Ring-closing metathesis reaction-based synthesis of new classes of polyether macrocyclic systems

Tetrahedron 71 (2015) 7758e7781

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Tetrahedron

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Ring-closing metathesis reaction-based synthesis of new classes of

polyether macrocyclic systems

*

Naveen, Srinivasarao Arulananda Babu

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali,

Manauli P.O., Punjab, 140306, India

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 1 April 2015

Received in revised form 5 June 2015

Accepted 17 June 2015

Available online 30 June 2015

Ring closing metathesis (RCM) reactions of suitable substrates having terminal oleﬁns, which are as-

sembled from various linkers and hydroxy benzaldehydes and syntheses of a wide range of 16e30

membered, new crown ether-type polyether, aza-polyether, bis aza-polyether macrocycles and dilactone

moiety embedded polyether macrocycles (macrolides) are reported. After the ring-closure reaction, in-

stallation of different functional groups and functional group modiﬁcation on the periphery of the

synthesized polyether/crown ether macrocycles obtained in the RCM reactions are accomplished using

the epoxidation, oxidation and catalytic hydrogenation-based synthetic transformations. Along this line,

Keywords:

Crown ether-type compounds

Epoxide and 1,2-diol

Grubbs’s catalyst

the syntheses of a variety of polyether macrocycles possessing epoxide or

a

-hydroxy ketone or 1,2-diol

-hydroxy ketone

functionalities at the periphery have been shown. Furthermore, the synthesized

a

functionality installed polyether macrocycles were subjected to the allylation and Reformatsky type

reactions to obtain homoallyl alcohol moiety-based and lactone ring-appended polyether macrocycles.

a

-Hydroxy ketone

Polyether macrocycles

Ring closing metathesis

1. Introduction

Since the Pederson’s discovery¹of ﬁrst crown ether molecule in

1967, crown ether/polyether molecules have been considered as

imperative classes of macrocyclic systems in supramolecular

chemistry.^2e4Besides their well-established ability to encapsulate

metal cations to form inclusion complexes, crown ether/polyether

macrocycles are famous for their uses in chemical industries. No-

tably, they exhibit several important applications/properties in

various research areas of biology and chemistry,^2e4such as, in

molecular recognition,^2gas sensors,^2hfor selective ion separation

and detection,^2i,jin phase transfer catalysis,^2kas synthetic building

blocks (e.g., ring-opening polymerization^2l), in electrochemical

processes^2mand as the model systems for mimicking some bi-

ological processes.²ⁿFurther, several polyether macrocycles are

known to be biologically active compounds⁴and particularly, some

of the polyether macrocycles are reported to exhibit the anticancer

and DNA interaction activities.⁴

Their importance in various areas of biology, chemistry and

material science has inspired the synthesis of widespread examples

of derivatized versions of archetypal (classical) crown ether sys-

tems (e.g., 18-crown-6 and dibenzo 18-crown-6 systems, Fig. 1) and

* Corresponding author. Tel.: þ91 172 2293165; fax: þ91 172 2240266; e-mail

Fig. 1. Examples of classical crown ether macrocycles and periphery modiﬁed poly-

ether macrocycles from this work.

address: sababu@iisermohali.ac.in (S.A. Babu).

http://dx.doi.org/10.1016/j.tet.2015.06.070

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7759

extensive research works have been carried out for the synthesis of

2. Results and discussion

varieties of crown ethers/polyether macrocycles involving various

synthetic methods.^2e11Noticeably, the functional group modiﬁca-

tion at the periphery and derivatization of crown ethers/polyethers

before or after the ring-closure reaction has received considerable

attention, there have been various impressive synthetic efforts in

this regard.⁵The synthesis of several periphery modiﬁed polyether

macrocyclic system and library of new symmetrical and less sym-

metrical crown ether/polyether macrocyclic systems were reported

by various research groups.^2e11

2.1. Synthesis of polyether macrocyclic systems

To begin with the synthesis of new crown ether-type/polyether

macrocycles via the ring closing metathesis (RCM) reaction, ini-

tially, we prepared the necessary starting materials having a gen-

eralized structure 4 starting from o-hydroxy benzaldehydes and

suitable linkers comprising aliphatic- or polyether chains

(Scheme 1). Various ortho-hydroxy benzaldehydes (1a) were

reacted with several linkers (1b) using the standard literature

methods, which furnished several bis-aldehydes connected via

various linkers having a generalized structure 2. The bis-aldehydes

2 were then subjected to the reduction of the aldehyde group with

NaBH₄followed by base-mediated O-allylation reaction, which

subsequently afforded several functionalized starting materials

containing terminal oleﬁns 4 (generalized structure) suitable for

ring closing metathesis reaction.

Ring closing metathesis reaction^7,8is one of the cornerstone

tools for the formation of carbonecarbon double bonds and cyclic

oleﬁns. Notably, numerous natural products and a variety of ﬁve-,

six- and seven-membered synthetic building blocks have been

constructed via the ring closing metathesis reaction. Further, this

methodology has been extensively used by many research groups

for synthesizing several medium- or large-sized macrocycles as

well as a variety of mechanically interlocked macrocyclic com-

Scheme 1. Synthesis of required starting materials.

pounds (e.g., catenanes and rotaxanes, etc.). Using the ring closing

metathesis (RCM) strategy, various research groups showed the

synthesis of crown ether and aza-crown ether types macrocycles

and amide functionality incorporated and lactone-based poly-

ether macrocycles.^8e12Along this line, we envisaged the synthesis

of a variety of new crown ether/polyether macrocyclic molecules

starting from simple starting materials, such as, hydroxy benzal-

dehydes and the post ring-closure functional derivatization and

periphery modiﬁcation of polyether macrocycles. In this regard,

recently, we revealed our preliminary works including the syn-

thesis of few examples of the periphery modiﬁed polyether

macrocyclic systems.^12aIn continuation of our interest on the

synthesis of new polyether macrocycles, herein, we present our

comprehensive synthetic work comprising, (a) the synthesis of

various 16e30 membered polyether macrocycles, macrocyclic

systems having nitrogen and sulfur heteroatoms in their linker

part, bis aza-polyether macrocycles and dilactone moiety em-

bedded polyether macrocycles (macrolides) via the ring closing

metathesis reaction, (b) the synthesis of periphery modiﬁed pol-

After assembling the required starting materials, we performed

the ring closing metathesis of the substrates 4 having terminal ole-

ﬁns. The ring closing metathesis reaction of the substrate 4a in the

presence of the Grubbs’s ﬁrst generation catalyst (2.5 mol %) fur-

nished the 16-membered macrocyclic oleﬁn 5a as a mixture of E/Z

diastereomers (dr¼5aA:5aB¼70:30) in 87% yield (entry 1, Table 1).

Then, the ring closing metathesis of substrates 4bed, which were

prepared using the aliphatic chain-based linkers resulted the mac-

rocyclic oleﬁns 5b (18-membered macrocycle), 5c (19-membered

macrocycle), and 5d (20-membered macrocycle) in 78, 71 and 73%

yields, respectively (E/Z ratio up to 86:14, entries 2e4, Table 1). Next,

the ring closing metathesis of the substrates 4eeh having various

substituents (e.g., Br, Cl and OMe) on the aromatic ring furnished the

corresponding functionalized macrocycles 5e (16-membered mac-

rocycle), 5f (16-membered macrocycle), 5g (16-membered macro-

cycle), and 5h (18-membered macrocycle) in 55e80% yields (E/Z ratio

up to 87:13, entries 5e8, Table 1). Afterwards, we carried out the ring

closing metathesis of the substrate 4i (derived using aromatic ring-

based linkers) successfully afforded the polyether macrocyclic ole-

ﬁn 5i (19-membered macrocycle, E/Z¼70:30, entry 9, Table 1).

Likewise, the ring closing metathesis of the substrate 4j (derived

using aromatic ring-based linker) successfully afforded the 20-

membered polyether macrocyclic oleﬁn 5jA (major, E-isomer) and

5jB (minor, Z-isomer), which were isolated in pure forms by column

chromatography puriﬁcation (E/Z ratio¼80:20, entry 10, Table 1).

yether macrocycles installed with the epoxide, a-hydroxy ketone,

1,2-diol functionalities and (c) the synthesis of lactone ring

appended and homoallyl alcohol moiety containing polyether

macrocycles from the

a-hydroxy ketone functionality installed

polyether macrocycles via the indium-mediated allylation and

Reformatsky type reactions.¹³

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The substrates 4k,l derived from o-hydroxy benzaldehyde and

the oxygen-based linkers were subjected to the ring closing me-

tathesis in the presence of the Grubbs’s ﬁrst generation catalyst,

which afforded the corresponding new polyether macrocycles 5k

(19-membered macrocycle) and 5l (22-membered macrocycle) in

75 and 80% yields (E/Z ratio up to 83:17, entries 11 and 12, Table 1).

The RCM reactions of the substrates 4m,n derived from 2-hydroxy-

1-naphthalaldehyde also gave the corresponding macrocyclic oleﬁn

systems 5m (19-membered macrocycle) and 5n (16-membered

macrocycle) in 87 and 85% yields (E/Z ratio up to 90:10, entries 13

and 14, Table 1). Next, the RCM reaction of the substrate 4o having

substituted terminal oleﬁns also gave the 19-membered macrocy-

clic oleﬁn system 5a (E/Z¼90:10). Subsequently, the substrates

4per having two terminal oleﬁns derived from m-hydroxy benz-

aldehyde also underwent the ring closing metathesis reaction in

the presence of the Grubbs’s catalyst and gave the corresponding

polyether macrocyclic oleﬁn systems 5p (18-membered macro-

cycle), 5q (20-membered macrocycle) and 5r (24-membered

macrocycle) in 38e55% yields (E/Z ratio up to 90:10, Scheme 2).

The ring closing metathesis reactions of the substrates 4s,t having

the trans alkene and alkyne units as rigid linkers successfully fur-

nished the corresponding macrocyclic oleﬁn systems 5s (18-

membered macrocycle) and 5t (18-membered macrocycle) in 88

and 55% yields (E/Z ratio up to 95:5, Scheme 2).

Subsequently, we planned to assemble the substrate 4u

(Scheme 3) having terminal oleﬁns and containing a nitrogen

heteroatom in the linker part. In this regard, treatment of 2,2⁰-

Table 1

RCM-based synthesis of polyether macrocycles 5aen^a

azanediyldiethanol (6) with benzyl chloride gave the 2,2⁰-(benzy-

lazanediyl)diethanol (8). Treatment of the substrate 8 with thionyl

chloride furnished N-benzyl-2-chloro-N-(2-chloroethyl)ethan-

amine (9). Then, the compound

9 was treated with 2-

hydroxybenzaldehyde (10a) in the presence of K₂CO₃to afford

the bis-aldehyde 2t having a nitrogen atom in the loop or linker.

Reduction of aldehyde group present in the substrate 2t with

NaBH₄gave the bis-alcohol substrate 3t. Then, O-allylation of bis-

alcohol 3t gave the substrate 4u having terminal oleﬁns and con-

taining a nitrogen heteroatom in the linker part. The ring closing

metathesis of the substrate 4u with Grubbs’s I generation catalyst

(5 mol %) gave the novel aza-polyether macrocycle 5u in 77% yield

(E/Z¼83:17, Scheme 3).

We also planned to elaborate the synthetic utility of the aza-

polyether macrocycle 5u by synthesizing the bis aza-polyether

macrocycle 12 via ring closing metathesis (RCM) followed by hy-

drogenation reaction starting from the substrate 4u (Scheme 4).

Accordingly, the substrate 4u was treated with Grubbs’s I genera-

tion catalyst for 6 h. After this period, the crude reaction mixture

was subjected for the catalytic hydrogenation, which gave the

debenzylated polyether macrocycle 11 (having a free secondary

amine group in the macrocyclic core). The reaction of two equiva-

lents of compound 11 with one equivalent of 1,4-bis(bromomethyl)

benzene in the presence of K₂CO₃at reﬂux temperature in MeCN

afforded the desired bis aza-polyether macrocycle 12 in 82% yield

(Scheme 4). Along this line, next we assembled the substrate 17

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7761

a

Based on the X-ray structures of 5jA (major, E-isomer), 5jB (minor, Z-

isomer) and 22a (major, E-isomer, Figure 2), the major isomers (5a, 5p-t) are

proposed to have the E-geometry in occurrence with the literature.^6g-l,10

Scheme 4. ^12cSynthesis of aza-polyether macrocycle 12 and thia polyether macrocycle

5v and dilactone macrocycle 5w.

Scheme 2. Synthesis of polyether macrocycles 5a and 5pet.

It is worth to mention that dilactone macrocyclides¹⁴were re-

ported to have ability to form metal encapsulated complexes with

metal cations and act as ion carriers, a literature survey revealed

that there are only limited numbers of methods available for syn-

thesizing macrocyclic dilactones. Consequently, with an intention

to expand the scope of this work, we planned to synthesize dilac-

tone macrocycles via the ring closing metathesis (RCM) using ap-

propriate starting materials. In this regard, we assembled different

types of bis allyl benzoate derivatives 21aec (Table 2) having ter-

minal oleﬁns from bis-carboxylic acids 20aec via DCC/DMAP cou-

pling reaction with allyl alcohol in anhydrous DCM as shown in

Table 2. Then, the ring closing metathesis reaction (RCM) of the

bis allyl benzoate derivatives 21aec in the presence of Grubbs’s

catalyst afforded the corresponding dilactone polyether macro-

cycles 22a (18-membered macrocycle), 22b (19-membered mac-

rocycle) and 22c (22-membered macrocycle) in 50e90% yields (E/Z

ratio up to 95:5, Table 2).

12c

Scheme 3.

Synthesis of aza-polyether macrocycle 5u.

Next, with the purpose of increasing the ring size of polyether/

crown ether macrocycles, we planned to construct various pre-

cursors 27aec (Table 3). In this regard, initially, we prepared bis

benzyl chlorides 23aec from the reaction of SOCl₂with the corre-

sponding bis benzyl alcohols 3 (entries 1 to 3, Table 3). Treatment of

bis benzyl chlorides 23aec with the potassium salt of salicylalde-

hyde 24 (formed by treating the salicylaldehyde with methanolic

KOH) afforded the corresponding bis aldehydes 25aec. Upon re-

duction of bis aldehydes 25aec with NaBH₄afforded the corre-

sponding bis benzyl alcohols 26aec. Then, treatment of the bis

benzyl alcohols 26aec with NaH and allyl bromide afforded the O-

allylated substrates 27aec having two terminal oleﬁns. The pre-

cursors 27aec are having extended chain lengths when compared

having two sulfur heteroatoms in the linker starting from salicy-

laldehyde and 2,2 (ethylenedioxy)diethanethiol by employing the

standard synthetic procedures as described in Scheme 4. The ring

closing metathesis reaction of the substrate 17 having two sulfur

heteroatoms in the linker in the presence of Grubbs’s II generation

catalyst (7 mol %) successfully afforded the 22-membered thia-

polyether macrocycle 5v in 68% yield (E/Z¼93:7, Scheme 4). Simi-

larly, the dilactoneebased macrocycle 5w was assembled starting

from 18a (Scheme 4).

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Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

Table 2

Synthesis of 18e22 membered dilactone crown ether/polyether (macrolides) macrocycles 22aec via RCM

to the starting materials described in Tables 1 and 2 and Schemes

1e4. After having the suitable precursors 27aec in hand, then, we

performed the ring closing metathesis reaction of the substrates

27aec in the presence of the Grubbs’s I generation catalyst, which

afforded the novel large sized crown ether/polyether macrocyclic

compounds 28a (26-membered macrocycle), 28b (28-membered

macrocycle) and 28c (30-membered macrocycle) in 52e62%

yields (E/Z ratio up to 90:10, Table 4). Similarly, we aimed to as-

semble the pyrrole ring-based precursor 29c having two terminal

oleﬁns (Scheme 5). Treatment of bis benzyl chloride 23a with

pyrrole-2-carboxyldehyde in the presence of NaH afforded the bis

aldehyde 29a. Upon reduction of bis aldehyde 29a with NaBH₄gave

the bis benzyl alcohol 29b. Treatment of the bis benzyl alcohol 29b

with NaH and allyl bromide afforded the O-allylated substrate 29c

having the two terminal oleﬁns connected to pyrrole moiety.

Subsequently, the ring closing metathesis (RCM) of the substrate

29c in the presence of the Grubbs’s I generation catalyst gave the

pyrrole ring-based macrocycle 29d in 67% yield ((E/Z ratio 75:25,

Scheme 5).

Next, we wished to perform the ring closing metathesis of the

homoallyl alcohol substrate 30a, and the RCM reaction of the

substrate 30a gave the macrocycle 30b^12dhaving two free OH

groups in <15 % yield as a mixture of isomers (Scheme 5). Disap-

pointed with this result, then, we protected the OH groups of

substrate 30a and the resulted substrate 31 was subjected to the

RCM reaction, which successfully gave the macrocyclic oleﬁn 32

having Z-geometry as the major isomer. Since this compound has

two chiral centers, the macrocycle 32^12ewas obtained as mixture of

diastereomers (R*,R*/R*,S*¼32A:32B¼1:1). Further, we aimed to

synthesize the periphery modiﬁed polyether macrocycles, such as,

the epoxide functionality installed polyether macrocyclic com-

pounds.¹⁵In this regard, the polyether macrocyclic oleﬁns 5a,b,k,l

(mixture of E/Z diastereomers) obtained from the RCM reaction of

the corresponding substrates (4a,b,k,l) were subjected to the

standard epoxidation reaction condition. Accordingly, we treated

the polyether macrocyclic compounds 5a,b,k,l with mCPBA, which

afforded the epoxide functionality installed polyether macrocyclic

systems 34aed, respectively (Table 5). This process gave an entry

into the new epoxide functionality installed polyether macrocyclic

systems starting from hydroxy benzaldehydes. As the macrocyclic

oleﬁn 5a was isolated as a mixture of diastereomers (entry 1, Table

1), the epoxidation of 5a gave the compound 34a as a mixture di-

astereomers (dr¼70:30). Similarly, the macrocycles 34bed were

also synthesized from the epoxidation reaction.

Next, we focused our attention in the post ring-closure func-

tional derivatization of polyether macrocycles. In this regard, the

macrocyclic oleﬁnic systems 5b,c obtained from the ring closing

metathesis of the substrates 4b,c were subjected to the Pd-

catalyzed hydrogenation reaction, which gave the polyether mac-

rocycles 33a (18-membered macrocycle) and 33b (19-membered

macrocycle) in 64 and 77% yields, respectively (Scheme 6). Like-

wise, the catalytic hydrogenation of the macrocyclic oleﬁn system

5k, furnished the polyether macrocycle 33c (19-membered mac-

rocycle) having an oxygen-based linker (Scheme 6). Notably, the

compounds 33aec appear to be stable under the catalytic hydro-

genation reaction and we did not get any compounds resulting

from the cleavage of the benzyloxy functional group present in the

macrocyclic systems 5b,c,k (Scheme 6).

2.2. Stereochemistry of polyether macrocyclic oleﬁns (Tables

1, 2 and 4 and Schemes 2e5).

Markedly, based on our trials we experienced that separating

the E/Z diastereomers obtained from the ring closing metathesis

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7763

Table 3

Assembling of starting materials 27aec having two terminal oleﬁns from bis-benzyl chlorides^a

reaction and epoxidation reaction was not easy. Notably, a survey of

literature also revealed that the puriﬁcation of polyether com-

pounds, especially, the macrocyclic oleﬁns, is reported to be

a challenging task.^6gel,10However, after a few attempts, we suc-

cessfully isolated the macrocyclic oleﬁns 5jA (major isomer), 5jB

(minor isomer) and 22a (major isomer) in pure forms by subjecting

the mixture of diastereomers to repetitive column chromatogra-

phy. The stereochemistry of the macrocyclic oleﬁns 5jA (E-isomer),

5jB (Z-isomer) and 22a (E-isomer), was unambiguously ascertained

based on the single-crystal X-ray structure analysis (Fig. 2). Along

this line, we also isolated the major isomer of the epoxide func-

tionality installed polyether macrocyclic system 34aA in pure form

and the major isomer 34aA was subjected to the X-ray structure

analysis. The X-ray structure of the epoxide functionality installed

polyether macrocyclic system 34aA (major isomer) is shown in

Fig. 2. The X-ray structure of the epoxide functionality appended

polyether macrocycle 34aA unequivocally revealed the major di-

astereomer to have a R,R (or S,S) conﬁguration at C4 and C5 ster-

eocenters and its corresponding macrocyclic oleﬁn 5a (major

compound 5a) should have the E-geometry. Furthermore, the ste-

reochemistry of the major isomer of the macrocyclic oleﬁn 22a (E-

isomer) also was unambiguously ascertained based on the single-

crystal X-ray structure analysis (Fig. 2).

