(3 + 3)-cyclodimerization of donor-acceptor cyclopropanes. three routes to six-membered rings

Article

pubs.acs.org/joc

(3 + 3)-Cyclodimerization of Donor−Acceptor Cyclopropanes. Three

Routes to Six-Membered Rings

Olga A. Ivanova,^†Ekaterina M. Budynina,^†,‡Alexey O. Chagarovskiy,^‡Igor V. Trushkov,^†,‡

and Mikhail Ya. Melnikov*^,†

^†Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russia

^‡Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Leninsky av.

117/2, Moscow 117997, Russia

S

* Supporting Information

ABSTRACT: The ability of donor−acceptor cyclopropanes

to (3 + 3)-cyclodimerize is disclosed. It has been found that

Lewis acid-induced transformations of 2-(hetero)-

arylcyclopropane-1,1-dicarboxylates containing electron-abun-

dant aromatic substituents led to the construction of six-

membered cyclic systems. Depending on the substrate

properties and the Lewis acid applied, three types of products

can be obtained: (1) 1,4-diarylcyclohexanes, (2) 1-aryl-1,2,3,4-

tetrahydronaphthalenes, and (3) 9,10-dihydroanthracenes.

azirines³⁸⁻⁴⁰), which can be considered as precursors of the

corresponding 1,3-dipoles.

INTRODUCTION

■

The cyclodimerizations of unsaturated compounds attract the

The (3 + 3)-cyclodimerization of three-membered carbo-

attention of organic chemists as atom-economic reactions

cycles is an almost unexplored field except for nickel-

allowing for one-step construction of cyclic molecules with a

catalyzed dimerizations of methylenecyclopropanes.^8,41

considerable increase of structure complexity. The most

Meanwhile, there is a special class of cyclopropanes, namely

investigated types of these processes are (2 + 2)-cyclo-

dimerization of alkenes, allenes, and ketenes and (4 + 2)-

donor−acceptor (D−A) cyclopropanes, which appear to be

very appropriate as candidates for (3 + 3)-cyclodimeriza-

cyclodimerization of dienes, affording four- and six-membered

tion.⁴²⁻⁴⁶They are considered to be well-proven synthetic

rings, respectively.^1,2On the other hand, (3 + n)-cyclo-

dimerizations are much less explored in spite of their great

equivalents of a three-carbon 1,3-zwitterionic synthon of I

type (Scheme 1) possessing a dual nature and showing both

potential for construction of a diversity of carbo- and

1,3-dipole-like⁴⁷⁻⁵⁴and dipolarophile-like⁵⁵⁻⁵⁷properties.

heterocycles.

However, to date there have not been any reports where

In general, there are three types of species that can

these two types of reactivity of D−A cyclopropanes were

participate in (3 + n)-cyclodimerizations: (1) 1,3-dipoles, (2)

combined in one reaction proceeding as (3 + 3)-cyclo-

1,3-biradicals, and (3) three-membered rings. Thus, (3 + 2)-

cyclodimerization of nitrile oxides is a preparative method of

dimerization and leading to the cyclohexane formation (I+I path,

furoxans synthesis.^3,4There are also scarce examples of other

Scheme 1).

(3 + 2)-cyclodimerizations,⁵⁻⁷among which the most important is

a formation of cyclopentanes from the corresponding cyclo-

propane derivatives.^8,9Alternatively, (3 + 3)-cyclodimerizations

have been reported for various 1,3-dipoles including nitrile

oxides,^10,11carbonyl oxides,¹²⁻¹⁴carbonyl imides,¹⁵nitrile

imides,^16,17carbonyl ylides,¹⁸thiocarbonyl ylides,¹⁹⁻²¹azome-

thine ylides,²²etc.^23,24(3 + 3)-Cyclodimerization has also been

reported for 1,3-biradicals, such as trimethylenemethanes;²⁵

however, this reaction usually proceeds with low yields and is

accompanied by formation of various side products.²⁶⁻²⁸

Additionally, there are limited reports of (3 + 3)-cyclo-

dimerization for three-membered heterocycles (oxiranes,²⁹⁻³¹

dioxiranes,³²thiiranes,^33,34thiirenes,³⁵aziridines,^36,37and

In addition, the alternative behavior of D−A cyclopropanes

as synthetic equivalents of unusual synthon II (Scheme 1) was

recently disclosed for cyclopropanes containing electron-rich

aromatic or heteroaromatic substituents.⁵⁸⁻⁶²For such cyclo-

propanes, the (hetero)aromatic ring takes place in reactions as

nucleophilic moiety. Therefore, the rival (3 + 3)-cyclo-

dimerization affording dihydroanthracenes (II+II path, Scheme 1)

can be hypothesized in this case.

Finally, a process combining the reactivity of D−A

cyclopropanes as equivalents of both synthon I and synthon

Received: August 2, 2011

Published: September 26, 2011

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Scheme 1. Three Hypothetical Paths of (3 + 3)-Cyclodimerization of Aryl-Derived D−A Cyclopropanes

Table 1. Cyclopropane-to-Cyclohexane (3 + 3)-Cyclodimerization of 1a−c

entry

1

solvent

LA (mol %)

T (°C)

time (h)

yield of 2 (%)

yield of 3 (%)

a

1

2

1a

1b

1c

CH₂Cl₂

C₂H₅NO₂

CH₃NO₂

C₆H₆

SnCl₄(120)

AlCl₃(100)

TiCl₄(120)

TiCl₄(200)

ZnCl₂(120)

ZnCl₂(200)

BF₃·Et₂O (120)

GaCl₃(40)

SnCl₄(200)

SnCl₄(220)

−20

−60

55

22

3

81

82

83

b

a

13

5

3

4

reflux

3

b

5

CH₂Cl₂

CH₃NO₂

C₆H₆

−25/1 h→5/22 h

−20/15 min→20/1.5 h

−20/15 min→20/3 h

5

70

c

6

27

17

7

traces

b

8

reflux

3

9

CH₂Cl₂

C₂H₄Cl₂

CH₂Cl₂

CH₃NO₂

CH₂Cl₂

CH₃NO₂

20

4

86

d

10

11

12

13

14

reflux

20

2

d

6

85

19

76

4

26

81

−20

50

20

2

a

b

The reaction mixture was then allowed to warm to room temperature for 0.5 h. Oligomeric and polymeric ring-opening products were only

c

d

formed. NMR yields. Product of cyclopropane isomerization 4 was also formed in 10% yield.

II should result in the formation of tetrahydronaphthalenes

(I+II path, Scheme 1). A single investigation mentioning an

intermediate formation of dimers through I+II path is related

to the synthesis of carbazoles from the indole-derived D−A

cyclopropanes.^59,60

In this study, we aimed to perform a (3 + 3)-cyclo-

dimerization of the (hetero)aryl-substituted D−A cyclo-

propanes. The challenge was to find appropriate conditions

for controlling of the chemoselectivity of the process. During

this investigation, we have revealed each of the three

dimerization pathways presented in Scheme 1 and determined

the main factors influencing these dimerizations. Herein we

report the results of our research opening new synthetic routes

to 1,4-diarylcyclohexanes, 1-aryl-1,2,3,4-tetrahydronaphtha-

lenes, and 9,10-dihydroanthracenes.

RESULTS AND DISCUSSION

■

Substrate Selection. For the present research, 2-aryl- and

2-heteroarylcyclopropane-1,1-dicarboxylates were chosen ac-

cording to the following prerequisites. First, they would give

cyclodimers of all three types represented in Scheme 1. Second,

these substrates revealed the tendency to easy ring-opening and

have previously demonstrated high reactivity in various Lewis

acid-induced transformations.⁴²⁻⁵⁷In the presence of strongly

activating Lewis acids, these cyclopropanes are readily

converted into 1,3-zwitterions⁶³in which anionic and cationic

centers are efficiently stabilized by two electron-withdrawing

ester groups and an electron-abundant (hetero)aromatic

substituent, respectively. Finally, these compounds are readily

accessible from (hetero)aromatic aldehydes through the

sequence of Knoevenagel/Corey−Chaykovsky reactions.^64,65

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Table 2. Cyclopropane-to-Cyclohexane (3 + 3)-Cyclodimerization of 2-[4-(Dialkylamino)phenyl]cyclopropane-1,1-

dicarboxylates 1d−h

entry

1,2

R

R′

LA (mol %)

T (°C)

time (h)

yield of 2 (%)

1

2

3

4

5

6

d

e

f

Me

Et

Me

SnCl₄(120)

TiCl₄(240)

TiCl₄(210)

55

50

60

3

76

86

18

84

58

83

3

Me

−(CH₂)₅−

−(CH₂)₄−

3

f

3

g

h

2.5

3

−(CH₂)₂O(CH₂)₂−

The chemoselectivity of the process is determined by the

relative reactivity of two nucleophilic sites (marked blue and

green in Scheme 1). Evidently, if both ortho-positions of an aryl

substituent are occupied, D−A cyclopropanes cannot react as

an equivalent of synthon II. Therefore, to perform a direct

dimerization via the I+I path and avoid two other paths (I+II

and II+II) we have chosen 2-(2,4,6-trimethoxyphenyl)-

cyclopropane-1,1-diesters as model substrates.

Oppositely, a (3 + 3)-cyclodimerization of D−A cyclo-

propanes into dihydroanthracenes via the II+II path implies

utilization of D−A cyclopropanes with aryl groups which are

prone to electrophilic attack onto the ortho-position. Therefore,

2-(3,4,5-trimethoxyphenyl)cyclopropane-1,1-dicarboxylate was

selected as a model compound for this reaction.

cyclohexane (3 + 3)-cyclodimerization. Thus, a series of

cyclopropanes 1d−h, which have a highly electron-donating

NR₂group at the para-position of the aromatic ring, was found

to smoothly transform into the corresponding cyclohexanes

2d−h in moderate to good yields (Table 2). For cyclopropanes

1f−h the utilization of SnCl₄led to low yields of 2, whereas

TiCl₄was employed efficiently. For all compounds except 1g,

which decomposed partially under reaction conditions, the

corresponding dimers were obtained in ca. 80% yields.

The cyclopropane-to-cyclohexane (3 + 3)-cyclodimerization

proceeded with excellent diastereoselectivity: according to the

NMR data, the cycloadducts 2a−h were formed as single

1

diastereomers. In comparison to H and ¹³C NMR spectra of

the parent cyclopropanes 1a−h, the corresponding spectra of

dimeric products 2a−h were characterized by a low-field shift

of resonances of alicyclic protons and carbon atoms. Addition-

ally, ¹H NMR spectra of 2a−h revealed the full coupling

patterns for the ABX-system of the protons involving into two

The formation of tetrahydronaphthalenes through I+II path

is a borderline case between two foregoing dimerizations, so the

prediction of substrates, which should afford these products, is

not so straightforward, as in two reactions above.

2

3

equivalent CH₂−CH fragments, namely J of ca. 14 Hz and J

of ca. 3−5 and 13−14 Hz, which are also characteristic for

saturated common rings.

Cyclopropane-to-Cyclohexane (3 + 3)-Cyclodimeriza-

tion (I+I Path). According to the above arguments, we initially

examined cyclopropanes 1a,b as model substrates. The

utilization of 1a,b with strong electron-donating substituent

vicinal to the diester moiety proved to be necessary but

insufficient condition to furnish (3 + 3)-cyclodimerization.

Thus, we have found that the weakly or moderately activating

Lewis acids (Yb(OTf)₃, Sn(OTf)₂, Sc(OTf)₃, Nd(OTf)₃) failed

to induce this reaction at all. To our delight, more activating

Lewis acids were revealed to promote the formation of

cyclohexanes 2a,b (Table 1). However, the utilization of

AlCl₃, BF₃·Et₂O, or GaCl₃was not efficient providing low yields

of 2a,b. The isomeric acyclic dimers 3a,b were usually formed

as major products in these reactions. Among the studied Lewis

acids, the best results were obtained with SnCl₄; in this case

cyclohexane 2a was formed in ca. 80% yield. The presence of a

bromine atom in aromatic substituent, as it is in 1c, had no

significant effect on the reaction outcome. Further variations of

the reaction conditions (solvent, temperature, duration, Lewis

acid loading) disclosed that this cyclodimerization was the most

efficient when it proceeded in CH₃NO₂at 50−55 °C in the

presence of 120−200 mol % of SnCl₄. Thus, the utilization of

more than stoichiometric amounts of Lewis acid was caused by

its competitive binding to methoxy groups or other donors of

an electron pair in an aromatic substituent.

The restricted rotation of aryl groups with bulky ortho-

substituents in cyclohexanes 2a,b led to magnetic non-

equivalency for protons of the aromatic rings and methoxy

groups which gave at room temperature two and three different

signals, respectively (for 2a, see Figure 1). Variable-temperature

¹H NMR study revealed that the coalescence of signals of

aromatic protons was achieved at 323 K. Using the approximate

Eyring equation, we estimated the energy barrier for rotation of

aryl groups in this molecule to be ca. 70 kJ/mol.

Structure of 2d was unambiguously proved by single-crystal

X-ray analysis.^66,67These data showed that 2 has a cis-

arrangement of aromatic substituents and the central six-

membered ring in the molecule adopts a twist-conformation

with quasi-equatorial location of the aromatic substituents

(Figure 2). The similarity in NMR spectra for all isolated

compounds 2 as well as single-crystal X-ray data for 2i (Figure 3,

see below) allowed us to conclude that all cyclohexanes 2

were formed in this (3 + 3)-cyclodimerization as cis-isomers

only.

The exclusive formation of cis-isomers of 2 seems to be quite

unusual as trans-1,4-disubstituted cyclohexanes are well-known

to be more preferable.^1,2Actually, our ab initio calculations at

HF/6-31G level showed that cis-2b in a twist-conformation has

6.9 kj/mol lower energy than the most stable chair conformer

We have found that the occupation of ortho-positions in

aromatic ring is not a necessary condition for cyclopropane-to-

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Figure 3. Single crystal X-ray structure of 2i.

C(Ar)HCH− fragment are ca. 17 Hz, confirming the

formation of 3 as E-isomers exclusively.

We suggest that the cyclopropane-to-cyclohexane (3 + 3)-

cyclodimerization proceeds by a mechanism which is shown in

Scheme 2. The coordination of strongly activating Lewis acid to

ester group(s) leads to the cyclopropane C(1)−C(2) bond

heterolysis affording zwitterion A. Its formation is in

accordance with results of a previous study of 2-arylcyclopro-

pane-1,1-dicarboxylate reactivity in the absence of highly

nucleophilic agents.⁶³A valid argument toward formation of

A is an isolation of side products 4 and 5 under milder reaction

conditions. Indeed, it was previously found that γ-aryl-γ-

butyrolactones 5 were formed from D−A cyclopropanes in the

presence of strongly activating Lewis acids as 1:1 mixtures of

two diastereomers,⁶⁸which is consistent with the intermediate

formation of zwitterion A. Similarly, styrylmalonates 4 are the

result of D−A cyclopropane isomerization by a stepwise

mechanism, where the first step is the Lewis acid-induced

heterolysis of the C−C bond in the small ring.⁶⁸Additionally,

polymeric products, which we observed under nonoptimized

reaction conditions, are formed via zwitterion A too.

1

Figure 1. Temperature dependence of 600 MHz H NMR spectrum

of 2a in CDCl₃.

The second step is the attack of nucleophilic center of one

zwitterionic species A onto the electrophilic center of another

one affording new zwitterion B. The formation of B is

supported by isolation of dimeric alkenes 3 either together with

2 or as single products under nonoptimized reaction conditions

(Table 1). Therefore, malonic anion fragment in intermediate

B has a dual reactivity. As a nucleophile, it interacts with

benzylic cation to yield cyclohexane 2 (path b). As a base, it

captures a proton from δ-position leading to acyclic dimer 3

(path c). A similar dual behavior of this moiety was previously

found for the D−A cyclopropanes isomerization into

styrylmalonates.⁶⁸

Cyclopropane-to-cyclohexane (3 + 3)-cyclodimerization is a

conceptually new efficient approach to the symmetrically

substituted cyclohexane derivatives. Moreover, to date there

have not been efficient diastereoselective approaches to cis-1,4-

diarylcyclohexanes.⁶⁹Therefore, cyclopropane-to-cyclohexane

(3 + 3)-cyclodimerization followed by appropriate transformations

Figure 2. Single crystal X-ray structure of 2d.

of trans-2b. This trend, namely the preference of cis-isomer over

trans-isomer, is observed in the series of various tetramethyl

2,5-bis(aryl)cyclohexane-1,1,4,4-tetracarboxylates.⁶⁷It can be

related to larger steric repulsions between ester groups and aryl

substituents in the chair-conformation of trans-2b vs those in

the twist-conformation of cis-2b. Similarly, significant steric

hindrances can occur in the chairlike transition state leading to

trans-2b, while twist-like transition state minimalizes them that

could be a possible reason for the exclusive formation of cis-2b.

