Title of Invention

"A PROCESS FOR THE PREPARATION OF HOMOALLYLIC ALCOHOLS"

Abstract This invention relates to a process for the preparation of homoallylic alcohols. Process relates to the preparation of homoallylic alcohols using novel Cu and tin halide in aqueous organic medium. Process consists of preparation of homoallylic alcohols from allyl halides and alkyl and aryl aldehydes utilizing stannous halide/ catalytic cupric halide in aqueous-organic interface. Homoallylic alcohols are the key intermediates of several natural products of commercial importance.
Full Text This invention relates to a process for the preparation of homoallylic
alcohols. Particularly it relates to the preparation of homoallylic alcohols using
novel Cu and tin halide in aqueous organic medium. More specifically, the
present invention describes a process for the preparation of homoallylic
alcohols from allyl halides and alkyl and aryl aldehydes utilizing stannous
halide/ catalytic cupric halide in aqueous-organic interface. Homoallylic
alcohols are the key intermediates of several natural products of commercial
importance. The major route for their synthesis involves Grignard reaction. Of
late, aqueous Barbier reactions have been employed for their synthesis due to
operational simplicity (C. J. Li, Tetrahedron 1996, 52, 5643 and Chem. Rev.
1993, 93, 2023). While a broad-spectrum of zero-valent metals have been
satisfactorily tested under various conditions, aqueous Barbier protocol with
metal salts are slowly emerging (Y. Masuyama, T.P. Takahara, Y. Kurusu,.
Tetrahedron Lett. 1989, 30, 3437, Y. Masuyama, Y. Nimura, Y. Kurusu,
Tetrahedron Lett. 1991, 32, 225, M. Sati, D. Sinou, Tetrahedron Lett. 1991, 32,
2025). With reference to carbonyl allylation, both preformed (J.A. Marshall,
Chem. Rev. 1996, 96, 31) as well as in-situ generated allylstannanes (M.
Pereyre, J.P. Quintard, A. Rahm, Tin in Organic Synthesis; Butterworths:
London, 1987) continue to evoke widespread interest due to their chemo, regio
and stereo selectivity aspects which culminated into the recent demonstration of
highly efficient catalytic asymmetric allylation (G.E. Keck, K.H. Tarbet, L.S.

Geraci, J. Am. Chem. Soc. 1993, 115, 8467, S. Weigand, R. Bruckner, Angew. Chem. Int. Ed.Engl. 1996,35,1077).
The principal object of the present invention is to provide a process for the preparation of homoallylic alcohols employing a novel copper (II)/tin(II) catalyst combination in aqueous-organic medium.
Accordingly, the present invention provides a process for the preparation of homoallylic alcohols which comprises; reacting allyl halides with aldehydes as herein described characterised in that using stannous halide and catalytic cupric halide such as herein described 1 to 50 mole% of aldehyde in presence of aqueous-organic medium wherein the ratio of allyl halides, aldehydes, stannous halides, cupric halide is 2:1:2:0:1 at a temperature range of 5 to 100°C under nitrogen for a period of 1 to 20
hrs, recovering the homoallylic alcohols by conventional chromatographic methods.
In an embodiment of the present process the stannous halide such as stannous chloride dihydrate or stannous chloride or stannous bromide may be used.
In an another embodiment of the present process the cupric halide cupric chloride dihydrate or cupric chloride or cupric bromide may be used.
In yet another embodiment the amount of cupric halide added may be varied for 1 mol% to 50 mol% with respect to reactant aldehyde.
In yet another embodiment the aqueous-organic medium used may be selected from dichloromethane-water chloroform-water tetrahydrofuran-water.

In yet another embodiment the allyl halide such as allyl or substituted allyl chloride, bromide or iodide may be used.
In yet another embodiment the aldehyde used may be selected from alkyl, aryl or heterocyclic aldehydes.
In yet another embodiment the reaction may be effected at a temperature between 5 to 100 degree Celsius.
In yet another embodiment the ratio of allyl halides aldehydes ^tannous halides, cupric halide ryfayyfae 2:2:0.1.
In yet another embodiment the recovery of homoallylic alcohol may be effected by column chromatography using silica gel column and element such as acetone/ hexane (3:97 v/v).
According to the present invention, the reaction of stannous chloride dihydrate with allyl bromide and various aldehydes in presence of catalytic cupric chloride dihydrate in dichloromethane-water (1:1 v/v) for 6-20 h gave rise to the desired homoallylic alcohol in excellent isolated yields. The reactions could also be performed with allyl chloride with increased reaction time and slightly lesser yield of alcohol. On the other hand, reactions without cupric chloride or in absence of water showed
heterocyclic functional groups. Also, allyl halides substituted at all three carbon carbon centers can be employed as shown in Table 1.
Table 1: Synthethis of Homoallylic alcohols [CH2=CH(R3)C(R1R2)CH(OH)R] from the reaction of aldehydes RCHO with allyl bromides
(Table Removed)