(which were obtained as a mixture of E/Z diastereomers) was made

using the ¹H, ¹³C, H,HeCOSY, HMQC NMR techniques. The charac-

teristic ¹³C signal of the OCH₂group (of the eOCH₂CH]CHCH₂Oe

moiety) in the compounds (major isomers) 5a, 5e and 5f appeared

at

d 69.7, 70.0 and 69.6 parts per million (ppm), respectively. Fur-

thermore, the ¹H and ¹³C signal assignments of the distinctly iso-

lated diastereomers 5jA and 5jB were also made using the ¹H, ¹³C,

H,HeCOSY, HMQC NMR techniques. The characteristic ¹³C signal of

the OCH₂group (of the eOCH₂CH]CHCH₂Oe moiety) in the

compound 5jA (major compound having the E-geometry) and 5jB

(minor compound having the Z-geometry) appeared at

d 70.9 and

67.1, respectively. These values indicated that the major and minor

compounds to have the E- and Z-geometry, respectively (in all the

RCM reactions, Table 1 and Scheme 2). The characteristic ¹³C signal

of the OCH₂group (of the eOCH₂CH]CHCH₂Oe moiety) of the

compound 5jB (minor compound having the Z-geometry) appeared

at up ﬁeld when compared to the ¹³C signal of the OCH₂group (of

the eOCH₂CH]CHCH₂Oe moiety) of the compound 5jA (major

compound having the E-geometry). These observations are in re-

semblance with the assignments made by Ibrahim et al. and Rao

et al., based on the NMR spectral values of the OCH₂group

(eOCH₂CH]CHCH₂Oe moiety) present in crown formazans and

related compounds having the Z- or E-geometry. On the basis of

these deliberations and the X-ray structures of the macrocyclic

oleﬁns 5jA (major, E-isomer), 5jB (minor, Z-isomer) and the de-

rivative 34aA (major isomer) and 22a (major, E-isomer), it is pro-

posed that the corresponding major isomers of the compounds

In addition to the unambiguous establishment of the stereo-

chemistry of compounds 5jA/5jB based on the X-ray structure

analysis of these compounds, the proton and carbon signal as-

signment of some of the other compounds, such as, 5a, 5e and 5f

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Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

Table 4

Synthesis of 26e30 membered large sized polyether macrocycles 28aec, via the

RCM reaction^a

12c

Scheme 5.

Synthesis of macrocyclic systems 29d and 32.

hydroxy ketone functionality appended polyether macrocyclic

compounds 35f,g in 40 and 39% yields, respectively (Table 6). Along

this line, the one-pot RCM followed by the oxone^Ò-mediated oxi-

dation reactions of the starting materials containing terminal ole-

ﬁns 4k,l and 21a (which were assembled from the oxygen-based

5aew, 22aec, 28aec and 29d formed in the RCM reactions of the

corresponding substrates 4aeu, 17, 18e, 21aec, 27 and 29c could

have the E-geometry in concurrence with the literature

reports^6gel,10(Tables 1, 2 and 4 and Schemes 2e5). Additionally, the

stereochemistry of macrocycles 32A (Z-isomer, R*,R*) and 32B (Z-

isomer, R*,S*) and their Z-geometry was also clearly conﬁrmed from

the X-ray structure analysis (Fig. 3).

and aromatic ring-based linkers) afforded the corresponding

a-

hydroxy ketone functionality appended polyether macrocyclic

compounds 35hej in 25e27% yields, (Table 6). Further, we elabo-

rated the utility of the

a-hydroxy ketone functionality installed

polyether macrocycles 35c,i by treating these compounds with allyl

bromide in the presence of indium powder in anhydrous THF,

which resulted the corresponding polyether/crown ether macro-

cycles 36a (63%) and 36b (60%) as a mixture of diastereomers

(Table 7) having a C-pivotal allyl group as a free handle. Our at-

tempts to separate the corresponding diastereomers of 36a and 36b

were failed. We also carried out the indium-mediated Reformatsky

Consequently, we chose to synthesize the

a-hydroxy ketone

functionality installed polyether macrocyclic systems (Table 6) and

to the best of our knowledge, no other research group reported the

synthesis of the a-hydroxy ketone functionality installed polyether

macrocyclic systems. For this purpose, we employed a one-pot

reaction strategy comprising the RCM followed by oxidation of

the starting materials containing terminal oleﬁns 4 (generalized

structure). The starting materials 4aed and 4g (which were as-

sembled from the aliphatic chain-based linkers) were initially

treated in the presence of the Grubbs’s catalyst (ﬁrst generation) for

10e14 h and then, we carried out the oxone^Ò-mediated oxidation

reaction¹⁶of the resulting macrocyclic oleﬁns without isolation,

reaction of the a-hydroxy ketone functionality installed polyether

macrocycles 35d,i with ethyl bromoacetate in THF, which, afforded

the corresponding lactone moiety appended novel polyether/

crown ether macrocycles 37a (30%) and 37b (23%) (Table 7).

Furthermore, we wished to modify the periphery of the poly-

ether macrocyclic oleﬁns obtained in this work by installing the 1,2-

diol functionality via a one pot sequential RCM reaction followed by

syn dihydroxylation of the starting materials containing terminal

oleﬁns 4 (generalized structure, Table 8).¹⁶The corresponding

substrate 4 or 21 was ﬁrst treated with Grubbs’s catalyst for the

required time and then the crude reaction mixture was dissolved in

which gave the novel

a-hydroxy ketone functionality installed

polyether macrocyclic compounds 35aee in 25e45% yields, re-

spectively (Table 6). The one-pot RCM followed by the oxone^Ò-

mediated oxidation reactions of the compounds 4i,j (which were

assembled from the aromatic chain-based linkers) afforded the a-

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7765

Table 5

Then, the synthesis of 1,2-diol functionality installed polyether

macrocycles 38e (43%) in one-pot sequential RCM and syn dihy-

droxylation oxidation reactions was accomplished from the com-

pound 4j (entry 5, Table 8). Finally, we carried out the RCM/

oxidation sequential reactions with benzoate based substrates 21c

and 21a, which furnished the 1,2-diol functionality installed

dilactone polyether macrocycles 38f (45%) and 38g (41%), re-

spectively (entries 6 and 7, Table 8). All the macrocycles 38aeg

were isolated as a mixture of diastereomers and we experienced

that the separation of diastereomers of 38aeg was not easy and our

attempts to separate the diastereomers were failed. The utility of

the 1,2-diol functionality installed crown ether-type macrocycle

has been described by synthesizing the boronate ester-based pol-

yether macrocyclic system 39 (Scheme 7). The esteriﬁcation of

boronic acid with macrocycle 38e in the presence of catalytic

amount of FeCl₃at rt gave boronate ester-based polyether macro-

cyclic system 39 in 90% yield as a mixture of diastereomers (dr

85:15, Scheme 7).

Assembling of epoxide moiety installed polyether macrocycles 34aed

In summary we have described the synthesis of several 16e30

membered new crown ether-type polyether and aza-polyether

macrocycles via the ring closing metathesis (RCM) reactions of

suitable substrates having terminal oleﬁns, which were assembled

from various linkers and hydroxy benzaldehydes. We have shown

the modiﬁcation of the oleﬁnic unit present at the periphery of the

synthesized crown ether/polyether macrocyclic systems using the

epoxidation, oxidation and catalytic hydrogenation-based syn-

thetic transformations. Accordingly, the synthesis of a variety of

polyether macrocycles possessing epoxide or

1,2-diol functionalities at the periphery has been accomplished.

Finally, the synthesized -hydroxy ketone functionality installed

a-hydroxy ketone or

a

polyether macrocycles were subjected to the allylation and Refor-

matsky type reactions to obtain homoallyl alcohol moiety-based

and lactone-appended polyether macrocycles. Overall, given the

importance of the polyether macrocycles in various ﬁelds of biology

and chemistry, in this paper, we have shown the synthesis of var-

ious new functionally modiﬁed polyether macrocycles. In concur-

rence with literature reports, we also experienced the separation of

diastereomers of macrocycles obtained in this work were chal-

lenging and we are in the process of ﬁnding a separation method to

effectively separate the some of the compounds, which were ob-

tained as a mixture of diastereomers and to overcome some of the

challenging limitations that we experienced.

3. Experimental section

3.1. General

Melting points are uncorrected. IR spectra of compounds were

recorded as thin ﬁlms or KBr pellets. ¹H and ¹³C NMR spectra of

compounds were recorded on 400 MHz and 100 MHz spectrome-

ters, respectively, using TMS as an internal standard. Column

chromatography was carried out on silica gel (100e200 mesh) or

neutral Al₂O₃. Reactions were carried out in anhydrous solvents

under a nitrogen atmosphere wherever required. Solutions were

dried using anhydrous Na₂SO4. Reagents/solvents were added to

the reaction ﬂask with the help of a syringe. Thin layer chroma-

tography (TLC analysis) was performed on silica plates or neutral

Al₂O₃plates and components were visualized by observation under

iodine. Isolated yields of all the products were reported (yields

were not optimized). The ring closing metathesis products were

isolated as a mixture of E/Z diastereomers and ¹H/¹³C data given

here for the major isomer present in the mixture (selectively picked

up) and in some cases, the ¹H/¹³C data given for both the di-

astereomers (see the Supplementary Data for ¹H/¹³C spectra of

compounds). Ratios of diastereomers were determined from the ¹H

NMR spectra of crude reaction mixtures or after isolation in some

Scheme 6. Catalytic hydrogenation of 5b,c,k and assembling of crown ether/polyether

macrocyclic systems 33aec.

EtOAc. Then, this EtOAc solution was added slowly to a suspension

of preformed Ce(IV)-periodate complex, which afforded the cor-

responding 1,2-diol functionality installed polyether macrocyclic

system 38 as mixture of diastereomers (because both E and Z iso-

mers are forming during the RCM reaction). Accordingly, the pol-

yether macrocycles 38a and 38b having aliphatic linkers were

synthesized from the precursors 4a and 4d in 23 and 30% yields,

respectively (entries 1 and 2, Table 8). The substrates 4k and 4l

(prepared using oxygen-based linkers) successfully afforded the

1,2-diol functionality installed crown ether-type macrocycles 38c

and 38d in 32 and 25% yields, respectively (entries 3 and 4, Table 8).

7766

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

19

Fig. 2.

X-ray (capped sticks model) structures of 5jA (major, E-isomer), 5jB (minor, Z-isomer), 22a (major, E-isomer), and 34A (major isomer).

cases. Compounds 2aed,^12b2i,k,l,m,o,r,s,^12b2j,^17a2n,^17b2p,^17c

2q,^17d3aed,^12b3i,k,l,m,o,r,s,^12b3p,q,^18a19a,b,^18b,c20a,b,^18b,c

19c,^12b20c,^12b23a,b,^18d30a,^12bare reported in the literature. The

compound 39^18ewas prepared using the procedure reported in the

literature.

3.2. General procedure for synthesis of bis-aldehydes 2

To a round-bottom ﬂask was added the corresponding phenol

derivative (12 mmol) in anhydrous DMF (20 mL) followed by an-

hydrous K₂CO₃(20 mmol, 2.78 g) and the RB ﬂask was dipped in to

19

Fig. 3.

X-ray (capped sticks model) structures of 32A (Z-isomer, R*,R*), 32B (Z-isomer, R*,S*), 35a and 35g.

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7767

Table 6

Table 7

Synthesis of the

a

-hydroxy ketone functionality installed polyether macrocycles

Indium-mediated allylation and Reformatky-type reaction of

a

-hydroxy ketone

35aej via one-pot RCM and oxone-mediated oxidation sequential reactions

functionality installed polyether macrocycles 35c,d and 35i

the crude reaction mixture was used after puriﬁcation by column

chromatography on silica gel (EtOAc/Hexanes) in the next step).

3.2.1. 6,6⁰-(Ethane-1,2-diylbis(oxy))bis(3-bromobenzaldehyde)

(2e). Following the general procedure, 2e was obtained as a brown

solid (3.83 g, 75%); mp 176e178 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2921, 2879, 1677, 1589, 1474 and 1175 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃þDMSO-d₆): d_H10.20 (2H, s), 7.77 (2H, s),

7.56e7.52 (2H, m), 6.88 (2H, dd, J₁¼8.4, J₂¼1.4 Hz), 4.39 (4H, s); ¹³

C

NMR (100 MHz, CDCl₃þDMSO-d₆): d_C187.7, 159.5, 138.3, 131.0,

126.2, 114.8, 114.1, 67.1; HRMS (ESI): MNa^þ, found 448.8981.

C₁₆H₁₂Br₂NaO₄requires 448.9000.

3.2.2. 2,2⁰-(Ethane-1,2-diylbis(oxy))bis(3,5-dichlorobenzaldehyde)

(2f). Following the general procedure, 2f was obtained as a brown

solid (4.13 g, 85%); mp 162e164 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.55; IR

a preheated oil bath (80 ^ꢀC) and stirred at 80 ^ꢀC for15 min. After

15 min, the temperature of the oil bath was raised to 110 ^ꢀC. Then,

to the hot reaction mixture, alkyl dibromide or alkyl dichloride

(5 mmol) was added in one portion. The resulting reaction mixture

was stirred at 110 ^ꢀC for 12 h and after this period the RB ﬂask was

allowed to cool to rt. Next the reaction mixture was poured on to

crushed ice (50e75 g). Then, the solid compound (bis-aldehyde)

that formed is ﬁltered through a ﬁltration funnel and used without

further puriﬁcation (in case, if bis-aldehyde is liquid; then, the

mixture (after adding water) was extracted by using ethyl acetate

(3ꢁ10 mL) and the combined organic layers were concentrated and

(CH₂Cl₂): n_max2965, 1688, 1585, 1482 and 778 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H10.41 (2H, s), 7.74 (2H, d, J¼2.6 Hz), 7.65 (2H,

d, J¼2.6 Hz), 4.51 (4H, s); ¹³C NMR (100 MHz, CDCl₃): d_C187.8, 155.9,

135.8, 131.4, 131.0, 129.7, 127.3, 74.1; HRMS (ESI): MNa^þ, found

428.9215. C₁₆H₁₀Cl₄NaO₄requires 428.9231.

3.2.3. 2,2⁰-(Ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde)

(2g). Following the general procedure, 2g was obtained as a brown

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Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

solid (2.97 g, 75%); mp 118e120 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2966, 2839, 1687, 1586, 1482 and 778 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H10.53 (2H, s), 7.44 (2H, t, J¼4.7 Hz), 7.17 (4H, d,

J¼4.5 Hz), 4.51 (4H, s), 3.89 (6H, s); ¹³C NMR (100 MHz, CDCl₃): d_C

190.5, 152.8, 151.1, 130.0, 124.3, 119.2, 117.9, 73.1, 56.0; HRMS (ESI):

MNa^þ, found 353.0990. C₁₈H₁₈NaO₆requires 353.1001.

Table 8

Synthesis of 16e22 membered, 1,2-diol functionality installed polyether macro-

cycles 38aeg in one-pot RCM and syn dihydroxylation oxidation reactions

3.2.4. 2,2⁰-(Butane-1,4-diylbis(oxy))bis(3-methoxybenzaldehyde)

(2h). Following the general procedure, 2h was obtained as a brown

solid (3.52 g, 82%); mp 115e117 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2974, 2853, 1686, 1668, 1484 and 767 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H10.47 (2H, s), 7.44e7.42 (2H, m), 7.16e7.14

(4H, m), 4.22 (4H, s), 3.90 (6H, s), 2.05 (4H, br s); ¹³C NMR (100 MHz,

CDCl₃): d_C190.3, 153.0, 151.8, 130.0, 124.1, 119.1, 118.0, 74.5, 56.0,

26.7; HRMS (ESI): MNa^þ, found 381.1304. C₂₀H₂₂NaO₆requires

381.1314.

3.2.5. 2,2⁰-(((Benzylazanediyl)bis(ethane-2,1-diyl))bis(oxy))di-

benzaldehyde (2t). Following the general procedure, 2t was ob-

tained as a colourless liquid (3.63 g, 75%); R_f(20% EtOAc/Hexanes)

0.45; IR (CH₂Cl₂): n_max2942, 2863, 1685, 1598 and 757 cm^{ꢂ1 1}H

;

NMR (400 MHz, CDCl₃): d_H10.47 (2H, s), 7.83 (2H, dd, J₁¼5.9,

J₂¼1.8 Hz), 7.52 (2H, t, J¼7.3 Hz), 7.38e7.27 (5H, m), 7.03 (2H, t,

J¼7.5 Hz), 6.92 (2H, d, J¼8.3 Hz), 4.18 (4H, t, J¼5.7 Hz), 3.87 (2H, s),

3.15 (4H, t, J¼5.7 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C189.7, 161.0,

139.1, 136.0, 128.6, 128.5, 128.5, 127.3, 124.9, 120.8, 112.4, 67.3, 60.1,

53.5; HRMS (ESI): MH^þ, found 404.1866. C₂₅H₂₆NO₄requires

404.1862.

3.3. General procedure for the synthesis of bis-alcohols 3aes,

26aec and 29b

To a mixture of the corresponding bis-aldehyde (3 mmol) in

ethanol (7 mL) was added NaBH₄(10 mmol) at room temperature.

The resulting reaction mixture was stirred at room temperature for

30 min. After this period, the reaction mixture was poured on to

cold water (20 mL) or crushed ice. Then, the solid compound (bis-

alcohol) is ﬁltered through a ﬁltration funnel and used without

further puriﬁcation. In case, if the corresponding bis-alcohol

product is liquid; the mixture (after adding water) was extracted

by using ethyl acetate (3ꢁ10 mL) and the combined organic layers

were concentrated and crude reaction mixture was used as such in

the next step without further puriﬁcation.

3.3.1. ((Ethane-1,2-diylbis(oxy))bis(4-bromo-2,1-phenylene))dime-

thanol (3e). Following the general procedure, 3e was obtained as

a brown solid (955 mg, 74%); mp 155e157 ^ꢀC; R_f(30% EtOAc/Hex-

anes) 0.52; IR (thin ﬁlm): n_max3301, 2922, 2852,1484 and 750 cm^ꢂ1

;

¹H NMR (400 MHz, DMSO-d₆): d_H7.43 (2H, s), 7.34 (2H, d, J¼7.9 Hz),

6.94 (2H, d, J¼8.6 Hz), 4.43 (4H, s), 4.26 (4H, s); ¹³C NMR (100 MHz,

DMSO-d₆): d_C154.6,133.6, 130.5, 129.6,114.2,112.8, 67.3, 57.8; HRMS

(ESI): MNa^þ, found 452.9300. C₁₆H₁₆Br₂NaO₄requires 452.9313.

Two OH protons were not appeared in the ¹H NMR.

3.3.2. ((Ethane-1,2-diylbis(oxy))bis(3,5-dichloro-2,1-phenylene))di-

methanol (3f). Following the general procedure, 3f was obtained as

a brown solid (903 mg, 70%); mp 139e141 ^ꢀC; R_f(30% EtOAc/Hex-

anes) 0.52; IR (thin ﬁlm): n_max3409, 2234, 1636, 1442 and

731 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃þDMSO-d₆): d_H7.38 (2H, br s),

7.30 (2H, br s), 4.73 (4H, s), 4.58 (2H, br s), 4.35 (4H, s); ¹³C NMR

(100 MHz, CDCl₃þDMSO-d₆): d_C150.9, 138.4, 129.7, 128.7, 128.0,

127.6, 72.5, 59.4; HRMS (ESI): MNa^þ, found 432.9522.

C₁₆H₁₄Cl₄NaO₄requires 432.9544.

3.3.3. ((Ethane-1,2-diylbis(oxy))bis(3-methoxy-2,1-phenylene))di-

methanol (3g). Following the general procedure, 3g was obtained

Scheme 7. Synthesis of boronate ester-based polyether macrocyclic system 39.

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7769

as a brown colour solid (841 mg, 85%); mp 58e60 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.52; IR (CH₂Cl₂): n_max3401, 2936, 1586, 1480 and

(CH₂Cl₂): n_max3401, 2927, 1589, 1288 and 751 cm^ꢂ1

;

¹H NMR

(400 MHz, CDCl₃): d_H7.42e7.25 (8H, m), 7.02e6.91 (8H, m), 5.15

(4H, br s), 4.69 (4H, br s), 4.16 (4H, t, J¼5.1 Hz), 3.80 (4H, t, J¼4.9 Hz),

3.59 (4H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C156.8, 156.6, 129.8,

129.5, 129.3, 128.8, 128.8, 125.3, 121.0, 120.8, 111.8, 111.8, 70.8, 69.6,

68.0, 65.9, 62.2; HRMS (ESI): MH^þ, found 575.2634. C₃₄H₃₉O₈re-

quires 575.2645. Two OH protons were not appeared in the ¹H

NMR.

749 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.06e7.03 (2H, m),

;

6.93e6.88 (4H, m), 4.68 (4H, s), 4.41 (4H, s), 3.85 (6H, s); ¹³C NMR

(100 MHz, CDCl₃): d_C152.4, 145.8, 134.8, 124.4, 121.8, 112.3, 72.6,

61.4, 55.8; m/z (CI) 334 (40, M^þ).

