Alkynyl halides in ruthenium(II)-catalyzed [2+2] cycloadditions of bicyclic alkenes

FULL PAPER

DOI: 10.1002/ejoc.200800424

Alkynyl Halides in Ruthenium(II)-Catalyzed [2+2] Cycloadditions of Bicyclic

Alkenes

Anna Allen,^[a][‡]Karine Villeneuve,^[a][‡‡]Neil Cockburn,^[a]Elisabeth Fatila,^[a]

Nicole Riddell,^{[a][‡‡‡]}and William Tam*^[a]

Keywords: Ruthenium / Cycloaddition / Bicyclic alkenes / Alkynyl halides / Homogeneous catalysis

Ru-catalyzed [2+2] cycloadditions between bicyclic alkenes

and alkynyl halides were found to occur in moderate to good

yields. The presence of the halide moiety greatly enhances

the reactivity of the alkyne component in the cycloaddition

and can be transformed into a variety of products that are

difficult or impossible to obtain by direct cycloaddition.

Germany, 2008)

Introduction

Alkynyl halides are useful building blocks in organic syn-

thesis. Traditionally, alkynyl halides were accessible through

the deprotonation of the corresponding terminal alkynes

with a strong base, followed by trapping with a halogenat-

ing agent.^[1]However, several mild and convenient methods

have been reported recently and thus have increased the at-

tractiveness of this class of compounds in organic synthe-

sis.^[2]The alkynyl halide moiety can be conceived as a dual

functionalized molecule in transition-metal-catalyzed reac-

tions (Scheme 1). In the presence of a low-valent transition

metal, the metal atom can insert into the carbon–halide

bond of the alkynyl halide 1 to form the σ-acetylene–metal

complex 2 (Type I). On the other hand, a halovinylidene–

metal complex 3 can also be obtained from the alkynyl

halide 1 through a 1,2-migration of the halogen (Type II).

Finally, the π-system of the acetylene can coordinate to the

metal center in an η²-fashion to form the π-acetylene com-

plex 4 (Type III).

Scheme 1. Potential reactivity pathways of alkynyl halides in transi-

tion-metal-catalyzed reactions.

thesized using this method. The formation of the halovinyl-

idene–metal complex 3 (Type II) is not common, but has

been observed when an alkynyl iodide was treated with a

tungsten complex, W(CO)₅(THF), to produce an iodovinyl-

idene–tungsten complex which underwent a 6π-electrocyc-

lization.^[7]The formation of the π-acetylene complex 4

(Type III) of alkynyl halides are also rare, probably due to

the potential problems associated with the oxidative inser-

tion of the metal atom into the carbon–halide bond (Type

I). Therefore, very few successful examples of any transi-

tion-metal-catalyzed cycloadditions with alkynyl halides,

which rely on the formation of the π-acetylene complex 4,

have been reported in the literature (Scheme 2).^[8]

The most extensive studies and applications of alkynyl

halides in transition-metal-catalyzed reactions are metal-

catalyzed cross-coupling reactions to form carbon–carbon

bonds by oxidative insertion of the metal atom into the car-

bon–halide bond (Type I). Useful building blocks such as

enynes,^[3]diynes,^[4]triynes,^[5]and ynamides^[6]have been syn-

We and others have studied various aspects of transition-

metal-catalyzed [2+2] cycloadditions between an alkene and

Biochemistry, Department of Chemistry, University of Guelph, an alkyne for the synthesis of cyclobutene rings, including

[a] Guelph-Waterloo Centre for Graduate Work in Chemistry and

Guelph, Ontario, N1G 2W1, Canada

the development of novel catalysts, the study of the intra-

Fax: +1-519-766-1499

molecular variant of the reaction, and the investigation on

the chemo- and regioselectivity of unsymmetrical sub-

strates.^[9–14]More recently, we have demonstrated the first

examples of asymmetric induction studies in ruthenium-cat-

alyzed [2+2] cycloadditions between symmetrical bicyclic

alkenes and alkynes bearing a chiral auxiliary, and excellent

levels of asymmetric induction (up to 98.8% ee, after re-

E-mail: wtam@uoguelph.ca

[‡] Current address: Department of Chemistry, Princeton Univer-

sity, Princeton, NJ 08544, USA

[‡‡] Current address: Department of Chemistry, University of

California, Irvine, CA 92697-2025, USA

[‡‡‡]Current address: Wellington Laboratories, 345 Southgate

Drive, Guelph, Ontario, N1G 3M5, Canada

Supporting information for this article is available on the

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

4178

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Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

investigation is important, because it provides valuable in-

formation on the compatibility and reactivity of alkynyl ha-

lides in ruthenium-catalyzed [2+2] cycloadditions, and also

provides a method to obtain cycloadducts that are imposs-

ible to obtain by direct cycloaddition.

Results and Discussion

Ruthenium-Catalyzed [2+2] Cycloadditions of

Norbornadiene (5) with Alkynyl Halides

An initial investigation into various alkynyl bromides

was first undertaken to determine the scope of their utility

(Table 2). The alkynyl bromides were easily prepared in

high yields through the treatment of their corresponding

terminal alkynes with N-bromosuccinimide (NBS) in the

presence of a catalytic amount of silver nitrate.^[15]In the

presence of 5 mol-% of the catalyst, Cp*RuCl(COD) (Cp*

= 1,2,3,4,5-pentamethylcyclopentadienyl, COD = cyclooc-

tadiene), [2+2] cycloadditions between the alkynyl bromide

8a (R = Ph) and norbornadiene (5) occurred smoothly at

both 25 and 60 °C to provide the corresponding exo cy-

cloadduct 9a in 78 and 82% yield (Table 2, Entries 1 and

2), respectively, as the only stereoisomer.^[16]As the electron-

donating capacity of the substituent increased, longer reac-

tion times (R = p-Me-C₆H₄, Table 2, Entry 4) and higher

temperatures (R = p-MeO-C₆H₄, Table 2, Entry 3) were re-

quired. It was also observed that steric hindrance associated

with the alkyne affected the rate of reaction (compare 8c

vs. 8d and 8e vs. 8f). It should be noted that less reactive

alkynes did not allow a full recovery of the net molar bal-

ance (i.e. the combined yields of the cycloadduct and the

recovered starting material did not add up to 100%). Alk-

ynyl bromides are not very stable under the reaction condi-

tions and subsequently, when the reaction takes place over

a long reaction time at higher temperatures, decomposition

occurs prior to completion of the cycloadddition reaction.

Control experiments showed that, thermal decomposition

of the alkynyl bromides was observed upon heating in

THF; and no decomposition was detected when the cy-

cloadducts was subjected to the same conditions.

Scheme 2. Transition-metal-catalyzed cycloaddition reactions of

alkynyl halides.

moval of the recoverable chiral auxiliary) in the cycload-

ditions were achieved.^[14e]Generally, excellent yields are ob-

tained in the Ru-catalyzed [2+2] cycloadditions between bi-

cyclic alkenes and electron-deficient alkynes (Table 1).

However, limitations in the type of suitable alkynes are in-

evitable, and low yields were obtained when non-electron-

deficient or bulky alkynes were used (Table 1). This prop-

erty of ruthenium-catalyzed [2+2] cycloadditions has, to

certain extent, limited the possible cycloadducts affordable

through this methodology.

Table 1. Ruthenium-catalyzed [2+2] cycloaddition between norbor-

nadiene and alkynes bearing different functional groups.

The effect of the halogen group on the cycloaddition re-

action was also studied (Table 3).^[17]Two series of substrates

were investigated (R = Ph and CO₂Et). In the ester series

(Table 3, Entries 1–3), the cycloadditions of all the alkynyl

chloride, bromide and iodide occurred smoothly even at

25 °C in 1–2 h to give the corresponding cycloadducts in

good yields. For the phenyl series, although longer reaction

[a] Yield of isolated cycloadducts 7. [b] See ref.^[14l][c] See ref.^[9c][d]

Homotrimerization of the terminal alkyne 6e was also observed,

see ref.^[9c]

Alkynyl halides are an interesting class of alkynes to ex- times are required (ca. 48 h) both the cycloadditions of alk-

plore, because their electron-withdrawing ability could po- ynyl chloride and bromide occurred smoothly at 25 and

tentially enhance the rate of the [2+2] cycloaddition reac- 60 °C to provide the corresponding cycloadducts in good

tion. The halide moiety could also be used for further func- yields (Table 3, Entries 4–7). An uncharacteristic difference

tionalization, thereby providing a complementary method in reactivity was observed for 1-iodo-2-phenylethyne (10d)

for the preparation of those cycloadducts that are difficult (Table 3, Entries 8 and 9). Other than the formation of the

or impossible to obtain by direct cycloaddition. In this pa- usual [2+2] cycloadduct 11d, a new addition product (12a),

per, we have extended our previous preliminary results^[8b]was also obtained in 26% yield. The structure and stereo-

and report a full account of the ruthenium-catalyzed [2+2] chemistry of this byproduct 12a was determined by using

cycloadditions of bicyclic alkenes with alkynyl halides. This mass spectrometry and ¹H, ¹³C (JMOD), COSY, HSQC

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A. Allen, K. Villeneuve, N. Cockburn, E. Fatila, N. Riddell, W. Tam

FULL PAPER

Table 2. Ruthenium-catalyzed [2+2] cycloaddition between norbor-

nadiene and alkynyl bromides.

Table 3. Ruthenium-catalyzed [2+2] cycloaddition between norbor-

nadiene and different alkynyl halides.

[a] Yield of isolated cycloadducts; yield of recovered alkyne in par-

erntheses. [b] Side product 12a was also obtained in 26%.

used in order to approach pseudo-first-order conditions).^[21]

The reactivity of each alkyne was assessed by evaluation of

the product ratio by capillary gas chromatography. The re-

sults of these reactivity studies are shown in Table 4. Alkyne

6a is one of the most reactive alkynes studied so far in ru-

thenium-catalyzed [2+2] cycloadditions, and it reacts ca.

100 times faster than unactivated alkynes such as 6b (R =

Ph, X = Me). When comparing the reactivity of alkynyl

halides 8a (X = Br) and 10c (X = Cl) with the alkyne 6a

(X = CO₂Et), cycloadditions with these alkynyl halides ap-

peared to occur even faster than with alkyne 6a. In fact,

the rate of the cycloaddition of 8a and 10c with norbornad-

iene (5) were two and nine times faster, respectively, than

that of 6a.

[a] Yield of isolated cycloadducts 9; yield of recovered alkyne in

parentheses.

and GOESY NMR experiments.^[18–20]The exo stereochem-

istry of both groups was established by GOESY NMR ex-

periments of product 12b, which was obtained by hydrogen-

ation of 12a. We believe that the presence of this product

can be explained by a combination of two factors. Because

the iodide is less electronegative than the bromide and chlo-

ride, and the rate of the reaction is increased by utilizing

strong electron-withdrawing groups, the cycloaddition oc-

curs at a much slower rate. In addition, because the C–I

bond is weaker than both the C–Br and C–Cl bonds, it is

easier for the ruthenium atom to oxidatively insert into the

C–I bond. To the best of our knowledge, this is the first

example of a ruthenium-catalyzed haloalkynylation of alk-

ynyl halide across a double bond.

Table 4. Relative rate of cycloaddition.

To estimate the reactivity of alkynyl halides in the ruthe-

nium-catalyzed [2+2] cycloadditions, the relative rate of the

ruthenium-catalyzed [2+2] cycloadditions of several alkynes

with norbornadiene was measured by competition experi-

ments between the alkyne 6a (R = Ph, X = COOEt) and

other alkynes (Table 4). A typical competition experiment

employed 4 equiv. of equimolar amounts of alkyne 6a (a

stock solution of known concentration was prepared for 6a)

and the alkyne 10c (R = Ph, X = Cl) with 1 equiv. of

norbornadiene (5) in the presence of 5 mol-% of

[a] Measured from competition experiments, see text; the number

Cp*RuCl(COD) in THF (large excesses of the alkynes were indicated is the average number from 3–5 runs.

4180 Eur. J. Org. Chem. 2008, 4178–4192

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Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

Ruthenium-Catalyzed [2+2] Cycloadditions of Other

Symmetrical Bicyclic Alkenes with Alkynyl Halides

time. Good yield was obtained in the Ru-catalyzed [2+2]

cycloadditions between the oxabenzonorbornadiene 14 and

the alkynyl chloride 10c (87%, Entry 5). However, the ad-

dition of an electron-donating group (OMe, Entry 7, oxa-

benzonorbornadiene 15, 55%) or an electron-withdrawing

group (Br, Entry 9, oxabenzonorbornadiene 16, 41%) on

the benzo group of the oxabenzonorbornadiene lead to a

significant decrease in the yields. Interestingly, this trend

was not observed for different oxabenzonorbornadienes 14–

16 when the alkynyl bromide 8a was used as the alkyne

partner. In fact, identical yields were observed when the

alkynyl bromide 8a was used in the Ru-catalyzed [2+2] cy-

cloadditions between the oxabenzonorbornadienes 14–16

(Entries 6, 8 and 10). The azabenzonorbornadiene 17 also

provided good yields of the [2+2] cycloadducts with the alk-

ynyl chloride 10c and the alkynyl bromide 8a (Entries 11

and 12). It is worth to mention that due to the two orienta-

tions of the BOC group on the nitrogen atom, both cy-

cloadducts 11m and 11n were isolated as a mixture of two

conformers (one with the BOC group pointing towards the

cyclobutene ring, another with the BOC group pointing

towards the benzene ring).

