Highly diastereoselective samarium diiodide induced ketyl cyclisations of indole and pyrrole derivatives - Scope and limitations

FULL PAPER

DOI: 10.1002/ejoc.200901455

Highly Diastereoselective Samarium Diiodide Induced Ketyl Cyclisations of

Indole and Pyrrole Derivatives – Scope and Limitations

Christine Beemelmanns,^[a]Virginie Blot,^[a,b]Steffen Gross,^[a,c]Dieter Lentz,^[a][‡]and

Hans-Ulrich Reissig*^[a]

Keywords: Samarium diiodide / Radical reactions / Ketyl coupling / Cyclization / Indoles / Pyrroles / Nitrogen heterocycles

Here we summarise our results for SmI₂-induced 5-exo-trig

to 8-exo-trig reductive cyclisations of suitably substituted in-

ferent proton sources SmI₂-induced cyclisations afforded

mainly one major type of diastereomer (thermodynamic con-

dole and pyrrole derivatives. All precursors were easily pre- trol), so the formation of three or four stereogenic centres is

pared by simple N-alkylation or N-acylation of indole and

pyrrole derivatives with the corresponding iodo alkanones,

acid chlorides or lactones. The SmI₂-induced cyclisations in

most cases provided tri- and tetracyclic derivatives, even in

the absence of HMPA, in good to very good yields and with

excellent diastereoselectivities. Extensive investigations of

the reaction conditions revealed that in the presence of dif-

controlled in one step. The mechanism of the SmI₂-induced

ketyl coupling is discussed in more detail on the basis of

these observations and two possible mechanistic pathways

are compared. The assumed intermediate samarium enolates

were also trapped with allyl iodide, furnishing interesting

polycyclic N-heterocycles bearing newly formed quaternary

centres as single diastereomers.

been developed for the generation of heterocycles incorpo-

rating the indole skeleton and modification its substitution

pattern, new general methods for the stereoselective con-

struction of N-heterocycles with novel substitution patterns

are still of considerable interest in synthetic organic chemis-

try.^[8]

Introduction

Since the introduction of samarium diiodide (SmI₂) as a

reagent for organic synthesis by Kagan^[1]in 1977, it has

found widespread applications in organic synthesis, pro-

moting a number of important and very useful transforma-

tions.^[2]SmI₂-mediated ketyl couplings with carbon–carbon

multiple bonds are perhaps the most useful reactions for

the creation of carbocycles and heterocycles of various ring

sizes^[3,4]and they have also successfully been exploited for

the synthesis of biologically active compounds or natural

products.^[2d]Our previously discovered intramolecular re-

ductive coupling of γ-aryl ketones^[4,5]or their nitrogen ana-

logues prepared from aniline derivatives^[6]provided func-

tionalised hexahydronaphthalene or hexahydroquinoline

derivatives, products with remarkable synthetic potential, in

moderate to good yields and with excellent diastereoselec-

tivities.^[7]In view of the importance of N-heterocycles, ind-

ole- and pyrrole-derived compounds in particular,^[8]we

subsequently turned our interest from aniline derivatives to

the cyclisations of ketones containing indole or pyrrole

moieties (Scheme 1).^[9]Although a variety of methods have

Scheme 1. SmI₂-induced cyclisations of γ-aryl ketones leading to

hexahydronaphthalene or hexahydroquinoline derivatives.

In our first experiments we had already demonstrated

that simple indole and pyrrole alkanones are promising pre-

cursors for SmI₂-induced ketyl-heteroaryl couplings, pro-

viding diastereomerically pure pyrrolizidine, benzannulated

pyrrolizidine and indolizidine derivatives in good yields.^[9]

These SmI₂-induced cyclisations hence constituted a new

method for the stereoselective conversion of easily available

indole and pyrrole derivatives into functionalised nitrogen-

containing polycyclic products. Encouraged by these results

we started a systematic investigation of these reductive

cyclisations and studied various appropriately substituted

[a] Institut für Chemie und Biochemie, Freie Universität Berlin,

Takustr. 3, 14195 Berlin, Germany

Fax: +49-30-83855367

E-mail: hans.reissig@chemie.fu-berlin.de

[b] Université de Nantes, CEISAM,

2, rue de la Houssinière BP-92208, 44322 Nantes, France

[c] BASF AG, GVA/ID-B009,

67056 Ludwigshafen, Germany

[‡] Responsible for X-ray crystal structure determination

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200900xxx.

2716

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

indole derivatives with success. Here we summarise our op-

timised and extended results for SmI₂-induced 5-exo-trig to

8-exo-trig cyclisations. We discuss the impacts of the use of

HMPA as an additive, of the proton sources and of the

temperature on the yields and diastereoselectivities. Since in

the beginning the observed relative configurations of the

obtained products were in part contradictory, we carried

out a combination of one-dimensional ¹H-NOE experi-

ments and X-ray analysis for the obtained cyclisation prod-

ucts. Gratifyingly, after revision of the relative configura-

tions of several products, the stereochemical outcomes now

appear to be highly consistent and predicable. During our

investigations Kise et al.^[10]successfully achieved electro-

chemical intramolecular reductive cyclisations of analogous

indole alkanones. Their results and calculations are also

discussed in this context.

Scheme 3. Representative syntheses of N-acylated indole precursors

from the carboxylic acids 11. TEA = triethylamine; DMAP = 4-

(dimethylamino)pyridine.

To investigate the influence of steric and electronic effects

on the cyclisations we synthesised the 2Ј-monosubstituted

and 2Ј,3Ј-disubstituted indole precursors 18, 20 and 21

(Scheme 4). The cyclisation precursor 18 was obtained in

satisfactory yield (59%) starting from the commercially

available ester 17. The disubstituted indole precursors 20

and 21 were obtained in three steps by the elegant indole

synthesis of Glorius et al.^[11]and subsequent acylation. In

order to achieve satisfactory degrees of conversion to the

desired 2Ј,3Ј-disubstituted cyclisation precursors larger ex-

cesses of levulinic acid chloride were required (2.5–

6.0 equiv.).

Results and Discussion

Synthesis of N-Alkylated and N-Acylated Indole and

Pyrrole Precursors

The syntheses of the required N-alkylated indole deriva-

tives were performed with the commercially available in-

doles 1 and 2 (Scheme 2) by treatment with sodium hydride

and subsequent addition of previously prepared acetal-pro-

tected 1-iodoalkanones of type 3.^[9c]Subsequent cleavage of

the ketals in the presence of p-toluenesulfonic acid afforded

the desired precursors 4–10 in good yields.

Scheme 4. Synthesis of precursors 18, 20 and 21 by N-acylation of

the 2-substituted and 2,3-disubstituted indole derivatives 17 and 19

with levulinic acid chloride.

Scheme 2. Representative syntheses of precursors 4–10 by alk-

ylation of indoles 1 and 2 with protected 1-iodoalkanones 3; PTSA

= p-toluenesulfonic acid.

Unfortunately, the acylation of 2-methyl- and 2-phenyl-

indole failed as a result of the very low nucleophilicities of

2-alkylated or 2-arylated indoles. Only 1-(2Ј,3Ј-dimethyl-

The related N-alkylated diethyl 3,4-pyrroledicarboxylate 1H-indol-1-yl)pentane-1,4-dione^[12]could be obtained in

precursors (Scheme 3) were obtained by an analogous pro- minor amounts (Ͻ5%).

cedure in slightly lower yields (62–79%, n = 1–4, R²= H;

The TBS-protected derivatives 23 and 24 (Scheme 5)

R³= Me).^[9c]The N-acylated indole derivatives 12 and 13 were smoothly prepared by treatment of 2 with the ε-lact-

were likewise obtained at room temperature under standard one 22^[13]by the Weinreb procedure,^[14]with AlMe₃acting

acylation conditions with acid chlorides derived from car- as base and Lewis acid, followed by standard procedures

boxylic acids 11.^[9b]Precursors 14–16, with longer or more for deprotection and protection.

hindered N-acyl side chains, were prepared at slightly

The alkyl iodide 25 was also prepared from 22 in four

higher temperature (40 °C) furnishing the desired products routine steps (ring-opening, protection, reduction and

in reasonable yields.

iodination)^[15]in good overall yield (four steps: 75%). Sub-

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2717

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

stead ascertained that in most cases diastereomers of type

II were obtained as major products, and that stereoisomers

III were only occasionally observed as minor byproducts.

Surprisingly, in one single case diastereomer IV was also

isolated, in 16% yield. Side reactions such as reduction to

the secondary alcohols V or formation of dihydroindoles

VI were observed to variable degrees depending on the sub-

strate structure and the applied reaction conditions. For N-

acylated indole precursors, SmI₂-promoted N-acyl cleavage

to afford methyl indole-3-carboxylate (2) was observed in

varying ratios.^[17]

The mechanism of the SmI₂-induced ketyl cyclisation is

assumed to follow either the first pathway as illustrated in

Scheme 7 or an alternative route shown in Scheme 8. In the

first mechanism the samarium ketyl B is formed in equilib-

rium from SmI₂and the ketone A. The ketyl radical B sub-

sequently adds to the activated aromatic system through a

six-membered chair-like transition state C. It is assumed

that for steric and electronic reasons the bulky samarium

alkoxide, presumably bearing three or four HMPA ligands,

favours an equatorial position, leaving the methyl group in

the axial position.^[18]In addition, it cannot be excluded that

previous Sm^(2+/3+)chelate formation involving the carbonyl

and the methoxycarbonyl groups significantly enhances the

rate of electron transfer to the ketone, also preorientating

the geometry of the transition state.^[19]The transition state

C depicted in Scheme 7 explains the cis configuration of

the bridgehead hydrogen and the resulting hydroxy group

in product E. Further electron transfer to the resulting radi-

cal by a second equivalent of SmI₂gives the samarium enol-

ate D. Subsequent protonation of the enolate D at either

the carbon or oxygen atom finally leads to the product E.

Scheme 5. Synthesis of the functionalised N-alkyl- and N-acylin-

dole precursors 23, 24, and 26. TBDM = tert-butyldimethyl; TBDP

= tert-butyldiphenyl; TBDMS = tert-butyldimethylsilyl.

sequent N-alkylation of 2, hydrolysis of the ketal and pro-

tection of the primary alcohol furnished the desired precur-

sor 26 in 91% yield.

Possible Mechanism and Transition States of SmI₂-Induced

Cyclisations of Indole Precursors

Investigations of SmI₂-induced reductive cyclisations of

N-alkylated and N-acylated indoles I were generally per-

formed at room temperature, if not otherwise stated, with

2.2–2.5 equiv. of SmI₂in THF and tBuOH or phenol as

proton sources and in part with HMPA as additive

(Scheme 6). HMPA strongly increases the reducing ability

of SmI₂, by ca. 0.8 V, and is required for many ketyl cou-

pling reactions.^[16]It is believed that up to four HMPA mo-

lecules are coordinated to SmI₂, enhancing the SET from

the metal to the carbonyl group. Gratifyingly, though, many

of the cyclisations investigated here proceeded even in the

absence of HMPA.

Scheme 7. Proposed mechanism and transition state for ketyl-

heteroaryl cyclisations (HMPA ligands and proton donors ROH at

the samarium are omitted for simplicity, but can certainly play an

important role in the outcome).

Under protic conditions, the configuration of the carbon

bearing the alkoxycarbonyl group is assumed ultimately to

be governed by thermodynamic control, which positions the

methoxycarbonyl group at the convex face of the molecule.

In individual cases epimerisation of diastereomers III to

Scheme 6. Product types and diastereomers isolated after SmI₂-in-

duced reactions of N-alkylated and N-acylated indole and pyrrole

derivatives.

In our previously published work we reported the forma- diastereomers II during workup and column chromatog-

tion of diastereomers III as major products of SmI₂-in- raphy has been observed. Additionally, over-reduction of

duced cyclisations of this type.^[9a]Meanwhile we have inves- ketyl radical B by a second equivalent of SmI₂would lead

tigated the cyclisation method in more detail and have in- to the undesired alcohol of type V.

2718

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

axially or pseudoequatorially.^[21]After a second electron

transfer, C–C bond formation and final protonation, the

cyclisation leads to products 29 or 30 depending on the pre-

orientation of the carbonyl group in the transition state. In

this reaction pathway, possible over-reduction of the radical

enolate G would result in the formation of the dihydro-

indole derivative VI.

The experimental results of Kise et al. strongly indicate

that both mechanisms operate during their electrochemical

cyclisations and that the described theoretical considera-

tions for precursors 4 and 6 should also be valid for the

homologous precursors leading to six- or seven-membered

rings.

During our investigations, we also observed the forma-

tion of diastereomers IV as minor products. In cases of

SmI₂-induced seven- and eight-membered ring formation,

alcohols of type V and dihydroindole derivatives of type VI

were isolated. These results similarly indicate that for the

SmI₂-induced cyclisations both reaction mechanisms are

possible. Because the main products always feature the

same configuration, we assume that the ketyl radical

mechanism is generally the more dominant pathway.

SmI₂-Induced Cyclisations of N-Alkylated Indole

Precursors

In early experiments, treatment of the N-alkylated indole

derivatives 4 and 5 with SmI₂(2.5 equiv.) in THF along

with an excess of HMPA (10.0 equiv.) and phenol

(2.0 equiv.) as proton source resulted in the formation of

the diastereomerically pure benzopyrrolizidine 27 and

benzoindolizidine 31 in good yields (Scheme 9).^[9a]In these

experiments small quantities (6%) of uncyclised secondary

alcohol were isolated, indicating that the reaction may pre-

dominantly proceed through the formation of a ketyl radi-

cal.

Scheme 8. Proposed mechanisms based on calculations and experi-

ments by Kise et al.

During our ongoing studies Kise et al.^[10a]reported the

closely related electroreductive cyclisation of the indole alk-

anones 4–7. Electroreduction of the indole derivative 4

(Scheme 8) was carried out with a Pb cathode and a divided

cell in propan-2-ol containing Et₄NBr as supporting elec-

trolyte, to afford the cyclisation product 27 in 66% yield,

together with alcohol 28 (12%). They also reported the elec-

troreduction of the indole derivative 6 (undivided cell, pro-

pan-2-ol containing Et₄NOTs), which yielded compound 29

(46%, presumably cyclisation product of type II)^[10b]and

diastereomer 30 (12%, cyclisation product of type IV), to-

gether with alcohol formation (16%).

Surprisingly, the cyclisation precursor 7 [methyl 1-(4-oxo-

pentyl)-1H-indole-3-carboxylate] gave a 30% yield of the

diastereomer of type IV. Based on their experimental re-

sults, Kise et al. performed DFT calculations, of the spin

and charge densities of the intermediate radical anions of

Scheme 9. SmI₂-induced cyclisations of N-alkylated indole deriva-

tives.^[9a]HMPA = hexamethylphosphoramide.