a isolated yields after chromatography based on aldehydes. bthe ratio was determined by 1H NMR. °reaction was performed at pH = 5 d reaction was performed at 0°C
It is noteworthy that allyl halides, substituted at the 3-position, showed exclusive γ-regioselectivity and high anti-selectivity (entry 4-10).
The present invention relies on mixing hydrated stannous chloride ( 2 equiv.) with cupric halide (0.1 equiv.) in water and adding to the resultant solution, a mixture of aldehyde (1 equiv.) and allyl halide (2 equiv.) in dichloromethane (3 mL). After the solution was stirred at room temperature for 6-20 h (TLC monitoring on Silica gel, eluent: ethyl acetate/hexane 1:4 v/v), the product was extracted with diethylether and subjected to Column chromatography (silica gel 60-120 mesh, eluent: acetone/hexane 3:97 v/v) to afford pure homoallylic alcohols.
The solvents which could be utilized in the synthesis of homoallylic alcohols according to the present invention are dichloromethane-water (1:1 vol./vol.), tetrahydrofuran-water (1:1 vol./vol.) and chloroform-water (1:1 vol./vol.). The catalyst could be cupric chloride, cupric bromide or cupric thiocyanate. The molar ratio of the catalyst with respect to stannous chloride could be varied from 5 to 50 mol%. The temperature of the present allylation reaction could be varied from 10 to 50 degree Celsius.
Detailed in-situ examination of the invented catalytic system suggested the formation of allyltrihaiostannane intermediate even in very high concentration of water.
The invention is described in the examples given below which are produced by way of illustrations only and therefore should not be constrained to limit the scope of the invention.
EXAMPLE 1
A mixture of 4-chlorobenzaldehyde (1.40 g, 1 equiv.) and 1 -bromobut-2-ene (2.7 g, 2 equiv.) in dichloromethane (30 ml) was slowly added to a stirred solution containing stannous chloride dihydrate (4.5 g, 2 equiv.) and cupric chloride dihydrate (170 mg, 0.1 equiv.) in water (30mL) and under nitrogen The solution was stirred at room temperature for 8 h (TLC monitoring on Silica gel, eluent: ethyl acetate/hexane 1:4 v/v) and then extracted three times with diethylether (50mL). The organic layer was washed with 5% aq. sodium bicarbonate (100mL), water (100mL), and brine (100ml). dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography (silica gel 60-120 mesh, eluent: acetone/hexane 3:97 v/v) afforded pure 1-(4-chlorophenyl)-2-methylbut-3-en-1-ol as a light yellow oil (1.76 g, 91% with respect to aldehyde).
EXAMPLE 2
A mixture of phenyl acetaldehvde (1.2 g, 1 equiv.) and 3-bromo-2-methyl propene (2.7 g, 2 equiv.) in tetrahydrofuran (25 ml) was slowly added to a stirred solution containing stannous chloride dihydrate (4.5 g, 2 equiv.) and cupric chloride dihydrate (170 mg, 0.1 equiv.) in tetrahydrofuran (25 ml) and under nitrogen The solution was stirred at room temperature for 12 h (TLC

monitoring on Silica gel, eluent: ethyl acetate/hexane 1:4 v/v) and then 15% aq. ammonium fluoride (50mL) added and extracted three times with diethylether (50mL). The organic layer was washed with brine (50mL), dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography (silica gel 60-120 mesh, eluent: acetone/hexane 3:97 v/v) afforded pure 1-(phenyl)-4-methylpent-4-en-2-ol as a light yellow oil (1.25 g,71% with respect to aldehyde).
EXAMPLE 3
A mixture of heptanal (1.14g, lequiv) and 1-bromo-but-2-ene (2.7g, 2equiv) in dichloromethane (30 ml) was slowly added to a stirred solution containing stannous chloride dihydrate (4.5 g, 2 equiv.) and cupric bromide (223 mg, 0.1 equiv.) in water (30mL) and under nitrogen The solution was stirred at room temperature for 18 h (TLC monitoring on Silica gel, eluent: ethyl acetate/hexane 1:5 v/v) and then extracted three times with diethylether (50mL).The organic layer was washed with 5% aq. sodium bicarbonate (100mL), water (lOOmL), and brine (100mL), dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography (silica gel 60-120 mesh, eluent: acetone/hexane 2:98v/v) afforded pure 3-methyl-dec-3-en-4-ol as a colorless oil (750 mg, 45% with respect to aldehyde).
EXAMPLE 4
A mixture of benzaldehyde (1.06g, lequiv) 3-bromo-1-phenyl-1-propene (3.94g, 2equiv) in tetrahydrofuran (30ml) was slowly added to a stirred solution

