Titanium-mediated carboxylation of alkynes with carbon dioxide

FULL PAPER

Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

Yvan Six^[a]

Dedicated to Professor William B. Motherwell

Keywords: Carbon dioxide / Carbonylation / Lactones / Metallacycles / Titanium

The regioselective carboxylation of nonactivated internal al-

describes an experimental protocol for the preparation of so-

kynes can be performed with carbon dioxide under atmo- lutions of (η²-cyclopentene)diisopropyloxytitanium. This

spheric pressure using a simple procedure based on the

chemistry of Sato-type diisopropyloxytitanacyclopropenes.

Various polysubstituted vinylcarboxylic acids and butenol-

ides can be prepared in this way. In addition, this paper

complex also reacts with carbon dioxide, and mediates pina-

col coupling of acetophenone.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2003)

Introduction

The Kulinkovich reaction provides a general route to

cyclopropanols from carboxylic esters in a simple one-step

procedure.^[1Ϫ4]In an extension discovered by de Meijere et

al., carboxylic amides can be used as substrates leading to

cyclopropylamines.^[3,5]In both cases, the commonly ac-

cepted mechanism operates through dialkoxytitanacyclo-

propane intermediates 1 (Scheme 1).

Scheme 2

volving

bis(cyclopentadienyl)titanacyclopropenes

are

known.^[16Ϫ19]

Titanacyclopropanes 1 are prepared most conveniently

from titanium alkoxides^[20]and Grignard reagents, but since

they are prone to decomposition according to the pathway

shown, they are normally generated in the presence of the

substrate to be transformed (Scheme 3).^[20,21]Using CO₂as

a substrate means that this standard procedure cannot be

applied, however, because of its well-known reaction with

Grignard reagents,^[22]and so a preformed solution of titan-

acyclopropane is required.

Scheme 1

These complexes have been shown to undergo ligand ex-

change with olefins^[6Ϫ8]and alkynes,^[9]leading to new dial-

koxytitanacyclopropanes and dialkoxytitanacyclopropenes

2, respectively (Scheme 2).

Results and Discussion

Complexes 1 and 2 behave as 1,2-dicarbanion equiva-

lents. Several synthetically useful transformations have been

developed based on their rich chemistry.^[3,10Ϫ15]To the best

of our knowledge, however, their reaction with carbon diox-

Preparation of (η²-Cyclopentene)diisopropyloxytitanium and

Its Reaction with Carbon Dioxide

Marek et al. have reported the successful preparation of

ide has not been investigated so far, although examples in- diisopropyloxy(η²-propene)titanium in diethyl ether at

Ϫ50 °C, albeit with unsatisfactory reproducibility.^[21]This

[a]

result encouraged us to try to work with the cyclopen-

tylmagnesium chloride/titanium tetraisopropoxide sys-

tem^[23]because we expected the 1,2-insertion side reaction

might be slower in this case (Scheme 4). (η²-Cyclopentene)-

Institut de Chimie des Substances Naturelles, UPR 2301 du

CNRS,

Avenue de la Terrasse, 91198 Gif-sur-Yvette, France

Fax: (internat.) ϩ 33-1/69077247

E-mail: Yvan.Six@icsn.cnrs-gif.fr

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Eur. J. Org. Chem. 2003, 1157Ϫ1171  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1157 $ 20.00ϩ.50/0

Y. S i x

FULL PAPER

Scheme 3

diisopropyloxytitanium (3) is also advantageous because it

is particularly suitable for ligand-exchange reactions.^[23,24]

Figure 1. ¹³C NMR spectrum of the crude product obtained when

preformed complex 3 is trapped with CO₂and then D₂O

Scheme 4

We warmed a diethyl ether solution of cyclopentylmag-

nesium chloride (3 equiv.) and titanium tetraisopropoxide

(1 equiv.) from Ϫ70 °C to Ϫ40 °C over 5 min, then main-

tained the solution at that temperature for additional 5 min.

After addition of CO₂gas under atmospheric pressure, and

then treatment with deuterium oxide, a classical workup

Scheme 5

procedure allowed us to isolate the resulting carboxylic ac- 4-d, decreases with time. This situation was also observed

ids (see Exp. Sect.). The crude product contained cyclopent- at Ϫ40 °C (Entries 1Ϫ4) after a few minutes.

anecarboxylic acid only, which was partially deuterated in

The use of an excess of Grignard reagent was beneficial.

the β-position as revealed by ¹³C NMR spectroscopy (Fig- Although good results were still obtained with 2.4 equiv. of

ure 1, a and b). In spite of poor resolution, the relative Grignard reagent, reducing this amount further led to lower

amount (r) of deuterated acid 4-d could be evaluated ap- yields (Entries 9Ϫ11). A possible explanation is that excess

proximately by measuring the relative intensities at the C-1 Grignard reagent ensures that the rate of formation of 3

and C-3 peaks. Thus, this experiment not only demonstrates remains high until all the titanium precursor has been con-

that complex 3 reacts with carbon dioxide, presumably via sumed. Since the formation and decomposition of complex

titanalactone 5 (Scheme 5), but also provides an indirect 3 occur simultaneously, this process would explain why the

means to assess roughly the amount of 3 formed. The pres- amount of 3 in the reaction mixture only decreases slowly

ence of non-deuterated cyclopentanecarboxylic acid pre- with time and is almost steady for several minutes, while

sumably stems from the reaction of carbon dioxide with the amount of the remaining Grignard reagent decreases

residual cyclopentylmagnesium chloride.

more rapidly.

This experiment was repeated several times under various

We also tried working with diisopropyl ether and THF

conditions. The results are presented in Table 1. The data as solvents (Entries 12Ϫ13). The results were less satisfact-

for the reaction conducted at Ϫ30 °C with 3.0 equiv. of ory with the former and no reaction was detected in THF

Grignard reagent (Entries 5Ϫ8) clearly show that the at Ϫ40 °C, which is consistent with earlier observations

amount of complex 3, estimated according to the yield of made by the group of Cha.^[23]

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Eur. J. Org. Chem. 2003, 1157Ϫ1171

Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

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Formation of 7 can be explained by [1,2] insertion of the

carbonyl group of acetophenone into the CϪTi bond of the

intermediate oxatitanacylopropane 6. Direct addition of 3

to the carbonyl group is evidently slower than the ligand

exchange yielding 6. Similar results have been obtained by

Eisch et al. using a different method.^[14]

Table 1. The reaction of complex 3 with carbon dioxide, followed

by trapping with D₂O; in each case, a solution of Ti(OiPr)₄and

cC₅H₉MgCl at Ϫ70 °C was warmed to temperature T over 5 min,

then maintained at that temperature for t min before the addition

of CO₂

Extending the Scope of the Reaction of

Titanacyclopropanes with Carbon Dioxide

As we have seen previously, trapping of intermediate 5

with deuterium oxide yields deuterated acid 4-d. It was

interesting to us to investigate the use of other trapping

reagents, and so oxygen^[26]was tested, leading to the forma-

tion of β-hydroxy acid 8 as a mixture of the two possible

diastereoisomers (Scheme 7). Radical intermediates may ac-

count for the loss of stereochemical integrity.

[a]

[b]

Estimated according to the yield of non-deuterated acid 4.

Same conditions as in Entry 9, except that the reaction mixture

was kept at Ϫ70 °C for 1 h before the addition of CO₂.

Scheme 7

In summary, the most simple and convenient procedure

we have found for the preparation of complex 3 is the fol-

lowing: fast (5 min) warming from Ϫ70 °C to Ϫ30 °C of a

diethyl ether solution of Ti(OiPr)₄(1.0 equiv.) and cyclo-

pentylmagnesium chloride (2.4 equiv.). The complex should

preferably be used immediately, but may be kept at Ϫ70 °C

for 1 h without too much decomposition (Entry 14).

Quenching with aldehydes was also investigated, but

without success. When using benzaldehyde and isobutyral-

dehyde, the expected products were not detected and only

unsubstituted cyclopentanecarboxylic acid, simple Grig-

nard addition adducts, and diols arising from pinacol coup-

ling, were observed.

From a synthetic point of view, it would obviously be

extremely useful to extend the reaction with carbon dioxide

to titanacyclopropanes other than 3. A few studies con-

cerning ligand exchange with olefins prior to CO₂addition

were undertaken, but the results were extremely modest

(Scheme 8) since only small amounts of the expected acids

9 and 10 were formed. Further work is needed to develop

this potentially useful transformation.

Application to the Pinacol Coupling of Acetophenone

Preparing solutions of (η²-cyclopentene)diisopropyloxy-

titanium 3 not only enables the study of its reaction with

carbon dioxide, but also with any reagent that is not com-

patible with Grignard reagents or titanium tetraisopropox-

ide. To illustrate this concept, acetophenone was added to

a preformed solution of complex 3 (Scheme 6). The pinacol

coupling product 7 was isolated in satisfactory yield (59%).

In contrast, generating 3 in the presence of acetophenone

resulted in a much lower yield (15%), the major product

being 1-phenylethanol stemming from the reaction of aceto-

phenone with cyclopentylmagnesium chloride.^[25]

Scheme 8

The Reaction of Titanacyclopropenes with Carbon Dioxide

The best conditions (Table 1, Entry 9) found for the

formation of deuterated cyclopentanecarboxylic acid 4-d

were used for the reaction repeated in the presence of 4-

octyne. Acid 4-d was still the major product, but deuterated

acid 11-d was also isolated, albeit in low yield and purity

(Scheme 9).

Scheme 6

Eur. J. Org. Chem. 2003, 1157Ϫ1171

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Scheme 9

Two conclusions can be drawn from this early experi-

ment. First, the titanacyclopropene 12 generated by ligand

exchange with the alkyne reacts with carbon dioxide and

deuterium oxide to give the corresponding acid 11-d. Sec-

ondly, the yield of 4-d indicates that a large amount of com-

plex 3 was still present in solution when the CO₂was added,

showing that ligand exchange with the alkyne is a relatively

slow process at Ϫ30 °C.

Figure 2. ¹³C NMR spectra of the crude products of the reaction

displayed in Scheme 10 with 2.4 (top) and 2.0 (bottom) equiv. of

Grignard reagent

Table 2. The reaction of titanacyclopropenes, generated from al-

kynes, with carbon dioxide

According to this observation, the carboxylation of

4-octyne was improved by maintaining the temperature

at Ϫ30 °C for 15 min before the addition of CO₂

(Scheme 10). It was also found that the purity of the crude

product was greatly enhanced by using 2.0 equiv. of Grig-

nard reagent instead of 2.4 (Figure 2). The ligand-exchange

reaction transforms complex 3 into the more stable titana-

cyclopropene 12, and decomposition of 3 becomes a less

significant pathway. In contrast to the situation where no

alkyne is present, using excess Grignard reagent is not re-

quired; it actually seems that it becomes a problem.

Scheme 10

We optimised the reaction one step further by using a

deficiency of alkyne, which led to higher conversions. The

results of reactions with several different alkynes are pre-

sented in Table 2.

The reaction appears to be fairly general, as a diverse was added at 0 °C over 2 h, and the yield was calculated on the

range of substituted alkynes leads to the expected alkene-

[a]

CO₂was added while warming from Ϫ70 °C to Ϫ30 °C over

[b]

[c]

30 min.

added at Ϫ30 °C over 1 h.

CO₂was added at Ϫ30 °C over 30 min.

CO₂was

[d]

1.0 equiv. of alkyne was used, CO₂

basis of recovered starting material. ^[e]Isolated by column chroma-

tography. Isolated by crystallisation.

