Dienolates of Cycloalkenones and α,β-Unsaturated Esters Form Diels–Alder Adducts by a Michael/Michael-Tandem Reaction Rather Than in One Step

DOI: 10.1002/ejoc.201801193

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European Journal of Organic Chemistry p. 562 - 573 (2019)

Update date:2022-08-11

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Authors:

Loesche, Ann-Christine

Brückner, Reinhard

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Article abstract of DOI:10.1002/ejoc.201801193

α,β-Unsaturated esters and lithium 1,3-dien-2-olates are known to furnish bicyclic lithium enolates by anionic Diels–Alder reactions. However, in principle, the respective products might form not only in a single step but also in two consecutive – or “tandem” – Michael additions, the first of which occurs intermolecularly, the second intramolecularly. Three cyclic lithium dienolates and four esters with a stereogenic C^α=C^β bond reacted to give Diels–Alder adducts (10 times) or failed to react (2 times). Seven of the reactive combinations furnished adducts wherein the configuration of the former ester moiety had in part inverted. This precludes concerted pathways as their origins. This was a surprise since donors at C-2 of the 1,3-diene accelerate normal electron-demand Diels–Alder reactions in the order alkyl < aryl < alkoxy ≈ trialkylsiloxy < acylamino. With Li^⊕O^? being a far better donor still, it is not obvious why the mechanism is non-concerted rather than concerted (and still more asynchronous).

Full text of DOI:10.1002/ejoc.201801193

A Journal of

Accepted Article

Title: Dienolates of Cycloalkenones and apha,beta-Unsaturated

Esters Form Diels-Alder Adducts by a Michael/Michael-Tandem

Reaction Rather Than in One Step

Authors: Reinhard Brückner and Ann-Christine Lösche

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801193

Link to VoR: http://dx.doi.org/10.1002/ejoc.201801193

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10.1002/ejoc.201801193

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((For Table of Contents))

Dienolates of Cycloalkenones and α,β-Unsaturated Esters Form

Diels-Alder Adducts by a Michael/Michael-Tandem Reaction Ra-

ther Than in One Step

Short Title: Michael/Michael Tandem Instead of 1-Step Diels-Alder Reactions

Ann-Christine Loesche, Reinhard Brückner

‡

MeO

concerted cycloaddition

MeO

workup:

MeO

1^stMichael addition

2^ndMichael addition

Cyclic lithium 1,3-dien-2-olates, like isophorone enolate, and α,β-unsaturated esters, like methyl acry-

late, deliver bicyclic lithium enolates by an anionic Diels-Alder reactions. In principle, they may material-

ize in a single step or by two consecutive Michael additions. Seven anionic Diels-Alder reactions involv-

ing esters with a stereogenic C^α=C^βbond proceeded such that the configuration in the ester moiety was

partly inverted. This precludes that these reactions proceed in one step.

Key topic for Table of Contents: Non-Concerted Cycloadditions

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Dienolates of Cycloalkenones and α,β-Unsaturated Esters Form

Diels-Alder Adducts by a Michael/Michael-Tandem Reaction Ra-

ther Than in One Step

Ann-Christine Loesche^[a]and Reinhard Brückner*^[a]

Abstract: α,β-Unsaturated esters and lithium 1,3-dien-2-olates are

known to furnish bicyclic lithium enolates by anionic Diels-Alder reac-

tions. However, in principle, the respective products might form not

only in a single step but also in two consecutive – or “tandem” – Mi-

chael additions, the first of which occurs intermolecularly, the second

intramolecularly. Three cyclic lithium dienolates and four esters with a

stereogenic C^α=C^βbond reacted to give Diels-Alder adducts (10

times) or failed to react (2 times). Seven of the reactive combinations

furnished adducts wherein the configuration of the former ester moiety

had in part inverted. This precludes concerted pathways as their ori-

gins. This was a surprise since donors at C-2 of the 1,3-diene accel-

erate normal electron-demand Diels-Alder reactions in the order alkyl

< aryl < alkoxy ~ trialkylsiloxy < acylamino. With Li O^ybeing a far

better donor still, it is not obvious why the mechanism is non-con-

certed rather than concerted and (still more) asynchronous.

Acrylonitrile is particularly sensitive with regard to how to form cy-

clohexenes with 1,3-dienes: If exo-oriented relative to cis-penta-

dienenitrile, there is a 3.2 kcal/mol advantage for the 1-step mech-

anism, if endo-oriented a 2.2 kcal/mol advantage for the radicaloid

2-step mechanism;¹²vs. trans-penta-1,3-diene, the concerted

transition state of acrylonitrile is favored over biradical formation

by 1.2 kcal/mol while vs. cis-penta-1,3-diene the grading is re-

versed and worth 3.9 kcal/mol.¹³1,3-Diene dimerizations also oc-

cur concertedly^14,15or via biradical intermediates.^16,17Dehydro

Diels-Alder reactions seem to proceed via 1,6-biradicals more

generally according to calculations.¹⁸

The considerable volume of literature on “Diels-Alder reactions via

1,6-biradicals” contrasts with hardly any literature on “Diels-Alder

reactions via 1,6-dipoles”. Partly this reflects that computer chem-

istry usually treats the gas phase where charges are barely stabi-

lized (except for delocalization by polarizing the remainder of the

molecule). However, in solution, this deficiency may be compen-

sated by solvation. This allows the Diels-Alder reaction of 1-(di-

methylamino)buta-1,3-diene with, for example, dimethyl (Z)-cis-

dicyanomaleate, to proceed via a 1,6-dipole.¹⁹Its cationic moiety

is stabilized by the +M-effect of the NMe₂group and its anionic

moiety by the −M-effects of the α-positioned acceptors and −I-ef-

fects of the β-acceptors. A conformational change diminishes the

steric repulsion before ring-closure provides dimethyl 3,4-dicya-

nocyclohex-3-enedicarboxylate (E)-selectively.²⁰1,6-Dipole inter-

mediates also arise in the Diels-Alder reaction of 1-(trimethylsil-

oxy)buta-1,3-diene with an annulated nitrobenzene,²¹in Diels-Al-

der reactions of 1-(dimethylamino)-3-(trimethylsiloxy)buta-1,3-di-

ene,²²and in one Diels-Alder reaction with inverse electron-de-

mand.²³

Introduction

The well-known [4+2]-cycloaddition – or Diels-Alder reaction –

was first described in 1928 in Otto Diels’ and Kurt Alder’s investi-

gation “Syntheses in the Hydroaromatic Series”.¹During the 90

years since, this reaction has been studied intensively²and has

been employed innumerable times³while its scope was expanded

time and again.^4,5,6

In Diels-Alder reactions, 1,3-dienes with two stereogenic C=C

bonds react suprafacially at C-1 vs. C-4. Dienophiles containing a

stereogenic C=C bond do so at C-1’ vs. C-2’. Perfect “simple dia-

stereoselectivities” of both kinds are mandatory for a “concerted”,

i. e., 1-step mechanism. The transition states of the latter benefit

from a stabilization first rationalized by the Woodward-Hoffmann

rules.⁷It should be noted, though, that these rules do not cover

the pros and cons of 2-step alternative mechanisms.

Allyl cations can undergo “cationic Diels-Alder reaction” with cer-

tain 1,3-dienes.²⁴At least for 1,1,3-triarylallyl cations a 2-step

course is plausible.^24aThis implies the formation of a carbenium-

ion as an intermediate.

At 185°C, 1,1,4,4-tetradeuterobuta-1,3-diene reacts with cis- vs.

trans-1,2-dideuteroethene stereospecifically.⁸This implies that

these respective Diels-Alder reaction proceed in 1 step.⁸The con-

certed transitions state was estimated from rate constants⁹or cal-

culated¹⁰to be stabilized by 5.7 kcal/mol⁹or by between 2.3 and

7.7 kcal/mol,¹⁰respectively. Dynamical trajectories calculated for

a 907°C Diels-Alder reaction between the non-deuterated isotop-

ologues butadiene and ethylene modified this view:¹¹at that tem-

perature 1.8% of the material react in 2 steps via a 1,6-biradical.¹¹

O^y-Substituted dienes can undergo the charge-reversed process,

i. e., “anionic Diels-Alder reactions”. The maximum number of

non-annulated dien-1-olates which engage in such Diels-Alder re-

actions is small.²⁵In some instances it is even arguable whether

the reactive species equals a dienolate (ref.^25b; ref.^25evs. ref.^25g).

It is noteworthy that dimethyl maleate and dimethyl fumarate react

stereospecifically with the dienolates described in ref.^25c(exam-

ple: Scheme 1, row 1); this is an excellent support for the 1-step

nature of these reactions. Several benzene-containing carboxylic

acid esters or homophthalic anhydrides react with lithium amides

to give what may be considered as 2,3-benzannulated 1,3-dieno-

lates with an O^y-substituent at C-1. These species and α,β-un-

saturated esters or ketones form Diels-Alder products of unknown

stereostructure; the latter continue to react until the anion of a so-

called “Hauser-Kraus annulation product”²⁶results²⁷(example:^26a

Scheme 1, row 2). The respective follow-up reactions make the

[a]

Dipl.-Chem. A.-C. Loesche, Prof. Dr. R. Brückner

Institut für Organische Chemie, Albert-Ludwigs-Universität

Albertstraße 21, 79104 Freiburg (Germany)

E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de

Homepage: http://www.brueckner.uni-freiburg.de

Supporting information for this article is given via a link at the end

of the document.

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

stereoselectivity criterion for assessing the concertedness of the

inaugural Diels-Alder reaction inapplicable.

anionic Diels-Alder reactions of 1,3-dien-1-olates:

Scheme 1, row 3], 14, and 15 and the benzyl crotonates trans-

and cis-17,³²benzyl tiglate (trans-18³³), and benzyl angelate (cis-

18³³; Figure 1). These esters were available with ≥ 99% isotopic

purity.^32,33We would have studied the corresponding benzyl deu-

teroacrylates trans- and cis-16 similarly if we had been able to

synthesize these substrates with ≥97% isomeric purity; however,

we hadn´t.³⁴We chose α,β-unsaturated benzyl rather than methyl

esters as a dienophile for making sure that they would not evap-

orate when attempting to isolate any non-consumed portion

thereof (see proviso in the next paragraph!).

Me₂

Me₂Al

OH O

0°C;

H₂O

80%

OMe

CO₂Me

(from dienol-

silane + MeLi,

then Me₂AlCl)

OMe O

THF,

–78°C;

methyl-

OEt

ation

SO₂Ph

lithium dienolates:

dienophiles:

SO₂Ph

OMe

70%

[unspecified

isomer(s)]

[from phthalide

+ LiN(iPr)₂]

BnO₂C

anionic Diels-Alder reactions of 1,3-dien-2-olates:

trans-16

trans-17

trans-18

MeO

H₂O

98%

THF,

MeO

BnO₂C

–23°C;

[from isophorone

+LiN(iPr)Cy]

cis-16

cis-17

cis-18

MeO

Figure 1: The lithium 1,3-dien-2-olates and two pairs of configurationally iso-

meric dienophiles which were combined inividually for undergoing anionic Diels-

Alder reactions.

CHCl₃,

r.t.;

H₂O

MeO

t-BuO₂C

tBuO₂C

>70%

What had been a stereogenic C=C double bond in the mentioned

benzyl esters would became a C−C single bond between a pair of

vicinal stereocenters in the resulting Diels-Alder products 19 and

27-30 (formulas: Table 1). Their 3D structures would tell whether

the respective ester had reacted suprafacially or antarafacially.