The scope of the Ru-catalyzed [2+2] cycloadditions of

alkynyl halides with different bicyclic alkenes was also in-

vestigated (Table 5).^[22]In general, moderate to good yields

were obtained in the Ru-catalyzed [2+2] cycloadditions be-

tween various bicyclic alkenes (5, 13–17) with the alkynyl

chloride 10c and the alkynyl bromide 8a. The cycload-

ditions of both the alkynyl chloride 10c and the alkynyl

bromide 8a with norbornadiene (5) gave much higher yields

than those with norbornene (13) (compare Entries 1 and

2 with Entries 3 and 4). This may be due to the fact that

norbornene is less reactive than norbornadiene in Ru-cata-

lyzed [2+2] cycloadditions,^[14o]and much longer reaction

time was needed for norbornene than for norbornadiene

(140 h for the cycloadditions with norbornene and only

48 h for norbornadiene), and thus the thermally unstable

alkynyl halides could decompose due to the longer reaction

Table 5. Ruthenium-catalyzed [2+2] cycloaddition between dif-

ferent bicyclic alkenes and alkynyl halides 8a and 10c.

Ruthenium-Catalyzed [2+2] Cycloadditions of

Unsymmetrical C1-Substituted Oxabenzonorbornadiene 18

with Alkynyl Halides

Because all the bicyclic alkenes studied above are sym-

metrical, no regiochemical information in the Ru-catalyzed

[2+2] cycloadditions with alkynyl halides can be obtained.

To investigate the regiochemical aspects of the Ru-catalyzed

[2+2] cycloadditions between unsymmetrical bicyclic al-

kenes and alkynyl halides, the C1-substituted oxabenzonor-

bornadiene 18 was prepared.^[14m]The Ru-catalyzed [2+2]

cycloadditions between the C1-substituted oxabenzonor-

bornadiene 18 with several alkynyl halides are shown in

Table 6.

Several trends can be seen from examining the results of

the cycloadditions. The alkynyl halides bearing an unsatu-

rated electron-withdrawing group, such as an ester (CO₂Et,

Entries 4–6) and a sulfone (SO₂Tol, Entry 7), show much

higher regioselectivity than the alkynyl halides bearing an

aromatic ring (Ph, Entries 1–3). The alkynes bearing an es-

ter or a sulfone substituent have ratios of regioisomers rang-

ing from 10:1 to Ͼ99:1, whereas those with a Ph group have

ratios Ͻ2:1. In all cases, the major regioisomer was 19

where the R substituent of the alkyne is placed farther away

from the C1 methyl ester. The major regioisomers were de-

termined through 1D GOESY NMR experiments.^[20]

A possible reason for the high regioselectivity with al-

kynes bearing unsaturated substituents lies in the preferred

ruthenapentacycle intermediate (Scheme 3). Oxidative cycli-

zation of the C1-substituted oxabenzonorbornadiene 18

and alkynyl halides bearing an ester group with

Cp*RuCl(COD), ruthenapentacycle A is most likely formed

preferentially due to the ability of the C1 carbonyl function-

ality of 18 to donate electron density to the ruthenium

[a] Isolated yield of isolated cycloadducts after column chromatog-

raphy.

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FULL PAPER

Table 6. Ruthenium-catalyzed [2+2] cycloaddition between C1-substituted oxabenzonorbornadiene 18 with alkynyl halides.

[a] The ratio of regioisomers was determined by GC or 400 MHz ¹H NMR spectroscopy; the regiochemistry of the cycloadducts were

determined by ¹D GOESY NMR experiments, see text. [b] Yield of isolated cycloadducts. [c] Other side products formed from the

isomerization of oxanorbornadiene 18 and cyclotrimerization of the alkynyl halides were also observed, see text. [d] No minor regioisomer

1

can be detected by 400 MHz H NMR spectroscopy.

Scheme 3. Possible explanation of regioselectivity.

metal center. The alkyne is preferentially oriented with the try 6). Apart from the decomposition of alkynyl halides at

ester functionality further from the metal atom, as it can higher reaction temperature, two other factors contributing

then participate in resonance, forming B, to delocalize the to the low yields of the cycloadditions: isomerization of the

electron density and therefore stabilize the intermediate ru- C1-substituted oxabenzonorbornadiene 18 to the corre-

thenapentacycle. Reductive elimination of A leads to the sponding naphthols 21 (Scheme 4) and the cyclotrimeri-

major regioisomer 19.

zation of alkynyl halides to the corresponding benzene deriv-

Another trend in the regioselectivity can be observed atives 22 and 23 (Scheme 5). In the majority of the reactions

when comparing the reactions with alkynes bearing the carried out, both the alkyne and the alkene components

ethyl ester moiety (Entries 4–6). As the halide moves down were involved in the formation of side products. In every

the periodic table (Cl to Br to I), the regioselectivity de- reaction at elevated temperatures, the oxabenzonorbornadi-

creases, with the alkynyl chloride 10a giving the best ratio ene 18 isomerized to the corresponding naphthols 21

of the series at 61:1; however, the regioselectivity was still (Scheme 4). Methyl 2-hydroxy-1-naphthoate (21a) was de-

good in all cases. A possible explanation of this trend re- termined to be the major isomer through comparison with

volves around the size of the halide; as the halide atom literature NMR spectra as well as by the characteristic

1

becomes larger moving from chloride to iodide, sterics may sharp singlet H NMR signal found at δ = 11.98 ppm, cor-

begin to play a larger role, resulting in more of cycloadduct responding to an intramolecular hydrogen-bonded aryl hy-

20 being produced with the halide atom further away from droxy proton. The naphthol 21a was found to be obtained

the C1 methyl ester of 18.

in a 7:1 ratio with methyl 4-hydroxy-1-naphthoate (21b). Al-

The yields that were obtained in the cycloaddition reac- though this isomerization was seen in every reaction above

tions with the oxabenzonorbornadiene 18 were all fairly room temperature, the alkene component was used in ex-

low, with the highest yield at 60% for the alkyne 10b (En- cess, and the amount of isomerization observed may not

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Eur. J. Org. Chem. 2008, 4178–4192

Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

have affected the yield substantially. This isomerization was found to undergo the trimerization. This could be attrib-

not observed when the reaction was run at room tempera- uted to the lower electronegativity of the iodide as well as

ture.

steric interactions due to its size. The lack of trimerization

is reflected in the large improvement in the yield obtained

for the cycloaddition when compared to the chloride and

bromide analogs (compare Entry 6 with Entries 4 and 5 in

Table 6).

Scheme 4. Isomerization of oxabenzonorbornadiene 18.

Synthetic Applications of Halogenated [2+2] Cycloadducts

In order to illustrate the synthetic usefulness of the re-

sulting halogenated cycloadducts, the cycloadduct 9a was

treated under a variety of reaction conditions to achieve

further functionalization. As shown in Scheme 6, lithium/

halide exchange followed by trapping with various electro-

philes led to the products 7b,c,e in moderate to good yields.

Suzuki coupling between 9a and phenylboronic acid pro-

vided 7d in 75%, and Sonogashira coupling between 9a and

phenylacetylene gave 24 in 64%. As previously shown in

Table 1, these products are difficult or impossible to obtain

by direct cycloaddition.

Scheme 5. Cyclotrimerization of alkynyl halides 10a and 8i.

The side products formed from the alkyne component

could be a much larger contributor to the diminished yields

of the reaction. Side products involving just the alkynyl ha-

lide proved to be problematic in the cycloadditions with

alkynes bearing the ester moiety (Entries 4–6). Both the

alkynyl chloride 10a and the bromide 8i produced a sub-

stantial amount of the trimerized alkyne benzene products

22 and 23 in almost a 1:1 ratio (Scheme 5). During the Ru-

catalyzed [2+2] cycloaddition of the oxabenzonorbornadi-

ene 18 with the alkynyl halides 10a and 8i (Table 6, En-

tries 4 and 5), the trimerized side products 22 and 23 were

obtained in almost a 1:1 ratio with the corresponding cy-

cloadducts. For the alkynyl chloride 10a, apart from ob-

taining 44% of the [2+2] cycloadducts 19d and 20d, the

benzenes 22a and 23a were also obtained in a 38% yield

(22a/23a ≈ 1:1), based on starting alkyne. For the alkynyl

bromide 8i, apart from obtaining 42% of the [2+2] cycload-

ducts 19e and 20e, the benzenes 22b and 23b were also ob-

tained in a 44% yield (22b/23b ≈ 1:1). To ensure these tri-

merized products were a result of the alkynes interacting

with the catalyst alone, control reactions were carried out

without the presence of the oxabenzonorbornadiene 18. It

was found that the alkynes were converted into the tri-

Scheme 6. Functionalization of cycloadduct 9a.

Conclusions

We have demonstrated the first examples of Ru-catalyzed

merized benzene products with almost quantitative yields. [2+2] cycloadditions between alkynyl halides and bicyclic

Through various experiments, it was also found that the alkenes (yields up to 89%). The presence of the halide moi-

alkynyl chloride 10a is more prone to the trimerization. ety is compatible in the ruthenium-catalyzed [2+2] cycload-

When the cycloaddition between the oxabenzonorbornadi- ditions and greatly enhances the reactivity of the alkyne

ene 18 and the alkynyl chloride 10a was attempted at room component in the cycloaddition. The halide moiety could

temperature, only the trimerized benzene products were ob- also be used for further functionalization, thereby providing

tained, and no improvement in the cycloadduct yield was a complementary method for the preparation of those cy-

observed. However, when the cycloaddition between oxa- cloadducts that are difficult or impossible to obtain by di-

benzonorbornadiene 18 and the alkynyl bromide 8i was car- rect cycloaddition. We have investigated the regiochemical

ried out at room temperature, no trimerized benzenes 22b/ aspects of the Ru-catalyzed [2+2] cycloadditions between

23b were observed, and the yield of the cycloadducts 19e the unsymmetrical C1-substituted oxabenzonorbornadiene

and 20e improved to 57%. As well, it was also found in the 18 and several alkynyl halides. A high level of regioselectivi-

control experiments that the alkynyl chloride requires less ties was observed with alkynyl halides bearing an unsatu-

time to convert completely to the benzenes when compared rated electron-withdrawing group such as an ester or a sul-

to the alkynyl bromide. The alkynyl iodide 10b was not fone. During this study, we have also discovered a novel

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1-Bromo-2-(3-fluorophenyl)ethyne (8f): According to the above ge-

neral procedure (A) with 1-ethynyl-3-fluorobenzene (0.5 mL,

4.324 mmol), NBS (935.2 mg, 5.197 mmol), and AgNO₃(98.1 mg,

0.578 mmol) in acetone (10 mL), the reaction mixture was stirred

at 25 °C for 2 h. The crude product was purified by column

chromatography (hexanes) to provide 8f (724.4 mg, 3.640 mmol,

haloalkynylation reaction between 1-iodo-2-phenylethyne

and

norbornadiene

catalyzed

by

the

catalyst

Cp*RuCl(COD). Further investigation of the origin, reac-

tivity and application of this novel type of ruthenium-cata-

lyzed haloalkynylation is ongoing in our laboratory.

84%) as a yellow oil. R = 0.66 (hexanes). IR (neat, NaCl): ν =

˜

f

3073 (w), 2228 (w), 2196 (m), 1783 (w), 1620 (w), 1608 (s), 1582

(s), 1485 (s), 1435 (s), 1271 (s), 1144 (s) cm^–1. H NMR (CDCl₃,

1

Experimental Section

400 MHz): δ = 7.14 (m, 4 H) ppm. ¹³C NMR (APT, CDCl₃,

100 MHz): δ = 162.2 (d, J = 247.0 Hz), 129.9 (d, J = 8.6 Hz), 127.9,

124.2 (d, J = 9.6 Hz), 118.8 (d, J = 23.0 Hz), 116.1 (d, J = 21.2 Hz),

78.9, 51.2 ppm. HRMS: calcd. for C₈H₄FBr 197.9480, found

197.9492.

