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Project Number: MQP – JPD – 0001

Synthesis of a Novel Multicyclic Organic Scaffold via a Photoinitiated Intramolecular Ylide-Alkene Cycloaddition Reaction

A Major Qualifying Project Report submitted to the Faculty

of the

WORCESTER POLYTECHNIC INSTITUTE

In partial fulfillment of the requirements for the Degree of Bachelor of Science

by

________________________________ Brian C. Costa

Submitted: April 30, 2009

Approved:

________________________________ Professor James P. Dittami

Advisor Department of Chemistry

i

Abstract

Access to a diverse array of druglike organic molecules via efficient total synthesis is of critical

importance for the exploration of new compounds of biological and medicinal interest. In

particular, any viable synthetic route to such molecules must incorporate precise control of

stereochemistry as well as the ability to tune medicinally relevant parameters such as acidity,

lipophilicity, and the incorporation of bioisosteres. Synthesis of a bioisosteric analog of the

opiate analgesic morphine was pursued using an intramolecular ylide-alkene cycloaddition as the

key step which would establish the configuration of the six stereocenters of the molecule in a

single operation. The novel structure of the target analog is expected to produce a compound

with compelling biological activity from a brief, diversifiable synthesis.

ii

Acknowledgments

I would like to thank Worcester Polytechnic Institute, the Department of Chemistry and

Biochemistry, Professor James P. Dittami, Ilie Fishtik, and Victor Kiryak.

iii

 

Table of Contents

Abstract .....................................................................................................................................................i 

Acknowledgments ............................................................................................................................... ii 

Table of Contents ................................................................................................................................ iii 

Table of Figures ....................................................................................................................................iv 

Introduction............................................................................................................................................1 

Results and Discussion........................................................................................................................8 

Experimental ....................................................................................................................................... 12 

General Methods .......................................................................................................................................... 12 

3Ethoxy2cyclohexenone (20).............................................................................................................. 13 

3(3Butenyl)2cyclohexenone (21b) .................................................................................................. 14 

2Amino6hydroxybenzothiazole (34)................................................................................................ 15 

6(But3enyl)7oxabicyclo[4.1.0]heptan2one (22b) ................................................................. 16 

3(2(1,3Dioxan2yl)ethyl)2(2aminobenzo[d]thiazol6yloxy)cyclohex2enone (31a)

............................................................................................................................................................................ 17 

3(But3enyl)2(naphthalen2yloxy)cyclohex2enone (36a) ................................................. 19 

3(But3enyl)2(naphthalen2yloxy)cyclohex2enone (36b)................................................. 20 

References............................................................................................................................................ 21 

Spectra................................................................................................................................................... 23 

 

iv

Table of Figures

Figure 1. 1H NMR Spectrum of 3-Ethoxy-2-cyclohexenone (20)……………………………….23

Figure 2. 1H NMR Spectrum of 3-(3-Butenyl)-2-cyclohexenone (21b)…………………………24

Figure 3. 1H NMR Spectrum of 2-Amino-6-hydroxybenzothiazole (34)………………………..25

Figure 4. 13C CPD Spectrum of 2-Amino-6-hydroxybenzothiazole (34)………………….…….26

Figure 5. 1H NMR Spectrum of 6-(but-3-enyl)-7-oxabicyclo[4.1.0]heptan-2-one (22b)…….….27

Figure 6. 1H NMR Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)………………………………………………………….……28

Figure 7. COSY Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a).................................................................................................29

Figure 8. 13C CPD Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)……………………………………………………………….30

Figure 9. 13C DEPT135 Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)…………………………………………………………………...31

Figure 10. Infrared Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)…………………………………………………………………...32

Figure 11. DSC Curve for 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)………………………………………………………………...…33

Figure 12. 1H NMR Spectra of 3-(but-3-enyl)-2-(naphthalen-2-yloxy)cyclohex-2-enone (36a) and (36b)………………………………………………………………………………………....34

1

Introduction

During the drug discovery and development process, useful products sometimes arise from the

interchange of groups that are closely related both chemically and structurally. These groups,

which tend to produce similar therapeutic effects in biological systems, are referred to as

bioisosteres.1 Catechol 1, for example, is seen in different forms in several different biologically

active compounds, including the opiate analgesic drug morphine 2 and the neurotransmitter

dopamine 3.

One bioisostere of catechol is the molecule benzothiazole, 4. Benzothiazole derivatives have in

the past been studied for their potentially useful biological activity as antimicrobials.2 Others

have shown moderate anti-inflammatory activity,3,4 while others still have been researched as

potential antitumor agents.5,6

The replacement of pharmacophores, the parts of molecules responsible for their biological or

pharmacological interactions, in existing biologically active compounds is therefore often done

HO

HO

1

HO

O

HO

N

2

HO

HO

NH2

3

N

S

4

2

in the hopes of generating new and potentially useful molecules that may lead to new

pharmaceuticals.