[f]

carboxylic acids. Nonetheless, some limitations have been

discovered. The expected acid was not isolated from the re-

action of 1,4-diphenylbuta-1,3-diyne (Entry 9); only triple-

bond reduction products were observed, the major one be- should be very reactive towards carbon dioxide, the ob-

ing enyne 20. 1,4-Bis(trimethylsilyl)buta-1,3-diyne and served dimerisation already reported by Sato et al.^[27]must

methyl octynoate were also unsuitable substrates, giving be a fast process. The resulting titanacyclopentadienes ap-

only complex mixtures of unidentified compounds. Ter- pear to be unreactive towards carbon dioxide under our

minal alkynes led to conjugated dienes 21 and 22 experimental conditions, probably because of their reduced

(Scheme 11). Since monosubstituted titanacyclopropenes ring strain as compared with titanacyclopropenes.

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Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

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The strong directing effect of CH₂OR groups has been

reported previously for the reaction of titanacyclopropenes

with aldehydes and ketones, and is probably due to their

electronic character.^[29]Most of the selectivities we have ob-

served, however, differ sharply from those reported for reac-

tions with aldehydes, ketones and imines.^[9,30]For instance,

the reactions of the complex derived from 1-trimethylsilyl-

oct-1-yne with these compounds display higher and oppos-

ite regioselectivities to those found in our reaction of the

same complex with carbon dioxide (Table 2, Entry 7).^[9,30]

This observation could be due in part to the small size of

carbon dioxide, making it less sensitive to steric effects, and

also possibly to differences in the reaction mechanisms.

Further synthetic and molecular modelling studies would

be helpful to get a better insight into these problems.

Scheme 11

1-Benzyloxyhex-2-yne did not give the expected vinyl-

carboxylic acid, but was converted instead into the corres-

ponding (Z)-disubstituted alkene 14 in good yield (Entry

3). We believe that in this case, the intermediate titanacyclo-

propene is stabilised strongly by coordination with the oxy-

gen atom of the ether group, thus making the reaction with

carbon dioxide more difficult. This is supported by the ob-

servation that replacing the benzyl group with a tert-butyl-

dimethylsilyl group solves the problem (Entry 4).

In a preliminary account of this work, we reported low

yields in a few cases where the starting alkynes were

sterically encumbered.^[28]For instance, vinylic acid 17 had

been isolated in only 19% yield from 1-phenyl-2-(trimethyl-

silyl)acetylene. We found that hydrolysing the titanacyclo-

propene intermediate without adding CO₂led, after puri-

fication, to analytically pure (Z)-alkene 23 in 65% yield

(Scheme 12). This observation demonstrated that the prob-

lem was due mainly to the carbon dioxide addition step:

simply performing these additions at higher temperatures

and for longer times improved the results for all of the less-

reactive substrates (Entries 4Ϫ6).

Substitution at the Second Carbon Atom of the Triple Bond

As we have seen earlier with the formation of 11-d

(Scheme 9), and in light of previously reported related

work,^[31,32]we hoped that the intermediate titanalactone

generated after the addition of carbon dioxide could be

treated with a variety of electrophiles (Scheme 13). This

idea proved to be correct and thus tetrasubstituted carb-

oxylated olefins were obtained (Table 3).

Scheme 13

Table 3. The reaction of titanacyclopropenes, generated from al-

kynes, with carbon dioxide and an electrophilic reagent; in each

case, CO₂was added while warming from Ϫ70 °C to Ϫ30 °C

over 30 min

Scheme 12

Selectivity Issues

The present method for the carboxylation of alkynes ap-

pears to be completely stereoselective, and poorly (Table 2,

Entry 7) to highly (Entry 2) regioselective. It is obvious

from the results that the observed regioselectivities do not

stem from steric factors alone. In the case of 1-(tert-butyldi-

methylsilyloxy)hex-2-yne (Entry 4), carboxylation occurs

preferentially at the carbon atom bearing the bulkiest

group, whereas in the case of 7-benzyloxyhept-2-yne (Entry

8), carboxylation at the least-hindered carbon atom is fa-

voured. In view of our results, a tentative classification for

the directing power of substituents in carboxylations at the

carbon atoms that bear them is the following: CH₂OTBS Ͼ

CH₃Ͼ TMS ഠ CH₂-alkyl Ͼ Ph.

[a]

[b]

Isolated by crystallisation.

graphy.

Isolated by column chromato-

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N-Bromosuccinimide (NBS) appeared to be superior to

For instance, electroreductive carboxylation of alkynes

bromine for the preparation of bromoalkenes (Entries 2 and using [Ni(bpy)₃](BF₄)₂requires a catalytic amount of nickel

3), whereas iodine and N-iodosuccinimide gave similar re- complex and accepts a wider range of substrates, but is far

sults (Entries 4 and 5). When benzaldehyde was used, the more limited in its functionalising of the second carbon

corresponding lactone was isolated (Entry 7). In contrast, atom of the triple bond.^[33]Also worthy of note is a recently

N-(2,2,2-trifluoroethylidene)benzylamine was poorly react- reported nickel-promoted alkylative carboxylation of al-

ive and only acid 11 was isolated. Further examples of the kynes.^[34]This reaction allows the formation of two

lactone formation were then studied because of their poten- carbonϪcarbon bonds, but is limited to terminal alkynes,

tial value as a synthetic method. The results are displayed which in turn cannot be used with our presently described

in Table 4.

procedure.

In principle, trisubstituted vinylcarboxylic acids may be

obtained from alkynes by [Cp₂TiCl₂]-catalysed hydromag-

nesiation.^[35]The regioselectivity pattern of this method,

which has been applied in a total synthesis,^[36]appears to

be very different from our own.

Table 4. The reaction of titanacyclopropenes, generated from

alkynes, with carbon dioxide and a carbonyl compound

Our method is also complementary to Sato’s intramolec-

ular nucleophilic acyl substitution (INAS), in which titana-

cyclopropene intermediates are involved as well.^[31,32]The

INAS reaction requires an oxygenated function at a definite

distance from the triple bond. This condition is not neces-

sary with the carboxylation described herein, whose scope,

therefore, is wider (Scheme 14). Although INAS reaction

products can be accessed using our method (Scheme 15),

the INAS reaction should be preferred when it is applicable

because of its complete regioselectivity.

[a]

CO₂was added while warming from Ϫ70 °C to Ϫ30 °C over

[b]

[c]

30 min.

added at 0 °C over 2 h.

Although the yield was not determined, this compound was the

major product as shown by NMR spectroscopy.

recrystallisation.

CO₂was added at Ϫ30 °C over 30 min.

CO₂was

[d]

[e]

Isolated by column chromatography.

[f]

Isolated by

Scheme 14

Since isobutyraldehyde and acetophenone failed to lead

to the corresponding butenolides (Entries 2 and 3), the

method seems to be limited just to nonbulky aldehydes. It

is, nonetheless, a fairly general procedure that benefits from

the good regioselectivity of the carbon dioxide addition.

Comparison with Other Methods: Advantages and

Drawbacks

The present carboxylation reaction has interesting poten-

tial because of its great complementarity with the other ex-

isting methods that do not require carbon monoxide.

Scheme 15

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Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

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tion of the Grignard reagent was calculated accordingly, a 50:50

ratio corresponding to a concentration of 2.0 .

Conclusions

A simple procedure based on the chemistry of titanacy-

clopropenes enables the carboxylation of nonactivated in-

ternal alkynes. The method is fairly general, and satisfactor-

Deuterated Acid 4-d: Cylopentylmagnesium chloride (2.0  in di-

ethyl ether, n equiv.) was added dropwise at Ϫ70 °C to a solution

of titanium tetraisopropoxide (1.0 equiv., 1.0 mmol, 0.30 mL) in

ily regioselective. The source of the carboxyl group is car- diethyl ether (10 mL). The resulting yellow mixture was warmed to

T °C over 5 min (when T was Ϫ30 °C, the mixture turned black).

After t min at T °C, the mixture was cooled down to Ϫ70 °C again,

and carbon dioxide was added for 30 min while the bath was

warmed to Ϫ30 °C. Deuterium oxide (0.5 mL) was added, the cold

bath was removed, and stirring was continued for 25 min. Aqueous

0.3  HCl (20 mL) and diethyl ether (10 mL) were added. The or-

ganic layer was separated, and the aqueous phase extracted with

diethyl ether (2 ϫ 20 mL). The combined organic layers were ex-

tracted with 1  aqueous NaOH solution (25 mL). The aqueous

phase was then washed with diethyl ether (25 mL), acidified using

concentrated aqueous HCl solution, and extracted with diethyl

ether (3 ϫ 20 mL). These last three organic phases were combined,

dried with magnesium sulfate, filtered, and concentrated, to yield

a colourless oil. ¹³C NMR spectroscopic analysis showed that the

product contained only cyclopentanecarboxylic acid and β-deuter-

ated cyclopentanecarboxylic acid 4-d, and allowed an estimation of

the amount of each. The results are gathered in Table 1. With n ϭ

2.4, T ϭ Ϫ30, and t ϭ 0, 0.11 g of crude product was obtained,

and cyclopentanecarboxylic acid was estimated to contain 58%

deuterium. The amount of non-deuterated acid was thus approxim-

ately 0.39 mmol, and the yield of 4-d was estimated to be 54%.

bon dioxide under atmospheric pressure. Moreover, the se-

cond carbon atom of the triple bond may also be

substituted, leading to tetrasubstituted olefins of well-de-

fined stereochemistry.

In the course of this work, an experimental protocol was

found to prepare solutions of (η²-cyclopentene)diisopropy-

loxytitanium (3) in diethyl ether, which may then be used in

ligand-exchange reactions where the presence of Grignard

reagents must be avoided.

Experimental Section

General Remarks: NMR spectra were recorded with AC250 (¹H

spectra at 250 MHz, ¹³C spectra at 62.9 MHz) and AM300 Bruker

spectrometers (¹H spectra at 300 MHz, ¹³C spectra at 75.5 MHz).

Chemical shifts are given in ppm, referenced to the peak of tetra-

methylsilane, defined at δ ϭ 0.00 ppm (¹H NMR), or the solvent

peak of CDCl₃, defined at δ ϭ 7.26 ppm (¹H NMR) or δ ϭ

77.0 ppm (¹³C NMR). Infrared spectra were recorded with a

PerkinϪElmer BX FT-IR spectrometer neat. Mass spectra (MS)

were obtained with Hewlett-Packard HP 5989B (chemical ionis-

ation, CI), Thermo Finnigan Automass (electronic impact, EI, 70

eV) and Micromass LCT (electrospray, ES^ϩ) spectrometers. Melt-

ing points were determined using a Büchi BS540 apparatus and

were not corrected. Flash column chromatography was performed

on SDS Chromagel silica gel 60 (35Ϫ70 µm). All reactions were

carried out under argon unless otherwise stated. The temperatures

mentioned are the temperatures of the cold baths or the oil baths

used. Analytical grade diethyl ether, DMF and toluene were pur-

chased from SDS and used as such. THF was distilled from so-

dium/benzophenone under argon. Carbon dioxide gas was ob-

tained by sublimation of dry ice, placed in separate flasks, and was

passed through calcium chloride before being bubbled through the

reaction mixtures. 7-Benzyloxyhept-2-yne and some of the 5-

phenylpent-4-yn-1-ol that we used were gifts from Mr. A. Parenty.

Some 5-phenylpent-4-yn-1-ol was prepared also by us according to

a literature procedure.^[37]1-Trimethylsilyloct-1-yne was prepared by

treating the lithium salt of 1-octyne with chlorotrimethylsilane.^[38]

1,4-Diphenylbuta-1,3-diyne was prepared by the Eglinton reaction

of phenylacetylene.^[39]Cyclopentylmagnesium chloride (2.0  solu-

tion in diethyl ether) was purchased from Aldrich or Fluka and

titrated using the following method: The solution (1.0 mL) was ad-

ded at 0 °C to p-anisaldehyde (4.0 mmol) in diethyl ether (10 mL)

under argon. After 15 min of stirring at room temperature, 0.3 

HCl aqueous solution (20 mL) and diethyl ether (10 mL) were ad-

ded. Stirring was continued until complete dissolution of the pre-

cipitate occurred. The organic layer was separated and the aqueous

layer extracted with diethyl ether (20 mL). The combined organic

layers were dried with magnesium sulfate and most of the solvent

was evaporated under vacuum. ¹H NMR spectroscopy of the crude

product revealed the formation of two alcohols, (p-methoxyphenyl)-

cyclopentylmethyl alcohol and (p-methoxyphenyl)methyl alcohol.

