Scholarly article on 2-(1-(methoxycarbonyl)-1,4-dihydropyridin-4-yl)-2-methylpropanoic acid 455258-20-5 from European Journal of Organic Chemistry p. 3724

FULL PAPER

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles: One-Pot Formation of

Polycyclic γ- and δ-Lactones from Pyridines and Pyrazines

Henri Rudler,*^[a]Bernard Denise,^[a]Yiming Xu,^[a]Andrée Parlier,^[a]and

Jacqueline Vaissermann^[a]

Keywords: Bis(trimethylsilyl)ketene acetals / Pyridines / Methyl chloroformate / Nucleophilic additions / γ- and δ-lactones /

Pyrazines

Bis(trimethylsilyl)ketene acetals react with pyridines, quino-

line and isoquinoline in the presence of stoichiometric

amounts of methyl chloroformate to give the corresponding

dihydropyridine-, dihydroquinoline- and dihydroisoquino-

line-substituted carboxylic acids in satisfactory yields. The

regio- and diastereoselectivities of the addition reactions, to-

gether with the presence or absence of rotamers, have been

established. The isolated acids react with peracids to give β-

hydroxy-δ-lactones through an intramolecular reaction. Sim-

ilar lactonizations could also be brought about directly from

the azaaromatic compounds in one-pot reactions with silica

gel, iodine or bromine. In these cases δ-lactones or β-halo-δ-

lactones were produced. The behaviour of pyrazines in these

transformations is peculiar, since methyl chloroformate on its

own induces the formation, through interaction with both ni-

trogen atoms, of polycyclic γ-lactones, a reaction formally

reminiscent of the double nucleophilic addition of the same

ketene acetals to (arene)tricarbonylchromium complexes.

Most of the new structures were assigned through X-ray

crystal structure determinations.

Germany, 2005)

Introduction

Pyridines are versatile starting materials for the synthesis

of complex heterocyclic compounds. Among their reactions,

the addition of nucleophiles attracted our attention espe-

cially: it is known that pyridine (1) and its derivatives, once

activated as in 2 (Scheme 1), react with a large variety of

nucleophiles to afford substituted dihydropyridines 3 and

4.^[1–8]Moreover, the resulting dihydropyridines can in turn

be reactivated via iminium intermediates 5 to undergo sec-

ond nucleophilic additions. These finally yield highly substi-

tuted tetrahydropyridines 6, products of overall double nu-

cleophilic addition reactions on the azaaromatic frame-

works, used in pioneering work by Wenkert^[9]for crucial

steps in the synthesis of alkaloids and also by Lavilla^[10,11]

in both inter- and intramolecular ways for the synthesis of

polycyclic systems starting from pyridines.

Scheme 1.

agents,^[12–14]such compounds could also be used for the

biomimetic reduction of Fischer carbene complexes.^[15–17]

The second was the dinucleophilic addition reactions, since

we had discovered that bis(trimethylsilyl)ketene acetals 7

constitute an original class of ketene acetals among nucleo-

philes,^[18–21]as they can behave as 1,3-carbon,oxygen dinu-

cleophiles 8 in one-pot reactions, as the result of successive

cleavage of both oxygen–silicon bonds (Scheme 2).

There were two points of interest in this regard for our

ongoing chemistry. The first was the formation of dihydropy-

ridines through mononucleophilic addition reactions, since

we had demonstrated that, besides the established impor-

tance of dihydropyridine derivatives as therapeutic

[a] Institut de Chimie Moléculaire, FR 2769, Laboratoire de Chi-

mie Organique, UMR 7611, Université Pierre et Marie Curie,

Tour 44–45,

4 place Jussieu, 75252 Paris Cedex 05, France

Fax: +33-1-44275504

E-mail: rudler@ccr.jussieu.fr

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Scheme 2.

3724

DOI: 10.1002/ejoc.200500162

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

This special reactivity allowed us to synthesize, inter alia, pyridines through the use of bis(trimethylsilyl)ketene acetals

γ-lactones, through formal [2+3] cycloadditions of these di- had not been described to the best of our knowledge, al-

nucleophiles to suitably activated carbon–carbon double though an early example of the addition of the bis(trimeth-

bonds

in

(arene)tricarbonylchromium

complexes ylsilyl)ketene acetal 7a derived from acetic acid and giving

(Scheme 3), in tricarbonyl(triene)chromium complexes and the corresponding ester has been outlined.^[32]We therefore

in (π-allyl)palladium complexes.^[22–27]

treated pyridine and a series of substituted pyridines, quino-

line and isoquinoline with the ketene acetals 7a–j derived

from saturated carboxylic acids,^[33]bearing various substit-

uents on the α-carbon atom, and also with those derived

from unsaturated carboxylic acids 7k–o.

Scheme 3.

Common to all of these transformations are the follow-

ing features: transition metals are involved stoichiometrically

or catalytically either in one or in the two steps of the nucle-

ophilic additions, and carboxylic acids or their derivatives

can be isolated as intermediates in the first steps of these

reactions.

In the case of azaaromatic compounds, this approach

might lead, without any metal, to polycyclic lactones 9, since

the two nucleophilic centres (Nu¹–Nu²= 8) are potentially

already present in the starting ketene acetals 7 (Scheme 4).

Confirmation of this hypothesis was reported in a prelimi-

nary communication.^[28]

Five types of reactions have been examined: (1) those

involving the simplest ketene acetal 7a (R¹= R²= H) and

pyridine and affording C-2 and C-4 regioisomers, each as a

mixture of rotamers;^[34,35](2) those involving symmetrically

substituted ketene acetals [e.g., 7b, R¹= R²= Me or 7c,

R¹R²= (CH₂)₅], which gave single isomers, again as mix-

tures of rotamers; (3) those involving monosubstituted ke-

tene acetals, such as 7h (R¹= H, R²= Ph), which also

gave single regioisomers but could give pairs of observable

diastereoisomers (for substituted pyridines) through the for-

mation of two adjacent stereogenic centres; (4) those involv-

ing substituted pyridines (e.g., 2-methylpyridine), which in

the case of R¹= R²= Me gave single isomers as apparently

unique rotamers but which for R¹϶ R²might give pairs of

observable diastereoisomers due to the fact that two adja-

cent stereogenic centres are formed; and (5) those involving

pyridines bearing an electron-attracting substituent, which

gave single isomers, in most cases with no discernible rota-

mers.

Scheme 4.

The purpose of this paper is firstly to describe and estab-

lish the scope and the limits of the first step in these trans-

formations, the monoaddition of bis(trimethylsilyl)ketene

acetals to pyridines, quinoline and isoquinoline, and sec-

ondly to outline the one-pot transformations of the same

substrates and pyrazines into polycyclic δ- and γ-lactones.

Reactions with Pyridine

When methyl chloroformate was added to a solution of

pyridine (1) and bis(trimethysilyl)ketene acetal 7a in dichlo-

romethane at room temperature, the formation of two fairly

polar, separable products was observed. According to their

physical data, these compounds are, as expected, two re-

gioisomers (Scheme 5). The ¹H NMR spectrum of each iso-

mer, taken at room temperature, was in agreement with the

presence of a 1:1 mixture of two rotamers. In the case of

the more abundant isomer 12a (48%) this was supported

by signals appearing for the two C(2)–H protons as two

distinct broad doublets at δ = 6.68 and 6.81 ppm (J = 8 Hz),

Results and Discussion

Formation of Acids

Reaction of Pyridines with the Bis(trimethylsilyl) Ketene

Acetals 7a–j Derived from Saturated Carboxylic Acids –

Scope of the Reaction

Enol ethers and a few alkyl(trimethylsilyl)ketene acetals all other protons giving single yet rather broad signals. This

have been shown by Akiba to add to pyridines in the pres- is also apparent in the ¹³C NMR spectrum, since the car-

ence of methyl chloroformate to afford 4-oxoalkyl- and 4- bon atoms of the two double bonds gave rise to four distinct

carbalkoxy-substituted pyridines regioselectively after oxi- signals, at δ = 123.2, 123.6 and 108.2, 108.6 ppm. The

dation.^[29,30]On the other hand, the addition of ketone eno- NMR spectrum of the minor product 13a (20%), showing

lates to pyridinium triflates has also been outlined.^[31]How- four vicinal protons of the 1,2-dihydropyridine, was also in

ever, the general, direct formation of carboxylic-substituted agreement with the presence of two rotamers. It is noteable

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3725

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

Scheme 5.

that the intermediate trimethylsilyl esters 10a and 11a could the ¹³C NMR spectra, since the carbon atoms of the two

be detected by NMR prior to hydrolysis. double bonds gave rise to four specific signals. Heating of

The symmetrically substituted ketene acetals 7b and 7c an NMR sample of 12h at 55 °C simplified its spectra to a

[R¹= R²= Me, R¹R²= (CH₂)₅], however, gave single prod- great extent (Figure 1), with four distinct signals for the vi-

ucts, again as 1:1 mixtures of two rotamers (Scheme 6).

nylic protons indicating the presence of a stereogenic centre.

Reactions with Substituted Pyridines

Deactivation of the pyridine nucleus towards nucleo-

philic additions is generally observed for electron-donating

substituents in the sequence C-3 Ͻ C-2 Ͻ C-4. Neverthe-

less, the expected addition products were obtained. Thus, 2-

picoline (14) reacted with the ketene acetal 7b (R¹= R²=

Me) to give a single product 15b as an oil in 70% yield

(Scheme 8).

Scheme 6.

Fast rotamer interconversion occurred upon heating of

chloroform solutions of 12b to 50 °C (see Supporting Infor-

mation).

In the cases of the monosubstituted ketene acetals 7d–j

(R¹= H, R²= Me, Et, iPr, tBu, Ph, SiMe₃, OPh), the out-

comes of the reactions (Scheme 7) were simpler than ex-

pected: only one regioisomer was formed, as two rotamers,

in each instance. Especially diagnostic were the signals in

Scheme 8.

1

The H NMR spectrum showed sharp signals for all the

protons, an indication of the absence of rotamers. This was

also confirmed by the ¹³C NMR spectrum, since all the

signals were single. Clearly, rotation around the partial C–

N double bond is completely inhibited by the presence of

the α-methyl group. A similar result was observed for 2-

vinylpyridine 16, which gave 17 (see Exp. Sect.). Interest-

ingly, 3-picoline (18) and the monosubstituted ketene acetal

7f (R²= iPr) (Scheme 9) gave a 65% yield of a separable

mixture of two diastereomeric C-4 addition products 19f

and 20f (de, 86%) and, as expected, 4-picoline gave only a

very low (10%) yield of an unstable C-2 addition product.

Scheme 7.

1

Figure 1. H NMR (400 MHz) spectra of 12h at various tempera-

tures.

Scheme 9.

3726

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

As far as pyridines 21, 23 and 25, each bearing the elec- 43b (90%) and 4-cyanopyridine (44) yielded a 1:1 mixture

tron-withdrawing phenyl group, are concerned, by far the of 45b and 46b (70%) (vide infra).

best result was obtained with 3-phenylpyridine (21), with

the C-4 addition product 22b being isolated in 90% yield.

Whilst 4-phenylpyridine (23) provided a single C-2 addition

product 24b in a low (30%) yield (Scheme 10), 2-phenylpyr-

idine (25) surprisingly reacted only in dichloromethane at

reflux, sluggishly affording (20% yield) a 1:1 mixture of the

expected acid 26b and of 12b, the result of the loss of the

[36–38]

phenyl substituent

(Scheme 11).

Scheme 12.

Reactivity of Pyridines towards Ketene Acetals 1k–o

Derived from Unsaturated Acids

Scheme 10.

Depending on the reaction conditions, electrophiles react

with enolates originating from conjugated ketene acetals

such as 7k to give either α- or γ-addition products (kinetic

vs. thermodynamic addition)^[39–44](Scheme 13). We had al-

ready observed that such ketene acetals could also behave

as 1,3-dinucleophiles since they add at low temperature to,

for example, (arene)tricarbonylchromium complexes to give

γ,δ-unsaturated γ-lactones.^[23,24]At room temperature, how-

ever, the same treatment gave α,β-unsaturated acids as the

result of γ-monoaddition reactions, so we investigated the

behaviour towards pyridine of a series of ketene acetals 7k–

o derived from but-3-enoic, 2-methylbut-3-enoic, 3-methyl-

3-butenoic, pent-4-enoic and hex-5-enoic acids.

Scheme 11.

The introduction of more strongly electron-withdrawing

groups was expected to have two opposite effects: (1) such

pyridines are less prone to react with methyl chloroformate,

whilst (2) in contrast, once activated as a pyridinium chlo-

roformates, they should be more reactive towards nucleo-

philes. A third effect might be observable by NMR in the

form of a lowering of the barrier to rotation around the N–

C double bond and as a consequence, the absence of rota-

mers at room temperature. This was indeed the case. Thus,

treatment of a series of 3-substituted pyridines (27, R =

COPh; 28, R = CO₂Me; 29, R = CO₂H, 30, R = CN; 31 R

= CONEt₂; 32, R = CHO) with the ketene acetals [R¹= R²

= Me, R¹R²= (CH₂)₅] provided the expected 3,4-disubsti-

tuted pyridines 33–38 in good to medium yields (90–42%)

(Scheme 12). 3-Benzoylpyridine and 7b, for example, af-

forded the expected C-4 addition product 33b. Unlike in the

previous examples, the various vinylic protons gave rise to

sharp signals, and no splitting of the signals for the carbons

of the double bonds was observed. It is thus clear that fast

rotation around the C–N bond of the carbamate takes place

even at room temperature. It is worthwhile to note here that

no Mukaiyama-type^[19,20]reaction was observed in the case

of 3-pyridinecarboxaldehyde (32), which gave the expected

C-4 addition product 38c. Because of steric hindrance, no

rotamers were observed in the case of the C-4 addition pro-

duct 40b (30% yield) originating from 2-benzoylpyridine

Scheme 13.

In the cases of the ketene acetals 7k–m, only products

originating from the γ-addition to the C-2 position of pyri-

dine were observed both at low temperature and at room

temperature (Scheme 14).

Scheme 14.

According to their ¹³C NMR spectra, these products are

(39), whereas methyl pyridine-4-carboxylate (41) gave a 2:1 indeed both conjugated carboxylic acids and 1,2-dihydropy-

inseparable mixture of the C-2 and C-4 isomers 42b and ridines, with the carbon atoms of the two conjugated

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3727

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

double bonds in 47k giving split signals at δ = 125.49 and

Moreover, in this latter example, each regioisomer was

124.93, 106.34 and 105.91, 122.43 and 122.84, and 121.21 formed as a mixture of diastereoisomers (de 30% for 51f),

and 121.05 ppm, which again indicates the presence of rota- which were also separated in the case of the more abundant

mers. Deactivation of the pyridine nucleus – as in nicotin- 51f.

amide, for instance – did not change the course of the reac-

Crystals of 51f (R¹= H, R²= iPr) suitable for an X-ray

tion since an 85% yield of the C-2 addition product 48k determination could be grown. A DIAMOND projection

was formed (see the Exp. Sect.). As expected, the ketene of this compound appears in Figure 2. Three points are

acetals derived from pent-4-enoic and hex-5-enoic acids worthy of comment: (1) the six atoms C(2), C(10), C(16),

gave the C-4 addition products 49n and 49o in 85 and 55% O(3), O(4) and N(1) are almost coplanar, the sum of the

yields, respectively, each as two rotamers (Scheme 15).

angles around the nitrogen atom being equal to 356°, an

observation that reflects the delocalization of the nitrogen

doublet with formation of an N–C double bond [N(1)–

C(16) = 1.363(3) Å] and a C–O single bond [C(16)–O(3) =

1.207(3) Å], (2) the introduced substituent at C-2 and the

carbamate function are in a trans-opposite relationship with

respect to the plane of the bicyclic system, so no intramol-

ecular hydrogen bond can exist between the acid and the

carbamate, and (3) an intermolecular hydrogen bond exists

between one acid group and the carbonyl group of the car-

bamate of a second molecule, giving rise to a zig-zag ar-

rangement in the crystal lattice (Figure 3).

Scheme 15.

Reactions of Bis(trimethylsilyl)ketene Acetals with

Quinolines and Isoquinolines

One of the drawbacks of most of the protected dihy-

dropyridines described up to now is their instability.^[1,10]In-

deed, easy degradation through aerial oxidation most often

takes place (vide infra). Since dihydroquinolines and dihy-

droisoquinolines are known to be more stable than simple

dihydropyridines,^[45]yet reactive enough to reduce carbene

complexes,^[46]and as the addition products are also poten-

tially important targets, attempts were made to introduce

acid functions in these substrates directly.