The objective of this project is to generate a multicyclic organic scaffold that somewhat

resembles morphine and incorporates the benzothiazole bioisostere in place of catechol. This

novel scaffold 5 is to be generated via a method developed in our laboratory. The cycloaddition

product will then be submitted for biological testing. We are particular interested in using the

bioassay known as “Biospectra Analysis” developed by R.A. Volkmann.7

Our synthetic plan for the construction of 5 is an extension of work pioneered by A.G. Schultz et

al. in his Heteroatom Directed Photoarylation Reaction.8 Their investigations showed that

various 2-aryloxyenones generated by the reaction of aromatic alcohols with isophorone epoxide

under basic conditions could be photocyclized to their respective dihydrofurans, as exemplified

by the photocyclization of 7 to 9 shown below.9 This photocyclization reportedly proceeds via

the carbonyl ylide intermediate 8, which then rearranges to the dihydrofuran product. Similar

results were reported for aryl vinyl sulfides.10

O

OH

H

H

CO2Et

N

S

H2N

5

O

O

ArOH, KH

THF-HMPA

O

O

X

O

O

XH

h!

6 7 8

O

O

X

H

H shift

9

3

Our interest in this work stemmed from a well-known [3+2] cycloaddition of ylide systems such

as 8 with alkenes.11,12 Thus, we proposed incorporation of pendant dipolarophiles in aryl vinyl X

systems such as I where X = S, O, or N-R. We anticipated that upon photolysis these would

cyclize to ylide systems II which could then undergo [3+2] cycloaddition to form the multicyclic

scaffold III. Indeed preliminary studies demonstrated that this was a feasible approach to

construct complex frameworks in a single experimental operation.

During the course of our research we observed that the kinds and ratios of photoproducts

obtained was dependent on reaction temperature, solvent, and substituents. Following is a brief

summary of some of our findings.

Photolysis of naphthyl vinyl sulfide 10 incorporating a 3-butenyl side chain was observed to

produce different major products as a consequence of different reaction temperatures.13

X

O

h!X

O

O

X

I II III

S

O

h!

RT to -78°C S

O

photocyclized product

S

OCH3

H

intramolecularadditionproduct

h!

110°C

83%81 - 100%

10

1112

4

Photolysis at room temperature or below in toluene resulted in the formation of ring-closed

product 11 in which no interaction of the side chain olefin with the ylide was observed.

Conversely, when the photoreaction was conducted at reflux temperature in toluene

intramolecular addition product 12 was observed. Control experiments demonstrated that both

light and heat were required to produce 12. Furthermore, these experiments demonstrated that

11 is not an intermediate in the formation of 12.

The mechanism for formation of 12 likely involves ylide intermediate 13a or b. Orbital

symmetry rules favor formation of 13a. However, spectroscopic studies in our laboratory

support the formation of at least two different ylides in similar photoreactions.14

Surprisingly, neither set of reaction conditions (low or high temperature) resulted in the

anticipated [3+2] product. We reasoned that this could be the result of the low reactivity of the

thiocarbonyl ylide toward simple unsubstituted alkenes.11,12,15 Accordingly, we examined aryl

vinyl photoprecursors which incorporated a more reactive electron-deficient alkene, as in 13c.

Indeed, these yielded intramolecular addition products at lower temperature. However, in all

cases where we used an aryl vinyl sulfide to generate a thiocarbonyl ylide, no [3+2] products

(such as 13d) were observed.17

S

O

H

13a, trans

S

O

H

13b, cis

5

We thus turned our attention to carbonyl ylide systems derived from aryl vinyl ethers, such as 14

and 17. These were expected to be more reactive than the corresponding sulfur ylides.

As expected, photolysis of the corresponding aryl vinyl ether 14 produced the

intramolecular addition product 15 as the major product at room temperature. This result

contrasts that of aryl vinyl sulfide 10 which yielded the intramolecular addition product 12 only

at 110°C.

Interestingly, when 14 was subjected to high temperature photolysis products 16 and 15 were

observed in a 4:1 ratio. Formation of 16 can be rationalized by photochemical ring closure to

provide ylide 14b followed by intramolecular [3+2] cycloaddition.

S

CO2Et

O

H

H

S

O

CO2Et

h!

13c 13d

RT

O

O

O

OCH3

H

intramolecularadditionproduct

38%

O

O

photocyclized product

54%

h!

110°C

+

14 15 16

6

Subsequent studies with 17, which incorporates an ethyl butenoate side chain, provided [3+2]

adduct 18 in 87% isolated yield upon photolysis at room temperature.16 This conversion

provides an effective method to assemble three rings and six chiral centers in a single

experimental operation.

With a method in hand to assemble scaffolds with topology similar to the morphine series, we

turned our attention to targets incorporating bioisosteric replacements for the aromatic ring in

morphine. Two such targets Va and Vb could be derived by photocyclization and subsequent

intramolecular addition of aryl vinyl ethers IVa and IVb. These in turn should be available via

methods developed in our lab for preparation of 14 and 17.16,17

O

O

14b

O

CO2Et

O

H

H

O

O

CO2Et

h!

