The tandem insertion of trimethylsilylcyanide and alkenes, alkynes, isocyanates or ketones into zirconacyclo-pentanes and -pentenes

TetrahedronLetters,Vol. 36, No. 23, pp. 4113-4116,1995

Pergamon

ElsevierScienceLtd Printedin GreatBritain 0040-4039/95$9.50+0.00 0040-4039(95)00652-4

The Tandem Insertion of Trimethylsilylcyanide and Alkenes, Alkynes, Isocyanates or Ketones into Zirconacyclo-pentanes and -pentenes.

Gareth D. Probert, Richard J. Whitby* Department of Chemistry, The University, Southampton, Hants S017 I BJ, U.K.

Steven J. Coote Glaxo Group Research, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.

Abstract. The tandeminsertionof trimethylsilylcyanideand alkenes,alkynes,ketone.s,or isocyanales into zirconacyclo-pentanesor -pentenesgivescyclopentylamineswith an alkyl,alkenyl,lhydroxyalkyl,or carboxamidesubstituentalphato the aminegroup.

The intramolecular co-cyclisation of alkenes and alkynes induced by 'zirconocene butene' is a useful method for the construction of carbocyclic and heterocyclic rings1. Efficient use of the transition metal demands a more productive elaboration of the intermediate zirconabicycles (e.g. 2) than the usual protonolysis2. We have reported 3 that insertion of isocyanides into such zirconacycles affords zirconocene ~q2-imine complexes4 which may be trapped with alkenes and alkynes to afford elaborated cyclopentylamines. We now report studies on the insertion of trimethylsilylcyanide(to afford primary amines) and the use of isocyanate traps to give unusual s-amino amides. Diene 1 was cleanly cyclised with zirconocene(1-butene), generated in situ from dibutylzirconocene5 to give the zirconacycle 2. Trimethylsilylcyanide (TMSCN) rapidly inserted at room temperature, presumably via the isocyanide isomer, to give the iminoacyl complex 3 (Scheme 1). Immediate methanolysis of 3 gave the trans-dimethyl cyclopentane 4 indicating that the insertion is reversible with the zirconacyclopentane 2 being more susceptible to hydrolysis than 36. On standing at room temperature a slow rearrangement of 3 to the rl 2imine complex 5 is observed by NMR, complete after around 4 hours. There is a competitive decomplexation of the zirconocene unit7 from 5 to give free imine 6, complete after 18 hours at room temperature. Methanolysis after 4 hours gave the amine 78 (45% yield) and the ketone 8 (33% yield). Other substrates for the 112imine complex 5 are unreactive towards 3 so may be present in situ. Trapping with 4-octyne is particularly efficient to give 9a 3b on protonolysis, but terminal alkynes also give acceptable overall yields of the allylic amine products 9b and 9e, and with excellent regiocontrol. More hindered internal alkynes give poor yields, the ketone 8 being the main product formed. Alkenes are poor substrates for acyclic N-trimethylsilyl zirconocene lq2-imine complexes9 and insertion into l,l-disubstituted examples is unknown. The failure of attempted trapping of 5 with 1-heptene was thus not surprising and we were pleased that ethylene and norbomene did give moderate yields of the adducts 10 and 11. Insertion of acetone into 5 gave the tertiary alcohol 12 in good yield after protonolysis. Unfortunately all attempts to insert alkyl and aryl aldehydes failed to give the desired products. 4113

4114

Fast 1 9

- SiMe3

2 R1

a npr

3]

V

R 1 Yield % npr

63

C H nBu 40 d nBu SiMe3 10

R j~.,~NM2 R

9

d,c.

Rt ~ e,c.

R

~

NH2

R

"~

""" "--'-44% 10

R~ ~ . ~ N R

4

F:I ~

~P2 !

5

SiMe31

f,c.

c ~ R ~ t T._ . ..,~. . ` NH2 "'"

H

-"CP2Zr" N

R 171

R ~" 7

.... ~

R 6"f

c

""

8

26% H2

~ I~]

g,c.

R~x/'~,N

h,c.

