Diastereoselective transformation of arenes into highly enantiomerically enriched substituted cyclohexadienes

2040

FEATURE ARTICLE

Diastereoselective Transformation of Arenes into Highly Enantiomerically

Enriched Substituted Cyclohexadienes

T

ransformationof

é

Arenes into

r

Substit

a

uted Cycloh

l

exadie

d

nes Bernardinelli, Sandra Gillet, E. Peter Kündig,* Ronggang Liu, Alberto Ripa, Lionel Saudan

Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland

E-mail: Peter.Kundig@chiorg.unige.ch; fax +41(22)3287396

Received 1 June 2001

Introduction

Abstract: Sequential addition of a C-nucleophile and a C-electro-

phile to enantiomerically pure arene tricarbonyl chromium com-

plexes 3a,b, 6, and 8b, containing aryl bound chiral oxazoline,

SAMP-hydrazone and chiral imine auxiliaries affording substituted

The search for expedient chemo- and regioselective trans-

formations of simple starting materials is an important

cyclohexadienes. C-Nucleophiles included alkyl-, vinyl-, and phe- task in organic synthesis. Arenes, the subject of this study,

nyl-lithium reagents. C-Electrophiles included methyl iodide, allyl

are widely available, highly stable and readily derivatized

bromide, benzyl bromide, and propargyl bromides. The 1,3-cylo-

through reactions such as electrophilic aromatic substitu-

hexadienes were obtained with a 1,5,6-substitution pattern. The re-

tion, nucleophilic aromatic substitution,¹ortho-lithiation

sults are consistent with a diastereoselective exo-nucleophilic

followed by reaction with electrophiles,²and metal cata-

addition to an ortho position of the complexed arene, followed by

addition of the electrophile to the metal center. With allyl, ben-zyl,

lyzed substitution and coupling reactions.³Routes to dif-

ferentially substituted aromatic products are thus well

established. Benzene and its derivatives are attractive

starting materials because they have the potential to pro-

vide a rapid entry into complex alicyclic synthetic build-

ing blocks containing unmasked functionality, new

carbon-carbon bonds and new stereogenic centers.⁴How-

ever, this route to functionalized non-aromatic six-mem-

bered carbocycles is not common because substitutive

dearomatization reactions require disruption of the aro-

matic -system and this severely limits the scope of viable

methodologies.

and propargyl groups, direct reductive elimination then yielded

trans-5,6-substituted products. With methyl iodide, reductive elim-

ination was preceded by CO insertion and acetyl cyclohexadienes

were formed exclusively whose in situ deprotonation/alkylation

gave products in which three C-substituents had been added across

an arene double bond with complete regio- and stereocontrol. The

two path-ways reflect migratory aptitude to carbonylation. An X-

ray structure determination of the phenyl oxazoline complex 3a al-

lowed a rationalization of observed diastereoselectivity. Asymmet-

ric induction was very high with the oxazoline and the SAMP-

hydrazone complexes (>90% de) whereas the chiral benzaldehyde

imine complex 8b afforded the substituted diene aldehydes in mod-

erate enantiomeric purity (34–58% ee). Changing the reaction me-

dium from THF to toluene in reactions with 8b resulted in products

of the opposite chirality.

Our research in this area has focused on (arene) Cr(CO)₃

complexes. The dearomatization sequence involves nu-

cleophilic addition to the arene, electrophile (H, alkyl, al-

lyl, propargyl) addition to the metal, followed by

reductive elimination and decomplexation to give the

Key words: diastereoselective dearomatization, cyclohexadiene,

arene Cr(CO)₃complexes, imine , oxazoline, SAMP-hydrazone

Scheme 1

Synthesis 2001, No. 13, 08 10 2001. Article Identifier:

1437-210X,E;2001,0,13,2040,2054,ftx,en;M02601ss.pdf.

ISSN 0039-7881

FEATURE ARTICLE

Biographical Sketches

Transformation of Arenes into Substituted Cyclohexadienes

2041

Gérald Bernardinelli was born

in 1945 in Nice, France. He stud-

ied chemical engineering at the

School of Engineering in Geneva

(diploma 1968) and then chemis-

try at the University of Geneva.

He received his diploma degree

in chemistry in 1973 and his PhD

in 1978 in the domain of structur-

al chemistry of macrocyclic

musks. From 1978 to 1983, he

was a Research Chemist in the

field of X-ray crystallography.

Since 1983 he is Head of the X-

ray structure determination unit

for organic and organometallic

compounds of the Faculty of Sci-

ences of the University of Gene-

va. His scientific interests are X-

ray diffraction analysis in rela-

tion to structural chemistry of

small and medium-sized mole-

cules.

Sandra Gillet was born in 1974

in Voiron, France. She studied

chemistry at the University Jo-

seph Fourier in Grenoble, France

and obtained her M.S. degree

(DEA) in 1997 with a research

project on the asymmetric syn-

thesis of (3S,4S)-4-amino-3-hy-

droxy-5-phenyl-pentanoic acid.

This work was carried out under

the direction of Dr. Andrew E.

Greene. Following a research pe-

riod at Rhône-Poulenc Agro in

Lyon, she joined the group of

Prof. E. P. Kündig in Geneva for

a year and contributed to the re-

search results presented in this

article.

E. Peter Kündig was born in

1946 in Weinfelden, Switzer-

land. He studied chemistry at the

Federal Institute of Technology

(ETH) in Zurich and obtained the

diploma degree in 1971. In the

same year he moved to the Uni-

versity of Toronto where he car-

ried out research on transition

metal carbonyl and dinitrogen

complex fragments by matrix

isolation techniques under the

guidance of Prof. G. A. S. Ozin.

He obtained his PhD degree in

Toronto in 1975 and then took up

a postdoctoral position at the

University of Bristol, UK, with

Dr. P. L. Timms. His studies

there focused on the synthesis of

organometallics via metal vapor/

ligand cocondensation. Thereaf-

ter, he joined the University of

Geneva, Switzerland, where he

started his own research in 1978

and where he is now Professor of

Organic Chemistry. His current

research interests center on the

development of new asymmetric

methodologies via transition

metals, their application in or-

ganic synthesis and on the design

of new chiral ligands and asym-

metric catalysts.

Ronggang Liu was born in 1962

in Tianjin, China. He received

his B.S. in 1983 and his M.S. in

1986 from Nankai University,

China. He carried out research at

the Institute of Chemistry of the

Academica Sinica in Beijing as

research assistant (1986–89) and

then joined the group of Prof. E.

P. Kündig in Geneva as graduate

student working on the dearoma-

tization of Cr(CO)₃bound are-

nes. After receiving his PhD

from the University of Geneva,

Switzerland, in 1993, he moved

to the University of Virginia as a

postdoctoral fellow in the group

of Prof. W. Dean Harman. He is

currently working as investigator

at GlaxoSmithKline Pharmaceu-

ticals, Inc. in King of Prussia,

Pennsylvania.

Alberto Ripa was born in 1962

in Milan, Italy. He received his

„Laurea“ in Chemistry from the

University of Milan in 1985,

working under the guidance of

Prof. C. Scolastico. He spent two

years (1986–88) at the Istituto di

Ricerche Farmacologiche Mario

Negri of Milan, working with

Prof. E. Mussini on asymmetric

synthesis of -aminophosphonic

acids. Following a short stay at

the University of Milan with

Prof. G. Jommi, he moved to the

University of Geneva in 1988 to

join Prof. E. P. Kündig’s group.

In 1991 he was appointed

„Maître Assistant“. During the

five-year stay in Geneva he car-

ried out research on the transfor-

mation of arene tricarbonyl

chromium complexes into cylco-

hexadienes and on the synthesis

of new chiral ligands. He re-

turned to Italy in early 1995 and

joined the Politecnico of Milan

as „Ricercatore“ (Assistant Pro-

fessor), working on transition-

metal-mediated stereospecific

polymerization of 1-alkenes and

1,3-dienes. In 1996, he took up a

position at the Central Laborato-

ries of REDA S.p.a., Milan,

where he is now Research and

Development Manager. His cur-

rent research interests focus on

the development of new materi-

als based on polymers.

Lionel Saudan was born in

Geneva, Switzerland in 1968. He

completed his undergraduate

studies in Chemistry at the Uni-

versity of Geneva in 1993. He

carried out graduate studies on

the asymmetric synthesis of new

chiral amines and their use in or-

ganic and organometallic synthe-

sis at the University of Geneva

under the supervision of Prof. E.

P Kündig and obtained his doc-

toral degree from the University

of Geneva in 1998. With a post-

doctoral grant from the Swiss

National Science Foundation he

then joined the group of Prof. J.

M. Tour at the University of

South Carolina and the following

year at Rice University, Houston,

working on the synthesis of new

macromolecules. He is currently

member of the Research Divi-

sion of Firmenich S.A. in Gene-

va

and

works

on

the

development of new organome-

tallic catalysts for the synthesis

of perfumery ingredients.

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

2042

G. Bernardinelli et al.

FEATURE ARTICLE

trans disubstituded cyclohexadiene. With alkyl halides re-

ductive elimination is preceded by migratory CO inser-

tion. Both the complexation and the one-pot procedure of

addition of two substituents across an arene double bond

in a regio- and stereoselective manner are reactions that

occur in high yield (Scheme 1).⁵

Resonance donor substituents on the ring direct attack to

the meta position^6–8while bulky substituents and acceptor

substituents direct preferentially para.⁹Functional groups

that can efficiently coordinate the incoming organolithi-

um reagent direct ortho.¹⁰

In this article we report details of our studies of asymmet-

ric variants of one of the four chiral dearomatization ap-

proaches that have been realized using this reaction

sequence. (Scheme 2)^11–13

Scheme 3

phile could be directed preferentially to one of the diaste-

reotopic ortho-positions of the complexed benzene. The

data reported here confirm this hypothesis and show that

the absolute configuration of the two new stereogenic cen-

ters can be easily controlled via the chiral auxiliaries.

Complexes 3a and 3b were synthesized by arene ex-

change with (naphthalene) Cr(CO)₃2.²⁰The SAMP hy-

drazone complex 6 and the benzaldehyde imine

complexes 8a and 8b were obtained by condensation of

(S)-1-amino-2-methoxymethylpyrrolidine (SAMP) 5, and

the enantiomerically pure amines 7a,b with (benzalde-

hyde) Cr(CO)₃4 (Scheme 4).

Scheme 2

The methodology described here is an arene bound chiral

auxiliary approach, with the auxiliary chosen to lead to di-

astereoselective ortho-addition to the complexed arene (1.

in Scheme 2)^14,15

Oxazoline complexes 3a and 3b reacted with alkyl-, vi-

nyl-, and phenyl-lithium reagents to give the correspond-

ing anionic cyclohexadienyl complexes 9. In situ

alkylation, allylation and propargylation afforded, after

oxidative decomplexation (by exposure to air), the highly

diastereomerically enriched cyclohexadienes 10–22. The

one-pot sequence was applied to a number of reactive nu-

cleophiles and electrophiles (Scheme 5, Table 1) and led

to products of high synthetic potential, given that oxazo-

lines are readily cleaved by N-alkylation and NaBH₄re-

duction to give the corresponding aldehydes.²¹

Aryl oxazoline (and also benzylidene cyclohexylamine)

complexes have been shown previously to undergo selec-

tive ortho-additions of C-nucleophiles. While the inter-

mediate anionic complex can be isolated and has been

structurally characterized,¹⁶for the transformations with

the electrophiles shown in Scheme 3 this is not required

and in situ procedures have been used throughout.¹⁷

The organolithium reagents MeLi, BuLi, vinylLi and

PhLi selectively added to the arene ortho position (1,4 ad-

dition reaction), no products arising from 1,2 addition or

from arene lithiation were observed.²²High diastereose-

lectivities were obtained with MeLi, BuLi and vinylLi,

whereas PhLi gave an approximate 4:1 mixture of diaste-

reoisomers in the reaction with complex 3a (entry 4) and

a much enhanced 11.5:1 mixture of diastereoisomers in

Results and discussion

For a diastereoselective approach we selected the chiral

phenyl oxazoline complexes 3a and 3b derived from L-

valinol and L-tert-leucinol,¹⁸the chiral phenyl SAMP-

hydrazone¹⁹complex 6 and the chiral imine complexes 8a

and 8b. We anticipated that the addition of a C-nucleo-

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2043

Table 1 Cyclohexadienes 10–22 Obtained by Alkylation, Allyla-

tion or propargylation from 3

Entry R

R’Li^a

R”X

Product Diast.

ratio^b

Yield

[%]

1

i-Pr MeLi

(3a)

allylBr

10a,b

96: 4

61

2

3

4

5

'

n-BuLi

vinylLi

PhLi

allylBr

11a,b

12a,b

13a,b

14a,b

96:4

54

48

81:19 60

85:15 86

vinylLi

TMS- -

CH₂Br^c

6

'

MeLi

TMS- -

CH₂Br^c

15a,b

93:7

77

7

8

9

'

MeLi

benzylBr

MeI^d

16a,b

21a,b

17a,b

95:5

51

54

58

t-Bu MeLi

(3b)

allylBr

>98:2

10

11

12

13

'

n-BuLi

PhLi

allylBr

18a,b

19a,b

>98:2

92:8

62

54

79

58

MeLi

propargylBr^c20a,b

MeI^d

22a,b

>98:2

^aReactions were carried out in THF or in THF-toluene, see experi-

mental section.

