Synthesis of 2,3,4,5-Tetrahydrobenzo[1,4]thiazepines via N-Acyliminium Cyclization

Article abstract of DOI:10.1021/acs.oprd.7b00260

We report an efficient and scalable synthesis of 7-methoxy-2,3,4,5-tetrahydrobenzo[1,4]thiazepine, the core structure of biologically active molecules like JTV-519 and S107. This synthetic route, starting with 4-methoxythiophenol and proceeding via acyliminum cyclization, gives the target product in four steps and 68% overall yield and is a substantial improvement over previously published processes. Nine additional examples of tetrahydrobenzo[1,4]thiazepine synthesis via acyliminium ring closure are also presented.

Full text of DOI:10.1021/acs.oprd.7b00260

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Full Paper
Synthesis of 2,3,4,5-tetrahydrobenzo[1,4]thiazepines
via N-acyliminium cyclization
Shixian Deng, Zhenzhuang Cheng, Charles Ingalls, Ferenc Kontes, Jiaming Yan, and Sandro Belvedere
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00260 • Publication Date (Web): 28 Sep 2017
Downloaded from http://pubs.acs.org on September 28, 2017
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Synthesis of 2,3,4,5ꢀtetrahydrobenzo[1,4]thiazepines
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via Nꢀacyliminium cyclization
Shixian Deng†,‡, Zhenzhuang Cheng†, Charles Ingalls†, Ferenc Kontes†, Jiaming Yan† and
Sandro Belvedere†,*
† ARMGO Pharma, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
‡ Department of Medicine, Columbia University College of Physicians and Surgeons, New
York, NY 10032, USA.
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TABLE OF CONTENTS GRAPHIC
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KEYWORDS
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1,4ꢀbenzothiazepine, Nꢀacyliminium cation, PictetꢀSpengler reaction, 7ꢀmembered ring
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formation
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ABSTRACT
We
report
an
efficient
and
scalable
synthesis
of
7ꢀmethoxyꢀ2,3,4,5ꢀ
tetrahydrobenzo[1,4]thiazepine, the core structure of biologically active molecules like JTVꢀ519
and S107. This synthetic route, starting with 4ꢀmethoxythiophenol and proceeding via
acyliminum cyclization, gives the target product in four steps and 68% overall yield, and is a
substantial improvement over previously published processes. Nine additional examples of
tetrahydrobenzo[1,4]thiazepine synthesis via acyliminium ring closure are also presented.
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Derivatives of 1,4ꢀbenzothiazepines, in particular 2,3,4,5ꢀtetrahydrobenzo[1,4]thiazepines, are
of great interest due to their activity on a wide range of biological targets in multiple disease
areas, including cardiovascular,1 neuromuscular,2 metabolic,3 CNS,4 oncological5 and antiꢀviral6
indications. Therefore, a general, practical and scalable synthesis for this class of molecules
would be very useful.
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Our group has been interested in identifying
a
route to 7ꢀmethoxyꢀ2,3,4,5ꢀ
tetrahydrobenzo[1,4]thiazepine (1), an important building block in the synthesis of biologically
active compounds such as JTVꢀ5191b and S1077 (Chart 1). A previous preparation in five steps
from 2ꢀnitroꢀ4ꢀmethoxy benzoic acid afforded 1 in 50% overall yield.1a This route included a
Sandmeyerꢀtype reaction requiring careful temperature control and a lithium aluminum hydride
reduction in refluxing THF, both of which pose significant difficulties when scaling beyond
gram quantities.
