A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the synthesis of praziquantel

Article abstract of DOI:10.1016/j.tet.2017.10.006

Starting from 3-methoxy N-acylpyrazinium salts, a new approach towards the synthesis of the antischistosomal drug praziquantel (PZQ) has been developed. Utilization of a palladium-catalyzed intramolecular Heck reaction to form dehydro-PZQ followed by a Hydrogenation step, in a stepwise or one-pot manner, allowed for the gram scale synthesis of PZQ in 4 or 5 steps and in good overall yields. This methodology proved to be well suited for generating the pyrazino[1,2-a] isoindole and pyrazino[1,2-a] benzazepine analogues of PZQ.

Full text of DOI:10.1016/j.tet.2017.10.006

Accepted Manuscript
A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the
synthesis of Praziquantel
Alfred L. Williams, Valentine R. St. Hilaire
PII:
S0040-4020(17)31014-1
10.1016/j.tet.2017.10.006
TET 29009
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 July 2017
Revised Date: 28 September 2017
Accepted Date: 3 October 2017
Please cite this article as: Williams AL, St. Hilaire VR, A palladium-catalyzed intramolecular Heck/
Hydrogenation approach towards the synthesis of Praziquantel, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.10.006.
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A palladium-catalyzed intramolecular
Heck/Hydrogenation approach towards the
synthesis of Praziquantel
Alfred L. Williams a, b, and Valentine R. St. Hilaire b, †
Leave this area blank for abstract info.
aDepartment of Pharmaceutical Sciences, North Carolina Central University, Durham, NC, 27707 United
States
bBiomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University,
Durham, NC 27707 United States

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Tetrahedron
journal homepage: www.elsevier.com
A palladium-catalyzed intramolecular Heck/Hydrogenation approach towards the
synthesis of Praziquantel
Alfred L. Williams a, b, and Valentine R. St. Hilaire b, †
aDepartment of Pharmaceutical Sciences, North Carolina Central University, Durham, NC, 27707 United States
bBiomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707 United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Starting from 3-methoxy N-acylpyrazinium salts, a new approach towards the synthesis of the
antischistosomal drug praziquantel (PZQ) has been developed. Utilization of a palladium-
catalyzed intramolecular Heck reaction to form dehydro-PZQ followed by a Hydrogenation step,
in a stepwise or one-pot manner, allowed for the gram scale synthesis of PZQ in 4 or 5 steps and
in good overall yields. This methodology proved to be well suited for generating the
pyrazino[1,2-a] isoindole and pyrazino[1,2-a] benzazepine analogues of PZQ.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
N-Acylpyrazinium Salts
ꢀ5-2-Oxopiperazine
Intramolecular Heck Reaction
Hydrogenation
Praziquantel
campaigns.5 Because of its widespread use, drug resistance is a
major concern so some researchers have been investigating new
ways into synthesizing analogues of PZQ.6 During our recent
investigation into the regioselective reduction of 3-subsituted N-
acylpyrazinium salts, we showed that the ꢀ5-2-oxopiperazine ring
system could be easily synthesized in one step and in very good
yield.7 We envisioned that this reaction could be very useful
towards making PZQ and its potential analogues by providing a
rapid entry into the synthesis of the substituted cyclic precursor
mentioned above.
1. Introduction
Over the years, praziquantel (PZQ) has been the drug mainly
used for the treatment of the parasitic disease Schistosomiasis
(bilharziasis).1 Recognized as one of many neglected tropical
diseases by the World Health Organization (WHO),
Schistosomiasis is caused by a trematode flatworm called a
Schistosoma.1,2 It has been estimated that more than 200 million
people are infected and calculated that 700 million people are at
risk of infection.3
The synthesis of PZQ has been reported by several groups.4
Starting from isoquinoline, the initial synthesis of this drug by
researchers at Merck used a Reissert reaction to generate a key
cyano dihydroisoquinoline intermediate which was then
transformed into PZQ in 4 steps.4i Kim and coworkers used a
Pictet-Spengler reaction towards the synthesis of PZQ. Under
acidic conditions, an amido acetal intermediate was cyclized to
generate the piperazine and isoquinoline ring system of PZQ in a
single step.4g A multicomponent approach developed by Cao et al
used an Ugi reaction followed by a Pictet-Spengler reaction to
give PZQ in 3 steps with an overall yield of 45%.4b Another
method that has received some attention involved using acidic or
radical conditions to generate PZQ from a phenethyl substituted
ꢀ5-2-oxopiperazine cyclic precursor.4f-g
PZQ is highly effective against all schistosome species that are
known to infect humans and is used in mass treatment
———
Figure 1. Retrosynthetic Analysis of PZQ.
Corresponding author. Email: awilliams@nccu.edu (A.Williams)
Current Address: Department of Chemistry, University of Miami, 1301
†
Memorial Drive, Coral Gables, FL 33146-0431

2
Tetrahedron
Our strategy towards synthesizing PZQ is depicted in Figure
ACCEPTED MANUSCRIPT
10
4a
4b
4c
4c
4c
4c
Cs2CO3 (1.2)
Cs2CO3 (1.2)
NaH (1.2)
Dioxane
Dioxane
DMF
46
40
46
57
85
88
1. Instead of using N-2-bromophenethyl substituted ꢀ5-2-
oxopiperazine 5 to form PZQ via a radical reaction, as mentioned
by Todd and coworkers,4f we propose that PZQ can be obtained
from 5 by first using a Pd-catalyzed intramolecular Heck reaction
to generate dehydro-PZQ 6 followed by the reduction of its
double bond.8 Intramolecular Heck reactions can tolerate a
variety of functionality and have been used to synthesize
biologically active small molecules.9 N-alkylation of ꢀ5-2-
oxopiperazine 3 with 2-bromophenethyl 4 should give us 5. As
11
12d
13d
14
NaH (3.0)
Toluene
Dioxane
THF
Cs2CO3 (1.1)
Cs2CO3 (1.5)
15e
aUnless otherwise specified, all reactions were heated at 80 oC for 36 h. bIsolated
c
yield. 2-Bromostyrene was produced when phenethyl halides 4a-b were used.
dReaction was heated for 48 h. Reaction with THF was heated to reflux.
e
we previously reported,
3 can be synthesized from the
regioselective reduction of 3-methoxy N-acylpyrazinium salt 2.7
In our ongoing efforts exploring the synthetic utility of
pyrazinium salts, herein we describe a new approach towards the
synthesis of the antischistosomal drug PZQ and its ring
contracted and expanded analogues.
