Temhdmn L.ertcrs. Vol32, No 33, pp4~94102, 1991

Prmted III Great Brltaln mlo-4039/91 $300+ I

Pergamon Ress ptc

Intramolecular Addition of Aryl Radicals to Vinylogous Urethanes: Studies Toward

Preparation of the Oxindole Portion of Gelsemine

Davtd J Hart’ and Shung C Wu

Department of Chemrstry, The Ohro State Unrversrty

120 W 18th Ave , Columbus, Ohto 43210

Abstract: Free radical cyclrzatton of vinylogous urethanes 5 and 12 gave sprro oxrndoles 6 and 13 + 14, in 95% and 84% yields, respecttvely Cyclizatlon ot protected geljemine Intermediate 1.9 resulted. in the tbrmation ofoxlndble 22 via a cycllzatton, 1,4_hydrogen atom transfer, reductron sequence

During the course of studtes dtrected toward the synthesis of gelsemine (1) we have evaluated several methods for

constructton of the oxtndole portron of the alkalotd ’ We have recently examined a vanatton of the method reported by

Jones* and our results are reported here

n-BusSnH, AIBN

CeHeCHs, A

(Reference 2)

Jones’ method revolves around the cyclrzatton of aryl radicals derived from o-bromo-N-acryloylanllldes (2 + 3) 3 We have

examrned a varrant of thts procedure that accomplrshes a reducttve n,a-annelatton of an oxrndole to cyclohexanone

denvatives as outlined below Thus, treatment of vrnylogous carbonate 4 wrth the drmethylalumtnrum amrde derived from o-

bromoanrltne followed by methylatron of the resulttng amide gave vrnylogous urethane 5 in 72% overall yield 4 Treatment of

5 wtth trr-n-butyltrn hydride (I 2 equivalents) and AIBN (0 1 equtvalent) in benzene (0 02 M in 5) at reflux gave oxrndole 6 In

95% yreld as an equal mrxture of diastereomers 5

1 o-BrCsH4NHAI(CHa)2

2 NaH, THF, CH31

n-BusSnH, AIBN

CsHs A

CH,O

6

100

The cyckzahon of aryl bromide 12 was next examined as a model for the projected synthesis of gelsemrne Cyclrzatron

substrate 12 was prepared from perhydronaphthalenone 7 using a four-step sequence 6 Treatment of ketone 7 wrth

potassrum hydnde and dlmethyl carbonate In THF gave P-ketoester 8 (78%) as a mixture of keto and enol tautomers 7.8

Warmrng a solution of 8 in methanol-tnmethyl orthoformate (3.7) tn the presence of Dowex50 (H+) for 1 h gave 10 in 48%

yield along wrth 46% of acetal 9 g Chromatographrc separahon of 9 and 10 followed by subjectmg 9 to the reaction

conditrons (4 cycles) gave 10 rn a 92% overall yield from 8 Vinylogous carbonate 10 was then converted to 11 (73%) and

cycllzahon substrate 12 (92%) under the same condrtrons used to convert 4 into 5 Treatment of 12 with tn-n-butyltrn

hydride under standard conditfons gave a separable mixture of 13 (mp 202-203.5oC) and 14 (mp 132-132 !YC), each In

42% Isolated yield The assrgnment of stereochemistry at C(3) In 13 and 14 was based on couplrng constants of 11 Hz and

5 Hz for H(3) In both Isomers, rndrcatlng an axfal drsposrtron for this proton The assrgnment of stereochemistry at C(4) In 13

was based on drfference nOe experiments that established the proxrmrty of Ho and the angular methoxymethyl group 1 o

b

e

11 R=H d <t2 R=CHa

(a) KH, (CHaO)zC=O, THP (b) CHQH. HC(OCHa)a, Dowex-50 (H+), A, lh (c) oBrCeH4NHAI(CHa)s, csHs, A, 2h (d) NaH, CHal, THF (e) rrBuaSnH (1 2 equrv), AIBN (0 1 equrv), CaHa, A, fnrtraf [12] = 6 02 M