Suprafacialiality would be mandatory for Diels-Alder reactions

consisting of a single step. Antarafaciality would be indicative of a

multi-step Diels-Alder mechanism – provided that no cis,trans

(E,Z) isomerizations interfered before or after the Diels-Alder step

proper. The unconsumed esters which we re-isolated after work-

up contained 14 rel-% isomerized material (trans-17 arising when

combining cis-17 and 7), 9% thereof (trans-17 arising when com-

bining cis-17 and 14; details: Scheme 2) or none (in the other 10

instances). That is, isomerization of the dienophile was a minor

risk under our reaction conditions. We could not gauge whether

the non-protonated Diels-Alder products epimerized under the re-

action conditions. For this to happen these ketone enolates must

exchange a proton with the ester moiety for giving ketone-con-

taining ester enolates. Even if this happened in the Diels-Alder

adducts of the benzyl crotonates trans- and cis-17 it is impossible

in the Diels-Alder adducts of benzyl tiglate (trans-18) and angelate

(cis-18).

Scheme 2 exemplifies the stereochemical issue which was the

object of our study. It depicts the conceivable outcomes of all

Diels-Alder reactions between the lithium enolate 7 and benzyl

crotonate trans-17. They might deliver up to 2 Diels-Alder prod-

ucts if the underlying enolates 20 form in 1 step: endo-trans-19

and exo-trans-19 (see blue arrows). However, if type-20 enolates

form in 2 steps, a maximum of 4 Diels-Alder products 19 might

result: not just endo-trans-19 and exo-trans-19, but also endo-cis-

19 and exo-cis-configured19 (see green arrows). Our experiment

(to be described below) would furnish 80% of a 40:60 mixture of

two Diels-Alder products: endo-trans-19 (incorporating the croto-

nate suprafacially) and endo-cis-19 (incorporating the crotonate

(from β-ketoester

+ Cs₂CO₃)

Scheme 1: Anionic Diels-Alder reactions of simple dienolates (rows 1, 3) and

special dienolates (row 2: Hauser-Kraus annulation; row 4: Deslongchamps an-

nulation). The respective 1,3-dien-1-olates (1^25c, 4^26a) or 1,3-dien-2-olates (7^28a

10^31a) stem from desilylating a dienolsilane followed by a transmetalation (row

1) or from deprotonating C,H acids (rows 2-4). The Diels-Alder products proper

are the alkoxides 2^25cand 5^26aor the enolates 8^28aand 12^31a. They may form

more stable anions under the reactions conditions (rows 2, 4) and render neutral

compounds (3^25c, 6^26a, 9^28a, and 13^31a) only after electrophilic work-up.− The pre-

sent study concerns anionic Diels-Alder reactions of the kind shown in row 3.

1,3-Dienolates with an O^y-substituent at C-2 transform electron-

deficient olefins into 6-membered rings, too. If such dienolates

contain no electron-withdrawing group they can add to α,β-un-

saturated esters or ketones and furnish a Diels-Alder product after

protic workup²⁸(example:^28aScheme 1, row 3). The steric course

of these reactions has not been studied systematically in the

past.²⁹This left their (non-)concertedness unassessed except cal-

culationally.³⁰The present study makes up for this void.

Finishing up, 1,3-dienolates with an O^y-substituent at C-2 plus an

electron-withdrawing group at C-1, for instance the dienolate

10,^31aScheme 1, row 4), undergo different 6-membered ring for-

mations, namely “Deslongchamps annulations³¹”. The follow-up

reactions under the reaction conditions – a protonation and a

deprotonation – obviate once more to assess the (non-)concert-

edness of the inaugural Diels-Alder step by the stereoselectivity

criterion.

Reactants and Analytical Strategy

We clarified the mechanism(s) of the Diels-Alder reactions be-

tween the cyclic lithium 1,3-dien-2-olates 7 [first subjected to a

reaction of that kind by exposure to methyl acrylate (→ 9,^28acf.

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European Journal of Organic Chemistry

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we added a THF solution of 2.0 equiv. of the respective benzyl

crotonate (trans-17,³²cis-17³²), tiglate (trans-18)³³or angelate

(cis--18³³) drop by drop. 17 min later we removed the dry ice from

the cooling bath so that the respective mixture reached room

antarafacially). The occurrence of the latter diastereomer proves

that ≥60% of this Diels-Alder reaction adheres to the 2-step mech-

anism. Occam´s razor suggests that one attributes even 100% of

this reaction, i. e., its entirety, to the 2-step mechanism; that is,

there is no need to hold two competing mechanisms for true.

temp. within 30 min. After 2 h at that temperature, we added 1

aq. HCl. Extractive workup provided a crude product. It allowed to

determine the diastereomeric composition by ¹H-NMR-

spectroscopy.

bicyclo[2.2.2]octanones formed in the reactions no. 1 and no. 2 of Table 1:

Purification by flash-chromatography on silica gel followed.³⁵

Diels-Alder products resulted from 10 of the 12 reactions summa-

rized in Table 1 and in up to 85% yield (reaction “no. 6”). 80%

yields followed (reactions “no. 2” and “no. 8”). No Diels-Alder

product at all was formed from the bulkiest dienolate, isophorone-

based 7, and the most sterically hindered esters, namely benzyl

angelate (cis-18; reaction “no. 3”) or benzyl tiglate (trans-18; re-

action “no. 4”). For probing whether the dienophiles lost their con-

figurational integrity before providing the Diels-Alder products – or

parallel to providing the Diels-Alder products – we (re)isolated

them flash-chromatographically, too; they eluted prior to the Diels-

Alder products.

The bicyclo[2.2.2]octanone-producing Diels-Alder reactions of

Table 1 provided mixtures of all 2 or 3 diastereomers formed. Bi-

nary mixtures of diastereomers resulted from reactions “no. 1” and

“no. 2” (endo-cis- + endo-trans-19), “no. 5” and “no. 6” (endo-cis-

- + endo-trans-27³⁶) as well as “no. 7” and “no. 8” (endo-cis- +

endo-trans-28). However, each of these three mixtures yielded

the respective constituents as single diastereomers after

purification by preparative HPLC. It is noteworthy that none of

these bicyclo[2.2.2]octanone-formations furnished an exo-dia-

stereomer.

Three of the bicyclo[2.2.1]heptanone-producing Diels-Alder reac-

tions of Table 1 afforded a single diastereomer at this stage: Re-

action “no. 9” gave endo-cis-29, reaction “no. 10” led to its dia-

stereomer endo-trans-29, and reaction “no. 12” furnished endo-

trans-30 exclusively. In contrast, the fourth bicyclo[2.2.1]heptan-

one-producing Diels-Alder reaction “no. 11” delivered a ternary

mixture of diastereomers (endo-cis- + endo-trans- + exo-trans-30)

Its constituents, too, were obtained diastereomerically pure by

preparative HPLC. They comprised the only exo-configured Diels-

Alder product of our study (exo-trans-30); however, the latter

amounted to no more than 8% of an 8:87:5 mixture with the two

endo-diastereomers. In line therewith no Diels-Alder product with

an exo-cis configuration was observed in our study at all.

BnO

^cisH

BnO

H^trans

H^A

**H

Me**

⁸H^B

Me*

endo-trans-19

endo-cis-19

NOE-correlations that proves endo or exo; NOE-correlations that proves cis or trans

BnO₂C

w'-up

endo-trans-19

40 rel-%

endo-trans-20

endo-cis-20

endo-cis-19

60 rel-%

proves 2-step

mechanism

(unless

endo-trans-

isomerizes

to give

BnO

endo-cis-20)

endo-trans-

endo-cis-

BnO₂C

1-step

mechanism

trans-

OBn

exo-cis-21

exo-trans-

CO₂Bn

w'-up

CO₂Bn

w'-up

exo-trans-19

exo-trans-20

exo-cis-20

exo-cis-19

Scheme 2: The anionic Diels-Alder reaction of the lithium enolate

7 (obtained

from isophorone and LDA) with the benzyl crotonate trans-17 as a mechanistic

probe: If type-20 enolates form in a single step, 2 Diels-Alder products 19 may

result (blue arrows), but if 20 forms in 2 steps, up to 4 Diels-Alder products 19

are conceivable (green arrows). The experiment furnished the Diels-Alder prod-

ucts endo-trans-19 and endo-cis-19 (Table 1). The latter stems from the enolate

endo-cis-20 which must arise in 2 steps rather than in 1.− At top: NOESY cross-

peaks proving the endo-configuration twice (lily arrows) and the trans- vs. cis-

orientation of 3-Me (orange arrows).

Figure 2: ORTEP plot of one of the two pseudosymmetric molecules in the

elemental cell of the monocrystalline bicyclo[2.2.2]octanone endo-trans-28;³⁷its

configuration is identical to that of its counter-part but its benzyl moiety assumes

a slightly different conformation.

Results

We generated the lithium 1,3-dien-2-olates 7, 14, and 15 in THF

at –78°C from the corresponding cycloalk-2-en-1-one (1.0 equiv.;

not depicted in Figure 1) and LDA (1.0 equiv.) within 45 min. Then

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European Journal of Organic Chemistry

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Table 1: Feasibility and simple diastereoselectivity of the bicyclo[2.2.2]octanone- or bicyclo[2.2.1]heptanone-forming anionic Diels-Alder reactions of our study. No

matter whether these reactions proceeded (numbered 1-2 and 5-12) or not (numbered 3-4), we isolated the unconsumed dienophile and determined its isomeric

composition. Diastereomorphous Diels-Alder products resulted as mixtures after flash-chromatography on silica gel³⁵but diastereopure after separation by HPLC.

Diels-Alder products, whose stereostructures are at odds with a 1-step mechanism but attributable to forming by a 2-step mechanism are depicted on an olive-

colored background.

0,1

BnO

OBn

0,1

LDA

BnO

–78°C, 17 min; –78°C→ roomt,

0,1

30 min; roomt, 2 h; work up with HCl

R = H or Me

(2 equiv.)

trans-

(2 equiv.)

endo-cis-

exo-cis-

cis-

endo-trans-

exo-trans-

dienophile

BnO₂

BnO₂C

cis-crotonate

trans-crotonate

angelate

tiglate

cis-17

trans-17

cis-18

trans-18

dienolate

no. 1

no. 2

no. 3

no. 4

yield of

Diels-Alder

product

59%

80%

BnO₂C

NO CONVERSION

endo-cis-19

endo-trans-19

endo-cis-

endo-trans-

unconsumed

dienophile

7% cis- mixed with 1% trans- reisolated

7% trans- reisolated

92% cis- reisolated

95% trans- reisolated

no. 5

no. 6

no. 7

no. 8

85%

54%

80%

70%

69%

BnO₂C

BnO₂

BnO₂C

endo-cis-

endo-trans-

endo-cis-

endo-trans-

endo-cis-

endo-trans-

unconsumed

dienophile

10% cis- mixed with 1% trans- reisolated

16% trans- reisolated

38% cis- reisolated

22% trans- reisolated

no. 9

no. 10

no. 11

no. 12

75%

68%

45%

BnO₂C

CO₂Bn

BnO₂

endo-cis-29

endo-trans-29

endo-trans-30

endo-cis-30 endo-trans-30 exo-trans-30

unconsumed

dienophile

24% cis- reisolated

23% trans- reisolated

37% cis- reisolated

28% trans- reisolated

bicyclo[2.2.2]octanones formed in the reactions no. 5 and no. 6:

bicyclo[2.2.2]octanones formed in the reactions no. 7 and no. 8:

H^trans

BnO

H^trans

BnO

^cisH

H^A

H**

H^A

**H

H**

⁸H*

⁸H^B

⁸H*

endo-trans-27

endo-cis-27

endo-cis-28

endo-trans-28

X-ray analysis: Figure 2

bicyclo[2.2.1]heptanones formed in the reactions no. 9 and no. 10:

bicyclo[2.2.1]heptanones formed in the reactions no. 11 and no. 12:

H^trans

BnO

^cisH

H^trans

BnO

^cisH

OBn

H^cis

H^A

H**

H^A

H**

**H

H**

H^B

endo-cis-

endo-trans-

exo-trans-

endo-trans-

NOE-correlations that proves endo or exo; NOE-correlations that proves cis or trans

Figure 3: Proofs of the relative configuration of the Diels-Alder adducts compiled in Table 1 [the respective bicyclo[2.2.2]octanones originated from the anionic

Diels-Alder reactions no. 1-2 (see top of Scheme 2 instead) and no. 5-12 while the respective bicyclo[2.2.1]heptanones originated from the anionic Diels-Alder

reactions no. 9-12]: NOESY-based NOE-correlations (500 MHz) CDCl₃or C₆D₆) established both the endo- vs. exo-orientation of the ester moiety vs. the ketone

group (lily arrows) and the cis- vs. trans-orientation of the ester moiety vs. the methyl group at C-3 (orange arrows). NOESY spectra in CDCl₃allowed to elucidate

the relative configurtion of the Diels-Alder adducts endo-cis-27,³⁶endo-trans-27,³⁶endo-trans-29, endo-trans-30, and exo-trans-30 whereas the NOESY spectra of

the Diels-Alder adducts endo-cis-19, endo-trans-19, endo-cis-28, endo-trans-28, endo-cis-29, and endo-cis-30 had to be registered in CDCl₃as well as in C₆D₆for

providing the same insights.

