Construction of 3-arylpropylamines using Heck arylations. the total synthesis of cinacalcet hydrochloride, alverine, and tolpropamine

Article abstract of DOI:10.1016/j.tet.2013.10.014

New synthetic routes toward the commercial drugs cinacalcet hydrochloride, alverine, and tolpropamine were developed using a Heck-Matsuda arylation as the key-step. Several reaction conditions were evaluated for the Heck-Matsuda reaction using allylamine derivatives and arenediazonium salts. For cinacalcet hydrochloride, N-formylamide provided the best result, furnishing the synthetic target in a very high overall yield (75% over five steps). For alverine, the best results were obtained using a double Heck-Matsuda strategy, providing alverine in an excellent overall yield (69%) from N-acetyl diallylamine in three steps. Tolpropamine was synthesized in a 46% yield over five steps using an efficient reductive Heck-Matsuda arylation between p-bromo-methylcinnamate with 3-chloro tolyldiazonium salt, generating the ,diaryl propionate that was converted to tolpropamine.

Full text of DOI:10.1016/j.tet.2013.10.014

Tetrahedron xxx (2013) 1e9
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Construction of 3-arylpropylamines using Heck arylations. The total
synthesis of cinacalcet hydrochloride, alverine, and tolpropamine
*
Patrícia Prediger, Allan Ribeiro da Silva, Carlos Roque Duarte Correia
~
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, CEP 13084-971 Campinas, Sao Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
New synthetic routes toward the commercial drugs cinacalcet hydrochloride, alverine, and tolpropamine
were developed using a HeckeMatsuda arylation as the key-step. Several reaction conditions were
evaluated for the HeckeMatsuda reaction using allylamine derivatives and arenediazonium salts. For
cinacalcet hydrochloride, N-formylamide provided the best result, furnishing the synthetic target in
a very high overall yield (75% over five steps). For alverine, the best results were obtained using a double
HeckeMatsuda strategy, providing alverine in an excellent overall yield (69%) from N-acetyl diallylamine
in three steps. Tolpropamine was synthesized in a 46% yield over five steps using an efficient reductive
HeckeMatsuda arylation between p-bromo-methylcinnamate with 3-chloro tolyldiazonium salt, gen-
Received 20 August 2013
Received in revised form 26 September 2013
Accepted 7 October 2013
Available online xxx
Keywords:
Heck reaction
Arenediazonium salts
Cinacalcet hydrochloride
Alverine
erating the b,b-diaryl propionate that was converted to tolpropamine.
Ó 2013 Published by Elsevier Ltd.
Tolpropamine
1. Introduction
The Heck reaction is a powerful and general synthetic method
used to construct CeC bonds in a controlled fashion.1 Its synthetic
flexibility and compatibility with most organic functional groups
make it one of the most explored reactions promoted by palla-
dium.2 Heck arylations employing arenediazonium salts instead of
the conventional aryl halides or aryl triflates are usually known as
HeckeMatsuda reactions, recognizing the first applications of are-
nediazonium salts by Matsuda in the late 1970s. Arenediazonium
salts, particularly the tetrafluoroborates and hexafluorophosphates,
are easy to prepare, thermally stable, and safe to work with in
a regular organic laboratory. These diazonium salts make Heck
arylations operationally easy, fast, green, and economical.3 Fur-
thermore, HeckeMatsuda reactions are typically carried out under
mild, aerobic, and phosphine-free conditions.4 In recent years, the
HeckeMatsuda reaction has been extensively explored as a key step
during the synthesis of several bioactive compounds, such as
kavalactones,5 (R)-tolterodine,6 marinoquinoline A,7 VPC01091,8
pentabromopseudilin,9 3-arylindanone,10 and others (Fig. 1).11
Recently, we have reported an efficient substrate-directed Heck
reaction for the arylating allylic O-protected alcohols12 and allyl-
amine derivatives.13 In these reactions, the regioselectivity is
Fig. 1. Bioactive compounds synthesized using the HeckeMatsuda arylation.
controlled by complexation between the cationic Pd(II) center and
the carbonyl moiety on the substrate, providing arylated products
with high stereo- and regioselectivities. Using this strategy, we
completed the stereoselective synthesis of the bioactive aryl allyl-
amines naftifine 4 and abamines 5 in good overall yields starting
from allylamines (Scheme 1).
* Corresponding author. Fax: þ55 19 37883023; e-mail address: roque@iqm.
unicamp.br (C.R.D. Correia).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.10.014
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2
P. Prediger et al. / Tetrahedron xxx (2013) 1e9
Scheme 3. Synthesis of protected allylamine 12.
Scheme 1. Synthesis of naftifine 4 and abamines 5.
Scheme 4. Synthesis of N-formyl allylamine 13.
Based on our previous success with this strategy and to further
demonstrate the viability of substrate directed HeckeMatsuda
arylations, we decided to apply the HeckeMatsuda arylation to-
ward the synthesis of therapeutic compounds, highlighting its ad-
vantages and limitations (Scheme 2): cinacalcet hydrochloride 6,
alverine 7, and tolpropamine 8.
Subsequently, these substrates were used in the
HeckeMatsuda arylations (Table 1). First, N-Boc allylamine 12
(0.25 mmol) was treated with 3-trifluoromethyl benzenediazo-
nium tetrafluoroborate 2a (0.3 mmol) under our previously
established conditions: Pd2(dba)3 (4 mol %) as the catalyst, NaOAc
as the base, and benzonitrile as the solvent.13 However, no Heck
products were observed under these conditions (Table 1, entry 1).
Next, we attempted the HeckeMatsuda reaction under the
same conditions while using N-Boc-allylamine 12 and 4-
methoxybenzenediazonium salt 2b. This salt was chosen due to
its higher thermal stability and the good results obtained with it
during the Heck arylation of allylamide derivatives.13 When salt 2b
Scheme 2. Our synthetic targets.
was used, the corresponding product 14b (
isomer) was observed in good yields (80%) with an undesired in-
ternal -arylated product (trans- -aryl/ -aryl ratio: 88/12, Table 1,
g-arylation, trans-
b
g
b
2. Results and discussion
entry 2). The successful arylation of 12 using methoxy substituted
arenediazonium salt 2b revealed that this slow Heck reaction
allowed the 3-trifluoromethyl benzenediazonium salt 2a to de-
compose. The decreased performance of olefin 12 was evident
2.1. Synthesis of cinacalcet hydrochloride 6
This compound is an attractive first target because it has
a complex structure and proven medicinal use. This drug was the
first member of the calcimimetic class approved by the United
States Food and Drug Administration; this compound is marketed
as Sensipar and Mimpara. Calcimimetics are a class of orally active
drugs that decrease the secretion of the parathyroid hormone (PTH)
by activating calcium receptors. Cinacalcet is used therapeutically
to treat secondary hyperthyroidism in patients with chronic kidney
disease after being submitted to dialysis and to treat elevated cal-
cium levels in patients with parathyroid carcinoma.14
from the formation of the
b-arylated adduct. The b-arylated
product may form due to the steric hindrance caused by the tert-
butyl and naphthylmethyl groups in the substrate; these groups
most likely destabilize the proposed cyclic cationic palladium in-
termediate (Scheme 5). This hypothesis was confirmed when we
combined less sterically demanding substrate 13 with diazonium
salt 2a. Corresponding adduct 14c was isolated in 98% yield with
complete regio- and stereocontrol favoring the
mer (Table 1, entry 3).
g
-aryl, trans iso-
Several syntheses of cinacalcet hydrochloride 6 have already
been described in the literature.15 Classical approaches, such as the
condensation of the amine with a carboxylic acid,16 Suzuki and
Heck-oxidative couplings,17 as well as two large-scale approaches
involving the ForstereDecker reaction18 and Grignard reagent ad-
dition to a vinyl chloride.19 The only Heck-based approach toward
the synthesis of cinacalcet was described by Evans and co-workers,
using a conventional Heck reaction between methyl acrylate and
aryl bromide.20
Table 1
Heck arylation of allylamines 12 and 13a
CH3
CH3
γ
Pd2(dba)3 (4 mol%)
N2BF4
+
naphthyl
N
R
naphthyl
NaOAc, PhCN
N
R
Ar
β
Ar
rt, 1h
1.1 equiv
1.0 equiv
2a-b
14a-c
We began our synthesis of cinacalcet hydrochloride 6 by gen-
erating the protected allylamines. Therefore, (R)-1-(naphthalen-1-
yl)ethanamine 9 was treated with allyl bromide 10, furnishing
secondary amine 11 in 85% yield (Scheme 3). Subsequently, an N-
protection with di-tert-butyl dicarbonate was carried out in ace-
tonitrile at room temperature. N-Boc-protected 12 was isolated in
73% yield. To synthesize formylated allylamine 13, the mixed an-
hydride was prepared from acetic anhydride and formaldehyde and
added to secondary amine 11. Formyl allylamine 13 was produced
in 90% yield (Scheme 4).
Entry
Allylamine
Ar
Yield (%)
1
2
3
12
12
13
3-CF3C6H4, 2a
4-OMeC6H4, 2b
3-CF3C6H4, 2a
14a, d
14b, 80b
14c, 98
a
The reaction was carried in air using an allylamine derivative (0.25 mmol),
a diazonium salt (0.3 mmol), Pd2(dba)3 (4 mol %), and sodium acetate (3 equiv,
0.75 mmol, 0.061 g) dissolved in benzonitrile (1 mL) at room temperature for 1 h.
b
This reaction provided two products that were difficult to separate (a single spot
by TLC). The 88/12 ratio for the
g-trans/b-substituted products was determined
using 1H NMR analysis of the crude reaction mixture.
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P. Prediger et al. / Tetrahedron xxx (2013) 1e9
3
Table 2
Heck arylations of 16aec with diazonium salts 2b,ca
Me
Me
L
Me
L
O
Ar
Me
O
Ar
Pd
H
Pd
Me
Me
Me
O
O
N
Me
N
H
H
Scheme 5. Rationale for the lower regioselectivity during the arylation of N-Boc al-
lylamine 12.
After synthesizing the desired adduct, we carried out the
HeckeMatsuda reaction followed by an in situ reduction of the
double bond. Therefore, the Heck arylation was carried out under
the usual conditions. When the arylation was complete, the system
was purged with H2 without changing the solvent or palladium
catalyst. Gratifyingly, the expected reduction product 15 was ob-
tained in 98% over the two steps (Scheme 6). Next, 15 was defor-
mylated before the hydrochloride was formed using hydrochloric
acid at reflux. Desired cinacalcet hydrochloride 6 was obtained in
quantitative yield with an excellent overall yield (75%) over five
steps (Scheme 6).
Entry
R
Ar
Compound, yield (%)
trans/cis
1
Boc, 16a
Boc, 16a
Boc, 16a
CO2Et, 16b
Ac, 16c
C6H5, 2c
C6H5, 2c
4-OMeC6H4, 2b
4-OMeC6H4, 2b
4-OMeC6H4, 2b
C6H5, 2c
17a, traces
17a, d
d
2b
3
d
17b, 70c
84/16
d
4
5
6
17c, complex mixture
17d, 68d
85/15
87/13
Ac, 16c
17e, 85
a
The reaction was carried under air, by using diallylamine derivative 16aec
(0.25 mmol), diazonium salt (0.6 mmol), Pd2(dba)3 (8 mol %), sodium acetate
(3 equiv, 0.75 mmol, 0.061 g), and benzonitrile (1 mL).
b
The reaction was carried out at 80 ꢀC.
The monoarylated product was isolated in 25% yield.