Scheme 4

^bDiastereomeric ratios were determined by ¹H NMR in the crude

product. The indication >98:2 means that a single diastereoisomer

was observed. The major diastereoisomers are 10a–22a.

^cAddition of HMPA together with the electrophile. This improved

yields by about 20%.

the reaction with complex 3b (entry 11). Higher diastere-

oselectivities in reactions with 3b compared to those with

3a are also apparent with MeLi and BuLi (compare entries

1 with 9 and 2 with 10). The lower diastereoselectivity of

the phenyl lithium reaction compared to the alkyl lithium

additions may reflect the lower degree of aggregation of

^dAddition of MeCN together with the electrophile gave a cleaner re-

action and improved yield.

PhLi in THF and its resulting higher reactivity.²³Trapping

with allyl bromide, propargyl bromide, or trimethylsilyl

propargyl bromide afforded the products 10–20. As found

previously and in keeping with the low migratory aptitude

to carbonylation of the propargyl group, propargylation at

the metal is followed by reductive elimination without pri-

or migratory CO insertion.^1,7The situation is less clear-cut

for the allyl group. In the substituted complexes used in

this study, the major products in the crude reaction mix-

ture, and the only products isolated after chromatography,

are the products without carbonylation. In contrast, the se-

quential addition of dithiane Li and allyl bromide to (ben-

zene) Cr(CO)₃exclusively yielded the carbonylated

product.²⁴Secondary products were observed in the crude

reaction mixtures of the reactions in entries 1–4, 7, and 9–

11 in amounts varying between 5% and 15%. They were

tentatively identified as the carbonylated products and

while their isolation was not practical, they account for the

lower yields of the allyl products compared to the propar-

Scheme 5

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

2044

G. Bernardinelli et al.

FEATURE ARTICLE

gyl products 14 and 15. Methyl iodide gave carbonylated

products exclusively. Enolate formation and methylation

from the sterically more accessible face then afforded

products 21 and 22. The relative configuration of the two

new stereogenic centers with respect to that of the auxilia-

ry was established unambiguously by a crystal structure

determination of 21a.^14aA rationale for the observed dias-

tereoselectivity and its increase on going from the i-propyl

oxazoline complex 3a to the t-butyl oxazoline complex 3b

is provided by the X-ray structure of complex 3a (Figure

1).^25,26

Scheme 6

In an earlier study, the SAMP-hydrazone complex 6 has

been shown to react with alkyl- and phenyl lithium re-

agent selectively at one of the two diastereotopic ortho-

positions. The resulting cyclohexadienyl complex could

be rearomatized by hydride abstraction without cleavage

of the arene Cr bond. Removal of the auxiliary then pro-

vided enantiomerically pure planar chiral ortho-substitut-

ed benzaldehyde complexes.²⁸Figure 2 shows an X-ray

structure determination of 6 with the presence of two rot-

amers (syn and anti) in the unit cell in a 1:1 ratio.²⁹

Figure 1 Perspective view of the crystal structure of 3a showing the

syn- (bottom) and anti-conformers (top)

The structure shows that both the syn-rotamers and the

anti-rotamers are present in the unit cell in a ratio of 1:1.

In the syn-rotamer the i-propyl group is located far away

from the Cr(CO)₃group so that there is no adverse steric

interaction between these two fragments. It is therefore

unlikely that one of the rotamers of 3a is strongly favored

and this should also hold for 3b. The organolithium re-

agent coordinates to the oxazoline nitrogen and then adds

to the exo-face of the arene. Product stereochemistry re-

flects a transition state in which the R substituent of the

chiral auxiliary syn to the metal fragment (Scheme 6). The

transition state arising from the anti-rotamer is disfavored

because of steric interactions between the R and R groups

(as usual, the organolithium reagents are represented as

monomers, even though aggregates may be the reacting

species). These interactions become more important with

the size of R and this readily accounts for the higher in-

duction by the t-butyl oxazoline in 3b compared to the i-

propyl analogue 3a. The model shown is in accordance

with the observed diastereoselectivity, with the observa-

tion of better induction by R = t-Bu than i-Pr and with the

subsequent finding of the same mode of action in chiral

oxazoline mediated diastereoselective ortho deprotona-

tions of ferrocenes.²⁷

Figure 2 Perspective view of the crystal structure of 6 showing the

syn- (top) and anti-conformers (bottom)

Dearomatization via sequential nucleophile/electrophile

addition to the phenyl SAMP-hydrazone complex 6 is

shown in Scheme 7.

Analysis of the crude reaction mixture by ¹H NMR spec-

troscopy showed that the diastereoselectivity was very

high and often exceeded the value given in the scheme.

1

The diastereomeric excess was probed by H NMR inte-

gration of the C-H singlet of the hydrazone function. This

method is reliable because conversion of the racemic al-

dehydes 30–33¹⁷had shown that singlets associated with

these hydrogens are distinct for each diastereoisomer.

Hydrolysis of 26a to 29a (50% H₂SO₄/MeOH) afforded

the highly enantioenriched aldehydes (–)-30–(–)-33

(Scheme 8). The reverse reaction, treatment of (–)-30 with

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2045

Scheme 8

Scheme 9

Scheme 7

tion to either of the two diastereotopic ortho positions of

the arene. A more rigid transition state can be expected by

the incorporation of a function capable of chelating the in-

coming PhLi reagent. Our choice fell on complex 8b and

as shown in entries 2–4, this led to moderate asymmetric

induction. A polar additive, HMPA or, preferably DMPU

because of its non-carcinogenic nature, after the stereode-

fining nucleophilic addition reaction gives a higher prod-

uct yield because it increases the efficiency of the

electrophile addition step (entries 2 and 3 versus entry 4).

Entries 2 and 3 also show that the reaction is stereospecif-

ic. Changing the reaction medium to toluene resulted in a

drop in yield presumably because the S_N2 reaction be-

tween the anionic cyclohexadienyl intermediate and the

electrophile is very slow.²⁴Remarkably, asymmetric in-

duction, while modest, is opposite in toluene from that

found in THF (entries 4 and 5). Models of transition states

SAMP-hydrazine gave 28a in 99% diastereomeric purity,

confirming that no partial racemization had occured dur-

ing SAMP hydrolysis. This analysis was also carried out

with 31–33. Structural assignment of the aldehydes (–)-

30–(–)-33 as shown in Scheme 8 is based on the compar-

ison of the sign of rotation of (–)-30 with that of the same

product obtained by conversion of 21a. This was done via

ketone protection of 21a as a dioxolane (ethylene glycol,

TsOH, toluene), followed by oxazoline N-alkylation

(MeOTf) and reduction (NaBH₄).

With the absolute configuration of (–)-30 known,^14athe

relative stereochemistry of 26–29a must be as shown in

Scheme 8. Asymmetric induction in the 1,4-addition of

organolithium reagents to complex 6 is interpreted in

terms of a preference of a chair-like transition state over

the boat-like transition state that is adopted in the addition

of the chelated organolithium reagent (Scheme 9).

Table 2 Formation of Chiral Compounds 34

Entry Complex Solvent Additive (S,S)-34:

(R,R)-34^a

ee

(%)

Yield

(%)

We next turned our attention to chiral imine auxiliaries.

Imines offer the advantage of being readily hydrolyzed

and do not require additional steps for removal. Moreover,

excellent ortho-selectivity in Cr(CO)₃complexed benzal-

dehyde imines has been demonstrated in both nucleo-

1

2

3

4

5

(S)-8a

(S)-8b

(R)-8b

(S)-8b

(R)-8b

THF

HMPA 50:50

HMPA 23:77

DMPU 79:21

0

70

71

78

50

54

58

38

34

philic

addition

reactions

and

in

lithiation

reactions.^16,17,28,30

toluene HMPA 69:31

toluene DMPU 67:33

First data with complexes 8a and 8b are shown in Scheme

10 and Table 2. The imine complex 8a afforded product

34 in good yield but as a racemate (entry 1). This was not

wholly unexpected because coordination of the incoming

organolithium compound to the imine nitrogen is not like-

ly to result in a transition state that favors selective addi-

^aThe ratio of enantiomers was determined by HPLC (column Daicel

OD). The absolute configuration was assigned on the basis of the sign

of optical rotation.

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

2046

G. Bernardinelli et al.

FEATURE ARTICLE

Cr(CO)₆was obtained from Strem Chemicals and used as received.

THF and diethylether were dried and distilled from sodium/ben-

zophenone ketyl under nitrogen before use. Toluene was distilled

over Na under nitrogen. BuLi (Fluka, 1.7 M), MeLi (Fluka, 1.6 M),

PhLi (Fluka, 1.6 M) were titrated before use.³³Tetravinyltin (Ald-

rich) was used as received. (S)-Valinol and (S)-tert-leucinol were

prepared by a literature method.¹⁸(4S)-4,5-Dihydro-4-(1,1-dimeth-

ylethyl)-2-phenyloxazole 1b was prepared by using Meyers proce-

dure.³⁴(–)-1-(S)-(2-Methoxy-phenyl)-ethyl)-amine [(–)-(S)-7b]³⁵

was synthesized using a method previously described for the prep-

aration of chiral non-racemic benzylic amines via alkylation of

based on Li-chelation can be drawn up for the nucleo-

philic addition but the dataset at this stage is too small to

make valid proposals. The switch in asymmetric induction

on going to a less polar solvent where chelation is stronger

but where the agglomeration state of the organolithium re-

agent also is larger indicates a change in transition state

geometry. The question is intriguing and will be investi-

gated more fully. While the results are preliminary, we

feel that their inclusion in this article is useful.

chiral imines.³⁶

(

⁶-Naphthalene) Cr(CO)₃2,^20,37and ( ⁶-benzalde-

hyde) Cr(CO)₃^10b,384 were prepared as previously described. All

other chemicals were purchased from Aldrich or Fluka and were pu-

rified following standard literature procedures.³⁹

Synthesis of Chiral [(arene) Cr(CO)₃] Complexes 3, 6, and 8

Tricarbonyl{ ⁶-[(4S)-4,5-dihydro-4-(1-methylethyl)oxazol-2-

yl]benzene}chromium (3a)

In a 50 mL anhyd reactor a mixture of 1a (5.33 g, 28.16 mmol) and

(

⁶-naphthalene) Cr(CO)₃2 (3.720 g, 14.08 mmol) in anhyd THF

(35 mL) was submitted to three freeze/pump/thaw cycles and then

heated at 70 °C under stirring and under nitrogen atmosphere in the

absence of light. After 16 h the reaction mixture was allowed to cool

to r.t. and the solvent was evaporated under vacuum. The residue

was dissolved in anhyd Et₂O (10 mL) and filtered through celite un-

der N₂. The orange solution was concentrated under vacuum. The

crude product was purified by flash chromatography (hexane Et₂O,

5:1). The yellow orange band was collected. Recrystallization of the

oily crude product from hexane Et₂O, 1:1 at 78 °C afforded 3a

(2.910 g, 61%) as a yellow solid; 3.25 g of ligand 1a (88% based on

unconverted ligand) was recovered, mp = 51–52 °C.

[ ]²⁰_D–140 (c 0.48, CHCl₃).

IR (hexane): 1926vs, 1922vs cm^–1.

¹H NMR (C₆D₆, 200 MHz): = 0.77 (d, 3 H, J = 6.7 Hz), 0.93 (d, 3

H, J = 6.7 Hz), 1.45–1.55 (m, 1 H, J = 6.7Hz), 3.60–3.90 and 4.20–

4.42 (m, 6 H), 5.70–5.77 (bd, 1 H, J = 6.6 Hz), 5.78–5.85 (bd, 1 H,

J = 6.2 Hz).

Scheme 10

In conclusion, we have shown that chiral auxiliaries capa-

ble of coordinating to the incoming organolithium reagent

can lead to high diastereoselectivity in the Cr(CO)₃medi-

ated dearomatization. With all three auxiliaries, reactions

are highly chemoselective (the organolithium reagents act

as nucleophiles rather than as bases) and regioselective

(exclusive 1,4-addition rather than 1,2-addition). The syn-

thetic protocols described in this article are useful for the

transformation of simple aromatics into highly enantio-

merically enriched alicyclic compounds with functional-

ity suitable for their use as a building block for complex

synthesis.

MS: m/z (%) 325 (3), 269 (2), 241 (33), 52 (100).

Anal. Calcd for C₁₅H₁₅CrNO₄: C, 55.38; H, 4.58; N, 4.31. Found: C,

55.42; H, 4.65; N, 4.38.

(4S)-4,5-Dihydro-4-(1,1-dimethylethyl)-2-phenyloxazole (1b)

A 250 mL two necked round bottom flask, equipped with a reflux

condenser, magnetic bar and rubber septum, were dried under vac-

uum with a heating gun. After cooling to r.t. under N₂, the flask was

charged with anhyd CH₂Cl₂(100 mL) and benzoylchloride (4.16

mL, 35.8 mmol). To this resulting solution was added via syringe a

solution of (S)-(+)-tert-leucinol (4.200 g, 35.8 mmol) and Et₃N (5

mL, 35.8 mmol) in CH₂Cl₂(22 mL) at 0 °C under N₂. The flask was

protected from light with aluminum paper and the solution was

stirred at room temperature overnight. The solvent was removed on

a rotary evaporator. The white solid was treated with SOCl₂(8.60

mL) at 0 °C under N₂. After stirring for 5 h at r.t., the solution was

diluted with Et₂O (50 mL), cooled to 0 °C and carefully treated with

aq NaOH (20%) until pH 7. The phases were separated and the aq

phase extracted with Et₂O (3 50 mL). The combined organic

phases were dried (MgSO₄), filtered, and evaporated. Bulb to bulb

distillation afforded 1b (6.520 g, 89%) as a white solid, mp = 32–

33 °C.

Reactions and manipulations involving organometallics were car-

ried out under an atmosphere of purified nitrogen using an inert gas/

vacuum double manifold and standard Schlenk techniques.³¹Col-

umn chromatography (f.c.) was carried out in air by the flash meth-

od described by Still (Silicagel: Merck 60).³²

1

All 200 MHz or 400 MHz H and 50.3 or 100.5 MHz ¹³C NMR

Spectra were recorded at room temperature on a Varian-XL-200

spectrometer or a Brucker 400 MHz spectrometer as indicated.

Chemical shifts are reported in parts per million (ppm) relative to

tetramethylsilane as the internal standard and referenced to the pro-

ton signal for the residual solvent (C₆D₆, = 7.15 for ¹H and

= 128.0 for ¹³C). Mass spectra were obtained on a Varian CH 4 or

SM 1 spectrometer, relative intensities are given in parentheses.

High-resolution mass spectra were measured on a VG analytical

7070E instrument (data system 11 250, resolution 7000). IR spectra

were recorded using NaCl cells on a Perkin-Elmer 1650 FT-IR

spectrometer. Melting points were determined on a Büchi 510 appa-

ratus and are not corrected. Elemental analyses were performed by

H. Eder, Service de Microchimie, Institut de Chimie Pharmaceu-

tique, Université de Genève.

[ ]²⁰_D–99.4 (c 1.3, CHCl₃).

IR (CH₂Cl₂): 2960s, 2905m, 2870m, 1652vs, 1495m, 1479m,

1450m, 1394m, 1356s, 1340m, 1306m, 1088s, 1072m, 1056m,

1024s, 996s cm^–1.

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2047

¹H NMR (CDCl₃, 200 MHz): = 0.94 (s, 9 H, C(CH₃)₃), 4.30 (dd,

1 H, J = 7.5 Hz), 4.22 (dd, 1 H, J = 7.5, 8.5 Hz), 4.34 (dd, 1 H,

J = 8.5, 10 Hz), 7.34–7.52 (m, 3 H), 7.91–7.99 (m, 2H).

[

⁶-Benzylidene-(1-(S)-phenyl-ethyl)-amine]tricarbonyl-

chromium (8a)

⁶-Benzaldehyde) Cr(CO)₃(2.425 g, 10.0 mmol), ( )-1-(S)-phe-

(

nyl-ethylamine (1.4 mL, 11.01 mmol, Fluka ee 96%), MgSO₄(10

g) and freshly distilled and degassed diethyl Et₂O (25 mL) were

placed into a Schlenk tube and stirred under N₂at r.t. for 43 h. After

filtration over celite, volatiles were removed in vacuum and the red

residue was recrystallized from hexane at 10 °C to give (+)-8a

(3.041 g, 87%) as an orange solid.

[ ]²⁰_D+158.8 (c 0.17, CHCl₃).

IR (CHCl₃): 1977s, 1909s, 1645w cm^-1.

¹H NMR (200 MHz, CDCl₃): = 1.56 (d, 3 H, J = 6.4 Hz), 4.52 (q,

1 H, J = 6.4 Hz), 5.4–5.5 (m, 3 H), 5.75 (d, 1 H, J = 6.7 Hz), 5.81

(d, 1 H, J = 6.1 Hz), 7.2–7.4 (m, 5 H), 7.87 (s, 1 H).

MS m/z (%): 345 (1, M⁺), 289 (29), 261 (100), 209 (10), 155 (93),

129 (12), 105 (33), 77 (8), 52 (79).

MS: m/z (%) 203 (3), 188 (3), 146 (100), 118 (19), 105 (20), 91 (21),

77 (18).

HRMS: m/z calcd for C₁₃H₁₇NO: 203.1310. Found: 203.1305.

Tricarbonyl{ ⁶-[(4S)-4,5-dihydro-4-(1,1-dimethylethyl)oxazol-

2-yl]benzene}chromium (3b)

Phenyloxazoline 1b (6.20 g, 30.50 mmol), ( ⁶-naphthalene)

Cr(CO)₃2 (4.03 g, 15.25 mmol), and THF (60 mL) were placed in

a 100 mL anhyd flask equipped with a reflux condenser, a magnetic

stirring bar and submitted to three freeze-pump-thaw cycles. The

solution was then refluxed in the dark for 24 h by means of an oil

bath at 80 °C. The dark reaction mixture was allowed to cool to r.t.

and stripped of volatiles in vacuum. The residue was taken up in an-

hyd Et₂O (50 mL) and the solution filtered over celite. After remov-

al of solvent, the yellow-orange oily residue was purified by flash

chromatography. After elution of ligand 1b and a first orange-red

band with hexane Et₂O, 6:1, a second yellow-orange band contain-

ing 3b was eluted with pure Et₂O. The crude product was recrystal-

lized from hexane Et₂O (ca. 4:1) at 78 °C to yield complex 3b

(4.12 g, 80%) as orange crystals, mp = 66–67 °C. Excess of ligand

1b was recovered quantitatively.

{

⁶-Benzylidene-[1-(S)-(2-methoxy-phenyl)-ethyl]-amine}tri-

carbonylchromium (8b)

⁶-Benzaldehyde) Cr(CO)₃(1.602 g, 6.61 mmol), (–)-1-(S)-(2-

(

methoxy-phenyl)-ethyl)amine ((–)-(S)-7b) (1.090 g, 7.20 mmol, ee

96%), MgSO₄(10 g) and freshly distilled and degassed Et₂O (50 ml)

were placed into a Schlenk tube and stirred under N₂at r.t. for 24 h.

After filtration over celite, volatiles were removed in vacuum at

–20 °C to give (+)-8b (2.416 g, 97%) as an orange solid, mp 70–

72 °C.

[ ]²⁰–176.5 (c 1, CHCl₃).

D

IR (CH₂Cl₂): 1985vs, 1925vs, 1889m, 1657s cm^-1.

¹H NMR (CDCl₃, 200 MHz): = 0.92 (s, 9 H), 3.98 (dd, 1 H, J = 8,

10 Hz), 4.22 (t, 1 H, J = 8Hz), 4.32 (dd, 1 H, J = 8, 10 Hz), 5.27 (t,

1 H, J = 6.1 Hz), 5.29 (t, 1 H, J = 6.6 Hz), 5.99 (d, 1 H, J = 6.6 Hz),

6.10 (d, 1 H, J = 6.1 Hz).

[ ]²⁰_D+94.6 (c 0.24, CH₂Cl₂).

IR (CH₂Cl₂): 1973s, 1900s, 1643w cm^-1.

¹H NMR (400 MHz, C₆D₆): = 1.64 (d, 3 H, J = 6.9 Hz), 3.43 (s, 3

H), 4.36–4.48 (m, 3 H), 5.03 (q, 1 H, J = 6.9 Hz), 5.11 (d, 1 H,

J = 6.4 Hz), 5.42 (d, 1 H, J = 6.4 Hz), 6.62 (d, 1 H, J = 7.4 Hz), 7.03

(dt, 1 H, J = 7.4, 1 Hz), 7.15 (dt, 1 H, J = 7.4, 1.5 Hz), 7.38 (s, 1 H),

7.79 (dd, 1 H, J = 7.4, 1.5 Hz).

MS: m/z (%) 339 (10), 283 (5), 255 (100), 171 (10), 155 (35), 52

(100).

HRMS: m/z calcd for C₁₆H₁₇CrNO₄: 339.0562. Found: 339.0542.

Anal. Calcd. for C₁₆H₁₇CrNO₄(339.31): C, 56.63; H, 5.05; N, 4.13.

Found: C, 56.64; H, 5.11; N, 4.11.

¹³C NMR (100 MHz, C₆D₆): = 23.6, 54.8, 62.4, 91.0, 91.2, 92.6,

92.9, 93.3, 100.9, 110.6, 121.1, 127.6, 128.1, 132.9, 155.5, 156.7,

232.5.

MS: m/z (%) 319 (32; M⁺– 2CO), 291 (95), 276 (29), 262 (3), 186

(11), 171 (18), 155 (87), 135 (36), 129 (12), 105 (11), 91 (12), 77

(10), 52 (100).

[

⁶-Benzylidene-(1S)-(2-methoxymethyl-pyrrolidin-1-yl)-

amine] tricarbonyl chromium (6)

⁶-Benzaldehyde) Cr(CO)₃(3.400 g, 14.0 mmol), (S)-1-amino-2-

(

(methoxymethyl)-pyrrolidine (SAMP, 1.900 g, 14.7 mmol), molec-

ular sieves (4 Å, 1 g) and freshly distilled and degassed Et₂O (50

mL) were placed into a Schlenk tube and stirred under N₂in the dark

at r.t. for 18 h. After filtration over celite, volatiles were removed in

vacuum and the yellow residue was recrystallized (hexane-

Et₂O, 1:1) to give (–)-6 (5.510 g, 91%) as a yellow solid, mp 74–

76 °C.