Integration of the aromatic and methoxy signals allowed the ratio

of products/unchanged aldehyde to be determined. The concentra-

1

4-d: ¹³C NMR: δ ϭ 25.7, 25.8, 29.6 (t, J ϭ 20.5 Hz), 29.9, 43.6,

183.5 ppm.

2,3-Diphenylbutane-2,3-diol (7): Cylopentylmagnesium chloride

(2.0  in diethyl ether, 2.4 equiv., 4.8 mmol, 2.4 mL) was added

dropwise at Ϫ70 °C to a solution of titanium tetraisopropoxide

(1.0 equiv., 2.0 mmol, 0.59 mL) in diethyl ether (20 mL). The re-

sulting yellow mixture was warmed to Ϫ30 °C over 5 min, at which

point it turned black. The mixture was then immediately cooled

down to Ϫ70 °C, and acetophenone (2.0 equiv., 4.0 mmol,

0.47 mL) was added. The cold bath was removed, stirring was con-

tinued for 2 h at 25 °C, and the red-brown mixture became orange.

Aqueous 0.3  HCl (40 mL) and diethyl ether (20 mL) were added.

The aqueous layer was saturated with sodium chloride, and the

organic layer was separated. The aqueous phase was extracted with

diethyl ether (4 ϫ 30 mL). The combined organic layers were dried

with magnesium sulfate, filtered and concentrated to afford a col-

ourless oil (0.51 g), which later crystallised. Recrystallisation

(cyclohexane) yielded analytically pure (dl)-7 (0.15 g). Flash chro-

matography of the mother liquor (ethyl acetate/heptane, gradient

from 0 to 30%) led to the isolation of a mixture of (dl)-7, (meso)-

7, and 1-phenylethanol (0.18 g; ratio 35:28:37 estimated by integra-

tion of the ¹H NMR spectrum). Estimated yields are thus: (dl)-7

(0.92 mmol, 46%), (meso)-7 (0.25 mmol, 13%), and 1-phenyle-

thanol (0.33 mmol, 8%).

[40,41]

(dl)-7:

Colourless crystals (needles), m.p. 122.0Ϫ123.4 °C

(ref.^[40]125Ϫ126 °C). C₁₆H₁₈O₂(242.32): calcd. C 79.31, H 7.49;

found C 79.36, H 7.63. IR: ν˜ ϭ 3490, 3401, 1445, 1139, 1062, 1026

cm^Ϫ1. ¹H NMR: δ ϭ 1.51 (s, 6 H), 2.55 (br. s, 2 H, OH), 7.17Ϫ7.26

(m, 10 H, Ph) ppm. ¹³C NMR: δ ϭ 25.0, 78.8, 127.0, 127.1,

127.3, 143.4 ppm.

[41]

1

(meso)-7:

Main differences: H NMR: δ ϭ 1.57 (s, 6 H), 2.34

(br. s, 2 H, OH) ppm. ¹³C NMR: δ ϭ 25.1, 78.6 ppm.

Eur. J. Org. Chem. 2003, 1157Ϫ1171

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1-Phenylethanol:^{[42] 1}H NMR: δ ϭ 1.45 (d, J ϭ 6.5 Hz, 3 H), 2.29

(br. s, 1 H, OH), 4.83 (q, J ϭ 6.5 Hz, 1 H), 7.20Ϫ7.38 (m, 5 H,

tions to a solution of 3-butene-1-ol (1.0 equiv., 40 mmol, 3.4 mL)

in THF (40 mL) at 0 °C. Tetrabutylammonium iodide (0.01 equiv.,

Ph) ppm. ¹³C NMR: δ ϭ 25.1, 70.3, 125.3, 127.3, 128.4, 145.8 ppm. 0.40 mmol, 0.15 g) was added, followed by the dropwise addition

of benzyl bromide (1.1 equiv., 44 mmol, 5.2 mL). After stirring at

20 °C for 130 min, the mixture, which had become white, was di-

luted with diethyl ether (100 mL), washed with 0.3  aqueous HCl

β-Hydroxycarboxylic Acid 8: Cylopentylmagnesium chloride (2.0 

in diethyl ether, 2.4 equiv., 4.8 mmol, 2.4 mL) was added dropwise

at Ϫ70 °C to a solution of titanium tetraisopropoxide (1.0 equiv.,

(100 mL), dried with magnesium sulfate, filtered and concentrated

2.0 mmol, 0.59 mL) in diethyl ether (20 mL). The resulting yellow

to afford a yellow liquid (8.1 g). Purification by flash column chro-

mixture was warmed to Ϫ30 °C over 5 min, at which point it turned

black. The mixture was then cooled down to Ϫ70 °C again, and

carbon dioxide was added for 30 min while the bath was warmed

matography (ethyl acetate/heptane, gradient from 0 to 10%) yielded

pure 4-benzyloxybut-1-ene (5.6 g, 35 mmol, 87%).

4-Benzyloxybut-1-ene:^[46]Colourless oil. ¹H NMR: δ ϭ 2.38 (qt,

J ϭ 7.0, 1.0 Hz, 2 H), 3.53 (t, J ϭ 7.0 Hz, 2 H), 4.52 (s, 2 H),

5.01Ϫ5.16 (m, 2 H), 5.84 (m, 1 H), 7.21Ϫ7.38 (m, 5 H) ppm. ¹³C

NMR: δ ϭ 34.2, 69.6, 72.9, 116.3, 127.5, 127.6, 128.3, 135.2,

138.4 ppm.

to Ϫ30 °C. The red-brown solution was cooled down to Ϫ70 °C

again, and oxygen was added for 30 min while the temperature was

raised to Ϫ30 °C, then kept at Ϫ30 °C for 30 min more. Saturated

aqueous Na₂S₂O₅solution (10 mL) was added. After 5 min of stir-

ring, 1  aqueous HCl solution (30 mL) and diethyl ether (20 mL)

were added, and the aqueous layer was saturated with sodium

chloride. The organic phase was separated and the aqueous phase

was extracted with diethyl ether (5 ϫ 40 mL). The combined or-

ganic layers were dried with magnesium sulfate, filtered and con-

centrated to afford a colourless oil (0.28 g). Purification by flash

column chromatography (diethyl ether/cyclohexane, gradient from

0 to 100%) yielded pure 8 (0.10 g, 0.79 mmol, 40%) as a mixture

Carboxylation: Using the same procedure as that for obtaining 9,

and starting from 4-benzyloxybut-1-ene (1.0 mmol), the crude

product (0.15 g) was obtained as a colourless oil containing mostly

1

cyclopentanecarboxylic acid, as shown by H NMR spectroscopic

analysis. The signals corresponding to acid 10 were also apparent,

and the yield was estimated by integration to be ca. 6%. Note:

Several other attempts were performed. The best result (8% yield)

was obtained with 0.6 equiv. of alkene, 1.0 equiv. of titanium tetra-

isopropoxide and 2.0 equiv. of Grignard reagent, and with the reac-

tion temperature being maintained at Ϫ30 °C for 15 min before the

addition of CO₂. No significant improvement was observed when

the alkene was added to preformed titanacyclopropane complex 3.

1

of the two possible diastereoisomers (cis/trans ഠ 55:45). H NMR

spectroscopic analysis revealed that the cis/trans ratio was about

59:41 in the crude product.

8:^[43,44]A mixture of the two isomers: colourless liquid. MS (EI):

m/z ϭ 112 [M^ϩ·Ϫ H₂O], 102, 73, 58, 55. IR: ν˜ ϭ 3397, 2961, 2879,

1

1709, 1414, 1346, 1305, 1210 cm^Ϫ1. H NMR: δ ϭ 1.55Ϫ2.15 (m,

10:^{[47] 1}H NMR: δ ϭ 2.38 (t, J ϭ 7.0 Hz, 2 H), 3.49 (t, J ϭ 6.0 Hz,

2 H), 4.50 (s, 2 H), 7.21Ϫ7.40 (m, 5 H) ppm; other signals were

concealed by those of cyclopentanecarboxylic acid. ¹³C NMR: δ ϭ

21.5, 29.0, 33.7, 69.7, 72.9, 127.6, 127.6, 128.4 ppm; other chemical

shifts could not be determined because of the small amount of

compound obtained.

6 H), 2.66Ϫ2.81 (m, 1 H), 4.42 (q, J ϭ 6.5 Hz, 0.45 H, trans iso-

mer), 4.50 (q, J ϭ 4.0 Hz, 0.55 H, cis isomer), 7.13 (br. s, 2 H, OH

and CO₂H) ppm. cis-8: ¹³C NMR: δ ϭ 21.9, 25.9, 33.9, 49.7, 73.9,

178.8 ppm. trans-8: ¹³C NMR: δ ϭ 22.0, 27.3, 33.9, 52.3, 76.3,

179.9 ppm.

Carboxylic Acid 9: Titanium tetraisopropoxide (1.0 equiv.,

1.0 mmol, 0.30 mL) was added at Ϫ70 °C to a solution of p-allylan-

isole (1.0 equiv., 1.0 mmol, 0.15 mL) in diethyl ether (10 mL). Cylo-

pentylmagnesium chloride (2.0  in diethyl ether, 2.4 equiv.,

2.4 mmol, 1.2 mL) was then added dropwise. The resulting yellow

mixture was warmed to Ϫ30 °C over 5 min, at which point it be-

came red-brown. After cooling back to Ϫ70 °C, carbon dioxide

was added over 30 min, during which time the bath was warmed

to Ϫ30 °C. The solution became red. Aqueous 0.3  HCl (20 mL)

and diethyl ether (10 mL) were then added. The organic layer was

separated and the aqueous extracted with diethyl ether (2 ϫ

20 mL). The combined organic layers were extracted with 1  aque-

ous NaOH solution (25 mL). The aqueous phase was washed with

diethyl ether (25 mL), acidified using concentrated aqueous HCl

solution, and then extracted with diethyl ether (3 ϫ 20 mL). These

last three organic phases were combined, dried with magnesium

sulfate, filtered and concentrated to afford a crude product (57 mg).

¹H NMR spectroscopic analysis indicated that the product con-

tained mostly cyclopentylcarboxylic acid. It revealed the presence

also of acid 9, which is a known compound.^[45]Integration of the

signals indicated that the yield of 9 was not more than 3%.

General Procedure for the Hydrocarboxylation of Alkynes: Titanium

tetraisopropoxide (2.0 equiv., 2.0 mmol, 0.59 mL) was added at

Ϫ70 °C to a solution of alkyne (1.0 equiv., 1.0 mmol) in diethyl

ether (20 mL). Cylopentylmagnesium chloride (2.0  in diethyl

ether, 4.0 equiv., 4.0 mmol, 2.0 mL) was then added dropwise. The

resulting yellow mixture was warmed to Ϫ30 °C over 5 min and

then maintained at Ϫ30 °C for 15 min, by which time it had turned

black. The mixture was cooled down to Ϫ70 °C again, and carbon

dioxide was added, either for 30 min while the bath was warmed

to Ϫ30 °C (variation A), for 30 min at Ϫ30 °C (variation B), or

for 1 h at Ϫ30 °C (variation C). Aqueous 0.3  HCl (40 mL) and

diethyl ether (20 mL) were then added. The organic layer was sep-

arated and the aqueous one extracted with diethyl ether (2 ϫ

30 mL). The combined organic layers were extracted with 1  aque-

ous NaOH solution (50 mL). The aqueous phase was washed with

diethyl ether (50 mL), acidified using concentrated aqueous HCl

solution, and then extracted with diethyl ether (3 ϫ 30 mL). These

last three organic phases were combined, dried with magnesium

sulfate, filtered and concentrated to afford the crude product, which

was then purified either by flash column chromatography or recrys-

tallisation.

