Org. Synth. 1989, 67, 180
DOI: 10.15227/orgsyn.067.0180
3'-NITRO-1-PHENYLETHANOL BY ADDITION OF METHYLTRIISOPROPOXYTITANIUM TO m-NITROBENZALDEHYDE
[Benzenemethanol, α-methyl-3-nitro-]
Submitted by René Imwinkelried and Dieter Seebach
1.
Checked by Cheryl A. Martin and K. Barry Sharpless.
1. Procedure
A dry,
500-mL, three-necked flask equipped with pressure-equalizing
100-mL dropping funnel,
argon inlet, and
magnetic stirrer is evacuated and flushed with
argon (three cycles). The flask is charged with
16.0 mL (57.7 mmol) of tetraisopropyl orthotitanate (Note 1) via a
plastic syringe and hypodermic needle and
2.1 mL (19.2 mmol) of titanium tetrachloride is added over 5 min, with gentle cooling of the flask in an
ice–water bath to give a viscous oil
(Note 2). After the addition of
70 mL of tetrahydrofuran (Note 3), the clear solution is stirred at room temperature for 30 min. The dropping funnel is charged with
62 mL (77 mmol, 1.24 M in hexane) of methyllithium (Note 4), which is added to the cooled (
ice bath)
tetrahydrofuran solution over a period of 25–30 min. During the addition the resulting suspension changes from orange to bright yellow. After the mixture has stirred at ice–bath temperature for 1 hr, a solution of
10.6 g (70 mmol) 3-nitrobenzaldehyde (Note 5) in 60 mL of tetrahydrofuran (Note 3) is added from the dropping funnel within 20–25 min at the same temperature. The mixture is stirred at 0–5°C for 1 hr and then
60 mL of 2 N hydrochloric acid is added. The organic phase is separated in a
separatory funnel and the aqueous phase is extracted with three
150-mL portions of diethyl ether. The combined organic phases are washed with
100 mL of saturated sodium bicarbonate solution and
100 mL of saturated sodium chloride solution and then dried over anhydrous
magnesium sulfate. After filtration the solution is concentrated on a
rotary evaporator and dried at 0.1 mm for 1 hr. The residue,
11.0–11.1 g (
94–95%) of an orange-brown viscous oil, sometimes solidifies on standing (mp
55–60°C); the purity of the crude product is at least 95% (estimated by
1H NMR). The product can be purified by short-path distillation at
120–125°C (0.15 mm) to give
9.9–10.4 g (
85–89%) of a yellow oil, which solidifies on standing at room temperature or at −30°C in a freezer, mp
60.5–62.0°C (lit.
2 mp
62°C)
(Note 6).
2. Notes
1.
Commercial tetraisopropyl orthotitanate [Ti(O-i-Pr)4] (Dynamit Nobel) and titanium tetrachloride (Fluka pract.) can be used without further purification. The checkers obtained
Ti(O-i-Pr)4 from Aldrich Chemical Company, Inc. and
titanium tetrachloride from Fluka. Distillation of Ti(O-
i-Pr)
4 did not improve the results.
2.
If the mixture is overcooled, the resulting
chlorotriisopropoxytitanium partially solidifies.
3.
Tetrahydrofuran was distilled from
potassium/
benzophenone immediately before use.
4.
The
methyllithium solution was obtained from Metallgesellschaft, Frankfurt. The checkers used
methyllithium (Aldrich Chemical Company, Inc.), salt-free 1.4
M in
ethyl ether, with no significant difference observed in the reaction.
5.
3-Nitrobenzaldehyde is Fluka purum, used without further purification. The checkers obtained it from Aldrich Chemical Company, Inc.
6.
The product obtained after distillation can be recrystallized from
benzene/petroleum ether (3:2, v : v) to give pale-yellow crystals (
91–95% from distilled product) with a melting point of
61–63°C. Attempts by the checkers to crystallize the crude reaction mixture were unsuccessful.
1H NMR (CDCl
3) δ: 1.54 (d, 3 H,
J = 6.5, CH
3), 2.3 (br, 1 H, OH), 5.00 (q,
J = 6.5, O-C-H), 7.5–7.7 (m, 2 H, arom. H), 8.0–8.25 (m, 2 H, arom. H); IR (KBr) cm
−1: 3260 (br, m), 2990 (m), 1580 (m), 1525 (s), 1340 (s), 1205 (m), 1170 (m), 810 (m), 740 (m), 690 (m).
