Catalytic, nucleophilic allylation of aldehydes with 2-substituted allylic acetates: Carbon-carbon bond formation driven by the water-gas shift reaction

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Catalytic, Nucleophilic Allylation of Aldehydes with 2‑Substituted

Allylic Acetates: Carbon−Carbon Bond Formation Driven by the

Water−Gas Shift Reaction

Scott E. Denmark* and Zachery D. Matesich

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States

S

* Supporting Information

ABSTRACT: The ruthenium-catalyzed allylation of aldehydes with

allylic acetates has been expanded to incorporate substituents at the

2-position of the allylic components. Allylic acetates bearing a variety

of substituents (CO₂-t-Bu, COMe, Ph, CH(OEt)₂, and Me)

undergo high-yielding additions with aromatic, α,β-unsaturated,

and aliphatic aldehydes. The conditions of the reaction were found

to be mild (75 °C, 24−48 h) and only required the use of 2−3 mol % of the triruthenium dodecacarbonyl catalyst under 40−80

psi of CO. The stoichiometries of water and allylic acetate employed were found to be critical to reaction eﬃciency.

Scheme 1

INTRODUCTION

■

The importance of synthetic methods that form carbon−carbon

bonds from carbonyl substrates cannot be overstated. One of

the most commonly employed methods to generate carbon−

carbon bonds is the metal-mediated allylation of aldehydes.¹⁻⁵

The capacity to form a homoallylic alcohol and two new

stereogenic centers makes allylations an especially powerful

transformation in building complexity. Technologies that aﬀord

both diastereo- and enantiomerically enriched products with

excellent selectivity and yield have been developed.⁶⁻⁸

The major drawback with many of the aforementioned

methods is the requirement of stoichiometric amounts of metal

reagents or additives. In response to this shortcoming, eﬀorts

have been directed to develop reactions that are catalytic in

metal.⁹⁻¹⁴One such method is the ruthenium-catalyzed

allylation reaction, recently reported from these laboratories,

which uses carbon monoxide as the stoichiometric reductant

and produces only AcOH and CO₂as the stoichiometric,

environmentally benign byproducts.¹⁵

been employed in the allylation reactions.²¹For example, it is

possible to substitute boron for tin in the allylation of

aldehydes, as shown in the works of Szabo

́

(eq 1) and

Murakami (eq 2) (Scheme 2).^22,23

Krische and co-workers have developed a catalytic,

enantioselective allylation of aldehydes that employs an

iridium-based transfer hydrogenation catalyst to produce

homoallylic alcohols in high yield and enantioselectivity starting

from allylic acetates, dienes, or allenes.²⁴This chemistry has

been successfully employed in the synthesis of various

polyketide natural products.²⁵In these reactions, the reducing

agent is either the alcohol precursor to the aldehyde

electrophile or a sacriﬁcial alcohol with an aldehyde (Scheme

3, eq 1 and eq 2). This method has found further application in

the formal allylation of epimerizable aldehydes though the

alcohol oxidation state (Scheme 3, eq 3).²⁶The transient nature

of the aldehyde that is formed reduces the opportunity for

epimerization to occur. Furthermore, only allylation of the

primary alcohol is observed, allowing for selective reactions on

BACKGROUND

■

1. Current Methods for the Metal-Catalyzed Carbonyl

Allylation Reaction. The interest in metal-catalyzed allylation

reactions is driven by the desire to avoid the generation of

inorganic wastes streams that can be diﬃcult to remove from

the desired product. The carbonyl-ene reaction has emerged as

one method for the production of homoallylic alcohols which is

eﬃcient as well as being general and highly selective.^13,16

Moreover, highly enantioselective variants have been developed

(Scheme 1).¹⁷

The use of catalytic amounts of palladium and rhodium has

found use in the formation of homoallylic alcohols.¹⁸⁻²⁰

Although the majority of these cases employ stoichiometric

amounts of tin, which is undesirable due to its toxicity and

diﬃcultly in removal from the products, other allyl sources have

Received: May 8, 2014

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Scheme 2

Scheme 4

Scheme 5

Scheme 3

2. Catalytic Nucleophilic Allylation of Aldehydes

Employing CO as the Reductant. A prior disclosure from

these laboratories described the potential for the use of

ruthenium catalytically in the allylation of aldehydes employing

allyl acetate (2a) and CO.¹⁵This development was inspired by

an early report form Watanabe et al., who reported the

formation of homoallylic alcohols under catalysis by ruthenium

and using a trialkylamine as the reducing agent. However, this

process suﬀered from the need for high temperatures and

pressures of CO, in addition to superstoichiometric amounts of

aldehyde (Scheme 6, eq 1).³⁰The discovery that the addition of

1.5 equiv of water allowed both the reaction temperature and

CO pressure to be signiﬁcantly decreased enabled the

development of a superior process (Scheme 6, eq 2).

Furthermore, the aldehyde became the limiting reagent, greatly

increasing the practicality of the reaction.

Scheme 6

compounds that contain secondary alcohols, thereby eliminat-

ing the need for protecting groups.

Progress has also been made by Krische and co-workers in

employing other metal catalysts in this method, speciﬁcally

ruthenium, while maintaining the reactivity proﬁle of the

iridium catalysts in the allylation reactions of allenes and dienes

with aldehydes.^27,28The ruthenium-catalyzed reactions have

also been rendered diastereo- and enantioselective through the

use of a chiral Brønsted acid cocatalyst (Scheme 4).²⁹

Alper and co-workers have recently shown that a rhodium-

catalyzed allylation reaction is also possible (Scheme 5).¹⁴

Through the use of an ionic diamine carbonyl rhodium

complex and a stoichiometric amount of Cs₂CO₃, several

aromatic and α,β-unsaturated aldehydes were successfully

allylated.

The original reaction conditions described by Watanabe

relied on a superstoichiometric amount of Et₃N whereas the

new conditions required only 0.1 equiv, suggesting that the

mechanisms are likely diﬀerent.³¹Although a secondary or

tertiary amine base is required, it does not act as the reducing

agent. Instead, the reducing potential in this variant of the

reaction is provided by the combination of water and CO,

namely through the agency of the water−gas shift reaction.³²⁻³⁴

Interestingly, further studies performed in these laboratories

revealed that the presence of a halide was critical for reaction

eﬃciency. Replacing RuCl₃·xH₂O with Ru₃(CO)₁₂aﬀorded the

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Scheme 7

allylation product in signiﬁcantly lower yield. However, the

addition of a soluble halide source resulted in yields comparable

to those seen in the RuCl₃·xH₂O reactions.¹⁵The presence of a

halide may act as a ligand on ruthenium(0), resulting in the

formation of an anionic ruthenium complex. This species would

be expected to have increased nucleophilic character, allowing

for a more facile oxidative addition.^35,36

On the basis of these observations, a catalytic cycle for this

reaction was formulated (Scheme 7). Following initial

reduction of ruthenium(III) (in the case of RuCl₃) to the

ruthenium(0) species (I) by CO, oxidative addition (OA) to

acetate 2a occurs to aﬀord the ruthenium(II) π-allyl species

(II). The nucleophilic allyl metal species (II) next inserts into

the aldehyde 1a via coordination of the carbonyl group to the

ruthenium(II) center (via the η¹form of II) to generate (III).

Hydrolysis of the alkoxide (III) then releases the homoallylic

alcohol product 3 and generates a ruthenium(II) hydroxide

species (IV). By means of the water−gas shift reaction, CO

undergoes a migratory insertion into the ruthenium(II)−OH

bond, followed by β-hydride elimination to release CO₂(as

shown in the inset). Subsequent reductive elimination of the

ruthenium(II) hydride intermediate regenerates the ruthe-

nium(0) complex (I).

3. Use of Substituted Allyl Sources. The majority of the

current carbonyl allylation methods employ only simple,

unsubstituted allyl sources. This clearly limits the potential

for the incorporation of more complex and functionalized

building blocks. The few examples that do employ substituted

allyl sources require superstoichiometric amounts of a metallic

reducing agent or involve the preformation of an allylic metal

species.^7,37Ideally, the substituted allyl should be available as a

shelf-stable reagent that requires only a substoichiometric

amount of metal in the addition to carbonyl compounds. This

value added process has been demonstrated recently in the

generation of α-exomethylene γ-butyrolactones with the use of

an allylic acetate containing an ester substituent.³⁸Clearly, the

potential for greater synthetic utility would be realized if a more

general process were developed to allow the use of variety of

functional groups as allyl substituents in the addition reaction.

The research described herein demonstrates incorporation of

various substituents at the 2-position of allylic acetates in the

ruthenium-catalyzed allylation reaction. As the proposed

catalytic cycle for the reaction involves the formation of a

ruthenium(II) π-allyl species (II), the use of substituents with

varying electronic and steric properties could oﬀer insights into

the reactivity characteristics of the allyl group on the reaction.

In addition, various nucleofuges on the allyl donor were used to

further optimize the catalytic process.

RESULTS

■

1. Catalytic Nucleophilic Allylation with 2-Methallyl

Acetate. 1.1. Optimization of Reaction Conditions. The

investigations began with 2-methallyl acetate 2b as the methyl

substituent creates a slightly more electron-rich ruthenium π-

allyl than allyl acetate (2a) without signiﬁcantly changing the

steric bulk or involving additional functional groups. In an

orienting study to determine a suitable ruthenium source for

the reaction, two catalysts (RuCl₃and Ru₃(CO)₁₂) that were

used previously were examined using the original reaction

conditions (Scheme 8).¹⁵A higher yield of product 3ab was

observed with Ru₃(CO)₁₂as compared to RuCl₃, 55% and 51%

respectively. In both cases, unreacted benzaldehyde 1a and

methallyl acetate 2b were recovered from the reactions,

indicating the low yield results from incomplete conversion

of the aldehyde, not the formation of byproducts.³⁹

Surprisingly, the use of either of the two ruthenium catalysts

produced 3ab in lower yield than what was previously observed

for the generation of 3aa from allyl acetate (Scheme 6, eq 2).¹⁵

This observation, combined with the presence of unreacted 2b,

suggested that acetate 2b is signiﬁcantly less reactive than allyl

acetate 2a. This property may be due in part to the decreased

Scheme 8

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Figure 1. Survey of methallyl electrophile nucleofuges in the allylation of benzaldehyde. pK_avalues of nucleofuge conjugate acids shown below the

line. All yields measured by GC analysis with tetradecane as the internal standard.

electrophilic character of 2b. Exchanging the acetate leaving

group of 2b for a leaving group that would increase the

electrophilic character could improve the yield of 3ab by

increasing the rate of formation of the ruthenium π-allyl. A

variety of 2-methallyl electrophiles, selected on the basis of the

pK_ain water of the conjugate acid of the nucleofuge (reference:

pK_aof AcOH is 4.76), were examined and the yields of 3ab are

compared in increasing order of pK_ain Figure 1.⁴⁰In general,

lower product 3ab yields were observed as the pK_avalues of the

nucleofuges decreased (trichloroacetate 2c, chloromethyl

acetate 2d, and ortho-chlorobenzoate 2e). The use of methallyl

phenyl ether (2k), which had the highest pK_avalue, also

resulted in a low product yield with a signiﬁcant amount of

unreacted electrophile. Nucleofuges with pK_avalues most

similar to acetate had product yields similar to acetate, with a

maximum of 60% for 3,5-chlorophenol (2i). The benzoate (2g)

and 2,4,6-tri-chlorophenol nucleofuges (2h) led to low product

yields (38% and 27% respectively) despite having pK_avalues

closer to that of acetic acid, indicating that there may be

additional factors to consider in the use of these groups.

Whereas 2i aﬀorded comparable product yields and less

unproductive consumption when compared to 2b, acetate

was selected as the leaving group for all subsequent studies due

to ease of substrate preparation and the formation of acetic acid

as the stoichiometric byproduct.

1−4, and entries 6 and 8). The use of 2 mol % of the catalyst

and 3.0 equiv 2b at 20 h was found to be the most eﬀective in

the production of 3ab, albeit still in moderate yield (Table 1,

entry 7).

Table 1. Eﬀect of 2ab Equivalents, Catalyst Loading, and

Time on Yield of 3ab

a

b

,c

b

Ru₃(CO)₁₂

(mol %)

time

(h)

2b

(equiv)

2b recovery

3ab yield

(%)

entry

(%)

1

2

3

4

5

6

7

8

1

2

20

40

20

40

1.2

2.0

1.4

2.0

1.2

2.0

3.0

2.0

0

6

53

60

49

52

39

55

61

53

2

0

10

36

11

a

b

TBACl loading 3 mol % with respect to Ru₃(CO)₁₂. Determined by

c

GC using tetradecane as the internal standard. Percentage recovered

The reaction of acetate 2b with benzaldehyde (1a) was

optimized with respect to substrate and catalyst loading and

reaction time (Table 1). Increasing the equivalents of 2b

resulted in higher yield of 3ab (Table 1, entries 1−2 and entries

5−7). Increasing the loading of catalyst to 2 mol % also

increased the yield (Table 1, entry 7). Extended reaction times

did not oﬀer any beneﬁt, as those reactions that were

performed for 40 h did not show any marked increase in

yield when compared to the 20 h experiments (Table 1, entries

with respect to the total equivalents of 2b.

1.2. Aldehyde Scope for Allylation Reactions. Using the

optimized conditions of 2 mol % of catalyst and 3.0 equiv of 2b,

found in Table 1, acetate 2b was reacted with a set of aldehydes

(Table 2). The reaction of aromatic (1a), α,β-unsaturated (1b),

and aliphatic (1c) aldehydes with acetate 2b aﬀorded the

desired products in good yields. The reaction concentration

was increased to 0.4 M from 0.2 M, and the equivalents of H₂O

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were increased to 3.5 equiv as other experiments revealed

signiﬁcant increases in yield with these changes (vide infra).

The use of (E)-cinnamaldehyde required the use of 80 psi of

CO to maintain the same level of aldehyde conversion as 1a

and 1c. Under these conditions, product 3bb from (E)-

cinnamaldehyde was partially reduced to 3cb, yielding an

inseparable mixture of 3bb/3cb in a 94:6 ratio.

preparative scale (1.0 mmol) (Table 3). The number of

equivalents of 2m employed in these reactions was the

minimum required for full conversion of 1. Acetate 2m is

relatively insensitive to the electronic properties of aromatic

aldehydes, as both electron-rich (1a and 1f) and electron-poor

substrates (1e) reacted in good yield. Although 4-nitro-

benzaldehyde (1d) provided a lower yield, it is possible that

some decomposition of product 3dm may have occurred.

Aliphatic and α,β-unsaturated aldehydes also reacted smoothly

(1c and 1b). Slightly lower yields for the more bulky substrates

(1g and 1i) were observed whereas the branched aldehyde (1h)

aﬀorded the product in good yield. Finally, heteroaromatic

aldehyde (1j) produced the desired homoallylic alcohol (3jm)

in a very good yield.

a,b

Table 2. Additions with 2-Methallyl Acetate (2b)

3. Catalytic Nucleophilic Allylation 2-Methylene-3-

oxobutyl Acetate. 3.1. Optimization of Reaction Con-

ditions. The compatibility of esters under the reaction

conditions encouraged the investigation of ketones as reaction

partners as part of the allylating reagent. Test nucleophile 2-

methylene-3-oxobutyl acetate 2n was examined to further

expand the scope of compatible functional groups. The eﬀects

of loading of 2n, catalyst, and reaction time were investigated

(Table 4). Increasing the loading of acetate 2n improved the

yield of 3an from 51% with 1.2 equiv to 73% with 2.0 equiv

(Table 4, entries 1−3). Despite some unreacted acetate 2n

remaining at 20 h, extending the reaction time to 40 h did not

increase product yield (Table 4, entries 3 and 4). However, an

increase in the Ru₃(CO)₁₂loading from 1 mol % to 2 mol % led

to a 94% yield of product after 20 h (Table 4, entry 4 and 5).

In the reactions of 2n with 1b and 1c for the formation of the

α,β-unsaturated and aliphatic addition products, 3bn and 3cn,

signiﬁcant amounts of unreacted aldehyde were observed. One

possibility for incomplete consumption of 2n is an insuﬃcient

amount of H₂O in the reaction. Without a suﬃcient amount of

H₂O, the catalytic turnover would be inhibited. To examine this

possibility, an investigation into the loading of H₂O was

performed (Table 5). Increasing the number of equivalents of

H₂O in the formation of 3bn appeared to have little eﬀect at 24

h, but at 48 h the conversion of 1b signiﬁcantly increased

(Table 5, entries 1−4). Increasing the number of H₂O

equivalents to 3.5 allowed for nearly complete conversion of

1c in 24 h for 3cn (Table 5, entries 5 and 6).

a

b

Reaction conditions: (A) 40 psi CO; (B) 80 psi CO. Yield of

isolated product.

2. Catalytic Nucleophilic Allylation with tert-Butyl 2-

(Acetoxymethyl)acrylate. 2.1. Optimization of Reaction

Conditions. Ethyl 2-(acetoxymethyl)acrylate 2l, which pos-

sesses an electron-withdrawing group, was next employed as

the allyl source, as ester substituted allyl reagents have been

successfully employed in other carbonyl allylation reactions.³⁸

When 2l was combined with 1a, full conversion of the aldehyde

was observed. However, upon isolation, in addition to the

expected homoallylic alcohol product (3al), an α-exomethylene

γ-butyrolactone (4al) (resulting from cyclization of 3al) was

formed (Scheme 9).

Scheme 9

3.2. Aldehyde Scope for Allylation Reactions. The

representative set of aldehydes was employed in reaction with

acetate 2n on a preparative scale (1.0 mmol) using the

conditions obtained in the optimization (Table 6). These

aldehydes reacted with acetate 2n in good yields to generate the

aromatic (3an), α,β-unsaturated (3bn), and aliphatic (3cn)

products.

4. Catalytic Nucleophilic Allylation 2-Phenylallyl

Acetate. 4.1. Reaction Optimization. The use of 2-phenylallyl

acetate 2o was next investigated to explore the suitability for

the installation of an aryl ring, a common structural motif, in

the product. The phenyl substituent should result in a less

electron-rich allyl species through induction and a removal of

electron density from the allyl, lowering the LUMO. This

should allow for a more facile oxidative addition, though to a

lesser extent than the ester substituent. The eﬀects of

concentration, time, catalyst loading, and acetate 2o equivalents

were examined (Table 7). Under the initial reaction conditions

based on acetate 2a, signiﬁcant amounts of benzaldehyde were

recovered (Table 7, entry 1). Increases in reaction time and

acetate 2o equivalents produced higher conversions of 1a

To avoid this undesired lactonization, tert-butyl 2-

(acetoxymethyl)acrylate (2m) was employed instead. This

modiﬁcation suppressed the formation of the lactone to a

signiﬁcant extent. To establish the reactivity pattern of 2m, a set

of aldehydes was examined in combination with 2m using

conditions similar those with 2a (see Supporting Information).

These initial conditions did not allow for the full conversion of

the aldehydes whereas the use of 2 mol % of Ru₃(CO)₁₂did

allow for uniformly high (>90%) conversions in reasonable

reaction times (20 h). Additional optimization determined that

an increase in concentration to 0.4 M resulted in a signiﬁcant

rate increase and as such, the 0.4 M concentration was used for

all further reactions (see Supporting Information).

2.2. Aldehyde Scope for Allylation Reactions. Using the

optimal conditions of 0.4 M and 2 mol % catalyst, the scope of

aldehyde in additions with acetate 2m was examined on a

E

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a,b

Table 3. Additions with tert-Butyl 2-(Acetoxymethyl)acrylate (2m)

a

b

Reaction conditions: (A) 1.6 equiv of acetate 2m; (B) 1.4 equiv of acetate 2m; (C) 1.2 equiv of acetate 2m. Yield of isolated product.

a

Table 4. Eﬀect of Catalyst Loading, Reaction Time, and

Table 5. Eﬀect of H₂O Loading on Allylation with 2n

Equivalents of 2n on Allylation of 1a

a

b,

c

b

Ru₃(CO)₁₂

(mol %)

time

(h)

2n

(equiv)

2n recovery

3an yield

entry

(%)

1

2

3

4

5

1

2

20

40

20

1.2

1.6

2.0

0

18

28

24

23

51

58

73

71

94

a

b

TBACl loading 3 mol % with respect to Ru₃(CO)₁₂. Determined by

c

GC analysis using tetradecane as the internal standard. Percentage

recovered is with respect to the total equivalents of 2n.

a

The products for the reactions were not isolated and as such, the

consumption of the starting aldehyde was used as a qualitative

(Table 7, entry 2). An increase in reaction concentration (w.r.t

1a) further increased the conversion of benzaldehyde (Table 7,

entry 3). Increasing the catalyst loading to 2 mol % and acetate

2o equivalents to 1.8 resulted in nearly the same benzaldehyde

conversion and a decreased reaction time of 20 h (Table 7,

entry 4). However, a small amount of 2o remained unreacted.

The observation of α-methylstyrene in the GC traces revealed

that the protonolysis pathway was an active means of

unproductively consuming 2o.

Here again, increasing the number of equivalents of H₂O

allowed for increased conversion of 1a with 2n (Table 5). To

investigate whether a similar eﬀect could be realized for acetate

2o, the amounts of H₂O in the allylation of 1 with acetate 2o

b

measurement of reaction eﬃciency. Determined by GC analysis using

tetradecane as the internal standard. Percentage recovered is with

c

respect to the total equivalents of 2n added.

was varied (Table 8). In general, increases in the amount of

H₂O led to higher product yields (Table 8, entries 1 and 3). An

increase in reaction time did not aﬀect much change in the

yields of 3ao (Table 8, entries 2 and 4). Signiﬁcantly higher

amounts of H₂O than 2o resulted in total consumption of

acetate and lower yields as compared to those reactions with

more similar ratios of H₂O to 2o (Table 8, entries 5 and 6).

With (E)-cinnamaldehyde, altering the reaction time, amount

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of H₂O, or the amount of 2o had little eﬀect on the yield of 3bo

(Table 8, entries 7−10).

Table 6. Additions with 2-Methylene-3-oxobutyl Acetate

(2n)

a,b

4.2. Aldehyde Scope for Allylation Reactions. Using the

conditions identiﬁed in the optimization, the allylation of the

representative aldehydes on a preparative scale (1.0 mmol) was

next performed with acetate 2o (Table 9). Thus, 1a, 1b, and 1c

reacted with 2o to give the desired products in good yields. For

(E)-cinnamaldehyde, a higher pressure of CO (80 psi) was

required to maintain the same level of conversion as with 1a

and 1c. Under these conditions, product 3bo from (E)-

cinnamaldehyde was partially reduced to 3co, yielding an

inseparable mixture of 3bo/3co in an 88:12 ratio.

a,b

Table 9. Addition with 2-Phenylallyl Acetate (2o)

a

Reaction conditions: (A) 2.0 equiv 2n, 24 h; (B) 2.4 equiv 2n, 48 h.

Yield of isolated product.

b

Table 7. Eﬀect of Concentration, Time, Catalyst, and 2o

a

Loading on the Allylation of 1a

1a

recovery

(%)

2o

recovery

(%)

b

ac

,

c,d

Ru₃(CO)₁₂

(mol %)

1a conc time

2o

entry

(M)

(h) (equiv)

a

Reaction conditions: (A) 2.8 equiv of 2o, 2.5 equiv of H₂O, 40 psi

CO, 48 h; (B) 2.8 equiv of 2o, 3.5 equiv of H₂O, 80 psi CO, 24 h; (C)

1

2

3

4

1

2

0.2

0.4

20

40

20

1.2

1.5

1.8

47

25

18

23

0

b

2.4 equiv of 2o, 1.5 equiv of H₂O, 40 psi CO, 24 h. Yield of isolated

product.

1

26

a

The products for the reactions were not isolated, and as such, the

consumption of the starting aldehyde was used as a qualitative

5. Catalytic Nucleophilic Allylation 2-(Diethoxymeth-

yl)allyl Acetate. 5.1. Aldehyde Scope for Allylation

Reactions. The aldehyde chemoselectivity of the carbonyl

allylation reaction has been clearly established based upon the

previously employed allylic acetates. However, it is desirable to

maintain an aldehyde functional group in the compound after

the addition. Thus, an allyl source containing a protected

aldehyde was prepared (2p). Using the conditions obtained in

the optimization for acetate 2m, the allylation of the model set

of aldehydes on a preparative scale (1.0 mmol) was performed

(Table 10). The aromatic (1a), α,β-unsaturated (1b), and

aliphatic (1c) aldehydes reacted with 2p in good yield. Under

these conditions, product 3bp from (E)-cinnamaldehyde was

partially reduced to 3cp, yielding an inseparable mixture of

3bp/3cp in an 88:12 ratio.

b

measurement of reaction eﬃciency. TBACl loading 3 mol % with

c

respect to Ru₃(CO)₁₂. Determined by GC analysis using tetradecane

d

as the internal standard. Percentage recovered is with respect to the

total equivalents of 2o added.

Table 8. Eﬀect of Time and H₂O and 2o Loading on

a

Allylation of 1

Table 10. Addition with 2-(Diethoxymethyl)allyl Acetate

a

(2p)

a

The products for the reactions were not isolated, and as such, the

consumption of the starting aldehyde was used as a qualitative

b

measurement of reaction eﬃciency. Determined by GC analysis using

c

tetradecane as the internal standard. Percentage recovered is with

respect to the total equivalents of 2o added.

a

Yield of isolated product.

G

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generated could also account for the appearance of the

reduction products observed in the products from additions

with (E)-cinnamaldehyde. In addition to acting as the water−

gas shift reaction catalyst, ruthenium is known to undergo

hydrogenation of alkenes.⁴³It is unlikely that the (E)-

cinnamaldehyde is being reduced before the allylation reaction

because the reduced product was not observed in all reactions

between (E)-cinnamaldehyde and the 2-substituted allyl

acetates. Curiously, when 2-methylene-3-oxobutyl acetate

(2n) was employed, only the desired product from the

addition to (E)-cinnamaldehyde was observed and while the

reduction product was observed with 2m, it was to a very small

extent. As both of these allylic acetates contain a carbonyl

functional group, it is possible that the carbonyl binds to the

ruthenium metal which could deactivate the reduction pathway

while still allowing for the formation of the homoallylic alcohol

products.

3. Eﬀects of Acetate Stoichiometry. Diﬀering amounts

of acetates 2 also had a small, but reproducible eﬀect on

product yields, even after the addition of suﬃcient allylic

acetate to make up for unproductive consumption was taken

into account. An increase in the relative concentration of allylic

acetate could correspond to an increased rate of the formation

of ruthenium(II) π-allyl complex II, thereby allowing for an

increased yield within the time of the reaction.

Another possible eﬀect of increased amounts of 2 on the

catalytic cycle involves the formation of AcOH, the byproduct

of the water−gas shift reaction. As the allylation reaction

progresses, it is likely that AcOH causes the further

protonolysis of the π-allyl complex II. Upon formation of the

π-allyl complex II, one of two pathways are available: (1) the

productive pathway that involves insertion of the π-allyl

complex II into the aldehyde which ultimately leads to the

formation of 3 or (2) the unproductive protonolysis pathway

that consumes 2. If these two pathways occur at roughly the

same rates, 2.0 equiv of 2 should be required to both fully

consume the aldehyde and account for protonolysis. In the

early stages of the reaction, the productive pathway is likely

more rapid as the complete consumption of the aldehydes with

less than 2 equiv of acetates 2 is observed. If the protonolysis

pathway is more rapid, at least 2 equiv of acetate 2 would

always be required for full conversion of the aldehydes. As the

reaction progresses; however, increased concentrations of

AcOH could increase the ability of the protonolysis reaction

to compete with the productive pathway. The total

consumption of aldehyde with less than 2.0 equiv of acetate,

as in the case of tert-butyl 2-(acetoxymethyl)acrylate (2m) and

2-(diethoxymethyl)allyl acetate (2p), reveals that the produc-

tive pathway is more rapid throughout the course of these

reactions.

4. Eﬀects of Nucleofuge on Reactivity of the 2-

Methallyl Subunit. The choice of leaving group on the

methallyl subunit was shown to have a profound eﬀect on the

production of homoallylic alcohol product. The yield of 3ab

decreases as the pK_aof the conjugate acid of the nucleofuge

becomes either less than or greater than acetate, indicating that

two mechanisms may be operative. Those 2-methallyl electro-

philes with conjugate acid pK_avalues higher than AcOH appear

to be operating under OA as the turnover-limiting step (TLS).

Their lower reactivity can be understood on the basis of their

poorer leaving group ability compared to acetate. The large

amount of unreacted electrophile remaining when compared to

the other allyl sources also supports this conclusion. However,

DISCUSSION

■

1. Eﬀect of Substitution at 2-Position of Allyl

Acetates. A variety of 2-substituted allylic acetates (2) were

found to eﬀectively engage in the carbonyl allylation reaction.

In general, those allylic acetates containing electron-with-

drawing substituents at the 2-position (i.e., tert-butyl ester,

methyl ketone, phenyl, and diethoxy acetal) were able to

produce the expected homoallylic alcohol products in high

yields. The use of an electron donating substituent (i.e.,

methyl) also led to the formation of the desired products, but

in somewhat diminished yield. This clearly points to the eﬀect

that the electronic nature of the substituent plays on the

reaction. It is likely that either conjugation or close proximity of

electron-deﬁcient elements in these substituents lowers the

LUMO of the allylic acetate. Therefore, the activation barrier

toward formation of the ruthenium(II) π-allyl complex (II)

should be lowered, allowing for a greater rate of formation. The

methyl group at the 2-position of 2-methallyl acetate (2b)

donates electron density into the allyl group though hyper-

conjugation and causes the allyl acetate to be less electrophilic,

raising the LUMO of the allylic acetate.

The use of the 2-substituted allylic acetates further illustrates

the functional group compatibility of the ruthenium-catalyzed

allylation reaction. Speciﬁcally, the use of the methyl ketone

and ester moieties reveals the chemoselectivity of the reaction

for the aldehyde, even when the ketone or ester component

was present in a much higher relative ratio (as high as 1:2.4). In

no cases was any addition product from self-condensation

observed. While the unintended formation of the α-exo-

methylene γ-butyrolactones was observed when an ethyl ester

was employed, the use of a tert-butyl ester avoided the

formation of this byproduct. It was also shown that the

aldehyde oxidation state can be retained in the addition product

by way of the diethoxy acetal. Even under the reaction

conditions which are acidic due to the stoichiometric formation

of acetic acid, no product from hydrolysis was observed.