As already established for carbon nucleophiles,^[47,48]the

ketene acetal 7a gave a single C-2 addition product 51a in

90% yield with quinoline (50) (Scheme 16). However, 7b

and 7f gave separable mixtures of the C-2 and C-4 isomers,

their respective ratios depending on the natures of the sub-

stituents (Scheme 17).

Figure 2. DIAMOND view of compound 51f.

It is thus likely, as confirmed by NMR, that this com-

pound exists as a single rotamer for steric reasons, the car-

bamate being in a constraint geometry with the methoxy

group oriented towards the aromatic ring.

Scheme 16.

The behaviour towards ketene acetals derived from un-

saturated carboxylic acids has also been examined: these

gave the expected C-2 addition products in good to excel-

lent yields (75–95%). In the case of the conjugated ketene

acetal 7k the thermodynamic product 53k was obtained

(Scheme 18; no rotamers present at room temperature), but

7m produced 53m as an inseparable mixture of two isomers

around the carbon–carbon double bond of the conjugated

acid. For the pentenoic acid derived ketene acetal 7n a 3:1

Scheme 17.

3728

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

Scheme 20.

Figure 3. Evidence for intermolecular hydrogen bonds in com-

pound 51f.

Scheme 21.

mixture of the C-2 and C-4 addition products 54n and 55n

(95% yield), each as two diastereoisomers, was isolated

(Scheme 19).

Scheme 22.

pyridines are electrophilic enough to react per se, though

the role of the chloride ions probably has to be taken into

account in the activation step.

Scheme 18.

Isoquinoline (56) in turn gave, as expected, only the C-1

addition products with 7a, 7b and 7d. At room temperature

these exist either as two rotamers (in the case of 57a, R¹=

Transformation of Pyridines and Derivatives into Lactones

A parallel between the interaction of bis(TMS)ketene

R²= H) or, for bulky substituents such as in 57b (R¹= R²acetals with (arene)tricarbonylchromium complexes and

= Me), as single rotamers (Scheme 20).

their interaction with pyridines in carbon–carbon bond-for-

Diastereoisomers were obtained in the cases of the mon- mation reactions had already been sketched out. In the first

osubstituted ketene acetals 7d (R¹= H, R²= Me, 57d; de case activation is linked to the coordination of the metal

20%) and 7n (R¹= H, R²= allyl, 58n; de 90%, Scheme 21), ion to the double bonds, whilst in the second case activation

each as two rotamers.

Finally, 7k gave the C-1 addition adduct 59k as two rota- methyl chloroformate. For the oxygen–carbon bond forma-

mers (Scheme 22). tion, the key point, in the case of (arene)chromium com-

is the result of interaction between the nitrogen atom and

It therefore appears that (1) the addition of ketene acetals plexes, is the interaction of the intermediate anionic com-

of type 7 to nitrogen-containing aromatic compounds can plex with an electrophile (oxidant), iodine, and the simulta-

be regarded as a transformation of broad scope, providing neous cleavage of the remaining silicon–oxygen bond. This

new carboxylic acid substituted dihydropyridines, -quino- affords a bicyclic γ-lactone.^[22,23]Pioneering work on nonbi-

lines and -isoquinolines, some of the reactions taking place omimetic transformations of dihydropyridines in their inter-

with high diastereoselectivity, and (2) no special activation action with various oxidants (electrophiles E⁺) has been re-

of the ketene acetals is necessary, since the various acylated ported in a series of recent papers by Lavilla and co-

Scheme 19.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3729

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

workers.^{[10,11,49,50]}Among those directly related to the

transformation of carboxylic acid bearing dihydropyridines

into lactones are their reactions with iodine in the presence

of nucleophiles and with peracids RCO₃H. In the intermo-

lecular version this gave rise to successive electrophilic (I⁺,

–

HO⁺) and nucleophilic (MeO^–, RCO₂) addition reactions

onto the dihydropyridine carbon–carbon double bonds

(Scheme 23).

Scheme 25.

Scheme 23.

Protolactonisation Reactions

Since 1,4-dihydropyridines are known to react with m-

chloroperbenzoic acid to give trans-hydroxy esters upon

intermolecular transient epoxide opening reactions induced

by m-chlorobenzoic acid,^[10]we could reasonably expect

double nucleophilic additions of bis(trimethyl)ketene ace-

tals to pyridines and related heterocycles. In other words,

acids of the general structure 12 (Scheme 24) might provide

lactones 60 under the same conditions, the intramolecular

reaction prevailing over the intermolecular reaction. This

was indeed confirmed and has appeared in a preliminary

communication.^[28]

Though the transformation of the dihydropyridine-sub-

stituted acids into hydroxylactones is interesting, the need

for isolation and purification of the rather unstable acids

(vide supra, Scheme 24) prior to their interaction with a

peracid was a drawback. The search for a direct, one-pot

transformation of the pyridines into lactones was therefore

essential, but attempts to transform the acids into lactones

by the classical protolactonization reaction failed.^[51,52]

The following observations gave us a first solution to this

problem: the interaction of the ketene acetal 7b with pyri-

dine in the presence of methyl chloroformate afforded the

expected dihydropyridine 12b (vide supra) after fast silica

gel chromatography, but during longer lasting purifications

by the same technique, a second, slightly more polar, pro-

duct (m.p. 108 °C, 5–10% yield) was isolated as a white so-

1

lid. The H NMR spectrum confirmed that only one single

disubstituted carbon–carbon double bond remained in the

new product. Indeed, signals for the NCH= and the CCH=

protons appear, as in the dihydropyridine 12b, at δ = 6.71

and 6.83 ppm (as two doublets) and at δ = 5.15 (complex

Scheme 24. Hydroxylactonisation reactions.

Thus, addition of 1.2 equiv. of m-chloroperbenzoic acid signal), respectively. The shapes and the multiplicities of

to a dichloromethane solution of the acid 12b gave, after 2 h these signals agree with the presence of rotamers. Two new

at room temperature and silica gel purification, a viscous oil singlets, each due to one proton, appear at low field, at δ =

1

(75%). According to the H NMR spectrum, no m-chloro- 6.27 and 6.41 ppm, whereas three high-field signals are also

benzoate substituent was present in the new compound, observed. The ¹³C NMR data confirmed the presence of

which, however, contained only one double bond (NCH=: the methoxycarbonyl group but also of a new signal for a

δ = 6.81 and 6.91 ppm; CH=: δ = 5.08 and 5.15 ppm) and carbonyl group at δ = 176.21, different from the carbonyl

existed as two rotamers. The presence of a lactone was con- group of the acid 12b (δ_C= 183.60 ppm), and also of a

firmed by the ¹³C NMR spectrum, which exhibits – besides methylene group at δ = 27.33 ppm. H–H and C–H COSY

signals at δ = 152.70 and 152.83 ppm – a signal at δ = NMR spectra finally allowed structure 63b to be assigned

174.05 ppm. Moreover, a signal typical of the NCHO pro- to this new compound (Scheme 26).

ton of a lactone appears at δ = 6.25 and 6.40 ppm (δ =

It is likely that the double bond of the dihydropyridine

80.83 and 81.21 ppm). Signals for a secondary alcohol at δ behaves as an ene carbamate, which is protonated on silica

= 4.79 ppm (δ = 45.60 ppm), together with H–H and H–C gel to give an electrophilic iminium salt. This interacts in-

NMR experiments, corroborated structure 60b.

tramolecularly with the carboxyl group to give a δ-lactone.

A few other examples confirmed the general behaviour The yield of this transformation could be improved firstly

of these acids towards peracids. Thus, under the same con- by heating the isolated acid 12b either in dichloromethane

ditions, the quinoline-derived acid 52b gave the hydroxy lac- or in benzene in the presence of silica gel (12b: SiO₂

=

tone 62b in 30% yield, whereas the deactivated dihydropyri- 2×10^–3mol: 1.5 g): this indeed provided the lactone 63b in

dines 33b and 33c afforded the hydroxy lactones 61b and much better yield (90% conversion by NMR) but upon pu-

61c in 50 and 35% yields, respectively (Scheme 25).

rification only 40% of the lactone could be recovered. Sec-

3730

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

according to the NMR spectra, of two rotamers at room

temperature.

Scheme 26.

ondly, silica gel could just be added to the crude trimethyl-

silyl ester 10b: this constituted the standard procedure since

it provided the lactone 63b much more rapidly (24 vs. 48 h)

in an almost quantitative yield. Similarly, treatment of

either the acid or its precursor with a molar solution of

HCl in diethyl ether (1 equiv.) provided an 80% yield (by

NMR) of the same lactone at room temperature after 4 h.

This latter reaction appeared to be reversible, however, as

evidenced by the formation of the corresponding acid upon

evaporation of the solvent.

Figure 4. DIAMOND view of compound 64b.

Further examples warrant a comment. Firstly, the trans-

formations of 10d and 10f generated by treatment of pyri-

dine with 7d and 7f and containing a stereogenic and a

prostereogenic centre, gave, as expected, mixtures of two

diastereoisomers [63d (4:1), separable in the case of 63f

(10:1)] (Scheme 27). Secondly, although an extra double

bond potentially capable of undergoing a lactonization re-

action was present in the acids 49n and 49o, the only iso-

lated products corresponded to 67n and 67o, again as mix-

tures of diastereoisomers (5:2) (Scheme 28).

Scope of the Reaction: Transformation of the Esters 10a–d

and 10f into the Lactones 63a–d and 63f – X-ray structures

of the Lactones 64b and 66b

The transformation of these esters into the related lac-

tones was general in scope, and the yields of the reactions,

under the standard conditions established for the prepara-

tion of 63b, were dependent on the natures of the substitu-

ents R¹and R²on the ketene acetals: the bulkier the sub-

stituents, the better the yields. This was also confirmed in

the case of 3-methylpyridine (18), which gave 64a and 64b.

The presence of a phenyl group on the pyridine ring in-

creased the yield of the transformation even further (21 Ǟ

65b, 80%). Finally, the structures of these new lactones

Scheme 27.

The one-pot transformations of quinoline and isoquino-

could be assessed through an X-ray crystal analysis of 64b. line were also examined. As far as quinoline was concerned,

A CAMERON projection (Figure 4) confirms the forma- the two acids 51b and 52b were separately subjected to the

tion of the six-membered lactone, with the two hydrogen standard conditions: 52b (R¹= R²= Me) gave a separable

atoms at the ring junction in a cis relationship. Moreover, mixture of the starting acid and the corresponding lactone

no major steric hindrance would impede the free rotation 66b (32% yield) (Scheme 29), the structure of which was

of the methoxycarbonyl group, consistent with the presence, again established by X-ray diffraction analysis (Figure 5).

Scheme 28.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3731

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

No lactone, however, was formed from 51b. Similarly, iso-

quinoline, which afforded only C-1 addition acids, did not

produce lactones.

Scheme 30.

According to its NMR spectra, 68b contains both a lac-

tone (δ_C= 173.8 ppm) and a methoxycarbonyl group (δ_C=

152.5 ppm). The presence of a single carbon–carbon double

bond, together with a high-field signal for a methine group

(δ_C= 13.6 ppm), and of a new low-field signal for one pro-

ton (δ_H= 5.09 ppm), are consistent with the addition of

both the carboxylate and iodide to the second carbon–car-

bon double bond with formation of an iodolactone. One-

and two-dimensional NMR experiments are fully in agree-

ment with a structure such as 68b.

Scheme 29.

Scope of the Transformation

Pyridine and simple substituted ketene acetals 7d and 7h

gave the same type of iodolactones 68d and 68h in 10 and

73% yields (see Exp. Sect.). Small crystals suitable for X-

ray analysis were grown from 68h and allowed the unambig-

uous assessment of their structure (Figure 6), the C–I bond

being trans to both the new carbon–carbon and carbon–

oxygen bonds.

Figure 5. DIAMOND view of compound 66b.

Iodo- and Bromolactonization Reactions: Peculiar

Behaviour of Bromine

One of the major and best studied transformations of

γ,δ-unsaturated carboxylic acids is their conversion into

halolactones in the presence of either iodine or bromine.^[53]

Figure 6. ORTEP view of compound 68h.

In order to obtain insight into the factors governing the

This can be carried out in the presence or in the absence of regiochemistry of the cyclization reaction, several substi-

water and a base. These transformations have even been tuted pyridines were also examined. Of interest were the

extended to unsaturated esters, alkylsilyl esters among transformations of the pyridines 41 and 44 (Scheme 31).

them.^[53]This reaction therefore seemed appropriate for the Pyridine 41 afforded an inseparable 2:1 mixture of the two

one-pot transformation of pyridine and its derivatives into regioisomeric acids 42b and 43b, via the corresponding

δ-lactones through the formation of intermediate unsatu- TMS esters, in 87% yield. The one-pot reaction fortunately

rated trimethylsilyl esters in which the polarities of the car- gave two separable iodolactones 70b and 71b (30 and 10%

bon–carbon double bonds would be set by the presence of yield). According to the NMR spectroscopic data, the lac-

the nitrogen atom. Thus, treatment of a mixture of pyridine tone 70b is similar to those obtained previously, whereas

and bis(TMS)ketene acetal 7b in dichloromethane, first the second product 71b is the result of the lactonization of

with 1 equiv. of methyl chloroformate at room temperature the C-2 acid 43b to C-6. Three carbonyl groups (signals at

and then, after 1 h, with an excess of iodine and aqueous at δ = 153.84, 163.83 and 172.46 ppm) are present in this

sodium hydrogencarbonate at room temperature gave, after compound, which also shows high- and low-field signals at

2 h at room temperature, a 90% yield of 68b (Scheme 30).

δ = 17.93 and 84.47 ppm. H–H and C–H COSY experi-

3732

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

Scheme 31.

Scheme 32.

ments are in agreement with structure 71b, in which the be isolated as white crystals (m.p. 161 °C) and its structure

lactone bridges the carbamate group, so no vinylogous ad- firmly established by X-ray diffraction crystallography (Fig-

dition of iodine to the dihydropyridine carbon–carbon ure 7).

double bond of 43b took place.

The direct iodolactonization of the acids 45b and 46b

(70%, 1:1 mixture) originating from 4-cyanopyridine (44),

however, provided a single iodolactone 72b in 22% yield

(Scheme 32).

A much better result was observed in the case of 2-ben-

zoylpyridine 33, which gave the lactone 73b in 87% yield,

the benzoyl group activating both the addition of the ketene

Scheme 34.

acetal and the addition of the iodonium ion. Although the

conversion of 3-bromo- and 3-hydroxypyridines (74 and 75)

into the corresponding acids occurred in satisfactory yields,

their direct transformation into the iodolactones 76b and

77b (observed in the form of the carbonate) were less satis-

factory, since extensive decomposition was observed during

the purification steps (isolated products 32 and 5% yields

vs. 53 and 40% yields before purification) (Schemes 33 and

34). The bromoiodolactone 76b, which shows the presence

of two rotamers in the NMR spectra, clearly displays two

broad singlets for the HC=N proton and a signal for the

quaternary CBr= carbon atom at δ = 99.35 ppm. It could

Figure 7. ORTEP view of compound 76b.

Dihydropyridines derived from unsaturated acids gave

the same types of iodolactones: no lactones involving the

external, monosubstituted double bonds were observed.

Thus, pyridine, upon successive treatment with the ketene

Scheme 33.

acetals 7n or 7o and then with iodine, gave the iodolactones

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3733

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

78n and 78o in 82 and 55% yields, respectively, and as mix- spectra of this new compound are indeed very close to those

tures of diastereoisomers (2:5 vs. 1:5).

of the bromoiodolactone 76b (vide supra).

Iodolactones from Quinoline and Isoquinoline

Quinoline (50) behaved like pyridine: a 60% yield of the

expected iodolactone 79b was obtained from its successive

treatment with the ketene acetal 7b and with iodine. Al-

though the intermediate acids were formed as a 4:1 mixture

of C-4/C-2 regioisomers, no lactone originating from the C-

2 isomer was observed (Scheme 35).

Scheme 35.

Scheme 37.

Even so, however, no iodolactone was obtained from iso-

quinoline (56) and 7b, whilst its treatment first with the ke-

tene acetal 7n and then with iodine, consistent with its be-

haviour in the protolactonization reaction, gave the tricyclic

As confirmed by the mass spectrum, through the pres-

ence of excess bromine, a second bromine atom had been

introduced in the substrate. This was confirmed as treat-

ment of the acid 12c with 1 equiv. of bromine indeed gave

the expected bromolactone 81c (with trace amounts of the

dibromolactone 82c). Interestingly, the same dibromolac-

tone 82c was obtained upon treatment of the iodolactone

68c with bromine (2 equiv.) (Scheme 37). Similarly, 4-cyano-

pyridine (44) led to dibromolactone 83c (see Exp. Sect.).

