Synthesis of Diverse 6-Oxa-allocolchicinoids by a Suzuki-Miyaura Coupling, Acid-Catalyzed Intramolecular Transacetalization Strategy

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DOI: 10.1002/ejoc.201500573

Synthesis of Diverse 6-Oxa-allocolchicinoids by a Suzuki–Miyaura Coupling,

Acid-Catalyzed Intramolecular Transacetalization Strategy

Dharmendra B. Yadav,^[a]Lebusetsa Taleli,^[b]Alet E. van der Westhuyzen,^[b]

Manuel A. Fernandes,^[a][‡]Maxim Dragoun,^[c]Aram Prokop,^[c]Hans-Günther Schmalz,^[d]

Charles B. de Koning,^[a]and Willem A. L. van Otterlo*^[a,b]

Keywords: Colchinoids / Intramolecular transacetalization / Antitumor agents / Cross-coupling / Heterocycles

The synthesis of allocolchicine analogues is of importance as

these compounds have been found to possess promising anti-

cancer activity by affecting tubulin polymerization. In this

paper, the synthesis of 28 novel substituted 6-oxa-allocol-

chicinoids is reported. The key steps involved in the synthe-

sis were a Suzuki–Miyaura coupling reaction, followed by an

acid-catalyzed intramolecular transacetalization to afford the

desired 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines. In ad-

dition, when thiophenol and phenol were used in the trans-

acetalization step, the 5-(phenylsulfanyl)-5,7-dihydrodi-

benzo[c,e]oxepine and 4-(5,7-dihydrodibenzo[c,e]oxepin-5-

yl)phenol skeletons were obtained, respectively. The cyto-

toxicity of the synthetic compounds was unfortunately not

impressive; however, one of the compounds was shown to

sensitize vincristine-resistant leukemia and lymphoma cells

to vincristine, a result vindicating further synthetic studies.

1. Introduction

Colchicine (1) and the related compound allocolchicine

(2a) have generated considerable interest due to their cyto-

toxicity, particularly in the cancer research arena (Fig-

ure 1).^[1]Both compounds were found to be tubulin-

assembly inhibitors, in this way disrupting cell cycles and

inducing apoptosis.^[2]For this reason, numerous research

groups have attempted total syntheses of these natural

products, as well as the generation of analogues with novel,

but controllable, bioactivities. Although colchicine (1) has

seen the bulk of interest, in recent years allocolchicine (2a)

has been the inspiration for the synthesis of a variety of

analogues.^[3]

Due to these interesting bioactivities, allocolchicine (2a),

N-acetylcolchicinol (N-acetylcolchinol, 2b), its methylated

derivative 2c and more soluble clinically applied analogues

such as 2d, have been synthesized.^[4]In addition, novel syn-

thetic targets have included allocolchicinoids with modified

Figure 1. Structures of colchicine (1) and allocolchicines 2.

B-,^[5]B,C-^[6]and C-ring^[7]systems, and even “B-ring-

opened”^[8]analogues have been synthesized and tested.

In terms of relevant examples, in 2009, Schmalz and co-

workers described synthetic access to a series of 6-oxa-

allocolchicinoids, which were synthesized by an innovative

[2+2+2] cycloaddition (Figure 2a).^[9]These compounds

were found to have interesting apoptosis-inducing proper-

ties. Furthermore, papers by Baudoin^[10]and Wallace^[11]

(Figure 2b) demonstrated how suitably substituted di-

benzo[c,e]oxepine skeletons gave rise to 6-oxa-allocolchic-

inoids with potent biological activities. For both papers, an

acid-mediated ring-closure afforded the seven-membered B-

ring system (as indicated for Wallace’s compound shown in

Figure 2b). Note should also be taken of work by Heo and

[a] Molecular Sciences Institute, School of Chemistry, University

of the Witwatersrand,

P. O. Wits 2050, Johannesburg, South Africa

E-mail: wvo@sun.ac.za

http://willemvanotterlo.co.za/

[b] Department of Chemistry and Polymer Science, University of

Stellenbosch,

Private Bag X1, Matieland 7602, Stellenbosch, South Africa

[c] Children’s Hospital Cologne, Department of Paediatric

Oncology,

Cologne, Germany

[d] Department of Chemistry, University of Cologne,

Cologne, Germany

[‡] Correspondent for X-ray crystallography

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500573.

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co-workers, who utilized a sequential Suzuki–Miyaura cou- tion reactions,^[12c]and the route shown in Figure 3 was thus

pling/aldol condensation strategy to synthesize a series of used.

dibenzo[a,c]cyclohepten-5-ones, although these compounds

appear not to have been tested for their ability to affect

tubulin polymerization (Figure 2c).^[12a]The work by Heo et

al. entailed an in-depth study on the key coupling condi-

tions, based on the biaryl coupling/cyclization strategies

towards the dibenzo[c,e]oxepine skeleton, so elegantly uti-

lized by Leonard^[13]and Kocienski^[14]in their asymmetric

syntheses of N-acetylcolchicinol (2b).

Figure 3. Key retrosynthetic disconnections resulting in 5-alkoxy-

5,7-dihydrodibenzo[c,e]oxepines.

Results and Discussion

To access the desired 5-alkoxy-5,7-dihydrodibenzo[c,e]-

oxepine skeleton 7, the synthetic strategy depicted in

Scheme 1 was investigated. The first synthetic task involved

the conversion of a small set of five commercially available

2-bromobenzaldehydes 12, namely 2-bromobenzaldehyde,

Figure 2. Representative examples of synthetic approaches re-

sulting in allocolchicine analogues.

2-bromo-5-methoxybenzaldehyde,

2-bromo-4,5-dimeth-

It is also important to note that the 7-position of the oxybenzaldehyde, 6-bromobenzo[d][1,3]dioxole-5-carbal-

allocolchicine B-ring (numbering shown in Figure 1) has dehyde and 2-bromo-3,4,5-trimethoxybenzaldehyde, into

also been varied, with a number of small functional groups their respective 1,3-dioxolanes 13. This was achieved by

seemingly being tolerated in this position with respect to using 1,2-ethanediol (4 equiv.), triethyl orthoformate and p-

maintaining bioactivity.^[9,15]With this in mind, and with the toluenesulfonic acid monohydrate as catalyst, to provide the

precedent set by Schmalz and Wallace in terms of the anti- 1,3-dioxolanes 13 in good yields (84–93%). The important

cancer activity of the dibenzo[c,e]oxepine (“6-oxa”) system, biaryl C–C bond was introduced by utilizing the Suzuki–

it was deemed valuable to look at compounds that com- Miyaura coupling of the five 1,3-dioxolanes using two dif-

bined both structural features (see Figure 2d). This manu- ferent types of reaction conditions, under standard heating

script thus describes a novel approach to the synthesis of (Method A), and the other under microwave-heating condi-

additional 6-oxa-allocolchicinoids, i.e. 5-alkoxy-5,7-di- tions (Method B).^[16]The yields for the biaryl products 14

hydrodibenzo[c,e]oxepines, readily synthesized by a strategy were generally good, with the microwave methodology

involving a Suzuki–Miyaura coupling reaction (compound giving better yields on the whole (see Table 1 for further

9 ⇒ 10 and 11), followed by an acid-catalysed intramolecu- information and Supporting Information for structures).

lar transacetalization (7 ⇒ 8), as shown in the retrosynthetic

The biarylcarbaldehydes 14a–k were subsequently re-

analysis in Figure 3. It should be noted here that the biaryl duced to their benzyl alcohols 15a–k in excellent yields

synthesis between substituted halobenzyl alcohols and (2- (Ͼ90%) by using sodium borohydride as the reductant. The

formylphenyl)boronic acids was also considered, in order to next step involved the critical transacetalization to afford

avoid the protection/deprotection sequence, as this has seen the ring-closed 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepine

some application;^[12b]however, work by Van der Eycken et products 16. To achieve this, the biaryl compounds 15 were

al. has shown that this approach can result in inseparable subjected to a substoichiometric amount of p-toluenesulf-

mixtures of biaryls due to intramolecular disproportiona- onic acid (PTSA) monohydrate in an alcoholic solvent to

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Diverse 6-Oxa-allocolchicinoids

Scheme 1. Synthesis of 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines 16. For yields of biaryl products 14 and 5-alkoxy-5,7-dihydrodibenzo-

[c,e]oxepines 16, see Tables 1 and 2, respectively.

Table 1. Yields for the synthesis of the biaryls 14 by way of a Suzuki–Miyaura coupling protocol.

[a] Coupling conditions: A: aryl bromide (1 equiv.), boronic acid (1.5 equiv.), NaHCO₃(3 equiv.), Pd(PPh₃)₄(5 mol-%) in DMF/H₂O

(1:1), 110 °C for 4–6 h under Ar; B: aryl bromide (1 equiv.), boronic acid (1.3 equiv.), NaHCO₃(3 equiv.), Pd(PPh₃)₄(5 mol-%) in DMF/

H₂O (1:1; 2 mL), microwave heating (125 W), 125 °C for 25 min, sealed tube.

deliver the desired seven-membered ring systems in accept- alcohols could be utilized in this reaction, with the initial

able yields (see Table 2 for further information and the Sup- focus being on shorter-chain alcohols such as methanol,

porting Information).^[17]It was found that a range of ethanol, n-propanol and n-butanol. To widen the scope of

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Table 2. Yields for the transacetalization of biaryls 15 with various alcohols to afford 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines 16.

15^[a]Substitution key Compound (yield [%])^[b]

MeOH (a)

R = Me

EtOH (b)

R = Et

nPrOH (c)

R = nPr

nBuOH (d)

R = nBu

Propargyl alcohol (e)

R = CH₂CCH

a

b

c

d

e

f

g

h

i

R¹, R², R³, R⁴, R⁵= H

16aa (71)

16ba (82)

16ca (83)

16da (90)

n.d.

16ab (74)

16bb (90)

16cb (85)

16db (72)

n.d.

16bc (86)

n.d.

16ad (78)

16bd (91)

16cd (85)

16dd (84)

n.d.

16be (67)

n.d.

16de (83)

n.d.

16ge (81)

n.d.

R¹, R², R³, R⁴= H; R⁵= OMe

R², R³, R⁴, R⁵= H; R¹= OMe

R³, R⁴, R⁵= H; R¹, R²= OMe

R³, R⁴= H; R¹, R², R⁵= OMe

n.d.

16ec (76)

16fc (85)

16gc (89)

16hc (84)

16ic (63)

R¹, R²= OMe; R⁴, R⁵= –OCH₂O–; R³= H n.d.

R¹, R²= OCH₂O; R³, R⁴, R⁵= H

16ga (72)

16ha (96)

R¹, R²= OCH₂O; R³, R⁴= H; R⁵= OMe

16hb (84)

n.d.

16hd (97)

16id (78)

R¹, R²= OCH₂O; R⁴, R⁵= OCH₂O; R³= H 16ia (89)

n.d.

[a] Use of substrate 15j resulted in multiple products, which could not be readily separated by chromatography. [b] After chromatographic

purification.

this approach, other alcohols, such as benzyl alcohol, allyl solution 16ah is in equilibrium with the corresponding

alcohol and propargyl alcohol, were also used in the trans- benzyl alcohol/benzaldehyde – see Experimental Section for

acetalization to give the desired cyclized products 16 in more details). The solved structure of the solid showed it

acceptable yields. The reason for utilizing the propargyl clearly contained the desired seven-membered 5,7-dihydro-

alcohol to obtain compounds 16be, 16de and 16ge, was to dibenzo[c,e]oxepin-5-ol ring system as can be seen in Fig-

investigate the possibility of utilizing this alkyne “handle” ure 5b.

for possible extension by way of a click reaction, as has

been done by several other research groups.^[18]In terms of

a limitation, it was observed that when the biarylylmethan-

ols 15 possessed a methoxy group in the “R³” position that

the ring-closure to the desired cyclized products 16 was not

successful. Even when the reaction temperature was in-

creased gently (ca. 40 °C) at best multiple inseparable prod-

ucts were seen by TLC analysis (of interest was that this

was less of a problem when utilizing phenol and thiophenol

as nucleophilic solvents – see next section).

To broaden the scope of alcohols that could be utilized

in the transacetalization of the biaryls 15, compounds 16cf

Figure 5. (a) Structure 5,7-dihydrodibenzo[c,e]oxepin-5-ol (16ah);

(b) single-crystal X-ray structure for 16ah (ORTEP diagram drawn

and 16dg were both obtained in reasonable yields when

using benzyl and allyl alcohol, respectively, demonstrating

that the synthetic method could be used to prepare 5-alk-

oxy-5,7-dihydrodibenzo[c,e]oxepines 16 with a wider variety

of substituents at the alkoxy portion of the molecule (struc-

tures shown in Figure 4).

at 50% probability level).

Finally, it was decided to investigate the transacetaliza-

tion reaction by using phenol and the related thiophenol as

the “alcohol” partners. Initial reactions of substrates 15a–c

with thiophenol gave products 17ai, 17bi and 17ci, respec-

tively, that had the expected incorporation of the

thiophenol to give the 5-(phenylsulfanyl)-5,7-dihydrodi-

benzo[c,e]oxepines structure containing an O,S-acetal

(Scheme 2, Table 3). However, for a number of reactions in-

volving substrates with more electron-donating groups (for

instance, 15h, 15j and 15k) the NMR spectra clearly indi-

cated the incorporation of two thiophenol groups into the

final product 18 (namely 18hi, 18ji and 18ki, respectively),

thus showing that the S,S-actetals had been formed instead

(Scheme 2, Table 3). An important clue towards the forma-

tion of these products was that the ArCH(SPh)₂proton for

these products resonated at δ ≈ 5.1 ppm (see related exam-

Figure 4. Further examples of 5-alkoxy-5,7-dihydrodibenzo[c,e]-

oxepines synthesized, with isolated yields in parentheses.

The transacetalization reaction was also performed in a ple in ref.^[19]with resonance at δ = 5.3 ppm), while for the

mixed THF/water medium to afford the hemiacetal 5,7-di- ArCH(SPh)(OCH₂Ar) systems the proton signal was found

hydrodibenzo[c,e]oxepin-5-ol (16ah; Figure 5a), which – at δ ≈ 6.2 ppm (further corroborated by examples in the

although prone to decomposition in the deuterated solvents literature; see for example ref.^[20]with related resonance at

used – gave single crystals of a sufficient quality for an X- δ = 5.69 ppm). Examination of the ¹³C NMR spectra also

ray diffraction study (a previous study has shown that in indicated the significant difference in the ArCH(SPh)₂vs.

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Diverse 6-Oxa-allocolchicinoids

Scheme 2. Synthesis of substituted 5-(phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepines 17, {2Ј-[bis(phenylsulfanyl)methyl][1,1Ј-biphenyl]-

2-yl}methanols 18 and 4-(5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenols 19.

Table 3. Yields for the synthesis of substituted 5-(phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepines 17, {2Ј-[bis(phenylsulfanyl)methyl][1,1Ј-

biphenyl]-2-yl}methanols 18 and 4-(5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenols 19.

15^[a]

Substitution key

Compound (yield [%])^[b]

Thiophenol (i)

Phenol (j)

a

b

c

d

e

g

h

j

R¹, R², R³, R⁴, R⁵= H

17ai (70)

17bi (86)

17ci (90)

n.d.

18hi (87)

18ji (90)

18ki (71)

19aj (73)

19bj (81)

19cj (80)

19dj (75)

19ej (75)

19gj (86)

19hj (85)

19jj (60)

19kj (60)

R¹, R², R³, R⁴= H; R⁵= OMe

R², R³, R⁴, R⁵= H; R¹= OMe

R³, R⁴, R⁵= H; R¹, R²= OMe

R³, R⁴= H; R¹, R², R⁵= OMe

R¹, R²= –OCH₂O–; R³, R⁴, R⁵= H

R¹, R²= –OCH₂O–; R³, R⁴= H; R⁵= OMe

R¹, R², R³= OMe; R⁴, R⁵= H

R¹, R², R³, R⁵= OMe; R⁴= H

k

[a] Compounds 15f and 15i not used as substrates. [b] After chromatographic purification.

ArCH(SPh)(OCH₂Ar) chemical shifts (δ ≈ 60 ppm for com-

pounds 18 vs. δ ≈ 90 ppm for compounds 17). In terms of

rationalizing why these differences were observed, it is pos-

tulated that the presence of multiple electron-donating

groups on the masked aldehyde-bearing ring decrease the

electrophilicity of the acetal system required for the cycliza-

tion.

