Post on 27-Jan-2021
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
BCC-I-010a 11 1 Z:\gateway jpdMQP
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
BCC-I-016a 10 1 Z:\gateway jpdMQP
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-
yloxy)cyclohex-2-enone (31a)
F2 [
pp
m]
6
4
2
0
F1 [ppm] 6 4 2
BCC-I-018q 14 1 Z:\gateway jpdMQP
30
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)
[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
BCC-I-018q 11 1 Z:\gateway jpdMQP
31
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)
[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
BCC-I-018q 13 1 Z:\gateway jpdMQP
32
Figure 10. Infrared Spectrum of 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-
yloxy)cyclohex-2-enone (31a)
33
Figure 11. DSC Curve for 3-(2-(1,3-dioxan-2-yl)ethyl)-2-(2-aminobenzo[d]thiazol-6-
yloxy)cyclohex-2-enone (31a)
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
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.