containing stannous chloride dihydrate (4.5 g, 2 equiv.) and cupric bromide (223 mg, 0.1 equiv.) in water (30mL) and under nitrogen The solution was stirred at room temperature for 10 h (TLC monitoring on Silica gel, eluent: ethyl acetate/hexane 1:5 v/v). The reaction mixture was worked up as before which afforded pure 1,2(diphenyl)-but-3-en-1-ol as a light yellow oil (1.62g, 72% with respect to aldehyde).
EXAMPLE 5
A mixture of 2-furaldehyde (960 mg, 1 equiv.) and 1-bromobut-2-ene (2.7 g, 2 equiv.) in dichloromethane (30 ml) was slowly added to a stirred solution containing stannous chloride dihydrate (4.5 g, 2 equiv.) and cupric chloride dihydrate (170 mg, 0.1 equiv.) in water (30mL) and under nitrogen at 10°C. The solution was stirred at 10°C for 12 h (TLC monitoring on Silica gel, eluent: ethyl acetate/hexane 1:5 v/v) and then worked up as before which afforded 1-(furfuryl)-2-methylbut-3-en-1-ol as a light yellow oil (530mg,35% with respect to aldehyde).


We Claim:
1. A process for the preparation of homoallyiic alcohols which comprises; i)
preparing a mixture of allyl halides and aldehyde such as herein described in
presence of aqueous-organic medium, ii) adding a solution containing stannous
halide and catalytic cupric halide 1 to 50 mole% of aldehyde to the said mixture
wherein the ratio of allyl halides, aldehydes, stannous halides, cupric halide is
2:1:2:0.1 at a temperature range of 5 to 100°C under nitrogen for a period of 1 to
20 hrs, iii) recovering the homoallyiic alcohols by conventional chromatographic
methods.
2. A process as claimed in claim 1 wherein stannous halide is selected from
stannous chloride dihydrate , stannous chloride or stannous bromide.
3. A process as claimed in claims 1 and 2 wherein cupric halide is selected from
cupric chloride dihydrate, cupric chloride or cupric bromide.
4. A process as claimed in claims 1-3 wherein the aqueous-organic medium used is
selected form dichloromethane-water,chloroform-water, tetrahydrofuran-water.
5. A process as claimed in claims 1-4 wherein the allyl halide is allyl or substituted
allyl chloride, bromide or iodide.
6. A process as claimed in claims 1-5 wherein the aldehyde used is selected from
alkyl, aryl or heterocyclic aldehydes.
7. A process as claimed in claims 1 to 6 wherein chromatography is effected using
silica gel column and eluent acetone/hexane (3:97 v/v).
8. A process for the preparation of homoallyiic alcohols substantially as herein
described with reference to the examples.

Documents:

3158-del-1998-abstract.pdf

3158-del-1998-claims.pdf

3158-del-1998-correspondence-others.pdf

3158-del-1998-correspondence-po.pdf

3158-del-1998-description (complete).pdf

3158-del-1998-form-1.pdf

3158-del-1998-form-13.pdf

3158-del-1998-form-19.pdf

3158-del-1998-form-2.pdf


Patent Number 215101
Indian Patent Application Number 3158/DEL/1998
PG Journal Number 10/2008
Publication Date 07-Mar-2008
Grant Date 21-Feb-2008
Date of Filing 28-Oct-1998
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI- 100 001, ,INDIA
Inventors:
# Inventor's Name Inventor's Address
1 SUJIT ROY INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY HYDERABAD 500007, ANDHRA PRADESH, INDIA
2 ABHIJIT KUNDU INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY HYDERABAD 500007, ANDHRA PRADESH, INDIA
PCT International Classification Number C07C 29/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA