Theoretical investigation of the reaction of dialkylzincs with α-alkoxycarbonyl radicals. Evaluation of α-bromoacrylates as radical acceptors in radical-polar crossover processes

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Theoretical Investigation of the Reaction of

Dialkylzincs with α-Alkoxycarbonyl

Radicals. Evaluation of α-Bromoacrylates as

Radical Acceptors in Radical-Polar

Crossover Processes

Leave this area blank for abstract info.

François Vibert, Julien Maury, Hugo Lingua, Eric Besson, Didier Siri, Michèle P. Bertrand* and Laurence

Feray*

Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire, UMR 7273, Equipes CMO and CT, Campus

Saint-Jérôme, Avenue Normandie-Niemen, 13397 Marseille Cedex 20, France

1

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Tetrahedron

journal homepage: www.elsevier.com

Theoretical investigation of the reaction of dialkylzincs with α-alkoxycarbonyl

radicals. Evaluation of α-bromoacrylates as radical acceptors in radical-polar

crossover processes

François Vibert, Julien Maury, Hugo Lingua, Eric Besson, Didier Siri, Michèle P. Bertrand∗ and Laurence

a,

Feray ∗

a

Aix-Marseille Université, CNRS, Institut de Chimie Radicalaire, UMR 7273, Equipes CMO and CT, Campus Saint-Jérôme, Avenue Normandie-Niemen, 13397

Marseille Cedex 20, France

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

The evaluation of ethyl α-bromoacrylate as radical acceptor in dialkylzinc radical-polar cascades

addresses the question of the parameters controlling homolytic substitution at zinc by α-

alcoxycarbonyl radicals. Under non-degassed medium ethyl α-bromoacrylate reacts with

diethylzinc to give a bromocyclopropane. The reaction involves successively radical addition,

Available online

S

H

2 at zinc, conjugate addition of the resulting enolate to the electrophilic substrate and ring

closure. Theoretical calculations were performed to get a better insight into the detailed

mechanism. They highlight the impact of zinc(II) chelation on the formal S 2 step. Additional

Keywords:

Dialkylzinc

Homolytic substitution

α-Alkoxy carbonyl radical

Radical-polar crossover reaction

Theoretical calculations

H

experiments performed in the presence of other electrophiles –aldehydes and acylsilanes – are

discussed.

2

—

——

∗

Laurence Feray Tel.: +33 (0)491288599; e-mail: laurence.feray@univ-amu.fr

Michele Bertrand. Tel.: +33 (0)491288597; e-mail: michele.bertrand@univ-amu.fr

2

Tetrahedron

ACCEPTED MANUSCRIPT

1

. Introduction

Over the last 15 years, radical reactions promoted by

O

2

RI

Et

2

Zn

Et

R

1

) Et

Et Zn + RI

2) NH Cl

2

Zn or

CO

Br

2

Et

2

CO Et

1,2,3

2

EtO

2

C

CO

2

Et

2

CO Et

dialkylzincs have experienced intensive development.

As part

R

Br

CH

2

R

1

4

of our interest in tin-free radical reactions, our group has

contributed to the growth of methodologies using dialkylzincs in

aerobic medium. The peculiar behavior of these organometallic

reagents that are both excellent radical precursors in the presence

of oxygen and good partners for bimolecular homolytic

substitution allowed the design of radical/polar crossover

reactions. This methodology has been applied to different types

of radical acceptors. We were able to achieve: the

diastereoselective synthesis of precursors of non-natural amino

Br

2

a R=Et

2b R=i-Pr

c R=t-Bu

2'a

2'b

2'c

2

Et Zn

2

OZnEt

Br

EtO

O

R

O

ZnEt

O

EtO

2

C

A

ZnEt

2

ZnEt

Br

R

Br

R

Br

R

Br

Et

A

B

C

D

O

ZnEt

Br

2

4,5

A

EtO

acids from addition to the C=N bonds of glyoxylic imines, the

6

2

EtO C

synthesis of γ-lactones and pyrrolizidines from diethyl fumarate,

Et

7

E

and that of γ-lactams from propiolamide. More recently,

R

Br

stereocontrolled trans-additions to diethyl acetylenedicarboxylate

were performed at room temperature. The reactivity of α-

bromoacrylates that remained unexplored is described in this

article. The data served as support to the theoretical investigation

of the transfer of alkylzinc group to α-alkoxycarbonyl radicals.

8

Scheme 1. Mechanism proposed for the reaction of ethyl α-

bromoacrylate with diethylzinc in non-degassed medium.

The resulting radical B leads to enolate C via the homolytic

fragmentation of a C-Zn bond. This step, which could also be

viewed as a formal homolytic substitution at the metal by a α-

alkoxycarbonyl radical intermediate, regenerates the chain carrier

radical. Once enolate C is formed, the reaction should evolve like

2

. Results and Discussion

Reactivity of ethyl α-bromoacrylate in the absence of any

additional electrophile

1

0

the Michael₁addition of Grignard reagents

or other

1

nucleophiles. Actually, the intermediate zinc enolate reacts with

The reactivity of ethyl α-bromoacrylate was first investigated

in the absence of any carbonyl compound. When ethyl α-

bromoacrylate was reacted with diethylzinc in non-degassed

dichloromethane at room temperature cyclopropane 2a was

a second molecule of the complexed substrate A through Michael

12

addition to give enolate D that undergoes ring closure to

provide cyclopropane 2a. Enolate D might also result from the

addition of the intermediate α-alkoxycarbonyl radical B to A

followed by homolytic cleavage of the C-Zn bond from

intermediate E (this alternative will be discussed on the ground

of theoretical calculations).

isolated as a single diastereomer in 71% optimized yield (Table

9

1

, entry 1, Scheme 1).

A straightforward mechanism is proposed in Scheme 1.

Owing to the presence of the bromine atom lone pairs, the

conversion of the radical acceptor into chelate A is plausible (this

will be further discussed on the ground of theoretical

calculations). According to this rationale, an ethyl radical, formed

through the reaction of diethylzinc with dioxygen in the initiation

step, adds to the activated double bond. When the need arises, an

alkyl radical generated via iodine atom transfer from the

corresponding alkyl iodide is added.

Indirect proofs that the cyclopropane resulted effectively from

an initial radical addition step were provided by experiments

performed in the presence of i-PrI (20 or 40 equiv) and t-BuI (20

equiv) (Table 1, entries 2-4).

The reaction achieved in the presence of a 20-fold excess of i-

PrI led to a mixture of 2b (major product) and 2a (minor

product). The reactivity of the substrate is such that the addition

of ethyl radical, which competes, with the formation of i-propyl

radical via iodine atom transfer from i-propyl iodide cannot be

avoided. In the presence of 40 equivalents of the secondary

iodide, the yield in isolated 2b was slightly improved (Table 1,

entries 2-3). The direct generation of i-propyl radical from the in

Table 1. Reaction of Et Zn with ethyl α-bromoacrylate (1)

2

under different experimental conditions

1

d

Entry

Conditions Products (isolated yields %)

H NMR ratio

situ reaction of i-Pr Zn with dioxygen was expected to be the

2

1

2

3

4

5

i

2a (71)

most appropriate route to 2b. However, due to the fast

consumption of this organometallic by reaction with dioxygen,

lower yields resulted (Table 1, entry 5).

a

b

c

2a (19)/2b (38)

2a (13)/2b (44)

2c (31)/2’c (nd)

2b (41)

41:59

29:71

Adding t-butyl radical at room temperature did not lead to the

expected cyclopropane derivative (2c) that was not detected in

the crude reaction mixture. Ring closure might be hindered by

the bulk of the neopentyl group, as the formation of a mixture of

the two diastereomers of the uncyclized dibrominated adduct 2c'

ii

Experimental conditions: i) Et

monitoring of the reaction showed that the substrate has disappeared after

hours, however the ring closure is not totally completed. For the sake of

homogeneity all reactions were quenched after standing other night.); ii)

i-Pr Zn (5 equiv), CH Cl , r.t., 18 h.

2 2 2

Zn (2 equiv), CH Cl , r.t., 18 h (The

1

was suspected from the analysis of the H NMR spectra of the

2

complex mixture. However, performing the reaction at 0°C

enabled the isolation of 2c in 31% yield and the formation of 2’c

as side product was ascertained from the analysis of an enriched

chromatographic fraction (Scheme 1, Table 1, entry 4).

2

a

i-PrI (20 equiv)

i-PrI (40 equiv)

t-BuI (20 equiv), 0 °C

determined on the crude reaction mixture.

b

c

d

It must be noted that these reactions could not be mediated

with dimethylzinc, which is an additional argument to discard a

3

polar mechanism for the addition step. A rad

A

ica

C

l c

C

ha

E

in

P

p

T

ro

E

ce

D

ss MAN

T

U

he

The formation of compounds formulated₁₈_,_,₃as Zn(OOR)₂,

Zn(OR)OOR, and Zn(OR) has been reported. Recent studies

reported by Mitzel have shown that in the presence of O in

S

o

C

xy

R

ge

I

n

P

at

T

ion of dialkylzincs has long been investigated.

could not be sustained in this case. Due to the higher C-Zn bond

dissociation energy, the release of methyl radical would be much

too slow.

2

1

9

excess, diethylzinc leads to EtZnOEt aggregates. In the

presence of a catalytic amount of O the complexation of organic

species with EtZnOEt species is unlikely. Even though, the latter

would also undergo homolytic substitution leading to the

In light of previous studies, the reactivity of the α-brominated

2

α-alkoxycarbonyl radical B regarding the S 2 step cannot be

H

13

explained on the simple ground of spin density at oxygen. In the

non complexed radical analogous to B where R=H, the spin

density at oxygen, calculated at the UB3LYP/6-

3a,20

generation of Et•,

effective Lewis acid.

only Et Zn species was considered as the

2

3

0

11++G(3df,3pd)//UB3LYP/6-31+G(d,p) level of theory, is

.152 for both the s-cis and the s-trans rotamers. It is lower than

A theoretical approach to the reaction pathways leading to

both rotamers of the intermediate enolate resulting from the

addition of Et was performed at the M06-2X/aug-cc-

the spin density at oxygen of the tertiary α-alkoxycarbonyl

radical resulting from the addition of methyl radical to methyl

methacrylate (0.176), which substrate failed to react according to

tandem ethyl radical addition/nucleophilic addition to

ꢀ

21,22

pVTZ//M06-2X/aug-cc-pVDZ level of theory

For the sake of

simplification methyl α-bromoacrylate was used as model

13

23

aldehydes.

substrate.

Coordination with Lewis acids that enhances the reactivity of

The s-cis conformer of the non complexed heterodienic

system is more stable than the s-trans conformer by only 0.4 kcal

14

the radical accepting double bond is well documented.

Similarly, the impact of coordination on the stabilization and the

per mol. In the presence of 2 equiv of Et Zn almost all the

2

2,15

reactivity of organozinc species is recognized.

The Lewis

substrate is coordinated to zinc. The s-trans conformer is

acidic character of diethylzinc should both accelerate the addition

stabilized by 8.9 kcal per mol by chelation, whereas the mono-

4b-d,14

of the nucleophilic alkyl radical,

and facilitate the S 2 step.

coordination of the s-cis conformer to Et Zn results in a 8.2 kcal

H

2

Literature data show that the tertiary α-alkoxycarbonyl radicals

per mol stabilization of the system.

which do undergo homolytic substitution at zinc are those which

16,17

lead to zinc enolates that can be stabilized upon chelation.

MeO

O

MeO

O

Br

(8.6)

(8.3)

MeO

O

TSab Br

^Zⁿ^E^t2

ZnEt₂

Br

(3.9)

TSbd

-0.5)

TSac

(a)

(b)

(0.0)

(-0.4)

(-0.3)

(

MeO

Br

O

Et

ZnEt

Et

ꢀ

(

f) + Et

MeO

Br

O

MeO

(-18.7)

O

ꢀ

ZnEt₂

(e) + Et

ZnEt₂

Et

(-27.3)

Et

Br

(+15.6)

(+7.3)

(d)

-34.3)

(

c)

(

-34.6)

Scheme 2. Energetic profile of reaction pathways leading to zinc enolates (e) and (f) (relative enthalpies are given in kcal per

mol)

A 3.9 kcal per mole rotational barrier was calculated for the

interconversion of rotamer (b) into (a). The energy difference

between the two conformers of the activated substrate is very

small (0.3 kcal per mol). Therefore, both rotamers should

participate in the reaction and the mechanism is likely to be more

complex than that shown in Scheme 1. The energetic profile of

the competitive routes is given in Scheme 2. The optimized

structures of the coordinated starting material, the transition

states and the reaction intermediates are represented in Figure 1.

In chelate (a), due to steric hindrance, the Zn-O distance is

longer than in complex (b) (2.60 Å/2.45 Å). As already stated,

the low interconversion barrier (3.9 kcal per mol) and the rather

small destabilization of (b) as compared to (a) (+0.3 kcal per

4

Tetrahedron

ACCEPTED MANUSCRIPT

mol) justify the investigation of ethyl radical addition to both

rotamers. Their reactivity is such that no transition state could be

located for the conjugate addition of Et to the activated double

bond until the step-by-step formation of the C-C bond was

investigated (0.01 Å steps from 2.73 Å to 1.54 Å for the

formation of intermediate (a); 0.02 Å steps from 2.63 Å to 2.23

Å for (b)). As shown in Scheme 2, the addition is highly

exothermic (-34.3 kcal per mol for both (a) and (b)). This is fully

consistent with the difficulty encountered in searching to locate a

transition structure for the two competitive processes. Actually,

both activation barriers are negligible. TSac and TSbd are very

early, the C-C bond distances (2.42 Å and 2.44 Å, respectively)

are much longer than the final 1.54 Å bond length in (c) and (d).