Under these conditions, the reaction resulted in low yields of 5
along with 4a and 4b undergoing an elimination reaction to give
2-bromostyrene which was detected by crude NMR. Using
Dioxane as the solvent gave a slight increase in yield (40-46%)
but only when Cs2CO3 was used as the base (Table 1, entry 7-11).
With the alkyl halides not giving us desirable yields, our
attention was directed towards using 2-bromophenethyl tosylate
4c.12 Reacting 4c with NaH gave us 5 in yields of 46% and 57%
(Table 1, entry 12-13). When 4c was reacted in the presence of
Cs2CO3 using Dioxane or THF as the solvent, we were pleased to
see that 5 was generated in 85% and 88% respectively after 36 h
(Table 1, entry 14-15).
2. Results/Discussion
Our journey into the synthesis of PZQ began by first
synthesizing ꢀ5-2-oxopiperazine 3 on a five gram scale (Scheme
1). To accomplish this, cyclohexanecarbonyl chloride was added,
over 10 min, to a solution of the commercially available food
additive 2-methoxypyrazine 1 and n-Bu3SnH in THF at 0 °C.
Formation of dihydropyrazine 2a was monitored by TLC. When
the reaction was completed after 20 min, the in situ generated 2a
was hydrolyzed to 3 by adding 1M HClaq in MeOH and stirring
the reaction mixture at 0 °C for 15 min. After the crude material
was isolated, purification by silica gel flash chromatography gave
3 in an excellent yield of 94% (Scheme 1).
Having now established our N-alkylating conditions, our
attention turned toward the formation of PZQ’s pyrazino[2,1-
a]isoquinoline ring system using an intramolecular Heck process.
(Table 2).
Table 2. Optimization of Intramolecular Heck Reaction to form
Dehydro-PZQ 6a
yield
Scheme 1. Synthesis of ꢀ5-2-oxopiperazine 3
entry Pd cat. (mol %)
ligand (mol%)
solvent
DMF
time (h)
(%)b
−
1c
Pd(PPh3)4 (1)
Pd(PPh3)4 (3)
Pd(PPh3)4 (5)
Pd(PPh3)4 (10)
Pd(PPh3)4 (20)
Pd(PPh3)4 (10)
Pd(PPh3)4 (20)
Pd(PPh3)4 (20)
Pd(PPh3)4 (20)
Pd(OAc)2 (1)
Pd(OAc)2 (3)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (20)
–
48
15
3
With 3 now in hand, exploration of the reaction conditions for
its N-alkylation to generate 5 was started. An initial attempt at
using 3 and 2-bromophenethyl alcohol in a Mitsunobu reaction
resulted in no product 5. Based on a report describing the N-
2
–
DMF
91
85
85
88
75
80
90
93
−
3
–
DMF
4
–
DMF
1
alkylations of 2-piperazinones,10
3 was reacted with 2-
5d
6e
7e
8
–
THF
44
41
22
21
21
48
48
1
bromophenethyl bromide 4a or chloride 4b in the presence of
–
2-MeTHF
2-MeTHF
Toluene
Dioxane
DMF
o
NaH, K2CO3, and Cs2CO3 in DMF at 80 C for 36 h. (Table 1,
entry 1-6).11
–
–
Table 1. N-Alkylation of 3a
9
–
10c
11
12
13
14
15
PPh3 (2)
PPh3 (6)
PPh3 (10)
PPh3 (20)
–
DMF
20
88
95
88
88
DMF
DMF
1
DMF
3
entry
phenethyl
base (equiv)
solvent
yield(%)b,c
–
DMF
1
aUnless otherwise specified, all reactions were carried out using 1.5 equiv of
Cs2CO3 as the base and heated at 80 C. Isolated yields. Product 6 was not
observed by LC/MS. dReactions performed in THF were heated to reflux. eWhen
2-MeTHF was used as the solvent, debrominated 5 was observed by crude NMR.
o
b
c
1
2
3
4
5
6
7
8
9d
4a
4a
4a
4b
4b
4b
4a
4b
4a
NaH (1.2)
DMF
–
K2CO3 (3.0)
Cs2CO3 (1.2)
NaH (1.2)
DMF
21
14
7
DMF
DMF
Reaction conditions that were reported in our synthesis of
imidazoisoindol-3-ones from 2-haloaryl imidazolinones were
first examined.13 Under these conditions, we were delighted to
see that using 3 mole % of Pd(PPh3)4 in DMF gave a 91% yield
of dehydro-PZQ 6 after 15 h (Table 2, entry 2). Reducing the
amount of this catalyst to 1 mole % resulted in no product being
K2CO3 (3.0)
Cs2CO3 (1.2)
K2CO3 (3.0)
K2CO3 (3.0)
Cs2CO3 (1.2)
DMF
14
18
13
3
DMF
Dioxane
Dioxane
THF
25

formed while increasing it to 5-10 mol % shortened the reaction
these analogs, 3 was first reacted with commercially available 2-
bromobenzyl bromide in the presence of NaH and TBAI using
THF/DMF (20:1) as the solvent to give the cyclic precursor 8 in
85% yield. Bromopropyl tosylate 4d12 was used to generate 11 in
86% yield using the optimized alkylating conditions described
above (Scheme 3). Next, our intramolecular Heck reaction was
used to generate the ring contracted and expanded dehydro-PZQ
analogs 9 and 12 in good yields of 85% and 84% respectively.16
Hydrogenation of 9 using Pd(OH)2/C proceeded smoothly to
produce the desired ring contracted PZQ 10 in 91 % yield
(Scheme 3). When Pd/C was used on 12, the reaction did not go
to completion after 72 h. Switching to a Pt/C catalyst gave ring
expanded PZQ 13 in a yield of 74% after 24 h (Scheme 3).
Although this new method proved to be very efficient at
providing PZQ and its analogues, streamlining our synthetic
process to reduce the number of steps was explored. Since both
our intramolecular Heck and Hydrogenation steps required the
use of a palladium catalyst, it became apparent to us that these
two steps could potentially be combined to perform a one-pot
intramolecular Heck/Hydrogenation reaction. A search of the
literature showed that Pd(OAc)2 and PPh3 in DMF used to
ACCEPTED MANUSCRIPT
times but lowered the yield (Table 2, entry 1,3-4). An
examination of the effects that different solvents such as THF, 2-
MeTHF, Toluene and Dioxane have on this reaction revealed that
10-20 mol % of Pd(PPh3)4 was required to give 6 in yields of 75-
93% (Table 2, entry 5-9).
Next, our catalyst system was switched to Pd(OAc)2 and PPh3
in DMF (Table 2, entry 10-13). When 1 mol % Pd(OAc)2 was
used, no reaction was observed. An increase to 3 mol %
produced only a 20% yield of 6 after 48 h (Table 2, entry 10-11).
Increasing Pd(OAc)2 to 5 and 10 mol % resulted in the reaction
going to completion in 1 h and giving yields of 6 in 88% and
95% respectively (Table 2, entry 12 and 13). When the reaction
was repeated without the PPh3 ligand, 6 was obtained in a yield
of 88% when using 10 and 20 mol % of Pd(OAc)2 (Table 2, entry
14-15).
With the optimization of our N-alkylation and intramolecular
Heck reactions completed, demonstration of their use towards the
gram scale synthesis of PZQ (Scheme 2) was performed.
Starting with 3.0 g of 3, N-alkylation with 3.4g of tosylate 4c
gave 5.2 g of the cyclic precursor 5 in an excellent yield of 92%.
Next, using Pd(PPh3)4 as our catalyst and 2.5 g of 5, the
intramolecular Heck reaction proceeded smoothly to completion
in 18 h to generate 1.9 g of dehydro-PZQ 6 in 94% yield.
Hydrogenation of 1.5 g of 6 in MeOH using H2 (balloon
convert
a variety of alkenes and aryl halides to their
corresponding Heck products followed by Hydrogenation (1 atm)
to give the desired alkanes.17
1
Table 3. One-Pot Intramolecular Heck/Hydrogenation Reaction
pressure) and Pd/C gave 1.4 g of PZQ in a yield of 93%. The H
and 13C NMR analysis of our PZQ was consistent with those
reported in the literature.4f By this new approach, PZQ was
provided in 5 steps with an overall yield of 72%.
entry
Pd cat. (mol %)
cosolvent (ratio)
time (h)a
yield (%)b
1
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
–
120
72
48
72
48
48
9
2
3c
MeOH (1:1)
MeOH (1:5)
EtOH (1:5)
THF (1:5)
74
5
4
5
–
aHydrogenation times at balloon pressure. bIsolated yields. cReaction was
performed on a 1 gram scale.
Scheme 2. Gram Scale Synthesis of PZQ
Encouraged by this work, an effort for incorporating this one-
pot methodology into our PZQ synthesis was launched (Table 3).
Since our Heck reaction works well in the absence of the PPh3
ligand (Table 2) we commenced by first generating dehydro-PZQ
6 by reacting 5 with 20 mol % of Pd(OAc)2 in DMF. By using
this procedure, we avoid the need to remove PPh3 during
purification. The reaction was monitored by LC/MS and went to
completion in 1 h. Next, the reaction mixture was allowed to stir
under a hydrogen atmosphere (balloon pressure) at room
temperature. After 48 h, no PZQ was detected as determined by
TLC. The reaction was allowed to continue and after 120 h, PZQ
was isolated in 48% yield (Table 3, entry 1).
Due to the success of using this methodology to synthesize
PZQ, its use towards the generation of pyrazino[1,2-a] isoindole
(ring contracted) 10 and pyrazino[1,2-a] benzazepine (ring
expanded) 13 analogues of PZQ was conducted (Scheme 3).
Currently, there is only one report describing the synthesis of
10.14
Due to the long reaction time and low yield in DMF, it was
surmised that a new solvent system needed to be identified for
the Hydrogenation step. It was noted that an excellent yield of
PZQ during the Hydrogenation of Heck product 6 using MeOH
as the solvent (Scheme 2) was obtained. From this result, it
seemed reasonable for us to look at its use as a cosolvent during
the Hydrogenation step of our one-pot process. After running
our Heck reaction again to completion, degassed MeOH was
added to the reaction mixture to give a 1:1 ratio of DMF/MeOH.
As mentioned above, the reaction was stirred under a hydrogen
atmosphere and after 72 h, PZQ was isolated in a disappointing
9% yield (Table 3, entry 2). Not to be dismayed, we decided to
Scheme 3. Synthesis of PZQ Analogues
Ring expanded 13 was shown to be made by cyclizing a α-
hydroxy lactam under acidic condition.15 Both compounds 10 and
13 were found to have anthelmintic activity.14,15 To synthesize

4
Tetrahedron
ACCEPTED MANUSCRIPT
increase the amount of the MeOH cosolvent to give a 1:5
EtOAc/hexanes (1/19, v/v)). A 1M solution of HCl in methanol
DMF/MeOH. To our excitement, a 74% yield of PZQ was
generated after allowing the hydrogenation to run for 48 h (Table
3, entry 3). When EtOH and THF were looked at to determine
their usefulness as cosolvents, low yields or no PZQ product
(Table 3, entry 4 and 5) were observed. The success of our one-
pot reaction allows us to now generate PZQ in 4 steps with an
overall yield of 61%.
(20.0 mL) was then added to the reaction mixture that was stirred
under nitrogen at 0 °C until reaction completion in 30 min as
determined by TLC (SiO2, EtOAc/hexanes (2/3, v/v). The
reaction mixture was quenched with 50 mL of water, extracted
with ethyl acetate (3 × 50 mL), washed with saturated sodium
bicarbonate (10 mL), and then dried over anhydrous Na2SO4.
Purification by silica gel flash column chromatography (100%
hexanes: to remove tin by-products, followed by
3. Conclusion
methanol/dichloromethane
2−5%)
afforded
4-
cyclohexanecarbonyl-1,2-dihydro-2-pyrazinone 3 (8.9 g, 94%) as
a pale yellow solid (mp 160−163 °C dec). H NMR (CDCl3, 500
In conclusion, we have successfully demonstrated the use of
3-methoxy N-acylpyrazinium salts towards the synthesis of the
antischistosomal drug praziquantel (PZQ). By this method, ꢀ5-2-
oxopiperazine 3 can be easily made in one step. N-Alkylation of
3 followed by an intramolecular Heck and Hydrogenation
reactions allowed us to obtain PZQ in 5 steps and in good overall
yield. Taking advantage of the versatility of the Pd catalyst, we
developed a one-pot intramolecular Heck/Hydrogenation reaction
which reduced the number of steps in our PZQ synthesis. This
synthetic approach was shown to be well suited for preparing
ring contracted and expanded analogues of PZQ. The ability to
use 3-methoxy N-acylpyrazinium salts towards the generation of
other biologically active small molecules and natural products is
currently underway in our laboratory.
1
MHz) δ 8.71 and 8.38 (2 brs due to rotamers, 1H), 6.70 and 6.23
(2d due to rotamers, J = 5.5 Hz, J = 6.0 Hz, 1H), 5.75 and 5.70
(2t due to rotamers, J = 5.0, J = 6.0 Hz, 1H), 4.32 (s, 2H), 2.53
and 2.43 (2t due to rotamers, J = 11.5 Hz, J = 12.0 Hz, 1H)
1.87−1.66 (m, 4H), 1.58−1.46 (m, 2H), 1.35−1.20 (m, 4H). 13C
NMR (CDCl3, 125 MHz) δ 174.1, 173.9, 166.6, 164.95, 109.5,
109.2, 109.1, 108.9, 108.7, 48.3, 45.42, 41.0, 40.8, 28.9, 25.7,
25.6; HRMS (ESI) m/z calcd for C11H16NaN2O2 [M + Na]+
231.1104, found 231.1106.
4.1.2. General Procedure for the Tosylation of Phenethyl
Alcohols. Representative Procedure for the Preparation of 2-
Bromophenethyl 4-toluenesulfonate (4c).18
4. Experimental section
To a solution of p-toluenesulfonyl chloride (2.84 g, 14.9
mmol) and triethylamine (6.3 mL, 45.2 mmol) in 15 ml of
anhydrous dichloromethane at 0 °C, was added over 10 min, 2-
bromophenethyl alcohol (2.0 g, 9.9 mmol) then stirred under
nitrogen at room temperature for 16 h. The reaction mixture was
quenched into water (15 mL) extracted into dichloromethane (2 ×
30 mL), washed with saturated NaHCO3 (15 mL) and then
purified by silica gel column flash chromatography
(EtOAc/hexanes 0−30%) to afford 2-bromophenethyl 4-
toluenesulfonate 4c (3.4 g, 96%) as a white crystalline solid. mp
4.1. General information
All solvents and reagents were obtained from commercial
sources and used without further purification unless otherwise
stated Toluene and THF were dried using a solid-cartridge
solvent purification system. All reactions were performed in
oven-dried glassware (either in round-bottom flasks or 25 ml
vials fitted with rubber septa) under an atmosphere of nitrogen
and the reaction progress was monitored by thin-layer
chromatography, GC/MS (EI) and/or LC/MS (ESI-APCI).
Analytical thin-layer chromatography was performed on
precoated 250 ꢁm layer thickness silica gel 60 F254 plates and
precoated 170−220 ꢁm layer thickness neutral aluminum oxide
Si 60 F254 plates. Visualization was by ultraviolet light and/or by
staining with phosphomolybdic acid (PMA). Purifications were
carried out on flash silica gel columns with EtOAc/hexanes
mixtures as eluent. Melting points were measured on a capillary
melting point apparatus and are uncorrected. Proton nuclear
magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on a 500
MHz spectrometer. Chemical shifts (δ) for proton are reported in
parts per million (ppm) downfield from tetramethylsilane and are
referenced to it (TMS 0.0 ppm). Coupling constants (J) are
reported in Hertz. Multiplicities are reported using the following
abbreviations: br = broad; s = singlet; d = doublet; t = triplet; q =
quartet; m = multiplet. Chemical shifts (δ) for carbon are reported
in parts per million (ppm) downfield from tetramethylsilane and
are referenced to residual solvent peaks: (CDCl3 77.0 ppm).
Rotameric ratios of all compounds were determined by 1H NMR.
HRMS data was recorded on an LC-TOF.
1
38−39 °C (lit: mp 39−39.5 °C); H NMR (CDCl3, 500 MHz) δ
7.68 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.5 Hz, 1H), 7.26 (d, J =
8.0 Hz, 2H), 7.24−7.13 (m 2H), 7.08 (td, J = 2.0 Hz, J = 2.5 Hz,
J = 7.0 Hz, J = 7.5 Hz, J = 8.0 Hz, 1H), 4.24 (t, J = 7.0 Hz, 2H),
3.08 (t, J = 7.0 Hz, J = 6.5 Hz, 2H), 2.42 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 144.6, 135.4, 132.8, 132.7, 131.4, 129.7,
128.6, 127.7, 127.5, 124.3, 68.7, 35.6, 21.5.
3-(2-Bromophenyl)propyl 4-toluenesulfonate (4d):18: 88%
1
yield; white crystalline solid; mp: 40−42 °C; H NMR (CDCl3,
500 MHz) δ 7.80 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H),
7.35 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.0, J = 8.0 Hz, 1H), 7.10 (d,
J = 6.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 2H), 4.06 (t, J = 6.0 Hz, J =
6.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 1.97 (quintet, J = 6.0, J =
6.5, J = 7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 144.8,
139.7, 133.9, 130.5, 129.9, 128.0, 127.9, 127.5, 124.3, 69.6, 32.0,
28.8, 21.6; HRMS (ESI) m/z calcd for C16H17NaBrO3S [M+Na]+
390.9980, found 390.9962.