2. Eﬀects of H₂O Loading. From consideration of the

proposed catalytic cycle, H₂O plays two roles: (1) the

hydrolysis of ruthenium(II) complex III yielding 3 and (2) as

the proton source for the unproductive consumption of the

allyl acetate. Therefore, beyond the necessary equivalents for

the turnover of the catalyst and this unproductive pathway,

additional equivalents of H₂O should have little inﬂuence on

the reaction. Yet, the addition of H₂O beyond the theoretically

required amounts was shown to increase the conversion of

aldehydes 1 (Table 5, entries 5 and 6). This observation

suggests a further role for H₂O in the catalytic cycle. A potential

additional role for H₂O in the reaction is that of a proton relay

during the water−gas shift reaction. A DFT study of several

possible mechanisms for the water−gas shift reaction indicates

that several transition states are lowered in energy when

additional H₂O molecules are included.⁴¹

An alternative explanation for the salutary eﬀects of H₂O in

the reaction is the inclusion of an oﬀ-cycle water−gas shift

reaction, in the production of H₂. In addition to the productive

pathway whereby ruthenium(II) is reduced to ruthenium(0), it

is also possible for Ru₃(CO)₁₂to catalyze the water−gas shift

reaction without undergoing oxidative addition (OA) with an

allylic acetate. Instead, it undergoes a more typical water−gas

shift reaction mechanism and reduces H₂O to form hydrogen

gas.⁴²This factor could account for the slight increase in yield

when an increase in the amount of H₂O was made. The H₂thus

H

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the 2-methallyl electrophiles with conjugate acid pK_avalues

lower than acetate also led to lower yields, despite containing

good leaving groups. Therefore, these substrates may react by a

mechanism in which the TLS follows the OA and the formation

of homoallylic alcohol product is hampered, but allows for the

consumption of the ruthenium π-allyl complex V. For example,

the nucleofuges for these substrates are poor ligands for

ruthenium(II) owing to their lower basicity. After OA, the

nucleofuge may bind weakly to the ruthenium catalyst and

could be easily displaced by H₂O, allowing the ruthenium(II) π-

allyl complex V to undergo a facile protonolysis, resulting in the

high levels of unproductive consumption of 2-methallyl

electrophile observed (Scheme 10). If the TLS occurs after

the formation of V, the decreased nucleophilicity of the

ruthenium(II) π-allyl complex V may decrease the rate of the

insertion of complex V into aldehyde 1. The protonolysis

pathway may then become more accessible than the formation

of the homoallylic alcohol product. The diﬀerence in the

amounts of consumed electrophile and generated product is

likely due to an unproductive consumption of the electrophiles.

(Table 3, 3im and 3gm). The decrease in yield for the

aldehydes with high steric hindrance can be attributed to the

diﬃculty for approach of the π-allyl II to the aldehyde. With

regard to aromatic aldehydes, a slight diﬀerence in yield

between electron-rich and electron-deﬁcient aldehydes was

noted for the addition with 2m. The use of electron-rich

aldehydes 1f and 1g aﬀorded lower yields than the electron-

neutral or electron-poor aldehydes 1a and 1e. Decreased

electron density in the aldehyde lowers the LUMO and thereby

reduces the energy of activation barrier for the addition.

CONCLUSIONS

■

The ruthenium-catalyzed, nucleophilic allylation of aldehydes

has been successfully expanded to include allylic acetates with

substituents at the 2-position. This substitution has allowed for

the introduction of additional functionality in the homoallylic

alcohol products, signiﬁcantly expanding the synthetic utility of

this reaction. Allylic acetates with electron-withdrawing

substituents are more eﬀective in the generation of products

from a variety of aromatic, α,β-unsaturated, and aliphatic

aldehydes. Electron-donating substituents on the allylic acetate

are less eﬀective, despite extensive optimization.

Scheme 10

During the course of this optimization, several variables were

discovered to have signiﬁcant inﬂuence on the eﬃciency of

formation of the homoallylic alcohols. A delicate balance

between the amounts of H₂O and acetate beyond the quantities

employed in the original reaction conditions was critical for the

allylation reaction because both components participate in

unproductive, oﬀ-cycle reactions to consume the acetate.

Further studies on the development of stereoselective variants

of this reaction are underway and will be reported in due

course.

A similar case can be posited for the unproductive

consumption of 2-methallyl 2,4,6-trichlorophenol (2h), despite

the higher pK_aof its conjugate acid as compared to AcOH. In

this case, the weak binding to ruthenium(II) could arise from

steric interactions (Scheme 11). After the formation of the

ruthenium π-allyl complex VIII, the ortho-chlorine atoms on

the phenol ligand would create unfavorable steric repulsion

with the ruthenium metal and ligands, allowing for the

displacement of the phenol by H₂O and subsequent

protonolysis of the H₂O-bound ruthenium π-allyl.

EXPERIMENTAL SECTION

■

General Allylation Procedure for Allylation Reactions of 2-

Substituted Allylic Acetates. In a glovebox, to a 10 mL, ﬂat-

bottomed, glass tube (1.5 × 6.5 cm) containing a Teﬂon-coated,

magnetic stir bar were added Ru₃(CO)₁₂(1, 2, or 3 mol %) and

TBACl (3, 6, or 9 mol %). The tube was covered with a rubber septum

before being removed from the glovebox. Outside the glovebox, the

tube was charged sequentially with 1,4-dioxane (2.5 mL), H₂O (1.5,

2.5, or 3.5 equiv), Et₃N (13.9 μL, 0.10 mmol, 0.1 equiv), allyl donor 2

(1.2, 1.4, 1.6, 2.0, 2.4, 2.8, or 3.0 equiv), and aldehyde 1 (1.00 mmol,

1.0 equiv) via syringe. The tube was placed in a six-well autoclave that

allows six separate reactions to be conducted at the same time. The

autoclave was sealed and connected to a carbon monoxide gas

cylinder. The autoclave was charged with CO gas (100 psi), and

pressure was released to a vented hood four times before the CO gas

was maintained at the speciﬁed pressure (40 or 80 psi) and the valves

for each cell were closed. The autoclave was mounted onto a magnetic

stirrer with a temperature probe inserted into the metal block of the

autoclave. The temperature was set at 75 °C, and stirring was started.

The temperature reached 75 °C within 30 min and was maintained for

the time speciﬁed (24 or 48 h). The autoclave was removed from the

stirrer and chilled in an ice/water bath. The temperature reached ∼20

°C within 40 min. The outlet was connected to a vented hood, and the

pressure in the autoclave was gently released. The inlet was then

connected to a nitrogen line, and the system was purged by N₂(which

was passed through a drying tube ﬁlled with Drierite) for 15 min

before the autoclave was opened. The reaction mixture was transferred

to a 20 mL, glass scintillation vial with the aid of 3 mL of diethyl ether.

The solvent was removed under reduced pressure by rotary

evaporation (25 °C, 20 mmHg).

Scheme 11

5. Aldehyde Scope. As part of the investigation of diﬀerent

allylic acetates, a variety of aldehyde substrates were examined.

In several of the cases, a minor change was required in the

reaction conditions to obtain high or complete conversion of

the slower acting aldehydes such as an increase in reaction time

(48 h) or an increase in CO pressure (80 psi). It has been

previously demonstrated that the use of (E)-cinnamaldehyde

may require more forcing conditions to react as rapidly as the

other aldehydes.¹⁴In general, the allylation reaction preferably

engages unhindered aldehydes. With sterically hindered

aldehydes, however, a moderate yield is still produced, 61%

for 2m with pivalaldehyde and 73% for 2m with 2-tolualdehyde

I

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Preparation of 2-Substituted Allylic Electrophiles.

warmed to room temperature and stirred for 2 h. The reaction mixture

was washed with aqueous HCl (3 M, 4.33 mL), the layers were

separated, and the aqueous layer was extracted with CH₂Cl₂(3 × 20

mL). The combined organic layers were washed with NaHCO₃(7 ×

10 mL), dried (MgSO₄), and ﬁltered, and the solvent was removed

under reduced pressure. The residue was puriﬁed via bulb-to-bulb

distillation (80 °C ABT, ∼1.3 mmHg) and then further puriﬁed via

MPLC silica gel chromatography (25 g SiO₂, hexane (100%) for 5

column volumes, then increase to CH₂Cl₂/hexane (1:9) over 8

column volumes) to aﬀord 2g (1.225 g, 70%) as a clear, colorless oil.

The spectroscopic data matched those from literature, and the sample

was free of any major impurities.⁴⁵

Preparation of 2-Methylallyl 2-Chlorobenzoate (2e). In a 100 mL,

round-bottomed, three-neck ﬂask (equipped with an Ar inlet, septum,

Teﬂon-coated stir bar, and glass stopper) in an ice/water bath at 0 °C

was added dropwise 2-chlorobenzoyl chloride (1.27 mL, 10 mmol, 1.0

equiv) via syringe to a solution of CH₂Cl₂(50 mL) containing 2-

methallyl alcohol (0.721 g, 0.841 mL, 10 mmol) and pyridine (1.05

mL, 13 mmol, 1.3 equiv) over the course of 15 min. The reaction

mixture was warmed to room temperature and stirred for 19 h. The

reaction mixture was washed with aqueous HCl (3 M, 4.33 mL), the

layers were separated, and the aqueous layer was extracted with

CH₂Cl₂(1 × 30 mL). The combined organic layers were washed with

NaHCO₃(7 × 10 mL), dried (MgSO₄), and ﬁltered, and the solvent

was removed under reduced pressure. The residue was puriﬁed via

MPLC silica gel chromatography (24 g SiO₂, hexane (100%) for 5

column volumes, then increased to CH₂Cl₂/hexane (1:9) over 8

column volumes, then CH₂Cl₂(100%) for 3 column volumes) to

aﬀord 2e (0.705 g, 33%) as a clear, colorless oil. Data for 2e: ¹H NMR

(500 MHz, CDCl₃) δ 7.86 (dd, J = 7.8, 1.7 Hz, 1H, C(11)H), 7.46

(dd, 1H, J = 8.1, 1.4 Hz C(8)H), 7.42 (td, 1H, J = 8.1, 7.5, 1.7 Hz,

C(9)H), 7.32 (td, J = 7.8, 7.5, 1.4 Hz, 1H, C(10)H), 5.10 (d, J = 1.3

Hz, 1H, C(1a)H), 5.00 (d, J = 1.3 Hz, 1H, C(1b)H), 4.76 (s, 2H,

C(3)H₂), 1.85 (s, 3H, C(4)H₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ

165.5 (C5), 139.7 (C2), 133.9 (C7), 132.7 (C9), 131.6 (C11), 131.2

(C8), 130.2 (C6), 126.7 (C10), 113.8 (C1), 69.0 (C3), 19.8 (C4); IR

(neat) 3080 (w), 2975 (w), 2943 (w), 1731 (m), 1660 (w), 1593 (w),

1473 (w), 1436 (w), 1378 (w), 1363 (w), 1296 (m), 1243 (m), 1163

(w), 1116 (m), 1048 (m), 984 (w), 946 (w), 906 (w), 816 (w), 791

(w), 744 (s), 723 (w), 691 (w), 649 (w), 571 (w); MS (EI⁺, TOF, 70

eV) 210.0 (M⁺, 3), 141.0 (32), 139.0 (100), 111.0 (15); HRMS (EI⁺,

TOF) calcd for C₁₁H₁₁O₂Cl 210.0448, found 210.0451; TLC R_f0.48

(EtOAc/hexane, 1:4) [UV, PA].

Preparation of 1,3,5-Trichloro-2-((2-methylallyl)oxy)benzene

(2h). In a 50 mL, round-bottomed, three-neck ﬂask (equipped with

a reﬂux condenser w/Ar inlet, septum, Teﬂon-coated stir bar, and glass

stopper) was added dropwise 3-chloro-2-methylprop-1-ene (0.979 mL,

10 mmol, 2 equiv) via syringe to a solution of acetone (15 mL),

K₂CO₃(864 mg, 6.25 mmol, 1.25 equiv), KI (83 mg, 0.5 mmol, 0.1

equiv), and 2,4,6-trichlorophenol (987 mg, 5 mmol) over the course of

10 min. The septa was replaced with a glass stopper and the ﬂask

placed into an oil bath (65 °C). Water was run through the reﬂux

condenser and the reaction stirred for 15 h. The reaction washed

through a Celite pad (1.0 cm × 3 cm) using acetone (20 mL). The

solvent was removed under reduced pressure. The residue was taken

back up into EtOAc (25 mL), washed with deionized water (25 mL)

and brine (15 mL), dried (MgSO₄), and ﬁltered, and solvent was

removed under reduced pressure. The residue was puriﬁed via silica gel

chromatography via MPLC (40 g SiO₂, 5 column volumes hexane

1

(100%)) to aﬀord 2h (1.10 g, 87%) as a white solid. Data for 2h: H

NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 0.6 Hz, 2H, C(7)H), 5.15

(dd, J = 2.0, 1.2 Hz, 1H, C(1a)H), 5.03 (dd, J = 2.0, 1.2 Hz, 1H,

C(1b)H), 4.40 (s, 2H, C(3)H₂), 1.94 (d, J = 1.2 Hz, 3H, C(4)H₃);

¹³C{¹H} NMR (125 MHz, CDCl₃) δ 150.5 (C5), 140.7 (C2), 130.3

C(6) × 2, 129.6 C(8), 128.9 C(7) × 2, 114.4 (C1), 77.2 C(3), 19.8

C(4); MS (EI⁺, 70 eV) 250.0 (M⁺, 78), 219.0 (15), 217.0 (61), 216.0

(15), 215.0 (100), 201.0 (15), 199.9 (29), 198.9 (12), 197.9 (95),

196.9 (29), 195.9 (99), 194.9 (35), 192.9 (13), 181.9 (12), 179.9 (12),

170.9 (17), 168.9 (55), 166.9 (57), 161.9 (10), 159.9 (15), 149.0 (10),

145.0 (12), 143.0 (12), 134.0 (17), 132.0 (27), 109.0 (11), 108.9 (18),

106.9 (29), 99.0 (21), 97.0 (65), 96.0 (10), 82.9 (10), 62.0 (16);

HRMS (EI⁺, TOF) calcd for C₁₀H₉OCl₃249.9719, found 249.9718;

TLC R_f0.72 (EtOAc/hexane, 1:4) [UV, PA].

Preparation of Ethyl (2-Methylallyl) Carbonate (2f). In a 100 mL,

round-bottomed, three-neck ﬂask (equipped with an Ar inlet, septum,

Teﬂon-coated stir bar, and glass stopper) in an ice/water bath at 0 °C

was added dropwise ethyl chloroformate (1.30 mL, 14.5 mmol, 1.45

equiv) via syringe to a solution of CH₂Cl₂(25 mL) containing 2-

methallyl alcohol (0.721 g, 0.841 mL, 10 mmol) and pyridine (1.17

mL, 14.5 mmol, 1.45 equiv) over the course of 15 min. The reaction

mixture was warmed to room temperature and stirred for 3.5 h. The

reaction mixture was washed with aqueous HCl (1 M, 2 × 20 mL), the

layers were separated, and the aqueous layer was extracted with

CH₂Cl₂(1 × 20 mL). The combined organic layers were washed with

NaHCO₃(3 × 10 mL), dried (MgSO₄), and ﬁltered, and the solvent

was removed under reduced pressure. The residue was puriﬁed via

bulb-to-bulb distillation (85 °C ABT, ∼4 mmHg) to aﬀord 2f (1.138

g, 79%) as a clear, colorless oil. The spectroscopic data matched those

from literature, and the sample was free of any major impurities.⁴⁴

Preparation of 1,3-Dichloro-5-((2-methylallyl)oxy)benzene (2i).