17 18

RT

7

O

O

R

O

OH

H

H

R

N

S

H2NN

S

H2N

IVa, R = H

b, R = CO2Et

Va, R = H

Vb, R = CO2Et

8

Results and Discussion

As described in the Introduction, we hoped to synthesize the photoprecursors 29a and b, which

have the catechol bioisostere benzothiazole included in it. Subjection to photolysis should then

yield the [3+2] cycloaddition products 5a and b via a photoinitiated intramolecular ylide-alkene

cycloaddition reaction.

Our approach to synthesis of 29 utilized the same strategy for preparation of 14 and 17.16,17 Thus

commercially available 19 was converted to 3-ethoxy-2-cyclohexenone 20 in the presence of p-

toluenesulfonic acid monohydrate (pTsOH•H2O) in ethanol/toluene with refluxing.18

Purification by fractional distillation afforded 20 as a clear oil. Reaction with the appropriate

Grignard reagents followed by acid hydrolysis in aqueous HCl/ethanol yielded the corresponding

enones 21a and b. Epoxidation under basic conditions provided 22a,b.

The requisite aminohydroxybenzothiazole 34 was prepared by treatment of commercially

available 2-amino-6-methoxybenzothiazole 33 with BBr3 in anhydrous CH2Cl2 (4 equiv.) at -10

to -12°C for 3 hours. This provided the HCl salt of 34. The free base was obtained in 59% yield

by neutralization of an aqueous solution of the salt with saturated aqueous NaHCO3, providing

34 as a grey solid with 97% purity by 1H NMR.

O

O

RO

O

RH

O

OH

H

H

RN

S

H2N

N

S

H2N

N

S

H2N

h! [3+2]

29a, R = H

b, R = CO2Et

30a, R = H

b, R = CO2Et

5a, R = H

b, R = CO2Et

9

Base-catalyzed epoxide opening of 22a with 2-amino-6-hydroxybenzothiazole 34 while

refluxing in tetrahydrofuran in the presence of N,N´-dimethylpropyleneurea gave rise to aryl

vinyl ether 31a in only 5% yield. When performed with epoxide 22b, the same procedure did

not yield any of the desired coupled product 31b.

N

SHO

NH2N

SH3CO

NH21) BBr3, -12°C

2) MeOH, -12°C to RT3) neutralization with sat. aq. NaHCO3

33 34

O

OH

O

O

O

R

O

O

O

R

OEtOH, p-TsOH•H2O

toluene, !

1) RMgBr

2) H3O+

H2O2, NaOH

19 20 21a,b 22a,b

a =

b =

KH (cat.)

DMPU, THF, refulx

O

R

O

N

SNH2

HO

O

R

O

N

S

NH2

22a,b 31a,b

10

After repeated failed attempts at performing the base-catalyzed epoxide opening, the procedure

was modified slightly with the hope the more favorable results could be obtained. It was

hypothesized that running a microwave-assisted coupling reaction would produce cleaner

product in less time and in greater yield. To test this, a model system was chosen in the form of

β-naphthol 35. The aryl vinyl ether 36 was synthesized by two methods. “Method A” refers to

the traditional procedure while “Method B” refers to the microwave-assisted synthesis. See

Table 1 below for results.

O

O

O

O

AcOH

reflux

O

O

O

H

N

S

N

SNH2NH2

31a 32

O

O1) O3, CH2Cl2, -78°C

2) CH3SCH3 N

SNH2

31b

O

O

N

SNH2

CO2Et

NaH/DMSO

Ph3P=CHCO2Et

29

O

OH

H

H

R

N

SH2N

5a, R = H

b, R = CO2Et

h!

h!

O

O HO

O

O

22a 35 36

Method A

or Method B

11

Table 1: Traditional versus Microwave-Assisted Synthesis of 36

Method Conditions Crude Yield Comments Product Designation

A KH, DMPU,

Refluxing in THF, ~48 hours

68% 1H NMR spectrum looks fairly clean 36a

B

KH, DMPU, Microwave-

assisted, 110°C, Max Power = 200

W

95%

1H NMR spectrum looks cleaner than that of the product made by Method

A

36b

As indicated by Table 1, the microwave-assisted synthesis afforded the desired aryl vinyl ether in

greater yield and in higher purity by NMR. Synthesis of 31b was then attempted by the same

procedure. Unfortunately, NMR of the crude material showed that this method only afforded

31b in a negligible amount. Future work demands adjusting the conditions of the microwave-

assisted coupling reaction so that 31b can be synthesized in greater yield.

Once the aryl vinyl ether synthesis is worked out, compound 31b could be tested directly in a

photoreaction whereas 31a will require conversion to the aldehyde 32 and subsequent Wittig

olefination to provide 29. An alternate route to 29 could potentially involve ozonolysis of 31b to

provide 32, followed by Wittig olefination as before.