Structures of acyclic dimers 3 were established by analysis of

NMR spectra. In particular, the ³J coupling constants for

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Scheme 2. Proposed Mechanism for Cyclopropane-to-Cyclohexane (3 + 3)-Cyclodimerization

Table 3. Optimization of Reaction Conditions for (3 + 3)-Cyclodimerization of 2-(4-Methoxyphenyl)cyclopropane-1,1-

dicarboxylates 1i,j

entry

R

Lewis acid (mol %)

solvent

T (°C)

time (h)

yield of 2 (%)

yield of 7 (%) (trans/cis ratio)

1

2

Me

Et

TiCl₄(120)

TiCl₄(200)

SnCl₄(100)

SnCl₄(150)

BF₃·OEt₂(100)

SnCl₄(100)

SnCl₄(200)

Me₃SiOTf (100)

AlCl₃(240)

CH₃NO₂

CH₂Cl₂

−25

−5 → 0

5

23

2

a

b

3

2

45

c

4

50

3

49 (93:7)

90 (95:5)

81 (91:9)

d

5

−20

24

2

6

C₆H₆

20

40

50

20

50

e

7

C₆H₆

59 (90:10)

8

CH₃NO₂

3

c

9

3

87 (91:9)

49 (95:5)

10

11

12

13

Et

30

22

3

70

c

38

40

Et

c

d

Et

−25

62

a

b

Chloride 6 was only formed in 80% yield. Lactone 5 was only formed in 70% yield. Oligomeric and polymeric ring-opening products were only

formed. Afterward the reaction mixture was allowed to warm to room temperature for 0.5 h. Compound 8 was obtained as a side product in 30%

d

e

yield (see Scheme 3 and related discussion).

of 2 into other cyclohexane derivatives provide convenient

access to these systems. The formed 2,5-diarylcyclohexane-

1,1,4,4-tetracarboxylates of type 2 are of particular interest as

direct precursors of liquid crystalline compounds⁷⁰or

anticholesteremic agents.⁷¹

cyclodimerization 2i in 45% yield (entry 3). Further increase in

reaction temperature did not result in better yield of 2i due to

the significant formation of oligomeric and polymeric ring-

opening products.

The utilization of SnCl₄unexpectedly resulted in alteration of

the reaction pathway from I+I to I+II (3 + 3)-cyclo-

dimerization. Thus, the treatment of 1i with 1 equiv of SnCl₄

in various solvents produced 7a in moderate to good yields

(entries 4−6). The careful optimization of reaction conditions

for dimerization of 1j showed that SnCl₄(1 equiv) induced the

formation of a tetraline 7b in high yield when the reaction was

performed in CH₃NO₂under moderate heating (entry 9).

However, when the same reaction was carried out at room

temperature, both tetraline 7b and cyclohexane 2j were

obtained in ca. 5:4 ratio (entry 10). The increase in a Lewis

acid loading allowed for suppression of 7b formation but did

not increase yield of cyclohexane 2j (entry 11). The utilization

of BF₃·Et₂O and TMSOTf did not lead to both 2 and 7

affording polymeric products only. Oppositely, AlCl₃was found

to furnish (3 + 3)-cyclodimer 2j in the reasonable yield

(entry 13).

(3 + 3)-Cyclodimerization of 2-(4-Methoxyphenyl)-

cyclopropane-1,1-dicarboxylates (I+I and I+II Paths). Other

substrates, which contain a phenyl group with a strongly

electron-donating substituent at the para-position and can

undergo (3 + 3)-cyclodimerization via the I+I path, are 4-

methoxyphenylcyclopropanes 1i,j. A short survey of Lewis acids

indicated that TiCl₄, which was a favorable initiator for

dimerization of 4-(dialkylamino)phenyl-containing D−A cyclo-

propanes 1f−h, was inefficient for dimerization of 4-

methoxyphenyl D−A cyclopropanes 1i,j. Thus, the treatment

of 1i with TiCl₄in CH₃NO₂at −25 °C only afforded chloride

6, the product of TiCl₄-induced cyclopropane ring-open-

ing^61,68,72(Table 3, entry 1). The reverse addition of 1i to a

TiCl₄solution at −5 to 0 °C yielded γ-butyrolactone 5 as a

single product (entry 2). Gratifyingly, the treatment of 1i with

TiCl₄at 5 °C allowed us to obtain the product of the (3 + 3)-

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Scheme 3. Proposed Mechanism for Cyclodimerizations of 4-Methoxyphenyl-Derived D−A Cyclopropanes 1i,j

Structures of 2i,j were assigned by comparison of their

spectral data with those for 2a−h and proved unambiguously

by single crystal X-ray analysis of 2i (Figure 3).^66,67Structures

of 7a,b were determined as discussed below.

the p-methoxyphenyl substituent is observed. The relative

stereochemistry of 8 was deduced from its NOESY spectrum.

The central benzo[c]pentalene core has the only possible

relative configuration, whereas aromatic substituent at C(1)

atom is arranged in a trans-position relative to the cyclo-

hexenone motif (Figure 4).

The mechanism that can be proposed for the (3 + 3)-

cyclodimerizations of 1i,j is shown in Scheme 3. The formation

of zwitterion B in the case of the cyclodimerization through I

+II path is the same as that for the cyclopropane-to-

cyclohexane dimerization (I+I path). The coupling between

benzylic cation and malonate moiety in B (path b in Scheme 3)

leads to cyclohexane 2, whereas electrophilic substitution at

ortho-position of an aromatic fragment furnishes tetraline 7

(path ortho-d). The transformation of B into 7 can also

proceed via initial electrophilic attack onto the activated ipso-

position of aromatic group resulting in intermediate C (path

ipso-d) followed by migration of electrophile to ortho-position.

The ipso-intermediate of C type was recently proposed for

dimerization of the indole-derived D−A cyclopropanes.⁷³The

competition between ortho- and ipso-attack is well-known and

regulated by a balance of steric and electronic factors.^1,2The

high electron-donating ability of para-methoxy group makes

more preferable the electrophilic attack to ipso-position.

Oppositely, the higher steric repulsions for ipso-attack make

ortho-attack more preferable. We confirmed the possibility

of ipso-attack by the isolation of unusual side-product 8

(Scheme 3) containing angularly fused benzo[c]pentalene

scaffold. It was formed in 30% yield when dimerization of 1i

was performed in benzene in the presence of 1.5 equiv of SnCl₄

(Table 3, entry 7).

Figure 4. Representative NOE responses for 8.

Cyclopropane-to-Tetrahydronaphthalene (3 + 3)-

Cyclodimerization (I+II Path). Cyclopropanes 1k,l and

1m,n containing 3,4-dialkoxyphenyl and thienyl groups,

respectively, were found to readily give cyclic dimers 7c−f via

I+II path of (3 + 3)-cyclodimerization (Table 4). The most

efficient promoter for these reactions was found to be SnCl₄.

The increase in donating ability of aryl substituent enhanced

the tendency to polymerization of initial cyclopropanes 1k−n.

To inhibit the polymerization, we added Lewis acid to a cooled

solution of a cyclopropane and then stirred the reaction mixture

under cooling (for 1k,n) or slowly heated it to temperature

specified in Table 4 (for 1l,m).

Compound 8 was formed as a single diastereomer. Its

structure was assigned by 1D and 2D COSY, HETCOR,

HMBC, and NOESY NMR spectral data. The following criteria

All structural assignments for 7a−f were made from analysis

1

of H and ¹³C NMR data. The presence of a benzannulated

1

central motif in the molecules of 7a−f was confirmed by a new

signal arising for a quaternary carbon atom of the aromatic ring

instead of the signal of a methine carbon. The ¹H NMR spectra

revealed resonances of two independent systems which are

formed by the protons of CH₂−CH fragment of a new six-

membered ring and CH−CH₂−CH aliphatic side chain. The

products 7c,d were formed as single regioisomers via

electrophilic attack onto C(6) rather than C(2) atom of

arene ring. Compounds 7a−f were formed as mixtures of

two diastereomers. The stereochemical assignments were

were used to elucidate the structure of 8. (1) In H NMR

spectrum three ABX systems correspond to the protons of

three isolated CH−CH₂fragments, which, according to the

HMBC, are connected to two different C(CO₂Me)₂groups in

such a way that one of the CHCH₂fragments is located

between two C(CO₂Me)₂groups. (2) The presence of a

cyclohexenone moiety is easily determined by characteristic

signals at δ_C154.9, 127.8, and 195.8 ppm assigned to three

consecutive carbon atoms of CHCHCO conjugated

system. (3) In the aromatic region, only one set of signals for

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Table 4. (3 + 3)-Cyclodimerization of D−A Cyclopropanes 1k−n via I+II Path

a

b

Afterwards the reaction mixture was allowed to warm to room temperature for 0.5 h. Reaction mixture was kept at 50 °C for additional 0.5 h.

accomplished on the basis of NOE experiments for the major

isomer of 7e (Figure 5). According to these data, the major

A fragment of 1-aryl-1,2,3,4-tetrahydronaphthalenes is

present in many lignans including biologically active ones.⁷⁴

Two of them (etoposide and teniposide) are now being used as

anticancer drugs.⁷⁵Therefore, the (3 + 3)-cyclodimerization of

D−A cyclopropanes via path I+II opens broad possibilities for

both synthetic and medicinal chemists.

Cyclopropane-to-Dihydroanthracene (3 + 3)-Cyclo-

dimerization (II+II Path). (3,4,5-Trimethoxyphenyl)-

cyclopropane 1o was found to be an excellent model for

(3 + 3)-cyclodimerization via the II+II path leading to

dihydroanthracene 9a in good yield (Scheme 1, Table 5) due

to the efficient activation of ortho-positions in an aromatic

substituent. The optimization of reaction conditions demon-

strated that this transformation proceeded efficiently at 50−

60 °C in the presence of 2 equiv of SnCl₄(entry 3). The

variation of reaction temperature or Lewis acid loading resulted

in diminished yield of 9a. Thus, utilization of 1.2 equiv of SnCl₄

afforded the target product 9a in 65% yield together with

the corresponding tetrahydronaphthalene 7g in 21% yield

(entry 2). The catalytic version of this transformation can be

performed using moderately activating Sn(OTf)₂(entry 4).

Moreover, dihydroanthracene 9a was obtained in this case in

higher yield and diastereoselectivity in comparison with SnCl₄-

induced reactions. Cyclopropanes 1p,q, containing 3,5- and 2,3-

dimethoxyphenyl groups, respectively, as donor substituents,

also produced dihydroanthracenes 9b,c when activated with 1−

1.5 equiv of SnCl₄or catalytic amounts of Sn(OTf)₂.

Diastereoselectivity of (3 + 3)-cyclodimerization of 1o,p was

Figure 5. Representative NOE responses for the trans-7e.

isomers of 7a−f have a trans-arrangement of aryl and 2,2-

bis(alkoxycarbonyl)ethyl substituents.

The mechanism of (3 + 3)-cyclodimerization of 1k−n via the

I+II path was described above using the example of 1i

dimerization (Scheme 3). It is noteworthy that cyclopropanes

1k,l have an additional donor alkoxy group at the C(3)

position. This group facilitates electrophilic attack onto both

ortho-positions (path ortho-d). Thus, the ipso-attack (path ipso-d)

seems to be redundant for the explanation of the obtained

results in this case. Additionally, the m-alkoxy group introduces

desymmetrization into the arene substituent leading to the

possibility of formation of two regioisomers during the

dimerization of these substrates. However, the cyclodimeriza-

tion in this case proceeded with excellent regioselectivity

exclusively producing regioisomers 7c,d via electrophilic

substitution at the 6-position of the aryl ring.

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ion A followed by its attack onto the starting cyclopropane 1

containing highly nucleophilic aromatic substituent⁷⁶(path f,

Scheme 4). Then Lewis acid induces opening of the second

cyclopropane into zwitterion D. The intramolecular attack of

the nucleophilic aromatic ring by electrophilic center in D

(path g, Scheme 4) completes the transformation.

Despite significant attention paid to various 9,10-dihydroan-

thracenes that is reflected to multiple publications dealing with

their chemical and biological properties, compounds of type 9

have not been studied yet mainly due to the complexity of their

synthesis. Therefore, this method of (3 + 3)-cyclodimerization

of the D−A cyclopropanes can be useful as an efficient

approach to these compounds.

Overall Mechanistic Scheme for (3 + 3)-Cyclodimeri-

zations of the D−A Cyclopropanes. Therefore, D−A

cyclopropanes with electron-abundant aromatic groups as

donor substituent revealed an ability to undergo three types

of (3 + 3)-cyclodimerization affording cyclohexanes 2,

tetrahydronaphthalenes 7, or 9,10-dihydroanthracenes 9. The

putative rationale of their formation is given above. Never-

theless, some mechanistic aspects should be specified.

The first question is a sequence of C−C bonds formation in

tetralines 7 via the I+II path. Above we postulated that the first

C−C bond is formed by the coupling of malonate anion with

benzyl cation of two zwitterions A furnishing intermediate B

and the formation of the second C−C bond is a result of S_EAr

reaction. However, the reverse sequence can be hypothesized,

which involves initial S_EAr reaction followed by coupling of

malonate anion with benzyl cation. For dimerization of 1i,j the

latter sequence is not appropriate as in these compounds arene

ring is activated to electrophilic substitution at the ortho-

position to methoxy group rather than to the ortho-position to

cyclopropyl moiety, while actually, the substitution proceeds at

the ortho-position to the cyclopropyl ring. Another argument

toward reaction path presented in Scheme 3 is the formation of

8 that is in accordance with intermediate B generation.

Moreover, S_EAr reaction should be accompanied by a proton

migration from arene to malonate moiety what prevents

participation of a latter nucleophilic site in further trans-

formation. Therefore, we are inclined to the mechanism of

tetraline 7 formation wherein anion−cation coupling precedes

S_EAr process rather than reverse sequence.

poor: anthracenes 9a,b were formed as mixtures of two

diastereomers in a slight excess of trans-isomer. In contrast,

dimerization of D−A cyclopropane 1q, possessing a methoxy

group in the ortho-position, proceeded with high diastereose-

lectivity affording mostly trans-9c.

The mass spectral data unambiguously proved the dimeric

composition of 9a−c, while NMR data evidenced a symmetric

structure of compounds synthesized. ¹H NMR spectra

completely revealed coupling patterns for a system of the

protons of two identical CHCH₂CH fragments. In the ¹³C

NMR spectra, a new signal of a quaternary carbon atom was

observed in the aromatic region instead of resonance of a

methine carbon that confirmed additional substitution in

aromatic ring. Furthermore, single-crystal X-ray data were

obtained for trans-9a and trans-9c providing unambiguous

proof for dihydroanthracene scaffold.⁶⁷

The construction of dihydroanthracene core of 9 from 1

consists in formation of two C−C bonds by two consecutive

S_EAr reactions (Scheme 4). It can be achieved by Lewis acid-

induced cyclopropane ring-opening with formation of zwitter-

Table 5. (3 + 3)-Cyclodimerization of D−A Cyclopropanes 1o−q via II+II Path

entry

1

(MeO)_n

Lewis acid (mol %)

solvent

T (°C)

time (h)

yield of 9 (%)

trans/cis ratio

1

2

3

4

5

6

7

8

1o

1p

1q

3,4,5-(MeO)₃

3,5-(MeO)₂

2,3-(MeO)₂

SnCl₄(5)

CH₃NO₂

50

60

50

60

55

100

3

a

SnCl₄(120)

SnCl₄(200)

Sn(OTf)₂(10)

SnCl₄(150)

Sn(OTf)₂(10)

SnCl₄(100)

Sn(OTf)₂(10)

3

65

54:46

58:42

63:37

55:45

64:36

>95:5

90:10

1

77

88

65

80

31

61

4.5

3

2

8

a

Tetrahydronaphthalene 7g (dr 72:28) was also isolated in 21% yield.

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Scheme 4. Proposed Mechanism for Aryl-Substituted Cyclopropane-to-Dihydroanthracene (3 + 3)-Cyclodimerization

Figure 6. Conformations of intermediate B leading to formation of (a) cis-2, (b) trans-7, and (c) cis-7.