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

The configurational assignments of the Diels-Alder products 19

and 27-30 shown in Table 1 and discussed in the two preceding

paragraphs are based on the following: (1) They take the crystal

structure analysis of the bicyclo[2.2.2]octanone endo-trans-28

With regard to interpeting our results a number of other aspects

must be left open. (1) What causes the simple diastereoselectivity

of the initial Michael addition? The answer should depend on

whether the transition state is akin to that of a highly asynchro-

nous 1-step Diels-Alder mechanism is or whether it is less com-

pact. (2) Are a 2-step Michael/Michael tandem mechanism and an

asynchronous yet concerted mechanism Diels-Alder alternatives

– and therefore possibly competing – or do they represent border-

line cases of a mechanistic continuum? In the absence of an an-

swer it should be noted that 3 of the 4 bicyclo[2.2.1]heptanone-

delivering anionic Diels-Alder reactions of Table 1 delivered pure

endo-adducts with complete retention of configuration. I. e., there

is no a-priori reason why they would form differently than in a sin-

gle step. Charge-free cyclopenta-1,3-dienes are far more reactive

1,3-dienes than charge-free cyclohexa-1,3-dienes in Diels-Alder

reactions with normal electron-demand. This is attributed to the

smaller amount of distortion energy required for the former vs. the

latter dienes for reaching the transition state.⁴⁰The same effect

might make lithium cyclopenta-1,3-dien-2-olates more amenable

than lithium cyclohexa-1,3-dien-2-olates to undergoing 1-step

Diels-Alder reactions. (3) Why can a Michael/Michael tandem

mechanism prevail over a concerted Diels-Alder mechanism at

all? Particularly if calculations found that cyclopenta-1,3-dien-2-

olate – cation-free, but coordinated with formic acid – Diels-Alder-

adds to acrolein in a single step?³⁰Too tough a question, we be-

lieve, for attempting an answer already here.

into account (Figure 2³⁷). (2) We assigned all H- and ¹³C-NMR

resonances nucleus-specifically, aided by the magnitude of ³J_H,H

couplings, the occurrence of W-typ J_H,Hcouplings, edHSQC

spectra (inter alia → identification of

), and HMBC

non-quaternary

spectra (inter alia → identification of ¹³C_quaternary). Extensive anal-

yses of 500.4 MHz NOESY spectra in CDCl₃and/or in C₆D₆(inter

alia → distinction of CH₃groups) supplemented some assign-

ments and unravelled all spatial neighborhoods. NOESY cross-

peaks which revealed (a) the endo- vs. exo-orientation of the ester

moiety vs. the ketone group and (b) the cis- vs. trans-orientation

of the ester moiety vs. 3-Me are represented in Figure 3 and at

the top of Scheme 2.

Conclusion

The second paragraph of this publication pointed out that 1-step

Diels-Alder reactions incorporate a dienophile by attacking it only

suprafacially and not even partly antarafacially. Or, differently ex-

pressed: 1-step Diels-Alder reactions proceed with complete re-

tention of the dienophile configuration and no inversion at all.

According to Table 1, 7 of the 10 anionic Diels-Alder reactions,

which we observed, behaved differently: Some of the respective

dienophile reacted antarafacially, or, with inversion of configura-

tion. These “exemptions” account for between 6 and 60% of the

respective total amount of Diels-Alder products formed. 60% an-

tarafacial attack of the dienophile were recorded for the reaction

of the isophorone-based dienolate 7 with the benzyl crotonate

trans-17 (reaction “no. 2” of Table 1; see also Scheme 2). The

second-highest amount of antarafacial attack / inversion of con-

figuration – 40% – occurred in the reaction of the methylcyclohex-

enone-based dienolate 14 with benzyl angelate (cis-18; reaction

“no. 7” of Table 1). The same benzyl angelate (cis-18) was the

only dienophile to react to some extent, namely 13%, anta-

rafacially with the 5-membered ring dienolate 15 (reaction “no. 11”

of Table 1), furnishing 5 rel-% endo-trans-30 and 8 rel-% exo-

trans-30. (Incidentally, the last-mentioned compound was the only

exo-configured Diels-Alder product obtained in our study.)

A key premise of our study was that the anionic Diels-Alder prod-

ucts were unable to epimerize before they were protonated to ren-

der the compounds which we finally isolated. If that is true, the 8

Diels-Alder adducts of Table 1 which incorporate the dienophile

antarafacially, must have formed differently than in 1 step. A 2-

step tandem process comprising two Michael additions is the

most likely course of events: An intermolecular Michael addition

starts (e. g. 7 + trans-17 → 21 in Scheme 2) and an intramolecular

Michael addition ensues (in Scheme 2: 21 → 20).

Experimental Section

General Working Technique and Analytic Techniques

All reactions were carried out under an N₂-atmosphere. Reaction flasks

were dried in vacuo with a heat gun prior to use. Liquids were added with

a syringe through a septum. Solids were added in an N₂-counterflow. THF

was distilled over potassium, i-Pr₂NH over CaH₂under an N₂-atmosphere

prior to use. Other solvents and reagents were purchased and used

without further purification. Flash chromatography:³⁵Macherey-Nagel

silica gel 60^®(230-400 mesh). All eluents were distilled prior to use.

Chromatography conditions are documented as in, for example, "[

C₆H₁₂:EtOAc = (v:v), mL] ... Ff-g", which means: a column with a

diameter of cm was packed with cm silica high, it was eluted with

C₆H₁₂and EtOAc in a ratio (v:v), fractions of the size of mL were

a × b cm,

taken, and the product was isolated from fractions f-g. Nuclear magnetic

resonance spectra: Bruker Avance 500 spectrometer (500 MHz and

125 MHz for ¹H and ¹³C respectively), Bruker Avance 400 spectrometer

(400 MHz and 100 MHz for ¹H and ¹³C respectively), Bruker Avance 300

spectrometer (300 MHz for H respectively) and Varian Mercury VX 300

spectrometer (300 MHz and 62.9 MHz for ¹H and ¹³C respectively)

referenced internally by the ¹H- and ¹³C NMR signals of the solvent [CDCl₃:

7.26 ppm (¹H) and 77.16 ppm (¹³C); C₆D₆: 7.16 ppm (¹H) and 128.06 ppm

(

¹³C); (CH₃)₄Si: 0.00 ppm (¹H) and 0.00 ppm (¹³C)]. ¹H NMR data are

reported as follows: chemical shift ( in ppm), multiplicity (s for singlet; d

for doublet; t for triplet; q for quartett, m for multiplet; m_cfor symmetrical

multiplet; br for broad signal), number of protons (concluded from the

integrals), coupling constant(s) (Hz), specific assignment or integral. ¹³C

NMR data are reported in terms of chemical shift and assignment. For AB

signals the high-field part was named A and the low-field part B. The atom

numbering used for NMR assignments follows the IUPAC nomenclature

unless noted otherwise. High-resolution mass spectra were obtained on

a Finnigan MAT 8200 instrument (EI: 70 eV; CI/NH₃: 110 eV) using an

orbitrap analyzer. Elemental analyses were obtained on a CHNS

analysator Elementar Vario EL. Melting points were determined in a

Büchi melting point apparatus using open glass capillaries and are

uncorrected. IR spectra were obtained on an FT-IR Perkin Elmer Paragon

Our findings and inferences for the underlying mechanism may

appear little surprising. However, previous interpretations of re-

lated Diels-Alder reactions as Michael/Michael tandem reactions

were purely speculative.²⁸The only experimentally founded inter-

pretation of this kind, of which we are aware, concerned a bicy-

clo[2.2.2]octanone³⁸and, to a lesser extent, one bicyclo[2.2.1]-

heptanone formation, both from a cis-configured αβ-unsubsti-

tuted ester. 78% of the respective ester reacted antarafacially en

route to a bicyclo[2.2.2]octanone³⁸and 25% reacted alike giving

a bicyclo[2.2.1]heptanone.³⁹

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

3), 29.26 (8-Me**), 31.44 (C-8), 32.16 (8-Me*), 36.52 (C-1), 44.38 (C-6),

48.97 (C-2), 50.99 (C-7), 62.13 (C-4), 66.08 (Ph-CH₂), 128.48 and 128.65

and 128.70 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.77 (C-1’’), 172.42 (COOR),

215.21 (C-5) ppm.⁴¹

1000 spectrometer as a film of the substance on a polyethylene-foil

(Spectra-Tech Inc.; self-absorption may compete in the regions 2920-

2850, 1480-1430, and 740-700 cm^–1).

In C₆D₆:

Benzyl

(rel-1S,2S,3S,4R)-1,3,8,8-Tetramethyl-5-

¹H NMR (500.42 MHz, C₆D₆):

= 0.66 (s, 3 H, 8-Me**), 0.75 (s, 3 H, 8-

oxobicyclo[2.2.2]octane-2-carboxylate (endo-cis-19) and Benzyl (rel-

1S,2S,3S,4R)-1,3,8,8-Tetramethyl-5-oxobicyclo[2.2.2]octane-2-

carboxylate (endo-trans-19)

Me*), 0.77 (s, 3 H, 1-Me), 0.83 (m_c, 2 H, 7-H₂), 0.86 (d, J_3-Me,3-H^trans= 7.6 Hz,

3 H, 3-Me), 1.62 (dd, J_6-H*,6-H**= 19.1 Hz, J_6-H*,2-H= 2.2 Hz, 1 H, 6-H*),

trans

1.65 (d, J_{4-H,3- H}^trans= 3.1 Hz, 1 H, 4-H), 2.28 (dqd, J_{3-H ,2-H}= 11.1 Hz, J_3-

6''

5''

4''

5''

4''

trans

H^trans

_,3-Me= 7.5 Hz, J_{3-H ,4-H}= 3.5 Hz, 1 H, 3-H^trans), 2.47 (dd, J_2-H,3-H

11.2 Hz, ⁴_2-H,6-H*= 2.2 Hz, 1 H, 2-H), 3.22 (dt, ²_6-H**,6-H*= 19.1 Hz, ⁴J_6-H**,7-

₂= 1.8 Hz, 1 H, 6-H**), AB signal ( _A= 4.94, _B= 4.92, _A,B= 12.2 Hz, 2

₂), 7.02-7.13 (m, 3 H, 3‘‘-H, 4‘‘-H, 5‘‘-H)*, 7.16-7.21 (m, 2 H, 2‘‘-

H, 6‘‘-H)*. *Assignments interchangeable.