12

Experimental

General Methods

Analytical thin-layer chromatography (TLC) was performed on precoated glass-backed silica

plates (0.25 mm thickness with a 254 nm fluorescent indicator). Visualization was performed

using a UV lamp (254 nm) and by staining with a p-anisaldehyde solution. Melting points were

determined on a TA Instruments DSC 2920 Modulated DSC. Infrared spectra (IR) were

recorded on a Bruker Vertex 70 Infrared Spectrometer with a 4 cm-1 resolution, scanning from

4000 to 650 cm-1 over 16 scans. 1H NMR spectra were recorded on a Bruker Avance III (500

MHz) NMR Spectrometer. Chemical shifts (δ) are reported in ppm relative to tetramethylsilane

(TMS) at 0.00. Carbon nuclear magnetic resonance spectra were recorded at 50.3 MHz. LC/MS

data was obtained on an Agilent Technologies 6130 Quadrupole LC/MS using an SB-C18 Rapid

Resolution 3.5 µm, 2.1x30 mm Zorbax HPLC cartridge column. Microwave-assisted reactions

were performed on a Personal Chemistry Emrys Optimizer Workstation in Emrys Process Vials

(2-5 mL). Flash chromatography was performed on an AnaLogix IntelliFlash 280 using 40-63

µm silica gel. Triethylamine-deactivated silica gel columns were prepared by washing the silica

gel with a mixture of hexane and triethylamine (10:1). The column was then rinsed with three

column volumes of hexane and one column volume of elution solvent to purge excess

triethylamine.

13

3-Ethoxy-2-cyclohexenone (20)

[See notebook page BCC-I-001. 1H NMR spectrum: Sep24-2008-MQP (10)]. To a solution of

1,3-cyclohexanedione (10.0 g, 89 mmol) in absolute ethanol (47 mL) was added p-

toluenesulfonic acid monohydrate (0.444 g, 2.33 mmol) in toluene (170 mL). A Dean-Stark trap

fitted with a reflux condenser was attached to the reaction flask and the reaction mixture was

heated at reflux with stirring. The ethanol/water/toluene azeotrope was removed periodically

over a period of one hour. The reaction was allowed to cool and stirred overnight at room

temperature. The following day, ethanol (60 mL) was added to the mixture and distillation was

resumed. Distillation was ceased when thin-layer chromatography (TLC) analysis indicated

consumption of the starting cyclohexanedione. The resulting dark brown reaction mixture was

washed with 4 x 25 mL portions of 10% aqueous sodium hydroxide in brine, water (until

neutral), and brine. The organic layer was dried (MgSO4). Solvent was removed under reduced

pressure to yield a dark amber oil. The same procedure was then repeated on a larger scale of

1,3-cyclohexanedione (57.543 g, 513 mmol). See notebook page BCC-I-002. The two crude

products were combined for a total 60.150 g of the dark amber oil. Purification via short-path

distillation yielded 20 as a clear oil (28.5 g, 33%): 1H NMR (CDCl3, 500 MHz) δ 1.08 (t, 3 H, J

= 7.0 Hz), 1.7 (q, 2 H, J = 6.6 Hz), 2.04 (t, 2 H, J = 6.9 Hz), 2.13 (t, 2 H, J = 6.3 Hz), 3.63 (q, 2

H, J = 7.07 Hz), 5.04 (s, 1 H).

O

O

O

OH

O

O

EtOH, p-TsOH•H2O

toluene, !

19 20

14

3-(3-Butenyl)-2-cyclohexenone (21b)

[See notebook page BCC-I-014. 1H NMR spectrum: BCC-I-014b (10)]. To a dry three-neck

round bottom flask fitted with a Claisen adapter and a reflux condenser was added freshly cut

magnesium turnings (2.52 g, 104 mmol). The apparatus was dried under vacuum and purged

with nitrogen. THF (18 mL) was added to the flask, followed by the slow addition of 4-bromo-1-

butene (9.24 g, 68.4 mmol). Upon the initiation of an exothermic reaction, anhydrous THF (18

mL) was added and the reaction mixture was allowed to reflux. After the exothermic reaction

subsided, 3-ethoxy-2-cyclohexenone (9.00 g, 64.2 mmol) was added slowly, resulting in the

evolution of heat. Anhydrous THF (10 mL) was added and the mixture was stirred for three

hours, after which saturated aqueous ammonium chloride (180 mL) was added. The resulting

yellow organic phase was extracted with dichloromethane. The combined organic phases were

washed with water and brine. Solvent was removed under reduced pressure. The resulting

yellow oil was combined with a solution of 1M HCl (18 mL) in ethanol (45 mL) and stirred for 1

hour. Solvent was removed under reduced pressure. The crude product was extracted with

dichloromethane. The combined organic phases were washed with water and brine and then

dried (MgSO4). Removal of solvent under reduced pressure yielded the crude product 21b as an

orange oil (7.1 g, 73%): 1H NMR (CDCl3, 500 MHz) δ 1.99 (q, 2 H, J = 6.5 Hz), 2.17-2.30 (m, 8

H), 4.91-5.00 (m, 2 H), 5.66-5.76 (m, 1 H), 5.88 (s, 1 H).