Secondly, utilization of phenol as the nucleophile gave an

initially unexpected product, in which from NMR spectro-

scopic evaluation it looked like a C–C bond had formed,

rather than the O,O-acetal. It was soon noted that exam-

ples, where phenol has reacted by way of a nucleophilic car-

bon atom rather than the oxygen atom of the phenol func-

tionality, are known in the literature.^[21]To confirm the

Figure 6. (a) Structure of compound 19kj; (b) single-crystal X-ray

structures for 19kj (ORTEP diagram drawn at 50% probability

level).

structure of these products, a single-crystal X-ray experi- of inhibition of cell proliferation, and compounds 16be,

ment was performed on product 19kj, which confirmed that 16da, 16ga, 16ia and 17ci had IC₅₀values in the range of

C–C bond formation had occurred (Figure 6).

50–100 μm. It has been shown in previous research that the

A number of the compounds were evaluated for their axial stereochemical configuration of colchicinoid com-

ability to attenuate the human leukemia cell-line Nalm6, pounds is critical in terms of their ability to slow cell growth

namely 16be, 16da, 16ga, 16ia, 17bi, 17ci and 19kj, as re- by the inhibition of tubulin polymerization,^[22]and it is

lated compounds prepared by Schmalz and co-workers had possible that the compounds synthesized in this study are

shown interesting activities.^{[7a,7c–7e,9,18b]}Unfortunately, the too flexible for the desired atropisomer to interact effec-

compounds only demonstrated moderate activity in terms tively with the tubulin binding site. In the future, it is our

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Et₂O were purified by distillation under nitrogen from sodium and

benzophenone. In addition, dichloromethane was dried by distil-

lation from calcium hydride. Unless otherwise mentioned, all other

reagents were purchased from commercial sources and were used

without further purification. Finally, reactions were performed un-

der a blanket of inert gas (Ar or N₂) unless specified. In the num-

bering of the compounds in the manuscript, the first alphabetical

letter refers to the biaryl substrate utilized and the second to the

nucleophilic solvent (a = MeOH, b = EtOH, c = nPrOH, d =

nBuOH, e = propargyl alcohol, f = benzyl alcohol, g = allyl

aim to synthesize related compounds, which are more rigid

and have less flexibility in terms of rotation around the bi-

aryl axis of the compounds. In addition, compound 16da

was also found to be able to sensitize vincristine-resistant

leukemia (Nalm6) and lymphoma (Bibo) cells to the drug

vincristine. At a concentration of 5 μm of 16da (lower than

the IC₅₀value for the compound alone) and 10 nm of vin-

cristine, over 75% of the vincristine-resistant Nalm6 cells

underwent apoptosis (although higher concentrations of

16da were required for the resistant Bibo cells; see Support- alcohol, h = water, i = thiophenol, j = phenol).

ing Information). The synergistic application of cytotoxic

agents is an important area of research in oncology,^[23]and

this interesting activity provides additional impetus for the

study of these 6-oxa-allocolchicinoids.

Experimental Procedures

General Procedure for the Preparation of 1,3-Dioxolanes 13: 1,2-

Ethanediol (4 equiv.), triethyl orthoformate (1 equiv.) and p-tolu-

enesulfonic acid monohydrate (0.1 equiv.) were added to a solution

of substituted 2-bromobenzaldehyde (1 equiv.) in THF (10 mL).

The reaction mixture was then heated at 65–70 °C for 3–5 h and

was poured into a solution of NaHCO₃(10%, 5 mL). This was

extracted with EtOAc (2ϫ 30 mL), after which the combined or-

ganic layers were washed with brine and dried with Na₂SO₄, fol-

lowed by concentration under reduced pressure. The residue was

Conclusions

In this paper, a novel synthesis of 28 6-oxa-allocolchicin-

oids (5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines) with vary- purified by silica gel column chromatography using suitable solvent

mixtures of EtOAc/hexane as eluent, to afford the desired 1,3-di-

oxolane compounds 13 as described below. The compounds were

fully characterized by spectroscopy (¹H and ¹³C NMR, IR and

HRMS) and their spectra compared well to those published in the

literature. The following known compounds were generated in this

way: 2-(2-bromophenyl)-1,3-dioxolane (13a) from 2-bromobenz-

aldehyde (12a) (reaction time 3 h; eluent: 20% EtOAc/hexane mix-

ture; yield 84%),^[25]2-(2-bromo-5-methoxyphenyl)-1,3-dioxolane

(13b) from 2-bromo-5-methoxybenzaldehyde (12b) (reaction time

5 h; eluent: 20% EtOAc/hexane mixture; yield 85%),^[26]2-(2-

ing substitution patterns has been reported. In addition,

three substituted 5-(phenylsulfanyl)-5,7-dihydrodibenzo-

[c,e]oxepines and nine 4-(5,7-dihydrodibenzo[c,e]oxepin-5-

yl)phenols were also synthesized. The key steps involved in

the synthesis were a palladium-mediated Suzuki–Miyaura

coupling to afford the intermediate biphenyl-2-carb-

aldehydes. After reduction of the biarylcarbaldehydes to the

respective alcohols, these compounds were cyclized by way

of an acid-catalyzed intramolecular transacetalization to af-

ford the desired 5-alkoxy-5,7-dihydrodibenzo[c,e]oxepines bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (13c) from 2-bromo-

4,5-dimethoxybenzaldehyde (12c) (reaction time 3 h; eluent: 20%

EtOAc/hexane mixture; yield 93%),^[27]5-bromo-6-(1,3-dioxolan-2-

yl)benzo[1,3]dioxole (13d) from 6-bromobenzo[d][1,3]dioxole-5-

carbaldehyde (12d) (reaction time 3 h; eluent: 20% EtOAc/hexane

mixture; yield 92%)^[28]and 2-(2-bromo-3,4,5-trimethoxyphenyl)-

1,3-dioxolane (13e) from 2-bromo-3,4,5-trimethoxybenzaldehyde

(12e) (reaction time 3 h; eluent: 20% EtOAc/hexane mixture; yield

86%).^[14]

(in addition to some related phenol and thiophenol ana-

logues). A number of the compounds were tested for their

ability to inhibit the proliferation of the human leukemia

cell-line Nalm6, and – unfortunately – the compounds were

only found to be active in the 50–100 μm range. However,

some preliminary results, indicating that compound 16da

was able to re-sensitize vincristine-resistant cell lines to this

important drug reaffirm that this class of small molecules

is well worth investigating. It should thus be noted that the

synthetic strategy employed to synthesize the allocolchicine

analogues, readily afforded small libraries of compounds

with diverse substitution patterns.

General Procedure for the Preparation of Biphenyl-2-carbaldehydes

14 by Suzuki–Miyaura Coupling

Method A. General Procedure for Classical Suzuki–Miyaura Reac-

tion: Aryl bromide (1 equiv.), boronic acid (1.5 equiv.), NaHCO₃

(3 equiv.), and Pd(PPh₃)₄(5 mol-%) were suspended in a mixture

of DMF/H₂O (1:1, 5 mL each) in a flame-dried flask. The mixture

was heated to 110 °C under Ar for 4–6 h. After completion of the

reaction (by TLC), the mixture was partitioned between EtOAc

and H₂O, the aqueous layer was extracted with EtOAc. The com-

bined organic layers were washed with brine, dried with Na₂SO₄,

and the solvent was removed under reduced pressure to yield the

crude product. This material was purified by flash silica gel column

chromatography using suitable mixtures of EtOAc/hexane as elu-

ent, to afford the desired substituted biphenyl-2-carbaldehydes 14.

Experimental Section

General Considerations: ¹H and ¹³C NMR spectra were recorded

either with a 300 or 500 MHz spectrometer at the frequency indi-

cated. IR spectra were recorded with Fourier transform spectrome-

ters. Mass spectra were recorded with a Kratos MS 9/50, VG 70E

MS or VG 70 SEQ mass spectrometer, a WatersAPI Q-TOF Ultima

or Waters GCT Premier mass spectrometer. Melting points were

determined with a standard hot-stage apparatus. All reactions were

monitored by TLC carried out on 0.2 mm aluminium silica gel (60

F₂₅₄) pre-coated plates by using UV light. Kieselgel 60 (particle size

0.063–0.200 mm) was used for conventional silica gel chromatog-

raphy. Commercially available reagents and solvents were purified

and dried when necessary by conventional techniques.^[24]THF and

Method B. General Procedure for Microwave (MW) Assisted

Suzuki–Miyaura Reaction: To

a flame-dried microwave vial

(10 mL), equipped with a stirring bar, were added 2-(2-bromo-

phenyl)dioxolane 13 (1 equiv.), boronic acid (1.3 equiv.), Pd(PPh₃)₄

(5 mol-%) and NaHCO₃(3 equiv.) in DMF/H₂O (1:1, 2 mL) to the

vial, after which it was sealed. The vial was then irradiated in a

microwave reactor at 125 °C and 125 W for 25 min. After cooling

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Diverse 6-Oxa-allocolchicinoids

of the vessel, the reaction mass was filtered, diluted with H₂O

(5 mL) and extracted with EtOAc (3ϫ 10 mL). The combined or-

ganic layers were washed with brine (20 mL), dried with Na₂SO₄

and concentrated under reduced pressure. The resulting residue was

purified by flash silica gel column chromatography using suitable

solvent mixtures of EtOAc/hexane as eluent to afford the following

desired substituted biphenyl-2-carbaldehydes 14.

367 (100) [M⁺+ Na], 345 (98) [M⁺+ H], 255 (70). HRMS: calcd.

for C₁₉H₂₀O₆[M⁺+ H] 345.1338, found 345.1339.

6-[2-(1,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl]benzo[1,3]dioxole-5-

carbaldehyde (14f): Eluent: 20% EtOAc/hexane mixture; yield 60%

(Method B); white solid; R_f= 0.39 (EtOAc/hexane, 1:1); m.p. 160–

163 °C. IR (neat, film): ν

= 1674, 1608, 1480, 1400, 1362, 1253,

˜

max

1201 cm^–1. H NMR (300 MHz; CDCl₃): δ = 9.54 (s, 1 H), 7.45 (s,

1 H), 7.18 (s, 1 H), 6.81 (s, 1 H), 6.67 (s, 1 H), 6.10 (2ϫs overlap-

ping, 2 H), 5.41 (s, 1 H), 4.11–4.02 (m, 2 H), 3.97 (s, 3 H), 3.90–

3.80 (m, 5 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 190.4, 151.6,

149.1, 149.0, 147.9, 140.6, 129.8, 129.7, 128.4, 113.4, 111.0, 109.1,

105.6, 102.1, 101.4, 65.2 (2 C), 56.0, 55.9 ppm. MS (EI): m/z (%)

= 359 (100) [M⁺+ H]. HRMS: calcd. for C₁₉H₁₈O₇[M⁺+ H]

359.1131, found 359.1133.

1

2Ј-(1,3-Dioxolan-2-yl)biphenyl-2-carbaldehyde (14a): Reaction time

4 h; eluent: 10% EtOAc/hexane mixture; yield 60% (Method A) or

75% (Method B); spectra corresponded well to those published in

the literature.^[29]

2Ј-(1,3-Dioxolan-2-yl)-4-methoxybiphenyl-2-carbaldehyde (14b): Re-

action time 4 h; eluent: 20% EtOAc/hexane mixture; yield 77%

(Method A); white solid; R_f= 0.53 (EtOAc/hexane, 3:7); m.p. 65–

68 °C. IR (neat, film): ν

= 2873, 1687, 1605, 1484, 1396, 1316,

2-[6-(1,3-Dioxolan-2-yl)benzo[1,3]dioxol-5-yl]benzaldehyde (14g):

Eluent: 20% EtOAc/hexane mixture; yield 86% (Method B); light

yellow solid; R_f= 0.56 (EtOAc/hexane, 2:3); m.p. 106–108 °C. IR

˜

max

1

1266, 1225, 1165 cm^–1. H NMR (300 MHz; CDCl₃): δ = 9.67 (s,

1 H), 7.68 (dd, J = 7.5, 1.5 Hz, 1 H), 7.51 (d, J = 2.8 Hz, 1 H),

7.47–7.39 (m, 2 H), 7.29 (d, J = 8.4 Hz, 1 H), 7.22–7.15 (m, 2 H), (neat, film): ν_max= 2893, 1694, 1595, 1503, 1477, 1418, 1390, 1255,

˜

5.49 (s, 1 H), 4.02–3.91 (m, 2 H), 3.90 (s, 3 H), 3.86–3.76 (m, 2 H) 1208 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 9.80 (s, 1 H), 8.02

ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 191.8, 159.3, 137.3, 136.5,

136.4, 135.3, 132.4, 131.2, 128.8, 128.3, 126.9, 120.6, 109.2, 101.9,

65.3, 65.2, 55.6 ppm. MS (EI): m/z (%) = 307 (25) [M⁺+ Na], 285

(dd, J = 7.7, 1.2 Hz, 1 H), 7.64–7.57 (m, 1 H), 7.54–7.47 (m, 1 H),

7.36 (dd, J = 7.5, 0.9 Hz, 1 H), 7.16 (s, 1 H), 6.69 (s, 1 H), 6.05 (s,

2 H), 5.33 (s, 1 H), 4.04–3.92 (m, 2 H), 3.85–3.73 (m, 2 H) ppm.

(100) [M⁺+ H], 279 (10), 223 (30). HRMS: calcd. for C₁₇H₁₆O₄¹³C NMR (75 MHz; CDCl₃): δ = 191.9, 147.9, 147.8, 143.2, 134.6,

[M⁺+ H] 285.1136, found 285.1138.

133.1, 131.4 (2 C), 130.0, 128.1, 126.8, 110.5, 106.8, 101.6, 101.3,

65.3, 65.2 ppm. MS (EI): m/z (%) = 321(100) [M⁺+ Na], 299 (98)

[M⁺+ H], 279 (15). HRMS: calcd. for C₁₇H₁₄O₅[M⁺+ H]

299.0919, found 299.0923.

2Ј-(1,3-Dioxolan-2-yl)-4Ј-methoxybiphenyl-2-carbaldehyde

(14c):

Reaction time 6 h; eluent: 10% EtOAc/hexane mixture; yield 70%

(Method A) or 90% (Method B); reddish liquid; R_f= 0.46 (EtOAc/

hexane, 3:7). IR (neat, film): ν

= 2885, 1688, 1600, 1471, 1392, 2-[6-(1,3-Dioxolan-2-yl)benzo[1,3]dioxol-5-yl]-5-methoxybenz-

˜

max

1273, 1224 cm^–1. H NMR (300 MHz; CDCl₃): δ = 9.74 (s, 1 H), aldehyde (14h): Eluent: 20 % EtOAc/hexane mixture; yield 83%

1

8.01 (d, J = 7.6 Hz, 1 H), 7.63–6.52 (m, 1 H), 7.52 (m, 1 H), 7.36

(d, J = 7.5 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 7.14 (d, J = 8.4 Hz,

1 H), 6.97 (dd, J = 8.3, 2.4 Hz, 1 H), 5.46 (s, 1 H), 3.99–3.89 (m,

(Method B); light orange solid; R_f= 0.40 (EtOAc/hexane, 3:7); m.p.

145–147 °C. IR (neat, film): ν = 2871, 1684, 1602, 1478, 1393,

˜

max

1309, 1276, 1239 cm^–1. H NMR (300 MHz; CDCl₃): δ = 9.74 (s,

1

2 H), 3.88 (s, 3 H), 3.86–3.75 (m, 2 H) ppm. ¹³C NMR (75 MHz; 1 H), 7.49 (d, J = 2.3 Hz, 1 H), 7.28–7.25 (m, 1 H), 7.17–7.14 (m,

CDCl₃): δ = 192.2, 159.7, 143.6, 137.3, 134.7, 133.0, 132.0, 131.7,

129.7, 127.9, 126.7, 114.7, 111.8, 101.8, 65.3, 65.2, 55.4 ppm. MS

(EI): m/z (%) = 285 (20) [M⁺+ H], 284 (100) [M⁺]: HRMS: calcd.

for C₁₇H₁₆O₄[M⁺+ H] 285.1127, found 285.1123.

2 H), 6.66 (s, 1 H), 6.03 (s, 2 H), 5.32 (s, 1 H), 4.05–3.94 (m, 2 H),

3.90 (s, 3 H), 3.85–3.75 (m, 2 H) ppm. ¹³C NMR (75 MHz; CDCl₃):

δ = 191.8, 159.3, 147.9, 147.8, 136.0, 135.5, 132.6, 131.2, 130.4,

120.8, 110.8, 109.3, 106.7, 101.6, 101.3, 65.3, 65.2, 55.6 ppm. MS

(EI): m/z (%) = 351 (15) [M⁺+ Na], 329 (75) [M⁺+ H], 239 (100).