The most common preparations of tetrahydroꢀ1,4ꢀbenzothiazepines, including 4ꢀ
thiochromanone ring expansion,4c, 8 start with 1,2ꢀdisubstituted phenyl derivatives, and generally
proceed through an intermediate benzothiazepineꢀ3ꢀone,9 benzothiazepineꢀ5ꢀone,1a, 4c, 10 or cyclic
imine,11 which is reduced in the final step using a hydride source. The use of a reducing agent
has been avoided in a few cases. 12ꢀ15
Only a relatively minor number of examples illustrate the preparation of tetrahydroꢀ1,4ꢀ
benzothiazepines from simpler phenyl derivatives that are not already ortho disubstituted, like
the use of Bischler–Napieralski conditions, followed by reduction of the intermediate imine.16 In
another method, the reaction of a 2ꢀ(phenylthio)ethanꢀ1ꢀamine with formaldehyde in the
presence of benzotriazole, followed by treatment with Lewis acid, yielded a benzothiazepine
carrying a Nꢀmethylbenzotriazole side chain.17
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We sought to obtain
1
starting from 4ꢀmethoxythiophenol, preparing 2ꢀ((4ꢀ
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8
methoxyphenyl)thio)ethanꢀ1ꢀamine (2, Scheme 1), and closing the tetrahydrothiazepine ring
employing a PictetꢀSpengler reaction with formaldehyde. This transformation is commonly used
to close the 6ꢀmembered rings of tetrahydroisoquinolines,18 but to our knowledge has been
reported only once for the closure of a tetrahydrothiazepine ring on an electronꢀrich catechol.19
Our attempts to apply the same methodology to the intermediate 2 were unsuccessful and
resulted in a mixture of products. Only the major component was isolated and identified as the
corresponding dimethylamine derivative (3, Scheme 1).a The lack of cyclization to the desired 7ꢀ
membered benzodiazepine product and the formation of this byproduct are likely the result an
insufficient reactivity of the intermediate iminium ion towards the aromatic ring to overcome the
stereoelectronic demands of 7ꢀmembered ring closure.
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To increase the reactivity of the intermediate, we turned to the use of an acyliminium. N-
Acyliminium ions are useful reactive intermediates for the construction of heterocyclic rings, and
are characterized by enhanced reactivity relative to the corresponding iminium ions used in the
Mannich and PictetꢀSpengler reactions.20 Their use to perform the closure of benzoꢀfused 7ꢀ
membered rings is well established,21 however only few examples refer to the preparation of 1,4ꢀ
benzothiazepines.22 Furthermore, these examples involve the generation of cyclic acyliminium
ions (e.g. 2ꢀoxoꢀ3,4ꢀdihydroꢀpyrrolium ions), resulting in the formation of tricyclic systems. In
our case, the target molecule 1 is fully unsubstituted on the thiazepine ring and therefore requires
the use formaldehyde, or a formaldehyde equivalent, as the source of C5, and of an activating
acyl group that can be removed easily after the cyclization step. It should be noted that a recent
publication has shown the synthesis of Nꢀtosylbenzothiazepines by PictetꢀSpengler cyclization of
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tosylamides using formaldehyde as the source of C5, however, the removal of the tosylates was
not reported.23
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In our synthesis of 1 (Scheme 2) we alkylated 4ꢀmethoxythiophenol with 2ꢀchloroethylamine
and converted the resulting 2ꢀ((4ꢀmethoxyphenyl)thio)ethanꢀ1ꢀamine 2 to the corresponding Cbz
derivative 4a. Treatment of this intermediate with paraformaldehyde in toluene in the presence of
pꢀtoluenesulfonic acid (PTSA) resulted in the formation of the ringꢀclosed N-Cbz
benzothiazepine 5a in 84% yield, via the putative acyliminium 6. Comparable results were
obtained using benzene or 1,2ꢀdichloroethane as solvent, but toluene was preferred due to its
lower toxicity. The Cbz group was easily removed by treatment with HBr in acetic acid, a
procedure that yielded the target compound as the solid HBr salt (1-HBr) in good purity without
chromatographic purification and was therefore preferred to catalytic hydrogenation. This
reaction sequence affords 1-HBr, starting from the commercially available 4ꢀ
methoxythiophenol, in 4 steps and 68% overall yield, and represents a significant improvement
over the previously reported preparations. Avoidance of the critical Sandmeyer reaction and
hydride reduction also makes this synthetic approach suitable for larger scaleꢀup.
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We have extended this easy synthetic approach to other examples with different substituents
on the aromatic ring (Table 1, products 5b ꢀ 5h). Changing the 4ꢀmethoxy group to 4ꢀmethyl
(4b) had no effect on the yield of the cyclization to 5b, while a slight decrease was observed for
the conversion of the 4ꢀthiomethoxy derivative 4c to 5c. In the case of the metaꢀsubstituted
methoxy derivative 4d, the two possible cyclization products were formed in a 13:1 ratio,
favoring the 8ꢀmethoxy derivative, in 53% combined yield.