3. Discussion
The addition of nucleophilic organometallic compounds (usually RLi or RMgX) to a carbonyl group—a key step in numerous syntheses—is not always straightforward. The addition reaction is complicated by the fact that aldehydes, ketones, and esters are not well differentiated; that other electrophilic functional groups, such as cyano, nitro, halo, and trialkylstannyl may interfere; and that proton abstraction or one electron-transfer processes rather than addition occur. For example, the addition of
methyllithium or
methylmagnesium iodide to
3-nitrobenzaldehyde under the same conditions used with
CH3Ti(OCH(CH3)2)3 (this procedure) leads to a complex mixture of products with formation of only
10–30% of
3'-nitro-1-phenylethanol.
3 In many cases these complications can be remedied by using derivatives of titanium and zirconium, compounds that have become increasingly important in organic syntheses during the past decade. Several review articles discuss different aspects.
3The nucleophilic
titanium and
zirconium reagents are readily available by simple transmetallation of the organolithium or Grignard reagents with (RO)
3TiCl, (RO)
3ZrCl, or (R
2N)
3TiX. The trialkoxychloro compounds are prepared by mixing the inexpensive, industrially available, titanates, Ti(OR)
4, or zirconates, Zr(OR)
4, with the appropriate amount of TiCl
4 or ZrCl
4. In contrast to compounds of most other heavy metals, few toxic effects of Ti(OR)
4 and Zr(OR)
4 are known, partly because they are very rapidly hydrolyzed by water and the resulting oxide–hydrates are insoluble (TiO
2 is a white pigment). Some of the reagents, RTi(OR')
3, can be isolated without difficulty. Thus,
CH3Ti(O-i-Pr)3s can be obtained as a bright-yellow oil that distills without decomposition at 50°C/0.001 mm.
4The organotitanium and -zirconium compounds, for the most part generated in situ, react highly selectively with carbonyl compounds. For example,
CH3Ti(O-i-Pr)3 reacts five orders of magnitude faster with benzaldehyde than with
acetophenone at room temperature.
5 Reagents of the type RTi(O-
i-Pr)
3 add smoothly to nitro- (see this procedure), iodo-, or cyanosubstituted benzaldehydes, and the reactions may be performed in chlorinated solvents or in
acetonitrile (for some examples, see Table I). The zirconium analogs have particularly low basicity and add in high yield to α- and β-tetralones.
6 The inclusion of chiral OR
* groups gives enantioselective reagents (up to ≥98% ee).
7,8,9 Allylic (RO)
3Ti derivatives react diastereoselectively only at the more highly substituted
carbon atom with aldehydes and even with unsymmetric ketones.
8,9,10 Titanates can be used as mild catalysts for the transesterification of compounds containing acid- or base-labile functional groups.
11
TABLE I
SOME PRODUCTS OF ORGANOTITANIUM TRIISOPROPOXIDES [RTi(OiPr)3] WITH FUNCTIONALIZED CARBONYL COMPOUNDS3,a
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aThe bonds formed during the reaction are drawn bold.
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Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
petroleum ether
3'-NITRO-1-PHENYLETHANOL
tetraisopropyl orthotitanate [Ti(O-i-Pr)4] (Dynamit Nobel)
CH3Ti(OCH(CH3)2)3
CH3Ti(O-i-Pr)3
Ti(O-i-Pr)4
hydrochloric acid (7647-01-0)
Benzene (71-43-2)
ethyl ether,
diethyl ether (60-29-7)
acetonitrile (75-05-8)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
Acetophenone (98-86-2)
carbon (7782-42-5)
Benzophenone (119-61-9)
potassium (7440-09-7)
methylmagnesium iodide (917-64-6)
magnesium sulfate (7487-88-9)
Tetrahydrofuran (109-99-9)
hexane (110-54-3)
Methyllithium (917-54-4)
titanium tetrachloride (7550-45-0)
zirconium
argon (7440-37-1)
titanium (7440-32-6)
Methyltriisopropoxytitanium (18006-13-8)
Benzenemethanol, α-methyl-3-nitro- (5400-78-2)
tetraisopropyl orthotitanate (546-68-9)
3-nitrobenzaldehyde,
m-Nitrobenzaldehyde (99-61-6)
chlorotriisopropoxytitanium
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