HRMS: calcd. for C₁₈H₁₆O₆[M⁺+ H] 329.1025, found 329.1037.

2Ј-(1,3-Dioxolan-2-yl)-4Ј,5Ј-dimethoxy-1,1Ј-biphenyl-2-carbaldehyde

(14d): Reaction time 6 h; eluent: 20% EtOAc/hexane mixture; yield

68% (Method A) or 80% (Method B); white crystalline solid; R_f= 6Ј-(1,3-Dioxolan-2-yl)-5,5Ј-bi(benzo[1,3]dioxolyl)-6-carbaldehyde

0.33 (EtOAc/hexane, 2:3); m.p. 114–116 °C. IR (neat, film): ν

=

(14i): Eluent: 20% EtOAc/hexane mixture; yield 60% (Method B);

white solid; R_f= 0.33 (EtOAc/hexane, 3:7); m.p. 162–165 °C. IR

˜

max

2888, 1689, 1594, 1517, 1475, 1451, 1393, 1344, 1282, 1268, 1233,

1198 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 9.77 (s, 1 H), 8.02 (neat, film): ν

= 2898, 1674, 1612, 1477, 1412, 1362, 1247 cm^–1.

˜

max

(dd, J = 7.7, 1.2 Hz, 1 H), 7.65–7.57 (m, 1 H), 7.55–7.48 (m, 1 H),

7.39 (dd, J = 7.5, 0.9 Hz, 1 H), 7.19 (s, 1 H), 6.70 (s, 1 H), 5.37 (s,

¹H NMR (500 MHz; CDCl₃): δ = 9.55 (s, 1 H), 7.43 (s, 1 H), 7.13

(s, 1 H), 6.77 (d, J = 2.2 Hz, 1 H), 6.65 (s, 1 H), 6.09 (d, J = 1.1 Hz,

1 H), 4.05–3.93 (m, 5 H), 3.87 (s, 3 H), 3.83–3.74 (m, 2 H) ppm. 1 H), 6.08 (d, J = 1.1 Hz, 1 H), 6.03 (s, 2 H), 5.36 (s, 1 H), 4.07–3.98

¹³C NMR (75 MHz; CDCl₃): δ = 192.1, 149.1, 149.0, 143.5, 134.7, (m, 2 H), 3.87–3.78 (m, 2 H) ppm. ¹³C NMR (125 MHz; CDCl₃): δ

133.0, 131.5, 130.1, 128.2, 128.0, 126.7, 113.4, 109.3, 101.6, 65.2,

= 190.2, 151.7, 148.03, 147.99, 147.94, 140.4, 131.0, 130.4, 129.9,

110.9, 110.6, 106.7, 105.8, 102.1, 101.6, 101.1, 65.34, 65.31 ppm.

65.1, 56.1, 56.0 ppm. MS (EI): m/z (%) = 337 (100) [M⁺+ Na], 315

(18) [M⁺+ H], 229 (18). HRMS: calcd. for C₁₈H₁₈O₅[M⁺+ H] MS (EI): m/z (%) = 365 (5) [M⁺+ Na], 343 (12) [M⁺+ H], 253

315.1233, found 315.1244.

(100). HRMS: calcd. for C₁₈H₁₄O₇[M⁺+ H] 343.0818, found

343.0820.

2Ј-(1,3-Dioxolan-2-yl)-4,4Ј,5Ј-trimethoxybiphenyl-2-carbaldehyde

(14e): Eluent: 30% EtOAc/hexane mixture; yield 65% (Method B),

red crystalline solid; R_f= 0.56 (EtOAc/hexane, 3:2); m.p. 117–

2Ј-(1,3-Dioxolan-2-yl)-4Ј,5Ј,6Ј-trimethoxy-1,1Ј-biphenyl-2-carb-

aldehyde (14j): Reaction time 6 h; eluent: 20% EtOAc/hexane mix-

ture; yield 65% (Method A) or 81% (Method B); red crystalline

120 °C. IR (neat, film): ν

= 2868, 1685, 1603, 1519, 1493, 1460,

˜

max

1392, 1345, 1313, 1263, 1242, 1203 cm^–1

.

¹H NMR (300 MHz; solid; R_f= 0.40 (EtOAc/hexane, 2:3); m.p. 80–83 °C. IR (neat,

CDCl₃): δ = 9.73 (s, 1 H), 7.51 (d, J = 2.8 Hz, 1 H), 7.32 (d, J = film): ν

= 2890, 1691, 1594, 1455, 1397, 1333, 1272, 1234,

˜

max

8.4 Hz, 1 H), 7.20–7.05 (m, 2 H), 6.69 (s, 1 H), 5.37 (s, 1 H), 4.08–

4.00 (m, 2 H), 3.98 (s, 3 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.84–3.77

1196 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 9.76 (s, 1 H), 8.03 (d,

J = 7.0 Hz, 1 H), 7.61 (d, J = 6.8 Hz, 1 H), 7.52 (d, J = 6.8 Hz, 1

(m, 2 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 192.0, 159.3, H), 7.35 (d, J = 6.8 Hz, 1 H), 7.05 (s, 1 H), 5.32 (s, 1 H), 3.96 (br.

149.0, 148.9, 136.2, 135.5, 132.7, 129.8, 128.5, 120.7, 113.8 (2 C), s, 5 H), 3.91 (s, 3 H), 3.85–3.77 (m, 2 H), 3.55 (s, 3 H) ppm. ¹³C

109.2, 101.6, 65.2, 65.1, 56.0, 55.9, 55.6 ppm. MS (EI): m/z (%) =

NMR (75 MHz; CDCl₃): δ = 192.1, 153.7, 151.2, 142.7, 138.9,

Eur. J. Org. Chem. 2015, 5167–5182

www.eurjoc.org

5173

W. A. L. van Otterlo

FULL PAPER

134.9, 133.0, 132.0, 131.4, 128.0, 126.7, 124.5, 105.5, 101.4, 65.3,

135.9, 130.8, 130.0, 129.1, 128.5, 127.4, 126.9, 114.8, 113.2, 102.6,

69.6, 67.1, 61.8, 55.5 ppm. MS (EI): m/z (%) = 287 (20) [M⁺+ H].

HRMS: calcd. for C₁₇H₁₇O₄[M⁺] 285.1127, found 287.1129.

65.2, 60.9, 60.7, 56.0 ppm. MS (EI): m/z (%) = 367 (15) [M⁺+ Na],

345 (40) [M⁺+ H], 255 (100). HRMS: calcd. for C₁₉H₂₀O₆[M⁺

H] 345.1338, found 345.1335.

+

[2Ј-(1,3-Dioxolan-2-yl)-4Ј,5Ј-dimethoxy-1,1Ј-biphenyl-2-yl]methanol

(15d): Yield 98%; white solid; R_f= 0.41 (EtOAc/hexane, 3:2); m.p.

6Ј-(1,3-Dioxolan-2-yl)-2Ј,3Ј,4,4Ј-tetramethoxybiphenyl-2-carb-

aldehyde (14k): Eluent: 20 % EtOAc/hexane mixture; yield 69 %

(Method B); red crystalline solid; R_f= 0.42 (EtOAc/hexane, 2:3);

100–103 °C. IR (neat, film): ν

= 3539, 2885, 1608, 1517, 1445,

˜

max

1402, 1345, 1234, 1206 cm^–1. ¹H NMR (500 MHz; CD₃OD, OH

signal not observed): δ = 7.55 (d, J = 7.7 Hz, 1 H), 7.40–7.36 (m,

1 H), 7.29–7.25 (m, 1 H), 7.17 (s, 1 H), 7.14 (d, J = 7.5 Hz, 1 H),

6.73 (s, 1 H), 5.27 (s, 1 H), 4.39 (d, J = 13.2 Hz, 1 H), 4.33 (d, J =

13.2 Hz, 1 H), 4.02–3.98 (m, 2 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.76

(t, J = 4.8 Hz, 2 H) ppm. ¹³C NMR (125 MHz; CD₃OD): δ =

150.7, 149.9, 140.9, 139.4, 134.7, 131.4, 128.9, 128.8, 128.5, 127.7,

114.2, 111.0, 102.7, 66.3, 66.2, 62.9, 56.5, 56.4 ppm. MS (EI): m/z

(%) = 339 (30) [M⁺+ Na], 317 (5) [M⁺+ H], 255 (100), 227 (85).

HRMS: calcd. for C₁₈H₂₀O₅[M⁺+ H] 317.1389, found 317.1387.

m.p. 85–88 °C. IR (neat, film): ν_max= 2941, 1682, 1596, 1456, 1390,

˜

1335, 1308, 1281, 1230, 1195 cm^–1. ¹H NMR (300 MHz; CDCl₃):

δ = 9.69 (s, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.28 (d, J = 2.8 Hz, 1

H), 7.18 (dd, J = 8.4, 2.8 Hz, 1 H), 7.04 (s, 1 H), 5.32 (s, 1 H),

4.06–3.97 (m, 2 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.85–

3.77 (m, 2 H), 3.54 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ

= 192.0, 159.3, 153.6, 151.4, 142.7, 135.8, 133.2, 131.7, 131.4, 124.3,

120.6, 109.4, 105.4, 101.3, 65.3, 65.2, 60.9, 60.7, 56.0, 55.5 ppm.

MS (EI): m/z (%) = 397 (65) [M⁺+ Na], 376 (15), 375 (100) [M⁺

+ H]. HRMS: calcd. for C₂₀H₂₂O₇[M⁺+ H] 375.1444, found

375.1449.

[2Ј-(1,3-Dioxolan-2-yl)-4,4Ј,5Ј-trimethoxybiphenyl-2-yl]methanol

(15e): Yield 92%; white solid; R_f= 0.30 (EtOAc/hexane, 3:2); m.p.

General Procedure for the Preparation of Benzyl Alcohols 15 by Re-

duction of Biphenyl-2-carbaldehydes 14: NaBH₄(1.5 equiv.) was

added to a solution of aldehyde 14 (1 equiv.) in MeOH (20 mL), at

0 °C with stirring and under Ar. The reaction mixture was then

stirred at room temp. for 1 h. After completion of the reaction (by

TLC), the reaction mixture was concentrated under reduced pres-

sure, diluted with H₂O and extracted with EtOAc. The organic

layer was then washed with brine, dried with Na₂SO₄and concen-

trated under reduced pressure to give the desired alcohols 16 in a

crude form. ¹H NMR spectroscopy indicated that these com-

pounds were essentially pure, and they were used as such in the

next step without additional purification (yields below given after

removal of solvent under vacuum and further drying under high

vacuum).

118–121 °C. IR (neat, film): ν

= 3494, 2890, 1606, 1520, 1493,

˜

max

1456, 1401, 1345, 1295, 1264, 1237, 1203 cm^{–1 1}H NMR

.

(500 MHz; CD₃OD, OH signal not observed): δ = 7.15 (s, 1 H),

7.13 (d, J = 2.7 Hz, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 6.83 (dd, J =

8.3, 2.7 Hz, 1 H), 6.70 (s, 1 H), 5.27 (s, 1 H), 4.35 (d, J = 13.5 Hz,

1 H), 4.29 (d, J = 13.5 Hz, 1 H), 4.03–4.00 (m, 2 H), 3.86 (s, 3 H),

3.83 (s, 3 H), 3.79 (s, 3 H), 3.77 (td, J = 4.8, 1.5 Hz, 2 H) ppm. ¹³

C

NMR (125 MHz; CD₃OD): δ = 160.9, 150.7, 149.8, 142.4, 134.6,

132.4, 131.4, 129.1, 114.5, 113.5, 113.0, 111.0, 102.7, 66.3, 66.2,

62.9, 56.5, 56.4, 55.7 ppm. MS (EI): m/z (%) = 369 (65) [M⁺+ Na],

347 (10) [M⁺+ H], 285 (100), 257 (40). HRMS: calcd. for C₁₉H₂₂O₆

[M⁺+ H] 347.1495, found 347.1493.

{6-[2-(1,3-Dioxolan-2-yl)-4,5-dimethoxyphenyl)]benzo[1,3]dioxol-5-

yl}methanol (15f): Yield 92%; white solid; R_f= 0.24 (EtOAc/hex-

[2Ј-(1,3-Dioxolan-2-yl)biphenyl-2-yl]methanol (15a): Yield 96 %;

colourless liquid; R_f= 0.35 (EtOAc/hexane, 2:3). IR (neat, film):

ν

˜

= 3405, 2885, 1474, 1443, 1393, 1203 cm^{–1 1}H NMR

.

ane, 3:2); m.p. 58–62 °C. IR (neat, film): ν

= 3421, 2886, 1606,

˜

max

1502, 1481, 1399, 1244, 1206 cm^–1. ¹H NMR (300 MHz; CDCl₃):

δ = 7.14 (s, 1 H), 7.00 (s, 1 H), 6.67 (s, 1 H), 6.62 (s, 1 H), 5.99 (s,

2 H), 5.43 (s, 1 H), 4.21–4.01 (m, 4 H), 3.95 (s, 3 H), 3.93–3.87 (m,

2 H), 3.85 (s, 3 H), 3.24–3.12 (m, 1 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 149.2, 148.6, 147.4, 146.5, 134.0, 132.9, 131.9, 127.2,

112.8, 109.8, 109.4, 108.7, 101.4, 101.2, 65.5, 64.9, 62.4, 56.0,

55.9 ppm. MS (EI): m/z (%) = 383 (100) [M⁺+ Na]. HRMS: calcd.

for C₁₉H₂₀O₇[M⁺+ Na] 383.1107, found 383.1108.

(300 MHz; CDCl₃): δ = 7.67–7.64 (m, 1 H), 7.53 (d, J = 7.5 Hz, 1

H), 7.43–7.37 (m, 3 H), 7.33–7.28 (m, 1 H), 7.20–7.13 (m, 2 H),

5.51 (s, 1 H), 4.35–4.23 (m, 2 H), 3.98–3.90 (m, 2 H), 3.85–3.76 (m,

2 H), 3.17–3.09 (m, 1 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ =

140.2, 139.5, 138.8, 135.1, 130.0, 129.8, 129.3, 129.0, 128.2, 127.9,

127.0, 126.7, 101.9, 65.6, 65.0, 62.7 ppm. MS (EI): m/z (%) = 279

(18) [M⁺+ Na], 242 (85), 224 (100). HRMS: calcd. for C₁₆H₁₆O₃

[M⁺+ Na] 279.0997, found 279.0997.

[2Ј-(1,3-Dioxolan-2-yl)-4-methoxybiphenyl-2-yl]methanol (15b):

Yield 94%; white solid; R_f= 0.33 (EtOAc/hexane, 3:7); m.p. 66–

{2-[6-(1,3-Dioxolan-2-yl)benzo[1,3]dioxol-5-yl]phenyl}methanol

(15g): Yield 91%; white solid; R_f= 0.30 (EtOAc/hexane, 2:3); m.p.

68 °C. IR (neat, film): ν

= 3476, 2898, 1606, 1463, 1428, 1397,

˜

max

117–120 °C. IR (neat, film): ν

= 3450, 2890, 1507, 1481, 1410,

˜

max

1303, 1230, 1159 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.66–7.63

(m, 1 H), 7.44–7.34 (m, 2 H), 7.14–7.08 (m, 3 H), 6.85 (dd, J = 8.4,

2.6 Hz, 1 H), 5.51 (s, 1 H), 4.33–4.20 (m, 2 H), 4.03–3.93 (m, 2 H),

3.85 (s, 3 H), 3.84–3.77 (m, 2 H), 3.16–3.09 (m, 1 H) ppm. ¹³C

NMR (75 MHz; CDCl₃): δ = 159.4, 140.9, 140.0, 135.5, 131.0,

130.8, 130.5, 129.0, 127.8, 126.6, 113.7, 113.1, 101.8, 65.6, 65.0,

62.8, 55.3 ppm. MS (EI): m/z (%) = 309 (15) [M⁺+ Na], 225 (100),

197 (65). HRMS: calcd. for C₁₇H₁₈O₄[M⁺+ H] 309.1103, found

309.1106.

