Synthesis of Macrocyclic Lactones via Ring Transformation of 4-(ω-Hydroxyalkyl)-1,3-oxazol-5(4H)-ones

Helv. Chim. Acta 2016, 99, 1 – 16

1

201600023

FULL PAPER

Synthesis of Macrocyclic Lactones via Ring Transformation of 4-(x-Hydroxyalkyl)-1,3-

oxazol-5(4H)-ones

by Stephan P. Fritschi^a)^†)^‡), Anthony Linden^a), and Heinz Heimgartner*^a)

a

€

) Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich (phone: +41-44-635 4282;

e-mail: heinz.heimgartner@chem.uzh.ch)

^†) Present address: Carbogen Amcis AG, Hauptstrasse 171, CH-4416 Bubendorf

The synthesis of a-benzamido-a-benzyl lactones 23 of various ring size was achieved either via ‘direct amide cyclization’

by treatment of 2-benzamido-2-benzyl-x-hydroxy-N,N-dimethylalkanamides 21 in toluene at 90 – 110° with HCl gas or by

‘ring transformation’ of 4-benzyl-4-(x-hydroxyalkyl)-2-phenyl-1,3-oxazol-5(4H)-ones under the same conditions. The

precursors were obtained by C-alkylations of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one (15) with THP- or TBDMS-protected x-

hydroxyalkyl iodides. Ring opening of the THP-protected oxazolones by treatment with Me₂NH followed by deprotection of

the OH group gave the diamides 21, whereas deprotection of the TBDMS series of oxazolones 25 with TBAF followed by

treatment with HCl gas led to the corresponding lactones 23 in a one-pot reaction.

Keywords: Lactones, 1,3-Oxazol-5(4H)-ones, Ring transformation, Direct amide cyclization, Alkylation, X-Ray crystallography.

enlargement reaction via nucleophilic attack of the OH

group onto C(5)=O of 2 to give lactones of type 6 (Scheme 1)

Introduction

Since the pioneering work of Erlenmeyer on the synthesis

of azlactones [1], 1,3-oxazol-5(4H)-ones have been recog-

nized as an important class of heterocycles [2]. Their syn-

thesis, reactivity, and use as intermediates in organic

synthesis have been described in several reviews [3], and

the continuing interest in the chemistry of 1,3-oxazol-5

(4H)-ones is documented by a large series of recent publi-

cations (e.g., [4]).

[9]. This reaction, called ‘direct amide cyclization’, has been

used extensively for the synthesis of Aib-containing

cyclodepsipeptides [9 – 11]. The same concept, under dif-

ferent reaction conditions, proved to be successful for the

preparation of Aib-containing cyclopeptides [11][12].

It was also shown that amino acid derivatives of type

8 under the conditions of the ‘direct amide cyclization’

react to give 13- to 15-membered lactams 10, albeit in

We became interested in 1,3-oxazol-5(4H)-ones as low yield (11 – 27%) [13] (Scheme 2). Most likely, 1,3-

intermediates in the ‘azirine/oxazolone method’ for the oxazol-5(4H)-ones 9 are formed as intermediates, which

synthesis of peptides containing a,a-disubstituted a-amino undergo a ring transformation via nucleophilic attack of

acids [5][6]. It has been shown that peptides of type 1

the amino group onto C(5)=O of 9. An analogous ring

with a C-terminal Aib-amide on treatment with HCl in transformation has been described recently by Rai et al.

toluene at elevated temperature form 1,3-oxazol-5(4H)- [4g] (Scheme 2): although 2-phenyl-1,3-oxazol-5(4H)-one

ones 2, which in the presence of nucleophiles sponta- (11) and the tosylated aziridine 12 in the ionic liquid

neously react under ring opening to give, e.g., esters 3

[6a][6c][6d] (Scheme 1). Furthermore, it was proposed

that the DCC-coupling of peptides containing a terminal

[bmim]OH at room temperature react to give the oxa-

zolone derivative 13, the corresponding pyrrolidine 14

was formed in the presence of I₂as a 96:4 mixture of cis/

Aib-acid with amino acid esters 4 leads to peptides 5 via trans-isomers. It has been shown that 13 is an intermedi-

an intermediate 1,3-oxazol-5(4H)-one 2 [6b – 6e] (cf. also ate, which undergoes ring transformation to yield 14 by

[4e][7]). The smooth and selective cyclization to give 1,3- treatment with I₂in [bmim]OH at room temperature.

oxazol-5(4H)-ones may be explained by the Thorpe–

Ingold (gem-dimethyl) effect [8].

Based on the results described above, it was of inter-

est to study the ‘direct amide cyclization’ of compounds

In Aib-amides of type 1 with an alcohol function in of type 8 bearing an OH instead of the NH₂group in the

R¹, the intermediate 2 undergoes a spontaneous ring side chain as well as the corresponding ring transforma-

tion of analogues of 9 with a (CH₂)_nOH group at C(4).

Preliminary experiments with compounds 8 with a

(CH₂)_nOH side chain were reported many years ago [14]

(cf. also [11]). In the present report, we describe the

‡

€ €

Part of the Ph.D. thesis of S. P. F., Universitat Zurich,

)

1995.

€

DOI: 10.1002/hlca.201600023

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Helv. Chim. Acta 2016, 99, 1 – 16

Scheme 1

Scheme 2

extension of the study in detail together with the crystal

structures of some of the prepared macrocyclic lactones.

selectively the alcohol function were unsuccessful, and

complex mixtures of products were formed. For this rea-

son, the mixtures of 17 and 18 were treated with

Me₂NH in MeCN at room temperature. After chromato-

graphic puriﬁcation, the diamides 20 were obtained and

subsequently deprotected by treatment with pyridinium

tosylate (Py ꢀ TsOH) in boiling EtOH [17] to give com-

Results and Discussion

Motivated by the results of the preliminary study [14], we

planned to prepare 1,3-oxazol-5(4H)-ones of type 17 with

THP-protected alkanol substituents at C(4) (Scheme 3). pounds 21 in good yields. Finally, the ‘direct amide

The alkylation of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one cyclization’ of 21b (n = 11), i.e., treatment of a solution

(15) [15] with 2-[(x-iodoalkyl)oxy]tetrahydropyrans 16 in toluene at reﬂux with HCl gas for ca. 2 h, gave the lac-

[16] in THF/HMPT with LDA at 15 – 20° led to mixtures tone 23b in 86% yield (with respect to 21b). Under the

of the desired C(4)-alkylated 1,3-oxazol-5(4H)-ones 17 same reaction conditions, 23a (n = 9) was obtained in

and the isomeric O-alkylated 1,3-oxazoles 18 (ratio ca. only 43% yield. In addition, 4-benzyl-4-(9-hydroxynonyl)-

2:1 to 4:1)¹). Unfortunately, all attempts to deprotect

2-phenyl-1,3-oxazol-5(4H)-one, the proposed intermediate

in the ‘direct amide cyclization’ is the corresponding

hydrochloride 22a (Scheme 3) – was isolated in 55%

yield. Obviously, in this case, the reaction time was too

short for complete conversion.

¹) In the case of the alkylation with 2-[(11-iodoundecyl)oxy]

tetrahydropyran (16b), butyl 2-benzamido-2-benzyl-13-[(tet-

rahydropyran-2-yl)oxy]tridecanoate (19, 11%) was isolated in

addition to 17b/18b.

The structures of the products 23 were conﬁrmed from

their spectroscopic data and by X-ray crystallography

(Fig. 1). Since for both molecules the space group is cen-

trosymmetric (P2₁/c), the compounds in the crystals are

racemic. Furthermore, in the case of 23a, the benzyl

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Helv. Chim. Acta 2016, 99, 1 – 16

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Scheme 3

Fig. 1. ORTEP Plot [18] of the molecular structures of the 12- and 14-membered lactones 23a (major conformation) and 23b (50% probability

ellipsoids, arbitrary numbering of atoms).

group is disordered over two nearly equally occupied con-

formations.

In summary, although the described protocol allows

leading to the O-protected derivatives in 81 – 99% yield

[16]²). The latter were transformed into the correspond-

ing iodo compounds 24 by treatment with excess NaI in

the synthesis of 14- and 12-membered lactones 23, the boiling acetone (Finkelstein reaction) [20]³). The subse-

reaction sequence via ring opening of 17, subsequent quent alkylation of the 1,3-oxazolone 15 using pure

deprotection of 20, and cyclization via the oxazolone 12-{[(tert-butyl)dimethylsilyl]oxy}-1-iodododecane

(24c,

intermediate 22 is not very straightforward. Deprotec-

tion of the alcohol function in 17 followed by ring trans-

n = 12) under the conditions described for the THP-

formation to give the lactone would be

a more

²) The desired O-protected x-bromoalkanols were, in some

cases, contaminated with variable amounts of the corre-

sponding O-protected x-chloroalkanols.

³) For the halogen exchange, the obtained mixtures of bromo

and chloro derivatives were used. Under the chosen reaction

conditions, only the bromo compounds were transformed to

the desired O-protected x-iodoalkanols [16]. For the subse-

quent alkylations of oxazolone 15, mixtures of iodo and

chloro derivatives were used.

attractive approach. Therefore, a different OH-protect-

ing group was desired, which could be cleaved without

destroying the oxazolone moiety in compounds of

type 17.

A suitable choice was the (tert-butyl)dimethylsilyl

(TBDMS) group, which allows deprotection by treatment

with F^ꢁions [19]. The x-bromoalkanols in DMF were

treated with TBDMSCl and imidazole at 25° for 1.5 h

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Helv. Chim. Acta 2016, 99, 1 – 16

Scheme 4

Table 1. Alkylations of 1,3-oxazol-5(4H)-one 15 with x-{[(tert-butyl)dimethylsilyl]oxy}-1-iodoalkanes 24^a) (Scheme 4)

Iodoalkane

n

Products

Yield [%]^b)

Ratio

25/26

9:1

24

Oxazolone 25

Oxazole 26

Esters 27 + 28

25/26

b

c

d

e

f

11

12

10

8

b

–

52

35

60

58

42

30

40

71

c

–

d

e

c (14%)

d (9%)

–

d

e

10:1

16:2

23:4

20:3

13:4

6:1

7

f

f (14%)^c)

g (13%)^c)

h (16%)^c)

–

g

h

i

6

g

3

h

i (61%)

h

i (10%)

2

c

^a) LDA, THF/HMPT (ca. 2:1 – 4:1), ꢁ78° – +15°. ^b) Yield of isolated products. ) Only butyl ester of type 27.

protected iodoalkanols 16 gave, after chromatographic

workup, the azlactone 25c as a viscous oil in 35% yield

(Scheme 4, Table 1)⁴). In a similar manner, 15 was alky-

in the case of 24i, the two products 25i and 26i with the

(CH₂)₂side chain, were obtained as pure compounds.

The ﬁrst experiments to deprotect the silylated primary

lated using the obtained x-{[(tert-butyl)dimethylsilyl] alcohol group in compounds 25 by treatment with pyri-

oxy}-1-iodoalkanes (24, n = 11, 10, 8 – 6, 3, 2)²). In all dinium ﬂuoride were unsuccessful, but the deprotection

cases, mixtures of the corresponding C- and O-alkylated

products 25 and 26 were formed, with the desired 25 as Thus, bubbling HCl gas through a solution of 25c

the major product, in some cases together with the cor-

and TBAF ꢀ 3 H₂O in toluene at 90 – 110° for 1.5 – 2 h

responding butyl ester of type 27 (Table 1). Separation led directly to the 15-membered lactone 23c, which was

of the products by ﬂash chromatography (FC; [21]) gave, isolated as a colorless crystalline material in 65% yield

in general, a mixture of 25 and 26, which was subse- (Scheme 4, Table 2). In one of the repetitions of the experi-

was achieved with tetrabutylammonium ﬂuoride (TBAF).

quently used for the ring transformation reaction. Only

ment, 35% of 23c were obtained side by side with 43%

of 4-benzyl-4-(12-hydroxydodecyl)-2-phenyl-1,3-oxazol-5

(4H)-one, the proposed deprotected intermediate. Under

acidic conditions (HCl), the corresponding hydrochloride

22c spontaneously underwent ring transformation to give

23c. The expected structure of 23c was supported by the

spectroscopic and analytical data, and ﬁnally established by

an X-ray crystal structure determination (Fig. 2).

⁴) In addition, a nonseparable mixture of butyl and but-3-

enyl 2-benzamido-2-benzyl-14-{[(tert-butyl)dimethylsilyl]oxy}

tetradecanoate (27c and 28c, resp., ca. 4:1) was obtained.

Their formation has been rationalized via nucleophilic ring

opening of azlactone 25a by Li butanolate (BuOLi) and Li

but-3-enolate, respectively. Small amounts of the latter are

formed by the reaction of THF with BuLi/HMPT at ꢁ30 to

20° [16].

The space group of 23c (Pbca) is centrosymmetric and

therefore the compound in the crystal is racemic. The 15-

membered ring is disordered in such a way that both

enantiomers are present at the same site. In this arrange-

ment, all atoms of the enantiomers occupy identical posi-

tions with the only detectable difference being the

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Helv. Chim. Acta 2016, 99, 1 – 16

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presence of the lactone carbonyl O-atom on both sides of

the quaternary C-atom of the 15-membered ring. The

ratio of the site occupation factor of the disordered sites

is approximately 10:1. The NH group of each molecule acts

and 15-membered, resp.) were good. As expected, the for-

mation of the medium-sized rings was more difﬁcult, and

the products were isolated in fair-to-low yields, with the

lowest one (10%) for the 11-membered lactone 23e. Fur-

as a donor for intermolecular H-bonds. The corresponding thermore, a comparison of the formation of the 14-mem-

acceptor atom is the O-atom of the amide group of a neigh-

bered lactone 23b via ‘direct amide cyclization’ of diamide

21b (Scheme 3) and via ‘ring transformation’ of 4-(11-

hydroxyundecyl)-1,3-oxazol-5(4H)-one 25b indicate that

the ﬁrst type of reaction is more efﬁcient (86 vs. 69%

yield).