9:^{[45] 1}H NMR: δ ϭ 2.36 (t, J ϭ 7.5 Hz, 2 H), 2.61 (t, J ϭ 7.5 Hz,

2 H), 3.79 (s, 3 H), 6.83 (d, J ϭ 8.5 Hz, 2 H), 7.10 (t, J ϭ 8.5 Hz,

2 H) ppm; other signals were concealed by those of cyclopent-

anecarboxylic acid. ¹³C NMR: δ ϭ 55.2, 113.8, 129.4 ppm; other

chemical shifts could not be determined because of the small

amount of compound obtained.

Note: When the isolation of nonacidic reaction products was de-

sired, all the organic layers that had been obtained before the acid-

ification of the aqueous phase with concentrated aqueous HCl so-

lution were combined, dried with magnesium sulfate, filtered and

concentrated. The resulting ‘‘nonacidic’’ crude product was then

purified either by flash column chromatography or recrystallis-

ation.

Carboxylic Acid 10. Preparation of the Starting Alkene: Sodium

hydride (60% in oil, 1.1 equiv., 44 mmol, 1.8 g) was added in por-

1164

Eur. J. Org. Chem. 2003, 1157Ϫ1171

Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

FULL PAPER

Carboxylic Acid 11: Preparation according to the General Proced-

13-d: Colourless crystals; m.p. 82.2Ϫ83.5 °C. MS (CI, NH₃): m/z ϭ

209 [MH^ϩϩ NH₃], 208 [MH^ϩϩ NH₃] (residual non-deuterated),

ure for the hydrocarboxylation of alkynes, starting from 4-octyne,

and applying variation A. The crude product (0.16 g) was purified 192 [MH^ϩ], 174. IR: ν˜ ϭ 2959, 2930, 1669, 1447, 1423, 1321, 1285,

by flash column chromatography (ethyl acetate/heptane, gradient

1230, 916 cm^{Ϫ1 1}H NMR: δ ϭ 0.98 (t, J ϭ 7.5 Hz, 3 H), 1.62

.

from 0 to 20%) to afford pure 11 (0.13 g, 0.83 mmol, 83%).

(sext, J ϭ 7.5, 2 H), 2.52 (m, 2 H), 7.10Ϫ7.45 (m, 5 H), 7.81 (s,

0.14 H, residual non-deuterated), 11.09 (br. s, 1 H, CO₂H) ppm.

¹³C NMR: δ ϭ 14.2, 22.5, 29.2, 128.5, 128.7, 129.4, 132.6, 135.4,

141.1 (no CϪD coupling was observed in the spectrum, but the

intensity of this peak was much lower than that of non-deuterated

13), 174.4 ppm.

11:^[48]Colourless liquid. MS (CI, NH₃): m/z ϭ 175, 174 [MH^ϩ

ϩ

NH₃], 157 [MH^ϩ], 139. IR: ν˜ ϭ 3401, 2962, 2933, 2873, 1686, 1638,

1

1289, 1113, 1069 cm^Ϫ1. H NMR: δ ϭ 0.92 (t, J ϭ 7.5 Hz, 3 H),

0.95 (t, J ϭ 7.5 Hz, 3 H), 1.38Ϫ1.55 (m, 4 H), 2.19 (q, J ϭ 7.5 Hz,

2 H), 2.27 (dd, J ϭ 8.0, 7.5 Hz, 2 H), 6.92 (t, J ϭ 7.5 Hz, 1 H),

11.11 (br. s, 1 H, CO₂H) ppm. ¹³C NMR: δ ϭ 13.9, 13.9, 22.0,

22.4, 28.4, 30.8, 131.8; 145.5, 173.8 ppm.

(Z)-Alkene 14. Preparation of the Starting Alkyne: Sodium hydride

(60% in oil, 1.1 equiv., 4.4 mmol, 0.18 g) was added to a solution

of 2-hexyn-1-ol (1.0 equiv., 4.0 mmol, 0.44 mL) in THF (4.0 mL)

at 0 °C. Tetrabutylammonium iodide (0.01 equiv., 40 µmol, 15 mg)

was added, followed by the dropwise addition of benzyl bromide

(1.1 equiv., 4.4 mmol, 0.52 mL). After stirring at 0 °C for 90 min,

the mixture was diluted with diethyl ether (50 mL), washed with 0.3

 aqueous HCl (50 mL) and water (50 mL), dried with magnesium

sulfate, filtered and concentrated to afford a yellow oil (0.97 g).

Purification by flash column chromatography (ethyl acetate/hept-

ane, gradient from 0 to 10%) yielded pure 1-benzyloxy-hex-2-yne

(0.51 g, 2.7 mmol, 67%).

Carboxylic Acid 13: Preparation according to the General Proced-

ure for the hydrocarboxylation of alkynes, starting from 1-phenyl-

1-pentyne, and applying variation A. The crude product (0.18 g)

was purified by flash column chromatography (ethyl acetate/hept-

ane, gradient from 0 to 30%) and recrystallisation (heptane) to af-

ford pure 13 (82 mg, 0.43 mmol, 43%). During the purification pro-

cess, a small amount of the other regioisomer was also isolated,

albeit as a mixture with an unidentified compound. ¹H NMR spec-

troscopic analysis of the crude product revealed that the regioselec-

tivity of the reaction was about 86:14 in favour of 13.

1-Benzyloxyhex-2-yne: Colourless oil. MS (CI, NH₃): m/z ϭ 207,

206 [MH^ϩϩ NH₃], 189 [MH^ϩ], 171, 145, 108. IR: ν˜ ϭ 2962, 2932,

13:^[49,50]Colourless crystals; m.p. 82.3Ϫ83.3 °C (ref. m.p. 82 °C^[49]

;

90Ϫ91 °C^[50]). MS (CI, NH₃): m/z ϭ 208 [MH^ϩϩ NH₃], 191

[MH^ϩ], 173. IR: ν˜ ϭ 2958, 2929, 1667, 1449, 1423, 1283, 1235, 914

cm^Ϫ1. ¹H NMR: δ ϭ 0.99 (t, J ϭ 7.5 Hz, 3 H), 1.63 (m, 2 H), 2.52

(m, 2 H), 7.29Ϫ7.45 (m, 5 H), 7.81 (s, 1 H), 11.90 (br. s, 1 H,

CO₂H) ppm. ¹³C NMR: δ ϭ 14.2, 22.5, 29.3, 128.5, 128.7, 129.4,

132.7, 135.5, 141.1, 174.5 ppm.

2869, 1455, 1259, 1134, 1074 cm^Ϫ^{1 1}H NMR: δ ϭ 0.99 (t, J ϭ

.

7.5 Hz, 3 H), 1.55 (sext, J ϭ 7.5 Hz, 2 H), 2.21 (tt, J ϭ 7.5, 2.0 Hz,

2 H), 4.15 (t, J ϭ 2.0 Hz, 2 H), 4.58 (s, 2 H), 7.24Ϫ7.38 (m, 5 H)

ppm. ¹³C NMR: δ ϭ 13.5, 20.7, 22.1, 57.7, 71.3, 75.9, 87.1, 127.7,

128.0, 128.3, 137.6 ppm.

Attempted Carboxylation: The general procedure for the hydrocarb-

oxylation of alkynes was applied, starting from 1-benzyloxy-hex-2-

yne, and applying variation A. The crude product (26 mg) con-

tained mostly cyclopentylcarboxylic acid as shown by NMR spec-

troscopy. Purification, however, of the ‘‘nonacidic’’ crude product

(0.20 g, yellow oil) by flash column chromatography (ethyl acetate/

heptane, gradient from 0 to 5%) afforded pure (Z)-alkene 14

(0.17 g, 0.87 mmol, 87%).

Regioisomer of 13:^{[49] 1}H NMR: δ ϭ 0.88 (t, J ϭ 7.5 Hz, 3 H), 1.45

(sext, J ϭ 7.5 Hz, 2 H), 2.09 (q, J ϭ 7.5 Hz, 2 H), 7.17Ϫ7.40 (m,

6 H) ppm. The signal for the CO₂H group could not be identified

precisely.

Deuterated Carboxylic Acid 13-d: Titanium tetraisopropoxide (2.0

equiv., 2.0 mmol, 0.59 mL) was added at Ϫ70 °C to a solution of

1-phenyl-1-pentyne (1.0 equiv., 1.0 mmol, 0.16 mL) in diethyl ether

(20 mL). Cylopentylmagnesium chloride (1.8  in diethyl ether, 4.0

equiv., 4.0 mmol, 2.2 mL) was then added dropwise. The resulting

yellow mixture was warmed to Ϫ30 °C over 5 min, then was main-

tained at Ϫ30 °C for 15 min, by which time it had turned black.

The mixture was cooled down to Ϫ70 °C again, and carbon dioxide

was added over 30 min, during which time the bath was warmed

to Ϫ30 °C. Deuterium oxide (1.0 mL) was added. The temperature

was increased slowly to 20 °C, and the mixture was stirred for 17

h. Aqueous 0.3  HCl (40 mL) and diethyl ether (20 mL) were ad-

ded. The organic layer was separated and the aqueous phase ex-

tracted with diethyl ether (2 ϫ 30 mL). The combined organic

layers were extracted with 1  aqueous NaOH solution (50 mL).

The aqueous phase was washed with diethyl ether (50 mL), acidi-

fied by using concentrated aqueous HCl solution, and then ex-

tracted with diethyl ether (3 ϫ 30 mL). These last three organic

phases were combined, dried with magnesium sulfate, filtered and

concentrated to afford a mixture of colourless crystals and liquid

(0.18 g), which was purified by recrystallisation from heptane. A

second crop of crystals was obtained by sequential flash column

chromatography (ethyl acetate/heptane, gradient from 0 to 20%)

and recrystallisation (heptane) of the mother liquor. Carboxylic

14:^[51]Colourless oil. MS (CI, NH₃): m/z ϭ 209, 208 [MH^ϩ

NH₃], 191 [MH^ϩ], 173, 108. IR: ν˜ ϭ 2958, 2928, 2861, 1452, 1095,

1074, 1028 cm^{Ϫ1 1}H NMR: δ ϭ 0.89 (t, J ϭ 7.5 Hz, 3 H), 1.38

ϩ

.

(sext, J ϭ 7.5 Hz, 2 H), 2.01 (m, 2 H), 4.07 (m, 2 H), 4.50 (s, 2 H),

5.54Ϫ5.67 (m, 2 H), 7.22Ϫ7.39 (m, 5 H) ppm. ¹³C NMR: δ ϭ 13.6,

22.7, 29.6, 65.7, 72.0, 126.1, 127.5, 127.7, 128.3, 133.6, 138.4 ppm.

Carboxylic Acid 15. Preparation of the Starting Alkyne:^[52]Chloro-

tert-butyldimethylsilane (1.2 equiv., 4.8 mmol, 0.72 g) was added

to a solution of 2-hexyn-1-ol (1.0 equiv., 4.0 mmol, 0.44 mL) and

imidazole (2.5 equiv., 10 mmol, 0.68 g) in DMF (1.0 mL) at 0 °C.

After 15 min of stirring at 20 °C, the mixture was diluted with

diethyl ether (50 mL), washed with 0.1  aqueous HCl (50 mL) and

water (50 mL), dried with magnesium sulfate, filtered and concen-

trated to afford a yellow oil (0.91 g). Purification by flash column

chromatography (ethyl acetate/heptane, gradient from 0 to 5%)

yielded pure 1-(tert-butyldimethylsilyloxy)hex-2-yne (0.70 g,

3.3 mmol, 83%).

