Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol- 4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications

1080

J. Med. Chem. 2006, 49, 1080-1100

Synthesis and Structure-Activity Relationships of 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine

Analogues as Potent, Noncompetitive Metabotropic Glutamate Receptor Subtype 5 Antagonists;

Search for Cocaine Medications

Yasuyoshi Iso,^†Ewa Grajkowska,^‡Jarda T. Wroblewski,^‡Jared Davis,^§Nicholas E. Goeders,^§Kenneth M. Johnson,

Subramaniam Sanker,^|Bryan L. Roth,^|Werner Tueckmantel,^#and Alan P. Kozikowski*^,†

Drug DiscoVery Program, Department of Medicinal Chemistry and Pharmacognosy, UniVersity of Illinois at Chicago, 833 South Wood Street,

Chicago, Illinois 60612, Department of Pharmacology, Georgetown UniVersity Medical Center, 3900 ReserVoir Road NW,

Washington, D.C. 20007, Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center,

ShreVeport, Louisiana 71130-3932, Department of Pharmacology and Toxicology, UniVersity of Texas Medical Branch,

301 UniVersity BouleVard, GalVeston, Texas 77555, Department of Biochemistry, Case Western ReserVe UniVersity School of Medicine,

CleVeland, Ohio 44106, and Acenta DiscoVery Inc., South Rita Road, Suite 300, Tucson, Arizona 85747

ReceiVed June 16, 2005

Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype

5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various

central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5

field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the

site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue

3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive

antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the

reinstatement of cocaine self-administration caused by the presentation of environmental cues previously

associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of

gaining a better understanding of the structural features relevant to its antagonist potency and with the

ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine.

These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists

than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists

that are 490 and 230 times, respectively, better than that of MTEP.

Introduction

mGluRs mediate multiple modulatory actions in the central

nervous system, ranging from the control of neuronal excit-

ability, participation in mechanisms of neurotoxicity, and

neuroprotection to the modulation of gene expression, learning,

memory, and expression of various behaviors. In particular,

recent evidence points to the role that one of the group I

receptors, mGluR5, may play in cocaine addiction.

While many efforts have focused on the discovery of cocaine

medication by designing drugs that act on the dopamine

transporter (DAT), less research has been directed to manipula-

tion of metabotropic glutamate receptor in controlling chemical

addictions. The metabotropic glutamate receptors (mGluRs)

constitute a family of seven-transmembrane domain, G protein-

coupled receptors and are characterized by the presence of large,

extracellular, N-terminal agonist-binding domains.¹mGluRs

cloned from mammalian tissues can be subdivided into three

groups based on sequence homology, pharmacology, and

intracellular signal transduction. Group I consists of mGluR1

and mGluR5 which stimulate phospholipase C, leading to

phosphoinositide hydrolysis and formation of two intracellular

second messengers: inositol triphosphate (IP₃), which induces

intracellular Ca²⁺release, and diacylglycerol (DAG), which can

stimulate protein kinase C activity. Group II (mGluR2 and

mGluR3) and group III (mGluR4, mGluR6, mGluR7, and

mGluR8) are negatively coupled to adenylate cyclase. Therefore,

their activation decreases intracellular cAMP levels. In addition,

many mGluR subtypes have been shown to induce either direct

or indirect modulation of various ion channels. As a group,

Group I mGluRs are characterized by a distinct pharmacology

and can be activated by a group-selective agonist (S)-3,5-

dihydroxyphenylglycine (DHPG),²as well as the mGluR5-

selective agonist 2-chloro-5-hydroxyphenylglycine (CHPG). The

existing competitive antagonists include 4-carboxy-3-hydroxy-

phenylglycine (4C3HPG), RS-1-aminoindan-1,5-dicarboxylic

acid (AIDA), and LY-367385, which show some selectivity for

mGluR1, but none are selective for mGluR5. More selective

are compounds acting as noncompetitive antagonists of group

I mGluRs. These include 7-hydroximinocyclopropa[b]chromene-

1a-carboxylic acid ethyl ester (CPCCOEt),³which is selective

for mGluR1, as well as 2-methyl-6-(phenylethynyl)pyridine

(MPEP)⁴and its analogue, 3-[(2-methyl-4-thiazolyl)ethynyl]-

pyridine (MTEP),⁵which are selective for mGluR5. These

compounds bind to amino acid residues located in the trans-

membrane domain of the group I mGluRs and inhibit receptor

activity without interfering with the binding of the primary

agonist (glutamate). Studies from several laboratories have

indicated that modifications of the MPEP and MTEP molecules

lead to a number of compounds which selectively inhibit

mGluR5 with potencies in the low nanomolar range.^4-6

MPEP has been suggested to bind to amino acid residues

located in the transmembrane region of the third and sixth

* To whom correspondence should be addressed. Phone: 312-996-7577.

Fax: 312-996-7107. E-mail: kozikowa@uic.edu.

^†University of Illinois at Chicago.

^‡Georgetown University Medical Center.

^§LSU Health Sciences Center.

University of Texas Medical Branch.

^|Case Western Reserve University School of Medicine.

^#Acenta Discovery Inc.

Published on Web 01/07/2006

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1081

transmembrane heptahelical domain of mGluR5.⁷Interestingly,

in the absence of the extracellular glutamate binding portion of

mGluR5, MPEP has been shown to act as an inverse agonist at

this site. Recent studies have provided evidence for the existence

of a full pharmacological spectrum of drugs that act at this

transmembrane site, including positive, negative, and neutral

modulators.^7cThus, it is possible that the design of MPEP- or

MTEP-based ligands could yield chemical entities capable of

fine-tuning the activity of this important modulatory site.

The expression pattern of mGluR5 suggests a possible role

in the effects of drugs of abuse. mGluR5 is highly expressed in

both the intrinsic and efferent projection neurons in the nucleus

accumbens and striatum, brain regions associated with the

behavioral effects of psychostimulant drugs. Perhaps the most

compelling study pointing to mGluR5 as a potential drug target

is one that demonstrated that the reinforcing and locomotor

stimulant effects of cocaine are absent in mGluR5 null mutant

mice.⁸Importantly, this effect appears to be mediated down-

stream of cocaine’s effect on dopaminergic neurons as there

was no difference between the wild type (WT) and null mutant

regarding cocaine-induced dopamine (DA) release in the ventral

striatum. It is important to note that acquisition of a food

reinforced task was not different between WT and null mutant

mice. Also relevant to this research is that MPEP, a selective

mGluR5 noncompetitive antagonist, blocked cocaine self-

administration by about 50% in C57BI/6J mice.

Figure 1. mGluR5 antagonists.⁵

ments designed to evaluate the potential of MTEP to disrupt

this association.

The development of the present class of noncompetitive

mGluR5 antagonists¹⁷began with the discovery through random

screening of a lead compound, 6-methyl-2-(phenylazo)pyridin-

3-ol and its structural modification to the analogue, 2-methyl-

6-((E)-styryl)pyridine, by Cosford and co-workers.¹⁸Both

compounds are high-nanomolar (IC₅₀) 0.37 and 0.29 µM,

Although the precise mechanism is unknown, it is quite

possible that the effect of mGluR5 antagonism is mediated on

striatal GABAergic output neurons that receive both dopamin-

ergic ventral tegmental area neurons and glutamatergic input

from the frontal cortex.⁹It is known that cocaine increases both

extracellular DA and glutamate levels in the nucleus accumbens

(NAc)¹⁰and that these effects are enhanced with repeated

administration.¹¹Activation of DA and mGluR5 in the NAc¹²

consequent to cocaine-induced DA and glutamate release could

act synergistically via their respective second messenger

systems. For example, acute administration of amphetamine has

been demonstrated to increase striatal phosphorylation of CREB,

Elk-1, and ERK1/2 in a manner that was blocked by MPEP.¹³

respectively) antagonists of the increase in intracellular [Ca²⁺

]

evoked by glutamate (at EC₈₀) at recombinant human mGluR5a,

but not mGluR1b or other mGluR subtypes. In addition,

2-methyl-6-((E)-styryl)pyridine is a weak (EC₅₀) 26.4 µM)

agonist at human mGluR4a. No activity (either agonist or

antagonist) was encountered for either compound at a selection

of human R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic

acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA)

receptors. Replacement of the CdC double bond in 2-methyl-

6-((E)-styryl)pyridine with a triple bond resulted in 2-methyl-

6-(phenylethynyl)pyridine (MPEP)⁴which exhibited a dramati-

cally improved mGluR5 antagonist activity (Figure 1). In the

case of the other mGluRs, the only other activity observed for

MPEP is very weak antagonism at mGluR6 (20% depression

of forskolin-stimulated cAMP level at 100 µM). Additionally,

it has been reported that MPEP exhibits weak antagonism at

NMDA receptors.¹⁹No activity was observed at several other

subtypes of ionotropic glutamate receptors.⁴

Other studies supporting this approach include the demonstra-

tion that MPEP dose-dependently reduced cocaine conditioned

place preference, while having no effect on place preference

for other drugs including nicotine and morphine.¹⁴Importantly,

and in opposition to the place preference data, MPEP has been

reported to inhibit nicotine self-administration in both rats and

mice, while having no effect on food maintained responding.¹⁵

Further, MPEP has been demonstrated to significantly inhibit

both acquisition and expression of conditioned place preference

to morphine in mice.¹⁶

These data suggest that MPEP may have inhibitory effects

on drug reward mechanisms in general, but they also point out

that subtle differences may exist between different methods of

evaluating drug effects on reward mechanism. These data also

suggest the value of using different models of drug reinforce-

ment in the evaluation of the therapeutic potential of drugs to

be used in drug addiction. One of the major problems in

maintaining abstinence from cocaine is that cocaine addicts often

relapse because environmental cues previously associated with

cocaine use can precipitate drug seeking and subsequent cocaine

self-administration, which in turn, causes further drug seeking.

For this reason it is important to understand the mechanisms

underlying the association between such environmental cues and

drug seeking. Therefore the current study also included experi-

Various SAR studies have been reported on MPEP by several

research groups.^{4,6c,6e,6g,6i,6j}including the synthesis of compounds

in which the pyridine ring was replaced by a thiazole ring. As

these later compounds suffered from poor water solubility, the

benzene ring of these thiazole analogues was replaced by a

pyridine ring. Of the compounds tested, only the 3-pyridyl

isomer, namely 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine

(MTEP),⁵exhibited satisfactory potency. Like MPEP, MTEP

is highly selective for mGluR5 vs other mGluRs; its antagonism

at NMDA receptors is strongly reduced although not completely

abolished, and no activity is observed at other ionotropic

glutamate receptors. Taken together, these data make MTEP a

desirable lead compound for further structural modifications.

1082 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Scheme 1. Key Intermediates 4-6 and 9^a

Iso et al.

Figure 2. Structure of the dimer formed in the homo-coupling reaction.

Scheme 2^a

^aReagents and conditions: (a) BBr₃, CH₂Cl₂, rt; (b) H₂O₂, aqueous

NaOH, EtOH, 60 °C.

the modified Sonogashira coupling reaction, and the respective

yields obtained for the coupling products.

All of the aryl or heteroaryl halides used in these reactions

were available commercially, with the exception of N-(3-

iodophenyl)acetamide, which was obtained by acetylation of

3-iodoaniline with acetyl chloride in the presence of triethyl-

amine. For the most part, these reactions proceeded in good

yield, although several took place in <40% yield. In these cases

the products of homo-coupling were observed. The competition

between the desired cross-coupling reaction pathway and the

undesired homo-coupling reaction that takes place in the

modified Sonogashira coupling reaction is likely dependent on

the reactivity of the aryl or heteroaryl halide that is used (Figure

2). The more reactive aryl iodides are the preferred partners

for obtaining the products of the cross-coupling reaction. For

the preparation of the MTEP analogues 37 and 38, the methoxy

group of 12 and the cyano group of 19 were converted to the

corresponding hydroxy or amide groups, respectively, using

standard conditions as shown in Scheme 2.²⁰

Next, we carried out modifications at the 2-position of the

thiazole ring of MTEP and also prepared analogues in which

its pyridine ring was replaced by a 3-fluorophenyl group as

shown in Schemes 3 and 4. The key intermediate 39 was readily

synthesized using the same method as in Scheme 1 by simply

using thiourea in place of thioacetamide. Intermediate 39 was

then subjected to the modified Sonogashira coupling reaction

to give two types of 2-aminothiazole derivatives, namely 40

and 41. Analogue 41 contains the 3-pyridyl moiety common to

MTEP while 40 contains a 3-fluorophenyl group in place of

MTEP’s pyridyl group. The MTEP analogue 10 bearing a

3-fluorophenyl moiety is known to be more potent as an

mGluR5 antagonist than MTEP (Table 2). The amine analogues

42-45 comprised of amide, urea, and carbamate groups were

obtained by reaction of 41 with the corresponding acid chloride,

isocyanate, or chloroformate, respectively, in the presence of

an appropriate base (Scheme 3).

^aReagents and conditions: (a) bis(trimethylsilyl)acetylene, AlCl₃,

CH₂Cl₂, 0 °C, 2 h and then 25 °C, 1 h; (b) thioacetamide, DMF, 25 °C, 17

h (and then 85 °C, 1.5 h for preparation of 5, 6, and 9); (c) bromine, CCl₄,

0 °C, 10 min.

Synthetic Methods

On the basis of the structure-activity relationship (SAR)

information that was available at the time we undertook the

present synthetic efforts, we chose to further explore the SAR

of MTEP in order to identify the best possible candidates for

use in our drug abuse studies. To begin our work, we first

prepared four different 2-methyl-5-substituted-4-(trimethylsila-

nylethynyl)thiazole derivatives 4, 5, 6, and 9. These four

compounds serve as key intermediates in the synthesis of the

MTEP analogues and were synthesized as shown in Scheme 1.

These intermediates 4-6 were obtained in a manner similar to

that reported in the synthesis of MTEP.⁵However, we found

that it was not necessary to purify compounds 1-3 and obtained

4-6 efficiently by simply employing the crude starting materi-

als. In the case of 9 having an aromatic substituent at the

5-position of the thazole ring, the benzylic chlorine atom in the

requisite 2-aryl-2-chloroacetyl chloride staring material is prob-

ably too labile to survive the subsequent AlCl₃-promoted

condensation reaction with bis(trimethylsilyl)acetylene. Accord-

ingly, R-halogenation was postponed until after this step. Thus,

after the AlCl₃-promoted condensation of benzoyl chloride with

bis(trimethylsilyl)acetylene, 7 was successfully brominated at

its benzylic position using bromine to give 8. Crude 8 was then

immediately subjected to the thiazole ring forming reaction with

thioacetamide to furnish the key intermediate 9 in good yield.

Next, using a one-pot modified Sonogashira coupling reaction,

the in situ desilylation of key intermediates 4-6 and 9 with

tetrabutylammonium fluoride (TBAF) and subsequent palladium

catalyzed cross-coupling reaction with the appropriate aryl or

heteroaryl halide was carried out in a manner similar to that

reported for the synthesis of certain thiazole derivatives of

MTEP.^5,6g

Other modifications at the 2-position of thiazole ring were

brought about through the bromide 46, which was obtained from

40 through the Sandmeyer reaction as detailed in Scheme 4.

Accordingly, the amine 40 was reacted with tert-butyl nitrite

and cupric bromide,²¹and the resulting bromide was then

subjected to the Suzuki, Sonogashira, or Stille cross-coupling

reactions. The Suzuki coupling reaction of 46 with 3,5-

difluorophenylboronic acid, the Sonogashira coupling reaction

of 46 with trimethylsilylacetylene or propargyl alcohol, and the

Stille coupling reaction of 46 with tributyl(vinyl)tin proceeded

In Table 1, we present a list of the aryl and heteroaryl halides

that were reacted with 4-6 and 9 as substrates, together with

two different sets of reaction conditions that were employed in

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1083

Table 1. Preparation of MTEP Analogues Using the Modified Sonogashira Coupling Reaction via an in Situ Desilylation Reaction

in the presence of the appropriate palladium catalyst and base

to give the coupling products 47, 48, 49, and 51, respectively.

Unfortunately, we found that 51 was too unstable to be isolated

in pure form, as it apparently polymerized during evaporation

to remove water after reverse-phase HPLC purification. Inter-

mediate 48 was desilylated by the usual method using TBAF

to furnish the terminal acetylene derivative 50.

methylpropionitrile) (AIBN) under heating, followed by Sn-

Si conversion using butyllithium and chlorotrimethylsilane and

finally desilylation with 1 N hydrochloric acid to give the

terminal olefin derivative 59.²²Attempts to bring about the

direction alkylation of bromide 28 using various organometalic

reagents such as cuprates or Grignard reagents with zinc chloride

and palladium catalysts were unsuccessful.

We next carried out modifications at the 5-position of pyridine

ring using the bromide 28 as shown in Scheme 5. We were

able to successfully convert the bromo group to an aryl or

alkynyl group using the Suzuki or Sonogashira coupling reaction

to afford 52-55. Compound 54 was desilylated as above using

TBAF to give the terminal acetylene derivative 56. This

acetylene 56 was converted to the trans-vinylstannane 57 by

hydrostannylation using tributyltin hydride and 2,2′-azobis(2-

To explore the effect of modifications at the 6-position of

the pyridine ring, we used the 6-methoxypyridine derivative 26

as the starting material as displayed in Scheme 6. At the

beginning of this study, efforts were made to cleave the methoxy

group of 26 using standard demethylation protocols consisting

of BBr₃(CH₂Cl₂, 0 °C to room temperature) or HBr in acetic

acid at room temperature in order to obtain the key pyridone

61. However, all of these typical demethylation methods resulted

1084 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

Scheme 3. Modifications at the 2-Position of the Thiazole Ring

the 5-position of the pyridine ring, we planed to synthesize the

terminal olefin derivative 68 via the trans-vinylstannane inter-

mediate 67. However, the hydrostannylation reaction of 66 was

complicated and failed to furnish the expected intermediate 67.

We therefore attempted to prepare 68 directly from 64 by

carrying out a Stille coupling reaction with tributyl(vinyl)tin

and a palladium catalyst. This reaction proceeded smoothly to

furnish the terminal olefin derivative 68.

(Synthesis of Amino Analogues)^a

To explore modifications at the 2-position of the pyridine

ring, we first prepared 3-iodo-2-methoxypyridine (69) according

to a literature procedure (Scheme 7).²⁴Crude compound 69 was

then subjected to the modified Sonogashira coupling reaction

involving in situ desilylation with TBAF as described above to

successfully furnish the 2-methoxypyridine derivative 70.

Intermediate 70 was then transformed to its mesylate 73,

chloride 74, and triflate 75 via the pyridone 72 in the same

fashion as described for the MTEP analogues modified at the

6-position. Again, the terminal acetylene 77 was obtained from

the triflate 75 by the Sonogashira coupling reaction followed

by desilylation.

It is also possible to modify the tether that links the two

(hetero)aryl rings. While many possibilities can be envisioned,

we explored only two such modifications as shown in Scheme

8. In one case the acetylene is replaced by a trans-olefin unit,

while in the other case the tether is replaced by an amide group.