0

boring molecule [N(1)–H^….O(3 ); H^….O = 2.12(2) A, N–

H^….O 172(2)°]. These H-bonds link the molecules into

extended chains which run parallel to the [001] direction

and can be described by a graph set motif of C(4) [22].

Under the same reaction conditions, oxazolones 25b

and 25d – 25h, used as mixtures with the corresponding

oxazoles 26, as well as the pure oxazolone 25i, were trans-

formed into the 14-, 13-, 11-, 10-, 9-, 6-, and 5-membered

ꢀ

The structures of the racemic lactones 23d – 23f were

also established by X-ray crystallography (Fig. 3). In 23f,

the amide NH group forms an intermolecular H-bond with

the C=O O-atom of the lactone group of a neighboring

[N(1)–H^….O(1⁰);

H^….O = 2.32(2) A,

N–

ꢀ

lactones 23 (Scheme 4, Table 2). The 6- and 5-membered molecule

lactones 23h and 23i were obtained in very good yields, and

H^….O = 150(2)°]. These interactions link pairs of molecules

also the yields of the large-ring lactones 23b and 23c (14- into centrosymmetric dimers. It is worth mentioning that in

the crystal structures of 23a, 23b, 23d, and 23e, the amide

NH group is not involved in intermolecular H-bonds. In all

cases, the H-atom of the NH group is located close to the

O-atom of the lactone C=O group, most likely resulting

from geometric restriction rather than being real H-bonds.

Furthermore, in all lactones except 23e, the Ph ring of the

benzamido group is not coplanar with the NH–C=O group.

Conclusions

This study demonstrates that macrocyclic lactones of type

23 can be prepared in fair-to-good yields from 2-benz-

amido-2-benzyl-N,N-dimethyl-x-hydroxyalkanamides 21

by treatment with HCl gas in boiling toluene, i.e., via ‘direct

amide cyclization’. This reaction occurs via formation of a

4-(x-hydroxyalkyl)-substituted

1,3-oxazol-5(4H)-one

hydrochloride 22 as an intermediate, in analogy to the reac-

tion of the corresponding x-aminoalkanamides to give

macrocyclic lactams [13]. The precursors 21 are accessible

by C-alkylation of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one

(15), subsequent ring opening with Me₂NH, and deprotec-

tion of the THP-protected OH group. Changing the protect-

ing group of the primary alcohol to the TBDMS-group

allows the direct transformation of the 1,3-oxazol-5(4H)-

ones 25 to the lactones 23. In this case, the intermediate 22 is

formed via F^ꢁmediated deprotection of the primary alcohol

followed by treatment with HCl gas in boiling toluene.

These results extend the use of 1,3-oxazol-5(4H)-ones

as reactive building blocks and intermediates in organic

synthesis. Intramolecular reactions with a nucleophilic

group attached to the amino acid residue at C(2) are the key

step in the preparation of cyclopeptides [12] and cyclodep-

sipeptides [9][10] containing a,a-disubstituted a-amino

acids, in which the 1,3-oxazol-5(4H)-ones are formed as

intermediates. On the other hand, the ‘direct amide cycliza-

tion’ of 2-acylamino acid N,N-dimethylamides of type 21

with a x-amino- or x-hydroxyalkyl substituent in the

a-position leads to lactams and lactones, respectively, via

an intermediate 1,3-oxazol-5(4H)-one bearing the nucle-

ophile-containing side chain at C(4). In this study,

Fig. 2. ORTEP Plot [18] of the molecular structure of the 15-mem-

bered lactone 23c (major conformation; 50% probability ellipsoids,

arbitrary numbering of atoms).

Table 2. Synthesis of lactones 23 via ring transformation of oxa-

zolones 25^a) (Scheme 4)

Oxazolone 25

n

Lactone 23

Ring size [n + 3]

Yield [%]^b)

b

c

d

e

f

11

12

10

8

b

c

d

e

f

14

15

13

11

10

9

69

65^c)

51

10

20

7

g

h

i

6

g

h

i

51

86

3

6

2

5

100

^a) ca. 1.9 mM solution of 25 in toluene, ca. 1.7 equiv. of TBAF ꢀ 3

H₂O, 90 – 110°, bubbling HCl gas through the solution for 1.5 – 2 h.

^b) Yield of isolated product; calculated on the amount of 25 in the

used mixture of 25/26. ^c) In one experiment (ca. 1 h), the reaction

was not complete. In addition to lactone 23c (35%), 43% of the cor-

responding deprotected 1,3-oxazol-5(4H)-one was isolated.

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Helv. Chim. Acta 2016, 99, 1 – 16

Fig. 3. ORTEP Plots [18] of the molecular structures of the lactones 23d – 23f (50% probability ellipsoids, arbitrary numbering of atoms).

1,3-oxazol-5(4H)-ones with a protected OH group in the side

chain at C(4) are used as starting materials for the ﬁrst time.

(Schwerzenbach, Switzerland), in CHCl₃(3% soln.) if not

1

otherwise indicated; m in cm^ꢁ1. H- and ¹³C-NMR spectra:

Bruker AC-300, Bruker ARX-300 or Bruker AM-400 spec-

~

1

trometer (Fallanden, Switzerland) at 300 or 400 ( H) and

€

We thank the analytical sections of our institute for spec-

tra and analyses, and F. Hoffmann-La Roche AG, Basel, 75.5 or 100 MHz (¹³C), resp., in CDCl₃; multiplicities of

for ﬁnancial support.

¹³C signals determined by the DEPT technique; d in ppm

rel. to Me₄Si as internal standard, J in Hz. ESI-MS: Finni-

gan TSQ-700 instrument (Langenselbold, Germany); EI

(70 eV) and CI (with isobutane): Finnigan SSQ-700 instru-

ment; m/z (rel. %).

Experimental Part

General Procedure 1 (GP 1; Alkylation of 4-Benzyl-2-

phenyl-1,3-oxazol-5(4H)-one (15)). To a stirred soln. of

LDA⁵) in THF/HMPT (ca. 2:1 – 4:1) at ca. ꢁ78°, a THF

1. General. See [13][16]. Solvents were puriﬁed by standard

procedures. TLC: Merck (Darmstadt, Germany) TLC glass

plates, silica gel 60F₂₅₄. Flash column chromatography (FC

[21]): silica gel 60 (Merck), 0.040 – 0.060 mm. M.p.:

Mettler-FP-5 apparatus (Greifensee, Switzerland); uncor-

rected. IR Spectra: Perkin Elmer-297 or 781 spectrometer

i

⁵) Either freshly prepared from BuLi and Pr₂NH in THF or

purchased from Fluka AG (Buchs, Switzerland).

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Helv. Chim. Acta 2016, 99, 1 – 16

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soln. of 15 was added, followed by the O-protected

x-iodoalkanol⁶). Then, the temp. was increased to 15 – 7.90 – 7.80 (m, 2 arom. H); 7.55 – 7.45 (m, arom. H);

20° and the mixture stirred for 5 – 16 h. The mixture was 7.45 – 7.35 (m, 3 arom. H); 7.35 – 7.25 (m, arom. H);

extracted with cold H₂O (0°, 29) and Et₂O (29), and 7.20 – 7.10 (m, 3 arom. H); 4.57 (dd-like, J = 6.9, 3.8,

Data for 17a: ¹H-NMR (300 MHz, CDCl₃):

dried (MgSO₄). Separation of the products by FC (hex-

ane/Et₂O 98:2 – 3:2) gave mixtures of the desired oxa-

OCHO); 3.95 – 3.80 (m, OCH_eq); 3.71 (td, J = 6.9, 9.5, 1

H of CH₂O); 3.55 – 3.45 (m, OCH_ax); 3.36 (dt, J = 6.7,

zolones 17 or 25 (major product) and the O-alkylated 9.6, 1 H of CH₂O); 3.21, 3.13 (AB, J = 13.3, PhCH₂);

oxazoles 18 or 26, as well as butyl and but-3-enyl esters of

type 19, 27, and 28.

General Procedure 2 (GP 2; Ring Opening of Oxa-

zolones 17 with Me₂NH). To a soln. of a mixture of 1,3-

2.05 – 1.95 (m, 2 H); 1.90 – 1.75 (m, 2 H); 1.80 – 1.65 (m,

2 H); 1.60 – 1.45 (m, 8 H); 1.45 – 1.15 (m, 8 H). ¹³C-

NMR (50 MHz, CDCl₃): 179.6 (s, C=O); 159.6 (s, C=N);

139.3, 134.3 (2s, 2 arom. C); 132.3 (d, arom. CH); 130.0

oxazol-5(4H)-one 17 and 1,3-oxazole 18 in MeCN at 24°, (d, 2 arom. CH); 128.5 (d, 2 arom. CH); 127.9 (d, 2 arom.

condensed Me₂NH was added. After stirring for 2 – 5 h CH); 127.6 (d, 2 arom. CH); 126.9 (d, arom. CH); 98.6 (d,

at 22 – 25°, the crude mixture of 20 and 18 was puriﬁed OCHO); 74.7 (s, C(4)); 67.4, 62.1 (2t, 2 CH₂O); 43.7 (t,

by FC (Et₂O/hexane 3:2) to give THP-protected diamide PhCH₂); 37.3, 30.6, 29.6 (3t, 3 CH₂); 29.2 (t, 2 CH₂); 29.1,

20.

29.0, 26.0, 25.4, 23.9, 19.5 (6t, 6 CH₂).

Selected data of 18a: ¹H-NMR (300 MHz, CDCl₃):

General Procedure 3 (GP 3; Deprotection of the THP-

ethers 20). A soln. of the protected alcohol 20 (1 equiv.) 7.95 – 7.90 (m, 2 arom. H); 7.60 – 7.55 (m, arom. H); 4.10

and pyridinium p-toluenesulfonate (Py ꢀ TsOH, 0.17 (t, J = 6.6, CH₂O); 3.84 (s, PhCH₂). ¹³C-NMR (50 MHz,

equiv.) in EtOH was heated at reﬂux for 2 h. After cool-

ing to 24°, the solvent was evaporated, the residue was

CDCl₃): 129.3 (s, arom. C); 128.4 (d, 2 arom. CH); 128.2

(d, 2 arom. CH); 128.1, 127.7, 125.6 (3d, 5 arom. CH);

dissolved in CH₂Cl₂, the soln. washed with sat. aq. 98.6 (d, OCHO); 74.6 (t, CH₂O); 31.0, 29.5, 29.4, 28.9,

Na₂CO₃soln. (29), and dried (MgSO₄). After ﬁltration 26.1, 25.53 (6t, CH₂); 25.45 (t, 2 CH₂); 25.3 (t, CH₂).

and evaporation of the solvent, the product 21 was puri-

ﬁed by FC (SiO₂; Et₂O).

General Procedure 4 (GP 4; Direct Amide Cyclization

of 21). Dry HCl gas⁷) was bubbled through a 1.9 mM soln.

2.2. With Tetrahydro-2-[(11-iodoundecyl)oxy]pyrane

(16b) [16]. According to GP1, a mixture of 15 (2.000 g,

7.96 mmol) in THF (20 ml), LDA (9.60 mmol) in THF

(30 ml) and HMPT (20 ml), and 16b (3.670 g, 9.60 mmol)

of 21 in toluene at 90 – 110° for 1.5 – 2 h. Then, the sol- in THF (20 ml) gave an oily mixture of 4-benzyl-2-phe-

vent was evaporated, and the crude product was puriﬁed nyl-4-[11-(tetrahydro-2H-pyran-2-yloxy)undecyl]-1,3-oxa-

by FC (SiO₂; hexane/Et₂O 4:1 – 1:1) to give lactone 23.

General Procedure 5 (GP 5; Ring Transformation of

25). Dry HCl gas⁷) was bubbled through a 1.9 mM soln. of

a mixture of 25 and 26 in toluene containing 1.7 equiv. of

zol-5(4H)-one (17b) and 4-benzyl-2-phenyl-5-{[11-

(tetrahydro-2H-pyran-2-yloxy)undecyl]oxy}-1,3-oxazole

(18b; 1.584 g, 39%) as well as butyl 2-benzamido-2-

benzyl-13-(tetrahydro-2H-pyran-2-yloxy)tridecanoate (19,

TBAF ꢀ 3 H₂O at 90 – 110° for 1.5 – 2 h. Evaporation of 0.631 g, 11%).

the solvent and FC of the residue (SiO₂, hexane/Et₂O

16:9 or 4:1) gave lactone 23.

Data of the mixture of 17b/18b (15:4): R_f(Et₂O/hex-

ane 1:1): 0.51. IR (CHCl₃): 3060w, 3010m, 2930s, 2860s,

2. Alkylations of 4-Benzyl-2-phenyl-1,3-oxazol-5(4H)- 1815s, 1655s, 1495m, 1465m, 1455m, 1440m, 1350m,

one (15) [15]. 2.1. With Tetrahydro-2-[(9-iodononyl)oxy] 1320m, 1290m, 1135m, 1120m, 1075s, 1025s, 970m, 895m,

pyran (16a) [16]. According to GP1, a mixture of 15 700s. CI-MS (isobutane): 506 (100, [M + 1]⁺), 422 (23), 85

(0.578 g, 2.30 mmol) in THF (5 ml), LDA (2.80 mmol) in

THF (6 ml) and HMPT (5 ml), and 16a (0.980 g, N 2.77; found: C 76.01, H 8.63, N 2.90.