3.3.4. ((Butane-1,4-diylbis(oxy))bis(3-methoxy-2,1-phenylene))di-

methanol (3h). Following the general procedure, 3h was obtained

as a brown solid (773 mg, 72%); mp 110e112 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.52; IR (CH₂Cl₂): n_max3335, 2869, 1471, 1455 and

3.3.10. (1,1⁰-(((Butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(-

methylene))bis(1H-pyrrole-2,1-diyl))dimethanol

(29b). Following

778 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.06 (2H, t, J¼7.9 Hz),

the general procedure, 29b was obtained as a colourless solid

6.96e6.88 (4H, m), 4.72 (4H, d, J¼5.9 Hz), 4.14 (4H, t, J¼5.8 Hz), 3.86

(6H, s), 2.61 (2H, t, J¼6.1 Hz), 2.03e2.01 (4H, m); ¹³C NMR

(100 MHz, CDCl₃): d_C152.5, 146.1, 134.7, 124.1, 120.8, 112.2, 73.0,

61.5, 55.8, 27.0; m/z (CI) 362 (25, M^þ).

(1.18 g, 83%); mp 113e115 ^ꢀC; R_f(30% EtOAc/Hexanes) 0.42; IR

(CH₂Cl₂): n_max3388, 2924, 1601, 1493 and 718 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.28e7.24 (2H, m), 6.91e6.86 (4H, m),

6.68e6.65 (4H, m), 6.17e6.11 (4H, m), 5.21 (4H, s), 4.52 (4H, s), 4.11

(4H, s), 2.03 (4H, br s), 1.85 (2H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C

155.8, 131.9, 128.7, 127.7, 126.8, 123.2, 120.8, 110.9, 109.1, 107.1, 67.5,

56.7, 45.7, 26.1; HRMS (ESI): MNa^þ, found 483.2256. C₂₈H₃₂N₂NaO₄

requires 483.2260.

3.3.5. (((1,4-Phenylenebis(methylene))bis(oxy))bis(2,1-phenylene))

dimethanol (3j). Following the general procedure, 3j was obtained

as a colourless solid (865 mg, 82%); mp 134e136 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.52; IR (thin ﬁlm): n_max3332, 2922, 1602, 1453 and

750 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃þDMSO-d₆): d_H7.40e7.17 (8H,

m), 6.94e6.86 (4H, m), 5.07 (4H, br s), 4.68 (4H, br s), 3.16 (2H, br s);

¹³C NMR (100 MHz, CDCl₃þDMSO-d₆): d_C156.1, 136.7, 129.8, 128.5,

128.4, 127.5, 120.9, 111.5, 69.6, 61.1; HRMS (ESI): MNa^þ, found

373.1404. C₂₂H₂₂NaO₄requires 373.1416.

3.4. General procedure for the synthesis of compounds 4aeu,

27aec and 29c

To a mixture of the corresponding diol compound (1 mmol) in

dry THF (3 mL) was added NaH (4 mmol, 55e60% suspension in

mineral oil) at room temperature. The mixture was stirred at room

temperature for 10 min and then, allyl bromide (5 mmol) was

added. The resulting mixture was stirred for 20 h at room tem-

perature. After this period, few drops of EtOH was added and stir-

red for 10 min and then, the resulting mixture was poured on to

water (20 mL) and was extracted by using ethyl acetate (3ꢁ10 mL).

The combined organic layers were dried over anhydrous Na₂SO₄

and the organic phase was concentrated and the resulting crude

reaction mixture was puriﬁed by silica gel column chromatography

by using EtOAc/Hexanes to afford the corresponding O-allylated

product.

3.3.6. ((Ethane-1,2-diylbis(oxy))bis(naphthalene-2,1-diyl))dimetha-

nol (3n). Following the general procedure, 3n was obtained as

a brown solid (863 mg, 77%); mp 182e184 ^ꢀC; R_f(30% EtOAc/Hex-

anes) 0.52; IR (thin ﬁlm): n_max3325, 2923, 2354, 1592, 1446 and

749 cm^ꢂ1; ¹H NMR (400 MHz, DMSO-d₆): d_H8.09 (2H, d, J¼8.6 Hz),

7.88 (2H, d, J¼9.1 Hz), 7.84 (2H, d, J¼8.1 Hz), 7.50 (2H, t, J¼7.9 Hz),

7.45 (2H, d, J¼9.1 Hz), 7.36 (2H, t, J¼7.5 Hz), 4.95 (4H, s), 4.47 (4H, s),

2.51 (2H, s); ¹³C NMR (100 MHz, DMSO-d₆): d_C154.1, 133.4, 130.1,

129.4, 128.6, 127.0, 124.4, 124.2, 122.9, 116.2, 69.2, 53.7; HRMS (ESI):

MNa^þ, found 397.1408. C₂₄H₂₂NaO₄requires 397.1416.

3.3.7. (((((Butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(-

m e t hyl e n e ) ) b i s ( o x y ) ) b i s ( 2 ,1 - p h e nyl e n e ) ) d i m e t h a n o l

(26a). Following the general procedure, 26a was obtained as

a brown colour solid (1.38 g, 90%); mp 111e113 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.42; IR (CH₂Cl₂): n_max3395, 2924, 1603, 1589, 1454 and

3.4.1. 1,2-Bis(2-((allyloxy)methyl)phenoxy)ethane (4a). Following

the general procedure, 4a was obtained after as a colourless liquid

(300 mg, 85%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2862,

1586, 1489, 1447 and 784 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.42

(2H, d, J¼7.0 Hz), 7.25 (2H, t, J¼7.9 Hz), 6.98 (2H, t, J¼7.3 Hz), 6.92

(2H, d, J¼8.2 Hz), 5.98e5.88 (2H, m), 5.31e5.12 (4H, m), 4.55 (4H, s),

4.34 (4H, s), 4.05e4.02 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C

156.1, 135.0, 128.9, 128.5, 127.4, 121.0, 116.8, 115.5, 71.5, 66.9, 66.9;

HRMS (ESI): MNa^þ, found 377.1723. C₂₂H₂₆NaO₄requires 377.1729.

751 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.42e7.26 (8H, m),

;

7.01e6.89 (8H, m), 5.13 (4H, br s), 4.69 (4H, br s), 4.07 (4H, br s), 2.77

(2H, br s), 1.95 (4H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C156.9,156.6,

129.6, 129.5, 129.2, 128.9, 128.8, 124.9, 120.8, 120.7, 111.7, 111.4, 67.7,

65.9, 62.5, 25.9; HRMS (ESI): MNa^þ, found 537.2247. C₃₂H₃₄NaO₆

requires 537.2253.

3.4.2. 1,4-Bis(2-((allyloxy)methyl)phenoxy)butane (4b). Following

the general procedure, 4b was obtained as a colourless liquid

(309 mg, 81%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2927,

1603, 1590, 1470 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.40

(2H, d, J¼6.8 Hz), 7.23 (2H, t, J¼8 Hz), 6.94 (2H, t, J¼7.3 Hz), 6.84 (2H,

d, J¼8.2 Hz), 6.00e5.93 (2H, m), 5.32 (2H, dd, J₁¼16.6, J₂¼1.7 Hz),

5.18 (2H, dd, J₁¼9.8, J₂¼1.5 Hz), 4.57 (4H, s), 4.07e4.03 (8H, m),

2.01e1.98 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C156.4,135.1,128.9,

128.6, 126.9, 120.5, 116.8, 111.1, 71.5, 67.5, 67.0, 26.2; HRMS (ESI):

MNa^þ, found 405.2029. C₂₄H₃₀NaO₄requires 405.2042.

3.3.8. (((((Hexanes-1,6-diylbis(oxy))bis(2,1-phenylene))bis(-

m e t hyl e n e ) ) b i s ( o x y ) ) b i s ( 2 ,1 - p h e nyl e n e ) ) d i m e t h a n o l

(26b). Following the general procedure, 26b was obtained as

a brown colour solid (1.47 g, 91%); mp 74e76 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.42; IR (CH₂Cl₂): n_max3401, 2927, 1603, 1589, 1454 and

750 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.45e7.27 (8H, m),

;

7.03e6.93 (8H, m), 5.17 (4H, br s), 4.73 (4H, br s), 4.03 (4H, br s),

2.96 (2H, br s), 1.80 (4H, br s), 1.50 (4H, br s); ¹³C NMR (100 MHz,

CDCl₃): d_C156.9, 156.8, 129.7, 129.5, 129.2, 128.9, 128.8, 125.1, 120.8,

120.6, 111.7, 111.5, 68.1, 65.9, 62.4, 29.1, 25.8; HRMS (ESI): MH^þ,

found 543.2736. C₃₄H₃₉O₆requires 543.2747.

3.4.3. 1,5-Bis(2-((allyloxy)methyl)phenoxy)pentane (4c). Following

the general procedure, 4c was obtained as a colourless liquid

(340 mg, 86%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2924,

1688, 1601, 1452 and 752 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.39

(2H, d, J¼8 Hz), 7.23 (2H, t, J¼5.9 Hz), 6.94 (2H, t, J¼7.5 Hz), 6.84 (2H,

d, J¼8.1 Hz), 6.00e5.93 (2H, m), 5.31 (2H, dd, J₁¼17.1, J₂¼1.7 Hz), 5.17

(2H, dd, J₁¼10.2, J₂¼1.6 Hz), 4.57 (4H, s), 4.06 (4H, td, J₁¼5.6,

3.3.9. (((((((Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy))

bis(2,1-phenylene)) bis(methylene))bis(oxy))bis(2,1-phenylene))di-

methanol (26c). Following the general procedure, 26c was obtained

as a colourless liquid (1.47 g, 74%); R_f(30% EtOAc/Hexanes) 0.42; IR

7770

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

J₂¼1.5 Hz), 4.00 (4H, t, J¼6.3 Hz), 1.89e1.84 (4H, m), 1.71e1.64 (2H,

m); ¹³C NMR (100 MHz, CDCl₃): d_C156.5, 135.1, 128.9, 128.5, 127.0,

120.4, 116.8, 111.1, 71.5, 67.8, 67.0, 29.1, 22.9; HRMS (ESI): MNa^þ,

found 419.2194. C₂₅H₃₂NaO₄requires 419.2198.

(400 MHz, CDCl₃): d_H7.44e7.35 (6H, m), 7.19 (2H, t, J¼7.4 Hz), 6.94

(2H, t, J¼7.3 Hz), 6.86 (2H, d, J¼1.7 Hz), 5.95e5.89 (2H, m), 5.27 (2H,

d, J¼17.1 Hz), 5.12 (2H, d, J¼10.2 Hz), 5.04 (4H, s), 4.60 (4H, s), 4.03

(4H, d, J¼5.2 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.2, 137.7, 135.1,

129.1, 128.9, 128.7, 127.3, 126.8, 126.0, 121.0, 116.8, 111.7, 71.6, 69.9,

67.2; m/z (CI): 430 (20, M^þ), 431 (35, MH^þ).

3.4.4. 1,6-Bis(2-((allyloxy)methyl)phenoxy)Hexanes (4d). Following

the general procedure, 4d was obtained as a colourless liquid

(348 mg, 85%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2938,

1603, 1455, 1242 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.39

(2H, d, J¼7.4 Hz), 7.22 (2H, t, J¼7.4 Hz), 6.93 (2H, t, J¼7.4 Hz), 6.83

(2H, d, J¼8.2 Hz), 5.99e5.93 (2H, m), 5.33 (2H, dd, J₁¼17.2,

J₂¼1.7 Hz), 5.17 (2H, dd, J₁¼10.2, J₂¼1.6 Hz), 4.56 (4H, s), 4.06 (4H, td,

J₁¼5.4, J₂¼1.4 Hz), 3.97 (4H, t, J¼6.4 Hz), 1.82 (4H, t, J¼6.4 Hz),

1.56e1.52 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C156.6,135.1,128.9,

128.5, 127.0, 120.4, 116.8, 111.1, 71.5, 67.8, 67.0, 29.3, 26.0; HRMS

(ESI): MNa^þ, found 433.2353. C₂₆H₃₄NaO₄requires 433.2355.

3.4.10. 1,4-Bis((2-((allyloxy)methyl)phenoxy)methyl)benzene

(4j). Following the general procedure, 4j was obtained as a col-

ourless liquid (344 mg, 80%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max3046, 2856, 1590, 1492, 1376 and 751 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H7.43 (6H, s), 7.22 (2H, t, J¼7.2 Hz), 6.96 (2H, t,

J¼7.4 Hz), 6.90 (2H, d, J¼8.2 Hz), 6.00e5.90 (2H, m), 5.30 (2H, dd,

J₁¼17.3, J₂¼1.4 Hz), 5.16 (2H, dd, J₁¼10.7, J₂¼1.3 Hz), 5.07 (4H, s), 4.62

(4H, s), 4.07 (4H, d, J¼5.5 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.2,

136.9, 135.0, 129.1, 128.7, 127.4, 127.3, 120.9, 116.9, 111.7, 71.6, 69.7,

67.2; HRMS (ESI): MNa^þ, found 453.2032. C₂₈H₃₀NaO₄requires

453.2042.

3.4.5. 1,2-Bis(2-((allyloxy)methyl)-4-bromophenoxy)ethane

(4e). Following the general procedure, 4e was obtained as a brown

solid (372 mg, 73%); mp 100e102 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55;

3.4.11. 2,2⁰-((Oxybis(ethane-2,1-diyl))bis(oxy))bis(((allyloxy)methyl)

benzene) (4k). Following the general procedure, 4k was obtained

as a colourless liquid (326 mg, 82%); R_f(10% EtOAc/Hexanes) 0.55;

IR (CH₂Cl₂): n_max2911, 2949, 2361, 1485 and 743 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.47 (2H, d, J¼2.5 Hz), 7.27 (2H, dd, J₁¼7.5,

J₂¼2.5 Hz), 6.69 (2H, d, J¼8.7 Hz), 5.90e5.80 (2H, m), 5.22 (2H, dd,

J₁¼17.2, J₂¼1.7 Hz), 5.10 (2H, dd, J₁¼10.3, J₂¼1.5 Hz), 4.39 (4H, s),

4.23 (4H, s), 3.96 (4H, td, J₁¼5.6, J₂¼1.4 Hz), ¹³C NMR (100 MHz,

CDCl₃): d_C154.9, 134.6, 131.3, 130.9, 129.7, 117.2, 113.6, 113.1, 71.7,

67.1, 66.2; HRMS (ESI): MNa^þ, found 532.9930. C₂₂H₂₄Br₂NaO₄re-

quires 532.9939.

IR (CH₂Cl₂): n_max2925, 2858, 1603, 1454 and 753 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.38 (2H, d, J¼6.7 Hz), 7.21 (2H, t, J¼8.5 Hz),

6.94 (2H, t, J¼7.4 Hz), 6.84 (2H, d, J¼8.2 Hz), 5.98e5.89 (2H, m), 5.28

(2H, dd, J₁¼17.2, J₂¼1.5 Hz), 5.15 (2H, d, J¼10.5 Hz), 4.56 (4H, s), 4.14

(4H, t, J¼4.9 Hz), 4.03 (4H, d, J¼5.5 Hz), 3.91 (4H, t, J¼4.8 Hz);¹³

C

NMR (100 MHz, CDCl₃): d_C156.3, 135.0, 128.9, 128.6, 127.2, 120.9,

116.8, 111.5, 71.5, 70.0, 67.9, 67.0; HRMS (ESI): MNa^þ, found

421.2004. C₂₄H₃₀NaO₅requires 421.1991.

3.4.6. 1,2-Bis(2-((allyloxy)methyl)-4,6-dichlorophenoxy)ethane

(4f). Following the general procedure, 4f was obtained as a col-

ourless liquid (367 mg, 75%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2927, 2855, 1636, 1446, 1250 and 775 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H7.35 (2H, d, J¼2.6 Hz), 7.32 (2H, d, J¼2.6 Hz),

5.95e5.88 (2H, m), 5.27 (2H, dd, J₁¼17.1, J₂¼1.7 Hz), 5.17 (2H, dd,

J₁¼10.4, J₂¼1.5 Hz), 4.59 (4H, s), 4.29 (4H, s), 4.04 (4H, td, J₁¼5.6,

J₂¼1.4 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C151.4, 135.3, 134.2, 129.8,

129.3, 128.4, 127.9, 117.5, 72.7, 71.8, 66.6; m/z (CI) 492 (100, M^þ).

3.4.12. 1,2-Bis(2-(2-((allyloxy)methyl)phenoxy)ethoxy)ethane

(4l). Following the general procedure, 4l was obtained as a col-

ourless liquid (371 mg, 84%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2924, 1688, 1601, 1452 and 752 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.36 (2H, d, J¼6 Hz), 7.19 (2H, t, J¼7.8 Hz), 6.92

(2H, t, J¼7.4 Hz), 6.81 (2H, d, J¼8.2 Hz), 5.98e5.88 (2H, m), 5.28 (2H,

dd, J₁¼17.4, J₂¼1.7 Hz), 5.15 (2H, dd, J₁¼10.4, J₂¼1.5 Hz), 4.54 (4H, s),

4.10 (4H, t, J¼5.0 Hz), 4.03 (4H, td, J₁¼5.5, J₂¼1.4 Hz), 3.83 (4H, t,

J¼5.0 Hz), 3.71 (4H, s); ¹³C NMR (100 MHz, CDCl₃): d_C156.3, 135.1,

128.9, 128.5, 127.1, 120.8, 116.8, 111.5, 71.5, 71.0, 69.9, 67.8, 67.0;

HRMS (ESI): MNa^þ, found 465.2250. C₂₆H₃₄NaO₆requires

465.2253.

3.4.7. 1,2-Bis(2-((allyloxy)methyl)-6-methoxyphenoxy)ethane

(4g). Following the general procedure, 4g was as a colourless liquid

(351 mg, 85%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2934,

1587, 1479, 1356 and 750 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H

;

7.06e7.03 (4H, m), 6.87e6.84 (2H, m), 5.97e5.89 (2H, m), 5.28 (2H,

dd, J₁¼17.1, J₂¼1.7 Hz), 5.14 (2H, dd, J₁¼10.4, J₂¼1.7 Hz), 4.67 (4H, s),

4.30 (4H, s), 4.02 (4H, td, J₁¼5.6, J₂¼1.4 Hz), 3.83 (6H, s); ¹³C NMR

(100 MHz, CDCl₃): d_C152.4, 145.9, 134.9, 132.6, 123.9, 120.9, 116.8,

111.7, 72.4, 71.4, 67.1, 55.8; HRMS (ESI): MNa^þ, found 437.1938.

3.4.13. 2,2⁰-((Oxybis(ethane-2,1-diyl))bis(oxy))bis(1-((allyloxy)

methyl)naphthalene) (4m). Following the general procedure, 4m

was obtained as a colourless liquid (383 mg, 77%); R_f(10% EtOAc/

Hexanes) 0.55; IR (CH₂Cl₂): n_max2930, 2854, 1585, 1468 and

692 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H8.11 (2H, d, J¼8.6 Hz), 7.76

(4H, t, J¼6.4 Hz), 7.50 (2H, t, J¼7.0 Hz), 7.35 (2H, t, J¼6.9 Hz), 7.25

(2H, d, J¼9.1 Hz), 6.01e5.91 (2H, m), 5.28 (2H, dd, J₁¼17.2,

J₂¼1.7 Hz), 5.14 (2H, dd, J₁¼10.2, J₂¼1.7 Hz), 5.04 (4H, s), 4.30 (4H, t,

C

₂₄H₃₀NaO₆requires 437.1940.

3.4.8. 1,4-Bis(2-((allyloxy)methyl)-6-methoxyphenoxy)butane

(4h). Following the general procedure, 4h was obtained as a col-

ourless liquid (344 mg, 78%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2853, 2838, 1475, 1455, 1274 and 747 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H7.01e6.99 (4H, m), 6.83e6.81 (2H, m),

5.97e5.90 (2H, m), 5.29 (2H, dd, J₁¼17.2, J₂¼1.7 Hz), 5.15 (2H, dd,

J₁¼10.5, J₂¼1.7 Hz), 4.57 (4H, s), 4.03 (8H, td, J₁¼5.7, J₂¼1.3 Hz), 3.79

(6H, s), 1.98e1.95 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C152.7,

146.3, 134.9, 132.4, 123.9, 121.2, 116.9, 111.8, 73.1, 71.4, 67.1, 55.7,

27.0; HRMS (ESI): MNa^þ, found 465.2243. C₂₆H₃₄NaO₆requires

465.2253.

J¼4.8 Hz), 4.07 (4H, td, J₁¼5.7, J₂¼1.4 Hz), 3.97 (4H, t, J¼4.8 Hz); ¹³

C

NMR (100 MHz, CDCl₃): d_C154.8, 135.2, 133.8, 130.3, 129.5, 128.2,

126.8, 124.1, 123.9, 119.7, 117.0, 115.1, 71.2, 70.3, 69.7, 62.3; HRMS

(ESI): MNa^þ, found 521.2301. C₃₂H₃₄NaO₅requires 521.2304.