1-(tert-Butyldimethylsilyloxy)hex-2-yne: Colourless liquid. MS (CI,

NH₃): m/z ϭ 231, 230 (MH^ϩ·ϩ NH₃), 214, 213 [MH^ϩ], 208, 206,

acid 13-d was obtained (79 mg, 0.41 mmol, 41%). The extent of 132. IR: ν˜ ϭ 2959, 2931, 2858, 1472, 1462, 1254, 1140, 1080, 837

deuterium incorporation was estimated to be 86% by ¹H NMR

spectroscopic analysis.

cm^Ϫ1. ¹H NMR: δ ϭ 0.12 (s, 6 H), 0.91 (s, 9 H), 0.97 (t, J ϭ 7.0 Hz,

3 H), 1.53 (sext, J ϭ 7.0 Hz, 2 H), 2.18 (tt, J ϭ 7.0, 2.0 Hz, 2 H),

Eur. J. Org. Chem. 2003, 1157Ϫ1171

1165

Y. S i x

FULL PAPER

4.30 (t, J ϭ 2.0 Hz, 2 H) ppm. ¹³C NMR: δ ϭ Ϫ5.1, 13.5, 18.3,

20.8, 22.0, 25.9, 52.0, 78.8, 85.3 ppm.

Carboxylation: The General Procedure for the hydrocarboxylation

of alkynes was applied starting from 5-(tert-butyldimethylsilyloxy)-

1-phenylpent-1-yne, and applying variation B. The workup, which

differed from the General Procedure, was carried out as follows:

Aqueous 0.3  HCl (40 mL) and diethyl ether (20 mL) were added.

The organic layer was separated, and the aqueous phase extracted

with diethyl ether (2 ϫ 30 mL). The combined organic layers were

dried with magnesium sulfate, filtered and concentrated to afford

Carboxylation: The General Procedure for the hydrocarboxylation

of alkynes was applied on half the scale, starting from 1-(tert-butyl-

dimethylsilyloxy)hex-2-yne (0.50 mmol, 106 mg), and applying

variation C. The workup, which differed from the general proced-

ure, was carried out as follows: Aqueous 0.3  HCl (40 mL) and

heptane (20 mL) were added. The organic layer was separated, and

the aqueous phase extracted with heptane (2 ϫ 30 mL). The com-

bined organic layers were dried with magnesium sulfate, filtered

and concentrated to afford a colourless oil (97 mg). ¹H NMR ana-

lysis revealed that the regioselectivity of the reaction was about

80:20 in favour of 15. Purification by flash column chromatography

(ethyl acetate/heptane, gradient from 0 to 10%) afforded an analyt-

ically pure mixture of 15 and its regioisomer (ratio ca. 81:19, 55 mg,

0.21 mmol, 42%).

1

of a mixture of colourless solid and oil (0.38 g). H NMR spectro-

scopic analysis revealed that the regioselectivity of the reaction was

about 85:15 in favour of 16. Purification by flash column chroma-

tography (ethyl acetate/heptane, gradient from 0 to 50%) afforded

the (Z)-alkene corresponding to simple reduction of the triple bond

(70 mg, 0.25 mmol, 25%), pure 16 (0.19 g) and a mixture of 16 and

its regioisomer (ratio ca. 25:75, 47 mg). The yield of carboxylated

products was thus 0.24 g (0.74 mmol, 74%).

Note: When variation A was applied, and with the general proced-

ure’s workup, 16 was found in the ‘‘nonacidic’’ crude product, and

the yield was only 38%. It seems that the carboxylate salt of 16

dissolves well in diethyl ether.

Note: When variation A was applied, and with the General Proced-

ure workup, the yield of 15 was only 19%. The (Z)-alkene corres-

ponding to simple reduction of the triple bond was isolated in

29% yield.

16: Colourless crystals, m.p. 83.2Ϫ83.8 °C. C₁₈H₂₈O₃Si (320.51):

calcd. C 67.46, H 8.81; found C 67.51, H 8.79. MS (CI, NH₃):

m/z ϭ 323, 322, 321 [MH^ϩ], 304, 303. IR: ν˜ ϭ 2926, 2850, 1686,

15: Colourless oil (solid at Ϫ7 °C). C₁₃H₂₆O₃Si (258.44): calcd. C

60.42, H 10.14; found C 60.55, H 9.99. MS (CI, NH₃): m/z ϭ 276

[MH^ϩϩ NH₃], 260, 259 [MH^ϩ], 241, 179. IR: ν˜ ϭ 2958, 2930,

1

1678, 1674, 1668, 1418, 1270, 1096, 959 cm^Ϫ1. H NMR: δ ϭ 0.03

(s, 6 H), 0.88 (s, 9 H), 1.80 (m, 2 H), 2.62 (m, 2 H), 3.68 (t, J ϭ

6.0 Hz, 2 H), 7.30Ϫ7.40 (m, 3 H), 7.42Ϫ7.48 (m, 2 H), 7.77 (s, 1

H), 11.21 (br. s, 1 H, CO₂H) ppm. ¹³C NMR: δ ϭ Ϫ5.3, 18.3, 24.1,

26.0, 32.1, 63.0, 128.6, 128.8, 129.7, 132.1, 135.3, 141.2, 174.2 ppm.

2857, 1691, 1256, 1084, 837 cm^Ϫ^{1 1}H NMR: δ ϭ 0.09 (s, 6 H),

.

0.89 (s, 9 H), 0.95 (t, J ϭ 7.5 Hz, 3 H), 1.51 (sext, J ϭ 7.5 Hz, 2

H), 2.30 (q, J ϭ 7.5 Hz, 2 H), 4.41 (s, 2 H), 7.03 (t, J ϭ 7.5 Hz, 1

H), 11.22 (br. s, 1 H, CO₂H) ppm. ¹³C NMR: δ ϭ Ϫ5.3, 13.9, 18.3,

21.9, 25.9, 30.7, 57.1, 130.7, 148.8, 172.2 ppm.

1

Regioisomer of 16: Colourless oil. H NMR: δ ϭ Ϫ0.01 (s, 6 H),

0.83 (s, 9 H), 1.63 (tt, J ϭ 7.5, 6.0 Hz, 2 H), 2.18 (q, J ϭ 7.5 Hz,

2 H), 3.56 (t, J ϭ 6.0 Hz, 2 H), 7.15Ϫ7.40 (m, 6 H), 9.73 (br. s, 1

H, CO₂H) ppm. ¹³C NMR: δ ϭ Ϫ5.4, 18.2, 25.9, 26.4, 31.8, 62.3,

127.6, 128.0, 129.7, 134.6, 147.5, 172.5 ppm.

1

Regioisomer of 15. Main Differences: H NMR: δ ϭ 0.91 (s, 9 H),

2.24 (t, J ϭ 8.0 Hz, 2 H), 4.38 (d, J ϭ 5.5 Hz, 2 H), 6.93 (t, J ϭ

5.5 Hz, 1 H) ppm. ¹³C NMR: δ ϭ 22.2, 28.8, 60.3, 131.2,

144.4 ppm.

(Z)-5-(tert-Butyldimethylsilyloxy)-1-phenylpent-1-ene: Colourless li-

quid. MS (CI, NH₃): m/z ϭ 294 [MH^ϩϩ NH₃], 293, 279, 278, 277

[MH^ϩ], 236, 162, 133, 132. IR: ν˜ ϭ 2954, 2928, 2856, 1471, 1255,

(Z)-1-tert-(Butyldimethylsilyloxy)hex-2-ene: Colourless liquid. MS

(CI, NH₃): m/z ϭ 232 [MH^ϩϩ NH₃], 215 [MH^ϩ], 165, 132, 100.

1

IR: ν˜ ϭ 2957, 2929, 2857, 1463, 1253, 1089, 836 cm^Ϫ1. H NMR:

1104, 835, 774 cm^{Ϫ1 1}H NMR: δ ϭ 0.01 (s, 6 H), 0.86 (s, 9 H),

.

δ ϭ 0.07 (s, 6 H), 0.91 (s, 9 H), 0.90 (t, J ϭ 7.5 Hz, 3 H), 1.38

(sext, J ϭ 7.5 Hz, 2 H), 2.01 (q, J ϭ 7.5 Hz, 2 H), 4.23 (d, J ϭ

7.0 Hz, 1 H), 5.37Ϫ5.57 (m, 2 H) ppm. ¹³C NMR: δ ϭ Ϫ5.1, 13.7,

18.4, 22.8, 26.0, 29.6, 59.5, 129.7, 130.7 ppm.

1.66 (tt, J ϭ 7.5, 6.5 Hz, 2 H), 2.38 (qd, J ϭ 7.5, 1.5 Hz, 2 H), 3.62

(t, J ϭ 6.5 Hz, 2 H), 5.65 (dt, J ϭ 11.5, 7.5 Hz, 1 H), 6.40 (dt, J ϭ

11.5, 1.5 Hz, 1 H), 7.14Ϫ7.35 (m, 5 H) ppm. ¹³C NMR: δ ϭ Ϫ5.3,

18.3, 25.1, 25.9, 33.1, 62.6, 126.5, 128.1, 128.7, 129.1, 132.5,

137.6 ppm.

Carboxylic Acid 16. Preparation of the Starting Alkyne:^[52]Chloro-

tert-butyldimethylsilane (1.2 equiv., 1.6 mmol, 0.24 g) was added to

a solution of 5-phenylpent-4-yn-1-ol (1.0 equiv., 1.3 mmol, 0.21 g)

and imidazole (2.5 equiv., 3.3 mmol, 0.23 g) in DMF (0.50 mL) at

0 °C. After 20 min of stirring at 0 °C and then 15 min at 20 °C,

the mixture was diluted with diethyl ether (25 mL), washed with 0.1

 aqueous HCl (25 mL) and water (25 mL), dried with magnesium

sulfate, filtered and concentrated to afford a colourless oil (0.39 g).

Purification by flash column chromatography (ethyl acetate/hept-

ane, gradient from 0 to 5%) yielded pure 1-phenyl-5-(tert-butyldi-

methylsilyloxy)pent-1-yne (0.35 g, 1.3 mmol, 97%).

Carboxylic Acid 17: Titanium tetraisopropoxide (1.0 equiv.,

2.0 mmol, 0.59 mL) was added at Ϫ70 °C to a solution of 1-phenyl-

2-(trimethylsilyl)acetylene (1.0 equiv., 2.0 mmol, 0.39 mL) in di-

ethyl ether (20 mL). Cyclopentylmagnesium chloride (2.1  in di-

ethyl ether, 2.0 equiv., 4.0 mmol, 1.9 mL) was then added dropwise.

The resulting yellow mixture was warmed to Ϫ30 °C over 5 min,

then was maintained at Ϫ30 °C for 15 min, by which time it had

turned black. Carbon dioxide was added at 0 °C over 2 h [after 1 h,

diethyl ether (15 mL) was added to compensate for evaporation].

Aqueous 0.3  HCl (40 mL) and diethyl ether (30 mL) were then

added. The organic layer was separated, and the aqueous phase

extracted with diethyl ether (2 ϫ 30 mL). The combined organic

5-(tert-Butyldimethylsilyloxy)-1-phenylpent-1-yne: Colourless li-

quid. C₁₇H₂₆OSi (274.48): calcd. C 74.39, H 9.55; found C 74.11, layers were extracted with 1  aqueous NaOH solution (50 mL).

H 9.77. MS (CI, NH₃): m/z ϭ 276, 275 [MH^ϩ], 132, 117. IR: ν˜ ϭ

2953, 2928, 2856, 1490, 1471, 1462, 1256, 1105, 1070, 835 cm^Ϫ1

The aqueous phase was washed with diethyl ether (50 mL), and the

combined organic phases were dried with magnesium sulfate, fil-

.