¹³C NMR (125.83 MHz, C₆D₆):

= 17.82 (3-Me), 24.11 (1-Me), 28.23 (C-

3), 28.95 (8-Me**), 31.00 (C-8), 32.05 (8-Me*), 36.41 (C-1), 44.40 (C-6),

48.92 (C-2), 50.69 (C-7), 61.91 (C-4), 65.85 (Ph- H₂), 128.43 and 128.69

^cisH

**H

H^A

Me**

2''

**H

Me**

3''

H^B

Me*

and

H^B

Me*

O *H

endo- cis-

endo-trans-

H, Ph-CH

C₂₀H₂₆O₃

314,43

With benzyl trans-crotonate (trans-17):

To a solution of diisopropylamine (0.277 m in THF, 2.6 mL, 73 mg,

0.72 mmol, 1.0 equiv.) nBuLi (2.47 m in hexane, 0.29 mL, 46 mg, 72 mmol,

1.0 equiv.) was added at –78°C. After 30 min a solution of isophorone

(99 mg, 0.72 mmol) in THF (1 mL) was added dropwise within 15 min. After

stirring for 30 min benzyl trans-crotonate (trans-17) (254 mg, 1.4 mmol,

2.0 equiv.) was added within 2 min. The reaction mixture was stirred at –

78°C for additional 15 min. Then the reaction mixture was warmed to

roomtemp. during 30 min and stirred for additional 2 h. The reaction was

quenched by the addition of hydrochloric acid (1 m, 2.5 mL). The layers

were separated. The aqueous layer was extracted with Et₂O (3 × 5 mL).

The combined organic layers were washed with brine (5 mL), dried over

MgSO₄and the solvent was removed under reduced pressure. The crude

(C-3’’, C-4’’, C-5’’)*, 128.94 (C-2’’, C-6’’)*, 136.47 (C-1’’), 172.17 (

COOR),

211.91 (C-5). *Assignments interchangeable.⁴¹

Elemental analysis

C₂₀H₂₆O₃(314.4 g/mol)

calc. C 76.40

found C 76.01

H 8.33

H 8.03

IR (film): ꢀ = 3440, 3090, 3055, 3035, 2955, 2930, 2370, 1725, 1505, 1585,

1490, 1455, 1400, 1335, 1355, 1325, 1300, 1290, 1255, 1245, 1220, 1180,

1160, 1145, 1115, 1100, 1080, 1010, 975, 900, 845, 795, 750, 700, 640,

600, 580, 555, 525, 515, 495, 475, 465, 455, 450 cm⁻¹

Characterisation of endo-trans-19:

In CDCl₃:

product was purified by flash chromatography (2.5

C₆H₁₂/EtOAc = 20:1). The title compounds [f20-25, 117 mg (endo-cis

20 cm, 25 mL,

¹H NMR (500.42 MHz, CDCl₃):

= 0.90 (s, 6 H, 1-Me and 8-Me*), 1.17 (s,

3 H, 8-Me**), 1.20 (d, J_3-Me,3-H^cis= 7.0 Hz, 3 H, 3-Me), AB signal (

_A= 1.41,

_B= 1.26, _A,6-H**= 3.5 Hz, 2

_A,B= 13.6 Hz, A part additionally split by d, ⁴

H, 7-H₂), 1.67 (d, ²

_6-H*,6-H**= 18.9 Hz, 1 H, 6-H*), 1.85 (s, 1 H, 4-H), 2.31

(m_c, 2 H, 2-H and 3-H^cis), 2.75 (dd, ²_6-H**,6-H*= 19.0 Hz, ⁴J_6-H**,7-H^A= 3.5 Hz,

1 H, 6-H**), AB signal ( _A= 5.14, _B= 5.13, _A,B= 12.2 Hz, 2 H, Ph-C ₂),

7.29-7.40 (m, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H).

¹³C NMR (125.83 MHz, CDCl₃):

= 19.74 (3-Me), 23.95 (1-Me), 32.00

(8-Me**), 32.56 (C-3), 33.30 (8-Me*), 33.45 (C-8), 37.06 (C-1), 43.88 (C-

6), 51.69 (C-7), 54.23 (C-2), 60.17 (C-4), 66.61 (Ph- H₂), 128.46 and

50:50); 80%] were obtained as yellowish oil.

The mixture of the diastereomers endo-cis 19

separated via preparative HPLC (Chiralpak, AD-H,

= 210 nm): 70 mg endo-cis 19 and 35 mg endo-trans

endo-trans

19 = 66:33); f25-35, 75 mg (endo-cis

endo-trans

-Heptan:EtOH 95:5;

-19 = 66:33 was

With benzyl cis-crotonate cis-(17):

To a solution of diisopropylamine (0.277 m in THF, 2.6 mL, 73 mg,

0.72 mmol, 1.0 equiv.) BuLi (2.47 m in hexane, 0.29 mL, 46 mg, 72 mmol,

128.68 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.79 (C-1’’), 174.87 (COOR),

213.56 (C-5).⁴¹

In C₆D₆:

1.0 equiv.) was added at –78°C. After 30 min a solution of isophorone

(99 mg, 0.72 mmol) in THF (1 mL) was added dropwise within 15 min. After

stirring for 30 min benzyl cis-crotonate cis-(17) (254 mg, 1.4 mmol,

2.0 equiv.) was added within 2 min. The reaction mixture was stirred at –

78°C for additional 15 min. Then the reaction mixture was warmed to

roomtemp. during 30 min and stirred for additional 2 h. The reaction was

quenched by the addition of hydrochloric acid (1 m, 2.5 mL). The layers

were separated. The aqueous layer was extracted with Et₂O (3 × 5 mL).

The combined organic layers were washed with brine (5 mL), dried over

MgSO₄and the solvent was removed under reduced pressure. The crude

¹H NMR (500.42 MHz, C₆D₆, 323K):

= 0.70 (s, 3 H, 1-Me), 0.76 (s, 3 H,

8-Me*), 0.79 (s, 3 H, 8-Me**), AB signal ( _A= 0.98, _B= 0.89, _A,B= 13.6 Hz,

A part additionally split by d, ⁴

_A,6-H**= 3.3 Hz, 2 H, 7-H₂) overlapped with

0.86 (d, J_3-Me,3-H^cis= 7.3 Hz, 2 H, 3-Me), 1.50 (dd, ²_6-H*,6-H**= 18.7 Hz, ⁴J_6-

_H*,2-H= 1.6 Hz, 1 H, 6-H*), 1.65 (s, 1 H, 4-H), 2.09 (dd, J_2-H,3-H^cis= 9.2 Hz,

⁴J_2-H,6-H*= 1.5 Hz, 1 H, 2-H), 2.36 (m_c, 1 H, 3-H^cis), 2.89 (dt, J_6-H**,6-H*

18.7 Hz, J_6-H**,7-H^A= 3.1 Hz, 1 H, 6-H**), 4.96 AB signal (

δ_A= 4.96, δ_B

product was purified by flash chromatography (2.5

C₆H₁₂/EtOAc = 20:1). The title compounds [f10-15, 38 mg (endo-cis

19 endo-trans 19 = 85:12); f18-23, 70 mg (endo-cis 19 endo-trans 19

20 cm, 25 mL,

4.96,

7.16-7.21 (m,

¹³C NMR (125.83 MHz, C₆D₆, 323K):

(8-Me**), 32.31 (C-3), 33.41 (8-Me*), 33.71 (C-8), 36.94 (C-1), 43.96 (C-

6), 51.70 (C-7), 54.59 (C-2), 60.17 (C-4), 66.38 (Ph- H₂), 128.41 and

128.70 and 128.74 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 138.61 (C-1’’), 174.55

OOR), 210.32 (C-5) ppm.⁴¹

Elemental analysis

_A,B= 12.2 Hz, 2 H, Ph-C

H, 2‘‘-H, 6‘‘-H)*. *Assignments interchangeable.

= 19.71 (3-Me), 23.98 (1-Me), 31.79

H₂), 7.01-7.13 (m, 3 H, 3‘‘-H, 4‘‘-H, 5‘‘-H)*,

75:25); 59%] were obtained as yellowish oil.

Characterisation of endo-cis-19:

In CDCl₃:

¹H NMR (500.42 MHz, CDCl₃):

= 0.84 (d, J_3-Me,3-H^trans= 7.0 Hz, 3 H, 3-

(

Me), 0.91 (s, 3 H, 8-Me*), 0.96 (s, 3 H, 1-Me), 1.09 (s, 3 H, 8-Me**), AB

signal (

_A= 1.31,

_B= 1.24, J_A,B= 13.6 Hz, A part additionally split by d,

C₂₀H₂₆O₃

g/mol)

(314.4

calc. C 76.40

H 8.33

⁴J_A,6-H**= 3.3 Hz, 2 H, 7-H₂), 1.78 (d, J_4-H,3-

overlapped with 1.78 (dd, ²J_6-H*,6-H**= 19.4 Hz, ⁴J_6-H*,2-H= 1.9 Hz, 1 H, 6-

= 2.9 Hz, 1 H, 4-H)

trans

found C 76.38 H 8.10

HRMS (pos. APCI): C₂₀H₂₇O₃(M+H⁺) calc. 315.19602 found 315.19620

IR (film): = 3440, 3065, 3035, 2960, 2925, 2870, 1725, 1500, 1455, 1400,

1385, 1370, 1360, 1330, 1275, 1265, 1250, 1210, 1175, 1170, 1120, 1065,

1010, 980, 905, 825, 805, 750, 700, 670 cm⁻¹

trans

H*), 2.68 (dqd, J_3-H

3.0 Hz, 1 H, 3-H^trans) overlapped with 2.72 (dd, J_2-H,3-H

= 11.0 Hz, J_3-H

= 7.1 Hz, J_3-H

,2-H

,3-Me

,4-H

ꢀ

trans

= 11.2 Hz, J_2-

_H,6-H*= 1.9 Hz, 1 H, 2-H), 3.01 (dd, ²

_6-H**,6-H*= 19.4 Hz, ⁴J_6-H**,7-H^A= 3.3 Hz,

H₂), 7.29-7.41 (m, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-

1 H, 6-H**), 5.10 (s, 2 H, Ph-C

H, 6‘‘-H) ppm.

¹³C NMR (125.83 MHz, CDCl₃):

δ = 17.65 (3-Me), 24.17 (1-Me), 28.21 (C-

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

Benzyl (rel-1S,2S,3S,4R)-1,3-Dimethyl-5-oxobicyclo[2.2.2]octane-2-

carboxylate (endo-cis-27) and Benzyl (rel-1S,2S,3S,4R)-1,3-Dimethyl-

5-oxobicyclo[2.2.2]octane-2-carboxylate (endo-trans-27)

128.67 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.79 (C-1’’), 172.16 (

COOR),

215.62 (C-5) ppm.⁴¹

HRMS (pos. APCI): C₂₀H₂₇O₃(M+H⁺) calc. 287.16472 found 287.16468

IR (film):

1250, 1214, 1150, 1104, 1090, 1078, 1032, 1002, 952, 910, 782, 735,

698 cm⁻¹

ꢀ = 3384, 3248, 2934, 2874, 1727, 1498, 1456, 1384, 1353, 1324,

6''

3''

6''

5''

4''

5''

4''

H^trans

^cisH

H^A

2''

**H

3''

H^B

and

O *H

Characterisation of endo-trans-27:

¹H NMR (500.42 MHz, CDCl₃, Me₄Si as a standard):

= 0.92 (s, 3 H, 1-

_7-A= 1.49, δ_7-B

endo- cis-

endo-trans-

Me), 1.09 (d, J_3-Me,3-H^trans= 7.0 Hz, 3 H, 3-Me), AB signal (

C₁₈H₂₂O₃

286.37

= 1.39, J_7-A,7-B= 13.4 Hz; A part additionally split by ddd, J_7-A,8-H**

11.2 Hz, J J_7-A,6-H**= 3.3 Hz; B part additionally split by dd,

_7-A,8-H*= 3.4 Hz, ⁴

With benzyl trans-crotonate (trans-17):

