This journal is©The Royal Society of Chemistry 2018 Chem. Commun.

Cite this:DOI: 10.1039/c8cc03764g

Diastereoselective addition of anisoles toN-tert-butanesulfinyl imines via four-memberedlithium cycles†

Leleti Rajender Reddy, * Sharadsrikar Kotturi, Yogesh Waman, Chirag Patel,Aditya Patwa and Rajesh Shenoy

A highly regio- and diastereo-selective ortho-lithiation/addition of

anisoles to N-tert-butanesulfinyl imines resulting in the selective

formation of chiral a-branched amines is described. This method

is also efficient for highly regioselective benzylic lithiation of

o-methylanisoles, followed by diastereoselective addition to

N-tert-butanesulfinyl imines.

Chiral a-branched amines are highly important structuralmotifs in the pharmaceutical industry1 and are present in manydrugs, drug candidates and natural products (Fig. 1).1–6 There-fore, general methods for their asymmetric synthesis are ofconsiderable importance. The stereoselective addition of orga-nometallic reagents to imines represents one of the mostconvergent and efficient approaches. In particular, the diastereo-selective addition of Grignard or lithium reagents to N-tert-butanesulfinyl imines has proven to be a particularly reliable andpopular method.7 F. A. Davis and co-workers have reported8a–c

an elegant method of lateral lithiation of o-tolunitrile followedby addition to N-p-tolylsulfinyl imines. Recently, Rajapakse andco-workers from Merck have reported the direct ortho-lithiation

of N-Boc anilines followed by addition to N-tert-butanesulfinylimines.8d,e In this context, we reasoned that a direct ortho-lithiation of anisoles and addition to the Davis–Ellman imineswould give a-branched amines, which has not been describedin the literature to the best of our knowledge.9,10 Herein, wereport a straightforward ortho-lithiation/addition of anisoles toN-tert-butanesulfinyl imines via four-membered lithium cycles.We envisaged that this synthetic effort could be of value in avariety of research applications, including the discovery of newbioactive substances.

At the outset of our investigation, we chose anisole (5a) asour model substrate. We were interested in using n-BuLi undermild conditions instead of the less stable, more expensive andhighly pyrophoric t-BuLi and s-BuLi for the deprotonation atlow temperature. Lithiation at 0 1C for 1 h in the absence of aligand followed by addition to N-tert-butanesulfinyl aldimines3a11 at �78 1C afforded the desired amine 7a in 90% yieldwith high diastereoselectivity (495 : 5) (Table 1, entry 1). Thediastereoselectivity of the reaction was determined to be 495 : 5by 1H NMR analysis of the crude product. The ‘‘495 : 5’’ drdenotes that the signals for only one diastereomer were observed.The structure and absolute configuration of (RS,S)-7a wereconfirmed by comparing the 1H NMR, 13C NMR, and specificrotation data ([a]25

D = �52.4 (c = 0.25, EtOH)) with literature data([a]25

D = �51.9 (c = 2.2, EtOH)).12 The use of commonly availableamine ligands such as TMEDA, DMPU and PMDTA did not giveany advantage with respect to yield and diastereoseletivity.

With these satisfactory reaction conditions in hand, we thenexamined the flexibility of the reaction using various aldimines(Table 1). Interestingly, several substituted aromatic N-tert-butanesulfinyl aldimines, such as o-chloro, p-methyl, andp-methoxy derivatives (3b–e), reacted with 5a leading to thecorresponding chiral amines (7b–e), (Table 1, entries 2–5) inexcellent yields (89–92%) and with high diastereomeric ratios(dr 95 : 5). Similarly, heterocyclic N-tert-butanesulfinyl aldimines,such as 2-furyl (3f) and 2-thiophenyl (3g), smoothly reacted with5a affording the corresponding amines 7f and 7g (Table 1,entries 5, 6) in 90% and 92% yields respectively (dr 95 : 5).

Fig. 1 a-Branched amines containing natural products and drug candidates.

Piramal Discovery Solutions, Pharmaceutical Special Economic Zone,

Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.