4.1.3. General Procedure for the Alkylation of 4-Cyclohexyl-
carbonyl-1,2-dihydro-2-pyrazinone
(3):
Representative
Procedure for the Preparation of 4-Cyclohexylcarbonyl-1-(2-
bromophenethyl)-1,2-dihydro-2-pyrazinone (5)
4.1.1. Preparation of 4-Cyclohexylcarbonyl-1,2-dihydro-2-
4-Cyclohexanecarbonyl-2-pyrazinone (3.0 g, 14.4 mmol),
cesium carbonate (7.13 g, 21.9 mmol) and 2-(2-
bromophenyl)ethyl 4-toluenesulfonate (5.63 g, 15.9 mmol) in 75
mL of anhydrous THF was flushed with nitrogen and then heated
at reflux for 36 h. The reaction mixture was quenched with 15
mL of water, extracted with ethyl acetate (3 × 40 mL), dried over
Na2SO4 then purified by silica gel flash column chromatography
(EtOAc/hexanes 5−75%) to afford 4-cyclohexylcarbonyl-1-(2-
pyrazinone (3)
To a solution of 2-methoxypyrazine (5.0 g, 45.4 mmol), in 40
ml of anhydrous THF was added tributyltin hydride (15.0 mL,
54.9 mmol) and the resulting solution stirred under nitrogen at 0
°C. Cyclohexylcarbonyl chloride (8.0 mL, 59.8 mmol) was
added over 10 min and stirring continued until reaction
completion in 20 min as determined by TLC (neutral alumina,

bromophenethyl)-1,2-dihydro-2-pyrazinone 5 (5.2 g, 92%) as an
a tan crystalline solid (68 : 32 mixture of rotamers). mp: 144−145
°C; 1H NMR (CDCl3, 500 MHz) δ 7.55 and 7.47 (2d due
rotamers, J = 8.0 Hz, J = 8.5 Hz) 1H), 7.31−7.15 (m, 3H), 7.33
and 6.77 (2s due to rotamers, 1H), 4.43 (s, 2H), 3.91 (t, J = 6.0
Hz, 2H), 2.92 (t, J = 5.5 Hz, J = 6.0 Hz, 2H), 2.65 and 2.50 (2t
due to rotamers, J = 11.5 Hz, J = 12.0 Hz, 1H), 1.92−1.68 (m,
5H), 1.63−1.49 (m, 2H), 1.50−1.20 (m, 3H); 13C NMR (CDCl3,
125 MHz) δ 174.1, 173.9, 163.9, 162.5, 134.1, 133.4, 128.6,
128.4, 128.2, 128.0, 127.8, 127.3, 123.2, 122.7, 121.6, 121.4,
106.2, 105.6, 48.3, 45.5, 41.1, 41.0, 38.6, 38.4, 29.0, 28.9, 28.8,
28.7, 25.7, 25.6; HRMS (ESI) m/z calcd for C19H23N2O2 [M+H]+
311.1754, found 311.1745.
ACCEPTED MANUSCRIPT
off-white to yellow amorphous solid (71:39 mixture of rotamers).
mp: 109−110 °C; 1H NMR (CDCl3, 500 MHz) δ 7.54 (d, J = 8.0
Hz, 1H), 7.25−7.20 (m, 2H), 7.13−7.09 (m, 1H), 6.63 and 6.10
(2d due to rotamers, J = 6.0 Hz, 1H), 5.52 and 5.40 (2d due to
rotamers, J = 6.0 Hz, 1H), 4.32 and 4.31 (2s due to rotamers,
2H), 3.77 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 7.0 Hz, J = 8.0 Hz, 2H),
2.53−2.38 (m, 1H), 1.89−1.66 (m, 5H), 1.58−1.46 (m, 2H),
1.36−1.19 (m, 3H); 13C NMR (CDCl3, 125 MHz) δ 173.8, 173.6,
163.7, 162.3, 137.5, 137.3, 132.9, 131.3, 131.1, 128.6, 127.7,
124.5, 114.0, 113.8, 109.5, 108.9, 48.7, 46.1, 46.0, 45.9, 40.9,
34.7, 28.9, 25.7; HRMS (ESI) m/z calcd for C19H24BrN2O2[M +
H]+ 391.1016, found 391.1009.
2-(Cyclohexanecarbonyl)-3,6,6a,10a-tetrahydropyrazino[2,1-
4-(Cyclohexanecarbonyl)-[3-(2-bromophenyl)propyl]-1,2-
a]isoindol-4-one (9): 85% yield; white crystalline solid (70:30
1
dihydro-2-pyrazinone (11): 86% yield; white crystalline solid
mixture of rotamers); mp19 166−168 °C; H NMR (CDCl3, 500
1
(78:22 mixture of rotamers); mp: 92−93°C; H NMR (CDCl3,
MHz) δ 7.55−7.44 (m, 1H), 7.41−7.29 (m, 3H), 6.75 (s, 1H),
4.92 and 4.91 (2s due to rotamers, 2H), 4.47 and 4.45 (2s due to
rotamers, 2H), 2.66 and 2.49 (2t due to rotamers, J = 11.5 Hz,
1H), 1.93−1.69 (m, 5H), 1.64−150 (m, 2H), 1.41−1.23 (m, 3H);
13C NMR (CDCl3, 125 MHz) δ 174.0, 173.8, 163.3, 161.7, 136.2,
135.5, 132.5, 132.2, 129.0, 128.8, 128.4, 128.3, 126.6, 123.5,
123.3, 120.0, 119.5, 101.5, 100.9, 50.6, 50.5, 48.6, 46.3, 41.4,
41.1, 29.1, 29.0, 25.8, 25.7, 25.5; HRMS (ESI) m/z calcd for
C18H21N2O2 [M+H]+ 297.1598, found 297.1589.
500 MHz) δ 7.52 (d, J = 7.5 Hz, 1H), 6.72 and 6.23 (2d due to
rotamers, J = 6.5 Hz, 1H), 5.65 and 5.58 (2d due to rotamers, J =
6.5 Hz, J = 6.0 Hz, 1H), 4.34 (s, 2H), 3.61 (t, J = 7.0 Hz, J = 7.5
Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), (m, 1H), (m, 2H, (m, 5H), (m,
2H), (m, 3H); 13C NMR (CDCl3, 500 MHz) δ:173.7, 173.6,
163.6, 162.3, 140.3, 132.9, 130.2, 127.9, 127.6, 124.3, 113.6,
113.3, 109.7, 109.3, 48.7, 45.9, 45.6, 45.4, 40.8, 33.3, 28.9, 28.8,
28.4, 28.2, 25.7, 25.6; HRMS (ESI) m/z calcd for
C20H25BrN2NaO2 [M + Na]+ 427.0992, found 427.0993.
2-(Cyclohexanecarbonyl)-3,6,7,8-tetrahydropyrazino[2,1-
4.1.4.