General: All reactions were carried out under dry nitrogen at am-

bient temperature unless otherwise stated. Standard column

chromatography was performed on 230–400 mesh silica gel (ob-

tained from Silicycle) by using flash column chromatography tech-

niques.^[23]Analytical thin-layer chromatography (TLC) was per-

formed on Merck precoated silica gel 60 F₂₅₄plates. All glassware

was flame-dried under dry nitrogen or oven-dried overnight. Infra-

red spectra were taken with a Bomem MB-100 or Nicolet FTIR

1-Bromo-4-(tert-butyldimethylsilyloxy)butyne (8h): According to the

above general procedure (A) with 4-(tert-butyldimethylsilyloxy)-

butyne (401.3 mg, 2.177 mmol), NBS (439.1 mg, 2.440 mmol), and

AgNO₃(61.0 mg, 0.310 mmol) in acetone (10 mL), the reaction

mixture was stirred at 25 °C for 15 min. The crude product was

purified by column chromatography (EtOAc/hexanes, 1:19) to pro-

vide 8h (433.5 mg, 1.647 mmol, 76%) as a colorless oil. R_f= 0.60

1

spectrophotometer. H and ¹³C NMR spectra were recorded with

Bruker Avance 300, 400 or 600 spectrometers. Chemical shifts for

¹H NMR spectra are reported in parts per million (ppm) from

tetramethylsilane with the solvent resonance as the internal stan-

dard (chloroform: δ = 7.26 ppm). Chemical shifts for ¹³C NMR

spectra are reported in parts per million (ppm) from tetramethylsil-

ane with the solvent as the internal standard (deuteriochloroform:

δ = 77.0 ppm). High-resolution mass spectra were recorded by

McMaster Regional Centre for Mass Spectrometry at McMaster

University, Hamilton, Ontario. Elemental analyses were performed

by Canadian Microanalytical Service Ltd., British Columbia or by

Quantitative Technologies Inc., New Jersey. Unless stated other-

wise, commercial reagents were used without purification. Solvents

were purified by distillation under dry nitrogen from potassium/

benzophenone (THF) and from 4 Å molecular sieves (Et₃N). Nor-

bornadiene (5) and norbornene (13) were purchased from Aldrich.

The alkynyl halides 8a–c,^[2d,15]8e,^[15,24]8g,^[15,25]8i,^[15,26]8j,^[15,27]

10a,^[17b]10b,^[15,28]10c,^[29]10d,^[15,30]the bicyclic alkenes 14–18,^[31,32]

and [Cp*RuCl(COD)]^[33]were prepared according to literature pro-

cedures.

(EtOAc/hexanes, 1:19). IR (neat): ν = 2956 cm^–1. (s), 2930 (s), 2883

˜

(s), 2858 (s), 2739 (w), 2711 (w), 1254 (m), 1112 (s) cm^–1. ¹H NMR

(CDCl₃, 400 MHz): δ = 3.73 (t, J = 7.0 Hz, 2 H), 2.41 (t, J =

7.0 Hz, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 77.5, 61.5, 39.0, 25.8, 24.0, 18.3, –5.3 ppm.

HRMS: calcd. for C₁₀H₁₉BrOSi 262.0389, found 262.0395.

Ruthenium-Catalyzed [2+2] Cycloadditions

General Procedure (B) for the Ru-Catalyzed [2+2] Cycloaddition Be-

tween Norbornadiene and Alkynyl Halides: A mixture of norborna-

diene (5, 3–5 equiv.), alkynyl halide (1 equiv.) and THF in an oven-

dried vial was added by a cannula to an oven-dried screw-cap vial

containing Cp*RuCl(COD) (weighed out from a dry box, 5–

10 mol-%) under nitrogen. The reaction mixture was stirred in the

dark at 25–65 °C for 1–168 h. The crude product was purified by

column chromatography to give the cycloadduct.

Cycloadduct 9a (Table 2, Entry 1): According to the above general

procedure (B) with norbornadiene (5, 93.2 mg, 1.01 mmol), alkynyl

bromide 8a (37.2 mg, 0.206 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (3.6 mg, 0.009 mmol). The reaction mixture was

stirred in the dark at 60 °C for 48 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9a

(46.2 mg, 0.169 mmol, 82%) as a pale yellow oil. R_f= 0.57 (hex-

anes). GC (HP-1 column): retention time = 13.453 min. IR (neat):

Synthesis of Alkynyl Bromides

General Procedure (A) for the Synthesis of the Alkynyl Bromides: N-

Bromosuccinimide (NBS, 1.2 equiv.) and silver nitrate (0.13 equiv.)

were added to a solution of a terminal alkyne (1 equiv.) in acetone

(10 mL). The reaction mixture was stirred at 25 °C for 15 min to

2 h. Upon completion, the reaction mixture was poured into an

ice/water bath, and the resulting aqueous solution was extracted

three times with diethyl ether. The organic phases were combined,

washed with brine, dried with MgSO₄, filtered, and concentrated

by rotary evaporation. The crude product was purified by column

chromatography (hexanes or ethyl acetate/hexanes mixture) to pro-

vide the alkynyl halides.

ν = 3060 (s), 2971 (s), 2949 (s), 2875 (w), 1947 (w), 1877 (w), 1801

˜

(w), 1748 (w), 1629 (m), 1598 (w), 1489 (s), 1447 (s), 1320 (s), 1253

(s), 1291 (s), 1253 (s), 1220 (m), 1190 (s), 1117 (w), 1083 (w), 1025

1

(w), 996 (w), 931 (s) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.72

(dm, J = 7.3 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.33 (dm, J =

7.3 Hz, 1 H), 6.23 (m_ABX, 2 H), 2.88 (d, J = 3.6 Hz, 1 H), 2.77 (m,

2

1 H), 2.76 (s, 1 H), 2.66 (br. s, 1 H), 1.47 (q_AB, J = 9.4 Hz, 2 H)

1-Bromo-2-(2-methylphenyl)ethyne (8d): According to the above

procedure (A) with 1-ethynyltoluene (0.5 mL, 3.969 mmol), NBS

(861.5 mg, 4.788 mmol), and AgNO₃(69.1 mg, 0.407 mmol) in ace-

tone (10 mL), the reaction mixture was stirred at 25 °C for 1 h. The

crude product was purified by column chromatography (EtOAc/

hexanes, 1:99) to provide 8d (645.1 mg, 3.307 mmol, 83%) as a yel-

low oil. R_f= 0.46 (hexanes). ¹H NMR (CDCl₃, 400 MHz): δ = 7.42

ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 145.6, 136.5, 135.9,

132.1, 128.42, 128.38, 125.6, 114.4, 52.2, 46.4, 40.2, 39.4, 38.4 ppm.

HRMS: calcd. for C₁₅H₁₃Br 272.0201, found 272.0180.

Cycloadduct 9b (Table 2, Entry 3): According to the above general

procedure (B) with norbornadiene (5, 150 µL, 1.39 mmol), alkynyl

bromide 8b (34.6 mg, 0.163 mmol), THF (0.30 mL), and

(d, 1 H, J = 7.9 Hz), 7.20 (m, 2 H), 7.13 (t, 1 H, J = 7.2 Hz), 2.44 Cp*RuCl(COD) (5.1 mg, 0.013 mmol). The reaction mixture was

(s, 3 H). ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 140.9, 132.4, stirred in the dark at 65 °C for 72 h. The crude product was purified

129.4, 128.6, 125.5, 122.5, 79.1, 52.8, 20.6 ppm. This is a known

compound and the spectroscopic data are identical to those re-

ported in the literature.^[34]

by column chromatography (EtOAc/hexanes, 1:99) to give the cy-

cloadduct 9b (31.2 mg, 0.103 mmol, 63%) as a white solid. M.p.

37–38 °C. R = 0.41 (EtOAc/hexanes, 1:19). IR (neat, NaCl): ν =

˜

f

4184

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Eur. J. Org. Chem. 2008, 4178–4192

Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

3127 (w), 3059 (m), 3034 (w), 2970 (s), 2949 (s), 2874 (w), 2836

(m), 2049 (w), 1887 (w), 1632 (m), 1603 (s), 1505 (s), 1461 (m),

126.2 (q, J = 5.8 Hz), 123.9 (q, J = 273.3 Hz), 119.7, 52.1, 50.2 (q,

J = 3.6 Hz), 40.2, 39.2, 39.0 ppm. HRMS: calcd. for C₁₆H₁₂F₃Br

1320 (s), 1301 (s), 1257 (s), 1174 (s), 931 (s), 832 (s), 710 (s) cm^–1. 340.0074, found 340.0070.

¹H NMR (CDCl₃, 400 MHz): δ = 7.65 (m, 2 H), 6.92 (m, 2 H),

Cycloadduct 9f (Table 2, Entry 10): Acording to the above general

6.21 (m, 2 H), 3.83 (s, 3 H), 2.83 (d, J = 3.7 Hz, 1 H), 2.73 (d, J =

3.7 Hz, 1 H), 2.72 (br. s, 1 H), 2.63 (br. s, 1 H), 1.47 (d, J = 9.3 Hz,

1 H), 1.42 (d, J = 9.3 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 100 MHz):

δ = 159.6, 145.0, 136.3, 135.9, 127.1, 125.1, 113.8, 111.5, 55.3, 52.0,

46.2, 40.2, 39.3, 38.5 ppm. HRMS: calcd. for C₁₆H₁₅OBr 302.0306,

found 302.0318.

procedure (B) with norbornadiene (5, 270 µL, 2.50 mmol), alkynyl

bromide 8f (61.0 mg, 0.307 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (5.7 mg, 0.015 mmol). The reaction mixture was

stirred in the dark at 65 °C for 72 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9f

(66.9 mg, 0.230 mmol, 75%) as a yellow oil. R_f= 0.40 (hexanes).

IR (neat, NaCl): ν = 3128 (w), 3062 (m), 2973 (s), 2950 (s), 2876

˜

Cycloadduct 9c (Table 2, Entry 4): According to the above general

procedure (B) with norbornadiene (5, 50 µL, 0.463 mmol), alkynyl

bromide 8c (30.0 mg, 0.153 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (4.1 mg, 0.011 mmol). The reaction mixture was

stirred in the dark at 25 °C for 72 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9c

(32.8 mg, 0.114 mmol, 75%) as a yellow solid. M.p. 30 °C; R_f=

(m), 1933 (w), 1856 (w), 1781 (w), 1743 (w), 1608 (s), 1582 (s), 1481

(s), 1444 (s), 1320 (s), 1265 (s), 1203 (s), 1174 (s), 1156 (s), 955 (s),

873 (s), 849 (s), 785 (s), 711 (s) cm^–1. ¹H NMR (CDCl₃, 400 MHz):

δ = 7.37 (m, 3 H), 7.02 (m, 1 H), 6.23 (m, 2 H), 2.86 (d, J = 3.7 Hz,

1 H), 2.77 (d, J = 3.7 Hz, 1 H), 2.75 (br. s, 1 H), 2.66 (br. s, 1 H),

1.45 (s, 2 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 162.8

(d, J = 245.9 Hz), 144.6, 136.4, 135.9, 134.1 (d, J = 7.8 Hz), 130.0

(d, J = 8.3 Hz), 121.3 (d, J = 2.6 Hz), 116.2, 115.2 (d, J = 21.4 Hz),

112.2 (d, J = 22.0 Hz), 52.2, 46.4, 40.1, 39.3, 38.3 ppm. HRMS:

calcd. for C₁₅H₁₂FBr 290.0106, found 290.0102.

0.56 (hexanes). IR (neat, NaCl): ν = 3127 (w), 3059 (m), 3025 (m),

˜

2972 (s), 2948 (s), 2875 (m), 1904 (w), 1791 (w), 1630 (m), 1608

(m), 1565 (m), 1506 (s), 1450 (s), 1319 (s), 1291 (s), 1255 (s), 1220

(m), 1191 (s), 931 (s), 819 (s), 707 (s) cm^–1. ¹H NMR (CDCl₃,

400 MHz): δ = 7.61 (d, J = 8.1 Hz, 2 H), 7.20 (d, J = 7.9 Hz, 2 H),

6.22 (m, 2 H), 2.86 (d, J = 3.7 Hz, 1 H), 2.75 (d, J = 3.5 Hz, 1 H),

2.74 (br. s, 1 H), 2.64 (br. s, 1 H), 2.36 (s, 3 H), 1.47 (d, J = 9.3 Hz,

1 H), 1.42 (d, J = 9.3 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃,

100 MHz): δ = 145.5, 138.4, 136.4, 135.9, 129.4, 129.1, 125.6, 113.1,

52.1, 46.3, 40.2, 39.4, 38.5, 21.5 ppm. HRMS: calcd. for C₁₆H₁₅Br

286.0357, found 286.0365.

Cycloadduct 9g (Table 2, Entry 12): According to the above general

procedure (B) with norbornadiene (5, 60 µL, 0.556 mmol), alkynyl

bromide 8g (30.6 mg, 0.190 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (5.6 mg, 0.015 mmol). The reaction mixture was

stirred in the dark at 60 °C for 72 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9g

(18.3 mg, 0.072 mmol, 38%) as a yellow oil. R_f= 0.62 (hexanes).

IR (neat, NaCl): ν = 3060 (w), 2958 (s), 2931 (s), 2872 (m), 1652

˜

Cycloadduct 9d (Table 2, Entry 6): According to the above general

procedure (B) with norbornadiene (5, 50 µL, 0.463 mmol), alkynyl

bromide 8d (34.1 mg, 0.175 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (3.4 mg, 0.009 mmol). The reaction mixture was

stirred in the dark at 25 °C for 72 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9d

(14.0 mg, 0.0487 mmol, 28%) as a yellow oil. R_f= 0.32 (hexanes).

(w), 1456 (m), 1379 (w), 1293 (w), 1241 (w), 1219 (w), 1192 (w),

1156 (w), 1059 (w), 960 (w), 695 (m) cm^–1. ¹H NMR (CDCl₃,

400 MHz): δ = 6.13 (m, 2 H), 2.58 (m, 1 H), 2.52 (br. s, 1 H), 2.50

(br. s, 1 H), 2.46 (d, J = 3.5 Hz, 1 H), 2.07 (m, 2 H), 1.40 (m, 6 H),

0.92 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (¹³C, CDCl₃, 100 MHz): δ

= 151.1, 136.3, 135.8, 113.9, 52.1, 47.9, 40.0, 38.9, 38.1, 28.7, 27.0,

22.8, 13.8 ppm. HRMS: calcd. for C₁₃H₁₇Br 252.0514, found

252.0520.

