g-Silylated a,b-unsaturated amides — Preparationby [1,5]-sigmatropic rearrangement and use asmasked dienolate equivalents in carbonylcondensations1

James R. Green, Babajide I. Alo, Marek Majewski, and Victor Snieckus

Abstract: The reaction of lithium dienolates derived from N,N-dialkylsenecioamides (1a–1c) with triorganosilyl electrophilesoccurs initially at the oxygen atom predominantly, and is followed by an O ? C silicon migration to afford the g-silylatedsenecioamides (4a–4h). The g-silylated senecioamide Z-4a undergoes fluoride-ion-mediated condensations with aromaticaldehydes to give kinetic a-(6) and thermodynamic g-(5) condensation product patterns comparable to lithium dienolates.The TiCl4-mediated reactions with aldehydes gives a-products (6) in a highly syn-selective manner. Possible transition-state models for the syn-selective condensations are discussed and a chair-like transition state featuring bidentate coordina-tion to titanium (11) is proposed.

Key words: silicon migration, amide dienolate, allylsilane, Hosomi–Sakurai reaction, stereoselective.

Resume : La reaction des dienolates de lithium derives des N,N-dialkylsenecioamides (1a–1c) avec des electrophilestriorganosilyles se produit dans un premier temps par le biais de l’atome d’oxygene et l’intermediaire subit une migrationO ? C de l’atome de silicium qui conduit eventuellement aux senecioamides g-silyles (4a–4h). Le senecioamide g-silyleZ-4a donne des reactions de condensation avec les aldehydes aromatiques, catalysees par l’ion fluorure, qui conduisent ala formation des produits de condensation cinetique, a-(6), et thermodynamique, g-(5) avec des patrons similaires a ceuxobserves pour les dienolates de lithium. Les reactions des aldehydes, catalysees par le TiCl4, conduisent aux produits a-(6)avec une haute selectivite syn. On discute de divers modeles d’etats de transition qui pourraient expliquer la selectivitesyn des condensations et on suggere que la meilleure explication est un etat de transition en forme de chaise comportantune coordination bidentate vers le titane (11).

Mots-cles : migration du silicium, dienolate amide, allylsilane, reaction de Hosomi–Sakurai, stereoselective.

[Traduit par la Redaction]

IntroductionFrom the considerable body of literature on dienolates de-

rived from a,b-unsaturated acid derivatives,2 including ourwork on a,b-unsaturated amides,3 a clear pattern of reactivityhas emerged, especially for carbon-based electrophiles. Inthe absence of additional heteroatom substitution, predomi-nant to exclusive a-carbonyl substitution is observed, withpreferential g-substitution products arising under thermody-namic conditions. Conversely, the seminal work of Casey4

demonstrated that dienolates derived from esters undergo ki-netic O-silylation to give vinyl ketene O,O-acetals,5 whichthen experience a [1,5]-sigmatropic O ? C silicon migrationto g-silylated products. An analogous migration has beenobserved in b-pyrrolidino vinyl ketene O,N-acetals,6 andO ? C or C ? O silicon migrations have been observedon related systems,7–9 for many cases after our initial re-port in this area.10 These combined results prompted thepresent systematic study on tertiary amide dienolate silyla-tion and the potential rearrangement of the resulting vinylketene N,O-acetals to g-silylated a,b-unsaturated amides(Scheme 1).

An additional incentive for the present study was theconsideration that, with few exceptions, the reactivity of g-silylated alkenoic acid derivatives has been restricted to elec-trophilic cyclizations on alkenes and epoxides.11,12 Given therich chemistry of allylsilanes,13 such g-silylated carbonylcompounds may be considered as storable dienolateequivalents. This is particularly relevant in the 3-methyl-2-butenamide (senecioamide) case, as the lithio dienolatesgive modest to poor a- kinetic aldol selectivity. Conse-quently, we set as a goal to test the functionalized allylsilanedienolate equivalent in fluoride- and Lewis acid mediatedaldol chemistry to provide a contribution to the area ofdiastereoselective C–C bond formation.10,14 The results of

Received 21 January 2009. Accepted 31 March 2009. Publishedon the NRC Research Press Web site at canjchem.nrc.ca on2 June 2009.

J.R. Green.1 Department of Chemistry, University of Windsor,Windsor, ON N9B 3P4, Canada.B.I. Alo. Department of Chemistry, University of Lagos, Akoka,Lagos, Nigeria.M. Majewski. Department of Chemistry, University ofSaskatchewan, Saskatoon, SK S7N 5C9, Canada.V. Snieckus.2,3 Department of Chemistry, University ofWaterloo, Waterloo, ON N21 3G1, Canada.

1Corresponding author (e-mail: jgreen@uwindsor.ca).2Corresponding author (e-mail: snieckus@queensu.ca).3Present address: Department of Chemistry, Queen’s University,Kingston, ON K7L 3N6, Canada.

745

Can. J. Chem. 87: 745–759 (2009) doi:10.1139/V09-054 Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

our studies concerning lithium dienolates derived from N,N-dialkylsenecioamides and their g-silylated reaction productsare presented herein.

Enolate silylation and silicon migrationreactions of senecioamides

N,N,3-Trimethyl-2-butenamide (N,N-dimethylsenecioa-mide) (1a) was deprotonated with LDA under the estab-lished conditions,3a and the resultant dienolate underwentsilylation with Me3SiCl to afford the vinylketene O,N-acetal(2a) (Scheme 2). Compound 2a was found not to be stableto an aqueous workup or chromatographic purification, butwas identified by 1H NMR spectroscopy; its characterizationas the Z-isomer was supported by NOE difference experi-ments showing an enhancement of the vinyl CH resonance(d 4.48) upon irradiation of the N-substituted methylresonances (d 2.26).15 Furthermore, 2a was trapped byDiels–Alder reaction with dimethyl acetylene dicarboxylateto give the phthalate ester 3 in low yield (Scheme 3) (seeSupplementary data).8 In normal practice, however, 2a washeated at reflux in THF for 18 h to afford two isomeric 4-

trimethylsilylated-2-butenamides, Z-4a and E-4a, in 74%and 2% yields, respectively. The stereochemistry of the twocompounds was determined on the basis of the downfield 1HNMR chemical shifts of the protons g and cis to the amidefunction relative to those g and trans to the carbonyl, andthe expected aromatic solvent induced shift (ASIS)16 of theg,cis- and g,trans-protons observed in their 1H NMR spectrain C6D6 (Scheme 2).

The basic protocol outlined above was extended to otherchlorosilanes (chlorotriethylsilane, chlorotriisopropylsilane,and chloromethyldiphenylsilane) and other senecioamides(1b, 1c), and the combined results are presented in Table 1.For reaction of the dienolates with MePh2SiCl, C-silylationdid not require the heating-to-reflux step, and it was there-fore omitted in these cases (Table 1, entries 4 and 8). In theisolated g-silylated products (4) other than 4a, the mostnoteworthy feature was the increased relative amounts of

Scheme 1. Reagents and conditions: (a) Me3SiCl; (b) D, THF.

Scheme 2. Reagents and conditions: (a) (i) LDA, THF, –78 8C; (ii) R13 SiCl, –78 8C to RT; (b) THF, D.

Table 1. g-Silylation results for senecioamides 1a, 1b, and 1c.

Entry R13 R2 Product Yield (%) Z:E

1 Me3 Me 4a 75 91:92 Et3 Me 4b 74 77:233 i-Pr3 Me 4c 35 63:374 MePh2 Me 4d 92a 36:645 Me3 Et 4e 74 53:476 Et3 Et 4f 67 31:697 Me3 i-Pr 4g 65 35:658 MePh2 i-Pr 4h 92a 59:41

aThe THF at reflux step was not carried out.

Scheme 3. Reagents and conditions: (a) DMAD, benzene, 0 8C.

746 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

the E-isomer to the point where the E-isomer predominatedin several instances (Table 1, entries 4, 6, and 7).

To further clarify the source of the g,E-isomer silylationproducts, the reaction of the dienolate of 1a with Et3SiClwas examined more closely prior to the reflux step by sub-jecting an aliquot of the product to an anhydrous workupand the remainder to a conventional aqueous workup. Forthe former aliquot, integration of the respective vinyl protonresonances in the 1H NMR spectrum showed a 23:77 ratiofor g-silylated products (Z- + E-4b) and the ketene O,N-acetal(2b). Conversely, the material subjected to aqueous workupgave Z-4b and E-4b in 4% and 16% yields, respectively.Comparing this to entry 2 in Table 1 (Z-4b, 58%; E-4b,18%), it is apparent that most of the g,Z-silylated productarose from the O- to C-[1,5]-silicon migration of thevinylketene O,N-acetal (2b), whereas the correspondingg,E-silylated product most likely resulted from direct attackon the dienolate (Scheme 4). In the cases with MePh2SiClas the electrophile, it is likely that both isomers of g-silylation products result from direct silylation, in keepingwith the relatively greater HSAB ‘‘softness’’ of MePh2SiCl,17

and in the fact that 2d and 2h are not actually formed in sig-nificant amounts.

The variation of E/Z ratios in these g-silylated amides isworthy of further comment. In the N,N-dimethyl amideseries, increasing amounts of E-isomers may reflect increas-ing direct g-silylation due to a greater reactivity with bulkierchlorotrialkylsilanes when the dienolate is in the s-transform. This proposal breaks down for the N,N-diisopropylamide series, as MePh2SiCl undergoes reaction by direct g-attack and yet gives predominantly Z-4h. The regiochemis-try for direct g-attack is clearly a more complex process inthese cases.

To establish the inter- or intra-molecularity of the [1,5]-silicon migration, a crossover experiment was performed.The lithium dienolates of 1a and 1b were allowed to react

at –78 8C with Et3SiCl and Me3SiCl, respectively, and, afterwarming to room temperature, the respective solutions ofthe two reactions were mixed in a 1:1 ratio and heated toreflux (19 h). Analytical HPLC of the resultant mixturerevealed the presence of g-silylation products Z-4b, E-4b,Z-4e, and E-4e, but not crossover products Z-4a, E-4a,Z-4f, or E-4f (Scheme 5) (see Supplementary data).8 Thisconstitutes strong evidence for the intramolecular nature ofthe [1,5]-silicon migrations of these silylated vinylketeneO,N-acetals.

With a facile method for generating g-silylated-a,b-unsaturated amides in hand, attention was turned to the con-densation chemistry of these compounds. Since Z-4a wasobtained with the highest stereoselectivity and possesses themost widely employed silyl group, the reactivity of thiscompound with carbonyl derivatives was pursued. As de-scribed below, fluoride- and Lewis acid mediated condensa-tion reactions were investigated.

Fluoride-mediated condensations of Z-4a

The reaction of Z-4a with benzaldehyde was induced bysubjecting its THF solution to a catalytic amount of n-Bu4NF(5 mol%) at RT to afford a mixture of g-hydroxyalkylatedcompounds Z-5a and E-5a in 58% and 14% yields, respec-tively (Scheme 6). This process was extended to other aro-matic aldehydes, and gave some interesting differences inthe reaction products (Table 2). Aromatic aldehydes bearingstrong electron-withdrawing groups (EWGs) gave mixturesof g-(5) and a-hydroxyalkylation products (6) (Table 2,entries 4 and 5); conversely, substrates not possessing theseEWGs gave only g-hydroxyalkylated products (Table 2,entries 1–3). Reaction with benzophenone resulted in theformation of the g-condensation products, but unless the re-action was performed at low temperature (–45 8C), theseunderwent elimination to give 7 (Table 2, entries 6 and 7).By contrast, attempted reaction with aliphatic aldehydes re-sulted in desilylation of Z-4a and isolation of only traceamounts of condensation products.