(13). Anal. calc. for C₃₂H₄₃NO₄(505.70): C 76.00, H 8.57,

2.77 mmol) in THF (5 ml) gave an oily mixture of 4-ben-

zyl-2-phenyl-4-[9-(tetrahydro-2H-pyran-2-yloxy)nonyl]-

Data for 17b: ¹H-NMR (300 MHz, CDCl₃):

7.90 – 7.80 (m, 2 arom. H); 7.55 – 7.50 (m, arom. H);

1,3-oxazol-5(4H)-one (17a) and 4-benzyl-2-phenyl-5-{[9- 7.45 – 7.35 (m, 2 arom. H); 7.25 – 7.10 (m, 5 arom. H);

(tetrahydro-2H-pyran-2-yloxy)nonyl]oxy}-1,3-oxazole (18a; 4.57 (dd-like, J = 4.3, 2.6, OCHO); 3.90 – 3.85 (m, 1H of

0.366 g, 33%).

CH₂O); 3.72 (dtd, J = 11.7, 6.9, 4.1, OCH_eq); 3.55 – 3.45

Data of the mixture of 17a/18a (2.2:1): R_f(Et₂O/hex- (m, 1 H of CH₂O); 3.45 – 3.30 (m, OCH_ax); 3.21, 3.13

ane 1:1): 0.48. IR (CHCl₃): 3060w, 3020w, 2930s, 2860s, (AB, J = 13.4, PhCH₂); 2.05 – 1.10 (m, 13 CH₂). ¹³C-

1815s, 1655s, 1450m, 1440m, 1320m, 1290m, 1135m, NMR (50 MHz, CDCl₃): 179.6 (s, C=O); 159.6 (s, C=N);

1120m, 1075m, 1060m, 1025s, 975m, 785s, 730s, 700s, 670s. 134.3 (s, arom. C); 132.8 (d, arom. CH); 130.0 (d, 2 arom.

CI-MS (isobutane): 478 (12, [M + 1]⁺), 394 (11), 133 CH); 128.5 (d, 2 arom. CH); 127.9 (d, 2 arom. CH); 127.6

(100), 85 (19). Anal. calc. for C₃₀H₃₉NO₄(477.65): C (d, 2 arom. CH); 127.0 (d, arom. CH); 125.3 (s, arom. C);

75.12, H 8.62, N 2.92; found: C 74.99, H 8.52, N 2.74.

98.6 (d, OCHO); 74.7 (s, C(4)); 67.5, 62.1 (2t, 2 CH₂O);

43.7 (t, PhCH₂); 37.3, 30.7, 29.6 (3t, 3 CH₂); 29.3 (t, 5

CH₂); 29.1, 26.1, 25.4, 23.9, 19.5 (5t, 5 CH₂).

Selected data of 18b: ¹H-NMR (300 MHz, CDCl₃):

7.95 – 7.90 (m, 2 arom. H); 7.35 – 7.25 (m, 2 arom. H);

⁶) In some cases, mixtures of x-iodo and x-chloro derivatives

were used [16].

⁷) HCl gas was bubbled through conc. H₂SO₄.

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Helv. Chim. Acta 2016, 99, 1 – 16

4.11 (t, J = 6.6, CH₂O); 3.84 (s, PhCH₂). ¹³C-NMR

(50 MHz, CDCl₃): 139.5 (s, arom. C); 129.3 (d, 2 arom.

CH); 128.2 (d, 2 arom. CH); 128.0 (d, 2 arom. CH); 126.0

1725m, 1660s, 1515s, 1485m, 1470m, 1460m, 1440m,

1255m, 1200m, 1095m, 840s, 705m.

1

Data of 27c: H-NMR (300 MHz, CDCl₃): 7.70 – 7.65

(d, 2 arom. CH); 125.6 (d, arom. CH); 98.6 (d, OCHO); (m, 2 arom. H); 7.50 – 7.45 (m, arom. H); 7.45 – 7.35 (m,

74.6 (t, CH₂O); 31.0, 25.5 (2t, CH₂). 2 arom. H); 7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 (m, 2

Data of 19: IR (CHCl₃): 3410w, 3005m, 2930s, 2860m, arom. H); 6.97 (br. s, NH); 4.35 – 4.30, 4.30 – 4.10 (2m,

1725m, 1660s, 1515s, 1485m, 1465m, 1455m, 1440m, CH₂O); 3.93, 3.17 (AB, J = 13.5, PhCH₂); 3.59 (t, J = 6.6,

1

1350m, 1240m, 1200m, 1130m, 1075m, 1030m, 705m. H- CH₂OSi); 2.85 – 2.75 (m, 1 H); 2.00 – 1.90 (m, 1 H);

NMR (300 MHz, CDCl₃): 7.75 – 7.65 (m, 2 arom. H); 1.75 – 1.65 (m, 2 H); 1.60 – 1.40 (m, 5 H); 1.40 – 1.15 (m,

7.50 – 7.45 (m, arom. H); 7.45 – 7.35 (m, 2 arom. H); 17 H); 0.99 (t, J = 7.3, Me); 0.89 (s, Me₃C); 0.04 (s,

7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 (m, 2 arom. H); Me₂Si). CI-MS (isobutane): 625 (100, [M + 1]⁺), 567 (18),

6.97 (s, NH); 4.57 (dd, J = 4.3, 2.8, OCHO); 4.27, 4.13 105 (44).

(2td, J = 6.6, 10.8, and 6.5, 10.8, resp., CH₂OC=O); 3.93,

3.17 (AB, J = 13.5, PhCH₂); 3.90 – 3.80, 3.55 – 3.45 (2m, 6.94 (s, NH); 5.90 – 5.70 (m, CH=); 5.50 – 5.51 (m,

CH₂O); 3.72, 3.37 (2td, J = 6.9, 9.6 and 6.7, 9.6, resp., CH₂=); 3.92 (A of AB, J = 13.5, 1 H of PhCH₂);

Selected data of 28c: ¹H-NMR (300 MHz, CDCl₃):

CH₂O); 2.85 – 2.75 (m, 1 H); 2.00 – 1.85 (m, 1 H); 2.55 – 2.45 (m,

1.85 – 1.15 (m, 14 CH₂); 0.99 (t, J = 7.4, Me). ¹³C-NMR [M + 1]⁺).

1 H). CI-MS (isobutane): 623 (29,

(50 MHz, CDCl₃): 173.5 (s, OC=O); 166.5 (s, NC=O);

136.4, 135.3 (2s, 2 arom. C); 131.2 (d, arom. CH); 129.6

2.4. With 11-[(tert-Butyl)dimethylsilyloxy]-1-iodounde-

cane (24b) [16]. According to GP1, a mixture of 15

(d, 2 arom. CH); 128.5 (d, 2 arom. CH); 128.0 (d, 2 arom. (0.330 g, 1.31 mmol) in THF (2 ml), LDA (1.31 mmol) in

CH); 126.7 (d, 3 arom. CH); 98.7 (d, OCHO); 67.6 (t, THF (3 ml) and HMPT (2 ml), and 24b (0.650 g,

CH₂O); 66.4 (s, C–N); 65.7 (t, CH₂OC=O); 62.2 (t, 1.58 mmol) in THF (2 ml) gave 4-benzyl-4-(11-{[tert-butyl

CH₂O); 40.6 (t, PhCH₂); 35.3, 30.7, 30.5, 29.7 (4t, 4 CH₂); (dimethyl)silyl]oxy}undecyl)-2-phenyl-1,3-oxazol-5(4H)-

29.43 (t, 2 CH₂); 29.38 (t, 3 CH₂); 29.3 (t, 2 CH₂); 26.1, one (25b) and 4-benzyl-5-[(11-{[tert-butyl(dimethyl)silyl]

25.4, 24.3, 19.6, 19.1 (5t, 5 CH₂); 13.6 (q, Me). CI-MS oxy}undecyl)oxy]-2-phenyl-1,3-oxazole (26b) (0.360 g,

(isobutane): 580 (5, [M + 1]⁺), 538 (3), 496 (100).

52%).

Data of the mixture of 25b/26b (9:1): R_f(Et₂O/hexane

cane (24c) [16]. According to GP1, a mixture of 15 1:1): 0.64. IR (CHCl₃): 3010w, 2935s, 2860s, 1815s, 1660m,

2.3. With 12-[(tert-Butyl)dimethylsilyloxy]-1-iododode-

(0.395 g, 1.57 mmol) in THF (3.8 ml), LDA (1.57 mmol)

1455m, 1290m, 1255m, 1095m, 1045m, 840s, 700s. CI-MS

in THF (2.5 ml) and HMPT (2.5 ml), and 24c (0.836 g, (isobutane): 536 (100, [M + 1]⁺). Anal. calc. for

1.96 mmol) in THF (2.5 ml) gave 4-benzyl-4-(12-{[tert- C₃₃H₄₉NO₃Si (535.85): C 73.93, H 9.22, N 2.61; found: C

butyl(dimethyl)silyl]oxy}dodecyl)-2-phenyl-1,3-oxazol-5

(4H)-one (25c; 0.300 g, 35%) as an oil and 0.141 g (ca.

73.87, H 9.29, N 2.79.

Data for 25b: ¹H-NMR (300 MHz, CDCl₃):

14%) of an inseparable mixture of butyl and but-3-en-1-yl 7.85 – 7.80 (m, 2 arom. H); 7.55 – 7.50 (m, 3 arom. H);

2-benzamido-2-benzyl-14-{[tert-butyl(dimethyl)silyl]oxy}

tetradecanoate (27c and 28c, resp.).

7.25 – 7.15 (m, 5 arom. H); 3.59 (t, J = 6.6, CH₂O); 3.22,

3.14 (AB, J = 13.4, PhCH₂); 2.05 – 1.95, 1.55 – 1.45 (2m,

Data of 25c: R_f(Et₂O/hexane 1:1): 0.67. IR (CHCl₃): 2 CH₂); 1.30 – 1.20 (m, 8 CH₂); 0.89 (s, Me₃C); 0.04 (s,

3060w, 2930s, 2860s, 1810s, 1655s, 1470m, 1460m, 1450m, Me₂Si). ¹³C-NMR (50 MHz, CDCl₃): 179.7 (s, C=O);

1320m, 1290m, 1255m, 1095m, 1045m, 970m, 895m, 840s, 159.7 (s, C=N); 134.4 (s, arom. C); 132.3 (d, arom. CH);

700s. ¹H-NMR (300 MHz, CDCl₃): 7.85 – 7.80 (m, 2 130.1 (d, 2 arom. CH); 128.5 (d, 2 arom. CH); 128.0 (d, 2

arom. H); 7.55 – 7.50 (m, arom. H); 7.45 – 7.40 (m, 2

arom. H); 7.20 – 7.15 (m, 5 arom. H); 3.59 (t, J = 6.6,

arom. CH); 127.7 (d, 2 arom. CH); 127.0 (d, arom. CH);

125.8 (s, arom. C); 74.8 (s, C(4)); 63.2 (t, CH₂O); 43.8 (t,

CH₂O); 3.22, 3.14 (AB, J = 13.3, PhCH₂); 2.05 – 1.95, PhCH₂); 37.4, 32.8, 29.5 (3t, 3 CH₂); 29.4 (t, 4 CH₂); 29.2

1.55 – 1.45 (2m, 2 CH₂); 1.25 – 1.10 (m, 9 CH₂); 0.89 (s, (t, CH₂); 25.9 (q, Me₃C); 25.7, 24.0 (2t, 2 CH₂); 18.3 (s,

Me₃C); 0.04 (s, Me₂Si). ¹³C-NMR (50 MHz, CDCl₃): Me₃CSi); ꢁ5.3 (q, Me₂Si).

179.7 (s, C=O); 159.7 (s, C=N); 134.3 (s, arom. C); 132.3

(d, arom. CH); 130.1 (d, 2 arom. CH); 128.6 (d, 2 arom.

CH); 128.0 (d, 2 arom. CH); 127.7 (d, 2 arom. CH); 127.0

(d, arom. CH); 125.7 (s, arom. C); 74.8 (s, C(4)); 63.2 (t,

Selected data of 26b: ¹H-NMR (300 MHz, CDCl₃):

7.95 – 7.90 (m, 2 arom. H); 7.35 – 7.25 (m, 3 arom. H);

4.11 (t, J = 6.6, CH₂O); 3.84 (s, PhCH₂).

2.5. With 10-[(tert-Butyl)dimethylsilyloxy]-1-iodode-

CH₂O); 43.8 (t, PhCH₂); 37.4, 32.8, 29.6 (3t, 3 CH₂); 29.5 cane (24d) [16]. According to GP1, a mixture of 15

(t, 2 CH₂); 29.4 (t, 3 CH₂); 29.2 (t, CH₂); 25.9 (q, Me₃C); (0.542 g, 2.09 mmol) in THF (3.2 ml), LDA (2.09 mmol)

25.7, 24.0 (2t, 2 CH₂); 18.3 (s, Me₃CSi); ꢁ5.4 (q, Me₂Si). in THF (5 ml) and HMPT (3.2 ml), and 24d (1.000 g,

CI-MS (isobutane): 551 (100, [M + 1]⁺), 493 (17). Anal. 2.51 mmol) in THF (3.22 ml) gave an oily mixture of 4-

calc. for C₃₄H₅₁NO₃Si (549.88): C 74.27, H 9.35, N 2.55;

found: C 74.26, H 9.62, N 2.71.

benzyl-4-(10-{[tert-butyl(dimethyl)silyl]oxy}decyl)-2-phenyl-

1,3-oxazol-5(4H)-one (25d) and 4-benzyl-5-[(10-{[tert-butyl

Data of the mixture of 27c/28c (3.8:1): R_f(Et₂O/hex- (dimethyl)silyl]oxy}decyl)oxy]-2-phenyl-1,3-oxazole (26d;

ane 1:1): 0.55. IR (CHCl₃): 3410w, 3000w, 2930s, 2860s, 0.662 g, 60%), as well as but-3-en-1-yl 2-benzamido-2-

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9

benzyl-12-{[(tert-butyl)dimethylsilyl]oxy}dodecanoate

(28d; 0.110 g, 9%).