Preparation
of
4-[(2-Bromophenyl)methyl]-1-
a][2]benzazepin-4-one (12): 84% yield; white crystalline solid
(76:24 mixture of rotamers); mp 162−164 °C; H NMR (CDCl3,
1
(cyclohexylcarbonyl)-2H-pyrazin-3-one (8)
500 MHz) δ [7.46 (d, J = 6.0 Hz) and 7.40−7.13 (m, 4H)], 6.87
and 6.31 (2s due to rotamers, 1H), 4.44 (brs, 2H), 3.67 (brs, 2H),
2.78 (t, J = 6.5 Hz, J = 7.0 Hz, 2H), 2.61 and 2.50 (2t due to
rotamers, J = 6.5 Hz, J = 7.0 Hz, 1H), 2.04−1.67 (m, 6H),
1.62−1.49 (m, 3H), 1.36−1.21 (m, 3H); 13C NMR (CDCl3, 125
MHz) δ 173.9, 173.8, 164.2, 162.9, 138.3, 137.7, 132.7, 129.5,
129.2, 129.1, 128.9, 128.2, 128.0, 127.3, 127.2, 126.8, 108.5,
107.7, 48.5, 45.6, 41.0, 39.8, 39.6, 30.2, 29.0, 28.9, 26.0, 25.9,
25.7, 25.0; HRMS (ESI) m/z calcd for C20H25N2O2 [M+H]+
325.1911, found 325.1917.
To a stirring mixture of 4-cyclohexanecarbonyl-2-pyrazinone
(1.5 g, 7.2 mmol), sodium hydride (0.33 g, 8.25 mmol) and
tetrabutylammonium iodide (0.030 g, 0.081 mmol) in 23 mL of
THF/DMF (20/1, v/v) under nitrogen at 0 °C was added a
solution of 2-bromobenzyl bromide (2.1 g, 8.4 mmol) in 4 mL of
THF/DMF (20/1, v/v) over 10 min. After stirring for 6 h, the
reaction went to completion as determined by TLC (SiO2,
EtOAc/hexanes (2/3, v/v)). The reaction mixture was quenched
with 6.0 mL of water, extracted with dichloromethane (2 × 50
mL), dried over anhydrous Na2SO4 then purified by silica gel
flash column chromatography (0−30% EtOAc/hexanes) to afford
4-[(2-bromophenyl)methyl]-1-(cyclohexylcarbonyl)-2H-pyrazin-
3-one 8 (2.3 g, 85%) as a yellow oil (79:21 mixture of rotamers).
1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J = 7.0 Hz, 1H) 7.38−7.12
(m, 3H), 6.73 and 6.24 (2d due to rotamers, J = 6.0 Hz, J = 6.5
Hz, 1H), 5.66 and 5.60 (2d due to rotamers, J = 6.0 Hz, J = 6.0
Hz, 1H), 4.85 and 4.83 (2s due to rotamers, 2H), 4.43 (s, 2H),
2.50 (t, J = 11.05 Hz, 1H), 1.94−1.74 (m, 4H), 1.62−1.41 (m,
2H), 1.26 (brs, 4H); 13C NMR (CDCl3, 125 MHz) δ 173.8, 163.9,
162.6, 135.1, 134.8, 133.1, 129.7, 129.5, 129.4, 127.9, 123.5,
113.2, 112.8, 110.0, 109.6, 48.8, 48.7, 48.5, 45.9, 40.9, 28.9,
28.8, 25.7, 25.6; HRMS (ESI) m/z calcd for C18H21BrN2NaO2 [M
+ Na]+ 399.0679, found 399.0684.
4.1.6. General experimental procedure for the Hydrogenation of
compounds 6, 9 and 12: Representative Procedure for the
Preparation
of
2-(Cyclohexanecarbonyl)-5,6,10b,4a-
tetrahydropyrazino[2,1-a]isoquinolin-4-one
(Praziquantel)
(PZQ)
A
mixture of 2-(cyclohexanecarbonyl)-6,7-dihydro-3H-
pyrazino[2,1-a]isoquinolin-4-one 6 (1.50 g, 4.83 mmol), and
Pd/C (0.23 g, 15 wt %) in 100 mL of methanol was degassed and
then stirred at room temperature for 19 h under hydrogen at
balloon pressure. The reaction mixture was filtered through a
bed of diatomaceous earth and volatiles stripped under vacuum to
afford 1.51 g of the crude PZQ. The crude material was purified
by flash silica gel column chromatography (5−75%
EtOAc/hexanes) to afford Praziquantel (PZQ) (1.40 g, 93%) as a
white crystalline solid (77:23 mixture of rotamers). mp: 137−138
°C (lit20 mp: 137−138 °C); 1H NMR (CDCl3, 500 MHz) δ
7.37−7.11 (m, 4H), 5.16 (dd, J = 13.5. Hz, J = 2.5. Hz, 1H),
4.94−4.74 (m, 2H), 4.47 and 4.37 (2d due to rotamers, J = 17.5
Hz, J = 13 Hz, 1H), 4.08 and 3.86 (2d due to rotamers, J = 18.0
Hz, J = 18.5 Hz, 1H), [3.26 (t, J = 10.5 Hz, J = 12.5 Hz,) and
3.04−2.75 (m, total 4H)], 2.61−2.41 (m, 1H), 1.97−1.65 (m, 4H),
1.65−1.45 (m, 2H), 1.45−1.19 (m, 4H). 13C NMR (CDCl3, 125
MHz) δ 174.8, 174.3, 165.6, 164.4, 135.5, 134.8, 132.8, 132.1,
129.7, 129.3, 127.7, 127.4, 127.1, 127.0, 125.5, 125.2, 55.8, 55.0,
49.6, 49.0, 46.3, 45.2, 40.8, 40.7, 39.1, 38.6, 29.5, 29.3, 29.0,
28.9, 28.7, 25.7; HRMS (ESI) m/z calcd for C19H25N2O2 [M+H]+
313.1911, found 313.1915.