The starting material compound 4, was first desylilated with

TBAF, and the resulting unstable and volatile intermediate 78

was immediately subjected to hydrostannylation by heating with

tributyltin hydride and AIBN to give the trans-vinylstannane

79. The vinylstannane 79 was successfully converted in turn to

the desired trans-olefin analogue 80 of MTEP by the Stille

coupling reaction with 3-iodopyridine. The amide analogues 81

and 82 were readily available from 2-methyl-thiazole-4-car-

boxylic acid by preparation of an activated acid derivative using

EDC or by reaction with thionyl chloride to generate the acid

chloride followed by coupling with the appropriate amine.

^aReagents and conditions: (a) bis(trimethylsilyl)acetylene, AlCl₃,

CH₂Cl₂, 0 °C, 2 h and then 25 °C, 1 h; (b) thiourea, DMF, 25 °C, 17 h; (c)

Pd(PPh₃)₄, CuI, NEt₃, TBAF, DMF, 80 °C.

in no reaction. When the demethylation reaction was carried

out under more vigorous conditions involving an excess of HBr

in AcOH with heating, the bromoolefin derivative 60 was

generated as a result of both hydrobromination of the alkyne

tether together with demethylation of the methoxy group.

Dehydrobromination of the bromoolefin 60 by potassium

hydroxide in refluxing methanol²³proceeded in good yield to

provide the desired pyridone 61. Conversion of 61 to its

mesylate 62, chloride 63, or triflate 64 was performed by

standard methods. Triflate 64 was subjected to the Suzuki or

Sonogashira coupling reaction followed by desilylation as above

to give the aryl pyridine derivative 65 or the terminal acetylene

derivative 66, respectively. As in the case of modification at

Finally, the preparation of oxazole analogues of MTEP is

summarized in Scheme 9. 2-Methyl-oxazole-4-carboxaldehyde

(85) was prepared according to a literature procedure.²⁵Thus,

the oxazoline 83 was obtained by reaction of DL-serine methyl

ester hydrochloride with ethyl acetimidate hydrochloride, and

the intermediate oxazoline 83 was then directly subjected to

oxidation using cupric bromide²⁶to afford the oxazole 84. The

methyl ester 84 was reduced with lithium aluminum hydride in

ether at -78 °C for 30 min to give the expected aldehyde 85,

which was immediately subjected to a Wittig reaction with

Scheme 4. Modifications at the 2-Position of the Thiazole Ring Starting from Amine 40^a

^aReagents and conditions: (a) t-BuONO, CuBr₂, MeCN, 80 °C, 15 min; (b) 3,5-difluorophenylboronic acid, Pd(PPh₃)₄, K₂CO₃(2 M aqueous solution),

DME, 85 °C, 15 h; (c) trimethylsilylacetylene or propargyl alcohol, Pd(PPh₃)₄, CuI, NEt₃, DMF, 85 °C, 1.5-3 h; (d) TBAF, THF, rt, 10 min; (e) tributyl(vinyl)tin,

PdCl₂(PPh₃)₂, LiCl, DMF, 85 °C, 15 h.

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1085

Table 2. SAR of the Pyridine Moiety of MTEP

^aIC₅₀values are expressed as mean ( SE, n ) 6. IC₅₀values represent the ability of compounds containing various aryl or heteroaryl groups (A) to

inhibit agonist-induced phosphoinositide hydrolysis.

carbon tetrabromide and triphenylphosphine to furnish the

dibromoolefin 86 in good yield. We next explored the applica-

tion of a procedure previously reported by Nicolaou in the

synthesis of thiazolyl acetylene derivatives.²⁷After dehydro-

bromination of the dibromoolefin 86 was performed by reaction

with 1 equiv of sodium bis(trimethylsilyl)amide and lithiation

was brought about using 1 equiv of MeLi, the intermediate

acetylide 87 was trapped with chlorotrimethylsilane to afford

the key intermediate 2-methyl-4-(trimethylsilylethynyl)oxazole

(88) in good yield. The above modified Sonogashira coupling

reaction involving in situ desilylation with TBAF using 88 as

a substrate once again proved successful, and we could procure

the oxazole analogues 89 and 90 in good yield. The details of

the synthesis of these oxazole analogues have been reported

separately.²⁸

Results and Discussion

Behavioral Experiments. All rats learned to self-administer

cocaine according to the established criteria in an average of

12.11 ((6.19) sessions. All animals met the criteria for

successful baseline responding in an average of 8.25 ((1.9)

sessions. All animals met the criteria for successful extinction

in an average of 5.85 ((2.78) sessions. The mean baseline

responses for cocaine prior to extinction was 157 ( 13 (baseline

control, not shown in Figure 3) and was reduced to 14.3 ( 1.1

under extinction (9.1% of baseline, Figure 3). Cue-induced

reinstatement increased the response number to about 40% of

baseline cocaine responding, Rats were pretreated with MPEP

(5 or 10 mg/kg), MTEP (5 or 10 mg/kg), or vehicle 30 min

before reinstatement testing to determine the effects of the drugs

on the ability of conditioned environmental stimuli to reinstate

1086 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

Scheme 5. Modifications at the 5-Position of the Pyridine Ring^a

was also affected by 10 mg/kg MTEP treatment during

reinstatement with a p < 0.05. None of the other treatments

had a significant effect on responding on the inactive lever.

That MPEP was without a significant effect in this study was

somewhat surprising in view of several studies that have shown

positive effects with MPEP on various aspects of nicotine or

cocaine self-administration.^16,29In the present study, this dis-

crepancy is most likely due to the small number of rats in both

the 5 and 10 mg/kg groups (as both doses appeared to have a

partial, though not significant, effect). Another potential cause

for the greater effect of MTEP relative to MPEP is that the

ED₅₀for MTEP for receptor occupancy in vivo is about one-

half that of MPEP.³⁰Similarly, MTEP has about the same

mGluR5 occupancy as MPEP at a 3-fold lower dose in rats

(although the reverse is true in mice³⁰). Thus, it is quite possible

that subtle differences in absorption, distribution, metabolism,

and elimination of these two drugs in different rat strains also

could have played a role. Most importantly, these data dem-

onstrate that MTEP has the ability to prevent reinstatement of

cocaine seeking by environmental cues associated with cocaine

availability. However, MTEP is not without behaviorally

important side-effects,³¹and it will be important to thoroughly

investigate other compounds (e.g., 19 and 59, see below) that

could lead to the development of clinically useful drugs for the

treatment of cocaine and, perhaps, drug addiction in general.

^aReagents and conditions: (a) 4-fluorophenylboronic acid or 4-meth-

oxyphenylboronic acid, Pd(PPh₃)₄, K₂CO₃(2 M aqueous solution), DME

or DMF, 85 °C, 16-22 h; (b) trimethylsilylacetylene or propargyl alcohol,

Pd(PPh₃)₄, CuI, NEt₃, DMF, 75 °C, 17 h; (c) TBAF, THF, rt, 10 min; (d)

Bu₃SnH, AIBN, toluene, 90 °C, 14 h; (e) BuLi, Me₃SiCl, THF, -15 °C to

rt; (f) 1 N HCl, THF, rt, 20 min.

extinguished cocaine-seeking behavior. A one-way ANOVA

indicated a significant effect of the treatment conditions on

responding on the active lever F(4,19) ) 40.45; p < 0.0001,

with responding on the active lever following vehicle pretreat-

ment during reinstatement significantly higher than responding

during extinction.

Tukey’s post hoc test shows a significant difference between

vehicle and 10 mg/kg MTEP (p < 0.01). None of the other

treatments showed a significant decrease in responding when

compared to vehicle (Figure 3). Responding on the inactive lever

Pharmacological Experiments and SAR. To assess the

activity of the newly synthesized MTEP analogues prepared in

this study, we tested them in a functional assay which measures

agonist-induced phosphoinositide hydrolysis using CHO cells

which stably express mGluR5. The CHO cell line expressing

these receptors has been created previously, and these assay

methods have now become fairly routine.³²Concentration-

Scheme 6. Modifications at the 6-Position of the Pyridine Ring^a

^aReagents and conditions: (a) 30% HBr in AcOH, 80 °C, 7.5 h; (b) KOH, MeOH, reflux, 1 h; (c) MsCl, NEt₃, CH₂Cl₂, rt; (d) POCl₃, 120 °C, 1.5 h; (e)

Tf₂O, NEt₃, CH₂Cl₂, 0 °C; (f) 4-fluorophenylboronic acid, Pd(PPh₃)₄, K₂CO₃(2 M aqueous solution), DME, 80 °C, 18 h; (g) trimethylsilylacetylene, Pd(PPh₃)₄,

CuI, NEt₃, DMF, 85 °C, 2 h; (h) TBAF, THF, rt, 10 min; (i) Bu₃SnH, AIBN, toluene, 90 °C; (j) tributyl(vinyl)tin, Pd(PPh₃)₄, DMF, 85 °C, 15 h.

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1087

Scheme 7. Modifications at the 2-Position of the Pyridine Ring^a

^aReagents and conditions: (a) i. LiMe, i-Pr₂NH, THF, 0 °C, 3 h; ii. I₂, THF, -60 °C, 30 min; (b) 4, Pd(PPh₃)₄, CuI, NEt₃, TBAF, DMF, 80 °C, 15 h;

(c) 30% HBr in AcOH, 80 °C, 6 h; (d) KOH, MeOH, reflux, 1 h; (e) MsCl, NEt₃, CH₂Cl₂, rt; (f) POCl₃, 120 °C, 1.5 h; (g) Tf₂O, NEt₃, CH₂Cl₂, 0 °C; (h)

trimethylsilylacetylene, Pd(PPh₃)₄, CuI, NEt₃, DMF, 85 °C, 4 h; (i) TBAF, THF, rt, 10 min.

Scheme 8. Modifications of the Tether^a

Scheme 9. Synthesis of Oxazole Analogues of MTEP^a

^aReagents and conditions: (a) TBAF, THF, rt, 10 min; (b) Bu₃SnH,

AIBN, toluene, 90 °C, 1 h; (c) 3-iodopyridine, PdCl₂(PPh₃)₂, LiCl, CuI,

DMF, 80 °C, 1.5 h; (c) 3-fluoroaniline, EDC, HOBt, NEt₃, CH₂Cl₂, rt, 18

h; (d) i. SOCl₂, DMF, toluene, 105 °C, 80 min; ii. 3-aminopyridine, CH₂Cl₂,

rt, 10 min.

^aReagents and conditions: (a) NEt₃, CH₂Cl₂, rt, 16 h; (b) CuBr₂, DBU,

hexamethylenetetramine, THF, rt, 2 h; (c) LiAlH₄, Et₂O, -78 °C, 30 min;

(d) CBr₄, PPh₃, CH₂Cl₂, 0 °C, 20 min; (e) NaHMDS, then MeLi, THF,

-78 °C; (f) Me₃SiCl, THF, -78 °C to rt; (g) 1-fluoro-3-iodobenzene or

3-iodopyridine, Pd(PPh₃)₄, CuI, Et₃N, Bu₄NF, DMF, 85 °C, 13 h.

response curves were performed using seven concentrations of

the drug with a total of six separate experiments being conducted

on active compounds. All IC₅₀values reported in Tables 2-6

represent means ( SEM.

The activities of compounds which contain various aryl or

heteroaryl groups in place of the 3-pyridinyl found in MTEP

are shown in Table 2. In general, the derivatives having a

3-substituted aryl group attached to the ethynyl group (10, 12)

are more potent than other aryl derivatives. On the other hand,

the derivatives having a 4-substituted aryl group (11) are less

potent. The analogue containing a 3,5-disubstituted aryl group

(21) shows a potency that is comparable to that of the

corresponding monosubstituted derivative (10). Overall, it is

clear that small, electron-withdrawing groups like CN or F

located at the 3-position of the aryl ring increase the potency

of these compounds as mGluR5 antagonists (19, 10). On the

other hand, introduction of polar groups such as NHAc, CONH₂,

or OH clearly results in a decrease in activity. In particular, we

point out that compound 19, which has a cyano group at the

3-position in aryl ring, is the most potent of the 58 compounds

reported in this article. Compound 19 has an IC₅₀value of 0.94

nM, and it is therefore 490-fold more potent than MTEP.

Unfortunately, few of the heteroaryl derivatives including the

fused ring derivatives (found in the right column of Table 2)

that we have synthesized are very potent in comparison to

MTEP. Both the pyrimidine derivative (30) and the pyrazine

derivative (31) containing two nitrogen atoms in the heteroaryl

ring are less potent than MTEP. Only the two thiazole

derivatives 32 and 33 reveal mGluR5 antagonist potencies

comparable to MTEP. The loss of potency for the fused ring

compounds may be due to the inability of the antagonist binding

site to accommodate these bulkier structures.

Next, we investigated the effects of substituents on the

thiazole ring in modulating mGluR5 antagonist activity (section

1 of Table 3). As the substituents located on the 5-position of

the thiazole ring became bulkier, compound potency decreased,

suggesting some limitations in the size of the binding pocket.

In the case of analogue 25 having the largest substituent, a

phenyl group, no detectable activity was measured.

The derivatives chemically modified at the 2-position of the

thiazole ring basically showed reduced activities compared to

1088 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

Table 3. Effects of Substituents on the Thiazole Ring

Figure 3. Effect of MTEP on cue-induced reinstatement of cocaine

self-administration. Responses are shown as a percentage of the

baseline.

the lead structures MTEP and 10 (sections 2 and 3 of Table 3).

For both sets of the aminothiazole bearing analogues of MTEP

and the analogues of 10, their functional activity appears to relate

to steric factors as opposed to substituent polarity. For those

derivatives containing larger substitutents as found in 43-45,

47, and 49, little or no activity was found.

The activities of MTEP analogues bearing a substituent at

the 2-, 5-, or 6-positions of the 3-pyridyl group of MTEP are

shown in Table 4. On the whole, the MTEP analogues

substituted at the 5-position of the 3-pyridyl moiety are more

potent as mGluR5 antagonists than those compounds containing

substituents at the 2- or 6-positions of the 3-pyridyl moiety.

All substituents introduced at the 5-position of 3-pyridyl

moiety led to an increase in functional potency as compared to

MTEP (section 1 of Table 4). The analogues (56 and 59)

possessing a sterically small, unsaturated group such as vinyl

or ethynyl at this position showed very potent activities. In

particular, compound 59 is the second most potent mGluR5

antagonist of all newly synthesized compounds reported herein.

Its IC₅₀value is 2 nM, which translates into a 230-fold increase

in potency relative to the activity measured for MTEP.

On the other hand, the MTEP analogues substituted at the

6-position of the 3-pyridyl moiety were generally less active

than other members of this series (section 2 of Table 4). Of

some interest, however, is the activity displayed by the

4-flurophenyl analogue 65, which shows an IC₅₀value of 10

nM. This is somewhat surprising in light of the poor activity

shown by the ethynyl and vinyl analogues 66 and 68, and we

therefore plan to explore this modification further.

In the case of the analogues substituted at the 2-position

(section 3 of Table 4), the 2-chloro compound was found to be

the most active with an IC₅₀of 45 nM. Both the methoxy and

ethynyl bearing compounds were less active than this chloro

compound. On the other hand, analogue 73 having a strongly

electron-withdrawing group mesyloxy group at the 2-postion

failed to show activity.

The activities of the derivatives that have been chemically

modified in the tether connecting the thiazole ring and aryl or

heteroaryl ring are shown in Table 5. The analogue 80 having

a trans-vinyl group as the tether in place of the ethynyl group

in MTEP showed 10-fold less activity than MTEP. For the

amide analogues 81 and 82 of MTEP and the fluorophenyl

compound 10, no activity was detectable.

^aIC₅₀values are expressed as mean ( SE, n ) 6. IC₅₀values represent

the ability of compounds containing various aryl or heteroaryl groups (A)

to inhibit agonist-induced phosphoinositide hydrolysis.

hopeful that the oxazole analogues of MTEP and 10 would retain

good mGluR5 activity (Table 6). However, again neither of these

compounds showed detectable activity. The lack of activity is

somewhat surprising, as the overall change in structure brought

about by replacing sulfur in the thiazole ring by oxygen is small.

Apparently, the differences caused by the presence of the

smaller, more electron withdrawing oxygen are sufficient to

prevent interaction of these oxazole analogues with the allosteric

binding site present in the intracellular domain of mGluR5.

These findings will undoubtedly be of value to probe through

molecular modeling studies.

For reasons relating to the anticipated toxicological effects

of the thiazole ring versus the oxazole ring system, we were

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1089

Table 5. Modification of the Tether

Table 4. Effects of Substituents on the Pyridine Ring

^aIC₅₀values are expressed as mean ( SE, n ) 6. IC₅₀values represent

the ability of compounds containing various aryl or heteroaryl groups (A)

to inhibit agonist-induced phosphoinositide hydrolysis.

Table 6. Oxazole Analogues

^aIC₅₀values are expressed as mean ( SE, n ) 6. IC₅₀values represent

the ability of compounds containing various aryl or heteroaryl groups (A)

to inhibit agonist-induced phosphoinositide hydrolysis.

Table 7. In Vitro Cloned mGluR5 Binding Affinity Data for Potent

mGluR5 Antagonists 19 and 59

^aIC₅₀values are expressed as mean ( SE, n ) 6. IC₅₀values represent

the ability of compounds containing various aryl or heteroaryl groups (A)

to inhibit agonist-induced phosphoinositide hydrolysis.

To further confirm the activity of the two most potent

compounds identified from the present SAR study, the binding

affinities of analogues 19 and 59 at the cloned mGluR5 were

measured. The binding studies were conducted using radio-

labeled [3H]-MPEP and transiently transfected 293-T cells

transfected with cloned mGluR5 cDNA. As is apparent from

Table 7, the K_ivalues obtained for binding to the cloned

mGluR5 correlate well with the IC₅₀values obtained from the

rat mGluR5 antagonist assay.

^aK_ivalues are expressed as nM. K_ivalues are analyzed by the

displacement by the test compounds (19, 59) of [3H]-MPEP from cloned

mGluR5 and represent the binding affinity of compounds (19, 59) to the

cloned mGluR5.

been made to each of the three regions of the lead molecule. In

general, we found that modifications to the thiazole moiety of

MTEP including its replacement by an oxazole group resulted

in a decrease in functional activity. Likewise, in the few cases

studied, replacement of the acetylenic tether by either a trans-

Conclusion

The present work delineates the chemical synthesis of a total

of 58 MTEP analogues in which chemical modifications have

1090 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

Completion of the FR4 schedule resulted in an intravenous infusion

of cocaine (0.25 mg/kg/infusion delivered in 200 µL 0.9% NaCl

delivered over 5.6 s) and the concurrent presentation of the house

light and tone compound stimulus. The criterion for “stable

responding” under the FR4 schedule of reinforcement was a

minimum of 10 days of exposure to this schedule that included 3

consecutive days when responding varied by less than 10%.

Responses on the inactive lever were counted but resulted in no

programmed consequences at any time.