IR (neat, NaCl): ν = 3127 (w), 3060 (m), 3017 (m), 2971 (s), 2951

˜

(s), 2875 (m), 1915 (w), 1622 (w), 1600 (w), 1564 (w), 1485 (s), 1449

(s), 1319 (s), 1293 (s), 1247 (s), 1221 (s), 1193 (s), 927 (s), 886 (s),

Cycloadduct 9h (Table 2, Entry 14): According to the above general

procedure (B) with norbornadiene (5, 65 µL, 0.60 mmol), alkynyl

bromide 8h (56.8 mg, 0.216 mmol), THF (0.50 mL), and

Cp*RuCl(COD) (6.2 mg, 0.016 mmol). The reaction mixture was

stirred in the dark at 65 °C for 69 h. The crude product was purified

by column chromatography (EtOAc/hexanes, 1:49) to give the cy-

cloadduct 9h (55.2 mg, 0.155 mmol, 72%) as a colorless oil. R_f=

1

803 (m), 760 (s), 722 (s), 711 (s), 695 (s) cm^–1. H NMR (CDCl₃,

400 MHz): δ = 7.64 (m, 1 H), 7.21 (m, 3 H), 6.22 (m, 2 H), 3.01

(d, J = 3.6 Hz, 1 H), 2.75 (d, J = 3.3 Hz, 1 H), 2.68 (br. s, 1 H),

2.60 (br. s, 1 H), 2.45 (s, 3 H), 1.58 (d, J = 9.3 Hz, 1 H), 1.44 (d, J

= 9.3 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 147.6,

136.5, 136.1, 136.0, 131.8, 130.8, 128.2, 127.8, 125.6, 116.5, 52.4,

50.0, 40.1, 39.5, 39.2, 21.1 ppm. HRMS: calcd. for C₁₆H₁₅Br

286.0357, found 286.0352.

0.60 (EtOAc/hexanes, 1:19). IR (neat): ν = 3129 cm^–1. (w), 3061

˜

(w), 2954 (s), 2930 (s), 2885 (m), 2857 (s), 1255 (s), 1102 (s) cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 6.13 (br. s, 2 H), 3.731 (t, J =

6.7 Hz, 1 H), 3.725 (t, J = 6.8 Hz, 1 H), 2.60 (br. s, 1 H), 2.49–2.52

(m, 3 H), 2.30 (t, J = 6.8 Hz, 2 H), 1.45 (br. d, J = 9.2 Hz, 1 H),

1.38 (br. d, J = 9.2 Hz, 1 H), 0.90 (s, 9 H), 0.06 (s, 6 H) ppm. ¹³C

NMR (APT, CDCl₃, 100 MHz): δ = 148.5, 136.4, 135.7, 115.7,

60.3, 52.5, 48.4, 40.1, 38.9, 38.0, 31.2, 25.9, 18.2, –5.3 ppm. HRMS:

calcd. for C₁₇H₂₇BrOSi 354.1015, found 354.1010.

Cycloadduct 9e (Table 2, Entry 7): According to the above general

procedure (B) with norbornadiene (5, 39 µL, 0.362 mmol), alkynyl

bromide 8e (33.8 mg, 0.136 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (4.1 mg, 0.011 mmol). The reaction mixture was

stirred in the dark at 65 °C for 72 h. The crude product was purified

by column chromatography (hexanes) to give the cycloadduct 9e

(19.4 mg, 0.0569 mmol, 42%) as a colorless oil. R_f= 0.48 (hexanes).

IR (neat, NaCl): ν = 3129 (w), 3063 (m), 2976 (s), 2877 (m), 1941

Cycloadduct 9i (Table 2, Entry 16): According to the above general

˜

(w), 1831 (w), 1604 (m), 1573 (w), 1485 (m), 1452 (m), 1317 (s), procedure (B) with norbornadiene (5, 47 µL, 0.44 mmol), alkynyl

1242 (m), 1172 (s), 1130 (s), 1039 (s), 933 (s), 762 (s), 698 (s) cm^–1. bromide 8i (26.0 mg, 0.147 mmol), THF (0.30 mL), and

¹H NMR (CDCl₃, 400 MHz): δ = 7.80 (d, J = 7.7 Hz, 1 H), 7.70

(d, J = 7.9 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.43 (t, J = 7.7 Hz,

1 H), 6.21 (m, 2 H), 3.12 (br. s, 1 H), 2.77 (d, J = 3.4 Hz, 1 H),

Cp*RuCl(COD) (4.4 mg, 0.017 mmol). The reaction mixture was

stirred in the dark at 25 °C for 1 h. The crude product was purified

by column chromatography (EtOAc/hexanes, 1:19) to give the cy-

2.69 (s, 1 H), 2.53 (s, 1 H), 1.50 (d, J = 9.4 Hz, 1 H), 1.45 (d, J = cloadduct 9i (33.6 mg, 0.125 mmol, 85%) as a colorless oil. R_f=

9.4 Hz, 1 H) ppm. ¹³C NMR (¹³C, CDCl₃, 100 MHz): δ = 145.6, 0.38 (EtOAc/hexanes, 1:19). IR (neat): ν = 3129 (w), 3062 (m), 2979

˜

136.9, 135.9, 131.6, 131.2, 130.2, 128.0, 127.1 (q, J = 30.7 Hz),

(s), 2958 (s), 1904 (m), 2882 (m), 1714 (s), 1623 (s), 1454 (m), 1304

Eur. J. Org. Chem. 2008, 4178–4192

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4185

A. Allen, K. Villeneuve, N. Cockburn, E. Fatila, N. Riddell, W. Tam

Cp*RuCl(COD) (5.4 mg, 0.014 mmol). The reaction mixture was

FULL PAPER

(s), 1198 (s), 1133 (s) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 6.21

1

(dd, J = 5.5, 3.1 Hz, 1 H), 6.16 (dd, J = 5.4, 3.1 Hz, 1 H), 4.23 (q, stirred in the dark at 60 °C for 48 h. The crude product was purified

J = 7.1 Hz, 2 H), 2.74 (m, 2 H), 2.67 (m, 1 H), 2.61 (br. s, 1 H), by column chromatography (hexanes) to give the cycloadduct 11c

1.45 (br. d, J = 9.6 Hz, 1 H), 1.36 (br. d, J = 9.7 Hz, 1 H), 1.32 (t,

(40.6 mg, 0.178 mmol, 82%) as a clear, colorless liquid. R_f= 0.58

J = 7.1 Hz, 3 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = (hexanes). GC (HP-1 column): retention time = 12.437 min. IR

161.2, 139.6, 137.1, 135.3, 133.1, 60.4, 52.7, 46.8, 39.9, 38.8, 37.8,

14.2 ppm. HRMS: calcd. for C₁₂H₁₃BrO₂268.0099, found

268.0089; C₁₂H₁₃BrO₂(269.14): calcd. C 53.55, H 4.87; found C

53.72; H 4.99.

(neat): ν = 3128 (w), 3060 (s), 2972 (s), 2950 (s), 2876 (m), 1947

˜

(w), 1878 (w), 1802 (w), 1752 (w), 1637 (s), 1598 (m), 1490 (s), 1448

(s), 1319 (s), 1293 (s), 1259 (s), 1222 (s), 1193 (s), 1125 (s), 1026

1

(m), 943 (s) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.65 (dm, J =

7.4 Hz, 2 H), 7.39 (tm, J = 7.4 Hz, 2 H), 7.31 (tm, J = 7.4 Hz, 1

H), 6.25 (dd, J = 5.5, 2.9 Hz, 1 H), 6.21 (dd, J = 5.5, 2.9 Hz, 1 H),

2.76 (br. s, 1 H), 2.75 (br. s, 1 H), 2.71 (br. s, 1 H), 2.70 (br. s, 1

H), 1.50 (d, J = 9.4 Hz, 1 H), 1.44 (dm, J = 9.4 Hz, 1 H) ppm.

¹³C NMR (APT, CDCl₃, 100 MHz): δ = 141.4, 136.6, 135.9, 132.0,

128.5, 128.1, 126.0, 125.6, 51.0, 43.7, 40.1, 39.5, 38.1 ppm. HRMS:

calcd. for C₁₅H₁₃Cl 228.0706, found 228.0701.

Cycloadduct 9j (Table 2, Entry 17): According to the above general

procedure (B) with norbornadiene (5, 60 µL, 0.56 mmol), alkynyl

bromide 8j (46.0 mg, 0.18 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (6.4 mg, 0.017 mmol). The reaction mixture was

stirred in the dark at 65 °C for 65 h. The crude product was purified

by column chromatography (EtOAc/hexanes, 1:19) to give the cy-

cloadduct 9j (30.3 mg, 0.086 mmol, 48%) as a colorless oil. R_f=

2

Cycloadduct 11d and Byproduct 12a (Table 3, Entry 8): According

to the above general procedure (B) with norbornadiene (5, 110 µL,

1.02 mmol), alkynyl iodide 10d (78.9 mg, 0.346 mmol), THF

(0.70 mL), and Cp*RuCl(COD) (10.5 mg, 0.0276 mmol). The reac-

tion mixture was stirred in the dark at 65 °C for 43 h. The crude

product was purified by column chromatography (hexanes) to give

the cycloadduct 11b (45.0 mg, 0.141 mmol, 41%) as a colorless oil

and the addition product 12a (28.8 mg, 0.090 mmol, 26%).

0.52 (EtOAc/hexanes, 1:4). IR (neat): ν = 3060 (m), 2974 (s), 2956

˜

(s), 2926 (m), 2881 (m), 1580 (s), 1315 (s), 1156 (s)1089 (s) cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.86 (d, J = 8.3 Hz, 2 H), 7.36

(d, J = 8.3 Hz, 2 H), 6.13 (m, 2 H), 2.86 (br. d, J = 3.5 Hz, 1 H),

2.67 (br. d, J = 3.5 Hz, 1 H), 2.62 (br. s, 1 H), 2.58 (br. s, 1 H),

2.45 (s, 3 H), 1.36 (dm, J = 9.9 Hz, 1 H), 1.12 (dm, J = 9.9 Hz, 1

H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 145.4, 145.0,

136.9, 136.4, 135.5, 131.7, 130.0, 128.0, 52.5, 48.9, 39.7, 38.8, 38.7,

21.7 ppm. C₁₆H₁₅BrO₂S (351.26): calcd. C 54.71, H 4.30; found C

54.58, H 4.42.

11d: R = 0.42 (hexanes). IR (neat): ν = 3058 (m), 3020 (w), 2971

˜

f

(s), 2947 (s), 2873 (w), 1482 (m), 1446 (m), 1319 (s) cm^–1. ¹H NMR

(CDCl₃, 400 MHz): δ = 7.76–7.78 (m, 2 H), 7.35–7.42 (m, 3 H),

6.22 (m, 2 H), 3.04 (br. d, J = 3.7 Hz, 1 H), 2.73–2.75 (m, 2 H), 2.55

(m, 1 H), 1.42 (m, 2 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ

= 153.4, 136.6, 136.2, 133.0, 129.1, 128.7, 125.2, 88.4, 53.5, 50.3,

40.8, 39.7, 39.2 ppm. HRMS: calcd. for C₁₅H₁₃I 320.0062, found

320.0069.

Cycloadduct 11a (Table 3, Entry 1): According to the above general

procedure (B) with norbornadiene (5, 60 µL, 0.56 mmol), alkynyl

chloride 10a (21.5 mg, 0.162 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (4.3 mg, 0.011 mmol). The reaction mixture was

stirred in the dark at 25 °C for 1 h. The crude product was purified

by column chromatography (EtOAc/hexanes, 1:19) to give the cy-

cloadduct 11a (27.1 mg, 0.121 mmol, 74%) as a colorless oil. R_f=

12a: R = 0.32 (hexanes). IR (neat): ν = 3163 (w), 3061 (s), 2984

˜

f

0.38 (EtOAc/hexanes, 1:19). IR (neat): ν = 3133 (w), 3062 (m), 2979

˜

(s), 2871 (m), 2203 (w), 1723 (m), 1665 (m), 1598 (s), 1490 (s), 1443

(s) cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.49–7.51 (m, 2 H),

7.29–7.33 (m, 3 H), 6.26 (dd, J = 5.6, 2.8 Hz, 1 H), 6.08 (dd, J =

5.6, 3.0 Hz, 1 H), 4.01 (dd, J = 7.5, 2.3 Hz, 1 H), 3.31 (br. s, 1 H),

3.08 (br. s, 1 H), 2.64 (dd, J = 7.5, 1.5 Hz, 1 H), 2.24 (d, J = 9.2 Hz,

1 H), 1.75 (dm, J = 9.2 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃,

100 MHz): δ = 137.8, 135.8, 131.5, 128.2, 127.9, 123.6, 94.5, 85.0,

54.3, 50.6, 45.3, 37.1, 32.1 ppm. HRMS: calcd. for C₁₅H₁₃I

320.0062, found 320.0058.