1392, 1318, 1245 cm^–1. ¹H NMR (300 MHz; CD₃OD, OH signal

not observed): δ = 7.54 (d, J = 7.6 Hz, 1 H), 7.41–7.32 (m, 1 H),

7.30–7.21 (m, 1 H), 7.11 (d, J = 6.7 Hz, 1 H), 7.05 (s, 1 H), 6.60

(s, 1 H), 5.99 (s, 2 H), 5.21 (s, 1 H), 4.39 (d, J = 13.4 Hz, 1 H),

4.32 (d, J = 13.4 Hz, 1 H), 4.01–3.97 (m, 2 H), 3.76–3.71 (m, 2 H)

ppm. ¹³C NMR (75 MHz; CD₃OD): δ = 149.4, 148.7, 140.9, 139.2,

135.7, 131.3, 130.3, 128.9, 128.3, 127.7, 110.5, 107.5, 102.8, 102.4,

66.2 (2 C), 62.8 ppm. MS (EI): m/z (%) = 301 (2) [M⁺+ H], 239

(100), 211 (35), 181 (20). HRMS: calcd. for C₁₇H₁₆O₅[M⁺+ H]

301.1067, found 301.1070.

[2Ј-(1,3-Dioxolan-2-yl)-4Ј-methoxybiphenyl-2-yl]methanol (15c):

Yield 98%; colourless liquid; R_f= 0.25 (EtOAc/hexane, 3:7). IR

(neat, film): ν_max= 2865, 1608, 1505, 1480, 1453, 1312, 1267, 1231,

{2-[6-(1,3-Dioxolan-2-yl)benzo[1,3]dioxol-5-yl]-5-methoxy-

˜

1

1194 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.52–7.46 (m, 3 H), phenyl}methanol (15h): Yield 90%; white solid; R_f= 0.37 (EtOAc/

7.43–7.29 (m, 2 H), 7.05–7.03 (m, 2 H), 5.52 (s, 1 H), 4.48 (s, 2 H), hexane, 1:1); m.p. 162–165 °C. IR (neat, film): ν

= 3420, 1608,

˜

max

3.88 (s, 3 H), 3.79–3.69 (m, 2 H), 3.55–3.46 (m, 2 H), 1.92 (br. s, 1

1480, 1409, 1236, 1156 cm^–1. ¹H NMR (500 MHz; CD₃OD, OH

H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.5, 141.2, 136.9, signal not observed): δ = 7.12 (d, J = 2.6 Hz, 1 H), 7.03 (s, 1 H),

5174

www.eurjoc.org

Eur. J. Org. Chem. 2015, 5167–5182

Diverse 6-Oxa-allocolchicinoids

7.01 (s, 1 H), 6.82 (dd, J = 8.4, 2.7 Hz, 1 H), 6.57 (s, 1 H), 5.99 (s,

1 H), 5.98 (s, 1 H), 5.22 (s, 1 H), 4.34 (d, J = 13.6 Hz, 1 H), 4.29

5-Methoxy-5,7-dihydrodibenzo[c,e]oxepine (16aa): Reaction solvent:

MeOH; PTSA·H₂O (15 mol-%); reaction time 5 min; eluent: 5%

(d, J = 13.6 Hz, 1 H), 4.02–3.99 (m, 2 H), 3.83 (s, 3 H), 3.77–3.75 EtOAc/hexane mixture; yield 71%; white solid; R_f= 0.51 (EtOAc/

(m, 2 H) ppm. ¹³C NMR (125 MHz; CD₃OD): δ = 161.0, 149.4,

148.6, 142.5, 135.6, 132.4, 131.3, 130.7, 113.4, 113.0, 110.9, 107.5,

102.8, 102.5, 66.3 (2 C), 62.9, 55.7 ppm. MS (EI): m/z (%) = 353

(10) [M⁺+ Na], 331 (2) [M⁺+ H], 269 (100), 241 (60), 211 (20).

HRMS: calcd. for C₁₈H₁₈O₆[M⁺+ H] 331.1182, found 331.1188.

hexane, 1:4); m.p. 50–53 °C. IR (neat, film): ν

= 2879, 1451,

˜

max

1388, 1368, 1200 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.58–7.32

(m, 8 H), 5.41 (s, 1 H), 4.50–4.42 (m, 2 H), 3.29 (s, 3 H) ppm. ¹³C

NMR (75 MHz; CDCl₃): δ = 141.1, 138.5, 136.3, 135.9, 129.2,

129.0, 128.6, 128.5, 128.0, 127.8, 127.7, 127.2, 103.2, 66.8,

55.4 ppm. MS (EI): m/z (%) = 249 (85) [M⁺+ Na], 229 (60), 195

(100). HRMS: calcd. for C₁₅H₁₄O₂[M⁺+ Na] 249.0891, found

249.0901.

[6Ј-(1,3-Dioxolan-2-yl)-5,5Ј-bi(benzo[1,3]dioxolyl)-6-yl]methanol

(15i): Yield 92%; white solid; R_f= 0.57 (EtOAc/hexane, 3:2); m.p.

168–170 °C. IR (neat, film): ν

= 3431, 2903, 1617, 1503, 1476,

˜

max

1413, 1394, 1326, 1245, 1212, 1182 cm^{–1 1}H NMR (500 MHz;

.

5-Ethoxy-5,7-dihydrodibenzo[c,e]oxepine (16ab): Reaction solvent

EtOH; PTSA·H₂O (15 mol-%); reaction time: 5 min; eluent: 5%

EtOAc/hexane mixture; yield 74%; white solid; R_f= 0.54 (EtOAc/

CD₃OD, OH signal not observed): δ = 7.03 (s, 1 H), 6.99 (d, J =

5.2 Hz, 1 H), 6.59–6.57 (m, 2 H), 6.00–5.97 (m, 2 H), 5.96–5.95 (m,

2 H), 5.27 (s, 1 H), 4.26–4.18 (m, 2 H), 4.05–4.01 (m, 2 H), 3.79–

3.77 (m, 2 H) ppm. ¹³C NMR (125 MHz; CD₃OD): δ = 149.4,

148.9, 148.7, 146.6, 135.5, 135.8, 132.6, 130.8, 111.3, 110.9, 108.7,

107.4, 102.8, 102.6, 102.4, 66.3 (2 C), 62.6 ppm. MS (EI): m/z (%)

= 367 (5) [M⁺+ Na], 283 (25), 255 (100), 225 (15). HRMS: calcd.

for C₁₈H₁₆O₇[M⁺+ Na] 367.0795, found 367.0794.

hexane, 1:4); m.p. 40–42·C. IR (neat, film): ν_max= 2973, 1452, 1390,

˜

1368, 1348, 1202 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.58–7.32

(m, 8 H), 5.49 (s, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.42 (d, J =

11.7 Hz, 1 H), 3.75 (dq, J = 9.4, 7.0 Hz, 1 H), 3.40 (dq, J = 9.4,

7.0 Hz, 1 H), 1.00 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 141.1, 138.5, 136.3, 136.1, 129.1, 128.8, 128.5, 128.4,

128.0, 127.7, 127.3, 127.2, 101.1, 66.7, 63.1, 15.0 ppm. MS (EI):

m/z (%) = 279 (100) [M⁺], 263 (30) [M⁺+ Na]. HRMS: calcd. for

C₁₆H₁₆O₂[M⁺+ Na] 263.1048, found 263.1059.

[6Ј-(1,3-Dioxolan-2-yl)-2Ј,3Ј,4Ј-trimethoxy-1,1Ј-biphenyl-2-yl]meth-

anol (15j): Yield 95%; white solid; R_f= 0.40 (EtOAc/hexane, 3:2);

m.p. 93–96 °C. IR (neat, film): ν_max= 3478, 2937, 1597, 1455, 1392,

˜

5-Butoxy-5,7-dihydrodibenzo[c,e]oxepine (16ad): Reaction solvent

nBuOH; PTSA·H₂O (15 mol-%); reaction time: 60 min; eluent: 5%

EtOAc/hexane mixture; yield 78%; colourless liquid; R_f= 0.57

1333, 1272, 1227, 1192 cm^–1. ¹H NMR (500 MHz; CD₃OD, OH

signal not observed): δ = 7.56 (d, J = 7.7 Hz, 1 H), 7.42–7.35 (m,

1 H), 7.30–7.24 (m, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.05 (s, 1 H),

5.22 (s, 1 H), 4.34 (d, J = 13.8 Hz, 1 H), 4.31 (d, J = 13.8 Hz, 1 H)

4.01–3.92 (m, 2 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.75–3.73 (m, 2 H),

3.51 (s, 3 H) ppm. ¹³C NMR (125 MHz; CD₃OD): δ = 154.5, 151.9,

144.3, 141.9, 134.5, 132.5, 131.9, 128.9, 128.8, 127.6, 127.4, 107.2,

102.4, 66.3, 66.2, 63.1, 61.4, 61.3, 56.6 ppm. MS (EI): m/z (%) =

367 (40) [M⁺+ Na], 347 (5) [M⁺+ H], 285 (85), 257 (100), 255

(30), 226 (20). HRMS: calcd. for C₁₉H₂₂O₆[M⁺+ H] 347.1494,

found 347.1488.

(EtOAc/hexane, 1:4). IR (neat, film): ν_max= 2865, 1604, 1480, 1452,

˜

1377, 1279, 1199 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.55–7.31

(m, 8 H), 5.48 (s, 1 H), 4.45 (m, 2 H), 3.70 (dt, J = 9.3, 6.7 Hz, 1

H), 3.32 (dt, J = 9.3, 6.2 Hz, 1 H), 1.40–1.31 (m, 2 H), 1.10–0.97

(m, 2 H), 0.75 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 141.2, 138.6, 136.4, 136.3, 129.1, 128.8, 128.5, 128.4,

127.9, 127.7, 127.5, 127.2, 101.7, 67.5, 66.8, 31.6, 19.0, 13.8 ppm.

MS (EI): m/z (%) = 291 (100) [M⁺+ Na], 233 (10), 295 (10), 258

(8). HRMS: calcd. for C₁₈H₂₀O₂[M⁺+ Na] 291.1361, found

291.1374.

[6Ј-(1,3-Dioxolan-2-yl)-2Ј,3Ј,4,4Ј-tetramethoxybiphenyl-2-yl]meth-

anol (15k): Yield 96%; white solid; R_f= 0.37 (EtOAc/hexane, 3:2);

5,7-Dihydrodibenzo[c,e]oxepin-5-ol (16ah): Reaction solvent: H₂O

and THF, PTSA·H₂O (15 mol-%); reaction time: 30 min; eluent:

30% EtOAc/hexane mixture; yield 90%; white solid; R_f= 0.49

m.p. 128–130 °C. IR (neat, film): ν

= 3445, 2882, 1596, 1483,

˜

max

1403, 1383, 1334, 1272, 1251, 1192 cm^–1. ¹H NMR (500 MHz;

CD₃OD): δ = 7.14 (d, J = 1.8 Hz, 1 H), 7.05–7.00 (m, 2 H), 6.83

(dd, J = 8.3, 2.2 Hz, 1 H), 5.23 (s, 1 H), 4.31 (d, J = 13.9 Hz, 1 H),

4.26 (d, J = 13.9 Hz, 1 H), 4.03–3.95 (m, 2 H), 3.89 (s, 3 H), 3.85

(s, 3 H), 3.84 (s, 3 H), 3.77–3.74 (m, 2 H), 3.50 (s, 3 H) ppm. ¹³C

NMR (125 MHz; CD₃OD, OH signal not observed): δ = 163.5,

156.9, 154.7, 146.8, 145.9, 135.5, 135.4, 131.1, 128.8, 115.3, 115.2,

109.6, 104.9, 68.8, 68.7, 65.6, 64.0, 63.9, 59.1, 58.2 ppm. MS (EI):

m/z (%) = 399 (100) [M⁺+ Na], 377 (5) [M⁺+ H], 359 (12). HRMS:

calcd. for C₂₀H₂₄O₇[M⁺+ Na] 399.1420, found 399.1424.

(EtOAc/hexane, 2:3); m.p. 94–96 C. IR (neat, film): ν

= 3408,

˜

max

2966, 1564, 1447, 1368, 1246, 1195 cm^–1. H NMR: In our hands

compound 16ah was not very stable in CDCl₃, although this com-

pound has been characterized before by Tamiya et al. who observed

that 16ah was in equilibrium with the corresponding ring-opened

benzyl alcohol/benzaldehyde.^[30]MS (EI): m/z (%) = 235 (100) [M⁺

+ Na], 229 (8), 195 (15). HRMS: calcd. for C₁₄H₁₂O₂[M⁺+ Na]

235.0735, found 235.0742. X-ray crystal structure details: Crys-

tallized from EtOAc/hexane, formula: C₁₄H₁₂O₂, M = 212.24, col-

1

our/shape

of

crystal:

white/needle,

crystal

size:

General Procedure for the Preparation of 5-Alkoxy-5,7-dihydrodi-

benzo[c,e]oxepines 16: To a solution of the substituted benzyl

alcohol 15 (0.7 mmol) in the alkanol (5 mL) was added p-tolu-

enesulfonic acid monohydrate (15–25 mol-%) at room temp. The

reaction mixture was then stirred at this temperature for 5–120 min

until the reaction was deemed complete (TLC). The solution was

then concentrated under reduced pressure, diluted with H₂O

(20 mL) and extracted with EtOAc (3ϫ 20 mL). The combined or-

ganic layers were washed with Na₂CO₃solution (20 mL, 10%), fol-

lowed by brine (20 mL), after which they were dried (Na₂SO₄) and

concentrated under reduced pressure. The resulting residue was

purified by flash silica gel column chromatography using suitable

solvent mixture of EtOAc/hexane as eluent to afford the desired 5-

alkoxy-5,7-dihydrodibenzo[c,e]oxepines.

0.49ϫ0.24ϫ0.10 mm, a = 12.8876(4) Å, b = 4.72220(10) Å, c =

17.3673(5) Å, V = 1052.47(5) Å³, β = 95.270(2)°, ρ_calcd.= 1.339 Mg/

m³, μ = 0.089 mm^–1, F(000) = 448, Z = 4, T = 173(2) K, 13187

reflections collected, 2535 [R(int) = 0.0685] independent reflections,

θ_max= 27.99°, 149 refined parameters, maximum residual electron

density: 0.262 and –0.190 eÅ^–3, R1 = 0.0510, wR2 = 0.1111.

CCDC-1024803 contains the supplementary crystallographic data

for this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

3,7-Dimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16ba): Reaction sol-

vent MeOH; PTSA·H₂O (15 mol-%); reaction time: 20 min; eluent:

5% EtOAc/hexane mixture; yield 82%; white solid; R_f= 0.58

Eur. J. Org. Chem. 2015, 5167–5182

www.eurjoc.org

5175

W. A. L. van Otterlo

FULL PAPER

(EtOAc/hexane, 3:7); m.p. 66–68 °C. IR (neat, film): ν

= 2835, 4.26 (dd, J = 15.9, 2.4 Hz, 1 H), 4.06 (dd, J = 15.9, 2.4 Hz, 1 H),

˜

max

1609, 1507, 1453, 1384, 1314, 1266, 1231 cm^–1. ¹H NMR

3.85 (s, 3 H), 2.33 (t, J = 2.4 Hz, 1 H) ppm. ¹³C NMR (75 MHz;

(300 MHz; CDCl₃): δ = 7.52–7.44 (m, 4 H), 7.41–7.35 (m, 1 H), CDCl₃): δ = 159.2, 138.5, 137.6, 134.9, 133.5, 129.4, 128.5, 128.4,

7.00 (dd, J = 8.4, 2.6 Hz, 1 H), 6.95 (d, J = 2.6 Hz, 1 H), 5.39 (s, 128.3, 127.4, 114.2, 114.0, 100.4, 79.4, 74.3, 67.1, 55.4, 53.9 ppm.

1 H), 4.46 (d, J = 11.7 Hz, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 3.87

MS (EI): m/z (%) = 303 (3) [M⁺+ Na], 225 (100), 197 (65). HRMS:

(s, 3 H), 3.33 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.3, calcd. for C₁₈H₁₆O₃[M⁺+ Na] 303.0997, found 303.1008.

138.2, 137.6, 135.5, 133.4, 129.1, 128.3, 128.2, 127.6, 127.4, 114.2,

3,5-Dimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16ca): Reaction sol-

vent: MeOH, PTSA·H₂O (15 mol-%); reaction time: 5 min; eluent:

10% EtOAc/hexane mixture; yield 83%; white solid; R_f= 0.43

114.0, 103.2, 67.0, 55.5, 55.4 ppm. MS (EI): m/z (%) = 279 (2) [M⁺

+ Na], 225 (100), 197 (60). HRMS: calcd. for C₁₆H₁₆O₃[M⁺+ Na]

279.0997, found 279.1006.