The studies outllned above (12 -?r 13 + 14) gave us hope that cycllzatron of the radrcal derrved from aryl bromide 19 would

provide at least some material with C(4) stereochemistry appropriate for the synthesis of gelsemine Cyclization substrate 19

was prepared followmg a protocol slmllar to that developed for the preparatioaof 12 Conversian of the known ketone 15 to

16 was StraIghtforward 1 It has been noted previously that 1.5 shows a propensity for enolrzation toward C(4) rather than

C(2) 1 Although 16 could be rsolated and punfred, it was more convenient to add HMPA and dimethyl sulfate to the crude

enolate Vmylogous carbonate 17 was obtained in 74% overall yield from 15 using this procedure Treatment of 17 with the

appropriate dimethyl alummlum amrde gave 18 (83%) Sequentral treatment of 18 with LDA and chloromethyl methyl ether

completed the synthesis of 19 (71%) ”

4101

15

a

b< 16 R=H 17 R=CHs

C

d< 18 R=H 19 R = CH20CH3

22 R=H 23 R=D

21 20

(a) KH (3 equlv), (CHsO)sC=O (10 equlv), THF (b) HMPA, (CHs)sSO4 (c) o-BrCsH4NHAI(CH3)2. CsHs, A, 2h (d) LDA (1 2 equtv), CHsOCHsCI (1 2 equrv), THF (e) n-BusSnH (1 2 equrv), AIBN (0 5 equiv), C6H6, A

Treatment of a 0 02 M soluhon of 19 In benzene at reflux wrth tn-n-butylttn hydnde (1 2 equtv) and AIBN (0 5 equrv) gave

oxtndole 22 (46%, mp 195-195 5OC) as the major product I2 The structure of 22 was rnrtrally assrgned on the basrs of

spectroscoptc data For example, the C(3) stereochemrcal assignment was based on the appearance of Hg as a doublet of

doublets at 6 4 28 (J = 11 6. 6 3 Hz) The stereochemistry at C(4) was assigned on the basis of dtfference nOe experiments

that establrshed the proxrmrty of Ho and the C(20) methoxymethyl group, and the stereochemistry of the olefin was

assrgned on the basis of nOe experiments that establrshed the proxrmrty of Hg and Ht7 Ultrmately, the structure of 22 was

confrrmed by X-ray crystallography is- we rmaglne that 22 IS chrwed~t~om cyclizatlon otttie lnltall~ tbrmeU~aryl~raUicai(l~9~ +

20) followed by tntramolecular 1,4-hydrogen transfer (20 + 21)14 and reduction (21 + 22) In accord with thts proposal,

treatment of 19 with tn-n-butylttn deutende gave 23 (36%)

In summary, a vanant of the Jones procedure that allows one to graft an oxtndole onto a cyclohexanone was developed

Stereochemical compltcatrons and an unexpected 1 ,Chydrogen transfer, however, were encountered when the procedure

was applred to a prolected intermediate In the syntheses of gelsemrne l5 Studies that deal wtth these complications as well

as development of thts procedure into a general method for a-arylatron of ketones are In progress t6

1.

2

3

4

5

r,hn1.,..1 -K. ~ Ha,. o_ -c ,. kh_rt.,. n .L ,. l_eec c -.s ,.RrnP,rh,. 8 ,.wu,..s .1 Rrg ChP,m ws,. 54,. 279

Jones., K, Tkmpsnn,. M. ,. Wr@ht, 5; d Ch.wn .S.m I Chmm Ccmmun WEi,. i.i.5 Wrghht.. c .Shu!km.,. M. ~. c,hne.s~ K.,

Thompson, M Tetrahedron Lett 1987, 6389 Jones, K , McCarthy, C Tetrahedron Lett 1989, 2657

