DOI: 10.1002/adsc.201200807

Guanidine-Catalyzed Triple Functionalization of g-SubstitutedAllenoates with Aldehydes by a Four-Step Reaction Cascade

Philipp Selig,a,* Aleksej Turockin,a and William Ravenb

a Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, GermanyFax: (+49)-241-809-2127; phone: (+ 49)-241-809-4697; e-mail: philipp.selig@rwth-aachen.de

b Institute of Inorganic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany

Received: September 7, 2012; Revised: October 25, 2012; Published online: January 15, 2013

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200807.

Abstract: The bicyclic guanidine 1,5,7-triazabicyclo-ACHTUNGTRENNUNG[4.4.0]dec-5-ene (TBD) was discovered as an effi-cient catalyst for the reaction of g-substituted allen-ACHTUNGTRENNUNGoates with aromatic aldehydes. 4H-1,3-Dioxin-6-yl-propanoates with four newly formed bonds andfour stereogenic centers were obtained in goodyields and excellent diastereoselectivities by twoconsecutive Morita–Baylis–Hillman reactions, ace-talization and intramolecular Michael addition. Thisfour-step reaction cascade not only significantly ex-pands the scope of catalytic allenoate functionaliza-tions but also highlights the potential of TBD to actas a multifunctional Lewis base catalyst.

Keywords: allenes; domino reactions; guanidines;Lewis bases; organocatalysis

The Lewis base-catalyzed nucleophilic activation ofallenoates has recently emerged as an extremely ver-satile synthetic methodology.[1,2] Following Lu�sgroundbreaking work in 1995,[3] tremendous progresshas been made primarily in the field of phosphine cat-alysis,[4] making it a useful tool in the synthesis of het-erocycles and natural products.[5] While activated ole-fins and imines were discovered as suitable reactionpartners for [3+2] additions early on,[3,6] it was notuntil 2005 that the first reaction between an allenoateand aldehydes was reported by Kwon et al.[7] The re-action resulted in the incorporation of two moleculesof aldehyde yielding formal [2+ 2+2] addition prod-ucts (Scheme 1). Modifications of the reaction condi-tions gave access to (dihydro)pyrones,[8] but the scopeof these transformations remained limited to g-unsub-stituted 2,3-butadienoates. The corresponding reactionof 2,3-pentadienoates, reported by He et al. in 2009,resulted in a bond formation from the former g-methyl substituent in the d-position and a [3 +2] addi-

tion product, but gave no g-substituted products what-soever.[9]

The striking difference in reactivity between g-un-substituted 2,3-butadienoates and their g-methyl sub-stituted 2,3-pentadienoate counterparts is explainedin a simplified fashion as follows. After the initial nu-cleophilic attack of the catalyst to the b-position ofthe allenoate, the resulting zwitterionic phosphoniumdienolate A behaves as a nucleophile at the a- or, asin the reaction with aldehydes, at the vinylogous g-po-sition. In the case of 2,3-pentadienoates, however,a rapid 1,4-proton transfer from the methyl substitu-ent to the a-position can occur, which gives rise toa phosphonium ylide B, now nucleophilic at the b-and vinylogous d-positions. For g-alkyl substituted al-lenoates, this umpolung reaction to ylide B effectively

Scheme 1. Reactions of allenoates with aromatic aldehydes.TBD=1,5,7-triazabicycloACHTUNGTRENNUNG[4.4.0]dec-5-ene.

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overrides the initial a-/g-nucleophilicity of the sub-strate-catalyst adduct.[10,11]

The prevalence of phosphonium ylides B as reac-tive intermediates has recently been exploited syn-thetically but also presents a severe limitation to thescope of phosphine-catalyzed allenoate reactions.[11]

Up to now, no g-functionalization of a g-substitutedallenoate with aldehydes has been reported.

A means to suppress unwanted ylide reactions maybe the use of nitrogen instead of phosphorus Lewisbases. Nitrogen-based nucleophiles are still usedrather infrequently in allenoate activations, and oftenshow divergent reactivity as compared to phosphinecatalysts.[12] Popular Lewis bases like DABCO,DMAP and DBU have been investigated in the reac-tion of 2,3-butadienoates and salicylic aldehydes,[13]

but no reaction with simple aldehydes like inScheme 1 was realized, possibly because these cata-lysts mainly act as Brønsted rather than as Lewisbases.[13c] Guanidines, on the other hand, are nowa-days well established as strong Brønsted base and hy-drogen bond catalysts,[14] yet their application as cata-lytic Lewis bases is much less developed.[15] Especiallybicyclic guanidines, however, show unique steric andelectronic properties which make them attractive as

nucleophilic catalysts.[16] To further explore thisemerging field of nucleophilic guanidine organocatal-ysis as well as expand the scope of Lewis base-mediat-ed allenoate functionalization, we decided to explorethe reaction of g-substituted allenoates with aromaticaldehydes using the prototypical [4.4.0]bicyclic guani-dine 1,5,7-triazabicyclo ACHTUNGTRENNUNG[4.4.0]dec-5-ene (TBD) asa catalyst (see Table 1).