(EtOAc/hexane, 1:4); m.p. 70–73 °C. IR (neat, film): ν

= 2874,

˜

max

1603, 1500, 1477, 1450, 1384, 1307, 1275, 1228, 1201 cm^–1. ¹H

NMR (300 MHz; CDCl₃): δ = 7.52–7.41 (m, 3 H), 7.39–7.29 (m, 2

H), 7.11 (d, J = 2.4 Hz, 1 H), 7.02 (dd, J = 8.4, 2.5 Hz, 1 H), 5.33

(s, 1 H), 4.49 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H) 3.87

(s, 3 H), 3.34 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.5,

140.8, 137.2, 135.9, 130.8, 129.7, 128.9, 128.5, 127.3, 127.0, 115.0,

112.4, 102.6, 67.0, 55.6, 55.5 ppm. MS (EI): m/z (%) = 257 (20)

[M⁺+ H]. 256, (100) [M⁺]. HRMS: calcd. for C₁₆H₁₆O₃[M⁺]

256.1099, found 256.1002.

7-Ethoxy-3-methoxy-5,7-dihydrodibenzo[c,e]oxepine (16bb): Reac-

tion solvent: EtOH, PTSA·H₂O (15 mol-%); reaction time: 60 min;

eluent: 5% EtOAc/hexane mixture; yield 90%; colourless viscous

liquid. R = 0.68 (EtOAc/hexane, 3:7). IR (neat, film): ν_max= 2865,

˜

f

1607, 1505, 1451, 1312, 1263, 1229 cm^–1. ¹H NMR (300 MHz;

CDCl₃): δ = 7.57 (d, J = 7.3 Hz, 1 H), 7.48–7.42 (m, 3 H), 7.40–

7.35 (m, 1 H), 6.99 (dd, J = 8.4, 2.6 Hz, 1 H), 6.95 (d, J = 2.6 Hz,

1 H), 5.46 (s, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.39 (d, J = 11.7 Hz,

1 H), 3.86 (s, 3 H), 3.80–3.73 (m, 1 H), 3.42 (dq, J = 9.4, 7.0 Hz,

1 H), 1.05 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃):

δ = 159.3, 138.3, 137.5, 135.8, 133.5, 129.0, 128.4, 128.1, 127.4,

127.3, 114.1, 114.0, 101.1, 66.9, 63.4, 55.4, 15.1 ppm. MS (EI): m/z

(%) = 489 (100), 293 (4) [M⁺+ Na], 225 (8). HRMS: calcd. for

C₁₇H₁₈O₃[M⁺+ Na] 293.1154, found 293.1161.

5-Ethoxy-3-methoxy-5,7-dihydrodibenzo[c,e]oxepine (16cb): Reac-

tion solvent: EtOH, PTSA·H₂O (15 mol-%); reaction time: 5 min;

eluent: 10% EtOAc/hexane mixture; (0.160 g, 0.593 mmol), yield

85%; colourless liquid. R_f= 0.50 (EtOAc/hexane, 1:4). IR (neat,

film): ν

=2862, 1607, 1504, 1479, 1453, 1310, 1266, 1231,

˜

max

3-Methoxy-7-propoxy-5,7-dihydrodibenzo[c,e]oxepine (16bc): Reac-

tion solvent: nPrOH, PTSA·H₂O (15 mol-%); reaction time:

30 min; eluent: 10% EtOAc/hexane mixture; yield 86%; white solid;

1193 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.51–7.41 (m, 3 H),

7.38–7.29 (m, 2 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.02 (dd, J = 8.4,

2.5 Hz, 1 H), 5.41 (s, 1 H), 4.49 (d, J = 11.7 Hz, 1 H), 4.41 (d, J =

11.7 Hz, 1 H), 3.88 (s, 3 H), 3.77 (dq, J = 9.0, 7.1 Hz, 1 H), 3.43

(dq, J = 9.0, 7.1 Hz, 1 H), 1.04 (t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR

(75 MHz; CDCl₃): δ = ppm. ¹³C NMR (75 MHz; CDCl₃): δ =

159.5, 140.8, 137.5, 135.9, 130.9, 129.6, 128.8, 128.5, 127.2, 127.0,

114.8, 112.2, 100.7, 66.9, 63.5, 55.5, 15.0 ppm. MS (EI): m/z (%) =

271 (100) [M⁺+ H], 270 (98) [M⁺]: HRMS: calcd. for C₁₇H₁₈O₃Na

[M⁺+ Na] 293.1154, found 293.1151.

1

R = 0.70 (EtOAc/hexane, 3:7); m.p. 84–86 °C. IR (neat, film): ν

˜

f

max

= 2865, 1604, 1479, 1459, 1313, 1263, 1228 cm^–1. ¹H NMR

(300 MHz; CDCl₃): δ = 7.55 (d, J = 7.4 Hz, 1 H), 7.48–7.42 (m, 3

H), 7.40–7.35 (m, 1 H), 7.01–6.95 (m, 2 H), 5.46 (s, 1 H), 4.45 (d,

J = 11.7 Hz, 1 H), 4.37 (d, J = 11.7 Hz, 1 H), 3.86 (s, 3 H), 3.68

(dt, J = 9.2, 6.7 Hz, 1 H), 3.31 (dt, J = 9.2, 6.3 Hz, 1 H), 1.50–1.39

(m, 2 H), 0.69 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 159.3, 138.3, 137.6, 135.8, 133.6, 129.0, 128.4, 128.1,

127.4, 127.3, 114.2, 114.1, 101.6, 69.6, 66.9, 55.4, 22.8, 10.4 ppm.

MS (EI): m/z (%) = 307 (2) [M⁺+ Na], 225 (100), 197 (65). HRMS:

calcd. for C₁₈H₂₀O₃[M⁺+ Na] 307.1310, found 307.1320.

5-Butoxy-3-methoxy-5,7-dihydrodibenzo[c,e]oxepine (16cd): Reac-

tion solvent: nBuOH, PTSA·H₂O (15 mol-%); reaction time: 5 min;

eluent: 10% EtOAc/hexane mixture; yield 85% (0.177 g,

0.593 mmol), white solid; R_f= 0.60 (EtOAc/hexane, 1:4); m.p. 30–

7-Butoxy-3-methoxy-5,7-dihydrodibenzo[c,e]oxepine (16bd): Reac-

tion solvent: nBuOH, PTSA·H₂O (15 mol-%); reaction time:

20 min; eluent: 5% EtOAc/hexane mixture; yield 91%; colourless

32 °C. IR (neat, film): ν

= 2954, 1606, 1502, 1478, 1451, 1310,

˜

max

1264, 1230, 1169 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.50–7.40

(m, 3 H), 7.38–7.25 (m, 2 H), 7.14 (d, J = 2.4 Hz, 1 H), 7.01 (dd,

J = 8.4, 2.4 Hz, 1 H), 5.41 (s, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.41

(d, J = 11.7 Hz, 1 H), 3.87 (s, 3 H), 3.78–3.58 (m, 1 H), 3.38–3.31

(m, 1 H), 1.38 (dt, J = 7.8, 6.6 Hz, 2 H), 1.15–1.03 (m, 2 H), 0.77

(t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.5,

140.9, 137.6, 135.9, 130.9, 129.7, 128.8, 128.5, 127.2, 126.9, 114.7,

112.5, 101.2, 67.8, 66.9, 55.4, 31.6, 19.0, 13.8 ppm. MS (EI): m/z

(%) = 299 (20) [M⁺+ H], 298 (100) [M⁺]: HRMS: calcd. for

C₁₉H₂₁O₃[M⁺– H] 297.1491, found 297.1481.

viscous liquid; R = 0.66 (EtOAc/hexane, 3:7). IR (neat, film): ν

˜

f

max

= 2955, 1607, 1506, 1452, 1312, 1263, 1229 cm^–1. ¹H NMR

(300 MHz; CDCl₃): δ = 7.54 (d, J = 7.4 Hz, 1 H), 7.47–7.39 (m, 3

H), 7.40–7.35 (m, 1 H), 6.99 (dd, J = 8.4, 2.6 Hz, 1 H), 6.95 (d, J

= 2.5 Hz, 1 H), 5.46 (s, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.39 (d, J

= 11.7 Hz, 1 H), 3.86 (s, 3 H), 3.73 (dt, J = 9.3, 6.7 Hz, 1 H), 3.34

(dt, J = 9.3, 6.2 Hz, 1 H), 1.40 (dt, J = 7.3, 6.6 Hz, 2 H), 1.09 (dq,

J = 8.1, 7.3 Hz, 2 H), 0.78 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR

(75 MHz; CDCl₃): δ = 159.3, 138.3, 137.6, 135.9, 133.6, 129.0,

128.4, 128.1, 127.4, 127.3, 114.2, 114.0, 101.7, 67.6, 66.9, 55.4, 31.7,

19.0, 13.8 ppm. MS (EI): m/z (%) = 337 (100), 321 (20) [M⁺+ Na],

297 (4) [M⁺– 1], 263 (8), 225 (10). HRMS: calcd. for C₁₉H₂₂O₃

[M⁺+ Na] 321.1467, found 321.1482.

5-(Benzyloxy)-3-methoxy-5,7-dihydrodibenzo[c,e]oxepine (16cf): Re-

action solvent: benzyl alcohol, PTSA·H₂O (15 mol-%); reaction

time: 20 min; eluent: 5% EtOAc/hexane mixture; yield 80%,

colourless liquid. R = 0.56 (EtOAc/hexane, 1:4). IR (neat):ν

=

˜

f

max

3-Methoxy-7-(prop-2-ynyl)oxy-5,7-dihydrodibenzo[c,e]oxepine

(film): 2861, 1608, 1481, 1453, 1314, 1268, 1233, 1171 cm^–1. ¹H

(16be): Reaction solvent: propargyl alcohol, PTSA·H₂O (15 mol- NMR (300 MHz; CDCl₃): δ = 7.64–7.24 (m, 8 H), 7.12–6.89 (m, 4

%); reaction time: 30 min; eluent: 10% EtOAc/hexane mixture;

yield 67%; white solid; R_f= 0.61 (EtOAc/hexane, 3:7); m.p. 61–

H), 5.59 (s, 1 H), 4.77 (d, J = 11.8 Hz, 1 H), 4.50 (s, 2 H), 4.41 (d,

J = 11.8 Hz, 1 H), 3.85 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃):

δ = 159.5, 141.2, 138.0, 137.3, 136.2, 133.1, 131.1, 130.0, 128.9,

63 °C. IR (neat, film): ν

= 3272, 2851, 1606, 1510, 1484, 1463,

˜

max

1400, 1313, 1265, 1247, 1229 cm^–1. ¹H NMR (300 MHz; CDCl₃): 129.8, 128.6, 128.1, 127.5, 127.3, 127.2, 127.1, 114.8, 113.2, 101.3,

δ = 7.5–7.46 (m, 4 H), 7.40–7.34 (m, 1 H), 6.98 (dd, J = 8.4, 2.6 Hz, 69.0, 67.1, 55.5 ppm. HRMS: calcd. for C₂₂H₂₀O₃Na [M⁺+ Na]

1 H), 6.92 (d, J = 2.6 Hz, 1 H), 5.79 (s, 1 H), 4.48–4.40 (m, 2 H),

355.1310: found 355.1307.

5176

www.eurjoc.org

Eur. J. Org. Chem. 2015, 5167–5182

Diverse 6-Oxa-allocolchicinoids

2,3,5-Trimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16da): Reaction

solvent: MeOH, PTSA·H₂O (15 mol-%); reaction time: 10 min; elu-

ent: 20% EtOAc/hexane mixture; yield 90%; colourless viscous li-

7.30 (m, 2 H), 7.13 (s, 1 H), 7.03 (s, 1 H), 5.75 (ddd, J = 16.4, 10.6,

5.4 Hz, 1 H), 5.46 (s, 1 H), 5.07–5.00 (m, 2 H), 4.49 (d, J = 11.6 Hz,

1 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.25–4.20 (m, 1 H), 4.00 (s, 1 H),

quid. R = 0.50 (EtOAc/hexane, 2:3). IR (neat, film): ν

= 2935, 3.96 (s, 6 H) ppm. ¹³C NMR (125 MHz; CDCl₃): δ = 149.3, 148.7,

˜

f

max

1601, 1514, 1452, 1346, 1277, 1214 cm^–1. ¹H NMR (300 MHz; 140.9, 136.2, 134.3, 131.0, 128.9, 128.7, 128.6, 127.4, 126.9, 116.4,

CDCl₃): δ = 7.55–7.44 (m, 2 H), 7.41–7.33 (m, 2 H), 7.11 (s, 1 H),

111.4, 110.3, 100.2, 68.4, 66.8, 56.1, 56.08 ppm. MS (EI): m/z (%)

7.03 (s, 1 H), 5.31 (s, 1 H), 4.49 (d, J = 11.6 Hz, 1 H), 4.41 (d, J = = 335 (4) [M⁺+ Na], 313 (5) [M⁺+ H], 255 (100), 227 (98), 225

11.6 Hz, 1 H), 3.96 (br. s, 6 H), 3.36 (s, 3 H) ppm. ¹³C NMR (15), 212 (12). HRMS: calcd. for C₁₉H₂₀O₄[M⁺+ H] 313.1440,

(75 MHz; CDCl₃): δ = 149.3, 148.7, 140.8, 136.2, 130.8, 128.9, found 313.1445.

128.7, 128.6, 127.4, 126.9, 111.4, 110.2, 102.2, 66.7, 56.1, 56.06,

2,3,9-Trimethoxy-5-propoxy-5,7-dihydrodibenzo[c,e]oxepine (16ec):

55.7 ppm. MS (EI): m/z (%) = 287 (100) [M⁺+ H], 279 (70), 273

Reaction solvent: nPrOH, PTSA·H₂O (15 mol-%); reaction time:

(30), 272 (60). HRMS: calcd. for C₁₇H₁₈O₄[M⁺+ H] 287.1283,

20 min; eluent: 10% EtOAc/hexane mixture; yield 76%; trans-

found 287.1285.

parent crystals. R_f= 0.47 (EtOAc/hexane, 2:3); m.p. 65–70 °C. IR

5-Ethoxy-2,3-dimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16db): Re-

action solvent: EtOH, PTSA·H₂O (15 mol-%); reaction time:

10 min; eluent: 20% EtOAc/hexane mixture; yield 72%; white solid;

R_f= 0.64 (EtOAc/hexane, 2:3); m.p. 100–103 °C. IR (neat, film):

(neat, film): ν

= 1609, 1497, 1459, 1256 cm^–1. ¹H NMR

˜

max

(300 MHz; CDCl₃): δ = 7.45 (d, J = 8.3 Hz, 1 H), 7.14 (s, 1 H),

7.01–6.95 (m, 3 H), 5.37 (s, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.37

(d, J = 11.6 Hz, 1 H), 3.95 (s, 6 H), 3.87 (s, 3 H), 3.73 (dt, J = 9.1,

6.7 Hz, 1 H), 3.35 (dt, J = 9.1, 6.5 Hz, 1 H), 1.50 (dq, J = 9.0,

ν

= 2969, 1607, 1516, 1445, 1348, 1279, 1261, 1218 cm^–1. ¹H

˜

max

NMR (300 MHz; CDCl₃): δ = 7.54–7.43 (m, 2 H), 7.40–7.31 (m, 2 6.9 Hz, 2 H), 0.75 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR (75 MHz;

H), 7.16 (s, 1 H), 7.02 (s, 1 H), 5.39 (s, 1 H), 4.49 (d, J = 11.6 Hz,

1 H), 4.39 (d, J = 11.6 Hz, 1 H) 3.97 (s, 3 H), 3.96 (s, 3 H), 3.80

(dq, J = 9.4, 7.1 Hz, 1 H), 3.45 (dq, J = 9.4, 7.0 Hz, 1 H), 1.07 (t,

J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 149.2,

148.7, 140.8, 136.1, 130.9, 128.9, 128.8, 128.6, 127.4, 126.9, 111.3,

110.0, 100.3, 66.7, 63.5, 56.1, 56.0, 15.0 ppm. MS (EI): m/z (%) =

323 (75) [M⁺+ Na], 302 (25), 301 (100) [M⁺+ H], 295 (15).

HRMS: calcd. for C₁₈H₂₀O₄[M⁺+ H] 301.1440, found 301.1440.

CDCl₃): δ = 159.0, 149.2, 148.3, 137.5, 133.3, 130.8, 128.5, 128.0,

114.2, 114.1, 111.1, 110.2, 100.8, 69.9, 66.8, 56.1, 56.0, 55.4, 22.9,

10.5 ppm. MS (EI): m/z (%) = 367 (12) [M⁺+ Na], 345 (15) [M⁺

+ H], 325 (10), 285 (100), 257 (45). HRMS: calcd. for C₂₀H₂₄O₅

[M⁺+ H] 345.1702, found 345.1700.