Extinction Training. Once stable responding under the FR4

schedule of self-administration was observed according to the

criteria described above, extinction training began. During extinc-

tion, responding on either lever produced no programmed conse-

quences, and no cocaine or cocaine-associated cues were delivered.

Successful extinction was determined individually for each rat

instead of exposing all rats to a predefined number of extinction

sessions.^33cThe rats were exposed to extinction training until

responding on the active lever decreased to below 20% of baseline

responding (i.e., average responding during the last 3 days of

cocaine self-administration) for at least 3 consecutive days.

Responding was not completely extinguished to allow for the

possibility of cue-induced reinstatement.

Reinstatement Testing. Once responding on the active lever

was successfully extinguished according to the criteria described

above, reinstatement testing commenced. Rats were placed into the

chambers, and each response on the active lever resulted in a 5.6

s presentation of the conditioned cue (the paired house light and

tone compound stimulus). Responses on the inactive lever were

counted but resulted in no scheduled consequences. Rats were

randomly pretreated (30 min) with either an i.p. injection of the

vehicle (5% emulphor in saline) or one of the two test drugs (MTEP

or MPEP) at a dose of either 5 or 10 mg/kg. Following the

reinstatement test, the rats were re-trained to self-administer cocaine

for a minimum of 5 days until stable self-administration was

observed as described above. These rats once again underwent

extinction training, and when the criteria for successful extinction

were met, they were once again tested for reinstatement with the

contingent presentation of the conditioned reinforcer. Prior to this

second test, the rats were pretreated with a compound (i.e., MPEP,

MTEP or vehicle) different than the one that they had received

during the first test.

Drugs. Cocaine HCl was obtained from the National Institute

on Drug Abuse (Research Triangle Park, NC) and was dissolved

in bacteriostatic, heparinized 0.9% saline. Cocaine was self-

administered at a dose of 0.25 mg/kg/infusion and was delivered

in a 200 µL volume over 5.6 s. MTEP and MPEP were suspended

in 5% emulphor in 0.9% saline. Two rats were previously exposed

to oxazepam (10 mg/ kg, i.p.) and CP 154,526 (20 mg/kg, i.p.).

Data Analysis. Data collected included the number of cocaine

infusions during self-administration and the number of responses

on the active and inactive levers during self-administration,

extinction, and reinstatement testing. Significance of the differences

between the various treatments was determined with a one-way

analysis of variance with the treatment administration during

reinstatement (i.e., vehicle, MTEP 5, MTEP 10, MPEP 5, or MPEP

10) and subject as the variables. Tukey’s all pairwise multiple

comparison procedures were then used to isolate differences

between groups.

Biological Evaluation. Phosphoinositide Hydrolysis Assay.³⁴

Recombinant cDNA for mGluR5a was stably transfected and

expressed in Chinese hamster ovary (CHO) cells.³⁵Cultured in 96-

well plates, the receptor-expressing cells were incubated with 0.75

µCi myo-[³H]inositol to label the cell membrane phosphoinositides.

Incubations with test compounds were carried out for 45 min at 37

°C in Locke’s buffer (156 mM NaCl, 5.6 mM KCl, 3.6 mM

NaHCO₃, 1 mM MgCl₂, 1.3 mM CaCl₂, 5.6 mM glucose, and 20

mM HEPES, pH 7.4) containing 20 mM LiCl, which blocks the

degradation of inositol phosphates (IPs). The reaction was termi-

nated by aspiration and addition of 0.1 M HCl. IPs were extracted

with 0.1 M HCl. [³H]IPs were separated by anion exchange

olefin or an amide was also not promising. This SAR informa-

tion thus suggests that the (2-methyl-1,3-thiazol-4-yl)ethynyl

group represents one of the best part structures valuable to

achieving mGluR5 antagonist activity. Further detailed chemical

modifications of the 3-pyridyl moiety in MTEP including its

replacement by a variety of aryl and heteroaryl groups possess-

ing various substituents located at different positions resulted

in several promising compounds. We found that when relatively

small groups such as vinyl or cyano were introduced into the

positions meta to the ethynyl group in either the pyridyl ring of

MTEP or the phenyl ring of its fluorophenyl analogue 10, large

enhancements in compound potency could be achieved. Among

the compounds synthesized and tested in this study, analogues

19 and 59 were found to be 490- and 230-fold more potent as

mGluR5 antagonists than MTEP. Moreover, the binding affini-

ties measured for these analogues using human mGluR5 from

cortical tissues correlated well with the antagonist potencies

measured using rat mGluR5. As our behavioral data clearly

demonstrate that MTEP has the ability to prevent reinstatement

of cocaine seeking by environmental cues associated with

cocaine availability, the identification of other MTEP analogues

that exhibit appropriate ADME and safety parameters should

be pursued in the quest for medications for drug addiction. The

SAR information available from the present research will be

used to guide our efforts in identifying other noncompetitive

mGluR5 antagonists for study in cocaine self-administration

experiments in rodents.

Experimental Section

Behavioral Methods. Subjects. Adult male Wistar rats (n ) 9,

Harlan Sprague Dawley) 80 to 100 days old at the start of the

experiments were used. Rats were tested for reinstatement following

pretreatment with MTEP, MPEP, and vehicle. All rats were housed

singly in cages equipped with a laminar flow unit and air filter in

a temperature- and humidity-controlled, AAALAC-accredited

animal care facility on a reversed 12 h light/dark cycle (lights on

at 18:00 h) with free access to water. Rats were also allowed free

access to food until their free-feeding body weights increased to

approximately 380-400 g. These rats were subsequently maintained

at 85 to 90% of their free-feeding body weights by supplemental

post-session feeding (Purina Rat Chow) throughout the course of

the experiments. All procedures were approved by the LSUHSC

Institutional Animal Care and Use Committee and were carried out

in accordance with the NIH “Principles of laboratory animal care”

(NIH publication No. 85-23).

Once the targeted weight was reached, rats (n ) 9) were injected

with sterile penicillin G procaine suspension (75,000 units, i.m.),

and immediately thereafter they were implanted with chronic

indwelling jugular catheters under pentobarbital anesthesia (50 mg/

kg, i.p.) with methylatropine nitrate pretreatment (10 mg/kg, i.p.)

using previously reported procedures.³³

Apparatus. Standard plastic and stainless steel operant condi-

tioning chambers contained within sound-attenuating enclosures

(Med-Associates, Inc.) were used to run the behavioral experiments.

Each experimental chamber was equipped with two response levers

(Med-Associates, Inc.) mounted on either side of the chamber with

a stimulus light located above each lever. A food pellet dispenser

was located between the two levers, and the lever on the right was

designated the “inactive” lever for the self-administration experi-

ments. The chambers were also equipped with a house light and

tone generator (Piezo, 66 decibels) to produce a compound stimulus

that was paired with each cocaine infusion. The enclosures

contained an exhaust fan that supplied ventilation and white noise

to mask extraneous sounds.

Self-Administration Training. Rats were trained to self-

administer cocaine by pressing one of the response levers under a

fixed-ratio 4 (FR4) schedule of reinforcement during daily 2 h

sessions conducted 5 days per week as previously described.^33c

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1091

chromatography and determined in duplicate by a liquid scintillation

counter (LKB, Uppsala, Sweden) as previously described.³⁶

Data were normalized to the maximal response induced by 1

mM glutamate for mGluR5. IC₅₀of the title compounds was

determined from the concentration-response curves using seven

concentrations in four to six separated experiments; values were

determined by fitting the normalized data to the logistic equation

by nonlinear regression using Sigma Plot (SPSS Science, Chicago,

IL).

mL, 20.0 mmol) and 2-chloropropionyl chloride (1.95 mL, 20.0

mmol) were combined in CH₂Cl₂(40 mL), and this solution was

added to the AlCl₃suspension dropwise from an addition funnel

over 40 min. The dark brownish-red solution was stirred at 0 °C

for 30 min, and the ice bath was removed. After 50 min at room

temperature, the reaction was cooled to 0 °C and quenched by slow

addition of 1.0 N HCl (50 mL). After the acidic solution was

extracted with diethyl ether (2 × 100 mL), the combined organic

layers were dried over MgSO₄and evaporated in vacuo to give

crude 4-chloro-1-trimethylsilyl-1-pentyn-3-one (2). This crude

compound 2 was dissolved in DMF (40 mL), and thioacetamide

(1.80 g, 24.0 mmol) was added in one portion. The mixture was

allowed to stir for 20 h at room temperature and then for 1.5 h at

85 °C. The mixture was diluted with EtOAc (250 mL), washed

with 0.1 N HCl (120 mL) and H₂O (2 × 120 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 20:1 to give 5 (1.80 g,

43%); ¹H NMR (CDCl₃) δ 0.26 (s, 9H), 2.49 (s, 3H), 2.63 (s, 3H).

5-Ethyl-2-methyl-4-(trimethylsilylethynyl)thiazole (6). Alu-

minum trichloride (AlCl₃) (4.00 g, 30.0 mmol) was suspended in

CH₂Cl₂(30 mL) and cooled in an ice bath. Bis(trimethylsilyl)-

acetylene (6.80 mL, 30 mmol) and 2-chlorobutyryl chloride (4.23

g, 30 mmol) were combined in CH₂Cl₂(60 mL), and this solution

was added to the AlCl₃suspension dropwise from an addition funnel

over 40 min. The dark brownish-red solution was stirred at 0 °C

for 30 min, and the ice bath was removed. After 50 min at room

temperature, the reaction was cooled to 0 °C and quenched by slow

addition of 1 N HCl (75 mL). After the acidic solution was extracted

with diethyl ether (2 × 150 mL), the combined organic layers were

dried over MgSO₄and evaporated in vacuo to give crude 4-chloro-

1-trimethylsilyl-1-hexyn-3-one (3). This crude compound 3 was

dissolved in DMF (60 mL), and thioacetamide (2.70 g, 36.0 mmol)

was added in one portion. The mixture was allowed to stir for 20

h at room temperature and then for 1.5 h at 85 °C. The mixture

was diluted with EtOAc (300 mL), washed with 0.1 N HCl (150

mL) and H₂O (2 × 150 mL), dried over MgSO₄, and evaporated

in vacuo. The residue was chromatographed on silica gel eluting

with hexanes-EtOAc 40:1 to give 6 (2.21 g, 33%); ¹H NMR

(CDCl₃) δ 0.26 (s, 9H), 1.29 (t, J ) 7.5 Hz, 3H), 2.64 (s, 3H),

2.90 (q, J ) 7.5 Hz, 2H).

Binding Assay for Cloned mGluR5. Radioligand binding assays

were performed essentially as previously detailed^6gwith the

following modifications: membranes from HEK293-T cells trans-

fected (FuGENE6 transfection Reagent, Roche.) with cloned

mGluR5 cDNA and rat brain membranes were used. The binding

assays were conducted in a total volume of 500 µL (50 mM Tris-

Cl, 0.9% NaCl, pH ) 7.4) using 3.0 nM [³H]-MPEP and various

concentrations of the unlabeled ligands in 96-well plates. The plates

were incubated at 20 °C for 90 min. The membranes were harvested

in polyethyleneimine-pretreated Whatman GF/C filters, dried,

incubated overnight with scintillation cocktail (Ecoscint A), and

counted in a scintillation counter. Nonspecific binding was deter-

mined using 10 µM MPEP, which was typically < 5% of total

binding. Data were analyzed using GraphPad Prizm V4.1.

General Chemistry Methods. All solvents and reagents were

used as obtained from commercial sources unless otherwise

indicated. All starting materials were also obtained from commercial

sources. All reactions were carried out under a positive pressure

of nitrogen. Glassware for water-sensitive reactions was dried in

an oven at 120 °C overnight. ¹H and ¹³C nuclear magnetic resonance

(NMR) spectra were recorded on an Avance 300 Bruker instrument

1

operating at 300 MHz for H and 75 MHz for ¹³C. Deuterated

chloroform (99.8% D) or methanol (99.8% D) was used as solvents.

Chemical shifts values (δ) are expressed in ppm downfield from

tetramethylsilane as internal standard, and coupling constants (J)

in Hertz. Exact masses were determined on a Micromass Q-TOF

time-of-flight mass spectrometer using positive mode electrospray

ionization. Anhydrous solvents were purchased from Aldrich

Chemical Co. Organic solutions were dried over anhydrous

magnesium sulfate (MgSO₄). Flash chromatography was performed

on silica gel Fluka Art. No. 60738. Analytical thin-layer chroma-

tography (TLC) was performed on Merck TLC glass plates

precoated with silica gel 60 F254 (detection by UV illumination at

254 nm and with iodine vapors). Analytical HPLC was performed

using a Shimadzu LC-10AD system, equipped with a SPD-10A

variable wavelength detector set at 254 nm. The HPLC data of

tested compounds including the chromatographic conditions can

be seen in the Supporting Information.

2-Methyl-4-(trimethylsilylethynyl)thiazole (4). Aluminum trichlo-

ride (AlCl₃) (9.31 g, 70.0 mmol) was suspended in CH₂Cl₂(70

mL) and cooled in an ice bath. Bis(trimethylsilyl)acetylene (15.7

mL, 70.0 mmol) and chloroacetyl chloride (5.6 mL, 70.0 mmol)

were combined in CH₂Cl₂(120 mL), and this solution was added

to the AlCl₃suspension dropwise from an addition funnel over 1

h. The dark brownish-red solution was stirred at 0 °C for 45 min,

and the ice bath was removed. After 50 min at room temperature,

the reaction was cooled to 0 °C and quenched by slow addition of

1.0 N HCl (175 mL). After the acidic solution was extracted with

diethyl ether (2 × 350 mL), the combined organic layers were dried

over MgSO₄and evaporated in vacuo to give crude 1-chloro-4-

trimethylsilyl-3-butyn-2-one (1). This crude compound 1 was

dissolved in DMF (120 mL), and thioacetamide (6.31 g, 84.0 mmol)

was added in one portion. The mixture was allowed to stir for 17

h at room temperature. The mixture was diluted with EtOAc (600

mL), washed with 0.1 N HCl (300 mL) and H₂O (2 × 300 mL),

dried over MgSO₄, and evaporated in vacuo. The residue was

chromatographed on silica gel eluting with hexanes-EtOAc 10:1

to give 4 (9.40 g, 69%); ¹H NMR (CDCl₃) δ 0.25 (s, 9H), 2.70 (s,

3H), 7.32 (s, 1H).

1-Phenyl-4-trimethylsilyl-3-butyn-2-one (7). Aluminum trichlo-

ride (AlCl₃) (6.67 g, 50.0 mmol) was suspended in CH₂Cl₂(50

mL) and cooled in an ice bath. Bis(trimethylsilyl)acetylene (11.3

mL, 50 mmol) and phenylacetyl chloride (6.62 mL, 50 mmol) were

combined in CH₂Cl₂(100 mL), and this solution was added to the

AlCl₃suspension dropwise from an addition funnel over 40 min.

The dark brownish-red solution was stirred at 0 °C for 30 min,

and the ice bath was removed. After 50 min at room temperature,

the reaction was cooled to 0 °C and quenched by slow addition of

1.0 N HCl (125 mL). After the acidic solution was extracted with

diethyl ether (2 × 250 mL), the combined organic layers were dried

over MgSO₄and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexane to give 7 (7.68 g, 71%);

¹H NMR (CDCl₃) δ 0.21 (s, 9H), 3.85 (s, 2H), 7.24-7.38 (m, 5H).

2-Methyl-5-phenyl-4-(trimethylsilylethynyl)thiazole (9). Com-

pound 7 (1.08 g, 5.0 mmol) was dissolved in CCl₄(30 mL) and

cooled in an ice bath. Bromine (0.26 mL, 5.0 mmol) was added to

the above solution dropwise over 10 min. The reaction mixture

was partitioned between CH₂Cl₂(50 mL) and saturated aqueous

NaHCO₃(40 mL). The organic layer was washed with H₂O (30

mL) and brine (30 mL), dried over MgSO₄, and evaporated in vacuo

to give crude 1-bromo-1-phenyl-4-trimethylsilyl-3-butyn-2-one (8).

This crude compound 8 was dissolved in DMF (10 mL), and

thioacetamide (451 mg, 6.0 mmol) was added in one portion. The

mixture was allowed to stir for 14 h at room temperature and then

for 1.5 h at 85 °C. The mixture was diluted with EtOAc (60 mL),

washed with 0.1 N HCl (30 mL) and H₂O (2 × 30 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 30:1 to give 9 (570 mg,

2,5-Dimethyl-4-(trimethylsilylethynyl)thiazole (5). Aluminum

trichloride (AlCl₃) (2.67 g, 20.0 mmol) was suspended in CH₂Cl₂

(20 mL) and cooled in an ice bath. Bis(trimethylsilyl)acetylene (4.48

1

42%); H NMR (CDCl₃) δ 0.27 (s, 9H), 2.70 (s, 3H), 7.34-7.45

(m, 3H), 7.86 (d, J ) 7.0 Hz, 2H).

1092 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

General Procedure for the Modified Sonogashira Coupling

Reaction Involving an in Situ Desilylation Reaction. Conditions

a. 2-Methyl-4-(trimethylsilylethynyl)thiazole (4) as a substrate and

the corresponding aryl or heteroaryl halide (1.1 equiv) were

combined in a flask containing deoxygenated DMF. To this mixture

were added Pd(PPh₃)₄(0.05 equiv), CuI (0.1 equiv), and triethyl-

amine (1.2 equiv). The mixture was warmed to 85 °C, and a solution

of Bu₄NF (1.0 M in THF) (1.1 equiv) was then added dropwise

over 15 min. TLC analysis demonstrated the reaction to be complete

after Bu₄NF addition. The reaction mixture was filtered through

Celite and partitioned between EtOAc and 0.1 N HCl. The organic

layer was washed twice with H₂O, dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with a hexanes-EtOAc solvent system to give the

corresponding product.

(positive mode) obsd mass (M + H)⁺, 284.0352; calcd mass

(C₁₃H₈F₃NOS + H)⁺, 284.0357.

3-[(2-Methyl-4-thiazolyl)ethynyl]benzonitrile (19). Hexanes-

1

EtOAc 5:1 for elution; yield 80%. H NMR (CDCl₃) δ 2.69 (s,

3H), 7.40 (s, 1H), 7.41 (t, J ) 7.9 Hz, 1H), 7.56 (d, J ) 7.7 Hz,

1H), 7.70 (d, J ) 7.8 Hz, 1H), 7.75 (s, 1H). ¹³C NMR (CDCl₃) δ

19.6, 86.2, 86.6, 113.3, 118.3, 124.0, 124.5, 129.8, 132.1, 135.3,

136.1, 136.4, 166.5. MS (ESI) m/z 225.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 225.0491; calcd mass

(C₁₃H₈N₂S + H)⁺, 225.0486.

N-[3-[(2-Methyl-4-thiazolyl)ethynyl]phenyl]acetamide (20).