3.4.14. 1,2-Bis((1-((allyloxy)methyl)naphthalen-2-yl)oxy)ethane

(4n). Following the general procedure, 4n was obtained as a brown

semi-solid (340 mg, 75%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂):

n_max2922, 1594, 1463, 1449 and 806 cm^{ꢂ1 1}H NMR (400 MHz,

;

CDCl₃): d_H8.13 (2H, d, J¼8.6 Hz), 7.84e7.80 (4H, m), 7.52 (2H, t,

J¼8.0 Hz), 7.37 (2H, t, J¼7.8 Hz), 7.30 (2H, d, J¼9.0 Hz), 5.96e5.90

(2H, m), 5.25 (2H, d, J¼17.2 Hz), 5.11 (2H, d, J¼10.4 Hz), 5.03 (4H, s),

4.49 (4H, s), 4.04 (4H, d, J¼5.6 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C

154.7, 135.1, 133.9, 130.4, 129.6, 128.2, 126.9, 124.1, 124.0, 119.9, 117.1,

3.4.9. 1,3-Bis((2-((allyloxy)methyl)phenoxy)methyl)benzene

(4i). Following the general procedure, 4i was obtained as a col-

ourless liquid (339 mg, 79%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2855, 1602, 1493, 1286 and 752 cm^{ꢂ1 1}H NMR

;

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7771

115.0, 71.2, 69.0, 62.3; HRMS (ESI): MNa^þ, found 477.2031.

₃₀H₃₀NaO₄requires 477.2042.

5.39e5.34 (2H, m), 5.25e5.22 (2H, m), 4.77 (4H, s), 4.60 (4H, s), 4.10

(4H, d, J¼5.6 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C155.0, 135.0, 129.0,

128.5, 127.5, 121.4, 116.9, 112.0, 82.4, 71.5, 66.8, 56.3; HRMS (ESI):

MNa^þ, found 401.1717. C₂₄H₂₆NaO₄requires 401.1729.

C

3.4.15. 1,2-Bis(2-(but-2-en-1-yloxy)methyl)phenoxy)ethane

(4o). Following the general procedure, 4o was obtained as a col-

ourless liquid (324 mg, 85%); R_f(10% EtOAc/Hexanes) 0.55; IR

3.4.21. 2-(2-((Allyloxy)methyl)phenoxy)-N-(2-(2-((allyloxy)methyl)

phenoxy)ethyl)-N-benzylethanamine (4u). Following the general

procedure, 4u was obtained as a colourless liquid (389 mg, 80%); R_f

(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2924, 2855, 1603, 1490

and 752 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.42 (4H, t, J¼6.8 Hz),

7.34 (2H, t, J¼7.1 Hz), 7.30e7.22 (3H, m), 6.98 (2H, t, J¼6.7 Hz), 6.83

(2H, d, J¼7.8 Hz), 6.00e5.92 (2H, m), 5.31 (2H, dd, J₁¼17.2,

J₂¼1.7 Hz), 5.19 (2H, dd, J₁¼10.4, J₂¼1.7 Hz), 4.58 (4H, s), 4.11 (4H, t,

J¼5.8 Hz), 4.05 (4H, td, J₁¼5.5, J₂¼1.4 Hz), 3.89 (2H, s), 3.10 (4H, t,

J¼5.8 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.2, 139.6, 135.0, 128.7,

128.7, 128.5, 128.3, 127.1, 126.9, 120.5, 116.8, 110.9, 71.5, 67.0, 66.8,

60.0, 53.4; HRMS (ESI): MH^þ, found 488.2812. C₃₁H₃₈NO₄requires

488.2801.

(CH₂Cl₂): n_max2930, 2854, 1601, 1488 and 692 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.46 (2H, d, J¼7.5 Hz), 7.31e7.27 (2H, m), 7.02

(2H, t, J¼7.4 Hz), 6.95 (2H, d, J¼7.5 Hz), 5.80e5.62 (4H, m), 4.57 (4H,

s), 4.38 (4H, s), 4.01 (4H, d, J¼6.1 Hz), 1.73 (6H, dd, J₁¼6.1, J₂¼1.1 Hz);

¹³C NMR (100 MHz, CDCl₃): d_C156.2,156.1, 129.3,129.0,128.5,128.5,

127.8, 127.7, 127.6, 127.67, 127.2, 121.0, 111.5, 71.3, 66.9, 66.9, 66.7,

65.9, 17.8, 13.2; HRMS (ESI): MNa^þ, found 405.2048. C₂₄H₃₀NaO₄

requires 405.2042. This compound was isolated as a mixture of E

and Z isomers and ¹H and ¹³C values corresponding to both isomers.

3.4.16. 1,2-Bis(3-((allyloxy)methyl)phenoxy)ethane (4p). Following

the general procedure, 4p was obtained as a colourless liquid

(297 mg, 84%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2855,

2360,1599,1488,1261 and 784 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.26 (2H, t, J¼7.8 Hz), 6.96e6.86 (6H, m), 6.00e5.90 (2H, m), 5.31

(2H, d, J¼15.8 Hz), 5.20 (2H, d, J¼9.4 Hz), 4.50 (4H, s), 4.32 (4H, s),

4.02 (4H, d, J¼5.6 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C158.8, 140.0,

134.7, 129.5, 120.3, 117.2, 114.0, 113.8, 71.9, 71.2, 66.5; m/z (CI): 354

(10, M^þ), 355 (15, MH^þ).

3.4.22. 1,4-Bis(2-((2-((allyloxy)methyl)phenoxy)methyl)phenoxy)bu-

tane (27a). Following the general procedure, 27a was obtained as

a colourless liquid (504 mg, 85%); R_f(10% EtOAc/Hexanes) 0.45; IR

(CH₂Cl₂): n_max3067, 2937, 1590, 1604 and 1751 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.58e7.52 (4H, m), 7.37e7.28 (4H, m),

7.08e6.95 (8H, m), 6.11e6.02 (2H, m), 5.44e5.39 (2H, m),

5.29e5.25 (2H, m), 5.23 (4H, br s), 4.75 (4H, br s), 4.18e4.15 (8H, m),

2.08e2.06 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C156.4, 156.0,

135.1,128.8,128.8,128.6,128.3,127.3,125.8,120.7,120.6,116.9,111.8,

111.0, 71.6, 67.5, 67.2, 65.2, 26.2; HRMS (ESI): MNa^þ, found 617.2888.

3.4.17. 1,4-Bis(3-((allyloxy)methyl)phenoxy)butane (4q). Following

the general procedure, 4q was obtained as a colourless liquid

(309 mg, 81%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2927,

2855,1601, 1585, 1386 and 783 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.23 (2H, t, J¼7.9 Hz), 6.91e6.80 (6H, m), 5.99e5.90 (2H, m), 5.30

(2H, d, J¼17.2 Hz), 5.20 (2H, d, J¼10.4 Hz), 4.48 (4H, s), 4.02 (4H, br

s), 4.01 (4H, br s), 1.96 (4H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C

159.1, 139.9, 134.8, 129.4, 119.9, 117.2, 113.8, 113.6, 72.0, 71.2, 67.4,

26.0; HRMS (ESI): MNa^þ, found 405.2033. C₂₄H₃₀NaO₄requires

405.2042.

C₃₈H₄₂NaO₆requires 617.2879.

3.4.23. 1,6-Bis(2-((2-((allyloxy)methyl)phenoxy)methyl)phenoxy)

Hexanes (27b). Following the general procedure, 27b was obtained

as a colourless liquid (510 mg, 82%); R_f(10% EtOAc/Hexanes) 0.45; IR

(CH₂Cl₂): n_max3067, 2859, 1604, 1454 and 751 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.54e7.48 (4H, m), 7.34e725 (4H, m),

7.04e6.92 (8H, m), 6.05e6.01 (2H, m), 5.41e5.36 (2H, m),

5.26e5.21 (2H, m), 5.21 (4H, br s), 4.73 (4H, br s), 4.16e4.14 (4H, m),

4.06 (4H, t, J¼12.5 Hz), 1.87 (4H, br s), 1.59 (4H, br s); ¹³C NMR

(100 MHz, CDCl₃): d_C156.4, 156.1, 135.1, 128.8, 128.7, 128.5, 128.1,

127.2, 125.8, 120.6, 120.5, 116.8, 111.7, 111.0, 71.5, 67.9, 67.2, 65.1,

29.3, 26.0; HRMS (ESI): MNa^þ, found 645.3185. C₄₀H₄₆NaO₆re-

quires 645.3192.

3.4.18. 1,8-Bis(3-((allyloxy)methyl)phenoxy)octane (4r). Following

the general procedure, 4r was obtained as a colourless liquid

(350 mg, 80%); R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2854,

1601, 1488, 1468, 1265 and 692 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.21 (2H, t, J¼8.1 Hz), 6.89e6.78 (6H, m), 5.98e5.88 (2H, m), 5.28

(2H, dd, J₁¼17.2, J₂¼1.7 Hz), 5.18 (2H, dd, J₁¼10.4, J₂¼1.6 Hz), 4.47

(4H, s), 4.01 (4H, td, J₁¼5.6, J₂¼1.4 Hz), 3.93 (4H, t, J¼6.5 Hz),

1.79e1.72 (4H, m),1.46e1.35 (8H, m); ¹³C NMR (100 MHz, CDCl₃): d_C

159.3, 139.9, 134.8, 129.4, 119.8, 117.2, 113.8, 113.6, 72.0, 71.1, 67.9,

29.4, 29.3, 26.0; HRMS (ESI): MNa^þ, found 461.2653. C₂₈H₃₈NaO₄

requires 461.2668.

3.4.24. 1,2-Bis(2-(2-((2-((allyloxy)methyl)phenoxy)methyl)phenoxy)

ethoxy)ethane (27c). Following the general procedure, 27c was

obtained as a colourless liquid (549 mg, 84%); R_f(20% EtOAc/Hex-

anes) 0.45; IR (CH₂Cl₂): n_max2924, 2856, 1604, 1452 and 753 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.49e7.43 (4H, m), 7.28e7.23 (4H, m),

7.02e6.95 (6H, m), 6.90 (2H, d, J¼8.1 Hz), 6.03e5.95 (2H, m),

5.37e5.31 (2H, m), 5.22e5.18 (6H, m), 4.67 (4H, br s), 4.18 (4H, t,

J¼4.7 Hz), 4.12e4.09 (4H, m), 3.86 (4H, t, J¼4.8 Hz), 3.70 (4H, br s);

¹³C NMR (100 MHz, CDCl₃): d_C156.3,155.8,135.0,128.8,128.7,128.5,

128.2, 127.2, 126.0, 120.9, 120.6, 116.8, 111.7, 111.4, 71.5, 71.0, 69.8,

67.8, 67.1, 65.0; HRMS (ESI): MNa^þ, found 677.3100. C₄₀H₄₆NaO₈

requires 677.3090.

3.4.19. (E)-1,4-Bis(2-((allyloxy)methyl)phenoxy)but-2-ene

(4s). Following the general procedure, 4s was obtained as a col-

ourless liquid (396 mg, 78%); R_f(10% EtOAc/Hexanes) 0.55; IR

(CH₂Cl₂): n_max2924, 2869, 1688, 1601, 1452 and 752 cm^ꢂ1; ¹H NMR

(400 MHz, CDCl₃): d_H7.45 (2H, d, J¼8.8 Hz), 7.29e7.25 (2H, m), 7.00

(2H, t, J¼9.3 Hz), 6.88 (2H, d, J¼9.3 Hz), 6.10 (2H, t, J¼2.7 Hz),

6.05e5.98 (2H, m), 5.39e5.21 (4H, m), 4.64 (8H, br s), 4.13e4.11

(4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C156.0, 135.0, 129.0, 128.5,

128.0, 127.1, 120.8, 116.9, 111.6, 71.5, 67.8, 67.0; HRMS (ESI): MNa^þ,

found 403.1873. C₂₄H₂₈NaO₄requires 403.1885.

3.4.25. 1,4-Bis(2-((2-((allyloxy)methyl)-1H-pyrrol-1-yl)methyl)phe-

noxy)butane (29c). Following the general procedure, 29c was ob-

tained as a colourless solid (437 mg, 81%); mp 60e62 ^ꢀC; R_f(20%

EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max2924, 2853, 1602, 1493,

3.4.20. 1,4-Bis(2-((allyloxy)methyl)phenoxy)but-2-yne

(4t). Following the general procedure, 4t was obtained as a col-

ourless liquid (313 mg, 83%); R_f(10% EtOAc/Hexanes) 0.55; IR

1259 and 750 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.24 (2H, t,

;

J¼7.4 Hz), 6.90e6.85 (4H, m), 6.72e6.63 (4H, m), 6.21e6.12 (4H, m),

5.90e5.80 (2H, m), 5.27e5.13 (8H, m), 4.43 (4H, s), 4.11 (4H, br s),

3.94 (4H, td, J₁¼5.6, J₂¼1.5 Hz), 2.03 (4H, br s); ¹³C NMR (100 MHz,

CDCl₃): d_C155.8, 134.8, 128.8, 128.4, 127.7, 127.0, 123.3, 120.6, 117.0,

(CH₂Cl₂): n_max2859, 1602, 1492, 1260 and 752 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.45 (2H, d, J¼7.4 Hz), 7.25 (2H, t, J¼7.9 Hz),

7.03 (2H, t, J¼7.4 Hz), 6.95 (2H, d, J¼8.1 Hz), 6.04e5.96 (2H, m),

7772

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

110.7, 110.5, 106.9, 69.9, 67.3, 63.5, 45.7, 26.1; HRMS (ESI): MNa^þ,

found 563.2880. C₃₄H₄₀N₂NaO₄requires 563.2886.

3.6.1. Diallyl 2,2⁰-((1,2-phenylenebis(methylene))bis(oxy))dibenzoate

(21a). Following the general procedure, 21a was obtained as

a colourless liquid (171 mg, 75%); R_f(20% EtOAc/Hexanes) 0.45; IR

(CH₂Cl₂): n_max3079, 2942, 1723, 1449 and 753 cm^{ꢂ1 1}H NMR

;

3.5. General procedure for the synthesis of compounds 25aec

(400 MHz, CDCl₃):

d

7.86 (2H, dd, J₁¼6.9, J₂¼1.8 Hz), 7.66e7.64 (2H,

m), 7.48e7.37 (4H, m), 7.10 (2H, d, J¼8.4 Hz), 7.01 (2H, t, J¼7.8 Hz),

6.02e5.92 (2H, m), 5.37e5.32 (6H, m), 5.23e5.19 (2H, m), 4.78 (4H,

td, J₁¼5.7, J₂¼1.4 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C165.9, 158.1,

134.6, 133.6, 132.2, 131.9, 128.6, 128.2, 120.5, 120.3, 118.3, 113.5, 68.8,

65.5; HRMS (ESI): MNa^þ, found 481.1632. C₂₈H₂₆NaO₆requires

481.1627.

The potassium salt of salicylaldehyde (30 mmol) was dissolved

in dry DMF (30 mL) and then, to this DMF solution, an appropriate

alkyl halide 23 was added. Then, the reaction mixture was heated at

110 ^ꢀC for 12 h. After this period, the reaction mixture was cooled to

room temperature, and the reaction mixture was poured on to

crushed ice. Then, the solid compound was ﬁltered through a ﬁl-

tration funnel and used without further puriﬁcation. In case, if the

bis-aldehyde is liquid; the mixture was extracted with ethyl acetate

(3ꢁ10 mL) and used in the next step after puriﬁcation by column

chromatography on silica gel (EtOAc/Hexanes).

3.6.2. Diallyl 2,2⁰-((1,3-phenylenebis(methylene))bis(oxy))dibenzoate

(21b). Following the general procedure, 21b was obtained as

a colourless liquid (160 mg, 70%); R_f(20% EtOAc/Hexanes) 0.45; IR

(CH₂Cl₂): n_max3087, 2934, 1715, 1599 and 751 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.88 (2H, dd, J₁¼7.1, J₂¼1.9 Hz), 7.57 (1H, s),

7.51e7.43 (5H, m), 7.04e7.00 (4H, m), 6.05e5.98 (2H, m), 5.42e5.22

(8H, m), 4.83 (4H, td, J₁¼5.1, J₂¼1.4 Hz); ¹³C NMR (100 MHz, CDCl₃):

d_C166.0, 158.1, 137.0, 133.5, 132.3, 131.9, 128.9, 126.5, 125.4, 120.7,

120.7, 118.1, 113.8, 70.5, 65.6; HRMS (ESI): MNa^þ, found 481.1625.

3.5.1. 2,2⁰-((((Butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(-

methylene))bis(oxy)) dibenzaldehyde (25a). Following the general

procedure, 25a was obtained as a brown solid (2.16 g, 85%); mp

154e156 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.42; IR (CH₂Cl₂): n_max2864,

1686,1598,1482, 1379 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

10.54 (2H, s), 7.83 (2H, d, J¼7.6 Hz), 7.49 (2H, t, J¼8.3 Hz), 7.43 (2H,

d, J¼7.1 Hz), 7.29 (2H, t, J¼7.6 Hz), 7.06e6.95 (6H, m), 6.88 (2H, d,

J¼8.2 Hz), 5.19 (4H, s), 4.06 (4H, s), 1.94 (4H, s);¹³C NMR (100 MHz,

CDCl₃): d_C190.0, 161.4, 156.2, 135.9, 129.4, 128.8, 128.3, 125.2, 124.4,

120.9, 120.7, 113.3, 111.1, 67.4, 66.1, 26.0; HRMS (ESI): MNa^þ, found

533.1934. C₃₂H₃₀NaO₆requires 533.1940.

C₂₈H₂₆NaO₆requires 481.1627.

3.6.3. Diallyl 2,2⁰-(((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bi-

s(oxy))dibenzoate (21c). Following the general procedure, 21c was

obtained as a colourless liquid (169 mg, 74%); R_f(20% EtOAc/Hex-

anes) 0.45; IR (CH₂Cl₂): n_max2925, 1727, 1601, 1491, 1260 and

751 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.83 (2H, dd, J₁¼7.3,

J₂¼1.8 Hz), 7.47e7.43 (2H, m), 7.01e6.98 (4H, m), 6.05e5.98 (2H,

m), 5.45e5.25 (4H, m), 4.80 (4H, td, J₁¼5.2, J₂¼1.4 Hz), 4.21 (4H, t,

J¼5.2 Hz), 3.91 (4H, t, J¼5.1 Hz), 3.78 (4H, s); ¹³C NMR (100 MHz,

CDCl₃): d_C166.0, 158.4, 133.5, 132.4, 131.7, 120.5, 120.5, 118.0, 113.6,

71.1, 69.6, 68.8, 65.4; HRMS (ESI): MNa^þ, found 493.1842.

3.5.2. 2,2⁰-((((Hexanes-1,6-diylbis(oxy))bis(2,1-phenylene))bis(-

methylene))bis(oxy)) dibenzaldehyde (25b). Following the general

procedure, 25b was obtained as brown solid (2.02 g, 75%); mp

117e119 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.42; IR (CH₂Cl₂): n_max2921,

2864, 1686, 1598, 1482 and 753 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃):

C₂₆H₃₀NaO₈requires 493.1838.

d_H10.55 (2H, s), 7.83 (2H, d, J¼7.6 Hz), 7.50 (2H, t, J¼7.1 Hz), 7.42

(2H, d, J¼7.1 Hz), 7.30 (2H, t, J¼7.9 Hz), 7.07 (2H, d, J¼8.3 Hz),

7.02e6.59 (4H, m), 6.89 (2H, d, J¼8.1 Hz), 5.21 (4H, s), 3.99 (4H, t,

J¼6.3 Hz), 1.77e1.74 (4H, m), 1.49e1.47 (4H, m);¹³C NMR (100 MHz,

CDCl₃): d_C190.0, 161.5, 156.4, 135.9, 129.4, 128.7, 128.3, 125.2, 124.5,

120.8, 120.5, 113.3, 111.2, 67.8, 66.1, 29.1, 25.9; HRMS (ESI): MNa^þ,

found 561.2249. C₃₄H₃₄NaO₆requires 561.2253.

3.7. General procedure for the ring closing metathesis (RCM)

reaction and synthesis of macrocycles 5aew, 22aec, 28aec,

29d and 32

A solution of the corresponding substrate having two terminal

oleﬁns (0.25 mmol) in anhydrous CH₂Cl₂(7 mL) and Grubbs’s cat-

alyst (ﬁrst or second generation, 2.5e5 mol %) was reﬂuxed for the

time indicated in the Tables/Schemes. Then, the mixture was con-

centrated in vacuum. The resulting residue was puriﬁed by silica gel

column chromatography (Hexanes/EtOAc) to afford the corre-

sponding macrocyclic compound as a mixture of E/Z isomers (ring

closing metathesis product, see the corresponding Tables/Schemes

for speciﬁc entries).