These multiple introduction of halides and halide exchange

reactions can be attributed to reversible opening and clo-

sure of the lactone ring.^[54]

1

iodolactone 80n as a mixture of diastereoisomers. The H

NMR spectrum confirmed the presence of the double bond

of the starting dihydroisoquinoline [C(4)–H, C(5)–H: δ =

5.84–6.00 and 6.80–7.00 ppm] and the absence of signals for

the terminal double bond of the intermediate trimethylsilyl

ester. The ¹³C NMR spectrum agrees with the formation of

a γ-lactone (δ = 175.07 ppm) and with the presence of iod-

ine, a low-field signal due to a methylene group occurring

at δ = 7.35 ppm (Scheme 36).

Miscellaneous: Air and Lead Tetraacetate Oxidation

Reactions

As already mentioned, even N-(methoxycarbonyl)dihy-

dropyridines are unstable to oxygen and give, by biomimetic

routes, pyridines via pyridinium derivatives, or polymeric

materials.^[55–61]Similar behaviour was observed for most of

the carboxylic acid substituted dihydropyridines here. Aside

from those bearing a quaternary carbon atom at C-4, dihy-

dropyridines of the general structure 12 underwent fast de-

gradation at room temperature, producing the substituted

Scheme 36.

Surprising Bromolactonization Reactions

Bromine, like iodine, is known to induce the formation pyridines through decarboxylation/demethoxycarbon-

of halolactones from unsaturated acids.^[53]In contrast to ylation. Thus, 12b, 12c and 12f, either at room temperature

iodine, bromine gave no well-defined products in the pres- or at reflux in toluene, in the presence of oxygen, gave the

ence of water. Starting from the acid 12c and an excess of pyridines 84b, 84c and 84f. In contrast, the acid derivatives

bromine in dichloromethane, however, did result in the for- 85 (R³= Me, NEt₂), which are far more stable than the

mation of a lactone (δ_CO= 171.75 ppm) as two rotamers corresponding acids, gave pyridines 86 through demeth-

82c (Scheme 37). Surprisingly, according to the NMR spec- oxycarbonylation at reflux in toluene. The fates of the nitro-

tra, the newly formed crystalline product did not corre- gen substituents in these degradation reactions could also

spond to the expected 81c: only one olefinic proton, giving be established: when starting from the N-(phenoxycarbonyl)-

a singlet at δ = 7.28 ppm (δ = 7.16 ppm for the second rot- dihydropyridine 87c, a 30% yield of phenyl carbonate 88

amer), remained, although the expected signal at δ = was obtained, together with the substituted pyridine 84c

4.92 ppm for the CHBr proton was present. The NMR (50%) (Scheme 38).

3734

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

dioxide. Classical termination reactions would then provide

the observed products.

The more functionalized acid 33c behaved similarly and

gave the lactone 94c (Scheme 40).

Scheme 40.

Peculiar Behaviour of Pyrazines towards Bis(trimethylsilyl)-

ketene Acetals: Direct Formation of γ-Lactones

Successive formations of iminium derivatives are the two

similar key steps allowing the direct transformation of pyri-

dines and their derivatives into δ-lactones, through success-

ive interactions of the nitrogen atom with a first electro-

phile, methyl chloroformate, and of a double bond of the

produced dihydropyridines with a second electrophile, an

acid or a halogen. However, the use of an excess of methyl

chloroformate did not give rise to the formation of lactones.

Nevertheless, this might be possible through the introduc-

tion of a second nitrogen atom in the aromatic ring, and

has been successively achieved in transformations of pyr-

azines into bicyclic γ-lactones.^[67]

Treatment of pyrazine 95 first with the ketene acetal 7b

and then with 3 equiv. of methyl chloroformate thus gave a

single crystalline product 96b in 47% yield after 2 h at room

temperature (Scheme 41). Both the mass spectrum and the

NMR spectroscopic data confirmed the formation of a bi-

cyclic lactone through addition of 1 equiv. of 7b to the dou-

bly activated pyrazine moiety.

Scheme 38.

Finally, in order to try to bring possible radical degrada-

tions to the fore, the acid 12c was subjected to treatment

with lead tetraacetate in benzene at reflux.^[62]Within min-

utes, this had resulted in the formation of a rather complex

mixture of products, which were separated and charac-

terized as 84c, 89c, the known lactone 63c, and the acetoxy

lactone 90c in 18, 20, 8, and 14% yields, respectively

(Scheme 39). It is likely that this transformation successively

involves the radicals 91c, 92c and 93c, with loss of carbon

Scheme 41.

Especially diagnostic signals for two methoxycarbonyl

groups appeared in the NMR spectrum at δ = 3.76 and

3.73 ppm, and for only two methyl groups, as singlets, origi-

nating from the ketene acetal 7b at δ = 1.35 and 1.09 ppm.

The ¹³C NMR spectroscopic data (δ_co= 178.2, 153.6 and

152.9 ppm) confirmed the presence of both a γ-lactone and

the two methoxycarbonyl groups. Pyrazine behaved simi-

larly with the ketene acetal 7c, affording the lactone 96c

in 58% yield. The structures of these lactones were finally

confirmed by an X-ray analysis (Figure 8). Addition of an

extra ring to pyrazine, as in quinoxaline 97, did not modify

Scheme 39.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3735

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

the course of the reaction since the corresponding lactone

98b was obtained in 75% yield.

Conclusions

In summary, a large series of new functionalized dihy-

dropyridines and their derivatives has been obtained in sat-

isfactory yields by treatment of nonactivated bis(trimethyl-

silyl)ketene acetals with activated azaaromatic compounds.

The transformation of these nitrogen-containing acids and,

more interestingly, of their trimethylsilyl ester precursors

into lactones of various sizes by an intramolecular one-pot

approach has been outlined. The scope and the limitations

of these reactions were established, confirming the high nu-

cleophilicity of ketene acetals^[68,69]and the great potential

properties of a special class of these derivatives, bis(tri-

methylsilyl)ketene acetals, as 1,3-carbon,oxygen dinucleo-

philes.

Experimental Section

Figure 8. DIAMOND view of compound 96c.

General Remarks: All reactions were performed under dry argon.

Solvents were distilled from sodium/benzophenone ketyl (diethyl

ether, tetrahydrofuran), phosphorus pentoxide (dichloromethane)

and saturated with argon. Merck silica gel (type 60, 0.063–

0.200 mm) was used for column chromatography. ¹H NMR: Bruker

AC 200 (200 MHz), Bruker ARX 400 (400 MHz). ¹³C NMR:

These transformations can be considered equivalent to

double nucleophilic additions of bis(trimethylsilyl)ketene

acetals to (arene)tricarbonylchromium complexes, since in

both cases a γ-lactone is formed as the result of a double

activation reaction, in the first example by a metal, in the Bruker AC 200 (50 MHz), Bruker ARX 400 (100 MHz). All NMR

spectra were recorded in CDCl₃unless stated otherwise, with

CHCl₃as internal standard. MS and HRMS: JEOL MS 700. M.p.:

Reichert melting point apparatus, the reported values are uncor-

rected. TLC: Merck silica gel plates (60 F₂₅₄, 0.25 mm).

second by an acylating agent, methyl chloroformate

(Scheme 42). The difference between the two systems lies in

the fate of the activating groups: in the last step of the me-

tal-driven reaction the metal ion is lost, leading to a metal-

free diene, whereas in the case of pyrazine the two meth-

oxycarbonyl groups remain on the new addition product,

which therefore contains only one carbon–carbon double

bond.

Synthesis of Bis(trimethylsilyl)ketene Acetals: The saturated and

conjugated ketene acetals were prepared in two steps (via trimethyl-

silyl esters) from the corresponding acids by reported pro-

cedures.^[33]Similarly, pent-4-enoic and hex-5-enoic acids gave com-

pounds 7n and 7o.

1,1-Bis(trimethylsilanyloxy)penta-1,4-diene (7n): 74% yield, liquid,

1

b.p. 80 °C/15 Torr. H NMR: δ = 0.25 (s, 18 H), 2.71(d, J = 6 Hz,

2 H), 3.60 (t, J = 6 Hz, 1 H), 4.90 (m, 2 H), 5.80 (m, 1 H) ppm.

¹³C NMR: δ = 0.3, 29.6, 80.0, 113.2, 139.9, 159.9 ppm.

1,1-Bis(trimethylsilanyloxy-hexa-1,5-diene (7o): 66% yield, liquid,

b.p. 90 °C/15 Torr. ¹H NMR: δ = 0.21 (m, 18 H), 2.96 (m, 4 H),

3.57 (s, 1 H), 4.99 (m, 2 H), 5.80 (m, 1 H) ppm. ¹³C NMR: δ =

0.5, 25.9, 35.0, 82.8, 115.0, 139.0, 150.8 ppm.

Synthesis of Dihydropyridines: A dichloromethane solution (10 mL)

of methyl chloroformate (5 mmol) was slowly added at room tem-

perature to a solution of bis(trimethylsilyl)ketene acetal (3.5 mmol)

and pyridine (2.5 mmol) in dichloromethane (40 mL). Stirring for

2 h followed by evaporation of the solvent gave an oil, which was

chromatographed on silica gel [AcOEt/petroleum ether (PE),

30:70].

Methyl 4-Carboxymethyl-4H-pyridine-1-carboxylate (12a): 48%

1

yield (0.24 g), white crystals, m.p. 87 °C. H NMR: δ = 2.42 (d, J

= 7.4 Hz, 2 H), 3.37 (m, 1 H), 3.41 (s, 3 H), 4.86 (m, 2 H), 6.68

and 6.81 (d, J = 8 Hz, 2 H), 9.00 (s, 1 H) ppm. ¹³C NMR: δ =

29.37, 42.99, 53.54, 108.21, 108.63, 123.22, 123.58, 151.90,

177.19 ppm. MS: calcd. for C₉H₁₄N₂O₄[M + NH₃]⁺215; found

215.

Methyl

4-(1-Carboxy-1-methylethyl)-4H-pyridine-1-carboxylate

(12b): 70% yield (0.35 g), white crystals, m.p. 98 °C. ¹H NMR: δ =

Scheme 42.

1.14 (s, 6 H), 3.37 (s, 1 H), 3.79 (s, 3 H), 4.85 (m, 2 H), 6.80 and

3736

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

6.95 (d, J = 7.5 Hz, 2 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 21.30,

40.19, 47.17, 53.57, 105.68, 106.02, 124.66, 124.96, 151.90,

183.60 ppm. HRMS: calcd. for C₁₁H₁₆NO₄[M + H]⁺226.100;

found 224.09.

53.40, 105.86, 106.21, 120.73, 121.20, 122.23, 124.43, 125.12,

153.78, 175.80 ppm.

Methyl 4-(1-Carboxy-1-methylethyl)-2-methyl-4H-pyridine-1-car-

boxylate (15b): 70% yield (0.39 g), yellow liquid. ¹H NMR: δ =

1.18 (s, 6 H), 2.10 (s, 3 H), 3.30 (s, 1 H), 3.74 (s, 3 H), 4.73–4.91

(m, 2 H), 6.92 (d, J = 8 Hz, 1 H), 11.00 (s, 1 H) ppm. ¹³C NMR:

δ = 20.93, 21.04, 22.07, 41.13, 47.10, 53.02, 107.16, 108.97, 127.76,

135.56, 152.56, 183.63 ppm. MS: calcd. for C₁₂H₂₀N₂O₄[M +

NH₃]⁺257; found 257.

Methyl 4-(1-Carboxycyclohexyl)-4H-pyridine-1-carboxylate (12c):

1

70% yield (0.47 g), white crystals, m.p. 120 °C. H NMR: δ = 1.4

(m, 10 H), 3.17 (s, 1 H), 3.78 (s, 3 H), 4.80 (m, 2 H), 6.81 and 6.94

(d, J = 7.5 Hz, 2 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 23.52–

30.08, 41.48, 52.96, 53.52, 105.45, 105,65, 124.45, 124.68, 151.90,

180.6 ppm. MS: calcd. for C₁₄H₂₂N₂O₄[M + NH₃]⁺283; found

283.

Methyl 4-(1-Carboxy-1-methylethyl)-2-vinyl-4H-pyridine-1-carbox-

ylate (17b): 40% yield (0.25 g), yellow liquid. ¹H NMR: δ = 0.99

(s, 3 H), 1.02 (s, 3 H), 3.17 (m, 1 H), 3.62 (s, 3 H), 4.82 (m, 2 H),

4.99 (m, 1 H), 5.25 (m, 1 H), 6.36 and 6.41 (d, 1 H), 6.79 (d, J =

8 Hz, 1 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 20.79, 21.20, 41.10,

47.15, 53.14, 107.88, 109.32, 112.87, 127.41, 134.43, 138.63, 152.40,

183.15 ppm. MS: calcd. for C₁₃H₂₀N₂O₄[M + NH₃]⁺251; found

251.

Methyl 4-(1-Carboxyethyl)-4H-pyridine-1-carboxylate (12d): 37%

yield (0.20 g), yellow liquid. ¹H NMR: δ = 1.03 (d, J = 8 Hz, 3 H),

2.35 (m, 1 H), 3.35 (d, J = 4 Hz, 1 H), 3.68 (s, 3 H), 4.66 (m, 2 H),

6.68 and 6.80 (d, J = 8 Hz, 2 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ

= 29.37, 35.17, 45.03, 53.34, 105.51, 106.01, 107.90, 108.14, 124.09,

151.76, 177.52 ppm.

Methyl 4-(1-Carboxy-1-methylethyl)-3-methyl-4H-pyridine-1-car-

boxylate (19b): 60% yield (0.38 g), white crystals, m.p. 100 °C. H

Methyl 4-(1-Carboxypropyl)-4H-pyridine-1-carboxylate (12e): 40%

yield (0.23 g), yellow liquid. H NMR: δ = 0.91 (t, J = 7 Hz, 3 H),

1

NMR: δ = 1.13 (s, 6 H), 1.64 (s, 3 H), 3.37 (s, 1 H), 3.78 (s, 3 H),

4.88 (m, 1 H), 6.64 and 6.77 (s, 1 H), 6.81 and 6.99 (m, 1 H), 11.00

(s, 1 H) ppm. ¹³C NMR: δ = 21.21, 25.88, 40.18, 46.65, 53.43,

105.32, 105.52, 115.08, 115.38, 121.43, 121.60, 124.51, 124.70,

151.87, 184.70 ppm. MS: calcd. for C₁₂H₂₀N₂O₄[M + NH₃]⁺257;

found 257.

1.58 (dt, J₁= J₂= 7 Hz, 2 H), 2.59 (t, J = 7 Hz, 1 H), 3.33 (s, 1

H), 3.78 (s, 3 H), 4.84 (m, 2 H), 6.75 and 6.84 (d, J = 7 Hz, 2 H),

11.00 (s, 1 H) ppm. ¹³C NMR: δ = 12.12, 21.06, 35.07, 53.46, 54.06,

106.56, 106.58, 107.97, 107.99, 123.75, 124.77, 151.90, 178.50 ppm.

Methyl

4-(1-Carboxy-2-methylpropyl)-4H-pyridine-1-carboxylate

1

(12f): 30% yield (0.18 g), liquid. H NMR: δ = 0.96 (t, J = 6.4 Hz,

6 H), 2.10 (m, 1 H), 2.19 (m, 1 H), 3.35 (m, 1 H), 3.77 (s, 3 H),

4.89 (m, 2 H), 6.71 and 6.84 (d, J = 8 Hz, 2 H), 10.2 (s, 1 H) ppm.

¹³C NMR: δ = 19.25, 20.85, 26.01, 32.60, 53.42, 59.27, 107.11,

107.18, 107.53, 123.58, 123.60, 151.85, 178.79 ppm. MS: calcd. for

C₁₂H₂₀N₂O₄[M + NH₃]⁺257; found 257.

Methyl 4-(1-Carboxycyclohexyl)-3-methyl-4H-pyridine-1-carboxyl-

ate (19c): 75% yield (0.53 g), white solid, m.p. 150 °C. ¹H NMR: δ

= 1.1–2.1 (m, 10 H), 1.77 (s, 3 H), 3.22 (d, J = 5.6 Hz, 1 H), 3. 85

(s, 3 H), 4.97 (m, 1 H), 6.72 and 6.85 (s, 1 H), 6.92 and 7.06 (d, J

= 8 Hz, 1 H), 10.5 (m, 1 H) ppm. ¹³C NMR: δ = 21.1–31.6, 47.17,

53.21, 53.85, 106.21, 115.03, 115.32, 122.14, 122.45, 125.08, 125.53,

152.43, 184.04 ppm. MS: calcd. for C₁₅H₂₄N₂O₄[M + NH₃]⁺297;

found 297.