HR-MS: m/z calcd for C₁₆H₁₇NOCr: 291.0715. Found: 291.0731.

Sequential Nucleophile/Electrophile Additions to Complexes 3a

and 3b

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-methyl-cyclohexa-1,3-dienyl]-4-

isopropyl-4,5-dihydro-oxazole (10a)

To a stirred solution of complex 3a (335.3 mg, 0.988 mmol) in THF

(10 mL) at 90 °C under N₂was added dropwise MeLi (0.732 mL

of a 1.62 M Et₂O solution, 1.185 mmol). The solution was warmed

to –78 °C over a period of 3 h and then allylbromide (0.865 mL, 10

equiv, freshly distilled from P₂O₅) was added. The solution was

slowly warmed to r.t. overnight and then the volatiles were removed

in vacuum. The residue was dissolved in Et₂O (40 mL) and washed

with sat. aq NH₄Cl (10 mL) and H₂O (2 5mL). The combined aq.

phases were extracted with Et₂O (3 10 mL). The combined organ-

ic phases were dried (MgSO₄), exposed to sunlight for a few hours,

filtered through celite and evaporated. HPLC analysis (hexane

EtOAc, 40:1; 5mL/min) showed a 95:5 ratio of the diastereoisomers

10a (major, 11.1 min) and 10b (10.1 min). Flash chromatography

(hexane-Et₂O, 7:1) afforded 10a (148.7 mg, 61%).

[ ]²⁰_D–10.0 (c 10, CH₂Cl₂).

IR (CH₂Cl₂): 1962vs, 1890vs, 1560s, 1460m, 1330m, 1220m,

1120m cm^-1.

¹H NMR (400 MHz, C₆D₆): = 1.40–1.50 (m, 1 H), 1.60–1.75 (m,

3 H), 2.58–2.68 (m, 1 H), 2.85–2.92 (m, 1 H), 3.18 (s, 3 H), 3.38

(dd, 1 H, J = 6.8,9.4 Hz), 3.54 (dd, 1 H, J = 3.3,9.4 Hz), 3.62–3.70

(m, 1 H), 4.41 (t, 1 H, J = 6.4 Hz), 4.71 (t, 2 H, J = 6.4 Hz), 5.27 (d,

2 H, J = 6.4 Hz), 6.24 (s, 1 H).

MS m/z (%): 354 (17), 298 (2), 270 (12), 165 (100), 52 (68).

HR-MS: m/z calcd for C₁₆H₁₈CrN₂O₄: 354.0671. Found: 354.0399.

[ ]²⁰–517.4 (c 1.04, CHCl₃).

D

IR (CH₂Cl₂): 3075w, 3065w, 3055w, 3050w, 3040w, 2965s,

2925m, 2910m, 2875m, 1652m, 1611s, 1466w, 1455w, 1404w,

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

2048

G. Bernardinelli et al.

FEATURE ARTICLE

1385w, 1362m, 1344m, 1307w, 1270m, 1241w, 1044m, 1018m,

1007m, 985m, 963m, 918m cm^-1.

HR-MS: m/z calcd for C₁₇H₂₃NO: 257.1779. Found: 257.1783.

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-phenyl-cyclohexa-1,3-dienyl]-4-

isopropyl-4,5-dihydro-oxazole (13a) and (+)-(4S)-2-[(5S,6R)-5-

Allyl-6-phenyl-cyclohexa-1,3-dienyl]-4-isopropyl-4,5-dihydro-

oxazole (13b)

The reaction was carried out as described for 10a on a scale of 1.0

mmol of 3a in THF-toluene (1:5, 48mL) at 78 °C with PhLi (601

mL of a 2 M cyclohexane solution, 1.202 mmol) and allylbromide.

¹H NMR analysis showed a 81:19 mixture of diastereoisomers 13a

and 13b (199.8 mg, 62%). Flash chromatography (hexane Et₂O,

6:1) afforded pure samples of both diastereoisomers. An analogous

experiment was carried out exactly as before but in THF as solvent.

This afforded a mixture of 13a and 13b in the ratio of 75:25 in 52%

yield.

¹H NMR (CDCl₃, 400 MHz): = 0.85 (d, 3 H, J = 6.8 Hz), 0.94 (d,

3 H, J = 6.8 Hz), 1.04 (d, 3 H, J = 6.8 Hz), 1.83–1.92 (m, 1 H),

1.93–2.16 (m, 3 H), 2.84 (bq, 1 H, J = 6.8), 3.95–4.27 (m, 3 H),

4.94–5.02 (m, 2 H), 5.70–5.82 (m, 1 H), 5.96 (ddt, 1 H, J = 1,5,9

Hz), 6.01 (dd, 1 H, J = 5,9 Hz), 6.59 (dd, 1 H, J = 1,5 Hz).

MS: m/z (%) 245 (5), 244 (5), 204 (9), 160 (15), 119 (100), 91 (52).

HR-MS: m/z calcd for C₁₆H₂₃NO: 245.1779. Found: 245.1816.

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-butyl-cyclohexa-1,3-dienyl]-4-

isopropyl-4,5-dihydro-oxazole (11a)

The reaction was carried out as described for 10a with BuLi and al-

lylbromide on a scale of 1.026 mmol of 3a in THF toluene [1:10

(11 mL), for the nucleophilic addition; 6:10 (16 mL) for the electro-

phile addition]. HPLC analysis (Silica spheri 5 mm, hexane

EtOAc, 20:1; 5mL/min) showed a 95:5 ratio of products assigned to

the diastereoisomers 11a (major, 6.5 min) and 11b (7.8 min). Flash-

chromatography (hexane Et₂O, 6:1) afforded 11a (52.5 mg) and a

mixture of 11a and 11b (30.1 mg, 62%).

13a

[ ]²⁰–486 (c 1.22, CHCl₃).

D

IR (CH₂Cl₂): 3085w, 3070w, 3060w, 3050w, 3035w, 2965s,

2925m, 2905m, 2880m, 1652m, 1641m, 1620vs, 1578w, 1500m,

1485w, 1470w, 1455w, 1422w, 1407w, 1385w, 1352m, 1305w,

1280w, 1262w, 1233m, 1052s, 1008m, 960m, 920m cm^-1.

An analogous experiment was carried out as above but in THF as

solvent to give a 94:6 mixture of 11a and 11b

1H NMR (CDCl₃, 400 MHz): = 0.81 (d, 3 H, J = 6.8Hz), 0.90 (d,

3 H, J = 6.8Hz), 1.82 (m, 1 H), 2.13–2.22 (m, 1 H), 2.24–2.32 (m, 1

H), 2.44–2.51 (m, 1 H), 3.88–4.00 and 4.10–4.16 (m, 3 H), 4.08 (s,

1 H), 5.04–5.13 (m, 2 H), 5.79–5.93 (m, 2 H), 6.11 (dd, 1 H, J = 5.2,

9.2 Hz), 6.93 (d, 1 H, J = 5.2 Hz), 7.13–7.27 (m, 5 H).

11a

[ ]²⁰_D–477 (c 2.32, CHCl₃).

IR (CH₂Cl₂): 3080w, 3040w, 2960vs, 2930vs, 2880s, 1648s,

1611vs, 1570w, 1480w, 1467m, 1440w, 1400w, 1385m, 1370w,

1348m, 1300w, 1266w, 1230w, 1045s, 1005m, 974m, 963m, 920s

cm^-1.

MS: m/z (%) 307 (3), 266 (100), 181 (40), 153 (19), 91 (8), 77 (10).

HR-MS: m/z calcd for C₂₁H₂₅NO: 307.1936. Found: 307.1910.

¹H NMR (CDCl₃, 400 MHz): = 0.85 (d, 3 H, J = 6.8Hz), 0.86 (t,

3 H, J = 6.8Hz), 0.95 (d, 3 H, J = 6.8Hz), 1.20–1.50 (m, 6 H), 1.80–

1.92 (m, 1 H), 1.94–2.03 (m, 1 H), 2.08–2.17 (m, 1 H), 2.26–2.34

(m, 1 H), 2.72–2.77 (m, 1 H), 3.96–4.10 and 4.14–4.25 (m, 3 H),

4.94–5.02 (m, 2 H), 5.70–5.82 (m, 1 H), 5.93 (dd, 1 H, J = 6,9 Hz),

5.99 (dd, 1 H, J = 5,9 Hz), 6.60 (d, 1H, J = 5Hz).

13b

[ ]²⁰_D+528 (c 1.035, CHCl₃).

IR (CH₂Cl₂): 3080w, 3043w, 2963s, 2904m, 2873m, 1652m,

1614vs, 1576w, 1493m, 1481w, 1467w, 1452w, 1402w, 1385w,

1367m, 1348w, 1300w, 1283w, 1231m, 1047s, 1001m, 959m,

919m cm^-1.

¹H NMR (CDCl₃, 200 MHz): = 0.57 (d, 3 H, J = 6.8 Hz), 0.63 (d,

3 H, J = 6.8 Hz), 1.50–1.65 (m, 1 H), 2.15–2.40 (m, 2 H), 2.45–2.60

(m, 1 H), 3.85–4.20 (m, 3 H), 3.98 (bs,1 H), 5.01–5.14 (m, 2 H),

5.75–6.00 (m, 2 H), 6.12 (dd, 1 H, J = 5.5, 9.5 Hz), 6.89 (d, 1 H,

J = 5.5 Hz), 7.10–7.30 (m, 5 H).

MS: m/z (%) 287 (15), 246 (100), 190 (30), 161 (28), 105 (30).

HR-MS: m/z calcd for C₁₉H₂₉NO: 287.2249. Found: 287.2235.

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-vinyl-cyclohexa-1,3-dienyl]-4-

isopropyl-4,5-dihydro-oxazole (12a)

Vinyllithium was prepared by adding MeLi dropwise (1.358 mL of

a 1.62 M Et₂O solution, 2.2 mmol) to a stirred solution of tetravinyl-

tin (0.133 mL, 0.73 mmol) in 10 mL of THF at 78 °C under N₂.

After 1 h the solution was cooled to 90 °C and complex 5a (339

mg, 1.00 mmol) was added as a solid, and the resulting solution was

gradually warmed to 78 °C over a period of 3 h. The reaction was

then carried out as described for 10a with allylbromide and 3a.

HPLC analysis showed two products, 12a (5.8 min) and 12b (6.5

min) in a 95:5 ratio. Flash chromatography (hexane Et₂O, 6:1)

gave a mixture of 12a and 12b (131 mg, 48%) as a colorless oil.

MS: m/z (%) 307 (3), 266 (100), 224 (8), 181 (42), 153 (18), 91 (10),

77 (8).

HR-MS: m/z calcd for C₂₁H₂₅NO: 307.1936. Found: 307.1910.

(4S)-4-Isopropyl-2-[(5R,6S)-5-(3-trimethylsilanyl-prop-2-ynyl)-

6-vinyl-cyclohexa-1,3-dienyl]-4,5-dihydro-oxazole (14a) and

(4S)-4-Isopropyl-2-[(5S,6R)-5-(3-trimethylsilanyl-prop-2-ynyl)-

6-vinyl-cyclohexa-1,3-dienyl]-4,5-dihydro-oxazole (14b)

The reaction was carried out as described for 12a with vinyl lithium

on a scale of 1.0 mmol of 3a in THF. HMPA (1.74 mL, 10 equiv)

was added immediately prior to the addition of trimethylsilyl prop-

argyl bromide. Flash chromatography (SiO₂, hexane-Et₂O, 7:1)

gave an inseparable mixture of the diastereoisomers 14a and 14b in

the ratio of 85:15 (283 mg, 86%).

[ ]²⁰-388.38, (c 2.22, CHCl₃).