We initially began our investigations with the reac-tion of ethyl 2,3-pentadienoate (1) and strongly acti-vated 4-nitrobenzaldehyde (2a) (Table 1, entry 1). Toour delight, TBD turned out to be a highly active cat-alyst and no d-functionalized products resulting fromunwanted ylide reactions were observable. As hopedfor, TBD enabled the C�C bond forming reactionoriginating from the dienolate intermediate A, butthe reaction did not yield the expected 5-methyl sub-stituted 1,3-dioxane-ylidene 3 either. Instead, we iso-lated diastereomerically pure (vide infra) 4H-1,3-dioxin-6-ylpropanoate 4a next to some aldol conden-sation side-product 5a.[17]

TBD thus leads to the incorporation of three mole-cules of aldehyde and an unprecedented triple func-tionalization of the a-,b- and g-positions of the alle-noate. The unwanted condensation, originating from

Table 1. Optimization of reaction conditions for electron-poor aromatic aldehydes.[a]

Entry Catalyst (mol%) Temp. [8C] Time [h] Yield of 4a [%][b] Side-products

1[c] TBD (10) 0 1.0 24 5a (16%)2 TBD (15) 0 0.5 24 6a (4%)3 TBD (20) + 25 24 35 6a (19%)4 TBD (20) �20 1.0 51 6a (traces)[d]

5 TBD (10) �20 1.0 34 6a (traces)[d]

6 TBD (15) �20 1.0 59 6a (traces)[d]

7[e] TBD (15) �20 2.0 50 –8 DBU (15) �20 1.0 26 –9 DMAP (15) �10 3.0 18 –10 DABCO (15) + 25 18 <5 –

[a] Reactions were performed on a 0.7–1.0 mmol scale with 4.0 equiv. of 2a in MeCN; c(1)=0.05–0.1 M.[b] Isolated yield of diastereomerically pure (dr>9/1) product.[c] THF was used as a solvent.[d] Not isolated.[e] 5.0 mmol of 1 used.

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allene-alkyne isomerization, was most efficiently sup-pressed in MeCN, but now considerable amounts ofa retro-aldol product 6a were formed.[18] The amountof 6a increased with longer reaction times and highertemperatures but could be reduced to <5% if the re-action was performed at �20 8C (Table 1, entries 2–4).Even lower temperatures were impractical due to thelimited solubility of both TBD and aldehyde. The op-timal catalyst loading was determined to be 15 mol%(Table 1, entries 4–6). The reaction scaled up well, al-lowing for the synthesis of 1.46 g 4a in a single run(Table 1, entry 7). In comparison with other commonnitrogen Lewis bases, TBD was by far the most activecatalyst, and activity decreased sharply from DBU toDMAP to DABCO (Table 1, entries 8–10). Amazing-ly, the endocyclic C,C-double bond of products 4a and6a was entirely stable against any isomerization intoconjugation. The retro-aldol reaction of 4a into 6a,however, was readily affected with any Brønsted base(e.g., NEt3, DBU) at room temperature. On the otherhand, only low yields of product 4a could be obtainedfrom 6a, as the aldol reaction of 6a and aldehyde 2awas extremely slow at �20 8C and entirely unselectivewith respect to the four obtained diastereoisomers athigher temperatures. Product 4a was thus very likelynot formed by a simple aldol addition to 6a but bya different mechanism.

Further mechanistic insight was gained from usingmore electron-rich aromatic aldehydes, for example,3,5-dimethoxybenzaldehyde (2b) (Scheme 2).

No aldol condensation products were observed, butas before, higher temperatures led to a retro-aldol re-action to 6b (Scheme 2, entry b). Differently from thereaction with 2a, however, we could now also observetwo new intermediates, namely the mono- and bis-Morita–Baylis–Hillman (MBH) products 7b and 8b

(Scheme 2, entry a).[17,19] These MBH intermediateswere generally formed as diastereomeric mixturesand were also observable as transient species in otherreactions with less reactive aldehydes. Using DMF in-stead of MeCN as a solvent accelerated the MBH re-actions and led to a cleaner overall reaction but hadonly a minor effect on the yield of product 4b(Scheme 2, entry c). Very short reaction times gaveno product 4b but only bis-MBH product 8b(Scheme 2, entry d). Subjecting isolated bis-MBHproducts to the reaction conditions resulted in furtherconversion but no reverse reactions were observed(see the Supporting Information).