¹H NMR: δ ϭ 0.08 (s, 6 H), 0.91 (s, 9 H), 1.80 (tt, J ϭ 7.0, 6.0 Hz, tered and concentrated to afford a colourless oil (0.24 g). Purifica-

2 H), 2.49 (t, J ϭ 7.0 Hz, 2 H), 3.76 (t, J ϭ 6.0 Hz, 2 H), 7.24Ϫ7.30 tion by flash column chromatography (heptane) led to the isolation

(m, 3 H), 7.35Ϫ7.41 (m, 2 H) ppm. ¹³C NMR: δ ϭ Ϫ5.3, 15.8, of starting 1-phenyl-2-trimethylsilylacetylene (0.19 g, 1.1 mmol,

18.4, 26.0, 31.8, 61.6, 80.7, 89.9, 124.0, 127.5, 128.2, 131.5 ppm.

54%). The aqueous phase was acidified using concentrated HCl

1166

Eur. J. Org. Chem. 2003, 1157Ϫ1171

Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

FULL PAPER

aqueous solution, and extracted with diethyl ether (3 ϫ 30 mL).

These last three organic phases were combined, dried with magnes-

ium sulfate, filtered and concentrated to afford colourless crystals

(0.15 g). ¹H and ¹³C NMR spectroscopic analyses revealed that the

regioselectivity of the reaction was about 81:19 in favour of 17.

Purification by flash column chromatography (ethyl acetate/hept-

ane, gradient from 0 to 20%) afforded pure 17 (99 mg, 0.45 mmol,

23%, i.e., 50% based on recovered starting material).

2 H, regioisomer), 3.47 (t, J ϭ 6.0 Hz, 2 H, 19), 4.50 (s, 2 H), 6.90

(t, J ϭ 7.5 Hz, 1 H, 19), 7.00 (q, J ϭ 7.0 Hz, 1 H, regioisomer),

7.21Ϫ7.38 (m, 5 H), 10.48 (br. s, 1 H, CO₂H) ppm. ¹³C NMR: δ ϭ

11.9, 14.5, 25.1, 28.6, 29.4, 29.5, 69.9, 70.2, 72.9, 127.3, 127.4,

127.5, 127.6, 128.3, 132.6, 138.4, 138.5, 140.3, 144.8, 173.3,

173.6 ppm.

(Z)-7-Benzyloxyhept-2-ene: Colourless liquid. MS (CI, NH₃):

m/z ϭ 222 [MH^ϩϩ NH₃], 220, 205 [MH^ϩ], 203, 108, 102. IR: ν˜ ϭ

Note: When variation A of the general procedure was applied, 17

2930, 2856, 1453, 1103 cm^{Ϫ1 1}H NMR: δ ϭ 1.44 (quint, J ϭ

.

was isolated in only 19% yield; (Z)-alkene 23 was the major prod- 7.0 Hz, 2 H), 1.59 (d, J ϭ 6.0 Hz, 3 H), 1.55Ϫ1.70 (m, 2 H), 2.05

uct, isolated in 46% yield.

(q, J ϭ 7.0 Hz, 2 H), 3.47 (t, J ϭ 6.5 Hz, 2 H), 4.50 (s, 2 H),

5.31Ϫ5.55 (m, 2 H), 7.21Ϫ7.38 (m, 5 H) ppm. ¹³C NMR: δ ϭ 12.8,

26.1, 26.6, 29.4, 70.3, 72.9, 124.0, 127.4, 127.6, 128.3, 130.4,

138.7 ppm.

17:^[53]Colourless crystals (needles), m.p. 104.4Ϫ105.7 °C.

C₁₂H₁₆O₂Si (290.35): calcd. C 65.41, H 7.32; found C 65.39, H

7.46. MS (EI): m/z ϭ 220 [M^ϩ·], 206, 205, 204, 131, 102, 75. IR:

ν˜ ϭ 2954, 1664, 1411, 1286, 1272, 1259, 1249, 842 cm^Ϫ1. ¹H NMR:

δ ϭ 0.08 (s, 9 H), 7.24Ϫ7.37 (m, 5 H), 8.34 (s, 1 H), 11.30 (br. s, 1

H, CO₂H) ppm. ¹³C NMR: δ ϭ 0.4, 128.0, 128.5, 128.6, 136.6,

137.6, 155.2, 177.4 ppm.

Enyne 20: This compound was obtained when the General Proced-

ure for the hydrocarboxylation of alkynes was applied, starting

from 1,4-diphenylbuta-1,3-diyne, and applying variation A. The

crude product (55 mg) contained a complex mixture of compounds,

as shown by NMR spectroscopy. Therefore, the ‘‘nonacidic’’ crude

product (0.18 g, brown oil) was purified by several flash column

chromatographies (ethyl acetate/heptane, gradient from 0 to 5%).

Enyne 20 (62 mg, 0.30 mmol, 30%) and (Z,Z)-1,4-diphenylbuta-

1,3-diene (11 mg, 52 µmol, 5%) were isolated. 1,4-Diphenylbut-1-

yne and 1,4-diphenylbut-2-yne were also observed, although we

were not able to obtain them in pure form. We find their formation

difficult to explain.

Carboxylic Acid 18: Preparation by using the General Procedure

for the hydrocarboxylation of alkynes, starting from 1-trimethylsi-

lyloct-1-yne, and applying variation B. The crude product (79 mg,

colourless oil) contained the expected acid 18, and the ‘‘nonacidic’’

crude product (0.20 g, colourless oil) contained the carboxylate salt

of 18. Both crude products were combined, dissolved in heptane

(100 mL), and then washed with 0.3  aqueous HCl (50 mL). A

new crude product (0.23 g) was obtained as a colourless oil after

filtration and concentration under reduced pressure. ¹H NMR

spectroscopic analysis revealed that the regioselectivity of the reac-

tion was about 58:42 in favour of 18. Purification by flash column

chromatography (ethyl acetate/heptane, gradient from 0 to 10%)

afforded a 59:41 mixture of 18 and its regioisomer (0.12 g,

0.53 mmol, 53%).

20:^[54,55]Yellow oil. ¹H NMR: δ ϭ 5.91 (d, J ϭ 12.0 Hz, 1 H), 6.68

(d, J ϭ 12.0 Hz, 1 H), 7.14Ϫ7.40 (m, 8 H), 7.48 (m, 1 H), 7.91 (d,

J ϭ 7.0 Hz, 1 H) ppm. ¹³C NMR: δ ϭ 88.3, 95.8, 107.4, 123.4,

128.3, 128.3, 128.4, 128.5, 128.7, 131.4, 136.5, 138.7 ppm.

(Z,Z)-1,4-Diphenylbuta-1,3-diene:^[56]Pale yellow oil. ¹H NMR: δ ϭ

6.65 (AB, ∆ν ϭ 41 Hz, J_ABϭ 8.0 Hz, 4 H), 7.22Ϫ7.45 (m, 10 H)

ppm. ¹³C NMR: δ ϭ 126.6, 127.3, 128.3, 129.2, 132.0, 137.3 ppm.

Mixture of 18 and Its Regioisomer (59:41): Colourless liquid. MS

(ES^ϩ): m/z ϭ 283, 279, 267 [M ϩ K^ϩ], 251 [M ϩ Na^ϩ], 246, 229

[MH^ϩ], 213, 211. HRMS (ES^ϩ): calcd. for C₁₂H₂₃Na₂O₂Si [M Ϫ

H^ϩϩ 2Na^ϩ] 273.1263, found 273.1242. IR: ν˜ ϭ 2957, 2928, 2858,

1,4-Diphenylbut-1-yne:^{[57] 1}H NMR: δ ϭ 2.69 (t, J ϭ 7.5 Hz, 2 H),

2.92 (t, J ϭ 7.5 Hz, 2 H) ppm. ¹³C NMR: δ ϭ 21.7, 35.2 ppm;

because of insufficient purity, the signals for the triple bond and

phenyl groups could not be assigned.

1682, 1251, 842 cm^Ϫ^{1 1}H NMR: δ ϭ 0.18 (s, 9 H, regioisomer),

.

0.25 (s, 9 H, 18), 0.89 (t, J ϭ 6.5 Hz, 3 H), 1.15Ϫ1.55 (m, 8 H),

2.30 (q, J ϭ 7.5 Hz, 2 H, 18), 2.37 (t, J ϭ 7.5 Hz, 2 H, regioisomer),

6.97 (s, 1 H, regioisomer), 7.35 (t, J ϭ 7.5 Hz, 1 H, 18), 11.73 (br.

s, 1 H, CO₂H) ppm. ¹³C NMR: δ ϭ Ϫ0.4, 0.7, 14.1, 22.6, 29.1,

29.6, 30.2, 31.7, 31.9, 133.1, 143.7, 147.3, 160.2, 173.0, 177.3 ppm.

1,4-Diphenylbut-2-yne:^{[58] 1}H NMR: δ ϭ 3.65 (s, 4 H) ppm. ¹³C

NMR: δ ϭ 25.2, 80.0 ppm; because of insufficient purity, the sig-

nals for the phenyl groups could not be assigned.

Diene 21: Compound 21 was obtained according to the General

Procedure for the hydrocarboxylation of alkynes, starting from

phenylacetylene, and applying variation A. The crude product

(55 mg) contained mostly cyclopentanecarboxylic acid, as shown

by NMR spectroscopy. Purification, however, of the ‘‘nonacidic’’

crude product (0.14 g, yellow crystals) by several recrystallisations

(diethyl ether or heptane) led to pure 21 (54 mg, 0.26 mmol, 52%).

Carboxylic Acid 19: Preparation obtained according to the General

Procedure for the hydrocarboxylation of alkynes, starting from 7-

1

benzyloxyhept-2-yne, and applying variation A. H NMR analysis

of the crude product (0.16 g, colourless oil) revealed that the re-

gioselectivity of the reaction was about 67:33 in favour of 19. Puri-

fication by flash column chromatography (ethyl acetate/heptane,

gradient from 2 to 20%) afforded a 63:37 mixture of 19 and the

other regioisomer (0.10 g, 0.41 mmol, 41%). Flash column chroma-

tography (ethyl acetate/heptane, gradient from 0 to 10%) of the

‘‘nonacidic’’ crude product (0.11 g, colourless oil) led to the isola-

21:^[59]Colourless crystals; m.p. 152.7Ϫ153.0 °C (ref.^[59]m.p. 153

1

°C). H NMR: δ ϭ 6.66 (m, 2 H), 6.94 (m, 2 H), 7.22 (m, 2 H),

7.32 (t, J ϭ 7.5 Hz, 4 H), 7.43 (m, 4 H) ppm. ¹³C NMR: δ ϭ 126.4,

tion of pure (Z)-7-benzyloxyhept-2-ene (33 mg, 0.16 mmol, 16%), 127.5, 128.6, 129.2, 132.8, 137.3 ppm.

the simple reduction product.

Diene 22: Compound 22 was obtained according to the General

Mixture of 19 and Its Regioisomer (63:37): Colourless liquid. MS

Procedure for the hydrocarboxylation of alkynes, starting from 1-

(CI, NH₃): m/z ϭ 268, 267, 266 [MH^ϩϩ NH₃], 251, 249 [MH^ϩ], octyne, and applying variation A. The crude product (63 mg) con-

248, 231. HRMS (ES^ϩ): calcd. for C₁₅H₂₀NaO₃[MNa^ϩ] 271.1310, tained essentially cyclopentylcarboxylic acid, as shown by NMR

found 271.1307. IR: ν˜ ϭ 2940, 2862, 1700, 1695, 1684, 1453, 1102

spectroscopy. Purification, however, of the ‘‘nonacidic’’ crude prod-

1

cm^Ϫ1. H NMR: δ ϭ 1.30Ϫ1.90 (m, 7 H), 2.21 (q, J ϭ 7.5 Hz, 2 uct (0.17 g, yellow oil) by flash column chromatography (heptane)

H, 19), 2.32 (t, J ϭ 7.5 Hz, 2 H, regioisomer), 3.45 (t, J ϭ 6.0 Hz,

Eur. J. Org. Chem. 2003, 1157Ϫ1171

led to a colourless liquid (75 mg), which proved to be a mixture of

1167

Y. S i x

FULL PAPER

bis(cyclopentane) and 22. We were not able to separate them. Had

22 been pure, its yield would have been 68%.