To a solution of diisopropylamine (0.285 m in THF, 5.0 mL, 144 mg,

1.42 mmol, 1.0 equiv.) BuLi (2.55 m in hexane, 0.56 mL, 92 mg,

_7-B,8-H*= 11.5 Hz,

_7-B,8-H**= 6.8 Hz, 2 H, 7-H₂), 1.70 (ddddd, J_8-H*,8-H**

trans

14.4 Hz,

_8-H*,7-B= 11.2 Hz,

_8-H*,7-A= 3.3 Hz,

_8-H*,4-H= 3.3 Hz, ⁴J_8-H*,3-H

= 1.4 Hz, 1 H, 8-H*), 1.81 (dd, ²

_6-H*,6-H**= 18.9 Hz, ⁴

_6-H*,2-H= 1.8 Hz, 1 H,

1.43 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

Methylcyclohexen-1-one (158 mg, 1.43 mmol) in THF (2 mL) was added

dropwise within 15 min. After stirring for 30 min benzyl trans-crotonate

(trans-17) (500 mg, 2.84 mmol, 2.0 equiv.) was added within 2 min. The

reaction mixture was stirred at –78°C for additional 15 min. Then the

reaction mixture was warmed to roomtemp. during 30 min and stirred for

additional 2 h. The reaction was quenched by the addition of hydrochloric

acid (1 m, 5 mL). The layers were separated. The aqueous layer was

extracted with Et₂O (3 × 10 mL). The combined organic layers were

washed with brine (10 mL), dried over MgSO₄and the solvent was

removed under reduced pressure. The crude product was purified by flash

6-H*), 1.97 (dddd, ²

_8-H**,8-H*= 14.1 Hz,

_8-H**,7-A= 11.3 Hz,

_8-H**,7-B= 6.7 Hz,

trans

J_8-H**,4-H= 2.6 Hz, 1 H, 8-H**), 2.09 (ddd, J_4-H,8-H= 3.5 Hz, J_4-H,3-H

1.9 Hz, J_4-H,8-H^**= 1.9 Hz, 1 H, 4-H), 2.12 (dd, J_2-H,3-H^trans= 7.9 Hz, ⁴J_2-H,6-H*

trans

= 1.8 Hz, 1 H, 2-H), 2.32 (dqdd, J_{3-H ,2-H}= 7.3 Hz, J_{3-H ,3-Me}= 6.9 Hz,

trans

J_{3-H ,4-H}= 1.6 Hz, ⁴J_{3-H ,8-H*}= 1.6 Hz, 1 H, 3-H^trans), 2.80 (dd, ²J_6-H**,6-H*

= 18.9 Hz, J_6-H**,7-A= 3.3 Hz, 1 H, 6-H**), Ab signal (δ_{Ph-CH -A}= 5.15,

δ_{Ph-CH -B}= 5.12, ²J _Ph-CH

_-B= 13.1 Hz; 2 H, Ph-CH₂), 7.30-7.41 (m,

-A, Ph-CH

2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.83 MHz, CDCl₃, Me₄Si as a standard):

18.03 (3-Me), 24.29 (1-Me), 32.34 (C-3), 34.55 (C-7), 36.46 (C-1), 45.63

(C-6), 48.48 (C-4), 55.14 (C-2), 66.57 (Ph- H₂), 128.40 and 128.43 and

= 17.91 (C-8),

chromatography [3.5

20 cm, 50 mL, (f1-22:

-C₆H₁₂/EtOAc = 5:1)]. The title

27 endo-cis 27 = 94:6, 85%) were

c-C₆H₁₂/EtOAc = 20:1; f23-

44: -C₆H₁₂/EtOAc = 10:1; f46-55:

compounds (f28-37, 347 mg endo-trans

128.69 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.83 (C-1’’), 174.64 (

COOR),

obtained as colorless oil.

215.24 (C-5) ppm.⁴¹

HRMS (pos. ESI): C₁₈H₂₂O₃Na (M+Na⁺) calc. 309.14666 found 309.14670

With benzyl cis-crotonate cis-(17):

IR (film):

1358, 1331, 1289, 1269, 1244, 1215, 1158, 1129, 1111, 1072, 1040, 1017,

1001, 909, 870, 751, 698 cm⁻¹

ꢀ = 3065, 3034, 2956, 2929, 2873, 1756, 1498, 1456, 1400, 1382,

To a solution of diisopropylamine (0.285 m in THF, 3.4 mL, 98 mg,

0.97 mmol, 1.0 equiv.) BuLi (2.40 m in hexane, 0.40 mL, 61 mg,

0.96 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

Methylcyclohexen-1-one (106 mg, 0.96 mmol) in THF (1.5 mL) was added

dropwise within 15 min. After stirring for 30 min benzyl cis-crotonate cis

Benzyl (rel-1S,2S,3R,4S)-1,2,3-Trimethyl-5-oxobicyclo[2.2.2]octane-

2-carboxylate (endo-trans-28) and Benzyl (rel-1S,2S,3S,4S)-1,2,3-

Trimethyl-5-oxobicyclo[2.2.2]octane-2-carboxylate (endo-cis-28)

(

17) (338 mg, 1.92 mmol, 2.0 equiv.) was added within 2 min. The reaction

mixture was stirred at –78°C for additional 15 min. Then the reaction

mixture was warmed to roomtemp. during 30 min and stirred for additional

2 h. The reaction was quenched by the addition of hydrochloric acid (1 m,

2 mL). The layers were separated. The aqueous layer was extracted with

Et₂O (3 × 5 mL). The combined organic layers were washed with brine

(5 mL), dried over MgSO₄and the solvent was removed under reduced

pressure. The crude product was purified by flash chromatography

6''

5''

4''

5''

4''

H^trans

^cisH

H^A

H**

2''

**H

H**

3''

H^B

and

H^B

O *H

endo-cis-

endo- trans-

C₁₉H₂₄O₃

300,40

(1.5

20 cm, 25 mL,

-C₆H₁₂/EtOAc = 20:1). The title compounds (f19-30,

189 mg, endo-trans

yellowish oil.

27 endo-cis 27 = 20:80, 69%) were obtained as

With benzyl tiglate (trans-18):

To a solution of diisopropylamine (0.20 mL, 1.4 mmol, 0.14 g, 1.0 equiv.)

in THF (5 mL) BuLi (2.55 m solution in hexane, 0.56 mL, 0.92 mg,

1.43 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

methylcyclohex-2-en-1-one (156 mg, 1.42 mmol) in THF (2 mL) was added

The mixture of the diastereomers endo-trans

separated via preparative HPLC (Chiralcel, OD-H, MeCN:H₂O = 50:50;

210 nm): 18 mg endo-trans 27 91 mg endo-cis 27

-27:endo-cis-27 = 20:80 was

dropwise within 15 min. After stirring for 30 min benzyl tiglate (trans-18

)

Characterisation of endo-cis-27:

¹H NMR (500.42 MHz, CDCl₃, Me₄Si as a standard):

540 mg, 2.84 mmol, 2 equiv.) was added within 2 min. The reaction mixture

was stirred at –78°C for additional 15 min. Then the reaction mixture was

warmed to roomtemp. during 30 min and stirred for additional 2 h. The

reaction was quenched by the addition of hydrochloric acid (2 m, 3 mL).

The layers were separated. The aqueous layer was extracted with Et₂O (3

× 5 mL). The combined organic layers were washed with brine (5 mL),

dried over MgSO₄and the solvent was removed under reduced pressure.

The crude product was purified by flash chromatography [3.5 × 20 cm,

= 0.87 (d, J_3-Me,3-

^trans= 7.5 Hz, 3 H, 3-Me), 0.99 (s, 3 H, 1-Me), AB signal (

δ_A= 1.53, δ_B

1.42,

_A,B= 13.5 Hz; A part additionally split by ddd,

_A,8-H*= 9.1 Hz*, J_A,8-

= 6.5 Hz*, J_A,6-H**= 3.3 Hz; B part additionally split by dd, J_B,8-H*

H**

10.1 Hz**,

_B,8-H**= 7.3 Hz**, 2 H, 7-H₂), 1.84 (m_c, 2 H, 8-H₂), 1.89 (dd, ²J_6-

trans

= 19.2 Hz, J_6-H*,2-H= 2.1 Hz, 1 H, 6-H*), 2.15 (ddd, J_4-H,3-H

H*,6-H**

3.0 Hz, J_4-H,8-H^*= 3.0 Hz, J_{4-H,8- H}^**= 3.0 Hz, 1 H, 4-H) 2.15 (dqd, J_3-H

trans

,2-

50 mL (f1-27:

52: -C₆H₁₂/EtOAc = 7:1; f53-65:

compound (f29-39, 340 mg, 80%, endo-cis-28

-C₆H₁₂/EtOAc = 20:1; f28-44:

-C₆H₁₂/EtOAc = 5:1)]. The title

endo-trans-28 = 12:88) was

c-C₆H₁₂/EtOAc = 10:1; f45-

trans

_H= 11.2 Hz, J_{3-H ,3-Me}= 7.4 Hz, J_{3-H ,4-H}= 3.3 Hz, 1 H, 3-H^trans), 2.82

(dd, J_2-H,3-H^trans= 11.2 Hz, ⁴_2-H,6-H*= 2.1 Hz, 1 H, 2-H), 3.05 (dd, ²J_6-H**,6-H*

= 19.2 Hz, J_6-H**,7-H= 3.2 Hz, 1 H, 6-H**), 5.11 (s, 2 H, Ph-C ₂), 7.29-

obtained as colorless oil.

The mixture of the diastereomers endo-cis-28

endo-trans-28 = 12:88 was

7.41 (m, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H) ppm. *^,**Assignments

interchangeable.

¹³C NMR (125.83 MHz, CDCl₃, Me₄Si as a standard):

separated via preparative HPLC (AD-H,

15 mg of endo-cis-28 and 212 mg endo-trans-28

n-Heptan:EtOH 93:7; λ = 214 nm):

= 17.73 (3-Me),

23.56 (C-8), 24.35 (1-Me), 33.35 (C-3), 33.95 (C-7), 35.48 (C-1), 46.15 (C-

6), 49.84 (C-4), 50.29 (C-2), 66.03 (Ph-CH₂), 128.43 and 128.59 and

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

With benzyl angelate cis-(18):To a solution of diisopropylamine (0.20 mL,

¹³C NMR (125.82 MHz, CDCl₃, Me₄Si as a standard):

15.29 (2-Me), 17.66 (C-8), 22.38 (1-Me) 30.51 (C-7), 33.62 (C-3), 39.62

(C-1), 48.58 (C-6), 49.30 (C-2), 49.99 (C-4), 66.79 (Ph- H₂), 128.21 and

128.31 and 128.64 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.87 (C-1’’), 176.48

OOR), 215.45 (C-5) ppm.⁴¹

δ = 13.98 (3-Me),

1.4 mmol, 0.14 g, 1.0 equiv.) in THF (5 mL)

hexane, 0.58 mL, 0.92 mg, 1.43 mmol, 1.0 equiv.) was added at –78°C.

After 30 min solution of 3-methylcyclohex-2-en-1-one (156 mg,

nBuLi (2.44 m solution in

1.42 mmol) in THF (2 mL) was added dropwise within 15 min. After stirring

for 30 min benzyl angelate cis-(18) (540 mg, 2.84 mmol, 2 equiv.) was

added within 2 min. The reaction mixture was stirred at –78°C for additional

15 min. Then the reaction mixture was warmed to roomtemp. during 30

min and stirred for additional 2 h. The reaction was quenched by the

addition of hydrochloric acid (2 m, 3 mL). The layers were separated. The

aqueous layer was extracted with Et₂O (3 × 5 mL). The combined organic

layers were washed with brine (5 mL), dried over MgSO₄and the solvent

was removed under reduced pressure. The crude product was purified by

In C₆D₆:

¹H NMR (500.32 MHz, C₆D₆):

= 0.61 (d, J_3-Me,3-H^cis= 7.3 Hz, 3 H, 3-Me),

0.65 (s, 3 H, 1-Me), 0.70 (ddd, ²

_7-H*,7-H**= 13.8 Hz,

_7-H*,8-H*= 11.3 Hz, J_7-

= 7.6 Hz, 1 H, 7-H*), 1.00 (s, 3 H, 2-Me), 1.26 (dddd, J_7-H**,7-H*

H*,8-H**

14.0 Hz,

_7-H**,8-H**= 10.8 Hz, ⁴

_7-H**,6-H**= 3.5 Hz,

_7-H**,8-H*= 2.6 Hz, 1 H,

7-H**), superintendet by 1.28 (ddddd, J_8-H*,8-H**= 13.9 Hz, J_8-H*,7-H*

cis

11.3 Hz, J_8-H*,4-H= 3.9 Hz, J_8-H*,7-H**= 2.5 Hz, J_8-H*,3-H= 1.5 Hz, 1 H,

8-H*), 1.46 (dddd, J_8-H**,8-H*= 13.9 Hz, J_8-H**,7-H**= 11.1 Hz, J_8-H**,7-H*

flash chromatography [2.5 × 20 cm, 25 mL, (f1-29:

f29-45: -C₆H₁₂/EtOAc = 10:1; f45-60: -C₆H₁₂/EtOAc = 7:1)]. The title

compound (f31-38, 230 mg, 54%, endo-cis-28 endo-trans-28 = 40:60) was

c-C₆H₁₂/EtOAc = 20:1;

7.8 Hz, ⁴

_8-H**,4-H= 2.6 Hz, 1 H, 8-H**), 1.66 (d, ²

_6-H*,6-H**= 18.8 Hz), 1.95

(ddd,

_4-H,8-H*= 3.7 Hz,

_4-H,8-H**= 1.9 Hz, J_4-H,3-H^cis= 1.9 Hz, 1 H, 4-H), 2.80

cis

obtained as colorless oil.

