Intramolecular Pd-catalyzed aryl-enone conjugate additions. Control of reductive vs non-reductive cyclization

Tetrahedron Letters, Vol. 36, No. 39, pp. 7047-7050, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00

Pergamon 0040-4039(95)01460-8

Intramolecular Pd-Catalyzed Aryl-Enone Conjugate Additions. Control of Reductive vs Non-Reductive Cyclization G r e g o r y K. Friestad and B r u c e P. B r a n c h a u d *

Department of Chemistry, Universityof Oregon,Eugene, OR 97403-1253, USA

Abstract: Pd-catalyzed aryl-enone cyclization of 1 leads to Heck-type non-reductive cyclization product 3 and

reductive cyclization product 4. Conditions have been developed to selectively form either 3 or 4 (or more highly functionalizod 10 vs 11 or 13 vs 14). The formation of non-reductivecyclization products (3, 11, 14) requires an unusual apparent trans I~-Helimination- some mechanisticpossibilitiesthat are consistentwith the data are proposed.

OH Several studies on synthetic approaches to the anticancer A m a r y l l i d a c e a e alkaloid H0 ~ . ~ 0 H pancratistatin I and two total syntheses, one of racemic pancratistatin2 and one of the natural (+)-pancratistatin, 3 have been published. During our model studies exploring synthetic NH strategies to use Heck-type cyclizations to form the key aryl-cyclohexyl bond, we attempted 0 " ~ OH 0 the tandem intramolecular/intermolecularHeck reaction sequence shown in Scheme 1. This type of strategy has been used successfully for a tandem Pd-mediated intramolecular (+)-PANCRATISTATIN cyclization followed by intermolecular alkyl-alkenyl cross coupling in a synthesis of a carbacyclin.4 The success of this strategy hinges on the fact that alkylpaUadium intermediate 2, with no 13-Hsyn to Pd, should be stable to p-H elimination and sufficiently long-lived that intermolecular trapping with styrene should occur. Pd-catalyzed tandem cyclization/cross-coupling reactions of 1 were attempted in the presence of styrene (2 equiv) or fl-tri-n-butylstannylstyrene5 (2 equiv) under standard conditions (10 mole% Pd(OAc)2, 20 mole% PPh3, Et3N, CD3CN, 80°C). Surprisingly, no tandem product 5 was detected, although some premature intermolecular cross coupling of the uncyclized arylpalladium intermediate derived from 1 occurred with the stannylstyrene reagent, indicating that the reaction conditions could support intermolecular cross coupling. Instead, high yields of mixtures of 3 and 46 were obtained. Reactions run without styrene gave similar results, with a quantitative combined yield of 3 and 4. 7 Scheme 1

3

1

2

4

~PhO~=c~2 / / ~ $

Fh

A critical difference between the example in Scheme 1 and the previously reported successful tandem cyclization/cross coupling sequence is that alkylpalladium intermediate 2 is not a simple alkylpalladium complex but is actually the keto tautomer of a palladium enolate (see structure 7 in Scheme 2). The formation of 3 is the result of an apparent trans elimination of palladium hydride from 2, a process which would not be expected to occur in a single elementary step from 2 to 3 based on the generally accepted stereoelectronic necessity for syn Pd p-H elimination. 8 Several examples of apparent trans I~-H elimination from alkylpalladium halide intermediates have recently appeared in the literature. 9 To our knowledge, there have been no definitive 7047