3.5.3. 2,2⁰-((((((Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bi-

s(oxy))bis(2,1-phenylene))bis(methylene))bis(oxy))dibenzaldehyde

(25c). Following the general procedure, 25c was obtained as

a brown solid (2.22 g, 78%); mp 58e60 ^ꢀC; R_f(20% EtOAc/Hexanes)

0.42; IR (CH₂Cl₂): n_max2932, 1688, 1598, 1456 and 752 cm^{ꢂ1 1}H

;

NMR (400 MHz, CDCl₃): d_H10.55 (2H, s), 7.84 (2H, dd, J₁¼6.2,

J₂¼1.8 Hz), 7.53e7.49 (2H, m), 7.43 (2H, d, J¼7.6 Hz), 7.32e7.28 (2H,

m), 7.10 (2H, d, J¼8.2 Hz), 7.03e6.98 (4H, m), 6.90 (2H, d, J¼8.2 Hz),

5.24 (4H, s), 4.17 (4H, t, J¼4.6 Hz), 3.83 (4H, t, J¼4.9 Hz), 3.65 (4H, s);

¹³C NMR (100 MHz, CDCl₃): d_C190.0, 161.4, 156.1, 135.9, 129.4, 128.7,

128.2, 125.2, 124.7, 121.0, 120.8, 113.4, 111.6, 70.9, 69.7, 67.8, 65.9;

HRMS (ESI): MNa^þ, found 593.2158. C₃₄H₃₄NaO₈requires 593.2151.

3.7.1. Compound 5a. Following the general procedure, 5a was ob-

tained as

a

colourless solid (70 mg, 87%) (E/Z¼70:30); mp

95e97 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2929,

2851, 1602, 1492 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.47

(2H, d, J¼8.0 Hz), 7.24 (2H, t, J¼7.8 Hz), 7.01 (2H, t, J¼7.8 Hz), 6.89

(2H, d, J¼8.0 Hz), 5.83e5.81 (2H, m), 4.14e4.12 (4H, m), 4.63 (4H, s),

4.28 (4H, s); ¹³C NMR (100 MHz, CDCl₃): d_C155.8,131.8, 128.6,128.3,

127.7, 121.4, 111.8, 69.7, 66.8, 64.0; HRMS (ESI): MNa^þ, found

349.1400. C₂₀H₂₂NaO₄requires 349.1415.

3.6. General procedure for the synthesis of compounds 21aec

To a solution of allyl alcohol (1.5 mmol), dicarboxylic acid 20

(0.5 mmol) and 4-(dimethylamino)pyridine (DMAP, 0.80 mmol) in

CH₂Cl₂(2.5 mL) was added 1,3-dicyclohexylcarbodiimide

(1.5 mmol) in small fractions. The reaction mixture was stirred at

room temperature for 2 h. The resulting pale yellow suspension was

ﬁltered through ﬁltration funnel. The ﬁltrate was concentrated and

puriﬁed by silica gel column chromatography (20% EtOAc/Hexanes)

to give the desired product.

3.7.2. Compound 5b. Following the general procedure, 5b was

obtained as a colourless liquid (69 mg, 78%); (E/Z¼86:14); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2939, 2365, 1687, 1492 and

754 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.36 (2H, d, J¼8.1 Hz), 7.23

(2H, t, J¼7.6 Hz), 6.92 (2H, t, J¼7.6 Hz), 6.83 (2H, d, J¼8.1 Hz),

5.92e5.90 (2H, m), 4.55 (4H, s), 4.24e4.12 (4H, m), 4.02 (4H, br s),

2.01e1.97 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C156.9, 130.2,

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7773

129.8, 128.9, 126.9, 120.4, 111.2, 70.4, 67.5, 66.5, 26.4; HRMS (ESI):

MNa^þ, found 377.1730. C₂₂H₂₆NaO₄requires 377.1723.

2854, 1598, 1493, 1238 and 756 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃):

d_H7.76 (1H, s), 7.74e7.26 (7H, m), 7.03e6.97 (4H, m) 5.87e5.84 (2H,

m), 5.12 (4H, s), 4.64 (4H, s), 4.17e4.16 (4H, m); ¹³C NMR (100 MHz,

CDCl₃): d_C156.0, 137.7, 130.5, 128.6, 128.5, 128.2, 127.4, 127.1, 126.4,

120.9, 111.5, 70.3, 69.7, 66.0; HRMS (ESI): MNa^þ, found 425.1738.

3.7.3. Compound 5c. Following the general procedure, 5c was ob-

tained as a colourless liquid (65 mg, 71%); (E/Z¼80:20); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2926, 1602, 1494, 1242 and

753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.39 (2H, d, J¼8.1 Hz), 7.21

(2H, t, J¼7.3 Hz), 6.92 (2H, t, J¼7.3 Hz), 6.81 (2H, d, J¼8.1 Hz), 5.88

(2H, br s), 4.54 (4H, s), 4.16 (4H, br s), 3.98 (4H, t, J¼4.5 Hz), 1.83 (4H,

br s), 1.74 (2H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C156.5, 130.4,

128.6, 128.5, 127.2, 120.4, 110.9, 70.7, 68.0, 66.1, 29.6, 24.4; HRMS

(ESI): MNa^þ, found 391.1886. C₂₃H₂₈NaO₄requires 391.1879.

C₂₆H₂₆NaO₄requires 425.1728.

3.7.10. Compound 5j. Following the general procedure, 5j (major

isomer, E) was obtained as a colourless solid (67 mg, 67% com-

bined yield of 5j/5j⁰) (E/Z¼80:20); mp 170e172 ^ꢀC; R_f(10% EtOAc/

Hexanes) 0.55; IR (KBr): n_max2935, 2857, 1602, 1454, 1249 and

754 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.51 (4H, s), 7.34e7.28

;

(4H, m), 7.05 (2H, d, J¼7.9 Hz), 6.97 (2H, t, J¼7.4 Hz), 5.63e5.61

(2H, m), 5.13 (4H, s), 4.47 (4H, s), 3.92e3.91 (4H, m); ¹³C NMR

(100 MHz, CDCl₃): d_C157.4, 136.9, 131.5, 130.0, 129.7, 128.5, 127.1,

120.9, 112.4, 70.9, 70.2, 67.8; HRMS (ESI): MNa^þ, found 425.1740.

3.7.4. Compound 5d. Following the general procedure, 5d was

obtained as a colourless liquid (69 mg, 73%); (E/Z¼80:20); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2925, 1603, 1456, 1248 and

752 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.31 (2H, d, J¼8.1 Hz), 7.23

(2H, t, J¼7.7 Hz), 6.90 (2H, t, J¼7.7 Hz), 6.84 (2H, d, J¼8.1 Hz),

5.88e5.86 (2H, m), 4.50 (4H, s), 4.12e4.10 (4H, m), 3.99 (4H, t,

J¼5.7 Hz), 1.82e1.79 (4H, m), 1.61e1.58 (4H, m); ¹³C NMR (100 MHz,

CDCl₃): d_C157.3, 130.3, 130.1, 129.1, 126.9, 120.4, 111.8, 70.7, 67.9,

67.3, 29.4, 26.0; HRMS (ESI): MNa^þ, found 405.2028. C₂₄H₃₀NaO₄

requires 405.2041.

C

₂₆H₂₆NaO₄requires 425.1728. Data given here for the major (E)

isomer and the ¹H and ¹³C NMR spectrum contain traces of minor

isomer 5j⁰. The minor isomer 5j⁰(Z) was isolated in very less

quantity <6 mg. ¹H NMR (400 MHz, CDCl₃): d_H7.41 (4H, s),

7.24e7.21 (4H, m), 6.94e6.88 (4H, m), 5.63e5.62 (2H, m), 5.02

(4H, s), 4.38 (4H, s), 3.90e3.89 (4H, m); ¹³C NMR (100 MHz,

CDCl₃): d_C130.8, 129.7, 128.5, 128.6, 120.9, 112.8, 70.5, 69.1, 67.1,

since the compound was isolated in <6 mg, few signals corre-

sponding to the quaternary carbons were not appeared in the ¹³C

spectrum.

3.7.5. Compound 5e. Following the general procedure, 5e was ob-

tained as a colourless solid (66 mg, 55%) (E/Z¼80:20); mp

143e145 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2931,

1628, 1486,1367, 1184 and 657 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.54 (2H, d, J¼2.4 Hz), 7.29 (2H, dd, J₁¼8.6, J₂¼2.5 Hz), 6.71 (2H, d,

J¼8.6 Hz), 5.77e5.74 (2H, m), 4.51 (4H, s), 4.20 (4H, s), 4.12e4.11

(4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C154.4, 132.0, 130.9, 130.7,

130.1, 114.0, 113.3, 70.0, 66.8, 63.4; HRMS (ESI): MH^þ, found

482.9796. C₂₀H₂₁Br₂O₄requires 482.9806.

3.7.11. Compound 5k. Following the general procedure, 5k was

obtained as a colourless liquid (69 mg, 75%) (E/Z¼67:33); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2926, 2364, 1603, 1494,

1246 and 753 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.41e7.37 (2H,

;

m), 7.24 (2H, t, J¼7.6 Hz), 6.95 (2H, t, J¼7.6 Hz), 6.83 (2H, d,

J¼8.2 Hz), 5.90e5.88 (2H, m), 4.57 (4H, s), 4.17e4.13 (8H, m), 3.96

(4H, t, J¼4.6 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.3, 130.4, 129.2,

128.7, 127.1, 120.8, 111.1, 70.5, 70.1, 68.1, 66.2; HRMS (ESI): MNa^þ,

found 393.1665. C₂₂H₂₆NaO₅requires 393.1677.

3.7.6. Compound 5f. Following the general procedure, 5f was ob-

tained after as a colourless solid (88 mg, 77%) (E/Z¼87:13); mp

118e120 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2927,

2852, 1629, 1446,1360 and 740 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.41 (2H, d, J¼2.5 Hz), 7.32 (2H, d, J¼2.5 Hz), 5.86e5.83 (2H, m), 4.65

(4H, s), 4.28 (4H, s), 4.10e4.08 (4H, m); ¹³C NMR (100 MHz, CDCl₃):

d_C151.5, 134.8,131.7, 129.9,129.4, 128.1, 73.1, 69.6, 63.6; HRMS (ESI):

MH^þ, found 463.0037. C₂₀H₁₉Cl₄O₄requires 463.0037.

3.7.12. Compound 5l. Following the general procedure, 5l was ob-

tained after as a colourless liquid (82 mg, 80%) (E/Z¼83:17); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2925, 2867, 1601, 1493, 1248

and 755 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.34 (2H, d, J¼7.8 Hz),

7.27e7.23 (2H, m), 6.96e6.92 (2H, m), 6.83 (2H, d, J¼7.8 Hz),

5.86e5.84 (2H, m), 4.53 (4H, s), 4.19e4.09 (8H, m), 3.93e3.90 (4H,

m), 3.83 (4H, s); ¹³C NMR (100 MHz, CDCl₃): d_C156.7, 130.2, 129.9,

129.1, 126.8, 120.7, 111.2, 71.5, 70.4, 69.9, 68.7, 67.1; HRMS (ESI):

MNa^þ, found 437.1929. C₂₄H₃₀NaO₆requires 437.1940.

3.7.7. Compound 5g. Following the general procedure, 5g was ob-

tained as

a

colourless solid (77 mg, 80%) (E/Z¼65:35); mp

126e128 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2936,

2360, 1588, 1479 and 779 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.06

(4H, d, J¼5.2 Hz), 6.85 (2H, t, J¼4.8 Hz), 5.90e5.87 (2H, m), 4.68 (4H,

s), 4.28 (4H, s), 4.07e4.05 (4H, m), 3.82 (6H, s); ¹³C NMR (100 MHz,

CDCl₃): d_C152.4, 146.2, 132.1, 131.4, 124.1, 121.8, 111.8, 69.4, 64.1,

55.8; HRMS (ESI): MNa^þ, found 409.1612. C₂₂H₂₆NaO₆requires

409.1627.

3.7.13. Compound 5m. Following the general procedure, 5m was

obtained as a colourless solid (102 mg, 87%) (E/Z¼74:26); mp

164e166 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (KBr): n_max2929,1625,

1453, 1240 and 801 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H8.10 (2H, d,

J¼8.5), 7.81e7.74 (4H, m), 7.52e7.47 (2H, m), 7.36e7.32 (2H, m),

7.25e7.21 (2H, m), 6.01e6.00 (2H, m), 5.05 (4H, s), 4.31e4.18 (8H,

m), 4.06e4.03 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C154.8, 133.8,

130.4, 130.3, 129.5, 128.3, 126.9, 123.8, 123.8, 119.8, 114.8, 70.5, 70.2,

70.1, 61.5; HRMS (ESI): MNa^þ, found 493.2008. C₃₀H₃₀NaO₅re-

quires 493.1990.

3.7.8. Compound 5h. Following the general procedure, 5h was

obtained as a colourless solid (80 mg, 78%) (E/Z¼85:15); mp

111e112 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2936,

1587, 1479, 1276 and 779 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H

;

7.06e7.00 (4H, m), 6.86 (2H, d, J¼7.5 Hz), 5.90 (2H, br s), 4.57 (4H, s),

4.14 (4H, s), 4.05 (4H, br s), 3.84 (6H, s), 1.93 (4H, br s); ¹³C NMR

(100 MHz, CDCl₃): d_C152.6, 146.5, 132.2, 130.2, 123.8, 121.5, 112.0,

73.4, 70.3, 66.6, 55.8, 26.9; HRMS (ESI): MNa^þ, found 437.1950.

3.7.14. Compound 5n. Following the general procedure, 5n was

obtained as a colourless solid (90 mg, 85%) (E/Z¼90:10); mp

158e160 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (KBr): n_max2911, 1594,

1347,1239 and 733 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H8.25 (2H, d,

J¼8.8 Hz), 7.90e7.84 (4H, m), 7.59 (2H, t, J¼7.6 Hz), 7.44 (2H, t,

J¼7.6 Hz), 7.33 (2H, d, J¼8.8 Hz), 6.12e6.10 (2H, m), 5.23 (4H, s), 4.50

(4H, s), 4.18e4.17 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C154.8,

134.0, 130.7, 130.5, 129.9, 128.3, 126.9, 124.4, 124.2, 120.5, 115.8, 70.1,

C

₂₄H₃₀NaO₆requires 437.1940.

3.7.9. Compound 5i. Following the general procedure, 5i was ob-

tained as

colourless solid (50 mg, 50%) (E/Z¼70:30); mp

149e151 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2921,

a

7774

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

68.9, 60.3; HRMS (ESI): MNa^þ, found 449.1710. C₂₈H₂₆NaO₄re-

quires 449.1728.

80e82 ^ꢀC; R_f(30% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2916,

2860, 1598, 1491 and 751 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.35

(2H, dd, J₁¼8.5, J₂¼1.6 Hz), 7.23 (2H, dt, J₁¼7.8, J₂¼1.7 Hz), 6.96 (2H,

dt, J₁¼7.1, J₂¼1.5 Hz), 6.89 (2H, d, J¼8.2 Hz), 6.21e6.20 (2H, m),

4.63e4.62 (4H, m), 3.87 (4H, s), 3.67 (4H, t, J¼6.8 Hz), 3.60 (4H, s),

2.70 (4H, t, J¼6.8 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.2, 130.6,

128.4, 128.2, 127.8, 121.1, 111.8, 70.9, 70.4, 68.0, 31.2, 30.3; HRMS

(ESI): MNa^þ, found 469.1479. C₂₄H₃₀NaO₄S₂requires 469.1483.

3.7.15. Compound 5p. Following the general procedure, 5p was

obtained as a colourless liquid (30 mg, 38%) (E/Z¼80:20); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2926, 1600, 1449, 1263 and

696 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.24e7.16 (4H, m),

;

6.85e6.82 (4H, m), 5.80e5.78 (2H, m), 4.51 (4H, s), 4.38 (4H, s),

4.01e4.00 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C159.1, 140.3,

129.9, 129.4, 120.6, 115.4, 115.0, 114.6, 71.6, 69.7, 67.5; HRMS (ESI):

MH^þ, found 327.1596. C₂₀H₂₃O₄requires 327.1596.

3.7.22. Compound 5w. Following the general procedure, 5w was

obtained as

a

brown solid (99 mg, 90%) (E/Z¼95:5); mp

107e109 ^ꢀC; R_f(30% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2918,

1724, 1600, 1451 and 756 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.82

(2H, dd, J₁¼8.1, J₂¼1.7 Hz), 7.45 (2H, t, J¼7.2 Hz), 7.02 (2H, t,

J¼7.3 Hz), 6.97 (2H, d, J¼8.4 Hz), 6.20 (2H, s), 4.67 (4H, br s),

4.48e4.45 (4H, m), 3.84e3.82 (4H, m), 3.73 (4H, s); ¹³C NMR

(100 MHz, CDCl₃): d_C167.2, 157.7, 133.4, 132.0, 128.0, 121.2, 120.9,

114.2, 70.7, 69.3, 68.9, 64.5; HRMS (ESI): MNa^þ, found 465.1513.

3.7.16. Compound 5q. Following the general procedure, 5q was

obtained as a colourless liquid (48 mg, 55%) (E/Z¼90:10); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2941, 2855, 1600, 1488 and

783 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.21 (2H, t, J¼7.9 Hz), 7.03

(2H, s), 6.81 (4H, t, J¼7.9 Hz), 5.89e5.88 (2H, m), 4.51 (4H, s), 4.11 (4H,

br s), 4.05e4.04 (4H, m), 2.01e1.98 (4H, m); ¹³C NMR (100 MHz,

CDCl₃): d_C159.2, 140.1, 129.5, 129.3, 119.6,114.4, 112.7, 71.2, 69.3, 67.9,

26.4; HRMS (ESI): MH^þ, found 355.1896. C₂₂H₂₇O₄requires 355.1909.

C₂₄H₂₆NaO₈requires 465.1525.

3.7.23. Compound 22a. Following the general procedure, 22a was

obtained as colourless solid (53 mg, 50%) (E/Z¼95:5); mp

181e183 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2923,

3.7.17. Compound 5r. Following the general procedure, 5r was

obtained as a colourless liquid (47 mg, 46%) (E/Z¼85:15); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2924, 1726, 1455, 1384 and

1708, 1600, 1451, 1300 and 754 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃):

;

748 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.24e7.19 (2H, m), 7.00

d

7.80 (2H, dd, J₁¼8.2, J₂¼1.8 Hz), 7.47e7.35 (6H, m), 7.04 (2H, dt,

(2H, br s), 6.81 (4H, t, J¼8.5 Hz), 5.91e5.89 (2H, m), 4.49 (4H, s),

4.04e4.03 (4H, m), 3.97 (4H, t, J¼6.1 Hz), 1.79e1.72 (4H, m),

1.53e1.46 (4H, m), 1.41e1.36 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C

159.5, 139.9, 129.3, 129.2, 119.6, 114.1, 113.3, 72.1, 67.7, 28.9, 28.5,

25.5; HRMS (ESI): MNa^þ, found 433.2374. C₂₆H₃₄NaO₄requires

433.2354.

J₁¼7.6, J₂¼0.9 Hz), 6.99 (2H, d, J¼8.3 Hz), 6.12e6.10 (2H, m), 5.38

(4H, s), 4.85e4.84 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C167.0,

157.9, 134.8, 133.2, 131.7, 128.7, 128.2, 127.5, 121.8, 121.2, 114.7, 69.9,

64.3; HRMS (ESI): MH^þ, found 431.1487. C₂₆H₂₃O₆requires

431.1495.

3.7.24. Compound 22b. Following the general procedure, 22b was

obtained as a colourless liquid (96 mg, 90%) (E/Z¼82:18); R_f(20%

EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max2927, 1704, 1599, 1451 and

3.7.18. Compound 5s. Following the general procedure, 5s was

obtained as a colourless liquid (77 mg, 88%) (E/Z¼95:5); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2851, 1589, 1493, 1452 and

754 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.86e7.82 (3H, m),

;

752 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.38 (2H, dd, J₁¼8.6,

7.47e7.34 (5H, m), 7.06e7.00 (4H, m), 6.16e5.66 (2H, m), 5.18 (4H,

s), 4.87e4.85 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C167.2, 157.8,

137.4, 133.5, 132.3, 128.4, 127.5, 127.4, 126.8, 121.1, 120.8, 113.9, 70.9,

64.5; HRMS (ESI): MNa^þ, found 453.1319. C₂₆H₂₂NaO₆requires

453.1314.