Methyl 4-(1-Carboxy-2,2-dimethylpropyl)-4H-pyridine-1-carboxyl-

ate (12g): 90% yield (0.56 g), white crystals, m.p. 180 °C. ¹H NMR:

δ = 1.01 (s, 9 H), 2.17 (d, J = 4 Hz, 1 H), 3.31 (d, J = 4 Hz, 1 H),

3.74 (s, 3 H), 4.90 (m, 2 H), 6.67 and 6.78 (d, J = 8 Hz, 2 H),

11.00(s, 1 H) ppm. ¹³C NMR: δ = 28.52, 32.16, 33.06, 34.67, 53.44,

107.84, 108.18, 109.51, 109.88, 123.06, 123.40, 151.83, 178.73 ppm.

Methyl 4-(1-Carboxy-2-methylpropyl)-3-methyl-4H-pyridine-1-car-

boxylate (19f and 20f): 65% yield (global) (0.42 g), liquid. Major

1

Compound: H NMR: δ = 0.84 (m, 6 H), 1.56 (s, 3 H), 2.08 (m, 1

H), 2.47 (m, 1 H), 3.37 (t, J = 4 Hz, 1 H), 3.84 (s, 3 H), 5.12 (m,

1 H), 6.64 and 6.82 (s, 1 H), 6.83 and 6.97 (d, J = 8 Hz, 1 H), 10.5

(s, 1 H) ppm. ¹³C NMR: δ = 19.71, 21.85, 22.74, 25.85, 27.50,

39.42, 53.79, 106.80, 107.16, 116. 41, 116.79, 120.27, 120.57,

123.70, 124.13, 152.28, 181.11 ppm. Minor Compound: ¹H NMR:

δ = 0.98 (m, 6 H), 1.76 (s, 3 H), 2.06 (m, 1 H), 2.41 (m, 1 H), 3.27

(t, J = 4 Hz, 1 H), 3.78 (s, 3 H), 4.89 (m, 1 H), 6.64 and 6.82 (s, 1

H), 6.83 and 6.97 (d, J = 8 Hz, 1 H), 10.5 (s, 1 H) ppm. ¹³C NMR:

δ = 19.99, 21.82, 22.09, 26.41, 38.20, 53.42, 104.90, 105.22, 115.71,

116.25, 120.12, 120.45, 124.28, 124.60, 152.30, 179.24 ppm. MS:

calcd. for C₁₃H₂₂N₂O₄[M + NH₃]⁺271; found 271.

Methyl 4-[Carboxy(phenyl)methyl]-4H-pyridine-1-carboxylate (12h):

75% yield (0.52 g), yellow liquid. H NMR: δ = 3.43 (s, 1 H), 3.60

1

(m, 1 H), 3.70 (s, 3 H), 4.45 and 5.00 (m, 1 H), 6.54 and 6.68 (d, J

= 6.6 Hz, 1 H), 6.68 and 6.82 (d, J = 6.6 Hz, 1 H), 7.30 (s, 5 H),

10.7 (s, 1 H) ppm. ¹³C NMR: δ = 36.15, 53.53, 59.95, 106.33,

106.76, 107.30, 107.72, 123.56, 123.88, 124.16, 124.94, 135.85 ppm.

MS: calcd. for C₁₅H₁₈N₂O₄[M + NH₃]⁺291; found 291.

Methyl 4-[Carboxy(trimethylsilanyl)methyl]-4H-pyridine-1-carbox-

1

ylate (12i): 70% yield (0.47 g), liquid. H NMR: δ = 0.17 (s, 9 H),

2.15 (d, J = 8 Hz, 1 H), 3.50 (m, 1 H), 3.79 (s, 3 H), 4.95 (m, 2 H),

6.71 and 6.84 (m, 2 H), 10.7 (s, 1 H) ppm. ¹³C NMR: δ = –0.88,

21.43, 32.32, 53.84, 108.75, 109.23, 109.80, 109.83, 123.48, 123.93,

124.16, 124.59, 152.23, 180.57 ppm.

Methyl

4-(1-Carboxy-1-methylethyl)-3-phenyl-4H-pyridine-1-car-

boxylate (22b): 90% yield (0.67 g), white solid, m.p. 154 °C. ¹H

NMR: δ = 0.83 (s, 3 H), 1.02 (s, 3 H), 3.75 (s, 3 H), 3.97 (d, J =

3.4 Hz, 1 H), 4.96 (m, 1 H), 6.9–7.3 (m, 7 H), 10.5 (s, 1 H) ppm.

¹³C NMR: δ = 18.71, 21.03, 42.57, 48.23, 53.66, 106.39, 120.02,

126.4–128.5, 140.53, 152.02, 183.45 ppm. C₁₇H₁₉NO₄(301.3): C

67.76, H 6.36, N 4.65; found C 67.64, H 6.52, N 4.48.

Methyl

4-[Carboxy(phenoxy)methyl]-4H-pyridine-1-carboxylate

1

(12j): 75% yield (0.54 g), white crystals, m.p. 120 °C. H NMR: δ

= 3.67 (m, 1 H), 3.77 (s, 3 H), 4.50 (d, J = 5.2 Hz, 1 H), 4.94 (m,

2 H), 6.8–7.2 (m, 7 H), 10.5 (s, 1 H) ppm. ¹³C NMR: δ = 36.88,

53.74, 80.05, 104.12, 104.25, 104.68, 104.72, 115.45, 122.09, 125.01,

125.20, 129.68, 151.98, 157.82, 174.20 ppm. HRMS: calcd. for

C₁₅H₁₆NO₅[M + H]⁺290.0950; found 289.0905.

Methyl

2-(1-Carboxy-1-methylethyl)-4-phenyl-2H-pyridine-1-car-

boxylate (24b): 30% yield (0.23 g), yellow liquid. ¹H NMR: δ =

1.15 (s, 6 H), 3.67 (s, 3 H), 5.21 and 5.32 (s, 1 H), 5.32–5.70 (m, 2

Methyl 2-Carboxymethyl-2H-pyridine-1-carboxylate (13a): 20% H), 6.80 and 6.98 (d, J = 3.6 Hz, 1 H), 7.2–7.3 (m, 5 H), 11.3 (s, 1

1

yield (0.10 g), viscous liquid. H NMR: δ = 2.52 (m, 2 H), 3.72 (s,

3 H), 5.19 (m, 2 H), 5.60 (m, 1 H), 5.91 (m, 1 H), 6.56 and 6.68

(d, J = 8 Hz, 1 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 29.28, 42.90,

H) ppm. ¹³C NMR: δ = 19.66, 50.13, 53.53, 57.53, 108.28, 114.48,

125.1–128.5, 138.63, 155.14, 182.12 ppm. MS: calcd. for

C₁₇H₂₂N₂O₄[M + NH₃]⁺319; found 319.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3737

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

Methyl

4-(1-Carboxy-1-methylethyl)-2-phenyl-4H-pyridine-1-car-

H), 3.38 (m, 1 H), 3.51 (s, 3 H), 4.96 (m, 1 H), 5.36 (m, 1 H), 6.92

(d, J = 8 Hz, 1 H), 7.4–7.7 (m, 5 H), 11.00 (s, 1 H) ppm. ¹³C NMR:

δ = 21.34, 21.47, 39.27, 47.23, 53.39, 107.31, 116.99, 126.73, 128.4–

137.7, 151.49, 182.73, 190.10 ppm.

1

boxylate (26b): 10% yield (0.08 g), liquid. H NMR: δ = 1.14 (s, 3

H), 1.16 (s, 3 H), 3.35 (s, 1 H), 3.72 (s, 3 H), 5.40 (m, 2 H), 7.02

(d, J = 4 Hz, 1 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 20.86, 41.87,

52.95, 53.47, 109.15, 112.91, 125.79, 125.8–138.4, 152.66,

183.15 ppm. C₁₇H₁₉NO₄(301.3): C 67.76, H 6.36, N 4.65; found C

68.55, H 6.37, N 4.65.

Methyl 2-(3-Carboxyallyl)-2H-pyridine-1-carboxylate (47k): 90%

yield (0.51 g), liquid. ¹H NMR: δ = 2.25 and 2.51 (m, 2 H), 3.72

(s, 3 H), 4.79 and 4.92 (m, 1 H), 5.25 (m, 1 H), 5.48 (m, 1 H), 5.80

(d, J = 15Hz, 1 H), 5.90 (m, 1 H), 6.58 and 6.72 (d, J = 7 Hz, 1

H), 6.99 (m, 1 H), 10.8 (s, 1 H) ppm. ¹³C NMR: δ = 37.06, 37.20,

51.21, 51.35, 53.43, 105.91, 106.34, 121.05, 121.21, 122.43, 122.84,

123.51, 124.93, 125.49, 146.35, 146.49, 153.95, 171.34 ppm. MS:

calcd. for C₁₁H₁₆N₂O₄[M + NH₃]⁺241; found 241.

Methyl 3-Benzoyl-4-(1-carboxy-1-methylethyl)-4H-pyridine-1-car-

boxylate (33b): 90% yield (0.74 g), white solid, m.p. 154 °C. ¹H

NMR: δ = 0.96 (s, 3 H), 1.01 (s, 3 H), 3.69 (s, 3 H), 4.07 (d, J =

6 Hz, 1 H), 5.05 (dd, J₁= 6 Hz, J₂= 8 Hz, 1 H), 6.80 (d, J = 8 Hz,

1 H), 7.2–7.6 (m, 6 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 20.19,

22.37, 39.27, 48.25, 54.28, 108.81, 118.45, 123.99, 128.4–137.6,

151.63, 182.16, 196.41 ppm. C₁₈H₁₉NO₅(329.3): C 65,64, H 5.81,

N 4.25; found C 65,93, H 5.88, N 4.18.

Methyl 2-(3-Carboxybut-2-enyl)-2H-pyridine-1-carboxylate (47l):

55% yield (0.33 g), liquid. ¹H NMR: δ = 1.73 and 1.75 (s, 3 H),

2.24 and 2.54 (m, 2 H), 3.74 (s, 3 H), 4.78 and 4.91 (m, 1 H), 5.20

and 5.30 (m, 1 H), 5.46 (m, 1 H), 5.87 (m, 1 H), 6.57 and 6.70 (d,

J = 6.4 Hz, 1 H), 6.83 and 6.88 (m, 1 H), 10.2 (s, 1 H) ppm. ¹³C

NMR: δ = 12.05, 12.43, 32.27, 33.42, 51.32, 53.36, 53.87, 105.77,

106.24, 121.4–129.8, 139.12, 141.17, 151.86, 153.90, 173.10 ppm.

Methyl 3-Benzoyl-4-(1-carboxycyclohexyl)-4H-pyridine-1-carboxyl-

ate (33c): 90% yield (0.83 g), white solid, m.p. 165 °C. H NMR: δ

= 1.0–2.0 (m, 10 H), 3.76 (s, 3 H), 4.02 (m, 1 H), 5.15 (m, 1 H),

6.90 (d, J = 8 Hz, 1 H), 7.4–7.7 (m, 6 H), 11.00 (s, 1 H) ppm. ¹³C

NMR: δ = 23.3–30.3, 40.44, 54.08, 54.28, 108.49, 118.53, 123.97,

129.2–137.7, 151.73, 180.58, 196.41.

1

Methyl

2-(3-Carboxy-2-methylallyl)-2H-pyridine-1-carboxylate

(47m): 25% yield (0.16 g), liquid. ¹H NMR: δ = 1.91, 1.96, 2.13

and 2.21 (s, 3 H), 2.6 (m, 2 H), 3.70 and 3.76 (s, 3 H), 4.82 (m, 1

H), 5.39 (m, 1 H), 5.50 (m, 1 H), 5.64 and 5.73 (s, 1 H), 5.92 (m,

1 H), 6.65 and 6.75 (d, J = 8 Hz, 1 H), 10.8 (s, 1 H) ppm. ¹³C

NMR: δ = 19.26, 26.05, 27.06, 30.94, 32.30, 36.48, 36.90, 42.17,

44.57, 50.16, 50.50, 51.10, 53.49, 106.30, 106.60, 108.59, 109.11,

117.52, 118.18, 118.39, 122.45, 122.95, 124.38, 124.59, 125.43,

157.86, 158.88, 171.65 ppm.

Dimethyl 4-(1-Carboxy-1-methylethyl)-4H-pyridine-1,3-dicarboxyl-

ate (34b): 65% yield (0.46 g), white solid, m.p. 161 °C. ¹H NMR: δ

= 0.99 (s, 3 H), 1.01 (s, 3 H), 3.65 (s, 3 H), 3.77 (m, 1 H), 3.82 (s,

3 H), 5.09 (dd, J₁= 6 Hz, J₂= 2 Hz, 1 H), 6.90 (d, J = 6 Hz, 1 H),

7.97 (m, 1 H), 11.0 (s, 1 H) ppm. ¹³C NMR: δ = 20.36, 21.93, 39.63,

48.52, 51.98, 54.62, 108.44, 109.30, 124.69, 134.93, 151.97, 168.41,

183.45 ppm. C₁₃H₁₇NO₆(283.3): C 55.12, H 6.05, N 4.94; found C

54.77, H 6.34, N 5.00.

Methyl 2-(3-Carboxyallyl)-3-diethylcarbamoyl-2H-pyridine-1-car-

1

boxylate (48k): 85% yield (0.69 g), liquid. H NMR: δ = 1.15 (m,

Dimethyl 4-(1-Carboxy-1-methylethyl)-4H-pyridine-1,3-dicarboxyl-

ate (35b): 42% yield (0.28 g), white solid, m.p. 340 °C. ¹H NMR

(MeOD): δ = 0.99 (s, 3 H), 0.96 (s, 3 H), 3.70 (d, J = 8 Hz, 1 H),

3.78 (s, 3 H), 5.04 (d, J = 8 Hz, 1 H), 6.87 (d, J = 8 Hz, 1 H), 7.92

(m, 1 H), 10.50 (s, 2 H) ppm. ¹³C NMR (MeOD): δ = 20.09, 23.42,

40.32, 49.80, 54.78, 109.73, 110.10, 125.22, 135.46, 153.11, 171.09,

180.37 ppm. C₁₂H₁₅NO₆(269.2): C 53.53, H 5.62, N 5.2; found C

53.90, H 6.23, N 5.29.

6 H), 2.52 (m, 2 H), 3.38 (m, 4 H), 3.77 (s, 3 H), 5.33 (m, 1 H),

5.33 and 5.43 (m, 1 H), 5.76 (d, J = 14 Hz, 1 H), 6.13 (m, 1 H),

6.75 and 6.85 (m, 1 H), 6.92 (m, 1 H), 11.5 (m, 1 H) ppm. ¹³C

NMR: δ = 13.41, 14.20, 36.33, 52.17, 53.66, 60.48, 123.4–127.5,

145.49, 145.79, 153.50, 154.22, 169.20, 170.21 ppm.

Methyl 4-(1-Carboxybut-3-enyl)-4H-pyridine-1-carboxylate (49n):

1

85% yield (0.51 g), liquid. H NMR: δ = 2.36 (m, 3 H), 3.41 (s, 1

H), 3.79 (s, 3 H), 4.82 (m, 2 H), 5.02 (m, 2 H), 5.76 (m, 1 H), 6.81

and 6.90 (d, J = 8 Hz, 2 H), 8.9 (m, 1 H) ppm. ¹³C NMR: δ =

31.94, 34.95, 51.67, 53.61, 106.76, 107.64, 116.92, 124.44, 135.43,

151.89, 179.48 ppm.

Methyl 4-(1-Carboxy-1-methylethyl)-3-cyano-4H-pyridine-1-carbox-

ylate (36b): 46% yield (0.29 g), white solid, m.p. 146 °C. ¹H NMR:

δ = 1.11 (s, 3 H), 1.26 (s, 3 H), 3.52 (d, J = 5 Hz, 1 H), 3.82 (s, 3

H), 4.94 and 4.98 (d, J = 5 Hz, 1 H), 6.85 (m, 1 H), 7.59 (s, 1 H),

11.2 (s, 1 H) ppm. ¹³C NMR: δ = 20.30, 22.05, 41.03, 48.22, 54.56,

90.24, 106.69, 119.12, 123.97, 138.23, 150.58, 181.57 ppm. MS:

calcd. for C₁₂H₁₇N₃O₄[M + NH₃]⁺268; found 268.