The starting material, N-(3-iodophenyl)acetamide, was obtained

quantitatively by reaction of 3-iodoaniline with acetyl chloride in

the presence of triethylamine. Compound 20: hexanes-EtOAc 1:2

1

for elution; yield 78%. H NMR (CDCl₃) δ 2.15 (s, 3H), 2.72 (s,

3H), 7.22 (br s, 2H), 7.36 (s, 1H), 7.54 (br s, 1H), 7.69 (br s, 1H),

8.33 (br s, 1H). ¹³C NMR (CDCl₃) δ 19.6, 24.9, 83.8, 89.0, 120.9,

122.9, 123.3, 123.3, 127.8, 129.4, 137.1, 138.7, 166.2, 169.4. MS

(ESI) m/z 257.3 (M + H)⁺. HRMS (positive mode) obsd mass (M

+ H)⁺, 257.0751; calcd mass (C₁₄H₁₂N₂OS + H)⁺, 257.0749.

4-(3,5-Difluorophenylethynyl)-2-methylthiazole (21). Hexanes-

4-(3-Methoxyphenylethynyl)-2-methylthiazole (12). Hexanes-

1

EtOAc 7:1 for elution; yield 78%. H NMR (CDCl₃) δ 2.76 (s,

3H), 3.83 (s, 3H), 6.93 (d, J ) 7.9 Hz, 1H), 7.11 (s, 1H), 7.17 (d,

J ) 7.6 Hz, 1H), 7.27 (t, J ) 7.9 Hz, 1H), 7.39 (s, 1H). ¹³C NMR

(CDCl₃) δ 19.5, 55.6, 83.7, 89.1, 115.7, 116.8, 122.8, 123.8, 124.6,

129.8, 137.2, 159.7, 166.0. MS (ESI) m/z 230.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 230.0639; calcd mass

(C₁₃H₁₁NOS + H)⁺, 230.0640.

1

EtOAc 7:1 for elution; yield 73%. H NMR (CDCl₃) δ 2.74 (s,

3H), 6.81 (tt, J₁) 8.9 Hz, J₂) 1.9 Hz, 1H), 7.05 (d, J ) 6.0 Hz,

2H), 7.42 (s, 1H). ¹³C NMR (CDCl₃) δ 19.6, 85.7, 86.8 (t, ⁴J_CF

)

4-(2-Fluorophenylethynyl)-2-methylthiazole (13). Hexanes-

1

4.0 Hz), 105.2 (t, ²J_CF) 25.4 Hz), 115.0 (dd, ²J_CF) 17.8 Hz, ⁴J_CF

EtOAc 7:1 for elution; yield 71%. H NMR (CDCl₃) δ 2.76 (s,

) 8.7 Hz), 123.8, 125.6 (t, ³J_CF) 11.8 Hz), 136.5, 163.1 (dd, ¹J_CF

3H), 7.12 (t, J ) 8.6 Hz, 1H), 7.15 (t, J ) 6.9 Hz, 1H), 7.29-7.39

3

) 249.2 Hz, J_CF) 13.4 Hz), 166.4. MS (ESI) m/z 236.2 (M +

(m, 1H), 7.44 (s, 1H), 7.56 (t, J ) 6.6 Hz, 1H). ¹³C NMR (CDCl₃)

2

H)⁺. HRMS (positive mode) obsd mass (M + Na)⁺, 258.0169; calcd

δ 19.7, 82.6, 88.7, 111.6 (d, J_CF) 15.6 Hz), 116.0 (d, J_CF

)

4

3

mass (C₁₂H₇F₂NS + Na)⁺, 258.0165.

20.7 Hz), 123.3, 124.4 (d, J_CF) 3.7 Hz), 130.8 (d, J_CF) 7.9

Hz), 132.5 (m), 134.0, 163.2 (d, ¹J_CF) 252.6 Hz), 166.2. MS (ESI)

m/z 218.4 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 218.0436; calcd mass (C₁₂H₈FNS + H)⁺, 218.0440.

3-[(2-Methyl-4-thiazolyl)ethynyl]pyridine (MTEP) (22). Hex-

anes-EtOAc 1:2 for elution; yield 52%. ¹H NMR (CDCl₃) δ 2.76

(s, 3H), 7.30 (dd, J₁) 7.4 Hz, J₂) 3.7 Hz, 1H), 7.45 (s, 1H), 7.85

(d, J ) 7.6 Hz, 1H), 8.58 (d, J ) 3.8 Hz, 1H), 8.80 (s, 1H). ¹³C

NMR (CDCl₃) δ 19.7, 85.8, 87.0, 120.2, 123.5, 123.5, 136.7, 139.0,

149.3, 152.8, 166.4. MS (ESI) m/z 201.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 201.0478; calcd mass

(C₁₁H₈N₂S + H)⁺, 201.0486.

3-[(2-Methyl-5-phenyl-4-thiazolyl)ethynyl]pyridine (25). Hex-

anes-EtOAc 2:3 for elution; yield 52%. ¹H NMR (CDCl₃) δ 2.76

(s, 3H), 7.28-7.33 (m, 1H), 7.38-7.51 (m, 3H), 7.79-7.87 (m,

3H), 8.57 (d, J ) 4.0 Hz, 1H), 8.77 (s, 1H). ¹³C NMR (CDCl₃) δ

19.8, 88.1, 88.2, 120.4, 120.4, 123.5, 128.6, 128.6, 129.2, 129.2,

129.3, 131.3, 138.8, 142.4, 149.2, 152.7, 164.4. MS (ESI) m/z 277.3

(M + H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 277.0800;

calcd mass (C₁₇H₁₂N₂S + H)⁺, 277.0799.

4-(2-Methoxyphenylethynyl)-2-methylthiazole (14). Hexanes-

1

EtOAc 5:1 for elution; yield 67%. H NMR (CDCl₃) δ 2.74 (s,

3H), 3.90 (s, 3H), 6.91 (t, J ) 8.0 Hz, 1H), 6.93 (t, J ) 7.5 Hz,

1H), 7.32 (t, J ) 7.7 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J ) 7.3 Hz,

1H). ¹³C NMR (CDCl₃) δ 19.7, 56.2, 85.7, 87.7, 111.0, 112.1, 120.8,

122.4, 130.5, 134.1, 137.6, 160.6, 165.8. MS (ESI) m/z 230.3 (M

+ H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 230.0639;

calcd mass (C₁₃H₁₁NOS + H)⁺, 230.0640.

2-Methyl-4-(m-tolylethynyl)thiazole (15). Hexanes-EtOAc 8:1

1

for elution; yield 72%. H NMR (CDCl₃) δ 2.36 (s, 3H), 2.76 (s,

3H), 7.15-7.29 (m, 2H), 7.37 (s, 1H), 7.40 (br s, 2H). ¹³C NMR

(CDCl₃) δ 19.7, 21.6, 83.5, 89.4, 122.4, 122.7, 128.7, 129.2, 130.0,

132.7, 137.4, 138.4, 166.0. MS (ESI) m/z 214.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 214.0697; calcd mass

(C₁₃H₁₁NS + H)⁺, 214.0690.

2-Methoxy-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (26). Hex-

anes-EtOAc 3:1 for elution; yield 68%. ¹H NMR (CDCl₃) δ 2.75

(s, 3H), 3.96 (s, 3H), 6.73 (d, J ) 8.6 Hz, 1H), 7.37 (s, 1H), 7.71

4-(3-Chlorophenylethynyl)-2-methylthiazole (16). Hexanes-

(dd, J₁) 8.6 Hz, J₂) 2.1 Hz, 1H), 8.38 (d, J ) 1.5 Hz, 1H). ¹³

C

1

EtOAc 7:1 for elution; yield 82%. H NMR (CDCl₃) δ 2.74 (s,

NMR (CDCl₃) δ 19.6, 54.1, 85.2, 86.1, 111.2, 112.7, 122.5, 137.1,

141.6, 150.7, 164.0, 166.1. MS (ESI) m/z 231.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 231.0595; calcd mass

(C₁₂H₁₀N₂OS + H)⁺, 231.0592.

3H), 7.28 (d, J ) 7.5 Hz, 1H), 7.31 (t, J ) 7.8 Hz, 1H), 7.39 (s,

1H), 7.43 (d, J ) 7.2 Hz, 1H), 7.54 (s, 1H). ¹³C NMR (CDCl₃) δ

19.7, 85.0, 87.7, 123.2, 124.6, 129.3, 130.0, 130.2, 131.9, 134.6,

136.9, 166.3. MS (ESI) m/z 234.1 (M + H)⁺. HRMS (positive

mode) obsd mass (M + H)⁺, 234.0136; calcd mass (C₁₂H₈ClNS +

H)⁺, 234.0144.

5-Fluoro-2-[(2-methyl-4-thiazolyl)ethynyl]pyridine (27). Hex-

anes-EtOAc 2:1 for elution; yield 66%. ¹H NMR (CDCl₃) δ 2.76

(s, 3H), 7.42 (td, J₁) 8.3 Hz, J₂) 2.7 Hz, 1H), 7.52 (s, 1H), 7.59

(dd, J₁) 8.6 Hz, J₂) 4.4 Hz, 1H), 8.49 (d, J ) 2.5 Hz, 1H). ¹³

C

2-Methyl-4-[[3-(trifluoromethyl)phenyl]ethynyl]thiazole (17).

1

NMR (CDCl₃) δ 19.6, 83.3, 87.3, 123.6 (d, ²J_CF) 19.0 Hz), 124.5,

Hexanes-EtOAc 7:1 for elution; yield 79%. H NMR (CDCl₃) δ

3

2

2.75 (s, 3H), 7.42 (s, 1H), 7.48 (t, J ) 7.8 Hz, 1H), 7.60 (d, J )

128.7 (d, J_CF) 4.8 Hz), 136.3, 139.1 (t, J_CF) 24.5 Hz), 139.4,

159.1 (d, ¹J_CF) 260.1 Hz), 166.3. MS (ESI) m/z 219.2 (M + H)⁺.

HRMS (positive mode) obsd mass (M + Na)⁺, 241.0206; calcd

mass (C₁₁H₇FN₂S + Na)⁺, 241.0212.

7.6 Hz, 1H), 7.72 (d, J ) 7.5 Hz, 1H), 7.83 (s, 1H). ¹³C NMR

1

(CDCl₃) δ 19.6, 85.3, 87.6, 123.4, 123.9, 124.1 (q, J_CF) 272.4

3

Hz) 125.5 (q, J_CF) 3.6 Hz), 128.9 (q, J_CF) 3.9 Hz), 129.3,

131.4 (q, ²J_CF) 32.8 Hz), 135.1, 136.7, 166.4. MS (ESI) m/z 268.4

(M + H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 268.0404;

calcd mass (C₁₃H₈F₃NS + H)⁺, 268.0408.

3-Bromo-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (28). Hex-

anes-EtOAc 4:1 for elution; yield 76%. ¹H NMR (CDCl₃) δ 2.77

(s, 3H), 7.47 (s, 1H), 7.99 (br t, J ) 1.7 Hz, 1H), 8.64 (d, J ) 1.8

Hz, 1H), 8.70 (s, 1H). ¹³C NMR (CDCl₃) δ 19.6, 84.3, 88.4, 120.5,

121.5, 124.2, 136.2, 141.1, 150.4, 150.6, 166.5. MS (ESI) m/z 279.3

(M + H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 278.9593;

calcd mass (C₁₁H₇BrN₂S + H)⁺, 278.9592.

2-Methyl-4-[[3-(trifluoromethoxy)phenyl]ethynyl]thiazole (18).

1

Hexanes-EtOAc 7:1 for elution; yield 29%. H NMR (CDCl₃) δ

2.77 (s, 3H), 7.22 (d, J ) 8.0 Hz, 1H), 7.39 (t, J ) 7.7 Hz, 1H),

7.43 (br s, 2H), 7.50 (d, J ) 7.5 Hz, 1H). ¹³C NMR (CDCl₃) δ

19.7, 85.1, 87.6, 119.1, 121.8, 123.4, 124.4, 124.8, 130.3, 130.5,

136.8, 149.4, 166.4. MS (ESI) m/z 284.2 (M + H)⁺. HRMS

2-Fluoro-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (29). Hex-

1

anes-EtOAc 3:1 for elution; yield 41% H NMR (CDCl₃) δ 2.77

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1093

(s, 3H), 6.96 (dd, J₁) 8.4 Hz, J₂) 2.7 Hz, 1H), 7.44 (s, 1H), 7.94

(td, J_t) 8.0 Hz, J_d) 2.1 Hz, 1H), 8.44 (s, 1H). ¹³C NMR (CDCl₃)

δ 19.7, 84.5, 86.9, 109.9 (d, ²J_CF) 38.1 Hz), 118.0 (d, ⁴J_CF) 4.8

Hz), 123.6, 136.5, 144.1 (d, ³J_CF) 8.3 Hz), 151.2 (d, ³J_CF) 15.5

Hz), 163.2 (d, ¹J_CF) 243.0 Hz), 166.5. MS (ESI) m/z 219.2 (M +

H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 219.0387; calcd

mass (C₁₁H₇FN₂S + H)⁺, 219.0392.

gel eluting with a hexanes-EtOAc solvent system to give the

corresponding product.

4-(3-Fluorophenylethynyl)-2-methylthiazole (10). Hexanes-

1

EtOAc 8:1 for elution; yield 62%. H NMR (CDCl₃) δ 2.76 (s,

3H), 7.04-7.12 (m, 1H), 7.24-7.38 (m, 3H), 7.42 (s, 1H). ¹³C

NMR (CDCl₃) δ 19.6, 84.7, 87.9, 116.4 (d, ²J_CF) 21.1 Hz), 118.9

(d, ²J_CF) 23.0 Hz), 123.2, 124.7 (d, ³J_CF) 9.4 Hz), 128.0 (d, ⁴J_CF

) 3.0 Hz), 130.4 (d, ³J_CF) 8.7 Hz), 136.9, 162.7 (d, ¹J_CF) 246.7

Hz), 166.3. MS (ESI) m/z 218.2 (M + H)⁺. HRMS (positive mode)

obsd mass (M + H)⁺, 218.0442; calcd mass (C₁₂H₈FNS + H)⁺,

218.0440.

5-[(2-Methyl-4-thiazolyl)ethynyl]pyrimidine (30). Hexanes-

1

EtOAc 1:1 for elution; yield 51%. H NMR (CDCl₃) δ 2.78 (s,

3H), 7.51 (s, 1H), 8.90 (s, 2H), 9.18 (s, 1H). ¹³C NMR (CDCl₃) δ

19.7, 82.2, 90.7, 119.7, 124.5, 136.0, 157.3, 159.1, 159.1, 166.7.

MS (ESI) m/z 202.3 (M + H)⁺. HRMS (positive mode) obsd mass

(M + H)⁺, 202.0432; calcd mass (C₁₀H₇N₃S + H)⁺, 202.0439.

4-(4-Fluorophenylethynyl)-2-methylthiazole (11). Hexanes-

1

EtOAc 8:1 for elution; yield 68%. H NMR (CDCl₃) δ 2.76 (s,

3H), 7.06 (t, J ) 8.6 Hz, 2H), 7.38 (s, 1H), 7.55 (td, J₁) 7.0 Hz,

2-[(2-Methyl-4-thiazolyl)ethynyl]pyrazine (31). Hexanes-

J₂) 3.1 Hz, 2H). ¹³C NMR (CDCl₃) δ 19.6, 83.5, 88.1, 116.1 (d,

1

EtOAc 1:1 for elution; yield 61%. H NMR (CDCl₃) δ 2.74 (s,

²J_CF) 22.2 Hz), 119.0 (d, ⁴J_CF) 3.5 Hz), 122.6, 134.1 (d, ³J_CF

)

3H), 7.55 (s, 1H), 8.49 (s, 1H), 8.57 (s, 1H), 8.77 (s, 1H). ¹³C NMR

(CDCl₃) δ 19.7, 85.5, 87.4, 125.6, 135.9, 140.2, 143.5, 144.9, 148.2,

166.6. MS (ESI) m/z 202.3 (M + H)⁺. HRMS (positive mode) obsd

mass (M + H)⁺, 202.0438; calcd mass (C₁₀H₇N₃S + H)⁺, 202.0439.

1

8.4 Hz), 137.2, 163.1 (d, J_CF) 250.2 Hz), 166.2. MS (ESI) m/z

218.2 (M + H)⁺. HRMS (positive mode) obsd mass (M + Na)⁺,

240.0258; calcd mass (C₁₂H₈FNS + Na)⁺, 240.0259.

3-[(2,5-Dimethyl-4-thiazolyl)ethynyl]pyridine (23). Hexanes-

2-Methyl-4-(2-thienylethynyl)thiazole (32). Hexanes-EtOAc

5:1 for elution; yield 28%. ¹H NMR (CDCl₃) δ 2.76 (s, 3H), 7.03

(dd, J₁) 5.0 Hz, J₂) 3.8 Hz, 1H), 7.33 (d, J ) 5.0 Hz, 1H), 7.34

(d, J ) 3.3 Hz, 1H), 7.39 (s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 82.4,

86.3, 122.6, 127.5, 128.2, 133.1, 137.3, 147.0, 167.0. MS (ESI)

m/z 206.2 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 206.0105; calcd mass (C₁₀H₇NS₂+ H)⁺, 206.0098.

2-Methyl-4-(3-thienylethynyl)thiazole (33). Hexanes-EtOAc

5:1 for elution; yield 80%. ¹H NMR (CDCl₃) δ 2.72 (s, 3H), 7.21

(d, J ) 4.5 Hz, 1H), 7.29 (d, J ) 4.5 Hz, 1H), 7.33 (s, 1H), 7.56

(s, 1H). ¹³C NMR (CDCl₃) δ 19.6, 83.4, 84.5, 121.9, 122.3, 125.8,

129.9, 130.3, 137.3, 166.1. MS (ESI) m/z 206.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + Na)⁺, 227.9914; calcd mass

(C₁₀H₇NS₂+ Na)⁺, 227.9918.

1

EtOAc 3:2 for elution; yield 55%. H NMR (CDCl₃) δ 2.57 (s,

3H), 2.68 (s, 3H), 7.30 (dd, J₁) 8.0 Hz, J₂) 5.1 Hz, 1H), 7.84

(d, J ) 7.9 Hz, 1H), 8.57 (d, J ) 4.1 Hz, 1H), 8.80 (s, 1H). ¹³C

NMR (CDCl₃) δ 12.8, 19.7, 86.5, 88.4, 120.5, 123.4, 134.1, 138.7,

138.8, 149.1, 152.6, 163.4. MS (ESI) m/z 215.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 215.0638; calcd mass

(C₁₂H₁₀N₂S + H)⁺, 215.0643.

3-[(5-Ethyl-2-methyl-4-thiazolyl)ethynyl]pyridine (24). Hex-

anes-EtOAc 3:2 for elution; yield 51%. ¹H NMR (CDCl₃) δ 1.35

(t, J ) 7.5 Hz, 3H), 2.69 (s, 3H), 2.99 (q, J ) 7.5 Hz, 2H), 7.30

(dd, J₁) 7.9 Hz, J₂) 4.0 Hz, 1H), 7.84 (d, J ) 7.8 Hz, 1H), 8.58

(d, J ) 4.0 Hz, 1H), 8.79 (s, 1H). ¹³C NMR (CDCl₃) δ 16.4, 19.7,

21.3, 86.5, 88.3, 120.6, 123.5, 132.7, 138.8, 146.5, 149.1, 152.6,

163.3. MS (ESI) m/z 229.2 (M + H)⁺. HRMS (positive mode) obsd

mass (M + H)⁺, 229.0797; calcd mass (C₁₃H₁₂N₂S + H)⁺,

229.0799.