We next employed N-alkylated 3-methoxycarbonyl-sub-

the indole alkanones 4 and 6 as depicted in Scheme 8. Their stituted indoles such as compounds 6–9. In our preliminary

data indicate that the carbonyl carbon at C-3 of the 1-in- experiments, electron-withdrawing substituents on the

dole alkanone 4 possesses the highest spin density and a heteroaryl moiety have usually shown the expected benefi-

high negative charge. Therefore, a ketyl (intermediate F) is cial effects in SmI₂-induced cyclisations.^[22]We first exam-

probably the active species in this cyclisation. In contrast, ined the possibility of cyclobutanol formation and therefore

the 3-methoxycarbonyl-substituted indole derivative

6

prepared a precursor analogous to 6, but with just one

shows the highest spin density at 2Ј-C, so after electron methylene group as spacer unit between the indole ring and

transfer the reactive intermediate should have the character the carbonyl group. Unfortunately, but not surprisingly, the

of a radical anion G.^[20]During the transition state of the reaction failed to give the corresponding tricyclic com-

addition, the carbonyl group can be oriented either pseudo- pound incorporating a four-membered ring;^[23]only the cor-

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2719

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

Because of the electron-poor nature of the heteroaryl

FULL PAPER

responding secondary alcohol, formed by reduction of the

ketone, was isolated. We next subjected 6 to SmI₂-induced moiety, the cyclisation of compound 6 could also be per-

cyclisations under various sets of reaction conditions, with formed in the absence of HMPA with either tBuOH or

the optimised results being summarised in Scheme 10. phenol as proton source. In both cases the ¹H NMR spectra

When the reaction was carried out in the presence of of the crude products indicated a 1:1 mixture of dia-

HMPA and phenol, compound 33 was obtained as the stereomers 29 and 32. Surprisingly, after column

slightly favoured product together with the expected prod- chromatography of the crude mixtures compound 29 was

uct 29 as second major component. The formation of 33 is isolated in both cases as the major diastereomer. These fin-

the result of an addition of the ketyl to the benzene ring dings strongly indicate that epimerisation at the carbon

rather than to the apparently activated 2-position of the atom bearing the alkoxycarbonyl group is very likely to oc-

indole moiety.^[9a,9b]The rearomatised compound 33 was cur during workup and/or purification on silica gel. The

most probably formed by spontaneous oxidation during configuration seems to be governed by thermodynamic con-

aqueous workup from the corresponding dihydroindole in- trol, which ultimately places the methoxycarbonyl group at

termediate. On the other hand, when the reaction was per- the convex face of the molecule.

formed in the presence of HMPA and with tBuOH as pro-

The successful cyclisation of the N-alkylated indole de-

ton source, compound 29 was isolated as the exclusive prod- rivatives 4–6 prompted us to investigate the formation of

uct in 90% yield and as single diastereomer!

medium-sized rings under these cyclisation conditions. The

SmI₂-induced 6-exo-trig to 8-exo-trig cyclisations of precur-

sors 7–9 (Scheme 11) furnished compounds 34–36 as single

diastereomers in good to very good yields after workup and

column chromatography.^[9]

Scheme 11. Results for the SmI₂-induced 6-exo-trig to 8-exo-trig

cyclisations of N-alkylated indole derivatives 7–9 with either

tBuOH or phenol as proton source.

Scheme 10. Results for the SmI₂-induced cyclisations of the N-

alkylated indole derivative 6, furnishing the tricyclic compounds

29, 32 and 33, under different sets of reaction conditions.

1

In every case the H NMR spectrum of the unpurified

product indicated the formation of only one major dia-

stereomer, assumed to be the thermodynamically favoured

These experiments demonstrate that the addition of product as depicted. Regioisomeric products of type 33

phenol, the more acidic proton source, seems to have a sig- were apparently not generated. Compound 7 was also suc-

nificant influence on the reactivities of the radical interme- cessfully subjected to HMPA-free cyclisation conditions

diates, favouring addition of a ketyl radical to the benzene with tBuOH or phenol as proton sources, again giving 34

moiety. In contrast, the combination of tBuOH and HMPA as the major product. The experiments illustrated in

seems to be less reactive but more selective with regard to Scheme 11 indicate that cyclisations to six-, seven- and

the desired 5-exo-trig cyclisation. Kinetic studies carried eight-membered rings are less sensitive with respect to the

out by Flowers^[16f]and Hoz^[24c,24d]have shown that proton added proton source. Because the initial assignments of the

sources such as TFE (trifluoroethanol) and phenol play an configurations for compounds 29 and 34^[9a,9b]were in con-

active role in the reaction mechanism, presumably due to tradiction with those established for compounds 35 and

coordination of the proton source or the corresponding alk- 36,^[9c]we investigated the relative configurations of all com-

oxide to the oxophilic Sm^IIor Sm^IIIspecies. Flowers et al., pounds in more detail. Differential NOE experiments with

for example, were able to demonstrate that phenol can have all products (irradiation of benzylic proton or methyl group

a rate order of 1 in SmI₂-mediated reductions of alkyl ha- gave NOE enhancements of around 3–5% between those

lides, whereas the less acidic tBuOH showed a reaction or- two proton signals) and reinterpretation of previously per-

der of 0.^[16f]Therefore, different modes of action in the elec- formed NOESY experiments^[25]clearly showed that in all

tron transfer mechanism and different radical intermediates cases the relative configurations of tricyclic compounds 29,

have to be considered.

32 and 34–36 were actually those depicted in Schemes 10

2720

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

and 11. A reversible protonation of the fairly acidic proton

adjacent to the methoxycarbonyl group and the benzene

ring provides the thermodynamically more stable dia-

stereomer, which is generally formed highly preferentially.

SmI₂-Induced Cyclisations of N-Acylated Indole Derivatives

Similarly to the N-alkylated precursors, the N-acylated

substrates 37 and 39^[26]furnished the desired tricyclic com-

pounds 38 and 40 (Scheme 12). Whereas the methyl ketone

37 smoothly cyclised to 38, the corresponding aldehyde 39

provided compound 40 only in low yield. Aldehydes are

generally less reliable starting materials for ketyl cyclisa-

tions and usually do not provide the expected products in

intramolecular ketyl aryl couplings.^[27]It is therefore re-

markable that at least moderate quantities of 39 underwent

the reductive cyclisation to 40. During our studies we ob-

served that indole derivatives bearing additional electron-

withdrawing groups strongly facilitate the cyclisations, be-

cause the aromatic system becomes considerably more elec-

tron-deficient. Consistently with this, the N-acylated indole

derivative 12 also underwent the SmI₂-induced cyclisation

in the absence of HMPA as additive (Scheme 13).^[9a,9b]With

tBuOH as proton source the tricyclic product 41 was

formed with essentially perfect diastereoselectivity and in

excellent yield. The relative configuration, as depicted in

Scheme 13, is consistent with compounds 29 and 34–36 and

was confirmed by NOE experiments (NOE enhancement

between 9-CH₃and 10-H ca. 4%). After a change from

tBuOH to phenol as proton source, compound 41 was ob-

tained in slightly decreased but still very good yield; the

γ-lactone 43 and traces of deacylation product were also

formed.^[24]Surprisingly, when no proton source was pres-

ent, the major product 41 was isolated in 55% yield to-

gether with its stereoisomer 42^[28]and γ-lactone 43 (16 and

13% yield, respectively).

Scheme 13. Results for SmI₂-induced cyclisations of the N-acylated

indole precursor 12.

bonyl group must be significantly more favoured than in

the presence of a proton source. The structure of 42 was

unequivocally corroborated by X-ray crystal structure

analysis and NOE experiments (Figure 1).

Figure 1. Molecule structure (ORTEP)^[29]of compound 42. Ther-

mal ellipsoids at 50% probability.

Analogously to the preparation of the N-alkylated com-

pounds 35 and 36 we also envisaged the synthesis of seven-

and eight-membered ring systems starting from N-acyl in-

dole derivatives. Unfortunately, for the N-acylated deriva-

tives 13 and 14, deacylation, dihydroindole formation (com-

pound 48) and reduction to the secondary alcohol (com-

pound 49) became increasingly predominant because the

Scheme 12. SmI₂-induced cyclisations of N-acylated indole deriva-

tives.^[9a]

The formation of the γ-lactone 43 can be explained in desired cyclisation is apparently considerably slower (than

terms of intramolecular attack of the samarium alkoxide on in the case of precursor 12). In order to obtain reasonable

the nearby methoxycarbonyl group. In the case of dia- yields of the desired products 44–47, the reaction conditions

stereomer 41 the given configuration prevents γ-lactone for- therefore had to be optimised for each precursor

mation because of the resulting high ring strain. The forma- (Scheme 14).

tion of stereoisomer 42 may be explained by consideration

For precursor 13 the best results were obtained in the

of the second cyclisation mechanism as depicted in presence of HMPA at 0 °C with tBuOH as proton source

Scheme 8. An analogous radical intermediate H, in which (62% yield). Without HMPA the 7-exo-trig cyclisations

the carbonyl group can be either axially or equatorially ori- proceeded only in low yields (Ͻ20%). Fortunately, for com-

entated in the transition state, is proposed. Under the pound 46 an X-ray crystal structure confirming the as-

shown aprotic conditions, an axial orientation of the car- sumed relative configuration could be obtained (Figure 2).

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2721

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

SmI₂-Induced Cyclisations of Precursors Containing

Cycloalkanone Moieties

SmI₂-induced ketyl couplings with precursors containing

cycloalkanone moieties were also examined. The N-alkyl-

ated indole derivative 10 (Scheme 15) efficiently afforded

the anticipated tetracyclic product 50 in 75% yield and with

very good diastereoselectivity (dr 94:6). In one step four

contiguous stereogenic centres were generated in a highly

selective manner. The structural assignment for the major

diastereomer as depicted in Scheme 15 is based on NOE

experiments and analogous to those found in our earlier

ketyl cyclisation experiments with other cyclohexanone de-

rivatives.^[30]

Scheme 14. Optimised results for the SmI₂-induced 7-exo-trig and

8-exo-trig cyclisations of N-acylated indole derivatives 13 and 14.

Scheme 15. SmI₂-induced 7-exo-trig cyclisation with the indole pre-

cursor 10 to afford the tetracyclic compound 50.

As depicted in Scheme 14, minor amounts of the tetracylic

γ-lactone 45 were isolated as well. The 8-exo-trig cyclisation

furnished the derivatives 46 and 47 in a combined yield of

ca. 50%. The ratio between ester and γ-lactone was slightly

dependent on the added proton source. In general, the more

acidic phenol afforded the ester in higher yields than

tBuOH, but also enhanced the formation of uncyclised re-

duced products such as 48 (up to 10%) and 49 (up to

15%).^[24]Similar dihydroindole formation in intermolecular

additions of samarium ketyls to indoles has been observed

in our group.^[9d]The γ-lactone formation can be explained

as previously and is facilitated by the increased proximity

of the intermediate samarium alkoxide and the methoxycar-

bonyl group. The relative configurations in all substrates

were confirmed by NOE experiments.

Inspired by this promising result, we performed analo-

gous reactions with the N-acylated precursors 15 and 16

(Scheme 16). As expected, the 6-exo-trig cyclisations pro-

ceeded smoothly in a highly diastereoselective fashion,

yielding the tetracyclic product 51 in very good yields and

as single diastereomers. The configuration of compound 51

was unequivocally corroborated by an X-ray crystal struc-

ture (Figure 3) and is analogous to those of compounds 50

and 52.

Scheme 16. SmI₂-induced ketyl couplings of the cyclohexanone and

cyclopentanone derivatives 15 and 16 leading to the tetracyclic

products 51 and 52.

In contrast, SmI₂-induced formation of the correspond-

ing seven-membered ring systems generally proceeded in

poor yields. Several sets of reaction conditions were investi-

gated for the cyclisation of 16 to compound 52, such as

higher temperatures and different proton sources, but in all

cases the irreversible deacylation reaction described above,

the reduction of the indole double bond and the reduction

of the carbonyl group to the secondary alcohol appeared to

be faster than the desired cyclisation.^[31]This disappointing

result has to be compared with the high efficacy of the for-

mation of product 50. The N-acyl moiety of 16 is certainly

Figure 2. Molecule structure (ORTEP)^[29]of compound 46. Ther-

mal ellipsoids at 50% probability.

2722

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

As well as 3Ј-substituted derivatives, the 2Ј-substituted

and 2Ј,3Ј-disubstituted indole precursors 18 and 20

(Scheme 18) were also subjected to the SmI₂-induced cycli-

sation conditions. We initially anticipated that deacylation

would be the dominant reaction, due to the sterically more

demanding substrates. Surprisingly, the ethyl ester 18 could

be converted into the cyclisation product 56 in 92% yield

and as single diastereomer without any need for addition

of HMPA! On addition of HMPA considerable amounts of

by-products were observed. The high efficacy of the cycli-

sation seems to be inconsistent with the polarity of the acti-

vated indole double bond, but may be explained in terms

of a chelate-controlled cyclisation. As is indicated by the

radical intermediates I and J, the samarium cation can be

coordinated both to the radical anion and to the oxygen of

the ester moiety, forming a highly ordered transition state

presumably favouring the diastereoselective cyclisation.

Disruption of this fixed geometry by, for example, HMPA

ligands can lead to more side reactions. The relative config-

uration of 56 was again confirmed by X-ray crystal struc-

ture analysis (Figure 5) and NOE experiments.

Figure 3. Molecule structure (ORTEP)^[29]of compound 51. Ther-

mal ellipsoids at 50% probability.

responsible for the faster reduction of the activated indole

double bond, but it may also cause higher rigidity of the

spacer unit and hence decrease the rate of the cyclisation

step to 52 in relation to competing side reactions.

To explore the scope and limitations of SmI₂-induced

cyclisations further, the chain-elongated and functionalised

substrates 23, 24 and 26 (Scheme 17) were subjected to the

standard cyclisation procedure. The best results were ob-

tained with tBuOH in the absence of HMPA, furnishing the

expected products 53, 54, and 55 in excellent yields. Almost

no purification was necessary because the products were

not contaminated with deacylation products or HMPA. A

change in the protective group had no influence on the out-

come of the transformation. The relative configuration of

compound 53 was again unequivocally corroborated by an

X-ray crystal structure (Figure 4).

Scheme 17. SmI₂-induced ketyl coupling of functionalised precur-

sors 22, 23 and 25.

Scheme 18. SmI₂-induced 6-exo-trig cyclisations of the 2Ј- and

2Ј,3Ј-substituted N-acylated indole derivatives 18 and 20.

On the other hand, the 2Ј,3Ј-disubstituted compound 20

furnished only a 29% yield of the expected highly substi-

tuted indole derivative 57. The relative configuration of

cyclisation product 57 was determined from distinct NOE

signals between 10-H and 9-CH₃(NOE: ca. 5–7%). In the

presence of HMPA the product 58 (up to 30%) and deacyl-

ation (ca. 50%) were observed. Compound 58 was appar-

ently formed by SmI₂-induced reductive C–C bond cleav-

age, as occasionally observed for 1,4-dicarbonyl com-

pounds.^[32]

Experiments with compound 21 (Scheme 4) and 1-(2,2Ј-

dimethyl-1H-indol-1-yl)pentane-1,4-dione have so far

failed. The phenyl substituent seems to be too bulky (free

rotation around C–C bond, radical intermediate K) for a

Figure 4. Molecule structure (ORTEP)^[29]of compound 53. Ther-

mal ellipsoids at 50% probability.

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2723

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

Scheme 19. Results for SmI₂-induced 5-exo-trig to 8-exo-trig cyclis-

ations of N-alkylated pyrrole derivatives with either tBuOH or phe-

nol as proton source.

Figure 5. Molecule structure (ORTEP)^[29]of compound 56. Ther-

mal ellipsoids at 50% probability.