2,3-Dimethoxy-5-propoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]-

cyclohepta[1,2-f]indene (16fc): Reaction solvent: nPrOH,

PTSA·H₂O (15 mol-%); reaction time: 30 min; eluent: 5% EtOAc/

hexane mixture; yield 85%; white solid; R_f= 0.50 (EtOAc/hexane,

5-Butoxy-2,3-dimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16dd): Re-

action solvent: nBuOH, PTSA·H₂O (15 mol-%); reaction time:

30 min; eluent: 20% EtOAc/hexane mixture; yield 84%; colourless

3:7); m.p. 88–90 °C. IR (neat, film): ν_max= 2860, 1607, 1428, 1267,

˜

1

1238 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.14 (s, 1 H), 7.00 (s,

liquid. R = 0.51 (EtOAc/hexane, 3:7). IR (neat, film): ν_max= 2956,

1 H), 6.93 (s, 1 H), 6.88 (s, 1 H), 6.01 (2 s overlapping, 2 H), 5.35

˜

f

1606, 1514, 1454, 1344, 1277, 1213 cm^–1. ¹H NMR (300 MHz; (s, 1 H), 4.37 (d, J = 11.7 Hz, 1 H), 4.26 (d, J = 11.7 Hz, 1 H),

CDCl₃): δ = 7.54–7.42 (m, 2 H), 7.40–7.30 (m, 2 H), 7.13 (s, 1 H),

3.95 (s, 6 H), 3.73 (dt, J = 9.2, 6.7 Hz, 1 H), 3.36 (dt, J = 9.2,

7.03 (s, 1 H), 5.40 (s, 1 H), 4.48 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 6.5 Hz, 1 H), 1.60–1.45 (m, 2 H), 0.78 (t, J = 7.4 Hz, 3 H) ppm.

11.6 Hz, 1 H), 3.96 (s, 6 H), 3.75 (dt, J = 9.3, 6.7 Hz, 1 H), 3.36

(dt, J = 9.3, 6.3 Hz, 1 H), 1.46–1.37 (m, 2 H), 1.11 (dq, J = 8.4,

¹³C NMR (75 MHz; CDCl₃): δ = 149.2, 148.5, 148.0, 146.7, 134.9,

130.9, 130.0, 128.8, 110.9, 109.9, 109.2, 107.5, 101.3, 100.6, 70.0,

7.3 Hz, 2 H), 0.79 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (75 MHz; 66.4, 56.1, 56.0, 22.9, 10.5 ppm. MS (EI): m/z (%) = 359 (100) [M⁺

CDCl₃): δ = 149.2, 148.7, 140.9, 136.3, 130.9, 129.0, 128.8, 128.7,

127.3, 126.9, 111.4, 110.2, 100.9, 67.8, 66.7, 56.1, 56.0, 31.6, 19.1,

13.8 ppm. MS (EI): m/z (%) = 351 (12) [M⁺+ Na], 329 (30) [M⁺

+ H], 255 (92), 227 (100). HRMS: calcd. for C₂₀H₂₄O₄[M⁺+ H]

329.1752, found 329.1750.

+ H], 357 (20). HRMS: calcd. for C₂₀H₂₂O₆[M⁺+ H] 359.1495,

found 359.1498.

7-Methoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta[1,2-f]ind-

ene (16ga): Reaction solvent: MeOH, PTSA·H₂O (15 mol-%); reac-

tion time: 10 min; eluent: 20% EtOAc/hexane mixture; yield 72%;

white solid; R_f= 0.57 (EtOAc/hexane, 3:7); m.p. 147–150 °C. IR

2,3-Dimethoxy-5-(prop-2-ynyloxy)-5,7-dihydrodibenzo[c,e]oxepine

(16de): Reaction solvent: propargyl alcohol, PTSA·H₂O (15 mol- (neat, film): ν

%); reaction time: 2 h; eluent: 20% EtOAc/hexane mixture; yield

= 2915, 1485, 1448, 1370, 1267, 1228, 1201 cm^–1.

˜

max

¹H NMR (300 MHz; CDCl₃): δ = 7.48–7.42 (m, 2 H), 7.40–7.30

83%; colourless liquid. R_f= 0.63 (EtOAc/hexane, 2:3). IR (neat,

(m, 2 H), 7.06 (s, 1 H), 6.99 (s, 1 H), 6.03 (2 s, overlapping, 2 H),

film): ν_max= 3282, 2935, 1598, 1513, 1488, 1452, 1397, 1345, 1278, 5.23 (s, 1 H), 4.48 (d, J = 11.6 Hz, 1 H), 4.40 (d, J = 11.6 Hz, 1

˜

1233, 1213 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.54 (d, J = H), 3.32 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 148.1,

7.5 Hz, 1 H), 7.50–7.42 (m, 1 H), 7.39–7.30 (m, 2 H), 7.07 (s, 1 H),

147.4, 140.7, 135.9, 132.6, 130.1, 128.9, 128.6, 127.5, 127.0, 108.5,

7.04 (s, 1 H) 5.72 (s, 1 H), 4.47 (s, 2 H), 4.27 (dd, J = 15.9, 2.2 Hz, 107.6, 102.0, 101.4, 66.7, 55.7 ppm. MS (EI): m/z (%) = 271 (100)

1 H), 4.09 (dd, J = 15.9, 2.3 Hz, 1 H), 3.97 (s, 6 H), 2.34 (t, J =

2.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 149.4, 148.6,

140.8, 136.2, 131.2, 128.9, 128.5, 128.1, 127.3, 127.0, 111.8, 111.1,

99.7, 79.4, 74.3, 73.8, 66.8, 56.1 (2 C) ppm. MS (EI): m/z (%) =

333 (15) [M⁺+ Na], 311 (5) [M⁺+ H], 295 (10), 255 (100), 227

(10) (95) 212. HRMS: calcd. for C₁₉H₁₈O₄[M⁺+ H] 311.1283,

found 311.1278.

[M⁺+ H], 269 (2). HRMS: calcd. for C₁₆H₁₄O₄[M⁺+ H] 271.0970,

found 271.0977.

7-Propoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta[1,2-f]ind-

ene (16gc): Reaction solvent: nPrOH, PTSA·H₂O (15 mol-%); reac-

tion time: 20 min; eluent: 10% EtOAc/hexane mixture; yield 89%;

white solid; R_f= 0.70 (EtOAc/hexane, 3:7); m.p. 65–68 °C. IR (neat,

film): ν

= 2965, 1503, 1478, 1452, 1420, 1375, 1346, 1265,

˜

max

5-(Allyloxy)-2,3-dimethoxy-5,7-dihydrodibenzo[c,e]oxepine (16dg): 1188 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.47–7.41 (m, 2 H),

1

Reaction solvent: allyl alcohol, PTSA·H₂O (15 mol-%); reaction

time: 2 h; eluent: 20% EtOAc/hexane mixture; yield 61%; colour-

less liquid. R_f= 0.66 (EtOAc/hexane, 2:3). ¹H NMR (300 MHz;

CDCl₃): δ = 7.53 (d, J = 6.8 Hz, 1 H), 7.49–7.42 (m, 1 H), 7.39–

7.39–7.29 (m, 2 H), 7.11 (s, 1 H), 6.99 (s, 1 H), 6.03 (2 s, overlap-

ping, 2 H), 5.30 (s, 1 H), 4.48 (d, J = 11.6 Hz, 1 H), 4.38 (d, J =

11.6 Hz, 1 H), 3.67 (dt, J = 9.2, 6.8 Hz, 1 H), 3.29 (dt, J = 9.2,

6.4 Hz, 1 H), 1.51–1.37 (m, 2 H), 0.69 (t, J = 7.4 Hz, 3 H) ppm.

Eur. J. Org. Chem. 2015, 5167–5182

www.eurjoc.org

5177

W. A. L. van Otterlo

FULL PAPER

¹³C NMR (75 MHz; CDCl₃): δ = 148.0, 147.4, 140.8, 135.9, 132.6, 108.1, 107.3, 101.3, 100.4, 70.0, 66.8, 55.4, 22.8, 10.5 ppm. MS (EI):

130.5, 128.8, 128.6, 127.5, 127.0, 108.4, 107.5, 101.4, 100.5, 69.9,

66.7, 22.8, 10.4 ppm. MS (EI): m/z (%) = 299 (20) [M⁺+ H], 279

(30), 239 (100), 211 (40). HRMS: calcd. for C₁₈H₁₈O₄[M⁺+ H]

299.1283, found 299.1293.

m/z (%) = 329 (20) [M⁺+ H], 269 (100), 241 (60), 211 (20). HRMS:

calcd. for C₁₉H₂₁O₅[M⁺+ H] 329.1389, found 329.1405.

7-Butoxy-3-methoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta-

[1,2-f]indene (16hd): Reaction solvent: MeOH, PTSA·H₂O (15 mol-

7-(2-Propynyloxy)-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta- %); reaction time: 20 min; eluent: 20 % EtOAc/hexane mixture;

[1,2-f]indene (16ge): Reaction solvent: propargyl alcohol, yield 97%; white solid; R_f= 0.66 (EtOAc/hexane, 3:7); m.p. 68–

PTSA·H₂O (15 mol-%); reaction time: 1 h, eluent: 10% EtOAc/hex-

ane mixture; yield 81%; white solid; R_f= 0.54 (EtOAc/hexane, 3:7);

70 °C. IR (neat, film): ν

= 2955, 1474, 1376, 1263, 1240,

˜

max

1182 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.38 (d, J = 8.3 Hz,

1

m.p. 65–68 °C. IR (neat, film): ν_max= 3274, 2869, 1501, 1477, 1450, 1 H), 7.09 (s, 1 H), 7.00–6.93 (m, 3 H), 6.02 (s, 1 H), 6.01 (s, 1 H),

˜

1417, 1365, 1344, 1266 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ =

5.27 (s, 1 H), 4.36 (d, J = 11.7 Hz, 1 H), 4.24 (d, J = 11.7 Hz, 1

7.50–7.41 (m, 2 H), 7.35–7.26 (m, 2 H), 7.02 (s, 1 H), 7.01 (s, 1 H), H), 3.86 (s, 3 H), 3.75 (dt, J = 9.3, 6.6 Hz, 1 H), 3.34 (dt, J = 9.3,

6.04 (s, 1 H), 6.03 (s, 1 H), 5.63 (s, 1 H), 4.46 (s, 2 H), 4.22 (dd, J 6.3 Hz, 1 H), 1.49–140 (m, 2 H), 1.20–1.10 (m, 2 H), 0.81 (t, J =

= 15.9, 2.2 Hz, 1 H), 4.05 (dd, J = 15.9, 2.3 Hz, 1 H), 2.32 (t, J =

2.2 Hz, 1 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 148.3, 147.3,

140.8, 135.9, 132.9, 129.4, 129.0, 128.5, 127.5, 127.1, 108.8, 108.3,

101.5, 99.5, 79.2, 74.3, 66.8, 54.1 ppm. MS (EI): m/z (%) = 299 (8)

7.3 Hz, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.1, 148.0,

146.9, 137.2, 133.2, 132.4, 129.9, 128.2, 114.2, 114.1, 108.1, 107.4,

101.3, 100.5, 68.1, 66.8, 55.4, 31.7, 19.1, 13.8 ppm. MS (EI): m/z

(%) = 365 (2) [M⁺+ Na], 343 (20) [M⁺+ H], 269 (100), 241 (60),

[M⁺+ Na], 239 (100), 227 (97), 177 (42). HRMS: calcd. for 211 (18). HRMS: calcd. for C₂₀H₂₂O₅[M⁺+ H] 343.1545, found

C₁₈H₁₄O₄[M⁺+ Na] 317.0790, found 317.0786; calcd. for

343.1557.

+

C₁₅H₁₁O₃[M – OCH₂CCH]⁺239.0708, found 239.0712.

5-Methoxy-5,7-dihydro-[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c][1,3]diox-

3,7-Dimethoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta[1,2-f]- olo[4Ј,5Ј:4,5]benzo[1,2-e]oxepine (16ia): Reaction solvent: MeOH,

indene (16ha): Reaction solvent: MeOH, PTSA·H₂O (15 mol-%); PTSA·H₂O (15 mol-%); reaction time: 60 min; eluent: 20% EtOAc/

reaction time: 20 min; eluent: 20% EtOAc/hexane mixture; yield

hexane mixture; yield 89%; white solid; R_f= 0.54 (EtOAc/hexane,

96%; white solid; R_f= 0.50 (EtOAc/hexane, 3:7); m.p. 121–123 °C.

3:7); m.p. 185–188 °C. IR (neat, film): ν

= 2894, 1475, 1429,

˜

max

IR (neat, film): ν_max= 2803, 1608, 1475, 1239, 1163 cm^–1. ¹H NMR 1390, 1357, 1244, 1210 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ =

˜

(300 MHz; CDCl₃): δ = 7.38 (d, J = 8.4 Hz, 1 H), 7.05 (s, 1 H), 7.04 (s, 1 H), 6.93 (s, 1 H), 6.90 (s, 1 H), 6.87 (s, 1 H), 6.02 (s, 4

6.98 (dd, J = 8.4, 2.7 Hz, 1 H), 6.93 (s, 2 H), 6.02 (d, J = 1.4 Hz, H), 5.19 (s, 1 H), 4.36 (d, J = 11.7 Hz, 1 H), 4.26 (d, J = 11.7 Hz,

1 H), 6.01 (d, J = 1.4 Hz, 1 H), 5.21 (s, 1 H), 4.45 (d, J = 11.6 Hz,

1 H), 4.36 (d, J = 11.6 Hz, 1 H), 3.86 (s, 3 H), 3.34 (s, 3 H) ppm.

1 H), 3.35 (s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 148.1,

147.1, 146.9, 134.7, 132.5, 129.9, 129.7, 109.4, 109.0, 108.2, 107.5,

¹³C NMR (75 MHz; CDCl₃): δ = 159.1, 148.1, 146.9, 137.2, 133.2, 107.4, 102.0, 101.4, 101.3, 66.4, 55.8 ppm. MS (EI): m/z (%) = 337

132.4, 129.6, 128.2, 114.2, 114.1, 108.2, 107.5, 102.0, 101.3, 66.8,

(5) [M⁺+ Na], 283 (25), 255 (100), 225 (12). HRMS: calcd. for

55.7, 55.4 ppm. MS (EI): m/z (%) = 323 (8) [M⁺+ Na], 301 (2) C₁₇H₁₄O₆[M⁺+ Na] 337.0697, found 337.0695.

[M⁺+ H], 269 (100), 241 (60), 211 (20). HRMS: calcd. for

5-Propoxy-5,7-dihydro-[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c][1,3]diox-

olo[4Ј,5Ј:4,5]benzo[1,2-e]oxepine (16ic): Reaction solvent: nPrOH,

PTSA·H₂O (15 mol-%); reaction time: 30 min; eluent: 10% EtOAc/

C₁₇H₁₆O₅[M⁺+ H] 301.1076, found 301.1086.

7-Ethoxy-3-methoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclohepta-

[1,2-f]indene (16hb): Reaction solvent: EtOH, PTSA·H₂O (15 mol- hexane mixture; yield 63%; white solid; R_f= 0.67 (EtOAc/hexane,

%); reaction time: 30 min; eluent: 10 % EtOAc/hexane mixture;

yield 84%; white solid; R_f= 0.61 (EtOAc/hexane, 3:7); m.p. 127–

3:7); m.p. 174–176 °C. IR (neat, film): ν

= 2866, 1502, 1477,

˜

max

1432, 1356, 1241, 1182 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ =

129 °C. IR (neat, film): ν

= 2874, 1610, 1474, 1429, 1376, 1305,

7.11 (s, 1 H), 6.93 (s, 1 H), 6.90 (s, 1 H), 6.87 (s, 1 H), 6.03–6.00

˜

max

1263, 1241, 1188 cm^–1. H NMR (500 MHz; CDCl₃): δ = 7.38 (d, (m, 4 H), 5.25 (s, 1 H), 4. 37 (d, J = 11.7 Hz, 1 H), 4.24 (d, J =

J = 8.4 Hz, 1 H), 7.12 (s, 1 H), 6.98 (dd, J = 8.4, 2.7 Hz, 1 H), 11.7 Hz, 1 H), 3.70 (dt, J = 9.2, 6.7 Hz, 1 H), 3.32 (dt, J = 9.2,

6.94–6.93 (m, 2 H), 6.02 (d, J = 1.4 Hz, 1 H), 6.01 (d, J = 1.4 Hz, 6.5 Hz, 1 H), 1.50 (dt, J = 14.0, 7.0 Hz, 2 H), 0.78 (t, J = 7.4 Hz,

1

1 H), 5.27 (s, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.34 (d, J = 11.6 Hz,

3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 148.04, 148.02, 147.2,

1 H), 3.86 (s, 3 H), 3.79 (dq, J = 9.4, 7.1 Hz, 1 H), 3.43 (dq, J = 146.8, 134.8, 132.5, 130.2, 129.7, 109.1, 108.0, 107.6, 107.2, 101.4,

9.4, 7.0 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR 101.3, 100.3, 70.1, 66.3, 22.9, 10.5 ppm. MS (EI): m/z (%) = 365

(125 MHz; CDCl₃): δ = 159.1, 148.0, 147.0, 137.1, 133.2, 132.4, (4) [M⁺+ Na], 283 (30), 255 (100), 225 (12). HRMS: calcd. for

129.9, 128.2, 114.2 (2 C), 108.1, 107.2, 101.3, 100.0, 66.8, 63.8, 55.4, C₁₉H₁₈O₆[M⁺+ Na] 365.1000, found 365.0998.

