Dialkylaminoacetonitrile Derivatives as Amide Synthons. A One-Pot Preparation of Heteroaryl Amides via a Strategy of Sequential SNAr Substitution and Oxidation Zhongxing Zhang, Zhiwei Yin, John F. Kadow, Nicholas A. Meanwell, and Tao Wang* Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492
FIGURE 1. Drugs with heteroaryl amide subunits.
[email protected] Received July 18, 2003
FIGURE 2. Alternative amide synthon. SCHEME 1
Abstract: Dialkylamino acetonitrile derivatives were utilized as alternative to cyanohydrin synthons for preparation of the corresponding heteroaryl dialkyl amides via a strategy of sequential base-mediated coupling and oxidation. The most advantageous oxidant, NiO2-H2O, can readily oxidize 2-substituted aminoacetonitriles to the corresponding amides under both basic and neutral conditions by forming cyanohydrins in situ.
Heteroaryl amides are both useful synthetic intermediates and important structural elements of several drugs and candidates, including the hypnotic agent rilmazafone and the HIV non-nucleoside reverse transcriptase inhibitor delavirdine (Figure 1).1,2 We have previously demonstrated that N,N-disubstituted aminoacetonitrile derivatives (1) are effective synthons of the corresponding amides 2 via a procedure that takes advantage of umpolung-like properties of 1, as summarized in Figure 2.3 The anion of 1, prepared by deprotonation using NaHDMS in THF, was reacted with an ester 3 to provide intermediate 4 (Scheme 1). The intermediate 4 was deprotonated in situ by the excess base present in the reaction mixture and the anion oxidized by adding Clorox, to afford the R-ketoamide 5 in good overall yield.3 We now report the extension of this concept to the preparation of heteroaryl amides 8 via a sequential SNAr substitution and oxidation, a convenient one-pot process summarized in Scheme 2. An important advantage of this process is that the oxidation of the intermediate 7 to (1) (a) Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M. J. Med. Chem. 1994, 37, 999. (b) Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.; Ishimaru, T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.; Doi, T.; Otsuka, M. J. Med. Chem. 1995, 38, 3106. (c) Kumar, S.; Singh, R.; Singh, H. Bioorg. Med. Chem. Lett. 1993, 3, 363. (d) Kawakubo, H.; Okazaki, K.; Nagatani, T.; Takao, K.; Hasimoto, S.; Sugihara, T. J. Med. Chem. 1990, 33, 3110. (e) Tanaka, A.; Sakai, H.; Motoyama, Y.; Ishikawa, T.; Takasugi, H. J. Med. Chem. 1994, 37, 1189. (2) (a) Hirai, K.; Sugimoto, H.; Ishiba, T.; Fujishita, T.; Tsukinoki, Y.; Hirose, K. J. Heterocycl. Chem. 1982, 19, 1363. (b) Romero, D. L.; Morge, R. A.; Genin, M. J.; Biles, C.; Busso, M.; Resnick, L.; Althaus, I. W.; Reusser, F.; Thomas, R. C.; Tarpley, W. G. J. Med. Chem. 1993, 36, 1505. (3) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org. Lett. 2002, 4, 1103.
SCHEME 2
amide 8 could occur under mild, neutral conditions using NiO2-H2O in THF4,5 at room temperature. Conceptually, it was anticipated that the strategy described in Scheme 1 could be extended to the construction of heteroaryl amides by taking advantage of the electron-withdrawing effect of the nitrogen atom in heterocyclic rings to activate a halogen at the adjacent (4) (a) George, M. V.; Balachandran, K. S. Chem. Rev. 1975, 75, 491. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. (c) Evans, D. A.; Minster, D. K.; Jordis, U.; Hecht, S. M.; Mazzu, A. L., Jr.; Meyers, A. I. J. Org. Chem. 1979, 44, 497. (d) Kadaba, P. K.; Edelstein, S. B. J. Org. Chem. 1990, 55, 5891. (e) Chen, C.-W.; Beak, P. J. Org. Chem. 1986, 51, 3325. (f) Levin, J. I.; Weinreb, S. M. J. Org. Chem. 1984, 49, 4325. (g) Jones, T. K.; Denmark, S. E. Helv. Chim. Acta 1983, 66, 2377. (h) Shen, M.; Schultz, A. G. Tetrahedron Lett. 1981, 22, 3347. (i) George, M. V. Org. Synth. Oxid. Met. Compd. 1986, 373. (5) (a) Mineo, S.; Ogura, H.; Nakagawa, K. Chem. Pharm. Bull. 1980, 28, 2835. (b) Konaka, R.; Kuruma, K. J. Org. Chem. 1971, 36, 1703. (c) Konaka, R.; Terabe, S.; Kuruma, K. J. Org. Chem. 1969, 34, 1334. (d) Easton, C. J.; Eichinger, S. K.; Pitt, M. J. Tetrahedron 1997, 53, 5609. 10.1021/jo030233j CCC: $27.50 © 2004 American Chemical Society
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Published on Web 01/22/2004
TABLE 1. Oxidative Conditions for Formation of Amide
TABLE 2. One-Pot Preparation of Heteroaryl Amide via
8 from Intermediate 7
an SNAr-Oxidation Strategy
entry
oxidanta
1 2 3 4 5 6 7 8 9 10 11
bleach NaBO3-4H2O TMSOOTMS Fe2O3 K3Fe(CN)6 VO(acac)2 CAN FeCl3 m-CPBA CuCl2 CuO
yieldb,c (%) entry 36 36 62 24 32 6 16 7 4 8 8
12 13 14 15 16 17 18 19 20 21 22
oxidanta
yieldb,c (%)
BaO2 MgO2 CaO2 SrO2 ZnO2 Li2O2 Na2O2 MnO2 H2O2-urea NiO2-H2O CCl3-CCl3
41 21 48 34 46 33 42 22 33 63 13
a 3 equiv of oxidant was used. b LC-MS yield. c Other species include intermediate 7a and unknown products.