64 in 87% yield. Unfortunately, the conversion of 65 into

66, which would have provided an eight-membered ring,

was not possible. Only traces of the expected product 66

were detected in the NMR spectra of the crude product

together with small amounts of starting material and un-

identified compounds.

SmI₂-mediated 6-exo-trig cyclisation, whereas the methyl

group of compound 20 is small enough to allow at least

partial cyclisation. With 1-(2,2Ј-dimethyl-1H-indol-1-yl)-

pentane-1,4-dione, complete decomposition of the starting

material was observed.

These results furthermore indicated that the choice of the

proton source and the addition of HMPA had a significant

impact on the cyclisation outcome. So far, however, no ge-

neral rule for the combination of the two has become clear.

Revision of the relative configurations of derivatives 60 and

62 was based on NOE experiments. Derivative 62, for in-

stance, shows distinct NOE enhancements between the pro-

ton at C-1 and the methyl group at C-8 (NOE ca. 5%) and

between the bridgehead proton 8a-H and the OH group

(NOE ca. 3%). Because the configurations of compounds

60 and 62^[9a,9b]were initially contradictory with that of

64,^[9c]we were now able to demonstrate conclusively that

the relative configurations of pyrrole and indole derivatives

are highly consistent. In order to study the selectivities and

reactivities of pyrrole derivatives in more detail, we tried to

prepare the analogous monosubstituted pyrrole derivatives,

but because of their high instabilities the required N-alkyl-

ated cyclisation precursors could not be obtained.^[9b]

SmI₂-Induced Cyclisations of N-Alkylated Pyrrole

Derivatives

In view of the importance of pyrrolizidine alkaloids^[8l–8p]

we also investigated SmI₂-induced cyclisations of N-alkyl-

ated pyrroles.^[33]Like the indole derivatives, the pyrrole pre-

cursors 59, 61 and 63 furnished the bicyclic products 60, 62

and 64 in good to very good yields (Scheme 19). The pyr-

role derivative 59 was successfully cyclised in the absence of

HMPA (full conversion according to the NMR spectra of

the crude product), but unfortunately the diastereomeric ra-

tio of the products was only ca. 4:1:1 in favour of the shown

product 60 (Scheme 19). With phenol as proton source an

increase in the reaction rate (faster disappearance of the

blue colour of the solution) was observed, but significant

amounts of starting material were isolated (10–20%). Un-

fortunately, we were not able to isolate the minor dia-

stereomers by HPLC and hence no further assignments of

the relative configurations of the byproducts could be

done.^[34]

SmI₂-Induced Cyclisations with Subsequent Alkylation of

the Intermediate Samarium Enolates

The pyrrole precursor 61 provided higher yields (85%)

in the SmI₂-mediated cyclisation but the diastereoselectivity

dropped in the absence of HMPA to almost 1:1. The second

The assumed intermediate samarium enolates (interme-

diastereomer is assumed to be the C-1 epimer, but no X- diate D, Scheme 7) from indole precursors 12, 23 and 26

ray crystal structure has so far been obtained and the NOE (Scheme 20) could be stereoselectively trapped with reactive

experiments afforded no distinct NOE enhancements be- electrophiles such as allyl iodide. As a result of steric shield-

tween the adjacent protons. In the presence of HMPA and ing of the concave face of the intermediate by the adjacent

tBuOH the cyclisation furnished product 62 in similar yield ring the attack occurs exclusively (Ͼ95:5) from the less hin-

but now as single diastereomer. Analogously with the in- dered side, leading to the functionalised derivatives 67, 68

dole derivative 12, the milder combination of HMPA and and 69 as single diastereomers (kinetic products). Only pu-

tBuOH seems to be very efficient for the 6-exo-trig cycli- rification by HPLC revealed traces (Ͻ5%) of the proton-

sation. For seven-membered ring formation, phenol and ated products 40, 53 and 55. The relative configurations of

HMPA were the additives of choice, affording compound 67–69 were determined by NOE experiments.^[35]Trapping

2724

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

experiments with other electrophiles and their synthetic po- urations could be corrected on the basis of NOE experi-

tential in the synthesis of interesting indole-containing ments and X-ray crystal structures. Analysis of the byprod-

heterocycles will be reported in due course.

ucts obtained from the cyclisation reactions indicates that

two possible reaction pathways might operate. On the one

hand, the formation of ketyl radicals is very likely (interme-

diates B and F) and, on the other hand, the enolate-stabi-

lised indole radical (intermediate G) can not be ruled out

as an intermediate for the cyclisation. We assume that under

the investigated conditions the reaction proceeds mainly via

the ketyl radical, because in all the cyclisations only one

diastereomer (type II) was isolated as the predominant

product.

Subsequent trapping experiments of the intermediate sa-

marium enolates with allyl iodide, leading to new highly

functionalised indole derivatives, were also performed. The

investigation of other suitable electrophiles and their appli-

cation in the synthesis of synthetically interesting building

blocks is currently under investigation and will be reported

in due course.

Scheme 20. Trapping experiments of samarium enolates derived

from indole derivatives 12, 23 and 26 with allyl iodide.

Experimental Section

General Methods: Reactions were generally performed under argon

in flame-dried flasks. Solvents and reagents were added by syringe.

Solvents were dried by standard procedures. Tetrahydrofuran

(THF) was either freshly distilled from sodium/benzophenone un-

der argon or transferred from a MB SPS-800-dry solvent system

Conclusions

We have demonstrated that di-, tri- and tetracyclic indole

and pyrrole derivatives can be synthesised in a highly dia-

stereoselective fashion through SmI₂-induced cyclisations of

suitably substituted precursors. For the reductive coupling

of compounds 6, 12, 18, 23, 24 and 26 no addition of

HMPA was required to achieve high conversion and excel-

lent diastereoselectivities. However, the addition of HMPA

was necessary to facilitate both the unfavoured 7-exo-trig

and 8-exo-trig cyclisation and to enhance the diastereoselec-

tivity in the cyclisations of the pyrrole derivatives 59, 61

and 63. In addition, trapping experiments with allyl iodide

gave higher yields in the presence of HMPA, probably due

to increased ion pair dissociation and consequently higher

reactivity of the samarium enolates. Investigation of the in-

fluence of the proton source revealed that for five- and six-

membered ring formation tBuOH gave the best results with

respect to yields and diastereoselectivities. Use of phenol as

an additive influenced the transformations in several ways:

firstly, increases in the reaction rates were observed, and

secondly, the protonation process was changed, resulting in

higher byproduct formation and lower diastereoselectivity.

Nevertheless, for the generation of seven- and eight-mem-

bered rings from N-acylated indole and pyrrole precursors

phenol was often the proton source of choice. In general,

fine-tuning of the reaction conditions was essential to

achieve reasonable yields of the desired cyclisation products

and to suppress side reactions such as deacylation or

alcohol and dihydroindole formation. We wish to highlight

the fact that under the optimised reaction conditions three

or four stereogenic centres can be controlled in one step,

giving indoles and pyrroles in cis-cis configurations with re-

spect to the hydroxy group, the bridgehead proton and the

methoxycarbonyl function (thermodynamically more stable

directly into

a flame-dried flask. Hexamethylphosphoramide

(HMPA) was distilled from calcium hydride (130 °C, 12 mbar) and

stored over molecular sieves (4 Å) under argon. SmI₂was either

freshly prepared in THF (see general procedure) or taken from a

previously prepared stock solution (0.1  in THF). Other reagents

were purchased and used as received without further purification

unless otherwise stated. Products were purified by flash chromatog-

raphy on silica gel (230–400 mesh, Merck or Fluka) or HPLC (Nu-

cleosil 50–5). Unless otherwise stated, yields refer to analytically

pure samples. NMR spectra were recorded with Bruker (AC 250,

WH 270, AC 500) and JOEL (ECX 400, Eclipse 500) instruments.

Chemical shifts are reported relative to TMS (¹H: δ = 0.00 ppm)

and CDCl₃(¹³C: δ = 77.0 ppm). Integrals are in accordance with

assignments and coupling constants are given in Hz. All ¹³C NMR

spectra are proton-decoupled. For detailed peak assignments 2D

spectra were measured (COSY, HMQC, HMBC, NOESY and

NOE if necessary). IR spectra were measured with a Nicolet 5 SXC

FT-IR spectrometer or with a Nexus FT-IR spectrometer fitted

with a Nicolet Smart DuraSample IR ATR. MS and HRMS analy-

ses were performed with Finnigan MAT 711 (EI, 80 eV, 8 kV),

MAT CH7A (EI, 80 eV, 3 kV) and Varian Ionspec QFT-7 (ESI-FT

ICRMS) instruments. Elemental analyses were carried out with a

CHN-Analyzer 2400 (Perkin–Elmer), a Vario EL or a Vario EL III.

Melting points were measured with a Reichert apparatus (Thermo-

var) and are uncorrected.

X-ray Crystallography: Single crystals for the X-ray diffraction ex-

periment were selected with the aid of a microscope and mounted

on the top of a glass fibre. Data were collected with a Bruker-AXS

SMART CCD diffractometer and Mo-K_αradiation (λ = 0.71073 Å,

graphite monochromator) at 133 K. The structures were solved by

direct methods and refined anisotropically (C, N, O) by least-

squares methods, with the hydrogen atoms being included on calcu-

lated positions (riding model) with the aid of the program SHELX-

compounds). The previously reported contradictory config- 97.^[36]

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2725

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

CCDC-757323 (for 46), -757324 (for 42), -757325 (for 51), -757326 (ATR): ν = 3110–3050 (ArH), 2980–2920 (CH), 1710 (C=O), 1530

˜

(for 53) and -757327 (for 56) contain the supplementary crystallo-

graphic data for this paper. These data can be obtained free of

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

(C=C) cm^–1. C₁₆H₁₇NO₄(287.3): calcd. C 66.89, H 5.96, N 4.88;

found C 66.67, H 5.88, N 4.91.

Ethyl 2-Methyl-1-(4-oxopentanoyl)-1H-indole-3-carboxylate (20):

As described in GP1, indole 19 (R = Me, 2.03 g, 10.0 mmol) was

dissolved in CH₂Cl₂(30 mL) and DMAP (122 mg, 1.00 mmol) and

Et₃N (2.5 mL, 17.9 mmol) were added. The mixture was cooled to

Representative Experimental Procedures: (Warning: HMPA has been

identified as a carcinogenic reagent. Appropriate glove protection is

required during handling. Reactions and chromatography should be 0 °C and previously prepared levulinic acid chloride (3.46 g,

performed in a well-vented hood).

25.9 mmol) was added to the reaction mixture, which was stirred

at room temperature for 2 d and worked up as stated above. The

mixture afforded 20 (1.20 g, 40%) as a yellow oil after purification

by column chromatography on silica gel (hexane/EtOAc 5:1 to 1:1).

¹H NMR (400 MHz, CDCl₃): δ = 1.46 (t, J = 7.1 Hz, 3 H,

CH₂CH₃), 2.27 (s, 3 H, 5-H), 2.96 (s, 3 H, 2Ј-CH₃), 3.04 (t, J =

6.1 Hz, 2 H, 2-H), 3.26 (t, J = 6.1 Hz, 2 H, 3-H), 4.43 (q, J =

7.1 Hz, 2 H, CH₂CH₃), 7.26–7.33 (m, 2 H, Ar), 7.80–7.86 (m, 1 H,

Ar), 8.13 (m, 1 H, Ar) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

14.4, 15.0 (2ϫq, CH₂CH₃, C-5), 29.7 (q, 2Ј-CH₃), 33.7, 38.4, 60.2

(3ϫt, C-2, C-3, CH₂CH₃), 111.0 (s, Ar), 114.0, 121.7, 123.7, 124.2

(4ϫd, Ar), 127.5, 134.9, 145.0, 165.3, 173.5, 206.2 (6ϫs, 3 ϫAr,

General Procedure for Acylation Reactions (GP1): SOCl₂

(1.5 equiv.) was added dropwise to the corresponding carboxylic

acid (1.3 equiv.). The resulting solution was stirred for 2 h with

exclusion of water. Excess SOCl₂was evaporated under reduced

pressure. The obtained carboxylic acid chloride was dissolved in

CH₂Cl₂(1 mL per mmol acid chloride) and added to a mixture

of the corresponding indole or pyrrole derivative (0.8–1.0 equiv.),

DMAP (0.05–0.10 equiv.) and Et₃N (1.1–1.3 equiv.) in CH₂Cl₂

(5 mL per mmol indole/pyrrole). The resulting mixture was stirred

overnight at the indicated temperature, quenched with sat. aq.

NH₄Cl solution and washed several times with water and brine.

The organic phase was dried with MgSO₄and filtered, and the

solvent was evaporated under reduced pressure. The obtained resi-

due was purified by column chromatography on silica gel (hexane/

EtOAc).

CO Et, C-1, C-4) ppm. IR (ATR): ν = 3085–3050 (ArH), 2980–

˜

2

2855 (CH), 1770, 1700 (C=O), 1560 (C=C) cm^–1. HRMS (ESI-

TOF): calcd. for C₂₄H₃₅NO₄: 324.1206 [M + Na]⁺; found 324.1204

[M + Na]⁺.

General Procedure for Preparation of SmI₂(GP2): Samarium (2.7–

2.9 equiv.) and 1,2-diiodoethane (2.5–2.7 equiv.) were suspended in

freshly distilled anhydrous THF (10 mL per mmol of Sm) under

argon and the solution was stirred at room temperature until its

colour had turned dark blue. The flask was then gently evacuated

to remove ethene and again purged with argon. Alternatively, SmI₂

was taken from a previously prepared stock solution (0.1  in

THF), synthesised by the following procedure: iodine (15.0 mmol,

1.0 equiv.) and samarium (18.0 mmol, 1.2 equiv.) were suspended

in THF (150 mL, 10 mL per 1.0 mmol I₂) under argon and the

solution was stirred at room temperature until its colour had

turned dark blue (1–5 h). The flask was then wrapped in aluminium

foil to exclude light and stored at room temperature.