Methyl 4-(1-Carboxypent-4-enyl)-4H-pyridine-1-carboxylate (49o):

1

55% yield (0.42 g), liquid. H NMR: δ = 1.60 and 2.00 (m, 4 H),

2.84 (m, 1 H), 3.82 (s, 3 H), 5.00 (m, 2 H), 5.60 and 5.78 (m, 2 H),

5.93 and 6.03 (d, J = 8 Hz, 1 H), 6.83 and 6.99 (d, J = 8 Hz, 1 H),

7.2 (m, 4 H), 9.8 (m, 1 H) ppm. ¹³C NMR: δ = 27.72, 31.74, 50.53,

53.75, 57.06, 111, 00, 111,25, 116.01, 124.8–131.0, 137.65, 154.51,

179.66 ppm.

Methyl 4-(1-Carboxy-1-methylethyl)-3-diethylcarbamoyl-4H-pyri-

1

dine-1-carboxylate (37b): 90% yield (0.73 g), liquid. H NMR: δ =

1.12 (m, 12 H), 3.27 (t, J = 7 Hz, 2 H), 3.58 (t, J = 7 Hz, 2 H),

3.81 (s, 3 H), 5.00 (m, 1 H), 6.88 (m, 1 H), 7.13 (m, 1 H), 8.9 (s, 1

H) ppm. ¹³C NMR: δ = 13.23, 20.82, 22.09, 41.70, 41.86, 48.03,

53.89, 107.49, 113.89, 123.84, 126.14, 151.79, 170.84, 180.83 ppm.

MS: calcd. for C₁₆H₂₄N₃O₅[M + NH₃]⁺342; found 342.

Methyl 2-Carboxymethyl-2H-quinoline-1-carboxylate (51a): 90%

1

yield (0.61 g), white solid, m.p. 123 °C. H NMR: δ = 2.32 (d, J =

6.5 Hz, 2 H), 3.64 (s, 3 H), 5.30 (dt, J₁= J₂= 6.5 Hz, 1 H), 5.96

(dd, J₁= 6.5 Hz, J₂= 9.2 Hz, 1 H), 6.35 (d, J = 9.2 Hz, 1 H), 6.9–

7.9 (m, 4 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 37.65, 49.05, 53.18,

111.94, 121.37, 124.5–133.6, 154.51, 176.04 ppm. MS: calcd. for

C₁₃H₁₇N₂O₄[M + NH₃]⁺265; found 265.

Methyl 4-(1-Carboxycyclohexyl)-3-formyl-4H-pyridine-1-carboxyl-

1

ate (38c): 50% yield (0.37 g), yellow solid, m.p. 160 °C. H NMR:

δ = 0.9–1.9 (m, 10 H), 3.68 (d, J = 5 Hz, 1 H), 3.86 (s, 3 H), 5.19

(dd, J₁= 5 Hz, J₂= 8 Hz, 1 H), 6.93 (d, J = 8 Hz, 1 H), 7.74 (s, 1

H), 9.38 (s, 1 H), 11.0 (s, 1 H) ppm. ¹³C NMR: δ = 22.2–28.85,

37.38, 52.75, 53.53, 107.94, 119.11, 123.38, 152.87, 179.00,

189.78 ppm.

Methyl

2-(1-Carboxy-1-methylethyl)-2H-quinoline-1-carboxylate

1

(51b): 20% yield (0.14 g), white solid, m.p. 150 °C. H NMR: δ =

0.97 (s, 3 H), 1.17 (s, 3 H), 3.78 (s, 3 H), 5.43 (d, J = 7.5 Hz, 1 H),

6.00 (dd, J₁= J₂= 7.5 Hz, 1 H), 6.61 (d, J = 7.5 Hz, 1 H), 7.0–7.4

(m, 4 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ = 19.51, 22.10, 48.63,

53.35, 57.62, 124.6–136.2, 153.94, 182.02 ppm.

Methyl 2-Benzoyl-4-(1-carboxy-1-methylethyl)-4H-pyridine-1-car-

1

boxylate (40b): 30% yield (0.25 g), liquid. H NMR: δ = 1.16 (s, 6

3738

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

Methyl 2-(1-Carboxy-2-methylpropyl)-2H-quinoline-1-carboxylate Methyl 4-(1-Carboxybut-3-enyl)-4H-quinoline-1-carboxylate (55n):

FULL PAPER

1

(51f): 55% yield (global) (0.40 g). Major Product: White solid, m.p.

Liquid. H NMR: δ = 2.0–2.6 (m, 3 H), 3.78 (m, 1 H), 3.87 (s, 3

190 °C. ¹H NMR: δ = 0.94 (d, J = 6.8 Hz, 3 H), 1.09 (d, J = 6.8 Hz,

H), 5.03 (m, 2 H), 5.31 (m, 1 H), 5.67 (m, 1 H), 7.2 (m, 4 H), 7.99

3 H), 1.96 (m, 1 H), 2.43 (dd, J₁= 4.8 Hz, J₂= 10.6 Hz, 1 H), 3.74 (d, J = 8 Hz, 1 H), 9.8 (s, 1 H) ppm. ¹³C NMR: δ = 32.01, 39.93,

(s, 3 H), 5.41 (m, 1 H), 6.09 (dd, J₁= 6 Hz, J₂= 9.6 Hz, 1 H), 6.59

(d, J = 9.6 Hz, 1 H), 7.10 (m, 2 H), 7.23 (m, 1 H), 7.47 (m, 1 H),

10.8 (s, 1 H) ppm. ¹³C NMR: δ = 17.60, 21.64, 26.88, 51.73, 53.31,

53.74, 125.0–127.8, 134.41, 154.88, 177.35 ppm. C₁₆H₁₉NO₄

(289.3): C 66.42, H 6.62, N 4.84; found C 65.96, H 6.58, N 4.84.

Minor Product: ¹H NMR: δ = 0.86 (d, J = 6.8 Hz, 3 H), 0.96 (d, J

= 6.8 Hz, 3 H), 1.95 (m, 1 H), 2.23 (dd, J₁= 4 Hz, J₂= 9 Hz, 1

H), 3.70 (s, 3 H), 5.26 (m, 1 H), 6.09 (dd, J₁= 6 Hz, J₂= 10 Hz, 1

H), 6.47 (d, J = 10 Hz, 1 H), 6.9–7.2 (m, 4 H), 10.5 (s, 1 H) ppm.

¹³C NMR: δ = 17.63, 21.54, 26.89, 51.00, 51.10, 53.30, 121.0–128.8,

155.19, 177.47 ppm.

52.63, 53.57, 109.03, 109.33, 117.16, 121.46, 125.2–128.49, 135.07,

136.83, 153.06, 179.37 ppm.

Methyl 1-Carboxymethyl-1H-isoquinoline-2-carboxylate (57a): 90%

yield (0.57 g), white solid, m.p. 126 °C. ¹H NMR: δ = 2.58 and 2.62

(d, J = 6 Hz, 2 H), 3.73 (s, 3 H), 5.81 (m, 2 H), 6.72 and 6.87 (d,

J = 12Hz, 1 H), 7.00 (m, 4 H), 11.00 (s, 1 H) ppm. ¹³C NMR: δ =

39.29, 49.05, 53.18, 111.94, 121.37, 124.5–133.6, 154.51,

176.04 ppm. MS: calcd. for C₁₃H₁₇N₂O₄[M + NH₃]⁺265; found

265.

Methyl 1-(1-Carboxy-1-methylethyl)-1H-isoquinoline-2-carboxylate

1

(57b): 90% yield (0.61 g), white solid, m.p. 158 °C. H NMR: δ =

2-[Carboxy(trimethylsilanyl)methyl]-2H-quinoline-1-carboxylate

(51i): 50% yield (0.42 g), liquid. H NMR (400 MHz): δ = 0.15 (s,

1.08 (s, 3 H), 1.21 (s, 3 H), 3.79 (s, 3 H), 5.75 (m, 2 H), 6.85 (d, J

= 4 Hz, 1 H), 7.0–7.3 (m, 4 H), 11.3 (s, 1 H) ppm. ¹³C NMR: δ

= 20.99, 22.41, 50.38, 53.67, 59.98, 110.91, 124.6–128.2, 154.88,

182.16 ppm. C₁₅H₁₇NO₄(275.3): C 65.64, H 5.81, N 4.25; found C

64.77, H 6.22, N 5.06.

1

9 H), 2.33 (d, J = 5.4 Hz, 1 H), 3.78 (s, 3 H), 5.57 (m, 1 H), 6.27

(dd, J₁= 4.4 Hz, J₂= 3 Hz, 1 H), 6.51 (d, J = 4.4 Hz, 1 H), 7.0–

7.2 (m, 4 H), 10.5 (m, 1 H) ppm. ¹³C NMR: δ = –1.97, 41.95, 50.38,

53.40, 125.0–127.7, 133.97, 152.98, 179.16 ppm. MS: calcd. for

C₁₆H₂₄N₂O₄Si [M + NH₃]⁺337; found 337.

Methyl 1-(1-Carboxyethyl)-1H-isoquinoline-2-carboxylate (57d):

1

58% yield (global) (0.38 g), white solid. Major Product: H NMR:

δ = 1.03 (m, 3 H), 2.75 (dq, J₁= J₂= 8 Hz, 1 H), 3.71 (s, 3 H),

5.51 and 5.63 (d, J = 8 Hz, 1 H), 5.82 and 5.91 (d, J = 8 Hz, 1 H),

6.72 and 6.89 (d, J = 8 Hz, 1 H), 6.9–7.2 (m, 4 H), 9.3 (s, 1 H) ppm.

¹³C NMR: δ = 13.43, 13.70, 44.97, 45.47, 43.18, 53.59, 56.59, 57.07,

110.19, 110.43, 124.5–130.5, 154.06, 154.26, 179.84, 179.94 ppm.

MS: calcd. for C₁₄H₁₈N₂O₄[M + NH₃]⁺279; found 279. Minor

4-(1-Carboxy-1-methylethyl)-4H-quinoline-1-carboxylate

(52b):

1

60% yield (0.41 g), white solid, m.p. 146 °C. H NMR: δ = 1.05 (s,

3 H), 1.13 (s, 3 H), 3.78 (d, J = 7.5 Hz, 1 H), 3.86 (s, 3 H), 5.31

(dd, J₁= J₂= 7.5 Hz, 1 H), 7.1–7.9 (m, 5 H), 11.00 (s, 1 H) ppm.

¹³C NMR: δ = 20.10, 22.27, 45.23, 48.65, 53.51, 110.35, 121.9–

137.7, 153.01, 183.73 ppm. MS: calcd. for C₁₅H₂₀N₂O₄[M + NH₃]⁺

293; found 293.

1

Product: H NMR: δ = 0.88 (m, 3 H), 2.85 (dq, J₁= J₂= 8 Hz, 1

H), 3.71 (s, 3 H), 5.45 and 5.59 (d, J = 8 Hz, 1 H), 5.84 and 5.93

(d, J = 8 Hz, 1 H), 6.78 and 6.93 (d, J = 8 Hz, 1 H), 7.0–7.2 (m, 4

H), 8.2 (s, 1 H) ppm. ¹³C NMR δ = 12.71, 12.83, 42.46, 42.66,

53.29, 53.63, 57.42, 57.95, 109.51, 109.77, 124.8–130.6, 153.71,

153.89, 179.21, 179.68 ppm.

Methyl 4-(1-Carboxy-2-methylpropyl)-4H-quinoline-1-carboxylate

(52f): 10% yield (0.08 g), liquid. H NMR: δ = 0.90 (d, J = 8 Hz,

1

3 H), 1.00 (d, J = 8 Hz, 3 H), 2.06 (m, 1 H), 2.34 (dd, J₁= 5 Hz,

J₂= 6 Hz, 1 H), 3.66 (m, 1 H), 3.82 (s, 3 H), 5.36 (dd, J₁= J₂=

6 Hz, 1 H), 6.9–7.2 (m, 4 H), 7.87 (d, J = 8 Hz, 1 H), 10 (s, 1

H) ppm. ¹³C NMR: δ = 21.54, 21.76, 27.38, 53.30, 53.48, 57.80,

111.12, 121.5–129.7, 153.04, 178.24 ppm.

Methyl

1-(1-Carboxybut-3-enyl)-1H-isoquinoline-2-carboxylate

(58n): 70% yield (global) (0.51 g), liquid. Major Product: ¹H NMR:

δ = 1.93 (m, 1 H), 2.28 (m, 1 H), 2.86 (m, 1 H), 3.78 (s, 3 H), 5.00

(m, 2 H), 5.63 (m, 2 H), 5.93 and 6.02 (d, J = 7 Hz, 1 H), 6.81 and

6.96 (d, J = 7 Hz, 1 H), 7.1 (m, 4 H), 10.2 (m, 1 H) ppm. ¹³C

NMR: δ = 32.21, 32.39, 47.93, 48.08, 53.40, 53.70, 56.81, 57.4,

110.04, 110.24, 117.14, 124.4–130.8, 134.54, 134.77, 153.69, 178.38,

178.79 ppm. Minor Product: ¹H NMR: δ = 2.28 (m, 1 H), 2.42 (m,

1 H), 2.86 (m, 1 H), 3.73 (s, 3 H), 5.00 (m, 2 H), 5.60 (m, 2 H),

5.91 and 6.00 (d, J = 7 Hz, 1 H), 6.77 and 6.94 (d, J = 7 Hz, 1 H),

7.1 (m, 4 H), 10.2 (m, 1 H) ppm. ¹³C NMR: δ = 32.60, 32.90, 50.29,

50.85, 53.40, 56.20, 60.60, 110.50, 110.86, 117.14, 124.4–130.8,

134.54, 134.77, 154.01, 178.38 ppm.

Methyl 2-(3-Carboxyallyl)-2H-quinoline-1-carboxylate (53k): 90%

yield (0.61 g), white solid, m.p. 110 °C. ¹H NMR: δ = 2.35 (m, 2

H), 3.79 (s, 3 H), 5.18 (m, 1 H), 5.74 (d, J = 15.4 Hz, 1 H), 6.01

(dd, J₁= 9 Hz, J₂= 5.6 Hz, 1 H), 6.52 (d, J = 9 Hz, 1 H), 6.98 (m,

1 H), 7.0–7.5 (m, 4 H), 10.7 (s, 1 H) ppm. ¹³C NMR: δ = 36.15,

51.53, 53.32, 123.4–127.9, 133.97, 146.50, 154.84, 171.36 ppm.

Methyl

2-(3-Carboxy-2-methylallyl)-2H-quinoline-1-carboxylate

1

(53m): 75% yield (global) (0.53 g), white solid. Major Product: H

NMR: δ = 2.25 (m, 5 H), 3.73 (s, 3 H), 5.27 (m, 1 H), 5.49 (s, 1

H), 6.03 (dd, J₁= 9 Hz, J₂= 6.2 Hz, 1 H), 6.50 (d, J = 9 Hz, 1 H),

7.0–7.5 (m, 4 H), 10.9 (s, 1 H) ppm. ¹³C NMR: δ = 19.25, 44.04,

50.72, 53.25, 118.12, 124.6–127.9, 133.74, 157.92, 171.66 ppm.

Methyl 1-(3-Carboxyallyl)-1H-isoquinoline-2-carboxylate (59k):

85% yield (0.50 g), white solid, m.p. 125 °C. ¹H NMR: δ = 2.47

and 2.57 (m, 2 H), 3.80 and 3.84 (s, 3 H), 5.39 and 5.55 (t, J =

6 Hz, 1 H), 5.66 and 5.74 (s, 1 H), 5.84 and 5.93 (d, J = 7.8 Hz, 1

H), 6.79 and 6.92 (d, J = 8 Hz, 1 H), 7.0–7.2 (m, 5 H), 10.9(s, 1

H) ppm. ¹³C NMR: δ = 38.60, 38.82, 53.60, 54.66, 55.26, 108.90,

109.19, 123.5–131.1, 146.43, 146.61, 153.49, 153.87, 171.32 ppm.

1

Minor Product: H NMR: δ = 1.94 (s, 3 H), 2.70 (m, 2 H), 3.74 (s,

3 H), 5.40 (m, 1 H), 5.77 (s, 1 H), 6.04 (dd, J₁= 9 Hz, J₂= 6.2 Hz,

1 H), 6.52 (d, J = 9 Hz, 1 H), 7.0–7.5 (m, 4 H), 10.9 (s, 1 H) ppm.

¹³C NMR: δ = 26.58, 36.20, 52.19, 53.25, 118.12, 124.6–129.2,

134.20, 158.69, 171.80 ppm. HRMS: calcd. for C₁₆H₁₈NO₄[M +

H]⁺288.119; found 288.123.

Hydroxylactonisation: m-Chloroperbenzoic acid (2.4 mmol) was

added to a dichloromethane solution (10 mL) of the acid (2 mmol).

After 2 h, the remaining acid was neutralized with an aqueous solu-

tion of sodium hydroxide (10%, 10 mL). Evaporation of the solvent

gave an oil, which was chromatographed on silica gel (AcOEt/PE,

30:70).