carbon atom. Potential substrates in this process include the heterocycles pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, pyrazole, oxazole, and thiazole derivatives in which the halogen atom R to the nitrogen atom is disposed toward facile displacement by nucleophiles via an SNAr substitution process. This process is depicted in Scheme 2 and relies upon the presence of excess base to generate the anion of intermediate 7 in situ, a process facilitated by the increased acidity of 7 compared to 1. Direct in situ oxidation of 7 and subsequent collapse of the hydroxylated product with the release of cyanide would be expected to provide the heteroaryl amide 8. The concept was initially examined under the conditions analogous to those established earlier for the reaction of 1 with esters.3 Thus, N,N-diethylacetonitrile (1a) was treated with an excess of NaHMDS and then exposed to 2,3-dichloropyrazine (6a) followed by the addition of excess bleach as the oxidant. However, this protocol afforded a mixture of the desired amide 8a and the unoxidized intermediate 7a (Table 1), prompting further optimization. Toward this objective, a panel of commercially available oxidants was evaluated in this process, as summarized in Table 1. The anion derived from 7a, generated in situ, was exposed to a variety of oxidants and the progress and outcome of these reactions monitored by LC-MS. From this survey, TMSO-OTMS and NiO2-H2O provided the best results, affording amide 8a in yields of 62% and 63%, respectively, based on LCMS analysis and after similar reaction times. Having established TMSO-OTMS and NiO2-2H2O as the optimal oxidants, extension of this one-pot procedure to a variety of heterocyclic halides was examined in order to generate the corresponding heteroaryl amides. The results, summarized in Table 2, demonstrate the synthetic utility of this protocol which proceeds in yields ranging from 38% to 79%. The sequential SNAr-oxidation procedure as conceived and described relies upon the direct oxidation of the
SCHEME 3
intermediate anion of 7. However, protonation of the intermediate anion of 7 may occur prior to oxidation. This process is particularly relevant for reagents containing water, such as NiO2-H2O and NaBO3-4H2O or those added as aqueous solutions, as with bleach (Table 1). To examine this facet of reactivity, intermediate 7a was isolated and exposed to the two most effective oxidants, TMSO-OTMS and NiO2-H2O. In the absence of any base, NiO2-H2O oxidized intermediate 7a to amide 8a in a yield of 67%, as determined by LC-MS, after simply stirring the mixture in THF at room temperature overnight (Scheme 3). In contrast, exposure of 7a to TMSOOTMS resulted in only unchanged starting material. However, when NaHMDS was introduced to generate the J. Org. Chem, Vol. 69, No. 4, 2004 1361
anion, both oxidants functioned effectively to provide amide 8a in similar yields (Scheme 3). The observation that the formation of a discrete anion was not required for oxidation with NiO2-H2O provided access to additional avenues of reactivity since the intermediate 7 can be constructed via alternate protocols.6,7 Most commonly, derivatives of 7 can readily be obtained by the reaction of an aldehyde and an amine in the presence of a source of cyanide.6 The preparation of amides 8 from intermediate of type 7 has generally relied upon the oxidation of the anionic form of intermediate 