Scheme 5. Overall Mechanistic Scheme Including Three (3 + 3)-Cyclodimerizations of D−A Cyclopropanes 1

The second question is the competition between formation

of cyclohexanes 2 and tetralines 7 from the same intermediate

B. This dual behavior can be explained by means of analysis of

the reactive conformations of intermediate B which are shown

in Figure 6. Eclipsed twist-like conformation a is a direct

precursor for the transition state leading to cyclohexane 2 with

a cis-arrangement of aromatic groups. Meanwhile, the staggered

conformations b and c favored for trans-7 and cis-7

construction, respectively, can be stabilized by interaction of

the electron-depleted benzyl cation and the electron-enriched

second aromatic ring resulting in a π−π* donor−acceptor

complex.^62,73In this case, chemoselectivity is provided by the

close proximity of two reaction centers, namely benzyl cation

and nucleophilic ortho-position of aryl substituent. Despite the

higher nucleophilicity of the malonyl anion,⁷⁷its attack in this

case is not competitive. The same preference of nucleophilic

site at the ortho-position of an aromatic substituent rather than

malonyl anion was recently found for heteroaryl-substituted

D−A cyclopropanes.⁵⁸⁻⁶²

recently in reactions of D−A cyclopropanes with enols^78,79and

aldehydes.⁵¹For example, cyclopropanes 1i,j form either

cyclohexanes 2i,k or tetrahydronaphthalenes 7a,b depending

on the reaction conditions. We checked the possibility of

rearrangement of one cyclodimer into another one. For this

purpose, we treated a solution of cyclohexane 2i in CH₃NO₂

with 5 equiv of SnCl₄or TiCl₄and heated the reaction mixture

under reflux for 2−24 h. Similarly, tetrahydronaphthalene 7a

was treated with 3 equiv of SnCl₄in benzene and heated at

50 °C for 5 h. No interconversion of 2i and 7a was observed

according to the NMR spectra. Similarly, we have not found

conversion of 7 into dihydroanthracene 9. Therefore, we

believe that cyclodimers 2, 7, and 9 are formed along three

independent paths a−b, a−d, and f−g, respectively. The overall

scheme of (3 + 3)-cyclodimerizations of the D−A cyclo-

propanes can be represented in the following way (Scheme 5).

On the whole, a balance of numerous factors, such as

substrate nature, activating ability of a Lewis acid, temperature,

solvent, etc., controls the outcome of the (3 + 3)-cyclo-

dimerization. The further studies on the reaction mechanism in

detail are now in progress.

One more possibility should be analyzed, which involves

initial formation of one cycloadduct followed by its rearrange-

ment into another product. Similar transformations were found

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Ar), 127.6 (C, Ar), 142.9 (C, Ar), 143.2 (C, Ar), 167.0 (CO₂Me),

170.2 (CO₂Me); IR (Nujol, cm⁻¹) 3450, 2975, 2895, 1735, 1630,

1593, 1518, 1445, 1380, 1290, 1220, 1138, 1080, 940, 897, 828, 780,

710; GC−MS m/z 292 (52) [M]⁺, 232 (51), 228 (82), 200 (21), 179

(59), 173 (100), 117 (30), 89 (57), 78 (29), 59 (70). Anal. Calcd for

C₁₅H₁₆O₆: C, 61.64; H, 5.52. Found: C, 61.79; H, 5.75.

CONCLUSION

■

In the present research, we demonstrated for the first time the

possibility of the Lewis acid-induced (3 + 3)-cyclodimerization

of 2-(hetero)arylcyclopropane-1,1-dicarboxylates with forma-

tion of three different types of six-membered cyclic systems. In

these processes three reaction centers of a D−A cyclopropane

molecule can be involved, namely C(1) atom of small ring and

ortho-carbon atom of an aromatic substituent as nucleophilic

sites and C(2) atom of cyclopropane as an electrophilic site. As

a result, the facile synthetic approach to 1,4-diarylcyclohexanes,

1-aryl-1,2,3,4-tetrahydronaphthalenes, and 9,10-dihydroanthra-

cenes from easily available reagents using inexpensive promotor

has been developed. The (3 + 3)-cyclodimerization leading to

1,4-diarylcyclohexanes proceeded with excellent diastereoselec-

tivity furnishing cis-isomer excusively, while diastereoselectivity

of 1-aryl-1,2,3,4-tetrahydronaphthalenes and 9,10-dihydroan-

thracenes construction varied from moderate to high with the

predominante formation of trans-isomers. To provide chemo-

selectivity of the processes, the careful optimization of reaction

conditions was undertaken which resulted in the development

of procedures affording these three types of products of

(3 + 3)-cyclodimerization in good yields.

Dimethyl 2-(3,5-Dimethoxyphenyl)cyclopropane-1,1-dicar-

boxylate (1p). Compound 1p was synthesized from dimethyl 2-

(3,5-dimethoxybenzylidene)malonate (10c), reaction time 1 h, and

isolated as white solid (0.98 g, 67%): mp 69−70 °C; ¹H NMR

2

3

(CDCl₃, 600 MHz) δ 1.68 (dd, J = 5.1 Hz, J = 9.2 Hz, 1H, CH₂),

2

3

2.10 (dd, J = 5.1 Hz, J = 8.0 Hz, 1H, CH₂), 3.13 (dd, J = 8.0 Hz,

³J = 9.2 Hz, 1H, CH), 3.41 (s, 3H, CH₃O), 3.71 (s, 6H, 2 × CH₃O),

4

3.74 (s, 3H, CH₃O), 6.26 (br.d, J = 2.0 Hz, 1H, CH, Ar), 6.28 (d,

⁴J = 2.0 Hz, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃, 150 MHz) δ 19.4

(CH₂), 32.6 (CH), 37.1 (C), 52.4 (CH₃O), 52.8 (CH₃O), 55.2 (2 ×

CH₃O), 99.6 (CH, Ar), 106.3 (2 × CH, Ar), 137.0 (C, Ar), 160.5 (2 ×

C, Ar), 167.0 (CO₂Me), 170.2 (CO₂Me); IR (Nujol, cm⁻¹) 2960,

2875, 1730, 1600, 1480, 1385, 1250, 1210, 1160, 1085, 1065, 940, 870,

840, 820, 775, 745. Anal. Calcd for C₁₅H₁₈O₆: C, 61.22; H, 6.16.

Found: C, 61.13; H, 6.11.

Diethyl 2-(3-Bromo-2,4,6-trimethoxyphenyl)cyclopropane-

1,1-dicarboxylate (1c). N-Bromosuccinimide (NBS, 0.10 g, 0.57

mmol) was added to a solution of diethyl 2-(2,4,6-trimethoxyphenyl)-

cyclopropane-1,1-dicarboxylate (1a) (0.20 g, 0.57 mmol) in CH₂Cl₂(6

mL) at −60 °C. The reaction mixture was slowly warmed to −20 °C

and stirred at that temperature until 1a was consumed (TLC

monitoring). Then the reaction mixture was quenched at −20 °C with

10% aqueous K₂CO₃(2 mL), warmed to room temperature, diluted

with H₂O (10 mL), and extracted with CH₂Cl₂(2 × 20 mL). The

combined organic extracts were dried with MgSO₄, concentrated in

vacuo, and purified by flash chromatography (eluent: hexane/ethyl

acetate 3:1) to yield 1c (223 mg, 91%) as a yellowish oil: R_f0.42

EXPERIMENTAL SECTION

■

General Procedure for the Synthesis of Cyclopropanes

1a,b,d−q.^64,65To a stirred suspension of NaH (0.24 g, 6 mmol) in

dry DMSO (10 mL) was added trimethylsulfoxonium iodide (1.32 g, 6

mmol) in a single portion at room temperature. Vigorous evolution of

hydrogen lasted ca. 10 min, after which the reaction mixture was

stirred for an additional 25 min. Then a solution of alkylidenemalonate

(5 mmol) in dry DMSO (2 mL) was added in a single portion. The

resulted mixture was stirred under the conditions specified, poured

into H₂O−ice (10 mL), and extracted with diethyl ether (5 × 5 mL).

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

dried with Na₂SO₄, and concentrated in vacuo. Cyclopropanes were

purified by column chromatography (SiO₂, eluent: diethyl ether).

Dimethyl 2-(4-Piperidinophenyl)cyclopropane-1,1-dicar-

boxylate (1f). Compound 1f was synthesized from dimethyl 2-(4-

piperidinobenzylidene)malonate (10a), reaction time 1 h, and isolated

1

(hexanes/ethyl acetate 2:1); H NMR (CDCl₃, 400 MHz) δ 0.88 (t,

3

2

³J = 7.1 Hz, 3H, CH₃), 1.24 (t, J = 7.1 Hz, 3H, CH₃), 1.75 (dd, J =

4.8 Hz, ³J = 9.4 Hz, 1H, CH₂), 2.37 (dd, ²J = 4.8 Hz, ³J = 8.3 Hz, 1H,

3

CH₂), 2.84 (dd, J = 8.3 Hz, J = 9.4 Hz, 1H, CH), 3.72 (s, 3H,

CH₃O), 3.74 (s, 3H, CH₃O), 3.78−3.83 (m, 2H, CH₂O), 3.80 (s, 3H,

CH₃O), 4.16−4.23 (m, 2H, CH₂O), 6.20 (s, 1H, CH, Ar); ¹³C NMR

(CDCl₃, 100 MHz) δ 13.7 (CH₃), 14.1 (CH₃), 21.3 (CH₂), 25.2

(CH), 35.3 (C), 55.8 (CH₂O), 56.3 (CH₂O), 60.6 (CH₃O), 60.8

(CH₃O), 61.2 (CH₃O), 92.2 (CH, Ar), 97.9 (C, Ar), 110.6 (C, Ar),

156.4 (C, Ar), 158.1 (C, Ar), 159.7 (C, Ar), 167.3 (CO₂Et), 170.1

(CO₂Et); IR (Nujol, cm⁻¹) 2995, 2935, 2865, 1730, 1600, 1590, 1460,

1400, 1325, 1290, 1210, 1185, 1130, 1035, 920, 880, 810, 745. Anal.

Calcd for C₁₈H₂₃BrO₇: C, 50.13; H, 5.38. Found: C, 50.04; H, 5.23.

General Procedure for the Lewis Acid-Induced Dimerization

of Cyclopropanes 1a−q. Lewis acid (AlCl₃, Sn(OTf)₂, ZnCl₂) or a

solution of Lewis acid (SnCl₄, TiCl₄) in dry solvent (1 mL) was added

to a vigorously stirred solution of cyclopropane 1 containing molecular

sieves 4 Å. The resulting mixture was kept under the conditions

specified and poured into 10 mL of saturated aqueous NaHCO₃. After

extraction with CH₂Cl₂(3 × 10 mL), the combined organic fractions

were washed with aqueous Trilon B (3 × 10 mL) and water (2 × 10

mL) and dried with Na₂SO₄. The solvent was evaporated under

vacuum, and the residue was purified by column chromatography

(SiO₂) to yield the desired product.

1

as an orange oil (1.06 g, 67%): R_f0.48 (diethyl ether/hexane 1:1); H

NMR (CDCl₃, 600 MHz) δ 1.52−1.57 (m, 2H, CH₂), 1.65−1.69 (m,

4H, CH₂), 1.70 (dd, ²J = 5.0 Hz, ³J = 9.5 Hz, 1H, CH₂), 2.15 (dd, ²J =

3

5.0 Hz, J = 7.9 Hz, 1H, CH₂), 3.08−3.12 (m, 4H, CH₂N), 3.15 (dd,

3

³J = 7.9 Hz, J = 9.5 Hz, 1H, CH), 3.37 (s, 3H, CH₃O), 3.76 (s, 3H,

3

CH₃O), 6.82 (d, J = 8.3 Hz, 2H, CH, Ar), 7.05 (d, J = 8.3 Hz, 2H,

CH, Ar); ¹³C NMR (CDCl₃, 150 MHz) δ 19.3 (CH₂), 24.2 (CH₂),

25.8 (2 × CH₂), 32.6 (CH), 37.1 (C), 50.4 (2 × CH₂N), 52.3

(CH₃O), 52.7 (CH₃O), 116.0 (2 × CH, Ar), 124.5 (C, Ar), 129.1 (2 ×

CH, Ar), 151.4 (C, Ar), 167.2 (CO₂Me), 170.4 (CO₂Me); IR (Nujol,

cm⁻¹) 2952, 2865, 2820, 1740, 1619, 1524, 1455, 1390, 1340, 1290,

1250, 1184, 1145, 1035, 930, 840, 781, 740; GC−MS m/z 318 (27),

317 (100) [M]⁺, 316 (57), 258 (31), 198 (88), 142 (24), 130 (30),

115 (83), 59 (34). Anal. Calcd for C₁₈H₂₃NO₄: C, 68.12; H, 7.30; N,

4.41. Found: C, 67.82; H, 7.14; N, 4.61.

Tetraethyl cis-2,5-Bis(2,4,6-trimethoxyphenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2a). A solution of 1a (350 mg, 1.0

mmol) in CH₃NO₂(14 mL) was treated with SnCl₄(280 mg, 0.13

mL, 1.1 mmol), and the resulting mixture was stirred at 55 °C for 3 h

affording 2a (292 mg, 83%) as a white foam: mp 153−154 °C; R_f0.50

(dietyl ether); ¹H NMR (CDCl₃, 400 MHz) δ 0.69 (t, ³J = 7.1 Hz, 6H,

2 × CH₃), 1.37 (t, ³J = 7.1 Hz, 6H, 2 × CH₃), 2.14 (dd, ²J = 13.7 Hz,

³J = 5.2 Hz, 2H, 2 × CH^aH), 3.36 (dd, ²J = 13.7 Hz, ³J = 13.6 Hz, 2H,

Dimethyl 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-

cyclopropane-1,1-dicarboxylate (1l). Compound 1l was synthe-

sized from dimethyl 2-[(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-

methylene]malonate (10b), reaction time 1 h, and isolated as a

white solid (1.12 g, 77%): mp 92−93 °C; R_f0.52 (diethyl ether/

1

2

hexane ether 1:2); H NMR (CDCl₃, 600 MHz) δ 1.65 (dd, J = 5.1

3

2

3

Hz, J = 9.3 Hz, 1H, CH₂), 2.05 (dd, J = 5.1 Hz, J = 8.0 Hz, 1H,

3

CH₂), 3.08 (dd, J = 8.0 Hz, J = 9.3 Hz, 1H, CH), 3.40 (s, 3H,

2 × CH^bH), 3.43−3.51 (m, 2H, OCH₂), 3.57−3.66 (m, 2H, OCH₂),

3.73 (s, 6H, 2 × OCH₃), 3.78 (s, 6H, 2 × OCH₃), 3.82 (s, 6H, 2 ×

OCH₃), 4.01−4.09 (m, 2H, OCH₂), 4.44−4.52 (m, 2H, OCH₂), 4.85

(dd, ³J = 5.2 Hz, ³J = 13.6 Hz, 2H, 2 × CH), 6.06 (br.s, 2H, 2 × CH,

Ar), 6.12 (br.s, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃, 100 MHz) δ 13.4

CH₃O), 3.72 (s, 3H, CH₃O), 4.16 (s, 4H, OCH₂CH₂O), 6.61 (dd,

4

³J = 8.4 Hz, ⁴J = 2.0 Hz, 1H, CH, Ar), 6.62 (d, J = 2.0 Hz, 1H, CH,

Ar), 6.70 (d, ³J = 8.4 Hz, 1H, CH, Ar); ¹³C NMR (CDCl₃, 150 MHz)

δ 19.3 (CH₂), 32.1 (CH), 37.0 (C), 52.3 (CH₃O), 52.7 (CH₃O), 64.2

(CH₂O), 64.3 (CH₂O), 116.9 (CH, Ar), 117.3 (CH, Ar), 121.4 (CH,

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(2 × CH₃), 14.2 (2 × CH₃), 29.9 (2 × CH), 30.3 (2 × CH₂), 54.5

(2 × OCH₃), 55.3 (2 × OCH₃), 56.8 (2 × OCH₃), 58.6 (2 × C), 60.2

(2 × OCH₂), 61.5 (2 × OCH₂), 90.9 (2 × CH, Ar), 91.4 (2 × CH,

Ar), 113.6 (2 × C, Ar), 159.3 (2 × C, Ar), 159.6 (2 × C, Ar), 159.9

(2 × C, Ar), 170.4 (2 × CO₂Et), 172.3 (2 × CO₂Et); IR (Nujol, cm⁻¹)

2930, 2870, 1720, 1600, 1480, 1380, 1335, 1160, 1125, 1070, 965, 880,

820, 740. Anal. Calcd for C₃₆H₄₈O₁₄: C, 61.35; H, 6.86. Found: C,

61.21; H, 7.01.

at 55 °C for 3 h affording 2e (160 mg, 86%) as a yellowish solid: mp

1

131−132 °C; R_f0.30 (diethyl ether/hexane 1:1); H NMR (CDCl₃,

3

400 MHz) δ 0.78 (t, J = 7.1 Hz, 6H, 2 × CH₃), 1.14 (t, J = 7.1 Hz,

6H, 2 × CH₃), 2.37 (dd, J = 14.4 Hz, J = 2.8 Hz, 2H, 2 × CH^aH),

2.90 (s, 12H, 2 × NMe₂), 3.18 (dd, ²J = 14.4 Hz, ³J = 13.2 Hz, 2H, 2 ×

CH^bH), 3.41−3.50 (m, 2H, OCH₂), 3.64−3.72 (m, 4H, 2 × CH,

OCH₂), 4.10−4.28 (m, 4H, 2 × OCH₂), 6.63 (d, ³J = 8.4 Hz, 4H, 4 ×

2

3

CH, Ar), 7.20 (d, J = 8.4 Hz, 4H, 4 × CH, Ar); ¹³C NMR (CDCl₃,

3

Tetramethyl cis-2,5-Bis(2,4,6-trimethoxyphenyl)-

cyclohexane-1,1,4,4-tetracarboxylate (2b). A solution of 1b

(160 mg, 0.5 mmol) in CH₃NO₂(7 mL) was treated with GaCl₃

(36 mg, 0.2 mmol), and the resulting mixture was stirred at 20 °C for

4 h affording 2b (42 mg, 26%) and 3b (31 mg, 19%). 2b: colorless

100 MHz) δ 13.4 (¹J_CH= 125 Hz, 2 × CH₃), 13.9 (¹J_CH= 125 Hz, 2 ×

CH₃), 33.0 (¹J_CH= 133 Hz, 2 × CH₂), 39.0 (¹J_CH= 130 Hz, 2 × CH),

40.8 (¹J_CH= 134 Hz, 4 × CH₃), 60.5 (2 × C), 60.9 (¹J_CH= 148 Hz,

2 × OCH₂), 61.4 (¹J_CH= 148 Hz, 2 × OCH₂), 112.2 (¹J_CH= 156 Hz,

4 × CH, Ar), 129.2 (2 × C, Ar), 129.3 (¹J_CH= 154 Hz, 4 × CH, Ar),

149.6 (2 × C, Ar), 170.1 (2 × CO₂Et), 172.1 (2 × CO₂Et); IR (Nujol,

cm⁻¹) 2940, 2875, 1725, 1615, 1530, 1375, 1185, 1045, 955, 825; MS

MALDI-TOF m/z calcd for C₃₄H₄₆N₂O₈610, found [M]⁺610. Anal.