1

(s), 2883 (m), 1716 (s), 1455 (s), 1306 (s) cm^–1. H NMR (CDCl₃,

400 MHz): δ = 6.22 (dd, J = 5.5, 3.0 Hz, 1 H), 6.16 (dd, J = 5.5,

3.0 Hz, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 2.74 (br. s, 1 H), 2.65 (m,

2 H), 2.61 (m, 1 H), 1.46 (br. d, J = 9.6 Hz, 1 H), 1.39 (br. d, J =

9.6 Hz, 1 H), 1.32 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 161.0, 143.5, 137.3, 135.3, 134.8, 60.4, 51.5,

44.1, 39.8, 39.0, 37.6, 14.2 ppm. HRMS: calcd. for C₁₂H₁₃ClO₂

224.0604, found 224.0604.

Cycloadduct 11b (Table 3, Entry 3): According to the above general

procedure (B) with norbornadiene (5, 35 µL, 0.32 mmol), alkynyl

iodide 10b (24.9 mg, 0.111 mmol), THF (0.30 mL), and

Cp*RuCl(COD) (3.2 mg, 0.0084 mmol). The reaction mixture was

stirred in the dark at 25 °C for 2 h. The crude product was purified

by column chromatography (EtOAc/hexanes, 1:19) to give the cy-

cloadduct 11b (31.2 mg, 0.0987 mmol, 89%) as a colorless oil. R_f

Cycloadduct 11e (Table 5, Entry 3): According to the above general

procedure (B) with norbornene 13 (288.4 mg, 3.06 mmol), alkynyl

chloride 10c (71.5 mg, 0.52 mmol), THF (1.6 mL), and

Cp*RuCl(COD) (7.5 mg, 0.02 mmol). The reaction mixture was

stirred in the dark at 65 °C for 140 h. The crude product was puri-

fied by column chromatography (hexanes) to give the cycloadduct

11e (53.9 mg, 0.234 mmol, 45%) as a pale yellow oil. R_f= 0.59

= 0.63 (EtOAc/hexanes, 1:4). IR (neat): ν = 3124 (w), 3058 (m),

˜

(hexanes). IR (neat): ν = 2952 (m), 2870 (m), 1635 (m), 1490 (w),

˜

2980 (s), 2910 (m), 2898 (m), 1708 (s), 1606 (s), 1303 (s), 1256 (s),

1447 (m), 1315 (w), 1239 (w), 1261 (w), 1204 (m), 1124 (w), 957

(s), 919 (m) cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.59 (m, 2 H),

7.35 (m, 2 H), 7.27 (m, 1 H), 2.74 (dd, J = 12.0, 3.5 Hz, 2 H), 2.26

(br. s, 1 H), 2.20 (br. s, 1 H), 1.65–1.59 (m, 2 H), 1.41 (br. d, J =

10.5 Hz, 2 H), 1.17–1.12 (m, 2 H), 1.04 (dt, J = 10.5, 1.3 Hz, 1 H)

ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 140.1, 132.4, 128.6,

128.1, 126.3, 121.0, 53.5, 46.3, 35.2, 33.0, 30.7, 28.2, 27.9 ppm.

HRMS: calcd. for C₁₅H₁₅Cl 230.0862, found 230.0868.

1

1132 (s) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 6.20 (dd, J = 5.5,

3.0 Hz, 1 H), 6.17 (dd, J = 5.4, 3.0 Hz, 1 H), 4.23 (q, J = 7.1 Hz,

2 H), 2.89 (br. d, J = 3.5 Hz, 1 H), 2.72 (br. s, 1 H), 2.66 (br. d, J

= 3.5 Hz, 1 H), 2.51 (br. s, 1 H), 1.42 (dm, J = 9.6 Hz, 1 H), 1.32

(t, J = 7.1 Hz, 3 H), 1.28 (dm, J = 9.6 Hz, 1 H) ppm. ¹³C NMR

(APT, CDCl₃, 100 MHz): δ = 161.6, 147.6, 136.8, 135.3, 108.8,

60.4, 53.7, 50.1, 40.0, 38.6, 38.1, 14.2 ppm. C₁₂H₁₃IO₂(316.14):

calcd. C 45.59, H 4.14; found C 45.68, H 4.01.

Cycloadduct 11f (Table 5, Entry 4): According to the above general

procedure (B) with norbornene (13, 235.5 mg, 2.51 mmol), alkynyl

bromide 8a (73.9 mg, 0.41 mmol), THF (1.6 mL), and

Cp*RuCl(COD) (8.4 mg, 0.02 mmol). The reaction mixture was

Cycloadduct 11c (Table 3, Entry 4): According to the above general

procedure (B) with norbornadiene (5, 66.0 mg, 0.716 mmol), alk-

ynyl chloride 10c (29.6 mg, 0.217 mmol), THF (0.35 mL), and

4186

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Eur. J. Org. Chem. 2008, 4178–4192

Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

stirred in the dark at 65 °C for 140 h. The crude product was puri-

fied by column chromatography (hexanes) to give the cycloadduct

11f (56.3 mg, 0.205 mmol, 50%) as a pale yellow oil. R_f= 0.52

147.36, 139.8, 133.6, 133.0, 131.4, 128.5 (2), 126.1, 122.7, 111.6,

111.5, 74.3, 73.3, 56.1, 56.0, 51.5, 44.6 ppm. HRMS: calcd. for

C₂₀H₁₇ClO₃340.0866, found 340.0861.

(hexanes). IR (neat): ν = 2950 (s), 2870 (m), 1628 (s), 1489 (w),

˜

Cycloadduct 11j (Table 5, Entry 8): According to the above general

procedure (B) with oxabenzonorbornadiene 15 (85.0 mg,

0.416 mmol), alkynyl bromide 8a (64.5 mg, 0.358 mmol), THF

(0.6 mL), and Cp*RuCl(COD) (8.6 mg, 0.023 mmol). The reaction

mixture was stirred in the dark at 65 °C for 160 h. The crude prod-

uct was purified by column chromatography (EtOAc/hexanes, 1:4)

to give the cycloadduct 11j (95.7 mg, 0.249 mmol, 70%) as a pale

1446 (w), 1314 (w), 1294 (w), 1255 (w), 1202 (w), 947 (m), 904 (m)

1

cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.67 (d, J = 7.2 Hz, 2 H),

7.36 (br. t, J = 7.5 Hz, 2 H) 7.29 (br. t, J = 7.3 Hz, 1 H) 2.90 (d, J

= 3.2 Hz, 1 H), 2.80 (d, J = 3.2 Hz, 1 H), 2.76 (br. s, 1 H) 2.17 (br.

s, 1 H) 1.68–1.56 (m, 2 H), 1.41 (br. d, J = 10.5 Hz, 1 H), 1.69–

1.14 (m, 2 H), 1.04 (d, J = 10.5 Hz, 1 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 144.1, 132.5, 128.5, 128.4, 125.9, 109.7,

54.5, 49.0, 35.1, 33.4, 30.7, 27.9, 27.7 ppm. HRMS: calcd. for

C₁₅H₁₅Br 274.0357, found 274.0362.

yellow powder. R = 0.49 (EtOAc/hexanes, 1:4). IR (neat): ν = 3079

˜

f

(w), 3060 (w), 2994 (w), 2953 (w), 2907 (w), 2834 (w), 1499 (m),

1461 (w), 1439 (w), 1401 (w), 1311 (w), 1259 (m), 1218 (w), 1178

(w), 1148 (w), 1106 (w), 1025 (w), 989 (w), 952 (w), 936 (w), 902

Cycloadduct 11g (Table 5, Entry 5): According to the above general

procedure (B) with oxabenzonorbornadiene 14 (44.0 mg,

0.31 mmol), alkynyl chloride 10c (33.2 mg, 0.24 mmol), THF

(0.8 mL), and Cp*RuCl(COD) (5.9 mg, 0.016 mmol). The reaction

mixture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (10% EtOAc/hexanes) to

give the cycloadduct 11g (59.0 mg, 0.208 mmol, 87%) as a pale

1

(w) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.79 (d, J = 7.1 Hz, 2

H), 7.41 (m, 3 H), 6.70 (d, J = 5.5 Hz, 2 H), 5.35 (s, 1 H), 5.31 (s,

1 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.22 (d, J = 3.5 Hz, 1 H), 3.09 (d,

J = 3.4 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ =

147.44, 147.40, 143.9, 133.4, 132.9, 131.6, 128.7, 128.5, 125.7,

111.6, 111.5, 111.3, 74.1, 73.5, 56.0, 55.7, 52.4, 47.0 ppm. HRMS:

calcd. for C₂₀H₁₇BrO₃384.0361, found 384.0365.

yellow powder. R = 0.49 (10% EtOAc/hexanes). IR (neat): ν =

˜

f

3055 (w), 3025 (w), 2999 (w), 2953 (w), 1636 (w), 1490 (m), 1458

(m), 1447 (m), 1267 (s), 1221 (w), 1197 (m), 1116 (m), 1025 (w),

982 (m), 954 (s), 902 (s) cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ =

7.74 (d, J = 8.1 Hz, 2 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.41–7.35 (m,

3 H), 7.26–7.24 (m, 2 H), 5.21 (s, 2 H), 3.11 (d, J = 3.5 Hz, 1 H),

3.05 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz):

δ = 144.6, 144.0, 140.0, 131.4, 128.5 (2), 126.93, 126.89, 126.1,

122.5, 119.9, 119.8, 76.1, 75.0, 52.0, 45.1 ppm. HRMS: calcd. for

C₁₈H₁₃ClO 280.0655, found 280.0650.

Cycloadduct 11k (Table 5, Entry 9): According to the above general

procedure (B) with oxabenzonorbornadiene 16 (100.6 mg,

0.33 mmol), alkynyl chloride 10c (37.0 mg, 0.27 mmol), THF

(0.8 mL), and Cp*RuCl(COD) (4.6 mg, 0.012 mmol). The reaction

mixture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (10% EtOAc/hexanes) to

give the cycloadduct 11k (48.1 mg, 0.110 mmol, 41%) as a pale

yellow powder. R = 0.58 (10% EtOAc/hexanes). IR (neat): ν =

˜

f

3059 (w), 3025 (w), 2999 (w), 2960 (w), 1638 (m), 1599 (m), 1490

(m), 1446 (m), 1360 (m), 1319 (m), 1287 (w), 1269 (m), 1194 (w),

1174 (m), 1117 (w), 1088 (m), 988 (w), 955 (s), 910 (s) cm^–1. ¹H

NMR (CDCl₃, 400 MHz): δ = 7.65–7.63 (m, 2 H) 7.58 (s, 1 H),

7.55 (s, 1 H), 7.42–7.38 (m, 2 H), 7.33 (m, 1 H), 5.10–5.10 (m, 2

H), 3.05 (d, J = 3.5 Hz, 1 H), 2.98 (d, J = 3.5 Hz, 1 H) ppm. ¹³C

NMR (APT, CDCl₃, 100 MHz): δ = 146.2, 145.6, 139.9, 131.5,

129.3, 129.1, 126.5, 125.84, 125.75, 123.2 (2), 122.6, 16.2, 17.1, 51.9,

45.1 ppm. HRMS: calcd. for C₁₈H₁₁Br₂ClO 435.8865, found

435.8860.

Cycloadduct 11h (Table 5, Entry 6): According to the above general

procedure (B) with oxabenzonorbornadiene 14 (47.5 mg,

0.33 mmol), alkynyl bromide 8a (41.8 mg, 0.23 mmol), THF

(0.8 mL), and Cp*RuCl(COD) (4.2 mg, 0.011 mmol). The reaction

mixture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (hexanes) to give the cy-

cloadduct 11h (52.0 mg, 0.161 mmol, 70%) as a pale yellow pow-

der. R = 0.45 (10% EtOAc/hexanes). IR (neat): ν = 3054 (w), 3023

˜

f

(w), 2997 (w), 2954 (m), 1731 (w), 1633 (w), 1597 (w), 1493 (m),

1464 (m), 1454 (m), 1262 (s), 1195 (m), 1173 (m), 1150 (w), 1024

(w), 982 (m), 942 (s), 901 (s) cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ

= 7.78–7.76 (m, 2 H) 7.43–7.40 (m, 2 H), 7.37–7.30 (m, 3 H), 7.21–

7.18 (m, 2 H), 5.16 (s, 1 H), 5.11 (s, 1 H), 3.18 (d, J = 3.5 Hz, 1

H), 3.04 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃,

100 MHz): δ = 144.4, 144.0, 143.7, 131.6, 128.8, 128.5, 128.97,

126.91, 125.7, 120.0, 119.98, 111.2, 76.0, 75.3, 53.0, 47.6 ppm.

HRMS: calcd. for C₁₈H₁₃BrO 324.0150, found 324.0154.

Cycloadduct 11l (Table 5, Entry 10): According to the above general

procedure (B) with oxabenzonorbornadiene 16 (65.6 mg,

0.32 mmol), alkynyl bromide 8a (38.5 mg, 0.28 mmol), THF

(0.8 mL), and Cp*RuCl(COD) (6.9 mg, 0.018 mmol). The reaction

mixture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (hexanes) to give the cy-

cloadduct 11l (77.4 mg, 0.16 mmol, 70%) as a pale yellow powder.