D

12a

IR (CH₂Cl₂): 3079w, 3042w, 2963s, 2927m, 2904m, 2863m, 1650s,

1637s, 1612vs, 1574w, 1467w, 1438w, 1401w, 1384w, 1346w,

1300w, 1231w, 1045w, 995m, 960m, 918s cm^-1.

14a (partial data)

¹H NMR (CDCl₃, 200 MHz): = 0.13 (s, 9 H), 0.84 (d, 3 H, J = 6.8

Hz) 0.93 (d, 3 H, J = 6.8 Hz) 1.70–1.95 (m, 1 H), 2.10–2.40 (m, 2

H), 2.45–2.58 (m, 1 H), 3.61 (d, 1 H, J = 6.0 Hz), 3.90–4.30 (m, 3

H), 4.98 (dt, 1 H, J = 1.5, 10.0 Hz), 5.07 (dt, 1 H, J = 1.5, 16.5 Hz),

5.80 (ddd, 1 H, J = 6.0, 10.0, 16.5 Hz), 5.96–6.11 (m, 2 H), 6.71 (bd,

1 H, J = 6.0 Hz).

1H NMR (CDCl₃, 200 MHz): = 0.84 (d, 3 H, J = 6.8 Hz), 0.92 (d,

3 H, J = 6.8 Hz), 1.70–2.40 (m, 4 H), 3.45 (d, 1 H, J = 6 Hz), 3.95–

4.28 (m, 3 H), 4.90–5.13 (m, 4 H_.), 5.65–6.10 (m, 4 H), 6.71 (dd, 1

H, J = 1.5, 5.0 Hz).

MS: m/z (%) 257 (8), 256 (10), 216 (73), 172 (22), 146 (21), 131

(100).

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2049

MS: m/z (%) 376 (6), 326 (8), 216 (83), 201 (32), 131 (100), 103

IR (CH₂Cl₂): 3077w, 3040w, 2960vs, 1947m, 2905m, 2870m,

(71), 73 (95).

1650m, 1612vs, 1573w, 1479m, 1403w, 1363m, 1348m, 1334m,

1300m, 1240m, 1210w, 1014m, 981m, 960m, 917m cm^-1.

HR-MS: m/z calcd for C₂₀H₁₉NOSi: 327.2018. Found: 327.2014.

¹H NMR (CDCl₃, 400 MHz): = 0.89 (s, 9 H), 1.03 (d, 3 H, J = 7.3

Hz), 1.89-2.03 (m, 1 H), 2.07-2.17 (m, 2 H), 2.87 (q, 1 H, J = 7.3

Hz), 3.91 (dd, 1 H, J = 6.7, 10.0 Hz), 4.08–4.18 (m, 2 H), 4.91–5.03

(m, 2 H), 5.69–5.80 (m, 1 H), 5.94 (dd, 1 H, J = 5.5, 9.6 Hz), 5.99

(dd, 1 H, J = 5.1, 9.6 Hz), 6.56 (d, 1 H, J = 5.1 Hz).

(4S)-4-Isopropyl-2-[(5R,6S)-6-methyl-5-(3-trimethylsilanyl-

prop-2-ynyl)-cyclohexa-1,3-dienyl]-4,5-dihydro-oxazole (15a)

The reaction was carried out in THF as described for 10a with MeLi

on a scale of 1.0 mmol of 3a. HMPA (1.74 mL, 10 equiv) was added

immediately prior to the addition of trimethylsilyl propargyl bro-

mide. GC analysis (initial T: 100 °C; initial time: 5 min; 10 °C/min;

major diastereoisomer 15a (19.6 min); minor diastereoisomer 15b

(19.8 min)) showed the formation of two products in the ratio of 93:

7. Purification by flash chromatogaraphy (hexane Et₂O, 7:1 to 5:1)

afforded the mixture of diasteroisomers (242.9 mg, 77%).

MS: m/z (%) 259 (20), 218 (100), 202 (68), 160 (40), 146 (20), 119

(50), 110 (20), 91 (30), 86 (65), 84 (100).

HR-MS: m/z calcd. for C₁₇H₂₅NO: 259.1936. Found: 259.1917.

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-butyl-cyclohexa-1,3-dienyl]-4-

tert-butyl-4,5-dihydro-oxazole (18a)

The reaction was carried out in THF (10 mL) with complex 3b

(339.3 mg, 1.0 mmol), BuLi and allylbromide. The procedure used

was that described for 11a. HPLC analysis showed the formation of

a single diastereoisomer. Flash chromatography (hexane–Et₂O, 5:1)

afforded 18a (192.9 mg, 62%).

15a

[ ]²⁰–301.6 (c 0.98, CHCl₃)

D

IR (CH₂Cl₂): 3042w, 2961vs, 2927m, 2900m, 2873m, 2171m,

1651m, 1612s, 1574m, 1467m, 1425m, 1044m, 1386m, 1364m,

1345m, 1301m, 1274s, 1252s, 1048m, 1019m, 973m, 909m, 845vs

cm^-1.

[ ]²⁰_D–443.2 (c 1.09, CHCl₃).

¹H NMR (CDCl₃, 200 MHz): = 0.13 (s, 9 H), 0.85 (d, 3 H, J = 6.8

Hz), 0.95 (d, 3 H, J = 6.8 Hz), 1.06 (d, 3 H, J = 7.1 Hz), 1.75–1.95

(m, 1 H), 2.05–2.35 (m, 3 H), 2.94 (q, 1 H, J = 7.1 Hz), 3.95–4.30

(m, 3 H), 5.96–6.10 (m, 2 H), 6.54–6.62 (m, 1 H).

IR (CH₂Cl₂): 3077w, 3039w, 2958vs, 2931s, 2870m, 1649m,

1613s, 1479m, 1462m, 1442m, 1364m, 1352m, 1354m, 1299m,

1027m, 960m, 917m cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.86 (m, 3 H), 0.88 (s, 9 H), 1.18–

1.50 (m, 6 H), 1.92–2.02 (m, 1 H), 2.07–2.17 (m, 1 H) 2.23–2.32 (m,

1 H), 2.73–2.80 (m, 1 H), 3.90 (dd, 1 H, J = 7.0, 10.0 Hz), 4.07 (dd,

1 H, J = 7.0 Hz), 4.15 (dd, 1 H, J = 7.0, 10.0 Hz), 4.93–5.04 (m, 2

H), 5.70–5.80 (m, 1 H), 5.91 (dd, 1 H, J = 5.5, 9.1 Hz), 5.98 (dd, 1

H, J = 5.5, 9.1 Hz), 6.58 (d, 1 H, J = 5.5 Hz).

MS: m/z (%) 315 (10), 300 (4), 272 (5), 204 (80), 160 (21), 119

(100), 91 (78), 73 (40), 59 (11).

HR-MS: m/z calcd for C₁₉H₂₉NOSi: 315.2018. Found: 315.2002.

(-)-(4S)-2-[(5R,6S)-5-Benzyl-6-methyl-cyclohexa-1,3-dienyl]-4-

isopropyl-4,5-dihydro-oxazole (16a)

MS: m/z (%) 301 (20), 260 (100), 244 (30), 204 (30), 161 (23), 146

(32), 105 (30), 91 (31), 86 (64), 84 (100).

The reaction was carried out as described for 10a with methyl lith-

ium and benzylbromide on a scale of 1.00 mmol of 3a in THF. GC

analysis (initial T: 150 °C; initial time: 5 min; 25 °C/min; major di-

astereoisomer 16a (12.4 min); minor diastereoisomer 16b (13.0

min)) showed the formation of two products in the ratio of 95:5. Pu-

rification by flash chromatography (hexane-Et₂O, 5:1) afforded the

mixture of diastereomisomers (150.6 mg, 51%). A sample of pure

16a was obtained by preparative HPLC (Silica spheri 5 mm,

250 10 mm column; hexane EtOAc, 20:1, 5mL/min).

HR-MS: m/z calcd for C₂₀H₃₁NO 301.2405. Found: 301.2384.

(–)-(4S)-2-[(5R,6S)-5-Allyl-6-phenyl-cyclohexa-1,3-dienyl]-4-

tert-butyl-4,5-dihydro-oxazole (19a) and (4S)-2-[(5S,6R)-5-

Allyl-6-phenyl-cyclohexa-1,3-dienyl]-4-tert-butyl-4,5-dihydro-

oxazole (19b)

The procedure followed was analogous to that described for 13 us-

ing complex 3b in place of 3a (1 mmol scale, THF toluene, 1:5, 48

mL), PhLi and allylbromide. HPLC analysis (hexane–EtOAc, 20:1,

5 mL/min, major 4.6 min, minor 6.0 min) showed two products in

the ratio of 92:8. Flash chromatography (hexane Et₂O, 6:1) afford-

ed 19a (164 mg, 51%) and 19b (9.0 mg, 3%).

[ ]²⁰–440.7 (c 4.19, CHCl₃).

D

IR (CH₂Cl₂): 3085w, 3070w, 3060w, 3055m, 3050m, 3035m,

2965vs, 2930s, 2905s, 2875s, 1052s, 1611vs, 1574w, 1496m,

1481w, 1467m, 1455m, 1407w, 1385w, 1363m, 1348m, 1304w,

1281w, 1274w, 1266w, 1240m, 1048s, 1022s, 974m cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.92 (d, 3 H, J = 6.8 Hz), 0.97 (d,

3 H, J = 7.2 Hz), 0.99 (d, 3 H, J = 6.8 Hz), 1.83–1.93 (m, 1 H),

2.27–2.34 (m, 1 H), 2.45 (dd, 1 H, J = 9.0, 13.0 Hz), 2.67 (dd, 1 H,

J = 7.0, 13.0 Hz), 2.81 (bq, 1 H, J = 7.2 Hz), 3.98–4.10 and 4.20–

4.25 (m, 3 H), 5.92 (dd, 1 H, J = 5.6, 9.2Hz), 6.03 (dd, 1 H, J = 5.6,

9.2Hz), 6.63 (d, 1 H, J = 5.2 Hz), 7.10–7.28 (m, 5 H).

19a

[ ]²⁰_D–484.1 (c 0.755, CHCl₃).

IR (CH₂Cl₂): 3080w, 3040w, 3027w, 2960s, 2905m, 2873m,

1650m, 1615vs, 1492m, 1452m, 1403m, 1364m, 1350m, 1300m,

1230m, 1050m, 1030m, 960m, 919m cm^-1.

¹H NMR (CDCl₃, 200 MHz): = 0.85 (s, 9 H), 2.06–2.35 (m, 2 H),

2.40–2.54 (m, 1 H), 3.80 (dd, 1 H, J = 7.5, 10 Hz), 3.98–4.17 (m, 3

H), 5.00–5.16 (m, 2 H), 5.64–5.95 (m, 2 H), 6.11 (dd, 1 H, J = 6.0,

10.0 Hz), 6.91 (d, 1 H, J = 5.5 Hz), 7.10–7.30 (m, 5 H).

MS: m/z (%) 296 (M+1, 3), 252 (1), 204 (31), 160 (26), 119 (90), 91

(100).

HR-MS: m/z calcd for C₂₀H₂₅NO: 295.1936. Found: 295.1915.

MS: m/z (%) 321 (5), 280 (100), 264 (35), 260 (38), 244 (15), 238

(15) 222 (25), 181 (40). HR-MS: m/z calcd for C₂₂H₂₇NO:

321.2092. Found: 321.2071.

(–)-(4S)-2-((5R,6S)-5-Allyl-6-methyl-cyclohexa-1,3-dienyl)-4-

tert-butyl-4,5-dihydro-oxazole (17a)

The reaction was carried out exactly as that described for 10a using

complex 3b in place of 3a, MeLi and allylbromide HPLC analysis

showed the formation of a single diastereoisomer. Flash chromatog-

raphy (hexane Et₂O, 8:1) afforded 17a (149.4 mg, 58%).