These condensations, if effected at lower temperatures(–45 8C) for short periods of time, required the use ofstoichiometric amounts of fluoride ion. Under such condi-tions, however, a-condensation products predominated asseparable syn/anti diastereomeric mixtures, together withsmall amounts of the g,Z-condensation products (Scheme 6,Table 3).

The identities of the condensation products were readilyestablished from their 1H NMR spectra. The a-products (6)

Scheme 4. Reagents and conditions: (a) R13SiCl, –78 8C to RT; (b)

THF, D.Scheme 5. Reagents and conditions: (a) THF, D, 19h.

Green et al. 747

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

were distinguished by virtue of the larger vicinal couplingconstant of the a-methine proton in the anti-diastereomer (J =6–7 Hz) relative to the syn-diastereomer (J = 4–5 Hz).18

The Z- and E-isomers of the g-condensation products (5)were most readily discriminated by the downfield ASIS ofthe allylic methyl groups of the Z-isomers, versus the up-field ASIS of the corresponding group in the E-isomers(Fig. 1).

The observation of predominant a-condensation products atlow temperatures and short reaction times but g-condensationproducts at higher temperatures and longer reaction times isa clear kinetic (a-) versus thermodynamic (g-) productcontrol situation similar to that observed for analogouslithium dienolate condensation chemistry.3a In the cases of4-nitrobenzaldehyde and pyridine-4-carboxaldehyde, theEWGs render the initial kinetic condensation favourable to

such a degree that reversibility is suppressed completely(4-nitrobenzaldehyde) or partially (pyridine-4-carboxaldehyde).We note that the amount of g-product with 4-nitrobenzaldehydeunder kinetic conditions is relatively high, although it is stillthe minor product. We attribute the nearly non-existent dia-stereoselectivity of the a-condensation in all cases to the re-

Scheme 6. Reagents and conditions: (a) (i) ArCRO, 5 mol% n-BuNF, THF, –78 8C to RT; (ii) NH4Cl(aq); (b) (i) ArCHO, 100 mol%n-BuNF, THF, –45 8C, 2 min; (ii) NH4Cl(aq).

Table 2. Fluoride-catalyzed condensations of Z-4a with aromatic aldehydes and benzophenone.

Entry ArCRO g-Product Yield (%), (Z:E) a-Product Yield (%), (syn:anti)1 PhCHO 5a 72, (80:20) —2 3,4-(MeO)2 C6H3CHO 5b 75, (65:35) —3 Pyridine-3-CHO 5c 70, (81:19) —4 Pyridine-4-CHO 5d 42, (100:0) 6d 37 (56:44)5 4-O2NC6H4CHO 5e 31, (100:0) 6e 48 (45:55)6 Ph2COa 5g, 5fb 68, (30:70) —7 Ph2CO 7 29, (33:67) —

aReaction conducted at –45 8C.bIsolated as the trimethylsilyl ether.

Fig. 1. Stereochemical assignments of aldol adducts.Table 3. Low-temperature stoichiometric fluoride-mediatedcondensations of Z-4a with aromatic aldehydes.

Entry ArCHO a-Producta- (%),(syn:anti) g- (%)

1 PhCHO 6a 64, (48:52) 62 3,4-(MeO)2 C6H3CHO 6b 52, (48:52) 63 Pyridine-4-CHO 6d 61, (44:56) 134 4-O2NC6H4CHO 6e 57, (45:55) 30

748 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

action proceeding via the nearly equal in energy acyclictransition states 8 and 9 (Scheme 7). While the pattern ofreactivity is consistent with a reaction proceeding via a freeenolate, we do not consider this as an unambiguous proof.Attempts to induce fluoride-ion-catalyzed reactions of silylketene acetal (2a) with benzaldehyde afforded only hydroly-sis products.19

TiCl4-mediated condensations of Z-4a witharomatic and aliphatic aldehydes andbenzophenone

The condensation reaction of the g-silylated amide Z-4awith benzaldehyde could also be initiated by a Mukaiyama-type process, often referred to as the Hosomi–Sakuraireaction,14d in the presence of stoichiometric amounts ofTiCl4 under mild conditions. The condensation was foundto occur with exclusive a selectivity and nearly complete syn-diastereoselectivity to give product 6a in reasonable yield(Scheme 8, Table 4). This process was extended to other ar-omatic and aliphatic aldehydes (6e–6j), with some caveats:aldehydes with Lewis basic sites (4-methoxybenzaldehydeand 3,4-dimethoxybenzaldehyde) gave only desilylation,without condensation, while branched aliphatic aldehyde(2-methylpropanal) gave much lower levels of diastereose-lection (syn/anti 6h = 59:41).

Alteration of this basic protocol was much less successful

in obtaining condensation products stereoselectively. Theuse of a monodentate Lewis acid (BF3�OEt2) and benzalde-hyde under otherwise identical conditions resulted only inminimal conversion (<10%) of Z-4a to syn-6a; even ex-cesses of BF3�OEt2 (4.4 equiv.) and PhCHO (4.8 equiv.)afforded syn-6a in only 7% yield (see Supplementary data).Similarly, allylsilane E-4a was much less reactive than Z-4aunder identical conditions. Even at higher temperature, at-tempted reaction of E-4a with benzaldehyde in the presenceof TiCl4 resulted mainly in the isolation of recovered start-ing material, along with only trace amounts of condensationproduct syn-6a and desilylation product 10a (see Supple-mentary data). In the alternative obvious approach,20 reac-tion of the lithium dienolate of 1a with TiCl4, followed bytreatment with benzaldehyde, resulted only in the formationof oligomeric materials (see Supplementary data).

The observed high syn diastereoselectivity in the TiCl4-mediated reactions of Z-4a with aromatic and linearaliphatic aldehydes is striking, particularly in light of therelated condensation reactions of g-stannyl- and g-germylsenecioic ‘‘esters’’ reported by Yamamoto21 andHudlicky,22 and indium-mediated Reformatsky reactions ofg-bromocrotonates,23 which generally show high antidiastereoselectivity.24 While experimentally the results arenicely complementary, clearly our results cannot be ration-alized in terms of an acyclic transition state with an anti-periplanar relationship between the allylsilane andaldehyde functions, as advanced by Yamamoto.25 A moreplausible explanation is based on the ability for bidentatecoordination to TiCl4, and the greater basicity of the amiderelative to the ester function.26 Working on the assumptionthat the predominant s-cis-conformation of the unsaturatedtertiary amide27 is maintained, we envisage a cyclic transi-tion state featuring coordination of both the amide and al-dehyde carbonyls to Ti, with the allylsilane functionpositioned in an exocylic mode. Formulating this transitionstate as a chair, with the aldehyde R group pseudoequato-rial and a synclinal orientation of the allylsilane andaldehyde (11), allows rationalization of the observed syn-

Table 4. TiCl4-mediated condensations of 4a with aldehydes andbenzophenone.

Entry R1R2CO a-Product Yield syn:anti1 PhCHO 6a 62 >97 : <32 4-O2NC6H4CHO 6e 73 97:33 n-PrCHO 6h 64 96:44 i-PrCHO 6i 68 59:415 EtCHO 6j 52 87:136 Ph2CO 6g 72 —

Scheme 7. Competitive transition states for kinetic fluoride-mediated condensations

Scheme 8. Reagents and conditions: (a) (i) R1R2CO, TiCl4, CH2Cl2, RT; (ii) NH4Cl(aq).

Green et al. 749

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

diastereomeric product (Scheme 9).28 Formation of the anti-diastereomer would require either a pseudoaxial aldehyde Rgroup (12), or boat transition state (13). In context of thisproposal, the analogous TiCl4-mediated condensations ofg-stannyl-/germyl-senecioic esters21,22 lead to reducedanti-diastereoselection, which may indicate destructivecompetition of analogous bidentate coordination in thesecases. In addition, it has been demonstrated that chiral sen-ecioyl oxazolidinones undergo n-Bu2BOTf-mediated reac-tions with aldehydes with high syn-selectivity and highdiastereofacial selectivity.29 For esters, however, the selec-tivity profile appears complementary to our work in thatthere is an apparent requirement for branching in aliphaticaldehydes to achieve high diastereoselectivity.30

The greater reactivity of Z-4a relative to E-4a may be ra-tionalized in two possible ways. In a chair transition statefor Z-4a, the depicted orientation (14) of the C–Si bond sug-gests potential intramolecular transfer of an apically ligatedchloride to a syn-oriented silicon (Scheme 10), an analogouspossibility does not exist for E-4a. This possibility has beenadvanced on occasion in Hosomi–Sakurai reactions,10,31 andin silyl ketene acetal-aldehyde and allylsilane-enone conden-sation chemistry,32 and has received computational supportat the DFT level.33 In contrast, careful experiments on intra-molecular condensations of aldehydes with chiral allylsi-lanes and allylstannanes are not consistent with thestereochemical outcome for such a syn-S0E orientation.34

The alternate plausible source of the greater reactivity ofZ-4a stems from the possibility of a stabilizing secondaryorbital overlap of the allylsilane (HOMO) with the aldehyde(LUMO) (15), which would not be available in the reactionpath of E-4a. Originally proposed for aldol condensationchemistry,35 this rationalization has been invoked in supportof synclinal orientations in allylstannane-aldehyde condensa-tions,28d,36 and should, in principle, be capable of extensionto Lewis acid mediated allylsilane-aldehyde condensations.

Pursuant to this question, transition states approximating14 and 15 were calculated at the DFT level. An ‘‘outside’’trimethylsilyl transition state corresponding to 11/15 was lo-

cated (16, Scheme 11); it features a relatively short formingbond (1.81 A), a significantly lengthened senecioamide C4–Si bond (2.00 A), and nearly equal amide C2–C3 and C3–C4 bonds (1.44 and 1.44 A). Furthermore, a senecioamideC4 – aldehyde oxygen distance (3.17 A) shorter than thesum of the van der Waals radii is found, consistent with aweak bonding interaction between the two atoms. In con-trast, an ‘‘inside’’ trimethylsilyl transition state correspond-ing to 14 was found to be 2.9 kcal mol–1 higher in energy(17). The nearest Cl–Si contact (3.85 A) is larger than thesum of the van der Waals radii. Consequently, the intramo-lecular transfer of chloride transition state 14 is not sup-ported in our system at this level of calculation.

In summary, we have shown that g-silylated senecioa-mides 4a–4h are easily obtained by [1,5] O?C silicon mi-gration or direct silylation of the corresponding enolates,depending upon the softness of silyl groups. The isomericg-(Z)-silylsenecioamides Z-4a – Z-4c, Z-4e – Z-4g are ob-tained by the O?C silicon migration but also are formedfrom the direct silylation reactions, whereas the correspond-ing E-isomers are exclusively or near-exclusively formedfrom the direct silylation process. The simplest g-silylse-neciomamide serves as a stable and easily stored (>1 yearat –20 8C) senecioamide dienolate equivalent. Fluoride-catalyzed reactivity of Z-4a with aromatic aldehydes or

Scheme 9.

Scheme 10.