Even though toluene was the solvent of choice for the cyclization of compounds 4a – 4d, 1,2ꢀ
dichloroethane could also be utilized to obtain those products in comparable yields (data not
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shown). However, 1,2ꢀdichloroethane was the preferred solvent for 4ꢀtrifluoromethoxy (4e) and
4ꢀhalo derivatives (4f – 4h, Table 1). In these cases the acyliminium intermediate underwent side
reactions in toluene leading to unidentified side products, whereas the cyclization proceeded
smoothly and in good yield in 1,2ꢀdichloroethane.
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The methyl carbamate 4i behaved very similarly to the Cbz derivative, resulting in 80% yield
of the corresponding cyclized material 5i. The methodology can also be applied to acetamide 4j,
which was converted to the target cyclic product 5j in 71% yield.
Conclusions
Herein we report a simple, scalable route to 2,3,4,5ꢀtetrahydrobenzo[1,4]thiazepines via
cyclization of N-acylꢀN-(2ꢀ(phenylthio)ethyl)methaniminium ions. We show the further
application of this route to a variety of substituted phenyl rings, with a carbamate or acetyl group
as the acyl moiety. The acyliminium intermediate can be generated via reaction with
paraformaldehyde in the presence of PTSA, and the N-acyl benzothiazepines resulting from the
cyclization are obtained in good yields. When a Cbz derivative is used, the corresponding
unsubstituted benzothiazepine can be easily obtained via a deprotection step. An important
example is the preparation, in 4 steps and 68% yield from 4ꢀmethoxy thiophenol, of 7ꢀmethoxyꢀ
2,3,4,5ꢀtetrahydrobenzo[1,4]thiazepine (1), which can then be elaborated to yield biologically
active molecules.
Experimental section
Solvents and reagents were of commercial grade and used without further purification. Flash
column chromatography was performed on a Teledyne Isco CombiFlash Rf+ instrument
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equipped RediSep Rf Gold Silica (20ꢀ40 µm) columns. Analytical UPLCꢀMS analyses were
performed on a Waters Acquity HꢀClass UPLC system equipped with a PDA detector, a Waters
3100 mass detector and a CORTECS UPLC C18, 1.6 µm, 2.1 mm x 50 mm column. The
following method was used: mobile phase A= 0.1 % formic acid in water, B= 0.1% formic acid
in acetonitrile; 1% B from t=0 to 0.1 minutes, linear gradient to 99% B at 1.9 min, 99% B at 2.0
min, linear gradient to 1% B at 2.1 min. NMR spectra were recorded on a 400 MHz Bruker
Avance III N instrument. HRMS data were obtained on a Bruker maXisꢀII ETD ESIꢀQqTOF
instrument equipped with Dionex Ultimateꢀ3000 LC system.
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2-(4-Methoxyphenylthio)ethanamine (2)
4ꢀMethoxythiophenol (21.0 g, 0.15 mol, 1.0 equiv.), 2ꢀchloroethylamine hydrochloride (17.4
g, 0.15 mol, 1.0 equiv.), K2CO3 (33.0 g, 0.24 mol, 1.6 equiv.) and N,Nꢀdiisopropylethylamine (2
ml, 11 mmol, 0.07 equiv.) were mixed in anhydrous THF (100 mL). The mixture was degassed
for 5 minutes under reduced pressure, and the reaction was then refluxed under argon for 16
hours. After cooling to room temperature, DCM (200 mL) was added and the solids were filtered
off. The filtrate was concentrated under reduced pressure. The remaining mixture was taken up
in water (100 mL), conc. HCl (20 mL) was added, and the solution was extracted with ethyl
acetate/hexanes (1:1, 2×100 mL). The aqueous layer was adjusted to pH 10 by addition of 2M
NaOH, and it was extracted with DCM (3×100 mL). The combined organic solution was dried
over Na2SO4 and filtered. Removal of the solvent under reduced pressure provided the product 2ꢀ
(4ꢀMethoxyphenylthio)ethanamine (2) as a white solid (27.3 g, 95% yield, UPLC purity at 210
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nm 98.5%). H NMR (400 MHz, DMSOꢀd6) δ (ppm) 7.35 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7
Hz, 2H), 5.22 (br, 2H), 3.73 (s, 3H), 2.94 (t, J = 6.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H). 13C NMR
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(100 MHz, DMSOꢀd6) δ (ppm) 159.0, 133.0, 125.4, 115.3, 55.7, 40.3, 35.9. LRMSꢀESI (m/z)
calc’d for C9H14NOS [M+H]+ 184.08, found 184.06.