In a 50 mL. round-bottomed, three-neck ﬂask (equipped with a reﬂux

condenser w/Ar inlet, septum, Teﬂon-coated stir bar, and glass

stopper) was added dropwise 3-chloro-2-methylprop-1-ene (0.979 mL,

10 mmol, 2 equiv) via syringe to a solution of acetone (15 mL),

K₂CO₃(864 mg, 6.25 mmol, 1.25 equiv), KI (83 mg, 0.5 mmol, 0.1

equiv), and 3,5-dichlorophenol (815 mg, 5 mmol) over the course of

10 min. The septa was replaced with a glass stopper and the ﬂask

placed into an oil bath (65 °C). Water was run through the reﬂux

condenser and the reaction stirred for 15 h. The reaction mixture was

washed through a Celite pad (1.0 cm × 3 cm) using acetone (20 mL).

The solvent was removed under reduced pressure. The residue was

taken back up into EtOAc (25 mL), washed with deionized water (25

mL) and brine (15 mL), dried (MgSO₄), and ﬁltered, and solvent was

removed under reduced pressure. The residue was puriﬁed via silica gel

chromatography via MPLC (40 g SiO₂, 5 column volumes hexane

(100%)) to aﬀord 2i (1.07 g, 98%) as a clear, colorless oil. Data for 2i:

Preparation of 2-Methylallyl Benzoate (2g). In a 100 mL, round-

bottomed, three-neck ﬂask (equipped with an Ar inlet, septum, Teﬂon-

coated stir bar, and glass stopper) in an ice/water bath at 0 °C was

added dropwise benzoyl chloride (1.74 mL, 15 mmol, 1.5 equiv) via

syringe to a solution of CH₂Cl₂(50 mL) containing 2-methallyl

alcohol (0.721 g, 0.841 mL, 10 mmol) and pyridine (1.05 mL, 13

mmol, 1.3 equiv) over the course of 15 min. The reaction mixture was

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¹H NMR (500 MHz, CDCl₃) δ 6.95 (t, J = 1.8 Hz, 1H, C(8)H), 6.81

(d, J = 1.8 Hz, 2H, C(6)H), 5.07 (d, J = 0.8 Hz, 1H, C(1a)H), 5.01 (d,

J = 0.8 Hz, 1H, C(1b)H), 4.40 (s, 2H, C(3)H₂), 1.81 (s, 3H, C(4)H₃);

¹³C{¹H} NMR (125 MHz, CDCl₃) δ 159.9 C(5), 140.0 C(2), 135.4

C(7) × 2, 121.3 C(8), 114.0 C(6) × 2, 113.5 C(1), 72.3 C(3), 19.4

C(4); MS (EI⁺, 70 eV) 216.0 (80), 203.0 (64), 201.0 (100), 181.0

(32), 164.0 (18), 162.0 (30), 133.0 (12), 109.0 (10), 63.0 (15);

HRMS (EI⁺, TOF) calcd for C₁₀H₁₀OCl₂216.0109, found 216.0107;

TLC R_f0.63 (EtOAc/hexane, 1:4) [UV, PA].

(m), 977 (m), 950 (m), 903 (w), 842 (w), 642 (w), 605 (w), 578 (w);

MS (EI⁺, 70 eV) 142.1 (M⁺, 5), 100.1 (35), 99.1 (100), 85.1 (30);

TLC R_f0.19 (EtOAc/hexane, 1:4) [KMnO₄]. Anal. Calcd for

C₇H₁₀O₃(142.15): C, 59.15; H, 7.09. Found: C, 58.94; H, 7.10.

Preparation of 2-(Diethoxymethyl)allyl Acetate (2p). In a 100 mL,

round-bottomed, three-neck ﬂask (equipped with an Ar inlet, septum,

Teﬂon-coated stir bar, and glass stopper) in an ice/water bath at 0 °C,

acetyl chloride (0.562 mL, 7.56 mmol, 1.05 equiv) was added dropwise

via syringe to a solution of CH₂Cl₂(38 mL) containing 5p (1.2 g, 7.49

mmol) and pyridine (0.788 mL, 9.74 mmol, 1.3 equiv) over the course

of 10 min. The reaction mixture was warmed to room temperature and

stirred for 1 h. The reaction was washed with CuSO₄(satd, 3 × 20

mL), the layers were separated, and the aqueous layer was extracted

with CH₂Cl₂(1 × 30 mL). The combined organic layers were dried

(MgSO₄) and ﬁltered, and the solvent was removed under reduced

pressure. The residue was puriﬁed via silica gel chromatography (130 g

SiO₂, 4.5 × 22 cm column, hexane (100%) → Et₂O/hexane (1:7)) and

then further puriﬁed via Kugelrohr distillation to aﬀord 2p (1.17 g,

77%) as a clear, colorless oil. Data for 2p: bp 125 °C (ABT, 15

Preparation of 1-((2-Methylallyl)oxy)-4-(triﬂuoromethyl)benzene

(2j). In a 50 mL, round-bottomed, three-neck ﬂask (equipped with a

reﬂux condenser w/Ar inlet, septum, Teﬂon-coated stir bar, and glass

stopper) was added dropwise 3-chloro-2-methylprop-1-ene (0.979 mL,

10 mmol, 2 equiv) via syringe to a solution of acetone (15 mL),

K₂CO₃(864 mg, 6.25 mmol, 1.25 equiv), KI (83 mg, 0.5 mmol, 0.1

equiv), and 4-triﬂuoromethylphenol (811 mg, 5 mmol) over the

course of 10 min. The septa was replaced with a glass stopper and the

ﬂask placed into an oil bath (65 °C). Water was run through the reﬂux

condenser and the reaction stirred for 15 h. The reaction was washed

through a Celite pad (1.0 cm × 3 cm) using acetone (20 mL). The

solvent was removed under reduced pressure. The residue was taken

back up into EtOAc (25 mL), washed with deionized water (25 mL)

and brine (15 mL), dried (MgSO₄), and ﬁltered, and solvent was

removed under reduced pressure. The residue was puriﬁed via silica gel

chromatography via MPLC (40 g SiO₂, 5 column volumes hexane

(100%)) to aﬀord 2j (918 mg, 85%) as a clear, colorless oil. Data for

2j: ¹H NMR (500 MHz, CDCl₃) δ 7.54 (d, 2H, C(7)H), 6.98 (d, 2H,

C(6)H), 5.11 (d, J = 1.4 Hz, 1H, C(1a)H), 5.04 (d, J = 1.4 Hz, 1H,

C(1b)H), 4.50 (s, 2H, C(3)H₂), 1.86 (s, 3H, C(4)H₃); ¹³C{¹H} NMR

(125 MHz, CDCl₃) δ 161.3 C(5), 140.3 C(2), 127.0 (q, J = 3.8 Hz,

C(7)), 124.6 (q, J = 271.1 Hz, C(9)), 123.06 (q, J = 32.7 Hz, C(8)),

114.86 C(6), 113.4 C(1), 72.0 C(3), 19.5 C(4); MS (EI⁺, 70 eV)

216.1 (M⁺, 100), 202.1 (10), 201.1 (90), 197.1 (14), 162.0 (30), 145.0

(23), 143.0 (13), 133.0 (10), 113.0 (10), 55.1 (84); HRMS (EI⁺,

TOF) calcd for C₁₁H₁₁OF₃216.0762, found 216.0759; TLC R_f0.62

(EtOAc/hexane, 1:5) [UV, PA].

1

mmHg); H NMR (500 MHz, CDCl₃) δ 5.38 (d, J = 2.0 Hz, 1H,

C(5a)H), 5.26 (dd, J = 2.0, 1.2 Hz, 1H, C(5b)H), 4.89 (s, 1H,

C(6)H), 4.63 (t, J = 1.2 Hz, 2H, C(3)H₂), 3.61 (dq, J = 9.4, 7.0 Hz,

2H, C(7a)H₂), 3.48 (dq, J = 9.4, 7.0 Hz, 2H, C(7b)H₂), 2.09 (s, 3H,

C(1)H₃), 1.22 (t, J = 7.0 Hz, 6H, C(8)H₃× 2); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 170.7 C(2), 141.1 C(4), 115.4 C(5), 101.2 C(6), 63.5

C(3), 61.7 C(7), 21.0 C(1), 15.2 C(8); IR (neat) 2977 (w), 2937 (w),

2879 (w), 1744 (m), 1444 (w), 1391 (w), 1371 (w), 1328 (w), 1269

(w), 1226 (m), 1118 (m), 1051 (m), 1028 (m), 1007 (m), 920 (w),

840 (w), 606 (w); MS (ESI) 225.2 (MNa⁺, 100), 158.2 (10), 157.2

(98), 143.1 (81), 129.2 (20); TLC R_f0.42 (EtOAc/hexane, 1:4) [PA].

Anal. Calcd for C₁₀H₁₈O₄(202.25): C, 59.39; H, 8.97. Found: C,

59.42; H, 9.24.

Preparation of Homoallylic Alcohols.

Preparation of 3-Methyl-1-phenylbut-3-en-1-ol (3ab). Following

the general allylation procedure, 1a (102 μL, 1.0 mmol), Ru₃(CO)₁₂

(12.8 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7 mg, 0.06 mmol, 0.06

equiv), 2b (374 μL, 3.0 mmol, 3.0 equiv), H₂O (63 μL, 3.5 mmol, 3.5

equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (47 g SiO₂, 3.5 ×

12.5 cm column, hexane (100%) then Et₂O/hexane (1:9)) provided

3ab (102 mg, 63%) as a colorless oil, which became a white solid in

the freezer (−27 °C). The spectroscopic data matched those from

Preparation of 2-Methylene-3-oxobutyl acetate (2n). In a 250

mL, round-bottomed, three-necked ﬂask (equipped with an Ar inlet,

septum, and glass stopper) in an ice/water bath at 0 °C was added

dropwise acetyl chloride (1.86 mL, 26 mmol, 1.3 equiv) via syringe to

a solution of CH₂Cl₂(100 mL) containing 5n (4.0 g, 1.89 mL, 20

mmol) and pyridine (2.1 mL, 26 mmol, 1.3 equiv) over the course of

10 min. The reaction mixture was warmed to room temperature and

stirred for 1 h. The reaction was quenched with aqueous HCl (1 M, 26

mL), layers were separated, and the aqueous layer was extracted with

CH₂Cl₂(1 × 30 mL). The combined organic layers were washed with

NaHCO₃(1 × 20 mL), dried (MgSO₄), and ﬁltered, and the solvent

was removed under reduced pressure. The residue was puriﬁed via

silica gel chromatography via MPLC (120 g SiO₂100% hexane for 13

column volumes then increase to EtOAc/hexane (1:9) for 17 column

volumes) and then further puriﬁed via Kugelrohr distillation to aﬀord

2n (2.3 g, 81%) as a clear, colorless oil. Data for 2n: bp 125 °C (ABT,

literature and was free of any major impurities.⁴⁶Data for 3ab: H

1

NMR (500 MHz, CDCl₃) δ 7.40−7.34 (m, 4H, C(2′,3′)H), 7.30−

7.26 (m, 1H, C(4′)H), 4.93 (s, 1H, C(4a)H), 4.87 (s, 1H, C(4b)H),

4.82 (t, 1H, J = 6.8 Hz, C(1)H), 2.44 (d, 2H, J = 6.8 Hz, C(2)H), 2.14

(s, 1H, OH), 1.77 (s, 3H, C(5)H); ¹³C{¹H} NMR (125 MHz, CDCl₃)

δ 144.2, 142.5, 128.5, 127.6, 125.9, 114.3, 71.5, 48.5, 22.5; MS (EI⁺,

TOF, 70 eV) 162.1 (M⁺, 2), 145.1 (3), 128.1 (4), 107.1 (100), 79.1

(53), 77 (25); TLC R_f0.31 (EtOAc/hexane, 1:4) [UV, KMnO₄].

1

2.1 mmHg), H NMR (500 MHz, CDCl₃) δ 6.13 (d, J = 1.1 Hz, 1H,

C(5a)H), 5.95 (t, J = 1.6 Hz, 1H, C(5b)H), 4.72 (t, J = 1.6 Hz, 2H

C(3)H), 2.29 (s, 3H, C(7)H), 2.02 (s, 3H, C(1)H); ¹³C{¹H} NMR

(125 MHz, CDCl₃) δ 198.0 C(6), 170.0 C(2), 143.2 C(4), 126.7

C(5), 61.9 (C3), 25.8 C(7), 20.8 C(1); IR (neat) 3335 (w), 3109 (w),

3004 (m), 2951 (m), 2358 (w), 2334 (w), 1752 (s), 1742 (s), 1736

(s), 1686 (s), 1676 (s), 1637 (m), 1438 (m), 1403 (m), 1369 (s),

1322 (m), 1300 (s), 1229 (s), 1144 (m), 1129 (m), 1049 (s), 1035

Preparation of (E)-5-Methyl-1-phenylhexa-1,5-dien-3-ol (3bb.).

Following the general allylation procedure, 1b (126 μL, 1.0 mmol),

K

dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

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Featured Article

Ru₃(CO)₁₂(6.4 mg, 0.01 mmol, 0.01 equiv), TBACl (8.3 mg, 0.03

mmol, 0.03 equiv), 2b (158 μL, 1.2 mmol, 1.2 equiv), H₂O (27 μL, 1.5

mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5

mL) were combined under 80 psi of CO at 75 °C for 24 h. Workup

and puriﬁcation by silica gel column chromatography (51 g SiO₂, 3.5 ×

13.5 cm column, hexane (100%) then Et₂O/hexane (1:9 → 1:4))

provided an inseparable mixture of 3bb/3cb in a 94:6 ratio (113 mg,

60%) as a colorless oil. The spectroscopic data for 3bb matched those

from literature when the peaks for 3cb were accounted for.⁴⁶Data for

Preparation of tert-Butyl 4-Hydroxy-2-methylene-4-phenylbuta-

noate (3am). Following the general allylation procedure, 1a (102 μL,

1.0 mmol), Ru₃(CO)₁₂(12.8 mg, 0.020 mmol, 0.02 equiv), TBACl

(16.9 mg, 0.060 mmol, 0.06 equiv), 2m (320.4 mg, 1.60 mmol, 1.6

equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1

equiv), and dioxane (2.5 mL) were combined under 40 psi of CO at

75 °C for 24 h. Workup and puriﬁcation by silica gel column

chromatography (radial silica gel chromatography 2 mm, EtOAc/

hexane (1:7) then radial silica gel chromatography 2 mm, Et₂O/

CH₂Cl₂(5% Et₂O) then 7.2 g SiO₂, 1 × 19.5 cm column, Et₂O/

hexane (3% Et₂O)) and then further puriﬁcation via Kugelrohr

distillation aﬀorded 3am (227 mg, 91%) as a clear, colorless oil. Data

1

3bb: H NMR (500 MHz, CDCl₃) δ 7.40−7.38 (m, 2H, C(4′)H),

7.32 (dd, J = 8.4, 6.8 Hz, 2H, C(5′)H), 7.26−7.22 (m, 1H, C(6′)H),

6.64 (dd, 1H, J = 15.9, 1.3 Hz, C(2′)H), 6.24 (dd, J = 15.9, 6.2 Hz,

C(1′)H), 4.93 (t, J = 1.7 Hz, 1H, C(4a)H), 4.87 (dd, J = 1.7, 1.0 Hz,

1H, C(4b)H), 4.50−4.41 (m, 1H, C(1)H), 2.40−2.30 (m, 2H,

C(2)H), 1.91 (s, 1H, OH), 1.82 (s, 1H, C(5)H); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 142.1, 142.1, 136.9, 131.9, 130.2, 130.2, 128.7, 128.7,

127.7, 127.7, 126.6, 126.6, 114.2, 70.1, 46.4, 22.7; MS (EI⁺, TOF, 70

eV) 188.1 (M⁺, 2), 170.1 (38), 155.1 (48), 133.1 (100), 115.1 (38),

91.1 (57); TLC R_f0.28 (EtOAc/hexane, 1:4) [UV, KMnO₄].