Calcd for C₃₄H₄₆N₂O₈: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.75;

H, 7.50; N, 4.41.

1

liquid; R_f0.45 (diethyl ether); H NMR (CDCl₃, 600 MHz) δ 2.13

2

3

(dd, J = 13.8 Hz, J = 5.2 Hz, 2H, 2 × CH^aH), 3.08 (s, 6H, 2 ×

OCH₃), 3.35 (dd, ²J = 13.8 Hz, ³J = 14.0 Hz, 2H, 2 × CH^bH), 3.67 (s,

6H, 2 × OCH₃), 3.79 (s, 12H, 4 × OCH₃), 3.82 (s, 6H, 2 × OCH₃),

4.80 (dd, ³J = 5.2 Hz, ³J = 14.0 Hz, 2H, 2 × CH), 6.08 (br.s, 2H, 2 ×

CH, Ar), 6.13 (br.s, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃, 150 MHz) δ

30.3 (2 × CH), 30.5 (2 × CH₂), 51.4 (2 × OCH₃), 52.2 (2 × OCH₃),

52.8 (2 × OCH₃), 55.3 (2 × OCH₃), 55.6 (2 × OCH₃), 57.2 (2 × C),

90.4 (2 × CH, Ar), 90.8 (2 × CH, Ar), 113.5 (2 × C, Ar), 159.2 (2 ×

C, Ar), 159.6 (2 × C, Ar), 160.1 (2 × C, Ar), 170.7 (2 × CO₂Me),

172.8 (2 × CO₂Me). Anal. Calcd for C₃₂H₄₀O₁₄: C, 59.25; H, 6.22.

Found: C, 59.17; H, 6.30.

Tetramethyl cis-2,5-Bis(4-piperidinophenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2f). A solution of 1f (200 mg, 0.63

mmol) in CH₃NO₂(15 mL) was treated with TiCl₄(290 mg, 0.17

mL, 1.55 mmol), and the resulting mixture was stirred at 50 °C for 3 h

affording 2f (168 mg, 84%) as a yellowish solid: mp 97−98 °C; R_f0.70

1

(diethyl ether); H NMR (CDCl₃, 400 MHz) δ 1.50−1.62 (m, 4H,

2

2 × CH₂), 1.64−1.75 (m, 8H, 4 × CH₂), 2.42 (dd, J = 14.4 Hz,

³J = 2.7 Hz, 2H, 2 × CH^aH), 3.09−3.14 (m, 8H, 4 × CH₂), 3.14 (s,

Tetraethyl cis-2,5-Bis(3-bromo-2,4,6-trimethoxyphenyl)-

cyclohexane-1,1,4,4-tetracarboxylate (2c). A solution of 1c

(200 mg, 0.464 mmol) in CH₃NO₂(15 mL) was treated with SnCl₄

(270 mg, 0.12 mL, 1.02 mmol), and the resulting mixture was stirred

at 50 °C for 2 h affording 2c (162 mg, 81%) as a white solid: mp 225−

2

3

6H, 2 × OCH₃), 3.22 (dd, J = 14.4 Hz, J = 13.1 Hz, 2H, 2 ×

CH^bH), 3.64 (dd, ²J = 2.7 Hz, ³J = 13.1 Hz, 2H, CH), 3.68 (s, 6H, 2 ×

3

OCH₃), 6.86 (d, J = 8.6 Hz, 4H, 4 × CH, Ar), 7.22 (d, J = 8.6 Hz,

4H, 4 × CH, Ar); ¹³C NMR (CDCl₃, 100 MHz) δ 24.2 (¹J_CH= 124

Hz, 2 × CH₂), 25.8 (¹J_CH= 125 Hz, 4 × CH₂), 32.8 (¹J_CH= 133 Hz,

2 × CH₂), 39.1 (¹J_CH= 133 Hz, 2 × CH), 50.7 (¹J_CH= 136 Hz, 4 ×

NCH₂), 52.0 (¹J_CH= 147 Hz, 2 × OCH₃), 52.8 (¹J_CH= 147 Hz, 2 ×

OCH₃), 60.5 (2 × C), 115.8 (4 × CH, Ar), 129.2 (4 × CH, Ar), 131.1

(2 × C, Ar), 151.1 (2 × C, Ar), 170.4 (2 × CO₂Me), 172.5 (2 ×

CO₂Me); IR (Nujol, cm⁻¹) 3310, 3015, 2965, 2860, 1735, 1445, 1370,

1270, 1230, 1170, 1080, 1000, 960, 935, 892, 800, 744, 690; HRMS

MALDI-TOF m/z calcd 634.3254 for C₃₆H₄₆N₂O₈, found [M]⁺

634.3250. Anal. Calcd for C₃₆H₄₆N₂O₈: C, 68.12; H, 7.30; N, 4.41.

Found: C, 67.95; H, 7.19; N, 4.41.

1

226 °C dec; R_f0.50 (diethyl ether); H NMR (CDCl₃, 400 MHz) δ

0.73 (t, ³J = 7.1 Hz, 6H, 2 × CH₃), 1.36 (t, ³J = 7.1 Hz, 6H, 2 × CH₃),

2

3

2

2.23 (dd, J = 13.8 Hz, J = 5.3 Hz, 2H, 2 × CH^aH), 3.33 (dd, J =

3

13.8 Hz, J = 13.5 Hz, 2H, 2 × CH^bH), 3.48−3.66 (m, 2H, OCH₂),

3.65−3.67 (m, 2H, OCH₂), 3.78 (s, 6H, 2 × OCH₃), 3.89 (s, 6H, 2 ×

OCH₃), 3.92 (s, 6H, 2 × OCH₃), 4.20−4.25 (m, 2H, OCH₂), 4.34−

3

4.39 (m, 2H, OCH₂), 4.78 (dd, J = 5.3 Hz, J = 13.5 Hz, 2H, 2 ×

CH), 6.27 (s, 1H, CH, Ar); ¹³C NMR (CDCl₃, 100 MHz) δ 13.4 (2 ×

CH₃), 14.1 (2 × CH₃), 30.5 (2 × CH₂), 31.9 (2 × CH), 54.8 (2 ×

OCH₃), 56.5 (2 × OCH₃), 58.5 (2 × C), 60.5 (2 × OCH₃), 61.2 (2 ×

OCH₂), 62.0 (2 × OCH₂), 92.6 (2 × CH, Ar), 98.4 (2 × C, Ar), 119.8

(2 × C, Ar), 155.8 (2 × C, Ar), 157.0 (2 × C, Ar), 158.7 (2 × C, Ar),

170.0 (2 × CO₂Et), 171.8 (2 × CO₂Et); IR (Nujol, cm⁻¹) 2940, 2875,

1725, 1595, 1465, 1370, 1340, 1220, 1200, 1115, 1055, 975, 930, 810;

MS MALDI-TOF m/z calcd for C₃₆H₄₆Br₂O₁₄860, found [M]⁺860.

Anal. Calcd for C₃₆H₄₆Br₂O₁₄: C, 50.13; H, 5.38. Found: C, 49.95; H,

5.32.

Tetramethyl cis-2,5-Bis(4-pyrrolidinophenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2g). A solution of 1g (200 mg, 0.66

mmol) in CH₃NO₂(14 mL) was treated with TiCl₄(300 mg, 0.18

mL, 1.6 mmol), and the resulting mixture was stirred at 60 °C for 2.5 h

affording 2g (116 mg, 58%) as a white solid: mp 241−242 °C dec; R_f

1

0.15 (diethyl ether); H NMR (CDCl₃, 600 MHz) δ 1.97−2.05 (m,

2

3

8H, 4 × CH₂), 2.42 (dd, J = 14.4 Hz, J = 2.7 Hz, 2H, 2 × CH^aH),

3.19 (s, 6H, 2 × OCH₃), 3.20 (dd, ²J = 14.4 Hz, ³J = 13.2 Hz, 2H, 2 ×

Tetramethyl cis-2,5-Bis[4-(dimethylamino)phenyl]-

cyclohexane-1,1,4,4-tetracarboxylate (2d). A solution of 1d

(350 mg, 1.264 mmol) in CH₃NO₂(16 mL) was treated with SnCl₄

(400 mg, 0.18 mL, 1.544 mmol), and the resulting mixture was stirred

at 55 °C for 3 h affording 2d (266 mg, 76%) as a yellowish solid: mp

CH^bH), 3.24−3.30 (m, 8H, 4 × CH₂N), 3.64 (dd, J = 2.7 Hz, J =

3

13.2 Hz, 2H, 2 × CH), 3.70 (s, 6H, 2 × OCH₃), 6.48 (d, ³J = 8.6 Hz,

4H, 4 × CH, Ar), 7.21 (d, J = 8.6 Hz, 4H, 4 × CH, Ar); ¹³C NMR

3

(CDCl₃, 150 MHz) δ 25.4 (¹J_CH= 131 Hz, 4 × CH₂), 33.1 (¹J_CH= 133

Hz, 2 × CH₂), 39.1 (¹J_CH= 130 Hz, 2 × CH), 47.7 (¹J_CH= 139 Hz,

4 × NCH₂), 51.9 (¹J_CH= 147 Hz, 2 × OCH₃), 52.6 (¹J_CH= 147 Hz, 2

× OCH₃), 60.8 (2 × C), 111.1 (4 × CH, Ar), 127.5 (2 × C, Ar),

129.3 (4 × CH, Ar), 147.0 (2 × C), 170.5 (2 × CO₂Me), 172.6 (2 ×

CO₂Me); IR (Nujol, cm⁻¹) 2940, 2875, 1725, 1615, 1530, 1470, 1380,

1340, 1260, 1230, 1180, 1120, 1055, 1040, 975, 940, 840, 825, 795,

740; HRMS MALDI-TOF m/z calcd for C₃₄H₄₂N₂O₈606.2941, found

[M]⁺606.2946. Anal. Calcd for C₃₄H₄₂N₂O₈: C, 67.31; H, 6.98; N,

4.62. Found: C, 67.29; H, 6.95; N, 4.62.

1

123−124 °C; R_f0.25 (diethyl ether/hexane 1:1); H NMR (CDCl₃,

400 MHz) δ 2.37 (dd, ²J = 14.3 Hz, ³J = 2.8 Hz, 2H, 2 × CH^aH), 2.89

2

(s, 12H, 4 × CH₃), 3.14 (s, 6H, 2 × OCH₃), 3.16 (dd, J = 14.3 Hz,

³J = 12.5 Hz, 2H, 2 × CH^bH), 3.63 (dd, ³J = 2.8 Hz, ³J = 12.5 Hz, 2H,

2 × CH), 3.67 (s, 6H, 2 × OCH₃), 6.64 (d, ³J = 8.8 Hz, 4H, 4 × CH,

3

Ar), 7.20 (d, J = 8.8 Hz, 4H, 4 × CH, Ar); ¹³C NMR (CDCl₃, 100

MHz) δ 32.9 (2 × CH₂), 39.0 (2 × CH), 40.6 (4 × CH₃), 52.0 (2 ×

OCH₃), 52.7 (2 × OCH₃), 60.6 (2 × C), 112.0 (4 × CH, Ar), 128.6

(2 × C, Ar), 129.2 (4 × CH, Ar), 149.5 (2 × C, Ar), 170.4 (2 ×

CO₂Et), 172.5 (2 × CO₂Et); IR (Nujol, cm⁻¹) 2950, 2880, 1730,

1610, 1525, 1375, 1235, 1170, 1045, 955, 892, 825, 720; MS MALDI-

TOF m/z calcd for C₃₀H₃₉N₂O₈555, found [M + H]⁺555. Anal.

Calcd for C₃₀H₃₈N₂O₈: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.75;

H, 7.15; N, 5.09.

Tetraethyl cis-2,5-Bis[4-(dimethylamino)phenyl]-

cyclohexane-1,1,4,4-tetracarboxylate (2e). A solution of 1e

(180 mg, 0.60 mmol) in CH₃NO₂(8 mL) was treated with SnCl₄

(190 mg, 0.085 mL, 0.73 mmol), and the resulting mixture was stirred

Tetramethyl cis-2,5-Bis(4-morpholinophenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2h). A solution of 1h (300 mg, 0.94

mmol) in CH₃NO₂(14 mL) was treated with TiCl₄(370 mg, 0.21

mL, 1.97 mmol), and the resulting mixture was stirred at 60 °C for 3 h

affording 2h (250 mg, 83%) as a cream-colored solid: mp 249−250 °C

1

dec; R_f0.80 (CH₂Cl₂/MeOH 20:1); H NMR (CDCl₃, 400 MHz) δ

2

3

2.42 (dd, J = 14.4 Hz, J = 2.7 Hz, 2H, 2 × CH^aH), 3.10−3.13 (m,

2

8H, 4 × CH₂), 3.14 (s, 6H, 2 × OCH₃), 3.17 (dd, J = 14.4 Hz,

³J = 13.1 Hz, 2H, 2 × CH^bH), 3.67 (dd, ³J = 2.7 Hz, ³J = 13.1 Hz, 2H,

8862

dx.doi.org/10.1021/jo201612w|J. Org. Chem. 2011, 76, 8852−8868

The Journal of Organic Chemistry

Article

2 × CH), 3.69 (s, 6H, 2 × OCH₃), 3.81−3.85 (m, 8H, 4 × CH₂), 6.81

³J = 3.6 Hz, ³J = 12.1 Hz, 1H, CH), 5.96 (d, ⁴J = 2.5 Hz, 1H, Ar), 6.02

3

4

3

(d, ³J = 8.7 Hz, 4H, 4 × CH, Ar), 7.24 (d, J = 8.7 Hz, 4H, 4 × CH,

(d, J = 2.5 Hz, 1H, Ar), 6.04 (s, 2H, Ar), 6.45 (d, J = 17.3 Hz, 1H,

3

Ar); ¹³C NMR (CDCl₃, 100 MHz) δ 32.5 (¹J_CH= 132 Hz, 2 × CH₂),

38.8 (¹J_CH= 130 Hz, 2 × CH), 48.9 (¹J_CH= 134 Hz, 4 × NCH₂), 51.4

(¹J_CH= 147 Hz, 2 × OCH₃), 52.3 (¹J_CH= 147 Hz, 2 × OCH₃), 60.1

(2 × C), 66.4 (¹J_CH= 144 Hz, 4 × OCH₂), 114.5 (4 × CH), 129.0

(4 × CH), 131.7 (2 × C), 149.7 (2 × C), 169.8 (2 × CO₂Me), 171.9

(2 × CO₂Me); IR (Nujol, cm⁻¹) 2960, 2880, 1725, 1620, 1525, 1470,

1385, 1275, 1250, 1225, 1130, 1060, 1045, 940, 845, 735; HRMS

MALDI-TOF m/z calcd for C₃₄H₄₂N₂O₁₀638.2839, found [M]⁺

638.2844. Anal. Calcd for C₃₄H₄₂N₂O₁₀: C, 63.94; H, 6.63; N, 4.39.

Found: C, 63.94; H, 6.58; N, 4.58.

CH), 6.77 (d, J = 17.3 Hz, 1H, CH); ¹³C NMR (CDCl₃, 100

MHz) δ 13.9 (2 × CH₃), 14.1 (2 × CH₃), 28.9 (CH₂), 39.3 (CH),

51.5 (CH), 54.9 (OCH₃), 55.1 (OCH₃), 55.2 (OCH₃), 55.4 (OCH₃),

55.5 (2 × OCH₃), 60.6 (OCH₂), 60.8 (OCH₂), 60.9 (2 × OCH₂),

64.0 (C), 90.1 (CH), 90.3 (CH), 90.5 (2 × CH), 107.2 (C), 108.1

(C), 120.0 (CH), 129.1 (CH), 159.2 (2 × C), 159.6 (C), 160.08 (C),

160.14 (C), 160.5 (C), 169.5 (CO₂Et), 170.1 (CO₂Et), 170.5

(CO₂Et), 172.9 (CO₂Et); IR (Nujol, cm⁻¹) 2960, 2860, 1730, 1600,

1470, 1380; MS MALDI-TOF m/z calcd for C₃₆H₄₈O₁₄704, found

[M]⁺704. Anal. Calcd for C₃₆H₄₈O₁₄: C, 61.35; H, 6.86. Found: C,

61.44; H, 6.75.