750 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

benzophenone shows product patterns analogous to thoseobserved in dienolate chemistry, 2,3a which is thereforeconsistent with, but not proof of, reaction via free enolates.The reaction of Z-4a with aromatic and aliphatic aldehydesmediated by TiCl4 gives syn-a-condensation products 6a–6h, and is proposed to proceed by a chair-like transitionstate featuring bidentate coordination to titanium (11). Fur-ther refinement by DFT calculations suggest involvementof the ‘‘outside TMS’’ 15 over the ‘‘inside TMS’’ 14 tran-sition state. Although limited in scope, the diastereoselec-tivity observed for the TiCl4-mediated reactions of a,b-unsaturated amides is complementary to that observed onanalogous stannyl- and germyl-senecioates.21,22

The utility of the reported chemistry for the constructionof diasteriomerically pure functionalized amides, especiallyin view of the recent availability of a mild method for amideto aldehyde conversion using the Schwartz reagent,37 andadaption to enantioinduction modes of reaction may createfurther opportunities in synthetic chemistry.

Experimental section

General methodsElemental analyses were performed by M-H-W Laborato-

ries, Phoenix, Arizona. Melting points were determined on aBuchi SMP-20 instrument and are uncorrected. Infraredspectra were determined on a PerkinElmer 983 spectropho-tometer. 1H NMR spectra were determined with BrukerWP-80, Bruker AM-250, and Bruker Avance-500 spectrom-eters. The spectra were recorded at 80 MHz in CDCl3 withtetramethylsilane as an internal standard unless otherwisestated. Spectral features are tabulated in the following order:chemical shift (d, ppm), number of protons; multiplicity

(s: singlet, d: doublet, t: triplet, q: quartet, sept: septet, m:multiplet, br: broad), coupling constant (J, Hz), number ofprotons; assignment. Low-resolution mass spectra were de-termined on a VG 7070F instrument at 20 eV unless other-wise stated. High-resolution mass spectra were determinedon a VG ZAB-E spectrometer. Analytical gas chromatogra-phy (GC) was performed on either a Hewlett Packard 5840A instrument or a Varian 6500 instrument using commer-cially available 10% SE-30 packed or capillary columns,respectively. Analytical thin layer chromatography (TLC)was performed using Merck precoated silica gel 60F-254 oraluminum oxide 150F-254 neutral (type T) sheets.Preparative TLC was performed using Merck silica gel60GF-254 with a plate thickness of 1 mm. Columnchromatography was carried out using silica gel 60 (0.063–0.20 mm and 0.04–0.063 mm). ‘‘Flash chromatography’’refers to the method reported by Still.38 Liquid chromatogra-phy was performed on a Varian 5000 Liquid Chromatographyemploying a reverse phase (C-18) column, and preparativeHPLC was done on a Waters PREP-500 with a SiO2 column.

All dry solvents were employed after distilling from the ap-propriate drying agent.39 Diethyl ether (Et2O), benzene, andtetrahydrofuran (THF) were distilled from benzophenone-ketyl immediately prior to use. Solutions of n-BuLi weretitrated with 2,5-dimethoxybenzyl alcohol as a standard.40

Diisopropylamine was dried and distillated over CaH2 andstored in brown bottles over 4 A molecular sieves in a des-sicator containing CaCl2. All other reagents were purifiedaccording to literature procedures. All lithiation reactions,and fluoride- or Lewis acid mediated reactions of Z-4a werecarried out under high purity nitrogen or argon (Linde).Tetra(n-butylammonium) fluoride (TBAF, 1 mol/L in THF)was allowed to sit over 4 A molecular sieves for approxi-

Scheme 11. DFT-minimized transition states of 15, 14, R = CH3.

Green et al. 751

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

mately 15 min prior to use. Amides 1a and 1c were preparedby literature procedures.3a

The term ‘‘–78 8C’’ refers to the temperature of a CO2 –acetone bath (normally –75 to –78 8C). The term ‘‘at –45 8C’’refers to a reaction done in an acetonitrile–CO2 slush bath(normally –45 to –50 8C). The term ‘‘at 0 8C’’ refers to a re-action done in an ice bath.

The phrase ‘‘workup in the usual manner’’ or ‘‘standardworkup’’ refers to addition of saturated aqueous NH4Cl tothe reaction mixture, followed by evaporation of the organicsolvent under reduced pressure, extraction of the residuewith CH2Cl2 or diethyl ether (Et2O), drying of the organicextract over MgSO4, followed by filtration, and subsequentevaporation to dryness under reduced pressure to afford thecrude product. Subsequent chromatography and (or) recrys-tallization and (or) distillation of the crude material affordedpure products.

DFT calculations were carried out using the B88-PW91method, and a DZVP basis set, using CAChe1 version6.1.12.33 (see Supplementary data). All stationary pointswere confirmed via frequency calculations.

General procedure for the formation of lithiumdienolates

Preparation of LDADiisopropylamine (5 mmol, 0.70 mL) was dissolved in

THF (25 mL) and cooled to 0 8C. To this solution, n-BuLi(5 mmol) was added by syringe injection over a period of~30 s. The solution was then stirred for a further 0.5 h at0 8C.

Lithiation with LDA

Procedure A — The amide in question was added bysyringe to 1.05 equiv. of LDA in THF at –78 8C such thatthe concentration in solution was roughly 0.2 mol/L. Thissolution was stirred at –78 8C for 1 h prior to electrophileaddition.

Procedure B — The amide in question was added bysyringe to 1.05 equiv. of LDA in THF at 0 8C such that theconcentration in solution was roughly 0.2 mol/L. Thissolution was stirred at 0 8C for 0.5 h prior to electrophileaddition.

Procedure C — The amide in question was added bysyringe to 1.05 equiv. of LDA in THF at RT such that theconcentration of the amide or amide dienolate in solutionwas roughly 0.2 mol/L. This solution was stirred at RT for1 h prior to electrophile addition.

Silylations of lithium dienolatesTo the solution of the lithium dienolate in THF at –

78 8C was added, by syringe, 1.1 equiv. of the chlorosi-lane. The resulting solution was stirred at –78 8C for0.5 h before the low temperature bath was removed andthe reaction mixture allowed to warm to RT. Unless thesilylating reagent was diphenylmethylsilyl chloride, the re-action mixture was then heated to reflux for the indicatedamount of time, after which a standard workup was per-formed. In the case of chloromethyldiphenylsilane, the re-

action mixture was subjected to a standard workupwithout prior heating.

N,N-diethylsenecioamide(N,N-diethyl-3-methyl-Z-butenamide) 1b

To a solution of senecioic acid (5.72 g, 57.1 mmol) inbenzene (60 mL) under a drying tube was added thionylchloride (9 mL, 123 mmol). The solution was allowed tostir overnight. The benzene and excess thionyl chloridewere removed by evaporation under reduced pressure, andthe resulting senecioyl chloride was slowly added to dieth-ylamine (20 mL, 193 mmol) in diethyl ether (75 mL). Theresulting mixture was subjected to filtration, and the filtratewas successively washed with H2O (50 mL), 10% aqueousNaOH (2 � 50 mL), and H2O (50 mL). The ethereal layerwas dried over MgSO4, subjected to filtration, and the fil-trate was concentrated in vacuo. Distillation of the crudeproduct gave 6.19 g (70%) of 1b, bp 37.5–38.5 8C at 0.02torr (1 torr = 133.322 Pa). IR (neat) nmax: 1653, 1624 cm–1.1H NMR, d: 1.14 (t, J = 7, 6H), 1.84 (s, 3H), 1.93 (s, 3H),3.37 (2 q, overlapping, J = 7, 4H), 5.81 (br s, 1H). MS m/e(rel. intensity): 155 (M+, 25), 140(27), 83(100). Anal. calcd.for for C9H17NO: C, 69.63; H, 11.04; N. 9.02. Found: C,69.70; H, 11.21; N, 9.18.

Z-N,N,3-trimethyl-1-trimethylsiloxyl-3-butadienamine 2aN,N-Dimethylsenecioamide 1a (1.916 g, 15.1 mmol) was

lithiated according to procedure C. Chlorotrimethylsilane(1.91 mL, 15.1 mmol) was then added to the solution at0 8C. After stirring for 20 min, the solvent was evaporatedunder reduced pressure, and hexane (20 mL) was added.This mixture was subjected to filtration through glass wool,and the hexane filtrate was evaporated under reducedpressure. An NMR spectrum of the crude product revealedthe presence of 2a. 1H NMR (C6D6) d: 0.18 (s, 9H), 2.06 (s,3H), 2.26 (s, 6H), 4.48 (s, 1H), 4.67, 5.16 (2 m, 2H).Irradiation of the resonance at 2.26 ppm gave rise to a 7%integrated enhancement of the 4.48 ppm peak. 13C NMR(C6D6): 0.4, 24.6, 40.6, 92.0, 109.3, 140.7, 155.1.

Z- and E-N,N,3-Methyl-4-trimethylsilyl-2-butenamide Z-4aand E-4a

N,N-Dimethylsenecioamide 1a (8.2 mL, 60 mmol) waslithiated according to procedure A and silylated withchlorotrimethylsilane (8.4 mL, 66 mmol) in the normalmanner for silylation (reflux 18 h) followed by a standardworkup. Preparative HPLC (5:2 hexane – ethyl acetate)gave, in order of elution: Z-4a (8.9 g, 74%), bp 50–53 8Cat 0.01 torr. IR (neat) nmax: 1646 cm–1. 1H NMR (C6D6) d:0.11 (s, 9H), 1.66 (d, J = 1.4, 3H), 2.41 (d, J = 0,6, 2H),2.54 (br s, 6H), 5.62 (br s, 1H). 13C (125 MHz) d: –1.0,25.9, 27.4, 34.9, 37.5, 113.3, 152.1, 168.4. MS m/e (rel.intensity): 199 (M+, 3), 184(100), 157(10), 58(20). Anal.calcd. for C10H21NOSi: C, 60.30; H, 10.55; N 7.04. Found:C, 60.22; H, 10.51; N, 7.01. E-4a (0.1915 g, 2%), bp 61–63 8C at 0.17 torr. IR (neat) nmax: 1610 cm–1. 1H NMR(C6D6) d: –0.05 (s, 9H), 1.46 (d, J = 0.7, 2H), 2.16 (d,J = 1.2, 3H), 2.51, 2.70 (2 br s, 6H), 5.60 (br s, 1H). MSm/e (rel. intensity): 199 (M+, 18), 184(100), 155(25),73(100). Anal. calcd. for C10H21NOSi: C, 60.30; H, 10.55;N 7.04. Found: C, 60.27; H, 10.61; N, 7.04. A third frac-

752 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

tion (0.9631 g, 13%) proved to be a mixture of the startingmaterial 1a and its deconjugated isomer 10a.3a

Z- and E-N,N,3-Trimethyl-4-triethylsilyl-2-butenamide Z-4b and E-4b

N,N-Dimethylsenecioamide, 1a (0.70 mL, 5.0 mmol), waslithiated according to procedure A, and the resulting dieno-late was silylated with 0.92 mL (5.5 mmol) of chlorotrie-thylsilane in the normal manner. After a standard workup,column chromatography gave, in order of elution: Z-4b(0.71 g, 58%), bp 83–84 8C at 0.17 torr. IR (neat) nmax:1642 cm–1. 1H NMR (C6D6) d: 0.5–1.2 (A2B3 spin system,15H), 1.69 (d, J = 1.2, 3H), 2.46 (s, 2H), 2.56 (br s, 6H),5.63 (br s, 1H). MS m/e (rel. intensity): 241 (M+, 4),226(93), 212(100), 198(45), 115(10), 87(27). HR-MS calcd.for C13H27NOSi: 241.1863. Found: 241.1847. E-4b (0.21 g,18%), bp 94–96 8C at 0.15 torr. IR (neat) nmax: 1642,1618 cm–1. 1H NMR (C6D6) d: 0.4–1.0 (A2B3 spin system,15H), 1.54 (d, J = 1.0, 2H), 2.19 (d, J = 1.5, 3H), 2.51,2.73 (2 br s, 6H), 5.68 (br s, 1H). MS m/e (rel. intensity):241 (M+, 8), 226(100), 212(76), 198(93). Anal. calcd. forC13H27NOSi: C, 64.67; H, 11.27; N 5.80. Found: C, 64.49;H, 11.11; N, 6.01.