1

for 3am: bp 100 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz,

CDCl₃) δ 7.38−7.35 (m, 2H, C(3′)H), 7.35−7.31 (m, 2H, C(2′)H),

7.26 (tt, J = 6.2, 1.7 Hz, 1H, C(4′)H), 6.15 (d, J = 1.6 Hz, 1H,

C(4a)H), 5.52 (d, J = 1.6 Hz, 1H, C(4b)H), 4.87 (dt, J = 8.6, 4.0 Hz,

1H, C(1)H), 2.95 (d, J = 3.2 Hz, 1H, OH), 2.75 (ddd, J = 14.0, 4.0, 1.1

Hz, 1H, C(2a)H), 2.62 (ddd, J = 14.0, 8.6, 0.9 Hz, 1H, C(2b)H), 1.51

(s, 9H, C(7)H₃× 3); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 167.2

C(5), 144.2 C(1′), 138.7 C(3), 128.5 C(2′), 127.6 C(4′), 127.5 C(4),

125.8 C(3′), 81.4 C(6), 73.4 C(1), 42.9 C(2), 28.2 C(7); IR (neat)

3438 (m), 3062 (w), 3029 (w), 3004 (w), 2977 (m), 2931 (m), 2359

(w), 2338 (w), 1708 (s), 1603 (m), 1493 (w), 1479 (w), 1453 (m),

1392 (m), 1368 (s), 1339 (m), 1313 (m), 1254 (m), 1214 (m), 1146

(s), 1050 (m), 950 (w), 912 (w), 879 (w), 850 (m), 817 (w), 755 (m),

737 (w), 70 (m), 637 (w); MS (CI⁺, 70 EV) 249.1 (MH⁺, 10), 193.0

(24), 175.0 (100), 129.0 (10), 107.0 (41), 79.0 (20), 77.0 (18); TLC

R_f0.30 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd for C₁₅H₂₀O₃

(248.32): C, 72.55; H, 8.12. Found: C, 72.30; H, 8.11.

Preparation of 5-Methyl-1-phenylhex-5-en-3-ol (3cb). Following

the general allylation procedure, 1c (132 μL, 1.0 mmol), Ru₃(CO)₁₂

(12.8 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7 mg, 0.06 mmol, 0.06

equiv), 2b (374, 3.0 mmol, 3.0 equiv), H₂O (63 μL, 3.5 mmol, 3.5

equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (49 g SiO₂, 3.5 × 13

cm column, hexane (100%) then Et₂O/hexane (1:9 → 1:4)) provided

3cb (128 mg, 67%) as a colorless oil. The spectroscopic data matched

those from literature and was free of any major impurities.⁴⁶Data for

3cb: ¹H NMR (500 MHz, CDCl₃) δ 7.30 (t, J = 7.6 Hz, 2H, C(5′)H),

7.25−7.16 (m, 3H, C(6′,4′)H), 4.90 (t, J = 1.8 Hz, 1H, C(4a)H), 4.82

(s, 1H, C(4b)H), 3.81−3.74 (m, 1H, C(1)H), 2.85 (dt, J = 13.7, 7.8

Hz, 1H, C(2′a)H), 2.72 (dt, J = 13.7, 8.1 Hz, 1H, C(2′b)H), 2.24 (dd,

J = 13.7, 3.9 Hz, 1H, C(2a)H), 2.15 (dd, J = 13.7, 9.2 Hz, 1H,

C(2b)H), 1.83−1.77 (m, 3H, OH and C(1′)H₂), 1.75 (s, 1H,

C(5)H); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 142.8, 128.6, 128.5,

125.9, 113.7, 68.2, 46.4, 38.9, 32.3, 22.6; MS (EI⁺, TOF, 70 eV) 190.1

(M⁺, 4), 135.1 (11), 134.1 (37), 117.1 (12), 92.1 (32), 91.0 (100);

TLC R_f0.30 (EtOAc/hexane, 1:4) [UV, KMnO₄].

Preparation of (E)-tert-Butyl 4-Hydroxy-2-methylene-6-phenyl-

hex-5-enoate (3bm). Following the general allylation procedure, 1b

(125.9 μL, 1.0 mmol), Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv),

TBACl (16.7 mg, 0.06 mmol, 0.06 equiv), 2m (280.3 mg, 1.4 mmol,

1.4 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol,

0.1 equiv), and dioxane (2.5 mL) were combined under 40 psi of CO

at 75 °C for 24 h. Workup and puriﬁcation by silica gel column

chromatography (62 g SiO₂, 3.5 × 17 cm column, CH₂Cl₂(100%) →

Et₂O/CH₂Cl₂(1% → 4% Et₂O) then 30 g SiO₂, 2.5 × 17 cm column,

CH₂Cl₂(100%) → Et₂O/CH₂Cl₂(3% Et₂O)) provided 3bm (230 mg,

84%) as a clear, slightly yellow oil. Data for 3bm: bp 150 °C (ABT,

Preparation of Ethyl 4-Hydroxy-2-methylene-4-phenylbutanoate

(3al). Following the general allylation procedure, 1a (81.6 μL, 0.8

mmol), Ru₃(CO)₁₂(5.1 mg, 0.008 mmol, 0.01 equiv), TBACl (6.6 mg,

0.024 mmol, 0.03 equiv), 2l (78.0 μL, 0.48 mmol, 1.2 equiv), H₂O

(21.6 μL, 1.2 mmol, 1.5 equiv), Et₃N (11.2 μL, 0.08 mmol, 0.1 equiv),

and dioxane (2.0 mL) were combined under 40 psi of CO at 75 °C for

20 h. Workup and puriﬁcation by silica gel column radial silica gel

chromatography 2 mm Et₂O/CH₂Cl₂(7% Et₂O)) provided 3al (130

mg, 74%) as a colorless oil and 4al (36 mg, 21%) as an impure white

solid. The spectroscopic data matched those from literature and was

1

10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 7.40−7.34 (m, 2H,

C(4′)H), 7.34−7.27 (m, 2H, C(5′)H), 7.27−7.19 (m, 1H, C(6′)H),

6.65−6.57 (m, 1H, C(2′)H), 6.23 (dd, J = 15.9, 6.2 Hz, 1H, C(1′)H),

6.19 (dd, J = 1.6, 0.6 Hz, 1H, C(4a)H), 5.63 (dt, J = 1.6, 1.0 Hz, 1H,

C(4b)H), 4.47 (dqd, J = 8.7, 4.3, 2.1 Hz, 1H, C(1)H), 2.69 (ddd, J =

13.9, 4.3, 1.1 Hz, 1H, C(2a)H), 2.59−2.47 (m, 2H, OH and C(2b)H)

1.49 (s, 9H, C(7)H₃× 3); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 167.2

C(5), 138.5 C(3), 136.9 C(3′), 131.8 C(2′), 130.2 C(1′), 128.6 C(5′),

127.7 C(6′), 127.5 C(4), 126.6 C(4′), 81.4 C(6), 71.9 C(1), 40.7

C(2), 28.2 C(7); IR (neat) 3420 (m), 3024 (m), 2977 (s), 2930 (m),

2871 (w), 1706 (s), 1629 (m), 1494 (m), 1476 (m), 1449 (m), 1392

(m), 1368 (s), 1337 (m), 1314 (s), 1255 (m), 1215 (m), 1148 (s),

1098 (m), 1070 (w), 1032 (m), 965 (s), 876 (w), 850 (m), 817 (w),

749 (s), 693 (s); MS (ESI) 297.2 (MNa⁺, 100), 242.2 (14), 201.0

(20); TLC R_f0.25 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd

for C₁₇H₂₂O₃(274.36): C, 74.42; H, 8.08. Found: C, 74.48; H, 8.35.

free of any major impurities in the case of 3al.^47,48Data for 3al: H

1

NMR (400 MHz, CDCl₃) δ 7.23−7.37 (m, 5H, C(aryl)H), 6.22 (d, J

= 1.2 Hz, 1H, C(4)H), 5.58 (d, J = 1.2 Hz, 1H, C(4′)H), 4.87 (ddd, J

= 8.4, 4.2, 3.6 Hz, 1H, C(1)H), 4.20 (q, J = 7.2 Hz, 2H, C(6)H), 2.92

(d, J = 3.6 Hz, 1H, C(OH)), 2.78 (dd, J = 14.1, 4.2 Hz, 1H, C(2a)H),

2.66 (dd, J = 14.1, 8.4 Hz, 1H, C(2b)H), 1.32 (t, J = 7.2 Hz, 3H,

C(7)H); MS (ESI) 221.0 (MH⁺, 17), 204.0 (14), 203.0 (100); TLC R_f

0.292 (Et₂O/CH₂Cl₂, 5% Et₂O) [UV, PA]. Data for 4al: TLC R_f0.71

(Et₂O/CH₂Cl₂5% Et₂O) [UV, PA].

L

dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

Preparation of tert-Butyl 4-Hydroxy-2-methylene-4-(4-

(triﬂuoromethyl)phenyl)butanoate (3em). Following the general

allylation procedure, 1e (136.6 μL, 1.0 mmol), Ru₃(CO)₁₂(12.8 mg,

0.020 mmol, 0.02 equiv), TBACl (16.9 mg, 0.060 mmol, 0.06 equiv),

2m (240.3 mg, 1.20 mmol, 1.2 equiv), H₂O (27 μL, 1.5 mmol, 1.5

equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (radial silica gel

chromatography 2 mm, EtOAc/hexane (1:4) then 16 g SiO₂, 2.5 × 8.5

cm column, Et₂O/hexane (1:7)) and then further puriﬁcation via

Kugelrohr distillation aﬀorded 3em (296 mg, 94%) as a white solid.

Data for 3em: bp 125 (ABT, 10⁻⁵mm Hg); mp 51−52 °C; ¹H NMR

(500 MHz, CDCl₃) δ 7.60 (d, J = 8.2 Hz, 2H, C(3′)H), 7.48 (d, J =

8.2 Hz, 2H, C(2′)), 6.16 (d, J = 1.5 Hz, 1H, C(4a)H), 5.53 (d, J = 1.5

Hz, 1H, C(4b)H), 4.94 (dt, J = 7.8, 3.5 Hz, 1H, C(1)H), 3.22 (d, J =

3.5 Hz, 1H, OH), 2.83−2.72 (m, 1H, C(2a)H), 2.65−2.53 (m, 1H,

C(2b)H), 1.51 (s, 9H, C(7)H₃× 3; ¹³C{¹H} NMR (125 MHz,

CDCl₃) δ 167.3 C(5), 148.2 C(1′), 138.2 C(3), 129.59 (q, J = 32.3

Hz, C(4′)), 128.11 C(4), 126.13 C(2′), 125.34 (q, J = 3.9 Hz, C(3′)),

124.4 (q, J = 271.9 Hz, C(5′)), 81.72 C(6), 72.9 C(1), 42.8 C(2), 28.1

C(7).; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.9 (versus external BF₃·

OEt₂standard); IR (neat) 3417 (w), 3006 (w), 2984 (w), 2931 (w),

1703 (s), 1633 (w), 1619 (w), 1422 (w), 1417 (w), 1408 (w), 1391

(w), 1370 (m), 1330 (s), 1257 (w), 1226 (w), 1162 (s), 1149 (s),

1126 (s), 1106 (m), 1068 (m), 1052 (w), 1015 (w), 955 (w), 948 (w),

875 (w), 849 (w), 835 (m), 819 (w), 756 (w), 689 (w), 654 (w), 605

(w); MS (EI⁺, 70 eV) 317.0 (MH⁺,4), 260.9 (32), 242.9 (100), 240.9

(42), 231.0 (15), 222.9 (16), 196.9 (19), 177.0 (15), 174.9 (96), 173.0

(24), 145.0 (20), 142.0 (52), 128.0 (20), 127.0 (75), 86.0 (48), 68.0

(18); TLC R_f0.26 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd

for C₁₆H₁₉F₃O₃(316.32): C, 60.75; H, 6.05. Found: C, 60.44; H, 6.01.

Preparation of tert-Butyl 4-Hydroxy-2-methylene-6-phenylhex-

anoate (3cm). Following the general allylation procedure, 1c (131.7

μL, 1.0 mmol), Ru₃(CO)₁₂(12.8 mg, 0.020 mmol, 0.02 equiv), TBACl

(16.9 mg, 0.060 mmol, 0.06 equiv), 2m (240.3 mg, 1.20 mmol, 1.2

equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1

equiv), and dioxane (2.5 mL) were combined under 40 psi of CO at

75 °C for 24 h. Workup and puriﬁcation by silica gel column

chromatography (radial silica gel chromatography 2 mm, EtOAc/

hexane (1:9) then 25 g SiO₂, 2 × 14 cm column, Et₂O/CH₂Cl₂(3%

Et₂O)) provided 3cm (216 mg, 78%) as a colorless oil. Data for 3cm:

1

bp 125 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ

7.31−7.25 (m, 2H, C(5′)H), 7.24−7.20 (m, 2H, C(4′)H), 7.20−7.15

(m, 1H, C(6′)H) 6.15 (d, J = 1.7 Hz, 1H, C(4a)H), 5.57 (d, J = 1.7

Hz, 1H, C(4b)H), 3.76 (dddd, J = 8.3, 6.0, 4.1, 2.4 Hz, 1H, C(2)H),

2.83 (dt, J = 13.8, 7.7 Hz, 1H, C(2′a)H), 2.70 (dt, J = 13.8, 8.2 Hz, 1H,

C(2′b)H), 2.57 (ddd, J = 13.9, 3.5, 1.1 Hz, 1H, C(2a)H), 2.49 (d, J =

4.1 Hz, 1H, OH), 2.36 (ddd, J = 13.9, 8.3, 0.9 Hz, 1H, C(2b)H), 1.78

(td, J = 8.2, 6.0 Hz, 2H, C(1′)H₂), 1.48 (s, 9H, C(7)H₃× 3); ¹³C{¹H}

NMR (125 MHz, CDCl₃) δ 167.2 C(5), 142.3 C(3′), 139.1 C(3),

128.6 C(4′), 128.5 C(5′), 127.0 C(4), 125.9 C(6′), 81.3 C(6), 70.2

C(1), 40.7 C(2), 39.1 C(1′), 32.2 C(2′), 28.1 C(7); IR (neat) 3426

(m), 3085 (w), 3062 (w), 3026 (w), 2977 (m), 2930 (m), 2863 (w),

1709 (s), 1630 (m), 1603 (w), 1495 (w), 1478 (w), 1541 (m), 1392

(m), 1368 (s), 1336 (m), 1313 (m), 1254 (m), 1217 (m), 1151 (s),

1078 (w), 1052 (w), 1031 (w), 946 (w), 849 (w), 819 (w), 747 (w),

700 (m); MS (CI⁺, 70 eV) 277.2 (MH⁺, 6), 221.1 (63), 203.1 (100),

185.1 (48), 157.1 (84), 125.1 (12), 117.1 (28), 91.1 (34); TLC R_f0.33

(EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd for C₁₇H₂₄O₃

(264.38): C, 73.88; H, 8.75. Found: C, 73.60; H, 8.84.

