Versatile and Direct Transformation of Secondary Amides Into Ketones by Deaminative Alkylation with Organocerium Reagents

DOI: 10.1002/ajoc.201200066

Versatile and Direct Transformation of Secondary Amides into Ketones by Deaminative Alkylation with Organocerium Reagents

Kai-Jiong Xiao, Ai-E Wang, Ying-Hong Huang, and Pei-Qiang Huang*[a]

Amides are a class of easily available and highly stable compounds. Secondary amides[1] also serve as powerful di- recting groups in CÀH activation.[2] Ketones are also a class of extremely versatile molecules that enable a number of fundamental transformations in organic synthesis.[3] Hence Scheme 1. Direct transformation of secondary amides into ketones. Tf O=trifluoromethanesulfonic anhydride; 2-F-Py=2-fluoropyridine. the transformation of amides into ketones[4] is of high rele- 2 vance in organic synthesis. However, because of the high stability of amides, their direct transformation into more re- from RLi and CeCl3 and cerium complexes generated [13] active ketones presents a formidable challenge. Although in situ from RMgX and CeCl3 are more efficient than or- a limited number of specially designed amides, such as ganomagnesium, organolithium, and organozinc species for Weinreb amides (N-methoxy-N-methylamides), have been this reaction. Optimal yields were achieved by using the prepared as intermediates for the conversion of carboxylic cerium complex nBuMgBr/CeCl3 (3.0 equiv). The optimal acids/esters into ketones,[4] such methods cannot be used protocol for one-pot transformation of secondary amides for the transformation of simple amides into ketones. into ketones was identified as successive treatment of a solu- Herein, we report a general one-pot method for the direct tion of the amide in dichloromethane and 2-fluoropyridine [5] conversion of secondary amides into ketones by using or- (1.2 equiv) with Tf2O (1.1 equiv, À788C, then 08C), and ganocerium species as the alkylating reagents. RM/CeCl3 (3.0 equiv, À788C), then hydrolysis with aqueous On the basis of carbonyl activation with trifluorometha- HCl. [6] nesulfonic anhydride (Tf2O), we have recently reported Under the optimized conditions, the scope of the trans- the direct conversion of tertiary lactams/amides into terti- formation was studied. As shown in Table 1, this method of ary alkyl amines by sequential reductive alkylation with converting secondary amides into ketones by deaminative Grignard and organolithium reagents.[7] As a continuation alkylation with organocerium reagents has a wide scope of this study, and in connection with our general interest in and broad functional group tolerance. the development of step-economical synthesis,[7a,8,9] we in- A wide array of aroyl (Table 1, entries 1–16), alkanoyl vestigated the Tf2O-activated reductive alkylation of secon- (Table 1, entries 17–25), and alkenoyl amides (Table 1, dary amides. We discovered that cerium complexes generat- entry 26) were converted into the corresponding ketones in ed in situ from RMgX and CeCl3, and organocerium re- high yields. The substituents on the N atom of the secon- [10] agents (RCeCl2) generated in situ from RLi and CeCl3 dary amides, regardless of whether they are N-n-alkyl were effective for the direct conversion of secondary (Table 1, entries 1–9, 15-18, 24–26), N-s-alkyl (Table 1, en- amides into ketones by activation with Tf2O and 2-fluoro- tries 10–14, 21–23) or N-aryl (Table 1, entry 19), do not pyridine (Scheme 1). have much influence on the reactivity. The reaction also The conversion of N-butylbenzamide (1a) into ketone 2a went smoothly with hindered amides, such as 1o (Table 1, was selected as a model reaction. An investigation of the entry 24). influence of the base revealed that the use of a base was The reaction is compatible with many functional groups necessary, and 2-fluoropyridine[11] gave the best results. The on the amides, including ethers (Table 1, entry 12), aromatic influence of the organometallic reagent was then explored bromides (Table 1, entry 13), tertiary aromatic amines in combination with 2-fluoropyridine (1.2 equiv) as the (Table 1, entry 14), thiophene (Table 1, entry 16), terminal [12] base. Organocerium reagents (RCeCl2) generated in situ C=C bonds (Table 1, entry 25), and even conjugated C=C [a] K.-J. Xiao, Dr. A.-E. Wang, Y.-H. Huang, Prof. Dr. P.-Q. Huang bonds (Table 1, entry 26). For a,b-unsaturated amide 1q, Department of Chemistry and only the 1,2-addition product 2u was obtained, which pro- Fujian Provincial Key Laboratory of Chemical Biology vides an alternative approach to enones[14] (Table 1, College of Chemistry and Chemical Engineering, Xiamen University entry 26). Xiamen, Fujian 361005 (P. R. China) With regard to the organocerium complexes, alkyl Fax : (+86)592-2186400 E-mail: [email protected] (Table 1, entries 1–4, 9–17, 19, 22, 24, 26), benzyl (Table 1, Supporting information for this article is available on the WWW entries 20, 21, 23, 25), aryl (Table 1, entries 6 and 7), and al- under http://dx.doi.org/10.1002/ajoc.201200066. kenyl cerium complexes (Table 1, entry 18) generated from