N,N-Dimethylsenecioamide, 1a (0.67 mL, 4.9 mmol) waslithiated according to procedure A. To the resulting dieno-late, at –78 8C, was added chlorotriethylsilane (0.92 mL,5.5 mmol). After stirring the solution for 0.5 h at –78 8C,the solution was allowed to warm to RT, and the solventswere removed under reduced pressure. A small amount ofthe residual material was removed; the 1H NMR spectrum(C6D6) of this sample showed d 4.35 (s, vinyl CH of 2b)and d 5.62 (br s, vinyl CH of Z- and E-4b) with rel.ative in-tegrals of 77:23. The rest of the material was worked up inthe usual manner, and the resultant crude product subjectedto preparative HPLC. Three fractions were isolated. The firstfraction (0.048 g, 4%) contained Z-4b (see above for spec-tral data). The second fraction (0.20 g, 16%) was shown tobe E-4b (see above for spectral data). The third fraction(0.34 g, 53%) was found to contain a mixture of the starting1a and its b,g-unsaturated isomer 10a.

Z- and E-N,N,3-Trimethyl-4-triisopropylsilyl-2-butenamideZ- and E-4c

N,N-Dimethylsenecioamide, 1a (0.66 mL, 4.8 mmol), waslithiated according to procedure A, and the resulting dieno-late was silylated with 1.2 mL of chlorotriisopropylsilane(5.5 mmol) in the normal manner (reflux 40 h). Followingstandard workup, the crude mixture was subjected to prepa-rative HPLC (ethyl acetate – hexane) to give, in order ofelution: Z-4c (0.31 g, 23% bp 80–85 8C at 0.005 torr. IR(neat) nmax: 1641 cm–1. 1H NMR (C6D6, 250 MHz) d: 1.1–1.3 (AB, spin system, 21H), 1.76 (d, J = 1.2, 3H), 2.40,2.71 (2 br s, 6H), 2.59 (s, 2H), 5.64 (s, 1H). MS m/e (rel.intensity): 283 (M+, 1), 268(6), 240(100), 226(18). HR-MScalcd. for C16H33NOSi: 283.2333. Found: 283.2314. E-4c(0.18 g, 14%), bp 70–4 8C at 0.005 torr. IR (neat) nmax:1641 cm–1. 1H NMR (C6D6) d: 1.05–1.2 (AB6 spin system,21H), 1.76 (d, J = 1.0, 3H), 2.51 (br s, 6H), 2.57 (s, 2H),5.64 (br s, 1H). MS m/e (rel. intensity): 283 (M+, 3),268(7), 240(100), 226(22). Anal. calcd. for C16H33NOSi: C,67.78; H, 11.73; N, 4.94. Found: C, 67.58; H, 11.96; N;

5.18. A mixture of the starting material and its deconjugateddouble bond isomer 10a (0.140 g, 23%).

Z- and E-N,N,3-Trimethyl-3-methyl-4-methyldiphenylsilyl-2-butenamide Z- and E-4d

N,N-Dimethylsenecioamide, 1a (0.275 mL, 2.0 mmol),was lithiated according to procedure A, and the resulting di-enolate was silylated with diphenylmethylsilyl chloride(0.46 mL, 2.2 mmol) in the normal manner (no reflux). Thecrude reaction mixture was subjected to preparative TLC(3:1 hexane – ethyl acetate) to give two fractions, in orderof elution: Z-4d (0.214 g, 33%), mp 56–58 8C (petroleumether). IR (CCl4) nmax: 1633, 1610 cm–1. 1H NMR d: 0.58(s, 3H), 1.64 (s, 3H), 2.83 (2 s, overlapping, 8H), 5.69 (s,1H), 7.2–7.7 (m, 10H). MS m/e (rel. intensity): 323 (M+,12), 308(100), 246(18), 232(22), 197(100). Anal. calcd. forC20H25NOSi: C, 74.25; H, 7.79; N, 4.33. Found: C, 74.48;H, 7.87; N, 4.38. E-4d (0.380 g, 59%), mp 50.5–51.5 8C(petroleum ether). IR (neat) nmax: 1639, 1613 cm–1. 1HNMR d: 0.63 (s, 3H), 1.87 (d, J = 1.0, 3H), 2.20 (s, 2H),2.64, 2.87 (2s, 6H), 5.55 (br s, 1H). MS m/e (rel. intensity):323 (M+, 4), 308(45), 232(12), 197(100). Anal. calcd. forC20H25NOSi: C, 74.25; H, 7.79; N, 4.33. Found: C, 74.07;H, 7.83; N, 4.33.

Z- and E-N,N-Diethyl-3-methyl-4-trimethylsilyl-2-butenamide Z- and E-4e

N,N-Diethylsenecioamide, 1b (0.780 g, 5.02 mmol), waslithiated according to procedure A, and the resulting dieno-late was silylated with chlorotrimethylsilane (0.7 mL,5.5 mmol) in the normal manner (reflux 17 h). The crudereaction mixture was subjected to preparative HPLC (3:1hexane – ethyl acetate) to give, in order of elution: Z-4e(0.446 g, 39%), bp 90–95 8C at 0.6 torr. IR (neat) nmax:1637, 1612 cm–1. 1H NMR (C6D6) d: 0.15 (s, 9H), 0.90 (br,12H), 1.68 (d, J = 1.5, H), 5.51 (s, 2H), 3.10 (br, 2H), 5.70(br s, 1H). MS m/e (rel. intensity): 227(2), 212(100), 73(30).Anal. calcd. for C12H25NOSi: C, 63.38; H, 11.08; N, 6.16.Found: C, 63.19; H, 10.92; N, 6.20. E-4e (0.395 g, 35%), bp65–70 8C at 0.005 torr. IR (neat) nmax: 1641, 1617 cm–1. 1HNMR (C6D6) d: –0.05 (s, 9H), 0.93 (br, 12H), 1.47 (d, J =1.0, 2H), 2.18 (d, J = 1.5, 3H), 3.16 (br, 2H), 5.66 (br s,1H). MS m/e (rel. intensity): 227 (M+, 8), 212(100),155(26), 73(113). Anal. calcd. for C12H25NOSi: C, 63.38; H,11.08; N, 6.16. Found: C, 63.64; H, 11.43; N, 6.57. A mix-ture of the starting material Z-4e and its deconjugated doublebond isomer 10b (0.0912 g, 12%).

Z- and E-N,N-Diethyl-3-nethyl-4-triethylsilyl-2-butenamideZ- and E-4f

N,N-Diethylsenecioamide, 1b (0.6606 g, 5.03 mmol) waslithiated according to procedure A, and the resulting dieno-late was silylated with chlorotriethylsilane (0.88 mL,5.5 mmol) in the usual manner (reflux, 18 h). After a stand-ard workup, flash chromatography (fine silica, 8:l hexane –ethyl acetate) yielded, in order of elution, two significantfractions: Z-4f (0.2805 g, 21%), bp 95–100 8C at 0.01 torr.IR (neat) nmax: 1637, 1614 cm–1. 1H NMR (C6D6) d: 0.5–1.2(m, 21H), 1.71 (d, J = 1.2, 3H), 2.54 (s, 2H), 3.05 (br, 4H),5.69 (br s, 1H). MS m/e (rel. intensity): 269 (M+, 3),254(100), 240(88), 226(22), HR-MS calcd. for C15H31NOSi:

Green et al. 753

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

269.2176. Found: 269.2152. E-4f (0.6270 g, 47%), bp 79–83 8C at 0.01 torr. IR (neat) nmax: 1641, 1616 cm–1. 1HNMR (C6D6) d: 0.3–1.1 (m, 21H), 1.55 (s, 2H), 2.22 (d, J =1.2, 3H), 3.15 (br, 4H), 5.73 (br s, 1H). MS m/e (rel. inten-sity): 269 (M+, 6), 254(100), 240(31), 226(23). Anal. calcd.for C15H31NOSi: C, 66.85; H, 11.59; N, 5.28. Found: C,67.04; H, 11.35; N, 5.28.

Z- and E-N,N-Diisopropyl-3-methyl-4-trimethylsilyl-2-butenamide Z- and E-4g

N,N-Diisopropylsenecioamide 1c (1.03 mL, 5 mmol) waslithiated according to procedure A. To the resulting solutionof the dienolate was added, at –78 8C, 0.70 mL (5.5 mmol)of chlorotrimethylsilane. The mixture was allowed to stirat –78 8C for 15 min before warming to RT, and subsequentheating to 40 8C for 36 h. After a standard workup, thecrude product was subjected to preparative HPLC (5:1 hex-ane – ethyl acetate), resulting, in order of elution, in twofractions: Z-4g (0.290 g, 23%), bp 57–60 8C at 0.02 torr. IR(neat) nmax: 1649, 1632 cm–1. 1H NMR (C6D6) d: 0.13 (s,9H), 1.15 (br, 12H), 1.67 (d, J = 1.4, 3H), 2.33 (s, 2H),3.54 (br, 2H), 5.64 (br s, 1H). MS m/e (rel. intensity): 255(M+, 4), 240(100), 212(66), 198(22), 171(25), 155(32),73(145). Anal. calcd. for C14H29NOSi: C, 65.82; H, 11.44;N, 5.48. Found: C, 66.00; H, 11.46; N, 5.58. E-4g, bp 64–66 8C at 0.02 torr. IR (neat) nmax: 1626 cm–1. 1H NMR(C6D6) d: –0.04 (s, 9H), 1.21 (br, 12H), 1.45 (s, 2H), 2.00(d, J = 1.2, 2H), 3.62 (br, 2H), 5.59 (br s, 1H). MS m/e (rel.intensity): 255 (M+, 11), 240(36), 212(38), 155(100),73(144). Anal. calcd. for C14H29NOSi: C, 65.82; H, 11.44;N, 5.48. Found: C, 65.66; H, 11:22; N, 5.49.