7048

mechanistic studies on this topic and the mechanisms may be different for different types of alkylpalladium intermediates. The studies reported herein were focused on developing conditions to favor either non-reductive cyclization or reductive cyclization, both synthetically useful outcomes of such aryl conjugate additions onto enones. Since our approach was based on mechanistic considerations our results provide some insight into possible mechanisms. Monitoring the course of cyclization reactions of 1 by 1H NMR (Table 1) showed that alkene 3 was favored early in the reaction (Entry 1), and reduction product 4 grew in relative proportion at later stages of the reactions (Entries 2 and 3). In standard Heck reactions, regeneration of the catalytically active Pd(0) species occurs via the equilibrium shown in Equation 1. The buildup of Et3N°HX as a reaction product should shift the equilibrium in Equation 1 so that higher transient concentrations of XPdlI(Ln)H should be present at later stages of the reaction. Thus it seemed most likely that XPdlI(Ln)H was responsible for the increased production of reduction product later in the reaction. Consistent with this hypothesis, addition of Et3NoHC1 increased the amount of 4 relative to 3 (Entry 4). Addition of AgNO3 to Heck-type reactions is known to lower XPdlI(Ln)H concentrations by scavenging HX. 10 Addition of AgNO3 to the otherwise standard cyclization of 1 suppressed the formation of reduction product 4 and enhanced the formation of non-reductive cyclization product 3 (Entry 5), consistent with our hypothesis. The use of formate as a reductant has been reported to lead to reduction products in Heck-type reactions when ~-H elimination is not possible, l I In the present case triethylammonium formate acted as a reductant (Entry 6) to give results similar to those observed in the presence of Et3N°HC1 (Entry 4), suggesting that formate is not acting as a reductant in this case and that XPdlI(Ln)H is the more likely source of reducing equivalents. Reduction product 4 was strongly favored in THF-d8 (Entry 7). THF-d8 is not the source of reducing equivalents in this reaction since no deuterium incorporation was observed. It is not obvious why THF should have such a dramatic effect on the reaction. Nevertheless, it is gratifying and synthetically useful to be able to make simple modifications of the reaction conditions to obtain largely nonreductive cyclization (alkene product 3) through addition of AgN03 (Entry 5) or reductive cyclization (alkane product 4) through the use of THF as solvent (Entry 7). XPdn(l_n)H + E t 3 N

-..,r~

Pd°(Ln) + EtaNHX

Eq. 1

Table 1a Entry 1 2 3

Additive none none

none Et3N.HCI, 2 equiv A~N03, 1 equiv Et~N.HO2CH, ' 2 equivc none

Solvent CD~iCN

CD~CN CD3CN CD~CN CD3CN CD3CN THF-d8

Conversionbr % 37 79 100 100 100 1 O0 d 100

Alkene 3:Alkane 4 80:20 63:37 55:45 32:68 91:9 28:72 8:92

aGeneralconditionsfor all reactions: 0.2Msubstrate,10 mole%Pd(OAc)2,20 mole%PPh3,2 equiv Et3N in CD3CN (as received) under Ar in standard5ram NMR tube. bReactionswere very clean - only 1, 3, and 4 were detected by 1H NMR spectroscopy; conversion = sum of IH NMR yields of 3 + 4 relative to remaining unreacted 1. CFormed in situ by addition of 2 equiv 91% formic acid to reaction mixture containing 4 equiv Et3N. dSide products detected; at complete consumption of 1 the combined yield of 3 + 4 = 52%; yield determined by integration of tH NMR spectra vs Ph3CH internal standard alter dilution with dielhyl ether and aqueous (0.1 N HCI) workup.

A plausible mechanism for the unusual trans I~-H elimination can be proposed (Scheme 2) involving oxo-~allylpalladiumintermediate 6 and its tautomers 2, 7, and 8, which are plausible intermediates having precedent in the Pd-catalyzed dehydrosilylation of silyl enol ethers. 12 Intermediate 2, having no syn ~H, should be longlived enough to eventually epimerize via oxo-x-allylpalladium 6 to an intermediate posessing syn 13-H (8). Normal syn p-H elimination then can occur from 8, producing alkene product 3. Reductions of 2, 6, 7, or 8