Cobalt (I) medrated cyckzatrons whrch deposrt a double bond In the six-membered ring have also been reported Clark

A J , Jones, K Abstracts of Papers, 200th Natronal Meeting of the Anencan Chemical Socrety, Washrngton, DC,

American Chemrcal Socrety Washrngton, DC, 1990. ORGN 213

Basha, A, Lrpton, M , Wemreb, S M Tefrahedron Lett 1977 4171

Spectral data (IR, MS, ‘H-NMR, j3C-NMR) were consistent with the structure assrgnment for this and all other

compounds reported herern

6 Compound 7 was prepared from the appropriate ketal-alcohol (Drerdmg, A S , Tomasewskr, A J J Am. Chem Sot

1955, 77,411) (1) NaH, CHal (2) pTsOH, CHzOH, Hz0

7

8

9

IO

Ruest, L , Blouin, G , Deslongchamps, P Syn Commun 1976, 169

NMR analysrs mdrcated the presence of both tautomers

11

rln_YfP,<P >t!&Xk~;.I. R.,MJXr;FY,.R. n ~.,.hlkefT,.'& .Ri@af$R. A .J Cham. Sor, l%i%. 1.344

lrradratron of one of the drastereotoprc protons of the C(20) methoxymethyl group (6 3 56) showed a 18% nOe at Ho (6

7 52) No such nOe was observed for oxrndole 14 Cycllzatron of the methoxymethyl enol ether correspondmg to 12

gave a 80% yield of 13 and 14 (1 1) in whrch the C(3) methyl ether IS replaced by a methoxymethyl ether Hydrolyses of

the methoxymethyl ether (HCI, THF, H20) provrdes the C(3) alcohol m 80-100% yield The implrcatrons for

regenerahng a C(3) carbonyl group and adfustrng stereochemrstry at C(3) and C(4) are obvious

Amrde 18 appeared to exrst as a single geometrical Isomer (‘H and 13C-NMR) whrle 19 was a mrxture of geometrlcal

Isomers at room temperature NMR signals due to the geometrical rsomers of 19 underwent coalescense at 420*K In

DMSO

12

13

Two minor products, whose structures have not been proven, were obtarned The molecular formula (by HRMS) of

one of these (C4oH43N305), obtarned In 18% yreld, rndrcates formation of a 1 1 adduct between a radical derived from

1.9 and-an lsObUtyrOnltrlre radical When 1 2 eqUlvalbnfS oftri-n-butyltir! tiyU.nUe (rnltiafconcentratlon = 0 02 M) and il 1

equivalents of AIBN were used, the conversron of starting material was incomplete Results obtained using hrgher

concentrations of trr-n-butyltrn hydride will be reported In a full account of this work

We ihank Dr J~udith Gallucci for performlng thus analysis at the Cnro State University Crystallography Facrlrty

Crystallographic detaris wrll be publrshed elsewhere

14

15

Intramolecular 1,4-hydrogen atom transfers are rare but known Beckwith, A L J , Ingold, K U In Rearrangements in

Ground and Exerted States, deMayo, P , Ed , Academic Press, New York, 1980, Vol 1, pp 182-219

For reports that deal with alternate methods for constructing the oxindole portron of gelsemrne see Flemrng, I , Loreto,

M. A., MJdL@..l P ~ 'Nalla~~,. I H. M. TeM~%?&ffn L3.f. ~982.Z-153 FIero~ng< L ~ I_nrr?& M. A.< VJdlx~> t M. H.,.

M.lrza~J.~. .1 P ,. d Ckm. .5x,_ FWm. kws 1,. 1986,. 349 Abelma.n.,. M. M. ,. clh,, T ,. Qu,-mao.,. I_ E .1 0-q Ch.em.

1987, 52, 4130

16 We thank the National Institutes of Health (GM-27647) for generous fmancral support

References and Notes

(Recelvecl in USA 1 May 1991)