The triarylated product was isolated in 25% yield.
c
d
we investigated the Heck reaction with 2b. To our satisfaction, the
expected coupling product (17b) was obtained in 70% isolated yield
with a trans/cis ratio of 84/16 (Table 2, entry 3).
Surprisingly, when using ethyl carbamate as the protecting
group, 2b did not furnish the expected Heck adduct (Table 2, entry
4). Due to these erratic results, we then decided to evaluate N-acetyl
protected allylamide 16c as a substrate for the Heck arylation.
When 16c was reacted with 2b, the desired Heck product 17d was
produced in a reasonable 68% yield with a trans/cis ratio of 85/15
(Table 2, entry 5). Although the stereoselectivity issue is irrelevant
in this case, it provides valuable information regarding the outcome
of the Heck reaction. We were able to isolate a triarylated product in
25% yield with the adduct 17d. Nevertheless, we applied the same
reaction conditions used during the arylation of 16c with 2c. This
time, the expected diarylated product 17e was obtained in 85% yield
with complete regiocontrol and good stereoselectivity favoring the
E isomer (ratio trans/cis 87/13, Table 2, entry 6). The outcome pro-
vided by the allylamide 16c was a bonus because this protecting
group fit into our strategy to prepare alverine with an ethyl group
on the nitrogen. After selecting the best substrate for the Heck re-
action, we carried out the one-pot Heck reaction/hydrogenation.
After the Heck arylation was complete, the system was purged with
H2 for 12 h at room temperature, similar to the procedure for
cinacalcet, to provide 18 in 72% isolated yield over two steps
(Scheme 7). Finally, the acetyl group was reduced using LiAlH4 (72%
yield) or AlH3 (96% yield), generating alverine (7) in only three steps
from 16c in excellent overall yield (69%) (Scheme 7).
Scheme 6. Synthesis of cinacalcet hydrochloride 6.
2.2. Synthesis of alverine 7
After completing the cinacalcet hydrochloride synthesis, we
turned our attention toward alverine (7). Alverine is a relaxant for
smooth muscle that is not under voluntary control, such as that
found in the gut and uterus. For example, the drug may act directly
in the gut muscle, causing it to relax while preventing muscle
spasms in conditions, such as irritable bowel syndrome and di-
verticulitis.21 The synthesis of alverine has been previously ac-
complished by alkylating secondary amines.22 We envisioned
a double substrate-directed Heck arylation with an allylamine de-
rivative followed by an in situ hydrogenation to synthesize alverine.
Because the protecting group on nitrogen is one of the groups
that complexes with the cationic palladium (II) species, the syn-
thetic approach began with a brief evaluation of the N-protecting
groups on the diallylamine moiety (Table 2). N-Boc diallylamine
16a was tested first because the Boc group was easy to install and
later remove. We decided to use the conditions optimized for
cinacalcet, except that 2 equiv of the benzenediazonium salt 2c and
8 mol % of the palladium catalyst were used (Table 2, entry 1).
However, under these reaction conditions, Heck adducts were not
observed. The reaction was subsequently carried out at 80 ꢀC, but
the desired Heck product was not observed (Table 2, entry 2).
Similar to the procedure adopted during the cinacalcet synthesis,
Scheme 7. Synthesis of alverine 7.
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4
P. Prediger et al. / Tetrahedron xxx (2013) 1e9
2.3. Synthesis of tolpropamine 8
room temperature and then at 45 ꢀC, slightly improved the yield of
the diarylated product (Table 3, entry 3). Warming the reaction
from 45 ꢀC to 60 ꢀC in the second step provided the diarylated
products in 61% yield with a better mono/diarylated ratio (0.4/1.0)
(Table 3, entry 4). The presence of the monoarylated adduct could
be attributed to the decomposition of the diazonium salt under the
reaction conditions; therefore, we decided to add the diazonium
salt with the catalyst in three portions (Table 3, entry 5). Gratify-
ingly, we no longer observed the monoarylated product. The dia-
rylated adducts were isolated in 80% yield as a complex mixture of
compounds (20/21/22 ratio of 80/15/5). Carrying out the reaction in
a microwave reactor led to a slight decrease in yield but provided
good selectivity (Table 3, entry 6).
Tolpropamine is an antihistamine and an antipruritic drug used
to treat skin conditions, such as allergies and itching.23 Previous
syntheses relied on the Wittig reaction to obtain the 1-phenyl-1-(p-
tolyl)ethane structure, followed by a hydroaminomethylation using
rhodium catalysis.24 However, this methodology does not enable
enantioselective syntheses to be developed for this drug.
The synthesis of tolpropamine contained the challenging con-
struction of a non-symmetrical diarylmethane moiety. Because
a minor amount of triarylated product was present during the Heck
arylation of olefin 16c (not shown in Scheme 7), we initially pro-
posed that the diarylation/hydrogenation of allyl phthalimide 19,
followed by deprotection/methylation would be somewhat
straightforward. This strategy would also facilitate the stereo-
selective synthesis of tolpropamine.
We turned our attention toward the Heck diarylation of allyl
phthalimide 19 using 2b for the model reaction (Table 3). Again,
this diazonium salt was chosen for its thermal stability and good
reactivity.13 Therefore, allyl phthalimide 19 (0.25 mmol) was
treated with diazonium salt 2b (1.0 mmol), using the previously
established conditions: Pd2(dba)3 (8 mol %) and NaOAc, in benzo-
Because the g,g-diarylated product 20 could not be obtained as
a single compound and the isomeric mixture is difficult to separate,
we envisioned a sequential arylation process as a viable alternative
(Scheme 8). The HeckeMatsuda monoarylation of allyl phthalimide
19 afforded a mixture of monoarylated products (23e25) in a 96/2/
2 ratio, from which the g-trans isomer could be isolated in 83% yield
after a recrystallization in chloroform. With 23 in hand, we carried
out the second arylation as described in Scheme 8 to obtain the
desired g,g-adduct 20 together with significant amounts of the b,g
nitrile at room temperature (Table 3, entry 1). Surprisingly, the
g-
adduct 21 (82% total yield in an 85:15 ratio).
trans-monoarylated product was obtained as the major product in
a 1.5/1.0 ratio of mono/diarylated products. The desired diarylated
products were isolated in 39% yield as an isomeric mixture favoring
g,g-diarylated adduct 20 (ratio 20/21/22: 84/10/6).