•

Br-Zn : 3,19 Å

O-Zn : 2,60 Å

O-Zn : 2,54 Å

O-Zn : 2,45 Å

(a)

TSab

(b)

Br-Zn : 3,20 Å

O-Zn : 2,48 Å

C-C : 2,42 Å

O-Zn : 2,36 Å

C-C : 2,44 Å

TSac

TSbd

O-Zn : 2,36 Å

C-Zn : 2,01 and 2,01 Å

C-C : 1,54 Å

Br-Zn : 3,32 Å

O-Zn : 2,44 Å

C-Zn : 2,02 and 2,00 Å

C-C : 1,54 Å

(d)

(c)

O-Zn : 1,84 Å

Br-Zn : 2,67 Å

O-Zn : 1,88 Å

(e)

(f)

Figure 1. Structures of reactants, transition states and reaction intermediates (a)-(f).

It is worth examining the structure of the resulting α-

alkoxycarbonyl radical intermediates (c) and (d). The C-Zn bond

lengths are 2.02 and 2.00 Å, respectively in (c) and 2.01 and 2.01

Å in (d), which means that none of the C-Zn bond can be

considered as substantially pre-cleaved (the C-Zn bond lengths

and 0.08 at bromine atom in (c), and 0.76 at carbon, 0.14 at

oxygen and 0.10 at bromine atom in (d)). The C-Zn bonds do not

evolve significantly while the C-C bond is being formed.

The theoretical approach indicates that only 7.3 kcal per mol

•

are necessary to release Et from intermediate (c), whereas the

are 1.99 Å in Et Zn). In both intermediates most of the spin

2

cleavage of the C-Zn bond necessitates more than twice as much

energy (15.6 kcal per mol) to reach enolate (f) from (d). At 20

density is distributed over the atoms of the α-alkoxycarbonyl

moiety (Mülliken spin density is 0.85 at carbon, 0.14 at oxygen

5

°

C, the homolysis of the C-Zn bond would

A

b

C

e

C

6

E

o

P

rd

T

er

E

s

D

of MA

m

N

ol)

U

,

S

co

C

ns

R

ist

I

e

P

nt with the failure to observe radical polar

T

13

magnitude faster from (c) than from (d). In other words,

calculations confirmed that the cleavage of the C-Zn bond is the

rate determining step; the more stable the zinc enolate, the faster

the overall process.

crossover reactions in this case, suggests that the slowing down

of the C-Zn bond homolysis enables competitive pathways like

telomerization to take place. Eventually the energy necessary to

release ethyl radical from intermediate (i) that would result from

•

the addition of Et to zinc-coordinated methyl acrylate was also

calculated. This experimentally fast reaction, leading to enolate

2

4

(

j) would necessitate only 10.1 kcal per mol (Scheme 3). The

trend observed for (c),(i), (d) and (g) is an additional argument to

discard the contribution of the pathway leading from (d) to (f) to

the global reaction. This theoretical investigation clearly points

out the importance of the stability of the zinc enolate formed in

the formal S 2 at zinc that is the rate-determining step in the

H

Figure 2. NBO view of the bonding interaction between Br

and Zn in enolate (e)

radical chain process. The ability of a given basic substituent to

form a chelated-zinc enolate outweighs its influence on the spin

density at oxygen in the intermediate enoxyl radical.

NBO calculations enables the visualization of the strong

overlap between one σ* C-Zn antibonding orbital and one out of

the three bromine atom lone pairs, which interaction accounts for

At this point, two routes alternative to the radical

fragmentation might be envisaged from (d) (Scheme 4). The first

one is the conversion of (d) into (c) via rotation around the s-

trans pivot. The calculated rotational barrier was determined by

executing a simple scan using the UM06-2X/6-31G(d) level of

theory, once located the transition state was optimized at the

M06-2X/aug-cc-pVTZ//M06- 2X/aug-cc-pVDZ level. This

allowed us to estimate a 8.1 kcal per mol rotational barrier for the

2

2.2 kcal per mol and contributes to the stronger stabilization of

(e) (Figure 2).

Formally the homolysis of the C-Zn bond from (d) is not

unlikely as regard to the global exothermicity of the whole

process. For the sake of comparison, we have calculated the

25

interconversion between (c) and (d). This rotation would cost

much less energy than the direct fragmentation of (d). This result

makes likely the whole reaction proceeding via intermediate (c).

•

energy that would be necessary to release Et from the only stable

rotamer of the α-alkoxycarbonyl radical (g) that would result

from the addition of ethyl radical to zinc coordinated methyl

methacrylate (Scheme 3). This much higher energy (20.2 kcal per

(h)

O-Zn : 1,84 Å

(j)

20,2 kcal per mol

O-Zn : 1,98 Å

C-Zn : 2,03 Å and 1,98 Å

10,1 kcal per mol

(g)

(i)

O-Zn : 2,32 Å

O-Zn : 2,36 Å

C-Zn : 2,027 Å and 2,01 Å

C-Zn : 2,01 Å and 2,01 Å

Scheme 3. Homolysis of C-Zn bond from radicals (g) and (i).

However, as previously suggested, another path could be

envisaged: the intermediate radical (d) might add to another

molecule of chelate (a) to give the dimeric α-alkoxycarbonyl

radical (k) that would immediately be converted into the expected

dimeric enolate in a way similar to the conversion of intermediate

Assuming the preexponential factor for the addition reaction is 4

order of magnitude smaller than the A factor for the β-

27

fragmentation, this means that, the rate constant for this

bimolecular addition would be about 7 orders of magnitude faster

than the fragmentation leading to (f). Thus even at 0.1 M

concentration, this bimolecular process would still be much faster

than the release of ethyl radical. At this point it is not possible to

(

c) into (e). This addition reaction is strongly exothermic (22.1

26

kcal per mol), its activation barrier should be 0.7 kcal per mol.

6

Tetrahedron

ACCEPTED MANUSCRIPT

conclude which ratio of the cyclopropanic product might derive

alkoxycarbonyl radical (k) at 0.2 M initial concentration.

from the conversion of intermediate (d) into the dimeric α-

TScd

(

11.7)

+

(a)

TSdk

(0.7)

(

d)

(

c)

(

0)

(

- 2.6)

(

k)

(

- 22.2)

Scheme 4. Possible evolutions of intermediate (d)

1

) Et

2

Zn

CO

Br

2

Et

O

C

1

EtO

2

R CHO

The outcome of ethyl α-bromoacrylate was also investigated

_R1

13

4

2) NH Cl

using triethylborane as mediator. Other potentially chelating

α,β-unsaturated esters such as alkylidene malonates were shown

to lead to enolates via tandem radical addition/homolytic

substitution that could be mediated either with dialkylzincs or

1

Et 3a

EtO

OZnEt

R¹

O

EtO

Et

2

C

28

1

triethylborane. On the ground of these results one could have

R CHO

expected the formation of cyclopropane 2a to proceed via the

ZnEt

Br

Et

Br

C

F

reaction of Et B with ethyl α-bromoacrylate under aerobic

3

conditions. Only telomeric materials were formed in the crude

reaction mixture, which means that only radical induced

polymerization was propagating under these experimental

conditions.

Scheme 5. Plausible radical induced Darzens “like”

epoxidation.

The theoretical calculations performed by Scaiano and Carra

have clearly demonstrated that coordination of boron to an

oxygen lone pair precedes homolytic substitution at boron in the

In the presence of an aldehyde or a ketone, a Darzens like

reaction leading to epoxides could be expected. The general

mechanism envisaged for this transformation is depicted in

Scheme 5. The enolate C should be trapped by the carbonyl

group to form the zinc alkoxide F. Nucleophilic displacement of

bromide anion would ultimately lead to epoxide 3a. Attempts to

trap intermediate C by 2 equivalents of benzaldehyde led again to

the exclusive formation of cyclopropane 2a. The aldehyde

carbonyl group is less reactive than ethyl α-bromoacrylate

toward the zinc enolate.

29

reaction of triethylborane with alkoxy radicals. The C-B bond is

6d

much stronger than the C-Zn bond, therefore coordination and

favorable stereoelectronic factors that weaken the bond are even

more mandatory for its homolytic cleavage to proceed. From our

theoretical approach we could conclude that due to steric

crowding, coordination of triethylborane to the substrate is too

energetic to proceed. It is plausible that the energy necessary to

cleave the C-B bond by reaction between the α-alkoxycarbonyl

radical and triethylborane is much higher than the activation

barrier for the addition of the same radical to ethyl α-

bromoacrylate which initiates the formation of telomeric

material.

EtO

2

C

Br

OH

n-Pr

2

C

O

CO

Br

2

Et

1) Et

Zn (2 equiv), EtO

-Pr

2 2

CH Cl , r.t., 18 h

2

PhCHO

n

(10 equiv)

1

3a

4

a

Reactivity of ethyl α-bromoacrylate in the presence of

electrophilic carbonyl compounds

2

) NH

4

Cl

7% (1:1)

28% (1:1)

45% (1:1)

-

or, reflux, 4 h, then NH

4

Cl

7

Scheme 6. Addition to ethyl α-bromoacrylat

of benzaldehyde.

A

e i

C

n

C

th

E

e p

P

r

T

es

E

en

D

ce MAth

N

e c

U

ha

S

ra

C

ct

R

eri

I

zation of 6c (entry 4). The addition of c-pentyl

P

T

radical proceeded similarly in the presence of 20 equivalents of

the corresponding iodide (entry 5). Closely related data were

obtained from the experiment conducted in the presence of c-

hexyl iodide (entry 6). When the reaction was conducted in the

presence of 20 equivalents of t-butyl iodide, the β-ketoester 5f

was isolated in 80% yield besides trace amount of 6f (entry 7).

At least 10 equivalents of aldehyde were needed to completely

avoid the formation of 2a (Scheme 6). Under these conditions, 3a

was isolated in only 7% yield, while the bromoalcohol 4a was

formed in 45% yield. Refluxing the mixture for 4 additional

hours slightly increased the yield in epoxide 3a, but these

conditions were detrimental as regard to aldol 4a that was

partially degraded.

Products 5c-f clearly resulted from the initial addition of an

alkyl radical generated via iodine atom transfer to ethyl radical.

Multiple pathways can be envisaged for the formation of β-

keto-esters 5. They are depicted in Scheme 7. The most

straightforward routes would proceed via a radical or a polar

Brook rearrangement step. The addition of an intermediate α-

alkoxycarbonyl radical to the acylsilane followed by radical 1,2-

migration of the TMS group would lead to the silylated enolate

of the final product 5 via the β-fragmentation of the resulting α-

Table 2. Reaction of Et Zn with ethyl α-bromoacrylate in the

2

presence of acylsilanes

CO Et Me

3

Si

R

CO Et

2

R

CO Et

2

1

) i) or ii)

O

+

OH

_R1

34

Br

O

alkoxy radical (Scheme 7, B→G→H→I). Intermolecular

2

) NH Cl

4

R¹

_R1

^Sⁱ^M^e3

1

5

6

(1.1 equiv)

radical addition to acylsilanes has never been reported, and the

alcohols that would result from the addition of the other carbon-

centered radicals present in the reaction medium were not

detected. However, the relay of zinc coordination to the basic

oxygen of the acylsilane would make pseudo unimolecular this

formally bimolecular process. Alternatively, the reaction might

proceed via the intermediate zinc enolate C that could add to the

carbonyl group to give the zinc alkoxide J. Polar Brook

1

Entry

R / R

Condi-

tions

Product (isolated yield%)

H NMR

e

ratio

1

2

3

4

5

Et / Ph

i

5a (92)

Et / Me

i-Pr / Me

5b (80)

a

i

5b (nd)/5c (41)/6c (nd)

5c (45)/6c (11)

5b (23)/5d (48)/6d (nd)

33:56:11

67:33

35

rearrangement would afford I, after elimination of ethylzinc

bromide. As pointed out by a referee, Brook rearrangement is a

reversible process that would be driven forward by a fast

ii

b

c-Pentyl

/

i

43:48:9

35a

Me

subsequent radical or polar elimination step.

c

R

COOEt

6

7

c-Hex / Me

t-Bu / Me

i

5b (13)/5e(25)/6e (15)

36:46:18

OZnEt

d

R¹

i

5f (80)/6f (trace amount)

L

-

BrSiMe

3

2 2 2 2

Experimental conditions: i) Et Zn (2 equiv), CH Cl , r.t., 18 h; ii) i-Pr Zn (2

COOEt

Br

EtO

O

equiv), CH

2

Cl

2

, r.t., 18 h.

R

O

R

Br

a

R¹SiMe

3

Brook

i-PrI (20 equiv),

R¹

SiMe

OZnEt

ZnEt

2

OZnEt

R

Br

3

b

c

e

c-PentylI (20 equiv),

EtO

B

C

J (R = Me, Ph)

1

c-HexylI (20 equiv), [d] t-BuI (20 equiv),

O

determined on the crude reaction mixture.

R

1

SiMe₃

COOEt

Br

COOEt

Br

R

COOEt

Br

The rather poor yield and the large number of equivalents that

COOEt

R

- BrZnEt

Brook

R

- Br

had to be used led us to check the reactivity of other electrophiles

and we started investigating the potential of acylsilanes in this

process. α-Trimethylsilyl ketones were used for this purpose

R¹

SiMe

R¹

_R1

^O^Sⁱ^M^e3

3

^O^Sⁱ^M^e3

O

OSiMe₃

ZnEt

G

H

I

K

(

Table 2). The carbonyl group of acyl silanes exhibits unique

30,31

Scheme 7. Plausible rearrangements leading to enolate I and

L precursors of 5a-f

reactivity and spectroscopic properties.

Due to the electronic

effect of silicon, the C=O bond is more polarized in α-

silylketones than in aldehydes. Acyl silanes have successfully

been used as radical acceptors and as electrophiles in tandem

36

The debromosilylation of J would also lead to 5 via enolate

L, (Scheme 7). β-Silyl carbonyl compounds are well known as

30,31,32

37

processes involving Brook rearrangement.

masked enones. Another route involving the formation of an

38,39

intermediate epoxysilane might be considered.