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Benzyl 2-(4-methoxyphenylthio)ethylcarbamate (4a)
To the flask containing 2ꢀ((4ꢀmethoxyphenyl)thio)ethanꢀ1ꢀamine (2, 24.0 g, 131 mmol, 1.0
equiv.), were added sodium bicarbonate (16.8 g, 200 mmol, 1.5 equiv.), water (100 mL) and
DCM (200 mL). Next, benzyl chloroformate (23.7 g, 139 mmol, 1.06 equiv., in 100 mL DCM)
was added dropwise at 0 °C. After addition, the reaction was stirred vigorously at room
temperature for 2 hours. Upon completion, the reaction mixture was transferred to a separatory
funnel, the organic layer was separated, and the aqueous layer was extracted with DCM (100
mL). The combined organic phase was dried over Na2SO4 and filtered. The solvent was removed
under reduced pressure, and the resulting solid was triturated with a mixture of THF/hexanes
(1:10, 200 mL) to obtain benzyl (2ꢀ((4ꢀmethoxyphenyl)thio)ethyl)carbamate (4a) as a white solid
1
(36.7 g, 89% yield, UPLC purity at 210 nm 98.6%). H NMR (400 MHz, CDCl3) δ (ppm) 7.35
(m, 7H), 6.83 (d, J = 8.7 Hz, 2H), 5.07 (m, 3H), 3.77 (s, 3H), 3.34 (q, J = 6.4 Hz, 2H), 2.93 (t, J
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= 6.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ (ppm) 159.3, 156.2, 136.5, 133.8, 128.6, 128.2,
128.1, 124.8, 114.8, 66.8, 55.4, 39.9, 36.0. LRMSꢀESI (m/z) calc’d for C17H20NO3S [M+H]+
318.12, found 318.12.
Benzyl 7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepine-4(5H)-carboxylate (5a)
To a mixture of benzyl (2ꢀ((4ꢀmethoxyphenyl)thio)ethyl)carbamate (4a, 16.0 g, 50 mmol, 1.0
equiv.) and PTSA (3.14 g, 16.5 mmol, 0.3 equiv.) in toluene (500 mL) stirred at 70 ºC, was
added paraformaldehyde (15.0 g, 500 mmol, 10 equiv.) in 5 portions over 5 hours. The reaction
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was then stirred at 70 ºC for 16 h. After cooling to room temperature, the solid was filtered off,
and the filtrate was washed with saturated aqueous NaHCO3 (100 mL). The organic layer was
dried over Na2SO4, filtered and concentrated under reduced pressure. 13.9 g Liquid was obtained
after the crude product was purified by silica gel column chromatography (0→25%
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EtOAc/hexanes
elution
gradient)
to
obtain
benzyl
7ꢀmethoxyꢀ2,3ꢀ
dihydrobenzo[f][1,4]thiazepineꢀ4(5H)ꢀcarboxylate (5a, 13.9 g, 84% yield, UPLC purity at 210
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nm 98.4%) as a colorless oil. H NMR (400 MHz, CDCl3, integration of 1 per H for minor
rotamer, 1.4 per H for major rotamer) δ (ppm) 7.46 (d, J = 8.8 Hz, 2.4H), 7.39ꢀ7.30 (m, 12H),
7.10 (d, J = 4.0 Hz, 1H), 6.74ꢀ6.69 (m, 3.8H), 5.08 (s, 2.8H), 5.08 (s. 2H), 4.62 (s, 2H), 4.59 (s,
2.8H), 3.99 (br, 4.3H), 3.82 (s, 3H), 3.58 (s, 4.2H), 2.79 (dd, J = 6.0, 6.0 Hz, 2.8H), 2.73 (dd, J =
4.0, 4.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 159.3, 159.1, 155.5, 154.9, 144.2, 144.1,
136.5, 136.4, 134.2, 134.1, 128.5, 128.2, 128.1, 128.0, 127.9, 126.8, 126.5, 116.6, 116.3, 113.1,
113,1, 67.5, 67.2, 55.4, 55.1, 53.6, 53.0, 51.7, 34.8, 34.4. HRMSꢀESI (m/z) calc’d for
C18H20NO3S [M+H]+ 330.1158, found 330.1157.