(qdd, J_3-H

= 7.3 Hz, J_3-H

= 1.4 Hz, J_3-H

= 1.4 Hz, 1 H, 3-

,8-H*

,3-Me

,4-H

H^cis) 3.05 (dd, ²

_6-H**,6-H*= 18.8 Hz, ⁴

_6-H**,7-H**= 3.6 Hz), AB signal (δ_1’-A

Characterisation of endo-cis-28:

4.91,

_1’-B= 4.87, ²

_{1’-A, 1’-B}= 12.4 Hz, 2 H, Ph-C ₂), 7.03 (m_c, 1 H, 4‘‘-H),

In CDCl₃:

7.08 (m_c, 2 H, 3‘‘-H, 5‘‘-H), 7.13-7.16 (m, 2 H, 2‘‘-H, 6‘‘-H) superintendet by

7.15 (s, C₆D₆₎ppm.

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 0.90 (d, J_3-Me,3-

¹³C NMR (125.81 MHz, C₆D₆):

= 13.72 (3-Me), 15.20 (2-Me), 17.56 (C-8),

21.34 (C-1), 30.34 (C-7), 33.92 (C-3), 39.39 (C-1), 48.66 (C-6), 49.33 (C-

2), 50.01 (C-4), 66.60 (Ph- H₂), 128.35 and 128.54 and 128.69 (C-2’’, C-

^trans= 7.4 Hz, 3 H, 3-Me), 0.91 (s, 3 H, 1-Me), 1.26 (m_c, 1 H, 7-H*), 1.41

(s, 3 H, 2-Me), 1.75-1.94 (m, 4 H, 8-H*, 8-H**, 3-H, 7-H**) superimposed

by 1.90 (d, ²_6-H*,6-H**= 19.2 Hz, 1 H, 6-H*), 2.11 (ddd, J_4-H,8-H^*= 2.7 Hz, J_4-

^**= 2.7 Hz, J_4-H,3-H^trans= 2.7 Hz, 1 H, 4-H), 3.06 (dd, ²

_6-H**,6-H*= 19.2 Hz,

₂), 7.29-7.39 (m, 5 H,

3’’, C-4’’, C-5’’, C-6’’), 136.45 (C-1’’), 176.10 (C

OOR), 212.15 (C-5) ppm.⁴¹

HRMS (pos. ESI): C₁₉H₂₄O₃Na(M+H⁺) calc. 323.1618 found 309.1620

Elemental analysis:

C₁₉H₂₄O₃(300.4 g/mol)

H,8-H

⁴J_6-H**,7-H**= 3.4 Hz, 1 H, 6-H**), 5.09 (s, 2 H, Ph-C

2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.82 MHz, CDCl₃, Me₄Si as a standard):

22.10 (2-Me), 22.17 (1-Me), 23.66 (C-8), 30.19 (C-7), 38.73 (C-1), 44.05

(C-3), 49.00 (C-6), 50.74 (C-4), 50.83 (C-2), 66.22 (Ph- H₂), 128.34 and

128.51 and 128.64 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.81 (C-1’’), 173.74

OOR), 215.64 (C-5) ppm.41

calc. C 75.97

found C 75.80

H 8.05

H 7.88

= 17.86 (3-Me),

IR (film):

2877, 1721, 1498, 1469, 1455, 1393, 1381, 1330, 1286, 1254, 1220, 1140,

1096, 1049, 1028, 960, 922, 894, 736, 698 cm⁻¹

ꢀ = 3432, 3362, 3325, 3280, 3240, 3186, 3114, 3067, 3032, 2958,

(

X-ray see Figure 2 and the supporting information.

In C₆D₆:

¹H NMR (500.32 MHz, C₆D₆):

Benzyl (rel-1S,2S,3S,4S)-1,3-Dimethyl-5-oxobicyclo[2.2.1]heptane-2-

carboxylate (endo-trans-29)

= 0.69 (s, 3 H, 1-Me), 0.70-0.80 (m, 1 H,

trans

7-H*), 0.86 (d, J_3-Me,3-H

= 7.3 Hz, 3 H, 3-Me), 1.16 (s, 3 H, 2-Me),

1.21-1.30 (m, 1 H, 8-H**), 1.33-1.46 (m, 3 H, 3-H^trans, 7-H**, 8-H*), 1.71 (d,

6''

_6-H*,6-H**= 18.9 Hz, 1 H, 6-H*), 1.95 (ddd, J_4-H,8-H= 2.8 Hz, J_4-H,8-H=

5''

4''

H^cis

trans

2''

**H

2.8 Hz, J_4-H,3-H

= 2.8 Hz, 1 H, 4-H), 3.23 (dd, J_6-H**,6-H*= 18.9 Hz,

₂), 7.03 (m_c, 1 H, 4‘‘-

H), 7.08 (m_c, 2 H, 3‘‘-H, 5‘‘-H), 7.16-7.19 (m, 2 H, 2‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.82 MHz, C₆D₆):

= 18.01 (3-Me), 22.09 (1-Me), 22.15 (2-

Me), 23.55 (C-8), 30.09 (C-7), 38.58 (C-2), 44.02 (C-3), 49.02 (C-6), 50.78

(C-1)*, 50.80 (C-4)*, 66.04 (Ph- H₂), 128.33 and 128.66 and 128.80 (C-

H**

3''

⁴J_6-H**,7-H**= 3.4 Hz, 1 H, 6-H**), 4.87 (s, 2 H, Ph-C

endo-trans-

C₁₇H₂₀O₃

272.34

2’’, C-3’’, C-4’’, C-5’’, C-6’’), 136.37 (C-1’’), 173.41 (

5) ppm.⁴¹*Assignments interchangeable.

COOR), 212.19 (C-

To a solution of diisopropylamine (0.277 m in THF, 3.4 mL, 97 mg,

0.96 mmol, 1.0 equiv.) BuLi (2.40 m in hexane, 0.40 mL, 62 mg,

HRMS (pos. APCI): C₁₉H₂₅O₃(M+H⁺) calc. 301.1798 found 309.1799

0.96 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

Methylcyclopenten-1-on (92 mg, 0.96 mmol) in THF (1,5 mL) was added

dropwise within 15 min. After stirring for 30 min benzyl trans-crotonate

(trans-17) (338 mg, 1.92 mmol, 2.0 equiv.) was added within 2 min. The

reaction mixture was stirred at –78°C for additional 15 min. Then the

reaction mixture was warmed to –40°C and stirred for additional 1 h. The

reaction was quenched by the addition of hydrochloric acid (1 m, 2.5 mL).

The layers were separated. The aqueous layer was extracted with Et₂O (3

× 5 mL). The combined organic layers were washed with brine (5 mL),

dried over MgSO₄and the solvent was removed under reduced pressure.

IR (film):

1350, 1282, 1229, 1213, 1159, 1128, 1090, 1060, 1030, 956, 926, 799,

733, 698 cm⁻¹

ꢀ = 3247, 2957, 2876, 2368, 2168, 1721, 1498, 1456, 1404, 1379,

Characterisation of endo-trans-28:

In CDCl₃:

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 0.87 (s, 3 H, 1-

Me), 0.99 (d, J_3-Me,3-H^cis= 7.3 Hz, 3 H, 3-Me), 1.18 (ddd, ²

_7-H*,8-H*= 10.9 Hz, J_7-H*,8-H**= 7.4 Hz, 1 H, 7-H*), 1.27 (s, 3 H, 2-Me), 1.65

J_7-H*,7-H**= 14.1 Hz,

(ddddd, ²

_8-H*,8-H**= 13.9 Hz,

_8-H*,7-H*= 11.3 Hz,

_8-H*,4-H= 3.9 Hz, J_8-H*,7-H**

_7-H**,7-H*= 13.9 Hz,

_7-H**,8-H*= 2.5 Hz, 1 H, 7-H**), 1.79

The crude product was purified by flash chromatography (1.5

25 mL,

20 cm,

= 2.5 Hz, ⁴J_{8-H*,3-H ,}= 1.5 Hz, 1 H, 8-H*), 1.76 (dddd, ²

cis

-C₆H₁₂/EtOAc = 20:1). The title compound (f13-26, 177 mg, 68%]

_7-H**,8-H**= 10.9 Hz, ⁴

_7-H**,6-H**= 3.4 Hz,

were obtained as colorless liquid.

cis

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 1.14 (d, J_3-Me,3-H

(d, J_6-H*,6-H**= 19.0 Hz), 1.96 (dddd, J_8-H**,8-H*= 14.1 Hz, J_8-H**,7-H**

10.7 Hz, J

_8-H**,7-H*= 7.8 Hz, ⁴J_8-H**,4-H= 2.2 Hz, 1 H, 8-H**), 2.05 (ddd, J_4-

= 7.0 Hz, 3 H, 3-Me), 1.32 (s, 3 H, 1-Me), 1.60 (ddd, ²

_7-H*,7-H**= 10.8 Hz,

_H,8-H*= 3.8 Hz, J

_4-H,8-H**= 1.9 Hz, J_4-H,3-H^cis= 1.9 Hz, 1 H, 4-H), 2.77 (qdd,

cis

J_7-H*,4-H= 1.5 Hz, J_7-H*,3-H= 1.5 Hz, 1 H, 7-H*), 1.77 (ddd, J_6-H*,6-H**

18.2 Hz, J_6-H*,2-H= 2.1 Hz, ⁴J_6-H*,4-H= 0.7 Hz, 1 H, 6-H*), 1.85 (ddd, J_7-

_H**,7-H*= 10.8 Hz, ⁴J_7-H**,6-H**= 4.5 Hz,

_7-H**,4-H= 1.1 Hz, 1 H, 7-H**), 2.26

(dd, J_{2-H,3 H}^cis= 5.6 Hz, ⁴J_2-H,6-H*= 2.1 Hz, 1 H, 2-H), 2.30 (dd, ²J_6-H**,6-H*

18.1 Hz, ⁴

_6-H**,7-H**= 4.5 Hz, 1 H, 6-H**), superintendet by 2.30 (br. s, 1 H,

4-H), 2.38 (qdd, J_{3-H ,3-Me}= 7.0 Hz, J_{3-H ,2-H}= 5.51 Hz, J_{3-H ,7-H*}= 1.5 Hz,

cis

J_{3-H ,3-Me}= 7.3 Hz, J_{3-H ,4-H}= 1.3 Hz, ⁴J_{3-H ,8-H*}= 1.3 Hz, 1 H, 3-H^cis) 2.92

(dd, ²

_6-H**,6-H*= 19.1 Hz, ⁴

_6-H**,7-H**= 3.7 Hz), AB signal (

δ_1’-A= 5.14, δ_1’-B

= 5.09, ²J_{1’-A, 1’-B}= 12.4 Hz, 2 H, Ph-C

H₂), 7.29-7.39 (m, 5 H, 2‘‘-H, 3‘‘-H,

4‘‘-H, 5‘‘-H, 6‘‘-H) ppm.

cis

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

1 H, 3-H^cis), AB signal (δ_Ph-CH^A= 5.17, δ_Ph-CH^B= 5.10, ²

_A,B= 12.4 Hz; 2 H,

IR (film):

ꢀ

= 3034, 2959, 2876, 1732, 1498, 1455, 1384, 1354, 1300, 1223,

1166, 1126, 1096, 1073, 1010, 873, 737, 715, 699 cm⁻¹

Ph-C

¹³C NMR (125.82 MHz, CDCl₃, Me₄Si as a standard):

20.49 (1-Me), 37.14 (C-3), 42.76 (C-7), 45.54 (C-6), 47.75 (C-1), 57.64

(C-4), 58.29 (C-2), 66.51 (Ph- H₂), 128.24 and 128.36 and 128.67 (C-2’’,

H₂), 7.30-7.39 (m_c, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H) ppm.