J₂¼1.6 Hz), 7.30 (2H, dt, J₁¼7.1, J₂¼1.4 Hz), 6.98 (2H, dt, J₁¼7.4,

J₂¼0.9 Hz), 6.89 (2H, dd, J₁¼8.5, J₂¼0.6 Hz), 6.17 (2H, t, J¼2.2 Hz),

5.99e5.97 (2H, m), 4.63e4.62 (4H, m), 4.61 (4H, s), 4.18e4.17 (4H,

m); ¹³C NMR (100 MHz, CDCl₃): d_C156.7, 130.4, 130.0, 129.2, 127.5,

126.9, 120.7, 111.6, 70.4, 67.5, 67.3; HRMS (ESI): MNa^þ, found

375.1573. C₂₂H₂₄NaO₄requires 375.1572.

3.7.25. Compound 22c. Following the general procedure, 22c was

obtained as a colourless liquid (56 mg, 51%) (E/Z¼90:10); R_f(20%

EtOAc/Hexanes) 0.42; IR (CH₂Cl₂): n_max2933, 2870, 1699, 1490 and

3.7.19. Compound 5t. Following the general procedure, 5t was

obtained as a colourless liquid (48 mg, 55%) (E/Z¼70:30); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2921, 1603, 1492, 1454 and

756 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.81 (2H, dd, J₁¼7.9,

J₂¼1.8 Hz), 7.45 (2H, t, J¼7 Hz), 7.01 (2H, t, J¼7.5 Hz), 6.93 (2H, d,

J¼8.2 Hz), 6.08e6.07 (2H, m), 4.88e4.87 (4H, m), 4.19 (4H, t,

J¼4.1 Hz), 3.93 (4H, t, J¼4.1 Hz), 3.84 (4H, s); ¹³C NMR (100 MHz,

CDCl₃): d_C167.1, 157.9, 133.5, 132.0, 128.1, 120.5, 120.5, 112.8, 71.5,

69.5, 64.5; HRMS (ESI): MNa^þ, found 465.1532. C₂₄H₂₆NaO₈re-

quires 465.1525.

751 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.40e7.26 (4H, m),

;

7.04e6.99 (2H, m), 6.88 (2H, t, J¼7.8 Hz), 5.94e5.91 (2H, m), 4.75

(4H, s), 4.58 (4H, s), 4.16e4.08 (4H, m); ¹³C NMR (100 MHz, CDCl₃):

d_C155.8, 155.7, 130.5, 130.5, 130.3, 129.9, 129.1, 128.9, 128.1, 127.8,

121.8, 121.7, 112.7, 112.6, 81.9, 81.8, 70.3, 66.9, 66.5, 65.6, 56.9, 56.8;

HRMS (ESI): MNa^þ, found 373.1418. C₂₂H₂₂NaO₄requires 373.1416.

3.7.26. Compound 28a. Following the general procedure, 28a was

obtained as a colourless liquid (73 mg, 52%) (E/Z¼75:25); R_f(20%

EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max2937, 2860, 1589, 1494 and

3.7.20. Compound 5u. Following the general procedure, 5u was

obtained as a colourless liquid (88 mg, 77%) (E/Z¼83:17); R_f(10%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2925, 2850, 1603, 1453 and

750 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.41e7.34 (4H, m),

;

753 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.41e7.24 (9H, m), 6.98

7.28e7.16 (4H, m), 7.01e6.80 (8H, m), 5.77e5.75 (2H, m), 4.93 (4H,

s), 4.52 (4H, m), 4.02e4.00 (8H, m), 1.87 (4H, br s); ¹³C NMR

(100 MHz, CDCl₃): d_C156.8, 156.7, 156.6, 130.0, 129.8, 129.6, 129.3,

129.2, 129.1, 128.9, 128.5, 128.4, 127.4, 125.6, 120.7, 120.6, 120.4,

120.3, 112.1, 111.3, 111.2, 70.3, 67.7, 67.5, 66.6, 66.4, 66.4, 66.3, 65.7,

26.2, 26.0; HRMS (ESI): MNa^þ, found 589.2566. C₃₆H₃₈NaO₆re-

quires 589.2566.

(2H, t, J¼7.4 Hz), 6.84 (2H, d, J¼8.2 Hz), 5.94e5.92 (2H, m), 4.60 (4H,

s), 4.19e4.18 (4H, m), 4.13 (4H, t, J¼5.9 Hz), 3.85 (2H, s), 3.20 (4H, t,

J¼5.9 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.5, 130.1, 129.5, 128.8,

128.7, 128.7, 128.4, 127.2, 126.9, 120.6, 111.2, 70.4, 67.2, 66.3, 58.7,

53.5; HRMS (ESI): MH^þ, found 460.2485. C₂₉H₃₄NO₄requires

460.2488.

3.7.21. Compound 5v. Following the general procedure, 5v was

obtained as a colourless solid (75 mg, 68%) (E/Z¼93:7); mp

3.7.27. Compound 28b. Following the general procedure, 28b was

obtained as a colourless liquid (92 mg, 62%) (E/Z¼80:20); R_f(20%

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7775

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2935, 2858, 1602, 1485 and

753 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.40e7.24 (4H, m),

completion of the reaction, the reaction mixture was ﬁltered by

using a layer of Celite pad and the ﬁltrate was evaporated under

vacuum and the resulting crude reaction mixture was puriﬁed by

silica gel column chromatography, which gave the compounds

33aec, respectively.

;

7.23e7.20 (4H, m), 6.98e6.83 (8H, m), 5.81e5.79 (2H, m), 5.02 (4H,

s), 4.56 (4H, s), 4.05e4.04 (4H, m), 3.97 (4H, t, J¼6.1 Hz), 1.72 (4H, br

s), 1.47 (4H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C156.8, 156.8, 156.7,

156.7, 129.9, 129.7, 129.4, 129.2, 129.1, 129.0, 128.8, 128.5, 128.4,

127.5, 125.6, 125.6, 120.6, 120.6, 120.4, 120.3, 120.3, 112.2, 112.1,

111.4, 111.3, 70.3, 67.9, 67.7, 66.7, 66.6, 66.3, 66.2, 65.8, 29.1, 29.1,

26.0, 25.8; HRMS (ESI): MNa^þ, found 617.2878. C₃₈H₄₂NaO₆re-

quires 617.2879.

3.8.1. Compound 33a. Following the general procedure, 33a was as

a colourless liquid (56 mg, 64%); R_f(20% EtOAc/Hexanes) 0.55; IR

(thin ﬁlm): n_max2927, 2827, 1600, 1453, 1247 and 752 cm^{ꢂ1 1}H

;

NMR (400 MHz, CDCl₃): d_H7.29e7.24 (4H, m), 6.88e6.92 (4H, m),

4.48 (4H, s), 4.07 (4H, br s), 3.54 (4H, t, J¼6.0 Hz), 2.04 (4H, br s),1.71

(4H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C157.6, 131.4, 129.5, 126.6,

120.3, 111.4, 70.0, 68.3, 67.6, 26.3, 26.0; HRMS (ESI): MNa^þ, found

379.1883. C₂₂H₂₈NaO₄requires 379.1885.

3.7.28. Compound 28c. Following the general procedure, 28c was

obtained as a colourless liquid (93 mg, 60%) (E/Z¼90:10); R_f(50%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2939, 2861, 1599, 1485 and

751 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.38 (4H, t, J¼7 Hz), 7.23

(4H, t, J¼7.4 Hz), 6.96e6.91 (6H, m), 6.82 (2H, d, J¼7.96 Hz),

5.76e5.75 (2H, m), 5.09 (4H, s), 4.51 (4H, m), 4.07 (4H, t, J¼4.6 Hz),

4.01e3.99 (4H, m), 3.76 (4H, t, J¼4.7 Hz), 3.59 (4H, s); ¹³C NMR

(100 MHz, CDCl₃): d_C156.7, 156.3, 129.9, 129.3, 129.0, 129.0, 128.6,

127.4,125.9,120.8,120.6,112.1,111.8, 71.0, 70.2, 69.7, 68.1, 66.5, 65.9;

HRMS (ESI): MNa^þ, found 649.2763. C₃₈H₄₂NaO₈requires 649.2777.

3.8.2. Compound 33b. Following the general procedure, 33b was

obtained as a colourless liquid (71 mg, 77%); R_f(20% EtOAc/Hex-

anes) 0.55; IR (thin ﬁlm): n_max2928, 2829, 1601, 1452, 1248 and

753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.31 (2H, d, J¼8.1 Hz) 7.24

(2H, t, J¼7.5 Hz), 6.91 (2H, t, J¼7.5 Hz), 6.86 (2H, d, J¼8.2 Hz), 4.52

(4H, s), 4.01 (4H, t, J¼5.5 Hz), 3.54 (4H, t, J¼6.0 Hz), 1.92e1.86 (4H,

m), 1.78e1.67 (6H, m); ¹³C NMR (100 MHz, CDCl₃): d_C157.5, 130.8,

129.2, 126.9, 120.5, 111.8, 69.8, 68.7, 67.7, 29.8, 25.9, 24.5; HRMS

(ESI): MNa^þ, found 393.2035. C₂₃H₃₀NaO₄requires 393.2041.

3.7.29. Compound 29d. Following the general procedure, 29d was

obtained as a colourless liquid (76 mg, 62%) (E/Z¼75:25); R_f(50%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2923, 2854, 1602, 1493,

1260 and 750 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.25 (2H, t,

3.8.3. Compound 33c. Following the general procedure, 33c was

obtained as a colourless solid (86 mg, 93%); mp 64e66 ^ꢀC; R_f(30%

EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2928, 2829, 1601, 1452,

J¼7.5 Hz), 6.92 (2H, d, J¼8.1 Hz), 6.88 (2H, t, J¼7.8 Hz), 6.76e6.74

(2H, m), 6.41 (2H, d, J¼7.4 Hz), 6.24e6.16 (4H, m), 5.80 (2H, br s),

5.29 (4H, s), 4.38 (4H, s), 4.15e4.13 (4H, m), 3.90e3.89 (4H, m),

2.12e2.10 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C155.4,128.8,128.1,

127.6, 126.4, 123.6, 120.8, 110.6, 110.5, 107.0, 69.0, 67.9, 64.2, 45.8,

26.6; HRMS (ESI): MH^þ, found 513.2738. C₃₂H₃₇N₂O₄requires

513.2753.

Following the general procedure, the ring closing metathesis of

substrate 31 and column chromatographic puriﬁcation afforded the

diastereomers 32A and 32B, (106 mg, 80%, combined yield of

diastereomers).

1248 and 753 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃):

; d 7.32e7.24 (4H,

m), 6.94 (2H, t, J¼7.8 Hz), 6.87 (2H, d, J¼8.0 Hz), 4.51 (4H, s), 4.16

(4H, t, J¼4.9 Hz), 4.03 (4H, t, J¼4.9 Hz), 3.55 (4H, t, J¼6.1 Hz),

1.71e1.68 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C157.2, 131.0, 129.3,

126.9, 120.9, 111.9, 70.3, 69.9, 68.5, 67.9, 25.8; HRMS (ESI): MNa^þ,

found 395.1826. C₂₂H₂₈NaO₅requires 395.1834.

3.9. General procedure for the synthesis of epoxide func-

tionality appended macrocyclic systems 34aed

3.7.30. Characterization data for the compound 32A. Colourless

solid, mp 167e169 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂):

n_max2930, 1717, 1602, 1490, 1274 and 711 cm^ꢂ1; ¹H NMR (400 MHz,

CDCl₃): d_H8.12 (4H, d, J¼7.1 Hz), 7.57e7.53 (2H, m), 7.44 (4H, t,

J¼7.6 Hz), 7.35 (2H, dd, J₁¼7.6, J₂¼1.4 Hz), 7.28e7.23 (2H, m),

7.00e6.94 (4H, m), 6.34 (2H, dd, J₁¼7.9, J₂¼3.4 Hz), 5.70 (2H, t,

J¼5 Hz), 4.46 (4H, s), 3.04e2.98 (2H, m), 2.84e2.76 (2H, m); ¹³C

NMR (100 MHz, CDCl₃): d_C165.7, 155.2, 132.9, 130.4, 129.7, 128.7,

128.4, 128.2, 126.0, 121.6, 113.0, 73.3, 67.4, 32.9; HRMS (ESI): MNa^þ,

found 557.1955. C₃₄H₃₀NaO₆requires 557.1940.

70 % mCPBA was added to the solution of substrate 5

(0.25 mmol) in CH₂Cl₂(2 mL) and the reaction mixture was

reﬂuxed for the required time (see the corresponding Table/

Scheme for the speciﬁc entries) and then, the mixture was diluted

with H₂O and extracted with CH₂Cl_2.The extract was washed with

saturated NaHCO₃solution, dried with Na₂SO₄. Removal of solvent

in vacuum followed by silica gel column chromatography gave the

compound 34aed in pure form as a mixture of diastereomers.

3.9.1. Compound 34a. Following the general procedure, 34a was

obtained as a mixture of diastereomers (44 mg, 52%, dr¼70:30)

after puriﬁcation by column chromatography on silica gel (30%

EtOAc/Hexanes). However, repetitive column puriﬁcation of the

mixture of diastereomers gave the major diastereomer 34aA in

pure form and the ¹H/¹³C data given here is for the major di-

astereomer 34aA; colourless solid, mp 126e128 ^ꢀC; R_f(30% EtOAc/

Hexanes) 0.55; IR (thin ﬁlm): n_max2925, 1602, 1494, 1249 and

724 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.36 (2H, d, J¼7.5 Hz), 7.29

(2H, t, J¼7.8 Hz), 6.98 (2H, t, J¼7.4 Hz), 6.91 (2H, d, J¼7.9 Hz), 4.67

(4H, s), 4.39e4.32 (4H, m), 3.87 (2H, dd, J₁¼8.9, J₂¼3.1 Hz), 3.38 (2H,

dd, J₁¼7.4, J₂¼5.7 Hz), 3.15e3.13 (2H, m); ¹³C NMR (100 MHz,

CDCl₃): d_C156.7, 130.5,129.3,126.3,121.1, 111.4, 68.7, 67.1, 66.8, 55.4;

HRMS (ESI): MNa^þ, found 365.1355. C₂₀H₂₂NaO₅requires 365.1364.

3.7.31. Characterization data for the compound 32B. Colourless

solid, mp 153e155 ^ꢀC; R_f(10% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂):

n_max2957, 2853, 1721, 1602, 1451, 1273 and 711 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H8.11e8.09 (4H, m), 7.56e7.51 (2H, m), 7.42

(4H, t, J¼7.6 Hz), 7.34 (2H, dd, J₁¼7.2, J₂¼1.4 Hz), 7.26e7.22 (2H, m),

6.98e6.93 (4H, m), 6.30 (2H, dd, J₁¼8.5, J₂¼1.4 Hz), 5.77 (2H, t,

J¼5.1 Hz), 4.52e4.45 (4H, m), 3.03e2.98 (2H, m), 2.67e2.59 (2H,

m); ¹³C NMR (100 MHz, CDCl₃): d_C165.7, 155.0, 132.9, 131.1, 130.5,

129.7, 128.6, 128.4, 128.3, 125.9, 121.8, 113.3, 73.9, 67.5, 33.6; HRMS

(ESI): MNa^þ, found 557.1947. C₃₄H₃₀NaO₆requires 557.1940.

3.8. General procedure for the hydrogenation reaction and

the synthesis of macrocycles 33aec

3.9.2. Compound 34b. Following the general procedure, 34b was

obtained as a colourless liquid (49 mg, 53%) (dr¼86:14); R_f(30%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max2922,1602,1455,1368,1240

and 755 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.21e7.17 (4H m), 6.84

To the solution of RCM products (5b,c,k) in anhydrous THF

(2 mL) was added Pd/C (10 mol %). The reaction mixture was stirred

at room temperature overnight under H₂atmosphere (1 atm). After

7776

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

(2H, t, J¼7.5 Hz), 6.79 (2H, d, J¼8.4 Hz), 4.55e4.47 (4H, m) 3.99 (4H,

s) 3.61e3.60 (4H, m), 3.12 (2H, t, J¼3.6 Hz), 1.98e1.96 (4H, m); ¹³C

NMR (100 MHz, CDCl₃): d_C157.4, 131.1, 129.7, 126.0, 120.3, 111.2,

69.8, 69.0, 67.5, 54.7, 26.2; HRMS (ESI): MNa^þ, found 393.1670.

72.4, 72.0, 69.1, 68.8, 55.8; HRMS (ESI): MNa^þ, found 441.1531.

₂₂H₂₆NaO₈requires 441.1525.

C

3.10.3. Compound 35c. Following the general procedure, 35c was

obtained as a colourless liquid (40 mg, 42%); R_f(50% EtOAc/Hex-

anes) 0.55; IR (CH₂Cl₂): n_max3446, 2927, 1727, 1602, 1494, 1248 and

C

₂₂H₂₆NaO₅requires 393.1677.

3.9.3. Compound 34c. Following the general procedure, 34c was

obtained as a colourless solid (43 mg, 45%) (dr¼67:33); mp

76e78 ^ꢀC; R_f(30% EtOAc/Hexanes) 0.55; IR (thin ﬁlm): n_max2926,

1602,1494,1363,1248 and 609 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.32e7.24 (4H, m), 6.97e6.92 (2H, m), 6.86 (2H, d, J¼8.2 Hz),

4.67e4.54 (4H, m), 4.16 (4H, t, J¼4.7 Hz), 4.03e3.97 (4H, m), 3.67

(4H, d, J¼4.0 Hz), 3.14 (2H, t, J¼3.7 Hz); ¹³C NMR (100 MHz, CDCl₃):

d_C156.9, 130.7, 129.4, 126.4, 120.9, 111.6, 70.3, 69.6, 68.4, 68.1, 54.7;

HRMS (ESI): MNa^þ, found 409.1613. C₂₂H₂₆NaO₆requires 409.1627.

754 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.31e7.24 (4H, m),

;

6.93e6.85 (4H, m), 4.58e4.41 (5H, m), 4.31 (1H, d, J¼16.9 Hz),

4.16e4.11 (3H, m), 4.07e4.02 (2H, m), 3.89 (1H, dd, J₁¼6.6,

J₂¼3.8 Hz), 3.74 (1H, dd, J₁¼6.2, J₂¼3.8 Hz), 3.50 (1H, d, J¼6.2 Hz),

2.10e1.99 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C208.5, 157.5,157.4,

131.8, 131.6, 130.1, 129.9, 125.6, 125.3, 120.6, 120.5, 111.5, 111.4, 75.1,

74.1, 70.6, 69.3, 68.9, 67.8, 67.3, 26.6, 26.1; HRMS (ESI): MNa^þ, found

409.1618. C₂₂H₂₆NaO₆requires 409.1627.

3.10.4. Compound 35d. Following the general procedure, 35d was

obtained as a colourless liquid (50 mg, 25%); R_f(50% EtOAc/Hex-

anes) 0.55; IR (CH₂Cl₂): n_max3470, 2938, 1731, 1602, 1590, 1454 and

3.9.4. Compound 34d. Following the general procedure, 34d was

obtained as a colourless solid (66 mg, 62%) (dr¼85:15); mp

115e117 ^ꢀC; R_f(30% EtOAc/Hexanes) 0.55; IR (KBr): n_max2925, 1635,

1456, 1240 and 742 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.31 (2H, d,

J¼7.8 Hz), 7.24 (2H, s), 6.92 (2H, t, J¼7.3 Hz), 6.82 (2H, d, J¼7.8 Hz),

4.66 (2H, d, J¼11.6 Hz), 4.58 (2H, d, J¼11.6 Hz) 4.13 (4H, br s), 3.90

(4H, br s), 3.83 (6H, s), 3.50e3.46 (2H, m), 3.06 (2H, br s); ¹³C NMR

(100 MHz, CDCl₃): d_C156.7, 130.0, 129.2, 126.5, 120.7, 111.3, 71.4,

70.3, 69.9, 68.7, 68.3, 54.4; HRMS (ESI): MNa^þ, found 453.1881.

753 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.38e7.27 (4H, m),

;

6.99e6.89 (4H, m), 4.73e4.31 (6H, m), 4.09e4.05 (4H, m), 3.94 (1H,

dd, J₁¼6.7, J₂¼3.4 Hz), 3.74 (1H, dd, J₁¼6.2, J₂¼3.9 Hz), 3.56 (1H, d,

J¼6.5 Hz), 1.96e1.82 (6H, m); ¹³C NMR (100 MHz, CDCl₃): d_C209.0,

157.2, 157.2, 130.8, 130.8, 129.6, 129.5, 125.5, 125.3, 120.5, 120.5,

111.4, 111.2, 75.0, 74.2, 71.0, 69.0, 68.8, 68.3, 68.2, 29.5, 29.5, 24.6;

HRMS (ESI): MNa^þ, found 423.1786. C₂₃H₂₈NaO₆requires 423.1784.

The OH proton was not visible in the ¹H NMR spectrum.

C

₂₄H₃₀NaO₇requires 453.1889.

3.10. General procedure for

appended macrocyclic systems 35aej

a

-hydroxy ketone functionality

3.10.5. Compound 35e. Following the general procedure, 35e was

obtained as a colourless liquid (72 mg, 35%); R_f(50% EtOAc/Hexanes)

0.55; IR (CH₂Cl₂): n_max3450, 2933, 1731, 1602, 1244 and 752 cm^ꢂ1

;

A solution of the corresponding substrate having two terminal

oleﬁns 4/21 (0.5 mmol) in CH₂Cl₂(14 mL) and Grubbs’s catalyst

(ﬁrstor second generation, 2.5e5 mol %) was reﬂuxed for appro-

priate time (see the corresponding Table/Scheme for the speciﬁc

entries). Then, the solvent was removed under vacuum and to the

resulting crude mixture was added EtOAc (3 mL), CH₃CN (3 mL) and

H₂O (1 mL) followed by oxone^Ò(5 equiv) and NaHCO₃(2.5 equiv).