Z- and E-N,N-Diisopropyl-3-methyl-4-methyldiphenylsilyl-2-butenamide Z- and E-4h

N,N-Diisopropylsenecioamide (0.9223 g, 5.03 mmol) waslithiated according to procedure A, and the resulting dieno-late was treated with chloromethyldiphenylsilane (1.16 mL,5.5 mmol) in the normal manner (no subsequent heating).After a standard workup, the crude product was subjected tocolumn chromatography (4:1 hexane – ethyl acetate), yield-ing, in order of elution, two fractions: Z-4h (1.025 g, 54%),mp 56–58 8C (hexane). IR (neat) nmax: 1636, 1615 cm–1. 1HNMR d: 0.58 (s, 3H), 1.26 (br, 12H), 1.56 (d, J = 1.5, 3H),2.80 (s, 2H), 3.78 (br, 2H), 5.68 (br s, 1H), 7.2–7.7 (m,10H). MS m/e (rel. intensity): 379 (M+, 7), 364(61),336(35), 295(23), 197(100). Anal. calcd. for C24H33NOSi:C, 75.60; H, 8.76; N, 3.69. Found: C, 75.72; H, 8.67; N,3.64. E-4h (0.7200 g, 38%), bp 170–175 8C at 0.005 torr.IR (neat) nmax: 1644, 1620 cm–1. 1H NMR d: 0.63 (s, 3H),1.12 (br, 12H), 1.77 (d, J = 1.2, 3H), 2.17 (s, 2H), 3.47 (br,2H), 5.46 (br s, 1H), 7.2–7.7 (m, 10H, 2C6H5). MS m/e (rel.intensity): 379 (M+, 7), 364(58), 336(34), 295(22), 197(100).Anal. calcd. for C24H33NOSi: C, 75.93; H, 8.76; N, 3;69;Found: C, 75.60; H, 8.53; N, 3.96.

TBAF-mediated aldol condensations of Z-4a

Thermodynamic conditionsTo a 0.3–0.4 mol/L solution of Z-4a in THF under an

inert atmosphere was added 1.2 equiv. of the aldehyde orketone in question. Five mol% of a 1 mol/L solution of tet-ra(n-butylammonium) fluoride (in THF) was then added by

syringe. The resulting brown solution was stirred at ambienttemperature for 16 h and worked up in the usual manner.

Kinetic conditionsTo a 0.3–0.4 mol/L solution of Z-4a in THF under an in-

ert atmosphere was added 1.2 equiv. of the aldehyde or ke-tone in question. The solution was cooled to –45 8C before a1 mol/L solution of TBAF (in THF) was added by syringe.The resulting solution was stirred at –45 8C for 2 min beforesaturated aqueous NH4Cl was added (at –45 8C), and astandard workup was performed.

TiCl4-mediated aldol condensations of Z-4aTo 1.2 equiv. of the aldehyde in question under an inert

atmosphere was added CH2Cl2 such that the eventual con-centration of Z-4a was 0.3 mol/L. This solution was cooledto 0 8C, 1.1 equiv. of TiCl4 was added by syringe, and themixture was allowed to stir for 5 min. At this point, a solu-tion of Z-4a, in a minimum amount of CH2Cl2, was addedby syringe. The ice-bath was immediately removed, and thereaction mixture was allowed to stir for 3 h during whichtime it reached ambient temperature. A standard workupwas then performed.

syn- and anti-Z-Hydroxyphenylmethyl-N,N,3-trimethyl-3-butenamide syn- and anti-6a

TiCl4-mediated reactionA mixture of compound Z-4a (0.3247 g, 1.63 mmol) and

benzaldehyde (0.20 mL) in the presence of TiC14 (0.20 mL)was allowed to react in the manner described earlier. After astandard workup, column chromatography (1:l hexane –ethyl acetate) gave one fraction, 0.2763 g, which proved tobe a 90:10 mixture (by 1H NMR integration) of syn-6a(67%) and starting material Z-4a (7%). Recrystallizationgave pure syn-6a, mp 59.5–61 8C (Et2O – petroleum ether)(Lit.3a 59–61 8C (Et2O – hexane)) whose 1H NMR spectraldata were identical to those reported.3a

TBAF-mediated reactionA mixture of compound Z-4a (0.3217 g, 1.61 mmol) and

benzaldehyde (0.20 mL) in the presence of TBAF (1.61 mLof a 1 mol/L solution) was allowed to react under the previ-ously described kinetic control conditions. After a standardworkup, the crude reaction mixture was subjected to prepa-rative TLC (5:2 ethyl acetate – hexane) to give, in order ofelution: syn-6a (0.1145 g, 30%), and 72:16:12 mixture (by1H NMR integration) (0.1610 g) of anti-6a (33%), Z-4a(6%), and desilylated material (7%). anti-6a was purifiedby recrystallization, mp 113–114 8C (CH2Cl2 – hexane)(Lit.3a 114–114.5 8C (Et2O)) and showed 1H NMR spectraldata consistent with those reported.3a

Z- and E-5-Hydroxy-N,N,3-trimethyl-5-phenyl-2-pentenamide Z- and E-5a

A mixture of compound Z-4a (0.3770 g, 1.89 mmol) andbenzaldehyde (0.23 mL) in the presence of TBAF (0.1 mLof a 1 mol/L solution) was allowed to react under the previ-ously described thermodynamic control conditions. Follow-ing a workup in the usual manner, separation by flashchromatography (fine silica, 4:l ethyl acetate – hexane)gave, in order of elution: Z-5a (0.2564 g, 58%), mp 75–

754 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

77 8C (CH2Cl2 – hexane) (Lit.3a 76–76.5 8C (CH2Cl2 – hex-ane)), and E-5a (0.0625 g, 14%) as an undistillable viscousoil. IR (neat) nmax: 1647, 1606 cm–1. 1H NMR d: 1.89 (d, J =1.2, 3H), 2.49 (d, J = 7, 2H), 2.81, 2.90 (2s, 6H), 3.51 (br,1H, exchangeable), 4.85 (t, J = 7, 1H), 5.76 (br s, 1H), 7.32(s, 5H). MS m/e (rel. intensity): 234 (M+ + l, 3), 215(11),127(100), 112(25). HR-MS calcd. for C14H19NO2 + H:234.1495. Found: 234.1492.

syn- and anti-2-(3,4-Dimethoxy)phenylhydroxyethyl-N,N,3-trimethyl-3-butenamide syn- and anti-6b

A mixture of compound Z-4a (0.2752 g, 1.38 mmol) and ve-ratraldehyde (0.3238 g) in the presence of TBAF (1.38 mL of a1 mol/L solution) was allowed to react under the previouslydescribed kinetic control conditions. After a standard workup,the crude reaction mixture was subjected to preparative TLC(5:2 ethyl acetate – hexane) yielding two fractions. The firstfraction (0.123 g) was identified by 1H NMR spectroscopy asa 79:21 mixture of syn-6b (25%) and desilylated starting ma-terial (7%) from which syn-6b was obtained by recrystalliza-tion, mp 102–103 8C (Et2O – hexane) (Lit.3a 100–1.5 8C(Et2O – hexane)). The second fraction (0.1197 g) was shownto be 81:19 mixture (by 1H NMR spectroscopy) of anti-6b(27%) and Z-5b (6%) from which anti-6b was obtained by re-crystallization, mp 120–12l 8C (Et2O) (Lit.3a 118 8C (CH2C12– hexane)). Products syn-6b and anti-6b showed 1H NMRspectral data consistent with those reported.3a

Z- and E-5-(3,4-Dimethoxy)phenyl-5-hydroxy-N,N,3-trimethyl-2-pentenamide Z- and E-5b

A mixture of compound Z-4a (0.4695 g, 2.36 mmol) andveratraldehyde (0.4695 g) in the presence of a catalyticamount of TBAF (0.12 mL of a 1 mol/L solution) was al-lowed to react under the previously described thermodynamiccontrol conditions, followed by workup under the usual con-ditions. The crude mixture was subjected to column chroma-tography, yielding three fractions. Fraction 1 (0.067 g, 12%)was shown to be desilylated starting material 1a/10a. Fraction2 (0.3520 g, 49%) was shown to be Z-5b, mp 78–80 8C(CH2C12 – hexane) (Lit.3a 78–80 8C (CH2Cl2 – hexane)) bycomparison with its 1H NMR spectra with that reported.3a

Fraction 3 (0.1880 g, 26%) proved to be E-5b as an undistil-lable viscous oil. IR (neat) nmax: 3378, 1646, 1608 cm–1. 1HNMR d: 1.93 (d, J = 1.2, 3H), 2.50 (d, J = 7, 2H), 2.90, 2.94(2s, 6H), 3.87, 3.89 (2s, 6H), 4.83 (t, J = 7, 1H), 5.82 (br s,1H), 6.8–7.0 (m, 3H), OH not observed. MS m/e (rel. inten-sity): 293 (M+, 3), 127(100), 112(27). HR-MS calcd. forC16H23NO4: 293.1628. Found: 293.1629.

Z- and E-5-Hydroxy-5-(3-pyridyl)-N,N,3-trimethyl-2-pentenamide Z- and E-5c

A mixture of compound Z-4a (0.3428 g, 1.72 mmol) and3-pyridinecarboxaldehyde (0.18 mL) in the presence of acatalytic amount of TBAF (0.17 mL of a 1 mol/L solution)was allowed to react under the previously described thermo-dynamic control conditions. Following a standard workup,the crude product was subjected to column chromatography(100% acetone) yielding two fractions. Fraction 1 wasshown to contain Z-5c (0.2289 g, 57%) as an undistillable,viscous oil. IR (neat) nmax: 3223, 1648, 1598 cm–1. 1HNMR d: 1.96 (d, J = 1.4, 3H, CH3), 2.32 (dd, J = 13 and

3.5, 1H), 3.01, 3.05 (2s, 6H), 3.0 (obscured, 1H), 4.89 (dd,J = 10 and 3, 1H), 6.16 (br s, 1H), 6.2 (br, 1H, exchange-able), 7.27 (m, 1H), 7.87 (m, 1H), 8.4–8.7 (m, 2H). MS m/e(rel. intensity): 235 (M+ + l, 4), 189(44), 162(29), 144(86),112(100). HR-MS calcd. for C13H18N2O2 + H: 235.1448.Found: 235.1452. Fraction 2 was shown to be E-5c(0.0536 g, 13%) as an undistillable, viscous oil. IR (neat)nmax: 3344, 1646, 1607 cm–1. 1H NMR d: 1.92 (s, 3H), 2.49(d, J = 7, 2H), 2.87, 2.91 (2s, 6H), 4.6 (br, 1H, exchange-able), 4.92 (t, J = 7, 1H), 5.81 (br s, lH), 7.28 (m, 1H), 7.73(m, 1H), 8.52 (m, 2H). MS m/e (rel. intensity): 234 (M+, 2),216(40), 171(44), 144(63), 127(100), 109(63). HR-MScalcd. for C13H18N2O2: 234.1369. Found: 234.1362.

syn- and anti-2-Hydroxy(4-pyridyl)methyl-N,N,3-trimethyl-3-butenamide syn- and anti-6d and Z-5-Hydroxy-5-(4-pyridyl)-N,N,3-trimethyl-2-pentenamide Z-5d

TBAF-mediated reactionA mixture of compound Z-4a (0.2720 g, 1.36 mmol) and

4-pyridinecarboxaldehyde (1.9 mL) in the presence of TBAF(1.37 mL of a 1 mol/L solution) was allowed to react underkinetic control conditions. After a standard workup, the re-sulting crude product was subjected to preparative TLC (in1: 1 ethyl acetate – acetone) to give, in order of elution,three fractions identified by 1H NMR spectroscopy: Fraction1 (0.0364 g, 13%) was shown to be starting Z-4a. Fraction 2was identified as a 1:l mixture of syn- and anti-6d(0.1718 g), while fraction 3 was shown to be a 35:65 mix-ture of anti-6d and Z- 5d (0.0646 g). The individual isomersof 6d were purified by recrystallization: syn-6d (27%), mp111–113 8C (CH2Cl2 – Et2O – hexane) (Lit.3a 98–99 8C(CH2Cl2 – hexane)), mixture mp 109–116 8C. anti-6d(34%), mp 125 8C (CH2Cl2 – hexane) (Lit.3a 128–129 8C(CH2Cl2 – hexane)). Compounds syn-6d and anti-6d showed1H NMR spectral data consistent with those reported.3a

Compound Z-5d (13%) was identified by its 1H NMR spec-trum (see below).

