such methodologies are known for ketone synthesis from isopropyl halides so far using nitrones. In this communication, we would like to report an efficient one pot synthesis of ketone from isopropyl halides using for the first time α-chloro nitrones^11,12  (1) as oxidizing reagent (Scheme-1, Table-1).

 

In addition, the side product (furan derivative, 2) obtained during ketone synthesis has been successfully used as dipolarophile in 1,3-Dipolar cycloaddition reaction with  nitrone 1 for the production of spiro cycloadduct 3 with high yield (86% ; Scheme-2). Simple nitrones can be also employed for the ketone synthesis but the oxidation side products are waste and the reaction is not atom efficient. Identical side products (2) and their use in cycloaddition reactions leading to regioselective spiro cycloadducts have been already reported in aldehyde synthesis using α-chloro nitrones (1)^13-16. α-chloro nitrones (1) are more reactive than normal nitrones due to the electron withdrawing effect of chlorine and therefore can act as more powerful oxidizing reagent than normal nitrones. Literature survey reveals that ketone synthesis using nitrone as active oxidizing reagent and further use of side product (obtained during ketone synthesis) as dipolarophile in cycloaddition reaction has not yet known and hence can be incorporated as an important application in  nitrone chemistry.

 

 

EXPERIMENTAL:

¹H NMR spectra were recorded with a Bruker Avance DPX 400 spectrometer (400 MHz, FT NMR) using TMS as internal standard. ¹³C NMR spectra were recorded on the same instrument at 100 MHz. The coupling constants (J) are given in Hz. IR spectra were obtained with a Perkin-Elmer RX 1-881 machine as film or KBr pellets for all the products. MS spectra were recorded with a Jeol SX-102 (FAB) instrument. The HRMS spectra were recorded on a Q – Tof micro instrument (YA – 105). TLC was carried out on Fluka silica gel TLC cards while column chromatography was performed with silica gel (E.Merck India) 60 – 200 mesh. All other reagents and solvents were purified after receiving from commercial suppliers. N-methylhydroxylamine was purchased from Aldrich Chemical Company and was used as received. N-phenylhydroxylamine was prepared following standard methods available in literature and has been used in various reported synthesis^17-20.

 

General procedure for synthesis of ketone (acetone) and furan derivative 2 (entry 1; Table 1)

       To a stirred solution of nitrone 1 (R=Me; 500mg, 3.0198 mmol) in dry ether (25 ml) was added pyridine (1 equivalent) and stirred at RT with a magnetic stirrer under N₂ atmosphere for 1 hr while the formation of transient nitrone 1a (not isolated) was  monitored by TLC (R_f = 0.38). Isopropyl bromide (371.1002mg, 1 equivalent) was added at this stage and the reaction mixture was stirred for another 3 hr till the intermediate compound 1b (not isolated) was developed (monitorted by TLC; R_f = 0.40). 2 gms of solid Na₂CO₃ was added at this stage and the reaction mixture was stirred for further 1 hr while the progress of the reaction was again monitored by TLC (R_f = 0.50, 0.96). The reaction was typically completed when the N-O bond was cleaved. Usual workup, removal of pyridine hydrochloride and silica gel column chromatographic purification using ethyl acetate-hexane provided furan derivative 2 (R=Me) as pale yellow gummy liquid (10% ; R_f = 0.50). During work-up furan derivative went into organic layer while aqueous part containing acetone was separated from water by fractional distillation (79%; R_f = 0.96). This procedure was followed for all the substrates listed in Table 1.

Spectroscopic data for acetone (entry 1)

Colourless liquid (79%); R_f = 0.96; IR (KBr): 2925 (s), 1720 (s) cm^-1; ¹H NMR (CDCl₃):  δ 2.13 (s, 6H, 2 Me protons); ¹³CNMR (CDCl₃): δ 202.00 (C=O), 31.46 (Me carbons); FAB – MS: m/z 58 (M⁺), 43 (B.P), 15; HRMS-EI: Calcd. for C₃H₆O (M), 58.0410, Found: M⁺, 58.0406.