7, generated under strongly basic conditions, using either oxygen gas or air in a process that requires extended reaction times.6a,d,8 The neutral conditions associated with NiO2-H2O-mediated oxidation of 7 provide a more convenient and mild reaction protocol that enhances the utility of the overall synthetic strategy. To demonstrate the scope of this process, several aminoacetonitrile derivatives, either synthesized or obtained from commercial sources, were exposed to NiO2H2O in THF. The results are compiled in Table 3 and reveal that these reactions generally proceed smoothly and efficiently to completion after 12 h. The only exception is entry 5, which required heating the reaction mixture to 50 °C in order to drive the reaction to completion. It is noteworthy that these mild conditions are compatible with heterocyclic nitrogen atoms, both aromatic and saturated, and isolated olefinic bonds (Table 3, entry 3). Possible mechanistic pathways for the NiO2-H2Omediated oxidation of derivatives of 7 are proposed in Scheme 4. In path A, single electron-transfer from the nitrogen atom of substrate to NiO2 would generate the radical cation 10. The subsequent loss of a hydrogen radical, possibly assisted by the adjacent nitrogen atom, would produce the cation 11a, stabilized as 11b. The reaction of 11a/11b with water would furnish the cyanohydrin 13, anticipated to decompose by elimination of HCN,10 to provide the observed product, amide 8. The (6) (a) Enders, D.; Amaya, A. S.; Pierre, F. New J. Chem. 1999, 23, 261. (b) Enders, D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659. (c) Jonas, R.; Pruecher, H.; Wurziger, H. Eur. J. Med. Chem. 1993, 28, 141. (d) Chuang, T.-H.; Yang, C.-C.; Chang, C.-J.; Fang, J.M. Synlett 1990, 733. (e) Boeckman, R. K., Jr.; Breining, S. R.; Arvanitis, A. Tetrahedron 1997, 53, 8941. (f) Mai, K.; Patil, G. Tetrahedron Lett. 1984, 25, 4583. (g) Heydari, A.; Fatemi, P.; Alizadeh, A.-A. Tetrahedron Lett. 1998, 39, 3049. (h) Katritzky, A. R.; Szajda, M.; Bayyuk, S. Synthesis 1986, 804. (7) (a) Besson, L.; Le Bail, M.; Aitken, D. J.; Husson, H.-P.; RoseMunch, F.; Rose, E. Tetrahedron Lett. 1996, 37, 3307. (b) Corrie, J. E. T.; Gradwell, M. J.; Papageorgiou, G. J. Chem. Soc., Perkin Trans. 1 1999, 2977. (c) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315. (d) Cossu, S.; Conti, S.; Giacomelli, G.; Falorni, M. Synthesis 1994, 1429. (e) Andres, C.; Pedrosa, R.; Pedrosa, R.; Perez-Encabo, A.; Vicente, M. Synlett 1992, 45. (f) Fuchigami, T.; Ichikawa, S. J. Org. Chem. 1994, 59, 607. (g) Yang, T.-K.; Yeh, S.-T.; Lay, Y.-Y. Heterocycles 1994, 38, 1711. (h) Michel, S.; Le Gall, E.; Hurvois, J.-P.; Moinet, C.; Tallec, A.; Uriac, P.; Toupet, L. Liebigs Ann. Recl. 1997, 259. (i) Sundberg, R. J.; Theret, M.-H.; Wright, L. Org. Prep. Proced. Int. 1994, 26, 386. (8) (a) Yuste, F.; Origel, A. E.; Brena, L. J. Synthesis 1983, 109. (b) Rozwadowska, M. D.; Brozda, D. Can. J. Chem. 1980, 58, 1239. (c) Dominguez, E.; Martinez de Marigorta, E.; Carrillo, L.; Fananas, R. Tetrahedron 1991, 47, 9253. (d) Royer, J.; Husson, H.-P. Heterocycles 1993, 36, 1493. (e) Leblanc, J.-P.; Gibson, H. W. J. Org. Chem. 1994, 59, 1072. (9) (a) Sugita, J. Nippon Kagaku Zasshi 1967, 88, 1235. (b) Sugita, J. Nippon Kagaku Zasshi 1967, 88, 668. (c) Golding, B. T.; Hall, D. R. J. Chem. Soc. D 1970, 1574. (d) Hawkins, E. G. E.; Large, R. J. Chem. Soc., Perkin Trans. 1 1974, 280.