O

O

O

MgBr1)

2) H3O+

20 21b

15

2-Amino-6-hydroxybenzothiazole (34)

[See notebook page BCC-I-010. 1H NMR spectrum: BCC-I-017a (12). 13C CPD spectrum:

Oct22-2008-jpdMQP (30). 13C DEPT-135 spectrum: Oct22-2008-jpdMQP (22)]. In a dried 100-

mL round bottom flask under nitrogen, 2-amino-6-methoxybenzothiazole (1.00 g, 5.55 mmol)

was suspended in anhydrous DCM (5.6 mL) with continuous stirring. The mixture was cooled to

approximately -12°C, at which time a 1 M solution of boron tribromide (28 mL, 28 mmol) was

added slowly. After stirring for three hours at -12°C, thin-layer chromatography (hexanes/ethyl

acetate (1:1)) showed consumption of starting material. The reaction was quenched with

methanol (2.8 mL) and allowed to warm to room temperature. After 2.5 hours, the precipitate

was collected by suction filtration, dissolved in water, and washed with ethyl acetate.

Neutralization of the aqueous phase with saturated aqueous NaHCO3 yielded 34 as a grey solid

(546 mg, 59%) that was collected by suction filtration and dried under vacuum. 1H NMR

(DMSO-d6, 500 MHz) δ 6.64 (d, 1 H, J = 8.4 Hz), 7.02 (d, 1 H), 7.08 (s, 2 H), 7.13 (d, 1 H, J =

8.5), 9.08 (s, 1 H); 13C NMR (DMSO-d6, 50.3 MHz) δ 107.4 (CH), 114.0 (CH), 118.5 (CH),

132.3 (C), 146.1 (C), 152.3 (C), 164.3 (C); LC/MS (ESI/APCI) m/e 167 [MH]+.

N

SHO

NH2N

SH3CO

NH21) BBr3, -12°C

2) MeOH, -12°C to RT3) neutralization with sat. aq. NaHCO3

33 34

16

6-(But-3-enyl)-7-oxabicyclo[4.1.0]heptan-2-one (22b)

[See notebook page BCC-I-016. 1H NMR spectrum: BCC-I-016a (10)]. Enone 21b (1.00 g,

6.657 mmol) was dissolved in methanol (6.30 mL), and hydrogen peroxide (35%, 1.57 mL) was

added. The solution was cooled to 0°C, and a solution of NaOH (6N, 0.571 mL) was added

slowly. The resulting mixture was stirred at room temperature for 1 h after which the solvent

was removed. The mixture was then partitioned between DCM and water. The organic phase

was washed with water and brine and dried (MgSO4). Removal of solvent under reduced

pressure yielded 22b as a clear oil (0.85 g, 76%): 1H NMR (CDCl3, 500 MHz) δ 1.63-2.23 (m,

10 H), 2.51 (d, 1 H, J = 17.9), 3.10 (s, 1 H), 4.98-5.08 (m, 2 H), 5.75-5.85 (m, 1 H).

O O

OH2O2, NaOH

21b 22b

17

3-(2-(1,3-Dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-yloxy)cyclohex-2-enone (31a)

[See notebook page BCC-0-018. 1H and 13C NMR spectrum: BCC-I-018q (10-14)]. To a

solution of epoxide 22a (2.26 g, 9.99 mmol) in anhydrous THF (20 mL) was added potassium

hydride (35% in mineral oil (0.11 g, 0.84 mmol) and 2-amino-6-hydroxybenzothiazole (1.99 g,

12.0 mmol) in anhydrous THF (25 mL). N,N´-Dimethylpropyleneurea, DMPU (1.7 mL, 14.06

mmol), was added, and the mixture was stirred at reflux temperature for 48 h. The solvent was

removed under reduced pressure, and the residue was partitioned between dichloromethane and

water. The aqueous phase was further extracted with dichloromethane, and the combined

extracts were washed with water and brine and dried (MgSO4). Removal of solvent at reduced

pressure, recrystallization from hexanes/ethyl acetate, and chromatography on silica gel

deactivated with triethylamine (100% ethyl acetate) gave 31a as a white solid (174 mg, 5%

yield) which requires further purification: mp 170.2 °C; IR (ATR) 3370, 2942, 1732, 1670, 1626,

1543, 1455 cm-1; 1H NMR (CDCl3, 500 MHz) δ 1.23-1.34 (m, 2.3 H), 1.66 (s, 1.8 H), 1.74-1.80

(m, 2.1 H), 1.98-2.11 (m, 3.9 H), 2.40 (t, 2 H, J = 8.07 Hz), 2.52-2.58 (m, 4 H), 3.65-3.72 (m, 2

H), 4.02-4.07 (m, 2 H), 4.46 (t, 1 H, J = 5.07 Hz), 5.09 (s, 2 H), 6.84 (dd, 1 H, J = 3.05 Hz, 2.53

Hz), 7.05 (d, 1 H, J = 2.54), 7.40 (d, 1 H, J = 9.00 Hz); 13C NMR (CDCl3, 125.8 MHz) δ 22.3

(CH2), 25.7 (CH2), 26.1 (CH2), 29.6 (CH2), 32.4 (CH2), 38.5 (CH2), 66.8 (CH2) (double

KH (cat.)

DMPU, THF, reflux

O

O

N

SNH2

HOO

O

N

SNH2

22a 31a

O

O

O

O

18

intensity), 101.4 (CH), 106.9 (CH), 113.8 (CH), 119.7 (CH), 132.7 (C), 144.3 (C), 147.0 (C),

151.9 (C), 153.7 (C), 164.1 (C), 193.3 (C); LC/MS (ESI/APCI) m/e 375 [MH]+.