Methyl 1-(6-Oxoheptanoyl)-1H-indole-3-carboxylate (14): As de-

scribed in GP1, indole 2 (1.75 g, 10.0 mmol) was dissolved in

CH₂Cl₂(50 mL) and DMAP (70 mg, 0.57 mmol) and Et₃N

(2.5 mL, 17.9 mmol) were added. The previously prepared 6-

oxoheptanoic acid chloride (1.80 g, 12.7 mmol) was dissolved in

CH₂Cl₂(10 mL) and added to the reaction mixture, which was then

stirred at 40 °C overnight and worked up as stated above. The mix-

ture afforded 14 (1.89 g, 63%) as a yellow solid after purification

by column chromatography on silica gel (hexane/EtOAc 4:1 to 1:1);

1

m.p. 116–118 °C. H NMR (400 MHz, CDCl₃): δ = 1.73 (quint, J

= 7.1 Hz, 2 H, 4-H), 1.85 (quint, J = 7.1 Hz, 2 H, 3-H), 2.54 (t, J

= 7.1 Hz, 2 H, 5-H), 2.99 (t, J = 7.1 Hz, 2 H, 2-H), 3.95 (s, 3 H,

OCH₃), 7.35–7.40 (m, 2 H, Ar), 8.14–8.16 (m, 2 H, Ar), 8.41 (m,

1 H, Ar) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.9, 23.7 (2ϫt,

C-3, C-4), 29.9 (q, C-7), 35.4, 43.1 (2ϫt, C-2, C-5), 51.5 (q, OCH₃),

113.6 (s, Ar), 116.4, 121.4, 124.7, 125.8 (4ϫd, Ar), 127.1 (s, Ar),

General Procedure for SmI₂-Induced Cyclisations with a Proton

Source (GP3): The indole derivative (1.0 equiv.) and the proton

source (1.0–10.0 equiv.) were dissolved in THF (16 mL per mmol

130.4 (d, Ar), 135.9, 164.3, 171.1, 208.2 (4ϫs, Ar, CO₂Me, C-1, C- indole/pyrrole) and argon was bubbled through the solution for 10–

6) ppm. IR (ATR): ν = 3125–2990 (ArH), 2945–2865 (CH), 1705– 20 min. The resulting solution was added in one portion to a solu-

1675 (C=O), 1550 (C=C) cm^–1. C₁₇H₁₉NO₄(301.1): calcd. C 67.76, tion of SmI₂(2.4 equiv.) in THF (with or without HMPA), which

˜

H 6.36, N 4.65; found C 67.71, H 6.54, N 4.65.

was stirred at the indicated temperature (0–40 °C). After 30–60 min

the reaction was quenched with sat. aq. NaHCO₃solution, the or-

ganic phase was separated, and the aqueous phase was extracted

three times with diethyl ether. The combined ether extracts were

washed with brine, dried with MgSO₄and filtered, and the solvents

were evaporated. The obtained residue was purified by column

chromatography on silica gel (hexane/EtOAc).

Ethyl 1-(4-Oxopentanoyl)-1H-indole-2-carboxylate (18): As de-

scribed in GP1, indole 17 (1.89 g, 10.0 mmol) was dissolved in

CH₂Cl₂(30 mL) and DMAP (122 mg, 1.00 mmol) and Et₃N

(2.5 mL, 17.9 mmol) were added. The mixture was cooled to 0 °C

and previously prepared levulinic acid chloride (3.46 g, 25.9 mmol)

was added to the reaction mixture, which was stirred at room tem-

perature for 2 d and worked up as stated above. The mixture af-

forded 18 (1.66 g, 59%) as a yellow oil after purification by column

chromatography on silica gel (hexane/EtOAc 5:1 to 3:1). ¹H NMR

Methyl (1S*,9aR*,9S*)-1-Hydroxy-1-methyl-2,3,9,9a-tetrahydro-

1H-pyrrolo[1,2-a]indole-9-carboxylate (29): As described in GP2

and GP3, samarium (249 mg, 1.65 mmol), 1,2-diiodoethane

(500 MHz, CDCl₃): δ = 1.39 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 2.20 (432 mg, 1.53 mmol), HMPA (1.1 mL, 6.1 mmol), indole

6

(s, 3 H, 5-H), 2.96 (t, J = 6.5 Hz, 3 H, 3-H), 3.14 (t, J = 6.5 Hz, 2 (150 mg, 0.61 mmol) and phenol (115 mg, 1.22 mmol) afforded 29

H, 2-H), 4.37 (q, J = 7.1 Hz, 2 H, CH₂CH₃), 7.22–7.29 (m, 1 H, (57 mg, 38%) and 32 (9 mg, 6%), both as colourless oils, and 33

Ar), 7.32 (s, 1 H, Ar), 7.41 (ddd, J = 1.3, 7.2, 8.5 Hz, 1 H, Ar),

7.61 (d, J = 7.9 Hz, 1 H, Ar), 8.03 (dd, J = 0.7, 8.5 Hz, 1 H,

(69 mg, 46%) as a colourless solid after purification by column

chromatography on silica gel (hexane/EtOAc 95:5 to 2:1). Alterna-

Ar) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (q, CH₂CH₃), tive: SmI₂in THF (12.0 mL, 1.20 mmol), HMPA (1.0 mL,

29.7 (q, C-5), 33.3, 38.7 (2ϫt, C-2, C-3), 61.6 (t, CH₂CH₃), 115.0,

118.1, 122.3, 123.6 (4ϫd, Ar), 127.1 (s, Ar), 127.8 (d, Ar), 129.4,

138.4, 161.8, 173.5, 206.3 (5ϫs, 2 ϫAr, CO₂Et, C-1, C-4) ppm. IR

5.60 mmol), indole 6 (120 mg, 0.49 mmol) and tBuOH (500 mg,

6.75 mmol) afforded 29 (110 mg, 90%) as a colourless oil after pu-

rification by column chromatography on silica gel (hexane/EtOAc

2726

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

95:5 to 2:1). ¹H NMR (500 MHz, CDCl₃): δ = 1.06 (s, 3 H, 1-CH₃),

1.88 (ddd, J = 3.6, 7.3, 12.5 Hz, 1 H, 2-H), 2.16 (td, J = 8.2,

7.13 (dt, J ≈ 1.0, 7.7 Hz, 1 H, 3-H), 7.22–7.24 (m, 1 H, 1-H) ppm.

¹³C NMR (126 MHz, CDCl₃): δ = 20.9 (q, 9-CH₃), 23.3, 40.7, 45.0

12.5 Hz, 1 H, 2-H), 2.53 (brs, 1 H, OH), 3.06 (ddd, J = 7.3, 8.2, (3ϫt, C-7, C-8, C-6), 47.3 (d, C-10), 52.6 (q, OCH₃), 70.4 (s, C-9),

10.4 Hz, 1 H, 3-H), 3.66 (ddd, J = 3.6, 8.2, 10.4 Hz, 1 H, 3-H),

3.74 (s, 3 H, OCH₃), 4.19 (d, J = 3.7 Hz, 1 H, 9-H), 4.29 (d, J =

3.7 Hz, 1 H, 9a-H), 6.57 (dd, J = 0.5, 7.9 Hz, 1 H, 5-H), 6.76 (dt,

J ≈ 1.0, 7.5 Hz, 1 H, 7-H), 7.14 (ddd, J = 0.5, 7.5, 7.9 Hz, 1 H, 6-

H), 7.23 (d, J = 7.5 Hz, 1 H, 8-H) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 21.8 (q, 1-CH₃), 41.0 (t, C-2), 47.8 (d, C-9), 50.1 (t,

C-3), 52.6 (q, OCH₃), 75.6 (d, C-9a), 76.8 (s, C-1), 110.3, 119.5,

125.0 (3ϫd, C-5, C-7, C-8), 127.0 (s, Ar), 129.2 (d, C-6), 153.8,

75.2 (d, C-9a), 107.0, 118.3, 124.6 (3ϫd, C-4, C-2, C-1), 125.2 (s,

C-10a), 128.6 (d, C-3), 150.7, 173.5 (2ϫs, C-4a, CO₂Me) ppm. IR

(ATR): ν = 3430 (OH), 3050 (ArH), 2950–2700 (CH), 1740 (C=O),

˜

1605 (C=C) cm^–1. MS (EI, 80 eV, 40 °C): m/z (%) = 261 (53) [M]⁺,

222 (21), 190 (100) [M – C₄H₇O]⁺. HRMS (EI, 80 eV, 40 °C): calcd.

for C₁₅H₁₉NO₃: 261.13649; found 261.13821. C₁₅H₁₉NO₃(261.3):

calcd. C 68.90, H 7.33, N 5.36; found C 68.56, H 7.14, N 5.17.

Methyl (9S*,9aR*,10R*)-9-Hydroxy-9-methyl-6-oxo-6,7,8,9,9a,10-

hexahydropyrido[1,2-a]indole-10-carboxylate (41): As described in

GP2 and GP3, samarium (150 mg, 1.00 mmol), 1,2-diiodoethane

(258 mg, 0.92 mmol), indole 12 (100 mg, 0.37 mmol) and phenol

(69 mg, 0.73 mmol) afforded 41 (95 mg, 93%) as a colourless solid

and 43 (5 mg, 5%) after purification by column chromatography

on silica gel (hexane/EtOAc 3:1 to 1:1). Alternative: SmI₂in THF

(50 mL, 5.00 mmol), indole 12 (550 mg, 2.01 mmol) and tBuOH

(1.25 g, 16.9 mmol) afforded 41 (538 mg, 97%) as a colourless solid

after purification by column chromatography on silica gel (hexane/

EtOAc 3:1 to 1:1). Alternative: SmI₂(12.0 mL, 1.20 mmol), HMPA

(0.90 g, 5.02 mmol) and indole 12 (140 mg, 0.51 mmol) afforded 41

(77 mg, 55%), 42 (22 mg, 16%) and 43 (16 mg, 13%) as colourless

solids after purification by column chromatography on silica gel

(hexane/EtOAc 5:1 to 1:1); m.p. 58–61 °C. ¹H NMR (500 MHz,

173.2 (2ϫs, Ar, CO Me) ppm. IR (ATR): ν = 3410 (OH), 3070–

˜

2

3000 (ArH), 2970–2875 (CH), 1740 (C=O), 1600 (C=C) cm^–1. MS

(EI, 80 eV, 70 °C): m/z (%) = 247 (35) [M]⁺, 189 (23) [M –

C₃H₆O]⁺, 130 (100), 84 (93) [M – C₄H₇O]⁺. HRMS (EI, 80 eV,

70 °C): calcd. for C₁₄H₁₇NO₃: 247.12084; found 247.12324.

C₁₄H₁₇NO₃(247.3): calcd. C 67.99, H 6.93, N 5.66; found C 67.24,

H 6.73, N 5.23.

Methyl (1S*,9S*,9aR*)-1-Hydroxy-1-methyl-2,3,9,9a-tetrahydro-

1H-pyrrolo[1,2-a]indole-9-carboxylate (32): ¹H NMR (500 MHz,

CDCl₃): δ = 0.81 (s, 3 H, 1-CH₃), 1.90 (dddd, J = 0.5, 1.3, 7.5,

12.3 Hz, 1 H, 2-H), 2.10–2.22 (m, 1 H, 2-H), 3.04 (ddd, J = 7.5,

10.6, 11.0 Hz, 1 H, 3-H), 3.62–3.72 (m, 1 H, 3-H), 3.91 (s, 3 H,

OCH₃), 4.17 (d, J = 9.7 Hz, 1 H, 9-H), 4.50 (d, J = 9.7 Hz, 1 H,

9a-H), 6.58 (d, J = 7.9 Hz, 1 H, 5-H), 6.76 (ddt, J = 0.4, 1.0, 7.5 Hz,

1 H, 7-H), 7.15 (t, J ≈ 7.5 Hz, 1 H, 6-H), 7.43 (dt, J = 1.3, 7.5 Hz, CDCl₃): δ = 1.24 (s, 3 H, 9-CH₃), 2.00 (ddd, J = 3.0, 8.2, 13.0 Hz,

1 H, 8-H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 22.2 (q, 1-CH₃),

40.5 (t, C-2), 47.1 (d, C-9), 49.3 (t, C-3), 52.7 (q, OCH₃), 73.5 (d,

C-9a), 76.0 (s, C-1), 109.0, 119.0 (2ϫd, C-5, C-7), 124.1 (s, Ar),

124.7, 128.7 (2ϫd, C-8, C-6), 154.3, 173.0 (2ϫs, Ar, CO₂Me) ppm.

1 H, 8-H), 2.04–2.09 (m, 1 H, 8-H), 2.56 (ddd, J = 8.2, 10.5,

18.5 Hz, 1 H, 7-H), 2.74 (ddd, J = 3.0, 7.6, 18.5 Hz, 1 H, 7-H),

2.87 (s, 1 H, OH), 3.83 (s, 3 H, OCH₃), 4.29 (d, J = 9.6 Hz, 1 H,

10-H), 4.64 (d, J = 9.6 Hz, 1 H, 9a-H), 7.09 (dt, J ≈ 1.0, 7.5 Hz, 1

IR (ATR): ν = 3425 (OH), 3050 (ArH), 2950–2900 (CH), 1700 H, 3-H), 7.29 (t, J = 7.8 Hz, 1 H, 2-H), 7.38 (t, J = 7.8 Hz, 1 H,

˜

(C=O), 1555 (C=C) cm^–1. MS (EI, 80 eV, 110 °C): m/z (%) = 247

(3) [M]⁺, 245 (28) [M – 2H]⁺, 198 (100). HRMS (EI, 80 eV, 110 °C):

calcd. for C₁₄H₁₅NO₃[M – 2H]: 245.11869; found 245.10569.

1-H), 8.17 (d, J = 8.1 Hz, 1 H, 4-H) ppm. ¹³C NMR (126 MHz,

CDCl₃): δ = 20.0 (q, 9-CH₃), 31.1, 36.5 (2ϫt, C-7, C-8), 47.6 (d,

C-10), 52.9 (q, OCH₃), 69.2 (d, C-9a), 69.8 (s, C-9), 117.0, 124.3,

124.4 (3ϫd, C-4, C-1, C-3), 126.5 (s, Ar), 129.0 (d, C-2), 142.0 (s,

Methyl 6-Hydroxy-6-methyl-4,5-dihydro-4H-pyrrolo[3,2,1-ij]quinol-

ine-1-carboxylate (33): M.p. 86 °C. ¹H NMR (500 MHz, CDCl₃):

δ = 1.70 (s, 3 H, 6-CH₃), 2.66 (ddd, J = 1.7, 7.0, 12.7 Hz, 1 H, 5-

H), 2.86 (dtd, J = 0.8, 9.3, 12.7 Hz, 1 H, 5-H), 3.97 (s, 3 H, OCH₃),

4.02 (ddd, J = 7.0, 9.3, 10.7 Hz, 1 H, 4-H), 4.27 (ddd, J = 1.7, 9.3,

10.7 Hz, 1 H, 4-H), 5.28 (brs, 1 H, OH), 7.23–7.29 (m, 3 H, 2-H,

Ar), 167.5, 172.2 (2ϫs, C-6, CO Me) ppm. IR (ATR): ν = 3375

˜

2

(OH), 3020 (ArH), 2950–2885 (CH), 1745, 1635 (C=O), 1590

(C=C) cm^–1. MS (EI, 80 eV, 120 °C): m/z (%) = 275 (52) [M]⁺, 257

(53) [M – H₂O]⁺, 198 (100), 176 (51). C₁₅H₁₇NO₄(275.3): calcd. C

65.44, H 6.22, N 5.09; found C 65.09, H 6.20, N 4.95.

7-H, 8-H), 8.00–8.04 (m, 1 H, 9-H) ppm. ¹³C NMR (126 MHz, Methyl (9R*,9aR*,10R*)-9-Hydroxy-9-methyl-6-oxo-6,7,8,9,9a,10-

CDCl₃): δ = 27.1 (q, 6-CH₃), 42.7, 43.4 (2ϫt, C-4, C-5), 51.3 (q, hexahydropyrido[1,2-a]indole-10-carboxylate (42): M.p. 158–160 °C.