All our efforts

As shown in Table 2, only 1 equivalent of acylsilane was

needed to completely suppress the competitive formation of

cyclopropane 2a.

to isolate an epoxysilane from our reactions failed, this

hypothesis was discarded.

33

Moreover, neither an epoxide nor a

bromoalcohol was detected in the crude mixture. Instead, β-keto-

esters 5a or 5b were isolated in 92% and 80% yield, respectively

As regard to the formation of small amounts of the reduced

products 6b-f, it is puzzling to note that this type of product

accounts at best for 10% yield when a secondary alkyl radical is

involved in the process. It is negligible in the presence of t-BuI

and not detected when diethylzinc is used alone. The most

plausible route would be the debromination of intermediate J via

(entries 1-2). The high reactivity of acyl silanes afforded an

additional proof that the very first step was indeed a radical and

not a polar addition. In the presence of 20 equivalents of i-PrI,

pure isolated β-ketoester 5c was isolated in 41% yield. In fact,

the crude product is an admixture very difficult to separate which

contains both 5b and 5c together with a small amount of the

debrominated adduct 6c. This explains the rather low yield in

pure isolated product 5c (entry 3). A comparable yield was

•

bromine atom transfer to Et or sec-R that would lead to a zinc

40

enolate as the precursor of 6.

A few additional experiments were carried out in the hope of

determining which out of the main two hypothesized pathways

obtained from i-Pr Zn. This experiment enabled the isolation and

2

8

Tetrahedron

was the most likely. The reactivity of et

A

hy

C

l

C

ac

E

ry

P

lat

T

e

E

was MAth

D

NU

an

10SCeq

R

uivIP

of benzaldehyde, a Darzens like process occurs.

T

investigated under the same experimental conditions. The results

are described in Scheme 8.

Acylsilanes were shown to be electrophilic partners more

reactive than aldehydes. In this case, the radical polar cascade is

likely to end up with a debromosilylation step, which affords β-

keto esters.

1

) Et2Zn (2 equiv),

CO

2

Et Me

3

Si

CO

2

Et

CO

2

Et

O

CH2Cl2, r.t., 18 h

_R1

SiMe

OH

3

OH

2) NH4Cl

R¹

(1.1 equiv)

_R1 = Ph 53% (90:10)

R¹= Me 49% (80:20)

b

4. Experimental Section

6

a

7a not detected

7b not detected

6

Computational details. All the calculations were performed

4

1

Scheme 8. Reaction of ethyl acrylate in the presence of

trimethylsilylketones

using the Gaussian 09 package. The geometry of all species was

optimized at the M06-2X/aug-cc-pVDZ level of theory. Single

point energy calculations were performed at the M06-2X/aug-cc-

pVTZ level of theory to obtain more accurate results. Vibrational

frequencies were calculated at the M06-2X/aug-cc-pVDZ to

insure that the obtained geometries were minima or transition

state structures and to calculate thermodynamics values. The

The reactions conducted on ethyl acrylate led after hydrolysis

to α-silyl alcohols 6a and 6b that were isolated in 53% and 49%

yield, respectively, as a mixture of diastereomers. No trace of

alcohol 7 (or the corresponding trimethylsilylethers) that would

result from Brook rearrangement was detected in the crude

reaction mixture, even when the reaction was performed in THF,

42

NBO calculations were performed at the M06-2X/aug-cc-pVDZ

level of theory. As recommended when calculating heavy atoms,

diffuse and polarized functions were used to take into account

nonbonding interactions with zinc accurately. For (k) and and

TSdk species, the calculations were performed at the M06-2X/6-

311++G(3df,3pd)//M06-2X/6-31G(d) level of theory for the sake

of saving time.

35

a solvent reputedly best suited to Brook rearrangement.

CO

2

Et

CO

2

Et

1

) Et

2

Zn (2 equiv),

, r.t., 18 h

Et

EtO

CO

2

Et Me

3

Si

R₁

O

CH Cl

2

OH

2

C

EtO

2

C

R

1

O

SiMe

3

2) NH

4

Cl

O

R

1

(

1.1 equiv)

8a R1 = Ph 64% (81:19)

R1 = Me 78% (52:48)

9a not detected

9b not detected

8b

CO

2

Et

General.

Et

R

1

EtO

H

2

C

EtZnO

Commercially available solvents were used as purchased. CH Cl

2

SiMe

3

2

(GC grade) was used as solvent, it was stored on molecular

sieves. Analytical thin layer chromatography was performed on

pre-coated silica gel plates. NMR spectra were recorded at 300

Scheme 9. Addition to diethyl fumarate in the presence of

acylsilanes

1

13

MHz and 400 MHz ( H) and 75 MHz and 100 MHz ( C) using

CDCl as the solvent. Chemical shifts (δ) are reported in ppm.

3

Experiments performed with diethylfumarate as the radical

acceptor also confirmed the absence of polar Brook

rearrangement. When diethyl fumarate was used as the substrate

in the presence of diethylzinc and α-trimethylsilyl ketones, the

trisubstituted silylated γ-lactones 8a or 8b were isolated as

mixtures of diastereomers in quite good yields (Scheme 9). Only

two out of the four formally possible diastereomers were formed

in this process. In all likelihood they result from the cyclization

of the zinc alkoxide H. It is to be noted that again, neither the α-

silyl alcohols 9 nor the corresponding silylethers that might be

expected from Brook rearrangement were detected in these

reactions. Even though these experiments do not conclusively

rule out a reversible Brook rearrangement, in the absence of

additional evidence, the hypothesis of a fast bromodesilylation

remains likely.

Signals due to residual protonated solvent or to the deuterated

solvent served as the internal standards to calibrate the spectra

1

13

(

H NMR, CHCl , 7.26 ppm; C NMR, CDCl , 77.16 ppm).

3

Multiplicity is indicated by one or more of the following

descriptors: s (singlet), d (doublet), t (triplet), q (quartet), quint

(quintet), non (nonuplet), m (multiplet), br (broad). The J values

are given in Hz. All melting points are uncorrected; they were

recorded in open capillary tubes using melting points apparatus.

4

3

2

-Bromo-acrylic

acid

ethyl

ester

(1)

and

4

benzoyltrimethylsilane were prepared according to known

procedures. Acetyltrimethylsilane is commercially available and

it was used without additional purification.

1

-Bromo-2-propyl-cyclopropane-1,2-dicarboxylic acid diethyl

ester (2a)

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was added

under argon to a room-temperature solution of 2-bromoacrylic

acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

3

. Conclusions

Ethyl α-bromoacrylate reacts in non-degassed medium with

with saturated NH Cl, the layers separated and the aqueous layer

diethylzinc to give a bromocyclopropane via a radical polar

cascade involving successively: radical addition, formation of a

zinc enolate, subsequent Michael addition to another molecule of

substrate, and eventually nucleophilic ring closure.

4

extracted twice with CH Cl . The combined organic phases were

2

dried over MgSO , filtered and concentrated under vacuum. The

4

residue was purified by column chromatography on silica gel

(

from 0 to 2% EtOAc in pentane) to isolate product 2a as a

1

Theoretical calculations, point out the role of the bromine

atom in accelerating homolytic substitution at zinc due to the

stabilization of the resulting enolate via chelation. This study

clearly establishes that the ability of a given basic substituent to

give rise to a chelated-zinc enolate outweighs the influence of the

spin density at oxygen in the intermediate α-alkoxycarbonyl

radical.

colorless oil (61 mg, 0.20 mmol, 71%). H NMR (400 MHz,

CDCl ) δ: 0.96 (3H, t, J = 7.3), 1.24 (3H, t, J = 7.0), 1.27 (3H, t,

3

J = 7.0), 1.25-1.28 (1H, superimposed m), 1.41-1.48 (2H, m),

1

.62-1.69 (1H, m), 2.12 (1H, ddd, J = 14.0, 10.8 and 4.3), 2.34

(

1H, dd, J = 6.5, 1.0), 4.12 (2H, q, J = 7.3), 4.17 (2H, q, J = 7.2).

1

3

C NMR (100 MHz, CDCl ) δ: 14.0 (CH ), 14.1 (CH ), 14.2

3

(

CH ), 20.4 (CH ), 27.4 (CH ), 36.5 (CH ), 37.5 (C), 38.8 (C),

3 2 2 2

6

1.5 (CH ), 62.6 (CH ), 167.7 (C=O), 169.7 (C=O). HRMS

2 2

+

Neither dimethylzinc nor triethylborane could be used as

alternative reagents in these reactions. In the presence of not less

(ESI): m/z: calcd for [MH ] C H O Br: 307.0539; found:

12 20 4

3

07.0540.

9

Diethyl

2b)

1-bromo-2-isobutylcyclopropane

A

-1,

C

2-d

C

ic

E

ar

P

bo

T

x

E

yla

D

te MA4.

N

16

U

(4

S

H

C

, q

R

,

I

J

P

=

T

7.0), 4.45 (1H, dd, J = 8.6 and 3.3). HRMS

+ +

(

(ESI) : m/z : calcd for [MH ] C H NO Br : 434.0360, found:

14

28

4

2

4

34.0359.

The reaction was performed under each of the following

experimental conditions:

-

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was

added under argon, at 0 °C, to a solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and

tert-butyl iodide (1.4 mL, 11.17 mmol, 20 equiv) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

-

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was

added, under argon, to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and

isopropyl iodide (1.1 mL, 11.17 mmol, 20 equiv) in non-

degassed dichloromethane (2.8 mL). After 18 h, the reaction was

quenched with saturated NH Cl, the layers separated and the

aqueous layer extracted twice with CH Cl . The combined

with saturated NH Cl, the layers separated and the aqueous layer

4

extracted twice with CH Cl . The combined organic phases were

2

4

dried over MgSO , filtered and concentrated under vacuum. The

4

2

residue was purified by column chromatography on silica gel

organic phases were dried over MgSO , filtered and concentrated

4

(

from 0 to 2% EtOAc in pentane) to isolate a fraction of pure 2c

25 mg) and a mixture of 2a and 2c in a 1:1.8 ratio (12 mg) i.e., a

under vacuum. The residue was purified by column

chromatography on silica gel (from 0 to 2% EtOAc in pentane) to

isolate a mixture of 2a and 2b in a 1:2 ratio, as a colorless oil (50

mg; 2a : 0.10 mmol, 19%; 2b : 0.20 mmol, 38%).

total amount of 0.17 mmol of 2c (31%). A trace amount of 2’c

was detected in the crude mixture.

1

2

c H NMR (400 MHz, CDCl ) δ: 0.97 (9H, s), 1.25 (3H, t, J

3

-

Running the same reaction in the presence of 40

=

7.0), 1.27 (3H, t, J = 7.0), 1.38 (1H, d, J = 6.8), 1.53 (1H, d, J =

equivalents of isopropyl iodide (2.2 mL, 22.34 mmol) led to a

mixture of 2a and 2b in a 0.3:1 ratio, as a colorless oil (51 mg;

a : 0.07 mmol, 13%; 2b : 0.25 mmol, 44%).

1

4

4.3), 2.42 (1H, dd, J = 14.3, 1.5), 2.54 (1H, dd, J = 6.8, 1.5),

13

.03-4.21 (4H, AB part of an ABX systems). C NMR (100

3

2

MHz, CDCl ) δ: 14.1 (CH ), 14.2 (CH ), 27.3 (CH ), 30.1 (CH ),

3

2

3

-

Diisopropylzinc (2.8 mL, 1 M in toluene, 5 equiv) was

32.3 (C), 36.2 (C), 38.4 (C), 47.3 (CH

2

), 61.6 (CH

2

), 62.8 (CH

2

),

added under argon to a room temperature solution of 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) in

non-degassed dichloromethane (2.8 mL). After 18 h, the reaction

167.7 (C=O), 170.1 (C=O). HRMS (ESI) : m/z : calcd for

[MNH ] C14H27NO Br : 352.1118, found: 352.1115.

4 4

+ +

Ethyl 3-phenyl-2-propyloxirane-2-carboxylate (3a)

was quenched with saturated NH Cl, the layers separated and the

4

aqueous layer extracted twice with CH Cl . The combined

Diethylzinc (1.12 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution of 2-bromo-acrylic

acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and benzaldehyde

(567 µL, 5.60 mmol, 10 equiv) in non-degassed dichloromethane

(2.8 mL). The mixture was stirred for 18 h at room temperature.

Then the reaction mixture was successively heated during 4 h,

2

organic phases were dried over MgSO , filtered and concentrated

4

under vacuum. The residue was purified by column

chromatography on silica gel (from 0 to 2% EtOAc in pentane) to

isolate 2b as a colorless oil (29 mg, 0.18 mmol, 41%).

1

H NMR (400 MHz, CDCl ) δ: 0.96 (6H, d, J = 6.5), 1.24

3

cooled at room temperature and quenched with saturated NH Cl.

4

(3H, t, J = 7.0), 1.27 (3H, t, J = 7.3), 1.25-1.32 (2H,

The layers were separated and the aqueous layer was extracted

twice with CH Cl . The combined organic phases were dried

superimposed m), 1.72-1.78 (1H, m), 2.33 (1H, ddd, J = 13.8,

2

4

=

.8, 1.3), 2.46 (1H, dd, J = 6.8, 1.5 Hz), 4.12 (2H, q, J = 7.3 Hz),

(

MgSO ), filtered and concentrated in vacuo. After purification

4

.14-4.22 (2H, AB part of an ABX system, J = 10.8, J_A_X= J_B_X

3

AB

13

by flash chromatography on silica gel (pentane/ethyl acetate from

00/0 to 95/5) 3a was isolated as a 55:45 mixture of two

7.3). C NMR (100 MHz, CDCl ) δ: 14.1 (CH ), 14.2 (CH ),

3

1

2

1.9 (CH ), 23.5 (CH ), 27.2 (CH), 27.7 (CH ), 37.1 (C), 38.0

3

2

diastereomers (37 mg, 0.16 mmol). The 28% yield is an estimate

(

C), 43.2 (CH ), 61.5 (CH ), 62.8 (CH ), 167.8 (C=O), 169.6

2 2 2

+ +

as a non-separable impurity was detected in the NMR spectra of

(C=O). HRMS (ESI) : m/z : calcd for [MH ] C H O Br :

1

13

22

4

the isolated product. H NMR (400 MHz, CDCl ) δ: 0.60 (3H, t, J

3

21.0696, found: 321.0693.