= 20.40 (3-Me),

Benzyl (rel-1S,2S,3R,4S)-1,3-Dimethyl-5-oxobicyclo[2.2.1]heptane-2-

carboxylate (endo-cis-30), Benzyl (rel-1S,2S,3S,4S)-1,3-Dimethyl-5-

C-3’’, C-4’’, C-5’’, C-6’’), 135.91 (C-1’’), 172.92 (

5) ppm.⁴¹

HRMS (pos. ESI): C₁₇H₂₄O₃N (M+NH₄⁺) calc. 290.1751 found 290.1752

COOR), 215.53 (C-

oxobicyclo[2.2.1]heptane-2-carboxylate

(endo-trans-30)

and

Benzyl (rel-1S,2R,3S,4S)-1,3-Dimethyl-5-oxobicyclo[2.2.1]heptane-2-

carboxylate (exo-trans-30)

IR (film):

1730, 1455, 1383, 1359, 1333, 1315, 1286, 1258, 1213, 1171, 1115, 1083,

1055, 1016, 752, 715, 699 cm⁻¹

ꢀ = 3259, 3245, 3186, 3169, 3067, 3038, 2961, 2930, 2874, 1746,

6''

5''

4''

5''

4''

5''

4''

H^trans

H^cis

2''

**H

2''

H^A

**H

3''

Benzyl (rel-1S,2S,3R,4S)-1,3-Dimethyl-5-oxobicyclo[2.2.1]heptane-2-

carboxylate (endo-cis-29)

O *H

H^B

endo- cis-30

endo-trans-30

exo-trans-30

6''

5''

4''

C₁₈H₂₂O₃

286.37

H^trans

2''

H^A

**H

3''

H^B

To a solution of diisopropylamine (0.54 mL, 388 mg, 3.84 mmol, 1.0 equiv.)

in THF (15 mL) BuLi (2.40 m in hexane, 1.60 mL, 246 mg, 3.84 mmol,

1.0 equiv.) was added at –78°C. After 30 min solution of 3-

Methylcyclopenten-1-on (368 mg, 3.84 mmol) in THF (5 mL) was added

dropwise within 15 min. After stirring for 30 min benzyl angelate cis- 18

(1.46 g, 7.68 mmol, 2.0 equiv.) was added within 2 min. The reaction

mixture was stirred at –78°C for additional 15 min. Then the reaction

mixture was warmed to –40°C and stirred for additional 1 h. The reaction

was quenched by the addition of hydrochloric acid (1 m, 10 mL). The layers

were separated. The aqueous layer was extracted with Et₂O (3 × 20 mL).

The combined organic layers were washed with brine (20 mL), dried over

MgSO₄and the solvent was removed under reduced pressure. The crude

endo-cis-

C₁₇H₂₀O₃

272.34

To a solution of diisopropylamine (0.277 m in THF, 3.4 mL, 97 mg,

0.96 mmol, 1.0 equiv.) BuLi (2.40 m in hexane, 0.40 mL, 62 mg,

0.96 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

Methylcyclopenten-1-on (92 mg, 0.96 mmol) in THF (1,5 mL) was added

dropwise within 15 min. After stirring for 30 min benzyl cis-crotonate cis-

(

)

(

17) (338 mg, 1.92 mmol, 2.0 equiv.) was added within 2 min. The reaction

mixture was stirred at –78°C for additional 15 min. Then the reaction

mixture was warmed to –40°C and stirred for additional 1 h. The reaction

was quenched by the addition of hydrochloric acid (1 m, 2.5 mL). The

layers were separated. The aqueous layer was extracted with Et₂O (3 ×

5 mL). The combined organic layers were washed with brine (5 mL), dried

over MgSO₄and the solvent was removed under reduced pressure. The

product was purified by flash chromatography [6 × 17 cm, 75 mL (f1-39:

C₆H₁₂/EtOAc = 20:1; f40-60: -C₆H₁₂/EtOAc = 10:1)]. The title compounds

(f43-60, 495 mg, 45%, endo-cis-30 endo-trans-30 exo-trans-30 = 87:5:8]

were obtained as colorless liquid.

crude product was purified by flash chromatography (1.5

× 20 cm, 25 mL,

-C₆H₁₂/EtOAc = 20:1). The title compound (f16-28, 197 mg, 75%] were

Characterisation of endo-cis-30:

obtained as colorless liquid.

In CDCl₃:

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 0.86 (d, J_3-Me,3-

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 0.88 (d, J_3-Me,3-

_7-A= 1.64, δ_7-B

_7-A,6-H**= 4.3 Hz,

_7-B,4-H**= 1.5 Hz, 7-H₂), 1.82

(dd, ²J_6-H*,6-H**= 18.5 Hz, ⁴J_6-H*,2-H= 2.0 Hz, 1 H, 6-H*), 2.51 (br. d, J_4-H,3-

^trans_,= 7.5 Hz, 3 H, 3-Me), 1.07 (s, 3 H, 2-Me), 1.08 (s, 3 H, 1-Me), 1.47

_Htrans= 7.4 Hz, 3 H, 3-Me), 1.27 (s, 3 H, 1-Me), AB signal (

= 1.60, ²_7-A,7-B= 10.5 Hz; A part additionally split by dd, ⁴

_7-A,4-H= 1.1 Hz; B part additionally split by d,

(dd, ²

18.0 Hz, 1 H, 6-H*), 2.25 (dd, ²

6-H**), 2.33 (dd, ²_7-H**,7-H*= 10.6 Hz, ⁴

(d, ⁴J_{4-H,3- H}^trans= 4.6 Hz, 1 H, 4-H), 3.09 (qd, J_{3-H ,3-Me}= 7.5 Hz, J_3-H

_H= 4.6 Hz, 1 H, 3-H^trans), AB signal (δ_Ph-CH^A= 5.16, δ_Ph-CH^B= 5.11, ²J_A,B

_7-H*,7-H**= 10.5 Hz,

_7-H*,4-H= 1.6 Hz, 1 H, 7-H*), 1.71 (d, ²J_6-H*,6-H**

_6-H**,6-H*= 18.0 Hz, ⁴

_6-H**,7-H**= 4.9 Hz, 1 H,

_7-H**,6-H**= 5.1 Hz, 1 H, 7-H**), 2.47

trans

,4-

= 4.8 Hz, 1 H, 4-H), 2.71 (dqd, J_3-Htrans,2-H= 12.0 Hz, J_{3-Htrans,3-Me}

Htrans

_3-Htrans,4-H= 4.6 Hz, 1 H, 3-H^trans), 2.84 (dd,

_2-H,3-Htrans= 11.7 Hz,

7.4 Hz,

⁴J_2-H,6-H*= 2.1 Hz, 1 H, 2-H), 3.05 (dd, J_6-H**,6-H*= 18.5 Hz, J_6-H**,7-A

12.5 Hz; 2 H, Ph-CH₂), 7.30-7.40 (m_c, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-

H) ppm.

4.3 Hz, 1 H, 6-H**), 5.11 (s, 2 H, Ph-CH₂), 7.35 (m_c, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H,

¹³C NMR (125.81 MHz, CDCl₃):

= 13.50 (3-Me), 14.10 (2-Me), 18.32

(1-Me), 41.30 (C-7), 41.35 (C-3), 48.87 (C-6), 51.16 (C-1), 51.34 (C-2),

57.15 (C-4), 66.86 (Ph- H₂), 128.20 and 128.30 and 128.63 (C-2’’, C-3’’,

5‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.82 MHz, CDCl₃, Me₄Si as a standard):

= 15.05 (3-Me),

20.62 (1-Me), 36.01 (C-3), 45.13 (C-7), 45.94 (C-6), 46.74 (C-1), 51.37

(C-2), 57.71 (C-4), 66.16 (Ph- H₂), 128.41 and 128.57 and 128.66 (C-2’’,

C-4’’, C-5’’, C-6’’), 135.88 (C-1’’), 177.18 (C

OOR), 216.12 (C-5) ppm.⁴¹

In C₆D₆:

C-3’’, C-4’’, C-5’’, C-6’’), 135.83 (C-1’’), 172.09 (COOR), 215.85 (C-

5) ppm.⁴¹

¹H NMR (500.32 MHz, C₆D₆):

0.80 (s, 3 H, 1-Me), 0.85 (s, 3 H, 2-Me), 1.02 (dd, ²

= 0.72 (d, J_3-Me,3-H^trans_,= 7.5 Hz, 3 H, 3-Me),

In C₆D₆:

_7-H*,7-H**= 10.3 Hz, J_7-

¹H NMR (500.32 MHz, C₆D₆):

= 0.91 (d,

0.93 (s, 3 H, 1-Me), AB signal ( _7-A= 1.01,

A part additionally split by d, _7-A,4-H= 1.5 Hz; B part additionally split by

dd, ⁴_7-B,4-H= 1.1 Hz, 7-H₂), 1.56 (dd, ²

_7-B,6-H**= 4.5 Hz, _6-H*,6-H**= 18.1 Hz,

⁴J_6-H*,2-H= 2.1 Hz, 1 H, 6-H*), 2.13 (dqd,

_3-Htrans,2-H= 11.7 Hz, J_{3-Htrans,3-Me}

_{3-Me,3-Htrans}= 7.3 Hz, 3 H, 3-Me),

= 1.5 Hz, 1 H, 7-H*), 1.28 (d, J_6-H*,6-H**= 17.9 Hz, 1 H, 6-H*), 1.94

(dd, J_6-H**,6-H*= 17.9 Hz, J_6-H**,7-H**= 4.7 Hz, 1 H, 6-H**), 2.19-2.24 (m,

H*,4-H

_7-B= 0.95, ²

_7-A,7-B= 10.4 Hz;

evaluable as dd, J_7-H**,7-H*= 10.3 Hz, J_7-H**,6-H**= 4.7 Hz, 1 H, 7-H**),

trans

superintendet by 2.21-2.24 (m, 1 H, 4-H), 2.99 (qd, J_{3-H ,3-Me}= 7.5 Hz,

trans

J_{3-H ,4-H}= 4.6 Hz, 1 H, 3-H^trans), AB signal (δ_Ph-CH^A= 4.93, δ_Ph-CH^B= 4.89,

= 7.2 Hz,

_3-Htrans,4-H= 4.6 Hz, 1 H, 3-H^trans), superintendet by 2.18 (br. d,

²J_A,B= 12.4 Hz; 2 H, Ph-C

H₂), 7.01-7.11 (m, 3 H, 3‘‘-H, 4‘‘-H, 5‘‘-H), 7.13-

J_4-H,3-Htrans= 5.0 Hz, 1 H, 4-H), 2.43 (dd, J_2-H,3-Htrans= 11.5 Hz, J_2-H,6-H*

2.2 Hz, 1 H, 2-H), 3.20 (dd, J_6-H**,6-H*= 18.2 Hz, ⁴J_6-H**,7-A= 4.4 Hz, 1 H,

7.17 (m, 2 H, 2‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.81 MHz, C₆D₆):

Me), 41.12 (C-7), 41.55 (C-3), 48.56 (C-6), 51.05 (C-2)*, 51.18 (C-1)*,

57.13 (C-4), 66.64 (Ph- H₂), 128.34 and 128.47 and 128.68 (C-2’’, C-3’’,

C-4’’, C-5’’, C-6’’), 136.48 (C-1’’), 176.81 (

*Assignments interchangeable.