7.45 – 7.35 (m, 2 arom. H); 7.20 – 7.10 (m, 5 arom. H);

3.57 (t, J = 6.6, CH₂O); 3.21, 3.14 (AB, J = 13.3, PhCH₂);

Data of the mixture of 25d/26d (10:1): R_f(Et₂O/hex- 2.05 – 1.95, 1.55 – 1.45 (2m, 2 CH₂); 1.45 – 1.20 (m, 5

ane 1:1): 0.63. IR (CHCl₃): 3065w, 2940s, 2860s, 1815s, CH₂); 0.88 (s, Me₃C); 0.03 (s, Me₂Si). ¹³C-NMR

1660s, 1500m, 1470m, 1465m, 1455m, 1325m, 1290m, (50 MHz, CDCl₃): 179.7 (s, C=O); 159.7 (s, C=N); 134.4

1260m, 1045m, 1025m, 840s, 700s. CI-MS (isobutane): 523 (s, arom. C); 132.3 (d, arom. CH); 130.1 (d, 2 arom. CH);

(100, [M + 1]⁺). Anal. calc. for C₃₂H₄₇NO₃Si (521.81): C

73.66, H 9.08, N 2.68; found: C 73.46, H 9.14, N 2.44.

128.5 (d, 2 arom. CH); 128.0 (d, 2 arom. CH); 127.7 (d, 2

arom. CH); 127.0 (d, arom. CH); 125.7 (s, arom. C); 74.8

Data for 25d: ¹H-NMR (300 MHz, CDCl₃): (s, C(4)); 63.1 (t, CH₂O); 43.8 (t, PhCH₂); 37.4, 32.7, 29.3

7.90 – 7.80 (m, 2 arom. H); 7.55 – 7.50 (m, arom. H); (3t, 3 CH₂); 29.2 (t, 2 CH₂); 25.9 (q, Me₃C); 25.6, 24.0 (2t,

7.45 – 7.35 (m, 2 arom. H); 7.20 – 7.10 (m, 5 arom. H); 2 CH₂); 18.3 (s, Me₃CSi); ꢁ5.3 (q, Me₂Si).

3.58 (t, J = 3.6, CH₂O); 3.21, 3.14 (AB, J = 13.4, PhCH₂);

Selected data of 26e: ¹H-NMR (300 MHz, CDCl₃):

2.05 – 1.95, 1.55 – 1.40 (2m, 2 CH₂); 1.35 – 1.10 (m, 7 7.95 – 7.90 (m, 2 arom. H); 7.35 – 7.25 (m, 2 arom. H);

CH₂); 0.88 (s, Me₃C); 0.04 (s, Me₂Si). ¹³C-NMR

(50 MHz, CDCl₃): 179.7 (s, C=O); 159.7 (s, C=N); 134.4

(s, arom. C); 132.3 (d, arom. CH); 130.1 (d, 2 arom. CH);

128.5 (d, 2 arom. CH); 128.0 (d, 2 arom. CH); 127.7 (d, 2

4.10 (t, J = 6.6, CH₂O); 3.84 (s, PhCH₂); 3.60 (t, J = 6.5,

CH₂O).

2.7. With 7-[(tert-Butyl)dimethylsilyloxy]-1-iodohep-

tane (24f) [16]. According to GP1, a mixture of 15

arom. CH); 127.0 (d, arom. CH); 125.7 (s, arom. C); 74.8 (0.588 g, 2.34 mmol) in THF (3 ml), LDA (3.5 mmol) in

(s, C(4)); 63.2 (t, CH₂O); 43.8 (t, PhCH₂); 38.4, 37.4, 32.8, THF (8 ml) and HMPT (5 ml), and 24f (1.000 g,

29.5, 29.4 (5t, 5 CH₂); 29.3 (t, 2 CH₂); 25.9 (q, Me₃C); 2.81 mmol) in THF (3 ml) gave an oily mixture of 4-ben-

25.7, 24.0 (2t, 2 CH₂); 18.3 (s, Me₃CSi); ꢁ5.3 (q, Me₂Si).

zyl-4-(7-{[tert-butyl(dimethyl)silyl]oxy}heptyl)-2-phenyl-

Selected data of 26d: ¹H-NMR (300 MHz, CDCl₃): 1,3-oxazol-5(4H)-one (25f) and 4-benzyl-5-[(7-{[tert-butyl

7.95 – 7.90 (m, 2 arom. H); 4.11 (t, J = 6.6, CH₂O); 3.83 (dimethyl)silyl]oxy}heptyl)oxy]-2-phenyl-1,3-oxazole (26f;

(s, PhCH₂); 3.60 (t, J = 6.6, CH₂OSi). ¹³C-NMR (50 MHz,

0.464 g, 42%) as well as butyl 2-benzamido-2-benzyl-9-

CDCl₃): 129.3 (d, arom. CH); 128.3 (d, 2 arom. CH); {[(tert-butyl)dimethylsilyl]oxy}nonanoate (27f; 0.173 g,

127.8 (d, arom. CH); 125.7 (d, 2 arom. CH); 125.4 (d, 14%).

arom. CH); 29.65, 29.59 (2t, CH₂).

Data of the mixture of 25f/26f (23:4): R_f(Et₂O/hexane

Data of 28d: R_f(Et₂O/hexane 1:1): 0.57. IR (CHCl₃): 1:1): 0.62. IR (CHCl₃): 3060w, 2935s, 2860s, 1815s, 1655s,

3060w, 3010m, 2940s, 2860s, 1730m, 1660s, 1520s, 1485s, 1495m, 1470m, 1460m, 1450m, 1320m, 1290m, 1255m,

1470m, 1255m, 1200m, 1095m, 835s, 705m. ¹H-NMR

(300 MHz, CDCl₃): 7.70 – 7.65 (m,

1095s, 1050m, 1005m, 970m, 890m, 840s, 700s. EI-MS: 479

arom. H); (12, M⁺), 251 (19), 115 (13), 105 (100). Anal. calc. for

2

7.50 – 7.35 (m, 3 arom. H); 7.20 – 7.15 (m, 3 arom. H); C₂₉H₄₁NO₃Si (479.73): C 72.61, H 8.61, N 2.92; found: C

7.10 – 7.00 (m, 2 arom. H); 6.94 (br. s, NH); 5.90 – 5.75 72.71, H 8.49, N 2.88.

1

(m, CH=); 5.20 – 5.10 (m, CH₂=); 4.35 – 4.25, 4.20 – 4.10

Data for 25f: H-NMR (300 MHz, CDCl₃): 7.85 – 7.80

(2m, CH₂OC=O); 3.92, 3.16 (AB, J = 13.5, PhCH₂); 3.58 (m, 2 arom. H); 7.55 – 7.50 (m, arom. H); 7.45 – 7.35 (m,

(t, J = 6.6, CH₂OSi); 2.85 – 2.75 (m, 1 H); 2.50 – 2.45 (m, 2 arom. H); 7.15 – 7.10 (m, 5 arom. H); 3.56 (t, J = 6.6,

CH₂); 2.00 – 1.90 (m, 1 H); 1.55 – 1.15 (m, 16 H); 0.89 (s, CH₂O); 3.21, 3.13 (AB, J = 13.3, PhCH₂); 2.10 – 1.95 (m,

Me₃C); 0.04 (s, Me₂Si). CI-MS (isobutane): 595 (100,

[M + 1]⁺).

CH₂); 1.50 – 1.00 (m, 5 CH₂); 0.89 (s, Me₃C); 0.02 (s,

Me₂Si). ¹³C-NMR (50 MHz, CDCl₃): 179.8 (s, C=O);

2.6. With 8-[(tert-Butyl)dimethylsilyloxy]-1-iodooctane 159.8 (s, C=N); 139.6, 134.6 (2s, 2 arom. C); 132.4 (d,

(24e) [16]. According to GP1, a mixture of 15 (0.389 g, arom. CH); 130.1 (d, 2 arom. CH); 128.6 (d, 2 arom. CH);

1.55 mmol) in THF (3.5 ml), LDA (1.9 mmol) in THF

128.1 (d, 2 arom. CH); 127.8 (d, 2 arom. CH); 127.1 (d,

(3.5 ml) and HMPT (2.4 ml), and 24e (0.700 g, arom. CH); 74.9 (s, C(4)); 63.2 (t, CH₂O); 43.8 (t,

1.89 mmol) in THF (2 ml) gave 4-benzyl-4-(8-{[tert-butyl PhCH₂); 37.4, 32.7, 29.4, 29.1 (4t, 4 CH₂); 26.0 (q, Me₃C);

(dimethyl)silyl]oxy}octyl)-2-phenyl-1,3-oxazol-5(4H)-one 25.6, 24.0 (2t, 2 CH₂); 18.3 (s, Me₃CSi); ꢁ5.3 (q, Me₂Si).

(25e) and 4-benzyl-5-[(8-{[tert-butyl(dimethyl)silyl]oxy}

octyl)oxy]-2-phenyl-1,3-oxazole (26e) (0.445 g, 58%) as

an oily mixture.

Data of the mixture of 25e/26e (8:1): R_f(Et₂O/hexane (s, Me₂Si). ¹³C-NMR (50 MHz, CDCl₃): 129.4 (s, arom.

1:1): 0.60. IR (CHCl₃): 3060w, 2930s, 2860s, 1815s, 1655s, C); 128.6 (s, 2 arom. C); 128.3 (s, arom. C); 125.4 (s,

1470m, 1465m, 1450m, 1320m, 1290m, 1255m, 1095s, C=N); 74.7 (t, CH₂O); 31.1, 29.4, 29.1, 26.1, 25.7, 25.0 (6t,

Selected data of 26f: ¹H-NMR (300 MHz, CDCl₃):

7.95 – 7.90 (m, 2 arom. H); 4.10 (t, J = 6.6, CH₂O); 3.81

(s, PhCH₂); 3.60 (t, J = 6.4, CH₂O); 0.89 (s, Me₃C); 0.05

1050m, 1020m, 1010m, 970m, 840s, 700s. CI-MS (isobu-

tane): 495 (5, [M + 1]⁺), 302 (100). Anal. calc. for

C₃₀H₄₃NO₃Si (493.76): C 72.98, H 8.78, N 2.84; found: C

73.21, H 8.98, N 2.91.

6 CH₂).

Data of 27f: R_f(Et₂O/hexane 1:1): 0.55. IR (CHCl₃):

3410w, 3060w, 3020w, 3005w, 2930s, 2860s, 1725m, 1660s,

1515m, 1485m, 1470m, 1320m, 1255m, 1095s, 840s, 700m.

Data for 25e: ¹H-NMR (300 MHz, CDCl₃): ¹H-NMR (300 MHz, CDCl₃): 7.70 – 7.65 (m, 2 arom. H);

7.85 – 7.80 (m, 2 arom. H); 7.55 – 7.50 (m, arom. H); 7.50 – 7.45 (m, arom. H); 7.45 – 7.35 (m, 2 arom. H);

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Helv. Chim. Acta 2016, 99, 1 – 16

7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 (m, 2 arom. H); CDCl₃): 7.70 – 7.65 (m, 2 arom. H); 7.50 – 7.45 (m, arom.

6.97 (br. s, NH); 4.30 – 4.20, 4.15 – 3.95 (2m, CH₂O); H); 7.45 – 7.35 (m, 2 arom. H); 7.20 – 7.15 (m, 3 arom.

3.93, 3.16 (AB, J = 13.5, PhCH₂); 3.65 – 3.55 (m, H); 7.05 – 7.00 (m, 2 arom. H); 6.97 (br. s, NH);

CH₂OSi); 2.85 – 2.80 (m, 1 H); 2.00 – 1.90 (m, 1 H); 4.30 – 4.20, 4.15 – 4.10 (2m, CH₂O); 3.93, 3.16 (AB,

1.70 – 1.60 (m, CH₂); 1.55 – 1.25 (m, 6 CH₂); 0.96 (t, J = 13.5, PhCH₂); 3.56 (t, J = 6.6, CH₂OSi); 2.90 – 2.75

J = 7.4, Me); 0.88 (s, Me₃C); 0.03 (s, Me₂Si). ¹³C-NMR

(50 MHz, CDCl₃): 173.5 (s, C=O); 166.4 (s, NC=O); 1.55 – 1.40 (m, 4 H); 1.40 – 1.25 (m, 6 H); 0.99 (t, J = 7.3,

(m, 1 H); 2.05 – 1.95 (m, 1 H); 1.80 – 1.70 (m, 2 H);

136.4, 135.3 (2s, 2 arom. C); 131.2 (d, arom. CH); 129.6

(d, 2 arom. CH); 128.6 (d, 2 arom. CH); 128.4 (d, 2

arom. CH); 126.7 (d, 3 arom. CH); 66.4 (t, CH₂O); 65.7

Me); 0.88 (s, Me₃C); 0.03 (s, Me₂Si). CI-MS: 541 (100,

[M + 1]⁺), 105 (25).

2.9. With 3-[(tert-Butyl)dimethylsilyloxy]-1-iodopro-

(s, C–N); 63.1 (t, CH₂O); 40.6 (t, PhCH₂); 35.3, 32.7, 29.3, pane (24h) [16]. According to GP1, a mixture of 15

29.2, 28.9, 28.4 (6t, 6 CH₂); 25.9 (q, Me₃C); 25.6, 24.3 (2t, (0.709 g, 2.82 mmol) in THF (4.5 ml), LDA (2.70 mmol)

2 CH₂); 18.2 (s, Me₃CSi); ꢁ5.4 (q, Me₂Si). EI-MS: 497 in THF (6.8 ml) and HMPT (4.5 ml), and 24h (1.049 g,

(12, [M – 57]⁺), 463 (8), 105 (75). Anal. calc. for 3.49 mmol) in THF (4.5 ml) gave an oily mixture of 4-

C₃₃H₅₁NO₄Si (553.86): C 71.57, H 9.28, N 2.53; found: C

70.62, H 9.89, N 2.32.

benzyl-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-phe-

nyl-1,3-oxazol-5(4H)-one (25h) and 4-benzyl-5-[(3-{[tert-

2.8. With 6-[(tert-Butyl)dimethylsilyloxy]-1-iodohexane butyl(dimethyl)silyl]oxy}propyl)oxy]-2-phenyl-1,3-oxazole

(24g) [16]. According to GP1, a mixture of 15 (0.490 g, (26h; 0.477 g, 40%), as well as butyl 2-benzamido-

1.95 mmol) in THF (5 ml), LDA (1.95 mmol) in THF

(5 ml) and HMPT (3 ml), and 24g (0.800 g, 2.34 mmol)

in THF (5 ml) gave an oily mixture of 4-benzyl-4-(6-

2-benzyl-5-{[(tert-butyl)dimethylsilyl]oxy}pentanoate (27h;

0.222 g, 16%).