Preparation of tert-Butyl 4-Hydroxy-2-methylene-4-(4-

nitrophenyl)butanoate (3dm). Following the general allylation

procedure, 1d (151.1 mg, 1.0 mmol), Ru₃(CO)₁₂(12.8 mg, 0.020

mmol, 0.02 equiv), TBACl (16.9 mg, 0.060 mmol, 0.06 equiv), 2m

(240.3 mg, 1.20 mmol, 1.2 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv),

Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (62 g, 3.5 × 17 cm

column, EtOAc/hexane (1:9 → 1:7 → 1:4) then Et₂O/CH₂Cl₂(3%

Et₂O)) and then further puriﬁcation via Kugelrohr distillation aﬀorded

3dm (190 mg, 65%) as a clear, yellow viscous oil. Data for 3dm: bp

Preparation of tert-Butyl 4-Hydroxy-4-(4-methoxyphenyl)-2-

methylenebutanoate (3fm). Following the general allylation

procedure, 1f (121.7 μL 1.0 mmol), Ru₃(CO)₁₂(12.8 mg, 0.020

mmol, 0.02 equiv), TBACl (16.9 mg, 0.060 mmol, 0.06 equiv), 2m

(240.3 mg, 1.20 mmol, 1.2 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv),

Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (radial silica gel

chromatography 2 mm, Et₂O/CH₂Cl₂(3% Et₂O) then radial silica gel

chromatography 2 mm, Et₂O/CH₂Cl₂(3% Et₂O) then 7.2 g SiO₂, 1 ×

15.5 cm column, CH₂Cl₂(100%) → Et₂O/CH₂Cl₂(3% Et₂O)) and

then further puriﬁcation via Kugelrohr distillation aﬀorded 3fm (232

mg, 83%) as a clear, colorless oil. Data for 3fm: bp 175 °C (ABT, 10⁻⁵

1

200 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 8.20

(dd, J = 8.7, 1.8 Hz, 2H, C(3′)H), 7.54 (dd, J = 8.7, 1.8 Hz, 1H,

C(2′)H), 6.15 (t, J = 1.5 Hz, 1H, C(4a)H), 5.51 (t, J = 1.2 Hz, 1H,

C(4b)H), 5.00 (dt, J = 7.6, 3.6 Hz, 1H, C(1)H), 3.50 (d, J = 3.5 Hz,

1H, OH), 2.80 (ddt, J = 14.1, 3.6, 1.0 Hz, 1H, C(2a)H), 2.58 (m, 1H,

C(2b)H), 1.52 (d, J = 1.5 Hz, 9H, C(7)H₃× 3); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 167.5 C(5), 151.5 C(1′), 147.3 C(4′), 137.9 C(3),

128.5 C(4), 126.6 C(2′), 123.7 C(3′), 82.1 C(6), 72.7 C(1), 42.9

C(2), 28.2 C(7); IR (neat) 3444 (m), 3078 (w), 2979 (s), 2932 (m),

2870 (w), 2451 (w), 1929 (w), 1807 (w), 1705 (s), 1630 (m), 1602

(s), 1522 (s), 1492 (m), 1478 (m), 1457 (m), 1431 (m), 1393 (s),

1368 (s), 1345 (s), 1314 (s), 1255 (s), 1217 (s), 1148 (s), 1109 (m),

1063 (s), 1013 (m), 954 (m), 880 (m), 853 (s), 820 (m), 751 (m),

737 (m), 701 (m), 659 (w), 616 (w); MS (EI⁺, 70 eV) 294.1 (MH⁺,

31), 238.1 (76), 220.0 (100), 152.0 (24), 142.1 (42), 135.0 (25), 106.0

(11), 105.0 (11), 86.1 (36); TLC R_f0.15 (EtOAc/hexane, 1:4) [UV,

KMnO₄]. Anal. Calcd for C₁₅H₁₉NO₅(293.32): C, 61.42; H, 6.53; N,

4.78. Found: C, 61.64; H, 6.51; N, 4.81.

1

mm Hg); H NMR (500 MHz, CDCl₃) δ 7.29 (d, J = 8.7 Hz, 2H,

C(2′)H), 6.88 (d, J = 8.7 Hz, 2H, C(3′)H), 6.14 (d, J = 1.7 Hz, 1H,

C(4a)H), 5.52 (d, J = 1.7 Hz, 1H, C(4b)H), 4.82 (dd, J = 8.4, 3.4 Hz,

1H, C(1)H), 3.80 (s, 3H, C(5′)H₃), 2.75−2.69 (m, 2H, OH and

C(2a)H), 2.62 (ddd, J = 13.9, 8.5, 0.9 Hz, 1H, C(2b)H), 1.51 (s, 9H,

C(7)H₃× 3); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 167.2 C(5), 159.1

C(4′), 138.9 C(3), 136.4 C(1′), 127.4 C(4), 127.1 C(2′), 113.9 C(3′),

81.3 C(6), 73.09 C(1), 55.4 C(5′), 42.8 C(2), 28.2 C(7); IR (neat)

3443 (m), 2996 (m), 2977 (s), 2931 (m), 2832 (m), 1710 (s), 1629

(m), 1613 (s), 1586 (m), 1513 (s), 1456 (m), 1439 (m), 1393 (m),

1368 (s), 1335 (m), 1303 (s), 1247 (s), 1214 (m), 1146 (s), 1109

(m), 1036 (s), 952 (w), 879 (w), 847 (m), 832 (m), 817 (m), 775

(w), 758 (w); MS (ESI) 301.2 (MNa⁺, 100), 242.2 (40), 205.0 (35),

102.1 (23); TLC R_f0.18 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal.

Calcd for C₁₆H₂₂O₄(278.35): C, 69.04; H, 7.97. Found: C, 68.75; H,

8.13.

M

dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

Preparation of tert-Butyl 4-Hydroxy-5,5-dimethyl-2-methylene-

hexanoate (3im). Following the general allylation procedure, 1i

(108.6 μL, 1.0 mmol), Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv),

TBACl (16.7 mg, 0.06 mmol, 0.06 equiv), 2m (280.3 mg, 1.4 mmol,

1.4 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol,

0.1 equiv), and dioxane (2.5 mL) were combined under 40 psi of CO

at 75 °C for 24 h. Workup and puriﬁcation by silica gel column

chromatography (31 g SiO₂3.5 × 8.5 cm column, Et₂O/hexane (1:7)

then 24.5 g SiO₂2.5 × 14 cm column, CH₂Cl₂(100%) → Et₂O/

CH₂Cl₂(3% Et₂O)) provided 3im (140 mg, 61%) as a clear, colorless

Preparation of tert-Butyl 4-Hydroxy-2-methylene-4-(2-tolyl)-

butanoate (3gm). Following the general allylation procedure, 1g

(115.6 μL, 1.0 mmol), Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv),

TBACl (16.7 mg, 0.06 mmol, 0.06 equiv), 2m (280.3 mg, 1.4 mmol,

1.4 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol,

0.1 equiv), and dioxane (2.5 mL) were combined under 40 psi of CO

at 75 °C for 24 h. Workup and puriﬁcation by silica gel column

chromatography (radial silica gel chromatography 2 mm, EtOAc/

hexane (1:7) then radial silica gel chromatography 2 mm, Et₂O/

CH₂Cl₂(5% Et₂O) then 7.2 SiO₂, 1 × 19.5 cm column, Et₂O/CH₂Cl₂

(3% Et₂O)) and then further puriﬁcation via Kugelrohr distillation

provided 3gm (192 mg, 73%) as a clear, colorless oil. Data for 3gm: bp

1

oil. Data for 3im: bp 75 °C (ABT, 10⁻⁵mm Hg); H NMR (500

MHz, CDCl₃) δ 6.15 (d, J = 1.7 Hz, 1H, C(4a)H), 5.58 (dt, J = 1.7,

1.0 Hz, 1H, C(4b)H), 3.30 (ddd, J = 10.4, 4.3, 2.0 Hz, 1H, C(1)H),

2.59 (ddd, J = 13.8, 2.0, 1.2 Hz, 1H, C(2a)H), 2.26 (d, J = 4.3 Hz, 1H,

OH), 2.16 (ddd, J = 13.8, 10.4, 0.8 Hz, 1H, C(2b)H), 1.50 (s, 9H,

C(7)H₃× 3), 0.94 (s, 9H, C(2′)H₃× 3); ¹³C{¹H} NMR (125 MHz,

CDCl₃) δ 167.4 C(5), 140.4 C(3), 126.6 C(4), 81.3 C(6), 78.9 C(1),

35.2 C(2), 35.1 C(1′), 28.2 C(7), 25.8 C(2′); IR (neat) 3475 (m),

3004 (m), 2961 (s), 2907 (m), 2870 (m), 1709 (s), 1631 (m), 1479

(m), 1460 (m), 1432 (w), 1393 (m), 1367 (s), 1337 (m), 1318 (m),

1288 (m), 1250 (m), 1223 (m), 1148 (s), 1068 (m), 1043 (w), 1009

(m), 944 (m), 910 (w), 864 (w), 850 (m), 818 (w), 756 (w), 675 (w),

628 (w); MS (CI⁺, 70 eV) 229.2 (MH⁺, 5), 156.0 (12), 155.1 (100),

137.1 (84), 109.1 (52), 101.1 (24), 89.1 (16), 87.0 (15); TLC R_f0.37

(EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd for C₁₃H₂₄O₃

(228.33): C, 68.38; H, 10.59. Found: C, 68.03; H, 10.74.

1

125 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 7.51

(dd, J = 7.5, 1.4 Hz, 1H), 7.23 (td, J = 7.5, 1.6 Hz, 1H, C(3′)H), 7.16

(td, J = 7.5, 1.4 Hz, 1H, C(4′)H), 7.12 (dd, J = 7.5, 1.6 Hz, 1H,

C(5′)H), 6.16 (d, J = 1.6 Hz, 1H, C(4a)H), 5.56 (d, J = 1.6 Hz, 1H,

C(4b)H), 5.15−5.01 (m, 1H, C(1)H), 2.88 (s, 1H, OH), 2.72 (ddd, J

= 14.0, 3.5, 1.1 Hz, 1H, C(2a)H), 2.57 (ddd, J = 14.0, 8.8, 0.9 Hz, 1H,

C(2b)H), 2.36 (s, 3H, C(7′)H₃), 1.51 (s, 9H, C(7)H₃× 3); ¹³C{¹H}

NMR (125 MHz, CDCl₃) δ 167.3 C(5), 142.4 C(6′), 139.0 C(3),

134.4 C(1′), 130.4 C(5′), 127.5 C(4), 127.3 C(4′), 126.3 C(3′), 125.3

C(2′), 81.4 C(6), 69.9 C(1), 41.6 C(2), 28.2 C(7), 19.2 C(7′); IR

(neat) 3441 (m), 3052 (w), 2977 (s), 2931 (m), 1914 (w), 1712 (s),

1630 (m), 1605 (w), 1479 (m), 1461 (m), 1393 (s), 1368 (s), 1337

(s), 1316 (s), 1281 (m), 1255 (s), 1215 (s), 1146 (s), 1111 (m), 1045

(s), 1011 (m), 946 (m), 879 (w), 850 (m), 818 (w), 754 (m), 726

(m), 676 (w), 632 (w), 607 (w); MS (EI⁺, 70 eV) 262.1 (M⁺, 1),

206.1 (11), 189.1 (11), 212.0 (12), 121.1 (100), 93.1 (24), 91.0 (17),

77.1 (13); TLC R_f0.31 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal.

Calcd for C₁₆H₂₂O₃(262.34): C, 73.25; H, 8.45. Found: C, 73.19; H,

8.26.

Preparation of tert-Butyl 4-Hydroxy-4-(4-methoxyphenyl)-2-

methylenebutanoate (3jm). Following the general allylation

procedure, 1j (93.5 mg, 1.0 mmol), Ru₃(CO)₁₂(12.8 mg, 0.020

mmol, 0.02 equiv), TBACl (16.9 mg, 0.060 mmol, 0.06 equiv), 2m

(240.3 mg, 1.20 mmol, 1.2 equiv), H₂O (27 μL, 1.5 mmol, 1.5 equiv),

Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were

combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (57 g SiO₂, 3.5 × 15

cm column, hexane (100%) → TBME/hexane (1:9 → 1:7) then 27 g

SiO₂, 2 × 27 cm column, CH₂Cl₂(100%) → Et₂O/CH₂Cl₂(3%

Et₂O)) and then further puriﬁcation via Kugelrohr distillation aﬀorded

3jm (215 mg, 85%) as a clear, colorless oil. Data for 3jm: bp 150 °C

Preparation of tert-Butyl 4-Hydroxy-6-methyl-2-methylenehep-

tanoate (3hm). Following the general allylation procedure, 1h (107.3

μL, 1.0 mmol), Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv), TBACl

(16.7 mg, 0.06 mmol, 0.06 equiv), 2h (280.3 mg, 1.4 mmol, 1.4 equiv),

H₂O (27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv),

and dioxane (2.5 mL) were combined under 40 psi of CO at 75 °C for

24 h. Workup and puriﬁcation by silica gel column chromatography

(48 g SiO₂3.5 × 13.5 cm column, hexane (100%) → Et₂O/hexane

(1:7) then 20 g SiO₂2.5 × 11 cm column, CH₂Cl₂(100%) → Et₂O/

CH₂Cl₂(3% Et₂O)) provided 3hm (192 mg, 84%) as a clear, colorless

oil. Data for 3hm: bp 75 °C (ABT, 0.18 mmHg); ¹H NMR (500 MHz,

CDCl₃) δ 6.15 (d, J = 1.7 Hz, 1H, C(4a)H), 5.57 (d, J = 0.9 Hz, 1H,

C(4b)H), 3.80 (tt, J = 8.3, 3.9 Hz, 1H, C(1)H), 2.53 (ddd, J = 13.9,

3.4, 1.1 Hz, 1H, C(2a)H), 2.27 (ddd, J = 13.9, 8.4, 0.9 Hz, 1H,

C(2b)H), 2.15 (s, 1H, OH), 1.80 (dddd, J = 13.2, 12.2, 8.7, 6.6 Hz,

1H, C(2′)H), 1.50 (s, 9H, C(7)H₃× 3), 1.42 (ddd, J = 14.1, 8.7, 5.6

Hz, 1H, C(1′a)H), 1.23 (ddd, J = 13.4, 8.7, 4.4 Hz, 1H, C(1′b)H),

0.92 (dd, J = 8.9, 6.6 Hz, 6H, C(3′)H₃× 2); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 167.2 C(5), 139.3 C(3), 126.8 C(4), 81.2 C(6), 68.8

C(1), 46.6 C(1′), 41.1 C(2), 28.2 C(7), 24.7 C(2′), 23.5 C(3′a), 22.2

C(3′b); IR (neat) 3443 (m), 2955 (s), 2930 (s), 2870 (m), 1886 (w),

1711 (s), 1631 (m), 1469 (m), 1455 (m), 1392 (m), 1368 (s), 1338

(s), 1314 (s), 1255 (m), 1214 (s), 1150 (s), 1070 (m), 1031 (m), 988

(w), 944 (m), 876 (w), 851 (m), 818 (w), 759 (w), 738 (w), 692 (w),

621 (w); MS (CI⁺, 70 eV) 229.2 (MH⁺, 36), 174.1 (13), 173.1 (97),

155.1 (92), 153.1 (10), 137.1 (39), 115.0 (19), 109.1 (100), 69.1 (10),

57.0 (82); TLC R_f0.28 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal.

Calcd for C₁₃H₂₄O₃(228.33): C, 68.38; H, 10.59. Found: C, 68.56; H,

10.54.

