Microwave-Irradiated Alkylations of Active Methylenes Under

Chapter 16

Microwave-Irradiated Alkylations of Active Methylenes Under Solid—Liquid Phase-Transfer Catalytic Conditions

Downloaded by UNIV OF SYDNEY on August 27, 2013 | http://pubs.acs.org Publication Date: February 1, 1997 | doi: 10.1021/bk-1997-0659.ch016

Yaozhong Jiang, Yuliang Wang, Runhua Deng, and Aiqiao Mi Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, People's Republic of China

Convenient procedures are described for a series of microwave promoted and phase transfer catalyzed alkylations on the active methylene compounds, including ethyl phenylsulfonylacetate, methyl Nbenzylidene glycinate, ethyl acetoacetate, ethyl phenylmercaptoacetate, diethyl malonate, and acetylacetone. These useful reactions can be carried out within several minutes in good yields, and most of the procedures are solvent-free.

Alkylation of the enolate anions of acidic methylene groups with alkyl halides or other alkylating agents has been profusely studied for many years, due to the importance of carbon-carbon bond formation in organic synthesis (1). Organic strong base were used in typical method to derive the carbanion, later inorganic base were used in phase transfer catalytic method. We have reported the solid-liquid phase transfer catalyzed (PTC) synthesis of amino acids via the alkylation of N-benzylidene glycinate (2-6). In the synthesis of phenylalanine, the alkylation with benzyl bromide could be carried out smoothly in good yield, but the alkylation with benzyl chloride could not take place under the same condition. For a large scale preparation of phenylalanine, benzyl chloride is much cheaper than benzyl bromide as alkylating agent. So it is reasonable to use some methods to increase the reactivity of reactants. In recent years microwave irradiation has been used in the organic synthesis to increase the activity and shorten the reaction time (7-11). So we have the idea to use this new method to develop a series of procedures for the alkylation of active methylenes, improving the synthesis of amino acids and other useful compounds. Here we would like to describe the summary of 28 alkylations on 6 methylene compounds. Results and Discussion The alkylation of sulfonylacetate by typical method had been used in the synthesis of 11,12-secoprostaglandins (12); and the phase transfer catalyzed alkylation has been car-

© 1997 American Chemical Society

In Phase-Transfer Catalysis; Halpern, M.; ACS Symposium Series; American Chemical Society: Washington, DC, 1997.

204

PHASE-TRANSFER CATALYSIS

ried out by stirring the reaction mixture for 1-4 hs at 40X. (13). Here we give an improved procedure to perform the rapid and efficient alkylation of ethyl phenylsulfonylacetate (compound 1) in microwave oven, using TEBA (triethylbenzyl ammonium chloride) as phase transfer catalyst.

™

^

f

-

^ S O J H C C E ,

1

2


Scheme 1 Most of the alkylation of 1 was simply achieved by microwave irradiation to the mixture of ethyl phenylsulfonylacetate, alkyl halide, potassium carbonate and TEBA for 2-3 minutes. But we failed to mix the substrate with bromide well in the synthesis of 2b and 2c, so we added 1ml of toluene to solve this problem Followed by isolation and purification gave monoalkylated products (2a-e) in 76-86% yield (Table I). All the pro ducts were characterised by IR, ^ - N M R and MS.

product 2a 2b 2c 2d 2e

Table L alkylation of ethyl phenylsulfonylacetate alkyl halide mol. ratio irradiation time isol. yield (RX:Subst.) (min) (%) C6H5CH2CI 3 76 1.4:1 76 p-ClC6H4CH Br 2 1:1 2-C H CH Br 2 86 i;i 79 n-OctylBr 3 1:1 n-BuBr 2:1 3 83 2

10

7

2

Phase transfer catalyzed alkylation of alkyl N-benzylidene glycinate (compound 3) has been successfully used in the synthesis of amino acids (2-6), and we improve the synthesis by using microwave irradiation. The synthetic route is as follows: R

-CH=NCH C0 CH 2

2

3

R

X

K

' 2C0 /PTC MICROWAVE 3

, |H O

+

3

H N-CHCOOH 2

3

R

4

Scheme 2

New method dramatically enhance the activity of the alkylation with benzyl chloride and other alkyl halide. All the alkylations are rapidly carried out in 1-2 minutes and give the monoalkylated products, which are stirred with IN HC1 at room


16.