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Table 1. Direct transformation of secondary amides 1 into ketones 2.[a]

Entry Substrate RM Product Entry Substrate RM Product (YieldACHTUNGRE [%])[b] (YieldACHTUNGRE [%])[b]

1 nBuMgBr 14 EtMgBr

2 1a nBuLi 2a (87) 15 nBuMgBr

3 1a iPrMgBr 16 nBuMgBr

4 1a 17 nBuMgBr

5 1a 18 1j

6 1a PhMgBr 19 nBuMgBr 2n (89)

7 1a 20 BnMgBr

8 1a 21 BnMgBr 2p (84)

9 nBuMgBr 2a (83) 22 nBuLi

10 nBuLi 2a (87) 23 1n BnMgBr

11 nBuLi 24 nBuMgBr

12 nBuLi 25 BnMgBr

13 nBuMgBr 26 nBuMgBr

[a] Reaction conditions: 1) Amide (1.0 mmol), 2-fluoropyridine (1.2 mmol), Tf2O (1.1 mmol), CH2Cl2 (4 mL), À788C, then 08C, 10 min; 2) RM/CeCl3 (3.0 mmol), À788C, 1 h; 3) aq. HCl (2m, 5 mL), RT, 2 h. [b] Yield of isolated product. Bn=benzyl; Hex=hexyl; Pent =pentyl.

