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

Synlett

Volumn , Issue 14, 2003, Pages 2139-2142

  Yoshida, Yasuo ^a   Umezu, Kazuto ^a   Hamada, Yusuke ^a   Atsumi, Naoya ^a   Tabuchi, Fumiya ^a  

^a Research and Development Department   (Japan)

Author keywords

Borane; Condensation reaction; Cyclopropanone; N cyclopropylanilines; Reductive dealkoxylation

Indexed keywords

ANILINE DERIVATIVE; SILANE DERIVATIVE; UNCLASSIFIED DRUG; [(1 ETHOXYCYCLOPROPYL)OXY]TRIMETHYLSILANE;

ARTICLE; BROMINATION; CYCLOPROPANATION; DRUG PURIFICATION; DRUG SYNTHESIS; GAS CHROMATOGRAPHY; POLYMERIZATION; REDUCTION;

EID: 0242659913     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2003-42072     Document Type: Article

References (14)

1. (a) Michael, S.; Uwe, P.; Klaus, G.; Andreas, K. EP0332033 A2, 1989.
2. (b) Mcguirk, P. R.; Conn, L. US Pat 5039682 A, 1991.
3. (a) Rühlmann, K. Synthesis 1971, 236.
4. (b) Salaün, J.; Marguerite, J. Org. Synth. 1985, 63, 147.
5. Kang, J.; Kim, K. S. J. Chem. Soc., Chem. Commun. 1987, 897.
6. Miller, S. A.; Gadwood, R. C. Org. Synth. 1989, 67, 210.
7. Employing AcOH and formic acid seemed to give the same results, but we used AcOH due to better handling and lower toxicity.
8. The crade 3′ also contains 2-3% of 1,1-dianilinocyclopropane as a by-product, which is readily dealkoxylated to give 4 and equimolar amount of aniline (see Scheme 3). (Equation presented)
9. Gillaspy, M. L.; Lefker, B. A.; Hada, W. A.; Hoover, D. J. Tetrahedron Lett. 1995, 36, 7399.
10. 4 to 2g could be reduced to 1.05 each without decreasing the yield of 4g.
11. 3 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.
12. 2O 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) (8.83 g, 89%); bp 71-73 °C/0.53 kPa.
13. 3-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-methoxyaniline (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.
14. 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).