=

7.2, M), 0.66 (3H, t, J = 7.1, m), 1.06 (3H, t, J = 7.0, m), 1.07

Diethyl 1-bromo-2-neopentylcyclopropane-1,2-dicarboxylate

2c) and diethyl 2,4-dibromo-2-neopentylpentanedioate (2’c)

(3H, t, J= 7.0), 1.03-1.21 (5H, m), 1.29-1.43 (3H, m), 4.00-4.15

(2H, m, m), 4.12 (2H, q, J = 7.0, M), 4.88 (1H, s), 5.42 (1H, s,

m), 7.05-7.43 (10H, m) (whenever different the signals of the two

diastereomers are identified as M or m for major an minor,

(

The reaction was performed under each of the following

experimental conditions:

13

respectively). C NMR (100 MHz, CDCl ) δ: 13.9 (CH ), 14.0

3

(

CH ), 14.6 (CH ), 15.1 (CH ), 17.9 (CH ), 18.0 (CH ), 32.7

-

Diethylzinc (1.12 mL, 1 M in heptane, 2 equiv) was

3 3 3 2 2

(CH ), 34.0 (CH ), 58.3 (C), 58.6 (C), 61.2 (CH ), 61.3 (CH ),

added under argon to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and

t-BuI (0.67 mL, 5.6 mmol, 10 equiv) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

2

7

1

7.9 (CH), 78.0 (CH), 127.5 (=CH), 127.6 (=CH), 127.7 (=CH),

28.1 (=CH), 128.2 (=CH), 128.3 (=CH), 140.0 (=C), 140.4

(=C), 175.5 (C=O), 175.7 (C=O). HRMS (ESI): m/z: calcd for

+

[

MH ] C H O : 235.1329; found: 235.1328.

with saturated NH Cl. The layers were separated and the aqueous

14 19

3

4

layer was extracted twice with CH Cl . The combined organic

2

-Bromo-2-(hydroxy-phenyl-methyl)-pentanoic acid ethyl

phases were dried (MgSO ), filtered and concentrated in vacuo.

4

ester (4a)

Product 2c was not detected in the crude complex mixture; the

residue was tentatively separated by flash chromatography on

silica gel (pentane/ethyl acetate from 100/0 to 90/10). The

Diethylzinc (1.12 mL, 1 M in heptane, 2 equiv) was added

under argon to a room temperature solution of 2-bromo-acrylic

acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and benzaldehyde

(567  L, 5.60 mmol, 10 equiv) in non-degassed dichloromethane

1

presence of 2’c was evidenced from the H NMR and MS

analyses of an enriched chromatographic fraction.

(

2.8 mL). After 18 h at room temperature, the reaction was

1

2

’c H NMR (400 MHz, CDCl ) characteristic signals for the

3

quenched with saturated NH Cl. The layers were separated and

the aqueous layer was extracted twice with CH Cl . The

combined organic phases were dried (MgSO ), filtered and

concentrated in vacuo. Filtration on a short pad of silica gel using

4

major diastereomer δ: 0.95 (9H, s), 1.23 (3H, t, J = 7.0), 1.28

3H, t, J = 7.0), 2.17 (1H, d, J = 14.8), 2.34 (1H, d, J = 14.8),

.88 (1H, dd, J = 15.1 and 3.3), 3.02 (1H, dd, J = 15.1 and 8.6),

2

(

2

4

1

0

Tetrahedron

edEDby MAN

first pentane/ethyl acetate in a 98/2 ra

A

tioCCfo

E

llo

P

w

T

E

U

thy

S

l

C

2

R

-a

I

cetyl-4-methylpentanoate (5c) and ethyl 2-(1-

P

T

pentane/ethyl acetate 40/60 as the eluent afforded two fractions.

The first one contained non-reacted benzaldehyde. In the second

fraction, bromoalcool 4a was detected together with 3a. After

separation by flash chromatography on silica gel (pentane/ethyl

acetate from 100/0 to 95/5), 4a was isolated as two diastereomers

hydroxy-1-(trimethylsilyl)ethyl)-4-methylpentanoate (6c)

These products were isolated from reactions performed under

each of the following experimental conditions:

-

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was

in 23% and 22% yields, respectively (79 mg, 0.25 mmol, 45%

overall yield). Diasteroisomer 1: H NMR (400 MHz, CDCl ) δ:

added under argon to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv),

isopropyl iodide (1.1 mL, 11.17 mmol, 20 equiv) and

acyltrimethylsilane (0.1 mL, 0.67 mmol, 1.2 eq) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

1

3

0

1

.89 (3H, t, J = 7.5), 1.31 (3H, t, J = 7.0), 1.28-1.43 (1H, m),

.48-1.63 (1H, m), 1.80 (1H, ddd, J = 14.1, 12.1 and 4.3), 1.96

(1H, ddd, J = 14.1, 11.5 and 4.3), 2.80-3.40 (1H, br s), 4.27 (2H,

q, J = 7.0), 5.10 (1H, s), 7.30-7.38 (3H, m), 7.39-7.46 (2H, m).

with saturated NH Cl, the layers separated and the aqueous layer

extracted twice with CH Cl . The combined organic phases were

4

13

C NMR (100 MHz, CDCl ) δ: 14.1 (CH ), 14.2 (CH ), 19.7

3

2

(

CH ), 39.7 (CH ), 62.8 (CH ), 76.0 (C), 78.0 (CH), 128.0

dried over MgSO , filtered and concentrated under vacuum.

From the H NMR analysis of the crude reaction mixture, a

2

4

1

(=CH), 128.3 (=CH), 128.7 (=CH), 138.0 (=C), 170.5 (C=O).

1

Diasteroisomer 2: H NMR (400 MHz, CDCl ) δ: 0.92 (3H, t, J =

0.6:1:0.2 ratio was measured for 5b:5c:6c. Purification by flash

chromatography on silica gel (from 0 to 2% EtOAc in pentane),

allowed the isolation of pure 5c as a colorless oil (43 mg, 0.23

mmol, 41%). The presence of 6c was ascertained from the next

experiment from which this product was isolated and fully

characterized.

3

7

1

3

.5), 1.24 (3H, t, J = 7.0), 1.44-1.67 (2H, m), 2.03 (1H, ddd, J =

4.3, 11.8 and 4.8), 2.14 (1H, ddd, J = 14.6, 11.3 and 5.0), 3.00-

.40 (1H, br s), 4.15-4.23 (2H, AB part of an ABX ), 5.08 (1H,

3

13

s), 7.30-7.35 (3H, m), 7.37-7.38 (2H, m). C NMR (100 MHz,

CDCl ) δ: 14.0 (CH ), 14.2 (CH ), 20.0 (CH ), 40.4 (CH ), 62.6

3

2

(

[

CH ), 74.2 (C), 79.2 (CH), 128.0 (=CH), 128.1 (=CH), 128.6

=CH), 138.0 (=C), 173.7 (C=O). HRMS (ESI): m/z: calcd for

2

-

Diisopropylzinc (1.12 mL, 1 M in toluene, 2 equiv) was

+

added under argon to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv) and

acyltrimethylsilane (0.1 mL, 0.67 mmol, 1.2 eq) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

MNH ] C H BrNO : 332.0856; found: 332.0858.

4

14 23

3

Ethyl 2-benzoylpentanoate (5a)

Diethylzinc (0.56 mL, 1 M in heptane, 2 equiv) was added

with saturated NH Cl, the layers separated and the aqueous layer

4

under argon to a room-temperature solution of 2-bromo-acrylic

acid ethyl ester (50 mg, 0.279 mmol, equiv) and

benzoyltrimethylsilane (55 mg, 0.307 mmol, 1.1 equiv) in non-

degassed dichloromethane (1.4 mL). After 18 h at room

temperature, the reaction was quenched with saturated NH Cl.

The layers were separated and the aqueous layer was extracted

twice with CH Cl . The combined organic phases were dried

extracted twice with CH Cl . The combined organic phases were

2

1

dried over MgSO , filtered and concentrated under vacuum.

4

1

From the H NMR analysis of the crude reaction mixture, a 1:0.5

ratio was determined for 5c:6c. Purification by flash

chromatography on silica gel (from 0 to 2% EtOAc in pentane)

allowed to isolate pure 5c (47 mg, 0.25 mmol, 45%) and 6c (16

mg, 0.06 mmol, 11%) as colorless oils.

4

2

(MgSO ), filtered and concentrated in vacuo. After purification

4

1

by flash chromatography on silica gel (pentane/ethyl acetate from

00/0 to 98/2) 5a was isolated as a colorless oil (60 mg, 0.26

5c : H NMR (400 MHz, CDCl ) δ: 0.90 (3H, d, J = 6.5), 0.91

3

1

(3H, d, J = 6.5), 1.27 (3H, t, J = 7.3), 1.53 (1H, non, J = 7.0),

1.67 (1H, ddd, J = 13.8, 7.5, 6.5), 1.79 (1H, ddd, J = 13.8, 8.3,

6.5), 2.22 (3H, s), 3.49 (1H, dd, J = 8.3, 6.5), 4.19 (2H, q, J =

1

mmol, 92%). H NMR (400 MHz, CDCl ) δ: 0.94 (3H, t, J =

3

7

4

7

.3), 1.16 (3H, t, J = 7.3), 1.33-1.44 (2H, m), 1.91-2.06 (2H, m),

13

.14 (2H, AB part of a ABX pattern), 4.30 (1H, t, J = 7.3), 7.43-

7.0). C NMR (100 MHz, CDCl ) δ: 14.2 (CH ), 22.3 (CH ),

3

3 3 3

13

.51 (2H, m), 7.55-7.61 (1H, m), 7.96-8.01 (2H, m). C NMR

22.6 (CH ), 26.4 (CH), 28.7 (CH ), 37.1 (CH ), 58.4 (CH), 61.4

3 3 2

(

100 MHz, CDCl ) δ: 14.0 (CH ), 14.1 (CH ), 21.0 (CH ), 31.1

(CH ), 170.2 (C=O), 203.6 (C=O). HRMS (ESI) : m/z : calcd for

2

+ +

3

2

(CH ), 54.3 (CH), 61.4 (CH ), 128.7 (2x=CH), 128.8 (2x=CH),

[MH ] C H O : 187.1329, found: 187.1327.

10 19 3

2

1

33.5 (=CH), 136.5 (=C) 170.2 (C=O), 195.4 (C=O). HRMS

+

1

6c : H NMR (400 MHz, CDCl ) δ: 0.06 (9H, s), 0.90 (3H, d,

3

(ESI): m/z: calcd for [MH ] C H O : 235.1329; found:

14 19 3

J = 6.5), 0.91 (3H, d, J = 6.8), 1.19 (3H, s), 1.28 (3H, t, J = 7.3),

2

35.1330.

1

.24-1.30 (1H, superimposed m), 1.39-1.47 (1H, m), 1.72 (1H,

45

Ethyl 2-acetylpentanoate (5b)

ddd, J = 13.6, 12.0, 4.0), 2.38 (1H, s), 2.62 (1H, dd, J = 11.8,

3

=

.0), 4.11-4.22 (2H, AB part of an ABX system, J = 10.8, J_A_X

3 AB

13

Diethylzinc (1.12 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution of 2-bromo-acrylic

acid ethyl ester (100 mg, 0.56 mmol, equiv) and

acetyltrimethylsilane (89 µL, 0.62 mmol, 1.1 equiv) in non-

degassed dichloromethane (2.8 mL). After 18 h at room

J_B_X= 7.0). C NMR (100 MHz, CDCl ) δ: -3.0 (CH ), 14.2

3 3

(CH ), 20.8 (CH ), 21.6 (CH ), 24.0 (CH ), 26.8 (CH), 36.0

3 3 3 3

1

(

CH ), 50.2 (CH), 60.5 (CH ), 66.9 (C), 175.8 (C=O). HRMS

2 2

+ +

(ESI) : m/z : calcd for [MNa ] C H O SiNa : 283.1700, found:

13 28 3

2

83.1697.

temperature, the reaction was quenched with saturated NH Cl.

4

The layers were separated and the aqueous layer was extracted

twice with CH Cl . The combined organic phases were dried

Ethyl 2-(cyclopentylmethyl)-3-oxobutanoate (5d)

2

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was added

(

MgSO ), filtered and concentrated in vacuo. After purification

4

under argon to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv),

cyclopentyl iodide (1.3 mL, 11.17 mmol, 20 equiv) and

acyltrimethylsilane (0.1 mL, 0.67 mmol, 1.2 eq) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

by flash chromatography on silica gel (pentane/ethyl acetate from

00/0 to 95/5) 5b was isolated as a colorless oil (77 mg, 0.45

1

mmol, 80%). H NMR (400 MHz, CDCl ) δ: 0.92 (3H, t, J =

3

7

2

.5), 1.27 (3H, t, J = 7.3), 1.21-1.37 (2H, m), 1.74-1.90 (2H, m),

.22 (3H, s), 3.41 (1H, t, J = 7.5), 4.19 (2H, q, J = 7.3). C NMR

13

with saturated NH Cl, the layers separated and the aqueous layer

4

(

100 MHz, CDCl ) δ: 13.9 (CH ), 14.2 (CH ), 20.8 (CH ), 28.8

3 3 3 2

extracted twice with CH Cl . The combined organic phases were

2

CH ), 30.4 (CH ), 59.9 (CH), 61.4 (CH ), 170.1 (C=O), 203.5

3

2

dried over MgSO , filtered and concentrated under vacuum.

4

C=O).