OCH₃), 75.1 (s, C-6), 98.1 (s, C-1), 110.2, 121.7, 122.1, 122.4 (4ϫd, ¹H NMR (500 MHz, CDCl₃): δ = 1.31 (s, 3 H, 9-CH₃), 1.97 (ddd,

C-2, C-7, C-8, C-9), 129.8, 132.0, 157.2, 167.3 (4ϫs, 3 ϫAr,

CO Me) ppm. IR (ATR): ν = 3435 (OH), 3050 (ArH), 2950–2900

J = 2.9, 8.0, 14.2 Hz, 1 H, 8-H), 2.04 (ddd, J = 8.0, 10.2, 14.2 Hz,

1 H, 8-H), 2.42 (s, 1 H, OH), 2.57 (ddd, J = 3.0, 8.0, 18.2 Hz, 1 H,

˜

2

(CH), 1665 (C=O), 1615, 1555 (C=C) cm^–1. MS (EI, 80 eV, 60 °C): 7-H), 2.68 (ddd, J = 8.0, 10.2, 18.2 Hz, 1 H, 7-H), 3.87 (s, 3 H,

m/z (%) = 245 (38) [M]⁺, 230 (3) [M – CH₃]⁺, 198 (100) [M – CH₃– OCH₃), 4.46 (d, J = 9.8 Hz, 1 H, 10-H), 4.62 (d, J = 9.8 Hz, 1 H,

CH₃OH]⁺, 170 (10) [M – CH₃– CH₃OH – CO₂]⁺. HRMS (EI, 9a-H), 7.03 (dt, J ≈ 1.0, 7.5 Hz, 1 H, 3-H), 7.22–7.24 (m, 1 H, 2-

80 eV, 60 °C): calcd. for C₁₄H₁₅NO₃: 245.10519; found 245.10733.

H), 7.28 (d, J = 7.6 Hz, 1 H, 1-H), 8.18 (d, J = 8.0 Hz, 1 H, 4-

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 25.8 (q, 9-CH₃), 29.1,

34.7 (2ϫt, C-7, C-8), 47.1 (d, C-10), 52.8 (q, OCH₃), 68.0 (s, C-9),

69.7 (d, C-9a), 117.2, 123.7, 124.3 (3ϫd, C-4, C-1, C-3), 127.2 (s,

Ar), 128.8 (d, C-2), 142.1 (s, Ar), 168.2, 171.9 (2ϫs, C-6,

Methyl (9S*,9aR*,10R*)-9-Hydroxy-9-methyl-6,7,8,9,9a,10-hexa-

hydropyrido[1,2-a]indole-10-carboxylate (34): As described in GP2

and GP3, samarium (165 mg, 1.10 mmol), 1,2-diiodoethane

(286 mg, 1.01 mmol), HMPA (0.7 mL, 4.1 mmol), indole

7

CO Me) ppm. IR (ATR): ν = 3355 (OH), 3060–3010 (ArH), 2975–

˜

2

(105 mg, 0.41 mmol) and phenol (76 mg, 0.82 mmol) afforded 34

(89 mg, 83%) as a colourless oil after purification by column

chromatography on silica gel (hexane/EtOAc 9:1 to 3:1). ¹H NMR

(500 MHz, CDCl₃): δ = 1.28 (s, 3 H, 9-CH₃), 1.53 (dt, J = 4.8,

13.0 Hz, 1 H, 8-H), 1.66–1.81 (m, 2 H, 7-H), 1.96–1.99 (m, 1 H, 8-

H), 2.55 (dt, J = 3.6, 11.5 Hz, 1 H, 6-H), 2.65 (s, 1 H, OH), 3.46

(dd, J = 1.0, 11.5 Hz, 1 H, 9a-H), 3.60 (dd, J = 4.5, 11.5 Hz, 1 H,

2930 (CH), 1730, 1635 (C=O), 1590 (C=C) cm^–1. HRMS (ESI-

TOF): calcd. for C₁₅H₁₇NO₄: 298.1050 [M + Na]⁺; found 298.1056

[M + Na]⁺.

(2aS*,9bS*,9cR*)-2a-Methyl-3,4,9b,9c-tetrahydro-1H-2-oxa-5a-

azacyclopenta[jk]fluorene-1,5(2aH)-dione (43): Sublimation

1

Ͼ160 °C. H NMR (500 MHz, CDCl₃): δ = 1.64 (s, 3 H, 2a-CH₃),

6-H), 3.84 (s, 3 H, OCH₃), 4.03 (dd, J = 1.0, 11.5 Hz, 1 H, 10-H), 2.18 (dt, J = 3.1, 15.3 Hz, 1 H, 3-H), 2.32–2.39 (m, 2 H, 3-H, 4-

6.49 (d, J = 7.7 Hz, 1 H, 4-H), 6.71 (dt, J ≈ 1.0, 7.5 Hz, 1 H, 2-H), H), 2.58 (ddd, J = 2.7, 3.1, 14.8 Hz, 1 H, 4-H), 4.30 (d, J = 8.2 Hz,

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2727

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

1 H, 9b-H), 4.67 (d, J = 8.2 Hz, 1 H, 9c-H), 7.13 (dt, J ≈ 1.0,

7.5 Hz, 1 H, 8-H), 7.33 (dt, J = 1.2, 8.0 Hz, 1 H, 7-H), 7.48 (d, J

(s, 1 H, 11a-H), 7.07 (dt, J = 0.8, 7.5 Hz, 1 H, 2-H), 7.26 (t, J ≈

7.7 Hz, 1 H, 3-H), 7.40 (d, J = 7.5 Hz, 1 H, 1-H), 8.07 (d, J =

= 7.6 Hz, 1 H, 9-H), 8.02 (d, J = 8.0 Hz, 1 H, 6-H) ppm. ¹³C NMR 8.1 Hz, 1 H, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.8 (t,

(100 MHz, CDCl₃): δ = 26.3 (q, 2a-CH₃), 32.1, 34.0 (2ϫt, C-4, C-

3), 48.0, 68.2 (2ϫd, C-9b, C-9c), 84.3 (s, C-2a), 115.8 (d, C-6),

C-10), 22.8 (q, 11-CH₃), 27.6, 35.9, 41.2 (3ϫt, C-9, C-7, C-8), 47.8

(d, C-12), 52.5 (q, OCH₃), 67.9 (d, C-11a), 74.8 (s, C-11), 117.8,

124.8 (s, Ar), 124.9, 125.3, 129.7 (3 ϫ d, C-9, C-7, C-8), 141.7, 124.2, 124.9 (3ϫd, C-4, C-2, C-1), 128.7 (s, Ar), 128.9 (d, C-3),

168.9, 173.2 (3ϫs, Ar, C-5, C-1) ppm. IR (ATR): ν = 3100–3040

142.8, 171.8, 173.1 (3ϫs, Ar, C-6, CO Me) ppm. IR (ATR): ν =

˜

2

(ArH), 3000–2850 (CH), 1760, 1680 (C=O) 1600 (C=C) cm^–1

.

3390 (OH), 3065–3040 (ArH), 2935–2865 (CH), 1735, 1655–1630

C₁₄H₁₃NO₃(243.1): calcd. C 69.12, H 5.29, N 5.76; found C 69.15,

H 5.40, N 5.75.

(C=O), 1590 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for

C

₁₇H₂₁NO₄: 326.1363 [M + Na]⁺, 342.1102 [M + K]⁺; found

326.1361 [M + Na]⁺, 342.1102 [M + K]⁺.

Methyl (10S*,10aR*,11R*)-10-Hydroxy-10-methyl-6-oxo-

7,8,9,10,10a,11-hexahydro-6H-azepino[1,2-a]indole-11-carboxylate

(44): As described in GP2 and GP3, SmI₂in THF (18 mL,

(2aS*,11bS*,11cR*)-2a-Methyl-3,4,5,6,11b,11c-hexahydro-2-oxa-

7a-azabenzo[a]cyclopenta[cd]azulene-1,7-dione (47): M.p. 158–

1.80 mmol), indole 13 (240 mg, 0.83 mmol) and tBuOH (1.10 g, 162 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.12 (s, 3 H, 2a-CH₃),

14.8 mmol) afforded 44 (150 mg, 62 %) and 45 (10 mg, 5 %) as

colourless solids after purification by column chromatography on

1.69–1.75 (m, 1 H, 5-H), 1.90–2.10 (m, 4 H, 5-H, 4-H, 3-H), 2.13

(dddd, J = 3.6, 6.9, 13.8, 18.8 Hz, 1 H, 3-H), 2.78–2.91 (m, 2 H, 6-

silica gel (hexane/EtOAc 5:1 to 1:1); m.p. 125–127 °C. ¹H NMR H), 4.51 (d, J = 10.0 Hz, 1 H, 11b-H), 5.18 (d, J = 10.0 Hz, 1 H,

(500 MHz, CDCl₃): δ = 0.98 (s, 3 H, 10-CH₃), 1.71–1.86 (m, 3 H, 11c-H), 7.15 (dt, J ≈ 0.9, 7.5 Hz, 1 H, 10-H), 7.32–7.35 (m, 1 H, 9-

8-H, 9-H, OH), 1.95–1.99 (m, 1 H, 8-H), 2.06–2.10 (m, 1 H, 9-H),

2.64–2.78 (m, 2 H, 7-H), 3.77 (s, 3 H, OCH₃), 4.56 (d, J = 3.8 Hz,

1 H, 11-H), 4.86 (d, J = 3.8 Hz, 1 H, 10a-H), 7.05 (dt, J = 0.8,

7.5 Hz, 1 H, 2-H), 7.24–7.26 (m, 1 H, 3-H), 7.42 (d, J = 7.5 Hz, 1

H), 7.51 (d, J = 7.6 Hz, 1 H, 11-H), 8.25 (d, J = 8.2 Hz, 1 H, 8-

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.7 (q, 2a-CH₃), 24.0,

24.1, 39.3, 39.6 (4ϫt, C-5, C-4, C-6, C-3), 48.2, 64.8 (2ϫd, C-11b,

C-11c), 90.3 (s, C-2), 117.3, 124.3 (2ϫd, C-8, C-11), 124.8 (s, Ar),

H, 1-H), 8.21 (d, J = 7.8 Hz, 1 H, 4-H) ppm. ¹³C NMR (126 MHz, 125.0, 129.7 (2ϫd, C-10, C-9), 143.2, 170.9, 172.5 (3ϫs, Ar, C-7,

CDCl₃): δ = 19.2 (q, 10-CH₃), 20.5, 38.6, 46.1 (3ϫt, C-7, C-8, C-

9), 47.6 (d, C-11), 52.8 (q, OCH₃), 69.0 (d, C-10a), 72.0 (s, C-10),

117.3, 123.9, 125.0 (3ϫd, C-4, C-1, C-2), 127.0 (s, Ar), 128.9 (d,

C-3), 142.8, 172.1, 172.6 (3ϫs, Ar, C-6, CO₂Me) ppm. IR (ATR):

C-1) ppm. IR (ATR): ν = 3110–3075 (ArH), 2985–2860 (CH),

˜

1760, 1660 (C=O), 1595 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₇NO₃: 294.1101 [M + Na]⁺, 310.0840 [M + K]⁺; found

294.1095 [M + Na]⁺, 310.0837 [M + K]⁺.

ν = 3405 (OH), 3040–3010 (ArH), 2965–2855 (CH), 1745, 1630

˜

Methyl (4aR*,12R*,12aR*,12bS*)-12b-Hydroxy-6-oxo-

1,2,3,4,4a,5,6,12,12a,12b-decahydroindolo[2,1-a]isoquinoline-12-

carboxylate (51): As described in GP2 and GP3, SmI₂in THF

(13.0 mL, 1.30 mmol), indole 15 (160 mg, 0.56 mmol), HMPA

(900 mg, 5.02 mmol) and tBuOH (400 mg, 5.40 mmol) afforded 51

(150 mg, 92%) as a colourless solid after purification by column

(C=O), 1590 (C=C) cm^–1. HRMS (ESI-TOF): calcd. 290.1387

[M + H]⁺, 312.1206 [M + Na]⁺; found 290.1342 [M + H]⁺,

312.1226 [M + Na]⁺. C₁₆H₁₉NO₄(289.1): calcd. C 66.42, H 6.62,

N 4.84; found C 66.03, H 6.67, N 4.77.

(2aS*,10bS*,10cR*)-2a-Methyl-3,4,5,6,10b,10c-hexahydro-2-oxa-

6a-azabenzo[a]cyclopenta[cd]azulene-1,6-dione (45): M.p. 157–

chromatography on silica gel (hexane/EtOAc 9:1, 4:1, 3:1); m.p.

160 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.02 (s, 3 H, 2a-CH₃), 180–184 °C. H NMR (400 MHz, CDCl₃): δ = 1.35–1.50 (m, 3 H,

1

1.85–1.97 (m, 1 H, 4-H), 2.00–2.05 (m, 1 H, 3-H), 2.07–2.14 (m, 1 2-H, 4-H), 1.55 (m, 2 H, 3-H), 1.60–1.70 (m, 2 H, 1-H), 2.00 (m, 1

H, 4-H), 2.21 (ddd, J = 2.4, 4.1, 12.1 Hz, 1 H, 3-H), 2.70 (ddd, J

= 2.4, 5.6, 14.0 Hz, 1 H, 5-H), 2.93 (dt, J = 2.9, 14.0 Hz, 1 H, 5-

H), 4.47 (d, J = 10.3 Hz, 1 H, 10b-H), 4.88 (d, J = 10.3 Hz, 1 H,

H, 4-H), 2.13 (s, 1 H, OH), 2.19 (m, 1 H, 4a-H), 2.67 (dd, J = 9.9,

18.6 Hz, 1 H, 5-H), 2.73 (dd, J = 8.9, 18.6 Hz, 1 H, 5-H), 3.86 (s,

3 H, OCH₃), 4.36 (d, J = 10.0 Hz, 1 H, 12-H), 4.62 (d, J = 10.0 Hz,

10c-H), 7.14 (dt, J ≈ 0.8, 7.5 Hz, 1 H, 9-H), 7.34 (t, J ≈ 7.8 Hz, 1 1 H, 12a-H), 7.08 (dt, J = 0.5, 7.5 Hz, 1 H, 2-H), 7.28 (t, J ≈ 7.8 Hz,

H, 8-H), 7.49 (d, J = 7.6 Hz, 1 H, 10-H), 8.10 (d, J = 8.1 Hz, 1 H,

1 H, 3-H), 7.37 (d, J = 7.6 Hz, 1 H, 1-H), 8.22 (d, J = 8.1 Hz, 1

7-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.9 (q, 2a-CH₃), H, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.8, 20.2, 24.8,

20.7, 38.4, 38.6 (3ϫt, C-3, C-4, C-5), 46.6, 67.0 (2ϫd, C-10b, C- 25.5, 35.4 (5ϫt, C-1, C-2, C-3, C-4, C-5), 39.4, 46.5 (2ϫd, C-4a,

10c), 86.4 (s, C-2a), 116.3 (d, C-7), 124.7 (s, Ar), 124.8, 124.9, 129.6

C-12), 53.0 (q, OCH₃), 70.0 (d, C-12a), 70.4 (s, C-12b), 117.1,

(3 ϫ d, C-10, C-9, C-8), 143.0, 171.4, 172.9 (3 ϫ s, Ar, C-6, C-

124.4, 124.5 (3ϫd, C-8, C-11, C-10), 126.7 (s, Ar), 129.2 (d, C-9),

1) ppm. IR (ATR): ν = 3105–3050 (ArH), 3000–2855 (CH), 1775, 142.1, 167.8, 172.4 (3ϫs, Ar, C-6, CO Me) ppm. IR (ATR): ν =

˜

2

1670 (C=O), 1595 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for

3360 (OH), 3225–3005 (ArH), 2955–2855 (CH), 1735, 1630 (C=O),

C₁₅H₁₅NO₃: 258.1125 [M + H]⁺, 280.0944 [M + Na]⁺; found 1590 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for C₁₈H₂₁NO₄:

258.1130 [M + H]⁺, 280.0950 [M + Na]⁺. C₁₅H₁₅NO₃(257.2):

calcd. C 70.02, H 5.88, N 5.44; found C 69.66, H 5.91, N 5.73.