15.1 ppm. MS (EI): m/z (%) = 337 (8) [M⁺+ Na], 315 (15) [M⁺

+

7-Butoxy-3-methoxy-5,7-dihydro-[1,3]dioxolo[4Ј,5Ј:4,5]benzo[1,2-c]-

benzo[e]oxepine (16id): Reaction solvent: nBuOH, PTSA·H₂O

(15 mol-%); reaction time: 30 min; eluent: 10% EtOAc/hexane mix-

H], 269 (100), 241 (60), 211 (20). HRMS: calcd. for C₁₈H₁₈O₅[M⁺

+ H] 315.1214, found 315.1238.

3-Methoxy-7-propoxy-5,7-dihydro-6,9,11-trioxabenzo[3,4]cyclo- ture; yield 78%; white solid; R_f= 0.62 (EtOAc/hexane, 3:7); m.p.

hepta[1,2-f]indene (16hc): Reaction solvent: nPrOH, PTSA·H₂O

(15 mol-%); reaction time: 60 min; eluent: 10% EtOAc/hexane mix-

146–148 °C. IR (neat, film): ν

= 2875, 1504, 1478, 1434, 1356,

˜

max

1243, 1183 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.09 (s, 1 H),

1

ture; yield 84%; white solid; R_f= 0.60 (EtOAc/hexane, 3:7); m.p. 6.93 (s, 1 H), 6.89 (s, 1 H), 6.86 (s, 1 H), 6.02–6.00 (m, 4 H), 5.25

94–98 °C. IR (neat, film): ν = 2969, 1474, 1432, 1378, 1310, (s, 1 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.24 (d, J = 11.6 Hz, 1 H),

1266, 1186 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.38 (d, J = 3.75 (dt, J = 9.2, 6.6 Hz, 1 H), 3.35 (dt, J = 9.2, 6.3 Hz, 1 H), 1.51–

˜

max

8.4 Hz, 1 H), 7.11 (s, 1 H), 7.00–6.93 (m, 3 H), 6.02 (d, J = 1.3 Hz,

1 H), 6.01 (d, J = 1.3 Hz, 1 H), 5.27 (s, 1 H), 4. 45 (d, J = 11.5 Hz,

1 H), 4.35 (d, J = 11.5 Hz, 1 H), 3.86 (s, 3 H), 3.70 (dt, J = 9.2,

6.7 Hz, 1 H), 3.31 (dt, J = 9.2, 6.4 Hz, 1 H), 1.54–1.43 (m, 2 H),

1.41 (m, 2 H), 1.28–1.13 (m, 2 H), 0.83 (t, J = 7.3 Hz, 3 H) ppm.

¹³C NMR (75 MHz; CDCl₃): δ = 148.04, 148.02, 147.1, 146.8,

134.8, 132.5, 130.2, 129.7, 109.1, 108.0, 107.6, 107.3, 101.4, 101.3,

100.4, 68.1, 66.3, 31.7, 19.1, 13.8 ppm. MS (EI): m/z (%) = 379 (2)

0.74 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = [M⁺+ Na], 283 (32), 255 (100), 225 (12). HRMS: calcd. for

159.1, 148.0, 146.9, 137.2, 133.2, 132.4, 129.9, 128.2, 114.2 (2 C),

C₂₀H₂₀O₆[M⁺+ Na] 379.1158, found 379.1166.

5178

www.eurjoc.org

Eur. J. Org. Chem. 2015, 5167–5182

Diverse 6-Oxa-allocolchicinoids

General Procedure for the Preparation of 5-(Phenylthio)-5,7-dihydro-

90.3, 68.2, 55.5 ppm. MS (EI): m/z (%) = 335 (15) [M⁺+ H], 334

dibenzo[c,e]oxepines 17 and {2Ј-[Bis(phenylsulfanyl)methyl]-1,1Ј-bi- (100) [M⁺]: HRMS: calcd. for C₂₁H₁₈O₂S [M⁺] 334.1027, found

phenyl-2-yl}methanols 18: p-Toluenesulfonic acid monohydrate

(15 mol-%) was added to a solution of the substituted benzyl

alcohol 15 (0.7 mmol) in benzenethiol (5 mL), at room temp. The

reaction mixture was then stirred at this temperature for 10–30 min

until the reaction was deemed complete (TLC). The solution was

then concentrated under reduced pressure, diluted with H₂O

(20 mL) and extracted with EtOAc (3ϫ 20 mL). The combined or-

ganic layers were washed with Na₂CO₃solution (20 mL, 10%), fol-

lowed by brine (20 mL), after which they were dried (Na₂SO₄) and

concentrated under reduced pressure. The resulting residue was

purified by flash silica gel column chromatography using suitable

solvent mixture of EtOAc/hexane as eluent to afford the desired 5-

(phenylthio)-5,7-dihydrodibenzo[c,e]oxepines as described below. It

should be noted that in three examples, the dithiophenyl com-

pounds 18 were isolated instead. For these three compounds

HRMS proved to be difficult to achieve as under most conditions,

the corresponding ring-closed O,S-thioacetal was obtained instead.

Compounds 18 were investigated by electrospray mass spectrome-

try (ESMS) and atmospheric pressure chemical ionization (APCI).

In addition, an atmospheric solids analysis probe (ASAP) was also

utilized, which is a solids technique that uses APCI to ionize mol-

ecules from the tip of a melting point tube (without the use of

solvent).

334. 1028.

[2-(6-{Bis(phenylsulfanyl)methyl}-1,3-benzodioxol-5-yl)-5-methoxy-

phenyl]methanol (18hi): Reaction solvent: thiophenol, PTSA·H₂O

(15 mol-%); reaction time: 2 h, eluent: 20% EtOAc/hexane mixture;

yield 87%, white viscous material; R_f= 0.37 (EtOAc/hexane, 2:3).

IR (neat):ν

= (film): 3047, 2893, 1605, 1570, 1496, 1472, 1353,

˜

max

1234, 1218, 1153, 1118 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ =

7.41 (s, 1 H), 7.31–7.15 (m, 9 H), 7.10 (d, J = 2.6 Hz, 1 H), 6.69

(dd, J = 8.4, 2.7 Hz, 1 H), 6.57–6.44 (m, 2 H), 6.05 (s, 2 H), 5.13

(s, 1 H), 4.29–4.04 (m, 2 H), 3.88 (s, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 159.5, 147.5, 146.9, 141.2, 134.0, 133.7, 133.2, 132.2,

131.3, 131.0, 129.8, 128.9, 128.8, 128.2, 112.9, 112.8, 109.7, 108.5,

101.4, 62.6, 58.5, 55.4 ppm. HRMS: no corresponding ions could

be identified in the mass spectrum of this compound; only the

cyclized 17hi was detected (calcd. for C₂₂H₁₉O₄S [M⁺+ H], found

379.1012), indicating cyclization under ionization. Please see text

in main body of paper and explanation above in general description

of the synthesis of compounds 17 and 18.

{6Ј-[Bis(phenylsulfanyl)methyl]-2Ј,3Ј,4Ј-trimethoxy-1,1Ј-biphenyl-2-

yl}methanol (18ji): Reaction solvent: thiophenol, PTSA·H₂O

(10 mol-%); reaction time: 12 h, eluent: 20% EtOAc/hexane mix-

ture; yield 90%, colourless liquid; R_f= 0.40 (EtOAc/hexane, 2:3).

IR (neat): ν

= (film) 2933, 2833, 1593, 1478, 1454, 1397, 1326,

˜

max

5-(Phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepine (17ai): Reaction

solvent: thiophenol, PTSA·H₂O (15 mol-%); reaction time: 10 min;

eluent: 5% EtOAc/hexane mixture; yield 70%; white solid; R_f=

1272, 1142 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.54 (d, J =

6.8 Hz, 1 H), 7.48–7.37 (m, 1 H), 7.33–7.11 (m, 10 H), 7.05–6.98

(m, 2 H), 6.87 (d, J = 6.8 Hz, 1 H), 5.09 (s, 1 H), 4.05–3.99 (m, 2

H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.49 (s, 3 H) ppm. ¹³C NMR

(75 MHz; CDCl₃): δ = 153.1, 150.1, 141.8, 140.5, 134.0, 133.7,

133.6, 133.3, 133.3 (2 C), 130.2 (4 C), 129.7, 128.9, 128.9, 128.5,

128.2, 128.2, 127.4 (2 C), 126.1, 108.0, 63.5, 61.2, 61.1, 58.3,

56.1 ppm. HRMS: calcd. for C₃₀H₃₀O₅S₂Na [M⁺+ Na] 557.1432,

found 557.1415; calcd. for C₃₀H₃₄NO₅S₂[M⁺+ NH₄] 552.1878,

found 552.1875.

0.54 (EtOAc/hexane, 1:4); m.p. 86–88 °C. IR (neat, film): ν

=

˜

max

2866, 1579, 1477, 1438, 1375, 1205 cm^{–1 1}H NMR (300 MHz;

.

CDCl₃): δ = 7.63–7.49 (m, 4 H), 7.46–7.44 (m, 2 H), 7.40–7.32 (m,

4 H), 7.24–7.16 (m, 3 H), 6.22 (s, 1 H), 4.62 (d, J = 11.7 Hz, 1 H),

4.55 (d, J = 11.7 Hz, 1 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ =

140.8, 139.5, 136.9, 136.5, 135.7, 131.3 (2 C), 129.4 (2 C), 129.2,

129.0, 128.7 (3 C), 128.3, 128.2, 127.8, 126.8, 90.2, 68.0 ppm. MS

(EI): m/z (%) = 327 (100) [M⁺+ Na], 229 (70), 217 (35), 195 (60).

HRMS: calcd. for C₂₀H₁₆OS [M⁺+ Na] 327.0820, found 327.0834.

{6Ј-[Bis(phenylsulfanyl)methyl]-2Ј,3Ј,4,4Ј-tetramethoxy-1,1Ј-biphen-

yl-2-yl}methanol (18ki): Reaction solvent: thiophenol, PTSA·H₂O

(15 mol-%); reaction time: 12 h, eluent: 20% EtOAc/hexane mix-

ture; yield 71%; colourless liquid; R_f= 0.54 (EtOAc/hexane, 2:3).

3-Methoxy-7-(phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepine (17bi):

Reaction solvent: thiophenol, PTSA·H₂O (15 mol-%); reaction

time: 30 min; eluent: 5% EtOAc/hexane mixture; yield 86%; white

solid; R_f= 0.50 (EtOAc/hexane, 1:4); m.p. 100–102 °C. IR (neat,

IR (neat): ν

= (film) 3054, 2932, 1593, 1476, 1431, 1398, 1324,

˜

max

1

1142 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.34–7.13 (m, 9 H),

7.10–7.01 (m, 3 H), 6.80 (s, 2 H), 5.15 (s, 1 H), 3.98 (br. s, 1 H),

3.96 (br. s, 1 H), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.48 (s,

3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.6, 153.0, 150.4,

141.8, 141.8, 134.0, 133.7, 133.6, 133.3, 133.2, 131.3, 128.9 (2 C),

128.8 (2 C), 128.2, 128.1, 125.8, 125.7, 114.2, 113.5, 108.0, 63.6,

61.2, 61.1, 58.1, 56.1, 55.3 ppm. HRMS: calcd. for C₂₉H₂₈O₄S₂Na

[M⁺+ Na] 527.1327, found 527.1310; calcd. for C₂₉H₃₂NO₄S₂[M⁺

+ NH₄] 522.1773, found 522.1769.

film): ν

= 2864, 1611, 1580, 1505, 1479, 1449, 1376, 1261,

˜

max

1230 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.54–7.44 (m, 3 H),

7.36–7.33 (m, 4 H), 7.25–7.16 (m, 3 H), 7.07 (dd, J = 8.4, 2.6 Hz,

1 H), 7.00 (d, J = 2.6 Hz, 1 H), 6.22 (s, 1 H), 4.57 (d, J = 11.7 Hz,

1 H), 4.52 (d, J = 11.7 Hz, 1 H), 3.88 (s, 3 H) ppm. ¹³C NMR

(75 MHz; CDCl₃): δ = 160.1, 139.4, 137.1, 136.2, 133.2, 131.2 (2

C), 129.4, 128.9 (2 C), 128.7 (3 C), 128.3, 127.7, 126.8, 114.8, 114.6,

90.4, 68.2, 55.4 ppm. MS (EI): m/z (%) = 373 (100), 357 (40) [M⁺

+ Na], 335 (25) [M⁺+ H], 317 (15). HRMS: calcd. for C₂₁H₁₈O₂S

[M⁺+ H] 335.1106, found 335.1109.

1

General Procedure for the Preparation of 5-Phenoxy-5,7-dihydrodi-

benzo[c,e]oxepines 19: p-Toluenesulfonic acid monohydrate (15–

25 mol-%) was added to a solution of the substituted benzyl

alcohol 15 (0.7 mmol) in phenol (5 mL) at room temp. The reaction

3-Methoxy-5-(phenylsulfanyl)-5,7-dihydrodibenzo[c,e]oxepine (17ci):

Reaction solvent: thiophenol, PTSA·H₂O (15 mol-%); reaction

time: 15 min; eluent: 20% EtOAc/hexane mixture; yield 90%; white

solid; R_f= 0.63 (EtOAc/hexane, 3:7); m.p. 87–90 °C. IR (neat, mixture was then stirred at this temperature for 5–48 h until the

film): ν

= 2861, 1608, 1580, 1478, 1438, 1376, 1287, 1253 cm^–1. reaction was deemed complete (TLC). The solution was then con-

˜

max

¹H NMR (300 MHz; CDCl₃): δ = 7.57–7.48 (m, 3 H), 7.43–7.34 centrated under reduced pressure, diluted with H₂O (20 mL) and

(m, 4 H), 7.23–7.13 (m, 3 H), 7.03 (dd, J = 8.5, 2.4 Hz, 1 H), 6.93 extracted with EtOAc (3ϫ 20 mL). The combined organic layers

(d, J = 2.3 Hz, 1 H), 6.17 (s, 1 H), 4.61, (d, J = 11.7 Hz, 1 H), 4.54 were washed with Na₂CO₃solution (20 mL, 10%), followed by

(d, J = 11.7 Hz, 1 H), 3.83 (s, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 159.5, 140.7, 137.7, 136.9, 135.5, 131.9, 131.3 (2 C),

brine (20 mL), after which they were dried (Na₂SO₄) and concen-

trated under reduced pressure. The resulting residue was purified

130.3, 129.4, 129.2, 128.7 (2 C), 128.1, 127.5, 126.9, 115.0, 113.6, by flash silica gel column chromatography using suitable solvent

Eur. J. Org. Chem. 2015, 5167–5182

www.eurjoc.org

5179

W. A. L. van Otterlo

FULL PAPER

mixture of EtOAc/hexane as eluent to afford the desired 5-phen-

time: 15 h; eluent: 30% EtOAc/hexane mixture; yield 75%; light

oxy-5,7-dihydrodibenzo[c,e]oxepines 19 as described below.

reddish solid; R_f= 0.33 (EtOAc/hexane, 2:3); m.p. 75–80 °C. IR

(neat, film): ν_max= 3427, 2939, 1610, 1495, 1448, 1401, 1337, 1308,

˜

4-(5,7-Dihydrodibenzo[c,e]oxepin-5-yl)phenol (19aj): Reaction sol-

vent: phenol, PTSA·H₂O (15 mol-%); reaction time: 5 h; eluent:

20 % EtOAc/hexane mixture; yield 73 %; white solid; R_f= 0.37

1252, 1204 cm^–1. ¹H NMR (300 MHz; CDCl₃): δ = 7.49 (d, J =

8.4 Hz, 1 H), 7.22 (s, 1 H), 7.20 (s, 1 H), 7.05 (dd, J = 8.4, 2.6 Hz,

1 H), 7.01–6.96 (m, 2 H), 6.80 (s, 1 H), 6.76 (s, 1 H), 6.36 (s, 1 H),

5.87 (br. s, 1 H), 5.29 (s, 1 H), 4.63 (d, J = 11.3 Hz, 1 H), 4.31 (d,

J = 11.3 Hz, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H), 3.65 (s, 3 H) ppm.