Data of the mixture of 25h/26h (13:4): R_f(Et₂O/hex-

{[tert-butyl(dimethyl)silyl]oxy}hexyl)-2-phenyl-1,3-oxazol- ane 1:1): 0.59. IR (CHCl₃): 3060w, 3005w, 2960s, 2930s,

5(4H)-one (25g) and 4-benzyl-5-[(6-{[tert-butyl(dimethyl) 2890m, 2860m, 1815s, 1657s, 1495m, 1470m, 1460m,

silyl]oxy}hexyl)oxy]-2-phenyl-1,3-oxazole (26g; 0.270 g, 1450m, 1320m, 1290m, 1260s, 1040m, 1025m, 970m, 945m,

30%) as well as butyl 2-benzamido-2-benzyl-8-{[(tert- 890m, 840s, 810m, 700s, 670m. CI-MS: 424 (100,

butyl)dimethylsilyl]oxy}octanoate (27g; 0.133 g, 13%).

Data of the mixture of 25g/26g (20:3): R_f(Et₂O/hex- C 70.88, H 7.85, N 3.31; found: C 70.84, H 8.04, N 3.51.

ane 1:1): 0.64. IR (CHCl₃): 3060w, 3020w, 3000w, 2935s,

Data for 25h: ¹H-NMR (300 MHz, CDCl₃):

[M + 1]⁺), 366 (20). Anal. calc. for C₂₅H₃₃NO₃Si (423.63):

2860s, 1810m, 1655s, 1495m, 1470m, 1460m, 1450m, 7.85 – 7.80 (m, 2 arom. H); 7.55 – 7.50 (m, arom. H);

1320m, 1290m, 1255s, 1095s, 1050m, 1025m, 1005m, 990m, 7.45 – 7.30 (m, 2 arom. H); 7.20 – 7.05 (m, 5 arom. H);

965m, 840s, 810m, 700s, 665m, 630m. CI-MS: 466 (100, 3.60 (t, J = 6.3, CH₂O); 3.23, 3.15 (AB, J = 13.4, PhCH₂);

[M + 1]⁺). Anal. calc. for C₂₈H₃₉NO₃Si (465.71): C 72.22, 2.10 – 2.00, 1.60 – 1.35 (2m, 2 CH₂); 0.87 (s, Me₃C); 0.02

H 8.44, N 3.01; found: C 72.18, H 8.66, N 3.22.

(s, Me₂Si). ¹³C-NMR (50 MHz, CDCl₃): 179.7 (s, C=O);

Data for 25g: ¹H-NMR (300 MHz, CDCl₃): 159.8 (s, C=N); 134.4 (s, arom. C); 132.5 (d, arom. CH);

7.90 – 7.80 (m, 2 arom. H); 7.60 – 7.45 (m, arom. H); 130.1 (d, 2 arom. CH); 128.6 (d, 2 arom. CH); 128.1 (d, 2

7.45 – 7.35 (m, 2 arom. H); 7.20 – 7.10 (m, 5 arom. H); arom. CH); 127.8 (d, 2 arom. CH); 127.1 (d, arom. CH);

3.55 (t, J = 6.5, CH₂O); 3.21, 3.13 (AB, J = 13.3, PhCH₂); 125.4 (s, arom. C); 74.6 (s, C(4)); 62.5 (t, CH₂O); 43.7 (t,

2.05 – 1.95, 1.55 – 1.50 (2m, 2 CH₂); 1.50 – 1.10 (m, 3 PhCH₂); 33.9, 27.4 (2t, 2 CH₂); 25.9 (q, Me₃C); 18.3 (s,

CH₂); 0.87 (s, Me₃C); 0.02 (s, Me₂Si). ¹³C-NMR

(50 MHz, CDCl₃): 179.6 (s, C=O); 159.7 (s, C=N); 134.3

Me₃CSi); ꢁ5.4 (q, Me₂Si).

Selected data of 26h: ¹H-NMR (300 MHz, CDCl₃):

(s, arom. C); 132.2 (d, arom. CH); 130.0 (d, 2 arom. CH); 7.95 – 7.85 (m, 2 arom. H); 4.24 (t, J = 6.3, CH₂O); 3.83

128.5 (d, 2 arom. CH); 128.0 (d, 2 arom. CH); 127.7 (d, 2

(s, PhCH₂); 3.75 (t, J = 6.0, CH₂O). ¹³C-NMR (50 MHz,

arom. CH); 127.0 (d, arom. CH); 125.7 (s, arom. C); 74.8 CDCl₃): 129.6 (s, arom. C); 129.2, 128.8, 128.5, 128.4,

(s, C(4)); 63.0 (t, CH₂O); 43.7 (t, PhCH₂); 37.3, 32.6, 29.2 127.9, 125.7 (6d, 10 arom. CH); 125.5 (s, arom. C); 71.6,

(3t, 3 CH₂); 25.9 (q, Me₃C); 25.4, 23.9 (2t, 2 CH₂); 18.2 (s, 59.1 (2t, 2 CH₂O); 45.9 (t, PhCH₂).

Me₃CSi); ꢁ5.4 (q, Me₂Si).

Data of 27h: R_f(Et₂O/hexane 1:1): 0.55. IR (CHCl₃):

Selected data of 26g: ¹H-NMR (300 MHz, CDCl₃): 3405w, 3005m, 2960s, 2935s, 2860m, 1725s, 1660s, 1520s,

7.95 – 7.90 (m, 2 arom. H); 7.35 – 7.25 (m, 2 arom. H); 1470m, 1450m, 1390m, 1350m, 1285m, 1255s, 1200s,

4.10 (t, J = 6.6, CH₂O); 3.83 (s, PhCH₂); 3.60 (t, J = 6.5, 1100s, 840s, 705w. ¹H-NMR (300 MHz, CDCl₃):

CH₂O); 0.89 (s, Me₃C); 0.05 (s, Me₂Si). ¹³C-NMR 7.75 – 7.60 (m, 2 arom. H); 7.60 – 7.35 (m, 3 arom. H);

(50 MHz, CDCl₃): 129.3 (s, arom. C); 128.3, 127.84,

127.78, 126.7, 126.1, 125.3 (6d, 10 arom. CH); 74.5 (t, 4.20 – 4.05 (2m, CH₂OC=O); 3.89, 3.20 (AB, J = 13.4,

CH₂O); 31.1, 29.3 (2t, 2 CH₂). PhCH₂); 3.75 – 3.50 (m, CH₂OSi); 2.85 – 2.70 (m, 1 H);

7.30 – 7.00 (m, 5 arom. H); 6.95 (br. s, NH); 4.35 – 4.20,

Data of 27g: R_f(Et₂O/hexane 1:1): 0.56. IR (CHCl₃): 2.20 – 2.00 (m, 1 H); 1.80 – 1.65 (m, CH₂); 1.65 – 1.40

3410w, 3060w, 3000m, 2935s, 2860s, 1730m, 1660s, 1530m, (m, 1 H); 1.40 – 1.20 (m, 1 H); 0.96 (t, J = 7.4, Me); 0.85

1517s, 1487s, 1470m, 1460m, 1390m, 1350m, 1285m, 1255s, (s, Me₃C); 0.00 (s, Me₂Si). CI-MS: 498 (100, [M + 1]⁺),

1200m, 1100s, 840s, 705s, 670m. ¹H-NMR (300 MHz,

440 (18), 105 (27).

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11

2.10. With 2-[(tert-Butyl)dimethylsilyloxy]-1-iodoethane arom. CH); 98.7 (d, OCHO); 67.4, 62.1 (2t, 2 CH₂O); 65.9

(24i) [16]. According to GP1, a mixture of 15 (0.309 g, (s, C–N); 38.6 (t, PhCH₂); 38.4 (q, Me₂N); 33.6, 30.7, 29.6,

1.23 mmol) in THF (2 ml), LDA (1.20 mmol) in

29.4 (4t, 4 CH₂); 29.3 (t, 2 CH₂); 29.2, 26.1, 25.4, 24.2, 19.6

THF (3 ml) and HMPT (2 ml), and 24i (0.414 g, (5t, 5 CH₂). CI-MS (isobutane): 523 (<5, [M + 1]⁺), 439

1.45 mmol) in THF (2 ml) gave pure 4-benzyl-4-(2-{[tert- (24), 349 (100), 347 (10), 85 (14). Anal. calc. for

butyl(dimethyl)silyl]oxy}ethyl)-2-phenyl-1,3-oxazol-5(4H)- C₃₂H₄₆N₂O₄(522.73): C 73.53, H 8.87, N 5.36; found: C

one (25i; 0.305 g, 61%), and pure 4-benzyl-5-[(2-{[tert- 73.30, H 8.65, N 5.16.

butyl(dimethyl)silyl]oxy}ethyl)oxy]-2-phenyl-1,3-oxazole

(26i; 0.048 g, 10%) as viscous oils.

3.2. N-[1-Benzyl-1-(N,N-dimethylcarbamoyl)-12-(tetra-

hydro-2H-pyran-2-yloxy)dodecyl]benzamide (20b). A mix-

Data of 25i: R_f(Et₂O/hexane 1:1): 0.48. IR (CHCl₃): ture of oxazolone 17b and oxazole 18b (1.026 g,

3060w, 3020w, 2935w, 2860w, 1820m, 1655m, 1470w, 2.03 mmol of 17b) dissolved in MeCN (50 ml) was treated

1450w, 1320w, 1290w, 1255m, 1225m, 1205s, 1110m, with Me₂NH according to GP 2 to give 1.110 g (88%) of

1095m, 1020m, 980w, 895w, 835m, 780s, 670s. ¹H-NMR

(300 MHz, CDCl₃): 7.95 – 7.90 (m,

20b as a colorless oil. R_f(Et₂O/hexane 1:1): 0.12. IR

arom. H); (CHCl₃): 3350m, 3060w, 3005s, 2930s, 2860s, 1660s, 1630s,

2

7.60 – 7.55 (m, arom. H); 7.55 – 7.45 (m, 2 arom. H); 1580m, 1505s, 1480s, 1455m, 1445m, 1400s, 1250m, 1120m,

7.25 – 7.20 (m, 5 arom. H); 3.75 – 3.65 (m, CH₂O); 3.26, 1075m, 1030s, 700m. ¹H-NMR (300 MHz, CDCl₃): 7.99

3.19 (AB, J = 13.3, PhCH₂); 2.60 – 2.45 (m, 1 H); 2.23 (dt, (br. s, NH); 7.75 – 7.70 (m, 2 arom. H); 7.50 – 7.35 (m, 3

J = 2.9, 13.9, 1 H); 0.85 (s, Me₃C); 0.00, –0.11 (2s, Me₂Si). arom. H); 7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 (m, 2

¹³C-NMR (50 MHz, CDCl₃): 179.5 (s, C=O); 160.3 (s, arom. H); 4.57 (dd-like, J = 4.4, 2.8, OCHO); 4.13, 3.22

C=N); 134.1 (s, arom. C); 132.2 (d, arom. CH); 130.3 (d, 2

(AB, J = 14.2, PhCH₂); 3.90 – 3.85 (m, OCH_eq); 3.72 (td,

arom. CH); 128.5 (d, 2 arom. CH); 127.9 (d, 2 arom. CH); J = 6.9, 9.6, 1 H of CH₂O); 3.55 – 3.45 (m, OCH_ax); 3.37

127.6 (d, 2 arom. CH); 127.0 (d, arom. CH); 126.2 (s, (td, J = 6.7, 9.6, 1 H of CH₂O); 3.45 – 2.85 (m, Me₂N);

arom. C); 71.6 (s, C(4)); 58.8 (t, CH₂O); 44.4 (t, PhCH₂); 2.00 – 1.15 (m, 13 CH₂). ¹³C-NMR (50 MHz, CDCl₃):

39.9 (t, CH₂); 25.6 (q, Me₃C); 18.0 (s, Me₃CSi); ꢁ6.0 (q, 171.0 (s, O=CNMe₂); 165.6 (s, PhC=O); 136.5, 135.6 (2s, 2

Me₂Si). CI-MS: 410 (100, [M + 1]⁺), 352 (77), 324 (39), arom. C); 131.0 (d, arom. CH); 129.4 (d, 2 arom. CH);

289 (27), 250 (10). Anal. calc. for C₂₄H₃₁NO₃Si (409.60): 128.3 (d, 2 arom. CH); 127.9 (d, 2 arom. CH); 126.6 (d, 2

C 70.38, H 7.63, N 3.42; found: C 70.12, H 7.30, N 3.19.

arom. CH); 126.5 (d, arom. CH); 98.6 (d, OCHO); 67.5,

Data of 26i: R_f(Et₂O/hexane 1:1): 0.58. IR (CHCl₃): 62.1 (2t, 2 CH₂O); 66.0 (s, C–N); 38.6 (t, PhCH₂); 38.4 (q,

3060w, 3030w, 2960m, 2935m, 1740m, 1680m, 1480m, Me₂N); 33.6, 30.6, 29.6 (3t, 3 CH₂); 29.4 (t, 5 CH₂); 29.2,

1470m, 1260s, 1225m, 1205s, 1130m, 1105m, 930m, 840m, 26.0, 25.3, 24.2, 19.5 (5t, 5 CH₂). CI-MS (isobutane): 552

1

755s (br.), 670s. H-NMR (300 MHz, CDCl₃): 7.85 – 7.80 (47, [M + 1]⁺), 467 (100), 422 (53), 105 (44), 85 (35).