13 R 1 % Yield a Et 44 b nBu 70 ¢ PhCH2 47 d H 14

H2

~

~ .... //~-OH 12, 52% " "

R/1N~3 ""~0~-~1~ R 1

Scheme 1. R,R = -CH2OC(CH3)2OCH 2- a. Cp2ZrBu2, -78°C - r.t., 2h; b. Me3SiCN, r.t., 5 rain.; c. i. MeOH, ii. H20; d. RIc-=CR 2, r.t., 16h; e. 1 atm ethene, 67°C, 2h; f. norbornene, r.t., 16h.; g. Me2CO, lh r.t.; h. R1NCO 16h, r.t. except for product d where Me3SiNCO was used. The formation of novel amino acid derivatives is an important target and we were delighted to find that a variety of isocyanates 1° inserted into 5 to provide a-amino amides 13a-d after protonolysis. Although the insertion of trimethylsilylisocyanate gave a poor yield, the primary amine moiety in 13(! is valuable for further elaboration. Cyclisation of 1,7-octadiene with zirconocene(1-butene) initially produces a mixture of the cis- and trans-zirconacyclopentanes, but this can be converted exclusively to the trans- isomer 14 by controlled heatingl 1. Insertion of TMSCN occurred readily at room temperature to give the imino acyl complex 15 but this did not appear to rearrange to the zirconocene q2-imine complex 16 either at room temperature or on heating. Despite this a range of substrates successfully u'apped 16 (Scheme 2), demonstrating that it is present in an unfavourable equilibrium with 15.

d,c.

Pr

c.

V49":~:

,/~-OH

65% 0 ~/

~

34%

Scheme 2. a. Cp2ZrBu2, -78°C - r.t., lhen 67°C, 3h. ; b. Me3SiCN, r.t., 5 rain.; c. i. MeOH, ii. H20; d. PrC-=CPr, r.t., 16h; e. Me2CO, lh, 50°C; f. EtNCO, lh, r.t.

4115

Co-cyclisation of 1-phenyl-hept-6-en-1-yne with zirconocene(1-butene) gave the unsaturated zirconacycle 17a. Addition of trimethylsilylcyanide rapidly gave the iminoacyl complex 18a but nmr studies showed no sign of rearrangement to the rl2-imine complex 19a either at room temperature or on heating. Despite this quenching with methanol gave the cyclopentenyl amine 20 implying the intermediacy of 19a. Trapping of the zirconocene rl2-imine complex 19a with 4-octyne was also successful giving a mixture of the expected product 21a and 22a, the result of an anti 1,3-amine rearrangement3c, on work-up. By comparison, insertion of ethylisocyanate and acetone gave the c-amino amide 23 and 1,2-aminoalcohol 24 without isolation of rearrangement products. In a similar fashion co-cyclisation of undec-l-en-6-yne to afford 17b followed by the tandem insertion of trimethylsilylcyanide and 4-octyne gave the cyclic amine 21b on protolytic work up. Notably in this case 1,3-amine rearrangement was not observed. R

R

ZrCp2

Ph

~

NH2 NSiMe3

17aR=Ph;

18a, b ~

R '

d,c. Pr

H

p/

20,41%

R

Pr

22a, R = Ph, 26%

r /

/

b R = nBu

Xpr

~ ~ P 2

Ph

\

--

~ O ~ -

~ ' ~ , u"

23, 44%

~...._

19a,b

21a, R = Ph, 26% 21b, R = Bu, 42%

Scheme 3. a. CP2ZrBu2, -78°C - r.t.; b. Me3SiCN, r.t. 5 min.; c. i. MeOH, r.t.;

ii. H20; d. PrC-=CPr, 16h, r.t.; e. Me2CO, 50°C, lh; f. EtNCO, 50°C, lh.

~ k

Ph J ~~ N H 2 "~ I-~"~' / ~ - O H 24, 40%

Overall we have shown that the tandem zirconocene induced co-cyclisation of 1,n-dienes or enynes, insertion of trimethylsilylcyanide, rearrangement, and insertion of various alkenes, alkenes, acetone, and isocyanates is an efficient route to various primary cyclopentylamines. Of particular note is the formation of a-amino amides. Acknowledgements. We wish to thank Glaxo Group Research and the EPSRC for support of this work through the CASE scheme. References and Notes.

1.

2.