E-mail: rajender.leleti@piramal.com

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc03764g

Received 10th May 2018,Accepted 23rd May 2018

DOI: 10.1039/c8cc03764g

rsc.li/chemcomm

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Likewise, several aliphatic N-tert-butanesulfinyl aldimines,such as cinnamyl, isopropyl, and isovaleryl derivatives (3h–j),also reacted with 5a to form amines (7h–j) (Table 1, entries 7–10)in 82–88% yield with good diastereomeric ratios (dr 90 : 10to 95 : 5).

To broaden the scope of this method, a number of represen-tative directed arenes such as ethoxybenzene (5b), 2-methoxyanisole (5c), and 4-methyl anisole (5d) were also evaluated. Theresults are shown in Table 2.

Interestingly the reaction of o-methyl anisole (5e) withn-BuLi under optimal reaction conditions selectively generatedbenzylic lithiation species (6e) instead of ortho-lithiation spe-cies (6a) (Fig. 2). The reaction of 6e with 3a at �78 1C affordedamine 8a, which was isolated in 86% yield with high diastereo-selectivity (495 : 5) (Scheme 2, entry 1). To check the furtherscope of these conditions, 6e was treated with several N-tert-butanesulfinyl aldimines such as 3d, 3f, and 3k leading to thecorresponding amines 8d, 8f, and 3k (Scheme 1, entries 2–4)

in excellent yields (80–90%) and good diastereomeric ratios(dr 90 : 10 to 95 : 5).

Finally, the sulfinyl group was readily cleaved under mildacidic conditions (1 N HCl in methanol at 0 1C for 30 min) toprovide free amine 9d and 10d in quantitative yield (Scheme 3).

Table 1 Direct ortho-lithiation of anisole and diastereoselective additionto various N-tert-butanesulfinyl aldiminesa

Entry Substrate (R) Product Yieldb (%) drc

1 3a: R = Ph 7a 90 495 : 52 3b: R = o-ClC6H4 7b 91 495 : 53 3c: R = p-MeC6H4 7c 90 495 : 54 3d: R = p-MeOC6H4 7d 89 495 : 55 3e: R = p-CF3C6H4 7e 92 495 : 56 3f: R = 2-furyl 7f 90 495 : 57 3g: R = 2-thiophenyl 7g 92 495 : 58 3h: R = cinnamyl 7h 82 90 : 109 3i: R = isopropyl 7i 88 495 : 510 3j: R = isovaleryl 7j 84 92 : 8

a All the reactions were performed using 1.0 equiv. of 3, 5.0 equiv. of 5aand n-BuLi (3.0 equiv.) at 0 to�78 1C for 2 h. b Isolated yield. c Diastereo-selectivity was determined by 1H NMR analysis. The ‘‘495 : 5’’ dr denotesthat the signals for only one diastereomer were observed.

Table 2 Addition of various arenes to various N-tert-butanesulfinyl aldimines(RS) 3da

Entry Reagent (R) Product Yieldb (%) drc

1 5a: R = OMe, R2 = H 7d 89 495 : 52 5b: R = OEt, R2 = H 7k 80 495 : 53 5c: R= OMe, R2 = 2-OMe 7l 75 495 : 54 5d: R = OMe, R2 = 4-Me 7m 90 495 : 5

a All the reactions were performed using 1.0 equiv. of 3, 5.0 equiv. of 5and n-BuLi (3.0 equiv.) at 0 to�78 1C for 2 h. b Isolated yield. c Diastereo-selectivity was determined by 1H NMR analysis. The ‘‘495 : 5’’ dr denotesthat the signals for only one diastereomer were observed.

Fig. 2 Reactive species.

Scheme 1 Approaches to ortho-lithiation and the asymmetric synthesisof amines.

Scheme 2 Direct lithiation of o-methylanisole and diastereoselectiveaddition to various N-tert-butanesulfinyl aldimines.