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either organolithium or Grignard reagents can be used for [2] a) M. Wasa, K. M. Engle, D. W. Lin, E. J. Yoo, J.-Q. Yu, J. Am. the one-pot synthesis of ketones. The reaction of amide 1a Chem. Soc. 2011, 133, 19598–19601; b) X. Wang, D. Leow, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 13864 –13867; c) S. L. Zultanski, with the allyl cerium complex generated from allylmagnesi- G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362– 15364; d) Q. Chen, um bromide proceeded with migration of the C=C bond to L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2011, 133, 428– 429. produce the conjugated enone 2d in 78% yield (Table 1, [3] M. B. Smith, J. March, Advanced Organic Chemistry: Reactions, entry 5). The use of alkenyl cerium complexes can also lead Mechanisms, and Structure, 6th ed., Wiley-Interscience, New York, to enones, such as 2p (Table 1, entry 18). The reaction of 2007. [15] [4] S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 –3818. amide 1a with aryl cerium complexes gave diaryl ketones [5] W. S. Bechara, G. Pelletier, A. B. Charette, Nat. Chem. 2012, 4, (Table 1, entries 6 and 7). It should be noted that function- 228– 234. This work appeared while we were submitting our own alized aryl magnesium reagents that were reported by Kno- manuscript. The two methods are complementary as a general chel et al.[16] can also be applied in this procedure (Table 1, method for the transformation of secondary amides to ketones in terms of the scope, reaction conditions, and nucleophiles used. entry 7). [6] For reviews on the chemistry of triflic acid and its derivatives, see: It is interesting that use of alkynyl cerium reagents gener- a) P. J. Stang, M. R. White, Aldrichimica Acta 1983, 16, 15 –22; ated from lithium acetylides yielded b-chloroenones, such as b) I. L. Baraznenok, V. G. Nenajdenko, E. S. Balenkova, Tetrahe- 2g (Table 1, entry 8), which are versatile building blocks for dron 2000, 56, 3077 –3119; for selected recent examples, see: the synthesis of heterocycles.[17] It seems that the addition of c) A. B. Charette, M. Grenon, A. Lemire, M. Pourashraf, J. Martel, J. Am. Chem. Soc. 2001, 123, 11829– 11830; d) M. Movassaghi, a chlorine ion occurred in situ after ynone formation. M. D. Hill, O. K. Ahmad, J. Am. Chem. Soc. 2007, 129, 10096– In conclusion, we have developed a simple, efficient, and 10097; e) S.-L. Cui, J. Wang, Y.-G. Wang, J. Am. Chem. Soc. 2008, general method for the direct transformation of secondary 130, 13526 –13527; f) G. Barbe, A. B. Charette, J. Am. Chem. Soc. amides into ketones. Considering the central role played by 2008, 130, 18–19. [7] a) K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang, Angew. ketones, this versatile and mild method opens up an avenue Chem. 2010, 122, 3101– 3104; Angew. Chem. Int. Ed. 2010, 49, in organic synthesis. Further development of this method 3037– 3040; for an application of the method, see: b) C. Gurot, for the synthesis of secondary amines and ketimines will be B. H. Tchitchanov, H. Knust, E. M. Carreira, Org. Lett. 2011, 13, reported elsewhere.[18] 780– 783. [8] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40– 49. [9] a) K.-J. Xiao, Y. Wang, K.-Y. Ye, P.-Q. Huang, Chem. Eur. J. 2010, Experimental Section 16, 12792 –12796; b) C.-P. Xu, Z.-H. Xiao, B.-Q. Zhuo, Y.-H. Wang, P.-Q. Huang, Chem. Commun. 2010, 46, 7834– 7836; c) R.-F. Yang, General procedure for the direct transformation of secondary amides P.-Q. Huang, Chem. Eur. J. 2010, 16, 10319 –10322; d) S.-C. Tuo, J.- 1 into ketones 2 L. Ye, A.-E. Wang, S.-Y. Huang, P.-Q. Huang, Org. Lett. 2011, 13, Trifluoromethanesulfonic anhydride (185 mL, 1.1 mmol, 1.1 equiv) was 5270– 5273. added dropwise to a cooled (À78 8C) solution of amide 1 (1.0 mmol, [10] For reviews on the applications of CeCl3 as an environmentally 1.0 equiv) and 2-fluoropyridine (103 mL, 1.2 mmol, 1.2 equiv) in di- benign promoter in organic synthesis, see: a) H.-J. Liu, K.-S. Shia, chloromethane (4 mL). The reaction was warmed to 0 8C in an ice bath X. Shang, B.-Y. Zhu, Tetrahedron 1999, 55, 3803– 3830; b) G. Barto- and stirred for 10 min. The mixture was then cannulated into a freshly li, E. Marcantoni, M. Marcolini, L. Sambri, Chem. Rev. 2010, 110, prepared solution of the organocerium complex (3.0 mmol, 3.0 equiv) in 6104– 6143. THF (15 mL) at À788C and stirred for 1 h. Aqueous HCl (2 m, 5 mL) [11] a) J. W. Medley, M. Movassaghi, J. Org. Chem. 2009, 74, 1341 – was added, then the mixture was warmed to RT and stirred for 2 h. The 1344; b) A. B. Charette, M. Grenon, Can. J. Chem. 2001, 79, 1694 – organic layer was separated and the aqueous phase was extracted with 1703. diethyl ether (3 10 mL). The combined organic layers were washed [12] T. Imamoto, Y. Sugiura, N. Takiyama, Tetrahedron Lett. 1984, 25, with brine, dried over anhydrous Na2SO4, filtered, and concentrated 4233– 4236. under reduced pressure. The residue was purified by chromatography on [13] T. Imamoto, N. Takiyama, K. Nakamura, T. Hatajima, Y. Kamiya, a silica gel column to afford the desired ketone 2. J. Am. Chem. Soc. 1989, 111, 4392– 4398. [14] Enones, Vol. 1 (Eds.: S. Patai, Z. Rappoport), Wiley, Chichester, 1989. Acknowledgements [15] J. R. Schmink, S. W. Krska, J. Am. Chem. Soc. 2011, 133, 19574– 19577. [16] For a review on highly functionalized organomagnesium reagents We are grateful for financial support from the National Basic Research (Knochel organomagnesium reagents), see: a) P. Knochel, W. Program (973 Program) of China (Grant No. 2010CB833200), the NSF Dohle, N. Gommermann, F. F. Kneisel, F. Kopp, T. Korn, I. Sap- of China (21072160 and 20832005), the Fundamental Research Funds ountzis, V. A. Vu, Angew. Chem. 2003, 115, 4438– 4456; Angew. for the Central Universities of China (Grant No. 201112G001), and Chem. Int. Ed. 2003, 42, 4302– 4320; for a selected example, see: a Scholarship Award for Excellent Doctoral Student granted by Ministry b) L. Boymond, M. Rottlnder, G. Cahiez, P. Knochel, Angew. of Education of China (2010). We are grateful to Prof. Dr. G. M. Black- Chem. 1998, 110, 1801– 1803; Angew. Chem. Int. Ed. 1998, 37, burn for valuable discussions. 1701– 1703. [17] a) A. E. Pohland, W. R. Benson, Chem. Rev. 1966, 66, 161–197; b) T. Iwai, T. Fujihara, J. Terao, Y. Tsuji, J. Am. Chem. Soc. 2012, Keywords: amides · CÀC bond formation · ketones · 134, 1268 –1274. organocerium reagents · synthetic methods [18] K.-J. Xiao, A.-E Wang, P.-Q. Huang, Angew. Chem. 2012, 124, 8439– 8442; Angew. Chem. Int. Ed. 2012, 51, 8314 –8317.

[1] For a recent method, see: W.-J. Yoo, C.-J. Li, J. Am. Chem. Soc. Received: July 17, 2012 2006, 128, 13064–13065. Published online: && &&, 0000

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Deaminative Alkylation Cerium makes it simple: A simple, efficient, and versatile CÀC bond- Kai-Jiong Xiao, Ai-E Wang, forming method for the direct transfor- Ying-Hong Huang, mation of secondary amides into &&&& &&&& Pei-Qiang Huang* — ketones by Tf2O-mediated deaminative alkylation with organocerium reagents Versatile and Direct Transformation of is described. A wide variety of ketones, Secondary Amides into Ketones by including a,b-unsaturated ketones, b- Deaminative Alkylation with Organo- chloroenones, diaryl ketones, and cerium Reagents ynones were synthesized by using this method.

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