4H-1,3-Dioxin-6-ylpropanoates 4 are thus verylikely formed via MBH intermediates 8 by an acetalformation and subsequent intramolecular oxa-Michaeladdition, which readily explains the observed endocy-clic, unconjugated double bond position. The highdegree of diastereoselectivity in the formation of 4stems from the diastereomeric ratios of bis-MBH pre-cursors 8 as well as the substrate selectivity in thefinal Michael addition step, and therefore differsgreatly from the observed lack of selectivity ina simple base-catalyzed aldol addition of 6. Base-cata-lyzed retro-aldol/aldol reactions occurring with longerreaction times or higher temperatures reduce theyield of 4 due to both decomposition and scramblingof the diastereomeric integrity. The TBD-catalyzedreaction thus differs fundamentally from the relatedphosphine-catalyzed transformations.[7,9] Rather thanjust functioning as a “nucleophilic trigger”,[9] TBDserves as a Lewis base catalyst in two consecutiveMBH reactions as well as a Brønsted base catalyst inan acetal formation and Michael addition. While wecannot entirely rule out an exclusive Brønsted base-catalyzed mechanism via isomeric b-alkynoate eno-

Scheme 2. Mechanism of the formation of 4H-1,3-dioxinyl-6-propanoate 4b via MBH-intermediates 7b and 8b with 25 mol%TBD.

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lates, the absence of aldol condensation products 5makes this pathway rather unlikely. Moreover, non-nucleophilic bases like NaH or K2CO3 were ineffec-tive in producing any defined products.

With a first understanding of our newly developedfour-step reaction sequence in hand, we set out tosynthesize a number of three-fold functionalizedproducts 4 by the reaction of allenoate 1 and variousaldehydes 2 (Table 2). Generally, electron-poor alde-hydes showed reactivity according to Table 1 andgave higher yields in MeCN (Method A). Benzalde-hyde and more electron-rich substrates reacted moreefficiently in DMF (Method B) and often allowed forthe observation/isolation of MBH intermediates,which were too short-lived to observe with more reac-tive aldehydes. The reaction gave generally yields of40–60% with electron-poor aromatic aldehydes, which

is remarkable in light of the complexity of the prod-ucts and the high degree of diastereoselectivity ob-tained.[20] Substituents in the ortho-, meta- and para-positions were well tolerated (Table 2, entries 1–3 and5–7).

Besides nitro- and halobenzaldehydes, carbonyl-,alkyl- and aryl-substituted aldehydes reacted well(Table 2, entries 10–14), but yields were reduced se-verely for electron-rich aromatic and heteroaromaticaldehydes (Table 2, entries 15–18). Even strongly hin-dered aliphatic pivaldehyde (2s) gave the desiredproduct, albeit in rather low yield. The scope of thereaction is limited to aromatic or other non-enolizablealdehydes due to the strong Brønsted basicity ofTBD, which leads to rapid and unselective self-aldolreactions of enolizable aldehydes (Table 2, entry 20).Of eight possible diastereoisomers, all products 4a–s were isolated in almost diastereomerically pureform, with <10% (often <5%) of combined minordiastereoisomers. The structural assignment of themain products as the “syn-anti-syn” isomer is basedon X-ray crystal structure analyses of three distinctcompounds (4g, 4m and 4s, see Figure 1)[21] and signif-icant similarities between the 1H/13C spectra of all iso-lated products, regarding chemical shifts, J-couplingsand characteristic anisotropic effects.

Phosphine-catalyzed reactions generally respondvery sensitively to even minor structural changes inthe allenoate. Our new TBD-catalyzed reaction, how-ever, was also applicable for allenoate 9[22] bearing thebranched i-Pr substituent in the g-position (Table 3).Yields of the products 11 were slightly lower than inthe g-Me case, but the reaction followed the samepathway and gave the same diastereoisomers asbefore. Moreover, also b-alkynoate 10[23] was a suitablesubstrate leading to n-Bu substituted products 12, as

Table 2. TBD-catalyzed four-step triple functionalization ofethyl 2,3-pentadienoate (1) with various aromatic aldehydes2.

Entry 2 : R Cond.[b] Product Yield [%][c]

1 2a : 4-NO2-C6H4 A 4a 592 2c : 3-NO2-C6H4 A 4c 41[d]

3 2d : 2-NO2-C6H4 A 4d 474 2e : 4-CF3-C6H4 A 4e 605 2f : 4-F-C6H4 A 4f 426 2g : 3-F-C6H4 A 4g 517 2h : 2-F-C6H4 A 4h 62[e]

8[f] 2i : 4-Cl-C6H4 A 4i 609 2j : 3-Br-C6H4 A 4j 4410 2k : 3-CHO-C6H4 A 4k 4511 2l : 4-CO2Me-C6H4 A 4l 6012 2m : C6H5 B 4m 4713 2n : 3-naphthyl B 4n 4914 2o : 3-Me-C6H4 B 4o 5015 2p : 3,4-OCH2O-C6H3 B 4p 3816 2b : 3,5-MeO-C6H3 B 4b 3317 2q : 4-MeO-C6H4 B 4q 2118 2r : 2-thienyl B 4r 1519 2s : t-Bu B 4s 2320 2t : Et B 4t 0

[a] Reactions were performed on a 0.7–1.0 mmol scale with4.0 equiv of 2 at �20 8C; c(1)= 0.05–0.1 M.