Table 3
HeckeMatsuda diarylation of allyl phthalimide 19a
#
Equiv,
2b
T (ꢀC)/time
Diarylated
yield (%)
Ratio 20/
21/22
Ratio mono/
diarylated
1
2
3
4
4
rt/12 h
60/2 h
39
42
49
84/10/6
83/11/6
80/12/8
1.5/1.0
1.2/1.0
0.9/1.0
(1) 1.2
(2) 1.2
(1) 1.2
(2) 1.2
(1) 1.2
(2) 1.2
(3) 1.2
(1) 1.2
(2) 1.2
(3) 1.2
(1) rt/1 h
(2) 45/3 h
(1) rt/1 h
(2) 60/3 h
(1) rt/1 h
(2) 60/1.5 h
(3) 60/1.5 h
(1) rt/1 h
4
5
61
80
83/11/6
80/15/5
0.4/1.0
0/1.0
Scheme 8. Synthesis of the diarylated adduct 20.
The modest regioselectivity of the second arylation step forced
us to review our strategy toward synthesizing tolpropamine. Sub-
sequently, we planned to synthesize tolpropamine using a re-
ductive HeckeMatsuda arylation of methyl cinnamate (28) and
arenediazonium salt 2, followed by amidation and posterior re-
duction, as depicted in Scheme 9.
6
71
83/11/6
0/1.0
(2)
(3)
m
m
W 60 ꢀC/1 h
W 60 ꢀC/1 h
a
The reaction was carried in air using allyl phthalimide 19 (0.25 mmol), 4-
methoxybenzenediazonium tetrafluoroborate 2b, Pd2(dba)3, and sodium acetate
(3 equiv, 0.75 mmol, 0.061 g) dissolved in benzonitrile (2 mL). The progress of the
reaction was monitored using the evolution of N2. The yields refer to mixtures of the
three isomers (a single spot by TLC). Compounds 20e22 were separated by pre-
parative HPLC and fully characterized. The ratio between the regioisomers and the
mono/diarylated products was based on the integrations of the appropriate signals
in the 1H NMR spectra. See the SD for further details.
To increase the consumption of the monoarylated adduct, we
carried out the reaction at 60 ꢀC (Table 3, entry 2). After 2 h, the
diazonium salt was completely consumed, but no significant im-
provements concerning the yields and product ratios were ob-
served (Table 3, entry 2). Adding the diazonium salt and the
Pd2(dba)3 portionwise (2ꢁ1.2 equiv; 2ꢁ2 mol %, respectively), at
Scheme 9. Alternative strategy for the synthesis of tolpropamine.
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P. Prediger et al. / Tetrahedron xxx (2013) 1e9
5
We began the new route with a Heck arylation using commer-
cially available 28a with the p-tolyldiazonium salt under the opti-
mized conditions: Pd(OAc)2 (7 mol %) in methanol at 60 ꢀC (Table 4,
entry 1).25 However, only traces of the desired Heck product 29a
were observed. When using NaOAc (2 equiv) as the base, the Heck
adduct was isolated in 42% yield, favoring the E-isomer 29a;
therefore, base was essential for the reaction (Table 4, entry 2). Using
4 equiv of the p-tolyldiazonium salt led to an increase in the yield of
29a (68%; Table 4, entry 3) but also a more complex reaction mix-
ture. Changing the base to a substituted pyridine generated only
trace amounts of the Heck adduct (Table 4, entry 4). Because the
electronics of the reaction partners are also important for a suc-
cessful Heck arylations, we evaluated different cinnamates and di-
azonium salts containing halogens; halogens may be easily removed
later. When using 1.5 equiv of 4-bromobenzene diazonium salt
and 4-methyl cinnamate 28b, low conversion of starting material
was observed (Table 4, entry 5). However, with methyl 4-
bromocinnamate 28c and 3-chloro-4-methylbenzenediazonium
tetrafluoroborate, the corresponding Heck adducts were isolated
in 60% yield with an E/Z ratio of 75:25 (Table 4, entry 6). Due to the
good performance of the 3-chloro-4-methylbenzenediazonium salt,
we carried out a reaction using this diazonium salt with methyl
cinnamate 28a using CaCO3 as the base, providing 29d in 88% yield
with good stereoselectivity (E/Z ratio, 71:29, Table 4, entry 7). No-
tably, 4-bromo-cinnamate (28c) provided 29c in 83% yield, strongly
favoring the isomer E (E/Z ratio of 92:8, Table 3, entry 8).
Scheme 10. Synthesis of tolpropamine 8.