Broene, R. D.; Buchwald, S. L. Science 1993, 261, 1696; Negishi, E.; Takahashi, T. Acc. Chent Res. 1994, 27, 124; Negishi, E. I. In Comprehensive Organic Synthesis; Trost, B.M.; Fleming, I. Eds.; Pergamon: Oxford, U.K, 1991; Vol. 5; pp 1163-1184; Uesaka, N.; Moil, M.; Okamura, K.; Date, T. J. Org. Chem- 1994, 59, 4542; Kemp, M. I.; Whitby, R. J.; Coote, S. J. Synlett 1994, 451. Carbonylation: Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi, T.; Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem- 1989, 54, 3521; Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negishi, E. Tetrahedron Lett. 1989, 30, 5105. Aldehyde insertion: Cop6ret, C.; Negishi, E.; Xi, Z.; Takahashi, T. Tetrahedron Lett. 1994, 35, 695. Halogenation: Nugent, W. A.; Taber, D. F. J. Ant Chem. Soc. 1989, 111, 6435. Metathesis with other elements: Fagan, P. J.; Nugent, W. A.; Calabrese, J. C. J. Am. Cheat Soc. 1994, 116, 1880; Carbenoid insertion: Luker, T.; Whitby, R. J. Tetrahedron Lett. 1994, 35, 785 and

4116

3. 4.

5. 6.

7 8.

9.

10.

11.

9465; Gordon, G.J.; Whitby, R.J. Synlett, 1995, 77. (a) Davis, J. M; Whitby, R. J.; Jaxa-Chamiec, A. Tetrahedron Lett. 1992, 33, 5655; (b)idem, ibid, 1994, 35, 1445; (c)idem, Synlett 1994, 111. Formation of zirconocene rl2-imine complexes by other methods: (a) Coles, N.; Whitby, R. J.; Blagg, J. Synlett 1990, 271; (b) idem, ibid, 1992, 143; (c) Coles, N.; Harris, M.C.J.; Whitby, R. J.; Blagg, J. Organometallics 1994, 13, 190; (d) Harris, M.C.J.; Whitby, R. J.; Blagg, J. Tetrahedron Lett. 1994, 35, 2431; (e) Buchwald, S.L.; Watson, B.T.; Wannamaker, M. W.; Dewan, J. C. J. Am. Chem. Soc. 1989, 111, 4486; (f) Grossman, R.B.; Davis, W. M.; Buchwald, S.L.J. Am. Chem. Soc. 1991, 113, 2321. (g) Jensen, M; Livinghouse, T. J. Am. Chem. Soc. 1989, 111, 4495; (h) Ito, H; Taguchi, T; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469. Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986, 27, 2829. This is in marked comparison to the insertion of cyclohexylisocyanide where protonolysis of the iminoacyl complex analogous to 3 gives the amine derived from the corresponding rl2-imine complex 3b. With titanocycles decomplexation of 'titanocene' (Cp2Ti) is the exclusive pathway: Berk, S.C.; Grossman, R.B.; Buchwald, S.L.J. Am. Chem. Soc., 1994, 116, 8593. All yields are based on the diene or enyne precursors. All new compounds were characterised by high field 1H- and 13C-nmr, IR and mass spectra, and either HRMS or combustion analysis. The relative stereochemistries shown in scheme 3 are based on precedent 3c and are not proven (all were single diastereomers). The problem seems to be thermodynamic - the formation of the azazirconacycopentanes is reversible, and sometimes unfavourable. Acyclic N-trimethylsilylzireonocene rl2-imine complexes insert alkenes in benzene, but not in THF where the solvent acts to stabilise the rl2-imine complex - ref 4e and Harris, M.C.J.; Whitby, R.J., Blagg, J., Tetrahedron Lett., submitted. PhNCO failed to insert. Prof. Norton has recently reported the insertion of isocyanates into acyclic zirconocene rl2-imine complexes: Gately, D.A.; Norton, J. R.; Goodson, P. A. J. Am- Chem. Soc. 1995, 117, 986. Aldta, M; Yasuda, H.; Yamamoto, H.; Nakamura, A. Polyhedron 1991, 10, 1; Taber, D.F.; Louey, J.P.; Wang, Y.; Nugent, W.A.; Dixon, D. A.; Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457.

(Received in UK 28 March 1995; accepted 7 April 1995)