Methyl 2-(1-Carboxybut-3-enyl)-2H-quinoline-1-carboxylate (54n):

1

95% yield (global with 55n) (0.67 g), liquid. H NMR: δ = 2.2–2.6

(m, 3 H), 3.75 (s, 4 H), 5.03 (m, 2 H), 5.27 (m, 1 H), 5.67 (m, 1

H), 6.07 (m, 1 H), 6.58 (d, J = 8 Hz, 1 H), 7.13 (m, 3 H), 7.51 (d,

J = 8 Hz, 1 H), 9.9 (m, 1 H) ppm. ¹³C NMR: δ = 32.01, 48.80,

53.22, 53.34, 117.45, 124.8–128.0, 134.54, 155.22, 178.18 ppm. MS:

calcd. for C₁₆H₂₀N₂O₄[M + NH₃]⁺287; found 287.

Methyl 9-Hydroxy-4,4-dimethyl-3-oxo-2-oxa-8-aza-bicyclo[3.3.1]-

non-6-ene-8-carboxylate (60b): 75% yield (0.36 g), liquid. ¹H NMR:

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3739

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

δ = 1.37 (s, 3 H), 1.42 (s, 3 H), 1.60 (s, 1 H), 2.39 (s, 1 H), 3.48 (s,

3 H), 4.79 (s, 2 H), 5.08 and 5.15 (m, 1 H), 6.25 and 6.40 (s, 1 H),

6.81 and 6.91 (d, J = 6 Hz, 1 H) ppm. ¹³C NMR: δ = 26.02, 27.17,

42.52, 42.60, 45.60, 46.17, 51.04, 80.83, 81.21, 103.52, 103.93,

121.84, 152.70, 152.83, 174.05 ppm.

1.26 (d, J = 8 Hz, 3 H), 1.83 and 2.26 (d, J = 14Hz, 2 H), 2.41 (m,

1 H), 2.58 (m, 1 H), 3.75 (s, 3 H), 5.07 (m, 1 H), 6.29 and 6.43 (s,

1 H), 6.65 and 6.78 (d, J = 8 Hz, 1 H) ppm.

Methyl 4-Isopropyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-car-

1

boxylate (63f): 32% yield (0.15 g), white solid. Major Product: H

NMR: δ = 0.95 (d, J = 6.5 Hz, 3 H), 0.99 (d, J = 6.5 Hz, 3 H),

1.86 (m, 1 H), 2.08 (m, 1 H), 2.2–2.4 (m, 2 H), 2.58 (m, 1 H), 3.74

(s, 3 H), 5.07 and 5.18 (t, J = 6.5 Hz, 1 H), 6.29 and 6.44 (s, 1 H),

6.71 and 6.84 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 20.82, 21.26,

23.71, 24.01, 25.31, 25.68, 29.82, 30.06, 53.03, 53.25, 53.66, 79.44,

79.72, 110.14, 110.69, 122.71, 122.95, 152.42, 171.74 ppm. Minor

Product: ¹H NMR: δ = 1.00 (d, J = 6.8 Hz, 3 H), 1.12 (d, J =

6.8 Hz, 3 H), 2.02 (m, 1 H), 2.2–2.4 (m, 3 H), 2.67 (m, 1 H), 3.79

(s, 3 H), 5.09 and 5.20 (t, J = 6.8 Hz, 1 H), 6.31 and 6.46 (s, 1 H),

6.71 and 6.85 (d, J = 3.2 Hz, 1 H) ppm. ¹³C NMR: δ = 20.64,

21.62, 23.74, 25.99, 26.24, 28.44, 29.02, 53.06, 53.47, 53.68, 78.95,

79.20, 107.33, 107.83, 122.75, 122.97, 152.41, 152.49, 171.65 ppm.

Methyl 6-Benzoyl-9-hydroxy-4,4-dimethyl-3-oxo-2-oxa-8-aza-bicy-

clo[3.3.1]non-6-ene-8-carboxylate (61b): 50% yield (0.86 g), white

1

solid, m.p. 190 °C. H NMR: δ = 1.17 (s, 3 H), 1.42 (s, 3 H), 3.35

(m, 1 H), 3.77 (s, 3 H), 4.68 (m, 1 H), 6.11 (m, 1 H), 7.3–7,7 (m, 7

H) ppm. ¹³C NMR: δ = 26.45, 28.08, 39.76, 43.73, 54.64, 58.49,

116.96, 128.5–137.4, 152.50, 175.06, 195.85 ppm. HRMS: calcd. for

C₁₈H₁₉NO₆[M + 1]⁺346.1212; found 346.1291.

Methyl 6Ј-Benzoyl-9Ј-hydroxy-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-

8-azabicyclo[3.3.1]non-6-ene)]-8Ј-carboxylate (61c): 35% yield

(0.26 g), yellow solid, m.p. 206 °C. ¹H NMR: δ = 1.1–1.8 (m, 10

H), 3.65 (s, 1 H), 3.74 (s, 3 H), 4.74 (m, 1 H), 6.08 (m, 1 H), 7.3–

7.6 (m, 7 H) ppm. ¹³C NMR: δ = 21.13–25.21, 37.30, 47.76, 54.60,

57.84, 117.09, 128.67–137.03, 152.51, 174.53, 195.78 ppm.

Methyl 6-Methyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-car-

boxylate (64a): Isolated as by-product of the preparation of the

Methyl

13-Hydroxy-12,12-dimethyl-11-oxo-10-oxa-8-azatricyclo-

1

acids; 16% yield (0.07 g), liquid. H NMR: δ = 1.65 (s, 3 H), 1.90

[7.3.1^1,9.0^2,7]trideca-2,4,6-triene-8-carboxylate (62b): 30% yield

(0.17 g), white solid, m.p. 140 °C. ¹H NMR: δ = 1.08 (s, 3 H), 1.50

(s, 3 H), 2.87 (s, 1 H), 3.00 (s, 1 H), 3.84 (s, 3 H), 4.66 (s, 1 H),

6.37 (s, 1 H), 7.0–7.3 (m, 4 H) ppm. ¹³C NMR: δ = 26.48, 29.18,

43.28, 48.83, 53.69, 60.51, 82.96, 120.56–133.42, 154.40,

174.96 ppm. MS: calcd. for C₁₅H₁₇NO₅[M]⁺291; found 291.

(m, 1 H), 2.20 (m, 1 H), 2.56 (m, 2 H), 3.71 (s, 3 H), 5.52 (m, 1

H), 6.26 and 6.40 (s, 1 H), 6.42 and 6.55 (s, 1 H) ppm. ¹³C NMR:

δ = 18.84, 26.74, 28.14, 35.36, 53.55, 78.84, 117.34, 117.66, 152.56,

169.12 ppm.

Methyl 4,4,6-Trimethyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-

1

carboxylate (64b): 50% yield (0.24 g), white solid, m.p. 122 °C. H

Protolactonisation: Dry silica gel (1.5 g, 25 mmol) was added to the

dichloromethane solutions obtained after the reaction between the

pyridines (2 mmol) and the acetals. Stirring for 2 h at reflux, fol-

lowed by evaporation of the solvent, gave an oil, which was chro-

matographed on silica gel (AcOEt/PE, 35:65).

NMR: δ = 1.23 (s, 3 H), 1.24 (s, 3 H), 1.70 (m, 4 H), 1.94 (m, 1

H), 2.52 (m, 1 H), 3.67 (s, 3 H), 6.11 and 6.23 (m, 1 H), 6.46 and

6.57 (s, 1 H) ppm. ¹³C NMR: δ = 22.33, 25.59, 28.58, 39.65, 43.38,

53.51, 78.93, 116.69, 118.03, 152.38, 176.23 ppm. MS: calcd. for

C₁₂H₁₇NO₄[M + 1]⁺240; found 240.

Methyl

3-Oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-carboxylate

Methyl 4,4-Dimethyl-3-oxo-6-phenyl-2-oxa-8-azabicyclo[3.3.1]non-

6-ene-8-carboxylate (65b): 80% yield (0.48 g), white solid, m.p.

172 °C. ¹H NMR: δ = 0.89 (s, 3 H), 1.28 (s, 3 H), 1.84 and 2.63

(m, 2 H), 2.87 (m, 1 H), 3.74 (s, 3 H), 6.27 and 6.40 (m, 1 H), 6.95–

7.14 (m, 6 H) ppm. ¹³C NMR: δ = 25.74, 28.26, 36.32, 43.61, 53.54,

78.91, 119.89, 121.31–128.52, 152.21, 176.23 ppm. C₁₇H₁₉NO₄

(301.3): C 67.76, H 6.36, N 4.65; found C 67.63, H 6.34, N 4.63.

(63a): 15% yield (0.06 g), liquid. ¹H NMR: δ = 1.43 (d, J = 6.5 Hz,

1 H), 1.96 and 2.11 (m, 2 H), 2.54 (m, 1 H), 3.38 (d, J = 6.5 Hz, 1

H), 3.75 (s, 3 H), 5.12 (m, 1 H), 6.30 and 6.43 (m, 1 H), 6.66 and

6.83 (m, 1 H) ppm. ¹³C NMR: δ = 25.17, 25.68, 28.85, 29.79, 47.69,

53.69, 78.87, 79.17, 111.90, 112.43, 122.08, 123.65, 156.65,

172.22 ppm.

Methyl 12,12-Dimethyl-11-oxo-10-oxa-8-azatricyclo[7.3.1^1,9.0^2,70]-

Methyl 4,4-Dimethyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-

carboxylate (63b): 40% yield (0.18 g), white solid, m.p. 108 °C. H

1

trideca-2(7),3,5-triene-8-carboxylate (66b): 32% yield (0.18 g),

1

NMR: δ = 1.30 (s, 6 H), 1.86 (m, 1 H), 2.10 (m, 1 H), 2.56 (m, 1

H), 3.77 (s, 3 H), 5.15 (m, 1 H), 6.27 and 6.41 (s, 1 H), 6.71 and

6.83 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 24.27, 25.50, 27.33,

34.31, 43.60, 53.68, 79.70, 79.91, 107.87, 108.37, 122.35, 122.10,

152.44,176.21 ppm. C₁₁H₁₅NO₄: C 58.66, H 6.71, N 6.22; found C

58.59, H 7.07, N 5.86.

white solid, m.p. 130 °C. H NMR: δ = 1.16 (s, 3 H), 1.49 (s, 3 H),

2.06 (m, 1 H), 2.77 (m, 1 H), 2.82 (m, 1 H), 3.88 (s, 3 H), 6.61 (m,

1 H), 7.0–7.3 (m, 3 H), 8.30 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ =

24.97, 26.07, 29.08, 41.91, 42.42, 53.75, 81.84, 120.6–134.0, 153.93,

175.80 ppm. C₁₅H₁₇NO₄(275.3): C 65.44; H 6.22, N 5.09; found C

64.90, H 6.23, N 4.81.

Methyl 3Ј-Oxospiro[cyclohexane-1,4Ј-(2-oxa-8-azabicyclo[3.3.1]non-

6-ene)-8-carboxylate (63c): 45% yield (0.24 g), white solid, m.p.

132 °C. ¹H NMR: δ = 1.48 (m, 11 H), 2.56 (m, 2 H), 3.75 (s, 3 H),

5.10 (m, 1 H), 6.22 and 6.36 (s, 1 H), 6.68 and 6.81 (d, J = 8 Hz,

1 H) ppm. ¹³C NMR: δ = 20.76–27.77, 32.41, 33.33, 47.14, 53.61,

78.62, 78.87, 107.12, 107.61, 122.52, 122.78, 152.40, 175.91 ppm.

C₁₄H₁₉NO₄(265.3): C 63.38, H 7.22, N 5.28; found: C 63.54, H

7.38, N 5.36.

Methyl 4-Allyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-carbox-

ylate (67n): 49% yield (0.23 g), liquid. H NMR: δ = 2.0–2.6 (m, 3

1

H), 2.85 and 2.91 (m, 1 H), 3.80 (s, 3 H), 5.0–5.1 (m, 3 H), 5.75

(m, 1 H), 6.36 and 6.48 (s, 1 H), 6.76 and 6.88 (d, J = 8 Hz, 1

H) ppm. ¹³C NMR: δ = 26.13, 28.43, 33.78, 47.09, 54.09, 79.88,

106.29, 106.708, 118.09, 118.64, 123.71, 135.47, 152.80,

172.36 ppm. MS: calcd. for C₁₂H₁₅NO₄[M + 1]⁺238; found 238.

Methyl

4-But-3-enyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-

Methyl 4-Methyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-car-

boxylate (63d): 25% yield (0.1 g), liquid. Major Product: ¹H NMR:

δ = 1.20 (d, J = 8 Hz, 3 H), 2.03 and 2.26 (d, J = 14 Hz, 2 H), 2.41

(m, 1 H), 2.58 (m, 1 H), 3.75 (s, 3 H), 5.07 (m, 1 H), 6.29 and 6.43

(s, 1 H), 6.67 and 6.80 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ =

carboxylate (67o): 48% yield (0.24 g), liquid. ¹H NMR: δ = 1.45

(m, 1 H), 2.00 (m, 3 H), 2.55 (m, 2 H), 4.62 and 4.69 (s, 1 H), 4.84

(m, 3 H), 6.12 and 6.26 (s, 1 H), 6.64, 6.67, 6.76 and 6.79 (d, J =

8 Hz, 1 H) ppm. ¹³C NMR: δ = 7.83, 12.62, 28.17, 28.79, 30.44,

30.84, 36.02, 36.25, 37.04, 37.44, 47.97, 53.94, 81.97, 82.39, 102.84,

14.15, 14.85, 28.15, 29.80, 42.15, 53.80, 76.46, 106.20, 106.81, 103.28, 106.57, 107.00, 116.03, 116.39, 136.26, 136.72, 152.23,

1

123.41, 125.46, 149.27, 173.02 ppm. Minor Product: H NMR: δ =

152.42, 169.87, 170.10 ppm.

3740

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

Iodolactonisation: Iodine (530 mg, 2.1 mmol) and a saturated solu-

tion of sodium hydrogencarbonate (10 mL) were added to the

dichloromethane solutions obtained after the reactions between the

pyridines (2 mmol) and the acetals. After 1 night, the mixture was

treated with a solution of sodium bisulfite in order to eliminate the

remaining iodine. The aqueous phase was washed twice with Et₂O

(10 mL). Concentration of the organic layers gave an oil, which was

chromatographed on silica gel (AcOEt/PE, 40:60).

Methyl

5-Cyano-9-iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo-

[3.3.1]non-6-ene-8-carboxylate (72b): 22% yield (0.17 g), yellow so-

lid, m.p. 194 °C. H NMR: δ = 1.50 (s, 3 H), 1.53 (s, 3 H), 3.82 (s,

3 H), 5.0 (m, 2 H), 6.23 and 6.37 (s, 1 H), 6.85 and 6.97 (d, J =

8 Hz, 1 H) ppm. ¹³C NMR: δ = 14.46, 24.82, 25.33, 47.64, 49.23,

54.99, 102.31, 118.44, 123.37, 152.37, 171.34 ppm.

1

Methyl

7-Benzoyl-9-iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo-

[3.3.1]non-6-ene-8-carboxylate (73b): 87% yield (0.79 g), yellow so-

lid, m.p. 158 °C. ¹H NMR: δ = 1.24 (s, 3 H), 1.33 (s, 3 H), 2.50

and 2.52 (dd, J₁= J₂= 2 Hz, 1 H), 3.47 (s, 3 H), 4.93 (m, 1 H),

5.41 and 5.44 (s, 1 H), 6.32 and 6.34 (d, J = 2 Hz, 1 H), 7.3 (m, 3

H), 7.77 (d, J = 7 Hz, 2 H) ppm. ¹³C NMR: δ = 13.07, 26.06, 27.04,

45.00, 46.83, 54.06, 83.80, 113.01, 128.67, 128.98, 133.25, 134.04,

135.79, 152.18, 172.94, 188.63 ppm. MS: calcd. for C₁₈H₂₁IN₂O₅

[M + NH₃]⁺473; found 473.

Methyl 9-Iodo-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-carbox-

ylate (68a): 50% yield (0.08 g), yellow liquid. ¹H NMR: δ = 2.9 (m,

3 H), 3.87 (s, 3 H), 4.76 (s, 1 H), 5.13 (m, 1 H), 6.32 and 6.46 (s, 1

H), 6.83 and 6.96 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 15.69,

33.63, 33.83, 39.42, 54.56, 82.50, 83.02, 106.68, 107.13, 122.54,

153.09, 167.41 ppm.