338.1363 [M + Na]⁺; found 338.1376 [M + Na]⁺. C₁₈H₂₁NO₄

(315.3): calcd. C 68.55, H 6.71, N 4.44; found C 68.63, H 6.93, N

4.29.

Methyl (11S*,11aR*,12R*)-11-Hydroxy-11-methyl-6-oxo-

6,7,8,9,10,11,11a,12-octahydroazocino[1,2-a]indole-12-carboxylate

(46): As described in GP2 and GP3, SmI₂(24.0 mL, 2.40 mmol),

indole 14 (301 mg, 1.00 mmol) and tBuOH (0.50 g, 6.75 mmol) af-

forded 46 (91 mg, 30%) and 47 (54 mg, 20%) as colourless solids

after purification by column chromatography on silica gel (hexane/

EtOAc 5:1 to 1:1). Compounds 48 and 49 were obtained in varying

yields (5–15 %) with use of phenol as proton source; m.p. 127–

Methyl (9R*,9aR*,10R*)-9-[2-(tert-Butyldimethylsiloxy)ethyl]-9-hy-

droxy-6-oxo-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-carb-

oxylate (53): As described in GP2 and GP3, SmI₂in THF (12.0

mL, 1.20 mmol), indole 23 (210 mg, 0.51 mmol) and tBuOH

(385 mg, 5.20 mmol) afforded 53 (206 mg, 96%) as a colourless so-

lid after purification by column chromatography on silica gel (hex-

ane/EtOAc 9:1, 4:1); m.p. 129–133 °C. ¹H NMR (500 MHz,

128 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.80 (s, 3 H, 11-CH₃), CDCl₃): δ = 0.09 [2 ϫ s, each 3 H, SiCH₃], 0.90 [s, 9 H, SiC-

1.63–1.65 (m, 1 H, 9-H), 1.70–1.80 (m, 3 H, 8-H, 9-H, 10-H), 1.90– (CH₃)₃], 1.57 (dt, J = 2.9, 14.6 Hz, 1 H, 9-CH₂), 1.88–1.92 (m, 1

1.95 (m, 2 H, 8-H, 10-H), 2.55 (td, J = 3.8, 8.2 Hz, 1 H, 7-H), 2.88–

2.94 (m, 1 H, 7-H), 3.70 (s, 3 H, OCH₃), 4.27 (s, 1 H, 12-H), 4.92

H, 9-CH₂), 2.06 (dddd, J = 1.3, 8.0, 10.8, 13.6 Hz, 1 H, 8-H), 2.24

(ddd, J = 2.8, 7.7, 13.6 Hz, 1 H, 8-H), 2.47 (ddd, J = 7.7, 10.8,

2728

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

18.3 Hz, 1 H, 7-H), 2.78 (ddd, J = 2.8, 8.0, 18.3 Hz, 1 H, 7-H),

3.84 (s, 3 H, OCH₃), 3.91–3.93 (m, 2 H, OCH₂), 4.37 (d, J = 9.1 Hz,

GP2 and GP3, SmI₂in THF (8.0 mL, 0.80 mmol), indole 20

(100 mg, 0.33 mmol) and tBuOH (244 mg, 3.30 mmol) afforded 57

1 H, 10-H), 4.40 (s, 1 H, OH), 4.75 (d, J = 9.1 Hz, 1 H, 9a-H), (29 mg, 29%) as a colourless oil and 58 (18 mg, 22%) as a colour-

7.06 (dt, J = 1.0, 7.6 Hz, 1 H, 2-H), 7.26 (t, J = 7.6 Hz, 1 H, 3-H),

less solid after purification by column chromatography on silica gel

7.31 (d, J = 7.6 Hz, 1 H, 1-H), 8.17 (d, J = 8.1 Hz, 1 H, 4-H) ppm. (hexane/EtOAc 9:1, 4:1). ¹H NMR (500 MHz): δ = 1.38 (t, J =

¹³C NMR (100 MHz, CDCl₃): δ = –5.7, –5.6 (2ϫq, SiCH₃), 18.0, 7.2 Hz, 3 H, CH₂CH₃), 1.42 (s, 3 H, 9-CH₃), 1.53 (s, 3 H, 9a-CH₃),

25.8 [s, q, SiC(CH₃)₃], 31.1, 31.6, 32.3, 47.1 (4ϫt, 9-CH₂, C-7, C-

8, CH₂OTBS), 52.8 (d, C-10), 60.0 (q, OCH₃), 69.3 (d, C-9a), 72.1 H), 2.54–2.64 (m, 1 H, 7-H), 2.70 (ddd, J = 1.3, 8.4, 18.8 Hz, 1 H,

(s, C-9), 116.9, 124.1, 124.3 (3ϫd, C-4, C-2, C-1), 127.2 (s, Ar), 7-H), 3.98 (s, 1 H, OH), 4.26–4.45 (m, 2 H, CH₂CH₃), 4.64 (s, 1

129.0 (d, C-3), 142.2, 167.6, 171.7 (3ϫs, Ar, C-6, CO₂Me) ppm. H, 10-H), 7.14 (dt, J = 0.9, 7.5 Hz, 1 H, 2-H), 7.30 (t, J ≈ 7.8 Hz,

1.86 (ddd, J = 1.3, 8.4, 13.6 Hz, 1 H, 8-H), 2.22–2.37 (m, 1 H, 8-

IR (ATR): ν = 3465 (OH), 2950–2855 (CH), 1740, 1660 (C=O), 1 H, 3-H), 7.42 (d, J = 7.6 Hz, 1 H, 1-H), 8.23 (d, J = 8.1 Hz, 1

˜

1600 (C=C) cm^–1. C₂₂H₃₃NO₄Si (419.2): calcd. C 62.98, H 7.93, N

3.34; found C 63.07, H 8.03, N 2.99.

H, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 18.4 (2ϫq,

CH₂CH₃, 9-CH₃), 24.9 (q, 9a-CH₃), 30.0, 31.0 (2ϫt, C-7, C-8),

53.2 (d, C-10), 62.4 (t, OCH₂CH₃), 71.4, 72.2 (2ϫs, C-9a, C-9),

117.8, 124.3 (2ϫd, C-4, C-2), 125.7 (s, Ar), 126.4, 128.6 (2ϫd, C-

1, C-3), 141.4, 167.1, 171.5 (3ϫs, Ar, CO₂Et, C-6) ppm. IR (ATR):

Methyl (9R*,9aR*,10R*)-9-[2-(tert-Butyldimethylsiloxy)ethyl]-9-hy-

droxy-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-carboxylate

(55): As described in GP3, SmI₂in THF (12.0 mL, 1.20 mmol),

indole 26 (200 mg, 0.51 mmol) and tBuOH (385 mg, 5.20 mmol)

afforded 55 (190 mg, 94%) as a colourless oil after purification by

ν = 3440 (OH), 3070, 3045 (ArH), 2975–2855 (CH), 1730–1700,

˜

1635 (C=O), 1595 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for

C₁₇H₂₁NO₄: 304.1543 [M + H]⁺, 326.1363 [M + Na]⁺; found

304.1562 [M + H]⁺, 326.1385 [M + Na]⁺.

1

column chromatography on silica gel (hexane/EtOAc 9:1, 4:1). H

NMR (500 MHz, CDCl₃): δ = 0.09 [2ϫs, each 3 H, SiCH₃], 0.90

[s, 9 H, SiC(CH₃)₃], 1.49–1.56 (m, 2 H, 7-H, 8-H), 1.73–1.75 (m, 1

H, 7-H), 1.83 (ddd, J = 5.5, 8.2, 15.0 Hz, 1 H, 9-CH₂), 1.93 (td, J

= 3.6, 15.0 Hz, 1 H, 9-CH₂), 2.23 (dd, J = 2.7, 10.1 Hz, 1 H, 8-H),

2.64 (dt, J = 3.4, 12.0 Hz, 1 H, 6-H), 3.57–3.59 (m, 1 H, 6-H), 3.62

(d, J = 11.0 Hz, 1 H, 9a-H), 3.81 (s, 3 H, OCH₃), 3.91 (m, 2 H,

CH₂OTBS), 3.94 (s, 1 H, OH), 4.09 (d, J = 11.0 Hz, 1 H, 10-H),

6.46 (d, J = 7.8 Hz, 1 H, 4-H), 6.68 (t, J ≈ 7.4 Hz, 1 H, 2-H), 7.10

(d, J = 7.8 Hz, 1 H, 3-H), 7.13 (d, J = 7.8 Hz, 1 H, 1-H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –5.6, –5.5 (2ϫq, SiCH₃), 18.0 [s,

SiC(CH₃)₃], 23.1 (t, C-7), 25.8 [q, SiC(CH₃)₃], 32.7, 36.1, 44.8

(3ϫt, 9-CH₂, C-8, C-6), 46.7 (d, C-10), 52.8 (q, OCH₃), 60.0 (t,

CH₂OTBS), 72.1 (s, C-9), 75.3 (d, C-9a), 106.8, 118.1, 124.1 (3ϫd,

C-4, C-2, C-1), 126.2 (s, Ar), 128.5 (d, C-3), 150.8, 173.0 (2ϫs, Ar,

Methyl 1-Acetyl-2-methyl-1H-indole-3-carboxylate (58): ¹H NMR

(400 MHz, CDCl₃): δ = 1.47 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 2.78

(s, 3 H, 2Ј-CH₃), 2.97 (s, 3 H, COCH₃), 4.43 (q, J = 7.1 Hz, 2 H,

CH₂CH₃), 7.31 (dd, J = 2.5, 3.6 Hz, 1 H, Ar), 7.84–7.91 (m, 2 H,

Ar), 8.12 (dd, J = 2.5, 6.6 Hz, 1 H, Ar) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 14.4, 15.1, 27.8 (3ϫq, CH₂CH₃, 2Ј-CH₃, COCH₃),

60.2 (t, CH₂CH₃), 111.1 (s, Ar), 114.1, 121.7, 123.8, 124.3 (4ϫd,

Ar), 127.4, 135.1, 144.7, 165.3, 170.9 (5ϫs, 3 ϫAr, CO₂Et,

NCOCH ) ppm. IR: ν = 3095–3050 (ArH), 2990–2855 (CH), 1700

˜

3

(C=O), 1560 (C=C) cm^–1. HRMS (ESI-TOF): calcd. for

C₁₄H₁₅NO₃268.0950 [M + Na]⁺; found 268.0955 [M + Na]⁺.

Diethyl (1S*,7S*,7aR*)-7-Hydroxy-7-methyl-5,6,7,7a-tetrahydro-

1H-pyrrolizine-1,2-carboxylate (60): As described in GP2 and GP3,

samarium (217 mg, 1.44 mmol), 1,2-diiodoethane (376 mg,

1.33 mmol), HMPA (0.9 mL, 5.3 mmol), pyrrole 59 (150 mg,

0.53 mmol) and phenol (100 mg, 1.07 mmol) afforded the product

60 (114 mg, 76%, dr ca. 4:1:1) and the starting material 59 (20 mg,

13%) after purification by column chromatography on silica gel

(hexane/EtOAc 2:1). Preparative HPLC (Nucleosil 50–5, hexane/

iPrOH 20%, 145 bar) afforded 60 (98 mg, 65%) as the analytical

pure product together with a mixture of diastereomers (16 mg,

11%), both fractions as pale yellow oils. Alternative: SmI₂(8.0 mL,

0.80 mmol), pyrrole 59 (85 mg, 0.30 mmol) and then tBuOH

(200 mg, 2.70 mmol) afforded the product 60 (63 mg, 75%, dr ca.

4:1:1) after purification by column chromatography on silica gel

CO Me) ppm. IR (ATR): ν = 3500 (OH), 3075–3030 (ArH), 2950–

˜

2

2800 (CH), 1745 (C=O), 1605 (C=C) cm^–1. HRMS (ESI-TOF):

calcd. for C₂₂H₃₅NO₄Si: 428.2228 [M + Na]⁺; found 428.2243 [M

+ Na]⁺.

Ethyl

(9S*,9aR*)-9-Hydroxy-9-methyl-6-oxo-6,7,8,9,9a,10-hexa-

hydropyrido[1,2-a]indole-9a-carboxylate (56): As described in GP2

and GP3, SmI₂in THF (24.0 mL, 2.40 mmol), indole 18 (300 mg,

1.05 mmol) and tBuOH (740 mg, 10.0 mmol) afforded 56 (280 mg,

92%) as a colourless solid after purification by column chromatog-

raphy on silica gel (hexane/EtOAc 9:1, 4:1); m.p. 145 °C (sublima-

tion Ͼ130 °C). ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (t, J =

7.1 Hz, 3 H, CH₂CH₃), 1.33 (s, 3 H, 9-CH₃), 1.84 (td, J = 8.8,

13.7 Hz, 1 H, 8-H), 1.99 (ddd, J = 2.8, 8.8, 13.7 Hz, 1 H, 8-H), 2.64

(dt, J = 7.8, 18.8 Hz, 1 H, 7-H), 2.64 (ddd, J = 2.8, 7.8, 18.8 Hz, 1

H, 7-H), 3.36 (d, J = 17.0 Hz, 1 H, 10-H), 3.62 (d, J = 17.0 Hz, 1

H, 10-H), 3.70 (s, 3 H, OH), 4.10–4.22 (m, 1 H, CH₂CH₃), 4.29

(qd, J = 7.1, 10.8 Hz, 1 H, CH₂CH₃), 7.05 (t, J = 7.5 Hz, 1 H, 2-

H), 7.18 (d, J = 7.5 Hz, 1 H, 1-H), 7.23 (t, J ≈ 7.8 Hz, 1 H, 3-H),

8.20 (d, J = 8.1 Hz, 1 H, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 13.8, 21.6 (2ϫq, CH₂CH₃, 9-CH₃), 30.8, 33.9, 35.4 (3ϫt, C-

7, C-8, C-10), 62.8 (t, CH₂CH₃), 72.0, 74.7 (2ϫs, C-9, C-9a), 116.6,

124.2, 124.3 (3ϫd, C-4, C-1, C-2), 126.9 (s, Ar), 127.9 (d, C-3),

1

(hexane/EtOAc 2:1). H NMR (500 MHz, CDCl₃): δ = 1.16, 1.18

(2ϫt, J = 7.1 Hz, each 3 H, CH₂CH₃), 1.21 (s, 3 H, 7-CH₃), 1.76

(ddd, J = 5.3, 7.5, 12.7 Hz, 1 H, 6-H), 1.99 (td, J = 8.0, 12.7 Hz, 1

H, 6-H), 3.13–3.18 (m, 1 H, 5-H), 3.35 (ddd, J = 5.3, 8.0, 10.8 Hz,

1 H, 5-H), 3.87 (dd, J = 1.0, 4.5 Hz, 1 H, 1-H), 3.90 (d, J = 4.5 Hz,

1 H, 7a-H), 4.04, 4.10 (2ϫq, J = 7.1 Hz, each 2 H, CH₂CH₃), 7.00

(d, J = 1.0 Hz, 1 H, 3-H) ppm; the OH signal could not be detected.