1

From the H NMR analysis of the crude reaction mixture, a

1

0

.9:1:0.2 ratio was determined for 5b:5d:6d. Pu

A

rif

C

ic

C

ati

E

on

P

b

T

y

E

fla

D

sh MAph

N

as

U

es

S

w

C

er

R

e

I

dried (MgSO ), filtered and concentrated in

4

P

T

chromatography on silica gel (from 0 to 2% EtOAc in pentane)

allowed the isolation of 59 mg of a 5b:5d mixture (0.3:1 ratio)

and 20 mg of the same products in a 1.3:1 ratio as colorless oils

vacuo. After purification by flash chromatography on silica gel

(pentane/ethyl acetate from 100/0 to 95/5) 5f was isolated as a

colorless oil (90 mg, 0.45 mmol, 80%). 5f : H NMR (400 MHz,

1

(5b, 0.13 mmol, 23%; 5d, 0.23 mmol, 48%).

CDCl ) δ: 0.88 (9H, s), 1.27 (3H, t, J = 7.3), 1.78 (1H, dd, J =

3

1

14.3 and 4.5), 1.91 (1H, dd, J = 14.3 and 7.5), 2.23 (3H, s), 3.47

5

d : H NMR (400 MHz, CDCl ) δ: 1.05-1.12 (2H, m), 1.27

13

3

(1H, dd, J = 7.5 and 4.5), 4.18 (2H, q, J = 7.3). C NMR (100

(

3H, t, J = 7.0), 1.20-1.45 (2H, superimposed m),1.49-1.52 (2H,

m), 1.55-1.68 (2H, m),1.70-1.95 (3H, m), 2.22 (3H, s), 3.45 (1H,

dd, J = 8.0, 6.8), 4.19 (2H, q, J = 7.3). C NMR (100 MHz,

CDCl ) δ: 14.2 (CH ), 25.1 (CH ), 25.2 (CH ), 28.8 (CH ), 32.5

CH ), 32.6 (CH ), 34.4 (CH ), 38.2 (CH), 59.5 (CH), 61.4 (CH ),

MHz, CDCl ) δ: 14.1 (CH ), 28.6 (CH ), 29.3 (3xCH ), 30.7 (C),

3

13

41.1 (CH

), 57.0 (CH), 61.5 (CH ), 170.8 (C=O), 203.4 (C=O).

2 2

+

HRMS (ESI): m/z: calcd for [MH ] C H O : 201.1485; found:

11

21

3

2

3

1

2

01.1486. The presence of 6f was evidenced from the H NMR

(

1

2

+

and MS analyses of an enriched chromatographic fraction. 6f : H

NMR (400 MHz, CDCl ) δ: characteristic signals δ: 0.08 (9H, s),

.88 (9H, s), 1.21 (3H, s), 1.28 (3H, t, J = 7.3), 1.40 (1H, dd, J =

14.3 and 1.3), 1.71 (1H, dd, J = 14.3 and 10.8), 1.81 (1H, s), 2.62

(1H, dd, J = 10.8 and 1.3), 4.08-4.23 (2H, AB part of an ABX

system, JAB = 10.8, JAX = JBX = 7.3). HRMS (ESI): m/z: calcd for

70.2 (C=O), 203.6 (C=O). HRMS (ESI) : m/z : calcd for [MH ]

+

3

C H O : 213.1485, found: 213.1485.

1

2

21

3

0

The presence of 6d in the crude reaction mixture was deduced

from from the presence of a characteristic dd, J = 12.0, and 3.0,

at 2.58 ppm.

3

+

[

MH ] C H O Si : 275.2037; found: 275.2038.

14 31 3

Ethyl 2-(cyclohexylmethyl)-3-oxobutanoate (5e) and ethyl 2-

(

cyclohexylmethyl)-3-hydroxy-3-(trimethylsilyl)butanoate (6e)

Ethyl 2-(1-hydroxy(phenyl)(trimethylsilyl) methyl) pentanoate

6a)

(

Diethylzinc (1.12 mL, 1 M in hexanes, 2 equiv) was added

under argon to a room-temperature solution containing 2-

bromoacrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv),

cyclohexyl iodide (1.45 mL, 11.17 mmol, 20 equiv) and

acyltrimethylsilane (0.1 mL, 0.67 mmol, 1.2 eq) in non-degassed

dichloromethane (2.8 mL). After 18 h, the reaction was quenched

Diethylzinc (0.9 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution containing acrylic

acid ethyl ester (50 µL, 0.45 mmol, equiv) and

benzoyltrimethylsilane (1.1 equiv, 90 mg, 1.1 mmol) in non-

degassed dichloromethane (2.3 mL). After 18 h at room

1

with saturated NH Cl, the layers separated and the aqueous layer

temperature, the reaction was quenched with saturated NH

The layers were separated and the aqueous layer was extracted

twice with CH Cl . The combined organic phases were dried

(MgSO ), filtered and concentrated in vacuo. After purification

by flash chromatography on silica gel (pentane/ethyl acetate from

100/0 to 98/2) 6a was isolated as a mixture of two diastereomers

4

Cl.

4

extracted twice with CH Cl . The combined organic phases were

2

dried over MgSO , filtered and concentrated under vacuum.

2

4

1

From the H NMR analysis of the crude reaction mixture, a

4

0

.8:1:0.4 ratio was determined for 5b:5e:6e. Purification by flash

chromatography on silica gel (from 0 to 2% EtOAc in pentane)

allowed the separation of 44 mg of a mixture containing 5b:5e in

a 0.5:1 ratio i.e., 5b (0.07 mmol, 13%) and 5e (0.14 mmol, 25%)

and 26 mg of 6e (0.08 mmol, 15%), as colorless oils.

in a 90:10 ratio (74 mg, 0.24 mmol, 53%). Major diastereomer:

1

H NMR (400 MHz, CDCl ) δ: -0.10 (9H, s   0.77 (3H, t, J =

3

7.3), 1.02-1.23 (3H, m), 1.35 (3H, t, J = 7.3), 1.64-1.80 (1H, m),

.04 (1H, dd, J = 11.8 and 3.3), 3.65 (1H, s), 4.15-4.35 (2H, AB

3

1

5

e : H NMR (400 MHz, CDCl ) δ: 0.86-0.95 (2H, m), 1.14-

3

13

3

part of a ABX pattern, J = 7.0), 7.10-7.35 (5H, m). C NMR

3

1

.18 (4H, m), 1.27 (3H, t, J = 7.0), 1.24-1.29 (1H, superimposed

(

100 MHz, CDCl ) δ: -3.0 (3xCH   13.9 (CH ), 14.3 (CH ),

3 3 3 3

m), 1.65-1.72 (5H, m), 1.75-1.82 (1H, m), 2.22 (3H, s), 3.52 (1H,

2

0.8 (CH ), 28.8 (CH ), 50.6 (CH), 61.0 (CH ), 72.7 (C), 124.5

2 2 2

13

dd, J = 8.0, 6.8), 4.19 (2H, q, J = 7.3). C NMR (100 MHz,

CDCl ) δ: 14.2 (CH ), 26.2 (CH ), 26.3 (CH ), 26.5 (CH ), 28.7

(

2=CH), 125.3 (=CH), 128.1 (2=CH), 144.1 (=C), 177.2 (C=O).

1

3

2

Minor diastereomer: H NMR (400 MHz, CDCl ) δ: -0.02 (9H,

3

(

CH ), 33.0 (CH ), 33.3 (CH ), 35.7 (CH ), 35.8 (CH), 57.7 (CH),

3 2 2 2

s   0.81 (3H, t, J = 7.3), 0.99 (3H, t, J = 7.3), 1.02-1.23 (3H,

6

1.4 (CH ), 170.3 (C=O), 203.7 (C=O). HRMS (ESI) : m/z :

2

+ +

m), 2.00-2.13 (1H, m), 3.19 (1H, dd, J = 11.8 and 3.8), 3.67 (1H,

calcd for [MH ] C H O : 227.1642, found: 227.1641.

3

13

23

3

s), 4.15-4.35 (2H, AB part of a ABX pattern, J = 7.0), 7.10-7.35

3

13

1

(

5H, m). C NMR (100 MHz, CDCl ) δ: -2.2 (3xCH   13.9

6

e : H NMR (400 MHz, CDCl ) δ: 0.06 (9H, s), 0.74-0.83

3

CH ), 14.2 (CH ), 21.4 (CH ), 31.4 (CH ), 52.2 (CH), 60.1

CH ), 70.5 (C), 124.6 (2x=CH), 125.6 (=CH), 127.9 (2x=CH),

47.7 (=C), 180.7 (C=O). HRMS (ESI): m/z: calcd for [MNa ]

(1H, m), 0.88-0.97 (2H, m), 1.12 (3H, s), 1.08-1.19 (3H,

3

2

superimposed m), 1.23 (3H, t, J = 7.3), 1.25-1.30 (2H,

superimposed m), 1.63-1.70 (4H, m), 1.84-1.88 (1H, m), 2.42

2

+

1

C H NaO Si: 331.1700; found: 331.1700.

(

1H, s), 2.66 (1H, dd, J = 12.0, 3.3), 4.08-4.27 (2H, AB part of an

17 28

3

13

ABX system, J = 10.8, J_A_X= J_B_X=7.0). C NMR (100 MHz,

3

AB

Ethyl 2-(1-hydroxy-1-(trimethylsilyl) ethyl) pentanoate (6b)

CDCl ) δ: -3.0 (CH ), 14.4 (CH ), 20.8 (CH ), 26.3 (CH ), 26.5

3

2

(

CH ), 26.7 (CH ), 32.5 (CH ), 34.5 (CH ), 34.6 (CH ), 36.4

Diethylzinc (1.92 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution containing ethyl

acrylate (100 mg, 0.998 mmol, 1 equiv) and acetyltrimethylsilane

(1.1 equiv, 157 µL, 1.1 mmol) in non-degassed dichloromethane

2

(

CH), 49.5 (CH), 60.5 (CH ), 66.9 (C), 175.8 (C=O). HRMS

2

+ +

(ESI) : m/z : calcd for [MNa ] C H O SiNa : 323.2013, found:

16 32 3

3

23.2013.

Ethyl 2-acetyl-4.4-dimethylpentanoate (5f) and ethyl 2-(1-

(5 mL). After 18 h at room temperature, the reaction was

quenched with saturated NH Cl. The layers were separated and

4

hydroxy-1-(trimethylsilyl)ethyl)-4,4-dimethylpentanoate (6f)

the aqueous layer was extracted twice with CH Cl . The

2

combined organic phases were dried (MgSO ), filtered and

Diethylzinc (1.12 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution containing 2-bromo-

acrylic acid ethyl ester (100 mg, 0.56 mmol, 1 equiv), t-BuI (0.67

mL, 5.6 mmol, 10 equiv) and acetyltrimethylsilane (1.1 equiv, 89

µL, 0.62 mmol) in non-degassed dichloromethane (2.8 mL).

After 18 h at room temperature, the reaction was quenched with

4

concentrated in vacuo. After purification by flash

chromatography on silica gel (pentane/ethyl acetate from 100/0

to 90/0) 6b was isolated as a mixture of two diastereomers in

3

9% (96 mg, 0.39 mmol) and 10% (24 mg, 0.10 mmol) yields,

1

respectively (80:20 ratio). Major diastereomer: H NMR (400

MHz, CDCl ) δ: 0.05 (9H, s   0.92 (3H, t, J = 7.5), 1.19 (3H,

saturated NH Cl. The layers were separated and the aqueous

3

4

s), 1.22-1.37 (2H, m), 1.28 (3H, superimposed t, J = 7.3), 1.46

layer was extracted twice with CH Cl . The combined organic

2

1

2

Tetrahedron

1

3

(

1H, dddd, J = 13.3, 9.8, 6.3 and 3.3), 1.7

A

1

C

(1

C

H,

E

d

P

dd

T

d,

E

J

D

=

MA

=

NU

7.0

),

S

4.

C

23

R

-4

I

.2

P

7

T

(2H, AB part of ABX ), 7.20-7.41 (5H, m). C

3

1

3.3, 11.5, 9.8 and 4.8), 2.28 (1H, br s), 2.52 (1H, dd, J = 11.8

NMR (100 MHz, CDCl ) δ: -2.9 (3xCH   11.5 (CH ), 14.4

3

13

and 3.3), 4.19 (2H, AB part of ABX₃). C NMR (100 MHz,

(CH ), 19.0 (CH ), 42.8 (CH), 54.7 (CH), 60.6 (CH ), 83.1 (C),

3 2 2

CDCl ) δ: -3.1   xCH  14.2 (CH ), 14.4 (CH ), 21.0 (CH ),

127.0 (4x=CH), 128.7 (=CH), 142.4 (=C), 172.2 (C=O), 175.0

3

+

2

1.3 (CH ), 29.0 (CH ), 51.9 (CH), 60.5 (CH ), 66.7 (C), 175.9

(C=O). HRMS (ESI): m/z: calcd for [MNH ] C H NO Si:

2

4

18 30

4

1

(

C=O). Minor diastereomer: H NMR (400 MHz, CDCl ) δ: 0.09

352.1939; found: 352.1939.

3

(

9H, s   0.92 (3H, t, J = 7.3), 1.19 (3H, s), 1.20-1.37 (2H, m),

Ethyl 4-ethyl-2-methyl-5-oxo-2-(trimethylsilyl)oxolane-3-

carboxylate (8b)

1

2

.29 (3H, superimposed t, J = 7.3), 1.54 (1H, dddd, J = 13.3,

0.3, 6.8 and 3.5), 1.85 (1H, dddd, J = 13.6, 12.1, 9.5 and 5.0),

13

.48 (1H, dd, J = 11.8 and 3.5), 4.17 (2H, AB part of ABX₃).