R = 0.52 (10% EtOAc/hexanes). IR (neat): ν = 3024 (w), 2999 (w),

˜

f

2959 (w), 2917 (w), 2849 (w), 1633 (w), 1597 (w), 1566 (w), 1489

(m), 1445 (m), 1359 (m), 1319 (m), 1286 (w), 1264 (m), 1172 (m),

1108 (w), 1087 (m), 988 (m), 945 (s), 910 (s) (s) cm^–1. ¹H NMR

(CDCl₃, 400 MHz): δ = 7.72–7.70 (m, 2 H), 7.58 (s, 2 H), 7.56 (s,

1 H), 7.43–7.35 (m, 3 H), 510 (s, 1 H), 5.06 (s, 1 H), 3.16 (d, J =

3.5 Hz, 1 H), 3.03 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 146.0, 145.5, 144.0, 131.7, 129.5, 129.1,

126.1, 125.87, 125.80, 123.22, 123.16, 111.1, 76.0, 75.4, 52.7,

47.5 ppm. HRMS: calcd. for C₁₈H₁₁Br₃O 479.8360, found

479.8355.

Cycloadduct 11i (Table 5, Entry 7): According to the above general

procedure (B) with oxabenzonorbornadiene 15 (64.4 mg,

0.315 mmol), alkynyl chloride 10c (37.4 mg, 0.275 mmol), THF

(0.6 mL), and Cp*RuCl(COD) (8.0 mg, 0.021 mmol). The reaction

mixture was stirred in the dark at 65 °C for 140 h. The crude prod-

uct was purified by column chromatography (EtOAc/hexanes, 1:4)

to give the cycloadduct 11i (51.1 mg, 0.150 mmol, 55%) as a pale

yellow powder. R = 0.44 (EtOAc/hexanes, 1:4). IR (neat): ν = 3001

˜

f

(w), 2956 (w), 2908 (w), 2835 (w), 1637 (w), 1614 (w), 1500 (s),

1463 (w), 1443 (w), 1439 (w), 1401 (w), 1259 (s), 1221 (w), 1181

(w), 1146 (w), 1116 (w), 1083 (w), 1026 (w), 993 (m), 984 (w), 958 Cycloadduct 11m (Table 5, Entry 11): According to the above gene-

1

(w), 945 (w), 904 (w) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.71 ral procedure (B) with azabenzonorbornadiene 17 (46.1 mg,

(d, J = 7.3 Hz, 2 H), 7.38 (m, 3 H), 6.70 (s, 2 H), 5.35 (s, 2 H), 0.268 mmol), alkynyl chloride 10c (35.1 mg, 0.257 mmol), THF

3.85 (s, 3 H), 3.83 (s, 3 H), 3.10 (d, J = 3.5 Hz, 1 H), 3.04 (d, J = (0.6 mL), and Cp*RuCl(COD) (6.0 mg, 0.016 mmol). The reaction

3.5 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 147.40, mixture was stirred in the dark at 65 °C for 120 h. The crude prod-

Eur. J. Org. Chem. 2008, 4178–4192

www.eurjoc.org

4187

A. Allen, K. Villeneuve, N. Cockburn, E. Fatila, N. Riddell, W. Tam

FULL PAPER

uct was purified by column chromatography (EtOAc/hexanes, 1:9)

to give the cycloadduct 11m (85.4 mg, 0.225 mmol, 88%, as a mix-

ture of two conformers due to the two different orientations of the

BOC group on the nitrogen atom) as a yellow oil. R_f= 0.30

338.0710, found 338.0706. C₂₀H₁₅ClO₃(338.79): calcd. C 70.91, H

4.46; found C 71.10, H 4.09.

Cycloadducts 19b and 20b (Table 6, Entry 2): According to the

above general procedure (B) with C1-substituted oxabenzonorbor-

nadiene 18 (100 mg, 0.495 mmol), alkynyl bromide 8a (70.0 mg,

0.389 mmol), THF (0.8 mL), and Cp*RuCl(COD) (7.0 mg,

0.018 mmol). The reaction mixture was stirred in the dark at 65 °C

for 48 h. The crude product was purified by column chromatog-

raphy (EtOAc/hexanes, 1.5:8.5) to give the cycloadducts 19b and

20b as a mixture of regioisomer [19b/20b = 1.7:1, determined by

GC (HP-1 column); retention time of major isomer = 31.581 min,

retention time of minor isomer = 33.025 min].

(EtOAc/hexanes, 1:9). IR (neat): ν = 3377 (w), 3057 (w), 3026 (w),

˜

2975 (w), 2930 (w), 1699 (s), 1634 (w), 1598 (w), 1530 (w), 1491

(w), 1477 (w), 1448 (w), 1390 (s), 1366 (m), 1290 (m), 1265 (w),

1232 (w), 1206 (m), 1166 (m), 1115 (w), 1090 (m), 1046 (w), 1026

(w), 954 (w) cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.69 (m, 2 H),

7.37 (m, 5 H), 7.20 (m, 2 H), 5.14 (m, 2 H), 2.93 (m, 2 H), 1.39 (s,

3 H), 1.02 (s, 6 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ =

153.8, 153.6, 144.0, 143.7, 143.6, 143.0, 141.5, 140.5, 131.9, 131.4,

128.7, 128.4, 126.8, 126.7, 126.6, 126.3, 126.1, 124.8, 120.3, 120.1,

79.7, 79.5, 60.2, 59.3, 58.7, 57.9, 52.8, 52.6, 45.7, 28.1, 27.7 ppm

(two sets of ¹³C signals were observed due to the two conformers

of the two different orientations of the BOC group on the nitrogen

atom). HRMS: calcd. for C₂₃H₂₂ClNO₂379.1339, found 379.1344.

19b: Fractional recrystalization of the above mixture from Et₂O/

pentane (2:8) afforded a pure sample of cycloadduct 19b as a white

solid (36.2 mg, 0.094 mmol, 25%); R_f= 0.32 (EtOAc/hexanes, 2:8);

m.p. 148–149 °C; assignment of structure based on 1D GOESY

NMR experiments. IR (CH Cl ): ν = 3070 (w), 2947 (w), 1761 (s),

˜

2

1737 (s), 1621 (w), 1487 (m), 1449 (m), 1352 (m), 1309 (m), 1261

(m), 1199 (s), 1104 (m), 1065 (m) cm^–1. ¹H NMR (CDCl₃,

300 MHz): δ = 7.75 (d, J = 6.9 Hz, 2 H), 7.55 (m, 1 H), 7.40 (m, 4

H), 7.27 (m, 2 H), 5.26 (s, 1 H), 4.00 (s, 3 H), 3.35 (d, J = 3.4 Hz,

1 H), 3.26 (d, J = 3.4 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃,

75 MHz): δ = 167.8, 144.5, 143.6, 142.1, 131.2, 129.2, 128.5, 127.7,

127.3, 125.9, 120.2, 120.0, 109.5, 83.3, 76.0, 54.9, 52.6, 49.0 ppm.

HRMS (EI): calcd. for C₂₀H₁₅BrO₃[M⁺] 382.0205, found

382.0210. C₂₀H₁₅BrO₃(383.24): calcd. C 62.68, H 3.95; found C

62.99, H 3.67.

Cycloadduct 11n (Table 5, Entry 12): According to the above gene-

ral procedure (B) with azabenzonorbornadiene 17 (67.7 mg,

0.278 mmol), alkynyl bromide 8a (40.9 mg, 0.226 mmol), THF

(0.6 mL), and Cp*RuCl(COD) (6.3 mg, 0.017 mmol). The reaction

mixture was stirred in the dark at 65 °C for 140 h. The crude prod-

uct was purified by column chromatography (EtOAc/hexanes, 1:9)

to give the cycloadduct 11n (66.6 mg, 0.157 mmol, 70%, as a mix-

ture of two conformers due to the two different orientations of the

BOC group on the nitrogen atom) as a yellow oil. R_f= 0.21

(EtOAc/hexanes, 1:9). IR (neat): ν = 3380 (w), 3057 (w), 2975 (w),

˜

2930 (w), 1698 (s), 1631 (w), 1597 (w), 1530 (w), 1490 (w), 1477

(w), 1460 (w), 1447 (w), 1390 (s), 1366 (m), 1289 (m), 1258 (w),

1230 (w), 1204 (w), 1166 (m), 1107 (w), 1090 (m), 1043 (w), 1025

20b: Purification of the mixture of cycloadducts by column

chromatography (CH₂Cl₂) afforded a pure sample of cycloadduct

20b as a pale yellow solid (21.6 mg, 0.056 mmol, 14%); R_f= 0.37

(EtOAc/hexanes, 2:8); m.p. 45–47 °C; assignment of structure based

1

(w), 958 (w), 941 (w) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.76

1

(m, 2 H), 7.39 (m, 5 H), 7.20 (m, 2 H), 5.11 (m, 2 H), 3.00 (m, 2

H), 1.40 (s, 3 H), 1.03 (s, 6 H) ppm. ¹³C NMR (APT, CDCl₃,

100 MHz): δ = 153.7, 153.4, 144.8, 144.6, 144.2, 144.0, 143.9, 143.6,

143.0, 132.1, 129.0, 128.4, 126.8, 126.6, 126.0, 125.8, 120.5, 120.1,

113.6, 112.0, 79.8, 79.6, 60.2, 59.5, 58.6, 58.2, 54.1, 53.8, 48.1, 47.9,

28.2, 27.8 ppm (two sets of ¹³C NMR signals were observed due

to the two conformers of the two different orientations of the BOC

group on the nitrogen atom). HRMS: calcd. for C₂₃H₂₂BrNO₂

423.0834, found 423.0838.

on 1D GOESY NMR experiments. H NMR (CDCl₃, 300 MHz):

δ = 7.67 (m, 3 H), 7.37 (m, 4 H), 7.27 (m, 2 H), 5.22 (s, 1 H), 3.57

(d, J = 3.4 Hz, 1 H), 3.56 (s, 3 H), 3.12 (d, J = 3.4 Hz, 1 H) ppm.

¹³C NMR (APT, CDCl₃, 75 MHz): δ = 168.6, 143.1, 142.9, 142.6,

131.2, 129.0, 128.3, 127.8, 127.3, 125.9, 120.4, 120.0, 112.2, 83.5,

75.5, 54.1, 52.2, 50.6 ppm. C₂₀H₁₅BrO₃(383.24): calcd. C 62.68, H

3.95; found C 62.87, H 3.76.

Cycloadducts 19c and 20c (Table 6, Entry 3): According to the

above general procedure (B) with C1-substituted oxabenzonorbor-

nadiene 18 (1.5 equiv.), alkynyl iodide 10d (35.8 mg, 0.158 mmol),

THF (0.4 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mix-

ture was stirred in the dark at 65 °C for 48 h. The crude mixture

was purified by column chromatography (EtOAc/hexanes, 1:9) to

obtain 19c and 20c [19b/20b = 1.4:1, determined by GC (HP-1

column); retention time of major isomer = 34.733 min, retention

time of minor isomer = 33.195 min] in a 41% combined yield.

Cycloadducts 19a and 20a (Table 6, Entry 1): According to the

above general procedure (B) with C1-substituted oxabenzonorbor-

nadiene 18 (1.5 equiv.), alkynyl chloride 10c (22.4 mg, 0.165 mmol),

THF (0.4 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mix-

ture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (10% EtOAc/hexanes) to

give an inseparable mixture of regioisomers 19a and 20a (17.0 mg,

1

0.0503 mmol, 31%; 19a/20a = 1.2:1, determined by H NMR) as

Cycloadduct 19c: Obtained as a yellow solid (EtOAc/hexanes, 1:9,

R_f= 0.20) (18.7 mg, 0.044 mmol, 27%). ¹H NMR (CDCl₃,

a pale orange powder. R_f= 0.30 (10% EtOAc/hexanes). IR (neat):

ν = 3055 (m), 3026 (m), 3004 (m), 2953 (m), 2850 (m), 1763 (s), 400 MHz): δ = 7.83–7.80 (m, 2 H), 7.56–7.53 (m, 1 H), 7.45–7.36

˜

1736 (s), 1638 (w), 1598 (w), 1577 (w), 1492 (m), 1457 (s), 1446 (s), (m, 5 H), 7.30–7.25 (m, 1 H), 5.25 (s, 1 H), 4.01 (s, 3 H), 3.40 (d,

1438 (s), 1354 (s), 1329 (s), 1268 (s), 1214 (s), 1198 (s), 1183 (m), J = 3.4 Hz, 1 H), 3.31 (d, J = 3.4 Hz, 1 H) ppm. ¹³C NMR (APT,

1159 (m), 1107 (s), 1061 (m), 1021 (m), 963 (m), 927 (m) cm^–1. H

NMR (CDCl₃, 400 MHz): δ = 7.74–7.72 (m, 1 H), 7.65–7.58 (m, 4

H), 7.42–7.31 (m, 7 H), 7.30–7.25 (m, 3 H), 5.64 (s, 0.7 H), 5.27 (s,

CDCl3, 75 MHz): δ = 167.7, 151.7, 143.4, 142.1, 131.8, 129.4,

1

128.4, 127.7, 127.3, 125.0, 120.1, 120.0, 81.4, 76.0, 55.2, 52.6,

52.0 ppm. IR (NaCl): ν = 3055 (w), 3026 (w), 2995 (w), 2951 (w),

˜

1 H), 3.82 (s, 2.2 H), 3.58 (s, 3 H), 3.46 (d, J = 3.4 Hz, 1 H), 3.08 2921 (w), 2850 (w), 1762 (s), 1737 (s), 1489 (m), 1457 (m), 1446

(d, J = 3.4 Hz, 1 H), 2.78 (d, J = 6.4 Hz, 0.7 H), 2.29 (d, J = (m), 1437 (m), 1353 (m), 1325 (m), 1289 (w), 1256 (m), 1211 (m),

6.4 Hz, 0.7 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 168.6,

1199 (m), 1160 (m), 1112 (m), 1068 (m), 1022 (w), 950 (m), 912

(m), 862 (w), 818 (w), 779 (m), 758 (m), 735 (m), 693 (m), 665 (w),

168.5, 145.8, 144.0, 143.0, 142.3, 138.7, 135.5, 130.8, 128.7, 128.3,

128.1, 127.7, 127.3, 127.2, 126.81, 126.77, 126.13, 126.10, 126.0, 639 (m), 587 (w), 559 (w) cm^–1. Also characterized by 1D GOESY

123.4, 120.2, 119.9, 119.8, 86.9, 83.6, 79.3, 75.1, 53.2, 52.5, 52.1,

NMR experiments. C₂₀H₁₅IO₃(430.24): calcd. C 55.83, H 3.51;

48.1, 34.6, 28.7 ppm. HRMS (CI): calcd. for C₂₀H₁₅ClO₃[M⁺] found C 56.12, H 3.20.