7049

by XPdII(Ln)H, Et3N'HX, or other reductants provide plausible pathways for the formation of reduced product 4. The mechanism in Scheme 2 accounts for formation of both reduced and non-reduced products, and is consistent with the results in Tables 1 and 2. A deuterium incorporation experiment, intended to test whether protonation by solvent (CD3OD) could lead to 4, was ambiguous; all four protons a to the carbonyl in 4 were exchanged under the reaction conditions. Et3N is known to function as a reductant in some Heck reactions. 13 Using NaOAc (4 equiv) as base instead of Et3N still led to the formation of a significant amount of reductive cyclization product 4 (3:4 = 89:11, 55% conversion), suggesting that Et3N is not the sole source of reducing equivalents. Other possible proposed mechanisms for trans 13-Helimination include a homolytic mechanism9e and a trans E2 elimination mechanism, l m The lack of deuterium incorporation in reduced product 4 using THFd8 as solvent (Entry 7 in Table 1) is inconsistent with a radical mechanism as is the lack of deuterium incorporation using the efficient D- donor 1-deuterio-l,l-diphenylmethanol. Analysis of the possibility of an E2 mechanism is complicated by the fact that Et3N can act as both a base and a source of reducing equivalents (see above). However, since Et3N is not the sole, and probably not the major, source of reducing equivalents (see above), the concentration of Et3N should have a significant effect on the reaction if an E2 mechanism is operative. One equivalent of Et3N was required for complete conversion, but increasing the concentration beyond 5 equivalents did not increase the proportion of elimination product, indicating that an E2 mechanism involving Et3N is probably not the major elimination pathway. Scheme 2

J

~

o

O 2 X4~ [HI

II

;,H,

;

normal syn ~H elimination trans I~-H elimination

We were able to obtain similar selectivities in cyclizations of the related substrates 9 and 12 (Table 2), 6,7 although yields were somewhat lower due to epimerization, elimination, and aromatization of the highly oxygenated substrates and products. Preparative-scale experiments focused on product isolation in pure form were performed on 12. Using the alkene-favoring conditions (20 mole% Pd(OAc)2, 40 mole% PPh3, AgNO3, Et3N, wet [- 1 equiv H20] acetonitrile solvent, reflux 4 hr) on 2.0 mmole, 1.17 grams of 12 provided a 70% isolated yield of crystalline 14 (isolated by crystallization from crude products; mp = 146-148 °C). Using the alkane-favoring conditions (20 mole% Pd(OAc)2, 40 mole% PPh3, 2 equiv Et3N, THF solvent, reflux 17 hr) on 1.0 mmole, 0.58 grams of 12 provided a 56% isolated yield (13:14 ratio = 85:15 in crude product by IH NMR) of crystalline 13 (isolated by silica gel chromatography; mp = 136-137 °C). OBn

X

9: X = H 12: X 2 =-OCH20-

OBn

X

10: X = H 13: X2 =-OCH20-

OBn

X

11: X = H 14: X2 =-OCH20-

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Table 2a

Entry 1 2 3 4 5 6 7

Substrate 9 9 9 9 12 12 12

Additive none Et3NHCI, 2 equiv AgN03, 1 equiv none none A~INO~,1 equiv none

Solvent

CDCm CD-~.,N CD~CN

Conversionbr % Alkeneaf % Alkanea~ % Alkene:Alkane 11, 41 10, 27 60:40 98 ;? Bmilll; Bill]il;m ~b'~'~/:

THF-d8 CD~CN CD~CN THF-d8

ililiP! 14, 42 14, 54 14, 9

13, 21 13,5 13, 47

67:33 92:8 16:84

aGeneralconditionsfor all reactions: 0.2Msubstrate,20 mole%Pd(OAc)2(PPh3)2,2 equivEt3Nin CD3CN(0.4%H20, v/v) under Ar in standard5ram NMR tube. bpercentconversionand yieldsdeterminedby integrationof 1H NMR spectravs Ph3CH internalstandardafter dilutionwith etherand aqueous(0.1 N HCI)workup. CAppropdatestartingmaterialsignals obscuredin 1HNMRspecb~, reactionassumed complete. Acknowledgement. This research was supported by NSF CHE 8806805, NSF CHE-9423782, Eli Lilly and Co., and a fellowship from the U.S. Dept. of Education Graduate Assistance in Areas of National Need Program (G. K. F.).

References and Notes 1.

2 3. 4. 5. 6. 7.

8. 9.

10.

11. 12. 13.

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(Received in USA 30 June 1995; revised 25 July 1995; accepted 28 July 1995)