19b

¹H NMR (CDCl₃, 200 MHz): = 0.56 (s, 9 H), 2.20–2.35 (m, 2 H),

2.46–2.58 (m, 1 H), 3.83 (dd, 1 H, J = 6.0,10.0 Hz), 3.96–4.10 (m,

3 H), 5.00–5.12 (m, 2 H), 5.77–6.00 (m, 2 H), 6.12 (dd, 1 H, J = 6.0,

10.0 Hz), 6.86 (d, 1 H, J = 6.0 Hz), 7.10–7.30 (m, 5 H).

[ ]²⁰_D–512.4 (c 0.835, CHCl₃).

Synthesis 2001, No. 13, 2040–2054 ISSN 0039-7881 © Thieme Stuttgart · New York

2050

G. Bernardinelli et al.

FEATURE ARTICLE

(–)-(4S)-2-[(5R,6S)-6-Methyl-5-propargyl-cyclohexa-1,3-

dienyl]-4-tert-butyl-4,5-dihydro-oxazole (20a)

¹H NMR (CDCl₃, 200 MHz): = 0.86 (d, 3 H, J = 6.7Hz), 0.89 (d,

3 H, J = 6.8 Hz), 0.96 (d, 6 H, J = 6.8 Hz), 1.23 (s, 3 H), 1.80–2.00

(m, 1 H), 3.07 (bq, 1 H, J = 6.7Hz), 3.98–4,30 (m, 3 H), 6.01 (dd, 1

H, J = 9.8, 5.4 Hz), 6.37 (bd, 1 H, J = 9.8 Hz), 6.59 (bd, 1 H, J = 5.4

Hz).

MeLi (1.6N in Et₂O, 1.2 mmol, 0.75 mL) was added to a solution of

oxazoline complex 3b (1.0 mmol) in THF (10 mL) at 90 °C. After

warming to 78 °C over a period of 4 h, HMPA (1.7 mL) and pro-

pargyl bromide (10 mmol, 0.7 mL) were added. The reaction mix-

ture was slowly warmed to r.t. and was stirred overnight. After

work-up as described for 10a, analysis of the crude mixture by GC.

showed the formation of a single product. Flash chromatography

(hexane Et₂O, 6:1) yielded 20a (202.2 mg, 79%).

MS: m/z (%) 218 (47), 204 (18), 133 (100), 105 (72).

HR-MS: m/z calcd for C₁₆H₂₃NO₂: 261.1728. Found: 261.1733.

Anal. Calcd for C₁₆H₂₃NO₂: C, 73.53; H, 8.87; N, 5.36. Found: C,

73.49; H, 8.79; N, 5.36.

[ ]²⁰_D–406.7 (c 0.595, CHCl₃).

21b

IR (CH₂Cl₂): 3303s, 3040w, 2961vs, 2904s, 2870s, 1651m, 1613s,

1574w, 1479w, 1402w, 1364w, 1349m, 1336w, 1299m, 1241m,

1209w, 1113w, 1067m, 1051m, 1036m, 984m, 964m cm^-1.

¹H NMR (CDCl₃, 200 MHz): = 0.887 (d, 3 H, J = 6.8Hz), 0.892

(d, 3 H, J = 6.9Hz), 0.94 (d, 3 H, J = 6.8Hz), 1.25 (s, 3 H), 1.82–

1.95 (m, 1 H), 2.22 (s, 3 H), 3.08 (dq, 1 H, J = 1.0, 6.9 Hz), 4.00–

4.30 (m, 3 H), 6.02 (dd, 1 H, J = 5.5,10 Hz), 6.39 (bd, 1 H,

J = 10Hz), 6.60 (bd, 1 H, J = 1.0, 5.5 Hz).

¹H NMR (CDCl₃, 200 MHz): = 0.87 (s, 9 H), 1.05 (d, 3 H, J = 7.1

Hz), 1.94 (t, 1 H, J = 2.6 Hz), 1.95-2.35 (m, 3 H), 2.99 (q, 1 H,

J = 7.1 Hz), 3.85- 4.20 (m, 3 H), 5.86-6.08 (m, 2 H), 6.55-6.60 (m,

1 H).

(–)-1-[(1S,6R)-5-((4S)-4-tert-Butyl-4,5-dihydro-oxazol-2-yl)-6-

methyl-cyclohexa-2,4-dienyl]-ethanone (22a)

MS: m/z (%) 258 (22), 257 (10), 218 (15), 200 (100), 161 (18), 160

(26), 146 (29), 119 (56), 118 (27), 117 (10), 115 (10), 108 (13), 105

(20), 91 (70).

The reaction was carried out exactly as that described for 21a but

using complex 3b in place of 3a on a 1.0 mmol scale. HPLC analy-

sis showed the formation of a single diastereoisomer. Flash chroma-

tography (hexane Et₂O, 3:1 to 100% Et₂O) afforded 22a (165 mg,

60%), mp = 79.5–80.5 °C.

HR-MS: m/z calcd for C₁₇H₂₃NO: 257.1779. Found: 257.1769.

(–)-1-[(1S,6R)-5-((4S)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-6-

methyl-cyclohexa-2,4-dienyl]-ethanone (21a) and 1-[(1R,6S)-5-

((4S)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-6-methyl-

[ ]²⁰_D–311 (c 1.05, CHCl₃).

IR (CH₂Cl₂): 3058w, 2965s, 2933m, 2905m, 2871m, 1703vs,

1651m, 1613s, 1479m, 1456m, 1400m, 1383m, 1364s, 1300m,

1236m, 1153m, 1098m, 1052m, 1007s, 956m, 888m cm^-1.

cyclohexa-2,4-dienyl]-ethanone (21b)

A pressure resistant Schlenk tube equipped with a pressure gauge

was charged with a solution of complex 3a (678 mg, 2.0 mmol) in

THF (20 mL). To this magnetically stirred solution at 90 °C under

N₂was added dropwise MeLi (1.48 mL of a 1.62M Et₂O solution,

2.40 mmol). The reaction was warmed to 78 °C over a period of 3

h and then MeI (1.25 mL, 10 equiv, distilled from P₂O₅) and anhyd

MeCN (20 mL) were added. The reaction vessel was placed in a liq-

uid N₂bath, evacuated, and placed under an atmosphere of CO. The

liquid N₂bath was replaced by a dry ice/acetone bath and pressure

of CO was increased to 4 bar. The reaction was left to warm to r.t.

and was stirred overnight. CO was vented and the excess MeI and

solvents were evaporated. The residue was dissolved in 20 mL of

anhyd THF and cannulated into a 60 mL anhyd Schlenk tube con-

taining a dispersion of NaH (240 mg, 3 equiv, 60% oil dispersion,

prewashed with anhyd pentane) in anhyd THF (5 mL) at 78 °C.

After 15 min HMPA (3.5 mL) and MeI (1.25 mL) were added, the

temperature was raised to 20 °C over a period of 4 h, and the solu-

tion stirred overnight. Volatiles were evaporated in vacuum, the res-

idue dissolved in Et₂O (30 mL), washed with a sat. NH₄Cl solution

(10 mL) and H₂O (2 10 mL). The combined aq phases were ex-

tracted with Et₂O (3 20 mL), and the combined organic phases

were dried (MgSO₄), filtered and evaporated. The crude product

mixture was analyzed by HPLC (hexane–EtOAc, 3:1; 5mL/min)

and found to consist of a mixture of products in a 95:5 ratio. Flash

chromatography (hexane Et₂O, 3:1, then 100% Et₂O) afforded 21a

(255 mg, 49%) and 21b (15 mg, 3% (impure)). A pure sample of

21b was obtained by preparative HPLC.

¹H NMR (CDCl₃, 400 MHz): = 0.90 (3 H, d, J = 7.2Hz), 0.92 (s,

9 H), 1.23 (s, 3 H), 2.23 (s, 3 H), 3.11 (dq, 1 H, J = 1.5,7.0 Hz),

3.90–3.98 (m, 1 H), 4.09–4.22 (m, 2 H), 6.03 (dd, 1 H, J = 5.5,9.9

Hz), 6.38 (d, 1 H, J = 9.9 Hz), 6.60 (d, 1 H, J = 5.5Hz).

MS: m/z (%) 275 (5), 232 (100), 218 (25), 188 (10), 174 (5), 160

(14), 133 (35), 105 (17). HR-MS: m/z calcd for C₁₇H₂₅NO₂:

275.1885. Found: 275.1883.

Anal. calcd for C₁₇H₂₅NO₂: C, 74.14, H, 9.15, N, 5.08. Found: C,

73.90, H, 9.06, N 4.93.

Sequential Nucleophile/Electrophile Additions to Complex 6

((2S)-2-Methoxymethyl-pyrrolidin-1-yl)-[(5R,6S)-6-methyl-5-

(3-trimethylsilanyl-prop-2-ynyl)-cyclohexa-1,3-

dienylmethylene]-amine (23a)

MeLi (1.27 N in Et₂O, 1.2 mmol, 0.945 mL) was added to a solution

of hydrazone complex 6 (354 mg, 1.0 mmol) in THF (10 mL) at

78 °C. After warming to 40 °C over a period of 2 h, the solution

was stirred at this temperature for an additional 2 h before being re-

cooled to 78 °C. HMPA (1.7 mL) and 3-trimethylsilylpropargyl

bromide (5 mmol, 0.7 mL) were added. The stirred reaction mixture

was slowly warmed to r.t. overnight. Purification by flash chroma-

tography (hexane Et₂O, 15:1) afforded 23a (248 mg, 72%). ¹H

NMR 400 MHz showed only traces (< 1%) of another diastereoiso-

mer.

[ ]²⁰_D–420 (c 0.41, CHCl₃).

IR (CH₂Cl₂): 3030w, 2985s, 2961s, 2926m, 2900m, 2876m, 2168m,

1545m, 1458m, 1368m, 1340m, 1114s, 1029w, 972w, 845vs cm^-1.

21a

Mp = 69–71 °C (MeOH).

¹H NMR (CDCl₃, 400 MHz): = 0.15 (s, 9 H), 1.02 (d, 3 H, J = 7.2

Hz), 1.80–2.00 (m, 4 H), 2.00–2.20 (m, 3 H), 2.90–3.00 (m, 2 H),

3.38 (s, 3 H), 3.45–3.55 (m, 4 H), 5.77 (d, 1 H, J = 5.5 Hz), 5.83 (dd,

1 H, J = 5.5, 9.2 Hz), 6.01 (dd, 1 H, J = 5.5, 9.2), 6.89 (s, 1 H).

[ ]²⁰–312.8 (c 1.05, CHCl₃).

D

IR (CH₂Cl₂): 3065w, 3050w, 2980vs, 2930s, 2905s, 2970s, 1707vs,

1652s, 1615vs, 1578w, 1466m, 1460m, 1405w, 1385m, 1366s,

13o3w, 1277w, 1270w, 1260w, 1237s, 1226s, 1151w, 1095m,

1007vs, 960m, 911w, 893w cm^-1.

MS: m/z (%) 344 (8), 299 (7), 233 (41), 173 (19), 114 (24), 70 (100).

HR-MS: m/z calcd for C₂₀H₃₂N₂OSi: 344.2283. Found: 344.2268.

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2051

[(5R,6S)-6-Butyl-5-(3-trimethylsilanyl-prop-2-ynyl)-cyclohexa-

1,3-dienylmethylene]-((2S)-2-methoxymethyl-pyrrolidin-1-yl)-

amine (24a)

(hexane Et₂O 20:1) to give 26a (168 mg, 58%). Integration of the

CH=N signals in the ¹H NMR spectrum of a sample analyzed before

chromatography showed a diastereoisomeric ratio of >98:2.

The reaction was carried out as described for 23a using complex 6

(354 mg, 1.0 mmol), 3-trimethylsilyl propargyl bromide and n-BuLi

(1.54 N in hexane, 1.2 mmol, 0.714 mL) as nucleophile. Purifica-

tion by flash chromatography (hexane Et₂O, 15:1) yielded 24a

(266 mg, 69%). The 400 MHz H NMR spectrum showed traces

(<1%) of another diastereoisomer.

[ ]²⁰_D–434.4 (c 1.44, CHCl₃).