Table – 1: Ketone (acetone) synthesis using α-chloro nitrones

 

Entry	Nitrone	Alkyl halidea	Productb	Time (hr)	Yieldc (% )
1	R=Me	Isopropyl bromide	Acetone	5	79
2	R=Me	Isopropyl chloride	Acetone	6	78
3	R=Me	Isopropyl iodide	Acetone	6	77
4	R=Ph	Isopropyl bromide	Acetone	5	77
5	R=Ph	Isopropyl chloride	Acetone	6	76
6	R=Ph	Isopropyl iodide	Acetone	6	75

^a Reaction condition : α-chloro nitrone (3.0198 mmol), isopropyl halide (1 equivalent), dry ether, N₂ atmosphere, RT

 ^b All the compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS, HRMS spectral data.

 ^c Isolated yield after purification.

 

Spectroscopic data for 2 (R=Me; α-N-methyl furan derivative; entry 1) [(E)-1-(dihydrofuran-2-(3H)-ylidene)-N-methyl methanamine)]

 Pale yellow gummy liquid (10%); R_f = 0.50; IR (KBr): 3120-3060 (br), 2835 (m), 1660 (s), 1450 (m), 1215 (m) cm^-1; ¹H NMR (CDCl₃): δ 4.81 (br, 1H, N-H), 4.56 (s, 1H, C=CH), 3.30 (N-Me), 2.50 - 2.16 (m, 6H); ¹³C NMR (CDCl₃): δ 105.26, 102.70 (double bonded carbons), 27.32, 25.00, 24.12 (3 CH₂ carbons); FAB – MS: m/z 113 (M⁺), 98, 97; HRMS-EI: Calcd. for C₆H₁₁ON (M), 113.0850, Found: M⁺, 113.0832. Anal. Found: C, 63.52; H, 9.67; N, 12.30. C₆H₁₁ON requires C, 63.67; H, 9.79; N, 12.38%.

 

Spectroscopic data for acetone (entry 4)

Colourless liquid (78%); R_f = 0.96; IR (KBr): 2920 (s), 1720 (s) cm^-1; ¹H NMR (CDCl₃): δ 2.10 (s, 6H, 2 Me protons); ¹³CNMR (CDCl₃): δ 201.40 (C=O), 32.15 (Me carbons); FAB – MS: m/z 58 (M⁺), 43 (B.P), 15; HRMS-EI: Calcd. for C₃H₆O (M), 58.0410, Found: M⁺, 58.0403.

 

Spectroscopic data for 2 (R=Ph; α-N-phenyl furan derivative; entry 4) [(E)-1-(dihydrofuran-2-(3H)-ylidene)-N-phenyl methanamine)]

Dark yellow viscous liquid (11.5%); R_f = 0.52; IR (KBr): 3154-3065 (br), 2865 (m), 1640 (s), 1440 (m), 1144 (m), 776 (s) cm^-1; ¹H NMR (CDCl₃): δ 7.83 (m, 5H, C₆H₅), 6.24 (br, 1H, N-H), 2.17 (s, 1H, C=CH), 1.79 - 1.18 (m, 6H); ¹³C NMR (CDCl₃): δ 136.00, 135.18, 134.00, 132.62 (aromatic carbons), 104.20, 101.15 (double bonded carbons), 28.55, 26.43, 24.00 (3 CH₂ carbons). FAB - MS (m/z): 175 (M⁺), 98, 97, 77. HRMS-EI: Calcd. for C₁₁H₁₃ON (M), 175.0993, Found; M⁺, 175.0976. Anal. Found: C, 75.28; H, 7.41; N, 7.88. C₁₁H₁₃ON requires C, 75.39; H, 7.47; N, 7.99%.