2.36 (t, J ϭ 7.5 Hz, 2 H), 2.54 (t, J ϭ 7.5 Hz, 2 H), 10.79 (br. s, 1

H, CO₂H) ppm. ¹³C NMR: δ ϭ 13.2, 13.7, 21.4, 21.8, 33.3, 39.3,

128.5; 133.9, 174.2 ppm.

22:^{[60,61] 1}H NMR: δ ϭ 0.88 (t, J ϭ 6.5 Hz, 6 H), 1.20Ϫ1.50 (m,

16 H), 2.04 (q, J ϭ 7.0 Hz, 4 H), 5.56 (m, 2 H), 5.99 (m, 2 H) ppm.

¹³C NMR: δ ϭ 14.1, 22.7, 29.0, 29.5, 31.9, 32.7, 130.4, 132.4 ppm.

Iodocarboxylic Acid 25: Compound 25 was obtained according to

the General Procedure for the halocarboxylation of 4-octyne, using

either iodine or N-iodosuccinimide as the halogenating reagent.

Using iodine, the crude product (0.19 g) was obtained as a colour-

less oil. Flash column chromatography (ethyl acetate/heptane, gra-

dient from 2 to 20%) afforded 25 (0.12 g, 0.44 mmol, 44%). With

N-iodosuccinimide, the crude product (0.22 g) was obtained as a

colourless oil. Flash column chromatography yielded 25 (0.12 g,

0.43 mmol, 43%).

(Z)-Alkene 23: Titanium tetraisopropoxide (2.0 equiv., 2.0 mmol,

0.59 mL) was added at Ϫ70 °C to a solution of 1-phenyl-2-trime-

thylsilylacteylene (1.0 equiv., 1.0 mmol, 0.20 mL) in diethyl ether

(20 mL). Cyclopentylmagnesium chloride (2.1  in diethyl ether,

4.0 equiv., 4.0 mmol, 1.9 mL) was then added dropwise. The re-

sulting yellow mixture was warmed to Ϫ30 °C over 5 min, then

maintained at Ϫ30 °C for 15 min. Aqueous 0.3  HCl (40 mL) and

heptane (20 mL) were added. The organic layer was separated, and

the aqueous phase extracted with heptane (2 ϫ 30 mL). The com-

bined organic layers were dried with magnesium sulfate, filtered

and concentrated to afford a colourless oil (0.17 g). Purification by

flash column chromatography (heptane) afforded analytically pure

23 (0.12 g, 0.65 mmol, 65%).

25: Colourless liquid. IR: ν˜ ϭ 2962, 2932, 2872, 1697, 1288 cm^Ϫ1

.

¹H NMR: δ ϭ 0.94 (t, J ϭ 7.5 Hz, 3 H), 0.96 (t, J ϭ 7.5 Hz, 3 H),

1.52 (sext, J ϭ 7.5 Hz, 2 H), 1.61 (sext, J ϭ 7.5 Hz, 2 H), 2.39 (t,

J ϭ 7.5 Hz, 2 H), 2.60 (t, J ϭ 7.5 Hz, 2 H), 11.50 (br. s, 1 H,

CO₂H) ppm. ¹³C NMR: δ ϭ 13.0, 13.7, 21.9, 22.6, 33.4, 43.2, 107.3;

140.1, 175.0 ppm.

23:^[62]Colourless liquid. C₁₁H₁₆Si (176.34): calcd. C 74.93, H 9.15;

found C 75.11, H 9.33. MS (EI): m/z ϭ 247, 246, 245, 73. IR: ν˜ ϭ

General Procedure for the Synthesis of Lactones from Alkynes: Tita-

nium tetraisopropoxide (2.0 equiv., 2.0 mmol, 0.59 mL) was added

at Ϫ70 °C to a solution of alkyne (1.0 equiv., 1.0 mmol) in diethyl

ether (20 mL). Cyclopentylmagnesium chloride (2.0  in diethyl

ether, 4.0 equiv., 4.0 mmol, 2.0 mL) was then added dropwise. The

resulting yellow mixture was warmed to Ϫ30 °C over 5 min, then

was maintained at Ϫ30 °C for 15 min, by which time it had turned

black. The mixture was cooled down to Ϫ70 °C again, and carbon

dioxide was added, either for 30 min while the bath was warmed

to Ϫ30 °C (variation A), for 30 min at Ϫ30 °C (variation B), or

for 2 h at 0 °C (variation C). The carbonyl compound (2.0 equiv.,

2.0 mmol) was then added, and the mixture was stirred at 20 °C

for 2 h. Aqueous 0.3  HCl (40 mL) and diethyl ether (20 mL) were

then added. The organic layer was separated, and the aqueous

phase extracted with diethyl ether (2 ϫ 30 mL). The combined or-

ganic layers were washed with 1  aqueous NaOH solution

(50 mL). The aqueous phase was extracted with diethyl ether

(50 mL). The combined organic phases were dried with magnesium

sulfate, filtered and concentrated to afford the crude product, which

was purified by flash column chromatography.

1

2958, 2898, 1593, 1571, 1492, 1247, 840 cm^Ϫ1. H NMR: δ ϭ 0.04

(s, 9 H), 5.82 (d, J ϭ 15.0 Hz, 1 H), 7.20Ϫ7.30 (m, 5 H), 7.36 (d,

J ϭ 15.0 Hz, 1 H) ppm. ¹³C NMR: δ ϭ 0.2, 127.3, 127.9, 128.1,

132.8, 140.1, 146.6 ppm.

General Procedure for the Halocarboxylation of 4-Octyne: Titanium

tetraisopropoxide (2.0 equiv., 2.0 mmol, 0.59 mL) was added at

Ϫ70 °C to a solution of 4-octyne (1.0 equiv., 1.0 mmol, 0.15 mL)

in diethyl ether (20 mL). Cyclopentylmagnesium chloride (2.0  in

diethyl ether, 4.0 equiv., 4.0 mmol, 2.0 mL) was then added drop-

wise. The resulting yellow mixture was warmed to Ϫ30 °C over 5

min, then was maintained at Ϫ30 °C for 15 min, by which time it

had turned black. The mixture was cooled down to Ϫ70 °C again,

and carbon dioxide was added for 30 min while the bath was

warmed to Ϫ30 °C. The halogenating reagent (2.0 equiv.,

2.0 mmol) was then added, and the mixture was stirred at 20 °C

for 2 h. Saturated aqueous sodium bisulfite (Na₂S₂O₅) solution

(20 mL) was added. After a few min of stirring, diethyl ether

(20 mL) and 1  aqueous HCl (20 mL) were added. The organic

layer was separated, and the aqueous phase extracted with diethyl

ether (2 ϫ 30 mL). The combined organic layers were extracted

with 1  aqueous NaOH solution (50 mL). The aqueous phase was

washed with diethyl ether (50 mL), acidified using concentrated

HCl aqueous solution, and then extracted with diethyl ether (3 ϫ

30 mL). These last three organic phases were combined, dried with

magnesium sulfate, filtered and concentrated to afford the crude

product, which was then purified by flash column chromatography.

Note: When the isolation of the acidic reaction products was de-

sired, the last (basic) aqueous layer was acidified using concen-

trated HCl aqueous solution, and extracted with diethyl ether (3 ϫ

30 mL). The combined organic phases were dried with magnesium

sulfate, filtered and concentrated. The resulting ‘‘acidic’’ crude

product was then purified by flash column chromatography.

Butenolide 26: Compound 26 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, starting from 4-octyne,

applying variation A, and using benzaldehyde. Flash column chro-

matography (ethyl acetate/heptane, gradient from 0 to 10%) of the

crude product (0.32 g) afforded pure 26 (0.12 g, 0.50 mmol, 50%).

Bromocarboxylic Acid 24: Compound 24 was obtained according

to the General Procedure for the halocarboxylation of 4-octyne,

using either bromine or N-bromosuccinimide as the halogenating

reagent. Using bromine, the crude product (0.15 g) was obtained

as a colourless oil. Flash column chromatography (ethyl acetate/

heptane, gradient from 0 to 20%) afforded 24 (62 mg, 0.26 mmol,

26%). With N-bromosuccinimide, the crude product (0.18 g) was

obtained as a colourless oil. Flash column chromatography yielded

24 (0.10 g, 0.43 mmol, 43%).

26:^[63]Viscous colourless oil. IR: ν˜ ϭ 2961, 2934, 2872, 1756, 1455,

1

1106, 1004 cm^Ϫ1. H NMR: δ ϭ 0.88 (t, J ϭ 7.5 Hz, 3 H), 0.96 (t,

J ϭ 7.5 Hz, 3 H), 1.35 (m, 1 H), 1.45 (m, 1 H), 1.61 (sext, J ϭ 7.5,

2 H), 1.96 (ddd, J ϭ 14.0, 9.0, 5.5 Hz, 1 H), 2.30 (t, J ϭ 7.5 Hz, 2

H), 2.33 (ddd, J ϭ 14.0, 9.5, 7.0 Hz, 1 H), 5.67 (s, 1 H), 7.18 (m,

2 H), 7.36 (m, 3 H) ppm. ¹³C NMR: δ ϭ 13.8, 13.9, 21.2, 21.5,

25.5, 28.4, 83.6, 126.8, 128.8, 129.1, 135.0, 163.2, 174.5 ppm.

24: Colourless liquid. MS (CI, NH₃): m/z ϭ 254 ([MH^ϩϩ NH₃],

⁸¹Br), 253, 252 ([MH^ϩϩ NH₃], ⁷⁹Br), 237 ([MH^ϩ], ⁸¹Br), 235

([MH^ϩ], ⁷⁹Br), 219, 217, 208. IR: ν˜ ϭ 2964, 2933, 2874, 1700, 1290

cm^Ϫ1. ¹H NMR: δ ϭ 0.95 (t, J ϭ 7.5 Hz, 3 H), 0.96 (t, J ϭ 7.5 Hz,

Butenolide 27: Compound 27 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, starting from 4-octyne,

3 H), 1.52 (sext, J ϭ 7.5 Hz, 2 H), 1.66 (sext, J ϭ 7.5 Hz, 2 H), applying variation B, and using propanal. Flash column chromato-

1168 Eur. J. Org. Chem. 2003, 1157Ϫ1171

Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

graphy (ethyl acetate/heptane, gradient from 0 to 10%) of the crude 2-trimethylsilylacetylene, applying variation C, and using trans-cin-

FULL PAPER

product (0.20 g) afforded analytically pure 27 (80 mg, 0.41 mmol,

41%).

namaldehyde. Several sequential flash column chromatographies

(ethyl acetate/heptane, gradient from 0 to 10%) of the crude prod-

uct (0.41 g) afforded a 50:50 mixture of 30 and trans-cinnamal-

dehyde (orange oil, 36 mg). Accordingly, the yield of 30 was estim-

ated to be ca. 8%.

27: Colourless oil. C₁₂H₂₀O₂(196.29): calcd. C 73.43, H 10.27;

found C 73.21, H 10.53. MS (EI): m/z ϭ 196 [M^ϩ·], 181, 139, 81,

69. IR: ν˜ ϭ 2963, 2935, 2874, 1752, 1462, 1120, 1074, 978 cm^Ϫ1

.