4.1.5. General Experimental Procedure for the intramolecular
Heck reaction: Representative Procedure for the Preparation of
2-(Cyclohexanecarbonyl)-6,7-dihydro-3H-pyrazino[2,1-
a]isoquinolin-4-one (6)
A mixture of 4-cyclohexylcarbonyl-1-(2-bromophenethyl)-
1,2-dihydro-2-pyrazinone (2.5 g, 6.4 mmol), cesium carbonate
(3.13 g, 9.61 mmol) and tetrakis(triphenylphosphine) palladium
(0) (0.25 g, 0.22 mmol) in 40 mL of anhydrous DMF was
degassed and then heated at 80 °C for 18 h under nitrogen. The
volatiles were stripped under vacuum then the solid residue
purified by silica gel flash column chromatography
(EtOAc/hexanes 5−75%) to afford 2-(cyclohexanecarbonyl)-6,7-
dihydro-3H-pyrazino[2,1-a]isoquinolin-4-one 6 (1.9 g, 94%) as

6
Tetrahedron
ACCEPTED MANUSCRIPT
2. Hotez, P. J.; Molyneux, D. H.; Fenwick, A.; Ottesen, E.; Sachs, S.
2-(Cyclohexanecarbonyl)-1,3,6,10b-tetrahydropyrazino[2,1-
a]isoindol-4-one (10)21: 91% yield; white crystalline solid (73:27
mixture of rotamers); mp: 180−181 °C. 1H NMR (CDCl3, 500
MHz) δ 7.44−7.32 (m, 3H), 7.30 (d, J = 6.5 Hz, 1H), 5.21 (dd, J
= 3.5 Hz, J = 13.0 Hz, 1H), 5.17 (d, J = 15 Hz, 1H), 5.03 and
4.93 (2d due to rotamers, J = 9.0 Hz, J = 9.5 Hz, 1H), 4.68−4.56
(m, 1H), 4.47 and 4.52 (2d due to rotamers, J = 17.5 Hz, J =
12.5 Hz, 1H), 4.11 and 3.82 (2d due to rotamers, J = 17.0 Hz, J
= 18.5 Hz, 1H), 3.20 and 2.71 (2t due to rotamers, J = 12.0 Hz,
1H), 2.57 and 2.47 (2m due to rotamers J = 3.0 Hz, 3.5 Hz, 11.0
Hz, 11.5 Hz, 12.0 Hz, 1H), 1.94−1.67 (m, 5H), 1.67−1.48 (m,
2H), 1.48−1.21 (m, 3H). 13C NMR (CDCl3, 125 MHz) δ 175.1,
174.6, 165.3, 164.1, 137.0, 136.7, 136.4, 136.1, 129.2, 128.9,
128.1, 127.94123.5, 123.2, 122.4, 122.1, 61.8, 61.3, 51.1, 50.9,
48.6, 47.64, 46.7, 43.8, 41.2, 29.3, 29.1, 29.0, 25.7. HRMS (ESI)
m/z calcd for C18H22N2NaO2 [M+Na]+ 321.1579, found 321.1570.
E.; Sachs, J. D. PLoS Med. 2006, 3, e102.
3. (a) King, C. H. Acta Trop. 2010, 113, 95-104. (b) King, C.H.;
Dangerfield-Cha, M. Chronic Illn. 2008, 4: 65-79 (c) Hotez, P. J.;
Molyneux, D. H.; Fenwick, A.; Kumaresan, J.; Sachs, S. E.;
Sachs, J. D.; Savioli, L. N. Engl. J. Med. 2007, 357, 1018-27.
4. (a) Sadhu, P. S.; Kumar, S. N.; Chandrasekharam, M.; Pica-
Mattoccia, L.; Cioli, D.; Rao, V. J. Bioorg. Med. Chem. Lett.
2012, 22, 1103-1106. (b) Cao, H.; Liu, H.; Doemling, A. Chem.
Eur. J. 2010 16, 12296-12298. (c) El-Fayyoumy, S.; Mansour, W.;
Todd, M. H. Tetrahedron Lett. 2006, 47, 1287-1290. (d)
Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron:
Asymmetry 2006, 17, 1415-1419.(e) Ma, C.; Zhang, Q.-F.; Tan,
Y.-B.; Wang, L. J. Chem. Res. 2004, 3, 186-187. (f) Todd, M. H.;
Ndubaku, C.; Bartlett, P. A. J. Org. Chem 2002, 67, 3985-3988.
(g) Kim, J. H.; Lee, Y. S.; Kim, C. S. Heterocycles. 1998, 48,
2279-2285. (h) Yuste, F.; Pallas, Y.; Barrios, H.; Ortiz, B.;
Sanchez-Obregon, R. J. Heterocycl. Chem. 1986, 23, 189-90. (i)
Seubert, J.; Pohlke, R.; Loebich, F. Experientia 1977, 33, 1036.
5. (a) Wang, W-L.; Song, L-J.; Chen, X.; Yin, X-R.; Fan, W-H.;
Wang,;G-P.; Yu, C-X.; Feng, B. Molecules 2013, 18, 9163-9178.
(b) Liu, H.; William, S.; Herdtweck, E.; Botros, S.; Domling, A.
Chem Biol Drug Des.2012, 1-8. (c) Sadhu, P. S.; Kumar, S. N.;
Chandrasekharam, M.; Pica-Mattoccia, L.; Cioli, D.; Rao, V. J.
Bioorg. Med. Chem. Lett. 2012, 22, 1103-1106. (d) Dong, Y.;
Chollet, J.; Vargas, M.; Mansour, N. R.; Bickle, Q.; Alnouti, Y.;
Huang, J.; Keiser, J.; Vennerstrom, J. L. Bioorg. Med. Chem. Lett.
2010. 20, 2481–2484. (e) Ronketti, F.; Ramana, V.; Chao-Ming,
X.; Pica-Mattoccia, L.; Ciolic, D.; Todd, M. H. Bioorg. Med.
Chem. Lett. 2007, 17, 4154–4157.