A mixture of compound Z-4a (0.3804 g, 1.908 mmol) and4-pyridinecarboxaldehyde in the presence of TBAF(0.10 mL of a 1 mol/L solution) was allowed to react underthermodynamic control conditions. After a standard workup,chromatography on aluminum oxide (activity III, 5:2 ethylacetate – hexane) gave two fractions. Fraction 1 (0.2813 g)was identified as a 2:l mixture of Z-5d (42%) and syn-6d(21%). Fraction 2 proved to be anti-6d (0.0743 g, 17%).Compound Z- 5d was further purified by repeated prepara-tive TLC, but remained a viscous, undistillable oil. IR(neat) nmax: 3229, 1637, 1598 cm–1. 1H NMR d: 1.95 (s,3H), 2.33 (d, J = 13 and 3, 1H), 3.00, 3.05 (2s, 6H), 3.0 (ob-scured, 1H), 4.85 (br d, J = 10, 1H), 6.17 (br s, 1H), 7.35,8.55 (AA’BB’ spin system, J = 6, 4H), OH not observed.MS m/e (rel. intensity): 235 (M+ + l, 2), 216(33), 127(100),112(68), 83(30). HR-MS calcd. for C13H18N2O2 + H:235.1448. Found: 235.1454.

syn- and anti-2-Hydroxy(4-nitro)phenylmethyl-N,N,3-trimethyl-3-butenamide syn- and anti-6e and Z-5-Hydroxy-5-(4-nitro)phenyl-N,N,3-trimethyl-2-pentenamide Z-5e

TiCl4-mediated reactionA mixture of compound Z-4a (0.3766 g, 1.89 mmol) and

Green et al. 755

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

4-nitrobenzaldehyde (0.3429 g) in the presence of TiC14(0.23 mL) was allowed to react under the previously de-scribed conditions. After a standard workup, the crude reac-tion product was subjected to column chromatography (3:2ethyl acetate – hexane) to give in order of elution: syn-6e(0.3578 9, 73%), mp 119.5–121 8C (Et2O – hexane). IR(CHCl3) nmax: 3404, 1624 cm–1. 1H NMR d: 1.64 (s, 3H),2.96 (s, 6H), 3.42 (d, J = 3.7, 1H), 4.51, 4.96 (2s, 2H), 5.26(s, 1H, exchangeable), 5.36 (d, J = 3.7, 1H), 7.54 and 8.18(AA’BB’ spin system, J = 9, 4H). MS m/e (rel. intensity):278 (M+, 1), 127(100), 112(90), 83(100). Anal. calcd. forC14H18N2O4: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.66;H, 6.51; N, 10.21. anti-6e (0.0047 g, 1%), mp 177–178 8C(CH2Cl2 – hexane). IR (CHCl3) nmax: 3443, 1626 cm–1. 1HNMR d, 1.69 (s, 3H),. 2.91, 2.94 (2s, 6H), 3.41 (d, J = 6,1H), 4.65–5.25 (m, 4H; on addition of D2O gives 4.73 (s,1H), 4.96 (s, 1H), 5.11 (d, J = 6, 1H)), 7.53, 8.19 (AA’BB’spin system, J = 8, 4H). MS m/e (rel. intensity): 278 (M+, 1),127(100), 112(38), 83(89). Anal. calcd.. for C14H18N2O4: C,60.42; H, 6.52; N, 10.07. Found: C, 60.54; H, 6.45; N, 10.06.

TBAF-mediated reactionA mixture of compound Z-4a (0.3061 g, 1.54 mmol) and

4-nitrobenzaldehyde (0.3139 g) in the presence of TBAF(1.55 mL of a 1 mol/L solution) was allowed to reactionunder the previously described kinetic control conditions.Following a standard workup, preparative (5:2 ethyl acetate– hexane) TLC of the crude product gave, in order of elution:recovered Z-4a (0.0096 g, 3%), syn-6e (0.1082 g, 25%), anda 51:49 mixture (by 1H NMR spectroscopy) of anti-6e (31%)and Z-5e (30%) (0.2631 g). Compound Z-5e was obtained bycrystallization, mp 113–115 8C (CH2Cl2 – Et2O – hexane). IR(CHCl3) nmax: 3194, 1650, 1598 cm–1. 1H NMR d: 1.95 (s,3H), 2.33 (dd, J = 13 and 3), 3.0 (obscured, 1H), 3.01, 3.06(2 s, 6H), 4.94 (m, 1H; on addition of D2O becomes dd, J =10 and 3), 6.18 (br s, 1H), 7.19 (d, J = 6, 1H, exchangeable),7.63, 8.20 (AA’BB’ spin system, J = 9, 4H). MS m/e (rel. in-tensity): 278 (M+, 2), 260(37), 216(39), 127(100), 112(97),83(100). Anal. calcd. for C14H18N2O4: C, 60.42; H, 6.52; N,10.07. Found: C, 60.35; H, 6.44; N, 9.93.

A mixture of compound Z-4a (0.3053 g, 1.53 mmol) and4-nitrobenzaldehyde (0.2905 g) in the presence of TBAF(0.08 mL of a 1 mol/L solution) was allowed to reactionunder the previously described thermodynamic controlconditions. After a standard workup, the crude product wassubjected to column chromatography (2:1 – 4:1 ethyl ace-tate – hexane) to give, in order of elution, two fractions:syn-6e (0.0926 g, 22%) and a 46:54 mixture of anti-6e(27%) and Z-5e (31%) (0.2468 g).

Z-5-Hydroxy-N,N,3-trimethyl-5,5-diphenyl-2-pentenamideZ-5g and Z- and E-N,N,3-trimethyl-5,5-diphenyl-5-trimethylsiloxy-2-pentenamide Z- and E-5f

TBAF-mediated reactionTo a solution of Z-4a (0.4794 g, 2.40 mmol) and

benzophenone (0.5461 g, 1.24 equiv.) in 5 mL of THFcooled to –45 8C was added TBAF (0.12 mL of a 1 mol/Lsolution in THF, 5 mol%). After stirring for 1 h at –45 8C,the reaction mixture was quenched with saturated aqueousNH4Cl (at –45 8C) and was worked up in the usual manner.The resultant crude product was subjected to flash chroma-

tography (fine silica, 3:1 – 9:l ethyl acetate – hexane), togive, in order of elution: Z-5f (0.1872 g, 20%). IR (neat)nmax: 1623 cm–1. 1H NMR (C6D6) d: –0.13 (s, 9H), 1.92 (s,3H), 2.34, 2.78 (2s, 6H), 3.76 (s, 2H), 5.57 (br s, 1H), 7.36(apparent s, 10H). This compound slowly underwentdesilylation on standing to give Z-5g, mp 143–145 8C(Et2O – petroleum ether). IR (CHCl3) nmax: 3191, 1643,1598. cm–1. 1H NMR d: 1.25 (s, 3H), 2.96, 3.03 (2 s, 6H),3.42 (s, 2H), 6.08 (br s, 1H), 7.1–7.7 (m, 10H), 7.41 (s, 1H,exchangeable). MS m/e (rel. intensity): 291 (M+ –18, 8),182(49), 128(41), 105(100), 84(24), 77(48), 72(32). Anal.calcd. for C20 H23NO2: C, 77.64; H, 7.49; N, 4.53. Found:C, 77.16; H, 7.46; N, 4.62. E-5f (0.4418 g, 48%), mp 65–67 8C (Et2O – petroleum ether). IR (CHCl3) nmax: 1646,1610 cm–1. 1H NMR (C6D6) d: –0.12 (s, 9H), 1.71 (s, 3H),2.36, 2.81 (2s, 6H), 3.18 (s, 2H), 5.45 (br s, 1H), 7.25 (s,10H). MS m/e (rel. intensity): 366 (M+ – 15, 2), 291(6),255(100), 199(28), 73(100). Anal. calcd. for C22H31NO2Si:C, 72.39; H, 8.19; N, 3.67. Found: C, 72.62; H, 8.25; N,3.80.

TiCl4-mediated reactionA mixture of compound Z-4a (0.211 g, 1.06 mmol) and

benzophenone (0.273 g) in the presence of TiC14 (0.23 mL)was allowed to react under the previously described condi-tions. After a standard workup, the crude reaction productwas subjected to column chromatography (3:1 ethyl acetate– hexane) to afford 6g (0.236 g, 72%), whose spectroscopicdata was shown to be identical with those reported.3a

Z- and E-N,N,3-Trimethyl-5,5-diphenyl-2,4-butadienamideZ- and E-7

A mixture of compound Z-4a (0.5210 g, 2.61 mmol) andbenzophenone (1.6385 g, 3 equiv.) in the presence ofTBAF (0.13 mL of a 1 mol/L solution) was allowed to re-act under thermodynamic conditions. After a standardworkup, the crude product was subjected to flash chroma-tography (4:1 – 9:1 ethyl acetate – hexane) to give a mix-ture of Z- and E-7 (0.2815 g, 29%), bp 145–150 8C at 0.01torr. IR (neat) nmax: 1630 cm–1. 1H NMR d: 1.56 and 1.81(s, 3H), 2.65 and 2.89 (s, 6H), 5.89 (br s, 1H), 6.55 and7.24 (obscured) (br s, 1H), 7.24 (s, 10H). The relative inte-grals of the 1.8 and 1.56 peaks established the ratio of E-7:Z-7 as 65:35. MS m/e (rel. intensity): 291 (M+, 38),219(100), 214(25), 204(49). HR-MS calcd. for C20H21NO:291.1624. Found: 291.1631.

syn- and anti-2-(1-Hydroxy-l-propyl)-N,N,3-trimethyl-3-butenamide syn- and anti-6h

A mixture of compound Z-4a (0.4114 g, 2.06 mmol) andbutanal (0.22 mL) in the presence of TiCl4 (0.25 mL) wasallowed to react under the previously described conditions.Following standard workup, the crude reaction product wassubjected to column chromatography (2:l hexane – ethylacetate) to give, in order of elution: syn-6h (0.2552 g,62%), mp 44–45 8C (Et2O – hexane) (Lit.3a 44–46 8C (Et2O– hexane)). anti-6h (0.0097 g, 2%), mp 68–70 8C (CH2Cl2 –hexane) (Lit.3a 70 8C (CH2Cl2 – hexane)) both of whichwere shown to exhibit 1H NMR spectral data consistentwith their structures,3a and a mixture of desilylated 2- and3-butenamides (0.0391 g, 14%).