3. Conclusion
In summary, we describe an efficient, mild, and operationally
simple room temperature Heck arylation in an open-flask using
allylamine derivatives and methyl cinnamates with arenediazo-
nium tetrafluoroborates. The HeckeMatsuda/hydrogenation re-
actions proceeded with superb regio- and stereochemical control to
afford the corresponding arylated allylamine derivatives in good to
excellent yields. Using this HeckeMatsuda method, new synthetic
routes toward three commercial drugs (cinacalcet hydrochloride,
alverine, and tolpropamine) were developed. For cinacalcet hy-
drochloride, the N-formylamide provided the best results, fur-
nishing the synthetic target in 75% yield over five steps. For
alverine, best results were obtained using a double HeckeMatsuda
strategy that provided the product in 69% yield overall from N-
acetyl diallylamine over three steps. The synthesis of tolpropamine
was achieved in 46% yield over five steps and featured a reductive
Heck arylation between p-bromo-methylcinnamate and 3-chloro
Table 4
Heck arylation of methyl cinnamates 28aeca
Entry
Base
(equiv)
2def
(equiv)
R1
R2
R3
E/Z
Compound,
yield (%)
1b
2
3
4
5
d
4, 2d
2, 2d
4, 2d
1.5, 2d
1.5, 2e
1.5, 2f
1.5, 2f
1.5, 2f
H
H
H
H
Me
Br
H
Me
Me
Me
Me
Br
Me
Me
Me
H
H
H
H
H
Cl
Cl
Cl
d
29a, trace
29a, 42
29a, 68
29a, trace
29b, trace
29c, 60
NaOAc (3)
NaOAc (3)
DTMPy (1)
NaOAc (3)
NaOAc (3)
CaCO3 (1)
CaCO3 (1)
100/0
95/5
d
tolyldiazonium salt; the resulting product, b,b-diaryl propionate,
was converted to tolpropamine in a straightforward manner.
d
6
75/25
71/29
92/8
7c
8c
29d, 88
29c, 83
4. Experimental section
4.1. General
Br
a
Reactions performed in the presence of methyl cinnamate 28aec (0.25 mmol),
arenediazonium salt 2def, Pd(OAc)2 (7 mol %), base, MeOH (5.0 mL) at 60 ꢀC, during
1 h.
Proton nuclear magnetic resonance spectra (1H NMR) were
obtained at 250 MHz, 300 MHz, 400 MHz, 500 MHz and 600 MHz.
The spectra were recorded in CDCl3, DMSO-d6, or MeOD solutions.
The chemical shifts are reported in parts per million and referenced
to the residual solvent peak or tetramethylsilane (TMS). The data
b
The reaction was stirred during 2 h.
The reaction was stirred for 1.5 h.
c
After establishing the best conditions to obtain the
HeckeMatsuda adduct 29c stereoselectively, we planned the ra-
cemic synthesis of tolpropamine
8
(Scheme 10). First,
are reported as follows: chemical shift (d), multiplicity, coupling
a HeckeMatsuda reaction was carried out to obtain 29c, followed
by hydrogenation in situ (NaHCO3 was added before purging with
H2 at room temperature). This procedure provided dehalogenated
and reduced adduct 30 in 92% yield using a one-pot procedure.
Next, 30 was hydrolyzed using refluxing KOH to obtain the corre-
sponding carboxylic acid 31 in 80% yield. The isolated carboxylic
acid was treated with dimethylamine, EDC$HCl, and HOBt, to pro-
vide dimethylamide 32 in 77% yield. Finally, amide 32 was reduced
with AlH3 at 60 ꢀC to complete the synthesis of tolpropamine (8) in
81% yield. Tolpropamine 8 was obtained in five steps in a 46%
overall yield.
constant (J) in Hertz and integrated intensity. Carbon-13 nuclear
magnetic resonance spectra (13C NMR) were obtained at 62.5 MHz,
75 MHz, 100 MHz, 125 MHz, and 150 MHz. The spectra were
recorded in CDCl3 or DMSO-d6 solutions. Abbreviations denoting
the multiplicity of a particular signal include s (singlet), sl (singlet
large), d (doublet), t (triplet), q (quartet), dd (double doublet), dt
(double triplet), ddd (double double doublet), tdd (triple double
doublet), and m (multiplet). The microwave reactions were con-
ducted in a CEM DiscoverÒ Microwave synthesizer. The equipment
consisted of a continuous, focused microwave-power delivery
system with an operator-selected power output ranging from 0 to
Please cite this article in press as: Prediger, P.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.014

6
P. Prediger et al. / Tetrahedron xxx (2013) 1e9
300 W. The reactions were performed in glass vessels (capacity
10 mL) sealed with a septum. Temperature measurements were
conducted using an infrared temperature sensor mounted in the
reaction vessel. All experiments were performed with stirring using
a rotating magnetic plate located below the floor of the microwave
cavity with a Teflon-coated magnetic stir bar inside the vessel. All
experiments were carried out with simultaneous cooling provided
by passing compressed air through the microwave cavity while
heating (option PowerMAX enabled). Column chromatography was
performed using silica gel (230e400 mesh) following the method
described by Still.26 Thin layer chromatography (TLC) was per-
formed using silica gel plates (GF254, 0.25 mm thickness). For vi-
sualization, the TLC plates were either placed under ultraviolet light
or stained with phosphomolybdic acid, followed by heating. Air-
and moisture-sensitive reactions were conducted in flame- or
oven-dried glassware equipped with a tightly fitted rubber septum
under a positive atmosphere of dry argon. The reagents and sol-
vents were handled using standard syringe techniques. Tempera-
tures above room temperature were maintained using a mineral oil
bath heated on a hotplate. All reagents purchased from commercial
suppliers were used as received, except the reagents that were
freshly distilled, as detailed in the Experimental section.
Some of the compounds synthesized by the HeckeMatsuda
reaction of the allylic systems were mixtures of structural isomers
that appeared as a single spot by TLC and were extremely difficult
to separate by flash chromatography. These products were ana-
lyzed as mixtures and the ratios between their components were
based on characteristic peaks belonging to each specific isomer in
the 1H NMR spectra. The reader should refer to the pure diarylated
isomers 20e22 isolated by preparative HPLC and fully character-
ized as pure compounds. Their spectra appear in the
Supplementary data section. When applicable, a reference is also
made to the presence of rotamers, which are common when
dealing with amides and formamides.
removed under reduced pressure to afford an oil residue. This re-
action mixture was washed with saturated NaHCO3 (3ꢁ30 mL) and
dried over MgSO4. After filtration, the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (hexanes/ethyl acetate 40:60 as eluent, Rf¼0.70) to
furnish compound 13 as a colorless oil. Yield: 1.17 g (90%). Rf¼0.70.