3-[(2-Methyl-4-thiazolyl)ethynyl]quinoline (34). Hexanes-

1

EtOAc 2:1 for elution; yield 52%. H NMR (CDCl₃) δ 2.76 (s,

3H), 7.46 (s, 1H), 7.57 (t, J ) 7.4 Hz, 1H), 7.73 (t, J ) 7.7 Hz,

1H), 7.78 (t, J ) 7.4 Hz, 1H), 8.09 (d, J ) 8.4 Hz, 1H), 8.33 (s,

1H), 9.02 (d, J ) 1.9 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 86.5,

87.0, 117.1, 123.5, 127.5, 127.8, 128.1, 129.8, 130.7, 136.8, 139.1,

147.4, 152.4, 166.4. MS (ESI) m/z 251.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 251.0640; calcd mass

(C₁₅H₁₀N₂S + H)⁺, 251.0643.

3-[(2-Methyl-4-thiazolyl)ethynyl]phenol (37). Compound 12

(122 mg, 0.53 mmol) was dissolved in CH₂Cl₂(5 mL) and cooled

in an ice bath. A solution of BBr₃(1.0 M in CH₂Cl₂) (0.64 mL,

0.64 mmol) was added dropwise. The reaction mixture was allowed

to stir for 4 h at room temperature and partitioned between EtOAc

(20 mL) and saturated aqueous NaHCO₃(10 mL). The organic layer

was washed with H₂O (2 × 10 mL), dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with hexanes-EtOAc 3:1 to give 37 (34.4 mg, 30%);

¹H NMR (CDCl₃) δ 2.77 (s, 3H), 6.89 (d, J ) 7.8 Hz, 1H), 7.08

(d, J ) 7.5 Hz, 1H), 7.21 (t, J ) 7.7 Hz, 1H), 7.21 (s, 1H), 7.37

(d, J ) 8.1 Hz, 1H), 7.38 (s, 1H). ¹³C NMR (CDCl₃) δ 19.4, 82.9,

89.9, 117.2, 119.0, 122.7, 123.5, 124.4, 130.0, 137.0, 156.6, 166.9.

MS (ESI) m/z 216.2 (M + H)⁺. HRMS (positive mode) obsd mass

(M + H)⁺, 216.0484; calcd mass (C₁₂H₉NOS + H)⁺, 216.0483.

3-[(2-Methyl-4-thiazolyl)ethynyl]benzamide (38). To a solution

of 19 (38.5 mg, 0.17 mmol) in ethanol (7 mL) were added a solution

of H₂O₂(35% in H₂O) (42 µL, 0.51 mmol) and 6.0 N aqueous

NaOH (34 µL, 0.20 mmol), and the reaction mixture was allowed

to stir for 40 min at 60 °C. After the mixture was partitioned

between EtOAc (50 mL) and 0.1 N HCl (25 mL), the organic layer

was washed with H₂O (25 mL), dried over MgSO₄, and evaporated

in vacuo. The residue was chromatographed on silica gel eluting

6-[(2-Methyl-4-thiazolyl)ethynyl]quinoxaline (35). Hexanes-

1

EtOAc 2:3 for elution; yield 38%. H NMR (CDCl₃) δ 2.79 (s,

3H), 7.51 (s, 1H), 7.91 (dd, J₁) 8.7 Hz, J₂) 1.7 Hz, 1H), 8.10

(d, J ) 8.7 Hz, 1H), 8.32 (d, J ) 1.4 Hz, 1H), 8.85 (d, J ) 1.6 Hz,

1H), 8.89 (d, J ) 1.6 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 86.7,

88.2, 123.8, 125.0, 130.1, 133.1, 133.2, 136.8, 143.2, 143.3, 145.7,

146.2, 166.5. MS (ESI) m/z 252.2 (M + H)⁺. HRMS (positive

mode) obsd mass (M + H)⁺, 252.0600; calcd mass (C₁₄H₉N₃S +

H)⁺, 252.0595.

5-[(2-Methyl-4-thiazolyl)ethynyl]-1H-indole (36). Hexanes-

1

EtOAc 3:1 for elution; yield 35%. H NMR (CDCl₃) δ 2.76 (s,

3H), 6.58 (s, 1H), 7.31-7.49 (m, 3H), 7.35 (s, 1H), 7.91 (s, 1H),

8.24 (br s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 81.5, 83.6, 103.5, 112.0,

114.8, 121.5, 125.4, 125.4, 126.2, 128.1, 136.6, 142.1, 165.1. MS

(ESI) m/z 239.3 (M + H)⁺. HRMS (positive mode) obsd mass (M

+ H)⁺, 239.0646; calcd mass (C₁₄H₁₀N₂S + H)⁺, 239.0643.

1

with EtOAc to give 38 (35 mg, 85%); H NMR (CD₃OD) δ 2.74

Conditions b. 2-Methyl-5-substituted-4-(trimethylsilylethynyl)-

thiazole (4, 5, or 6) as a substrate and the corresponding aryl or

heteroaryl halide (1.1 equiv) were combined in a flask containing

deoxygenated DMF. To this mixture were added (PPh₃)₂PdCl₂(0.1

equiv), PPh₃(0.1 equiv), CuI (0.1 equiv), Bu₄NI (1.1 equiv), and

triethylamine (1.2 equiv). The mixture was warmed to 85 °C, and

a solution of Bu₄NF (1.0 M in THF) (1.1 equiv) was then added

dropwise over 15 min. TLC analysis demonstrated the reaction to

be complete after Bu₄NF addition. The reaction mixture was filtered

through Celite and partitioned between EtOAc and 0.1 N HCl. The

organic layer was washed twice with H₂O, dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

(s, 3H), 7.52 (t, J ) 7.7 Hz, 1H), 7.71 (s, 1H), 7.72 (d, J ) 7.8 Hz,

1H), 7.91 (t, J ) 7.7 Hz, 1H), 8.07 (s, 1H). ¹³C NMR (CD₃OD) δ

17.7, 83.7, 87.8, 123.1, 123.7, 123.7, 128.0, 129.0, 130.8, 134.6,

136.3, 167.6, 170.2. MS (ESI) m/z 243.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 243.0600; calcd mass

(C₁₃H₁₀N₂OS + H)⁺, 243.0592.

4-(Trimethylsilylethynyl)-2-thiazolylamine (39). AlCl₃(5.2 g,

39.0 mmol) was suspended in CH₂Cl₂(40 mL) and cooled in an

ice bath. Bis(trimethylsilyl)acetylene (8.8 mL, 39.0 mmol) and

chloroacetyl chloride (3.1 mL, 39.0 mmol) were combined in CH₂-

Cl₂(80 mL), and this solution was added to the above AlCl₃

1094 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

suspension dropwise from an addition funnel over 50 min. The dark

brownish-red solution was stirred at 0 °C for 30 min, and the ice

bath was removed. After 50 min at room temperature, the reaction

was cooled to 0 °C and quenched by slow addition of 1.0 N HCl

(100 mL). After the acidic solution was extracted with diethyl ether

(2 × 200 mL), the combined organic layers were dried over MgSO₄

and evaporated in vacuo to give crude 1-chloro-4-trimethylsilyl-

3-butyn-2-one (1). This crude compound 1 was dissolved in DMF

(80 mL), and thiourea (3.56 g, 46.8 mmol) was added in one portion.

The mixture was allowed to stir for 20 h at room temperature,

diluted with EtOAc (300 mL), washed with 0.1 N HCl (170 mL)

and H₂O (2 × 170 mL), dried over MgSO₄, and evaporated in

vacuo. The residue was chromatographed on silica gel eluting with

1-(2,4-Difluorophenyl)-3-[4-(3-pyridylethynyl)-2-thiazolyl]-

urea (44). To a solution of 41 (20.1 mg, 0.10 mmol) in THF (5

mL) were added 2,4-difluorophenyl isocyanate (16 µL, 0.13 mmol)

and 4-(dimethylamino)pyridine (1.2 mg, 10 µmol), and the reaction

mixture was allowed to stir for 16 h at room temperature. After

the mixture was partitioned between EtOAc (30 mL) and 0.1 N

HCl (15 mL), the organic layer was washed with saturated aqueous

NaHCO₃(15 mL) and H₂O (15 mL), dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with hexanes-EtOAc 1:1 to give 44 (26.3 mg, 72%);

¹H NMR (CD₃OD) δ 6.86 (t, J ) 8.5 Hz, 2H), 7.16 (s, 1H), 7.32

(dd, J₁) 7.5 Hz, J₂) 3.8 Hz, 1H), 7.83 (d, J ) 7.5 Hz, 1H),

8.04-8.15 (m, 1H), 8.52 (d, J ) 3.8 Hz, 1H), 8.70 (s, 1H). ¹³C

NMR (CD₃OD) δ 86.1, 89.9, 105.4 (t, ²J_CF) 25.2 Hz), 114.5 (dd,

²J_CF) 18.3 Hz, ⁴J_CF) 7.7 Hz), 119.1, 120.9 (dd, ²J_CF) 18.1 Hz,

1

hexanes-EtOAc 3:1 to give 39 (4.13 g, 54%); H NMR (CDCl₃)

δ 0.25 (s, 9H), 4.92 (br s, 2H), 6.77 (s, 1H).

3

⁴J_CF) 8.1 Hz), 123.0, 123.8 (t, J_CF) 12.9 Hz), 124.6, 133.3,

4-(3-Fluorophenylethynyl)-2-thiazolylamine (40) and 4-(3-

Pyridylethynyl)-2-thiazolylamine (41). Compounds 40 and 41

were obtained by the reaction of 39 with 1-fluoro-3-iodobenzene

or 3-iodopyridine, respectively, using the above “condition a” in

the General Procedure for the Modified Sonogashira Coupling

Reaction. The reaction mixture was partitioned between EtOAc and

H₂O instead of 0.1 N HCl at the final work up in the synthesis of

41.

139.0, 149.2, 152.7, 155.6 (dd, ¹J_CF) 248.5 Hz, ³J_CF) 13.1 Hz),

1

3

158.0, 159.3 (dd, J_CF) 251.2 Hz, J_CF) 12.9 Hz), 166.6. MS

(ESI) m/z 357.2 (M + H)⁺. HRMS (positive mode) obsd mass (M

+ H)⁺, 357.0623; calcd mass (C₁₇H₁₀F₂N₄OS + H)⁺, 357.0622.

[4-(3-Pyridylethynyl)-2-thiazolyl]carbamic Acid Methyl Ester

(45). To a solution of 41 (12.0 mg, 60 µmol) in CH₂Cl₂(5 mL)

were added methyl chloroformate (6 µL, 72 µmol) and triethylamine

(13 µL, 90 µmol), and the reaction mixture was allowed to stir for

10 min at room temperature. After the mixture was partitioned

between EtOAc (20 mL) and 0.1 N HCl (10 mL), the organic layer

was washed with saturated aqueous NaHCO₃(10 mL) and H₂O

(10 mL), dried over MgSO₄, and evaporated in vacuo. The residue

was chromatographed on silica gel eluting with hexanes-EtOAc

Compound 40. Hexanes-EtOAc 2:1 for elution; yield 72%. ¹H

NMR (CDCl₃) δ 5.03 (br s, 2H), 6.84 (s, 1H), 7.04-7.11 (m, 1H),

7.21-7.34 (m, 3H). ¹³C NMR (CDCl₃) δ 85.1, 87.2 (d, ⁴J_CF) 3.5

2

Hz), 114.1, 116.3 (d, J_CF) 21.2 Hz), 118.8 (d, J_CF) 22.9 Hz),

3

4

3

124.8 (d, J_CF) 9.6 Hz), 128.0 (d, J_CF) 2.9 Hz), 130.4 (d, J_CF

) 8.7 Hz), 133.0, 162.7 (d, J_CF) 246.7 Hz), 167.3. MS (ESI)

1

m/z 219.2 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 219.0397; calcd mass (C₁₁H₇FN₂S + H)⁺, 219.0392.

Compound 41. Hexanes-EtOAc 1:2 for elution; yield 60%. ¹H

NMR (CDCl₃) δ 5.00 (br s, 2H), 6.88 (s, 1H), 7.30 (dd, J₁) 8.0

Hz, J₂) 3.8 Hz, 1H), 7.82 (d, J ) 7.9 Hz, 1H), 8.57 (d, J ) 3.8

Hz, 1H), 8.78 (s, 1H). ¹³C NMR (CDCl₃) δ 85.1, 87.5, 114.6, 120.3,

123.4, 132.9, 138.9, 149.2, 152.7, 167.1. MS (ESI) m/z 202.3 (M

+ H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 202.0440;

calcd mass (C₁₀H₇N₃S + H)⁺, 202.0439.

1:1 to give 45 (12.8 mg, 82%); H NMR (CDCl₃) δ 3.90 (s, 3H),

7.24 (s, 1H), 7.31 (dd, J₁) 7.8 Hz, J₂) 3.8 Hz, 1H), 7.85 (d, J

) 7.7 Hz, 1H), 8.59 (d, J ) 3.9 Hz, 1H), 8.73 (br s, 1H), 8.84 (s,

1H). ¹³C NMR (CDCl₃) δ 53.9, 86.7, 87.9, 118.7, 123.7, 130.0,

132.2, 139.0, 149.0, 153.0, 159.7, 165.0. MS (ESI) m/z 260.2 (M

+ H)⁺. HRMS (positive mode) obsd mass (M + Na)⁺, 282.0316;

calcd mass (C₁₂H₉N₃O₂S + Na)⁺, 282.0313.

2-Bromo-4-(3-fluorophenylethynyl)thiazole (46). To a solution

of 40 (310 mg, 1.42 mmol) in acetonitrile (20 mL) were added

tert-butyl nitrite (0.21 mL, 1.56 mmol) and copper(II) bromide (349

mg, 1.56 mmol), and the reaction mixture was allowed to stir for

15 min at 85 °C. After the mixture was concentrated under reduced

pressure, the concentrate was partitioned between diethyl ether (30

mL) and H₂O (15 mL). After the mixture was filtered through

Celite, the organic layer was washed with brine (15 mL), dried

over MgSO₄, and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 20:1 to give 46

N-[4-(3-Pyridylethynyl)-2-thiazolyl]acetamide (42). To a solu-

tion of 41 (20.1 mg, 0.10 mmol) in CH₂Cl₂(5 mL) were added

under ice cooling acetyl chloride (8 µL, 0.11 mmol) and triethyl-

amine (17 µL, 0.12 mmol), and the reaction mixture was allowed

to stir for 10 min at the same temperature. After the mixture was

partitioned between EtOAc (20 mL) and saturated aqueous NaHCO₃

(10 mL), the organic layer was washed with H₂O (10 mL), dried

over MgSO₄, and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 1:2 to give 42

1

(343 mg, 86%); H NMR (CDCl₃) δ 7.08-7.16 (m, 2H), 7.27-

7.39 (m, 3H). ¹³C NMR (CDCl₃) δ 82.2, 93.2, 115.1, 117.1 (d,

1

(21.7 mg, 89%); H NMR (CDCl₃) δ 2.35 (s, 3H), 7.30 (s, 1H),

2

3

²J_CF) 21.3 Hz), 119.1 (d, J_CF) 23.2 Hz), 123.2 (d, J_CF) 9.1

7.32 (dd, J₁) 7.8 Hz, J₂) 3.8 Hz, 1H), 7.84 (d, J ) 7.8 Hz, 1H),

8.60 (d, J ) 4.1 Hz, 1H), 8.84 (s, 1H), 10.15 (br s, 1H). ¹³C NMR

(CDCl₃) δ 23.7, 82.2, 85.5, 119.4, 123.6, 129.3, 131.4, 139.0, 149.3,

152.7, 160.0, 168.8. MS (ESI) m/z 244.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 244.0539; calcd mass

(C₁₂H₉N₃OS + H)⁺, 244.0545.

3

4

Hz), 128.3, 130.9 (d, J_CF) 8.5 Hz), 136.8 (d, J_CF) 2.8 Hz),

138.5, 162.9 (d, ¹J_CF) 246.1 Hz). MS (ESI) m/z 282.2 (M + H)⁺.

HRMS (positive mode) obsd mass (M + H)⁺, 281.9389; calcd mass

(C₁₁H₅BrFNS + H)⁺, 281.9388.

2-(3,5-Difluorophenyl)-4-(3-fluorophenylethynyl)thiazole (47).

Compound 46 (64 mg, 0.23 mmol) and 3,5-difluorophenylboronic

acid (40 mg, 0.25 mmol) were combined in a flask containing

deoxygenated ethylene glycol dimethyl ether (DME) (10 mL). To

this mixture were added Pd(PPh₃)₄(13 mg, 0.012 mmol) and 2.0

M aqueous solution of K₂CO₃(115 µL, 0.23 mmol). The mixture

was allowed to stir for 15 h at 85 °C, filtered through Celite, and

partitioned between EtOAc (60 mL) and 0.1 N HCl (30 mL). The

organic layer was washed with saturated aqueous NaHCO₃(30 mL)

and H₂O (30 mL), dried over MgSO₄, and evaporated in vacuo.

The residue was chromatographed on silica gel eluting with

hexanes-EtOAc 20:1 to give 47 (42.8 mg, 59%); ¹H NMR (CDCl₃)

δ 6.94 (t, J ) 8.5 Hz, 1H), 7.13 (t, J ) 7.7 Hz, 1H), 7.32-7.48

N-[4-(3-Pyridylethynyl)-2-thiazolyl]benzamide (43). To a solu-

tion of 41 (12.0 mg, 60 µmol) in CH₂Cl₂(5 mL) were added benzoyl

chloride (8 µL, 66 µmol) and triethylamine (10 µL, 72 µmol), and

the reaction mixture was allowed to stir for 20 min at room

temperature. After the mixture was partitioned between EtOAc (20

mL) and 0.1 N HCl (10 mL), the organic layer was washed with

saturated aqueous NaHCO₃(10 mL) and H₂O (10 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 1:1 to give 43 (16.9

1

mg, 92%); H NMR (CDCl₃) δ 7.31 (dd, J₁) 7.5 Hz, J₂) 3.8

Hz, 1H), 7.33 (s, 1H), 7.53-7.64 (m, 3H), 7.83 (d, J ) 7.2 Hz,

1H), 7.96 (d, J ) 7.3 Hz, 2H), 8.58 (d, J ) 3.8 Hz, 1H), 8.81 (s,

1H), 9.82 (br s, 1H). ¹³C NMR (CDCl₃) δ 86.3, 91.3, 119.4, 123.2,

124.9, 128.1, 128.1, 129.5, 129.5, 131.9, 132.1, 133.6, 139.0, 149.2,

152.7, 159.0, 166.0. MS (ESI) m/z 306.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + Na)⁺, 328.0521; calcd mass

(C₁₇H₁₁N₃OS + Na)⁺, 328.0521.