19

3-(But-3-enyl)-2-(naphthalen-2-yloxy)cyclohex-2-enone (36a)

[See notebook page BCC-I-025. 1H NMR spectrum: DJS-I-022a (10)]. Potassium hydride (30

wt% dispersion in mineral oil, 0.04 g) was measured into a dried 25 mL round bottom flask.

Under nitrogen, a solution of β-naphthol (0.09 g, 0.602 mmol) in anhydrous THF (2 mL) was

added. A solution of epoxide 22a (0.10 g, 0.602 mmol) in anhydrous THF (2 mL) was added,

followed by DMPU (0.1 mL, 0.827 mmol). The reaction mixture was stirred at reflux

temperature for 48 h. The solvent was removed under reduced pressure, and the resulting oil was

partitioned between diethyl ether and 10% NaOH in saturated aqueous sodium hydroxide. The

organic phase was washed with the 10% NaOH solution, water, and brine. The organic phase

was dried (MgSO4). Removal of the solvent at reduced pressure yielded 36a as a yellow oil (120

mg, 68% crude yield).

O

O HO

O

O

22a 35 36a

KH (cat.), DMPU

THF, relux

20

3-(But-3-enyl)-2-(naphthalen-2-yloxy)cyclohex-2-enone (36b)

[See notebook page BCC-I-028. 1H NMR spectrum: BCC-I-028a (10)]. Potassium hydride (30

wt% dispersion in mineral oil, 0.04 g) was measured into a microwave reaction vial. Under

nitrogen, a solution of β-naphthol (0.09 g, 0.602 mmol) in anhydrous THF (2 mL) was added. A

solution of epoxide 22a (0.10 g, 0.602 mmol) in anhydrous THF (2 mL) was added, followed by

DMPU (0.1 mL, 0.827 mmol). The vial was placed in the microwave, which was run for 2 h at a

constant temperature of 110°C with a maximum power setting of 200 W and a fixed hold time.

The solvent was removed under reduced pressure, and the resulting oil was partitioned between

diethyl ether and 10% NaOH in saturated aqueous sodium hydroxide. The organic phase was

washed with the 10% NaOH solution, water, and brine. The organic phase was dried (MgSO4).

Removal of the solvent at reduced pressure yielded 36b as a yellow oil (167 mg, 95% crude

yield).

O

O HO

OO

22a 35 36b

KH (cat.), DMPU

THF, microwave,110°C, 200 W max,

2 hours

21

References

1 For a review of bioisosteres see: Chen, X.; Wang, W. in Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic: New York, 2003 Vol. 38, p 333.

2 El-Naggar, A.M.; El-Salam, A.M.A.; Gommaa, A.M. “Synthesis of Some Biologically Active 2-Aminobenzothiazole Derivatives with Tosylamino, Phthalylaminoacyl, Aminoacyl, N-Tosyldi- & Tri-peptidyl Substituents at 2-Position” Indian Journal of Chemistry 1980, 19B, 1068.

3 Goyne, W.E., Medicinal Chemistry, Vol. II, edited by A. Burger (Wiley Interscience, New York), 1970, 953.

4 Shen, T.Y., Anti-inflammatory agents, Vol. I, edited by R.A. Scherrer & M.W. Whithouse (Academic Press, New York), 1974, 179.

5 Mortimer, C.G.; Wells, G.; Crochard, J.P.; Stone, E.L., Bradshaw, T.C.; Stevens, M.F.G.; Westwell, A.D. “Antitumor Benzothiazoles. 26. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a Simple Fluorinated 2-Arylbenzothiazole, Shows Potent and Selective Inhibitory Activity against Lung, Colon, and Breast Cancer Cell Lines” J. Med. Chem. 2006, 49, 179. 6 Aiello, S.; Wells, G.; Stone, E.L.; Kadri, H.; Bazzi, R.; Bell, D.R.; Stevens, M.F.G.; Matthews, C.S.; Bradshaw, T.D.; Westwell, A.D. “Synthesis and Biological Properties of Benzothiazole, Benzoxazole, and Chromen-4-one Analogues of the Potent Antitumor Agent 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648)” J. Med. Chem. 2008, 51, 5135. 7 Fliri, A.F.; Loging, W.T.; Thadeio, P.F.; Volkmann, R.A. J. Med. Chem. 2005, 48 (22), 6918.

8 For reviews see: Schultz, A. G. “Photochemical Six Electron Heterocyclization Reactions” Acc. Chem. Res. 1983, 16, 210; Schultz, A. G.; Motyka, L. “Photochemical Heterocyclizations of Systems Isoelectronic With the Pentadienyl Anion” in Organic Photochemistry, A. Padwa, Ed. Marcel Dekker, New York, 1983 Vol. 6, p. 1.