C

Diethylzinc (1.21 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution containing diethyl

fumarate (100 mg, 0.61 mmol, 1 equiv) and acetyltrimethylsilane

(96 µL, 0.67 mmol, 1.1 equiv) in non-degassed dichloromethane

(3 mL). After 18 h at room temperature, the reaction was

NMR (100 MHz, CDCl ) δ: -2.5  3xCH  14.2 (CH ), 14.5

3

(

[

CH ), 21.4 (CH ), 24.6 (CH ), 30.8 (CH ), 53.4 (CH), 60.3

CH ), 67.0 (C), 176.1 (C=O). HRMS (ESI): m/z: calcd for

3 2 3 2

2

+

MNa ] C H NaO Si: 269.1543; found: 269.1545.

12

26

3

quenched with saturated NH Cl. The layers were separated and

4

Ethyl

carboxylate (8a)

4-ethyl-5-oxo-2-phenyl-2-(trimethylsilyl)oxolane-3-

the aqueous layer was extracted twice with CH Cl . The

2

combined organic phases were dried (MgSO ), filtered and

4

Diethylzinc (0.62 mL, 1 M in heptane, 2 equiv) was added

under argon to a room-temperature solution containing diethyl

fumarate (50 µL, 0.31 mmol, 1 equiv) and benzoyltrimethylsilane

concentrated in vacuo. After purification by flash

chromatography on silica gel (pentane/ethyl acetate from 100/0

to 90/10) 8b was isolated as a mixture of two diastereomers in a

1

(60 mg, 0.34 mmol, 1.1 equiv) in non-degassed dichloromethane

1.7 mL). After 18 h at room temperature, the reaction was

52:48 ratio (130 mg, 0.48 mmol, 78%). Major diastereomer: H

(

NMR (400 MHz, CDCl ) δ:        H, s   0.98 (3H, t, J

3

quenched with saturated NH Cl. The layers were separated and

= 7.5), 1.28 (3H, t, J = 7.5), 1.39 (3H, s), 1.55-1.68 (1H, m),

1.88-2.02 (1H, m), 2.70 (1H, dt, J = 5.5 and 8.8), 3.31 (1H, d, J =

4

the aqueous layer was extracted twice with CH Cl . The

2

13

combined organic phases were dried (MgSO ), filtered and

8.5), 4.20 (2H, q, J = 7.3). C NMR (100 MHz, CDCl ) δ: -

4

3

concentrated in vacuo. After purification by flash

chromatography on silica gel (pentane/ethyl acetate from 100/0

to 90/10) 8a was isolated as mixture of two diastereomers in a

3.3  3xCH   12.7 (CH ), 14.4 (CH ), 19.8 (CH ), 20.1

3

(CH ), 46.3 (CH), 50.5 (CH), 60.8 (CH ), 78.6 (C), 170.0 (C=O),

2

1

176.8 (C=O). Minor diastereomer: H NMR (400 MHz, CDCl )

3

8

1:19 ratio (66 mg, 0.20 mmol, 64%). A pure sample of the

δ: 0.12   H, s   1.00 (3H, t, J = 7.5), 1.27 (3H, t, J = 7.5),

1.42 (3H, s), 1.55-1.68 (1H, m), 1.88-2.02 (1H, m), 2.90 (1H,

ddd, J = 9.3, 7.8 and 5.5), 3.06 (1H, d, J= 7.5), 4.10-4.20 (2H,

major one could be separated from the chromatographic

fractions. Major diastereomer: H NMR (400 MHz, CDCl ) δ:

0

1

3

13

.06 (9H, s   0.73 (3H, t, J = 7.5), 1.07 (3H, t, J = 7.5), 1.42

m). C NMR (100 MHz, CDCl ) δ: -2.9  3xCH   12.7

3

(1H, ddq, J = 14.3, 9.5 and 7.5), 1.98 (1H, ddq, J = 14.3, 5.3 and

(CH ), 14.3 (CH ), 19.3 (CH ), 23.7 (CH ), 43.0 (CH), 52.9 (CH),

3 3 2 3

7

3

.5), 2.87 (1H, ddd, J = 9.3, 8.3 and 5.0), 3.65 (2H, q, J = 7.3),

.84 (1H, d, J = 8.3), 7.10-7.32 (5H, m). C NMR (100 MHz,

61.0 (CH ), 78.1 (C), 170.0 (C=O), 178.1 (C=O). HRMS (ESI):

2

13

+

m/z: calcd for [MH ] C H O Si: 273.1517; found: 273.1517.

13

25

4

CDCl ) δ: -2.9 (3xCH   12.7 (CH ), 13.5 (CH ), 20.4 (CH ),

3

2

4

1

6.7 (CH), 52.5 (CH), 60.6 (CH ), 84.3 (C), 126.4 (4x=CH),

Acknowledgments

2

28.1 (=CH), 140.7 (=C), 169.8 (C=O), 176.1 (C=O). Minor

1

diastereomer: H NMR (400 MHz, CDCl ) δ: -0.06 (9H,

The ANR is gratefully acknowledged for funding.

3

s   0.88 (3H, t, J = 7.5), 1.34 (3H, t, J = 7.5), 1.48 (1H, ddq, J

=

14.3, 9.3 and 7.3), 1.86 (1H, ddq, J = 15.3, 5.8 and 7.5), 2.33

(1H, ddd, J = 9.5, 7.0 and 5.8), 2.70-2.82 (1H, m), 3.59 (1H, d, J

References and notes

I. J. Am. Chem. Soc. 2003, 125, 12698–12699. (c) Lewinski, J.;

Sliwinski, W.; Dranka, M.; Justyniak, I.; Lipkowski, J. Angew. Chem.,

Int. Ed. 2006, 45, 4826–4829. (d) Lewinski, J.; Suwala, K.; Kubisiak,

M.; Ochal, Z.; Justyniak, I.; Lipkowski, J. Angew. Chem., Int. Ed.

1

.

For reviews and representative examples, see: (a) Bazin, S.; Feray, L.;

Bertrand, M. P. Chimia 2006, 60, 260–265. (b) Akindele, T.; Yamada,

K.-I.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345–355. (c) Yamada,

K.-I.; Nakano, M.; Maekawa, M.; Akindele, T.; Tomioka, K. Org. Lett.

2

008, 47, 7888–7789. (e) Lewinski, J.; Suwala, K.; Kaczorowski, T.;

Galezowski, M.; Gryko, D. T.; Justyniak, I.; Lipkowski, J. Chem.

Commun. 2009, 215–217. (f) Lewinski, J.; Koscielski, M.; Suwala, K.;

Justyniak, I. Angew. Chem., Int. Ed. 2009, 48, 7017–7020. (g)

Makoski, L.; Zelga, K.; Petrus, R.; Kubicki, D.; Zarzycki, P.; Sobota,

P.; Lewinski, J. Chem.―Eur. J. 2014, 20, 14790-14799. (h) Kubisiak,

M.; Zelga, K.; Bury, W.; Justyniak, I.; Budny-Godlewski, K.; Ochal,

Z.; Lewinski, J. Chem. Sci. 2015, 6, 3102-3108.

2

008, 10, 3805-3808. (d) Yamada, K.-I.; Umeki, H.; Maekawa, M.;

Yamamoto, Y.; Akindele, T.; Nakano, M.; Tomioka, K. Tetrahedron

008, 64, 7258-7265. (e) Yamada, K.-I.; Maekawa, M.; Akindele, T.;

Yamamoto, Y.; Nakano, M.; Tomioka, K. Tetrahedron 2009, 65, 903-

08. (f) Cohen, T.; Gibney, H.; Ivanov, R.; Yeh, E. A.-H.; Marek, I.;

2

9

Curran, D. P. J. Am. Chem. Soc. 2007, 129, 15405-15409. (g) Huang,

W.; Ye, J.-L.; Zheng, W.; Dong, H.-Q.; Wei, B.-G. J. Org. Chem.

4

.

(a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998,

2

013, 78, 11229-11237.

(a) Denes, F.; Cutri, S.; Pérez-Luna, A.; Chemla, F. Chem.―Eur. J.

006, 12, 6506-6513. (b) Giboulot, S.; Pérez-Luna, A.; Botuha, C.;

7

80-782. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P.

2

.

Synlett 1999, 1148-1150. (c) Bertrand, M. P.; Feray, L.; Nouguier, R.;

Perfetti, P. J. Org. Chem. 1999, 64, 9189-9193. (d) Bertrand, M. P.;

Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P. Tetrahedron 2000, 56,

2

Ferreira, F.; Chemla, F. Tetrahedron Lett. 2008, 49, 3963-3966. (c)

Pérez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. Chem.―Eur. J.

3

2

951-3961. (e) Bertrand, M. P.; Feray, L.; Gastaldi, S. C. R. Chimie

002, 5, 623-638. (f) Cougnon, F.; Feray, L.; Bazin, S.; Bertrand, M.

2

008, 14, 8784-8788. (d) Chemla, F.; Dulong, F.; Ferreira, F.; Nüllen,

M. P.; Pérez-Luna A. Synthesis 2011, 1347-1360.

P. Tetrahedron 2007, 63, 11959-11964.

3

For mechanistic investigations of the reaction of alkylzincs with

dioxygen, see : (a) Maury, J.; Feray, L.; Bazin, S.; Clement, J.-L.;

Marque, S. R. A.; Siri, D.; Bertrand, M. P. Chem.―Eur. J. 2011, 17,

5.

For closely related studies, see: (a) Miyabe, H.; Nishimura, A.;

Fujishima, Y.; Naito, T. Tetrahedron 2003, 59, 1901-1907. (b) Miyabe,

H.; Konishi, C.; Naito, T. Org. Lett. 2000, 2, 1443-1445. (c) Miyabe,

H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T. Tetrahedron

1

586-1595. (b) Lewinski, J.; Marciniac, W.; Lipkowski, J.; Justyniak,

1

3

ACCEPTED MANUSCRIPT

2

000, 56, 2413-2420. (d) Miyabe, H.; Ushiro, C.; Ueda, M.;

24.

It is worth highlighting that the structure of (j) is that of a C-enolate,

whereas (e), (f) and (h) are O-enolates. For structural data on solid

state zinc-enolate see: Hlavinka, M. L.; Hagadorn, J. R.

Organometallics 2006, 25, 3501-3507.

Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176-185.

(a) Bazin, S.; Feray, L.; Vanthuyne, N.; Bertrand, M. P. Tetrahedron

005, 61, 4261-4274. (b) Bazin, S.; Feray, L.; Vanthuyne, N.; Siri, D.;

6.

2

Bertrand, M. P. Tetrahedron 2007, 63, 77-85. (c) Maury, J.; Feray, L.;

Perfetti, P.; Bertrand, M. P. Org. Lett. 2010, 12, 3590-3593. (d) Maury,

J.; Mouysset, D.; Feray, L.; Marque, S. R. A.; Siri, D.; Bertrand, M. P.

Chem.—Eur. J. 2012, 18, 3241- 3247.

Feray, L.; Bertrand, M. P. Eur. J. Org. Chem. 2008, 3164-3170.

Maury, J.; Feray, L.; Bertrand, M. P. Org. Lett. 2011, 13, 1884-1887.

The same result was obtained by slowly introducing air in the reaction

mixture through a syringe pump. All further reactions were performed

in non-degassed dichloromethane. On the ground of previous report,

the relationship between the two esters groups should be cis (more than

25.

2

One might also envisage decomplexation of Et Zn followed by

rotation. The stabilization of the enoxyl radical intermediate is 10.3

kcal per mol for (c) and 9.2 kcal per mole for (d). Such a route that

would necessitate an additional rotational energy close to 9 kcal per

mol can be excluded.

7.

8.

9.

26.

27.

For the sake of saving time this calculation was made at the UM06-

2X/6-311++(3df,3pd)//UM06-2X/6-31G(d) level of theory.

3

-1 -1

log(A/m mol s ) is on average 9.2 for alkyl radical addition, for β-

scission reactions, the pre-exponential factor varies between 12.8 and

14.8, see: Fischer, H; Radom, L. Angew. Chem. 2001, 113, 1380–1414;

Angew. Chem. Int. Ed. 2001, 40, 1340–1371.

1

ppm shift between the two cyclopropanic protons signals), see ref.

1.

28.

For the dialkylzinc mediated addition of α–alkoxy radicals, see: (a).

Yamada, K.-I.; Konishi, T.; Nakano, M.; Fujii, S.; Cadou, R.;

Yamamoto, Y.; Tomioka, K. J. Org. Chem. 2012, 77, 5775−5780. (b)

Yamada, K.-I.; Maekawa, M.; Akindele, T.; Nakano, M.; Yamamoto,

Y.; Tomioka, K. J. Org. Chem. 2008, 73, 9535–9538. For

triethylborane mediated reactions, see; (c) Liu, J.-Y.; Jang, Y.-J.; Lin,

W.-W.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2003, 68, 4030-4038.

Carra, C.; Scaiano, J. C. Eur. J. Org. Chem. 2008, 26, 4454-4459.

(a) Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev.,

1990, 19, 147-195. (b) Moser, W. H. Tetrahedron 2001, 57, 2065-

2084.

10.

For selected examples, see: (a) Chen, C.; Xi, C.; Jiang, Y.; Hong, X.

Tetrahedron Lett. 2004, 45, 6067-6069. (b) Chen, C.; Xi, C.; Jiang, Y.;

Hong, X. Synlett 2005, 911-914.

1

1.

2.

Joucla, M.; Fouchet, B.; Le Brun, J.; Hamelin, J. Tetrahedron Lett.

1

985, 26, 1221-1224.

1

Our reaction must be related to the report by Van Koten of the

synthesis of β-lactams from the reaction of diethylzinc with glyoxylic

imines, see: (a) Van Vliet, M. R. P.; Jastrzebski, J. T. B. H.; Klaver, W.

J.; Goubitz, K.; Van Koten, G. Recl. Trav. Chim. Pays-Bas, 1987, 106,

29.

30.

1

32-134. (b) Van der Steen, F. H.; Kleijn, H.; Jastrzebski, J. T. B. H.;

Van Koten, G. J. Org. Chem. 1991, 56, 5147-5158.