2

(m, 6H). ¹³C NMR (CDCl₃) δ 82.6, 92.9, 106.5 (t, J_CF) 25.4

2

4

Hz), 109.8 (dd, J_CF) 18.2 Hz, J_CF) 9.1 Hz), 115.3, 117.0 (d,

²J_CF) 21.3 Hz), 119.1 (d, J_CF) 23.2 Hz), 124.1 (d, J_CF) 9.4

2

3

4

3

Hz), 128.3 (d, J_CF) 3.2 Hz), 130.5 (d, J_CF) 8.6 Hz), 135.6 (t,

³J_CF) 10.0 Hz), 139.9, 162.7 (d, J_CF) 247.3 Hz), 163.7 (dd,

1

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1095

¹J_CF) 250.4 Hz, ³J_CF) 12.7 Hz), 165.3. MS (ESI) m/z 338.3 (M

+ Na)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 316.0415;

calcd mass (C₁₇H₈F₃NS + H)⁺, 316.0408.

24 h at 90 °C, filtered through Celite, and partitioned between

EtOAc (60 mL) and 0.1 N HCl (30 mL). The organic layer was

washed with H₂O (2 × 30 mL), dried over MgSO₄, and evaporated

in vacuo. The residue was chromatographed on silica gel eluting

3-[4-(3-Fluorophenylethynyl)-2-thiazolyl]-2-propyn-1-ol (49).

Compound 46 (50 mg, 0.18 mmol) and propargyl alcohol (13 µL,

0.22 mmol) were combined in a flask containing deoxygenated

DMF (8 mL). To this mixture were added Pd(PPh₃)₄(10.4 mg, 9

µmol), CuI (3.4 mg, 18 µmol), and triethylamine (30 µL, 0.22

mmol). The mixture was allowed to stir for 1.5 h at 85 °C, filtered

through Celite, and partitioned between EtOAc (50 mL) and 0.1 N

HCl (25 mL). The organic layer was washed with H₂O (2 × 25

mL), dried over MgSO₄, and evaporated in vacuo. The residue was

chromatographed on silica gel eluting with hexanes-EtOAc 2:1

1

with hexanes-EtOAc 2:1 to give 53 (18.6 mg, 32%); H NMR

(CDCl₃) δ 2.78 (s, 3H), 3.89 (s, 3H), 7.04 (d, J ) 8.4 Hz, 2H),

7.46 (s, 1H), 7.54 (d, J ) 8.4 Hz, 2H), 8.02 (s, 1H), 8.72 (s, 1H),

8.77 (s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 55.8, 82.2, 86.9, 115.1,

117.1, 123.5, 128.6, 129.6, 136.2, 136.8, 147.6, 150.6, 152.0, 160.5,

167.0. MS (ESI) m/z 307.3 (M + H)⁺. HRMS (positive mode) obsd

mass (M + H)⁺, 307.0902; calcd mass (C₁₈H₁₄N₂OS + H)⁺,

307.0905.

3-[5-[(2-Methyl-4-thiazolyl)ethynyl]-3-pyridyl]-2-propyn-1-

ol (55). Compound 28 (36 mg, 0.13 mmol) and propargyl alcohol

(9 µL, 0.16 mmol) were combined in a flask containing deoxy-

genated DMF (5 mL). To this mixture were added Pd(PPh₃)₄(14.9

mg, 13 µmol), CuI (2.5 mg, 13 µmol), and triethylamine (25 µL,

0.16 mmol). The mixture was allowed to stir for 22 h at 85 °C,

filtered through Celite, and partitioned between EtOAc (50 mL)

and 0.1 N HCl (25 mL). The organic layer was washed with H₂O

(2 × 25 mL), dried over MgSO₄, and evaporated in vacuo. The

residue was chromatographed on silica gel eluting with hexanes-

1

to give 49 (17.1 mg, 37%); H NMR (CDCl₃) δ 1.79 (br, 1H),

4.57 (s, 2H), 7.07-7.14 (m, 1H), 7.24-7.38 (m, 3H), 7.55 (s, 1H).

¹³C NMR (CDCl₃) δ 51.7, 78.4, 83.7, 88.6, 93.4, 116.8 (d, ²J_CF

)

2

3

21.3 Hz), 119.0 (d, J_CF) 23.1 Hz), 124.3 (d, J_CF) 9.5 Hz),

4

3

124.7, 128.1 (d, J_CF) 3.0 Hz), 130.5 (d, J_CF) 8.6 Hz), 138.2,

148.2, 162.7 (d, ¹J_CF) 246.9 Hz). MS (ESI) m/z 258.2 (M + H)⁺.

HRMS (positive mode) obsd mass (M + H)⁺, 258.0386; calcd mass

(C₁₄H₈FNOS + H)⁺, 258.0389.

2-Ethynyl-4-(3-fluorophenylethynyl)thiazole (50). Compound

46 (50 mg, 0.18 mmol) and trimethylsilylacetylene (30 µL, 0.22

mmol) were combined in a flask containing deoxygenated DMF

(8 mL). To this mixture were added Pd(PPh₃)₄(10.4 mg, 9 µmol),

CuI (3.4 mg, 18 µmol), and triethylamine (30 µL, 0.22 mmol). The

mixture was allowed to stir for 3 h at 85 °C, filtered through Celite,

and partitioned between EtOAc (60 mL) and 0.1 N HCl (30 mL).

The organic layer was washed with H₂O (2 × 30 mL), dried over

MgSO₄, and evaporated in vacuo to give crude 4-(3-fluorophenyl-

ethynyl)-2-(trimethylsilylethynyl)thiazole (48). This crude com-

pound 48 was dissolved in THF (10 mL), then tetrabutylammonium

fluoride solution (1.0 M in THF) (0.18 mL, 0.18 mmol) was added.

After being stirred for 10 min at room temperature, the mixture

was partitioned between EtOAc (60 mL) and 0.1 N HCl (30 mL).

The organic layer was washed with H₂O (2 × 30 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 7:1 to give 50 (20.9

1

EtOAc 1:1 to give 55 (11.9 mg, 36%); H NMR (CDCl₃) δ 1.83

(d, J ) 6.1 Hz, 1H), 2.77 (s, 3H), 4.55 (d, J ) 6.2 Hz, 2H), 7.47

(s, 1H), 7.87 (t, J ) 1.8 Hz, 1H), 8.63 (d, J ) 1.7 Hz, 1H), 8.71

(d, J ) 1.8 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.6, 51.8, 82.2, 85.0,

87.3, 88.9, 115.0, 117.0, 124.0, 141.2, 142.5, 151.6, 151.6, 167.0.

MS (ESI) m/z 255.2 (M + H)⁺. HRMS (positive mode) obsd mass

(M + H)⁺, 255.0598; calcd mass (C₁₄H₁₀N₂OS + H)⁺, 255.0592.

3-Ethynyl-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (56). Com-

pound 28 (42 mg, 0.15 mmol) and trimethylsilylacetylene (26 µL,

0.18 mmol) were combined in a flask containing deoxygenated

DMF (5 mL). To this mixture were added Pd(PPh₃)₄(17.5 mg, 15

µmol), CuI (2.9 mg, 15 µmol), and triethylamine (25 µL, 0.18

mmol). The mixture was allowed to stir for 16 h at 75 °C, filtered

through Celite, and partitioned between EtOAc (50 mL) and 0.1 N

HCl (25 mL). The organic layer was washed with H₂O (2 ×

25 mL), dried over MgSO₄, and evaporated in vacuo to give

crude 3-[(2-methyl-4-thiazolyl)ethynyl]-5-(trimethylsilylethynyl)-

pyridine (54). This crude compound 54 was dissolved in THF (5

mL), then tetrabutylammonium fluoride solution (1.0 M in THF)

(0.15 mL, 0.15 mmol) was added. After being stirred for 10 min at

room temperature, the mixture was partitioned between EtOAc (50

mL) and 0.1 N HCl (25 mL). The organic layer was washed with

H₂O (2 × 25 mL), dried over MgSO₄, and evaporated in vacuo.

The residue was chromatographed on silica gel eluting with

hexanes-EtOAc 3:1 to give 56 (26.2 mg, 78%); ¹H NMR (CDCl₃)

δ 2.77 (s, 3H), 3.26 (s, 1H), 7.47 (s, 1H), 7.92 (t, J ) 1.8 Hz, 1H),

8.66 (d, J ) 1.7 Hz, 1H), 8.74 (d, J ) 1.7 Hz, 1H). ¹³C NMR

(CDCl₃) δ 19.7, 79.9, 81.8, 84.8, 87.8, 119.4, 119.8, 124.0, 136.4,

141.7, 151.9, 152.1, 166.5. MS (ESI) m/z 225.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 225.0489; calcd mass

(C₁₃H₈N₂S + H)⁺, 225.0486.

1

mg, 51%); H NMR (CDCl₃) δ 3.52 (s, 1H), 7.05-7.14 (m, 1H),

7.32-7.37 (m, 1H), 7.43-7.52 (m, 1H), 7.56 (s, 1H), 7.74 (dd, J₁

) 13.9 Hz, J₂) 7.3 Hz, 1H). ¹³C NMR (CDCl₃) δ 79.5, 80.9,

2

83.3, 87.5, 115.2 (d, J_CF) 21.1 Hz), 117.0 (d, J_CF) 23.2 Hz),

3

4

119.3 (d, J_CF) 9.4 Hz), 124.7, 128.3 (d, J_CF) 2.9 Hz), 130.5

3

1

(d, J_CF) 8.5 Hz), 135.2, 138.4, 164.0 (d, J_CF) 249.4 Hz). MS

(ESI) m/z 228.3 (M + H)⁺. HRMS (positive mode) obsd mass (M

+ H)⁺, 228.0278; calcd mass (C₁₃H₆FNS + H)⁺, 228.0283.

3-(4-Fluorophenyl)-5-[(2-methyl-4-thiazolyl)ethynyl]pyri-

dine (52). Compound 28 (90 mg, 0.32 mmol) and 4-fluorophenyl-

boronic acid (49 mg, 0.35 mmol) were combined in a flask

containing deoxygenated DME (15 mL). To this mixture were added

Pd(PPh₃)₄(37 mg, 32 µmol) and 2.0 M aqueous solution of K₂-

CO₃(0.16 mL, 0.32 mmol). The mixture was allowed to stir for

16 h at 85 °C, filtered through Celite, and partitioned between

EtOAc (60 mL) and 0.1 N HCl (30 mL). The organic layer was

washed with saturated aqueous NaHCO₃(30 mL) and H₂O (30 mL),

dried over MgSO₄, and evaporated in vacuo. The residue was

chromatographed on silica gel eluting with hexanes-EtOAc 3:2

to give 52 (28.3 mg, 30%); ¹H NMR (CDCl₃) δ 2.80 (s, 3H), 7.21

(t, J ) 8.5 Hz, 2H), 7.47 (s, 1H), 7.57 (td, J₁) 6.8 Hz, J₂) 3.0

Hz, 2H), 8.02 (s, 1H), 8.77 (s, 2H). ¹³C NMR (CDCl₃) δ 19.7,

3-[(2-Methyl-4-thiazolyl)ethynyl]-5-[2-(tributylstannyl)vinyl]-

pyridine (57). To a solution of 56 (160 mg, 0.71 mmol) in toluene

(20 mL) were added tributyltin hydride (0.19 mL, 0.71 mmol) and

2,2′-azobis(isobutyronitrile) (AIBN) (12 mg, 71 µmol), and the

reaction mixture was allowed to stir for 14 h at 90 °C. After the

solvent was removed under reduced pressure, the residue was

chromatographed on silica gel eluting with hexanes-EtOAc 4:1

2

3

1

85.7, 87.4, 116.6 (d, J_CF) 21.7 Hz), 123.6, 129.3 (d, J_CF) 8.2

to give 57 (129 mg, 35%); H NMR (CDCl₃) δ 0.89 (t, J ) 7.1

4

Hz), 133.4, 133.4, 135.6 (d, J_CF) 2.9 Hz), 136.6, 137.1, 147.7,

Hz, 9H), 0.92-1.13 (m, 6H), 1.32 (sextet, J ) 7.2 Hz, 6H), 1.42-

1.58 (m, 6H), 2.77 (s, 3H), 5.58 (s, 1H), 6.09 (s, 1H), 7.44 (s, 1H),

7.62 (s, 1H), 8.35 (s, 1H), 8.62 (s, 1H).

151.2, 163.5 (d, ¹J_CF) 248.2 Hz), 166.5. MS (ESI) m/z 295.3 (M

+ H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 295.0707;

calcd mass (C₁₇H₁₁FN₂S + H)⁺, 295.0705.

3-[(2-Methyl-4-thiazolyl)ethynyl]-5-vinylpyridine (59). Com-

pound 57 (82 mg, 0.16 mmol) was dissolved in THF (10 mL) and

cooled at -15 °C. A solution of butyllithium (2.5 M in hexanes)

(77 µL, 0.19 mmol) was added dropwise to the above solution,

and the reaction mixture was stirred for 10 min at -15 °C. After

chlorotrimethylsilane (50 µL, 0.4 mmol) was added dropwise, the

mixture was stirred at -15 °C for 30 min, at 0 °C for 30 min, then

3-(4-Methoxyphenyl)-5-[(2-methyl-4-thiazolyl)ethynyl]pyri-

dine (53). Compound 28 (53 mg, 0.19 mmol) and 4-methoxy-

phenylboronic acid (32 mg, 0.21 mmol) were combined in a flask

containing deoxygenated DMF (10 mL). To this mixture were added

Pd(PPh₃)₄(22 mg, 19 µmol) and 1.0 M aqueous solution of K₂-

CO₃(0.19 mL, 0.19 mmol). The mixture was allowed to stir for

1096 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

at room temperature for 30 min and partitioned between EtOAc

(50 mL) and H₂O (25 mL) with addition of saturated aqueous

NaHCO₃so as to neutralize the acid present in the mixture. The

organic layer was washed with brine (25 mL), dried over MgSO₄,

and evaporated in vacuo to give crude 3-[(2-methyl-4-thiazolyl)-

ethynyl]-5-[2-(trimethylsilyl)vinyl]pyridine (58). This crude com-

pound 58 was dissolved in THF (2 mL), and 1.0 N HCl (1 mL)

was added. After being stirred for 20 min at room temperature, the

mixture was partitioned between EtOAc (30 mL) and diluted

aqueous NaHCO₃(15 mL). The organic layer was washed with

H₂O (15 mL), dried over MgSO₄, and evaporated in vacuo. The

residue was chromatographed on silica gel eluting with hexanes-

119.0, 123.8, 124.4, 136.4, 141.4, 151.3, 152.6, 166.6. MS (ESI)

m/z 235.2 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 235.0101; calcd mass (C₁₁H₇ClN₂S + H)⁺, 235.0097.

Trifluoromethanesulfonic Acid 5-[(2-Methyl-4-thiazolyl)eth-

ynyl]-2-pyridyl Ester (64). To a solution of 61 (50 mg, 0.23 mmol)

in CH₂Cl₂(18 mL) cooled in an ice bath were added triethylamine

(38 µL, 0.28 mmol) and trifluoromethanesulfonic anhydride (43

µL, 0.25 mmol), and the reaction mixture was stirred for 10 min at

the same temperature. After the mixture was partitioned between

CH₂Cl₂(20 mL) and 0.1 N HCl (15 mL), the organic layer was

washed with saturated aqueous NaHCO₃(15 mL) and H₂O (15 mL),

dried over MgSO₄, and evaporated in vacuo to give compound 64,

which was used in the following step without further purification

(80 mg, quant); ¹H NMR (CDCl₃) δ 2.77 (s, 3H), 7.17 (d, J ) 8.5

Hz, 1H), 7.46 (s, 1H), 7.91 (dd, J₁) 8.1 Hz, J₂) 2.0 Hz, 1H),

8.57 (d, J ) 1.5 Hz, 1H).

1

EtOAc 2:1 to give 59 (18.8 mg, 52%); H NMR (CDCl₃) δ 2.77

(s, 3H), 5.46 (d, J ) 11.0 Hz, 1H), 5.88 (d, J ) 17.6 Hz, 1H), 6.71

(dd, J₁) 17.6 Hz, J₂) 11.0 Hz, 1H), 7.45 (s, 1H), 7.91 (s, 1H),

8.58 (s, 1H), 8.68 (s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 85.8, 87.1,

117.7, 117.7, 123.5, 133.0, 133.0, 135.6, 136.7, 147.8, 151.5, 166.4.

MS (ESI) m/z 227.3 (M + H)⁺. HRMS (positive mode) obsd mass

(M + Na)⁺, 249.0461; calcd mass (C₁₃H₁₀N₂S + Na)⁺, 249.0463.

Bromoolefin 60. Compound 26 (430 mg, 1.87 mmol) and a

solution of hydrogen bromide (33 wt % in acetic acid) (3.0 mL,

excess) were combined in a flask. The mixture was allowed to stir

for 14 h at 80 °C in the sealed flask and was carefully poured into

ice-cold saturated aqueous NaHCO₃(30 mL). The mixture was

extracted with EtOAc (2 × 50 mL), and the combined organic layers

were washed with H₂O (2 × 40 mL), dried over MgSO₄, and

evaporated in vacuo to give 60, which was used in the following

step without further purification (500 mg, 90%); ¹H NMR (CDCl₃)

δ 2.76 (s, 3H), 6.60 (d, J ) 9.4 Hz, 1H), 7.36 (s, 1H), 7.59 (d, J

) 9.4 Hz, 1H), 7.66 (s, 1H), 8.13 (s, 1H), 12.3 (br s, 1H).