7-Methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine hydrobromide (1-HBr salt)
A solution of HBr in acetic acid (33%, 30 mL) was slowly added to benzyl 7ꢀmethoxyꢀ2,3ꢀ
dihydrobenzo[f][1,4]thiazepineꢀ4(5H)ꢀcarboxylate (5a, 13.0 g, 39.5 mmol) dissolved in DCM
(10 mL). After the addition, carbon dioxide started to develop and a white solid began to form.
The mixture was allowed to stand at room temperature for 1 hour after the end of the addition.
Diethyl ether (400 mL) was added and the mixture was stirred for 30 minutes. The solid was
collected by filtration and washed with additional diethyl ether. The white solid was dried under
vacuum to give 7ꢀmethoxyꢀ2,3,4,5ꢀtetrahydrobenzo[f][1,4]thiazepine hydrogen bromide (1, 10.4
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g, 96% yield, UPLC purity at 210 nm 99.1%). 1H NMR (400 MHz, DMSOꢀd6) δ (ppm) 8.99 (br,
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2H), 7.52 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.4, 2.8 Hz, 1H), 4.41 (s,
7
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2H), 3.77 (s, 3H), 3.49 (m, 2H), 2.96 (m, 2H). C NMR (100 MHz, DMSOꢀd6) δ (ppm) 159.7,
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138.7, 134.4, 128.1, 118.8, 115.0, 56.0, 51.3, 50.4, 30.9. HRMSꢀESI (m/z) calc’d for C10H14NOS
[M+H]+ 196.0791, found 196.0788.
General method for the preparation of 4b-j
Thiophenol alkylation
The starting thiophenol (1.1 equiv.) and 2ꢀbromoethylamine hydrobromide (1.0 equiv.) were
suspended in anhydrous THF (0.5 M concentration). Potassium carbonate (2.0 equiv.) and
Hünig’s base (0.5 equiv.) were added. The reaction was stirred at 50 ºC for 2ꢀ4 days until
disappearance of 2ꢀbromoethylamine as monitored by MS. Upon completion, the reaction
mixture was cooled to ambient temperature, concentrated to near dryness and poured into water.
This mixture was transferred to a separatory funnel and extracted with CH2Cl2 (2×). The
combined organic phase was dried over Na2SO4, filtered and concentrated. The crude product
was taken up in Et2O, and conc. HCl was added slowly with vigorous stirring to cause
precipitation of the product hydrochloride salt. The solid 2ꢀ(phenylthio)ethanꢀ1ꢀamine HCl salt
was filtered, washed with additional Et2O, dried under vacuum and taken to the next step.
Carbamate formation/acylation
The starting 2ꢀ(phenylthio)ethanꢀ1ꢀamine HCl salt (1.0 equiv.) was suspended in anhydrous
CH2Cl2 (0.15 M concentration), and the mixture was cooled to 0 ºC in an ice bath. Triethylamine
(2.2 equiv.) was then added, and vigorous stirring was maintained until all the starting material
dissolved and the solution became homogeneous. The desired chloroformate, acyl chloride or
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acyl anhydride (1.1 equiv.) was then added, the ice bath was removed, and the reaction was
stirred at ambient temperature for 15 min or until complete consumption of starting material as
monitored by HPLC. Upon completion, the reaction mixture was diluted additional CH2Cl2 and
washed with 1 M HCl and sat. aq. Na2CO3 (25 mL), dried over Na2SO4, filtered and
concentrated. Depending on its purity level, the resulting crude product was either used directly
in the next step, or triturated with a mixture of hexanes/THF (20:1) and filtered, or purified by
silica gel chromatography prior to taking it forward.
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The products 4b-4j were characterized by 1H NMR, 13C NMR and LRMSꢀESI. See Supporting
Information.