 

General procedure for cycloaddition reaction of nitrone 1 (R = Ph) with furan derivative 2 (R = Ph)  

To a stirred solution of N–phenyl-α-chloro nitrone 1 (R = Ph; 61.8375 mg, 0.2855 mmol) in dry ether (25 ml) was added 2 (R = Ph, 50 mg, 0.2855 mmol, 1 equivalent) and stirred at RT with a magnetic stirrer under N₂ atmosphere for 6 hr. The progress of the reaction was monitored by TLC (R_f = 0.46). After completion of the reaction, the solvent was evaporated using a rotary evaporator to afford crude cycloadduct 3 which was purified by column chromatography using ethyl acetate - hexane and was obtained as dark red viscous liquid 3 (85% ; Scheme 2).

 

(S)-4-chloro-4-((3S,4S,5R)-2-phenyl-4-(phenylamino)-1,6-dioxa-2-azaspiro[4.4]nonan-3-yl) butan-1-ol  3

 3: Dark red viscous liquid. Yield 85%, R_f = 0.46; IR (KBr): 3480 – 3296 (br), 2960 (m), 2422 (m), 1620 (s), 1480 (s), 1265 (m), 1044 (m), 780 (s) cm^-1; ¹H NMR (CDCl₃): δ 6.98 - 6.92 (m, 10H, 2 X C₆H₅), 5.84 (dd, 1H, J = 8.55, 8.20 Hz, C₃H), 5.00 (br, 1H, CH₂OH, exchanged in D₂O), 3.60 (dt, 1H, J = 8.34, 8.08 Hz, C₄H), 3.40 (s, 1H, N – H proton of NHPh), 2.68 (dt, J = 8.60, 8.84 Hz, 1H, CHCl), 1.90 (dt, 2H, J = 6.82, 6.64 Hz, C_3’H), 1.50 – 1.12 (m, 4H); ¹³C NMR (CDCl₃): δ 137.40, 136.10, 135.42, 133.00, 132.05, 130.54, 129.00, 128.13 (aromatic carbons), 94.16 (CHCl), 87.50 (C₅), 74.12 (C₃), 53.00 (C₄), 31.34, 28.00, 27.18, 25.00, 24.30, 22.92 (6 CH₂ carbons); MS (m/z): 404 (M⁺+2), 402 (M⁺), 325, 310, 309, 218 (B.P), 107, 91, 77. HRMS-EI: Calcd. for C₂₂H₂₇O₃N₂Cl (M), 402.1710, Found; M⁺, 402.1702. Anal. Found: C, 65.58; H, 6.69; N, 6.85. C₂₂H₂₇O₃N₂Cl requires C, 65.64; H, 6.76; N, 6.96%.

 

RESULTS AND DISCUSSION:

α-chloro nitrones (1) are moderately stable and can be isolated while transient nitrone 1a could not be isolated because of its high unstability and undergoes decomposition at room temperature. The lone pair of electron of the OH group of α-chloro nitrone facilitates intramolecular S_N2 reaction in presence of pyridine and is actually the driving force for the development of transient nitrone 1a. Nitrone 1a reacts very quickly with different isopropyl halides (S_N2 reaction) and develops an intermediate compound 1b. The labile N-O bond of 1b undergoes cleavage²¹ when the reaction mixture is stirred with solid sodium carbonate which plays an important role for the development of ketone and furan derivative 2 as side product in a Kornblum type process (Scheme-1;Table-1).