¹³C NMR (126 MHz, CDCl₃): δ = 14.0, 14.3 (2ϫq, CH₂CH₃), 22.2

(q, 7-CH₃), 40.4, 46.9 (2ϫt, C-6, C-5), 47.5 (d, C-1), 59.3, 61.1

(2ϫt, OCH₂), 76.7 (s, C-7), 77.9 (d, C-7a), 105.4 (s, C-2), 152.7 (d,

142.4, 167.9, 174.8 (3ϫs, Ar, CO Et, C-6) ppm. IR (ATR): ν =

˜

2

C-3), 165.0, 174.2 (2ϫs, CO) ppm. IR (ATR): ν = 3445 (OH),

˜

3265 (OH), 3025 (ArH), 2980–2940 (CH), 1720, 1625 (C=O), 1595

(C=C) cm^–1. HRMS (ESI-TOF): calcd. for C₁₆H₁₉NO₄: 290.1387

[M + H]⁺, 312.1206 [M + Na]⁺; found 290.1396 [M + H]⁺,

312.1219 [M + Na]⁺.

2980–2905 (CH), 1735, 1690 (C=O), 1590 (C=C) cm^–1. MS (EI,

120 °C, 80 eV): m/z (%) = 283 (22) [M]⁺, 238 (19) [M – C₂H₅O]⁺,

220 (5) [M – C₂H₅O – H₂O]⁺, 210 (56), 164 (100). HRMS (100 °C,

80 eV): calcd. for C₁₄H₂₁NO₅: 283.14197; found 283.14346.

Ethyl

(9S*,9aR*)-9-Hydroxy-9,9a-dimethyl-6-oxo-6,7,8,9,9a,10- C₁₄H₂₁NO₅(283.3): calcd. C 59.35, H 7.47, N 4.94; found C 59.39,

hexahydropyrido[1,2-a]indole-10-carboxylate (57): As described in

H 7.22, N 4.37.

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2729

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

Mixture of Diastereomers: Major compound in the mixture: ¹H

NMR (500 MHz, CDCl₃): δ = 1.21, 1.24 (2ϫt, J = 7.1 Hz, each 3

H, CH₂CH₃), 1.36 (s, 3 H, 7-CH₃), 1.93 (dt, J = 9.9, 13.3 Hz, 1 H,

solution of SmI₂/HMPA. After the colour of the solution had

turned brown-yellow, allyl iodide (3.0–10.0 equiv.) was added in

one portion. After 30–60 min the reaction was quenched with sat.

6-H), 2.04 (ddd, J = 2.6, 6.6, 13.3 Hz, 1 H, 6-H), 3.33–3.40 (m, 2 aq. NaHCO₃solution, the organic phase was separated, and the

H, 5-H), 3.79 (d, J = 4.8 Hz, 1 H, 7a-H), 4.04 (dd, J = 1.2, 4.8 Hz, aq. phase was extracted three times with diethyl ether. The com-

1 H, 1-H), 4.05–4.29 (m, 4 H, CH₂CH₃, overlap with the signals of bined ether extracts were washed with brine, dried with MgSO₄

the minor diastereomer), 7.14 (d, J = 1.2 Hz, 1 H, 3-H) ppm. ¹³C

and filtered, and the solvents were evaporated. The resulting crude

NMR (126 MHz, CDCl₃): δ = 14.1, 14.4 (2ϫq, CH₂CH₃), 22.6 (q, product was purified by flash chromatography on silica gel with

7-CH₃), 39.9 (t, C-6), 46.1 (d, C-1), 46.6 (t, C-5), 59.3, 61.0 (2ϫt, hexane/ethyl acetate mixtures; in individual cases additional purifi-

OCH₂), 74.2 (s, C-7), 77.6 (d, C-7a), 105.7 (s, C-2), 153.5 (d, C-3),

cation by HLPC yielded the pure compounds.

165.3, 168.6, 169.5, 169.6 (4ϫs, CO for both compounds) ppm.

Minor compound in the mixture: H NMR (500 MHz, CDCl₃): δ =

Methyl (9R*,9aR*,10S*)-10-Allyl-9-[2-(tert-butyldimethylsiloxy)-

ethyl]-9-hydroxy-6,7,8,9,9a,10-hexahydropyrido[1,2-a]indole-10-carb-

oxylate (69): As described in GP4, samarium (216 mg, 1.44 mmol),

1,2-diiodoethane (372 mg, 1.32 mmol), HMPA (895 mg,

5.00 mmol), indole 26 (200 mg, 0.49 mmol) and then allyl iodide

(0.45 mL, 4.90 mmol) afforded 69 (218 mg, 73%) as a colourless

solid after purification by column chromatography on silica gel

1

1.24, 1.25 (2ϫt, J = 7.1 Hz, each 3 H, CH₂CH₃), 1.45 (s, 3 H, 7-

CH₃), 2.17–2.21 (m, 2 H, 6-H), 3.23 (ddd, J = 4.8, 7.0, 11.7 Hz, 1

H, 5-H), 3.67–3.72 (m, 1 H, 5-H), 3.65, 4.00 (2ϫd, J = 7.4 Hz,

each 1 H, 7a-H, 1-H), 4.05–4.29 (m, 4 H, CH₂CH₃, overlap with

the signals of the major diastereomer), 7.14 (s, 1 H, 3-H) ppm. ¹³

C

NMR (126 MHz, CDCl₃): δ = 13.9, 14.0 (2ϫq, CH₂CH₃), 23.7 (q,

7-CH₃), 40.2, 40.9 (2ϫt, C-5, C-6), 50.1 (d, C-7a), 61.4, 62.8 (2ϫt,

OCH₂), 67.2 (d, C-1), 76.6 (s, C-7), 105.7* (s, C-2), 153.5* (d, C-

3), 165.3, 168.6, 169.5, 169.6 (4ϫs, CO for both compounds) ppm

(* overlap with the signals of the major diastereomer).

1

(hexane/EtOAc 4:1); m.p. 83–85 °C. H NMR (500 MHz, CDCl₃):

δ = 0.29, 0.31 (2ϫs, each 3 H, SiCH₃), 0.86 [s, 9 H, SiC(CH₃)₃],

1.45 (dt, J = 3.2, 13.3 Hz, 1 H, 7-H), 1.51–1.77 (m, 4 H, 8-H, 9-

CH₂), 2.13 (td, J = 2.5, 13.3 Hz, 1 H, 7-H), 2.70–2.78 (m, 2 H, 6-

H, CH₂CH=), 2.97 (ddt, J = 1.3, 6.3, 8.2 Hz, 1 H, CH₂CH=), 3.31

(s, 1 H, 10a-H), 3.69 (s, 3 H, OCH₃), 3.64–3.81 (m, 3 H, 6-H,

CH₂OTBS), 4.09 (s, 1 H, OH), 5.04–5.07 (m, 2 H, CH₂=), 5.59–

5.68 (m, 1 H, CH=), 6.64 (d, J = 7.5 Hz, 1 H, 1-H), 6.66 (dt, J =

1.1, 7.5 Hz, 1 H, 2-H), 7.09 (dd, J = 1.1, 7.5 Hz, 1 H, 3-H), 7.11

(dt, J = 1.0, 7.5 Hz, 1 H, 4-H) ppm. ¹³C NMR (126 MHz, CDCl₃):

δ = –5.6 (q, SiCH₃), 18.0 [s, SiC(CH₃)₃], 22.3 (t, C-7), 25.8 [q,

SiC(CH₃)₃], 31.9, 36.8 (2ϫt, C-8, 9-CH₂), 43.2 (t, CH₂CH=), 44.9

IR (ATR): ν = 3450 (OH), 2980–2905 (CH), 1735, 1690 (C=O),

˜

1590 (C=C) cm^–1. MS (EI, 120 °C, 80 eV): m/z (%) = 283 (16)

[M]⁺, 238 (12) [M – C₂H₅O]⁺, 220 (4) [M – C₂H₅O – H₂O]⁺, 210

(6), 164 (100).

For diastereomeric mixture: HRMS (120 °C, 80 eV): calcd. for

C₁₄H₂₁NO₅: 283.14197; found 283.14355.

Diethyl

hydro-1H-1,2-indolizinedicarboxylate (62): As described in GP2 and

GP3, SmI₂(12.0 mL, 1.20 mmol), pyrrole 61 (150 mg, 0.51 mmol) 125.2, 128.3 (2ϫd, C-3, C-1), 129.8 (s, Ar), 133.8 (d, CH=), 150.5,

(1S*,8S*,8aR*)-8-Hydroxy-8-methyl-1,5,6,7,8,8a-hexa- (t, C-6), 52.0 (q, OCH₃), 56.7 (s, C-10), 59.9 (t, OCH₂), 73.3 (s, C-

9), 78.3 (s, C-10a), 106.3, 117.5 (2ϫd, C-4, C-2), 118.9 (t, CH₂=),

and tBuOH (385 mg, 5.20 mmol) afforded 62 (125 mg, 85%, dr 1:1)

as a colourless solid after purification by column chromatography

on silica gel (hexane/iPrOH, 95:5 to 85:15 or hexane/EtOAc 1:1).

Preparative HPLC separation (Nucleosil 50–5, 4ϫ250, CH₂Cl₂,

145 bar) afforded 62 as the analytically pure product. Alternative:

SmI₂(12.0 mL, 1.20 mmol), HMPA (0.9 mL, 5.3 mmol), pyrrole

61 (150 mg, 0.51 mmol) and tBuOH (385 mg, 5.20 mmol) afforded

product 62 (129 mg, 84%) after purification by column chromatog-

raphy on silica gel (hexane/EtOAc 2:1); m.p. 93–95 °C. ¹H NMR

(500 MHz, CDCl₃): δ = 1.20 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 1.21

174.7 (2ϫs, Ar, CO₂Me) ppm. C₂₅H₃₉NO₄Si (445.3): calcd. C

67.37, H 8.82, N 3.14; found C 67.08, H 8.49, N 3.16.

Supporting Information (see also the footnote on the first page of

this article): Detailed description of all experimental procedures

and analytical data (including NOE experiments) for all com-

pounds.

Acknowledgments

(s, 3 H, 8-CH₃), 1.26 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 1.50 (dt, J = Support of this work by the Volkswagen-Stiftung, the Deutsche

4.4, 13.0 Hz, 1 H, 7-H), 1.54–1.69 (m, 2 H, 6-H, 7-H), 1.89 (ddd, Forschungsgemeinschaft (DFG), the Fonds der Chemischen Indus-

J = 2.3, 4.4, 13.0 Hz, 1 H, 6-H), 2.23 (s, 1 H, OH), 2.95 (dt, J =

3.9, 12.4 Hz, 1 H, 5-H), 3.43 (dd, J = 4.8, 12.7 Hz, 1 H, 5-H), 3.54 C. B.), the Alexander von Humboldt-Stiftung (fellowship for V. B.),

(d, J = 8.8 Hz, 1 H, 8a-H), 3.87 (dd, J = 1.0, 8.8 Hz, 1 H, 1-H), the Schering-Stiftung (fellowship for S. G.), and Bayer Schering

trie, the Studienstiftung des deutschen Volkes (fellowships for

4.06–4.10 (m, 2 H, CH₂CH₃), 4.11 (q, J = 7.1 Hz, 2 H, CH₂CH₃), Pharma AG is most gratefully acknowledged. We also thank Prof.

7.10 (d, J = 1.0 Hz, 1 H, 3-H) ppm. ¹³C NMR (126 MHz, CDCl₃): F. Glorius for providing the 2,3-disubstituted indole precursor. The

δ = 14.0, 14.4 (2ϫq, CH₂CH₃), 20.4 (q, 8-CH₃), 23.4, 39.0, 46.4

(3ϫt, C-6, C-7, C-5), 47.3 (d, C-1), 58.9, 61.1 (2ϫt, CH₂CH₃),

help of W. Münch and C. Groneberg with HPLC separations and

that of the NMR service for the numerous NOE experiments is

70.1 (s, C-8), 74.8 (d, C-8a), 98.1 (s, C-2), 150.1 (d, C-3), 165.6, gratefully acknowledged. We also thank Dr. R. Zimmer for his cru-

174.4 (2ϫs, CO Et) ppm. IR (KBr): ν = 3445 (OH), 3075 (=CH), cial help during the preparation of this manuscript.

˜

2

2980–2860 (CH), 1720, 1655 (C=O), 1580 (C=C) cm^–1. MS (EI,

80 °C, 80 eV): m/z (%) = 297 (8) [M]⁺, 279 (6) [M – H₂O]⁺, 252 (4)

[1] a) J.-L. Namy, H. B. Kagan, Nouv. J. Chim. 1977, 1, 5–7; b) P.

[M – C₂H₅O]⁺, 224 (100) [M – C₄H₅O₂]⁺. C₁₅H₂₃NO₅(297.4):

Girard, J.-L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,

calcd. C 60.59, H 7.79, N 4.71; found C 60.50, H 7.51, N 4.59.

2693–2698.

[2] For selected recent reviews on SmI₂-promoted reactions: a)

G. A. Molander, C. R. Harris, Chem. Rev. 1996, 96, 307–338;

b) F. A. Khan, R. Zimmer, J. Prakt. Chem. 1997, 339, 101–

104; c) G. A. Molander, C. R. Harris, Tetrahedron 1998, 54,

3321–3354; d) A. Krief, A.-M. Laval, Chem. Rev. 1999, 99,

745–777; e) H. B. Kagan, Tetrahedron 2003, 59, 10351–10372;

f) M. Berndt, S. Gross, A. Hölemann, H.-U. Reissig, Synlett

General Procedure for SmI₂-Induced Cyclisation and Subsequent

Alkylation (GP4): HMPA (10.0 equiv.) was added to a solution of

SmI₂and the blue-purple solution was stirred for 15 min. The in-

dole derivative (1.0 equiv.) was dissolved in THF (16 mL per mmol

indole) and argon was bubbled through the solution for 10–20 min.

The resulting solution was added in one portion to the deep blue

2730

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Ketyl Cyclisations of Indole and Pyrrole Derivatives

2004, 422–438; g) D. J. Edmonds, D. Johnston, D. J. Procter,

Chem. Rev. 2004, 104, 3371–3404; h) K. Gopalaiah, H. B. Ka-

gan, New J. Chem. 2008, 32, 607–637; i) I. M. Rudkin, L. C.

Miller, D. J. Procter, Organomet. Chem. 2008, 34, 19–45; j)

K. C. Nicolaou, S. P. Ellery, J. S. Chen, Angew. Chem. 2009,

121, 7276–7301; Angew. Chem. Int. Ed. 2009, 48, 7140–7165;

k) D. J. Procter, R. A. Flowers II in Organic Synthesis by Using

Samarium Diiodide, Royal Society of Chemistry, Cambridge,

2009.

For the formation of medium-sized carbocycles and heterocy-

cles through intramolecular samarium ketyl additions to alkene

and alkyne units, see: a) F. A. Khan, R. Czerwonka, R. Zim-

mer, H.-U. Reissig, Synlett 1997, 995–997; b) E. Nandanan,

C. U. Dinesh, H.-U. Reissig, Tetrahedron 2000, 56, 4267–4277;

c) A. Hölemann, H.-U. Reissig, Synlett 2004, 2732–2735; d)

H.-U. Reissig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L.

Shaikh, R. Zimmer, Eur. J. Org. Chem. 2006, 4419–4428; e) J.

