Practical Synthesis of N-Cyclopropylanilines via Direct Condensation of Anilines with [(1-Ethoxycyclopropyl)oxy]trimethylsilane

Abstract

N-Cyclopropylanilines were obtained in high yield through the condensation reaction of anilines with [(1-ethoxycyclopropyl)oxy]trimethylsilane by a simple two-steps operating process, without purification of the intermediate, 1-alkoxy-1-anilinocyclopropane.

Key words

N-cyclopropylanilines - condensation reaction - reductive dealkoxylation - borane - cyclopropanone

References

• 1a Michael S, Uwe P, Klaus G, and Andreas K. inventors; EP  0332033 A2. 
• 1b Mcguirk PR, and Conn L. inventors; US Pat  5039682 A. 
• 2a Rühlmann K. Synthesis  1971,  236 
• 2b Salaün J. Marguerite J. Org. Synth.  1985,  63:  147 
• 3 Kang J. Kim KS. J. Chem. Soc., Chem. Commun.  1987,  897 
• 4 Miller SA. Gadwood RC. Org. Synth.  1989,  67:  210 
• 7 Gillaspy ML. Lefker BA. Hada WA. Hoover DJ. Tetrahedron Lett.  1995,  36:  7399 

5

Employing AcOH and formic acid seemed to give the same results, but we used AcOH due to better handling and lower toxicity.

6

The crude 3′ also contains 2-3% of 1,1-dianilinocyclo-propane as a by-product, which is readily dealkoxylated to give 4 and equimolar amount of aniline (see Scheme [3] ).

8

For example, the molar ratio of BF₃·THF and NaBH₄ to 2g could be reduced to 1.05 each without decreasing the yield of 4g.

9

When NaBH₄/AlCl₃ was used in Step 2, the reaction proceeded smoothly, but 14% of N,N-dicyclopropyl-3,4-difluoro-2-methoxyaniline was found in the product (entry 9). The reason why such large amount of this by-product was formed is not clear (normally <1%). But intermolecular migration of cyclopropyl group seemed have occurred in this reagent system.

10

Typical reaction procedure (entry 7) is as follows: Into a 200 mL four-necked flask fitted with a reflux condenser, a magnetic stirrer and a thermometer were fed 3,4-difluoro-2-methoxyaniline (2g, 7.96 g, 50 mmol), AcOH (12.0 g, 200 mL) and MeOH (50 mL). After [(1-ethoxycyclo-propyl)oxy]-trimethylsilane (1, 10.0 g, 57.4 mmol) was added dropwise at r.t., the reaction mixture was refluxed at 67-69 °C for 3 h under N₂ atmosphere. Then the mixture was concentrated in vacuo using a rotary evaporator, to obtain crude oil 3g′ (11.52 g) which contained 90.1% of N-(1′-methoxy)cyclopropyl-3,4-dimethoxyaniline and 2.7% of N-(1′-ethoxy)cyclopropyl-3,4-dimethoxyaniline, analyzed by GC and GC-MS.
Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer and a thermometer were fed NaBH₄ (3.78 g, 100 mmol) and anhyd THF (50 mL). After cooling to 5 °C and adding BF₃·Et₂O complex (14.19 g, 100 mmol) dropwise, the mixture was stirred under N₂ atmosphere for 1 h at 5 °C. Then, crude 3g′ dissolved in THF (25 mL) was added dropwise at 5-10 °C in a time period of 20 min. After stirring at r.t. for 5 h, at reflux temperature for 2 h, and recovering THF (60 mL) by distillation, the mixture was cooled to r.t. and poured into water (300 mL). Then the resulting mixture was extracted with Et₂O (2 × 100 mL). The Et₂O layer was washed with water (2 × 100 mL) and dried over anhyd Na₂SO₄ followed by the removal of Et₂O by a rotary evaporator, to obtain a crude oil (10.56 g). The oil was subjected to distillation under reduced pressure to give N-cyclopropyl-3,4-difluoro-2-methoxy-aniline (4g) (8.83g, 89%); bp 71-73 °C/0.53 kPa.

11

The effect of alcohol used in Step1 was studied in the following manner: 3,4-Difluoro-2-methoxyaniline(2g) was employed to react in both EtOH and i-PrOH. The molar ratio of reagents and volume of alcohol (L/mol) was identical with that in entry 7. After refluxing in EtOH for 5 h, 87.1% of N-(1′-ethoxy) cyclopropyl-3,4-dimethoxyaniline was formed (determined by GC). Employing the conditions described in Step 2 (2g:NaBH₄:BF₃·THF = 1:1.2:1.2) at r.t. for 1 h and at 60 °C for 6 h, N-cyclopropyl-3,4-difluoro-2-methoxy-aniline (4g) was isolated in 83% yield. On the other hand, Step 1 in i-PrOH required higher temperature and substitution of the ethoxy group in 3′ by i-PrOH proceeded rather sluggishly. Thus after reaction at 70 °C for 4 h and refluxing (87 °C) for 4 h, 62.8% of N-(1′-isopropoxy)-cyclopropyl-3,4-dimethoxyaniline and 14.5% of N-(1′-ethoxy) cyclopropyl-3,4-dimethoxyaniline were formed (isopropoxy/ethoxy = 81:19, determined by GC). On the contrary, most of the ethoxy groups in 3′ were replaced by methoxy group when MeOH was used (see Table [1] ). After following Step 2 (at r.t. for 1 h and 60 °C for 6 h at the same reagent ratio as in EtOH), 70% of 4g was isolated. Thus in Step 1 the compositions of crude 3g′ obtained by these reactions were somewhat different from that in MeOH, but this did not give a large effect on Step 2. The lower yield of 4g in EtOH and i-PrOH than that in MeOH arises from the production of relatively large amount (ca 5-10%) of 1,1-bis(3,4-difluoro-2-methoxyanilino) cyclopropane as the
by-product (see ref. 6). From these points it can be gathered that employing MeOH as solvent in Step 1 gave the best yield of 4.

12

When 2-nitroaniline (50 mmol), [(1-ethoxycyclopropyl)-oxy] trimethylsilane(1) (57.5 mmol), AcOH (200 mmol), and MeOH (50 mL) were mixed and refluxed for 15 h, 7.3% of N-(1′-methoxy)cyclopropyl-2-nitroaniline was produced (determined by GC and GC-MS).