(m, 2 arom. H); 7.35 – 7.25 (m, 3 arom. H); 7.25 – 7.15 Anal. calc. for C₃₄H₅₀N₂O₄(550.80): C 74.14, H 9.15, N

(m, 4 arom. H); 7.15 – 7.05 (m, arom. H); 4.10 (t-like, 5.09; found: C 74.04, H 9.29, N 5.31.

J = 5.0, CH₂O); 3.80 (t-like, J = 5.0, CH₂OSi); 3.76 (s,

4. Deprotection of the THP-ethers 20. 4.1. N-[1-Ben-

PhCH₂); 0.82 (s, Me₃C); 0.00 (s, Me₂Si). CI-MS: 410 (100, zyl-1-(N,N-dimethylcarbamoyl)-10-hydroxydecyl]benza-

[M + 1]⁺). Anal. calc. for C₂₄H₃₁NO₃Si (409.60): C 70.38, mide (21a). According to GP 3, a soln. of 20a (0.170 g,

H 7.63, N 3.42; found: C 70.21, H 7.50, N 3.29. 0.33 mmol) in EtOH (4 ml) was treated with Py ꢀ TsOH

3. Ring Opening of Oxazolones 17 with Me₂NH. 3.1. (0.014 g, 0.05 mmol) to give 0.101 g (70%) of 21a as a

N-[1-Benzyl-1-(N,N-dimethylcarbamoyl)-10-(tetrahydro-

2H-pyran-2-yloxy)decyl]benzamide (20a). A mixture of

oxazolone 17a and oxazole 18a (0.200 g, 0.42 mmol of

17a) dissolved in MeCN (13 ml) was treated with Me₂NH

colorless wax. R_f(Et₂O/hexane 1:1): 0.13. IR (CHCl₃):

3620w, 3350w, 3060w, 3005m, 2930s, 2860m, 1655m, 1625s,

1505s, 1480s, 1400m, 715m, 700m. ¹H-NMR (300 MHz,

CDCl₃): 8.01 (br. s, NH); 7.75 – 7.70 (m, 2 arom. H);

according to GP 2 to give 0.193 g (89%) of 20a as a col- 7.50 – 7.35 (m, 3 arom. H); 7.20 – 7.15 (m, 3 arom. H);

orless oil. R_f(Et₂O/hexane 1:1): 0.12. IR (CHCl₃): 3250w, 7.00 – 6.95 (m, 2 arom. H); 4.12, 3.22 (AB, J = 14.3,

3060w, 3005m, 2930s, 2860m, 1655m, 1625s, 1505s, 1480s, PhCH₂); 3.61 (t, J = 6.5, CH₂O); 3.50 – 2.80 (br. s, 1 H,

1

1455m, 1440m, 1395m, 1120m, 1075m, 1030m, 700m. H- Me₂N); 2.05 – 1.90 (m, 1 H); 1.70 – 1.45 (m, 3 H);

NMR (300 MHz, CDCl₃): 8.00 (br. s, NH); 7.60 – 7.80 1.45 – 1.20 (m, 12 H). ¹³C-NMR (50 MHz, CDCl₃): 171.0

(m, 2 arom. H); 7.50 – 7.35 (m, 3 arom. H); 7.20 – 7.10 (s, O=CNMe₂); 165.7 (s, PhC=O); 136.4, 135.4 (2s, 2 arom.

(m, 3 arom. H); 7.05 – 6.95 (m, 2 arom. H); 4.55 (dd-like, C); 131.0 (d, arom. CH); 129.4 (d, 2 arom. CH); 128.3 (d,

J = 4.4, 2.7, OCHO); 4.12, 3.21 (AB, J = 14.3, PhCH₂); 2 arom. CH); 127.9 (d, 2 arom. CH); 126.6 (d, 2 arom.

3.90 – 3.80 (m, OCH_eq); 3.71 (td, J = 6.9, 9.6, 1 H of

CH); 126.5 (d, arom. CH); 65.9 (s, C–N); 62.5 (t, CH₂O);

CH₂O); 3.55 – 3.40 (m, OCH_ax); 3.36 (dt, J = 6.7, 9.6, 1 H 38.6 (t, PhCH₂); 38.4 (q, Me₂N); 33.5, 32.5, 29.3, 29.2,

of CH₂O); 3.40 – 2.90 (m, 2 H, Me₂N); 2.05 – 1.00 (m, 10 29.1, 29.0, 25.5, 24.1 (8t, 8 CH₂). CI-MS (isobutane): 439

CH₂). ¹³C-NMR (50 MHz, CDCl₃): 171.0 (s, O=CNMe₂); (72, [M + 1]⁺), 394 (100), 366 (8), 347 (22), 317 (6).

165.7 (s, PhC=O); 136.6, 135.6 (2s, 2 arom. C); 131.0 (d,

4.2. N-[1-Benzyl-1-(N,N-dimethylcarbamoyl)-12-hydro-

arom. CH); 129.5 (d, 2 arom. CH); 128.3 (d, 2 arom. CH); xydodecyl]benzamide (21b). According to GP 3, a soln.

127.9 (d, 2 arom. CH); 126.7 (d, 2 arom. CH); 126.6 (d, of 20b (0.130 g, 0.24 mmol) in EtOH (3 ml) was treated

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Helv. Chim. Acta 2016, 99, 1 – 16

with Py ꢀ TsOH (0.010 g, 0.04 mmol) to give 0.080 g

toluene (165 ml) with HCl gas according to GP 4 gave

(71%) of 21b as a colorless wax. R_f(Et₂O/hexane 1:1): 23b (0.196 g, 86%) as colorless crystals. R_f(Et₂O/hexane

0.17. IR (CHCl₃): 3620w, 3350w, 3005m, 2930s, 2860m, 1:1): 0.52. M.p. 115.8 – 116.0°. IR (CHCl₃): 3410w, 3020w,

1655m, 1625s, 1505s, 1480s, 1400m, 700m. ¹H-NMR

(300 MHz, CDCl₃): 8.00 (br. s, NH); 7.75 – 7.70 (m, 2

arom. H); 7.50 – 7.35 (m, 3 arom. H); 7.20 – 7.15 (m, 3

3005w, 2935s, 2860m, 1725m, 1660s, 1515s, 1485s, 1460m,

1345m, 1235m, 1200m, 700m. ¹H-NMR (300 MHz,

CDCl₃): 7.75 – 7.70 (m, 2 arom. H); 7.50 – 7.45 (m, 1

arom. H); 7.05 – 7.00 (m, 2 arom. H); 4.12, 3.22 (AB, arom. H); 7.45 – 7.35 (m, 2 arom. H); 7.20 – 7.15 (m, 3

J = 14.3, PhCH₂); 3.63 (t, J = 6.6, CH₂O); 3.45 – 2.85 (br. arom. H); 7.07 (br. s, NH); 7.05 – 7.00 (m, 2 arom. H);

s, Me₂N); 2.05 – 1.90 (m, 1 H); 1.63 (br. s, OH); 4.45 (td-like, J = 10.7, 2.2, 1 H of CH₂O); 4.10 – 4.00 (m,

1.60 – 1.50 (m, 2 H); 1.45 – 1.00 (m, 17 H). ¹³C-NMR 1 H of CH₂O); 3.99, 3.16 (AB, J = 13.4, PhCH₂); 2.86 (td-

(50 MHz, CDCl₃): 171.0 (s, O=CNMe₂); 165.7 (s, like, J = 13.4, 4.5, 1 H); 2.00 – 1.95 (m, 1 H); 1.75 – 1.55

PhC=O); 136.4, 135.5 (2s, 2 arom. C); 131.0 (d, arom. (m, 2 H); 1.55 – 1.20 (m, 14 H); 1.20 – 0.95 (m, 2 H). ¹³C-

CH); 129.4 (d, 2 arom. CH); 128.3 (d, 2 arom. CH); 127.9

(d, 2 arom. CH); 126.7 (d, 2 arom. CH); 126.6 (d, arom.

NMR (50 MHz, CDCl₃): 174.0 (s, C=O); 166.5 (s,

NC=O); 136.6, 135.4 (2s, 2 arom. C); 131.4 (d, arom. CH);

CH); 66.1 (s, C–N); 62.6 (t, CH₂O); 38.7 (t, PhCH₂); 38.4 129.6 (d, 2 arom. CH); 128.6 (d, 2 arom. CH); 128.2 (d, 2

(q, Me₂N); 33.6, 32.6 (2t, 2 CH₂); 29.3, 29.28, 29.2 (3t, 6

CH₂); 25.6, 24.2 (2t, 2 CH₂). CI-MS (isobutane): 467 (94,

arom. CH); 127.0 (d, 3 arom. CH); 67.0 (s, C(3)); 65.0 (t,

CH₂O); 41.0 (t, PhCH₂); 34.7, 27.9, 26.1, 25.9, 25.8, 24.1,

[M + 1]⁺), 422 (100), 375 (8). Anal. calc. for C₂₉H₄₂N₂O₃24.0, 22.6, 22.5, 21.3 (10t, 10 CH₂). CI-MS (isobutane):

(466.67): C 74.64, H 9.07, N 6.00; found: C 74.23, H 9.09,

N 6.16.

422 (100, [M + 1]⁺), 330 (13). Anal. calc. for C₂₇H₃₅NO₃

(421.58): C 76.93, H 8.37, N 3.32; found: C 76.82, H 8.21,

N 3.36.

5. Lactone-Formation via Direct Amide Cyclization of

Diamides 21. 5.1. N-(3-Benzyl-2-oxo-1-oxacyclododecan-3-

yl)benzamide (23a). The reaction of 21a (0.085 g, mination were grown from Et₂O/hexane.

Suitable crystals for the X-ray crystal structure deter-

0.19 mmol) in toluene (101 ml) with HCl gas according to 6. Lactone-Formation via Ring Transformations of

GP 4 gave 23a (0.032 g, 43%) as colorless crystals and 4- Oxazolones 25. 6.1. N-(3-Benzyl-2-oxo-1-oxacyclopentade-

benzyl-4-(9-hydroxynonyl)-2-phenyl-1,3-oxazol-5(4H)-one

(0.041 g, 55%).

can-3-yl)benzamide (23c). Treatment of a soln. of 25c

(0.208 g, 0.35 mmol) in toluene (190 ml) with TBAF

Data of 23a: R_f(Et₂O/hexane 1:1): 0.47. M.p. (0.194 g, 0.62 mmol) according to GP 5 gave 23c (0.108 g,

137.5 – 138.5°. IR (CHCl₃): 3410w, 3060w, 3010w, 2935m, 65%) as colorless crystals⁸). R_f(Et₂O/hexane 1:1): 0.55.

1725m, 1660s, 1520s, 1490s, 1470m, 1455m, 1350m, 1235m, M.p. 120.0 – 121.6°. IR (CHCl₃): 3410w, 3060w, 3010w,

1200m, 720s, 705s, 670s. ¹H-NMR (300 MHz, CDCl₃): 2935s, 2860m, 1725m, 1660s, 1515s, 1487s, 1455m, 1390m,

1

7.70 – 7.65 (m, 2 arom. H); 7.50 – 7.35 (m, 3 arom. H); 1347m, 1285m, 1240m, 1200m, 705s. H-NMR (300 MHz,

7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 (m, 2 arom. H,

CDCl₃): 7.75 – 7.65 (m, 2 arom. H); 7.50 – 7.45 (m, 1

NH); 4.80 – 4.75, 4.00 – 3.90 (2m, CH₂O); 3.96, 3.22 (AB, arom. H); 7.45 – 7.40 (m, 2 arom. H); 7.20 – 7.15 (m, 3

J = 13.5, PhCH₂); 2.85 – 2.75, 2.25 – 2.05 (2m, 2 H); arom. H); 7.05 – 7.00 (m, 2 arom. H, NH); 4.60 – 4.50,

1.70 – 1.60 (m, 3 H); 1.55 – 0.90 (m, 11 H). ¹³C-NMR 4.10 – 4.00 (2m, CH₂O); 3.95, 3.16 (AB, J = 13.4, PhCH₂);

(50 MHz, CDCl₃): 173.9 (s, C=O); 166.6 (s, NC=O); 2.85 – 2.80, 2.10 – 1.95 (2m, 2 H); 1.80 – 1.60 (m, CH₂);

136.6, 135.3 (2s, 2 arom. C); 131.4 (d, arom. CH); 129.6

1.50 – 1.05 (m, 9 CH₂). CI-MS (isobutane): 436 (100,

(d, 2 arom. CH); 128.6 (d, 2 arom. CH); 128.2 (d, 2 arom. [M + 1]⁺), 344 (7). Anal. calc. for C₂₈H₃₇NO₃(435.61): C

CH); 126.8 (d, 3 arom. CH); 67.2 (s, C(3)); 65.5 (t, 77.20, H 8.56, N 3.22; found: C 77.08, H 8.54, N 3.16.

CH₂O); 40.5 (t, PhCH₂); 32.8, 26.3 (2t, 2 CH₂); 25.8 (t, 2

CH₂); 22.9, 22.1, 21.4, 20.7 (4t, 4 CH₂). CI-MS (isobu-

tane): 395 (100, [M + 1]⁺), 303 (94). Anal. calc. for

C₂₅H₃₁NO₃(393.53): C 76.30, H 7.94, N 3.56; found: C

76.28, H 7.98, N 3.42.

Suitable crystals for the X-ray crystal structure deter-

mination were grown from Et₂O/hexane.

6.2. N-(3-Benzyl-2-oxo-1-oxacyclotetradecan-3-yl)benz-

amide (23b). Treatment of a soln. of the mixture 25b/26b

(0.200 g, 0.37 mmol, i.e., 0.180 g, 0.34 mmol 25b) in

toluene (213 ml) with TBAF (0.221 g, 0.70 mmol) accord-

ing to GP 5 gave 23b (0.099 g, 69%) as colorless crystals

Suitable crystals for the X-ray crystal structure deter-

mination were grown from Et₂O/hexane.