TLC stain: ultraviolet and iodine. ½a D20
ꢂ
þ122.8 (c 0.57, MeOH). 1H
NMR: CDCl3, 250 MHz, 25 ꢀC, (ppm) rotamers (The 1H NMR shows
d
the presence of two rotamers in a ratio of 0.34/0.66): 8.55 (s, 0.34H),
8.20 (s, 0.66H), 8.01e7.82 (m, 3H), 7.57e7.42 (m, 4H), 6.42 (q,
J¼7.0 Hz, 0.66H), 5.73e5.21 (m, 1.34H), 5.01e4.81 (m, 2H),
4.01e3.93 (m, 0.34H), 3.66e3.29 (m, 1.66H), 1.81 (d, J¼7.0 Hz, 1H),
1.69 (d, J¼7.0 Hz, 2H). 1H NMR: DMSO-d6, 500 MHz,120 ꢀC,
d (ppm):
8.36 (s, 1H), 8.05 (d, J¼8.0 Hz, 1H), 7.94e7.86 (m, 2H), 7.64e7.48 (m,
4H), 5.95 (sl,1H), 5.55e5.44 (m,1H), 4.94e4.84 (m, 2H), 3.68 (s, 2H),
1.71 (d, J¼6.8 Hz, 3H). 13C NMR: DMSO-d6,125 MHz,120 ꢀC,
d (ppm):
162.4,162.4,135.5,135.2,134.7,133.6,133.3,133.1,131.2,130.7,128.7,
128.5, 128.4, 126.3, 125.6, 125.6, 125.0, 124.9, 124.3, 122.8, 122.6,
116.3, 116.1, 51.7, 45.4, 42.8, 19.7, 17.0.
4.2.3. (R)-(E)-N-(1-(Naphthalen-1-yl)ethyl)-N-(3-(3-(tri-
fluoromethyl)phenyl)allyl)formamide (14c). To an open round-
bottomed flask (or a test tube) equipped with a magnetic stir bar
were added Pd2(dba)3 (4 mol %, 10 mg), sodium acetate (3 equiv,
0.75 mmol, 0.061 g), and benzonitrile (1.0 mL). To the resulting
suspension was added allylamine derivative 13 (0.30 mmol,
0.071 g), followed by 3-(trifluoromethyl)benzenediazonium tetra-
fluoroborate (0.25 mmol, 0.065 g). The reaction was stirred at room
temperature for 1 h. Subsequently, the reaction mixture was fil-
tered through a plug of silica gel with ethyl acetate and concen-
trated under reduced pressure. The product was purified by flash
chromatography (hexanes/ethyl acetate 60:40 as eluent, Rf¼0.65)
to provide the corresponding arylated product 14c as a colorless oil.
Yield: 0.091 g (98%). Rf¼0.65. TLC stain: ultraviolet and phospho-
molybdic acid. ½a D20
ꢂ
þ4.5 (c 0.42, MeOH). The 1H NMR and 13C NMR
4.2. Synthesis of cinacalcet hydrochloride 6
spectra show the presence of two rotamers in 0.40:0.60 ratio. 1H
NMR: CDCl3, 250 MHz, 25 ꢀC,
d (ppm): 8.62 (s, 0.4H), 8.26 (s, 0.6H),
4.2.1. (R)-N-(1-(Naphthalen-1-yl)ethyl)prop-2-en-1-amine
(11).27 Amine 9 (0.48 mL, 3.0 mmol), triethylamine (0.44 mL,
3.2 mmol), and THF (6.0 mL) were placed in a flame dried round-
bottomed flask equipped with a magnetic stir bar under a nitro-
gen atmosphere. Next, allyl bromide 10 (0.26 mL, 0.3 mmol) was
added dropwise. The system was stirred for 12 h before EtOAc
(20 mL) was added. The reaction was washed with saturated
NaHCO3 (3ꢁ10 mL) and extracted; the combined organic layers
were dried over MgSO4. After filtration, the solvent was removed
under reduced pressure to afford a yellow oil corresponding to (R)-
N-(1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine. The product was
then purified by flash chromatography (hexanes/ethyl acetate
40:60 as the eluent, Rf¼0.55) to provide compound 11 as a yellow
8.0 (d, J¼8.4 Hz, 0.6H), 7.91 (d, J¼8.4 Hz, 0.4H), 7.81e7.74 (m, 2H),
7.59e7.38 (m, 5H), 7.30e7.25 (m, 1.2H), 7.15e7.12 (m, 0.8H), 7.01 (s,
1H), 6.47 (q, J¼6.9 Hz, 0.6H), 6.01e5.87 (m, 1H), 5.74 (dt, J¼6.4,
16.0 Hz, 0.4H), 5.56 (q, J¼7.0 Hz, 0.4H), 5.40 (dt, J¼6.4, 16.0 Hz,
0.6H), 4.17 (dd, J¼5.7, 16.0 Hz, 0.4H), 3.71e3.61 (m, 1.6H), 1.82 (d,
J¼7.0 Hz, 1.2H), 1.71 (d, J¼7.0 Hz, 1.8H). 1H NMR: 500 MHz, DMSO-
d6, 120 ꢀC,
d
(ppm): 8.43 (sl, 1H), 8.09 (d, J¼8.2 Hz, 1H), 7.83 (t,
J¼8.5 Hz, 2H), 7.67 (d, J¼7.0 Hz, 1H), 7.56e7.38 (m, 5H), 7.27e7.21
(m, 2H), 6.18 (d, J¼16.0 Hz, 1H), 6.00 (sl, 1H), 5.78e5.72 (m, 1H),
3.91e3.78 (m, 2H), 1.75 (d, J¼6.7 Hz, 3H). 13C NMR: 125 MHz,
DMSO-d6, 25 ꢀCdrotamers,
d (ppm): 162.7,162.6,137.2, 137.0,135.0,
134.8, 133.3, 133.1, 131.4, 130.9, 129.6, 129.4, 129.3, 129.0 (q,
J¼31.0 Hz, 1C), 128.9, 128.7, 128.5, 128.4, 127.5, 126.4, 125.6, 125.1,
125.1, 124.7 (q, J¼272.0 Hz, 1C), 124.5, 123.6 (q, J¼3.5 Hz, 1C), 122.9,
122.8,121.9 (q, J¼3.5 Hz,1C), 51.6, 45.3, 44.6, 41.5,19.5, 16.8. IR (film,
cmꢃ1): 1666, 1512, 1395, 1331, 1164, 1124. MS (EI): 384 (Mþ1), 309,
230, 155. HRMS calcd for C23H21F3NO: 384.1573. Found¼384.1575.