2-(4-Fluorophenyl)-5-[(2-methyl-4-thiazolyl)ethynyl]pyri-

dine (65). Compound 64, which was freshly prepared from

compound 61 (50 mg, 0.23 mmol) according to the above method,

and 4-fluorophenylboronic acid (35 mg, 0.25 mmol) were combined

in a flask containing deoxygenated DME (15 mL). To this mixture

were added Pd(PPh₃)₄(27 mg, 23 µmol) and 2.0 M aqueous solution

of K₂CO₃(0.12 mL, 0.24 mmol). The mixture was allowed to stir

for 18 h at 80 °C, filtered through Celite, and partitioned between

EtOAc (50 mL) and 0.1 N HCl (25 mL). The organic layer was

washed with saturated aqueous NaHCO₃(25 mL) and H₂O (25 mL),

dried over MgSO₄, and evaporated in vacuo. The residue was

chromatographed on silica gel eluting with hexanes-EtOAc 3:1

to give 65 (21 mg, 31%); ¹H NMR (CDCl₃) δ 2.82 (s, 3H), 7.22-

7.27 (m, 2H), 7.56 (s, 1H), 7.82 (d, J ) 8.4 Hz, 1H), 7.93 (dd, J₁

) 8.3 Hz, J₂) 2.2 Hz, 2H), 8.17 (d, J ) 8.3 Hz, 1H), 9.03 (s,

5-[(2-Methyl-4-thiazolyl)ethynyl]-1H-pyridin-2-one (61). To

a solution of 60 (500 mg, 1.68 mmol) in methanol (60 mL) was

added KOH (236 mg, 4.2 mmol), and the reaction mixture was

allowed to reflux for 1 h. After the solution was concentrated under

reduced pressure to 10 mL, the concentrate was partitioned between

EtOAc (60 mL) and 0.1 N HCl (30 mL). The aqueous layer was

saturated with NaCl and extracted again with EtOAc (50 mL), and

the combined organic layers were dried over MgSO₄and evaporated

in vacuo. The residue was chromatographed on silica gel eluting

2

1H). ¹³C NMR (CDCl₃) δ 19.7, 87.2, 91.9, 117.0 (d, J_CF) 21.4

3

Hz), 122.0, 125.0, 129.4 (d, J_CF) 8.1 Hz), 131.8, 135.4, 139.8

4

1

(d, J_CF) 2.8 Hz), 146.5, 153.7, 157.3, 162.3 (d, J_CF) 252.3

Hz), 166.7. MS (ESI) m/z 295.3 (M + H)⁺. HRMS (positive mode)

obsd mass (M + H)⁺, 295.0710; calcd mass (C₁₇H₁₁FN₂S + H)⁺,

295.0705.

3-Ethynyl-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (66). Com-

pound 64, which was freshly prepared from compound 61 (80 mg,

0.37 mmol) according to the above method, and trimethylsilyl-

acetylene (63 µL, 0.44 mmol) were combined in a flask containing

deoxygenated DMF (10 mL). To this mixture were added Pd(PPh₃)₄

(43 mg, 37 µmol), CuI (7 mg, 37 µmol), and triethylamine (62 µL,

0.44 mmol). The mixture was allowed to stir for 16 h at 75 °C,

filtered through Celite, and partitioned between EtOAc (60 mL)

and 0.1 N HCl (30 mL). The organic layer was washed with H₂O

(2 × 30 mL), dried over MgSO₄, and evaporated in vacuo. To a

solution of the residue in THF (10 mL) was added tetrabutylam-

monium fluoride solution (1.0 M in THF) (0.37 mL, 0.37 mmol).

After being stirred for 10 min at room temperature, the mixture

was partitioned between EtOAc (60 mL) and 0.1 N HCl (30 mL).

The organic layer was washed with H₂O (2 × 30 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 3:1 to give 66 (44 mg,

53%); ¹H NMR (CDCl₃) δ 2.77 (s, 3H), 3.28 (s, 1H), 7.47 (s, 1H),

7.49 (s, 1H), 7.81 (dd, J₁) 8.0 Hz, J₂) 1.8 Hz, 1H), 8.77 (d, J

) 1.5 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 79.5, 82.9, 85.5, 88.9,

119.9, 123.9, 127.2, 136.5, 139.0, 141.6, 152.9, 166.5. MS (ESI)

m/z 225.2 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 225.0484; calcd mass (C₁₃H₈N₂S + H)⁺, 225.0486.

5-[(2-Methyl-4-thiazolyl)ethynyl]-2-vinylpyridine (68). Com-

pound 64, which was freshly prepared from compound 61 (40 mg,

0.19 mmol) according to the above method, and tributyl(vinyl)tin

(59 µL, 0.20 mmol) were combined in a flask containing deoxy-

genated DMF (10 mL). To this mixture was added Pd(PPh₃)₄(11

mg, 10 µmol). The mixture was allowed to stir for 15 h at 85 °C,

filtered through Celite, and partitioned between EtOAc (60 mL)

and aqueous KF (30 mL). The organic layer was washed with 0.1

N HCl (30 mL) and H₂O (2 × 30 mL), dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with hexanes-EtOAc 5:2 to give 68 (12.6 mg, 30%);

1

with EtOAc-MeOH 30:1 to give 61 (129 mg, 94%); H NMR

(CDCl₃) δ 2.77 (s, 3H), 6.60 (d, J ) 9.4 Hz, 1H), 7.36 (s, 1H),

7.59 (d, J ) 9.4 Hz, 1H), 7.66 (s, 1H), 12.7 (br s, 1H). ¹³C NMR

(CDCl₃) δ 19.6, 84.6, 84.7, 103.2, 120.9, 122.7, 136.8, 138.8, 144.1,

164.4, 166.5.

Methanesulfonic Acid 5-[(2-Methyl-4-thiazolyl)ethynyl]-2-

pyridyl Ester (62). To a solution of 61 (30 mg, 0.13 mmol) in

CH₂Cl₂(15 mL) cooled in an ice bath were added triethylamine

(23 µL, 0.16 mmol) and methanesulfonyl chloride (12 µL, 0.14

mmol), and the reaction mixture was stirred for 10 min at room

temperature. After the mixture was partitioned between CH₂Cl₂(20

mL) and 0.1 N HCl (15 mL), the organic layer was washed with

saturated aqueous NaHCO₃(15 mL) and H₂O (15 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 2:1 to give 62 (38 mg,

1

quant); H NMR (CDCl₃) δ 2.77 (s, 3H), 3.54 (s, 3H), 7.13 (d, J

) 8.3 Hz, 1H), 7.47 (s, 1H), 7.96 (dd, J₁) 8.3 Hz, J₂) 2.0 Hz,

1H), 8.52 (d, J ) 1.5 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 41.3,

84.3, 87.9, 115.7, 119.5, 124.0, 136.3, 143.4, 151.1, 156.9, 166.6.

MS (ESI) m/z 295.2 (M + H)⁺. HRMS (positive mode) obsd mass

(M + H)⁺, 295.0219; calcd mass (C₁₂H₁₀N₂O₃S₂+ H)⁺, 295.0211.

2-Chloro-5-[(2-methyl-4-thiazolyl)ethynyl]pyridine (63). Com-

pound 61 (70 mg, 0.32 mmol) and POCl₃(2.0 mL, excess) were

combined in a flask, and the mixture was allowed to stir for 1.5 h

at 120 °C. After quenching by addition of ice, the mixture was

partitioned between EtOAc (50 mL) and saturated aqueous NaHCO₃

(20 mL). The organic layer was washed with H₂O (20 mL), dried

over MgSO₄, and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 3:1 to give 63

(46.6 mg, 62%); ¹H NMR (CDCl₃) δ 2.77 (s, 3H), 7.35 (d, J ) 8.3

Hz, 1H), 7.46 (s, 1H), 7.80 (dd, J₁) 8.2 Hz, J₂) 2.0 Hz, 1H),

8.58 (d, J ) 1.5 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 84.6, 88.1,

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1097

¹H NMR (CDCl₃) δ 2.77 (s, 3H), 5.56 (d, J ) 10.9 Hz, 1H), 6.26

(d, J ) 17.5 Hz, 1H), 6.84 (dd, J₁) 17.4 Hz, J₂) 10.7 Hz, 1H),

7.35 (d, J ) 8.1 Hz, 1H), 7.44 (s, 1H), 7.81 (d, J ) 6.7 Hz, 1H),

8.76 (s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 86.2, 87.4, 118.6, 119.9,

121.0, 123.3, 136.7, 139.4, 142.0, 152.5, 155.1, 167.0. MS (ESI)

m/z 227.3 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 227.0647; calcd mass (C₁₃H₁₀N₂S + H)⁺, 227.0643.

55 µmol) and methanesulfonyl chloride (4 µL, 51 µmol), and the

reaction mixture was stirred for 10 min at room temperature. After

the mixture was partitioned between CH₂Cl₂(10 mL) and 0.1 N

HCl (7 mL), the organic layer was washed with saturated aqueous

NaHCO₃(7 mL) and H₂O (7 mL), dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with hexanes-EtOAc 1:1 to give 73 (13 mg, quant);

¹H NMR (CDCl₃) δ 2.76 (s, 3H), 3.58 (s, 3H), 7.30 (dd, J₁) 6.9

Hz, J₂) 3.1 Hz, 1H), 7.55 (s, 1H), 7.99 (d, J ) 7.2 Hz, 1H), 8.31

(d, J ) 3.3 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 41.6, 81.6, 91.3,

112.5, 122.7, 124.8, 136.4, 143.3, 147.4, 157.5, 166.4. MS (ESI)

m/z 295.1 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 295.0208; calcd mass (C₁₂H₁₀N₂O₃S₂+ H)⁺, 295.0211.

2-Chloro-3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (74). Com-

pound 72 (15 mg, 69 µmol) and POCl₃(1.5 mL, excess) were

combined in a flask, and the mixture was allowed to stir for 1.5 h

at 120 °C. After quenching by addition of ice, the mixture was

partitioned between EtOAc (30 mL) and saturated aqueous NaHCO₃

(15 mL). The organic layer was washed with H₂O (15 mL), dried

over MgSO₄, and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 2:1 to give 74

3-Iodo-2-methoxypyridine (69).²⁴A solution of methyllithium

(1.6 M in diethyl ether) (60 mL, 96 mmol) was added dropwise to

THF (80 mL) cooled to -40 °C. 2-Methoxypyridine (5.57 mL,

53.4 mmol) and isopropylamine (0.16 mL, 1.14 mmol) were

successively added dropwise to this solution, and the reaction

mixture was stirred for 3 h at 0 °C. After the mixture was cooled

below -40 °C again, a THF solution (50 mL) of iodine (14.9 g,

58.7 mmol) was added dropwise from an addition funnel over 30

min below -40 °C. The reaction mixture was stirred at -60 °C

for 30 min and treated successively with concentrated HCl (50 mL)

and sodium thiosulfate (25 g, 100 mmol) in H₂O (200 mL). After

basification with K₂CO₃, the mixture was saturated with NaCl and

extracted with diethyl ether (2 × 500 mL). The combined organic

layers were dried over MgSO₄and concentrated under reduced

pressure. The precipitated solid was removed by filtration, and the

filtrate was evaporated in vacuo to give crude product 69 (6.76 g),

which was used in subsequent reactions without purification.

2-Methoxy-3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (70). Com-

pound 4 (650 mg, 3.3 mmol) and crude compound 69 (2 g) were

combined in a flask containing deoxygenated DMF (15 mL). To

this mixture were added Pd(PPh₃)₄(191 mg, 0.17 mmol), CuI (63

mg, 0.33 mmol), and triethylamine (0.55 mL, 4.0 mmol). The

mixture was warmed to 85 °C, and Bu₄NF (863 mg, 3.3 mmol)

was then added dropwise over 15 min. The reaction mixture was

allowed to stir for 15 h at 85 °C, filtered through Celite, and

partitioned between EtOAc (100 mL) and 0.1 N HCl (50 mL). The

organic layer was washed with H₂O (2 × 50 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 5:2 to give 70 (312 mg,

41%); ¹H NMR (CDCl₃) δ 2.76 (s, 3H), 4.05 (s, 3H), 6.90 (dd, J₁

) 7.2 Hz, J₂) 5.1 Hz, 1H), 7.44 (s, 1H), 7.80 (d, J ) 5.9 Hz,

1H), 8.16 (d, J ) 3.5 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.6, 54.4,

84.0, 88.9, 107.1, 116.8, 123.1, 137.1, 142.2, 147.1, 164.1, 166.1.

MS (ESI) m/z 231.2 (M + H)⁺. HRMS (positive mode) obsd mass

(M + H)⁺, 231.0592; calcd mass (C₁₂H₁₀N₂OS + H)⁺, 231.0592.

Bromoolefin 71. Compound 70 (150 mg, 0.65 mmol) and

hydrogen bromide solution (33 wt % in acetic acid) (2.0 mL, excess)

were combined in a flask. After the mixture was allowed to stir

for 6 h at 80 °C in the sealed flask, it was carefully poured into

ice-cold saturated aqueous NaHCO₃(20 mL). The mixture was

extracted with EtOAc (2 × 40 mL), and the combined organic layers

were washed with H₂O (2 × 40 mL), dried over MgSO₄, and

evaporated in vacuo to give the intermediate 71, which was used

in the following step without further purification (193 mg, quant);

¹H NMR (CDCl₃) δ 2.76 (s, 3H), 6.38 (t, J ) 6.9 Hz, 1H), 7.40 (d,

J ) 6.1 Hz, 1H), 7.93 (d, J ) 7.1 Hz, 1H), 8.09 (s, 1H), 8.34 (s,

1H), 11.8 (br s, 1H).

1

(9.7 mg, 59%); H NMR (CDCl₃) δ 2.78 (s, 3H), 7.26 (dd, J₁)

5.0 Hz, J₂) 2.7 Hz, 1H), 7.51 (s, 1H), 7.91 (d, J ) 7.5 Hz, 1H),

8.38 (d, J ) 3.2 Hz, 1H). ¹³C NMR (CDCl₃) δ 19.7, 83.9, 91.0,

120.4, 122.3, 124.3, 136.4, 141.9, 149.0, 152.8, 166.5. MS (ESI)

m/z 235.3 (M + H)⁺. HRMS (positive mode) obsd mass (M +

H)⁺, 235.0092; calcd mass (C₁₁H₇ClN₂S + H)⁺, 235.0097.

Trifluoromethanesulfonic Acid 5-[(2-Methyl-4-thiazolyl)eth-

ynyl]-2-pyridyl Ester (75). To a solution of 61 (28 mg, 0.13 mmol)

in CH₂Cl₂(10 mL) cooled in an ice bath, triethylamine (22 µL,

0.16 mmol) and trifluoromethanesulfonic anhydride (24 µL, 0.14

mmol) were added, and the reaction mixture was stirred for 10

min at the same temperature. After the mixture was partitioned

between CH₂Cl₂(15 mL) and 0.1 N HCl (15 mL), the organic layer

was washed with saturated aqueous NaHCO₃(15 mL) and H₂O

(15 mL), dried over MgSO₄, and evaporated in vacuo. The residue

was chromatographed on silica gel eluting with hexanes-EtOAc

1

2:1 to give 75 (36 mg, 80%); H NMR (CDCl₃) δ 2.77 (s, 3H),

7.41 (dd, J₁) 7.3 Hz, J₂) 5.0 Hz, 1H), 7.57 (s, 1H), 8.04 (d, J

) 7.0 Hz, 1H), 8.36 (d, J ) 3.4 Hz, 1H).

3-[(2-Methyl-4-thiazolyl)ethynyl]-2-(trimethylsilylethynyl)py-

ridine (76). Compound 75 (20 mg, 58 µmol) and trimethylsilyl-

acetylene (10 µL, 70 µmol) were combined in a flask containing

deoxygenated DMF (5 mL). To this mixture were added Pd(PPh₃)₄

(6.8 mg, 6 µmol), CuI (1.2 mg, 6 µmol), and triethylamine (98 µL,

70 µmol). The mixture was allowed to stir for 4 h at 85 °C, filtered

through Celite, and partitioned between EtOAc (30 mL) and 0.1 N

HCl (15 mL). The organic layer was washed with H₂O (2 × 15

mL), dried over MgSO₄, and evaporated in vacuo. The residue was

chromatographed on silica gel eluting with hexanes-EtOAc 2:1

1

to give 76 (8.3 mg, 49%); H NMR (CDCl₃) δ 0.31 (s, 9H), 2.77

(s, 3H), 7.41 (dd, J₁) 7.2 Hz, J₂) 4.3 Hz, 1H), 7.43 (s, 1H), 7.85

(d, J ) 7.9 Hz, 1H), 8.54 (d, J ) 3.6 Hz, 1H).

2-Ethynyl-3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (77). Com-

pound 76 (6.0 mg, 20 µmol) was dissolved in THF (3 mL), then

tetrabutylammonium fluoride solution (1.0 M in THF) (20 µL, 20

µmol) was added. After being stirred for 10 min at room

temperature, the mixture was partitioned between EtOAc (25 mL)

and 0.1 N HCl (10 mL). The organic layer was washed with H₂O

(2 × 10 mL), dried over MgSO₄, and evaporated in vacuo. The

residue was chromatographed on silica gel eluting with hexanes-

EtOAc 3:2 to give 77 (4.4 mg, 98%); ¹H NMR (CDCl₃) δ 2.77 (s,

3H), 3.45 (s, 1H), 7.29 (dd, J₁) 6.8 Hz, J₂) 4.2 Hz, 1H), 7.49 (s,

1H), 7.88 (d, J ) 7.7 Hz, 1H), 8.56 (d, J ) 4.1 Hz, 1H). ¹³C NMR

(CDCl₃) δ 19.7, 81.5, 81.8, 85.1, 90.3, 123.1, 123.1, 124.1, 136.7,

139.6, 144.3, 149.4, 166.4. MS (ESI) m/z 225.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 225.0490; calcd mass

(C₁₃H₈N₂S + H)⁺, 225.0486.

3-[(2-Methyl-4-thiazolyl)ethynyl]-1H-pyridin-2-one (72). To

a solution of 70 (193 mg, 0.65 mmol) in methanol (25 mL) was

added KOH (91 mg, 1.6 mmol), and the reaction mixture was

allowed to reflux for 1 h. After the solution was concentrated under

reduced pressure to 4 mL, the concentrate was partitioned between

EtOAc (30 mL) and 0.1 N HCl (15 mL). The aqueous layer was

saturated with NaCl and extracted again with EtOAc (30 mL), and

the combined organic layers were dried over MgSO₄and evaporated

in vacuo. The residue was chromatographed on silica gel eluting

1

with EtOAc-MeOH 20:1 to give 72 (103 mg, 73%); H NMR

(CDCl₃) δ 2.74 (s, 3H), 6.34 (t, J ) 6.7 Hz, 1H), 7.46 (s, 1H),

7.54 (d, J ) 5.6 Hz, 1H), 7.78 (d, J ) 6.5 Hz, 1H), 13.6 (br s, 1H).

¹³C NMR (CDCl₃) δ 19.6, 84.5, 89.3, 107.5, 115.4, 123.3, 135.9,

137.0, 145.5, 164.8, 166.1.

Methanesulfonic Acid 3-[(2-Methyl-4-thiazolyl)ethynyl]-2-

pyridyl Ester (73). To a solution of 72 (10 mg, 46 µmol) in CH₂-

Cl₂(3 mL) cooled in an ice bath were added triethylamine (8 µL,

2-Methyl-4-[2-(tributylstannyl)vinyl]thiazole (79). Compound

4 (586 mg, 3.0 mmol) was dissolved in THF (6 mL), then

tetrabutylammonium fluoride solution (1.0 M in THF) (3.0 mL,

1098 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3

Iso et al.