Data of 4-benzyl-4-(9-hydroxynonyl)-2-phenyl-1,3-oxa- (see 5.2).

zol-5(4H)-one: IR (CHCl₃): 3620w, 3060w, 3010w, 2930s,

6.3. N-(3-Benzyl-2-oxo-1-oxacyclotridecan-3-yl)benz-

2860m, 1815s, 1660s, 1455m, 1320m, 1290m, 1050m, amide (23d). Treatment of a soln. of the mixture 25d/26d

1025m, 980m, 700s. ¹H-NMR (300 MHz, CDCl₃): (0.199 g, 0.38 mmol, i.e., 0.189 g, 0.36 mmol 25d) in

7.90 – 7.80 (m, 2 arom. H); 7.60 – 7.50 (m, 1 arom. H); toluene (189 ml) with TBAF (0.212 g, 0.67 mmol)

7.50 – 7.40 (m, 2 arom. H); 7.20 – 7.10 (m, 5 arom. H);

⁸) In an experiment with incomplete transformation of 25c

(0.200 g, 0.36 mmol), in addition to 0.055 g (35%) of 23c,

was obtained 4-benzyl-4-(12-hydroxydodecyl)-2-phenyl-1,3-

oxazol-5(4H)-one (0.068 g, 43%).

3.62 (t, J = 6.6, CH₂O); 3.21, 3.14 (AB, J = 13.4, PhCH₂);

2.05 – 1.95, 1.60 – 1.50 (2m, 2 CH₂); 1.25 (br. s, 6 CH₂).

5.2. N-(3-Benzyl-2-oxo-1-oxacyclotetradecan-3-yl)ben-

zamide (23b). The reaction of 21b (0.250 g, 0.54 mmol) in

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according to GP 5 gave 23d (0.075 g, 51%) as colorless (m, 2 arom. H); 7.50 – 7.45 (m, 1 arom. H); 7.45 – 7.35

crystals. R_f(Et₂O/hexane 1:1): 0.49. M.p. 139.5 – 140.5°. (m, 2 arom. H); 7.20 – 7.15 (m, 3 arom. H); 7.03 (br. s,

IR (CHCl₃): 3410w, 3060w, 3000w, 2930s, 2860m, 1720s, NH); 7.00 – 6.95 (m, 2 arom. H); 4.83 (ddd, J ꢂ 12.4, 5.3,

1660s, 1515s, 1485s, 1460m, 1385m, 1345m, 1285m, 1250m, 3.0, 1 H of CH₂O); 4.15 – 4.05 (m, 1 H of CH₂O); 3.93,

1195m, 700m. ¹H-NMR (300 MHz, CDCl₃): 7.75 – 7.70 3.05 (AB, J = 13.5, PhCH₂); 3.00 – 2.95, 2.40 – 2.30 (2m,

(m, 2 arom. H); 7.50 – 7.45 (m, 1 arom. H); 7.45 – 7.35

(m, 2 arom. H); 7.20 – 7.15 (m, 3 arom. H); 7.05 – 7.00 1.05 – 0.85 (m, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 174.2

(m, 2 arom. H, NH); 4.65 (ddd, J = 10.8, 9.3, 3.2, 1 H of (s, C=O); 166.7 (s, NC=O); 136.0, 135.4 (2s, 2 arom. C);

2 H); 2.20 – 2.05 (m, 1 H); 1.85 – 1.25 (m, 8 H);

CH₂O); 4.03 (ddd, J = 10.9, 4.9, 3.3, 1 H of CH₂O); 3.96, 131.3 (d, arom. CH); 129.6 (d, 2 arom. CH); 128.5 (d, 2

3.18 (AB, J = 13.5, PhCH₂); 2.85 – 2.75, 2.15 – 2.05 (2m, arom. CH); 128.1 (d, 2 arom. CH); 126.8 (d, 3 arom. CH);

2 H); 1.80 – 1.50 (m, CH₂); 1.40 – 1.05 (m, 7 CH₂). ¹³C-

68.0 (t, CH₂O); 65.5 (s, C(3)); 41.5 (t, PhCH₂); 29.9, 25.8,

NMR (50 MHz, CDCl₃): 173.9 (s, C=O); 166.5 (s, 24.9, 23.8, 23.1, 22.2 (6t, 6 CH₂). EI-MS: 365 (5, M⁺), 274

NC=O); 136.5, 135.3 (2s, 2 arom. C); 131.4 (d, arom. CH); (100), 105 (83), 91 (29), 77 (63). Anal. calc. for

129.6 (d, 2 arom. CH); 128.8 (d, arom. CH); 128.5 (d, 2 C₂₃H₂₇NO₃(365.48): C 75.58, H 7.45, N 3.83; found: C

arom. CH); 128.1 (d, 2 arom. C); 126.8 (d, 2 arom. CH); 75.56, H 7.63, N 3.97.

67.0 (s, C(3)); 66.2 (t, CH₂O); 40.9 (t, PhCH₂); 34.4, 27.9

Suitable crystals for the X-ray crystal structure deter-

(2t, 2 CH₂); 26.6 (t, 2 CH₂); 25.6, 24.9, 24.5, 24.0, 21.6 (5t, mination were grown from Et₂O/hexane.

5 CH₂). CI-MS (isobutane): 408 (100, [M + 1]⁺). Anal.

calc. for C₂₆H₃₃NO₃(407.56): C 76.62, H 8.16, N 3.44;

found: C 76.88, H 8.09, N 3.53.

6.6.

N-(3-Benzyl-2-oxo-1-oxacyclononan-3-yl)benz-

amide (23g). Treatment of a soln. of the mixture 25g/26g

(0.172 g, 0.37 mmol, i.e., 0.160 g, 0.23 mmol 25g) in

toluene (200 ml) with TBAF (0.210 g, 1.21 mmol) accord-

ing to GP 5 gave 23g (0.075 g, 51%) as colorless crystals.

R_f(Et₂O/hexane 1:1): 0.56. M.p. 107.0 – 111.0°. IR

Suitable crystals for the X-ray crystal structure deter-

mination were grown from Et₂O/hexane.

6.4. N-(3-Benzyl-2-oxo-1-oxacycloundecan-3-yl)benz-

amide (23e). Treatment of a soln. of the mixture 25e/26e (CHCl₃): 3410w, 3000m, 2930m, 2855w, 1730s, 1660s,

(0.348 g, 0.70 mmol, i.e., 0.331 g, 0.67 mmol 25e) in 1515s, 1485s, 1460m, 1380m, 1345m, 1290m, 1240m, 1195s,

toluene (373 ml) with TBAF (0.383 g, 1.21 mmol) accord-

ing to GP 5 gave 23e (0.026 g, 10%) as colorless crystals.

1085m, 970m, 925m, 880m, 700m. ¹H-NMR (300 MHz,

CDCl₃): 7.70 – 7.65 (m, 2 arom. H); 7.50 – 7.45 (m, 1

R_f(Et₂O/hexane 1:1): 0.49. M.p. 150.5 – 151.5°. IR arom. H); 7.45 – 7.35 (m, 2 arom. H); 7.25 – 7.15 (m, 3

(CHCl₃): 3410w, 3050w, 3000w, 2940m, 2930m, 2855w, arom. H); 7.15 – 7.05 (m, 2 arom. H); 6.83 (br. s, NH);

1720s, 1660s, 1530s, 1485s, 1470m, 1395m, 1385m, 1360m, 4.85 – 4.75 (m, 1 H of CH₂O); 4.15 (dt, J = 10.8, 6.7, 1 H

1340m, 1230m, 1195m, 700w. ¹H-NMR (300 MHz,

CDCl₃): 7.75 – 7.70 (m, 2 arom. H); 7.50 – 7.45 (m, 1

arom. H); 7.45 – 7.40 (m, 2 arom. H); 7.20 – 7.15 (m, 3

of CH₂O); 3.81, 3.37 (AB, J = 13.6, PhCH₂); 2.65 – 2.55

(m, 1 H); 2.13 (ddd, J = 14.4, 6.6, 3.5, 1 H); 1.80 – 1.70

(m, 2 H); 1.70 – 1.55 (m, 2 H); 1.55 – 1.30 (m, 4 H). CI-

arom. H); 7.08 (br. s, NH); 7.00 – 6.95 (m, 2 arom. H); MS (isobutane): 352 (100, [M + 1]⁺). Anal. calc. for

4.80 (td-like, J = 10.8, 1.3, 1 H of CH₂O); 4.00 (ddd, C₂₂H₂₅NO₃(351.45): C 75.19, H 7.17, N 3.99; found: C

J = 11.2, 5.2, 1.8, 1 H of CH₂O); 3.90, 3.10 (AB, J = 13.4, 74.92, H 7.42, N 4.23.

PhCH₂); 3.00 – 2.90, 2.15 – 2.05 (2m, 2 H); 1.95 – 1.85

(m, 1 H); 1.70 – 1.50 (m, 5 H); 1.35 – 1.15 (m, 6 H). ¹³C-

6.7. N-[3-Benzyltetrahydro-2-oxo-2H-pyran-3-yl]benz-

amide (23h). Treatment of a soln. of the mixture 25h/26h

NMR (50 MHz, CDCl₃): 174.0 (s, C=O); 166.6 (s, (0.181 g, 0.43 mmol, i.e., 0.112 g, 0.26 mmol 25h) in

NC=O); 136.3, 135.3 (2s, 2 arom. C); 131.3 (d, arom. CH); toluene (230 ml) with TBAF (0.238 g, 0.75 mmol) accord-

129.5 (d, 2 arom. CH); 128.5 (d, 2 arom. CH); 128.1 (d, 2 ing to GP 5 gave 23h (0.069 g, 86%) as colorless crystals

arom. CH); 126.8 (d, 3 arom. CH); 67.0 (s, C(3)); 66.1 (t, and 4-benzyl-5-[(3-hydroxypropyl)oxy]-2-phenyl-1,3-oxa-

CH₂O); 41.2 (t, PhCH₂); 30.6, 25.6, 25.2, 25.0, 23.9, 21.4,

20.3 (7t, 7 CH₂). CI-MS (isobutane): 380 (100, [M + 1]⁺),

zole (0.016 g, 30% with respect to 26h).

Data of 23h: R_f(Et₂O/hexane 1:1): 0.48. M.p.

289 (18), 105 (53). Anal. calc. for C₂₄H₂₉NO₃(379.51): C 155.7 – 156.7°. IR (CHCl₃): 3440w, 3060w, 3010m, 2970w,

75.96, H 7.70, N 3.69; found: C 75.88, H 7.93, N 3.53.

Suitable crystals for the X-ray crystal structure deter-

mination were grown from Et₂O/hexane.

2860w, 1730s, 1660s, 1510s, 1480s, 1455m, 1400m, 1280m,

1260s, 1170s, 1120m, 1100m, 1075m, 975m, 705m. ¹H-

NMR (300 MHz, CDCl₃): 7.70 – 7.65 (m, 2 arom. H);

6.5.

amide (23f). Treatment of a soln. of the mixture 25f/26f

N-(3-Benzyl-2-oxo-1-oxacyclodecan-3-yl)benz- 7.55 – 7.50 (m, 1 arom. H); 7.50 – 7.30 (m, 5 arom. H);

7.25 – 7.20 (m, 2 arom. H); 6.09 (br. s, NH); 4.65 – 4.55,

(0.267 g, 0.56 mmol, i.e., 0.227 g, 0.47 mmol 25f) in 4.45 – 4.35 (2m, CH₂O); 3.52, 3.16 (AB, J = 13.3, PhCH₂);

toluene (295 ml) with TBAF (0.307 g, 0.97 mmol) accord-

ing to GP 5 gave 23f (0.034 g, 20%) as colorless crystals.

2.45 – 2.40 (m, CH₂); 1.90 – 1.80 (m, CH₂). ¹³C-NMR

(50 MHz, CDCl₃): 172.4 (s, C=O); 166.6 (s, NC=O);

R_f(Et₂O/hexane 1:1): 0.43. M.p. 85.0 – 87.4°. IR (CHCl₃): 134.3, 133.6 (2s, 2 arom. C); 131.7 (d, arom. CH); 130.2

3405s, 3240w, 3060w, 3020w, 3005w, 2940w, 2860w, (d, 2 arom. CH); 128.7 (d, 2 arom. CH); 128.4 (d, 2 arom.

1720m, 1660s, 1520s, 1490s, 1470m, 1455m, 1390m, 1370m, CH); 127.6 (d, arom. C); 126.9 (d, 2 arom. CH); 69.8 (t,

1240w, 705w. ¹H-NMR (300 MHz, CDCl₃): 7.75 – 7.70 CH₂O); 58.9 (s, C(3)); 43.4 (t, PhCH₂); 31.2, 21.5 (2t, 2

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CH₂). CI-MS (isobutane): 310 (100, [M + 1]⁺). Anal. calc.

for C₁₉H₁₉NO₃(309.37): C 73.77, H 6.19, N 4.53; found: C

74.02, H 6.38, N 4.65.