oil. Yield: 0.53 g (85%). TLC stain: ultraviolet and ninhydrin. ½a D20
ꢂ
þ11.2 (c 2.03, MeOH). 1H NMR: CDCl3, 250 MHz,
d (ppm): 8.12 (d,
J¼7.6 Hz, 1H), 7.80e7.76 (m, 1H), 7.67e7.61 (m, 2H), 7.43e7.37 (m,
3H), 5.90 (ddt, J1¼17.0 Hz, J2¼10.4 Hz, J3¼6.5 Hz, 1H), 5.13e5.00 (m,
2H), 4.60 (q, J¼6.5 Hz, 1H), 3.15e3.12 (m, 2H), 1.43 (d, J¼6.5 Hz, 3H).
13C NMR: CDCl3, 62.5 MHz,
d
(ppm): 140.8, 136.8, 133.7, 131.1, 128.7,
4.2.4. (R)-N-(1-(Naphthalen-1-yl)ethyl)-N-(3-(3-(trifluoromethyl)
phenyl)propyl)formamide (15). To an open round-bottomed flask
(or a test tube) equipped with a magnetic stir bar were added
Pd2(dba)3 (4 mol %, 10 mg), sodium acetate (3 equiv, 0.75 mmol,
0.061 g), and benzonitrile (1.0 mL). To the resulting suspension was
added allylamine derivative 13 (0.30 mmol, 0.071 g), followed by 3-
(trifluoromethyl)benzenediazonium tetrafluoroborate (0.25 mmol,
0.065 g). The reaction was stirred at room temperature for 1 h.
Subsequently, the system was purged with hydrogen and left stir-
ring with a balloon of H2 for 12 h. Afterward, the reaction mixture
was filtered through a plug of silica with ethyl acetate and
126.9, 125.4, 125.0, 122.7, 122.4, 115.4, 52.5, 50.1, 23.3.
4.2.2. (R)-N-Allyl-N-(1-(naphthalen-1-yl)ethyl)formamide
(13). Acetic anhydride (141.0 mmol, 14 mL) and formic acid
(142.0 mmol, 5.35 mL) were added to a flame dried round-
bottomed flask equipped with a magnetic stir bar under a nitro-
gen atmosphere. The system was warmed to 60 ꢀC and stirred for
1 h. Next, the system was cooled to 0 ꢀC, and amine 11 was added
(5.45 mmol,1.15 g) dropwise. The reaction was warmed to 50 ꢀC and
stirred for another hour. Upon completion (TLC), the solvent was
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P. Prediger et al. / Tetrahedron xxx (2013) 1e9
7
concentrated under reduced pressure. The product was purified by
flash chromatography (hexanes/ethyl acetate 60:40 as eluent,
Rf¼0.65) to provide arylated product 15 as a colorless oil. Yield:
0.092 g (98%). Rf¼0.65. TLC stain: ultraviolet and phosphomolybdic
CDCl3, 250 MHz, 25 ꢀC,
d
(ppm): 7.31e7.12 (m, 10H), 3.34 (t,
J¼7.5 Hz, 2H), 3.17 (t, J¼7.5 Hz, 2H), 2.58 (t, J¼7.5 Hz, 4H), 1.96 (s,
3H), 1.90e1.77 (m, 4H). 13C NMR: 62.5 MHz, CDCl3, 25 ꢀC,
d
(ppm):