31.

32.

(a) Yoshida, J.-I., Itoh, M.; Matsunaga, S.-I.; Isoe, S. J. Org. Chem.

1992, 57, 4877-4882. (b) Apeloig, Y.; Zharov, I.; Bravo-Zhivotovskii,

D.; Ovchinnikov, Y.; Struchkov, Y. J. Organomet. Chem. 1995, 499,

73-82. (c) Bock, H.; Seidl, H. J. Am. Chem. Soc. 1969, 91, 355-361.

For representative examples of radical cyclizations onto acylsilanes,

see: (a) Tang, K.-H.; Liao, F.-Y.; Tsai, Y.-M. Tetrahedron 2005, 61,

2037–2045. (b) Jiaang, W.-T.; Lin, H.-C.; Tang, K.-H.; Chang, L.-B.;

Tsai, Y.-M. J. Org. Chem. 1999, 64, 618-628. (c) Chang, S.-Y.; Jiaang,

W.-T.; Cherng, C.-D.; Tang, K.-H.; Huang, C.-H.; Tsai, Y.-M. J. Org.

Chem. 1997, 62, 9089-9098. (d) Curran, D. P.; Diederichsen, U.;

Palovich, M. J. Am. Chem. Soc. 1997, 119, 4797-4803.

1

3.

4.

Bazin, S.; Feray, L.; Siri, D.; Naubron, J.-V.; Bertrand, M. P. Chem.

Commun. 2002, 2506-2507 and references cited therein. For related

references concerning homolytic subtitution at boron by enoxyl and α-

alkoxycarbonyl radicals, see: (a) Lung-min, W.; Fischer, H. Helv.

Chim. Acta 1983, 66, 138-147. (b) Ollivier, C.; Renaud, P. Chem. Rev.

2

001, 101, 3415-3434.

1

For representative examples of the incidence of Lewis acids on the rate

and stereoselectivity of radical additions, see: Yang, Y.-H.; Sibi, M.

Stereoselective Radical Reactions: Synthetic Strategies and

Applications in Encyclopedia of Radicals in Chemistry, Biology and

Materials, Chatgiglialoglu, C. and Studer, A., Eds., Wiley, Chichester,

33.

34.

35.

Dimethylzinc could not be used as partner in these reactions as it

spontaneously adds to acylsilanes to give polymeric materials. This did

not occur with diethylzinc.

2

012, pp.655-691.

1

5.

6.

Jammi, S.; Mouysset, D.; Siri, D.; Bertrand, M. P.; Feray, L. J. Org.

Chem. 2013, 78, 1589-1603.

(a) Chen, Z.; Zhang, Y.-X.; An, Y.; Song, X.-L.; Wang, Y.-H.; Zhu,

L.-L.; Guo, L. Eur. J. Org. Chem. 2009, 5146-5152. (b) Yamada, K.-I.;

Maekawa, M.; Akindele, T.; Nakano, M.; Yamamoto, Y.; Tomioka, K.

J. Org. Chem. 2008, 73, 9535-9538.

For closely related processes, see: (a) Tsai, Y.-M.; Chang, S.-Y. J.

Chem. Soc., Chem. Commun. 1995, 981-982. (b) Huang, C.-H.; Chang,

S.-Y.; Wang, N.-S.; Tsai, Y.-M. J. Org. Chem. 2001, 66, 8983-8991.

For Zn-promoted Brook rearrangement in tandem processes, see: (a)

Unger, R.; Weisser, F.; Chinkov, N.; Stanger, A.; Cohen, T.; Marek, I.

Org. Lett. 2009, 11, 1853-1856. (b) Unger, R.; Cohen, T.; Marek, I.

Eur. J. Org. Chem. 2009, 1749-1756. (c) Smirnov, P.; Einat Katan, E.;

Mathew, J.; Kostenko, A.; Karni, M.; Nijs, A.; Bolm, C.; Apeloig, I.;

Marek, I. J. Org. Chem. 2014, 79, 12122−12135 and references cited

therein.

1

7.

(a) Miyabe, H.; Asada, R.; Yoshida, K.; Takemoto, Y. Synlett 2004,

5

6

40-542. (b) Miyabe, H.; Asada, R.; Takemoto, Y. Tetrahedron 2005,

1, 385-393.

1

2

8. Seyferth, D. Organometallics 2001, 20, 2940–2955, and previous

references therein.

9

.

Jana, S. ; Berger, R. J. F. ; Frohlich, R. ; Pape, T. ; Mitzel, N. W. Inorg.

Chem. 2007, 46, 4293-4297.

36.

37.

For selected examples of halodesilylation, see: (a) Brook, A. G.; Duff,

J. M.; Hitchcock, P.; Mason, R. J. Organomet. Chem. 1976, 113, C13-

C16. (b) Brook, A. G.; Duff, J. M.; Reynolds, W. F. J. Organomet.

Chem. 1976, 121, 293-306. (c) Gouyon, T.; Sauvêtre, R.; Normant, J.-

F. J. Organomet. Chem. 1990, 394, C37-C44.

(a) Fleming, I.; Goldhill, J. J. Chem. Soc., Chem. Commun. 1978, 176-

177. (b) Fleming, I.; Goldhill, J. J. Chem. Soc., Perkin 1 1980, 1493-

1498. (c) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem. Soc., Perkin 1

1981, 2520-2526.

(a) Whitham, G. Science of Synthesis, 2002, 4, 633-646 and previous

references cited therein. For some selected examples see: (b) Hudrlik,

P. F. J. Am. Chem. Soc. 1977, 99, 1993-1996. (c) Hudrlik, P. F.

Tetrahedron Lett. 1979, 20, 2233-2236. (d) Hudrlick, P. F.; Ma, D.;

Bhamidipati, R. S.; Hudrlick, A. M. J. Org. Chem. 1996, 61, 8655-

0. In light of EPR experiments a radical chain mechanism was proposed

for the oxygenation reaction. This mechanism is in perfect agreement

with the pioneering proposal of Davies and Roberts, see : (a) Davies,

A. G.; Roberts, B. P. J. Chem. Soc. (B) 1968, 1074–1078. (b) Davies,

A. G.; Griller, D.; Roberts, J. Chem. Soc. (B) 1971, 1823–1829. (c)

Davies, A. G.; Roberts, B. P. Acc. Chem. Res. 1972, 387–392.

21.

Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241.

For recent theoretical investigations of zinc organometallic

intermediates with similar methodologies, see: (a) Dranka, I.;

Kubisiak, M.; Justyniak, I.; Lesiuk, M.; Kubicki, D.; Lewinski, J.

Chem. Eur. J. 2011, 17, 12713-12721; (b) Aiken, K. S.; Eger, W. A.;

Williams, C. M.; Spencer, C. M.; Zercher, C. K. J. Org. Chem. 2012,

38.

22.

7

7, 5942-5995. (c) Eger, W. A.; Zercher, C. K.; Williams, C. M. J.

8

658. (e) Kazunobu, K. Chem. Lett. 2001, 432-433.

Org. Chem. 2010, 75, 7322–7331.

3

9.

0.

(a) Stork, G.; Colvin, E. J. Am. Chem. Soc. 1971, 93, 2080-2081. (b)

Stork, G.; Jung, M. E.; Noel, Y. J. Am. Chem. Soc. 1974, 96, 3684-

23.

Slight energy differences are induced by optimizing the conformation

of the ethyl groups in the diethylzinc moiety (from 0.5 to 2 kcal per

mol depending on the structure) in all cases the most stable conformer

was considered.

3

686.

•

4

It is nevertheless hard to consider that Et , more reactive as an atom

transfer agent, would be trapped by preferential addition or other

14

Tetrahedron

ACCEPTED MANUSCRIPT

competitive processes to the exclusion of any bromine atom transfer, as

6

a was not detected.

4

1.

Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H.

B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;

Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato,

M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;

Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;

Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,

H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;

Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.

N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;

Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam,

N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;

Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.

J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma,

K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;

Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.;

Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009.

NBO 6.0. Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.;

Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.;

Weinhold F. (Theoretical Chemistry Institute, University of Wisconsin,

Madison, WI, 2013); http://nbo6.chem.wisc.edu/

42.

43.

44.

45.

Jalil, A. A.; Kurono, N.; Tokuda, M. Tetrahedron 2002, 58, 7477-

7

484.

Patrocinio, A. F.; Moran, P. J. S. J. Organomet. Chem. 2000, 603, 220-

24.

2

Jalal, S.; Chand, K.; Kathuria, A.; Sharma, S. K.; Singh, P.; Priya, N.;

Raj, H. G.; Gupta, B. Bioorg. Chem 2012, 40, 131-136.

ACCEPTED MANUSCRIPT

Theoretical Investigation of the Reaction of Dialkylzincs with α-

Alkoxycarbonyl Radicals. Evaluation of α-Bromoacrylates as

Radical Acceptors in Radical-Polar Crossover Processes

François Vibert, Julien Maury, Hugo Lingua, Eric Besson, Didier Siri, Michèle P. Bertrand*

and Laurence Feray*

Aix-Marseille Université CNRS, Institut de Chimie Radicalaire UMR 7273, Equipes CMO et CT

1

3397 Cedex 20, Marseille, France.

michele.bertrand@univ-amu.fr; laurence.feray@univ-amu.fr

Computational data

NMR spectra

2-20

21-60

1

ACCEPTED MANUSCRIPT

Computational data

Cartesian coordinates at the M06-2X/aug-cc-pVDZ level of theory.