9 Schultz, A.G.; Lucci, R.D.; Fu, W.Y.; Berger, M.H.; Erhardt, J.; Hagmann, W.K. "Heteroatom Directed Photoarylation. Synthetic Potential of the Heteroatom Oxygen" J. Am. Chem. Soc. 1978, 100, 2150. 10 Schultz, A.G.; Fu, W.Y.; Lucci, R.D.; Kurr, B.G.; Lo, K.M.; Boxer, M. "Heteroatom Directed Photoarylation. Synthetic Potential of the Heteroatom Sulfur" J. Am. Chem. Soc. 1978, 100, 2140. 11 Huisgen, R. Angew. Chem. Int. Ed. Engl., 2, 565, 633 (1963).

12 Huisgen, R.; Grashey, R.; Sauer, J in “The Chemistry of the Alkenes,” S. Patai, Ed., Interscience: New York, 1964.

22

13 Dittami, J.P.; Ramanathan, H.; Breining, S. “Intramolecular Addition Reactions During Heteroatom Directed Photoarylation” Tetrahedron Lett. 1989, 30, 795.

14 Dittami, J.P.; Luo, Y.; Moss, D.; McGimpsey, W.G. “Photochemistry or Aryl Vinyl Sulfides and Aryl Vinyl Ethers: Evidence for the Formation of Thiocarbonyl and Carbonyl Ylides” J. Org. Chem. 1996, 61, 6256-6260.

15 For a discussion of the theory of dipolar cycloaddition reactions see Houk, K. in 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed.; Wiley Interscience: New York 1984 V. 2.

16 Dittami, J.P.; Nie, X.Y.; Nie, H.; Ramanathan, H.; Breining, S. “Intramolecular Addition Reactions of Carbonyl Ylides Formed during Photocyclization of Aryl Vinyl Ethers” J. Org. Chem. 1991, 56, 5572-5578.

17 Dittami, J.P.; Nie, X.Y.; Nie, H.; Ramanathan, H.; Buntel, C.; Rigatti, S. “Tandem Photocyclization-Intramolecular Addition Reactions of Aryl Vinyl Sulfides. Observation of a Novel [2+2] Cycloaddition-Allylic Sulfide Rearrangement” J. Org. Chem. 1992, 57, 1151-1158.

18 Gannon, W.F.; House, H.O. “3-Ethoxy-2-cyclohexenone” Organic Syntheses, 1960, 40,

23

Spectra

Figure 1. 1H NMR Spectrum of 3-Ethoxy-2-cyclohexenone (20)

[pp

m]

6

5

4

3

2

1

- 0

[rel] 0 5 10 15

0.9548

2.0107

4.1152

2.0734

3.0000

3-ethoxy-2-cyclohexenone

post distillation, fraction 2

BCC-I-012c 10 1 Z:\gateway jpdMQP

24

Figure 2. 1H NMR Spectrum of 3-(3-Butenyl)-2-cyclohexenone (21b)

[pp

m]

6

4

2

[rel] 0 5 10

2.0149

2.0854

8.0592

0.92391.0000

BCC-I-014a 10 1 Z:\gateway jpdMQP

25

Figure 3. 1H NMR Spectrum of 2-Amino-6-hydroxybenzothiazole (34)

[pp

m]

10

8

6

4

2

[rel] 0 2 4 6 8

0.9763

1.9235 0.99030.9875

1.0000

crude 2-amino-6-hydroxybenzothiazole


26

Figure 4. 13C CPD Spectrum of 2-Amino-6-hydroxybenzothiazole (34)

[pp

m]

20

0

15

0

10

0

50

0

[rel] - 0.0 0.5 1.0 1.5 2.0 2.5

Oct22-2008-jpdMQP 30 1 Z:\gateway jpdMQP

27

Figure 5. 1H NMR Spectrum of 6-(but-3-enyl)-7-oxabicyclo[4.1.0]heptan-2-one (22b)

[pp

m]

6

4

2

[rel] 0 5 10 15

1.0409

1.0000

1.0802

2.1101

10.1513

crude epoxide


28

Figure 6. 1H NMR Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-

yloxy)cyclohex-2-enone (31a)

[pp

m]

6

4

2

[rel] 0 5 10 15 20 25

1.0000

0.9457

1.0087

2.0504

1.0224

0.52142.0821

2.0998

4.1454

2.0754

3.9477

2.1317

1.8353

2.2888

BCC-I-018q 10 1 Z:\gateway jpdMQP

29

Figure 7. COSY Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-


F2 [

pp

m]

6

4

2

0

F1 [ppm] 6 4 2


30

Figure 8. 13C CPD Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-


[pp

m]

200

150

100

50

0

[rel] - 0.0 0.5 1.0 1.5 2.0

193.2633

164.0906

153.6763151.9007

147.0312144.3386

132.7072

119.6663

113.7808

106.8552

101.3850

77.270077.016176.7616

66.8374

38.5224

32.346629.552026.132625.682522.2881


31

Figure 9. 13C DEPT135 Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-


[pp

m]

200

1

50

100

50

0

[rel] - 5 0 5 10 15 20

119.6663

113.7793

106.8532

101.3842

66.8408

38.5236

32.346329.553126.136925.683222.2888


32

Figure 10. Infrared Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-


33

Figure 11. DSC Curve for 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-


34

Figure 12. 1H NMR Spectra of 3-(but-3-enyl)-2-(naphthalen-2-yloxy)cyclohex-2-enone (36a)

and (36b)