General method for the conversion of 4b-j to 5b-j
The starting material (1.0 equiv.) was dissolved in anhydrous toluene or 1,2ꢀdichloroethane
(concentration: 0.1 M). Paraformaldehyde (corresponding to 10 equiv. of formaldehyde) and pꢀ
toluenesulfonic acid monohydrate (0.3ꢀ0.7 equiv.) were added. The reaction was then stirred at
70 ºC until disappearance of starting material as monitored by HPLC analysis. Upon completion,
the reaction mixture was allowed to cool to room temperature before it was diluted with ethyl
acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was
dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel column
chromatography to obtain the desired benzothiazepine product as colorless oil. The reactions
were carried out at the following scale of starting material: 4b, 1.0 mmol; 4b, 1.0 mmol; 4c, 1.5
mmol; 4d, 1.8 mmol; 4e, 0.8 mmol; 4f, 1.7 mmol; 4g, 0.3 mmol; 4h, 1.1 mmol; 4i, 5.7 mmol; 4j,
2.0 mmol.
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The products 5b-5j were characterized by H NMR, 13C NMR and HRMSꢀESI. See
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Supporting Information.
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SCHEMES
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Scheme 1
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H3CO
NH
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S
1
Not observed
(CH2O)n
PTSA (x equiv.)
70 °C
H3CO
H3CO
NH2
SH
S
Solvent
16 h
2
H3CO
CH3
Yield of 3
UPLC Isolated
N
S
CH3
Solvent
Toluene
Dioxane
x
0.3
1.0
28%
78%
-
3
Main product
72%
Scheme 2
O
Cl
O
Cl
H3CO
H3CO
NH2 HCl
H3CO
NHCbz
S
NH2
NaHCO3, H2O
DCM
S
SH
K2CO3, DIPEA
THF
95%
4a
2
89%
(CH2O)n
PTSA
70 °C
Cbz
HBr
NH
H3CO
33% HBr
H3CO
H3CO
N
AcOH
96%
N
Toluene
84%
S
S
Cbz
S
5a
1-HBr
6
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CHARTS.
Chart 1
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TABLES.
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Table 1. Conversion of substituted 2ꢀ(phenylthio)ethanꢀ1ꢀamine to the corresponding 1,4ꢀ
8
9
tetrahydrobenzothiazepine.a
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O
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OBn
N
H3CO
8
S
5b, 89% b
5e, 73% d
5h, 67% e
5c, 67% b
5f, 76% e
5i, 80% g
5d, 53% b,c
5g 71% f
5j, 71% h
a
b
c
Yield of purified product. x= 0.3, toluene, 18 h. 8ꢀmethoxyꢀ and 6ꢀmethoxyꢀ2,3,4,5ꢀ
tetrahydrobenzo[1,4]thiazepine obtained in 13:1 ratio (UPLC). x= 0.7, DCE, 18 h. x= 0.3,
DCE, 18 h. f x= 0.3, DCE, 1 h. g x= 0.3, toluene, 6.5 h. h x= 0.7, DCE, 46 h.
d
e
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ASSOCIATED CONTENT
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Supporting Information.
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ꢀ Procedure, characterization and mechanistic hypothesis for the formation of compound 3.
ꢀ Characterization of compounds 4b-j, 5b-j.
ꢀ 1H NMR Spectra of compounds 1-HBr, 3, 5a-j.
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AUTHOR INFORMATION
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Corresponding Author
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* Sandro Belvedere
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ARMGO Pharma, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591
Phone: (914)ꢀ425ꢀ0000
Eꢀmail: sbelvedere@armgo.com
Notes
a Compound 3 was isolated and identified by H and 13C NMR and HRMS. We hypothesize
that fomaldehyde is behaving as the reducing agent necessary for its formation. See Supporting
Information for compound characterization and mechanistic hypothesis.
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ACKNOWLEDGMENT
We thank the Medicinal Chemistry department in SERVIER Research Institute, particularly
JeanꢀLouis Péglion, Patrice Desos and Christophe Poitevin for helpful discussions. Mass
Spectral data were obtained at CUNY Advanced Science Research Center.
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ABBREVIATIONS
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DCE, 1,2ꢀdichloroethane; DCM, dichloromethane; DIPEA, N,NꢀDiisopropylethylamine; PTSA,
pꢀtoluenesulfonic acid.
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