Titanium(IV)isopropoxide reductive amination , Hive Novel Discourse

Rhodium
(Chief Bee)
10-04-02 12:21
No 364157

Titanium(IV)isopropoxide reductive amination
(Rated as: excellent)

Facile preparation of N-methyl secondary amines by titanium(IV)isopropoxide-mediated reductive amination of carbonyl compounds
JCS Perkin Trans 1, 2527-31 (1998)

A simple, mild and efficient procedure for obtaining N-methyl secondary amines from aldehydes and ketones is reported. Treatment of carbonyl compounds with methylamine hydrochloride, triethylamine and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction and straightforward aqueous work-up, affords clean products in good to excellent yields.

Reductive amination of MDP2P with MeNH2.HCl, Ti(iPrO)4, NaBH4 and Et3N

A mixture of 3,4-Methylenedioxyphenyl-2-propanone (1.78g, 10 mmol), titanium(IV)isopropoxide (5.9ml, 20 mmol), methylamine hydrochloride (1.35 g, 20 mmol) and triethylamine (2.79ml, 20 mmol) in 15ml absolute ethanol (or methanol) was stirred (preferably under inert atmosphere) room temp for 8–10 h. Sodium borohydride (0.57g, 15 mmol) was then added and the resulting mixture was stirred for an additional 7–8 h at ambient temperature. The reaction was then quenched by pouring into 30ml 2M aqueous ammonia, the resulting inorganic precipitate was filtered off, and washed with 50ml dichloromethane. The organic layer was separated and the remaining aqueous layer was extracted once with 50ml dichloromethane. The combined organic extracts were next extracted once with hydrochloric acid (1 M, 25ml) to separate the neutral materials. The acidic aqueous extracts were washed once with 50ml dichloromethane, then treated with dilute aqueous sodium hydroxide to pH 10–12, and extracted with 3x50ml dichloromethane. The combined organic extracts were washed with 50ml brine, dried over MgSO4 and concentrated in vacuo to afford N-Methyl-3,4-Methylenedioxyphenyl-2-aminopropane in good yield.

GC_MS
(Hive Bee)
10-04-02 12:47
No 364164

titanium(IV)isopropoxide

What Ti(iPrO)4 did they use? When I do a quick search, there is a difference between extra pure vacuum distilled (99.99%) and "normal" Ti(iPrO)4. The difference can be important, since the price difference is ca 100-fold.
There are some other articles on your site (../rhodium /redamin.titanium.html), but they don't mention the grade either. It looks something to put on my "to do" list though... crazy

WOMAN.ZIP: Great Shareware, but be careful of viruses...

Barium
(Hive Bee)
10-04-02 14:58
No 364191

Regular Ti(iPrO)4 works just fine.

Regular Ti(iPrO)4 works just fine. With this system one can get quite good yields of primary amines as well. The dry enviroment makes ammonia keen to form the imine. But as for simplicity and yields, I´d say Sunlights ketone/Pd/amine/formate is hard to beat.

Catalytic hydrogenation freak

Lego
(Hive Bee)
01-29-04 21:16
No 485344

Reductive amination with Ti(iPrO)4/NaBH4
(Rated as: excellent)

Chemoselective reductive alkylation of ammonia with carbonyl compounds:
synthesis of primary and symmetrical secondary amines

Bruhaspathy Miriyala,a Sukanta Bhattacharyyab,* and John S. Williamsona

Tetrahedron 60 (2004) 1463–1471 (http://lego.chemistry.tripod.com/Journals/RedAm.pdf)
DOI:10.1016/j.tet.2003.12.024

Abstract: An efficient, general procedure for highly chemoselective reductive mono-alkylation of ammonia with ketones is reported.
Treatment of ketones with ammonia in ethanol and titanium(IV) isopropoxide, followed by in situ sodium borohydride reduction, and a
straightforward workup afforded primary amines in good to excellent yields. Reductive alkylation of ammonia with aldehydes, on the other
hand, afforded the corresponding symmetrical secondary amines selectively.

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Scheme 1. Primary amines from ketones

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Table 1. Synthesis of primary amines from ketones

Entry	Starting ketone	Product primary amine	Yield (%)	Purity (%)^a
1	Benzophenone	1-Phenylethylamine	88	98
2	4-Methoxybenzophenone	1-(4-Methoxyphenyl)-ethylamine	91	97
3	4-Fluorobenzophenone	1-(4-Fluorophenyl)-ethylamine	65	99
4	4-Trifluorobenzophenone	1-(4-Trifluorophenyl)-ethylamine	83	99
5	4-Trifluoromethoxybenzophenone	1-(4-Trifluoromethoxyphenyl)-ethylamine	83	97
6	Propiophenone	1-Phenylpropylamine	89	99
7	4-Phenyl-2-butanone	2-Amino-4-phenylbutane	88	98
8	4-phenylbut-3-en-2-one	1-Methyl-3-phenylprop-2-enylamine	89	98
9	2,4-Dimethoxyphenylacetone 2,4-DiMeO-P2P	2,4-Dimethoxyamphetamine	87	97
10	4-Fluorophenylacetone 4-F-P2P	4-Fluoramphetamine	78	99
11	Benzophenone	1,1-diphenylmethanamine	78	98
12	1-benzoylpiperidin-4-one	1-benzoylpiperidin-4-amine	96	100
13	ethyl 4-oxopiperidine-1-carboxylate	ethyl 4-aminopiperidine-1-carboxylate	93	100
14	1-BOC-4-oxopiperidine	1-BOC-4-aminopiperidine	88	98
15	1,4-dioxaspiro[4.5]decan-8-one 1-Ethylenacetal-1,4-dicyclohexandion	Amino-4-cyclohexanoneethylenacetal	91	99
16	Cyclohexylphenylketone	1-cyclohexyl-1-phenylmethanamine	72	98
17	Cyclopentanone	Cyclopropylamine	90	99
18	Cycloheptanone	Cycloheptylamine	88	98
19	2-Adamantanone	1-Aminoadamantan	93	100
20	Diisopropylketon	1-Isopropyl-2-methylpropylamine	85	100