a

2

7

C

H

-1.53000

-1.71900

-2.44400

-2.25600

-3.39900

0.16200

-2.96300

-0.84300

1.23800

-3.18300

-2.97700

-2.52400

-4.23100

2.68000

3.27600

2.18000

3.62100

4.16300

4.37800

3.07100

0.05900

0.18200

0.29500

-0.99700

-0.47100

1.20900

-0.07900

1.06100

-0.25100

1.61500

2.55400

1.11400

1.85700

-0.70900

-0.83800

-1.09900

-2.01400

-2.00300

-2.73800

-2.24100

-0.96000

-1.88500

-0.89800

0.24300

0.20500

0.29800

1.19500

-1.35400

-0.26500

-2.32900

-1.43600

-0.45700

-0.19400

0.72900

0.00500

-0.69300

0.79900

1.31200

0.94000

-0.27100

-0.56300

-1.28600

0.25600

-1.11800

-2.19300

-0.62600

-0.92000

-1.12100

-1.14200

-2.10000

-0.95100

0.00500

-1.74800

-0.97000

1.86900

2.95000

2.32300

1.55900

3.81500

3.33100

2.56000

Br

O

Zn

C

H

C

H

C

H

C

H

b

2

ACCEPTED MANUSCRIPT

2

7

C

H

-1.23300

-0.68700

-0.52100

0.44700

-0.88800

-2.92700

-1.57200

0.47400

2.02400

-1.05600

-0.65600

-0.26300

-1.90500

3.16000

2.91800

4.21100

3.03200

2.00100

3.67000

3.31300

1.04000

1.53600

1.05100

-0.02000

0.93700

2.57800

1.50100

-0.73600

-0.46100

0.92800

-1.40500

-1.14700

-2.42400

-0.81800

1.82300

1.18800

-0.22700

3.14900

3.53100

3.12700

3.74400

-0.85500

-1.90500

-0.86900

-0.00200

0.02500

-0.37300

1.04300

0.22600

-0.40700

1.32400

-0.04300

-0.10000

-0.12900

-1.50300

-0.61600

-1.35100

-1.78400

-1.44200

0.01800

-0.21400

-0.87200

0.38200

-0.02700

-0.97200

0.72800

0.31100

-1.14500

-1.37400

-0.82200

-2.41700

-2.79700

-3.23300

-2.22900

2.07100

3.37800

2.16800

1.91700

4.24800

3.58900

3.33200

Br

O

Zn

C

H

C

H

C

H

C

H

c

3

ACCEPTED MANUSCRIPT

3

4

C

H

1.25700

0.61100

2.60600

2.60200

2.81600

0.33100

1.40700

-0.52300

-2.17400

0.79800

0.51400

-0.09200

1.55600

-3.52400

-4.35800

-3.96300

-2.95800

-2.61600

-3.70400

-2.09500

3.70500

5.07800

3.69400

3.46500

5.85400

5.33600

5.09900

-1.16400

-0.47300

-1.87000

-0.41700

0.01300

-1.18700

0.30100

-0.09100

-0.08800

-0.76800

0.53200

1.44300

0.81500

-0.12500

-0.82200

-1.22500

0.46200

-1.39500

-2.43400

-0.81900

-1.33800

-0.75200

-0.17300

-1.34700

-1.70300

-1.15300

-2.43500

-2.26600

-0.42000

0.24000

-1.33000

-0.71900

-0.44200

0.52400

1.14600

1.97100

2.98200

2.51900

1.55200

3.80000

3.44200

2.50600

1.02400

-0.04400

-0.65500

0.99500

-1.70700

2.10200

1.01000

0.39500

3.26600

3.06900

3.54100

4.04900

-0.44600

-0.87100

0.37100

-1.51000

-2.39900

-1.85500

-1.12700

-0.55100

-0.49800

0.06400

-1.58000

-0.86700

0.53000

-1.11700

1.28000

0.34900

1.92300

1.97600

0.90200

-0.34700

-0.27000

Br

O

Zn

C

H

C

H

C

H

C

H

C

H

4

ACCEPTED MANUSCRIPT

d

3

4

C

H

1.61300

0.84100

1.08000

1.56100

-0.00100

3.36500

1.42000

-0.27400

-2.27300

0.61600

0.35700

-0.29800

1.23600

-2.56000

-1.84100

-2.27100

-3.97800

-4.29300

-4.05900

-4.71700

-2.28100

-3.27200

-2.46300

-1.25400

-3.20900

-4.30900

-3.09400

1.30000

0.77700

2.37300

0.78300

0.93000

1.29700

-0.29700

0.14000

-0.14900

0.73500

-0.58200

-1.52100

-0.75900

-0.58700

1.08100

1.12900

-0.10700

1.90200

2.83500

1.36500

2.09600

0.11100

0.87500

-0.82100

0.50500

1.45500

0.62400

-0.25200

-0.57800

-1.65500

0.35500

-0.88300

-1.84700

-1.36600

-2.61200

0.48600

0.01200

0.71400

1.40300

0.77800

-0.90100

-0.20500

-0.71500

1.45900

1.75900

1.36500

-0.31900

-1.86300

-0.38100

-0.16600

-2.72100

-2.21000

-2.99500

-3.59800

1.80900

2.14600

2.32300

2.25100

1.79900

3.34200

1.95400

-2.11800

-2.58300

-2.67700

-2.38400

-3.66400

-2.36600

-2.07300

2.54800

3.89900

2.61000

2.23800

4.66700

4.21900

3.84100

Br

O

Zn

C

H

C

H

C

H

C

H

C

H

e

5

ACCEPTED MANUSCRIPT

2

7

C

H

-1.33700

-0.63600

-2.81500

-3.05700

-3.22500

-0.30800

-1.37700

0.65500

1.88400

-0.66400

0.07900

-0.16200

-1.42200

3.67100

3.58800

3.87100

4.83500

4.68000

5.78600

4.96200

-3.48900

-4.99900

-3.25400

-3.05600

-5.47100

-5.45200

-5.24200

0.12300

-0.31700

-0.11400

-0.44200

-1.32800

-0.62000

-0.32300

-0.02300

0.01600

0.03800

-0.17600

0.61900

-1.15100

-0.11300

0.17900

0.92900

-0.77700

0.53400

1.50300

0.59600

-0.21600

0.79100

0.61500

1.66200

0.98700

1.49800

0.45100

-0.25200

1.26900

-0.04400

-0.65200

0.95900

-1.50500

2.40900

1.41200

-0.01600

3.63200

3.75800

3.67200

4.41600

-0.86200

-1.66200

-1.36700

0.07400

0.56600

-0.47300

0.86500

-0.65400

-0.77500

-0.02700

-1.64600

-1.22100

0.21200

-1.40400

Br

O

Zn

C

H

C

H

C

H

C

H

f

6

ACCEPTED MANUSCRIPT

2

7

C

H

-1.15400

-0.95800

-0.04500

-0.40400

0.77000

-2.92200

-2.02000

0.22900

1.87200

-1.75000

-1.23700

-1.13900

-2.73000

0.51900

1.65500

0.84900

-0.31100

2.04000

2.49100

1.30900

3.76000

4.22200

4.38500

3.88900

5.26700

4.15300

3.61800

-0.27700

0.21300

-0.01900

0.35400

0.93200

0.99300

0.26100

-0.17300

-0.10800

-0.11300

-0.29100

0.60100

-1.17600

-0.38900

-0.98000

-0.79700

-1.60700

-1.53700

-1.76100

-0.24200

-0.23000

-0.11000

1.21700

-0.35600

-0.93300

1.15700

2.04600

1.49300

1.04300

-1.27600

-2.13700

-0.86500

-0.96900

1.86500

1.62200

0.78700

3.25500

3.63400

3.46700

3.72900

-1.78500

-2.78500

-0.93700

-2.23900

-3.13500

-2.33700

-3.65800

0.22200

-0.40100

1.09100

-0.49400

-0.73400

0.31400

-1.27500

Br

O

Zn

C

H

C

H

C

H

g

7

ACCEPTED MANUSCRIPT

3

7

C

H

O

1.37800

0.88700

2.74900

2.75900

3.02600

1.79800

-0.25200

-2.16500

1.33200

0.99700

0.50100

2.18700

-3.14700

-4.08400

-3.44500

-2.30300

-2.07400

-2.81100

-1.34400

3.79600

5.19400

3.78000

3.50700

5.93000

5.50200

5.22200

-1.58400

-1.99900

-1.97900

-0.48700

-1.64900

-3.09100

-1.60200

0.50900

-0.02400

-0.23200

1.11900

0.34400

0.35300

-0.48500

0.16300

0.50100

-0.89800

-1.35600

-0.43000

-0.17000

-2.22300

-1.63600

-2.83500

-2.84800

1.05900

1.42500

0.45800

2.25000

2.94200

2.84100

1.91600

0.96400

0.80700

0.61700

2.02400

1.38100

-0.24600

1.16100

-1.32100

-0.81700

-2.34000

-1.43300

-1.47200

-0.74500

0.18800

1.44700

1.11600

1.76400

2.31300

-0.72900

0.90000

1.94600

0.88100

-1.19700

-1.19400

0.09300

-2.23500

-3.09600

-1.87000

-2.50000

-1.15200

-0.70900

-2.02600

-1.63300

-0.80900

-2.41000

-2.05600

0.10300

0.69100

-0.93800

0.09400

0.11600

0.68400

1.73000

1.64500

3.03700

1.50500

1.60800

3.84900

3.12800

3.24400

0.85500

1.76200

0.11100

1.14100

Zn

C

H

C

H

C

H

C

H

C

H

C

H

h

8

ACCEPTED MANUSCRIPT

3

0

C

H

O

1.31500

0.76800

2.79700

2.98600

3.27000

1.57900

-0.52500

-1.85500

0.95900

0.21900

0.46900

1.76700

-3.52200

-3.39500

-3.59700

-4.80900

-4.77500

-5.68900

-4.98100

3.46800

4.95800

3.31500

2.96400

5.42600

5.47800

5.12000

0.41600

-0.34300

-0.10900

0.99100

-0.30300

0.42700

0.10600

0.60200

1.48900

0.79100

-0.08300

-0.08100

-0.01200

0.00500

-0.79100

0.97900

-0.10300

-0.03200

-0.78400

0.93700

-0.31000

-1.28700

-0.31100

0.44700

-0.61200

-0.39300

-1.48300

-0.84000

-1.27300

-0.18400

0.46400

0.53000

1.33500

-0.41800

0.77800

0.89100

-0.49200

-1.12100

0.47900

1.97300

1.12800

-0.14300

3.24800

3.38700

3.38000

3.97600

-1.19700

-1.98900

-1.71100

-0.40700

0.09300

-1.06500

0.36800

-1.14500

-1.39200

-0.49300

-2.09700

-1.84900

-0.44700

-2.06000

-1.50400

-1.41400

-1.74700

-2.40400

Zn

C

H

C

H

C

H

C

H

C

H

i

9

ACCEPTED MANUSCRIPT

3

4

C

H

O

-0.96300

-0.74400

-2.29900

-2.29600

-3.06000

-1.87400

0.36600

1.98100

-1.68000

-1.08500

-1.15900

-2.68100

1.45000

2.07600

1.64800

-0.03100

-0.27300

-0.31300

-0.70300

-2.68800

-4.05400

-2.68500

-1.91800

-4.32000

-4.83300

-4.06000

2.68600

2.49900

3.75500

2.19200

2.87500

3.02700

1.44200

-0.06500

-0.70000

-0.95800

-1.04000

-0.73500

-1.09300

-1.29700

-1.03400

-1.09900

0.25700

-1.04500

-0.17500

-1.95900

-1.00400

1.88200

2.74500

1.68700

2.26100

2.48200

3.14700

1.45000

0.75800

0.98800

1.10900

1.33200

2.05100

0.43300

0.65200

-1.01200

-0.55200

-1.20000

-1.98600

-1.28800

0.39200

-0.37200

-1.03200

0.73000

-1.30700

-2.34500

-0.74900

1.45400

1.25300

0.18400

2.87200

3.17400

3.17500

3.30500

1.24100

0.97100

2.30600

1.06400

0.01500

1.65200

1.38000

-1.29000

-1.92700

-0.25000

-1.82300

-1.91000

-1.38800

-2.97200

-1.20800

-2.66500

-1.03200

-1.05900

-3.39100

-2.85800

-2.91400

-1.31100

Zn

C

H

C

H

C

H

C

H

C

H

j

1

0

ACCEPTED MANUSCRIPT

2

7

C

H

O

0.00000

1.34500

1.19600

1.98800

1.21500

-1.02600

-1.38100

1.20600

0.75800

0.63000

2.25300

-2.77900

-3.55400

-2.34200

-3.41600

-3.87300

-4.20100

-2.67400

2.08000

3.42400

2.22700

1.43900

3.93300

4.08600

3.29300

-0.61800

0.00000

1.48100

-0.71600

-1.77400

-0.29000

2.05400

2.15200

-0.17400

3.47900

3.92800

3.78600

3.77400

-0.24900

-0.96000

-0.67300

1.11700

1.55800

1.03600

1.83700

-0.64900

-1.37000

0.40400

-1.09400

-1.32200

-0.91900

-2.42900

-0.30100

0.00000

-0.26300

-0.78300

-0.10300

0.00500

-1.47200

-0.21600

0.67600

-1.09600

-0.31500

-2.87800

-2.55600

-3.79300

-3.18100

-2.28600

-3.94600

-3.54900

1.34100

1.30500

1.61500

2.11700

2.27500

0.55300

1.04400

0.86000

Zn

C

H

C

H

C

H

C

H

ethyl

7

1

ACCEPTED MANUSCRIPT

C

H

0.01000

0.51100

-1.01600

0.51100

-0.06400

-0.69400

0.00000

0.89000

0.00000

-0.89000

-0.93100

0.93100

0.79400

-1.09700

-1.10500

-1.09700

1.35100

ZnEt₂

1

5

Zn

C

H

C

H

C

H

-0.00000

1.87200

2.04800

1.97100

2.94900

2.90300

3.96400

2.83700

-1.87200

-2.94900

-1.97100

-2.04900

-3.96400

-2.83600

-2.90300

-0.00000

0.67800

1.18800

1.45700

-0.39800

-1.18000

0.02500

-0.89600

-0.67800

0.39900

-1.45700

-1.18800

-0.02500

0.89700

1.18100

-0.05500

-0.06500

-1.02400

0.70700

0.15100

-0.61900

0.12100

1.12300

-0.06400

0.15100

0.70700

-1.02400

0.12100

1.12300

-0.61900

TS a<->b

2

7

C

-1.10100

-0.33000

0.45300

1.44400

0.75100

-0.07400

1

2

ACCEPTED MANUSCRIPT

C

H

Br

O

Zn

C

H

C

H

C

H

C

H

-0.71700

-1.28100

0.18200

-2.64100

-0.66800

0.50400

1.62900

0.03800

1.11300

-0.16500

-0.34600

2.94500

2.38000

3.60900

3.79000

3.15500

4.45400

4.42900

0.42500

-0.34100

0.99900

-0.29200

-1.03000

0.34300

-0.94700

0.03800

1.95300

2.50100

2.40500

-0.12400

0.19300

-0.89000

-0.12800

-0.57200

-0.38700

-1.63800

-0.22400

0.85800

1.54900

1.49700

-0.07100

-0.71900

0.48800

-0.73100

-0.97200

0.02900

-1.65400

-1.60700

-0.47000

0.64200

0.72100

-0.71300

0.45600

-0.20100

2.69700

1.12000

-1.02100

3.68900

3.60100

3.54600

4.64900

0.13000

0.77900

-0.47100

1.01900

1.63900

1.69600

0.41600

-2.37400

-3.25500

-3.01800

-1.83000

-3.95300

-3.85900

-2.65300

-

1

•_T_S= i 37.0 cm

TS a<->c

3

4

C

H

1.21600

0.64300

2.35100

2.66400

2.82800

-0.07100

1.12600

-0.05900

-0.93700

0.89500

0.05300

-0.59800

0.78200

1.34000

0.99400

1

3

ACCEPTED MANUSCRIPT

Br

O

Zn

C

H

C

H

C

H

C

H

C

H

0.26400

1.48700

-0.47000

-2.22100

0.94400

0.66600

0.06100

1.73900

-3.50700

-4.35500

-3.93800

-2.88400

-2.53700

-3.59700

-2.01300

4.20300

5.35700

4.03600

3.79500

6.30100

5.47500

5.24600

-1.29800

-0.79800

-1.99700

-0.45300

-0.32600

-1.62200

-0.06000

-1.67400

-0.24100

-0.57700

-1.08500

0.43900

-1.09700

-2.14800

-0.51800

-0.99100

-0.96000

-0.50000

-1.42100

-2.05700

-1.65500

-2.86500

-2.51300

-0.68900

0.25500

-1.32500

-1.04500

-0.27600

0.75400

1.02200

2.10600

3.07900

2.64400

1.82600

3.97600

3.42300

2.60800

2.16300

1.18600

0.32500

3.38500

3.25500

3.67400

4.12500

-0.30100

-0.82900

0.60300

-1.17600

-2.13700

-1.40300

-0.68600

-0.54800

-0.55400

0.31900

-1.49200

-0.76000

0.41600

-1.33100

0.98900

-0.09200

1.64900

1.64200

0.33600

-0.73100

-0.75600

-1

•_T_S= i 270.3 cm

TS b<->d

3

4

C

H

Br

O

Zn

C

H

1.58600

0.83000

1.03200

1.55300

-0.01400

3.37200

1.43600

-0.27000

-2.27000

0.68300

0.45400

-0.24800

1.32700

-2.46600

0.06600

-0.75600

1.18500

1.77400

1.40400

-0.40300

-1.87200

-0.42100

-0.17900

-2.70100

-2.14600

-3.01500

-3.55600

1.82000

-0.25300

0.71400

-0.76400

-1.51500

-0.55900

-0.65700

1.09000

1.13300

-0.10400

1.98800

2.90300

1.50400

2.19800

0.01400

C

1

4

Article Doi

Theoretical investigation of the reaction of dialkylzincs with α-alkoxycarbonyl radicals. Evaluation of α-bromoacrylates as radical acceptors in radical-polar crossover processes

DOI: 10.1016/j.tet.2015.09.045

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2015.09.045

Full text of DOI:10.1016/j.tet.2015.09.045

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