Tetramethyl cis-2,5-Bis(4-methoxyphenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2i). A solution of TiCl₄(290 mg, 0.17

mL, 0.15 mmol) in CH₃NO₂(1 mL) was added to a solution of 1i

(200 mg, 0.75 mmol) in CH₃NO₂(7 mL) at −20 °C. The resulting

mixture was allowed to warm to 5 °C for 1 h, kept at this temperature

for 2 h, and worked up as described above to yield 2i (90 mg, 45%) as

colorless crystals: mp 174−175 °C; R_f0.44 (diethyl ether/hexane 1:1);

Tetramethyl (5E)-3,6-Bis(2,4,6-trimethoxyphenyl)hex-5-ene-

1,1,4,4-tetracarboxylate (3b). Method A. BF₃·OEt₂(78 mg, 0.07

mL, 0.55 mmol) was added in one portion to a solution of 1b (150

mg, 0.46 mmol) in CH₂Cl₂(8 mL) at room temperature. The

resulting mixture was heated under reflux for 6 h and worked up as

described above to yield 3b (128 mg, 85%).

2

3

¹H NMR (CDCl₃, 400 MHz) δ 2.41 (dd, J = 14.4 Hz, J = 2.8 Hz,

2H, 2 × CH^aH), 3.15 (s, 6H, 2 × OCH₃), 3.19 (dd, ²J = 14.4 Hz, ³J =

13.2 Hz, 2H, 2 × CH^bH), 3.68 (dd, ³J = 2.8 Hz, ³J = 13.2 Hz, 2H, 2 ×

Method B. ZnCl₂(300 mg, 2.2 mmol) was added in one portion to

a solution of 1b (180 mg, 0.55 mmol) in CH₂Cl₂(7 mL). The

resulting mixture was heated under reflux for 6 h and worked up as

described above to yield 3b (154 mg, 86%): colorless foam; mp 70−71

°C; R_f0.48 (diethyl ether); ¹H NMR (CDCl₃, 400 MHz) δ 2.53 (ddd,

CH), 3.71 (s, 6H, 2 × OCH₃), 3.79 (s, 6H, 2 × OCH₃), 6.82 (d, ³J =

3

8.7 Hz, 4H, 4 × CH, Ar), 7.28 (d, J = 8.7 Hz, 4H, 4 × CH, Ar); ¹³

C

3

2

²J = 13.6 Hz, J = 3.5 Hz, J = 8.4 Hz, 1H, CH^aH), 2.78 (ddd, J =

13.6 Hz, ³J = 6.2 Hz, ³J = 12.2 Hz, 1H, CH^bH), 3.12 (dd, ³J = 6.2 Hz,

³J = 8.4 Hz, 1H, CH), 3.43 (s, 3H, OCH₃), 3.52 (s, 3H, OCH₃), 3.62

(s, 3H, OCH₃), 3.65 (s, 6H, 2 × OCH₃), 3.69 (s, 3H, OCH₃), 3.71 (s,

3H, OCH₃), 3.75 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.78 (s, 3H,

NMR (CDCl₃, 100 MHz) δ 32.9 (2 × CH₂), 39.1 (2 × CH), 52.0

(2 × OCH₃), 52.9 (2 × OCH₃), 55.2 (2 × OCH₃), 60.5 (2 × C),

113.2 (4 × CH, Ar), 129.7 (4 × CH, Ar), 132.7 (2 × C, Ar), 158.4

(2 × C, Ar), 170.3 (2 × CO₂Me), 172.4 (2 × CO₂Me); IR (Nujol,

cm⁻¹) 2950, 2860, 1720, 1610, 1520, 1465, 1380, 1135, 1040, 935,

850, 745; GC−MS m/z 528 (85) [M]⁺, 347 (94), 265 (72), 207 (80),

145 (94), 134 (100), 121 (45); MS MALDI-TOF m/z calcd for

C₂₈H₃₂O₁₀528, found [M]⁺528. Anal. Calcd for C₂₈H₃₂O₁₀: C, 63.63;

H, 6.10. Found: C, 63.75; H, 6.15.

3

4

OCH₃), 4.37 (dd, J = 3.5 Hz, J = 12.2 Hz, 1H, CH), 5.96 (d, J =

2.3 Hz, 1H, CH, Ar), 6.01 (d, J = 2.3 Hz, 1H, CH, Ar), 6.02 (s, 2H,

4

2 × CH, Ar), 6.38 (d, ³J = 17.0 Hz, 1H, CH), 6.70 (d, ³J = 17.0 Hz,

1H, CH); ¹³C NMR (CDCl₃, 100 MHz) δ 29.0 (CH₂), 39.4 (CH),

51.3 (CH), 51.9 (OCH₃), 52.0 (OCH₃), 52.2 (2 × OCH₃), 55.0

(OCH₃), 55.1 (OCH₃), 55.2 (OCH₃), 55.5 (OCH₃), 55.6 (2 ×

OCH₃), 64.3 (C), 90.2 (CH), 90.4 (CH), 90.7 (2 × CH), 106.9 (C),

108.0 (C), 120.1 (CH), 128.8 (CH), 159.2 (2 × C), 159.8 (C),

160.0 (C), 160.3 (C), 160.4 (C), 169.8 (CO₂Me), 170.2 (CO₂Me),

171.1 (CO₂Me), 171.4 (CO₂Me); IR (Nujol, cm⁻¹) 2940, 2870, 1730,

1605, 1470, 1380, 1335, 1240, 1205, 1160, 1130, 1070, 1030, 960, 820,

730; MS MALDI-TOF m/z calcd for C₃₂H₄₀O₁₄648, found [M]⁺648.

Anal. Calcd for C₃₂H₄₀O₁₄: C, 59.25; H, 6.22. Found: C, 59.30; H,

6.39.

Tetraethyl cis-2,5-Bis(4-methoxyphenyl)cyclohexane-

1,1,4,4-tetracarboxylate (2j). AlCl₃(150 mg, 1.1 mmol) was

added in one portion to a solution of 1j (130 mg, 0.45 mmol) in

CH₃NO₂(9 mL) at −20 °C. The resulting mixture was allowed to

warm to room temperature for 1 h, kept at this temperature for 1 h,

and worked up as described above to yield 2j (80 mg, 62%) as

colorless crystals: mp 105−106 °C; R_f0.21 (diethyl ether/hexane 1:1);

3

¹H NMR (CDCl₃, 400 MHz) δ 0.78 (t, J = 7.1 Hz, 6H, 2 × CH₃),

1.15 (t, ³J = 7.1 Hz, 6H, 2 × CH₃), 2.39 (dd, ²J = 14.4 Hz, ³J = 2.9 Hz,

2

3

2H, 2 × CH^aH), 3.17 (dd, J = 14.4 Hz, J = 12.7 Hz, 2H, 2 ×

CH^bH), 3.43−3.48 (m, 2H, OCH₂), 3.63−3.71 (m, 2H, OCH₂), 3.77

(s, 6H, 2 × OCH₃) 3.78 (dd, ³J = 2.9 Hz, ³J = 12.7 Hz, 2H, 2 × CH),

4.09−4.26 (m, 4H, 2 × OCH₂), 6.79 (d, ³J = 8.8 Hz, 4H, 4 × CH, Ar),

7.28 (d, ³J = 8.8 Hz, 4H, 4 × CH, Ar); ¹³C NMR (CDCl₃, 100 MHz)

δ 13.4 (2 × CH₃), 13.9 (2 × CH₃), 33.1 (2 × CH₂), 39.1 (2 × CH),

55.2 (2 × OCH₃), 60.3 (2 × C), 61.0 (2 × OCH₂), 61.6 (2 × OCH₂),

113.1 (4 × CH, Ar), 129.8 (4 × CH, Ar), 133.2 (2 × C, Ar), 158.4

(2 × C, Ar), 169.9 (2 × CO₂Et), 171.9 (2 × CO₂Et); IR (Nujol, cm⁻¹)

2955, 1720, 1615, 1520, 1460, 1380, 1130, 1115, 1055, 870, 850; MS

MALDI-TOF m/z calcd for C₃₂H₄₀O₁₀584, found [M]⁺584. Anal.

Calcd for C₃₂H₄₀O₁₀: C, 65.74; H, 6.90. Found: C, 65.60; H, 6.93.

Tetraethyl (5E)-3,6-Bis(2,4,6-trimethoxyphenyl)hex-5-ene-

1,1,4,4-tetracarboxylate (3a). AlCl₃(70 mg, 0.53 mmol) was

added in one portion to a solution of 1a (180 mg, 0.51 mmol) in

CH₂Cl₂at −50 °C (10 mL). The resulting mixture was warmed to

−25 °C and kept at this temperature for 1 h, and then it was warmed

up to 5 °C, kept at this temperature for additional 22 h, and worked up

as described above to yield 3a (126 mg, 70%) as a colorless oil: R_f0.54

Tetraethyl (5E)-3,6-Bis(3-bromo-2,4,6-trimethoxyphenyl)-

hex-5-ene-1,1,4,4-tetracarboxylate (3c). A solution of SnCl₄

(216 mg, 0.097 mL, 0.83 mmol) in CH₂Cl₂(1 mL) was added to a

solution of 1c (180 mg, 0.42 mmol) in CH₂Cl₂(8 mL) at −20 °C.

The resulting mixture was kept at −20 °C for 20 h, warmed to room

temperature, and worked up as described above to yield 3c (136 mg,

75%) as a colorless solid: mp 107−108 °C; R_f0.55 (diethyl ether); ¹H

3

NMR (CDCl₃, 600 MHz) δ 1.11 (t, J = 7.2 Hz, 3H, CH₃), 1.20 (t,

³J = 7.2 Hz, 3H, CH₃), 1.23 (t, ³J = 7.2 Hz, 3H, CH₃), 1.31 (t, ³J = 7.2

2

3

Hz, 3H, CH₃), 2.55 (ddd, J = 14.0 Hz, J = 6.5 Hz, J = 4.0 Hz, 1H,

CH^aH), 2.73 (ddd, J = 14.0 Hz, J = 7.0 Hz, J = 11.6 Hz, 1H,

2

3

CH^bH), 3.18 (dd, J = 6.5 Hz, J = 7.0 Hz, 1H, CH), 3.63 (s, 3H,

OCH₃), 3.64 (s, 3H, OCH₃), 3.72 (s, 3H, OCH₃), 3.74 (s, 3H,

OCH₃), 3.76−3.80 (m, 2H, OCH₂), 3.85−3.93 (m, 2H, OCH₂), 3.86

(s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 4.11−4.17 (m, 3H, OCH₂), 4.30

(dq, ²J = 9.0 Hz, ³J = 7.2 Hz, 1H, OCH₂), 4.39 (dd, ³J = 11.6 Hz, ³J =

4.0 Hz, 1H, CH), 6.22 (s, 1H, CH, Ar), 6.23 (s, 1H, CH, Ar), 6.28 (d,

3

³J = 17.1 Hz, 1H, CH), 6.73 (d, J = 17.1 Hz, 1H, CH); ¹³C

3

1

3

(diethyl ether); H NMR (CDCl₃, 400 MHz) δ 1.12 (t, J = 7.1 Hz,

NMR (CDCl₃, 150 MHz) δ 13.5 (2 × CH₃), 13.7 (2 × CH₃), 29.1

(CH₂), 41.1 (CH), 50.7 (CH), 54.6 (OCH₃), 55.0 (OCH₃), 55.9 (2 ×

OCH₃), 60.1 (OCH₃), 60.4 (OCH₃), 60.5 (OCH₂), 60.6 (OCH₂),

60.8 (OCH₂), 61.0 (OCH₂), 64.2 (C), 91.7 (CH), 92.1 (CH), 97.5

(C), 98.0 (C), 113.1 (C), 114.4 (C), 120.2 (CH), 131.2 (CH), 155.6

(C), 156.0 (C), 156.3 (C), 157.6 (C), 157.8 (C), 158.9 (C), 168.9

(CO₂Et), 169.3 (CO₂Et), 169.8 (CO₂Et), 170.2 (CO₂Et); IR (Nujol,

cm⁻¹) 2940, 2870, 1730, 1600, 1475, 1380, 1320, 1120, 1025, 925,

815, 730; MS MALDI-TOF m/z calcd for C₃₆H₄₆Br₂O₁₄860, found

3

3H, CH₃), 1.20 (t, J = 7.1 Hz, 3H, CH₃), 1.27 (t, J = 7.1 Hz, 3H,

CH₃), 1.31 (t, ³J = 7.1 Hz, 3H, CH₃), 2.55 (ddd, ²J = 13.6 Hz, ³J = 3.6

Hz, ³J = 8.8 Hz, 1H, CH^aH), 2.82 (ddd, ²J = 13.6 Hz, ³J = 5.6 Hz, ³J =

12.1 Hz, 1H, CH^bH), 3.07 (dd, ³J = 5.6, ³J = 8.8 Hz, 1H, CH), 3.52 (s,

3H, OCH₃), 3.66 (s, 6H, 2 × OCH₃), 3.70 (s, 3H, OCH₃), 3.77 (s,

3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.83−3.96 (m, 2H, OCH₂), 4.05

(dq, ²J = 10.8 Hz, ³J = 7.1 Hz, 1H, OCH₂), 4.12−4.27 (m, 4H,

2

3

OCH₂), 4.34 (dq, J = 10.6 Hz, J = 7.1 Hz, 1H, OCH₂), 4.43 (dd,

8863

dx.doi.org/10.1021/jo201612w|J. Org. Chem. 2011, 76, 8852−8868

The Journal of Organic Chemistry

Article

[M]⁺860. Anal. Calcd for C₃₆H₄₆Br₂O₁₄: C, 50.13; H, 5.38. Found C,

49.95; H, 5.49.

2.17 (m, 2H+2H, CH₂, A + B), 2.29−2.36 (m, 1H, CH₂, A), 2.58−

2

3

4

2.67 (ddd, J = 14.6 Hz, J = 3.2 Hz, J = 1.1 Hz, 1H, CH₂, B), 2.77

2

3

4

Dimethyl 6-Methoxy-1-(3-methoxy-2-(methoxycarbonyl)-3-

oxopropyl)-4-(4-methoxyphenyl)-3,4-dihydronaphtalene-2,2-

(1H)-dicarboxylate (7a). A solution of SnCl₄(260 mg, 0.12 mL, 1.0

mmol) in CH₃NO₂(1 mL) was added to a solution of 1i (260 mg,

1.00 mmol) in C₆H₆(13 mL) at room temperature, and the resulting

mixture was stirred for 24 h affording 7a (210 mg, 81%, dr 91:9).