^a Purity was determined by GC or LC-MS

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Scheme 2. Symmetrical secondary amines from aldehydes

Table 2. Synthesis of symmetrical secondary amines from aldehydes

Entry	Starting aldehyde	Product secondary amine	Yield (%)	Purity (%)^a
21	Benzaldehyde	Dibenzylamine	76	99
22	2-Methylbenzaldehyde	Di-(2-methylbenzyl)-amine	70	99
23	3-Methylbenzaldehyde	Di-(3-methylbenzyl)-amine	71	99
24	4-Methylbenzaldehyde Toluylaldehyde	Di-(4-methylbenzyl)-amine	78	98
25	4-Methoxybenzaldehyde Anisaldehyde	Di-(4-methoxbenzyl)-amine	50	98
26	4-Fluorbenzaldehyde	Di-(4-fluorobenzyl)-amine	75	98
27	4-Trifluorobenzaldehyde	Di-(4-trifluorobenzyl)-amine	70	100
28	4-Dimethylaminobenzaldehyde	Di-(4-dimethylaminobenzyl)-amine	62	100
29	3,4-Methylendioxybenzaldehyde Piperonal	Di-(3,4-methylendioxybenzyl)-amine	77	97
30	3-Benzyloxybenzaldehyde	Di-(3-benzyloxybenzyl)-amine	67	97
31	Indole-3-carbaldehyde	Di((1H-indol-3-ylmethyl)-amine	65	98
32	2-Methylphenylacetaldehyde	Di-(2-phenylpropyl)-amine	58	98
33	4-Phenylbutyraldehyde	Di-(4-phenylbutyl)-amine	75	100
34	Cyclohexanonecarbaldehyde	Di-(cyclohexylmethyl)amine	68	98

^a Purity was determined by GC or LC-MS

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4. Experimental
The starting aldehydes and ketones, reagents and solvents were used as obtained from their respective suppliers without further purification. Two molar solutions of ammonia in ethanol are commercially available and were obtained from Aldrich Chemical Company, USA. IR spectra were recorded with CHCl3 as solvent (Bruker Vector 33 FTIR). 1H NMR spectra were run in CDCl3 at 400 MHz on a Bruker AM 400 spectrometer. Chemical shifts are reported in ppm referenced to TMS. Liquid chromatography and electrospray ionization mass spectrometry (EIMS) were performed with a Waters 2690 Separation Module HPLC system and a Waters/Micromass ZQ 2000 mass spectrometer in the positive ion detection mode. Components were resolved using a Waters Symmetry C18 5 mm HPLC column (2.1 x 50 mm). Flash chromatography was performed on silica gel (200–400 mesh, Natland). Analytical TLC was performed on pre-coated silica gel plates with fluorescent indicators using purified solvents, followed by iodine visualization, as necessary. All products were characterized by their 1H NMR, IR and mass spectral data; identities of known compounds were established by comparison of their NMR spectral data with the values reported in the literature. The purities of the product primary and secondary amines were determined by using GC or LC–MS analysis.

4.1. General procedure for the synthesis of primary amines from ketones
A mixture of the ketone (10 mmol), titanium(IV) isopropoxide (6.0 mL, 20 mmol) and ammonia in ethyl alcohol (2 M, 25 mL, 50 mmol) was stirred under argon in a capped flask at ambient temperature for 6 h. Sodium borohydride (0.6 g, 15 mmol) was then added and the resulting mixture was stirred at room temperature for an additional 3 h. The reaction was then quenched by pouring into ammonium hydroxide (2 M, 25 mL), the resulting inorganic precipitate was filtered off, and washed with ethyl acetate (25 mL x 2). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2).
The combined organic solution was next extracted with hydrochloric acid (1 M, 30 mL) to separate the neutral materials. The acidic aqueous extracts were washed with ethyl acetate (50 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10–12, and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried (Na₂SO₄), and concentrated in vacuo to afford the corresponding primary amine.

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4.2. General procedure for the synthesis of symmetrical secondary amines from aldehydes
A slurry of the aldehyde (10 mmol), titanium(IV) isopropoxide (6.0 mL, 20 mmol), ammonium chloride (1.1 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in absolute ethanol (20 mL) was stirred under argon in a capped flask at ambient temperature for 6 h. Sodium borohydride (0.6 g, 15 mmol) was then added and the resulting mixture was stirred at room temperature for an additional 3 h. The reaction was then quenched by pouring into ammonium hydroxide (2 M, 25 mL), the resulting inorganic precipitate was filtered off, and washed with ethyl acetate (25 mL x 2).
The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic extracts were dried over Na₂SO₄, concentrated in vacuo and purified over silica gel by flash chromatography using hexanes/ethyl acetate to afford the corresponding symmetrical secondary amines.

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The tendency is to push it as far as you can