0.510(12). Similarity restraints were applied to the chemi-

cally equivalent bond lengths and angles involving all dis-

ordered C-atoms, while neighboring atoms within and

between each disordered conformation were restrained to

Data of 4-Benzyl-5-[(3-hydroxypropyl)oxy]-2-phenyl-

1

1,3-oxazole: H-NMR (300 MHz, CDCl₃): 7.90 – 7.85 (m, have similar atomic displacement parameters. In the case

2 arom. H); 7.50 – 7.30 (m, 3 arom. H); 7.30 – 7.20 (m, 4 of 23c, the 15-membered ring is disordered in such a way

arom. H); 7.20 – 7.10 (m, 1 arom. H); 4.19 (t, J = 6.1,

that both enantiomers are present at the same site. In this

CH₂O); 3.80 (s, PhCH₂); 3.72 (t, J = 6.0, CH₂O); 1.89 arrangement, all atoms occupy identical positions, with

(pent, J = 6.0, CH₂); 1.80 – 1.40 (br. s, OH). the only detectable difference being the presence of the

6.8. N-[3-Benzyltetrahydro-2-oxofuran-3-yl]benzamide lactone C=O O-atom of the 15-membered ring on both

(23i). Treatment of a soln. of 25i (0.109 g, 0.27 mmol) in sides of the quaternary C-atom. This requires that O(1)

toluene (140 ml) with TBAF (0.151 g, 0.48 mmol) accord-

ing to GP 5 gave 23i (0.080 g, 100%) as colorless crystals.

and C(4) are similarly disordered across common sites.

Atoms C(4) and O(1A) were constrained to have identi-

R_f(Et₂O/hexane 1:1): 0.50. M.p. 170.2 – 171.2°. IR cal atomic coordinates and atomic displacement parame-

(CHCl₃): 3420w, 3070w, 3020w, 2930w, 2860w, 1775s, ters. Similar constraints were applied to C(4A) and O(1).

1670s, 1515s, 1485s, 1290m, 1185m, 1165m, 1025m, 710m. The site occupation factors of the disordered sites was

¹H-NMR (300 MHz, CDCl₃): 7.75 – 7.70 (m, 2 arom. H); reﬁned and converged at 0.912(4) for the major con-

7.60 – 7.50 (m, 1 arom. H); 7.50 – 7.40 (m, 2 arom. H); former. For all compounds, the non-H-atoms were reﬁned

7.40 – 7.30 (m, 3 arom. H); 7.30 – 7.25 (m, 2 arom. H); anisotropically. The amide H-atoms were placed in the

6.63 (br. s, NH); 4.36 (td, J = 9.3, 2.4, 1 H of CH₂O); 3.61 positions indicated by difference electron density maps

(td, J = 9.5, 7.3, 1 H of CH₂O); 3.33, 3.25 (AB, J = 13.2, and their positions were allowed to reﬁne together with

PhCH₂); 2.87 (ddd, J = 13.4, 7.3, 2.5, 1 H); 2.77 (td, individual isotropic displacement parameters. All remain-

J = 9.7, 13.4, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 177.0 (s, ing H-atoms were placed in geometrically calculated posi-

C=O); 166.8 (s, NC=O); 133.8, 133.3 (2s, 2 arom. C); tions and reﬁned using a riding model where each H-atom

132.0 (d, arom. CH); 130.0 (d, 2 arom. CH); 128.8 (d, 2

was assigned a ﬁxed isotropic displacement parameter with

arom. CH); 128.6 (d, 2 arom. CH); 127.8 (d, arom. CH); a value equal to 1.2U_eqof its parent C-atom. The reﬁne-

127.0 (d, 2 arom. CH); 65.9 (t, CH₂O); 60.1 (s, C(3)); 41.6 ment of each structure was carried out on F²using full-

(t, PhCH₂); 33.2 (t, CH₂). CI-MS (isobutane): 296 (100, matrix least-squares procedures, which minimized the func-

2

2 2

[M + 1]⁺), 250 (21). Anal. calc. for C₁₈H₁₇NO₃(295.34): tion rw (F_o– F_c) . A correction for secondary extinction

C 73.20, H 5.80, N 4.74; found: C 73.13, H 5.69, N 4.62.

was applied in the cases of 23c – 23e. In the cases of 23b

7. X-Ray Crystal Structure Determination of 23a – f and 23d, twenty and one reﬂection, resp., whose intensities

(see Table 3 and Figs. 1 – 3)⁹). The measurements for were considered to be extreme outliers, were omitted from

23a, 23b, and 23d – 23f were made on a Nicolet-R3

the ﬁnal reﬁnement. Neutral atom scattering factors for

diffractometer using graphite-monochromated MoKa radi- non-H-atoms were taken from [24], and the scattering fac-

ꢀ

ation (k 0.71073 A), and those for 23c on a Rigaku tors for H-atoms were taken from [25]. Anomalous disper-

AFC5R diffractometer using graphite-monochromated sion effects were included in F_c[26]; the values for f⁰and f″

MoK_aradiation and a 12 kW rotating anode generator.

The intensities were corrected for Lorentz and polariza-

were those of [27]. The values of the mass attenuation coef-

ﬁcients are those of [28]. The SHELXL97 program [29] was

tion effects, but not for absorption. Equivalent reﬂections used for all calculations.

were merged. The data collection and reﬁnement parame-

ters are given in Table 3, and views of the molecules are

shown in Figs 1 – 3¹⁰). The structures were solved by

direct methods using SHELXS86 [23], which revealed the

positions of all non-H-atoms. The benzyl group of 23a is

disordered over two conformations as a result of a small

rotation about the C(2)–C(19) bond. Two sets of positions

were deﬁned for the atoms of the Ph ring and the site

occupation factor of the major conformation reﬁned to

REFERENCES

[1] E. Erlenmeyer, Liebigs Ann. Chem. 1893, 275, 1.

[2] A. El-Mekabaty, Int. J. Modern Chem. 2013, 2, 40.

[3] H. E. Carter, in ‘Organic Reactions’, Ed. R. Adams, Wiley,

New York, 1946, Vol. III, p. 198; E. Baltazzi, Quart. Rev. (Lon-

don) 1955, 9, 150; J. S. Fisk, R. A. Mosey, J. J. Tepe, Chem.

Soc. Rev. 2007, 36, 1432; N. M. Hewlett, C. D. Hupp, J. J. Tepe,

Synthesis 2009, 2825; S. Bala, M. Saini, S. Kamboj, Int. J. Chem-

Tech Res. 2011, 3, 1102; A. Piperno, A. Scala, F. Risitano, G.

Grassi, Curr. Org. Chem. 2014, 18, 2691.

⁹) CCDC-1447397 – 1447402 contain the supplementary crys-

tallographic data for this article. These data can be obtained

free of charge from The Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/getstructures.

¹⁰) For 23a and 23b, the obtainable crystal quality was sub-

optimal, and this is reﬂected in the quality of the crystal

structure reﬁnement results, although both structures are

quite unambiguous.

[4] a) A. R. Genady, H. Nakamura, Org. Biomol. Chem. 2011, 9,

7180; b) H. Fujita, M. Kunishima, Chem. Pharm. Bull. 2012, 60,

907; c) A. M. El-Saghier, E. F. Alwedi, N. M. Fawzy, J. Hetero-

cycl. Chem. 2012, 49, 664; d) A.-J. K. Al Abodi, N. Majed, A.

K. Sahar, R. I. H. Al-Bayati, Am. J. Org. Chem. 2012, 2, 143; e)

G. Danger, A. Michaut, M. Bucchi, L. Boiteau, J. Canal, R.

Plasson, R. Pascal, Angew. Chem., Int. Ed. 2013, 52, 611; f) M.

Parveen, A. Ali, S. Ahmed, A. M. Malla, M. Alam, P. S. Per-

eira Silva, M. Ramos Silva, D.-U. Lee, Spectrochim. Acta Part

€

www.helv.wiley.com

16

Helv. Chim. Acta 2016, 99, 1 – 16

ner, Tetrahedron 2005, 61, 1871; T. Jeremic, A. Linden, H. Heim-

A: Mol. Biomol. Spectr. 2013, 104, 538; g) V. K. Rai, N.

Sharma, A. Kumar, Synlett 2013, 24, 97; h) S. Yugandar, A.

Acharya, H. Ila, J. Org. Chem. 2013, 78, 3948; i) M.-Q. Zhou, J.

Zuo, B.-D. Cui, J.-Q. Zhao, Y. You, M. Bai, Y.-Z. Chen, X.-M.

Zhang, W.-C. Yuan, Tetrahedron 2014, 70, 5787; k) B. Jedrze-

€

gartner, J. Pept. Sci. 2008, 14, 1051; I. Dannecker-Dorig, A.

Linden, H. Heimgartner, Collect. Czech. Chem. Commun. 2009,

€

74, 901; I. Dannecker-Dorig, A. Linden, H. Heimgartner, Helv.

Chim. Acta 2011, 94, 993; F. S. Arnhold, A. Linden, H. Heimgart-

ner, Helv. Chim. Acta 2014, 97, 619; F. S. Arnhold, A. Linden, H.

Heimgartner, Helv. Chim. Acta 2015, 98, 155; F. S. Arnhold, A.

Linden, H. Heimgartner, Helv. Chim. Acta 2015, 98, 232.

[13] S. P. Fritschi, A. Linden, H. Heimgartner, Heterocycles 2009,

79, 985.

ꢁ

jewska, M. Gordel, J. Szeremeta, P. Krawczyk, M. Samoc, J.

Org. Chem. 2015, 80, 9641; l) A. S. A. Youssef, K. A. Kandeel,

W. S. I. Abou-Elmagd, D. S. A. Haneen, J. Heterocycl. Chem.

2016, 53, 809; m) K. F. Suzdalev, M. N. Babakova, J. Hetero-

cycl. Chem. 2016, DOI: 10.1002/jhet.2382.

[5] H. Heimgartner, Israel J. Chem. 1986, 27, 3; H. Heimgartner, in

‘Amino Acids: Chemistry, Biology and Medicine’, Eds. G.

Lubec, G. A. Rosenthal, ESCOM, Leiden 1990, p. 29; H. Heim-

gartner, Angew. Chem., Int. Ed. Engl. 1991, 30, 238.

[14] D. Obrecht, H. Heimgartner, Tetrahedron Lett. 1984, 25, 1717.

[15] D. F. DeTar, R. Silverstein, F. F. Rogers Jr., J. Am. Chem. Soc.

1966, 88, 1024; F. M. F. Chen, K. Kuroda, N. L. Benoiton, Syn-

thesis 1979, 230.

€

[6] a) D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1981, 64, 482;

b) P. Wipf, H. Heimgartner, Helv. Chim. Acta 1986, 69, 1153; c)

D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1987, 70, 102; d)

P. Wipf, H. Heimgartner, Helv. Chim. Acta 1987, 70, 354; e) P.

Wipf, H. Heimgartner, Helv. Chim. Acta 1988, 71, 140; f) P.

Wipf, H. Heimgartner, Helv. Chim. Acta 1990, 73, 13.

[16] S. P. Fritschi, Ph.D. thesis, University of Zurich, 1995.

[17] N. Miyashita, A. Yoshikoshi, P. A. Grieco, J. Org. Chem. 1977,

42, 3772.

[18] C. K. Johnson, ORTEP II, Report ORNL-5138, Oak Ridge

National Laboratory, Oak Ridge, Tennessee, 1976.

[19] E. J. Corey, A. Venkateswarlu, J. Am. Chem. Soc. 1972, 94,

6190; T. W. Greene, P. G. M. Wuts, ‘Protective Groups in

Organic Synthesis’, John Wiley & Sons, Inc., New York, 2nd

edn., 1991, p. 31.

€

[7] D. Obrecht, C. Spiegler, P. Schonholzer, K. Muller, H. Heim-

gartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666.

[8] R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc. Trans.

1915, 107, 1080; S. M. Bachrach, J. Org. Chem. 2008, 73, 2466;

C. Galli, G. Giovanelli, G. Illuminati, L. Mandolini, J. Org.

Chem. 1979, 44, 1258; B. Simonot, G. Rousseau, Tetrahedron

Lett. 1993, 34, 4527.

[20] H. Finkelstein, Ber. Dtsch. Chem. Ges. 1910, 43, 1528.

[21] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.

[22] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew.

Chem., Int. Ed. 1995, 34, 1555.

[9] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1984, 67, 526;

D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1987, 70, 329;

D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1990, 73, 221.

[10] K. N. Koch, A. Linden, H. Heimgartner, Helv. Chim. Acta

2000, 83, 233; K. N. Koch, A. Linden, H. Heimgartner, Helv.

Chim. Acta 2000, 83, 1881; K. N. Koch, A. Linden, H. Heim-

gartner, Tetrahedron 2001, 57, 2311; B. Iliev, A. Linden, H.

Heimgartner, Helv. Chim. Acta 2003, 86, 3215; B. Iliev, A. Lin-

[23] G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467.

[24] E. N. Maslen, A. G. Fox, M. A. O’Keefe, ‘International Tables

for Crystallography’, Ed. A. J. C. Wilson, Kluwer Academic

Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477.

[25] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys.

1965, 42, 3175.

[26] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.

[27] D. C. Creagh, W. J. McAuley, ‘International Tables for Crystal-

lography’, Ed. A. J. C. Wilson, Kluwer Academic Publishers,

Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219.

€

den, H. Heimgartner, Tetrahedron 2006, 62, 1079; P. Kottgen,

A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89, 731.

[11] H. Heimgartner, F. S. Arnhold, S. P. Fritschi, K. N. Koch, J. E.

F. Magirius, A. Linden, J. Heterocycl. Chem. 1999, 36, 1539; H.

Heimgartner, in ‘Modern Problems of Organic Chemistry’, Eds.

M. A. Kuznetsov, R. R. Kostikov, M. S. Baird, St. Petersburg,

Publishing House Lema, 2011, Vol. 15, p. 75.

[28] D. C. Creagh, J. H. Hubbell, ‘International Tables for Crystal-

lography’, Ed. A. J. C. Wilson, Kluwer Academic Publishers,

Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.

[29] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112.

[12] T. Jeremic, A. Linden, H. Heimgartner, Chem. Biodiversity 2004,

1, 1730; T. Jeremic, A. Linden, H. Heimgartner, Helv. Chim. Acta

2004, 87, 3056; T. Jeremic, A. Linden, K. Moehle, H. Heimgart-

Received January 27, 2016

Accepted April 15, 2016

€

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Synthesis of Macrocyclic Lactones via Ring Transformation of 4-(ω-Hydroxyalkyl)-1,3-oxazol-5(4H)-ones

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