Next, the reaction mixture was stirred at rt for 1 h and after this

period, the reaction mixture was diluted with water and extracted

with EtOAc. The combined extracts were dried with anhydrous

Na₂SO₄and concentrated under vacuum and the crude mixture was

puriﬁed by silica gel column chromatography (EtOAc/Hexanes), to

¹H NMR (400 MHz, CDCl₃): d_H7.34e7.28 (4H, m), 6.97e6.89 (4H, m),

4.66e4.34 (6H, m), 4.09e4.05 (4H, m), 3.82e3.61 (4H, m), 1.89e1.57

(8H, m); ¹³C NMR (100 MHz, CDCl₃): d_C208.4, 157.5, 157.4, 131.0,

130.9, 129.8, 129.8, 125.6, 125.5, 120.5, 120.4, 111.6, 111.5, 75.1, 74.1,

70.9, 69.2, 67.8, 67.8, 29.1, 29.0, 26.1, 26.0; HRMS (ESI): MNa^þ, found

437.1936. C₂₄H₃₀NaO₆requires 437.1940.

3.10.6. Compound 35f. Following the general procedure, 35f was

obtained as a colourless liquid (43 mg, 40%); R_f(50% EtOAc/Hex-

anes) 0.55; IR (CH₂Cl₂): n_max3436, 2925, 1728, 1666, 1600, 1494,

1240 and 755 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.76 (1H, s),

;

7.42e7.28 (7H, m), 6.97 (4H, t, J¼7.6 Hz), 5.14e5.06 (4H, m),

4.67e4.50 (4H, m), 4.39e4.37 (1H, m) 4.28 (2H, dd, J₁¼23.1,

J₂¼17.5 Hz), 3.87 (1H, dd, J₁¼6.6, J₂¼3.6 Hz), 3.68 (1H, dd, J₁¼6.6,

J₂¼3.6 Hz), 3.54 (1H, d, J¼6.6 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C

208.9, 157.0, 156.9, 137.6, 137.5, 131.0, 130.9, 129.8, 129.6, 128.5,

127.2, 126.6, 126.0, 125.7, 121.1, 121.0, 112.2, 111.9, 75.1, 74.2, 70.9,

70.4, 70.2, 69.0, 68.9; HRMS (ESI): MNa^þ, found 457.1620.

afford the corresponding a-hydroxy ketone functionality appended

macrocycle (see the corresponding Table/Scheme for the speciﬁc

entries).

3.10.1. Compound 35a. Following the general procedure, 35a was

obtained as a colourless solid (40 mg, 45%), mp:116e117 ^ꢀC; R_f(30%

EtOAc/Hexanes) 0.55; IR (KBr): n_max3449, 2928,1728,1600,1493 and

755 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃):d_H7.35e7.26 (4H, m), 7.01e6.90

(4H, m) 4.60 (3H, dd, J₁¼15.4, J₂¼11.2 Hz), 4.46e4.41 (3H, m),

4.39e4.29 (4H, m), 4.24 (1H, d, J¼17.3 Hz), 3.90 (1H, dd, J₁¼6.6,

C₂₆H₂₆NaO₆requires 457.1627.

3.10.7. Compound 35g. Following the general procedure, 35g was

obtained as a colourless solid (42 mg, 39%), mp 134e136 ^ꢀC; R_f(50%

EtOAc/Hexanes) 0.55; IR (KBr): n_max3446, 2925, 1728, 1601, 1455,

J₂¼4.0 Hz), 3.67 (1H, dd, J₁¼6.7, J₂¼4.0 Hz), 3.52 (1H, d, J¼5.7 Hz); ¹³

C

NMR (100 MHz, CDCl₃): d_C208.2,157.2,157.0,132.0,131.8,129.9,125.7,

125.6, 121.2, 120.9, 111.2, 111.1, 74.7, 73.4, 71.4, 69.1, 68.2, 66.7, 66.4;

HRMS (ESI): MNa^þ, found 381.1310. C₂₀H₂₂NaO₆requires 381.1314.

1248 and 755 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.45 (4H, d,

;

J¼1.6 Hz), 7.35e7.31 (2H, m), 7.27e7.24 (2H, m), 7.07 (2H, d,

J¼8.2 Hz), 6.99e6.95 (2H, m), 5.05 (4H, d, J¼7.9 Hz), 4.52e4.43 (2H,

m), 4.41e4.33 (2H, m), 4.18 (2H, d, J¼18.4 Hz), 3.99 (1H, d,

J¼18.4 Hz), 3.57 (1H, dd, J₁¼6.8, J₂¼3.3 Hz), 3.34 (1H, dd, J₁¼6.9,

J₂¼3.3 Hz), 3.09 (1H, d, J¼4.8 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C

208.2, 157.3, 157.2, 137.1, 136.7, 130.9, 130.8, 129.9, 129.8, 129.6,

129.5,127.1,126.6,121.4, 121.3,113.0,112.8, 74.9, 74.6, 71.3, 71.1, 71.0,

69.5, 69.4; HRMS (ESI): MNa^þ, found 457.1621. C₂₆H₂₆NaO₆requires

457.1627.

3.10.2. Compound 35b. Following the general procedure, 35b was

obtained as a colourless liquid (71 mg, 34%); R_f(50% EtOAc/Hex-

anes) 0.55; IR (CH₂Cl₂): n_max3470, 2942, 2839, 1731, 1588, 1481,

1281 and 751 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.03e6.91 (3H,

m), 6.88e6.87 (3H, m), 4.73 (1H, d, J¼10.9 Hz), 4.57 (2H, t,

J¼10.3 Hz), 4.46e4.16 (8H, m), 4.01 (1H, dd, J₁¼10.1, J₂¼3.4 Hz), 3.70

(1H, dd, J₁¼10.1, J₂¼3.45 Hz), 3.81 (3H, s), 3.78 (3H, s), 3.53 (1H, br

s); ¹³C NMR (100 MHz, CDCl₃): d_C208.4, 152.8, 152.7, 146.8, 146.7,

131.3, 131.1, 124.3, 124.0, 123.3, 122.6, 112.9, 112.6, 74.9, 74.4, 72.9,

3.10.8. Compound 35h. Following the general procedure, 35h was

obtained as a colourless liquid (50 mg, 25%); R_f(50% EtOAc/

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7777

Hexanes) 0.55; IR (CH₂Cl₂): n_max3415, 2927, 2874, 1728, 1601 and

754 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.26 (2H, d, J¼7.8 Hz), 7.21

(2H, d, J¼8.6 Hz), 6.91e6.87 (2H, m), 6.82 (2H, d, J¼8.1 Hz),

4.61e3.28 (8H, m), 4.27e3.85 (9H, m), 3.70e3.67 (1H, m); ¹³C NMR

(100 MHz, CDCl₃): d_C208.9, 157.1, 156.9, 131.0, 131.0, 129.7, 129.6,

125.9, 125.7, 121.0, 120.9, 111.8, 111.6, 75.0, 74.1, 71.0, 70.1, 70.1, 69.0,

69.0, 68.2, 68.2; HRMS (ESI): MNa^þ, found 425.1571. C₂₂H₂₆NaO₇

requires 425.1576.

NMR (100 MHz, CDCl₃): d_C156.9, 156.8, 135.5, 133.7, 132.4, 130.3,

130.1, 129.4, 129.2, 127.3, 126.6, 126.4, 120.8, 117.9, 117.1, 111.7, 111.6,

74.7, 73.3, 72.8, 71.7, 71.2, 71.1, 70.7, 69.9, 69.8, 69.7, 69.0, 68.8, 68.4,

68.2, 38.6; HRMS (ESI): MNa^þ, found 511.2318. C₂₇H₃₆NaO₈requires

511.2308. The OH protons were not visible in the ¹H NMR spectrum.

3.12. Procedure for the synthesis of lactone appended mac-

rocyclic systems 37a,b

3.10.9. Compound 35i. Following the general procedure, 35i was

obtained as a colourless liquid (57 mg, 26%); R_f(50% EtOAc/Hex-

anes) 0.35; IR (CH₂Cl₂): n_max3441, 2926, 1730, 1602, 1494 and

To a solution of the corresponding substrate 35 (0.12 mmol) in

dry THF (2 mL) was added ethyl bromoacetate (4 equiv) followed by

indium powder (2 equiv) with vigorous stirring. The reaction

mixture was stirred at rt for 24 h. After this period, the reaction

mixture was diluted by adding water and extracted with EtOAc. The

combined extracts were dried with anhydrous Na₂SO₄and con-

centrated under vacuum and the crude mixture was puriﬁed by

silica gel column chromatography (EtOAc/Hexanes), which affor-

ded the corresponding compound 37 (see the corresponding Table/

Scheme for the speciﬁc entries).

751 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.24e7.17 (4H, m),

;

6.89e6.77 (4H, m), 4.58e4.33 (6H, m), 4.10e4.06 (4H, m),

3.84e3.70 (12H, m); ¹³C NMR (100 MHz, CDCl₃): d_C208.9, 157.0,

130.8, 130.7, 129.7, 129.5, 125.9, 125.8, 120.9, 120.8, 111.6, 111.6, 75.0,

74.0, 71.0, 70.9, 69.9, 68.9, 68.8, 68.0, 68.0; HRMS (ESI): MNa^þ,

found 469.1835. C₂₄H₃₀NaO₈requires 469.1838.

3.10.10. Compound 35j. Following the general procedure, 35j was

obtained as a colourless liquid (62 mg, 27%); R_f(50% EtOAc/Hex-

3.12.1. Compound 37a. Following the general procedure, 37a was

obtained as a colourless liquid (16 mg, 30%, single isomer); R_f(50%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max3460, 2934, 1783, 1455 and

anes) 0.35; IR (CH₂Cl₂): n_max3425, 2953, 1716, 1600 and 753 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.91 (1H, d, J¼7.7 Hz), 7.84 (1H, d,

J¼7.6 Hz), 7.56e7.33 (6H, m), 7.15e6.99 (4H, m), 5.60e5.13 (6H, m),

4.72e4.52 (3H, m), 3.41 (1H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C

203.0, 167.3, 166.2, 158.5, 158.2, 135.9, 134.3, 133.9, 133.4, 132.9,

132.2, 129.6, 128.9, 128.1, 127.9, 121.3, 121.2, 120.4, 119.7, 114.4, 114.1,

73.7, 69.4, 69.2, 67.0, 66.0; HRMS (ESI): MNa^þ, found 485.1221.

755 cm^ꢂ^{1 1}H NMR (400 MHz, CDCl₃): d_H7.35e7.27 (4H, m),

;

6.99e6.91 (4H, m), 4.76 (2H, dd, J₁¼7.9, J₂¼3.3 Hz), 4.61e4.46 (3H,

m), 4.12e4.01 (5H, m), 3.87e3.81 (2H, m), 3.57 (2H, d, J¼4.6 Hz),

2.75 (1H, d, J¼17.8 Hz), 2.44 (1H, d, J¼17.8 Hz), 1.97e1.84 (6H, m);

¹³C NMR (100 MHz, CDCl₃): d_C174.7, 157.7, 157.6, 131.5, 131.4, 130.2,

129.8, 125.6, 124.9, 120.7, 120.6, 111.9, 111.4, 80.8, 77.5, 72.8, 69.5,

69.0, 68.8, 68.3, 67.2, 39.8, 29.7, 29.6, 24.7; HRMS (ESI): MH^þ, found

443.2068. C₂₅H₃₁O₇requires 443.2070.

C

₂₆H₂₂NaO₈requires 485.1212.

3.11. Procedure for the synthesis of macrocyclic systems 36a,b

To a solution of the corresponding substrate 35 (0.12 mmol) in

anhydrous THF (2 mL) was added allyl bromide (4 equiv) followed

by indium metal powder (2 equiv) with vigorous stirring. The re-

action mixture was stirred at rt for 24 h. After this period, the re-

action mixture was diluted with water and extracted with EtOAc.

The combined extracts were dried with anhydrous Na₂SO₄and

concentrated under vacuum and puriﬁcation of the crude reaction

mixture by silica gel column chromatography (EtOAc/Hexanes)

afforded the corresponding allylated compound as a mixture of

diastereomers (see the corresponding Table/Scheme for the speciﬁc

entries).

3.12.2. Compound 37b. Following the general procedure, 37b was

obtained as a colourless liquid (30 mg, 23%, single isomer); R_f(40%

EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max3421, 2917, 2874, 1737, 1781,

1494 and 755 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.32e7.25 (4H,

m), 6.97 (2H, t, J¼7.4 Hz), 6.89 (2H, dd, J₁¼7.1, J₂¼3.2 Hz), 4.70e4.46

(4H, m), 4.25e4.08 (4H, m), 3.93e3.53 (14H, m), 2.75 (1H, d,

J¼17.8 Hz), 2.58 (1H, d, J¼17.8 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C

174.9, 157.3, 157.2, 131.3, 131.0, 130.0, 129.8, 125.9, 125.5, 120.9,

120.8, 111.8, 111.6, 81.6, 77.4, 72.9, 71.1, 71.0, 69.9, 69.6, 69.4, 68.2,

68.1, 68.0, 40.2; HRMS (ESI): MNa^þ, found 511.1944. C₂₆H₃₂NaO₉

requires 511.1944.

3.11.1. Compound 36a. Following the general procedure, 36a was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

3.13. General procedure for the synthesis of macrocyclic sys-

tems 38aeg having syn-1,2-dihydroxy functionality

umn chromatography as

a colourless liquid (32 mg, 63%)

(dr¼65:35); R_f(50% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max3469,

2919, 2873,1589,1603 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.25e7.17 (4H, m), 6.88e6.79 (4H, m), 5.85e5.76 (1H, m), 5.05e4.97

(2H, m), 4.54e4.01 (8H, m), 3.73e3.31 (5H, m), 3.04 (2H, br s),

2.35e1.94 (6H, m); ¹³C NMR (100 MHz, CDCl₃): d_C157.6, 157.6, 157.5,

133.8, 133.5, 132.0, 131.9, 131.8, 131.6, 130.0, 129.9, 129.8, 125.9,

125.8, 125.6, 125.5, 120.5, 120.5, 120.4, 118.1, 117.8, 111.5, 111.3, 111.3,

111.1, 74.9, 74.4, 73.8, 73.3, 72.7, 72.5, 72.0, 71.7, 69.4, 69.2, 69.1, 68.9,

67.8, 67.6, 67.4, 39.6, 38.5, 26.5, 26.5, 26.2; HRMS (ESI): MNa^þ,

found 451.2115. C₂₅H₃₂NaO₆requires 451.2097.

A solution of the corresponding substrate having two terminal

oleﬁns 4/21 (0.50 mmol) in CH₂Cl₂(14 mL) and Grubbs’s catalyst

(ﬁrst or second generation, 2.5e5 mol %) was reﬂuxed for an ap-

propriate time (see the Table/Scheme for speciﬁc entry). Then, the

solvent was removed under vacuum and the resultant crude re-

action mixture (macrocyclic oleﬁn) was used as such for the next

step. Subsequently, in an another RB ﬂask, a suspension of NaIO₄

(1.5 equiv) in H₂O (0.3 mL) was treated with CeCl₃$7H₂O (0.1 equiv)

and heated gently until the reaction colour was bright yellow, at

this point the suspension was diluted with MeCN (3 mL) and cooled

to 0 ^ꢀC. Then, to this yellow suspension was added the macrocyclic

oleﬁn obtained in the ﬁrst step prepared as a solution (in 3 mL of

EtOAc). Then, the combined organic reaction mixture was stirred at

3.11.2. Compound 36b. Following the general procedure, 36b was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless liquid (35 mg,

60%) (dr¼80:20); R_f(50% EtOAc/Hexanes) 0.55; IR (CH₂Cl₂): n_max

0

^ꢀC until the oxidation reaction was complete (approximately

30 min). After this, the reaction was quenched with the addition of

solid Na₂SO₃and Na₂SO₄and stirred for 10 min. Then, the solution

was ﬁltered through ﬁltration funnel and the ﬁltrate was dried over

anhydrous Na₂SO₄, concentrated under vacuum and the crude

mixture was puriﬁed by silica gel column chromatography (EtOAc/

3464, 2923, 2855, 1639, 1494 and 753 cm^{ꢂ1 1}H NMR (400 MHz,

;

CDCl₃): d_H7.33e7.26 (4H, m), 6.99e6.95 (2H, m), 6.89e6.86 (2H,

m), 5.94e5.86 (1H, m), 5.10e5.06 (2H, m), 4.65e4.53 (4H, m),

4.19e4.16 (4H, m), 3.94e3.45 (13H, m), 2.40 (2H, d, J¼7.2 Hz); ¹³C

7778

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

Hexanes), to afford the corresponding macrocyclic system 38 as

a mixture of diastereomers (see the corresponding Table/Scheme

for the speciﬁc entries).

45%) (dr¼80:20); R_f(50% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

3448, 2928, 1699, 1490 and 756 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃):

d_H7.82 (2H, d, J¼7 Hz), 7.45 (2H, t, J¼7.6 Hz), 7.01 (2H, t, J¼7.4 Hz),

6.92 (2H, d, J¼8.4 Hz), 4.47e4.43 (4H, m), 4.19e4.14 (6H, m),

3.93e3.74 (10H, m); ¹³C NMR (100 MHz, CDCl₃): d_C167.4, 157.7,

133.6, 132.3, 120.7, 120.5, 112.8, 71.4, 69.9, 68.6, 68.4, 65.8; HRMS

(ESI): MNa^þ, found 499.1590. C₂₄H₂₈NaO₁₀requires 499.1580.

3.13.1. Compound 38a. Following the general procedure, 38a was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography as

a colourless liquid (41 mg, 23%)

(dr¼70:30); R_f(30% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max3412,

2924,1602,1494,1258 and 751 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

7.27e7.22 (4H, m), 6.90 (2H, dt, J₁¼7.8, J₂¼0.9 Hz), 6.88e6.84 (2H,

m), 4.53e4.44 (4H, m), 4.32e4.29 (4H, m), 3.74e3.72 (2H, m),

3.59e3.51 (4H, m), 2.81 (1H, br s), 2.70 (1H, br s); ¹³C NMR

(100 MHz, CDCl₃): d_C157.3, 157.1, 132.0, 131.8, 129.9, 129.8, 126.3,

121.0, 121.0, 111.3, 111.2, 71.4, 71.3, 70.9, 68.5, 68.0, 66.9, 66.8; HRMS

(ESI): MNa^þ, found 383.1473. C₂₀H₂₄NaO₆requires 383.1471.

3.13.7. Compound 38g. Following the general procedure, 38g was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a brown solid (95 mg, 41%)

(dr¼90:10); mp 174e176 ^ꢀC; IR R_f(50% EtOAc/Hexanes) 0.45;

(CH₂Cl₂): n_max3386, 2923, 1704, 1600, 1453, 1260 and 750 cm^ꢂ1; ¹H

NMR (400 MHz, CDCl₃): d_H7.81 (2H, dd, J₁¼6.1, J₂¼1.8 Hz),

7.53e7.42 (6H, m), 7.08e7.04 (4H, m), 5.31 (4H, dd, J₁¼13.8,

J₂¼11.8 Hz), 4.40e4.30 (4H, m), 3.99e3.97 (2H, m), 2.29e2.28 (2H,

m); ¹³C NMR (100 MHz, CDCl₃): d_C167.3, 157.7, 134.7, 133.5, 132.0,

129.7, 128.9, 121.3, 121.2, 113.9, 68.9, 68.9, 65.5; HRMS (ESI): MH^þ,

found 465.1546. C₂₆H₂₅O₈requires 465.1549.

3.13.2. Compound 38b. Following the general procedure, 38b was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless liquid (62 mg,

30%) (dr¼80:20); R_f(50% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

3456, 2936, 2866, 1602, 1454 and 753 cm^ꢂ1

;

¹H NMR (400 MHz,

3.14. Procedure for the synthesis of 1,2-bis(2-(2-(chlor-

omethyl)phenoxy)ethoxy)ethane (23c)

CDCl₃): d_H7.33e7.29 (4H, m), 6.96e6.90 (4H, m), 4.61e4.48 (4H, m),

4.06 (4H, t, J¼5.8 Hz), 3.89e3.60 (6H, m), 3.05e3.03 (2H, m),

1.89e1.88 (4H, m),1.65e1.63 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C

157.7, 131.3, 129.8, 126.1, 120.4, 111.6, 72.0, 70.2, 69.2, 67.8, 29.2,

25.9; HRMS (ESI): MNa^þ, found 439.2116. C₂₄H₃₂NaO₆requires

439.2097.