Saadi, D. Lentz, H.-U. Reissig, Org. Lett. 2009, 11, 3334–3337;

f) J. Saadi, H.-U. Reissig, Synlett 2009, 2089–2092; and litera-

ture cited therein.

For the intramolecular additions of samarium ketyl to aryl

groups, see: a) C. U. Dinesh, H.-U. Reissig, Angew. Chem.

1999, 111, 874–876; Angew. Chem. Int. Ed. 1999, 38, 789–791;

b) M. Berndt, I. Hlobilová, H.-U. Reissig, Org. Lett. 2004, 6,

957–960; c) F. Aulenta, M. Berndt, I. Brüdgam, H. Hartl, S.

Sörgel, H.-U. Reissig, Chem. Eur. J. 2007, 13, 6047–6062; d)

U. K. Wefelscheid, M. Berndt, H.-U. Reissig, Eur. J. Org.

Chem. 2008, 3635–3646; e) U. K. Wefelscheid, H.-U. Reissig,

Adv. Synth. Catal. 2008, 350, 65–69.

For related SmI₂-promoted aryl–carbonyl couplings, see: a) H.-

G. Schmalz, S. Siegel, J. W. Bats, Angew. Chem. 1995, 107,

2597–2599; Angew. Chem. Int. Ed. Engl. 1995, 34, 2383–2385;

b) J.-S. Shiue, M.-H. Lin, J.-M. Fang, J. Org. Chem. 1997, 62,

4643–4649; c) C.-W. Kuo, J.-M. Fang, Synth. Commun. 2001,

31, 877–892; d) H. Ohno, S. Maeda, M. Okumura, R. Wakay-

ama, T. Tanaka, Chem. Commun. 2002, 316–317; e) H. Ohno,

R. Wakayama, S. Maeda, H. Iwasaki, M. Okumura, C. Iwata,

H. Mikamiyama, T. Tanaka, J. Org. Chem. 2003, 68, 5909–

5916; f) H. Ohno, M. Okumura, S. Maeda, H. Iwasaki, R.

Wakayama, T. Tanaka, J. Org. Chem. 2003, 68, 7722–7732.

Prod. Rep. 2007, 24, 843–868; for selected reviews dealing with

indolizidines, see: i) A. S. Howard, J. P. Michael, in The Alka-

loids, vol. 28 (Ed.: A. Brossi), Academic Press, New York, 1986,

pp. 183–308; j) A. D. Elbein, R. J. Molyneux, in Alkaloids:

Chemical and Biological Perspectives, vol. 5 (Ed.: S. W. Pel-

letier), Wiley, New York, 1987, pp. 1–54; k) R. Ben-Othman,

M. Othman, K. Ciamala, M. Knorr, C. Strohmann, B.

Decroix, Tetrahedron 2009, 65, 4846–4854; for selected reviews

on pyrrolizidine derivatives, see: l) C. Christophersen, in: The

Alkaloids, vol. 24 (Ed.: A. Brossi), Academic Press, Orlando,

1985, pp. 25–98; m) D. J. Robins, Nat. Prod. Rep. 1995, 12,

413–418; n) J. R. Liddell, Nat. Prod. Rep. 2000, 17, 455–462;

o) S. Agarwal, S. Cämmerer, S. Filali, W. Fröhner, J. Knöll,

M. P. Krahl, K. R. Reddy, H.-J. Knölker, Curr. Org. Chem.

2005, 9, 1601–1614; p) A. Brandi, F. Cardona, S. Cicchi, F. M.

Cordero, A. Goti, Chem. Eur. J. 2009, 15, 7808–7821; and lit-

erature cited therein.

a) S. Gross, H.-U. Reissig, Org. Lett. 2003, 5, 4305–4307; b) S.

Gross, Dissertation, Freie Universität Berlin, 2003; c) V. Blot,

H.-U. Reissig, Eur. J. Org. Chem. 2006, 4989–4992; d) V. Blot,

H.-U. Reissig, Synlett 2006, 2763–2766; e) C. Beemelmanns,

H.-U. Reissig, Org. Biomol. Chem. 2009, 7, 4475–4480.

a) N. Kise, T. Mano, T. Sakurai, Org. Lett. 2008, 10, 4617–

4620; b) Because Kise and co-workers assigned their obtained

products with reference to our first reported NMR spectro-

scopic data in ref.^[9a], we assume that the correct relative config-

uration of their obtained product is as depicted in Schemes 8,

10 and 11.

S. Würtz, S. Rakshit, J. Neumann, T. Dröge, F. Glorius, Angew.

Chem. 2008, 120, 7340–7343; Angew. Chem. Int. Ed. 2008, 47,

7230–7233.

For the preparation of 1-(2Ј,3Ј-dimethyl-1H-indol-1-yl)pen-

tane-1,4-dione see the Supporting Information.

C. Heathcock, T. W. Geldern, Heterocycles 1987, 25, 75–78.

A. Basha, M. Lipton, S. M. Weinreb, Tetrahedron Lett. 1977,

18, 4171–4174.

For the preparation of alkyl iodide 20 see the Supporting Infor-

mation.

Selected publications for the role of HMPA, see: a) J. Inanaga,

M. Ishikawa, M. Yamaguchi, Chem. Lett. 1987, 1485–1486; b)

Z. Hou, Y. Wakatsuki, J. Chem. Soc., Chem. Commun. 1994,

1205–1206; c) E. Prasad, R. A. Flowers II, J. Am. Chem. Soc.

2002, 124, 6895–6899; d) A. Dahlén, G. Hilmersson, Eur. J.

Inorg. Chem. 2004, 3393–3403; e) T. Inokuchi, J. Org. Chem.

2005, 70, 1497–1500; f) R. A. Flowers II, Synlett 2008, 1427–

1439; g) D. V. Sadasivam, P. K. S. Antharjanam, E. Prasad,

R. A. Flowers II, J. Am. Chem. Soc. 2008, 130, 7228–7229; h)

H. Farran, S. Hoz, Org. Lett. 2008, 10, 865–867.

R. Yanada, N. Negoro, K. Bessho, K. Yanada, Synlett 1995,

1261–1263.

a) A. L. J. Beckwith, Tetrahedron 1981, 37, 3073–3100; b) D. C.

Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959–974.

[3]

[9]

[4]

[5]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[6]

[7]

For the intramolecular additions of samarium ketyl to aniline

derivatives, see: a) S. Gross, H.-U. Reissig, Synlett 2002, 2027–

2030; b) R. S. Kumaran, I. Brüdgam, H.-U. Reissig, Synlett

2008, 991–994.

Reviews dealing with synthetic applications of dearomatising

processes: for reductive dearomatisations, see: a) L. N. Mander,

Synlett 1991, 134–144; b) T. J. Donohoe, R. Garg, C. A. Ste-

venson, Tetrahedron: Asymmetry 1996, 7, 317–344; c) A.

Schultz, Chem. Commun. 1999, 1263–1271; for nucleophilic de-

aromatisations, see: d) J. Clayden, M. N. Kenworthy, Synthesis

2004, 1721–1736; e) F. López-Ortiz, M. J. Iglesias, I.

Fernández, C. M. A. Sánchez, G. R. Gómez, Chem. Rev. 2007,

107, 1580–1691; f) G. Barbe, G. Pelletier, A. B. Charette, Org.

Lett. 2009, 11, 3398–3401; for transition-metal-mediated de-

aromatisations, see: g) T. Bach, Angew. Chem. 1996, 108, 795–

796; Angew. Chem. Int. Ed. Engl. 1996, 35, 729–730; h) A. R.

Pape, K. P. Kaliappan, E. P. Kündig, Chem. Rev. 2000, 100,

2917–2940; for oxidative dearomatisations, see: i) S. Quideau,

L. Pouységu, D. Deffieux, Synlett 2008, 467–495; and refer-

ences cited therein.

For selected reviews on indole synthesis and indole-containing

natural products, see: a) R. J. Sundberg in The Chemistry of

Indoles, Academic Press, New York, 1970; b) R. J. Sundberg in

Indoles, Academic Press, London, 1996; c) J. Bonjoch, J. Bosch,

in: The Alkaloids, vol. 48 (Ed.: G. A. Cordell), Academic Press,

San Diego, 1996, pp. 75–189; d) G. W. Gribble, J. Chem. Soc.

Perkin Trans. 1 2000, 1045–1075; e) J. Bonjoch, D. Solé, Chem.

Rev. 2000, 100, 3455–3482; f) M. Somei, F. Yamada, Nat. Prod.

Rep. 2005, 22, 73–103; g) G. R. Humphrey, T. Kuethe, Chem.

Rev. 2006, 106, 2875–2911; h) K. Higuchi, T. Kawasaki, Nat.

[17]

[18]

[19]

[20]

For examples of chelate-controlled SmI₂-promoted reactions,

see refs.^[2g–2i]

For a similar reported mechanism, see: a) J.-S. Shiue, J.-M.

Fang, J. Chem. Soc., Chem. Commun. 1993, 1277–1278; b) S.-

C. Lin, F.-D. Yang, J.-S. Shiue, S.-M. Yang, J.-M. Fang, J. Org.

Chem. 1998, 63, 2909–2917.

It should be mentioned that in cyclohexane the A value of a

methyl group is higher than the A value of a hydroxy group.

For A values, see: a) N. L. Allinger, L. A. Freiberg, J. Org.

Chem. 1966, 31, 894–897; b) J. A. Hirsch, Top. Stereochem.

1967, 1, 199–222. In view of the very high oxophilicities of

samarium cations we assume that Sm^(2+/3+)ions are partially

coordinated to the carbonyl group (in particular in the absence

of HMPA). The complexed carbonyl group should thus prefer

mainly an equatorial position.

[21]

[8]

[22]

For effects of electron-withdrawing substituents in SmI₂-in-

duced reactions, see ref.^[4d,5d–5f]

Eur. J. Org. Chem. 2010, 2716–2732

www.eurjoc.org

2731

C. Beemelmanns, V. Blot, S. Gross, D. Lentz, H.-U. Reissig

FULL PAPER

[23]

[28] Only in the SmI₂-induced cyclisation of indole precursor 6 was

the formation of the diastereomer of type IV observed. For all

other indole derivatives SmI₂-induced cyclisations only af-

forded diastereomers of type II and the corresponding γ-lac-

tones.

For SmI₂-mediated 4-exo-trig cyclisation, see: a) K. Weinges,

S. B. Schmidbauer, H. Schick, Chem. Ber. 1994, 127, 1305–

1309; b) D. Johnston, C. M. McCusker, D. J. Procter, Tetrahe-

dron Lett. 1999, 40, 4913–4916; c) D. Johnston, C. F.

McCusker, K. Muir, D. J. Procter, J. Chem. Soc. Perkin Trans.

1 2000, 681–684; d) T. K. Hutton, K. W. Muir, D. J. Procter,

Org. Lett. 2003, 5, 4811–4814; e) D. J. Edmonds, K. W. Muir,

D. J. Procter, J. Org. Chem. 2003, 68, 3190–3198; f) D. Bradley,

G. Williams, K. Blann, Eur. J. Org. Chem. 2004, 3286–3291;

for other metal-mediated radical 4-exo cyclisations, see, for ex-

ample: g) J. Friedrich, K. Walczak, M. Dolg, F. Piestert, T.

Lauterbach, D. Worgull, A. Gansäuer, J. Am. Chem. Soc. 2008,

130, 1788–1796 and ref. cited therein.

[29] ORTEP-3 for windows, L. J. Farrugia, J. Appl. Crystallogr.

1997, 30, 565.

[30] For examples of cyclohexanone derivatives, see refs.^{[2g,3d,4c,9c,9e]}

[31] Reductions to dihydroindole derivatives were only observed for

sterically more demanding ketones, indicating that the reaction

rate for the formation of the ketyl radical is decreasing signifi-

cantly with steric demand.

[32] For similar C–C bond cleavage, see: D. Bradley, G. Williams,

K. Blann, C. W. Holzapfel, J. Org. Chem. 2000, 65, 2834–2836;

A. Schartz, C. Seger, Monatsh. Chem. 2001, 132, 855–858;

D. B. G. Williams, J. K. Blann, J. Caddy, J. Org. Prep. Proc.

2001, 33, 565–602; ref.^[2g,9b]and ref. cited therein.

[33] For related acyl radical cyclisations onto pyrroles, see: a) D. J.

Hart in Radicals in Organic Synthesis, Vol. 2 (Eds.: P. Renaud,

M. P. Sibi), Wiley-VCH, Weinheim, 2001, pp. 279–300; b) S. M.

Allin, W. R. S. Barton, W. R. Bowman, T. McInally, Tetrahe-

dron Lett. 2001, 42, 7887–7890; c) M. Yoshida, M. Kitamura,

K. Narasaka, Bull. Chem. Soc. Jpn. 2003, 76, 2003–2008; and

ref. cited therein.

[34] After HPLC purification of the reaction mixture compound 60

and an inseparable mixture of the minor diastereomers were

isolated.

[35] For a closely related alkylated substrate an X-ray analysis was

obtained and will be reported in due course. D. Lentz, C. Be-

emelmanns, H.-U. Reissig, Freie Universität Berlin, unpub-

lished results.

[24]

Phenol has been shown to have an accelerating effect on SmI₂-

induced cyclisation. In some cases the combination of HMPA

and phenol in the SmI₂-induced cyclisation has proved to be

too reactive, leading to various side reactions such as deacyla-

tion. For further kinetic studies with different proton sources

in SmI₂-induced reactions, see: a) S. Hoz, A. Yacovan, I. Bilkis,

J. Am. Chem. Soc. 1996, 118, 261–262; b) A. Dahlén, G. Hil-

mersson, Tetrahedron Lett. 2001, 42, 5565–5569; c) G. Kleinert,

A. Tarnopolsky, S. Hoz, Org. Lett. 2005, 7, 4197–4200; d) M.

Amiel-Levi, S. Hoz, J. Am. Chem. Soc. 2008, 131, 8280–8284;

and ref.^[16f,16h]

.

[25] The earlier assumption of all-cis-configured products was due

to COSY artefacts in the recorded NOESY spectra. These arte-

facts are particularly well known for substrates with large vici-

nal diaxial coupling constants, see: S. Macura, Y. Huang, D.

Suter, R. R. Ernst, J. Magn. Reson. 1981, 43, 259–281. For a

recent review dealing with NMR-based structure elucidation,

see: E. E. Kwon, S. G. Huang, Eur. J. Org. Chem. 2008, 2671–

2688.

[36] SHELX97 - Programs for Crystal Structure Analysis (Re-

lease 97–2). G. M. Sheldrick, Institut für Anorganische

Chemie der Universität, Tammanstrasse 4, 3400 Göttingen,

Germany, 1998.

[26] For the synthesis of the starting materials 37 and 39 see the

Supporting Information.

[27] a) M. Berndt, H.-U. Reissig, unpublished results; b) M. Berndt,

Dissertation, Freie Universität Berlin, 2003.

Received: December 14, 2009

Published Online: March 30, 2010

2732

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2716–2732

Article Doi

Highly diastereoselective samarium diiodide induced ketyl cyclisations of indole and pyrrole derivatives - Scope and limitations

DOI: 10.1002/ejoc.200901455

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200901455

Full text of DOI:10.1002/ejoc.200901455

Products guided by the article

R&D Labs maybe for 1233241-64-9

Relevant to this article

Hot Product