[b] A: with 15 mol% TBD in MeCN, B: with 25 mol% TBDin DMF.

[c] Isolated yield of diastereomerically pure (dr>9/1) prod-uct.

[d] 5c isolated in 9% yield.[e] dr=85/15.[f] 25 mol% TBD used.

Figure 1. X-ray crystal structure of product 4m.[21]

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the alkyne was quickly isomerized into its isomericallene by TBD.[24] Accordingly, the reaction wasequally effective for different batches of allenoateswhich typically contained varying amounts of their re-spective alkynoate isomers, and no vigorous purifica-tion was necessary.

In summary, we have developed a novel triple func-tionalization of g-substituted allenoates with alde-hydes catalyzed by the bicyclic guanidine TBD. Thetransformation is operationally simple and yieldshighly functionalized 4H-1,3-dioxin-6-ylpropanoates 4with four stereogenic centers in a diastereoselectivefashion. First investigations indicate a mechanisticpathway consisting of two consecutive Morita–Baylis–Hillman reactions, an acetalization and an oxa-Mi-chael cyclization in which TBD acts both as a Lewisand a Brønsted base catalyst. A five-step cascade re-action could be realized with the additional alkyne-allene isomerization of substrate 10. The presentedtransformation not only represents the first a,b,g-tri-functionalization of allenoates in one pot, but alsohighlights the potential of TBD to act as an efficientLewis base catalyst in addition to its well-knownBrønsted basic properties. Further investigations re-garding the synthetic potential of the obtained dense-ly functionalized products as well as the possibility ofan enantioselective reaction using chiral guanidinecatalysts are currently in progress.

Experimental Section

Typical Procedures

Method A: Ethyl 2,3-pentadienoate (1, 108 mg, 856 mmol)and 4-nitrobenzaldehyde (2a, 518 mg, 3.42 mmol, 4.0 equiv.)were dissolved in MeCN (17 mL) and the solution cooled to�25 8C with a dry ice/acetone bath. TBD (17.9 mg,128 mmol, 15 mol%) was added all at once, and the mixturestirred between �20 8C and �25 8C (bath temperature) forone hour. The reaction was quenched by the addition ofsolid NH4Cl (excess), the mixture warmed to room tempera-ture, filtered and the solids washed with CH2Cl2 (2� 10 mL).After evaporation of the solvents, the residue was purifiedby flash column chromatography (Si, 3.0 �20 cm, pentane/EtOAc =60/40!50/50) to give product 4a as a slightlyyellow, crystalline solid; yield: 290 mg (501 mmol, 59%, dr =95/5).

Method B: Ethyl 2,3-pentadienoate (1, 90 mg, 713 mmol)and 3,5-dimethoxybenzaldehyde (2b, 474 mg, 2.85 mmol,4.0 equiv.) were dissolved in DMF (14 mL) and the solutioncooled to �25 8C with a dry ice/acetone bath. TBD (24.8 mg,178 mmol, 25 mol%) was added all at once, and the mixturestirred between �20 8C and �25 8C (bath temperature) for4.0 h. The reaction was quenched by the addition of saturat-ed NH4Cl solution (25 mL) and the mixture warmed toroom temperature. The mixture was extracted with EtOAc(2 �30 mL) and the combined organic phases were washedwith saturated NH4Cl solution (25 mL), 5% aqueous LiCl(25 mL) and saturated NaCl solution (25 mL), dried overNa2SO4, filtered and the solvent evaporated. The residuewas purified by flash column chromatography (Si, 3.0 �20 cm, pentane/EtOAc=60/40!50/50) to give product 4b asa colorless oil; yield: 145 mg (323 mmol, 33%, dr>95/5).

Acknowledgements

We thank the Fonds der Chemischen Industrie for financialsupport (Liebig-Scholarship to P.S., PhD scholarship toA.T.) and Prof. Dr. U. Englert, Institute of Inorganic Chemis-try, RWTH Aachen University, for X-ray structure determina-tions. Special thanks go to Prof. Dr. D. Enders, Institute ofOrganic Chemistry, RWTH Aachen University, for the gener-ous provision of laboratory space and chemicals.

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Entry 2 : Ar Yield 11 [%][b]

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