756 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

syn- and anti-2-(1-Hydroxy-2-propyl)-N,N,3-trimethyl-3-butenamide syn- and anti-6i

A mixture of compound Z-4a (0.3818 g, 1.92 mmol) and2-methylpropanal (0.21 mL) in the presence of TiC14(0.23 mL) was allowed to react under the previously de-scribed conditions. After workup in the usual manner, thecrude reaction product was subjected to column chromatog-raphy (1:1 – 2:1 ethyl acetate – hexane) to give, in order ofelution, two fractions: syn-6i (0.1520 g, 40%), mp 74–74.5 8C (hexane). IR (neat) nmax: 3373, 1619 cm–1. 1H NMRd: 0.96 (m, 6), 1.83 (obscured, 1), 1.83 (s, 3H), 2.95, 3.03(2s, 6H), 3.41 (d, J = 4.4, 1H), 3.63 (m, 1H), 4.01 (br s, 1H,exchangeable), 4.01, 4.08 (2 s, 2H). MS m/e (rel. intensity):199, (M+, 2), 156(31), 127(11)0), 112(95), 83(100), 72(100) .Anal. calcd. for C11H21NO,: C, 66.30; H, 10.62; N, 7.03.Found: C, 66.34; H, 10.62; N, 7.05. anti-6i (0.1062 g, 28%),mp 111.5–112.5 8C (hexane). IR (CHCl3) nmax: 3400,1624 cm–1. 1H NMR d: 0.96 (d, J = 7, 6H), 1.77 (obscured,1H), 1.77 (s, 3H), 2.96, 3.00 (2s, 6H), 3.34 (d, J = 5.9, 1H),3.72 (m, 1H), 3.94 (0.5 of ABq, J = 7, 1H, exchangeable),4.86, 4.99 (2s, 2H). MS m/e (rel. intensity): 199 (M+, 4),156(37), 127(100), 112(41), 83(98), 72(82). Anal. calcd. forC11H21NO2: C, 66.30; H, 10.62; N, 7.03. Found: C, 66.46; H,10.61; N, 7.08.

syn- and anti-2-(1-Hydroxy-2-ethyl)-N,N,3-trimethyl-3-butenamide syn- and anti-6j

A mixture of compound Z-4a (0.1075 g, 0.539 mmol) andpropanal (58 mL) in the presence of TiC14 (65 mL) was al-lowed to react under the previously described conditions.After workup in the usual manner, the crude reaction prod-uct was subjected to preparative TLC (3:2 ethyl acetate–hexane) to yield, in order of elution, two fractions: syn-6j(0.0450 g, 45% yield), bp 72–77 8C at 0.1 torr. IR (neat)nmax 3440, 1634 cm–1. 1H NMR (500 MHz) d: 0.96 (t, J =7.2, 3H), 1.40–1.55 (m, 2H), 1.81 (s, 3H), 2.94, 3.00 (2s,6H), 3.20 (d, J = 4.0, 1H), 3.93 (m, 1H), 4.28 (br s, 1H, ex-changeable), 4.83 (s, 1H), 5.08 (t, J = 1.5, 1H), 13C NMR:10.5, 21.9, 27.0, 35.6, 37.3, 54.0, 73.0, 116.8, 139.7, 173.5.MS m/e (rel. intensity): 185 (M+, 14), 126 (100), 111 (29),83 (31). HR-MS calcd. for C10H19NO2: 185.1405 (M+),167.1312 (M+ – H2O). Found: 185.1416, 167.1310. A 53:47mixture of anti-6j (7%) and desilylated butenamides (6%)(0.0111g); pure anti-6j was obtained by recrystallization,mp 80–82 8C (hexane). IR (neat) nmax: 3415, 1623 cm–1. 1HNMR (500 Mz) d: 0.96 (t, J = 7.3), 1.43 (m, 1H), 1.54 (m,1H), 1.73 (s, 3H), 2.94, 2.97 (2s, 6H), 3.16 (d, J = 6.8, 1H),3.85 (m, 1H), 4.84 (s, 1H), 4.97 (m, 1H). 13C NMR: 10.2,20.8, 21.2, 35.6, 37.2, 56.1, 72.8, 115.4, 140.5, 172.8. MSm/e: 185 (M+, 13), 127 (75), 125 (100), 111(24). HR-MScalcd.. for C10H19NO2: 185.1405 (M+). Found: 185.1416.

Supplementary dataThe experimental procedures and spectral data for the

preparation of 3, the crossover experiment of 1a and 1b, theattempted TiCl4 mediated reaction of E-4a with benzalde-hyde, the BF3�OEt2 mediated reaction of Z-4a with benzal-dehyde, the attempted generation of the titanium dienolateof 1a, the attempted fluoride mediated reaction of 2a withbenzaldehyde, and the minimized structures and final Carte-sian coordinates and energies for the calculated transition

states 16 and 17, have been deposited as Supplementarydata for this article available on the journal Web site(canjchem.nrc.ca) or may be purchased from the Depositoryof Unpublished Data, Document Delivery, CISTI, NationalResearch Council Canada, Ottawa, ON K1A 0R6, Canada.DUD 3932. For more information on obtaining material, re-fer to cisti-icist.nrc-cnrc.gc.ca/cms/unpub_e.shtml.

AcknowledgementsWe are grateful to the Natural Sciences and Engineering

Research Council of Canada (NSERC) for support of oursynthetic programs. We also wish to thank Prof. JamesGauld, Dr. Haining Liu, and Prof. Charles MacDonald (Uni-versity of Windsor) for assistance with the DFT calculationson the allylsilane – aldehyde transition states.

References(1) Dedicated to Peter Beak, in recognition of a career of rigor-

ous physical organic studies, which enduringly enriched thefield of carbanionic chemistry.

(2) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.Chem. Rev. 2000, 100, 1929 doi:10.1021/cr990247i. PMID:11749280.; (b) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner,G. L. Angew. Chem., Int. Ed. 2005, 44, 4682 doi:10.1002/anie.200462338.; (c) Green, J. R. In Science of synthesis;Majewski, M. and Snieckus, V., Eds; Georg Thieme Verlag:Stuttgart, 2006; Vol. 8, pp. 427–486; (d) Casinos, I.; Mes-tres, R. J. Chem. Soc., Perkin Trans 1978, 1, 1651 doi:10.1039/p19780001651.; (e) Dugger, R. W.; Heathcock, C. H.J. Org. Chem. 1980, 45, 1181. doi:10.1021/jo01295a002.

(3) (a) Majewski, M.; Mpango, G. B.; Thomas, M. T.; Wu, A.;Snieckus, V. J. Org. Chem. 1981, 46, 2029 doi:10.1021/jo00323a012.; (b) Majewski, M.; Green, J. R.; Snieckus, V.Tetrahedron Lett. 1986, 27, 531 doi:10.1016/S0040-4039(00)84032-0.; (c) Green, J. R.; Majewski, M.; Snieckus, V. Can.J. Chem. 2006, 84, 1397. doi:10.1139/V06-112.

(4) Casey, C. P.; Jones, C. R.; Tukada, H. J. Org. Chem. 1981,46, 2089. doi:10.1021/jo00323a022.

(5) (a) For reviews on ketene acetals, see: Schneider, C. InScience of synthesis; de Meijere, A., Ed.; Georg ThiemeVerlag: Stuttgart, 2005; Vol. 24, pp. 293–322; (b) Mahrwald,R. Chem. Rev. 1999, 99, 1095 doi:10.1021/cr980415r.PMID:11749441.; (c) For a review on ketene O,N-acetals,see: Kantlehner, W. In Science of synthesis; de Meijere, A.,Ed.; Georg Thieme Verlag: Stuttgart, 2005; Vol. 24,pp. 337–446; (d) For reviews on the chemistry of vinyl ke-tene acetals, see: Kalesse, M. Top. Curr. Chem. 2005, 244,43; (e) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.Chem. Rev. 2000, 100, 1929. doi:10.1021/cr990247i. PMID:11749280.

(6) Williard, P. G.; Tata, J. R.; Schlessinger, R. H.; Adams, A.D.; Iwanowicz, E. J. J. Am. Chem. Soc. 1988, 110, 7901.doi:10.1021/ja00231a065.

(7) (a) In esters, see: Kang, G. J.; Chan, T. H. Can. J. Chem.1985, 63, 3102 doi:10.1139/v85-512.; (b) Barton, T. J.;Goure, W. F.; Witiak, J. L.; Wulff, W. D. J. Organomet.Chem. 1982, 225, 87 doi:10.1016/S0022-328X(00)86813-8.;(c) Bellassoued, M.; Ennigrou, R.; Gaudemar, M. J. Organo-met. Chem. 1988, 338, 149 doi:10.1016/0022-328X(88)80497-2.; (d) Asakura, T.; Kojima, T.; Miura, T.; Iwasawa,N. Angew. Chem., Int. Ed. 2006, 45, 6874. doi:10.1002/anie.200602188.

(8) (a) In ketones and aldehydes, see: Shih, C.; Swenton, J. S. J.

Green et al. 757

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

Org. Chem. 1982, 47, 2668 doi:10.1021/jo00134a032.; (b)Fish, P. V. Synth. Commun. 1996, 26, 433 doi:10.1080/00397919608003634.; (c) Bartoli, G.; Bosco, M.; Dalpozzo,R.; De Nino, A.; Iantorno, E.; Tagarelli, A.; Palmieri, G.Tetrahedron 1996, 52, 9179 doi:10.1016/0040-4020(96)00468-1.; (d) Pirrung, M. C.; Fallon, L.; Zhu, J.; Lee, Y. R.J. Am. Chem. Soc. 2001, 123, 3638 doi:10.1021/ja002370t.PMID:11457095.; (e) Asakura, T.; Kojima, T.; Miura, T.;Iwasawa, N. Angew. Chem., Int. Ed. 2006, 45, 6874. doi:10.1002/anie.200602188.

(9) For a review of silicon migrations, see: Mitsuo, K.; Iwamoto,T. In Chemistry of organic silicon compounds; Rappoport,Z., Apeloig, Y., Eds.; Wiley: Chichester, 2001; Vol. 3,pp. 853–948.

(10) For the preliminary report, see: Green, J. R.; Snieckus, V.Tetrahedron Lett. 1986, 27, 535. doi:10.1016/S0040-4039(00)84033-2.

(11) (a) Armstrong, R. J.; Weiler, L. Can. J. Chem. 1983, 61,2530 doi:10.1139/v83-436.; (b) Pettersson, L.; Magnuson,G.; Frejd, T. Acta Chem. Scand. 1993, 47, 196 doi:10.3891/acta.chem.scand.47-0196.; (c) Wennerberg, J.; Polla, M.;Frejd, T. J. Org. Chem. 1997, 62, 8735 doi:10.1021/jo971082l.; (d) Nakada, M.; Kojima, E.-i.; Iwata, Y. Tetrahe-dron Lett. 1998, 39, 313 doi:10.1016/S0040-4039(97)10554-8.; (e) Aggarwal, V. K.; Bethel, P. A.; Giles, R. J. Chem.Soc., Perkin Trans 1999, 1, 3315 doi:10.1039/a906589j.; (f)Beszant, S.; Giannini, E.; Zanoni, G.; Vidari, G. TetrahedronAsymmetry 2002, 13, 1245 doi:10.1016/S0957-4166(02)00335-X.; (g) Pettersson, L.; Frejd, T. J. Chem. Soc., PerkinTrans. 2001, 1, 789 doi:10.1039/b010101j.; (h) Beszant, S.;Giannini, E.; Zononi, G.; Vidari, G. Eur. J. Org. Chem.2003, 3958. doi:10.1002/ejoc.200300276.

(12) (a) For broader study of electrophilic reactivity with alkeno-ates, see: Yamamoto, Y.; Hatsuya, S.; Yamada, J.-i. J. Org.Chem. 1990, 55, 3118 doi:10.1021/jo00297a030.; (b) Fan,R.; Hudlicky, T. Tetrahedron Lett. 1989, 30, 5533 doi:10.1016/S0040-4039(01)93792-X.; (c) For amination reactions,see: Loreto, M. A.; Pompei, F.; Tardella, P. A.; Tofavi, D.Tetrahedron 1997, 53, 15853. doi:10.1016/S0040-4020(97)10045-X.