(1RS,4RS)-7a (major isomer): white crystals; mp 72−73 °C; R_f0.28

(diethyl ether/hexane 1:1); ¹H NMR (CDCl₃, 400 MHz) δ 2.02 (ddd,

²J = 13.6 Hz, ³J = 5.1 Hz, ³J = 10.6 Hz, 1H, CH₂), 2.12 (ddd, ²J = 13.6

(ddd, J = 14.6 Hz, J = 7.2 Hz, J = 1.3 Hz, 1H, CH₂, A), 2.91 (dd,

²J = 14.6 Hz, ³J = 8.7 Hz, 1H, CH₂, B), 3.17 (s, 3H, OCH₃, A), 3.41−

3.46 (m, 1H+1H, CH, A, B), 3.52 (dd, ³J = 10.2 Hz, ³J = 5.1 Hz, 1H,

CH, B), 3.63 (s, 3H, OCH₃, B), 3.65 (s, 3H, OCH₃, B), 3.66 (s, 3H,

OCH₃, A), 3.67 (s, 3H, OCH₃, A), 3.68 (s, 3H, OCH₃, B), 3.72−3.75

(m, 1H, CH, A), 3.77 (s, 3H, OCH₃, B), 3.80 (s, 3H, OCH₃, B), 3.81

(s, 3H, OCH₃, A), 3.83 (s, 3H, OCH₃, A), 3.84 (s, 3H, OCH₃, B),

3.85 (s, 3H, OCH₃, A), 3.86 (s, 3H, OCH₃, B), 3.89−3.92 (m, 1H,

CH, A), 3.90 (s, 3H, OCH₃, A), 3.94 (s, 3H, OCH₃, B), 3.96 (s, 3H,

OCH₃, A), 4.27 (dd, ³J = 3.2 Hz, ³J = 8.7 Hz, 1H, CH, B), 6.32 (s, 1H,

CH, Ar, B), 6.39 (s, 1H, CH, Ar, A), 6.46 (dd, ³J = 8.3 Hz, ⁴J = 2.0 Hz,

1H, CH, Ar, B), 6.58 (d, ⁴J = 2.0 Hz, 1H, CH, Ar, B), 6.68 (s, 1H+1H,

CH, Ar, A + B), 6.74 (d, ³J = 8.3 Hz, 1H, CH, Ar, B), 6.75 (d, ³J = 8.3

Hz, 1H, CH, Ar, A), 6.79 (s, 1H, CH, Ar, A), 6.84 (d, ³J = 8.3 Hz, 1H,

CH, Ar, A); ¹³C NMR (CDCl₃, 100 MHz) for mixture of

diastereomers δ 32.1 (CH₂, A), 33.0 (CH₂, A), 33.3 (CH₂, B), 33.7

(CH₂, B), 40.5 (CH, A), 40.7 (2 × CH, A, B), 42.6 (CH, B), 49.8

(CH, B), 49.9 (CH, A), 52.1 (OCH₃), 52.57 (2 × OCH₃), 52.64

(OCH₃), 52.68 (2 × OCH₃), 52.81 (OCH₃), 52.84 (OCH₃), 55.56

(OCH₃), 55.61 (OCH₃), 55.68 (2 × OCH₃), 55.76 (2 × OCH₃),

55.81 (2 × OCH₃), 57.1 (C, B), 58.5 (C, A), 110.6 (CH, A), 111.1

(CH, B), 111.3 (CH, B), 111.6 (2 × CH, A + B), 112.1 (CH, A),

112.5 (CH, B), 113.0 (CH, A), 120.5 (CH, B), 121.0 (CH, A), 127.8

(C, A), 128.7 (C, B), 129.5 (C, B), 129.7 (C, A), 138.7 (2 × C, A, B),

147.1 (2 × C, A), 147.3 (C, B), 147.6 (2 × C, A, B), 147.8 (C, B),

148.5 (C, A), 149.1 (C, B), 169.16 (CO₂Me, B), 169.22 (CO₂Me, A),

169.4 (CO₂Me, A), 169.5 (CO₂Me, B), 170.2 (CO₂Me, B), 170.3

(CO₂Me, B), 170.6 (CO₂Me, A), 170.8 (CO₂Me, A); IR (Nujol,

cm⁻¹) 2950, 2870, 1735, 1520, 1470, 1380, 1250, 1160, 1035, 820,

730; MS MALDI-TOF m/z calcd for C₃₀H₃₆O₁₂Na 601, found [M +

Na]⁺601. Anal. Calcd for C₃₀H₃₆O₁₂: C, 61.22; H, 6.16. Found: C,

61.51; H, 6.28.

2

3

Hz, ³J = 3.0 Hz, ³J = 10.3 Hz, 1H, CH₂), 2.34 (dd, J = 14.4 Hz, J =

11.9 Hz, 1H, CH₂), 2.75 (ddd, ²J = 14.4 Hz, ³J = 7.2 Hz, ⁴J = 1.5 Hz,

1H, CH₂), 3.44 (ddd, ³J = 3.0 Hz, ³J = 10.6 Hz, ⁴J = 1.5 Hz, 1H, CH),

3

3.60 (dd, J = 5.1 Hz, J = 10.3 Hz, 1H, CH(CO₂Me)₂), 3.61 (s, 3H,

OCH₃), 3.64 (s, 3H, OCH₃), 3.66 (s, 3H, OCH₃), 3.79 (s, 3H,

3

OCH₃), 3.80 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃), 3.90 (dd, J = 7.2

3

4

Hz, J = 11.9 Hz, 1H, CH), 6.35 (d, J = 2.7 Hz, 1H, CH, Ar), 6.73

(dd, ³J = 8.6 Hz, ⁴J = 2.7 Hz, 1H, CH, Ar), 6.86 (br.d, ³J = 8.6 Hz, 2H,

2 × CH, Ar), 7.09−7.11 (m, 3H, 3 × CH, Ar); ¹³C NMR (CDCl₃, 100

MHz) δ 33.2 (CH₂), 33.9 (CH₂), 40.1 (CH), 42.8 (CH), 49.5

(CH(CO₂Me)₂), 52.7 (OCH₃), 52.8 (3 × OCH₃), 55.2 (OCH₃), 55.3

(OCH₃), 58.6 (C), 112.3 (CH, Ar), 114.1 (2 × CH, Ar), 115.2 (CH,

Ar), 129.6 (2 × CH, Ar), 129.9 (C, Ar), 130.3 (CH, Ar), 137.8 (C,

Ar), 138.5 (C, Ar), 158.3 (2 × C, Ar), 169.4 (CO₂Me), 169.5

(CO₂Me), 170.3 (CO₂Me), 170.5 (CO₂Me); IR (Nujol, cm⁻¹) 2960,

2870, 1735, 1610, 1515, 1470, 1360, 1055, 845, 740; GC−MS m/z

528 (96) [M]⁺, 362 (32), 347 (100), 265 (72), 207 (63), 145 (72),

134 (70), 121 (25); MS MALDI-TOF m/z calcd for C₂₈H₃₂O₁₀528,

found [M]⁺528. Anal. Calcd for C₂₈H₃₂O₁₀: C, 63.63; H, 6.10. Found:

C, 63.81; H, 6.21.

Diethyl 1-[3-Ethoxy-2-(ethoxycarbonyl)-3-oxopropyl]-6-me-

thoxy-4-(4-methoxyphenyl)-3,4-dihydronaphthalene-2,2(1H)-

dicarboxylate (7b). A solution of SnCl₄(260 mg, 0.12 mL, 1.0

mmol) in CH₃NO₂(1 mL) was added to a solution of 1j (290 mg, 1.0

mmol) in CH₃NO₂(13 mL) at −25 °C. The resulting mixture was

warmed to room temperature for 3 h and worked up as described

above to yield 7b (240 mg, 80%, dr 90:10). (1RS,4RS)-7b (major

Dimethyl 9-(2″,3″-Dihydro-1″,4″-benzodioxin-6″-yl)-6-[3′-

methoxy-2′-(methoxycarbonyl)-3′-oxopropyl]-2,3,8,9-

tetrahydronaphtho[2,3-b][1,4]dioxine-7,7(6H)-dicarboxylate

(7d). A solution of SnCl₄(318 mg, 0.14 mL, 1.22 mmol) in C₂H₅NO₂

(1 mL) was added to a solution of 1l (210 mg, 0.82 mmol) in

C₂H₅NO₂(13 mL) at −40 °C. The resulting mixture was allowed to

warm to room temperature during 3 h and worked up as described

above to yield 7d (85 mg, 40%, dr 57:43) as colorless oil. R_f0.17

1

isomer): colorless oil; R_f0.31 (diethyl ether/hexane 1:1); H NMR

3

(CDCl₃, 400 MHz) δ 1.13 (t, ³J = 7.1 Hz, 3H, CH₃), 1.23 (t, J = 7.1

Hz, 3H, CH₃), 1.30 (t, ³J = 7.1 Hz, 3H, CH₃), 1.36 (t, ³J = 7.1 Hz, 3H,

2

3

CH₃), 2.03 (ddd, J = 13.7 Hz, J = 4.7 Hz, J = 10.9 Hz, 1H, CH₂),

2.17 (ddd, ²J = 13.7 Hz, ³J = 3.2 Hz, ³J = 10.3 Hz, 1H, CH₂), 2.34 (dd,

²J = 14.4 Hz, ³J = 11.9 Hz, 1H, CH₂), 2.75 (ddd, ²J = 14.4 Hz, ³J = 7.2

1

(hexane/ethyl acetate 2:1); (6RS,9RS)-7d (major isomer): H NMR

2

3

(CDCl₃, 600 MHz) δ 2.03 (ddd, J = 13.7 Hz, J_1′,2′= 4.6 Hz, J_1′,6

=

10.9 Hz, 1H, C(1′)H₂), 2.16 (ddd, ²J = 13.7 Hz, ³J_1′,6= 3.0 Hz, ³J_1′,2′

Hz, ⁴J = 1.5 Hz, 1H, CH₂), 3.50 (ddd, ³J = 3.2 Hz, ³J = 10.9 Hz, ⁴J =

1.5 Hz, 1H, CH), 3.55 (dd, ³J = 4.7 Hz, ³J = 10.3 Hz, 1H,

CH(CO₂Me)₂), 3.62 (s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 3.92 (dd,

³J = 7.2 Hz, ³J = 11.9 Hz, 1H, CH), 4.05−4.17 (m, 4H, OCH₂), 4.18−

4.37 (m, 4H, OCH₂), 6.36 (d, ⁴J = 2.7 Hz, 1H, CH, Ar), 6.73 (dd, ³J =

8.6 Hz, ⁴J = 2.7 Hz, 1H, CH, Ar), 6.86 (br.d, ³J = 8.6 Hz, 2H, 2 × CH,

Ar), 7.09−7.11 (m, 3H, 3 × CH, Ar); ¹³C NMR (CDCl₃, 100 MHz) δ

13.9 (CH₃), 14.0 (2 × CH₃), 14.2 (CH₃), 33.2 (CH₂), 33.7 (CH₂),

39.9 (CH), 42.8 (CH), 49.7 (CH(CO₂Et)₂), 55.0 (OCH₃), 55.3

(OCH₃), 58.6 (C), 61.4 (OCH₂), 61.5 (2 × OCH₂), 61.8 (OCH₂),

112.2 (CH, Ar), 114.1 (2 × CH, Ar), 115.0 (CH, Ar), 129.6 (2 × CH,

Ar), 130.2 (C, Ar), 130.5 (CH, Ar), 138.1 (C, Ar), 138.6 (C, Ar),

158.3 (2 × C, Ar), 169.1 (CO₂Et), 169.2 (CO₂Et), 169.9 (CO₂Et),

170.1 (CO₂Et); IR (Nujol, cm⁻¹) 2990, 1740, 1610, 1510, 1470, 1380,

1050, 870, 850; HRMS MALDI-TOF m/z calcd for C₃₂H₄₀O₁₀

584.2621, found [M]⁺584.2618. Anal. Calcd for C₃₂H₄₀O₁₀: C,

65.74; H, 6.90. Found: C, 65.84; H, 7.08.

2

3

4

10.5 Hz, 1H, C(1′)H₂), 2.57 (ddd, J = 14.8 Hz, J_8,9= 5.0 Hz, J_8,6

2

3

0.9 Hz, 1H, C(8)H₂), 2.86 (dd, J = 14.8 Hz, J_8,9= 9.0 Hz, 1H,

C(8)H₂), 3.34−3.36 (m, 1H, C(6)H), 3.36 (s, 3H, OCH₃), 3.50 (dd,

³J_2′,1′= 4.6 Hz, ³J_2′,1′= 10.5 Hz, 1H, C(2′)H), 3.65 (s, 3H, OCH₃), 3.74

(s, 3H, OCH₃), 3.82 (s, 3H, OCH₃), 4.09 (br. dd, ³J_9,8= 5.0 Hz, ³J_9,8

=

9.0 Hz, 1H, C(9)H), 4.16−4.24 (m, 8H, CH₂O), 6.31 (d, ⁴J_10,9= 0.7

3

4

Hz, 1H, C(10)H), 6.55 (dd, J = 8.3 Hz, J = 2.2 Hz, 1H, C(7″)H),

6.58 (d, ⁴J = 2.2 Hz, 1H, C(5″)H), 6.70 (s, 1H, C(5)H), 6.76 (d, J =

3

8.3 Hz, 1H, C(8″)H); ¹³C NMR (CDCl₃, 150 MHz) δ 31.2 (CH₂),

33.8 (CH₂), 40.0 (CH), 41.2 (CH), 49.9 (CH), 52.4 (OCH₃), 52.6

(OCH₃), 52.7 (OCH₃), 52.8 (OCH₃), 57.2 (OCH₂), 60.4 (C), 64.3

(OCH₂), 64.4 (2 × OCH₂), 116.9 (CH, Ar), 117.1 (CH, Ar), 117.3

(CH, Ar), 118.1 (CH, Ar), 121.9 (CH, Ar), 130.3 (C, Ar), 130.4 (C,

Ar), 139.2 (C, Ar), 141.8 (C, Ar), 142.0 (C, Ar), 142.4 (C, Ar), 143.2

(C, Ar), 169.4 (CO₂Me), 169.5 (CO₂Me), 170.8 (CO₂Me), 170.9

(CO₂Me). (6RS,9SR)-7d (minor isomer): ¹H NMR (CDCl₃, 600

2

3

MHz) δ 1.99 (ddd, J = 13.7 Hz, J_1′,2′= 4.8 Hz, J_1′,6= 10.5 Hz, 1H,

Dimethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-1-(3-me-

thoxy-2-(methoxycarbonyl)-3-oxopropyl)-3,4-dihydronaphta-

lene-2,2(1H)-dicarboxylate (7c). A solution of SnCl₄(318 mg,

0.14 mL, 1.22 mmol) in CH₃NO₂(1 mL) was added to a solution of

1k (300 mg, 1.02 mmol) in CH₃NO₂(14 mL) at −25 °C. The

resulting mixture was kept at −25 °C for 22 h, warmed to room

temperature, and worked up as described above to yield 7c (210 mg,

71%, dr 55:45) as colorless oil: R_f0.44 (diethyl ether/methanol 20:1);

¹H NMR (CDCl₃, 400 MHz) for mixture of diastereomers δ 1.98−

C(1′)H₂), 2.08 (ddd, ²J = 13.7 Hz, ³J_1′,6= 3.0 Hz, ³J_1′,2′= 10.5 Hz, 1H,

2

3

C(1′)H₂), 2.28 (dd, J = 14.4 Hz, J_8,9= 12.1 Hz, 1H, C(8)H₂), 2.69

(ddd, ²J = 14.4 Hz, ³J_8,9= 7.1 Hz, ⁴J_8,6= 1.6 Hz, 1H, C(8)H₂), 3.32−

3

3.33 (m, 1H, C(6)H), 3.64 (dd, J_2′,1′= 4.8 Hz, J_2′,1′= 10.5 Hz, 1H,

C(2′)H), 3.66 (s, 3H, CH₃), 3.68 (s, 3H, CH₃), 3.70−3.71 (m, 1H,

C(9)H), 3.78 (s, 3H, CH₃), 3.83 (s, 3H, CH₃), 4.16−4.24 (m, 8H,

CH₂O), 6.34 (d, ⁴J = 0.7 Hz, 1H, C(10)H), 6.64 (dd, ³J = 8.2 Hz, ⁴J =

2.1 Hz, 1H, C(7″)H), 6.65 (d, ⁴J = 2.1 Hz, 1H, C(5″)H), 6.66 (s, 1H,

8864

dx.doi.org/10.1021/jo201612w|J. Org. Chem. 2011, 76, 8852−8868

The Journal of Organic Chemistry

Article

3

C(5)H), 6.80 (d, J = 8.2 Hz, 1H, C(8″)H); ¹³C NMR (CDCl₃, 150

(C(4)H), 36.3 (C(5)H₂), 38.3 (C(7)H), 50.4 (CH(CO₂Me)₂), 52.3

(OCH₃), 52.7 (3 × OCH₃), 59.6 (C), 125.1 (CH, Th), 125.2 (CH,

Th), 125.9 (CH, Th), 134.5 (C, Th), 135.4 (C, Th), 136.9 (C, Th),

138.3 (C, Th), 145.7 (C, Th), 169.3 (2 × CO₂Me), 170.2 (CO₂Me),

MHz) δ 33.0 (CH₂), 33.8 (CH₂), 40.5 (CH), 42.3 (CH), 49.5 (CH),

52.63 (OCH₃), 52.67 (OCH₃), 52.72 (OCH₃), 52.85 (OCH₃), 58.6

(OCH₂), 58.9 (C), 64.3 (OCH₂), 64.4 (2 × OCH₂), 116.9 (CH, Ar),

117.2 (CH, Ar), 117.7 (CH, Ar), 118.4 (CH, Ar), 121.4 (CH, Ar),

129.9 (C, Ar), 130.8 (C, Ar), 139.2 (C, Ar), 141.8 (C, Ar), 142.2 (C,

Ar), 142.5 (C, Ar), 143.5 (C, Ar), 169.3 (CO₂Me), 169.5 (CO₂Me),

170.3 (CO₂Me), 170.4 (CO₂Me); IR (Nujol, cm⁻¹) 2945, 2865, 1735,

1595, 1510, 1475, 1380, 1300, 1220, 1085, 900, 825, 755, 735; MS

MALDI-TOF m/z calcd for C₃₀H₃₂O₁₂Na 607, found [M + Na]⁺607.

Anal. Calcd for C₃₀H₃₂O₁₂: C, 61.64; H, 5.52. Found: C, 61.53; H,

5.75.