1

(ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 7.24−7.21 (m,

1H, C(4′)H), 7.01−6.90 (m, 2H, C(3′)H and C(2′)H), 6.17 (t, J =

1.2 Hz, 1H, C(4a)H), 5.59 (t, J = 1.3 Hz, 1H, C(4b)H), 5.19−5.05

(m, 1H, C(1)H), 3.01 (dd, J = 4.0, 0.9 Hz, 1H, OH), 2.86 (ddd, J =

14.0, 4.2, 1.0 Hz, 1H, C(2a)H), 2.75 (ddd, J = 14.0, 8.5, 0.9 Hz, 1H,

C(2b)H), 1.51 (d, J = 0.8 Hz, 9H, C(7)H₃× 3); ¹³C{¹H} NMR (125

MHz, CDCl₃) δ 167.1 C(5), 148.3 C(1′), 138.2 C(3), 127.9 C(4),

126.7 C(3′), 124.4 C(4′), 123.5 C(2′), 81.5 C(6), 69.7 C(1), 42.9

C(2), 28.2 C(7); IR (neat) 3431 (m), 2977 (m), 2926 (m), 1704 (s),

1632 (m), 1393 (m), 1368 (s), 1340 (m), 1316 (m), 1255 (m), 1222

(m), 1152 9s), 1037 (m), 951 (m), 876 (w), 850 (m), 818 (m), 751

(w), 698 (m); MS (ESI) 277.1 (MNa⁺, 100), 242.3 (33), 181.0 (10);

TLC R_f0.31 (EtOAc/hexane, 1:4) [UV, KMnO₄]. Anal. Calcd for

C₁₃H₁₈O₃S (254.34): C, 61.39; H, 7.13. Found: C, 61.33; H, 7.07.

Preparation of 5-Hydroxy-3-methylene-5-phenylpentan-2-one

(3an). Following the general allylation procedure, 1a (102 μL, 1.0

mmol), Ru₃(CO)₁₂(12.8 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7

N

dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

mg, 0.06 mmol, 0.06 equiv), 2n (284.1 mg, 2.0 mmol, 2.0 equiv), H₂O

(63 μL, 3.5 mmol, 3.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and

dioxane (2.5 mL) were combined under 40 psi of CO at 75 °C for 24

h. Workup and puriﬁcation by silica gel column chromatography (50 g

SiO₂, 2.5 × 27 cm column, EtOAc/hexane (1:9 w/1% Et₃N → 1:5 →

1:4) then radial silica gel chromatography 2 mm Et₂O/CH₂Cl₂(15%

Et₂O)) provided 3an (141 mg, 74%) as a colorless oil. Data for 3an:

¹H NMR (500 MHz, CDCl₃) δ 7.39−7.32 (m, 4H, C(3′H and

C(2′)H), 7.30−7.24 (m, 1H, C(4′)H), 6.10 (s, 1H, C(4a)H), 5.82 (d,

J = 1.0 Hz, 1H, C(4b)H), 4.83 (dt, J = 8.1, 3.7 Hz, 1H, C(1)H), 2.90

(d, J = 3.7 Hz, 1H, OH), 2.77 (ddd, J = 13.9, 4.0, 1.0 Hz, 1H,

C(2a)H), 2.65 (ddd, J = 13.9, 8.4, 0.9 Hz, 1H, C(2b)H), 2.38 (s, 3H,

C(6)H₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 201.3 C(5), 145.7

C(3), 144.3 C(1′), 128.8 C(4), 128.4 C(2′), 127.5 C(4′), 125.8 C(3′),

73.4 C(1), 41.6 C(2), 25.9 C(6); IR (neat) 3411 (w), 3088 (w), 3063

(w), 3030 (w0, 2925 (w), 1671 (m), 1628 (w), 1494 (w), 1453 (w),

1426 (w), 1365 (w), 1325 (w), 1186 (w), 1126 (w), 1081 (w), 1052

(w), 1027 (w), 1016 (w), 947 (w), 876 (w), 760 (w), 699 (m), 652

(w), 609 (w); MS (EI⁺, 70 eV) 190.1 (M⁺, 25), 173.1 (38), 172.1 (18),

129.1 (21), 128.1 (15), 108.1 (18), 107.1 (100), 105.0 (44), 85.1 (34),

84.1 (34), 79.1 (98), 78.1 (16), 77.1 (78), 69.0 (67), 50.7 (25);

HRMS (CI⁺, TOF) calcd for C₁₂H₁₄O₂190.0994, found 190.0995;

TLC R_f0.09 (EtOAc/hexane, 1:4) [UV, PA].

1:3) then radial silica gel chromatography 2 mm Et₂O/CH₂Cl₂(7%

Et₂O)) provided 3cn (152 mg, 70%) as a colorless oil. Data for 3cn:

¹H NMR (500 MHz, CDCl₃) δ 7.28 (t, J = 7.6 Hz, 2H, C(5′)H),

7.24−7.15 (m, 3H, C(6′)H and C(4′)H), 6.13 (s, 1H, C(4a)H), 5.91

(s, 1H, C(4b)H), 3.70 (tq, J = 8.1, 4.3 Hz, 1H, C(1)H), 2.82 (ddd, J =

13.8, 9.0, 6.7 Hz, 1H, C(2′a)H), 2.68 (ddd, J = 13.8, 9.1, 7.1 Hz,

1H,C(2′b)H), 2.57 (ddd, J = 13.8, 3.5, 1.0 Hz, 1H, C(2a)H), 2.42−

2.31 (m, 5H, OH, C(2b)H, and C(6)H₃), 1.76 (ddd, J = 10.6, 9.1, 3.5

Hz, 2H, C(1′)H₂); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 201.3 C(5),

146.2 (3), 142.3 C(3′), 128.6 C(4), 128.5 C(4′), 128.4 C(5′), 125.9

C(6′), 70.5 C(1), 39.5 C(2), 39.3 C(1′), 32.2 C(2′), 25.9 C(6); IR

(neat) 3435 (w), 3027 (w), 2926 (w), 2857 (w), 1674 (w), 1627 (w),

1603 (w), 1496 (2), 1454 (w), 1430 (w), 1366 (w), 1324 (w), 1154

(w), 1126 (w), 1076 (w), 1053 (w), 1030 (w), 943 (w), 866 (w), 748

(w), 601 (m), 650 (w), 565 (w); MS (EI⁺, 70 eV) 218.1 (M⁺, 5),

200.1 (39), 117.1 (35), 109.1 (15), 105.1 (11), 96.1 (17), 95.1 (12),

91.1 (100), 85.1 (20), 84.1 (23), 79.1 (12), 77.1 (14), 69.0 (35), 65.0

(21); HRMS (CI⁺, TOF) calcd for C₁₄H₁₈O₂, 218.1307; found,

218.1305; TLC R_f0.08 (EtOAc/hexane, 1:4) [UV, PA].

Preparation of 1,3-Diphenylbut-3-en-1-ol (3ao). Following the

general allylation procedure, 1a (101.9 μL, 1.0 mmol), Ru₃(CO)₁₂

(19.2 mg, 0.03 mmol, 0.03 equiv), TBACl (25.0 mg, 0.09 mmol, 0.09

equiv), 2o (493.3 mg, 2.8 mmol, 2.8 equiv), H₂O (45 μL, 2.5 mmol,

2.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)

were combined under 40 psi of CO at 75 °C for 48 h. Workup and

puriﬁcation by silica gel column chromatography (62 g SiO₂, 3.5 ×

18.5 cm column, hexane (100%) then EtOAc/hexane (1:9)) provided

3ao (166 mg, 74%) as a white solid. The spectroscopic data matched

those from literature, and the sample was free of any major

Preparation of (E)-5-Hydroxy-3-methylene-7-phenylhept-6-en-2-

one (3bn). Following the general allylation procedure, 1b (126 μL, 1.0

mmol), Ru₃(CO)₁₂(12.8 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7

mg, 0.06 mmol, 0.06 equiv), 2n (340.9 mg, 2.4 mmol, 2.4 equiv), H₂O

(63 μL, 3.5 mmol, 3.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and

dioxane (2.5 mL) were combined under 40 psi of CO at 75 °C for 48

h. Workup and puriﬁcation by silica gel column chromatography (55 g

SiO₂, 2.5 × 31 cm column, EtOAc/hexane (1:9 w/1% Et₃N → 1:9 →

1:3 → 1:2) then radial silica gel chromatography 2 mm Et₂O/CH₂Cl₂

(5% → 7% Et₂O)) provided 3bn (158 mg, 73%) as a colorless oil.

Data for 3bn: ¹H NMR (500 MHz, CDCl₃) δ 7.37 (dd, J = 8.2, 1.3 Hz,

2H, C(4′)H), 7.31 (dd, J = 8.2, 6.8 Hz, 2H, C(5′)H), 7.23 (tt, J = 6.8,

1.3 Hz, 1H, C(6′)H), 6.59 (d, J = 15.0 Hz, 1H C(2′)H), 6.20 (dd, J =

15.0, 6.2 Hz, 1H, C(1′)H), 6.15 (s, 1H, C(4a)H), 5.95 (s, 1H,

C(4b)H), 4.41 (tt, J = 6.2, 3.1 Hz, 1H, C(1)H), 2.69 (ddd, J = 13.8,

4.4, 0.9 Hz, 1H, C(2a)H), 2.59−2.48 (m, 2H, OH and C(2b)H), 2.37

(s, 3H, C(6)H₃); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 201.2 C(5),

145.5 C(3), 136.8 C(3′), 131.8 C(1′), 130.2 C(2′), 128.9 C(4), 128.7

C(5′), 127.7 C(6′), 126.6 (4′), 71.8 C(1), 39.5 C(2), 26.0 C(6); IR

(neat) 3410 (w), 3026 (w), 1671 (w), 1628 (w), 1600 (w), 1494 (w),

1449 (w), 1428 (w), 1395 (w), 1366 (w), 1326 (w), 1182 (w), 1130

(w), 1098 (w), 1071 (w), 1024 (w), 967 (m), 944 (w), 873 (w), 750

(m), 693 (m); MS (EI⁺, 70 eV) 216.1 (M⁺, 18), 198.1 (11), 155.1

(11), 134.1 (10), 133.1 (100), 132.1 (11), 131.0 (42), 115.1 (40),

105.1 (20), 104.1 (11), 103.1 (17), 91.1 (28), 85.1 (13), 79.1 (10),

77.1 (24), 69.0 (11), 54.9 (2), 50.7 (11); TLC R_f0.07 (EtOAc/

hexane, 1:4) [UV, PA]. Anal. Calcd for C₁₄H₁₆O₂(216.28): C, 77.75;

H, 7.46. Found: C, 77.79; H, 7.33.

impurities.⁴⁹Data for 3ao: H NMR (500 MHz, CDCl₃) δ 7.45−

1

7.38 (m, 2H, C(4′, 8)H), 7.36−7.18 (m, 8H, C(2′, 3′, 6, 7), 5.37 (d, J

= 1.4 Hz, 1H, C(4a)H), 5.12 (d, J = 1.4 Hz, 1H, C(4b)H), 4.68 (ddd, J

= 9.0, 4.3, 2.3 Hz, 1H, C(1)H), 2.96 (ddd, J = 14.3, 4.3, 1.3 Hz, 1H,

C(2a)H), 2.81 (ddd, J = 14.3, 9.0, 0.9 Hz, 1H, C(2b)H), 2.06 (d, J =

2.3 Hz, 1H, OH); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ 145.1, 144.0,

140.4, 128.6, 128.5, 127.9, 127.9, 126.4, 125.9, 115.8, 72.2, 46.1; MS

(EI⁺, 70 eV) 224.1 (M⁺, 1), 207.1 (11), 206.1 (67), 205.1 (35), 204.1

(13), 203.1 (16), 202.1 (13), 191.1 (28), 190.1 (10), 165.1 (10), 129.1

(14), 128.1 (25), 119.1 (10), 118.1 (100), 117.1 (27), 115.1 (32),

107.0 (83), 106.0 (14), 105.0 (21), 103.1 (17), 91.1 (41), 79.1 (51),

78.0 (20), 77.0 (58), 51.0 (18); TLC R_f0.25 (EtOAc/hexane, 1:5)

[UV, PA].

Preparation of (E)-1,5-Diphenylhexa-1,5-dien-3-ol (3bo). Follow-

ing the general allylation procedure, 1b (126 μL, 1.0 mmol),

Ru₃(CO)₁₂(19.2 mg, 0.03 mmol, 0.03 equiv), TBACl (25.0 mg,

0.09 mmol, 0.09 equiv), 2o (493.3 mg, 2.8 mmol, 2.8 equiv), H₂O (63

μL, 3.5 mmol, 3.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and

dioxane (2.5 mL) were combined under 80 psi of CO at 75 °C for 24

h. Workup and puriﬁcation by silica gel column chromatography (58 g

SiO₂, 3.5 × 17 cm column, Et₂O/hexane (1:9 → 1:5 → 1:3 → 1:2))

provided an inseparable mixture of 3bo/3co in an 88:12 ratio (166

mg, 74%) as a colorless oil. The spectroscopic data for 3bo matched

those from literature when the peaks for 3co were accounted for.⁵⁰

Preparation of 5-Hydroxy-3-methylene-7-phenylheptan-2-one

(3cn). Following the general allylation procedure, 1c (132 μL, 1.0

mmol), Ru₃(CO)₁₂(12.8 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7

mg, 0.06 mmol, 0.06 equiv), 2n (284.1 mg, 2.0 mmol, 2.0 equiv), H₂O

(63 μL, 3.5 mmol, 3.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and

dioxane (2.5 mL) were combined under 40 psi of CO at 75 °C for 24

h. Workup and puriﬁcation by silica gel column chromatography (49 g

SiO₂, 2.5 × 28 cm column, EtOAc/hexane (1:9 w/1% Et₃N → 1:5 →

1

Data for 3bo: H NMR (500 MHz, CDCl₃) δ 7.48−7.40 (m, 2H,

C(6′, 8)H), 7.41−7.15 (m, 10H, C(5′, 4′, 6, 7)H), 6.54 (dd, J = 15.9,

1.1 Hz, 1H, C(2′)H), 6.22 (ddd, J = 15.9, 6.4, 0.7 Hz, 1H, C(1′)H),

5.43 (d, J = 1.4 Hz, 1H, C(4a)H), 5.22 (d, J = 1.2 Hz, 1H, C(4b)H),

4.36 (dddd, J = 8.0, 6.3, 5.0, 1.2 Hz, 1H, C(1)H), 2.91 (ddd, J = 14.1,

5.0, 1.1 Hz, 1H, C(2a)H), 2.79 (ddd, J = 14.1, 8.0, 0.9 Hz, 1H,

O

dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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C(2b)H), 1.87 (s, 1H, br OH); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ

144.6, 140.3, 136.6, 131.4, 130.1, 128.4, 128.4, 127.6, 127.5, 126.3,

126.2, 115.7, 70.5, 43.8; MS (EI⁺, 70 eV) 250.1 (M⁺, 4), 233.1 (15),

232.1 (83), 231.1 (12), 217.1 (15), 216.1 (11), 215.1 (19), 202.1 (12),

154.1 (12), 153.1 (12), 143.1 (12), 141.1 (35), 133.1 (74), 129.1 (11),

128.1 (25), 119.1 (11), 118.1 (55), 117.1 (31), 116.1 (11), 115.1 (49),

105.1 (10), 103.1 (21), 92.1 (14), 91.1 (100), 78.0 (15), 77.0 (24);

TLC R_f0.21 (EtOAc/hexane, 1:5) [UV, PA].