To a solution of ((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))

bis(oxy))bis(2,1-phenylene))dimethanol (5 mmol) in dry DCM

(15 mL) was added SOCl₂(10 mmol) drop wise at room temperature

and the reaction mixture was stirred for 3 h. Then, the mixture was

concentrated in vacuum and used as such (without further puriﬁ-

cation) in the next step. The compound 23c was obtained as

a brown colour liquid (1.79 g, 90%); R_f(20% EtOAc/Hexanes) 0.45; IR

3.13.3. Compound 38c. Following the general procedure, 38c was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless liquid (64 mg,

32%) (dr¼80:20); R_f(50% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

(CH₂Cl₂): n_max2923, 2873, 1602, 1453 and 752 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.33 (2H, dd, J₁¼7.1, J₂¼1.5 Hz), 7.27e7.23 (2H,

m), 6.92 (2H, t, J¼7.5 Hz), 6.86 (2H, d, J¼8.1 Hz), 4.65 (4H, s), 4.17

(4H, t, J¼5.0 Hz), 3.89 (4H, t, J¼4.7 Hz), 3.76 (4H, s); ¹³C NMR

(100 MHz, CDCl₃): d_C156.6,130.6,130.0,126.2,121.0,112.1, 71.1, 69.7,

68.2, 41.7; HRMS (ESI): MNa^þ, found 421.0944. C₂₀H₂₄Cl₂NaO₄re-

quires 421.0949.

3445, 2926, 2873, 1590, 1452 and 754 cm^{ꢂ1 1}H NMR (400 MHz,

;

CDCl₃): d_H7.33e7.28 (4H, m), 6.97 (2H, dt, J₁¼7.1, J₂¼0.94 Hz), 6.92

(2H, d, J¼8.6 Hz), 4.69e4.50 (5H, m), 4.21e3.91 (9H, m), 3.71e3.66

(4H, m), 2.99 (2H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C157.4, 131.4,

131.4, 129.8, 126.3, 126.3, 121.0, 112.0, 71.5, 71.4, 70.8, 70.2, 70.0,

69.0, 68.9, 68.5, 68.4; HRMS (ESI): MNa^þ, found 427.1730.

C

₂₂H₂₈NaO₇requires 427.1733.

3.15. Procedure for the synthesis of compound 29a

3.13.4. Compound 38d. Following the general procedure, 38d was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless liquid (56 mg,

25%) (dr¼87:17); R_f(50% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

To a mixture of 23a (1 mmol) in dry DMF (2 mL) was added NaH

(4 mmol, 55e60 % suspension in mineral oil) at room temperature.

The mixture was stirred at room temperature for 15 min and then,

1H-pyrrole-2-carbaldehyde (2 mmol) was added to the reaction

mixture. Next, the resulting mixture was stirred for 20 h at room

temperature. After this period, few drops of EtOH was added and

stirred for 10 min and then, the reaction mixture was poured on to

water (20 mL) and extracted with ethyl acetate (3ꢁ10 mL). The

combined organic layers were dried over anhydrous Na₂SO₄and

concentrated and the crude reaction mixture was puriﬁed by silica

gel column chromatography (30% EtOAc/Hexanes) to afford the

3412, 2924, 1602, 1494, 1258 and 751 cm^{ꢂ1 1}H NMR (400 MHz,

;

CDCl₃): d_H7.31e7.27 (4H, m), 6.95 (2H, dt, J₁¼7.4, J₂¼0.9 Hz), 6.88

(2H, d, J¼8.5 Hz), 4.60 (2H, s), 4.19e4.17 (5H, m), 3.94e3.73 (16H,

m), 3.02 (1H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C157.2, 131.0, 129.6,

126.3, 120.8, 111.6, 71.7, 71.1, 70.9, 70.0, 69.1, 68.2; HRMS (ESI):

MNa^þ, found 471.1998. C₂₄H₃₂NaO₈requires 471.1995.

3.13.5. Compound 38e. Following the general procedure, 38e was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless solid (93 mg, 43%)

(dr¼80:20); mp 161e163 ^ꢀC; R_f(50% EtOAc/Hexanes) 0.45; IR

compound 29a, as a colourless solid (322 mg, 73%); mp

125e127 ^ꢀC; R_f(20% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max2924,

2854,1663,1604,1452 and 755 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

9.58 (2H, s), 7.28e7.24 (3H, m), 6.98e6.86 (9H, m), 6.25e6.23 (2H,

m), 5.59 (4H, s), 4.09 (4H, br s), 2.00 (4H, br s); ¹³C NMR (100 MHz,

CDCl₃): d_C179.4, 156.2, 131.7, 129.1, 128.8, 126.0, 124.5, 120.7, 111.0,

109.8, 67.4, 47.2, 26.0; HRMS (ESI): MH^þ, found 457.2126.

(CH₂Cl₂): n_max3450, 2929, 1460, 1490 and 756 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.48 (4H, s), 7.38e7.28 (4H, m), 7.10 (2H, d,

J¼7.9 Hz), 6.99 (2H, t, J¼7.4 Hz), 5.10 (4H, d, J¼1.9 Hz), 4.48 (4H, s),

3.50e3.30 (6H, m), 2.67 (2H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C

157.4, 136.9, 131.1, 129.8, 129.1, 127.0, 121.2, 112.7, 72.7, 70.7, 69.9,

69.4; HRMS (ESI): MNa^þ, found 459.1790. C₂₆H₂₈NaO₆requires

459.1784.

C₂₈H₂₉N₂O₄requires 457.2127.

3.16. Procedure for the synthesis of ((((benzylazanediyl)bis(-

ethane-2,1-diyl))bis(oxy))bis(2,1-phenylene))dimethanol (3t)

3.13.6. Compound 38f. Following the general procedure, 38f was

obtained (as a mixture of diastereomers) after puriﬁcation by col-

umn chromatography on silica gel as a colourless liquid (107 mg,

To a mixture of bis-aldehyde 2t (1 mmol) in ethanol/THF (3 mL

and 3 mL) was added NaBH₄(10 mmol) at room temperature. The

resulting mixture was stirred at room temperature for 30 min. After

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

7779

this period, the reaction mixture was poured on to cold water

(20 mL). Then, the mixture was extracted using ethyl acetate

(3ꢁ10 mL) and was puriﬁed by silica gel column chromatography

by using (30% EtOAc/Hexanes) as a colourless liquid (930 mg, 92%);

R_f(30% EtOAc/Hexanes) 0.42; IR (CH₂Cl₂): n_max3381, 2922, 1602,

1492 and 753 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H7.40e7.22 (9H,

m), 6.94 (2H, t, J¼7.5 Hz), 6.84 (2H, d, J¼8.1 Hz), 4.58 (4H, s), 4.15

(4H, t, J¼5.2 Hz), 3.81 (2H, s), 3.01 (4H, t, J¼5.3 Hz); ¹³C NMR

(100 MHz, CDCl₃): d_C156.9, 137.5, 130.0, 129.4, 129.3, 129.0, 128.5,

127.4, 121.0, 111.8, 65.9, 61.9, 59.7, 53.7; HRMS (ESI): MH^þ, found

408.2178. C₂₅H₃₀NO₄requires 408.2175. Two OH protons were not

appeared in the ¹H NMR.

organic layers were dried over anhydrous Na₂SO₄and the organic

phase was concentrated, and the resulting crude reaction mixture

was puriﬁed by silica gel column chromatography (20% EtOAc/

Hexanes) to give the desired product 31 as a colourless liquid

(421 mg, 75%); R_f(20% EtOAc/Hexanes) 0.65; IR (CH₂Cl₂): n_max2931,

1720, 1602, 1452, 1275 and 711 cm^ꢂ1; ¹H NMR (400 MHz, CDCl₃): d_H

8.08 (4H, d, J¼7.1 Hz), 7.53 (2H, t, J¼6.8 Hz), 7.42 (6H, t, J¼7.7 Hz),

7.27 (2H, t, J¼7.7 Hz), 6.98 (4H, d, J¼7.9 Hz), 6.48 (2H, q, J¼7.2 Hz),

5.85e5.77 (2H, m), 5.06e4.97 (4H, m), 4.51 (1H, d, J¼6.4 Hz), 4.45

(2H, s), 4.38 (1H, d, J¼6.3 Hz), 2.73e2.69 (4H, m); ¹³C NMR

(100 MHz, CDCl₃): d_C165.6, 165.5, 155.2, 133.7, 132.9, 130.6, 130.6,

129.6, 129.2, 129.2, 128.8, 128.4, 126.6, 126.5, 121.1, 117.7, 117.7, 112.0,

112.0, 70.6, 70.5, 67.1, 67.0, 39.7; HRMS (ESI): MNa^þ, found

585.2258. C₃₆H₃₄NaO₆requires 585.2253. Isolated as a mixture of

diastereomers (50:50) and ¹H and ¹³C NMR values corresponding to

both isomers.

3.17. Procedure for the synthesis of 1,12-bis(2-(allyloxy)phe-

nyl)-5,8-dioxa-2,11-dithiadodecane (17)

To a suspension of 2,2⁰-(ethane-1,2-diylbis(oxy))diethanethiol

16 (2 mmol) in ethanol (10 mL) at room temperature was added

KOH (4 mmol). The reaction was stirred at room temperature for

1 h. Then, to this solution, a solution of 1-(allyloxy)-2-(chlor-

omethyl)benzene 15 (4 mmol) in toluene (5 mL) was added drop

wise. The resulting mixture was stirred for additional 1 h and then,

the reaction mixture was ﬁltered. Filtrate was added to the DCM

(20 mL) and washed with H₂O (3ꢁ10 mL). The combined organic

layers were dried over anhydrous Na₂SO₄and the organic phase

was concentrated, and the resulting crude reaction mixture was

puriﬁed by silica gel column chromatography (20% EtOAc/Hexanes)

to give the desired product 17 as a colourless liquid (663 mg, 70%);

R_f(20% EtOAc/Hexanes) 0.42; IR (CH₂Cl₂): n_max2923, 1745, 1384,

3.20. Procedure for the synthesis of compound 11 from 4u

A solution of the substrate 4u (0.25 mmol) in CH₂Cl₂(7 mL) and

Grubbs’s catalyst (ﬁrst generation, 5 mol %) was reﬂuxed for 6 h.

Then, the mixture was concentrated in vacuum and to the resulting

crude mixture was added dry THF (2 mL) and Pd/C (10 mol %). Then,

the reaction mixture was stirred at room temperature overnight

under H₂atm (1 atm). Next, the reaction mixture was ﬁltered by

using a layer of Celite pad and the ﬁltrate was evaporated under

vacuum and the resulting crude reaction mixture was puriﬁed by

silica gel column chromatography to afford the compound 11 as

a colourless liquid (58 mg, 63%) R_f(40% EtOAc/Hexanes) 0.55; IR

1260 and 750 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.30e7.19 (4H,

(CH₂Cl₂): n_max2932, 2856, 1590, 1366 and 753 cm^{ꢂ1 1}H NMR

;

m), 6.92 (2H, t, J¼7.44 Hz), 6.87 (2H, d, J¼8.2 Hz), 6.12e6.04 (2H, m),

5.48e5.43 (2H, m), 5.31e5.28 (2H, m), 4.59 (4H, td, J₁¼5.1,

J₂¼1.5 Hz), 3.82 (4H, s), 3.63 (4H, t, J¼7.1 Hz), 3.60 (4H, s), 2.69 (4H,

t, J¼7.1 Hz); ¹³C NMR (100 MHz, CDCl₃): d_C156.2, 133.3, 130.4, 128.2,

127.3, 120.6, 117.2, 111.9, 70.9, 70.2, 68.8, 30.9, 30.7; HRMS (ESI):

MNa^þ, found 497.1804. C₂₆H₃₄NaO₄S₂requires 497.1796.

(400 MHz, CDCl₃): d_H7.31e7.26 (4H, m), 6.97e6.91 (4H, m), 4.54

(4H, s), 4.24 (4H, t, J¼4.6 Hz), 3.55e3.53 (4H, m), 3.21 (4H, t,

J¼4.6 Hz), 1.71e1.69 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C157.1,

131.0, 129.5, 126.4, 120.8, 111.9, 69.5, 68.1, 67.5, 49.0, 25.9; HRMS

(ESI): MH^þ, found 372.2179. C₂₂H₃₀NO₄requires 372.2175. The NH

proton was not visible in the ¹H NMR spectrum.

3.18. General procedure for the synthesis of compound 18e

3.21. Procedure for the synthesis of compound 12 from 11

To a solution of 2-(allyloxy)benzoic acid 18c (1 mmol), 2,2⁰-

(ethane-1,2-diylbis(oxy))diethanol 18d (0.5 mmol) and 4-(dime-

thylamino)pyridine (DMAP, 1 mmol) in CH₂Cl₂(2.5 mL) was added

1,3-dicyclohexylcarbodiimide (1.5 mmol) in small fractions. The

reaction mixture was stirred at room temperature for 2 h. The

resulting pale yellow suspension was ﬁltered through ﬁltration

funnel. The ﬁltrate was concentrated and puriﬁed by silica gel

column chromatography (20% EtOAc/Hexanes) to give the desired

product 18e as a colourless liquid (117 mg, 50%); R_f(20% EtOAc/

Hexanes) 0.65; IR (CH₂Cl₂): n_max2872, 1726, 1600, 1450 and

A solution of the substrate 11 (0.08 mmol), 1,4-bis(-

bromomethyl)benzene (0.04 mmol), anhydrous K₂CO₃(0.10 mmol)

in dry CH₃CN was reﬂuxed for 30 h. After this period, the reaction

mixture was allowed to cool at room temperature and this solution

was added to H₂O (5 mL). Then, the mixture was extracted with

ethyl acetate (3ꢁ10 mL), the combined organic layers were dried

over anhydrous sodium sulfate and concentrated. Puriﬁcation of

the crude reaction mixture by silica gel column chromatography

(40% EtOAc/Hexanes) afforded the compound 12 as a colourless

liquid (55 mg, 82%); R_f(30% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

756 cm^ꢂ1

;

¹H NMR (400 MHz, CDCl₃): d_H7.84 (2H, dd, J₁¼6.9,

3040, 2925, 2855, 1603, 1494 and 752 cm^{ꢂ1 1}H NMR (400 MHz,

;

J₂¼1.8 Hz), 7.47e7.42 (2H, m), 7.00e6.95 (4H, m), 6.11e6.04 (2H, m),

5.54e5.49 (2H, m), 5.32e5.29 (2H, m), 4.64 (4H, td, J₁¼4.9,

J₂¼1.6 Hz), 4.46 (4H, t, J¼5 Hz), 3.83 (4H, t, J¼4.9 Hz), 3.72 (4H, s);

¹³C NMR (100 MHz, CDCl₃): d_C166.1, 158.2, 133.4, 132.8, 131.8, 120.4,

120.4, 117.5, 113.6, 70.6, 69.5, 69.3, 63.9; HRMS (ESI): MNa^þ, found

493.1848. C₂₆H₃₀NaO₈requires 493.1838.

CDCl₃): d_H7.37 (4H, s), 7.34 (4H, dd, J₁¼8.3, J₂¼1.6 Hz), 7.29e7.24

(4H, m), 6.95 (4H, t, J¼7.4 Hz), 6.86 (4H, d, J¼8.1 Hz), 4.53 (8H, s),

4.13 (8H, t, J¼5.9 Hz), 3.86 (4H, s), 3.59 (8H, t, J¼6.1 Hz), 3.24 (8H, t,

J¼5.9 Hz), 1.75e1.74 (8H, br s); ¹³C NMR (100 MHz, CDCl₃): d_C157.2,

138.5, 130.7, 129.2, 128.7, 126.7, 120.5, 111.3, 70.1, 68.1, 67.2, 58.5,

53.6, 26.0; HRMS (ESI): MH^þ, found 845.4746. C₅₂H₆₅N₂O₈requires

845.4741.

3.19. Procedure for the synthesis of ((ethane-1,2-diylbis(oxy))

bis(2,1-phenylene))bis(but-3-ene-1,1-diyl) dibenzoate (31)

3.22. Procedure for the synthesis of pinacol boronate moiety

installed macrocyclic crownophane 39

To

a

suspension of 1,1⁰-((ethane-1,2-diylbis(oxy))bis(2,1-

phenylene))bis(but-3-en-1-ol) 30a (1 mmol) in DCM (4 mL) at

room temperature was added MgBr₂(2.5 equiv), Et₃N (4 equiv) and

(PhCO)₂O (3 equiv). The reaction was stirred at room temperature

for 12 h, after this period, the reaction mixture was diluted with

DCM and washed with satd solution of NaHCO₃. The combined

To a solution of aryl boronic acid (0.12 mmol) in anhydrous THF

(2 mL) was sequentially added a solution of FeCl₃(5 mol %) in H₂O

(0.5 mL), imidazole (0.36 mmol) and the diol substrate 38e

(0.12 mmol). The resulting reaction mixture was stirred at room

temperature for 3 h. The reaction mixture was diluted with H₂O

7780

Naveen, S.A. Babu / Tetrahedron 71 (2015) 7758e7781

ꢁ

ꢁ ꢀ

22 , 6301; (b) Kralj, M.; Tusek-Bozic, L.; Frkanec, L. ChemMedChem 2008 , 3 , 1478;

(5 mL) and extracted with Et₂O (3ꢁ8 mL). The combined organic

extracts were dried over Na₂SO₄and solvent was evaporated under

vacuum. The resulting oil was then puriﬁed by a ﬁltration through

a silica gel plug (eluting with Et₂O) to afford the macrocyclic

compound 39 as a mixture of diastereomers (dr¼85:15); colourless

liquid (56 mg, 90%); R_f(50% EtOAc/Hexanes) 0.45; IR (CH₂Cl₂): n_max

€

ꢀ

(c) Huszthy, P.; Tunde Toth, T. Per. Pol. Chem. Eng. 200 7 , 51 , 45.

5. For selected articles/reviews dealing on the periphery modiﬁcation of crown

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1; (b) Delgado, M.; Martin, J. D. Tetrahedron Lett. 1997 , 38 , 8387; (c) Ibrahim, Y.;

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2922, 1603, 1493, 1455, 1259, 1091 and 750 cm^{ꢂ1 1}H NMR

;

(400 MHz, CDCl₃): d_H7.90 (2H, dd, J₁¼6.7, J₂¼1.3 Hz), 7.48 (4H, s),

7.44e7.32 (7H, m), 7.08 (2H, d, J¼7.7 Hz), 6.99 (2H, t, J¼6.3 Hz), 5.14

(4H, s), 4.57 (4H, dd, J₁¼18.4, J₂¼10.8 Hz), 4.24e4.22 (2H, m),

3.42e3.35 (4H, m); ¹³C NMR (100 MHz, CDCl₃): d_C157.2,137.0,135.1,

131.5, 131.4, 129.7, 128.8, 127.7, 127.0, 121.1, 112.8, 78.6, 72.6, 70.4,

69.2; HRMS (ESI): MNa^þ, found 545.2128. C₃₂H₃₁BNaO₆requires

545.2111.

Acknowledgements

€

Konig, B.; Horn, C. Synlett 1996 , 1013; (e) Ibrahim, Y. A.; Behbehani, H.; Ibrahim,

This work was funded by IISER-Mohali. We thank the NMR,

HRMS and X-ray facilities of IISER-Mohali. Naveen thanks the UGC

for a SRF fellowship.

M. R. Tetrahedron Lett. 2002 , 43 , 4207; (f) Arico, F.; Mobian, P.; Kern, J. M.;

Sauvage, J. P. Org. Lett. 2003 , 5 , 1887; (g) Umemiya, T.; Takeuchi, D.; Osakada, K.

J. Organomet. Chem. 2006 , 691 , 5260; (h) Malhas, R. N.; Ibrahim, Y. A. Synthesis

2006 , 3261; (i) Ibrahim, Y. A. J. Mol. Catal. A: Chem. 2006 , 254 , 43; (j) Iwamoto,

H.; Itoh, K.; Nagamiya, H.; Fukazawa, Y. Tetrahedron Lett. 2003 , 44 , 5773; (k)

Maynard, H. D.; Grubbs, R. H. Macromolecules 1999 , 32 , 6917; (l) Guidry, E. N.;

Cantrill, S. J.; Stoddart, J. F.; Grubbs, R. H. Org. Lett. 2005 , 7 , 2129.

Supplementary data

7. For selected articles/reviews dealing on the RCM-based synthesis of small rings

to macrocycles, see: (a) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed.

Supplementary data (Copies of the ¹H NMR and ¹³C NMR spectra

of all key intermediates and ﬁnal products) associated with this

article can be found in the online version, at http://dx.doi.org/

10.1016/j.tet.2015.06.070. These data include MOL ﬁles and InChi-

Keys of the most important compounds described in this article.

ꢀ

2006 , 45 , 6086; (b) Schmidt, B. J. Mol. Catal. A: Chem. 2006 , 254 , 53; (c) Do-

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19. Crystallographic data of X-ray crystal structures of the compounds 5jA (major,

E-isomer, CCDC 921754), 5jB (minor, Z-isomer, CCDC 921753), 22a (CCDC

1056418), 32A (R*,R*, CCDC 1056420), 32B (R*,S*, CCDC 1056417), 34aA (major

isomer, CCDC 908393), 35a (CCDC 1056419) and 35d (CCDC 910641) have been

deposited with the Cambridge Crystallographic Data Centre.

€

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Ring-closing metathesis reaction-based synthesis of new classes of polyether macrocyclic systems

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