[pp

m]

8

6

4

2

[rel] 0 2 4 6 8 10 12 14 BCC-I-028a 10 1 Z:\gateway jpdMQP


DJS-I-022a 10 1 Z:\gateway jpdMQP

Scale : 1.5363

35

1 For a review of bioisosteres see: Chen, X.; Wang, W. in Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic: New York, 2003 Vol. 38, p 333. 2 El-Naggar, A.M.; El-Salam, A.M.A.; Gommaa, A.M. “Synthesis of Some Biologically Active 2-Aminobenzothiazole Derivatives with Tosylamino, Phthalylaminoacyl, Aminoacyl, N-Tosyldi- & Tri-peptidyl Substituents at 2-Position” Indian Journal of Chemistry 1980, 19B, 1068.

3 Goyne, W.E., Medicinal Chemistry, Vol. II, edited by A. Burger (Wiley Interscience, New York), 1970, 953.

4 Shen, T.Y., Anti-inflammatory agents, Vol. I, edited by R.A. Scherrer & M.W. Whithouse (Academic Press, New York), 1974, 179.

5 Mortimer, C.G.; Wells, G.; Crochard, J.P.; Stone, E.L., Bradshaw, T.C.; Stevens, M.F.G.; Westwell, A.D. “Antitumor Benzothiazoles. 26. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a Simple Fluorinated 2-Arylbenzothiazole, Shows Potent and Selective Inhibitory Activity against Lung, Colon, and Breast Cancer Cell Lines” J. Med. Chem. 2006, 49, 179. 6 Aiello, S.; Wells, G.; Stone, E.L.; Kadri, H.; Bazzi, R.; Bell, D.R.; Stevens, M.F.G.; Matthews, C.S.; Bradshaw, T.D.; Westwell, A.D. “Synthesis and Biological Properties of Benzothiazole, Benzoxazole, and Chromen-4-one Analogues of the Potent Antitumor Agent 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (PMX 610, NSC 721648)” J. Med. Chem. 2008, 51, 5135. 7 Fliri, A.F.; Loging, W.T.; Thadeio, P.F.; Volkmann, R.A. J. Med. Chem. 2005, 48 (22), 6918.

8 For reviews see: Schultz, A. G. “Photochemical Six Electron Heterocyclization Reactions” Acc. Chem. Res. 1983, 16, 210; Schultz, A. G.; Motyka, L. “Photochemical Heterocyclizations of Systems Isoelectronic With the Pentadienyl Anion” in Organic Photochemistry, A. Padwa, Ed. Marcel Dekker, New York, 1983 Vol. 6, p. 1.

9 Schultz, A.G.; Lucci, R.D.; Fu, W.Y.; Berger, M.H.; Erhardt, J.; Hagmann, W.K. "Heteroatom Directed Photoarylation. Synthetic Potential of the Heteroatom Oxygen" J. Am. Chem. Soc. 1978, 100, 2150. 10 Schultz, A.G.; Fu, W.Y.; Lucci, R.D.; Kurr, B.G.; Lo, K.M.; Boxer, M. "Heteroatom Directed Photoarylation. Synthetic Potential of the Heteroatom Sulfur" J. Am. Chem. Soc. 1978, 100, 2140. 11 Huisgen, R. Angew. Chem. Int. Ed. Engl., 2, 565, 633 (1963).

36

12 Huisgen, R.; Grashey, R.; Sauer, J in “The Chemistry of the Alkenes,” S. Patai, Ed., Interscience: New York, 1964.

13 Dittami, J.P.; Ramanathan, H.; Breining, S. “Intramolecular Addition Reactions During Heteroatom Directed Photoarylation” Tetrahedron Lett. 1989, 30, 795.

14 Dittami, J.P.; Luo, Y.; Moss, D.; McGimpsey, W.G. “Photochemistry or Aryl Vinyl Sulfides and Aryl Vinyl Ethers: Evidence for the Formation of Thiocarbonyl and Carbonyl Ylides” J. Org. Chem. 1996, 61, 6256-6260.

15 For a discussion of the theory of dipolar cycloaddition reactions see Houk, K. in 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed.; Wiley Interscience: New York 1984 V. 2.

16 Dittami, J.P.; Nie, X.Y.; Nie, H.; Ramanathan, H.; Breining, S. “Intramolecular Addition Reactions of Carbonyl Ylides Formed during Photocyclization of Aryl Vinyl Ethers” J. Org. Chem. 1991, 56, 5572-5578.

17 Dittami, J.P.; Nie, X.Y.; Nie, H.; Ramanathan, H.; Buntel, C.; Rigatti, S. “Tandem Photocyclization-Intramolecular Addition Reactions of Aryl Vinyl Sulfides. Observation of a Novel [2+2] Cycloaddition-Allylic Sulfide Rearrangement” J. Org. Chem. 1992, 57, 1151-1158. 18 Gannon, W.F.; House, H.O. “3-Ethoxy-2-cyclohexenone” Organic Syntheses, 1960, 40, 41.

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