IR (CH₂Cl₂): 3070s, 2990s, 2950s, 2850s, 1700s, 1665s, 1550m,

1450m, 1350m, 1110s cm^-1.

1

¹H NMR (CDCl₃, 400 MHz): = 0.85 (d, 3 H, J = 6.8 Hz), 1.20 (s,

3 H), 1.80–2.05 (m, 4 H), 2.24 (s, 3 H), 2.98–3.06 (m, 1 H), 3.13

(dq, 1 H, 1.5, 6.8 Hz), 3.38 (s, 3 H), 3.32–3.40 (m, 1 H), 3.44 (dd, 1

H, J = 9.2, 15.8 Hz), 3.60 (dd, 1 H, J = 3.7, 9.2 Hz), 3.62–3.69 (m,

1 H), 5.78 (d, 1 H, J = 5.5 Hz), 6.00 (dd, 1 H, J = 5.5, 10.0 Hz), 6.15

(d, 1 H, J = 10.0 Hz), 6.93 (s, 1 H).

[ ]²⁰_D–318 (c 0.445, CHCl₃).

IR (CH₂Cl₂): 3052w, 3038w, 2959s, 2932s, 2900s, 2863s, 2854s,

2822m, 2169s, 1545m, 1459m, 1368m, 1340m, 1322m, 1305m,

1278m, 1223m, 1198m, 1116s, 1030m, 971m, 900m, 846s cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.15 (s, 9 H), 0.91 (br.t, 3 H,

J = 6.0 Hz), 1.20–1.40 (m, 6 H), 1.80–2.05 (m, 4 H), 2.05–2.12 (m,

1 H, J = 8.8, 16.6 Hz, H-C-C(5’)), 2.19–2.26 (m, 1 H, J = 6.6, 16.6

Hz), 2.24–2.25 (m, 1 H), 2.85–3.00 (m, 2 H), 3.37 (s, 3H), 3.40–

3.47 (m, 4 H), 5.73–5.80 (m, 2 H), 5.99 (dd, 1 H, J = 5.1, 8.8 Hz),

6.89 (s, 1 H).

MS: m/z (%) 290 (59), 247 (100), 215 (9), 187 (31), 114 (35), 70

(98).

HR-MS: m/z calcd for C₁₇H₂₆N₂O₂: 290.1994. Found 290.1985.

1-{(6R)-6-Butyl-5-[(2S)-2-methoxymethyl-pyrrolidin-1-

ylimino)-methyl]-1(S)-methyl-cyclohexa-2,4-dienyl}-ethanone

(27a)

The reaction used BuLi as nucleophile and was carried out as de-

scribed for 26a to give 27a (225.9 mg, 68%). H NMR of CH=N

MS: m/z (%) 386 (10), 341 (5), 275 (27), 173 (21), 114 (26), 70

(100).

1

HR-MS: m/z calcd for C₂₃H₃₈N₂OSi: 386.2753. Found: 386.2706.

(7.03 and 7.06) showed a diastereoisomeric ratio of 99:1.

[ ]²⁰_D–99.9 (c 1.33, CHCl₃).

((2S)-2-Methoxymethyl-pyrrolidin-1-yl)-[(5R,6S)-6-phenyl-5-

(3-trimethylsilanyl-prop-2-ynyl)-cyclohexa-1,3-

dienylmethylene]-amine (25a)

IR (CH₂Cl₂): 3045m, 2931s, 2872s, 1699vs, 1642w, 1544m,

1458m, 1354m, 122m, 1198w, 1119s, 909s cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.81 (t, 3 H, J = 7.0 Hz), 1.19–1.30

(m, 5 H), 1.19 (s, 3 H), 1.40–1.50 (m, 1 H), 1.82–2.10 (m, 4 H), 2.24

(s, 3 H), 2.96–3.03 (m, 1 H), 3.14–3.18 (m, 1 H), 3.38 (s, 3 H), 3.38–

3.50 (m, 2 H), 3.59–3.65 (m, 2 H), 5.80 (d, 1 H, J = 5.6 Hz), 5.97

(dd, 1 H, J = 5.6, 10.1 Hz), 6.20 (d, 1 H, J = 10.1 Hz), 7.03 (s, 1 H).

The reaction was carried out as described for 23a using complex 6

(354 mg, 1.0 mmol), 3-trimethylsilylpropargyl bromide and PhLi (2

N in cyclohexane Et₂O, 1.2 mmol, 0.6 mL) as the nucleophile. Pu-

rification by flash chromatography (hexane Et₂O, 20:1 to 10:1)

yielded 25a (297.5 mg, 73%). The 400 MHz H NMR spectrum

showed traces (<1%) of another diastereoisomer.

1

MS: m/z (%) 332 (8), 289 (24), 187 (20), 114 (26), 70 (100), 45 (42).

HR-MS: m/z calcd for C₂₀H₃₂N₂O₂: 332.2464. Found 332.2510.

[ ]²⁰_D–371.8 (c 0.6, CHCl₃).

IR (CH₂Cl₂): 3054w, 3029w, 2961s, 2915m, 2898m, 2818m, 2170s,

1631w, 1599w, 1545s, 1493m, 1452m, 1366m, 1339s, 1322m,

1224m, 1198m, 1121m, 1032m, 1005w, 971w, 908m, 845s cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.21 (s, 3 H), 1.80–2.00 (m, 4 H),

2.25–2.41 (m, 2 H), 2.51–2.57 (m, 1 H), 2.93–3.01 (m, 1 H), 3.08

(s, 3 H), 3.16–3.53 (m, 4 H), 4.32 (s, 1 H), 5.76 (dd, 1 H, J = 5.9, 9.2

Hz), 6.08–6.16 (m, 2 H), 6.88 (s, 1 H), 7.10–7.30 (m, 5 H).

1-{5-[((S)-2-Methoxymethyl-pyrrolidin-1-ylimino)-methyl]-

(1S,6R)-1-methyl-6-vinyl-cyclohexa-2,4-dienyl}-ethanone (28a)

The reaction used vinyllithium as the nucleophile (generated from

tetravinyltin/MeLi) and was carried out as described for 26a to give

28a (181 mg, 60%). ¹H NMR of the CH=N signals (6.91 and 6.93)

showed a diastereoisomeric ratio of 180:1.

[ ]²⁰_D–433.6 (c 0.90, CHCl₃).

MS: m/z (%) 407 (26), 406 (23), 361 (18), 295 (26), 180 (16), 173

(24), 114 (18), 96 (21), 70 (100).

IR (CH₂Cl₂): 3078w, 3039w, 2976s, 2929s, 2880s, 1702vs, 1633m,

1544s, 1452m, 1352s, 1306w, 1224m, 1122s, 1094s, 909s cm^-1.

HR-MS: m/z (%) calcd for C₂₅H₃₄N₂OSi: 406.2440. Found:

¹H NMR (CDCl₃, 400 MHz): = 1.24 (s, 3 H), 1.82–2.07 (m, 4 H),

2.20 (s, 3 H), 2.99–3.06 (m, 1 H), 3.32–3.40 (m, 1 H), 3.37 (s, 3 H),

3.43 (dd, 1 H, J = 7.0, 9.2 Hz), 3.60 (dd, 1 H, J = 3.3, 9.2 Hz), 3.64–

3.70 (m, 1 H), 3.73 (d, 1 H, J = 9.2 Hz), 4.95 (dd, 1 H, J = 2.2, 9.9

Hz), 5.19 (dd, 1 H, J = 2.2, 17.0 Hz), 5.66 (ddd, 1 H,

J = 9.2,9.9,17.0 Hz), 5.83 (d, 1 H, J = 5.5 Hz), 6.02 (dd, 1 H,

J = 5.5, 10.3 Hz), 6.20 (d, 1 H, J = 10.3 Hz), 6.93 (s, 1 H).

406.2440.

1-{5-[(2S)-2-Methoxymethyl-pyrrolidin-1-ylimino)-methyl]-

(1S,6R)-1,6-dimethyl-cyclohexa-2,4-dienyl}-ethanone(26a)

A pressure resistant Schlenk tube equipped with a pressure gauge

was charged with a solution of complex 6 (354 mg, 1.0 mmol) in

THF (15 mL). To the stirred, cold ( 78 °C) solution under N₂was

added dropwise MeLi (0.688 mL of a 1.6 M Et₂O solution, 1.1

mmol). The reaction was warmed to 40 °C over a period of 2 h,

stirred at this temperature for 1 h, recooled to 78 °C and then treat-

ed with MeI (0.620 mL, 10 equiv) and HMPA (1.7 mL). 4 bar of CO

was then pressed onto the solution. The reaction was left to warm

slowly to r.t. and stirred overnight. CO was vented and the excess

of MeI and solvents were evaporated. The crude red oil was taken

up in Et₂O hexane and filtered through a plug of silica gel. After

concentration, the residue was dissolved in THF (15 mL), cooled to

78 °C and reacted with EtONa (0.60 mL of a 2.64 M solution in

EtOH) and MeI (0.50 mL, 8 mmol). The temperature was raised

slowly to r.t. and was stirred overnight. Volatiles were removed in

vacuum and the crude product submitted to flash chromatography

MS: m/z (%) 302 (14), 259 (27), 187 (15), 144 (31), 129 (71), 70

(100), 45 (90).

HR-MS: m/z calcd for C₁₈H₂₆N₂O₂: 302.1994. Found 302.1965.

1-{5-[((S)-2-Methoxymethyl-pyrrolidin-1-ylimino)-methyl]-

(1S,6R)-1-methyl-6-phenyl-cyclohexa-2,4-dienyl}-ethanone 29a

The reaction used PhLi as the nucleophile and was carried out as de-

scribed for 26a to give 29a (214 mg, 61%). ¹H NMR of the CH=N

signals (6.84 and 6.86) showed a diastereoisomeric ratio of 140:1.

[ ]²⁰_D–712 (c 0.68, CHCl₃).

IR (CH₂Cl₂): 3052w, 2976w, 2880m, 1702vs, 1543s, 1452s, 1352s,

1223w, 1121s, 900w cm^-1.

2052

G. Bernardinelli et al.

FEATURE ARTICLE

¹H NMR (CDCl₃, 400 MHz): = 1.38 (s, 3 H), 1.80 (s, 3 H), 1.80-

195 (m, 4 H), 3.18–3.30 (m, 1 H), 3.22 (s, 3 H), 3.26 (dd, 1 H,

J = 6.6, 9.6 Hz), 3.47 (dd, 1 H, J = 3.3, 9.6 Hz), 3.58–3.67 (m, 1 H),

4.17 (s, 1 H), 5.98 (dd, 1 H, J = 1.1, 4.8 Hz), 6.15–6.22 (m, 2 H),

6.84 (s, 1 H), 7.10–735 (m, 5 H).

Adduct 30

Treatment of 26a (106.5 mg, 0.367 mmol), as described in the gen-

eral procedure, afforded 30¹⁷(52.3 mg, 80%). Transformation to the

SAMP hydrazone and intgration of the ¹H NMR CH=N resonance

showed a de >98%.

MS: m/z (%) 352 (20), 309 (100), 291 (10), 263 (10), 194 (32).

HR-MS: m/z calcd for C₂₂H₂₈N₂O₂: 352.2151. Found 352.2179.

[ ]²⁰–600.3 (c 0.348, CHCl₃).

D

Adduct 31

Treatment of 27a (154.5 mg, 0.465 mmol), as described in the gen-

eral procedure, afforded 31 (79.8 mg, 78%). Transformation to the

SAMP hydrazone and intgration of the ¹H NMR CH=N resonance

showed a de >98%.

Removal of the Chiral Auxiliary in 21a and in 26a-29a

Adduct 30.