Methyl 9-Iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-

ene-8-carboxylate (68b): 60% yield (0.42 g), yellow liquid. ¹H

NMR: δ = 1.20 and 1.30 (s, 6 H), 2.33 (d, J = 6 Hz, 1 H), 3.78 (s,

3 H), 5.09 (m, 2 H), 6.19 and 6.34 (s, 1 H), 6.75 and 6.87 (d, J =

8 Hz, 1 H) ppm. ¹³C NMR: δ = 13.64, 26.12, 27.26, 44.37, 44.51,

46.66, 54.08, 82.69, 83.18, 104.99, 105.42, 121.79, 152.50, 152.67,

173.88 ppm. HRMS: calcd. for C₁₁H₁₅INO₄[M + H]⁺352.0046;

found 352.0040.

Methyl

6-Bromo-9-iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo-

[3.3.1]non-6-ene-8-carboxylate (76b): 32% yield (0.28 g), white so-

lid, m.p. 161 °C. H NMR: δ = 1.38 (s, 3 H), 1.52 (s, 3 H), 2.62 (s,

1

1 H), 3.81 (s, 3 H), 4.95 (m, 1 H), 6.13 and 6.29 (s, 1 H), 7.13 and

7.26 (s, 1 H) ppm. ¹³C NMR: δ = 12.50, 26.14, 28.12, 46.43, 52.92,

54.39, 81.25, 81.69, 99.35, 122.89, 151.65, 172.85 ppm. MS: calcd.

for C₁₁H₁₃BrINO₄[M]⁺: 429, 430; found 447, 448. C₁₁H₁₃BrINO₄

(430.0): C 30.72, H 3.05, N 3.26; found C 31.01, H 3.03, N 3.27.

Methyl

9Ј-Iodo-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-8-azabicy-

Dimethyl 9-Iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-

ene-6,8-dicarboxylate (77b): 5% yield (0.05 g), white solid, m.p.

192 °C. H NMR: δ = 1.35 and 1.37 (s, 6 H), 2.60 (m, 1 H), 3.80

(s, 6 H), 4.93 (m, 1 H), 6.16 and 6.32 (s, 1 H), 7.02 and 7.11 (s, 1

H) ppm. ¹³C NMR: δ = 10.50, 10.73, 25.61, 27.40, 27.50, 45.99,

47.29, 47.66, 54.28, 55.58, 81.79, 82.32, 114.46, 131.93, 132.36,

132.90, 133.10, 151.94, 153.49, 172.81 ppm.

clo[3.3.1]non-6-ene)]-8Ј-carboxylate (68c): 90% yield (0.75 g), yel-

1

low solid, m.p. 158 °C. H NMR: δ = 1.1–2.0 (m, 10 H), 2.73 and

1

2.76 (s, 1 H), 3.78 (s, 3 H), 5.0 (m, 2 H), 6.14 and 6.29 (s, 1 H),

6.75 and 6.87 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 14.38, 21.66,

25.50, 33.63, 33.82, 38.79, 50.75, 54.36, 81.95, 82.44, 104.55,

105.02, 122.39, 152.75, 173.89 ppm.

Methyl 9-Iodo-4-methyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-

8-carboxylate (68d): 10% yield (0.07 g), yellow liquid. H NMR: δ

= 1.25 and 1.28 (s, 3 H), 2.63 (m, 1 H), 2.85 (m, 1 H), 3.80 (s, 3

H), 4.69 and 4.79 (m, 1 H), 5.05 (m, 1 H), 6.22 and 6.38 (m, 1 H),

6.79 (m, 1 H) ppm. ¹³C NMR: δ = 12.56, 15.25, 16.14, 39.15, 44.57,

54.10, 82.52, 97.44, 122.47, 146.49, 170.77 ppm.

Methyl 4-Allyl-9-iodo-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-

carboxylate (78n): 82% yield (0.60 g), yellow liquid. H NMR: δ =

1

2.10 (m, 1 H), 2.30 (m, 1 H), 2.60 (m, 2 H), 3.79 (s, 3 H), 5.00 (m,

1 H), 5.10 (m, 3 H), 5.70 (m, 1 H), 6.25 and 6.41 (s, 1 H), 6.81 and

6.92 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 12.34, 33.72, 36.29,

49.59, 54.16, 82.35, 107.00, 117.5, 122.60, 134.00, 152.61,

169.60 ppm.

Methyl 9-Iodo-3-oxo-4-phenyl-2-oxa-8-azabicyclo[3.3.1]non-6-ene-8-

1

carboxylate (68h): 73% yield (0.58 g), white solid, m.p. 134 °C. H

Methyl 4-But-3-enyl-9-iodo-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-

NMR: δ = 2.17 and 2.28 (d, J = 6.5 Hz, 1 H), 2.87 (m, 1 H), 3.88

(s, 3 H), 4.80 (m, 1 H), 5.29 (m, 1 H), 6.37 and 6.53 (m, 1 H), 6.89

and 7.02 (d, J = 8 Hz, 1 H), 7.1–7.4 (m, 5 H) ppm. ¹³C NMR: δ =

15.90, 40.53, 41.07, 41.61, 54.26, 55.94, 82.61, 83.10, 104.35,

104.81, 122.39, 127.3–129.5, 135.97, 152.60, 168.78 ppm.

1

ene-8-carboxylate (78o): 50% yield (0.38 g), liquid. H NMR: δ =

1.5 (m, 1 H), 2.00 (m, 3 H), 2.56 (m, 2 H), 3.66 (s, 3 H), 4.61 and

4.69 (s, 1 H), 4.84 (m, 3 H), 6.12 and 6.26 (s, 1 H), 6.64 and 6.67

and 6.76 and 6.79 (d, J = 8 Hz, 1 H) ppm. ¹³C NMR: δ = 16.31,

28.17, 30.85, 36.02, 36.25, 37.40, 37.44, 47.98, 48.10, 53.94, 81.87,

82.39, 102.84, 103.28, 106.57, 107.00, 116.03, 116.39, 121.74,

122.49, 136.26, 136.72, 152.23, 152.42, 170.10, 172.43 ppm. MS:

calcd. for C₁₃H₁₆INO₄[M + 1]⁺378; found 378.

Dimethyl 9-Iodo-4,4-dimethyl-3-oxo-2-oxa-8-azabicyclo[3.3.1]non-6-

ene-5,8-dicarboxylate (70b): 30% yield (0.25 g), white solid, m.p.

194 °C. ¹H NMR: δ = 1.33 (s, 3 H), 1.36 (s, 3 H), 3.76 (s, 3 H),

3.81 (s, 3 H), 5.18 and 5.21 (s, 1 H), 5.37 and 5.45 (d, J = 4 Hz, 1

H), 6.24 and 6.39 (s, 1 H), 6.74 and 6.87 (d, J = 4 Hz, 1 H) ppm.

¹³C NMR: δ = 17.63, 23.93, 25.17, 49.46, 52.75, 54.30, 82.60, 83.09,

105.32, 105.78, 121.14, 121.36, 152.23, 152.40, 168.33, 173.21 ppm.

C₁₃H₁₆INO₆(409.2): C 38.16, H 3.94, N 3.42; found C 37.98, H

3.98, N 3.40.

Methyl

13-Iodo-12,12-dimethyl-11-oxo-10-oxa-8-azatricyclo-

[7.3.1^1,9.0^2,7]trideca-2(7),3,5-triene-8-carboxylate (79b): 60% yield

(0.48 g), yellow solid, m.p. 136 °C. ¹H NMR: δ = 1.14 (s, 3 H), 1.48

(s, 3 H), 3.84 (s, 1 H), 3.85 (s, 3 H), 5.37 (m, 1 H), 6.60 (m, 1 H),

7.01–7.31 (m, 4 H) ppm. ¹³C NMR: δ = 18.35, 25.48, 26.56, 45.19,

50.7, 53.69, 84.41, 120.27–137.29, 153.45, 173.42 ppm. MS: calcd.

for C₁₅H₁₇INO₄[M + 1]⁺402; found 402.

Dimethyl 8-Iodo-4,4-dimethyl-2-oxo-3-oxa-9-azabicyclo[3.3.1]non-6-

1

ene-7,9-dicarboxylate (71b): 10% yield (0.08 g), liquid. H NMR: δ

Methyl 1-(5-Iodomethyl-2-oxo-tetrahydrofuran-3-yl)-1H-isoquino-

line-2-carboxylate (80n): 70% yield (0.58 g), yellow liquid. ¹H

NMR: δ = 2.00 (m, 1 H), 2.39 (m, 1 H), 2.97 and 3.00 (m, 1 H),

= 1.24 (s, 3 H), 1.29 (s, 3 H), 3.77 (s, 3 H), 3.80 and 3.82 (s, 3 H),

4.63 and 4.76 (d, J = 5 Hz, 1 H), 5.12 and 5.14 (s, 1 H), 6.55 and

6.69 (s, 1 H), 6.97 and 7.01 (d, J = 5 Hz, 1 H) ppm. ¹³C NMR: δ 3.13 and 3.32 (m, 2 H), 3.82 (s, 3 H), 4.19 and 4.43 (m, 1 H), 5.60

= 17.93, 18.36, 22.25, 25.77, 25.96, 46.74, 47.00, 52.72, 53.25, 53.90,

and 5.68 (m, 1 H), 5.84 and 6.00 (m, 1 H), 6.80 and 6.89 (m, 1 H),

54.43, 84.47, 85.01, 130.32, 130.82, 134.12, 134.78, 153.49, 153.84, 7.0–7.4 (m, 4 H) ppm. ¹³C NMR: δ = 7.35, 30.45, 46.96, 54.02,

163.83, 172.21, 172.46 ppm. MS: calcd. for C₁₃H₁₇INO₆[M + 1]⁺

410; found 410.

54.71, 55.02, 76.08, 108.32, 110.66, 124–129, 153.83, 175.07 ppm.

MS: calcd. for C₁₆H₁₉IN₂O₄[M + NH₃]⁺431; found 431.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3741

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

Bromolactonisation: Bromine (1 or 2 equiv.) was added to a dichlo-

romethane solution (10 mL) of the acid (2 mmol), cooled to –78 °C.

After heating to room temp. and treatment with a solution of so-

dium bisulfite in order to eliminate the remaining bromine, the

aqueous layer was washed twice with Et₂O (10 mL). Concentration

gave an oil, which was chromatographed on silica gel (AcOEt/PE,

40:60).

gave 86b, which for R³= OMe is similar to a compound (60%

yield) described in the literature.^[66]Similarly, 87c gave 84c (50%),

88 (30%), and a trace of lactone 63c.

N,N-Diethyl-2-(pyridin-4-yl)isobutyramide (86b, R³= NEt₂): 42%

yield, liquid. ¹H NMR: δ = 0.69 (t, J = 7 Hz, 3 H), 1.05 (t, J =

7 Hz, 3 H), 1.45 (s, 6 H), 2.73 (d, J = 7 Hz, 2 H), 3.27 (q, J = 7 Hz,

2 H), 7.08 (d, J = 6 Hz, 2 H), 8.48 (d, J = 6 Hz, 2 H) ppm. ¹³C

NMR: δ = 12.63, 13.63, 27.88, 40.71, 41.82, 46.78, 120.19, 150.07,

155.80, 173.71.

Methyl

9Ј-Bromo-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-8-azabicy-

clo[3.3.1]non-6-ene)]-8Ј-carboxylate (81c): 40% yield (0.28 g), yel-

low solid, m.p. 116 °C. ¹H NMR: δ = 1.2–2.0 (m, 10 H), 2.79 (d, J

= 4.5 Hz, 1 H), 3.79 (s, 3 H), 4.78 and 4.82 (s, 1 H), 4.96 and 5.06

(t, J = 6.5 Hz, 1 H), 6.13 and 6.29 (s, 1 H), 6.77 and 6.90 (d, J =

8 Hz, 1 H) ppm. ¹³C NMR: δ = 20.57, 21.27, 25.20, 33.43, 33.55,

36.81, 37.06, 37.70, 50.09, 54.00, 80.18, 80.62, 103.14, 103.54,

122.10, 152.53, 152.72, 173.64 ppm. MS: calcd. for C₁₄H₁₉BrNO₄

[M + 1]⁺344; found 344.

Lead Acetate Oxidation: A benzene solution containing 12c (1.8 g,

6.8 mmol) and Pb(OAc)₄(3.8 g, 8.1 mmol) was heated at reflux for

2 h. Evaporation of the solvent, followed by extraction with dichlo-

romethane and filtration of the brown residue, gave an oil, which

was chromatographed on silica gel (CH₂Cl₂/PE, 70:30).

1-(Pyridin-4-yl)cyclohexyl Acetate (89c): 20% yield (0.30 g), white

1

solid, m.p. 106 °C. H NMR: δ = 1.1–1.8 (m, 10 H), 2.09 (s, 3 H),

Methyl 6Ј,9Ј-Dibromo-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-8-azabi-

cyclo[3.3.1]non-6-ene)]-8Ј-carboxylate (82c): 70% yield (0.59 g), yel-

7.22 (d, J = 4 Hz, 2 H), 8.55 (d, J = 4 Hz, 2 H) ppm. ¹³C NMR: δ

=

22.08, 25.42, 35.95, 53.92, 81.57, 119.96, 150.42, 154.91,

1

low solid, m.p. 138 °C. H NMR: δ = 1.2–2.1 (m, 10 H), 3.04 (s, 1

169.72 ppm.

H), 3.80 (s, 3 H), 4.89 and 4.93 (s, 1 H), 6.06 and 6.21 (s, 1 H),

7.16 and 7.29 (s, 1 H) ppm. ¹³C NMR: δ = 20.43, 20.58, 24.17,

31.36, 34.00, 35.65, 35.94, 45.79, 49.25, 53.34, 78.09, 78.56, 96.06,

96.77, 122.79, 124.39, 139.34, 150.67, 171.75 ppm. C₁₄H₁₇Br₂NO₄

(420.9): C 39.74, H 4.05, N 3.31; found C 40.42, H 4.03, N 3.15.

Methyl 9Ј-Acetoxy-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-8-azabicy-

clo[3.3.1]non-6-ene)]-8Ј-carboxylate (90c): 14% yield (0.30 g), white

1

solid, m.p. 126 °C. H NMR: δ = 1.2–1.8 (m, 10 H), 2.08 (s, 3 H),

2.95 (m, 1 H), 3.79 (s, 3 H), 4.69 (m, 1 H), 4.85 (m, 1 H), 6.78–

6.88 (m, 2 H) ppm. ¹³C NMR: δ = 20.95, 21.92, 22.57, 25.19, 29.31,

31.82, 36.39, 48.05, 53.86, 72.11, 73.02, 102.37, 102.63, 124.37,

153.18, 169.18, 179.04 ppm. MS: calcd. for C₁₆H₂₂NO₆[M + 1]⁺

324; found 324.

Methyl 6,9-Dibromo-5-cyano-4,4-dimethyl-3-oxo-2-oxa-8-azabicy-

clo[3.3.1]non-6-ene-8-carboxylate (83b): 36% yield (0.30 g), liquid.

¹H NMR: δ = 1.58 (s, 3 H), 1.63 (s, 3 H), 3.85 (s, 3 H), 5.04 (s, 1

H), 6.20 and 6.35 (s, 1 H), 7.28 and 7.40 (s, 1 H) ppm. ¹³C NMR:

δ = 24.16, 24.43, 26.18, 37.82, 38.07, 49.55, 54.90, 78.92, 79.49,

115.06, 124.82, 150.99, 170.18, 170.77.

Methyl 9Ј-Acetoxy-6Ј-benzoyl-3Ј-oxospiro[cyclohexane-1,4Ј-(2-oxa-

8-azabicyclo[3.3.1]non-6-ene)]-8Ј-carboxylate (94c): 14% yield

(0.30 g), yellow solid, m.p. 170 °C. ¹H NMR: δ = 1.2–1.9 (m, 10

H), 2.04 (s, 3 H), 3.75 (m, 1 H), 3.84 (s, 3 H), 5.04 (dd, J₁= 2 Hz,

J₂= 6 Hz, 1 H), 6.95 (d, J = 2 Hz, 1 H), 7.3–7.7 (m, 6 H) ppm.

¹³C NMR: δ = 20.75, 21.14, 22.07, 24.98, 30.33, 34.13, 40.99, 48.04,

54.55, 73.06, 73.23, 118.32, 128.75, 129.37, 132.71, 136.10, 152.75,

168.90, 177.92, 194.41 ppm. MS: calcd. for C₂₀H₂₂NO₇[M + 1]⁺

428; found 428.

Miscellaneous

Preparation of the Acid Derivatives: The reactions were carried as

above with the corresponding mono(TMS)ketene acetals Me₂C=

C(OSiMe₃)(OEt) and Me₂C=C(OSiMe₃)(NEt₂) for 85 or with

ClCO₂Ph for 87.