3.0 mmol) was added. After being stirred for 10 min at room

temperature, the mixture was partitioned between diethyl ether (50

mL) and H₂O (20 mL). The organic layer was washed with H₂O

(20 mL), dried over MgSO₄, and evaporated carefully under slightly

reduced pressure. The volatile residue consisting of intermediate

78 was immediately dissolved in toluene (15 mL), tributyltin

hydride (0.81 mL, 3.0 mmol) and AIBN (20 mg, 0.12 mmol) were

added, and the reaction mixture was allowed to stir for 1 h at 90

°C. After the solvent was removed under reduced pressure, the

residue was chromatographed on silica gel eluting with hexane to

2-Methyloxazole-4-carboxylic Acid Methyl Ester (84).²⁵To

a stirred suspension of ethyl acetimidate hydrochloride (6.18 g, 50

mmol) and DL-serine methyl ester hydrochloride (7.78 g, 50 mmol)

in CH₂Cl₂(100 mL) was added dropwise over 25 min a solution

of triethylamine (15 mL, 108 mmol) in CH₂Cl₂(35 mL). After 16

h the solids were removed by filtration and washed with ether. The

filtrate was concentrated, and the resulting solid residue was washed

several times with ether. The combined organic extracts were

concentrated to give crude 4,5-dihydro-2-methyloxazole-4-carboxy-

lic acid methyl ester (83) as yellow oil. Hexamethylenetetramine

(17.5 g, 125 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

(18.7 mL, 125 mmol) were added to a stirred suspension of CuBr₂

(27.9 g, 125 mmol) at 0 °C. After 20 min, the above crude

compound 83 was added, and the reaction mixture was stirred at

room temperature for 2 h. The solvent was removed in vacuo, and

the residue was partitioned between EtOAc (150 mL) and saturated

aqueous NH₄Cl:saturated aqueous NH₄OH (1:1, 100 mL). The

aqueous layer was extracted with EtOAc (150 mL), and the

combined organic layers were washed with saturated aqueous NH₄-

Cl:saturated aqueous NH₄OH (1:1, 100 mL), 10% citric acid (100

mL), saturated aqueous NaHCO₃(100 mL), and brine, then dried

over MgSO₄and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 3:2 to give 84

(4.09 g, 58%); ¹H NMR (CDCl₃) δ 2.54 (s, 3H), 3.93 (s, 3H), 8.16

(s, 1H).

1

give 79 (385 mg, 31%); H NMR (CDCl₃) δ 0.88 (t, J ) 7.5 Hz,

9H), 0.92 (q, J ) 8.7 Hz, 6H), 1.30 (sextet, J ) 7.0 Hz, 6H), 1.48

(sextet, J ) 7.3 Hz, 6H), 2.69 (s, 3H), 6.39 (d, J ) 13.1 Hz, 1H),

6.83 (s, 1H), 7.32 (d, J ) 13.3 Hz, 1H).

(E)-3-[2-(2-Methyl-4-thiazolyl)vinyl]pyridine (80). Compound

79 (41.4 mg, 0.10 mmol) and 3-iodopyridine (19 mg, 0.12 mmol)

were combined in a flask containing deoxygenated DMF (5 mL).

To this mixture were added PdCl₂(PPh₃)₂(7.0 mg, 10 µmol), CuI

(1.9 mg, 10 µmol), and LiCl (4 mg, 0.10 mmol). After the mixture

was allowed to stir for 1.5 h at 80 °C, it was filtered through Celite,

then partitioned between EtOAc (30 mL) and aqueous KF (15 mL).

The organic layer was washed with 0.1 N HCl (15 mL) and H₂O

(2 × 15 mL), dried over MgSO₄, and evaporated in vacuo. The

residue was chromatographed on silica gel eluting with hexanes-

EtOAc 1:2 to give 80 (6.5 mg, 32%); ¹H NMR (CDCl₃) δ 2.64 (s,

3H), 6.53 (d, J ) 12.6 Hz, 1H), 6.78 (d, J ) 12.5 Hz, 1H), 7.14 (s,

1H), 7.64-7.73 (m, 1H), 8.32 (d, J ) 7.1 Hz, 1H), 8.66 (s, 1H),

9.14 (s, 1H). ¹³C NMR (CDCl₃) δ 19.7, 119.8, 122.4, 132.5, 133.3,

133.8, 137.5, 146.5, 148.6, 152.3, 164.7. MS (ESI) m/z 203.3 (M

+ H)⁺. HRMS (positive mode) obsd mass (M + H)⁺, 203.0647;

calcd mass (C₁₁H₁₀N₂S + H)⁺, 203.0643.

2-Methyloxazole-4-carboxaldehyde (85). LiAlH₄solution (1.0

M in THF) (31.9 mL, 31.9 mmol) was added to a solution of 84 in

diethyl ether (200 mL) at -78 °C. After 30 min, a saturated aqueous

solution of sodium acetate (100 mL) was added, and the mixture

was extracted with diethyl ether (2 × 100 mL). The combined

organic layers were dried over MgSO₄and evaporated carefully

under slightly reduced pressure (caution: compound 85 readily

sublimes). The residue was chromatographed on silica gel eluting

2-Methylthiazole-4-carboxylic Acid 3-Fluorophenylamide (81).

To a solution of 2-methylthiazole-4-carboxylic acid (49 mg, 0.34

mmol) in CH₂Cl₂(5 mL) were added 1-(3-dimethylaminopropyl)-

3-ethylcarbodiimide hydrochloride (EDC‚HCl) (72 mg, 0.37 mmol),

1-hydroxybenzotriazole (HOBt) (51 mg, 0.37 mmol), and triethyl-

amine (95 µL, 0.68 mmol), and the reaction mixture was stirred

for 18 h at room temperature. After the mixture was partitioned

between EtOAc (30 mL) and 0.1 N HCl (15 mL), the organic layer

was washed with saturated aqueous NaHCO₃(15 mL) and H₂O

(15 mL), dried over MgSO₄, and evaporated in vacuo. The residue

was chromatographed on silica gel eluting with hexanes-EtOAc

1

with hexanes-EtOAc 2:1 to give 85 (994 mg, 42%); H NMR

(CDCl₃) δ 2.56 (s, 3H), 8.19 (s, 1H), 9.92 (s, 1H). ¹³C NMR

(CDCl₃) δ 14.0, 141.2, 145.6, 163.4, 184.0.

4-(2,2-Dibromovinyl)-2-methyloxazole (86). To a solution of

CBr₄(2.88 g, 8.68 mmol) in CH₂Cl₂(10 mL) cooled in an ice bath

was added dropwise a solution of triphenylphosphine (4.53 g, 17.4

mmol) in CH₂Cl₂(10 mL), and the reaction mixture was stirred

for 10 min at the same temperature. A solution of 85 (241 mg,

2.17 mmol) in CH₂Cl₂(10 mL) was added dropwise to the reaction

mixture with continued cooling, and the mixture was stirred for 20

min at the same temperature. After addition of H₂O (20 mL), the

mixture was extracted with CH₂Cl₂(40 mL), and the organic layer

was washed with saturated aqueous NaHCO₃(20 mL) and saturated

aqueous NH₄Cl (20 mL), dried over MgSO₄, and evaporated in

vacuo. The residue was chromatographed on silica gel eluting with

hexanes-EtOAc 6:1 to give 86 (500 mg, 86%); ¹H NMR (CDCl₃)

δ 2.45 (s, 3H), 7.35 (s, 1H), 8.13 (s, 1H). ¹³C NMR (CDCl₃) δ

14.1, 90.8, 129.3, 137.0, 137.8, 161.2.

1

4:1 to give 81 (58.6 mg, 73%); H NMR (CDCl₃) δ 2.75 (s, 3H),

6.84 (t, J ) 7.1 Hz, 1H), 7.27-7.38 (m, 1H), 7.33 (s, 1H), 7.71 (d,

J ) 10.8 Hz, 1H), 8.06 (s, 1H), 9.26 (br s, 1H). ¹³C NMR (CDCl₃)

δ 19.5, 107.5 (d, ²J_CF) 26.3 Hz), 111.4 (d, ²J_CF) 21.4 Hz), 115.4

(d, ⁴J_CF) 2.9 Hz), 124.4, 130.5 (d, ³J_CF) 9.3 Hz), 139.7 (d, ³J_CF

1

) 11.0 Hz), 149.8, 159.3, 163.5 (d, J_CF) 244.7 Hz), 166.7. MS

(ESI) m/z 237.2 (M + H)⁺. HRMS (positive mode) obsd mass (M

+ Na)⁺, 259.0323; calcd mass (C₁₁H₉FN₂OS + Na)⁺, 259.0318.

2-Methylthiazole-4-carboxylic Acid 3-Pyridylamide (82). To

a suspension of 2-methylthiazole-4-carboxylic acid (49 mg, 0.34

mmol) in toluene (10 mL) were added thionyl chloride (73 µL, 1.0

mmol) and DMF (5 µL, 65 µmol), and the reaction mixture was

allowed to stir for 80 min at 105 °C. The reaction mixture was

evaporated in vacuo, and the residue was dissolved again in CH₂-

Cl₂(10 mL). After 3-aminopyridine (64 mg, 0.68 mmol) was added

to this solution, the mixture was stirred for 10 min at room

temperature. The mixture was partitioned between EtOAc (50 mL)

and saturated aqueous NaHCO₃(15 mL), and the aqueous layer

was saturated with NaCl and extracted again with EtOAc (50 mL).

The combined organic layers were dried over MgSO₄and evapo-

rated in vacuo. The residue was chromatographed on silica gel

eluting with EtOAc to give 82 (45.5 mg, 61%); ¹H NMR (CDCl₃)

δ 2.74 (s, 3H), 7.30 (dd, J₁) 7.5 Hz, J₂) 4.6 Hz, 1H), 8.06 (s,

1H), 8.32 (d, J ) 8.0 Hz, 1H), 8.38 (s, 1H), 8.77 (s, 1H), 9.27 (br

s, 1H). ¹³C NMR (CDCl₃) δ 19.5, 124.1, 124.7, 127.1, 135.0, 141.6,

145.7, 149.5, 159.7, 166.8. MS (ESI) m/z 220.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 220.0548; calcd mass

(C₁₀H₉N₃OS + H)⁺, 220.0545.

2-Methyl-4-(trimethylsilylethynyl)oxazole (88). To a solution

of 86 (258 mg, 0.97 mmol) in THF (10 mL) cooled at -78 °C was

added sodium hexamethyldisilazide (NaHMDS) solution (1.0 M

in THF) (0.97 mL, 0.97 mmol) dropwise over 3 min. The mixture

was stirred for 45 min at -78 °C, then methyllithium solution (1.6

M in diethyl ether) (1.21 mL, 1.94 mmol) was added dropwise

over 6 min. After a further 75 min, chlorotrimethylsilane (0.62 mL,

4.9 mmol) was added dropwise, and the reaction mixture was stirred

at -78 °C for 3 h. Then, the mixture was allowed to slowly warm

to room temperature over 100 min. After addition of saturated

aqueous NH₄Cl (20 mL), the mixture was extracted with diethyl

ether (2 × 30 mL), and the combined organic layers were dried

over MgSO₄and evaporated in vacuo. The residue was chromato-

graphed on silica gel eluting with hexanes-EtOAc 25:1 to give 88

1

(146 mg, 84%); H NMR (CDCl₃) δ 0.25 (s, 9H), 2.46 (s, 3H),

7.68 (s, 1H). ¹³C NMR (CDCl₃) δ 0.1, 14.2, 94.7, 98.9, 124.1, 141.8,

161.8.

4-[(3-Fluorophenyl)ethynyl]-2-methyloxazole (89). Compound

88 (43 mg, 0.24 mmol) and 1-fluoro-3-iodobenzene (31 µL, 0.26

mmol) were combined in a flask containing deoxygenated DMF

Synthesis and SAR of MTEP Analogues

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1099

Tehrani, L.; Cosford, N. D.; Smith, N. D. 2-(2-[3-(pyridin-3-yloxy)-

phenyl]-2H-tetrazol-5-yl) pyridine: a highly potent, orally active,

metabotropic glutamate subtype 5 (mGlu5) receptor antagonist.

Bioorg. Med. Chem. Lett. 2004, 14, 5473-5476. (c) Poon, S. F.;

Eastman, B. W.; Chapman, D. F.; Chung, J.; Cramer, M.; Holtz, G.;

Cosford, N. D.; Smith, N. D. 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-

tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally

bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor

antagonist. Bioorg. Med. Chem. Lett. 2004, 14, 5477-5480. (d)

Smith, N. D.; Poon, S. F.; Huang, D.; Green, M.; King, C.; Tehrani,

L.; Roppe, J. R.; Chung, J.; Chapman, D. P.; Cramer, M.; Cosford,

N. D. Discovery of highly potent, selective, orally bioavailable,

metabotropic glutamate subtype 5 (mGlu5) receptor antagonists

devoid of cytochrome P450 1A2 inhibitory activity. Bioorg. Med.

Chem. Lett. 2004, 14, 5481-5484. (e) Eastman, B.; Chen, C.; Smith,

N. D.; Poon, S.; Chung, J.; Reyes-Manalo, G.; Cosford, N. D.;

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generation of a focused library using a solution-phase Suzuki coupling

methodology. Bioorg. Med. Chem. Lett. 2004, 14, 5485-5488. (f)

Bonnefous, C.; Vernier, J. M.; Hutchinson, J. H.; Chung, J.; Reyes-

Manalo, G.; Kamenecka, T. Dipyridyl amides: potent metabotropic

glutamate subtype 5 (mGlu5) receptor antagonists. Bioorg. Med.

Chem. Lett. 2005, 15, 1197-1200. (g) Alagille, D.; Baldwin, R. M.;

Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.; Tamagnan, G. D.

Synthesis and receptor assay of aromatic-ethynyl-aromatic derivatives

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4648.

(5 mL). To this mixture, was added Pd(PPh₃)₄(14 mg, 12 µmol),

CuI (4.6 mg, 24 µmol), and triethylamine (40 µL, 0.29 mmol). The

mixture was warmed to 85 °C, and Bu₄NF (63 mg, 0.24 mmol)

was then added dropwise over 15 min. The reaction mixture was

allowed to stir for 13 h at 85 °C, filtered through Celite, and

partitioned between EtOAc (40 mL) and 0.1 N HCl (15 mL). The

organic layer was washed with H₂O (2 × 15 mL), dried over

MgSO₄, and evaporated in vacuo. The residue was chromatographed

on silica gel eluting with hexanes-EtOAc 7:1 to give 89 (41 mg,

85%); ¹H NMR (CDCl₃) δ 2.50 (s, 3H), 7.03-7.12 (m, 1H), 7.22

(d, J ) 8.8 Hz, 1H), 7.29-7.35 (m, 1H), 7.31 (s, 1H), 7.77 (s,

2

1H). ¹³C NMR (CDCl₃) δ 14.2, 80.5, 91.4, 116.5 (d, J_CF) 21.2

2

3

Hz), 118.7 (d, J_CF) 22.9 Hz), 123.8, 124.7 (d, J_CF) 9.4 Hz),

4

3

127.9 (d, J_CF) 3.1 Hz), 130.4 (d, J_CF) 8.6 Hz), 141.6, 162.2,

162.7 (d, ¹J_CF) 246.8 Hz). MS (ESI) m/z 202.3 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 202.0661; calcd mass (C₁₂H₈-

FNO + H)⁺, 202.0668.

3-[(2-Methyl-4-oxazolyl)ethynyl]pyridine (90). Compound 88

(43 mg, 0.24 mmol) and 3-iodopyridine (42 mg, 0.26 mmol) were

combined in a flask containing deoxygenated DMF (5 mL). To

this mixture were added Pd(PPh₃)₄(14 mg, 12 µmmol), CuI (4.6

mg, 24 µmol), and triethylamine (40 µL, 0.29 mmol). The mixture

was warmed to 85 °C, and Bu₄NF (63 mg, 0.24 mmol) was then

added dropwise over 15 min. The reaction mixture was allowed to

stir for 13 h at 85 °C, filtered through Celite, and partitioned

between EtOAc (40 mL) and 0.1 N HCl (15 mL). The organic

layer was washed with H₂O (2 × 15 mL), dried over MgSO₄, and

evaporated in vacuo. The residue was chromatographed on silica

gel eluting with hexanes-EtOAc 1:2 to give 90 (23 mg, 52%); ¹H

NMR (CDCl₃) δ 2.51 (s, 3H), 7.31 (t, J ) 9.0 Hz, 1H), 7.80 (s,

1H), 7.81 (d, J ) 9.0 Hz, 1H), 8.58 (br s, 1H), 8.78 (br s, 1H). ¹³

C

NMR (CDCl₃) δ 14.3, 83.0, 89.4, 123.2, 123.5, 123.7, 138.8, 141.8,

149.3, 152.6, 162.3. MS (ESI) m/z 185.2 (M + H)⁺. HRMS

(positive mode) obsd mass (M + H)⁺, 185.0709; calcd mass

(C₁₁H₈N₂O + H)⁺, 185.0715.

(7) (a) Pagano, A.; Ruegg, D.; Litschig, S.; Stoehr, N.; Stierlin, C.;

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non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and

7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester

interact with overlapping binding pockets in the transmembrane

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2000, 275, 33750-33758. (b) Malherbe, P.; Kratochwil, N.; Zenner,

M. T.; Piussi, J.; Diener, C.; Kratzeisen, C.; Fischer, C.; Porter, R.

H. Mutational analysis and molecular modeling of the binding pocket

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Gonsaud, M.; Acher, F.; Praˆezeau, L.; Pin, J. P. Heptahelical domain

of metabotropic glutamate receptor 5 behaves like rhodopsin-like

receptors. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 378-383.

(8) Chiamulera, C.; Epping-Jordan, M. P.; Zocchi, A.; Marcon, C.;

Cottiny, C.; Tacconi, S.; Corsi, M.; Orzi, F.; Conquet, F. Reinforcing

and locomotor stimulant effects of cocaine are absent in mGluR5

null mutant mice. Nat. Neurosci. 2001, 4, 873-874.

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nucleus accumbens contribute to amphetamine-induced locomotion.

J. Pharmacol. Exp. Ther. 1998, 284, 317-322.

(10) Smith, J. A.; Mo, Q.; Guo, H.; Kunko, P. M.; Robinson, S. E. Cocaine

increases extraneuronal levels of aspartate and glutamate in the

nucleus accumbens. Brain. Res. 1995, 683, 264-269.

(11) Pierce, R. C.; Bell, K.; Duffy, P.; Kalivas, P. W. Repeated cocaine

augments excitatory amino acid transmission in the nucleus accum-

bens only in rats having developed behavioral sensitization. J.

Neurosci. 1996, 16, 1550-1560.

(12) Tallaksen-Greene, S. J.; Kaatz, K. W.; Romano, C.; Albin, R. L.

Localization of mGluR1a-like immunoreactivity and mGluR5-like

immunoreactivity in identified populations of striatal neurons. Brain.

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Acknowledgment. We are indebted to Shionogi & Co., Ltd.

for their financial support of the sabbatical leave of Y.I. We

are indebted to the NIH (DA06013 to N.E.G. and DA10458 to

A.P.K.) for their support of this work.

Supporting Information Available: HPLC, HRMS, and el-

emental analysis data for compounds in Tables 2-5. This material

is available free of charge via the Internet at http://pubs.acs.org.

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JM050570F

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Synthesis and structure-activity relationships of 3-[(2-methyl-1,3-thiazol- 4-yl)ethynyl]pyridine analogues as potent, noncompetitive metabotropic glutamate receptor subtype 5 antagonists; search for cocaine medications

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