Microwave-Irradiated Alkylations of Active Methylenes 205

JIANG ET AL.

temperature for 14 hs, then with 6N HC1 at 60°C for 8-10 hs to offer amino acids (4ae). The results are summarized (Table Π). All the products were characterized by IR, ^ - N M R and elemental Analyses.

Table Π. The synthesis of amino acids alkyl halide irradiation time (min) 4a: Phenylalanine PhCH Cl 1 4b: Aspartic acid BrCH C0 Et 1 PhCH OCH Cl 1 4c: Serine CH (CH ) Br 2 4d: Leucine product

2

2

2


2

2

3

2

3

overall yield (%) 62.5 61.4 43.6 54.5

The alkylation of acetoacetate (compound 5) were used in the typical synthesis of ketone and carboxylic acid, and the PTC alkylation could be carried out (14-18). The improved procedure by microwave irradiation can perform a rapid and efficient alkyla tion of ethyl acetoacetate, using TBAC (tetra-butyl ammonium chloride) as phase transfer catalyst without solvent.

S^ '

TO CH COCH C0 E, 3

2

2

TC

5

CH CoLo E. 3

2

6 Scheme 3

The alkylation of 5 was simply achieved by microwave irradiation to the mixture of ethyl acetoacetate, alkyl halide, potassium hydroxide-potassium carbonate (1:4) and PTC for 3-4.5 minutes. Followed by isolation and purification gave monoalkylated products (6a-e) in 59-82% yield. The microwave power scale and the irradiation time were changed according to the activity of alkyl halide (Table HI). All the products were characterised by IR, ^ - N M R and MS.


Table HI. Alkylation of ethyl acetoacetate alkyl halide mol. ratio power irradiation time (RX:Subst.) level (min) CH=CHCH Br 1:1 2 3 4 PhCH Cl 3 1:1 m-O^OCôH^Cl 5 3.5 1:1 p-ClCeJiiCH.Br 4 4 1:1 CH (CH ) Br 4.5 1.2:1 6 2

2

3

2

3

isol. yield (%) 81 69 82 59 61

Β. M . Trost and co-workers (19) have led the development and utilization of the sulphenylation-oxidation-dehydrosulphenylation sequence to provide 2-unsaturated es-


206

PHASE-TRANSFER CATALYSIS

ters. Here we develop a alternative procedure for a rapid and convenient synthesis of 2-phenylmercaptoesters via the alkylation of phenylmercaptoacetate (compound 7) in the absence of solvent in microwave oven, using TBAC (tetra-butyl ammonium chloride) as phase transfer catalyst.

™££££°· 7

8


Scheme 4 The rapid PTC alkylations of 7 with a series of halides were easily performed in 650W domestic microwave oven to yield the α-alkylated products (8a-e) in 58-83% isolated yield. The microwave power scale and the irradiation time were changed according to the activity of alkyl halide (Table IV). All the products were characterised bylR, ^-NMRand MS. When p-chlorobenzyl bromide was used, we fail to mix it with substrate well, so we add 1 mL of toluene to solve this problem We used 2 equivlent of alkyl halide, and obtained the dialkylated product.


Table IV. Alkylation of ethyl phenylmercaptoacetate alkyl halide mol. ratio power irradiation time isol. yield (RX:Subst.) level (min) (%) 83 4.5 PhCH Cl 3 1:1 67 3.5 CH =CHCH Br 1:1 2 61 4 p-ClC

Microwave-Irradiated Alkylations of Active Methylenes Under

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