Methyl

4-(1-Methoxycarbonyl-1-methylethyl)-4H-pyridine-1-car-

1

boxylate (85b, R³= Me): 70% yield (0.42 g), liquid. H NMR: δ =

Reaction of Pyrazine: A dichloromethane solution (10 mL) of

1.03 (s, 6 H), 3.26 (s, 1 H), 3.58 (s, 3 H), 3.70 (s, 3 H), 4.65 (m, 2

methyl chloroformate (10 mmol) was slowly added at room tem-

H), 6.71 and 6.83 (d, J = 8 Hz, 2 H) ppm. ¹³C NMR: δ = 20.74, perature to a solution of bis(trimethylsilyl)ketene acetal (3.5 mmol)

39.79, 46.50, 51.06, 52.70, 105.03, 105.39, 120.45, 123.88, 124.10, and pyridine (2.5 mmol) in dichloromethane (40 mL). Stirring for

149.16, 150.98, 176.39 ppm.

2 h, followed by evaporation of the solvent, gave an oil, which was

chromatographed on silica gel (AcOEt/PE, 70:30).

Methyl

4-(1-Diethylcarbamoyl-1-methylethyl)-4H-pyridine-1-car-

boxylate (85b, R³= NEt₂): 50% yield (0.37 g), liquid. H NMR: δ

Dimethyl 7,7-Dimethyl-6-oxo-4a,6,7,7a-tetrahydrofuro[2,3-b]pyraz-

ine-1,4-dicarboxylate (96b): 47% yield (0.34 g), white solid, m.p.

1

= 1.03 (t, J = 7.5 Hz, 6 H), 1.11 (s, 6 H), 3.27 (q, J = 7.5 Hz, 4 H),

3.48 (s, 1 H), 3.73 (s, 3 H), 4.70 (m, 2 H), 6.73 and 6.87 (d, J = 70 °C. ¹H NMR: δ = 1.09 (s, 3 H), 1.35 (s, 3 H), 3.73 (s, 3 H), 3.76

8 Hz, 2 H) ppm. ¹³C NMR: δ = 13.45, 23.05, 40.27, 41.96, 47.12,

53.28, 106.70, 106.91, 124.25, 124.61, 151.86, 174.93 ppm. MS:

calcd. for C₁₅H₂₇N₃O₃[M + NH₃]⁺298; found 298.

(s, 3 H), 4.80 and 4.89 (d, J = 9 Hz, 1 H), 6.2 (m, 3 H) ppm. ¹³C

NMR: δ = 19.80, 25.90, 44.29, 53.77, 53.96, 60.70, 80.70, 110.36,

110.85, 153.04, 153.67, 178.28 ppm.

Phenyl 4-(1-Carboxycyclohexyl)-4H-pyridine-1-carboxylate (87c):

95% yield (0.78 g), white solid, m.p. 106 °C. ¹H NMR: δ = 1.1–2.0

Dimethyl

7Ј,7Ј-Dimethyl-6Ј-oxospiro[cyclohexane-1,4Ј-(4a,6,7,7a-

tetrahydrofuro[2,3-b]pyrazine)]-1Ј,4Ј-dicarboxylate (96c): 58% yield

(m, 10 H), 3.17 (s, 1 H), 4.90 (m, 2 H), 6.75 and 6.87 (d, J = 8 Hz, (0.47 g), white solid, m.p. 130 °C. ¹H NMR: δ = 1.6–1.8 (m, 10 H),

2 H), 7.2 (m, 5 H), 10.5 (s, 1 H) ppm. ¹³C NMR: δ = 23.49, 26.23, 3.74 (s, 3 H), 3.77 (s, 3 H), 4.91 (d, J = 8 Hz, 1 H), 6.17 (m, 3

30.73, 41.42, 52.87, 106.40, 106.95, 120.89, 121.46, 124.61, 126.30, H) ppm. ¹³C NMR: δ = 21.09, 21.54, 25.07, 28.80, 34.92, 46.21,

129.45, 149.87, 150.55, 181.51 ppm.

54.06, 61.45, 80.97, 111.54, 112.23, 154.41, 154.10, 176.88 ppm.

MS: calcd. for C₁₅H₂₃N₂O₆[M + NH₃]⁺342; found 342.

Aerial Oxidation of Dihydropyridines: A dichloromethane or tolu-

ene solution of the dihydropyridine 12 was kept in contact with air

for several days. After concentration, the oil, which was chromato-

graphed on silica gel (AcOEt/EP 30:70), gave 84b, 84c, and 84f

(yields: 80, 50, and 60%), the properties of which are similar to

those of the known products.^[63–65]The same process applied to 85b

Dimethyl 3,3-Dimethyl-2-oxo-2,3,3a,9a-tetrahydrofuro[2,3-b]quinox-

aline-4,9-dicarboxylate (97b): 75% yield (0.50 g), white solid, m.p.

165 °C. ¹H NMR: δ = 1.25 (s, 3 H), 1.46 (s, 3 H), 3.83 (s, 3 H),

3.92 (s, 3 H), 5.25 (d, J = 8 Hz, 1 H), 7.05 (d, J = 8 Hz, 1 H), 7.3

(m, 4 H) ppm. ¹³C NMR: δ = 18.82, 26.57, 44.04, 53.71, 53.89,

3742

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Bis(trimethylsilyl)ketene Acetals as C,O-Dinucleophiles

FULL PAPER

[28]

[29]

[30]

[31]

[32]

H. Rudler, B. Denise, A. Parlier, J.-C. Daran, Chem. Commun.

2002, 940.

K.-Y. Akiba, Y. Nishihiro, M. Wada, Tetrahedron Lett. 1983,

24, 5269.

A. Katritzky, S. Zhang, T. Kurz, M. Wang, Org. Lett. 2001, 3,

2807.

66.21, 85.26, 125.63, 125.81, 126.30, 129.58, 130.71, 153.58, 155.05,

178.03 ppm.

Crystallographic Data: Crystallographic data (excluding structure

factors) for the structures 51f, 64b, 66b, 68h, 76b and 98b reported

in this paper have been deposited with the Cambridge Crystallo-

graphic Data Centre as supplementary publication nos. CCDC-

232996, -232999, -232997, -178733, -263793 and -233000, respec-

tively. Copies of the data can be obtained free of charge on applica-

tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:

int. code + 44-1223-336-033; E-mail: deposit@ccdc.cam.ac.uk].

D. L. Comins, M. Sandelier, T. Abad Grillo, J. Org. Chem.

2001, 66, 6829 and references cited therein.

S. Raussou, R. Gosmini, P. Mangeney, A. Alexakis, M. Com-

merçon, Tetrahedron Lett. 1994, 35, 5433.

C. Ainsworth, Y. Kuo, J. Organomet. Chem. 1972, 46, 73.

M. Oki, Applications of Dynamic NMR Spectroscopy to Or-

ganic Chemistry, VCH, Deerfield Beach, 1985 and references

cited therein.

B. D. Smith, D. M. Goodenough-Lashua, J. E. D’Souza, K. J.

Norton, L. M. Schmidt, J. C. Tung, Tetrahedron Lett. 2004, 45,

2747.

For chloroformate-induced cleavage of carbon-carbon bonds,

see J. D. Hobson, J. G. McCluskey, J. Chem. Soc. C 1967, 2015.

J. A. King, G. L. Bryant, Jr, J. Org. Chem. 1992, 57, 5136.

J. H. Cooley, E. J. Evain, Synthesis 1989, 1.

W. Brady, M. O. Agho, J. Heterocycl. Chem. 1983, 20, 501.

M. Bellassoued, M. Gaudemar, J. Organomet. Chem. 1988,

338, 149.

M. Bellassoued, R. Ennigrou, M. Gaudemar, J. Organomet.

Chem. 1990, 393, 19.

M. Bellassoued, M. Gaudemar, J. Organomet. Chem. 1984,

263, C21.

F. L. Harris, L. Weiler, Tetrahedron Lett. 1984, 25, 1336.

M. Mladdenova, M. Bellassoued, Synth. Commun. 1993, 23,

3955.

F. Bohlmann, Chem. Ber. 1952, 85, 390 and references cited

therein.

H. Rudler, C. Alvarez, B. Denise, A. Parlier, J. Vaissermann, J.

Organomet. Chem. 2003, 684, 105.

F. Diaba, C. Le Houerou, M. Grignon-Dubois, P. Gerval, J.

Org. Chem. 2000, 65, 907.

F. Amiot, L. Cointeaux, E. J. Silve, A. Alexakis, Tetrahedron

2004, 60, 8221 and references cited therein.

R. Lavilla, O. Coll, M. Nicolàs, B. A. Sufi, J. Torrents, J. Bosch,

Eur. J. Org. Chem. 1999, 2997.

R. Lavilla, R. Kumar, O. Coll, C. Masdeu, A. Spada, J. Bosch,

E. Espinosa, E. Molins, Chem. Eur. J. 2000, 6, 1763.

R. Linstead, J. Chem. Soc. 1933, 583.

C. Kuroda, C. Y. Tang, M. Tanabe, M. Funakoshi, Bull. Chem.

Soc. Jpn. 1999, 72, 1587.

S. Ranganathan, K. M. Muraleedharan, N. K. Vaish, N. Jayar-

aman, Tetrahedron 2004, 60, 5273.

A. Boto, R. Hern’andez, Y. de Leon, E. Suarez, J. Org. Chem.

2001, 66, 7796.

M.-Z. Jin, L. Yang, L. M. Wu, Y.-C. Liu, Z.-L. Liu, Chem.

Commun. 1998, 2451.

[33]

[34]

Supporting Information (see footnote on page 1 of this article):

Room-temperature ¹H NMR (400 MHz) spectra of 12b, 12d, 12h

1

and H NMR (400 MHz) spectra of 12b at various temperatures:

[35]

[36]

[1] D. M. Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223 and refer-

ences cited therein.

[2] R. Kumar, R. Chandra, Adv. Heterocycl. Chem. 2001, 78, 269.

[3] A. Sausins, G. Duburs, Heterocycles 1988, 27, 291.

[4] J. P. Kutney, Heterocycles 1977, 7, 593.

[5] D. L. Comins, S. O’Connor, Adv. Heterocycl. Chem. 1988, 44,

199.

[37]

[38]

[39]

[40]

[6] J. Bosch, M.-L. Bennasar, M. Amat, Pure Appl. Chem. 1996,

[41]

[42]

68, 557.

[7] T. Itoh, H. Hasegawa, K. Nagata, Y. Matsuya, M. Okada, A.

Ohsawa, Chem. Pharm. Bull. 1994, 42, 1768.

[8] M. Wada, Y. Nishihara, K.-Y. Akiba, Tetrahedron Lett. 1985,

26, 3267.

[9] E. Wenkert, C.-J. Chang, H. P. S. Chawla, D. W. Cochran,

E. W. Hagaman, J. C. King, K. Orito, J. Am. Chem. Soc. 1976,

98, 3645.

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[10] For a recent review see R. Lavilla, J. Chem. Soc., Perkin Trans.

1 2002, 1141.

[11] R. Lavilla, A. Spada, I. Carranco, J. Bosch, J. Org. Chem. 2001,

66, 1487.

[12] R. Peri, S. Padmanabhan, A. Rutledge, S. Singh, D. J. Triggle,

J. Med. Chem. 2000, 43, 2906 and references cited therein.

[13] M. J. Kukla, H. J. Breslin, A. Gill, J. Med. Chem. 1990, 33,

223.

[14] A. Sobolev, M. C. R. Franssen, B. Vigante, B. Cekavicus, R.

Zhalubovskis, H. Kooijman, A. L. Spek, G. Duburs, A.

de Groot, J. Org. Chem. 2002, 67, 401.

[15] H. Rudler, A. Parlier, V. Certal, G. Lastennet, M. Audouin, J.

Vaissermann, Eur. J. Org. Chem. 2004, 2471.

[16] H. Rudler, M. Audouin, A. Parlier, B. Martin-Vaca, R. Gou-

mont, T. Durand-Réville, J. Vaissermann, J. Am. Chem. Soc.

1996, 118, 12045.

[17] H. Rudler, B. Martin-Vaca, M. Nicolas, M. Audouin, J. Vais-

sermann, Organometallics 1998, 17, 361.

[18] M. A. Brook, Silicon in Organic, Organometallic, and Polymer

Chemistry, Wiley-Interscience, New York 1999 and references

cited therein.

[19] T. Mukaiyama, K. Banno, K. Narasaka, J. Am. Chem. Soc.

1974, 96, 7503.

[20] T. Mukaiyama, Org. React. 1982, 28, 203.

[21] K. Takai, C. H. Heathcock, J. Org. Chem. 1985, 50, 3247.

[22] H. Rudler, V. Comte, M. Bellassoued, E. Garrier, J. Vaisserm-

ann, J.-C. Daran, C. R. Acad. Sci., Ser. IIc: Chim. 2000, 3, 113.

[23] M. Bellassoued, E. Chelain, J. Collot, H. Rudler, J. Vaisserm-

ann, Chem. Commun.1999, 187.

[24] H. Rudler, V. Comte, E. Garrier, M. Bellassoued, E. Chelain,

J. Vaissermann, J. Organomet. Chem. 2001, 621, 284.

[25] H. Rudler, C. Alvarez, A. Parlier, E. Perez, B. Denise, Y. Xu,

J. Vaissermann, Tetrahedron Lett. 2004, 45, 2409.

[26] H. Rudler, A. Parlier, F. Cantagrel, M. Bellassoued, Chem.

Commun. 2000, 771.

[51]

[52]

[53]

[54]

[55]

[56]

[57]

D. J. Wallace, A. D. Gibb, I. F. Cottrell, D. J. Kennedy, K. M. J.

Brands, U. H. Dolling, Synthesis 2001, 1784.

R. S. Varma, D. Kumar, J. Chem. Soc., Perkin Trans. 1 1999,

1755.

K.-Y. Ko, J.-Y. Kim, Tetrahedron Lett. 1999, 40, 3207.

E. Le Gall, C. Gosmini, J.-Y. Nedelec, J. Périchon, Tetrahedron

2001, 57, 1923.

[58]

[59]

[60]

S. H. Mashraqui, M. A. Karnik, Tetrahedron Lett. 1998, 39,

4895.

[61]

[62]

[63]

R. H. Böcker, F. P. Guengerich, J. Med. Chem. 1986, 29, 1596.

A. J. Birch, J. Slobbe, Tetrahedron Lett. 1976, 17, 2079.

A. R. Katritzky, H. Beltrami, M. P. Sammes, J. Chem. Soc.,

Perkin Trans. 1 1980, 2480.

D. L. Boger, J. S. Panek, J. Org. Chem. 1981, 46, 2179.

H. Pines, D. Wunderlich, J. Am. Chem. Soc. 1959, 81, 2568.

M. P. Sammes, C. M. Lee, A. R. Katrizky, J. Chem. Soc., Perkin

Trans. 1 1982, 2476.

[64]

[65]

[66]

[27] H. Rudler, P. Harris, A. Parlier, F. Cantagrel, B. Denise, M.

Bellassoued, J. Vaissermann, J. Organomet. Chem. 2001, 624,

186.

Eur. J. Org. Chem. 2005, 3724–3744

www.eurjoc.org

3743

H. Rudler, B. Denise, Y. Xu, A. Parlier, J. Vaissermann

FULL PAPER

[67] For a preliminary communication see, H. Rudler, B. Denise, Y.

Xu, J. Vaissermann, Tetrahedron Lett. 2005, 46, 3449–3451.

[68] T. Tokuyasu, H. Mayr, Eur. J. Org. Chem. 2004, 2791–2796.

[69] A. D. Dilman, H. Mayr, Eur. J. Org. Chem. 2005, 1760–1764.

Received: March 4, 2005

Published Online: July 20, 2005

3744

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3724–3744

Article Doi

Bis(trimethylsilyl)ketene acetals as C,O-dinucleophiles: One-pot formation of polycyclic γ- and δ-lactones from pyridines and pyrazines

DOI: 10.1002/ejoc.200500162

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200500162

Full text of DOI:10.1002/ejoc.200500162

Products guided by the article

R&D Labs maybe for 455258-20-5

Relevant to this article

Diastereoselective and enantioselective preparation of nor-mevaldic acid surrogates through desymmetrisation methodology. Enantioselective synthesis of (+) and (-) nor-mevalonic lactones

Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives

Broonsted acid-promoted hydrocyanation of arylalkenes

Base-catalyzed hydroamination of aromatic olefins - An efficient route to 1-aryl-4-(arylethyl)piperazines

Synthesis and reactivity of organoplatinum-rhenium heterobimetallic complexes having sulfur ligands