Dimethyl 7-(3-Methoxy-2-(methoxycarbonyl)-3-oxopropyl)-

4-(thiophene-2-yl)-4,5-dihydrobenzo[b]thiophene-6,6(7H)-di-

carboxylate (7e). A solution of SnCl₄(260 mg, 0.12 mL, 1.00

mmol) in CH₃NO₂(1 mL) was added to a solution of 1m (200 mg,

0.83 mmol) in CH₃NO₂(13 mL) at −20 °C. The resulting mixture

was heated to 50 °C within 0.5 h, stirred at this temperature for 0.5 h,

and worked up as described above to yield 7e (156 mg, 78%, dr 71:29)

as a colorless oil: R_f0.46 (CH₂Cl₂). (4RS,7RS)-7e (major isomer): ¹H

1

170.3 (CO₂Me); (4RS,7SR)-7f (minor isomer): H NMR (CDCl₃,

400 MHz) δ 1.99−2.13 (m, 2H, CH₂), 2.34 (d, ⁴J = 0.9 Hz, 3H, Me),

2.43 (d, ⁴J = 0.9 Hz, 3H, Me), 2.41−2.46 (m, 1H, CH₂), 2.82 (dd, ²J =

3

14.2 Hz, J = 6.5 Hz, 1H, CH₂), 3.57 (dd, J = 3.0, J = 9.8 Hz, 1H,

CH), 3.69 (s, 3H, OCH₃), 3.72 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃),

3.83 (s, 3H, OCH₃), 3.80−3.86 (m, 1H, CH(CO₂Me)₂), 4.00 (dd,

³J = 6.5 Hz, ³J = 10.9 Hz, 1H, CH), 6.31 (d, ⁴J = 0.9 Hz, 1H, Th), 6.58

(dd, ³J = 3.3 Hz, ⁴J = 0.9 Hz, 1H, Th), 6.68 (d, ³J = 3.3 Hz, 1H, Th);

¹³C NMR (CDCl₃, 100 MHz) δ 15.3 (CH₃), 15.4 (CH₃), 33.4 (CH₂),

33.7 (C(5)H₂), 36.3 (CH), 36.8 (C(7)H), 49.9 (CH(CO₂Me)₂), 52.6

(OCH₃), 52.7 (OCH₃), 52.9 (OCH₃), 53.0 (OCH₃), 58.0 (C), 124.3

(CH, Th), 124.5 (CH, Th), 125.5 (CH, Th), 134.3 (C, Th), 135.7 (C,

Th), 137.7 (C, Th), 138.3 (C, Th), 145.7 (C, Th), 169.27 (CO₂Me),

169.32 (CO₂Me), 169.8 (2 × CO₂Me); IR (Nujol, cm⁻¹) 2965, 2930,

2869, 1740, 1660, 1460, 1380, 1255, 1087, 1054, 800; GC−MS m/z

508 (12) [M]⁺, 376 (38), 317 (354), 281 (49), 207 (100), 191 (10).

Anal. Calcd for C₂₄H₂₈O₈S₂: C, 56.68; H, 5.55. Found: C, 56.43; H,

5.45.

2

NMR (CDCl₃, 600 MHz) δ 2.23−2.29 (m, 2H, CH₂), 2.64 (dd, J =

3

2

3

14.3 Hz, J = 5.3 Hz, 1H, CH₂), 2.86 (dd, J = 14.3 Hz, J = 6.9 Hz,

1H, CH₂), 3.33 (s, 3H, OCH₃), 3.57 (dd, ³J = 6.1 Hz, ³J = 6.6 Hz, 1H,

CH), 3.73 (s, 3H, OCH₃), 3.76 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃),

3.81−3.83 (m, 1H, CH(CO₂Me)₂), 4.47 (dd, ³J = 5.3 Hz, ³J = 6.9 Hz,

1H, CH), 6.52 (br. d, ³J = 3.5 Hz, 1H, CH, Th), 6.74 (d, ³J = 5.2 Hz,

Dimethyl 5,6,7-Trimethoxy-1-[3-methoxy-2-(methoxycar-

bonyl)-3-oxopropyl]-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-

naphthalene-2,2(1H)-dicarboxylate (7g). A solution of SnCl₄

(193 mg, 0.086 mL, 0.74 mmol) in CH₃NO₂(1 mL) was added to

a solution of 1o (200 mg, 0.62 mmol) in CH₃NO₂(6 mL) at room

temperature. The resulting mixture was heated to 60 °C, stirred at this

temperature for 3 h, and worked up as described above to yield 7g (50

mg, 21%, dr 72:28) and 9a (130 mg, 65%, dr 54:46). (1RS,4RS)-7g

(major isomer): colorless oil, R_f0.50 (diethyl ether); ¹H NMR

3

1H, CH, Th), 6.83 (dd, J = 3.5 Hz, J = 5.1 Hz, 1H, CH, Th), 7.12

(d, ³J = 5.2 Hz, 1H, CH, Th), 7.16 (dd, J = 5.1 Hz, ⁴J = 1.0 Hz, 1H,

3

CH, Th); ¹³C NMR (CDCl₃, 150 MHz) δ 32.9 (CH₂), 35.2 (C(4)H),

36.3 (C(5)H₂), 38.3 (C(7)H), 50.4 (CH(CO₂Me)₂), 52.4 (OCH₃),

52.66 (OCH₃), 52.69 (OCH₃), 52.70 (OCH₃), 58.0 (C), 122.8 (CH,

Th), 124.0 (CH, Th), 125.4 (CH, Th), 126.2 (CH, Th), 127.8 (CH,

Th), 134.7 (C, Th), 138.1 (C, Th), 148.2 (C, Th), 169.2 (CO₂Me),

169.3 (CO₂Me), 169.7 (CO₂Me), 170.1 (CO₂Me). (4RS,7SR)-7e

2

(CDCl₃, 400 MHz) δ 2.09−2.14 (m, 2H, CH₂), 2.19 (dd, J = 14.8

3

2

3

Hz, J = 10.4 Hz, 1H, CH₂), 2.91 (dd, J = 14.8 Hz, J = 8.8 Hz, 1H,

3

CH₂), 3.21 (s, 3H, OCH₃), 3.43 (dd, J = 8.6 Hz, J = 9.0 Hz, 1H,

CH), 3.61 (s, 3H, OCH₃), 3.63 (s, 3H, OCH₃), 3.66−3.70 (m, 1H,

CH), 3.75 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.79 (s, 6H, 2 ×

OCH₃), 3.82 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 3.90 (s, 3H,

OCH₃), 4.07 (dd, ³J = 8.8 Hz, ³J = 10.4 Hz, 1H, CH), 6.35 (s, 2H, 2 ×

CH, Ar), 6.46 (s, 1H, CH, Ar); ¹³C NMR (CDCl₃, 100 MHz) δ 33.1

(¹J = 130 Hz, CH₂), 33.2 (¹J = 132 Hz, CH₂), 39.4 (¹J = 130 Hz, CH),

41.7 (¹J = 138 Hz, CH), 49.9 (¹J = 132 Hz, CH(CO₂Me)₂), 52.6 (¹J =

148 Hz, CO₂CH₃), 52.7 (¹J = 148 Hz, CO₂CH₃), 52.8 (¹J = 148 Hz,

CO₂CH₃), 52.9 (¹J = 148 Hz, CO₂CH₃), 55.6 (¹J = 144 Hz, OCH₃),

56.1 (¹J = 144 Hz, 2 × OCH₃), 58.6 (C), 59.6 (¹J = 144 Hz, OCH₃),

60.4 (¹J = 145 Hz, OCH₃), 60.9 (¹J = 146 Hz, OCH₃), 103.9 (¹J = 157

Hz, 2 × CH, Ar), 107.8 (¹J = 158 Hz, CH, Ar), 122.6 (C, Ar), 133.2

(C, Ar), 136.1 (C, Ar), 141.4 (C, Ar), 144.4 (C, Ar), 152.2 (C, Ar),

152.5 (C, Ar), 153.3 (2 × C, Ar), 169.2 (CO₂Me), 169.5 (CO₂Me),

169.9 (CO₂Me), 170.1 (CO₂Me); IR (Nujol, cm⁻¹) 2970, 2855, 1745,

1602, 1505, 1480, 1366, 1245, 1120, 1007, 875; HRMS MALDI-TOF

m/z calcd for C₃₂H₄₀O₁₄648.2412, found [M]⁺648.2418. Anal. Calcd

for C₃₂H₄₀O₁₄: C 59.25; H, 6.22. Found: C, 59.23, H, 6.38.

1

2

(minor isomer): H NMR (CDCl₃, 600 MHz) δ 2.06 (ddd, J = 13.9

Hz, ³J = 4.6 Hz, ³J = 10.3 Hz, 1H, CH₂), 2.13 (ddd, ²J = 13.9 Hz, ³J =

3.3 Hz, ³J = 10.7 Hz, 1H, CH₂), 2.43 (dd, J = 14.4 Hz, J = 11.3 Hz,

2

3

2

3

4

1H, CH₂), 2.90 (ddd, J = 14.4 Hz, J = 6.6 Hz, J = 1.0 Hz, 1H,

CH₂), 3.68 (s, 3H, OCH₃), 3.71 (s, 3H, OCH₃), 3.80 (s, 3H, OCH₃),

3.80−3.82 (m, 1H, CH), 3.83 (s, 3H, OCH₃), 3.83−3.85 (m, 1H,

3

CH), 4.18 (dd, J = 6.6 Hz, J = 11.3 Hz, 1H, CH) 6.65 (d, J = 5.1

Hz, 1H, CH, Th), 6.90 (br.d, ³J = 3.5 Hz, 1H, CH, Th), 6.95 (dd, ³J =

3.5 Hz, ³J = 5.2 Hz, 1H, CH, Th), 7.07 (d, ³J = 5.2 Hz, 1H, CH, Th),

7.18 (br. d, ³J = 5.1 Hz, 1H, CH, Th); ¹³C NMR (CDCl₃, 150 MHz) δ

33.4 (CH₂), 33.9 (C(5)H₂), 36.0 (CH), 37.0 (C(7)H), 49.9

(CH(CO₂Me)₂), 52.69 (OCH₃), 52.70 (OCH₃), 52.95 (OCH₃),

52.97 (OCH₃), 59.8 (C), 123.4 (CH, Th), 123.9 (CH, Th), 124.6

(CH, Th), 126.7 (CH, Th), 127.4 (CH, Th), 135.9 (C, Th), 137.0 (C,

Th), 147.8 (C, Th), 169.1 (CO₂Me), 169.3 (CO₂Me), 169.7

(CO₂Me), 170.1 (CO₂Me); IR (film, cm⁻¹) 2955, 2870, 1745, 1440,

1250, 1160, 1080, 925, 850, 800, 715; HRMS MALDI-TOF m/z calcd

for C₂₂H₂₄O₈S₂480.0913, found [M]⁺480.0950. Anal. Calcd for

C₂₂H₂₄O₈S₂: C, 54.99; H, 5.03. Found: C, 54.85; H, 5.15.

Tetramethyl (1RS,3aSR,5aRS,9aSR)-1-(4-Methoxyphenyl)-7-

oxo-3a,4,6,7-tetrahydro-1H-cyclopenta[c]indene-3,3,5,5-

(2H,5aH)-tetracarboxylate (8). A solution of SnCl₄(287 mg, 0.13

mL, 1.1 mmol) in C₆H₆(1 mL) was added to a solution of 1i (200 mg,

0.76 mmol) in C₆H₆(10 mL) at 40 °C, and the resulting mixture was

kept at this temperature for 2 h affording 7a (120 mg, 59%, dr 90:10)

and 8 (60 mg, 30%). 8: colorless crystals; mp 159−160 °C; R_f0.40

Dimethyl 7-(3-Methoxy-2-(methoxycarbonyl)-3-oxopropyl)-

2-methyl-4-(5-methylthiophene-2-yl)-4,5-dihydrobenzo[b]-

thiophene-6,6(7H)- dicarboxilate (7f). A solution of SnCl₄(260

mg, 0.12 mL, 1.00 mmol) in CH₃NO₂(1 mL) was added to a solution

of 1n (200 mg, 0.79 mmol) in CH₃NO₂(9 mL) at −20 °C. The

resulting mixture was kept at −20 °C for 6 h, warmed to room

temperature, and worked up as described above to yield 7f (130 mg,

54%, dr 56:44) as a yellow oil: R_f0.25−0.35 (diethyl ether/hexane

1

2

(diethyl ether); H NMR (600 MHz, CDCl₃) 0.78 (dd, J = 18.7 Hz,

³J = 7.8 Hz, 1H, C(6)H₂), 1.34 (dd, J = 12.5 Hz, J = 10.6 Hz, 1H,

2

3

2

1

C(4)H₂), 2.30 (br.d, J = 18.7 Hz, 1H, C(6)H₂), 2.36 (ddd, J = 12.8

Hz, ³J = 4.6 Hz, ⁴J = 1.0 Hz, 1H, C(2)H₂), 2.57 (dd, ²J = 12.5 Hz, ³J =

8.6 Hz, 1H, C(4)H₂), 2.84 (br.d, ³J = 7.8 Hz, 1H, C(5a)H), 2.89 (dd,

²J = 12.8 Hz, ³J = 14.6, Hz, 1H, C(2)H₂), 2.94 (dd, ³J = 14.6 Hz, ³J =

4.6 Hz, 1H, C(1)H), 3.47 (s, 3H, OCH₃), 3.64−3.67 (m, 1H,

C(3a)H), 3.69 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 3.79 (s, 3H,

OCH₃), 3.80 (s, 3H, OCH₃), 5.86 (d, ³J = 10.3 Hz, 1H, C(8)H), 6.84

(d, ³J = 7.8 Hz, 2H, C(3′)H, C(5′)H), 6.95 (dd, ³J = 10.3 Hz, ⁴J = 1.7

1:1). (4RS,7RS)-7f (major isomer): H NMR (CDCl₃, 400 MHz) δ

4

2.20−2.29 (m, 2H, CH₂), 2.38 (br. s, 3H, Me), 2.41 (d, J = 0.9 Hz,

3H, Me), 2.56 (dd, ²J = 14.2 Hz, ³J = 5.6 Hz, 1H, CH₂), 2.78 (dd, ²J =

14.2 Hz, ³J = 6.8 Hz, 1H, CH₂), 3.40 (s, 3H, OCH₃), 3.45 (dd, ³J = 6.1

3

Hz, J = 6.3 Hz, 1H, CH), 3.74 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃),

3.79 (s, 3H, OCH₃), 3.80−3.86 (m, 1H, CH(CO₂Me)₂), 4.28 (dd,

³J = 5.6 Hz, ³J = 6.8 Hz, 1H, CH), 6.34 (d, ³J = 3.3 Hz, 1H, Th), 6.39

(d, ⁴J = 0.9 Hz, 1H, Th), 6.48 (dd, ³J = 3.3, ⁴J = 1.0 Hz, 1H, Th); ¹³

C

3

NMR (CDCl₃, 100 MHz) δ 15.3 (2 × CH₃), 32.8 (CH₂), 35.3

Hz, 1H, C(9)H), 7.13 (br.d, J = 7.8 Hz, 2H, C(2′)H, C(6′)H); ¹³C

8865

dx.doi.org/10.1021/jo201612w|J. Org. Chem. 2011, 76, 8852−8868

The Journal of Organic Chemistry

Article

NMR (150 MHz, CDCl₃) 33.9 (C(2)H₂), 34.0 (C(6)H₂), 35.5

(C(4)H₂), 45.7 (C(5a)H), 48.7 (C(1)H), 51.9 (CH₃), 52.1

(C(3a)H), 52.3 (CH₃), 52.4 (CH₃), 52.8 (CH₃), 53.6 (C(9a)), 54.8

(CH₃), 61.7 (C), 61.9 (C), 114.3 (C(3′)H, C(5′)H), 127.1 (C(8)H),

127.8 (C(1′)), 128.4 (C(2′)H, C(6′)H), 154.5 (C(9)H), 158.8

(C(4′)), 169.6 (CO₂Me), 170.1 (CO₂Me), 170.3 (CO₂Me), 171.9

(CO₂Me), 195.8 (C(7)). Anal. Calcd for C₂₇H₃₀O₁₀: C 63.03; H, 5.88.

Found: C, 63.23, H, 5.94.

52.5 (2 × OCH₃), 55.2 (2 × OCH₃), 55.4 (2 × OCH₃), 96.7 (2 ×

CH, Ar), 104.6 (2 × CH, Ar), 119.5 (2 × C, Ar), 142.2 (2 × C, Ar),

157.4 (2 × C, Ar), 159.2 (2 × C, Ar), 169.7 (2 × CO₂Me), 170.2 (2 ×

CO₂Me); IR (Nujol, cm⁻¹) 3000, 2955, 2840, 1735, 1610, 1585, 1489,

1456, 1437, 1346, 1327, 1262, 1200, 1145, 1107, 1055, 1025, 831; MS

MALDI-TOF m/z calcd for C₃₀H₃₆O₁₂588, found [M]⁺588. Anal.

Calcd for C₃₀H₃₆O₁₂: C, 61.22; H, 6.16. Found: C, 60.99; H, 6.01.