Preparation of (E)-5-(Diethoxymethyl)-1-phenylhexa-1,5-dien-3-

ol (3bp). Following the general allylation procedure, 1b (126 μL, 1.0

mmol), Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7

mg, 0.06 mmol, 0.06 equiv), 2p (323.8 mg, 1.6 mmol, 1.6 equiv), H₂O

(27 μL, 1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and

dioxane (2.5 mL) were combined under 40 psi of CO at 75 °C for 24

h. Workup entailed washing the reaction mixture with NaHCO₃(3 ×

5 mL) in a separatory funnel and extracting with Et₂O (2 × 5 mL)

before drying over MgSO₄and removing solvent. The residue was

then puriﬁed via silica gel column chromatography (42.5 g SiO₂, 2.0 ×

23.5 cm column, Et₂O/hexane (1:9 w/1% Et₃N → 1:6 → 1:3 → 1:1)

providing a nearly inseparable mixture of 3bp/3cp in an 88:12 ratio

(203 mg, 73%) as a colorless oil. A small portion of 3bp was

successfully isolated via sacriﬁcial puriﬁcation (radial silica gel

chromatography 2 mm, Et₂O/hexane (1:2 w/1% Et₃N → 1:2)),

providing pure 3bp (63 mg, 23%) with which all characterization data

Preparation of 1,5-Diphenylhex-5-en-3-ol (3co). Following the

general allylation procedure, 1c (131.7 μL, 1.0 mmol), Ru3(CO)12

(19.2 mg, 0.03 mmol, 0.03 equiv), TBACl (25.0 mg, 0.09 mmol, 0.09

equiv), 2o (422.8 mg, 2.4 mmol, 2.4 equiv), H₂O (27 μL, 1.5 mmol,

1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)

were combined under 40 psi of CO at 75 °C for 24 h. Workup and

puriﬁcation by silica gel column chromatography (64 g SiO₂, 3.5 × 19

cm column, hexane (100%) then Et₂O/hexane (1:9 → 1:4)) provided

3co (198 mg, 78%) as a clear, colorless oil. The spectroscopic data

matched those from literature and was free of any major impurities.⁵¹

Data for 3co: ¹H NMR (500 MHz, CDCl₃) δ 7.39 (dt, J = 8.2, 1.2 Hz,

2H, C(aryl)H), 7.33 (dd, J = 8.4, 6.4 Hz, 2H, C(aryl)H), 7.31−7.24

(m, 3H, C(aryl)H), 7.20−7.15 (m, 3H, C(aryl)H), 5.42 (t, J = 1.1 Hz,

1H, C(4a)H), 5.17 (t, J = 1.1 Hz, 1H, C(4b)H), 3.71 (m, 1H, C(1)H),

2.85−2.76 (m, 2H, C(2′a, 2a)H), 2.66 (ddd, J = 14.1, 9.3, 6.9 Hz, 1H,

C(2′b)H), 2.58 (dd, J = 14.1, 8.1 Hz, 1H, C(2b)H), 1.82 (dtd, J = 9.3,

6.7, 5.9, 2.7 Hz, 2H, C(1′)H₂), 1.68 (d, J = 1.6 Hz, 1H, OH); ¹³C{¹H}

NMR (125 MHz, CDCl₃) δ 145.5, 142.2, 140.7, 128.6, 128.5, 127.9,

126.4, 125.9, 115.5, 69.2, 44.0, 38.8, 32.2; MS (EI⁺, 70 eV) 252.0 (M⁺,

6), 234.0 (12), 147.0 (28), 119.0 (31), 118.0 (100), 117.0 (40), 115.0

(18), 105.0 (16), 103.0 (15), 92.0 (23), 91.0 (100), 78.0 (21), 77.0

(17), 65.0 (13); TLC R_f0.23 (EtOAc/hexane, 1:5) [UV, PA].

1

was obtained. Data for 3bp: bp 125 °C (ABT, 10⁻⁵mm Hg); H

NMR (500 MHz, CDCl₃) δ 7.38 (dd, J = 8.1, 1.4 Hz, 2H, C(4′)H),

7.30 (dd, J = 8.4, 6.8 Hz, 2H, C(5′)H), 7.22 (t, J = 7.3 Hz, 1H,

C(6′)H), 6.64 (dd, J = 15.9, 1.4 Hz, 1H, C(2′)H), 6.25 (dd, J = 15.9,

6.0 Hz, 1H, C(1′)H), 5.27 (d, J = 1.8 Hz, 1H, C(4a)H), 5.17 (d, J =

1.8 Hz, 1H, C(4b)H), 4.75 (s, 1H, C(5)H), 4.47 (dtd, J = 8.0, 5.6, 4.9,

3.1 Hz, 1H, C(1)H), 3.68 (ddq, J = 18.4, 9.5, 7.1 Hz, 2H, C(6a)H₂),

3.52 (ddt, J = 11.3, 9.4, 7.0 Hz, 2H, C(6b)H₂), 3.46 (d, J = 3.4 Hz, 1H,

OH), 2.53 (ddd, J = 14.2, 3.5, 1.1 Hz, 1H, C(2a)H), 2.39 (ddd, J =

14.1, 8.8, 0.8 Hz, 1H, C(2b)H), 1.25 (dd, J = 7.0 Hz, 6H, C(7)H₃× 2;

¹³C{¹H} NMR (125 MHz, CDCl₃) δ 143.1 C(3), 137.3 C(3′), 132.4

C(1′), 129.6 C(2′), 128.6 C(5′), 127.5 C(6′), 126.6 C(4′), 117.8

C(4), 104.7 C(5), 71.8 C(1), 62.9 C(6a), 62.7 C(6b), 40.0 C(2),

15.21 C(7a), 15.18 C(7b); IR (neat) 3423 (w), 3025 (w), 2976 (w),

2937 (w), 2877 (w), 1651 (w), 1600 (w), 1495 (w), 1448 (w), 1393

(w), 1372 (w), 1372 (w), 1329 (w), 1160 (w), 1109 (w), 1054 (m),

1009 (w), 966 (w), 916 (w), 748 (w), 693 (m); MS (ESI) 299.2

(MNa⁺, 79), 291.3 (34), 283.2 (10), 264.2 (15), 219.2 (16), 218.2

(100), 213.1 (40), 186.1 (10), 185.1 (57), 184.1 (15), 169.1 (14),

168.1 (15), 167.1 (73), 157.1 (13); TLC R_f0.46 (EtOAc/hexane, 1:4)

[UV, PA]. Anal. Calcd for C₁₇H₂₄O₃(276.38): C, 73.88; H, 8.75.

Found: C, 74.23; H, 8.89.

Preparation of 3-(Diethoxymethyl)-1-phenylbut-3-en-1-ol (3ap).

Following the general allylation procedure, 1a (101.9 μL, 1.0 mmol),

Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7 mg, 0.06

mmol, 0.06 equiv), 2p (323.8 mg, 1.6 mmol, 1.6 equiv), H₂O (27 μL,

1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane

(2.5 mL) were combined under 40 psi of CO at 75 °C for 24 h.

Workup and puriﬁcation by silica gel column chromatography (38 g

SiO₂, 2.5 × 21.5 cm column, Et₂O/hexane (1:9 w/1% Et₃N → 1:5 →

1:3)) provided 3ap (180 mg, 72%) as a colorless oil. Data for 3ap: bp

Preparation of 5-(Diethoxymethyl)-1-phenylhex-5-en-3-ol (3cp).

Following the general allylation procedure, 1c (131.7 μL, 1.0 mmol),

Ru₃(CO)₁₂(12.79 mg, 0.02 mmol, 0.02 equiv), TBACl (16.7 mg, 0.06

mmol, 0.06 equiv), 2p (323.8 mg, 1.6 mmol, 1.6 equiv), H₂O (27 μL,

1.5 mmol, 1.5 equiv), Et₃N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane

(2.5 mL) were combined under 40 psi of CO at 75 °C for 24 h.

Workup and puriﬁcation by silica gel column chromatography (37 g

SiO₂, 2.5 × 21.5 cm column, Et₂O/hexane (1:9 w/1% Et₃N → 1:5 →

1:3)) provided 3cp (221 mg, 79%) as a colorless oil. Data for 3cp: bp

1

100 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 7.43−

7.37 (m, 2H, C(3′)H), 7.33 (dd, J = 8.3, 6.9 Hz, 2H, C(2′)H), 7.28−

7.21 (m, 1H, C(4′)H), 5.26 (d, J = 1.2 Hz, 1H, C(4a)H), 5.11 (d, J =

1.2 Hz, 1H, C(4b)H), 4.89−4.84 (m, 1H, C(1)H), 4.74 (s, 1H,

C(5)H), 3.78−3.62 (m, 3H, OH and C(6a)H₂), 3.51 (ddq, J = 21.8,

9.4, 7.0 Hz, 2H, C(6b)H₂), 2.57 (ddd, J = 14.2, 3.4, 1.0 Hz, 1H,

C(2a)H), 2.50 (ddt, J = 14.2, 9.3, 0.8 Hz, 1H, C(2b)H), 1.26 (dt, J =

11.7, 7.0 Hz, 6H, C(7)H₃× 2); ¹³C{¹H} NMR (125 MHz, CDCl₃) δ ;

144.7 C(1′), 143.4 C(3), 128.4 C(2′), 127.3 C(4′), 125.9 C(3′), 117.8

C(4), 104.7 C(5), 73.8 C(1), 63.0 C(6a), 62.6 C(6b), 42.1 (2), 15.22

C(7a), 15.18 C(7b); IR (neat) 3429 (w), 3029 (w), 2976 (w), 2878

(w), 1651 (w), 1606 (w), 1494 (w), 1453 (w), 1393 (w), 1329 (w),

1162 (w), 1111 (w), 1053 (m), 1007 (w), 976 (w), 916 (w), 757 (w),

699 (m); MS (ESI) 273.3 (MNa⁺, 4), 147.2 (14), 146.2 (32), 123.3

(11), 116.3 (16), 115.3 (100), 107.1 (95); TLC R_f0.24 (EtOAc/

hexane, 1:4) [UV, PA]. Anal. Calcd for C₁₅H₂₂O₃(250.34): C, 71.97;

H, 8.86. Found: C, 72.17; H, 8.87.

1

100 °C (ABT, 10⁻⁵mm Hg); H NMR (500 MHz, CDCl₃) δ 7.32−

7.24 (m, 2H, C(4′)H), 7.24−7.20 (m, 2H, C(5′)H), 7.19−7.14 (m,

1H, C(6′)H), 5.22 (d, J = 1.7 Hz, 1H, C(4a)H), 5.10 (d, J = 1.7 Hz,

1H, C(4b)H), 4.70 (s, 1H, C(5)H), 3.77 (dddt, J = 9.2, 7.7, 4.8, 3.2

Hz, 1H, C(1)H), 3.65 (ddq, J = 19.6, 9.4, 7.0 Hz, 2H, C(6a)H₂), 3.48

(tq, J = 9.3, 7.0 Hz, 2H, C(6b)H₂), 3.22 (d, J = 3.2 Hz, 1H, OH), 2.83

(ddd, J = 13.7, 9.8, 5.9 Hz, 1H, C(2′a)H), 2.70 (ddd, J = 13.7, 9.7, 6.8

Hz, 1H, C(2′b)H), 2.43−2.32 (m, 1H, C(2a)H), 2.23 (ddd, J = 14.1,

9.2, 0.8 Hz, 1H, C(2b)H), 1.78 (tdd, J = 9.8, 7.7, 5.2 Hz, 2H,

C(1′)H₂), 1.23 (td, J = 7.0, 5.7 Hz, 6H, C(7)H₃× 2); ¹³C{¹H} NMR

(125 MHz, CDCl₃) δ 143.7 C(3), 142.6 C(3′), 128.6 C(5′), 128.4

C(4′), 125.8 C(6′), 117.3 C(4), 104.8 C(5), 70.4 C(1), 63.0 C(6a),

P

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The Journal of Organic Chemistry

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62.7 C(6b), 39.8 C(2), 39.3 C(1′), 32.4 C(2′), 15.20 C(7a), 15.16

C(7b); IR (neat) 3448 (w), 3029 (w), 2977 (w), 2930 (w), 2874 (w),

1648 (w), 1603 (w), 1496 (w), 1454 (w), 1395 (w), 1372 (w), 1329

(w), 1111 (w), 1055 (m), 1011 (w), 916 (w), 733 (w), 699 (m) MS

(ESI) 301.4 (MNa⁺, 100), 187.3 (38), 119.3 (14), 105.3 (12); TLC R_f

0.23 (EtOAc/hexane, 1:4) [UV, PA]. Anal. Calcd for C₁₇H₂₆O₃

(278.39): C, 73.35; H, 9.41. Found: C, 73.41; H, 9.48.

(23) Shimizu, H.; Igarashi, T.; Miura, T.; Murakami, M. Angew.

Chem., Int. Ed. 2011, 50, 11465−11469.

(24) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,

130, 6340−6341.

(25) Dechert-Schmitt, A.-M. R.; Schmitt, D. C.; Gao, X.; Itoh, T.;

Krische, M. J. Nat. Prod. Rep. 2014, 31, 504−513.

(26) Dechert-Schmitt, A.-M. R.; Schmitt, D. C.; Krische, M. J. Angew.

Chem., Int. Ed. 2013, 52, 3195−3198.

(27) Ngai, M.-Y.; Skucas, E.; Krische, M. J. Org. Lett. 2008, 10, 2705−

2708.

ASSOCIATED CONTENT

■

S

* Supporting Information

(28) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008,

130, 6338−6339.

Optimization studies, GC response factors/retention times, and

¹H and ¹³C NMR spectra. This material is available free of

charge via the Internet at http://pubs.acs.org.

(29) Zbieg, J. R.; Yamaguchi, E.; McInturff, E. L.; Krische, M. J.

Science 2012, 336, 324−327.

(30) Tsuji, Y.; Mukai, T.; Kondo, T.; Watanabe, Y. J. Organomet.

Chem. 1989, 369, C51−C53.

AUTHOR INFORMATION

■

(31) It was originally determined by the work of Kondo and co-

workers that the use of Et₃N was required for catalyst turnover, not

CO. See: Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.-a.; Watanabe, Y.

Organometallics 1995, 14, 1945−1953.

Corresponding Author

*Tel: (217) 333-0066. Fax: (217) 333-3984. E-mail:

sdenmark@illinois.edu.

(32) Ford, P. C. Acc. Chem. Res. 1981, 14, 31−37.

(33) Laine, R. M.; Crawford, E. J. J. Mol. Catal. 1988, 44, 357−387.

(34) Jacobs, G.; Davis, B. H. Catalysis 2007, 20, 122−285.

(35) Han, S. H.; Geoffroy, G. L.; Dombek, B. D.; Rheingold, A. L.

Inorg. Chem. 1988, 27, 4355−4361.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

(36) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26−47.

(37) Tan, Z.; Wan, X.; Zang, Z.; Qian, Q.; Deng, W.; Gong, H. Chem.

Commun. 2014, 50, 3827−3830.

We are grateful to the National Science Foundation for

generous ﬁnancial support (NSF CHE-1012663 and

CHE1151566).

(38) Montgomery, T. P.; Hassan, A.; Park, B. Y.; Krische, M. J. J. Am.

Chem. Soc. 2012, 134, 11100−11103.

(39) The exact amount of unreacted benzaldehyde 1a in each

reaction was not able to be quantiﬁed due to partial oxidation to

benzoic acid during puriﬁcation.

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dx.doi.org/10.1021/jo501004j | J. Org. Chem. XXXX, XXX, XXX−XXX

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Catalytic, nucleophilic allylation of aldehydes with 2-substituted allylic acetates: Carbon-carbon bond formation driven by the water-gas shift reaction

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