 

The synthetic potentiality of furan derivative (obtained also as side product in aldehyde synthesis) has been already reported^13-15 in the regioselective synthesis of 5-substituted spiro cycloadducts (3)^22,23,24 exclusively with nitrone 1 (Scheme-2) and the spectroscopic data of 2 and 3 in both the synthesis (aldehyde and ketone) has been found to be identical as well. The furan derivatives have been isolated from organic layer while acetone from aqueous mixture after completion of reaction. The yield of isolated acetone (75–79%) was comparatively less than aldehydes reported earlier^14,15 using the same methodology because after a certain amount of acetone was removed from aqueous mixture by fractional distillation the resulting solution became stable due to formation of azeotropic mixture and resisted fractional distillation. The results are summarized in Table-1. The beauty of the reaction lies in addition of pyridine at the begining to generate transient nitrone 1a and is only capable of developing furan derivative 2 utilized as a new efficient dipolarophile in 1,3-Dipolar cycloaddition reaction and thereby the reaction as a whole becomes atom efficient. At the outset of this work it was not clear about the development of transient nitrone 1a but after completion of the study and spectral analysis of side product 2 the development of transient nitrone 1a was confirmed. The products especially acetone is a known compound and spectral data of the synthesized acetone is almost identical to the values found in literature. For example, a single sharp singlet signal at δ 2.12 and 202.00 in the NMR spectrum (¹H, ¹³C respectively) along with molecular ion peak at 58, base peak at 43 in the MS spectrum give strong evidence in favour of acetone formation. The R_f value of the synthesized acetone was found in the solvent front due to its volatility (difficult to identify since evaporates rapidly) and was compared with acetone obtained from commercial suppliers. The oxidation side product 2 was obtained as single isomer having E configuration in all the cases and the yield of the side product was almost 10–13% when isolated in pure condition.

 

The spiro cycloadduct 3 was obtained as regioselective single isomer predominantly in 1,3-DCR of α-chloro nitrone 1 with side product 2 having high yield (85%) when isolated in pure condition. The stereochemistry of the 5-substituted regioselective spiro cycloadduct 3 was rationalized by considering the multiplicity of the proton signals at 3-H, 4-H and CHCl asymmetric centres along with their coupling constant values.²⁵ In the ¹H NMR spectrum of cycloadduct 3, 3-H resonates around δ_H 5.84 ppm while 4–H around δ_H 3.60 ppm and the coupling constant is J_3,4 ~ 8.36 Hz implying a cis relationship between H-3 and H-4. The CHCl proton also resonates around δ_H 2.68 ppm. The 3-H and CHCl protons are also syn as evidenced from their coupling constant values (J_3,CHCl ~ 8.70 Hz). ¹H NMR spectrum of 3 also shows significant long range coupling between H-4 with H-3’ and vice-versa. In the mass spectrum, in addition to molecular ion peak prominent base peak value is obtained for the cycloadduct and significant M⁺+2 peak of characteristic relative height is also obtained for 3 which may be due to isotopic abundance of Cl³⁷ atom. Studies of HRMS spectra show almost exact mass for the majority of the compounds. A preferential conformation for the spiro regioselective isoxazolidine derivative 3 may be represented in Figure 1.

 

CONCLUSION:

Finally, we developed a new atom efficient methodology for the ketone synthesis using α-chloro nitrone as oxidizing reagent and considered further reaction carried out on the side product with α-chloro nitrones in 1,3-Dipolar cycloaddition reaction for the development of stereochemically important spiro cycloadducts. The formation of the desired cycloadducts were obtained in good yields within a short reaction time. The newly developed side products (furan derivatives, 2) are equally effective as dipolarophile in cycloaddition reactions like other conventional dipolarophiles used for cycloaddition reactions. The notable advantages offered by this method are one pot synthesis, simple operation, easy workup, mild and faster reaction conditions with high yield of products.

 

ACKNOWLEDGEMENTS:

Authors are thankful to Dr.M.P Kharel, Principal, Sikkim Government College for providing facilities and constant encouragement. We are pleased to acknowledge the financial support from UGC, New Delhi (Grant no:34-304/2008-SR) and also to SAIF-CDRI, Lucknow for providing spectral data.

 

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Received on 04.08.2010        Modified on 22.08.2010

Accepted on 05.09.2010        © AJRC All right reserved