¹³C NMR (75 MHz; CDCl₃): δ = 159.4, 155.1, 148.8, 148.1, 136.4,

133.7, 133.4, 132.2, 130.7, 128.7 (2 C), 128.2, 115.1 (2 C), 114.6,

114.5, 112.1, 110.6, 76.6, 68.2, 56.0, 55.8, 55.5 ppm. MS (EI): m/z

(%) = 379 (45) [M⁺+ H], 377 (20), 349 (100). HRMS: calcd. for

C₂₃H₂₂O₅[M⁺+ H] 379.1545, found 379.1549.

(EtOAc/hexane, 3:7); m.p. 160–164 °C. IR (neat, film): ν_max= 3248,

˜

1601, 1511, 1448, 1368, 1236 cm^–1. ¹H NMR (300 MHz; CDCl₃):

δ = 7.60–7.49 (m, 3 H), 7.47–7.40 (m, 3 H), 7.30–7.20 (m, 3 H),

6.82 (d, J = 7.6 Hz, 1 H), 6.79 (s, 1 H), 6.77 (s, 1 H), 5.35 (s, 1 H),

5.13 (s, 1 H), 4.69 (d, J = 11.4 Hz, 1 H), 4.35 (d, J = 11.4 Hz, 1 H)

ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 155.1, 141.2, 140.8, 138.2,

134.9, 131.9, 129.4, 129.1, 128.9 (2 C), 128.7, 128.4 (2 C), 128.1,

127.7, 127.5, 115.1 (2 C), 76.6, 68.0 ppm. MS (EI): m/z (%) = 290

(15) [M⁺], 289 (100) [M⁺+ H]. HRMS: calcd. for C₂₀H₁₆O₂[M⁺

+ H] 289.1229, found 289.1222.

4-(5H,7H-6,9,11-Trioxabenzo[3,4]cyclohepta[1,2-f]inden-7-yl)phenol

(19gj): Reaction solvent: phenol, PTSA·H₂O (15 mol-%); reaction

time: 15 h; eluent: 20% EtOAc/hexane mixture; yield 86%; light

yellow solid; R_f= 0.50 (EtOAc/hexane, 3:7); m.p. 82–85 °C. IR

4-(9-Methoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol (19bj): Re-

action solvent: phenol, PTSA·H₂O (20 mol-%); reaction time: 8 h;

eluent: 20% EtOAc/hexane mixture; yield 81%; light yellow solid;

(neat, film): ν

= 3303, 1612, 1503, 1476, 1449, 1364, 1213 cm^–1.

˜

max

¹H NMR (500 MHz; CDCl₃): δ = 7.52–7.48 (m, 2 H), 7.42–7.37

(m, 2 H), 7.19 (s, 1 H), 7.17 (s, 1 H), 7.00 (s, 1 H), 6.77 (s, 1 H),

6.75 (s, 1 H), 6.33 (s, 1 H), 5.96–5.93 (m, 2 H), 5.73 (br. s, 1 H),

5.20 (s, 1 H), 4.67 (d, J = 11.3 Hz, 1 H), 4.31 (d, J = 11.3 Hz, 1 H)

ppm. ¹³C NMR (125 MHz; CDCl₃): δ = 155.2, 147.5, 147.3, 141.2,

134.9, 134.8, 132.5, 131.8, 129.4, 129.0, 128.8 (2 C), 128.1, 127.2,

115.1 (2 C), 109.1, 107.9, 101.3, 76.0, 67.9 ppm. MS (EI): m/z (%)

= 355 (2) [M⁺+ Na], 333 (45) [M⁺+ H], 303 (100), 239 (28),

209 (60). HRMS: calcd. for C₂₁H₁₆O₄[M⁺+ H] 333.1127, found

333.1136.

R = 0.43 (EtOAc/hexane, 3:7); m.p. 65–70 °C. IR (neat, film): ν

˜

f

max

= 3311, 1610, 1579, 1504, 1478, 1440, 1424, 1376, 1304, 1289, 1260,

1

1229, 1187 cm^–1. H NMR (500 MHz; CDCl₃): δ = 7.52–7.45 (m,

2 H), 7.41–7.37 (m, 1 H), 7.24 (d, J = 8.2 Hz, 1 H), 7.21 (s, 1 H),

7.20 (s, 1 H), 7.05 (dd, J = 8.4, 2.6 Hz, 1 H), 6.99 (d, J = 2.6 Hz,

1 H), 6.84 (d, J = 7.8 Hz, 1 H), 6.78 (s, 2 H), 6.76 (s, 1 H), 5.43

(br. s, 1 H), 5.35 (s, 1 H), 4.63 (d, J = 11.4 Hz, 1 H), 4.34 (d, J =

11.4 Hz, 1 H), 3.87 (s, 3 H) ppm. ¹³C NMR (125 MHz; CDCl₃): δ

= 159.7, 155.1, 140.7, 138.0, 136.3, 133.7, 132.1, 128.9 (2 C), 128.8,

128.7, 128.4, 127.5, 127.4, 115.1 (2 C), 114.7, 114.5, 76.8, 68.2,

55.5 ppm. MS (EI): m/z (%) = 319 (25) [M⁺+ H], 289 (100), 225

(18), 195 (72). HRMS: calcd. for C₂₁H₁₈O₃[M⁺+ H] 319.1334,

found 319.1332.

4-(3-Methoxy-5H,7H-6,9,11-trioxabenzo[3,4]cyclohepta[1,2-f]inden-

7-yl)phenol (19hj): Reaction solvent: phenol, PTSA·H₂O (20 mol-

%); reaction time: 20 h; eluent: 30% EtOAc/hexane mixture; yield

85%; light yellow solid; R_f= 0.40 (EtOAc/hexane, 2:3); m.p. 85–

4-(3-Methoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol (19cj): Re-

action solvent: phenol, PTSA·H₂O (15 mol-%); reaction time: 5 h;

eluent: 20% EtOAc/hexane mixture; (0.177 g, 0.588 mmol), yield

80%; light yellow solid; R_f= 0.36 (EtOAc/hexane, 3:7); m.p. 67–

90 °C. IR (neat, film): ν

= 3278, 1608, 1499, 1473, 1367,

˜

max

1235 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.44 (d, J = 8.4 Hz,

1 H), 7.21 (s, 1 H), 7.18 (s, 1 H), 7.04 (dd, J = 8.4, 2.4 Hz, 1 H),

6.98–6.96 (m, 2 H), 6.79 (s, 1 H), 6.76 (s, 1 H) 6.31 (s, 1 H), 5.95

(s, 2 H), 5.41 (br. s, 1 H), 5.20 (s, 1 H), 4.62 (d, J = 11.3 Hz, 1 H),

4.30 (d, J = 11.3 Hz, 1 H), 3.86 (s, 3 H) ppm. ¹³C NMR (75 MHz;

CDCl₃): δ = 159.4, 155.0, 147.4, 146.8, 136.2, 134.8, 133.6, 132.1,

128.7 (2 C), 128.4, 115.3, 115.1 (2 C), 114.7, 114.5, 109.1, 107.6,

1

70 °C. IR (neat, film): ν

= 1607, 1514, 1478, 1450, 1368, 1277,

˜

max

1217 cm^–1. H NMR (500 MHz; CDCl₃): δ = 7.58 (d, J = 7.0 Hz,

1 H), 7.56–7.50 (m, 2 H), 7.47 (d, J = 6.3 Hz, 1 H), 7.44–7.40 (m,

1 H), 7.24 (s, 1 H), 7.23 (s, 1 H), 7.01 (dd, J = 8.4, 2.7 Hz, 1 H),

6.78 (s, 1 H), 6.76 (s, 1 H), 6.48 (d, J = 2.6 Hz, 1 H), 5.85 (br. s, 1

H), 5.38 (s, 1 H), 4.74 (d, J = 11.5 Hz, 1 H), 4.41 (d, J = 11.4 Hz,

1 H), 3.75 (s, 3 H) ppm. ¹³C NMR (125 MHz; CDCl₃): δ = 159.3,

155.2, 141.0, 139.7, 134.6, 133.4, 131.5, 129.3, 129.0, 128.8 (3 C),

127.8, 127.2, 115.1 (2 C), 114.9, 113.2, 76.6, 68.1, 55.2 ppm. MS

(EI): m/z (%) = 319 (12) [M⁺+ H], 318 (100) [M⁺]: HRMS: calcd.

for C₂₁H₁₈O₃[M⁺+ H] 319.1334, found 319.1343.

1

101.2, 76.2, 68.1, 55.5 ppm. MS (EI): m/z (%) = 363 (35) [M⁺

+

H], 269 (32), 241 (28), 239 (30). HRMS: calcd. for C₂₂H₁₈O₅[M⁺

+ H] 363.1232, found 363.1241.

4-(1,2,3-Trimethoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol

(19jj): Reaction solvent: phenol, PTSA·H₂O (25 mol-%); reaction

time: 48 h; eluent: 20% EtOAc/hexane mixture; yield 60%; light

yellow viscous liquid. R_f= 0.47 (EtOAc/hexane, 2:3). IR (neat,

4-(2,3-Dimethoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol (19dj):

Reaction solvent: phenol, PTSA·H₂O (20 mol-%); reaction time:

12 h; eluent: 30% EtOAc/hexane mixture; yield 75%; light yellow

solid; R_f= 0.36 (EtOAc/hexane, 2:3); m.p. 75–80 °C. IR (neat,

film): ν_max= 3372, 2935, 1596, 1515, 1484, 1449, 1402, 1322, 1228,

˜

1

1194 cm^–1. H NMR (500 MHz; CDCl₃): δ = 7.75 (d, J = 7.7 Hz,

1 H), 7.51–7.47 (m, 1 H), 7.44 (d, J = 7.1 Hz, 1 H), 7.41–7.37 (m,

1 H), 7.24 (s, 1 H), 7.22 (s, 1 H), 6.82 (s, 1 H), 6.80 (s, 1 H), 6.13

(s, 1 H), 5.68 (br. s, 1 H), 5.13 (s, 1 H), 4.66 (d, J = 11.1 Hz, 1 H),

4.30 (d, J = 11.1 Hz, 1 H), 3.93 (s, 3 H), 3.66 (s, 3 H), 3.61 (s, 3 H)

ppm. ¹³C NMR (125 MHz; CDCl₃): δ = 155.2, 152.8, 150.3, 142.1,

136.7, 134.8, 134.6, 131.6, 129.8, 129.2, 128.9 (2 C), 128.1, 127.9,

126.4, 115.1 (2 C), 107.8, 75.6, 67.9, 61.0, 60.9, 55.7 ppm. MS (EI):

m/z (%) = 379 (8) [M⁺+ H], 349 (100), 255 (18). HRMS: calcd.

for C₂₃H₂₂O₅[M⁺+ H] 379.1545, found 379.1547.

film): ν

= 3428, 1601, 1510, 1442, 1399, 1334, 1203 cm^–1. ¹H

˜

max

NMR (300 MHz; CDCl₃): δ = 7.59–7.49 (m, 2 H), 7.45–7.37 (m, 2

H), 7.24 (s,1 H), 7.21 (s, 1 H), 7.05 (s, 1 H), 6.81 (s, 1 H), 6.78 (s,

1 H), 6.37 (s, 1 H), 5.48 (s, 1 H), 5.29 (s, 1 H), 4.68 (d, J = 11.3 Hz,

1 H), 4.32 (d, J = 11.3 Hz, 1 H), 3.95 (s, 3 H), 3.66 (s, 3 H) ppm.

¹³C NMR (75 MHz; CDCl₃): δ = 155.0, 148.8, 148.6, 141.3, 135.1,

133.4, 132.2, 131.1, 129.5, 128.9, 128.8 (2 C), 127.9, 127.1, 115.1 (2

C), 112.0, 110.7, 76.3, 68.0, 56.1, 55.8 ppm. MS (EI): m/z (%) =

349 (28) [M⁺+ H], 320 (25), 319 (90), 255 (25), 225 (100). HRMS:

calcd. for C₂₂H₂₀O₄[M⁺+ H] 349.1440, found 349.1443.

4-(1,2,3,9-Tetramethoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol

(19kj): Reaction solvent: phenol, PTSA·H₂O (25 mol-%); reaction

4-(2,3,9-Trimethoxy-5,7-dihydrodibenzo[c,e]oxepin-5-yl)phenol time: 48 h; eluent: 20% EtOAc/hexane mixture; yield 60%; light

(19ej): Reaction solvent: phenol, PTSA·H₂O (20 mol-%); reaction yellow solid; R_f= 0.37 (EtOAc/hexane, 2:3); m.p. 155–160 °C. IR

5180

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Eur. J. Org. Chem. 2015, 5167–5182

Diverse 6-Oxa-allocolchicinoids

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(neat, film): ν_max= 3410, 2928, 1609, 1511, 1486, 1452, 1402, 1315,

˜

1

1240 cm^–1. H NMR (300 MHz; CDCl₃): δ = 7.68 (d, J = 8.5 Hz,

1 H), 7.24 (s, 1 H), 7.22 (s, 1 H), 7.04 (dd, J = 8.5, 2.5 Hz, 1 H),

6.99 (d, J = 2.5 Hz, 1 H), 6.82 (s, 1 H), 6.79 (s, 1 H), 6.12 (s, 1 H),

5.48 (br. s, 1 H), 5.14 (s, 1 H), 4.60 (d, J = 11.1 Hz, 1 H), 4.29 (d,

J = 11.1 Hz, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.66 (s, 3 H), 3.60

(s, 3 H) ppm. ¹³C NMR (75 MHz; CDCl₃): δ = 159.2, 155.1, 152.4,

150.2, 142.2, 136.3, 134.3, 131.8, 130.9, 128.9 (3 C), 126.4, 115.1 (2

C), 114.1, 114.0, 107.9, 75.8, 68.1, 61.0, 60.8, 55.8, 55.4 ppm. MS

(EI): m/z (%) = 431(3) [M⁺+ Na], 409 (8) [M⁺+ H], 379 (100).

HRMS: calcd. for C₂₄H₂₄O₆[M⁺+ H] 409.1651, found 409.1656.

X-ray crystal structure details: crystallized from EtOAc/hexane,

formula: C₂₄H₂₄O₆, M = 408.43, colour/shape of crystal: light yel-

low/needle, crystal size: 0.24ϫ0.20ϫ0.18 mm, a = 9.8231(3) Å, b

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= 16.7434(5) Å, c = 12.7590(4) Å, V = 2078.57(11) Å³, ρ_calcd.

=

1.305 Mg/m³, μ = 0.094 mm^–1, F(000) = 864, Z = 4, T = 173(2) K,

14465 reflections collected, 5017 [R(int) = 0.0685] independent re-

flections, θ_max= 28.00°, 436 refined parameters, maximum/mini-

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wR2 = 0.1113. CCDC-1024804 contains the supplementary crystal-

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Biological Evaluations: Preliminary testing was performed on the

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apoptosis assays for nuclear DNA fragmentation quantified by

FACS flow cytometric determination. For a full description of the

methods involved in the preliminary evaluation of the compounds,

see the supporting information of ref.^[7e]For details of the

synergism experiments between 16da and vincristine on vincristine-

resistant cell lines, please refer to the Supporting Information.

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This work was supported by the National Research Foundation

(NRF), Pretoria, the University of the Witwatersrand (University

and Science Faculty Research Councils) and Stellenbosch Univer-

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thanks the University of the Witwatersrand Research Office and

the NRF for a postdoctoral fellowship. L. T. and A. v. d. W. also

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Received: May 6, 2015

Published Online: July 8, 2015

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Article Doi

Synthesis of Diverse 6-Oxa-allocolchicinoids by a Suzuki-Miyaura Coupling, Acid-Catalyzed Intramolecular Transacetalization Strategy

DOI: 10.1002/ejoc.201500573

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