A 100 mL round bottom flask, equipped with a Dean-Stark trap,

was charged with ketone 21a (184.4 mg, 0.705 mmol), p-toluensul-

fonic acid monohydrate (135.4 mg, 0.712 mmol), ethylene glycol

(0.250 mL, 6 equiv, 4.23 mmol), and anhyd toluene (45 mL) in an

inert atmosphere. The solution was heated at reflux with azeotropic

removal of water and the reaction was monitored by TLC. Addition-

al portions of ethylene glycol (0.5+1 mL) were added after 12 h and

24 h. The solution was cooled to r.t. and washed with aq NaHCO₃

solution (10 mL). The aqueous phase was washed with Et₂O (3 10

mL), and the combined organic phases were dried (MgSO₄), filtered

and evaporated. Flash chromatography (hexane Et₂O, 20:1 to 10:1)

afforded the ketal 4(S)-4,5-dihydro-4-(1-methylethyl)-2-{(5S,6R)-

5,6-dimethyl-5-[2-methyl1,3-dioxolan-2-yl]cyclohexa-1,3-dien-1-

yl}oxazole (129.3 mg, 60%) as a white solid, mp = 81–82 °C.

[ ]²⁰_D–452 (c 0.544, CHCl₃).

IR (CH₂Cl₂): 2959w, 2935m, 2862w, 1702m, 1672vs, 1567m,

1467w, 1173m cm^-1.

¹H NMR (CDCl₃, 400 MHz): = 0.79 (t, 3 H, J = 8.0 Hz), 1.00–1.50

(m, 6 H,), 1.17 (s, 3 H), 2.23 (s, 3 H), 3.06–3.12 (m, 1 H), 6.18 (dd,

1 H, J = 5.2, 9.6 Hz), 6.72–6.77 (m, 2 H), 9.61 (s, 1 H).

MS: m/z (%)220 (1), 177 (3), 163 (13), 121 (90), 57 (100).

HR-MS: m/z calcd. for C₁₄H₂₀O₂: 220.1463. Found 220.1421.

Adduct 32

Treatment of 28a (120.1 mg, 0.397 mmol), as described in the gen-

eral procedure, afforded 32¹⁷(55.2 mg, 73%). Transformation to the

SAMP hydrazone and integration of the ¹H NMR CH=N resonance

showed a single diastereoisomer.

[ ]²⁰_D–129.8 (c 1.6, CHCl₃).

IR (CH₂Cl₂): 3046w, 2965vs, 2936s, 2888s, 1650s, 1610vs, 1574w,

1481w, 1456m, 1400m, 1380s, 1365s, 1338w, 1301w, 1228s,

1173vs, 1148m, 1104m, 1091m, 1070m, 1046vs, 1020vs, 999s,

952s, 882m cm^-1.

[ ]²⁰_D–531 (c 0.570, CHCl₃).

¹H NMR (CDCl₃, 200 MHz): = 0.84 (d, 3 H, J = 6.8 Hz), 0.94 (d,

3 H, J = 6.8Hz), 1.06 (d, 3 H, J = 6.8 Hz), 1.12 (s, 3 H), 1.33 (s, 3

H), 1.80–2.00 (m, 1 H), 2.77 (bq, 1 H, J = 6.8 Hz), 3.90–4.30 (m, 5

H), 5.94–5.97 (m, 2 H), 6.54–6.58 (m,1 H).

Adduct 33

Treatment of 29a (62.1 mg, 0.176 mmol), as described in the gener-

al procedure, afforded 33¹⁷(33.8 mg, 80%). Transformation to the

SAMP hydrazone and integration of the ¹H NMR CH=N resonance

showed a single diastereoisomer.

MS: m/z (%) 304 (10), 303 (50), 290 (30), 260 (100), 246 (25), 231

(20), 219 (61), 204 (80), 188 (30), 87 (100).

[ ]²⁰_D– 857 (c 0.586, CHCl₃).

Anal. Calcd for C₁₈H₂₇NO₃: C, 70.79; H, 8.91; N, 4.58. Found: C,

70.61; H, 8.89; N, 4.57.

Sequential Nucleophile/Electrophile Additions to Complexes 8a

and 8b

To a stirred solution of the above ketal (73.2 mg, 0.239 mmol) in an-

hyd CH₂Cl₂(3 mL) was added MeOTf (0.052 mL, 2 equiv, distilled

from P₂O₅) at 20 °C under N₂. After 1.5 h TLC indicated that all

starting material was converted into a baseline product. NaBH₄(30

mg, 0.789 mmol, 3.3 equiv) in 2 mL of anhyd THF MeOH, 3:1

was added via cannula transfer. After 15 min. sat. aq NH₄Cl (1 mL)

was added. Extraction CH₂Cl₂(10 mL) and flash chromatography

(hexane Et₂O, 2:1) afforded aldehyde 30¹⁷(18 mg, 56%).

To a stirred solution of complex 8a or 8b (1 mmol) in THF or in tol-

uene (5 mL) was added dropwise a solution of PhLi (0.726 mL of a

1.66 M solution in cyclohexane Et₂O, 1.2 mmol) at –78 °C. The

solution was warmed to –50 °C and stirred at this temperature for 2

h. After recooling to 78 °C, the co-solvant (HMPA or DMPU, 5

mmol, see Table 5) and TMS propargyl bromide (2.5 mmol) were

added. The solution was left to slowly warm to r.t. and this was

stirred for 16 h. Volatiles were removed in vacuum. The crude prod-

uct was taken up in Et₂O and filtered over silica gel. Flash chroma-

tography (hexane Et₂O, 19:1) afforded aldehyde 34. GC: column

OV-1701; H₂3 mL/min, 70 °C, 1 min, 10 °C/min, 250 °C: t_R16.0

min. HPLC: column Chiracel OD-H; hexane–iPrOH, 99.5:0.5;

1mL/min; 254 nm: ( )-(R,R)-34 t_R= 13 min, (+)-(S,S)-34 t_R= 17

min. A 4:1 mixture of the enantiomers (+)-(S,S)-34:( )-(R,R)-34

showed an [ ]²⁰_D= +480.0 (c = 0.46, CHCl₃).

[ ]²⁰_D–594 (c 1.27, CHCl₃).

Recovery of Aldehdes 30-33 from SAMP Hydrazone Dienes

26a-29a; General procedure

The hydrazone compound (1 equiv) was dissolved in MeOH (1 mL/

mmol hydrazone). Aq H₂SO₄(50%, 2 mL/mmol hydrazone) was

added and the reaction was stirred, until there was no hydrazone de-

tected by TLC (12–20 h). The solution was diluted with H₂O (10

mL). Extraction with Et₂O (3 10 mL) and washing of the organic

phase with H₂O, aq NaHCO₃, brine and dried over MgSO₄. Flash

chromatography (hexane Et₂O, 5:1) afforded the aldehydes 26a-

29a.⁴⁰

IR (CHCl₃): 3009w, 2961w, 2819w, 2719w, 2172m, 1676s, 1572m,

1492w, 1453w, 1405w, 1324w, 1251m, 1174m, 1034w, 845s cm^-1.

¹H NMR (200 MHz, CDCl₃): = 0.17 (s, 9 H), 2.24 (dd, J = 16.7,

8.4, 1 H), 2.38 (dd, J = 16.7, 6.4, 1 H), 2.65–2.80 (m, 1 H), 4.11 (s,

1 H), 6.3 (m, 2 H), 6.97 (dd, J = 5.1, 1.2 1 H), 7.1–7.3 (m, 5 H), 9.55

(s,1 H).

¹³C NMR (50 MHz, CDCl₃): 0.1 (CH₃), 25.1 (CH₂), 38.9 (CH), 41.9

(CH), 87.1 (C), 103.9 (C), 123.3 (CH), 126.9 (CH), 127.1 (CH),

128.6 (CH), 138.1 (C), 138.2 (CH), 141.0 (CH), 141.9 (C), 192.6

(CHO).

MS: m/z (%) 294 (3, M⁺), 203 (26), 183 (15), 155 (100).

FEATURE ARTICLE

Transformation of Arenes into Substituted Cyclohexadienes

2053

HR-MS: m/z calcd for C₁₉H₂₂SiO: 294.144. Found: 294.145.

(19) Enders, D.; Klatt, M. Encyclopedia of Reagents for Organic

Reactions, Vol. 1; Paquette, L. A., Ed.; John Wiley & Sons:

Chichester, 1995, 178.

(20) Kündig, E. P.; Perret, C.; Spichiger, S.; Bernardinelli, G. J.

Organomet. Chem. 1985, 286, 183–200.

(21) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.

(22) In the absence of the Cr(CO)₃group, phenyl oxazolines react

with n-BuLi to give products arising from ortho-arene

lithiation. See ref 21.

Acknowledgement

Financial support of this work by the Swiss National Science Foun-

dation (grants 20-52’478.97 and 21-63854.00) is gratefully ack-

nowledged. We thank Mr. J. P. Saulnier, Mr. A. Pinto, and Mrs. D.

Klink for NMR and MS measurements.

(23) Jackman, L. M.; Scarmoutzos, L. M. J. Am. Chem. Soc.

1984, 106, 4627.

(24) Kündig, E. P.; Cunningham, J. A. F.; Paglia, P.; Simmons,

D. P.; Bernardinelli, G. Helv. Chim. Acta 1990, 73, 386.

(25) Crystal structure determination of 3a:

References

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Cr(CO)₃(C₁₂H₁₅NO), Mr = 325.3; = 0.782 mm^-1,

dx = 1.451 g.cm^-3, monoclinic, P21, Z = 4, a = 11.0923(10),

b = 11.2412(7), c = 12.0144(12)Å, = 96.471(11)°,

V = 1488.5(2)Å³, yellow prism 0.10 x 0.20 x 0.26. Cell

dimensions and intensities were measured at 200 K on a Stoe

IPDS diffractometer with graphite-monochromated Mo K

radiation ( = 0.71069 Å). 22868 measured reflections, 7125

unique reflections of which 3728 were observables (|Fo| > 4

(Fo)); Rint for equivalent reflections 0.069. Data were

corrected for absorption (T min, max = 0.8492, 0.9441).

Full-matrix least-squares refinement based on F using

weight of 1/[ ²(Fo)+ 0.0003(Fo)²] gave final values

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Hydrogen atoms were placed in calculated positions.

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been deposited to the Cambridge Crystallographic Data

Base (deposition No. CCDC163963, CCDC163964 for 3a

and 6 respectively). Copies of the data can be obtained free

of charge on application to the CCDC, 12 Union Road,

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Cr(CO)₃(C₁₃H₁₈N₂O), Mr = 354.3; = 0.689 mm^-1,

dx = 1.415 g.cm^-3, monoclinic, P21, Z = 4, a = 10.229(2),

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V = 1663.6(6)Å³, yellow prism 0.11 × 0.24 × 0.24. Cell

dimensions and intensities were measured at room

temperature on a Philips PW1100 diffractometer with

graphite-monochromated Mo K ]radiation ( = 0.71069 Å).

Two reference reflections measured every 60 min showed

variation of about 10%; all intensities were corrected for this

drift. 10 < h <10; 0 < k < 14; 0 < l < 12 and all anti

reflections; 4522 measured reflections, 4194 unique

reflections of which 3155 were observables (|Fo| > 4 (Fo));

Rint for equivalent reflections 0.031. Data were corrected

for absorption (T min, max = 0.8814, 0.9245). Full-matrix

least-squares refinement based on F using weight of 1/

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Electronic Conference on Heterocyclic Chemistry ’98

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[

wR2 = 0.047 and Flack parameter x = 0.02(6). Hydrogen

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methoxymethyl substituant of the anti-conformer is

disordered. Two disordered fragments have been refined

with population parameters of 0.70 and 0.30 for C12b-O1b-

C13b and C12b’-O1b’-C13b’ respectively. The partial

decomposition of the crystal during data collection and the

presence of the disorder, led to relatively large uncertainties

in the final coordinates.

2054

G. Bernardinelli et al.

FEATURE ARTICLE

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Article Doi

Diastereoselective transformation of arenes into highly enantiomerically enriched substituted cyclohexadienes

DOI: 10.1055/s-2001-17704

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Article abstract of DOI:10.1055/s-2001-17704

Full text of DOI:10.1055/s-2001-17704

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