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TABLE 3. Oxidation of N,N-Disubstituted Aminoacetonitriles to Amide by Nickel Peroxide
a Isolated yield. b LC-MS yield. c Two hours at 50 °C. weeks at room temperature.
d
Three
SCHEME 4. Possible Mechanistic Pathways of NiO2-H2O Oxidation
intermediate 11a/11b could also form via path B, initiated by an abstraction of the hydrogen atom R to the cyano group in 7 by NiO2-H2O to afford the carbon-based radical 12.5 While combination of two molecules of 12 would provide a pathway for dimerization,4a,9 electron transfer from the radical 12 to NiO2 would lead to the intermediate cation 11a/11b. There is also the possibility that hydroxyl radical, derived from nickel peroxide, could combine with the carbon radical 12 to afford the cyanohydrin 13 directly (path C).5d Support for the formation of cation 11a/11b, via path A or path B, was obtained by treating N,N-diethylamino(10) The reaction and the subsequent workup should be undertaken with care in a well-ventilated hood due to the possibility of HCN liberation.
SCHEME 5
tolerant of a range of oxidatively sensitive functionality. The extension of this methodology to the synthesis of hydrocarbon-based aromatic amides from aryl halides is under active investigation. Experimental Section
acetonitrile (7d) with NiO2-H2O in the presence of n-propylamine (Scheme 5). Under these conditions, the amidine 14 was formed in 84% yield, as determined by LC-MS, along with small amounts of the amides 8d (4%) and 15 (8%). The formation of 14 and 15 is consistent with the interception of the intermediate cation 11a/11b by n-propylamine. Path C is considered to be unlikely for two major reasons. First, alkylamine radical formation has not been observed at room temperature, which implies a low possibility of producing 17 via the direct combination of radicals.4a,4i Second, while hydroxyl radical is readily formed from nickel peroxide,5d its direct combination with carbon radical 12 to afford cyanohydrin 13 is presumably not competitive with cation formation, based on the observed products in the presence of n-propylamine. In summary, the utility of dialkylaminoacetonitrile derivatives as umpolung-based amide synthons11 has been applied to the preparation of N,N-disubstituted heteroaryl amides.12 Mild, neutral conditions to effect the oxidation of a dialkylaminoacetonitrile to the corresponding amide using NiO2-H2O were discovered that are
General Methods. Heterocyclic halides 6 (Tables 1 and 2), substituted acetonitriles 7i-k (Table 3), N,N-diethylaminoacetonitrile 1, and oxidative agents (Table 1) are commercially available and were used as received. 1H and 13C NMR spectra were obtained at 500 MHz with samples dissolved in CD3OD or CDCl3. General Procedures for the Preparation of Heteroaryl Amides As Exemplified by the Preparation of Compound 8c. General Procedure for the Preparation of Heteroaryl Amides Using TMSO-OTMS. NaHMDS (8.2 mL, 1.0 M in THF, 8.2 mmol) was added to a solution of 2-chlorobenzoxazole (0.4 mL, 3.5 mmol) and N,N-diethylaminoacetonitrile (0.55 mL, 4.2 mmol) in dry THF (50 mL). After the mixture was stirred for 10 h at room temperature, TMSO-OTMS (1.4 g, 7.8 mmol) was added and the resulting mixture stirred a further 10 h at room temperature. The reaction mixture was quenched with saturated Na2SO3 solution, the aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over MgSO4. Concentration in vacuo afforded a residue which was purified by silica gel chromatography to provide benzoxazole-2-carboxylic acid, diethylamide 8c (420 mg, 55%). General Procedure for the Preparation of Heteroaryl Amides Using NiO2-H2O. NaHMDS (12 mL, 1.0 M in THF, 12 mmol) was added to a solution of 2-chlorobenzoxazole (0.57 mL, 5.0 mmol) and N,N-diethylaminoacetonitrile (0.84 mL, 6.5 mmol) in dry THF (80 mL). After the mixture was stirred for 10 h at room temperature, NiO2-H2O (2.2 g, 20 mmol) was added and the resulting mixture stirred a further 10 h at room temperature. Insoluble solids were filtered off and washed with MeOH. Concentration of filtrate in vacuo afforded a residue which was purified by silica gel chromatography to provide benzoxazole-2-carboxylic acid, diethylamide 8c (720 mg, 66%).
Acknowledgment. We thank Mr. Alan Xiang-dong Wang for valuable discussions. We are also very grateful to Dr. Li Pan for assistance in obtaining exact mass spectral data. Supporting Information Available: 1H and 13C spectra and HRMS data of compounds 7a, 8a-l, and 14. This material is available free of charge via the Internet at http://pubs.acs.org. JO030233J (12) N-Monosubstituted aminoacetonitrile derivatives are oxidized to the corresponding cyanoimines, as summarized in the example shown below:
(11) (a) Larock, R. C. In Comprehensive Organic Transformation; Wiiley-VCH: New York, 1989; p 865. (b) Hase, T. A. In Umpoled Synthons: A Survey of Sources and Uses in Synthesis; Wiley-Interscience: New York, 1987.
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