HRMS (pos. ESI): C₁₈H₂₆O₃N (M+NH₄⁺) calc. 304.1907 found 304.1910

δ = 13.44 (3-Me), 13.98 (2-Me), 18.17 (1-

6-H**), 4.90 (s, 2 H, Ph-C

7.17 (m, 2 H, 2‘‘-H, 6‘‘-H) superintendet by 7.15 (s, C₆D₆) ppm.

¹³C NMR (125.82 MHz, C₆D₆):

= 15.23 (3-Me), 20.40 (1-Me), 36.02 (C-

3), 44.71 (C-7), 45.83 (C-6), 46.47 (C-1), 51.35 (C-2), 57.64 (C-4), 65.96

(Ph- H₂), 128.38 and 128.67 and 128.83 (C-2’’, C-3’’, C-4’’, C-5’’, C-6’’),

136.50 (C-1’’), 171.87 (

H₂), 7.01-7.10 (m, 3 H, 3‘‘-H, 4’’-H, 5‘‘-H), 7.13-

OOR), 213.00 (C-5) ppm.⁴¹

OOR), 212.78 (C-5) ppm.⁴¹

HRMS (pos. ESI): C₁₇H₂₄O₃N (M+NH₄⁺) calc. 290.1751 found 290.1754

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

IR (film):

ꢀ

= 3259, 3246, 3183, 3179, 3063, 2958, 2901, 2873, 1725, 1719,

Me), 41.57 (C-7), 46.02 (C-3), 48.93 (C-6), 49.47 (C-1), 52.41 (C-2), 57.18

(C-4), 66.26 (Ph-

C-5’’, C-6’’), 135.91 (C-1’’), 174.12

HRMS (pos. ESI): C₁₈H₂₆O₃N (M+NH₄⁺) calc. 304.1907 found 304.1909

IR (film): = 3239, 3043, 3036, 2957, 2843, 1744, 1719, 1477, 1432, 1379,

1302, 1274, 1251, 1201, 1168, 1117, 1099, 1078, 1059, 1043, 1015, 942,

925, 841, 718, 697 cm⁻¹

H₂), 128.32 and 128.42 and 128.65 (C-2’’, C-3’’, C-4’’,

1478, 1396, 1370, 1317, 1271, 1258, 1211, 1172, 1129, 1091, 1062, 1033,

1011, 972, 931, 809, 741, 699 cm⁻¹

OOR), 216.11 (C-5) ppm.⁴¹

Characterisation of endo-trans-30:

ꢀ

cis

¹H NMR (500.32 MHz, CDCl₃, Me₄Si as a standard):

= 7.4 Hz, 3 H, 3-Me), 1.23 (s, 3 H, 2-Me), 1.29 (s, 3 H, 1-Me), 1.46 (ddd,

²J_7-H*,7-H**= 11.1 Hz, _7-H*,4-H= 1.7 Hz, ⁴J_7-H*,3-H^cis= 1.7 Hz, 1 H, 7-H*), 1.83

(dd, ²_6-H*,6-H**= 18.4 Hz, ⁴_6-H*,4-H= 0.9 Hz, 1 H, 6-H*), 1.98 (ddd, ²J_7-H**,7-

_H*= 11.1 Hz, ⁴

_7-H**,6-H**= 4.6 Hz, _7-H**,4-H= 1.1 Hz, 1 H, 7-H**), 2.08 (dd,

²J_6-H**,6-H*= 18.4 Hz, ⁴_6-H**,7-H**= 4.6 Hz, 1 H, 6-H**), 2.19 (br. d, ⁴J_4-H,6-H*

0.8 Hz, 1 H, 4-H), 2.81 (qd, J_{3-H ,3-Me}= 7.4 Hz, ⁴J_{3-H ,7-H*}= 1.7 Hz, 1 H, 3-

δ = 1.04 (d, J_3-Me,3-H

Benzyl (rel-1S,2S,3S,4S)-1,3-Dimethyl-5-oxobicyclo[2.2.1]heptane-

2-carboxylate (endo-trans-30)

6''

5''

4''

cis

H^cis

2''

**H

H^cis), AB signal (δ_Ph-CH= 5.13, δ_Ph-CH= 5.09, J_A,B= 12.4 Hz; 2 H,

Ph-C ₂), 7.29-7.40 (m_c, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H) ppm.

¹³C NMR (125.81 MHz, CDCl₃, Me₄Si as a standard):

= 15.79 (3-Me),

17.80 (1-Me, 2-Me), 38.60 (C-3), 39.91 (C-7), 49.05 (C-6), 49.74 (C-1),

53.58 (C-2), 57.75 (C-4), 66.67 (Ph- H₂), 128.16 and 128.32 and 128.66

H**

3''

endo-trans-30

C₁₈H₂₂O₃

286.37

(C-2’’, C-3’’, C-4’’, C-5’’, C-6’’), 135.88 (C-1’’), 176.13 (

5) ppm.⁴¹

COOR), 215.77 (C-

To a solution of diisopropylamine (0.277 m in THF, 3.4 mL, 97 mg,

0.96 mmol, 1.0 equiv.) BuLi (2.40 m in hexane, 0.40 mL, 62 mg,

HRMS (pos. ESI): C₁₈H₂₆O₃N (M+NH₄⁺) calc. 304.1907 found 304.1908

0.96 mmol, 1.0 equiv.) was added at –78°C. After 30 min a solution of 3-

Methylcyclopenten-1-on (92 mg, 0.96 mmol) in THF (1,5 mL) was added

IR (film):

1386, 1309, 1263, 1243, 1214, 1176, 1133, 1098, 1080, 1066, 1049, 1021,

959, 926, 831, 736, 698 cm⁻¹

ꢀ = 3247, 3063, 3037, 2969, 2877, 1745, 1723, 1483, 1455, 1412,

dropwise within 15 min. After stirring for 30 min benzyl tiglate (trans-18

)

(365 mg, 1.92 mmol, 2.0 equiv.) was added within 2 min. The reaction

mixture was stirred at –78°C for additional 15 min. Then the reaction

mixture was warmed to –40°C and stirred for additional 1 h. The reaction

was quenched by the addition of hydrochloric acid (1 m, 2.5 mL). The

layers were separated. The aqueous layer was extracted with Et₂O (3 ×

5 mL). The combined organic layers were washed with brine (5 mL), dried

over MgSO₄and the solvent was removed under reduced pressure. The

Characterisation of exo-trans-30:

¹H NMR [500.32 MHz, CDCl₃, contains 6 Mol-% EtOAc, an unknown

cis

substance (

= 1.25) and Me₄Si as a standard]:

= 0.98 (d, J_3-Me,3-H

7.5 Hz, 3 H, 3-Me), 1.25 (s, 3 H, 2-Me), 1.39 (s, 3 H, 1-Me), 1.46 (dd, ²J_7-

_H*,7-H**= 10.9 Hz, _6-H*,6-H**= 18.6 Hz,

_7-H*,4-H= 1.5 Hz, 1 H, 7-H*), 1.86 (d, ²

1 H, 6-H*), 1.94 (br. dd, ²J_7-H**,7-H*= 10.8 Hz, ⁴J_7-H**,6-H**= 5.1 Hz, 1 H, 7-

crude product was purified by flash chromatography (1.5

× 20 cm, 25 mL,

cis

H**), 2.13 (qd, J_{3-H ,3-Me}= 7.4 Hz, ⁴J_{3-H ,4-H}= 4.6 Hz, 1 H, 3-H^cis), 2.40 (dd,

-C₆H₁₂/EtOAc = 20:1). The title compound (f12-26, 193 mg, 70%] were

cis

obtained as colorless liquid.

J_4-H,3-H= 4.7 Hz, J_4-H,7-H**= 0.8 Hz, 1 H, 4-H), 2.83 (dd, J_6-H**,6-H*

18.6 Hz, ⁴

= 5.05, ²

_6-H**,7-H**= 5.0 Hz, 1 H, 6-H**), AB signal (δ_Ph-CH^A= 5.12, δ_Ph-CH

_A,B= 12.3 Hz; 2 H, Ph-CH₂), 7.29-7.39 (m_c, 5 H, 2‘‘-H, 3‘‘-H, 4‘‘-

Keywords: diastereoselectivity

•

Diels-Alder reactions

•

H, 5‘‘-H, 6‘‘-H) ppm.

¹³C NMR [125.81 MHz, CDCl₃, contains an unknown substance (

endo/exo selectivity • Michael additions • tandem reactions

= 29.79

ppm) and Me₄Si as a standard]:

δ = 16.23 (3-Me), 17.99 (1-Me) 25.56 (2-

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revealed the following annotations regarding their mechanism (in all

cases without compelling evidence) 77% referred to “Michael/Michael

tandem reactions”, 3% to an “anionic induced domino reaction”, and 7%

to “possibly a Michael/Michael tandem reaction but maybe a 1-step re-

action”.

a) R. Sustmann, M. Rogge, U. Nüchter, H. Bandmann, Chem. Ber. 1992,

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The syntheses of benzyl the benzyl crotonates cis- and trans-17 are de-

scribed in the Supporting Information.

The syntheses of benzyl tiglate (trans-18) and benzyl angelate (cis-18)

are described in the Supporting Information.

The syntheses of the deuterated neophyl acrylates cis- and trans-16 and

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the analogous benzyl ester provided a 94:6 mixture of the Diels-Alder

adducts endo-trans- and endo-cis-27 (Table 1). This suggests that the

minor diastereomer of ref.^28bwas endo-cis- rather than exo-trans-config-

ured.− b) Ref.^28hreported that the lithium dienolate 14 and tert-butyl

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trans-configured Diels-Alder adduct. For the reason explained in ref.^36a

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exo-trans-configured.

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The crystallographic data of the Diels-Alder product endo-trans-28 are

contained in CCDC 1859116. They can be obtained free of charge from

the Cambridge Crystallographic Data Centre via the link

www.ccdc.cam.ac.uk/data_request/cif.

10.1002/ejoc.201801193

European Journal of Organic Chemistry

FULL PAPER

the reaction conditions from (at least mainly) kinetic to (purely) thermo-

dynamic control.

a) B. J. Levandowski, K. N. Houk, J. Org. Chem. 2015, 80, 3530-3537.−

b) Cf. also F. M. Bickelhaupt, K. N. Houk, Angew. Chem. 2017, 129,

H. Nagaoka, K. Shibuya, K. Kobayashi, I. Miura, M. Muramatsu, Y.

Yamada, Tetrahedron Lett. 1993, 34, 4039-4042: 78% of the ester re-

acted antarafacially and 22% suprafacially in a THF solution whose tem-

perature was gradually raised from −78°C to room temp.

10204-10221; Angew. Chem. Int. Ed. 2017, 56, 10070-10086.

All C-Atoms (non-quaternary, quaternary, and in the methyl groups) were

assigned NMR-spectroscopically (edHSQC, HMBC).

H. Miyaoka, T. Baba, H. Mitome, Y. Yamada, Tetrahedron Lett. 2001, 42,

9233-9236: 25% of the ester reacted antarafacially and 75% supra-

facially in a THF solution at −78°C. When the temperature was gradually

raised to room temp. thereafter, 88% of the ester reacted antarafacially

and 12% suprafacially. The authors showed that the latter conditions pro-

voked an isomerization of the formerly dominating product, i. e., changed

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Dienolates of Cycloalkenones and α,β-Unsaturated Esters Form Diels–Alder Adducts by a Michael/Michael-Tandem Reaction Rather Than in One Step

DOI: 10.1002/ejoc.201801193

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