(13) (a) Chabaud, L.; James, P.; Landais, Y. Eur. J. Org. Chem.2004, 3173 doi:10.1002/ejoc.200300789.; (b) Sarkar, T. K.In Science of synthesis; Fleming, I., Ed.; Georg Thieme Ver-lag: Stuttgart, 2002; Vol. 4, pp. 837–926; (c) Brook, M. A.Silicon in organic, organometallic, and polymer chemistry;Wiley: New York, 2000; Chap. 16; (d) Luh, T.-Y.; Liu, S.-T. In Chemistry of organic silicon compounds; Rappoport,Z., Apeloig, Y., Eds.; Wiley: Chichester, 1998; Vol. 2, Pt.3, pp. 1793–1868; (e) Fleming, I.; Barbero, A.; Walter, D.Chem. Rev. 1997, 97, 2063 doi:10.1021/cr941074u. PMID:11848898.; (f) Langkopf, E.; Schinzer, D. Chem. Rev. 1995,95, 1375 doi:10.1021/cr00037a011.; (g) Fleming, I.; Duno-gues, J.; Smithers, R. Org. React. 1989, 37, 57; (h) Majetich,G. In Organic synthesis: theory and applications; Hudlicky,T, Ed.; JAI: Greenwich, 1989; Vol. 1, pp. 173–240.

(14) (a) Denmark, S. E.; Lee, W. Chem. Asian J. 2008, 3, 327doi:10.1002/asia.200700300. PMID:18022982.; (b) Kalese,M.; Hassfeld, J. In Asymmetric synthesis: the essentials;Christmann, M., Brase, S., Eds.; Wiley-VCH: Weinheim,2007; pp. 105–109; (c) Hosokawa, S.; Tatsuta, K. Mini Rev.Org. Chem. 2008, 5, 1 doi:10.2174/157019308783498197.;(d) Jacques, T.; Marko, I. E.; Popisil, J. In Multicomponentreactions; Zhu, J, Bienayme, H., Eds.; Wiley-VCH, 2005;pp. 398–452.

(15) (a) For an analogous NOE-based assignment of the alkenestereochemistry of vinylketene acetals, see: Bell, S. H.;Cameron, D. W.; Feutrill, G. I.; Skelton, B. W.; White, A. H.Tetrahedron Lett. 1985, 26, 6519 doi:10.1016/S0040-4039(00)99042-7.; (b) Adams, A. D.; Schlessinger, R. H.;Tata, J. R.; Venit, J. J. J. Org. Chem. 1986, 51, 3068. doi:10.1021/jo00365a045.

(16) Berger, S.; Braun, S. 200 and more NMR experiments: Apractical course, Wiley-VCH: Weinheim, 2004; pp. 277–279.

(17) (a) For examples of the influence of phenyl groups in silylhalides on O- versus C-silylation, see: Larson, G. L.;Fuentes, L. M. J. Am. Chem. Soc. 1981, 103, 2418 doi:10.1021/ja00399a052.; (b) Akai, S.; Kitagaki, S.; Naka, T.;Yamamoto, K.; Tsuzuki, Y.; Matsumoto, K.; Kita, Y. J.Chem. Soc., Perkin Trans. 1996, 1, 1705. doi:10.1039/p19960001705.

(18) (a) House, H. O.; Crumrine, D.; Teranishi, A. Y.; Olmstead,H. D. J. Am. Chem. Soc. 1973, 95, 3310 doi:10.1021/ja00791a039.; (b) Heathcock, C. In Asymmetric synthesis;Morrison, J. D., Ed.; Academic Press: New York, 1983;Vol. 3, pp. 111–212.

(19) (a) For support of an ion-paired enolate intermediate, see:Biddle, M. M.; Reich, H. J. J. Org. Chem. 2006, 71, 4031doi:10.1021/jo0522409. PMID:16709041.; (b) For examplesof results strongly implicating a pentacoordinated siliconateion in a similar pKa range, see: Takahashi, O.; Maeda, T.;Mikami, K.; Nakai, T. Chem. Lett. 1986, 1355. doi:10.1246/cl.1986.1355.

(20) (a) Reetz, M.; Peter, R. Tetrahedron Lett. 1981, 22, 4691doi:10.1016/S0040-4039(01)83014-8.; (b) Evans, D. A.;Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J. Am.Chem. Soc. 1990, 112, 8215 doi:10.1021/ja00178a082.;(c) Ghosh, A. K.; Shevlin, M. In Modern aldol reactions;Mahrwald, R., Ed.; Wiley-VCH: Weinhein, 2004; pp. 60–125.

(21) Yamamoto, Y.; Hatsuya, S.; Yamada, J.-i. J. Org. Chem.1990, 55, 3118. doi:10.1021/jo00297a030.

(22) Fan, R.; Hudlicky, T. Tetrahedron Lett. 1989, 30, 5533.doi:10.1016/S0040-4039(01)93792-X.

(23) (a) Kaur, P.; Singh, P.; Kumar, S. Tetrahedron 2005, 61,8231 doi:10.1016/j.tet.2005.06.045.; (b) Hansen, F. G.;Bundgaard, E.; Madsen, R. J. Org. Chem. 2005, 70, 10139.doi:10.1021/jo051645q. PMID:16292857.

(24) We and Hudlicky have chosen to define diastereomer no-menclature by the more conventional consideration of thecarbonyl function as part of the main chain. Consequently,the syn- and anti-diastereomers of our work correspond tothe anti- and syn-diastereomers, respectively, of theYama-moto and Kumar reports.

(25) (a) Yamamoto, Y.; Yitagai, Y.; Naruta, Y.; Maruyama, K. J.Am. Chem. Soc. 1980, 102, 7107 doi:10.1021/ja00543a040.;(b) For a more complete discussion of the possible opentransition states in Hosomi–Sakurai reactions, see: Tietze, L.F.; Kinzel, T.; Schmatz, S. J. Am. Chem. Soc. 2006, 128,11483 doi:10.1021/ja062528v. PMID:16939272.; (c) For areview on diastereoselection in Mukaiyama aldol reactions,see: Mahrwald, R. Chem. Rev. 1999, 99, 1095. doi:10.1021/cr980415r. PMID:11749441.

(26) Maria, P.-C.; Gal, J.-F. J. Phys. Chem. 1985, 89, 1296.doi:10.1021/j100253a048.

(27) (a) Montaudo, G.; Librando, V.; Caccamese, S.; Maravigna,P. J. Am. Chem. Soc. 1973, 95, 6365 doi:10.1021/ja00800a033.; (b) Kruk, C.; Spaargaren, K. Spectrochim.Acta [A] 1971, 27, 77.

758 Can. J. Chem. Vol. 87, 2009

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.

(28) (a) For synclinal transition-state proposals in allylsilane car-bonyl condensations, cyclic, see: Denmark, S. E.; Weber, E.J. Helv. Chim. Acta 1983, 66, 1655 doi:10.1002/hlca.19830660604.; (b) For acyclic, see: Jain, N. F.; Takenaka,N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475 doi:10.1021/ja962877x.; (c) For allylstannanes, cyclic, see: Den-mark, S. E.; Weber, E. J. J. Am. Chem. Soc. 1984, 106,7970 doi:10.1021/ja00337a053.; (d) For allylstannanes, acyc-lic, see: Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Ab-bott, D. E. J. Org. Chem. 1994, 59, 7889. doi:10.1021/jo00104a054.

(29) (a) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tet-rahedron Lett. 1986, 27, 4957 doi:10.1016/S0040-4039(00)85106-0.; (b) Galatsis, P.; Millan, S. D.; Ferguson, G. J.Org. Chem. 1997, 62, 5048. doi:10.1021/jo961904z.

(30) Moreau, B.; Ginisty, M.; Alberico, D.; Charette, A. B. J.Org. Chem. 2007, 72, 1235. doi:10.1021/jo062099j. PMID:17256906.

(31) (a) Gevorgyan, V.; Kadota, I.; Yamamoto, Y. TetrahedronLett. 1993, 34, 1313 doi:10.1016/S0040-4039(00)91783-0.;(b) Nishigaichi, Y.; Takuwa, A. Tetrahedron Lett. 2002, 43,3045 doi:10.1016/S0040-4039(02)00409-4.; (c) Nishigaichi,Y.; Takuwa, A. Tetrahedron Lett. 2003, 44, 1405. doi:10.1016/S0040-4039(02)02867-8.

(32) (a) Goasdoue, G.; Goasdoue, N.; Gaudemar, M. J. Organo-met. Chem. 1984, 263, 273 doi:10.1016/0022-328X(84)85032-9.; (b) Chan, T. H.; Aida, T.; Lau, P. W. K.; Gorys,V.; Harpp, D. N. Tetrahedron Lett. 1979, 4029 doi:10.1016/S0040-4039(01)86495-9.; (c) Schinzer, D.; Solyom, S.;

Becker, M. Tetrahedron Lett. 1985, 26, 1831. doi:10.1016/S0040-4039(00)94749-X.

(33) Bottoni, A.; Costa, A. L.; Di Tommaso, D.; Rossi, I.;Tagliavini, E. J. Am. Chem. Soc. 1997, 119, 12131. doi:10.1021/ja9723693.

(34) (a) Denmark, S. E.; Almstead, N. G. J. Org. Chem. 1994, 59,5130 doi:10.1021/jo00097a008.; (b) Denmark, S. E.; Hosoi,S. J. Org. Chem. 1994, 59, 5133 doi:10.1021/jo00097a009.;(c) [see also:] Schlosser, M.; Franzini, L.; Bauer, C.; Leroux,F. Chem. Eur. J. 2001, 7, 1909. doi:10.1002/1521-3765(20010504)7:9<1909::AID-CHEM1909>3.0.CO;2-H.

(35) (a) Mulzer, J.; Bruntrup, G.; Finke, J.; Zippel, M. J. Am.Chem. Soc. 1979, 101, 7723 doi:10.1021/ja00520a020.;(b) Mulzer, J.; Zippel, M.; Bruntrup, G.; Segner, J.; Finke,J. Liebigs Ann. Chem. 1980, 1108. doi:10.1002/jlac.198019800710.

(36) (a) Young, D.; Kitching, W. Aust. J. Chem. 1985, 38, 1767;(b) Denmark, S.; Weber, E. J.; Wilson, T. M.; Willson, T.M. Tetrahedron 1989, 45, 1053; (d) [Review:] Gung, B. W.Org. React. 2004, 64, 1.

(37) (a) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem.Soc. 2000, 122, 11995 doi:10.1021/ja002149g.; (b) Zhao, Y.;Snieckus, V. Unpublished results.

(38) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,2923. doi:10.1021/jo00408a041.

(39) Perrin, D. D.; Amarego, W. L.; Mitra, A. Purification oflaboratory chemicals, 2nd ed; Pergamon: Oxford, 1980.

(40) Winkle, M. R.; Lansinger, J. M.; Ronald, R. C. J. Chem.Soc., Chem. Commun. 1980, 87. doi:10.1039/c39800000087.

Green et al. 759

Published by NRC Research Press

Can

. J. C

hem

. Dow

nloa

ded

from

ww

w.n

rcre

sear

chpr

ess.

com

by

UN

IV C

HIC

AG

O o

n 11

/10/

14Fo

r pe

rson

al u

se o

nly.