1

¹H NMR: δ ϭ 0.92 (t, J ϭ 7.5 Hz, 3 H), 0.98 (t, J ϭ 7.5 Hz, 3 H),

30: H NMR: δ ϭ 0.11 (s, 9 H), 5.66 (dd, J ϭ 7.5, 1.0 Hz, 1 H),

1.35Ϫ1.65 (m, 5 H), 1.99 (dqd, J ϭ 14.5, 7.5, 3.5 Hz, 1 H), 2.19 5.90 (dd, J ϭ 15.5, 7.0 Hz, 1 H), 6.65 (dd, J ϭ 15.5, 1.0 Hz, 1 H),

(ddd, J ϭ 14.0, 9.0, 5.5 Hz, 1 H), 2.23 (m, 2 H), 2.46 (ddd, J ϭ

7.19Ϫ7.44 (m, 10 H) ppm. ¹³C NMR: δ ϭ Ϫ1.0, 85.4, 122.7, 126.7,

14.0, 9.0, 7.0 Hz, 1 H), 4.80 (dd, J ϭ 7.0, 3.5 Hz, 1 H) ppm. ¹³C 128.4, 129.6, 134.6, 175.8 ppm; not all signals could be assigned

NMR: δ ϭ 8.3, 13.8, 14.0, 21.3, 21.5, 25.0, 25.5, 28.4, 82.3, 127.8,

because of the presence of trans-cinnamaldehyde on the spectrum.

162.8, 174.4 ppm.

Butenolide 31: Compound 31 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, on a 2.2-mmol scale,

starting from 5-tert-butyldimethylsilyloxy-1-phenylpent-1-yne, ap-

plying variation B, and using hexanal. Two sequential flash column

chromatographies (ethyl acetate/heptane, gradient from 0 to 20%)

of the crude product (1.2 g) afforded pure 31 (0.18 g) and a mixture

of 31 and the other possible regioisomer (0.28 g) as colourless oils.

The total amount of lactones was thus 0.46 g (1.1 mmol, 52%). The

ratio of the two products was about 85:15 after the first column

Butenolide 28: Compound 28 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, starting from 1-phenyl-

1-pentyne, applying variation B, and using benzaldehyde. Flash col-

umn chromatography (ethyl acetate/heptane, gradient from 0 to

10%) of the crude product (0.31 g), followed by recrystallisation

(heptane), afforded a mixture of 28 and of the other possible re-

gioisomer (ratio ca. 78:22 in favour of 28, 0.13 g, 0.46 mmol, 46%).

The ratio of the two products was about the same in the crude

1

chromatography, as shown by H NMR analysis.

product as shown by H NMR analysis. A second recrystallisation

led to the isolation of analytically pure 28 as a single regioisomer

(92 mg, 0.33 mmol, 33%).

31: Colourless oil. MS (EI): m/z ϭ 346, 345, 115, 91, 75, 73, 57.

HRMS (ES^ϩ): calcd. for C₂₄H₃₈NaO₃Si [MNa^ϩ] 425.2488, found

425.2469. IR: ν˜ ϭ 2955, 2929, 2858, 1754, 1255, 1099, 835, 775

28: Colourless crystals, m.p. 79.5Ϫ80.7 °C. C₁₉H₁₈O₂(278.35):

calcd. C 81.99, H 6.52; found C 81.86, H 6.49. IR: ν˜ ϭ 2962, 2932,

1753, 1455, 1094, 1006 cm^Ϫ1. ¹H NMR: δ ϭ 0.98 (t, J ϭ 7.5 Hz, 3

H), 1.69 (m, 2 H), 2.48 (m, 2 H), 6.14 (s, 1 H), 7.13Ϫ7.23 (m, 4

H), 7.24Ϫ7.37 (m, 6 H) ppm. ¹³C NMR: δ ϭ 14.0, 21.5, 26.2, 83.6,

127.2, 127.7, 128.7, 129.0, 129.4, 131.4, 134.9, 159.1, 174.0 ppm.

cm^Ϫ^{1 1}H NMR: δ ϭ 0.00 (s, 3 H), 0.02 (s, 3 H), 0.82 (m, 3 H),

.

0.86 (s, 9 H), 1.10Ϫ1.48 (m, 7 H), 1.65Ϫ1.90 (m, 3 H), 2.51 (m, 2

H), 3.63 (m, 2 H), 5.31 (m, 1 H), 7.30Ϫ7.50 (m, 5 H) ppm. ¹³C

NMR: δ ϭ Ϫ5.4, 13.9, 18.3, 21.0, 22.4, 24.0, 25.9, 31.1, 31.3, 32.8,

62.5, 81.8, 127.7, 127.7, 129.0, 129.6, 131.6, 159.8, 174.2 ppm.

Regioisomer of 31. Main Differences: ¹H NMR: δ ϭ 2.00 (m, 1 H),

2.45 (m, 1 H), 2.84 (m, 1 H), 3.55Ϫ3.70 (m, 2 H), 5.00 (dd, J ϭ

7.0, 3.0 Hz, 1 H), 7.25Ϫ7.45 (m, 5 H) ppm. ¹³C NMR: δ ϭ 14.0,

32.2, 62.1, 81.6, 128.4 ppm.

1

Regioisomer of 28. Main Differences: H NMR: δ ϭ 0.84 (t, J ϭ

7.5 Hz, 3 H), 1.30Ϫ1.58 (m, 2 H), 2.08 (ddd, J ϭ 14.5, 9.5, 5.5 Hz,

1 H), 2.57 (ddd, J ϭ 14.5, 10.0, 7.0 Hz, 1 H), 5.85 (s, 1 H) ppm.

¹³C NMR: δ ϭ 21.2, 29.0, 134.7, 164.4 ppm.

δ-Hydroxy Acid 32: This compound was obtained by removing the

TBS group of acid 16 according to a literature procedure.^[64]Water

(1.0 mL) and acetic acid (3.0 mL) were added to a solution of silyl

ether 16 (1.0 equiv., 0.59 mmol, 0.19 g) in THF (1.0 mL). The mix-

ture was stirred for 200 min at 20 °C, then concentrated under va-

cuum (heptane was used as an azeotrope to remove acetic acid

thoroughly) to give a viscous colourless oil (0.13 g) that later crys-

tallised. Recrystallisation (heptane/ethyl acetate) afforded analytic-

ally pure 32 (82 mg, 0.40 mmol, 67%).

Butenolide 29: Compound 29 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, starting from 1-phenyl-

1-pentyne, applying variation B, and using trans-cinnamaldehyde.

Flash column chromatography (ethyl acetate/heptane, gradient

from 0 to 20%) of the crude product (0.40 g) afforded a mixture of

29 and of the other possible regioisomer (ratio ca. 81:19 in favour

of 29, 0.18 g, 0.58 mmol, 58%). The ratio of the two products was

1

about 88:12 in the crude product as shown by H NMR analysis.

Mixture of 29 and Its Regioisomer (81:19): Pale yellow oil. MS

(ES^ϩ): m/z ϭ 306, 305 [MH^ϩ], 261, 185, 161, 117. HRMS (ES^ϩ):

calcd. for C₂₁H₂₀NaO₂[M ϩ Na^ϩ] 327.1361, found 327.1350. IR:

32: Colourless crystals; m.p. 98.5Ϫ99.5 °C. C₁₂H₁₄O₃(206.24):

calcd. C 69.89, H 6.84; found C 70.01, H 6.86; MS (EI): m/z ϭ 206

[M^ϩ·], 188, 187, 160, 143, 142, 129, 128, 116, 115, 91. IR: ν˜ ϭ 3330,

ν˜ ϭ 2961, 1752, 1448, 1112, 1086, 1068, 1001, 967 cm^Ϫ1

.

2925, 1672, 1421, 1036 cm^{Ϫ1 1}H NMR: δ ϭ 1.87 (dd, J ϭ 7.5,

.

1

29: H NMR: δ ϭ 0.95 (t, J ϭ 7.5 Hz, 3 H), 1.63 (m, 2 H), 2.44

(m, 2 H), 5.80 (d, J ϭ 7.5 Hz, 1 H), 5.92 (dd, J ϭ 16.0, 7.5 Hz, 1

H), 6.74 (d, J ϭ 16.0 Hz, 1 H), 7.15Ϫ7.50 (m, 10 H) ppm. ¹³C

NMR: δ ϭ 14.1, 21.4, 26.4, 82.3, 123.2, 126.7, 128.7, 128.3, 128.5,

128.9, 129.7, 135.1, 158.5, 173.8 ppm.

6.0 Hz, 2 H), 2.66 (t, J ϭ 7.5 Hz, 2 H), 3.70 (t, J ϭ 6.0 Hz, 2 H),

7.20Ϫ7.50 (m, 7 H), 7.84 (s, 1 H) ppm. ¹³C NMR: δ ϭ 23.3, 31.9,

62.0, 128.6, 128.9, 129.4, 131.7, 135.2, 141.7, 173.5 ppm.

Lactone 33: A solution of δ-hydroxy acid 32 (1.0 equiv. 0.36 mmol,

75 mg) in toluene (5.0 mL) was stirred under reflux for 6 h. After

cooling, the solvent was evaporated under vacuum to afford a col-

ourless liquid (69 mg). Purification by flash column chromato-

graphy (ethyl acetate/heptane, gradient from 5 to 30%) yielded pure

33 (66 mg, 0.35 mmol, 97%).

1

Regioisomer of 29. Main Differences: H NMR: δ ϭ 0.93 (t, J ϭ

7.5 Hz, 3 H), 2.65 (ddd, J ϭ 14.0, 9.5, 7.0 Hz, 1 H), 5.49 (d, J ϭ

8.5 Hz, 1 H), 6.01 (dd, J ϭ 16.0, 8.5 Hz, 1 H), 6.86 (d, J ϭ 16.0 Hz,

1 H) ppm. ¹³C NMR: δ ϭ 21.2, 29.0, 82.8, 123.0, 136.0 ppm.

Butenolide 30: Compound 30 was obtained according to the Gen-

eral Procedure for the synthesis of lactones, starting from 1-phenyl-

33: Colourless oil. MS (EI): m/z ϭ 188 [M^ϩ·], 187, 129, 128, 118,

115, 102, 91. IR: ν˜ ϭ 1708, 1612, 1447, 1260, 1172, 1121, 1071,

Eur. J. Org. Chem. 2003, 1157Ϫ1171

1169

Y. S i x

FULL PAPER

978, 772 cm^Ϫ1. ¹H NMR: δ ϭ 1.97 (tt, J ϭ 6.5, 5.0 Hz, 2 H), 2.88

(td, J ϭ 6.5, 2.0 Hz, 2 H), 4.39 (t, J ϭ 5.0 Hz, 2 H), 7.30Ϫ7.50 (m,

5 H), 7.91 (t, J ϭ 2.0 Hz, 1 H) ppm. ¹³C NMR: δ ϭ 22.9, 25.8,

68.6, 125.7, 128.5, 129.1, 130.1, 134.8, 141.4, 166.9 ppm.

pounds are not suitable for further ligand exchange with al-

kynes: R. Mizojiri, H. Urabe, F. Sato, J. Org. Chem. 2000, 65,

6217Ϫ6222. More recently, Eisch et al. have reported the pre-

paration of solutions of (diisopropyloxy)titanacyclopropanes,

using a novel method, see ref.^[14]

When cyclopentylmagnesium chloride (1.2 equiv.) was added

to acetophenone (1.0 equiv.) in diethyl ether under the same

temperature and time conditions as for the preparation of diol

7, 1-phenylethanol was isolated in 62% yield.

M. B. Smith, J. March, Advanced Organic Chemistry: Reac-

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Acknowledgments

This work was funded by the Centre National de la Recherche Sci-

entifique (C.N.R.S.). We wish to thank Professor Samir Z. Zard,

ˆ

Mr. Arnaud Parenty, Dr. Jean-Marc Campagne and Dr. Benoıt

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Crousse for the gifts of several reagents and starting compounds.

We are also grateful to the people who carried out the elemental

analyses and the mass spectra of our compounds.

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Titanium-Mediated Carboxylation of Alkynes With Carbon Dioxide

FULL PAPER

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Received October 25, 2002

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[O02595]

Eur. J. Org. Chem. 2003, 1157Ϫ1171

1171

Article Doi

Titanium-mediated carboxylation of alkynes with carbon dioxide

DOI: 10.1002/ejoc.200390170

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Authors:

Article abstract of DOI:10.1002/ejoc.200390170

Full text of DOI:10.1002/ejoc.200390170

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