Tetramethyl 2,2′-[(1,2,5,6-Tetramethoxy-9,10-dihydroan-

thracene-9,10-diyl)di(methylene)]dimalonate (9c). Sn(OTf)₂

(14 mg, 0.034 mmol) was added to a solution of 1q (100 mg, 0.340

mmol) in CH₃NO₂(3.4 mL) at room temperature. The resulting

mixture was heated to 100 °C, stirred at this temperature for 4 h, and

worked up as described above to yield 9c (66 mg, 66%, dr 90:10).

(9RS,10SR)-9c (major isomer): colorless crystals; mp 153−154 °C; R_f

0.5 (diethyl ether); H NMR (CDCl₃, 400 MHz) δ 2.44 (ddd, ²J = 14.1

Tetramethyl 2,2′-[(1,2,3,5,6,7-Hexamethoxy-9,10-dihy-

droanthracene-9,10-diyl)di(methylene)]dimalonate (9a). A sol-

ution of SnCl₄(339 mg, 0.15 mL, 1.3 mmol) in CH₃NO₂(1 mL) was

added to a solution of 1o (210 mg, 0.65 mmol) in CH₃NO₂(12 mL)

at −20 °C. The resulting mixture was heated to 50 °C, stirred at this

temperature for 1 h, and worked up as described above to yield

(9RS,10SR)-9a (93 mg, 44%) and (9RS,10RS)-9a (67 mg, 32%): dr

58:42. (9RS,10SR)-9a (major isomer): white crystals; mp 214−

215 °C; R_f0.42 (diethyl ether); ¹H NMR (CDCl₃, 600 MHz) δ 2.47 (ddd,

²J = 14.2 Hz, ³J = 5.8 Hz, ³J = 4.7 Hz, 2H, 2 × CH^aH), 2.63 (dd, ³J =

3

Hz, J = 4.7 Hz, J = 6.3 Hz, 2H, 2 × CH^aH), 2.65 (dd, J = 6.3 Hz,

³J = 6.9 Hz, 2H, 2 × CH), 2.98 (ddd, ²J = 14.1 Hz, ³J = 6.9 Hz, ³J = 3.9

Hz, 2H, 2 × CH^bH), 3.36 (s, 6H, 2 × OCH₃), 3.42 (s, 6H, 2 ×

OCH₃), 3.88 (s, 6H, 2 × OCH₃), 3.96 (s, 6H, 2 × OCH₃), 4.57 (dd,

3

2

3

5.8 Hz, J = 6.8 Hz, 2H, 2 × CH), 2.86 (ddd, J = 14.2 Hz, J = 6.8

3

³J = 3.9 Hz, ³J = 4.7 Hz, 2H, 2 × CH), 6.90 (d, J = 8.7 Hz, 2H, 2 ×

Hz, J = 3.8 Hz, 2H, 2 × CH^bH), 3.39 (s, 6H, OCH₃), 3.45 (s, 6H,

3

OCH₃), 3.90 (s, 12H, OCH₃), 4.01 (s, 6H, OCH₃), 4.45 (dd, ³J = 3.8

3

CH, Ar), 7.06 (d, J = 8.7 Hz, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃,

Hz, J = 4.7 Hz, 2H, 2 × CH), 6.61 (s, 2H, 2 × CH, Ar); ¹³C NMR

3

100 MHz) δ 35.8 (2 × CHAr), 38.1 (2 × CH₂), 47.8 (2 ×

CH(CO₂Me)₂), 52.1 (2 × OCH₃), 52.2 (2 × OCH₃), 55.9 (2 ×

OCH₃), 60.6 (2 × OCH₃), 112.0 (2 × CH, Ar), 123.6 (2 × CH, Ar),

129.4 (2 × C, Ar), 130.0 (2 × C, Ar), 146.2 (2 × C, Ar), 150.8 (2 × C,

Ar), 169.6 (2 × CO₂Me), 169.8 (2 × CO₂Me); IR (Nujol, cm⁻¹) 2945,

2865, 1735, 1725, 1602, 1500, 1470, 1295, 1220, 1105, 1088, 1042,

1000, 830; MS MALDI-TOF m/z calcd for C₃₀H₃₆O₁₂588, found

[M]⁺588. Anal. Calcd for C₃₀H₃₆O₁₂: C, 61.22; H, 6.16. Found: C,

61.32; H, 6.18.

(CDCl₃, 150 MHz) δ 36.1 (2 × CHAr), 37.9 (2 × CH₂), 47.6 (2 ×

CH(CO₂Me)₂), 52.2 (4 × OCH₃), 55.9 (4 × OCH₃), 60.7 (2 ×

OCH₃), 106.2 (2 × CH, Ar), 121.9 (2 × C, Ar), 131.6 (2 × C, Ar),

140.7 (2 × C, Ar), 150.9 (2 × C, Ar), 152.5 (2 × C, Ar), 169.79 (2 ×

CO₂Me), 169.84 (2 × CO₂Me); IR (Nujol, cm⁻¹) 2970, 2855, 1745,

1602, 1505, 1480, 1366, 1245, 1120, 1007, 875. Anal. Calcd for

C₃₂H₄₀O₁₄: C, 59.25; H, 6.22. Found: C, 59.23; H, 6.33. (9RS,10RS)-

1

9a (minor isomer): colorless oil; R_f0.58 (diethyl ether); H NMR

(CDCl₃, 600 MHz) δ 2.21−2.34 (m, 4H, 2 × CH₂), 3.66 (dd, ³J = 7.3

Arylidenemalonates were synthesized according to the reported

procedures.^64,65All compounds, except 10a−c, were described earlier.

Dimethyl 2-(4-Piperidinobenzylidene)malonate (10a). Con-

densation of 4-(piperidin-1-yl)benzaldehyde (2.0 g, 10.5 mmol) with

dimethyl malonate (1.40 g, 10.6 mmol) in benzene (20 mL) in the

presence of piperidine (0.04 mL, 0.6 mmol) and acetic acid (0.12 mL,

2.2 mmol) yielded 10a (2.9 g, 91%) as a yellow solid: mp 96−97 °C

(from ethyl acetate/hexane 1:1); ¹H NMR (CDCl₃, 400 MHz) δ

1.59−1.75 (m, 6H), 3.25−3.49 (m, 4H), 3.83 (s, 3H, CH₃O), 3.89 (s,

3

Hz, J = 8.1 Hz, 2H, 2 × CH), 3.75 (s, 6H, 2 × OCH₃), 3.78 (s, 6H,

2 × OCH₃), 3.88 (s, 6H, 2 × OCH₃), 3.90 (s, 6H, 2 × OCH₃), 3.92 (s,

6H, 2 × OCH₃), 4.17 (dd, ³J = 6.9 Hz, ³J = 8.5 Hz, 2H, 2 × CH), 6.77

(s, 2H, Ar); ¹³C NMR (CDCl₃, 150 MHz) δ 37.6 (2 × CHAr), 39.3

(2 × CH₂), 50.2 (2 × CH(CO₂Me)₂), 52.4 (2 × OCH₃), 52.5 (2 ×

OCH₃), 55.6 (2 × OCH₃), 56.0 (2 × OCH₃), 60.7 (2 × OCH₃), 107.9

(2 × CH, Ar), 124.6 (2 × C, Ar), 134.8 (2 × C, Ar), 140.3 (2 × C,

Ar), 150.7 (2 × C, Ar), 152.1 (2 × C, Ar), 169.6 (2 × CO₂Me), 170.1

(2 × CO₂Me). Anal. Calcd for C₃₂H₄₀O₁₄: C, 59.25; H, 6.22. Found:

C, 59.34; H, 6.35.

3

3H, CH₃O), 6.84 (d, J = 8.9 Hz, 2H, 2 × CH, Ar), 7.32 (d, J = 8.9

Hz, 2H, 2 × CH, Ar), 7.67 (s, 1H, CH); ¹³C NMR (CDCl₃, 150

MHz) δ 23.3 (CH₂), 26.0 (2 × CH₂), 47.7 (2 × NCH₂), 52.4

(OCH₃), 52.5 (OCH₃), 114.3 (2 × CH, Ar), 121.3 (C), 123.2 (C),

131.5 (2 × CH, Ar), 142.8 (CH), 152.7 (C), 165.1 (CO₂Me), 167.9

(CO₂Me); IR (Nujol, cm⁻¹) 2965, 2870, 1730, 1605, 1522, 1460,

1387, 1280, 1230, 1180, 1130, 928, 827, 770, 740; GC−MS m/z 304

(17), 303 (100) [M]⁺, 272 (28), 212 (15), 184 (15), 156 (10), 129

(17), 115 (10), 102 (12), 59 (52). Anal. Calcd for C₁₇H₂₁NO₄: C,

67.31; H, 6.98; N, 4.62. Found: C, 67.58; H, 6.96; N, 4.80.

Tetramethyl 2,2′-[(1,3,5,7-Tetramethoxy-9,10-dihydroan-

thracene-9,10-diyl)di(methylene)]dimalonate (9b). Sn(OTf)₂

(14 mg, 0.034 mmol) was added to a solution of 1p (100 mg, 0.340

mmol) in CH₃NO₂(3.4 mL) at room temperature. The resulting

mixture was heated up to 60 °C, stirred at this temperature for 4 h, and

worked up as described above to yield 9b (80 mg, 80%, dr 64:36).

(9RS,10SR)-9b (major isomer): colorless crystals; mp 124−125 °C; R_f

1

2

0.4 (diethyl ether); H NMR (CDCl₃, 600 MHz) δ 2.42 (ddd, J =

14.1 Hz, ³J = 5.1 Hz, ³J = 3.7 Hz, 2H, 2 × CH^aH), 2.67 (dd, ³J = 5.1

Dimethyl 2-[(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-

methylene]malonate (10b). Condensation of [1,4]benzodioxane-

6-carbaldehyde (2.0 g, 12.2 mmol) with dimethyl malonate (1.61 g,

12.2 mmol) in benzene (20 mL) in the presence of piperidine (0.12

mL, 1.22 mmol) and acetic acid (0.35 mL, 6.1 mmol) yielded 10b (3.2

g, 95%) as a white solid: mp 82−83 °C (from ethyl acetate/hexane

1:1); ¹H NMR (CDCl₃, 600 MHz) δ 3.73 (s, 3H, CH₃O), 3.78 (s, 3H,

CH₃O), 4.08−4.10 (m, 2H, CH₂O), 4.12−4.14 (m, 2H, CH₂O), 6.77

3

2

3

Hz, J = 8.0 Hz, 2H, 2 × CH), 2.98 (ddd, J = 14.1 Hz, J = 8.0 Hz,

³J = 3.9 Hz, 2H, 2 × CH^bH), 3.34 (s, 6H, 2 × OCH₃), 3.46 (s, 6H, 2 ×

OCH₃), 3.83 (s, 6H, 2 × OCH₃), 3.87 (s, 6H, 2 × OCH₃), 4.48 (dd,

³J = 3.7 Hz, ³J = 3.9 Hz, 2H, 2 × CH), 6.34 (d, J = 2.4 Hz, 2H, 2 ×

4

CH, Ar), 6.44 (d, J = 2.4 Hz, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃,

4

150 MHz) δ 35.7 (¹J_CH= 133 Hz, 2 × CHAr), 36.6 (¹J_CH= 132 Hz,

2 × CH₂), 47.5 (¹J_CH= 129 Hz, 2 × CH(CO₂Me)₂), 52.2 (4 × OCH₃),

55.3 (4 × OCH₃), 97.2 (2 × CH, Ar), 103.2 (2 × CH, Ar), 117.0 (2 ×

C, Ar), 138.4 (2 × C, Ar), 157.9 (2 × C, Ar), 159.2 (2 × C, Ar), 169.9

(2 × CO₂Me), 170.1 (2 × CO₂Me). Anal. Calcd for C₃₀H₃₆O₁₂: C,

61.22; H, 6.16. Found: C, 60.95; H, 5.97. (9RS,10RS)-9b (minor

3

4

(d, ³J = 8.4 Hz, 1H, CH, Ar), 6.86 (dd, J = 8.4 Hz, J = 2.2 Hz, 1H,

CH, Ar), 6.89 (d, ⁴J = 2.2 Hz, 1H, CH, Ar), 7.56 (s, 1H, CH); ¹³C

NMR (CDCl₃, 150 MHz) δ 52.5 (OCH₃), 52.6 (OCH₃), 64.1

(OCH₂), 64.6 (OCH₂), 117.7 (CH, Ar), 118.5 (CH, Ar), 123.4 (C),

123.8 (CH, Ar), 126.1 (C), 142.4 (CH), 143.6 (C), 146.1 (C),

164.7 (CO₂Me), 167.4 (CO₂Me); GC−MS m/z 278 (100) [M]⁺, 247

(28), 218 (58), 189 (14), 179 (49), 160 (38), 76 (16), 59 (27); IR

(Nujol, cm⁻¹) 2950, 2875, 1720, 1640, 1615, 1580, 1505, 1470, 1440,

1380, 1320, 1300, 1250, 1170, 1140, 1000, 980, 960, 940, 920, 895,

880, 845, 780, 730, 720. Anal. Calcd for C₁₄H₁₄O₆: C, 60.43; H, 5.07.

Found: C, 60.55; H, 5.18.

1

isomer): colorless oil; R_f0.66 (diethyl ether); H NMR (CDCl₃, 600

2

3

MHz) δ 2.24 (ddd, J = 13.9 Hz, J = 7.1 Hz, J = 8.2 Hz, 2H, 2 ×

2

3

CH^aH), 2.37 (ddd, J = 13.9 Hz, J = 7.1 Hz, J = 8.1 Hz, 2H, 2 ×

CH^bH), 3.66 (dd, ³J = 7.1 Hz, ³J = 8.1 Hz, 2H, 2 × CH), 3.72 (s, 6H,

2 × OCH₃), 3.78 (s, 12H, 4 × OCH₃), 3.85 (s, 6H, 2 × OCH₃), 4.26

(dd, ³J = 7.1 Hz, ³J = 8.2 Hz, 2H, 2 × CH), 6.35 (d, ⁴J = 2.3 Hz, 2H,

2 × CH, Ar), 6.57 (d, ⁴J = 2.3 Hz, 2H, 2 × CH, Ar); ¹³C NMR (CDCl₃,

150 MHz) δ 37.1 (¹J_CH= 131 Hz, 2 × CHAr), 38.8 (¹J_CH= 134 Hz,

2 × CH₂), 50.3 (¹J_CH= 133 Hz, 2 × CH(CO₂Me)₂), 52.4 (2 × OCH₃),

Dimethyl 2-(3,5-Dimethoxybenzylidene)malonate (10c). Con-

densation of 3,5-dimethoxybenzaldehyde (0.5 g, 3.0 mmol) with

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Article

dimethyl malonate (0.4 g, 3.0 mmol) in benzene (6 mL) in the

presence of piperidine (0.03 mL, 0.3 mmol) and acetic acid (0.09 mL,

1.5 mmol) yielded 10c (0.72 g, 85%) as white solid: mp 68−69 °C. ¹H

NMR (CDCl₃, 600 MHz) δ 3.80 (s, 6H, 2 × CH₃O), 3.87 (s, 6H, 2 ×

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4

CH₃O), 6.52 (t, J = 2.2 Hz, 1H, CH, Ar), 6.60 (d, J = 2.2 Hz, 2H,

2 × CH, Ar), 7.72 (s, 1H, CH); ¹³C NMR (CDCl₃, 150 MHz) δ

52.6 (2 × OCH₃), 55.4 (2 × OCH₃), 103.2 (CH, Ar), 107.2 (2 × CH,

Ar), 126.0 (C), 134.5 (C), 142.8 (CH), 161.0 (2 × C), 164.4

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218 (49), 190 (23), 181 (48), 162 (24), 59 (31); IR (Nujol, cm⁻¹

)

2940, 2875, 1725, 1600, 1475, 1380, 1250, 1210, 1170, 1085, 1060,

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Found: C, 60.27; H, 5.76.

ASSOCIATED CONTENT

■

S

* Supporting Information

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(28) Witt, O.; Mauser, H.; Friedl, T.; Wilhelm, D.; Clark, T. J. Org.

Chem. 1998, 63, 959−967.

NMR spectra of synthesized compounds, crystal X-ray

structures of trans-9a and trans-9c (CIF), and results of ab

initio calculations. This material is available free of charge via

the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

■

(31) Concellon, J. M.; Bernad, P. L.; del Solar, V.; Garcia-Granda, S.;

Diaz, M. R. Adv. Synth. Catal. 2008, 350, 477−481.

(32) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847−

2853.

Corresponding Author

*E-mail: melnikov@excite.chem.msu.ru.

ACKNOWLEDGMENTS

(33) Kobayashi, Y.; Kumadaki, I.; Ohsawa, A.; Sekine, Y.; Ando, A.

■

Heterocycles 1977, 6, 1587−1592.

We thank Prof. K. A. Lyssenko (INEOS RAS) and Dr. V. B.

Rybakov (Department of Chemistry, MSU) for X-ray analysis.

This work was financially supported by the Russian Foundation

of Basic Research (Project 09-03-00244-a).

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