4188

www.eurjoc.org

Eur. J. Org. Chem. 2008, 4178–4192

Alkynyl Halides in Ru^II-Catalyzed Cycloadditions of Bicyclic Alkenes

Cycloadduct 20c: Obtained as a yellow solid (EtOAc/hexanes, 1:9,

R_f

400 MHz): δ = 7.75–7.72 (m, 2 H), 7.65–7.61 (m, 1 H), 7.43–7.34 zene derivatives 22b and 23b as an orange oil (13.1 mg, 0.025 mmol,

retention time of minor isomer 20e = 26.684 min] an off-white so-

=

0.28) (9.2 mg, 0.021 mmol, 14%). ¹H NMR (CDCl₃, lid, together with an inseparable mixture of cyclotrimerization ben-

(m, 5 H), 7.30–7.27 (m, 1 H), 5.11 (s, 1 H), 3.71 (d, J = 3.4 Hz, 1

H), 3.53 (s, 3 H), 3.08 (d, J = 3.4 Hz, 1 H), 1.54 (s, 3 H) ppm. ¹³C

NMR (APT, CDCl₃, 75 MHz): δ = 168.6, 150.1, 1430 (2), 142.0,

131.7, 129.2, 128.3, 127.7, 127.3, 125.1, 120.4, 120.1, 85.0, 76.0,

44%).

Cycloadducts 19e and 20e: R_f= 0.36 (EtOAc/hexanes, 1:4). IR

(neat): ν = 3650 (w), 3552 (w), 3412 (w), 3054 (m), 2983 (m), 2955

˜

(m), 2905 (m), 1765 (s), 1739 (s), 1716 (s), 1627 (s), 1458 (s), 1439

(s), 1311 (s), 1200 (s), 1185 (s), 1130 (s), 1108 (s), 1063 (m), 1029

(m), 968 (m) cm^–1. ¹H NMR (CDCl₃, 300 MHz): δ = 7.46–7.43 (m,

1 H), 7.29–7.26 (m, 1 H), 7.19–7.17 (m, 2 H), 5.20 (s, 1 H), 4.21

(q, J = 7.1 Hz, 2 H), 3.90 (s, 1 H), 3.20 (d, J = 3.3 Hz, 1 H), 3.07

(d, J = 3.3 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H); visible peaks for

minor isomer: δ = 7.54 (m, 1 H), 5.11 (s, 1 H), 3.86 (s, 3 H), 3.15

(d, J = 3.5 Hz, 1 H), 2.99 (d, J = 3.6 Hz, 1 H) ppm. ¹³C NMR

54.9, 53.7, 52.1 ppm. IR (NaCl): ν = 3052 (w), 3027 (w), 2995 (w),

˜

2949 (w), 2847 (w), 1763 (s), 1735 (s), 1489 (m), 1456 (m), 1437

(m), 1354 (m), 1328 (m), 1257 (m), 1211 (m), 1197 (m), 1178 (w),

1159 (m), 1109 (m), 1072 (m), 1054 (m), 1016 (w), 951 (m), 910

(w), 863 (w), 781 (m), 756 (s), 694 (m), 635 (m) cm^–1. Also charac-

terized by 1D GOESY NMR experiments. C₂₀H₁₅IO₃(430.24):

calcd. C 55.83, H 3.51; found C 55.54, H 3.88.

Cycloaddition Between C1-Substituted Oxabenzonorbornadiene 18 (APT, CDCl₃, 75 MHz): δ = 167.3, 160.6, 143.3 (2), 141.4, 138.4,

and Alkynyl Chloride 10a (Table 6, Entry 4): According to the

above general procedure (B) with C1-substituted oxabenzonorbor-

nadiene 18 (1.5 equiv.), alkynyl chloride 10a (44.9 mg, 0.339 mmol),

THF (0.8 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mix-

ture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (10% EtOAc/hexanes) to

give an inseparable mixture of regioisomers, cyclobutenes 19d and

20d [50.2 mg, 0.150 mmol, 44%; 19d/20d = 61:1, determined by GC

(HP-1 column): retention time of major isomer 19d = 32.528 min,

retention time of minor isomer 20d = 33.033 min] as a yellow oil,

together with an inseparable mixture of cyclotrimerization benzene

derivatives 22a and 23a as a yellow oil (16.9 mg, 0.043 mmol, 38%).

128.0, 127.4, 120.4, 120.2, 83.0, 75.9, 60.9, 55.3, 52.7, 49.5,

14.2 ppm. Also characterized by 1D GOESY NMR experiments.

C₁₇H₁₅BrO₅(379.21): calcd. C 53.85, H 3.99; found C 53.48, H

4.36.

Cyclotrimerization Benzene Derivatives 22b and 23b: R_f= 0.50

(EtOAc/hexanes, 1:4). IR (neat): ν = 2984 (m), 2939 (w), 2905 (w),

˜

1739 (br., s), 1551 (m), 1524 (w), 1466 (m), 1445 (m), 1405 (m),

1384 (m), 1375 (m), 1353 (w), 1335 (w), 1290 (br., s), 1221 (br., s),

1179 (m), 1157 (m), 1092 (m), 1017 (s), 946 (w) cm^–1. ¹H NMR

(CDCl₃, 400 MHz): δ = 4.49–4.33 (m, 8 H), 1.65–1.24 (m, 12 H)

ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 164.6, 164.5, 164.3,

164.2, 141.4, 138.3, 137.3, 134.4, 125.5, 123.0, 117.5, 116.3, 62.9,

62.84, 62.78, 13.8 ppm. C₁₅H₁₅Br₃O₆(530.99): calcd. C 33.93, H

2.85; found C 33.60, H 3.03.

Cycloadducts 19d and 20d: R_f= 0.30 (10% EtOAc/hexanes). IR

(neat): ν = 3053 (w), 2982 (m), 2955 (m), 2925 (w), 2853 (w), 1765

˜

(s), 1739 (s), 1716 (s), 1635 (m), 1458 (m), 1439 (m), 1316 (m), 1252

(m), 1202 (m), 1187 (m), 1135 (m), 1107 (m), 1063 (m), 1031 (m),

969 (m), 955 (m), 938 (m), 925 (m) cm^–1. ¹H NMR (CDCl₃,

400 MHz): δ = 7.53–7.51 (m, 1 H), 7.36–7.34 (m, 1 H), 7.29–7.25

(m, 2 H), 5.29 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 3.98 (s, 3 H),

3.23 (d, J = 3.4 Hz, 1 H), 3.07 (d, J = 3.4 Hz, 1 H), 1.36 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 167.4,

160.3, 143.4, 141.3, 138.8, 133.6, 128.0, 127.4, 120.3, 120.1, 82.7,

76.1, 60.9, 54.5, 52.8, 47.1, 14.2 ppm. HRMS (CI): calcd. for

C₁₇H₁₅ClO₅[M⁺] 334.0608, found 334.0605. Also characterized by

1D GOESY NMR experiments. C₁₇H₁₅ClO₅(334.76): calcd. C

61.00, H 4.52; found C 60.76, H 4.86.

Cycloadducts 19f and 20f (Table 6, Entry 6): According to the above

general procedure (B) with C1-substituted oxabenzonorbornadiene

18 (1.5 equiv.), alkynyl iodide 10b (35.5 mg, 0.158 mmol), THF

(0.4 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mixture

was stirred in the dark at 65 °C for 48 h. The crude product was

purified by column chromatography (EtOAc/hexanes, 1:4) to give

an inseparable mixture of regioisomers 19f and 20f [41.1 mg,

0.101 mmol, 60%; 19f/20f = 10:1, determined by GC (HP-1 col-

umn): retention time of major isomer 19f = 30.040 min, retention

time of minor isomer 20f = 29.698 min] as a yellow oil. R_f= 0.35

(EtOAc/hexanes, 1:4). IR (neat): ν = 3072 (m), 3052 (m), 3983 (m),

˜

2955 (m), 2903 (w), 2851 (w), 2256 (m), 1716 (s), 1611 (s), 1444 (s),

Cyclotrimerization Benzene Derivatives 22a and 23a: R_f= 0.45

1354 (m), 1275 (m), 1201 (m), 1124 (m), 1107 (m), 1065 (m), 1049

1

(EtOAc/hexanes, 1:4). IR (neat): ν = 2985 (s), 2940 (m), 2907 (m), (m), 1029 (m), 967 (m), 951 (m), 911 (m) cm^–1. H NMR (CDCl₃,

˜

2874 (w), 1744 (br., s), 1563 (m), 1540 (m), 1466 (m), 1446 (m),

400 MHz): δ = 7.54–7.52 (m, 1 H), 7.36–7.34 (m, 1 H), 7.30–7.24

1417 (m), 1381 (m), 1361 (m), 1224 (br., m), 1106 (m), 1018 (br., (m, 2 H), 5.29 (s, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 3.28 (m, 2 H),

1

s), 956 (w), 914 (m) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 4.50– 1.38 (t, J = 7.1 Hz, 3 H); visible peaks for minor isomer δ = 5.11

4.35 (m, 8 H), 1.42–1.34 (m, 12 H) ppm. ¹³C NMR (APT, CDCl₃, (s, 1 H), 3.95 (s, 3 H), 3.51 (d, J = 3.2 Hz, 1 H), 3.06 (d, J = 3.2 Hz,

100 MHz): δ = 163.6, 163.4, 163.0, 162.9, 147.7, 137.1, 135.1, 133.6,

1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ = 167.0, 160.9,

133.0, 131.7, 130.0, 127.9, 63.00, 62.96, 62.86, 62.78, 14.0,

146.2, 142.9, 141.3, 127.9, 127.3, 120.3, 120.0, 102.3, 83.1, 75.3,

13.9 ppm. HRMS (CI): calcd. for C₁₅H₁₅Cl₃O₆[M⁺] 395.9934, 60.7, 55.5, 52.5, 52.3, 14.1; visible peaks for minor isomer: δ =

found 395.9922. C₁₅H₁₅Cl₃O₆(397.64): calcd. C 45.31, H 3.80; 127.8, 127.3, 120.6, 75.2, 53.7 ppm. HRMS (CI): calcd. for

found C 45.68, H 3.51.

C₁₇H₁₅IO₅[M⁺] 425.9964, found 425.9950. Also characterized by

1D GOESY NMR experiments. C₁₇H₁₅IO₅(426.21): calcd. C

47.91, H 3.55; found C 47.57, H 3.89.