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In summary, we have reported the highly regioselectivedirect ortho-lithiation of anisoles followed by diastereoselectiveaddition to N-tert-butanesulfinyl imines via four-memberedlithium cycles. This method is also found to be efficient forhighly regioselective benzylic lithiation of o-methylanisolesfollowed by diastereoselective addition to N-tert-butanesulfinylimines via five-membered lithium cycles. Extension of this workis currently in progress.

Conflicts of interest

There are no conflicts to declare.

Notes and references1 (a) Over 5000 compounds containing these pharmacophores are cur-

rently in advanced stages of biological testing: MDL Drug Data Report,MDL Information Systems, Inc., San Leandro, CA, 2010; (b) A. Elbeinand R. I. Molyneux, Alkaloids, Chemical and Biological Perspectives,ed. S. W. Pelletier, John Wiley, New York, 1990; (c) The Alkaloids:Chemistry and Biology, ed. G. A. Cordell, Academic Press, San Diego,2000, vol. 54; (d) M. J. Fray, G. Bish, A. D. Brown, P. V. Fish, A. Stobie,F. Wakenhut and G. A. Whitlock, Bioorg. Med. Chem. Lett., 2006,16, 4345; (e) M. J. Fray, G. Bish, P. V. Fish, A. Stobie, F. Wakenhutand G. A. Whitlock, Bioorg. Med. Chem. Lett., 2006, 16, 4349;( f ) P. M. Sher, W. N. Washburn and J. D. Godfrey, Jr., US Pat.,US6436914B1, 2002; (g) M. Tomita, J. Pharm. Soc. Jpn., 1939, 59, 207;(h) T. R. Govindachari, K. Nagarajan and C. V. Ramad, J. Chem. Soc.,1958, 983; (i) J. Fotie, D. Bohle, O. Scott, M. Olivier, M. A. Gomez andS. Nzimiro, J. Nat. Prod., 2007, 70, 1650.

2 (a) H. Kakeya, M. Morishita, K. Kobinata, M. Osono, M. Ishizuka andH. Osada, J. Antibiot., 1998, 51, 1126; (b) H. Kakeya, M. Morishita,H. Koshino, T. Morita, K. Kobayashi and H. Osada, J. Org. Chem.,1999, 64, 1052.

3 (a) J. A. Grant, J. M. Riethuisen, B. Moulaert and C. DeVos, Ann.Allergy, Asthma, Immunol., 2002, 88, 190; (b) J. H. Day, A. K. Ellis andE. Rafeiro, Drugs Today, 2004, 40, 415; (c) G. M. Walsh, Curr. Med.Chem., 2006, 13, 2711.

4 C. J. Opalka, T. E. D’Ambra, J. J. Faccone, G. Bodson and E. Cossement,Synthesis, 1995, 766.

5 S. N. Calderon, R. B. Rothman, F. Porreca, J. L. Flippen-Anderson,R. W. McNutt, H. Xu, L. E. Smith, E. J. Bilsky, P. Davis and K. C. Rice,J. Med. Chem., 1994, 37, 2125.

6 J. Lloyd, H. J. Finlay, W. Vacarro, T. Hyunh, A. Kover, R. Bhandaru,L. Yan, K. Atwal, M. L. Conder, T. Jenkins-West, H. Shi, C. Huang,D. Li, H. Sun and P. Levesque, Bioorg. Med. Chem. Lett., 2010,20, 1436.

7 (a) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem. Res., 2002,35, 984; (b) D. A. Pflum, D. Krishnamurthy, Z. Han, S. A. Wald andC. H. Senanayake, Tetrahedron Lett., 2002, 43, 923; (c) N. Plobeck andD. Powell, Tetrahedron: Asymmetry, 2002, 13, 303; (d) Z. Han,D. Krishnamurthy, P. Grover, Q. K. Fang, D. A. Pflum andH. Senanayake, Tetrahedron Lett., 2003, 44, 4195; (e) K. W. Kellsand J. M. Chong, Org. Lett., 2003, 5, 4215; ( f ) I. R. Cooper, R. Grigg,M. J. Hardie, W. S. MacLachlan, V. Sridharan and W. A. Thomas,Tetrahedron Lett., 2003, 44, 2283; (g) J. R. Rech and P. E. Floreancig,Org. Lett., 2003, 5, 1495; (h) P. M. Jung, R. Beaudegnies,A. De Mesmaeker and S. Wendeborn, Tetrahedron Lett., 2003,44, 293; (i) F. Chemla and F. Ferreira, Synlett, 2004, 983; ( j) S. D.Kuduk, R. M. DiPardo, R. K. Chang, C. Ng and M. G. Bock, Tetra-hedron Lett., 2004, 45, 6641; (k) L. P. Jayathilaka, M. Deb andR. F. Standaert, Org. Lett., 2004, 6, 3659.