2-(Cyclohexanecarbonyl)-1,3,6,7,8,12b
hexahydropyrazino[2,1-a][2]benzazepin-4-one (13)22: 74% yield;
white crystalline solid (70:30 mixture of rotamers); mp 187−189
°C; 1H NMR (CDCl3, 500 MHz) δ 7.36−7.10 (m, 4H), 4.94−4.70
(m, 1H), 4.50−4.25 (m, 2H), [4.11 (d, J = 17.0 Hz), 3.97 (d, J =
13.5 Hz), 3.85 (d, J = 19.0 Hz), 1H], 3.70−3.53 (m, 2H),
3.04−2.98 (m, 2H), 2.79−2.62 (m, 1H), 2.45 (t, J = 11.0 Hz, J =
11.5 Hz, 1H), 2.33−2.08 (m, 1H), 1.97−1.45 (m, 7H), 1.39−1.19
(m, 3H). 13C NMR (CDCl3, 125 MHz) δ 174.9, 174.4, 162.7,
164.5, 138.6, 138.5, 135.6, 135.0, 130.9, 130.6, 128.9, 128.5,
127.3, 127.1, 63.2, 61.4, 48.5, 48.4, 46.3, 44.3, 44.0, 42.6, 40.9,
40.8, 31.6, 30.5, 29.5, 29.1, 29.0, 25.7, 25.3, 25.1; HRMS (ESI)
m/z calcd for C20 H26 N2 O2 [M+H]+ 327.2067, found 327.2071.
6. (a)Sharma, L. K.; Cupit, P. M.; Goronga, T.; Webba, T. R.;
Cunningham, C. Bioorg. Med. Chem. Lett. 2014, 24, 2469–2472.
(b) Zheng, Y.; Dong, L.; Hua, C.; Zhao, B.; Yang, c.; Xia, C.
Bioorg. Med. Chem. Lett. 2014, 24, 4223–4226.
7. Williams, A. L.; St Hilaire, V. R.; Lee, T. J. Org. Chem 2012, 77,
4097–4102.
8. To the best of our knowledge, only one other method for making
dehydro-PZQ 6 has been reported in the literature. This method
involves the oxidation of PZQ with sulfur: Kiec-Kononowicz, K.
Archiv. Pharm. 1989, 322, 795-799.
9. (a) Icelo-Avila, E.; Amador-Sanchez, Y. A.; Polindara-Garcia, L.
A.; Miranda, L. D. Org. Biomol. Chem. 2017, 15, 360-372. (b)
Chen, A.; Zhao, K.; Zhang, H.; Gan, X.; Lei, M.; Hu, L. Monatsh
Chem 2012, 143, 825–830. (c) Wakchaure, P. B.; Easwar, S.;
Argade, N. P. Synthesis 2009, 10, 1667-1672. (d) Kirschbaum, S.;
Waldmann, H. J. Org. Chem. 1998. 63, 4936-4946. (e)
Kirschbaum, S.; Waldmann, H. Tetrahedron Lett. 1997, 38, 2829-
2832.
10. Shukla, U. K.; Khanna, J. M.; Sharma, S.; Anand, N.; Chatterjee,
R. K.; Sen, A. B. Indian J. Chem., Sect B 1983, 22B, 664-668.
11. 2-Bromophenethyl bromide and chloride were synthesized from
the corresponding alcohol.(a) Fensome, A.; Goldberg, J. A.;
McComas, C. C.; Mann, C. W.; Melenski, E. G.; Sabatucci, J. P.;
Woodward, R. P. WO 2008073956, 2008. (b) Bilodeau, F.;
Brochu, M-C.; Guimond, N.; Thesen, K. H.; Forgione, P. J. Org.
Chem. 2010, 75, 1550-1560.
4.1.7. Procedure for the one-pot Heck/Hydrogenation reaction:
Preparation
of
2-(Cyclohexanecarbonyl)-5,6,10b,4a-
tetrahydropyrazino[2,1-a]isoquinolin-4-one
(Praziquantel)
(PZQ):20
4-Cyclohexylcarbonyl-1-(2-bromophenethyl)-1,2-dihydro-2-
pyrazinone 5 (1.0 g, 2.56 mmol), cesium carbonate (1.25 g, 3.84
mmol) and palladium acetate (115 mg, 0.512 mmol) in 20 mL of
anhydrous DMF was degassed, stirred at 80 °C for 2.5 h under
nitrogen then cooled to ambient temperature. Next, anhydrous
methanol (100 mL) was added to the reaction mixture that was
again degassed, and then stirred under balloon pressure hydrogen
at ambient temperature for 48 h. The reaction mixture was
filtered through a bed of diatomaceous earth, volatiles stripped
under vacuum then the solid residue purified by silica gel flash
column chromatography (EtOAc/hexanes 5−75%) to afford
Praziquantel (PZQ) (0.59 g, 74%) as a white crystalline solid.
12. Tosylates 4c and 4d were prepared using standard literature
preparations. See experimental section..
13. Dandepally, S. R.; Williams, A. L. Tetrahedron Lett. 2009, 50,
1395–1398.
Acknowledgments
We gratefully acknowledge the Golden LEAF Foundation,
Rocky Mount, NC, for financial support in setting up the BRITE
Institute. We thank Dr. Srinivasa R. Dandepally (BRITE) for his
technical assistance on the N-alkylation reaction. HRMS data
were obtained at the North Carolina State University Department
of Chemistry Mass Spectrometry Facility.
14. Yang, Y.; Sun, D.; Yang, C.; Zhang, L. CN 102321088, 2012.
15. Brewer, M. D.; Burgess, M. N.; Dorgan, R. J. J.; Elliott, R. L.;
Mamalis, P.; Manger, B. R.; Webster, R. A. B. J. Med.Chem.
1989, 32, 2058-2062.
16. See supplementary data for dehydro-PZQ analogs 9 and 12 1H and
13C NMR spectra’s.
17. Geoghegan, K.; Kelleher, S.; Evans, P. J. Org. Chem 2011, 76,
2187-2194.
Appendix A. Supplementary data
18. Tosylates 4c and 4d were synthesized from the corresponding
alcohol: (a) Chandrasekhar, J.; Kozikowski, A. P.; Liu, J;
Tueckmantel, W.; Walker, J. R. WO 2010045212, 2010. (b)
Banwell, M. G.; Flynn, B. L. U.S 64691714, 2002.
Supplementary data related to this article can be found at
19. Decomposes with extensive charring at ~120 °C.
20. (a) Kim, J. H.; Lee, V. S.; Park, H.; Kim, C. S. Tetrahedron 1998,
54, 7395−7400. (b) Todd, M. H.; Ndubaku, C.; Bartlett, P. A. J.
Org. Chem 2002, 67, 3985-3988.
References and notes
21. Used Pd(OH)2/C as the catalyst.
22. Used Pt/C as the catalyst.
1. Cioli, D.; Pica-Mattoccia, L.; Archer, S. Pharmacol. Ther. 1995,
68, 35-85.

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