Cycloaddition Between C1-Substituted Oxabenzonorbornadiene 18

and Alkynyl Bromide 8i (Table 6, Entry 5): According to the above

general procedure (B) with C1-substituted oxabenzonorbornadiene

18 (1.5 equiv.), alkynyl bromide 8i (29.9 mg, 0.169 mmol), THF

(0.4 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mixture

was stirred in the dark at 65 °C for 48 h. The crude product was

purified by column chromatography (EtOAc/hexanes, 1:4) to give

an inseparable mixture of regioisomers, cyclobutenes 19e and 20e

[26.6 mg, 0.070 mmol, 42%; 19e/20e = 18:1, determined by GC

(HP-1 column): retention time of major isomer 19e = 28.335 min,

Cycloadducts 19g and 20g (Table 6, Entry 7): According to the

above general procedure (B) with C1-substituted oxabenzonorbor-

nadiene 18 (1.5 equiv.), alkynyl bromide 8j (45.3 mg, 0.175 mmol),

THF (0.4 mL), and Cp*RuCl(COD) (5 mol-%). The reaction mix-

ture was stirred in the dark at 65 °C for 48 h. The crude product

was purified by column chromatography (EtOAc/hexanes, 3:7) to

give 19g (16.8 mg, 0.036 mmol, 21%; 19g/20g = Ͼ99:1, no minor

regioisomer can be detected by 400 MHz ¹H NMR) as a yellow

Eur. J. Org. Chem. 2008, 4178–4192

www.eurjoc.org

4189

A. Allen, K. Villeneuve, N. Cockburn, E. Fatila, N. Riddell, W. Tam

FULL PAPER

solid. R = 0.17 (EtOAc/hexanes, 1:4). IR (neat): ν = 3055 (m),

butyllithium in pentane (1.7 , 0.55 mL, 0.94 mmol) was added to

˜

f

3009 (m), 2955 (m), 2925 (m), 2855 (m), 1763 (s), 1739 (s), 1594 a solution of 9a (101.6 mg, 0.372 mmol) in THF (2 mL) at –70 °C

(s), 1493 (w), 1458 (m), 1439 (m), 1402 (w), 1323 (s), 1268 (w), 1236 under N₂over 5 min. The reaction mixture was stirred for 30 min,

(w), 1202 (m), 1156 (s), 1108 (m), 1092 (m), 1079 (m), 963 (m), 923

and chlorotrimethylsilane (0.15 mL, 1.18 mmol) was then slowly

added. After stirring at –70 °C for 45 min, the reaction mixture was

1

(m) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.85 (d, J = 8.3 Hz, 2

H), 7.37–7.32 (m, 3 H), 7.25–7.15 (m, 3 H), 4.98 (s, 1 H), 3.87 (s, warmed to 25 °C for 30 min. The reaction was quenched with water

3 H), 3.21–3.19 (m, 2 H), 2.39 (s, 3 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 166.8, 145.6, 144.1, 142.4, 141.1, 136.1,

130.2, 128.6 (2), 127.7, 126.6, 120.5, 120.0, 83.3, 75.5, 55.0, 52.8,

51.0, 21.8 ppm. HRMS (ESI): calcd. for C₂₁H₁₇BrO₅S [M +

NH₄]⁺478.0324, found 478.0313. C₂₁H₁₇BrO₅S (461.33): calcd. C

54.68, H 3.71; found C 54.31, H 3.89.

and the mixture extracted 3 times with diethyl ether. The organic

layers were combined, washed with brine, dried with magnesium

sulfate, and concentrated by rotary evaporation. The crude product

was purified by column chromatography to give 7c (86.2 mg,

0.324 mmol, 87%) as a pale yellow oil.

Cyclobutene 7c: R = 0.47 (hexanes). IR (neat): ν = 3125 (w), 3058

˜

f

(m), 2964 (s), 2923 (s), 2870 (w), 1249 (s) cm^–1. H NMR (CDCl₃,

1

Isomerization of C1-Substituted Oxabenzonorbornadiene 18

(Table 6, Entries 1–7 and Scheme 4): According to the above gene-

ral procedure (B) with C1-substituted oxabenzonorbornadiene 18

(1.5 equiv.), various alknyl halides (Table 6) in THF, and

Cp*RuCl(COD) (5 mol-%). The reaction mixture was stirred in the

dark at 65 °C for 48 h. Apart from the [2+2] cycloadducts, the

naphthols 21a and 21b were obtained as an inseparable mixture of

regioisomers as a white solid in 10–56%, 21a/21b = 7:1, determined

400 MHz): δ = 7.34 (m, 2 H), 7.26 (m, 2 H), 7.17 (m, 1 H), 6.07

(m, 2 H), 2.64 (br. d, J = 3.7 Hz, 1 H), 2.51 (br. s, 1 H), 2.41 (br.

s, 1 H), 2.20 (br. d, J = 3.6 Hz, 1 H), 1.31 (d, J = 8.9 Hz, 1 H),

1.15 (d, J = 8.9 Hz, 1 H), 0.14 (s, 9 H) ppm. ¹³C NMR (APT,

CDCl₃, 100 MHz): δ = 158.5, 166.4, 135.8, 135.7, 135.0, 128.3,

127.6, 125.9, 45.2, 43.1, 39.8, 39.7, 38.4, –0.9 ppm. HRMS: calcd.

for C₁₈H₂₂Si 266.1491, found 266.1484. C₁₈H₂₂Si (266.46): calcd.

C 81.14, H 8.32; found C 81.01, H 8.40.

1

by H NMR spectroscopy of the crude product.

Lithium/Halide Exchange of 9a Followed by Trapping with Methanol

To Give Cyclobutene 7e (Scheme 6): A solution of tert-butyllithium

in pentane (1.7 , 0.28 mL, 0.48 mmol) was added to a solution of

9a (51.3 mg, 0.188 mmol) in THF (0.5 mL) at –70 °C under N₂

over 5 min. The reaction mixture was stirred for 30 min, and dry

methanol (23 µL, 0.57 mmol) was then slowly added. After stirring

at –70 °C for 45 min, the reaction mixture was warmed to 25 °C

for 30 min. The reaction was quenched with water and the mixture

extracted 3 times with diethyl ether. The organic layers were com-

bined, washed with brine, dried with magnesium sulfate, and con-

centrated by rotary evaporation. The crude product was purified by

column chromatography to give 7e (17.1 mg, 0.0901 mmol, 48%) as

a pale yellow oil. This is a known compound, and the spectroscopic

data are identical to those reported in the literature.^[36]

Naphthols 21a and 21b: R_f= 0.60 (EtOAc/hexanes, 1:9). IR (neat):

ν = 3305 (w), 3053 (m), 3008 (m), 2955 (m), 2934 (m), 2853 (w),

˜

1715 (m), 1662 (s), 1637 (s), 1599 (m), 1578 (m), 1506 (m), 1463

(m), 1439 (s), 1409 (m), 1368 (m), 1340 (s), 1273 (s), 1257 (s), 1194

(m), 1156 (m), 1091 (m), 992 (m) cm^–1. ¹H NMR (CDCl₃,

400 MHz): δ = 11.98 (s, 1 H), 8.41 (d, J = 8.1 Hz, 1 H), 7.76 (d, J

= 8.5 Hz, 2 H), 7.62–7.49 (m, 2 H), 7.28 (d, J = 9.0 Hz, 1 H), 3.99

(s, 3 H) ppm; visible peaks of minor isomer: δ = 8.91 (d, J = 8.4 Hz,

1 H), 8.18 (d, J = 7.2 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.88 (d,

J = 7.8 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ =

171.4, 160.9, 137.2 (2), 129.4, 127.4, 125.7, 124.2, 123.9, 118.6,

105.6, 52.3 ppm. These are known compounds, and the spectro-

scopic data are identical to those reported in the literature.^[35]

Functionalization of the Cycloadduct 9a

Suzuki Coupling Between 9a and Phenylboronic Acid To Give Cyclo-

butene 7d (Scheme 6): A mixture of 9a (52.8 mg, 0.193 mmol),

phenylboronic acid (44.7 mg, 0.367 mmol), tris(dibenzylideneace-

tone)dipalladium(0) (12.1 mg, 0.0132 mmol), cesium fluoride

(125.1 mg, 0.905 mmol), and tris(tert-butyl)phosphane (10% in

hexane, 60 µL, 0.020 mmol) in deoxygenated THF (0.4 mL) was

prepared in an oven-dried screw-cap vial under argon. The reaction

mixture was stirred at 25 °C for 24 h. The crude product was puri-

fied by column chromatography (hexanes) to give 7d (39.3 mg,

Lithium/Halide Exchange of 9a Followed by Trapping with Methyl

Iodide To Give Cyclobutene 7b (Scheme 6): A solution of tert-butyl-

lithium in pentane (1.7 , 0.28 mL, 0.48 mmol) was added to a

solution of 9a (52.2 mg, 0.191 mmol) in THF (0.50 mL) at –70 °C

under N₂over 5 min. The reaction mixture was stirred for 30 min,

and dry methyl iodide (40 µL, 0.64 mmol) was then slowly added.

After stirring at –70 °C for 45 min, the reaction mixture was

warmed to 25 °C for 30 min. The reaction was quenched with water

and the mixture extracted 3 times with diethyl ether. The organic

layers were combined, washed with brine, dried with magnesium

sulfate, and concentrated by rotary evaporation. The crude product

was purified by column chromatography to give 7b (32.1 mg,

0.155 mmol, 81%) as a pale yellow oil.

1

0.145 mmol, 75%) H NMR (CDCl₃, 400 MHz): δ = 7.60 (d, J =

7.2 Hz, 4 H), 7.34–7.38 (m, 4 H), 7.26–7.30 (m, 2 H), 6.24 (br. s, 2

H), 2.75 (br. s, 2 H), 2.70 (br. s, 2 H), 1.60 (br. d, J = 9.0 Hz, 1 H),

1.37 (br. d, J = 9.0 Hz, 1 H) ppm. This is a known compound,

and the spectroscopic data are identical to those reported in the

literature.^[37]

Cyclobutene 7b: R_f= 0.63 (hexanes). GC (HP-1 column): retention

time = 11.437 min. IR (neat): ν = 3062 (m), 2964 (s), 2929 (s), 2854

˜

Sonogashira Coupling Between 9a and Phenylacetylene To Give Cy-

clobutene 24 (Scheme 6): A mixture of 9a (29.4 mg, 0.110 mmol),

tetrakis(triphenylphosphane)palladium (6.3 mg, 0.0055 mmol),

triethylamine (15 µL, 0.11 mmol), copper iodide (2.1 mg,

0.011 mmol), phenylacetylene (12 µL, 0.11 mmol) and deoxy-

genated THF (0.60 mL) was prepared in an oven-dried screw-cap

vial under argon. The reaction mixture was stirred at 65 °C for

24 h. The crude product was purified by column chromatography

(hexanes) to give 24 (20.4 mg, 0.0692 mmol, 64%) as a white solid.

(w), 1715 (m), 1686 (m), 1603 (m), 1499 (m), 1447 (s), 1370 (m),

1

1322 (s), 1220 (w), 1071 (m) cm^–1. H NMR (CDCl₃, 400 MHz): δ

= 7.40 (d, J = 7.7 Hz, 2 H), 7.34 (t, J = 7.7 Hz, 2 H), 7.20 (t, J =

7.7 Hz, 1 H), 6.16 (m_ABX, 2 H), 2.65 (s, 1 H), 2.55 (br. s, 1 H), 2.53

(s, 1 H), 2.27 (br. s, 1 H), 2.01 (s, 3 H), 1.37 (d, J = 8.8 Hz, 1 H),

1.27 (d, J = 8.8 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ =

141.3, 139.7, 135.9, 135.7, 135.3, 128.4, 126.5, 125.7, 45.7, 42.7,

40.0, 39.2, 38.1, 14.2 ppm. HRMS: calcd. for C₁₆H₁₆208.1252,

found 208.1258.

Cyclobutene 24: M.p. 56–57 °C. R = 0.48 (hexanes). IR (neat): ν =

˜

f

Lithium/Halide Exchange of 9a Followed by Trapping with Cholotri-

methylsilane To Give Cyclobutene 7c (Scheme 6): A solution of tert-

3058 (s), 3029 (m), 2969 (s), 2940 (s), 2874 (w), 1949 (w), 1880 (w),

1

1486 (s), 1447 (s) cm^–1. H NMR (CDCl₃, 400 MHz): δ = 7.77 (d,

4190

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Eur. J. Org. Chem. 2008, 4178–4192

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J = 7.1 Hz, 2 H), 7.52–7.55 (m, 2 H), 7.29–7.42 (m, 6 H), 6.20–

6.25 (m, 2 H), 2.76 (br. s, 2 H), 2.74 (br. d, J = 3.9 Hz, 1 H), 2.63

(br. d, J = 3.8 Hz, 1 H), 1.53 (br. d, J = 9.1 Hz, 1 H), 1.39 (br. d,

J = 9.1 Hz, 1 H) ppm. ¹³C NMR (APT, CDCl₃, 100 MHz): δ =

150.9, 136.1, 133.9, 131.6, 128.5, 128.4, 128.3, 125.8, 123.4, 121.6,

96.2, 85.3, 46.1, 43.7, 40.2, 39.6, 38.9 ppm. HRMS: calcd. for

C₂₃H₁₈294.1409, found 294.1418. C₂₃H₁₈(294.40): calcd. C 93.84,

H 6.16; found C 93.62, H 6.30.

[10]

[11]

[12]

Supporting Information (see footnote on the first page of this arti-

1

cle): H and ¹³C NMR spectra of all new compounds that do not

have elemental analysis.

[13]

[14]

Acknowledgments

This work was supported by Merck Frosst Centre for Therapeutic

Research, Natural Sciences and Engineering Research Council of

Canada (NSERC), and Boehringer Ingelheim (Canada) Ltd. A. A.,

K. V. and E. F. thank NSERC for providing postgraduate (CGS M

and CGS D) and summer undergraduate scholarships (USRA).

N. C. thanks the Ontario Government for providing a postgraduate

scholarship (OGS). Dr. Robert Jordan and Mr. Gavin C. Tsui are

thanked for preliminary experiments.

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Received: April 29, 2008

Published Online: July 9, 2008

4192

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Article Doi

Alkynyl halides in ruthenium(II)-catalyzed [2+2] cycloadditions of bicyclic alkenes

DOI: 10.1002/ejoc.200800424

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