8 (a) F. A. Davis and P. K. Mohanty, J. Org. Chem., 2002, 67, 1290;(b) F. A. Davis, P. K. Mohanty, D. M. Burns and Y. W. Andemichael,Org. Lett., 2000, 2, 3901; (c) F. A. Davis, J. Y. Melamed and S. S.Sharik, J. Org. Chem., 2006, 71, 8761; (d) H. A. Rajapakse, M. B. Young,H. Zhu, S. Charlton and N. N. Tsou, Tetrahedron Lett., 2005, 46, 8909;(e) A. Grajewska and M. D. Rozwadowska, Tetrahedron: Asymmetry,2008, 18, 2910.

9 (a) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem. Res., 2002, 35,984; (b) J. A. Ellman, Pure Appl. Chem., 2003, 75, 39; (c) F. Ferreira,C. Botuha, F. Chemla and A. Perez-Luna, Chem. Soc. Rev., 2009, 38,1162; (d) M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev.,2010, 110, 3600; (e) F. A. Davis, J. Org. Chem., 2006, 71, 8993.

10 (a) V. Snieckus, Chem. Rev., 1990, 90, 879; (b) M. C. Whisler,S. MacNeil, V. Snieckus and P. Beak, Angew. Chem., Int. Ed., 2004,43, 2206; (c) P. Steffen, C. Unkelbach, M. Christmann, W. Hiller andC. Strohmann, Angew. Chem., Int. Ed., 2013, 52, 9836; (d) J. T.Jastrzebski, A. M. Arink, J. Kleijn, T. W. Braam, M. Lutz, A. L.Spek and G. van Koten, J. Am. Chem. Soc., 2013, 135, 13371;(e) V. Mallardo, R. Rizzi, F. C. Sassone, R. Mansueto, F. M. Perna,A. Salomone and V. Capriati, Chem. Commun., 2014, 50, 8655;( f ) G. Rouquet, D. C. Blakemore and S. V. Ley, Chem. Commun.,2014, 50, 8908; (g) D. W. Slocum, T. K. Reinscheld, C. B. White,M. D. Timmons, P. A. Shelton, M. G. Slocum, R. D. Sandlin,E. G. Holland, D. Kusmic, J. A. Jennings, K. C. Tekin, Q. Nguyen,S. J. Bush, J. M. Keller and P. E. Whitley, Organometallics, 2013,32, 1674.

11 N-tert-Butanesulfinyl aldimines are prepared as per our previouslyreported procedures: (a) L. R. Rajender, H. Bin, M. Prashad andK. Prasad, Org. Lett., 2008, 10, 3109; (b) L. R. Rajender, G. D. Sonia,Y. Liu and M. Prashad, J. Org. Chem., 2010, 75, 2236; (c) L. R.Rajender, P. G. Aditya, V. Eric and Y. Liu, J. Org. Chem., 2012,77, 1095; (d) L. R. Rajender, P. G. Aditya and Y. Liu, J. Org. Chem.,2011, 76, 3409; (e) L. R. Rajender, M. Prashad and K. Prasad, J. Org.Chem., 2012, 77, 6296; ( f ) L. R. Rajender and M. Prashad, Chem.Commun., 2010, 46, 222.

12 M. Marina, S. Dmitry, B. Sergey, L. Edvards and S. Edgars, J. Org.Chem., 2010, 75, 2357.

Scheme 3 Deprotection of the sulfinamide group.

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