170.0, 141.4, 140.5, 128.3, 128.18, 128.11, 128.0, 126.0, 125.6, 47.9,
45.2, 33.1, 32.7, 30.0, 29.0, 21.3. MS (EI): 296 (Mþ1), 254, 136, 119,
91. HRMS calcd for C20H26NO: 296.2014. Found¼296.2019.
acid. ½a 2D0
ꢂ
þ41.7 (c 0.55, MeOH). The 1H NMR and 13C NMR spectra
show the presence of two rotamers in a 0.4:0.6 ratio. 1H NMR:
CD3OD, 500 MHz, 25 ꢀC,
d (ppm): 8.64 (s, 0.40H), 8.19 (s, 0.6H),
8.06e8.02 (m, 1H), 7.92e7.85 (m, 2H), 7.62 (d, J¼7.2 Hz, 0.6H),
7.59e7.55 (m, 1H), 7.54e7.49 (m, 1.4H), 7.48e7.43 (m, 1H),
7.40e7.37 (m, 1H), 7.33e7.26 (m, 1H), 6.97e6.95 (m, 0.8H),
6.80e6.79 (m, 1.2H), 6.39 (q, J¼7.0 Hz, 0.6H), 5.75 (q, J¼7.0 Hz,
0.4H), 3.41e3.35 (m, 0.4H), 3.14 (dt, J¼6.7, 14.7 Hz, 0.6H), 3.03 (dd,
J¼7.8, 14.7 Hz, 0.6H), 2.94e2.89 (m, 0.4H), 2.26e2.09 (m, 2H), 1.75
(d, J¼7.0 Hz, 1.2H), 1.66 (d, J¼7.0 Hz, 1.8H), 1.26e1.18 (m, 0.4H),
0.92e0.84 (m, 1.6H). The 1H NMR and 13C NMR spectra show the
presence of two rotamers in 0.46:0.54ratio. 1H NMR: DMSO-d6,
4.3.2. N-Ethyl-3-phenyl-N-(3-phenylpropyl)propan-1-amine
(7).22 To a flame dried round-bottomed flask containing THF and
a magnetic stir bar at 0 ꢀC was added AlCl3 (0.06 mmol, 0.008 g)
under a nitrogen atmosphere. After 5 min, a solution of LiAlH4
(0.2 mmol, 0.2 mL, 2.0 M in THF) was added dropwise. The reaction
was then stirred for 10 min, followed by the addition of amide 18
(0.1 mmol, 0.029 g) in THF (1.0 mL). The system was warmed to
room temperature and left to stir for 1.5 h. Next, a saturated NaHCO3
solution (20 mL) was added, and the organic phase was extracted
with EtOAc (3ꢁ20 mL). The organic layers were combined, dried
over MgSO4, filtered, and evaporated under reduced pressure. The
product was purified by flash chromatography (hexanes/ethyl ac-
etate 50:50 as eluent) to provide the arylated product 7 as a color-
less oil. Yield: 0.026 g (96%). Rf¼0.35. TLC stain: ultraviolet and
500 MHz, 120 ꢀC,
d (ppm): 8.61 (s, 0.46H), 8.21 (s, 0.54H), 8.09e8.05
(m,1H), 7.92 (s,1H), 7.87 (d, J¼8.0 Hz,1H), 7.63e7.37 (m, 6H), 7.18 (s,
1H), 7.04 (s, 1H), 6.29 (s, 0.54H), 5.68 (s, 0.46H), 3.29 (s, 0.46H), 3.06
(s, 0.54H), 2.31e2.26 (m, 2H), 1.72 (s, 1.38H), 1.63 (s, 1.62H),
1.26e1.12 (m, 2H). 13C NMR: 125 MHz, DMSO-d6, 25 ꢀCdrotamers,
d
(ppm)¼165.5, 165.2, 144.0, 143.5, 135.9, 135.8, 135.4, 135.2, 133.4,
phosphomolybdic acid. 1H NMR: CD3OD, 250 MHz, 25 ꢀC,
d (ppm):
132.9, 132.8, 131.5 (q, J¼31.0 Hz, 1C), 130.3, 130.2, 130.1, 129.9, 127.9,
127.8, 127.2, 127.1, 126.3, 126.1, 125.7, 125.7 (q, J¼271.0 Hz, 1C), 125.6
(q, J¼271.0 Hz, 1C), 125.6 (q. J¼3.5 Hz, 1C), 124.2, 123.7, 123.6 (q,
J¼3.5 Hz, 1C), 54.4, 47.5, 44.6, 41.7, 33.8, 33.4, 33.1, 30.7, 20.0, 17.1. IR
(film, cmꢃ1): 1665, 1329, 1163, 1122, 1073. MS (EI): 386 (Mþ1), 258,
7.26e7.09 (m, 10H), 2.57e2.38 (m, 10H), 1.76e1.64 (m, 4H), 0.95 (t,
J¼7.1 Hz, 3H). 13C NMR: 62.5 MHz, CD3OD, 25 ꢀC,
d (ppm): 143.2,
129.4, 129.3, 126.8, 53.6, 48.3, 34.7, 28.9, 11.5. MS (EI): 282 (Mþ1),
164, 119, 91. HRMS calcd for C20H28N: 282.2222. Found¼282.2232.
232, 212, 155. HRMS calcd for
C
23H23F3NO: 386.1732.
4.4. Synthesis of tolpropamine 8
Found¼386.1729.
4.4.1. 2-(3,3-Bis(4-methoxyphenyl)allyl)isoindoline-1,3-dione
(20). A flask was charged with allyl phthalimide 19 (0.25 mmol,
0.046 g), 4-methoxybenzenediazonium tetrafluoroborate 2b,
Pd2(dba)3, sodium acetate (3 equiv, 0.75 mmol, 0.061 g), and ben-
zonitrile (2 mL). The reaction was left to stir, and the progress of the
reaction was monitored by the evolution of N2. After bubbling
stopped, EtOAc (10 mL) was added. The reaction mixture was fil-
tered through a plug of silica and concentrated under reduced
pressure. The residue was purified by flash chromatography (hex-
anes/ethyl acetate as eluent, 7:1) to provide the corresponding aryl
allylamines as a white solid (single spot on TLC). The yields refer to
mixtures of the three isomers (a single spot on TLC). Compounds
20e22 were separated by preparative HPLC and fully characterized.
The ratio of the regioisomers was based on the integrations of the
appropriate signals in the 1H NMR spectrum. See the SD for further
details.
4.2.5. (R)-N-(1-(Naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phe-
nyl)propan-1-amine hydrochloride (6).28 To an open round-
bottomed flask (or a test tube) equipped with a magnetic stir bar
were added reduced adduct 15 (0.077 g, 0.2 mmol) and HCl
(1.0 mL). Subsequently, the system was heated to reflux for 12 h.
Afterward, the solvent was removed under reduced pressure to
afford a reaction mixture that was purified by flash chromatogra-
phy (ethyl acetate/methanol 90:10 as eluent, Rf¼0.30) to provide
product 6 as a white solid. Yield: 0.078 g (100%). Rf¼0.30. TLC stain:
ultraviolet and ninhydrin. ½a D20
ꢂ
ꢃ27.4 (c 0.51, MeOH). 1H NMR:
CD3OD, 600 MHz,
d
(ppm): 8.18 (d, J¼8.4 Hz, 1H), 7.95 (dd, J¼3.7,
7.9 Hz, 2H), 7.77 (d, J¼7.1 Hz, 1H), 7.65e7.56 (m, 3H), 7.45e7.36 (m,
4H), 5.38 (d, J¼6.5 Hz, 1H), 3.11e3.06 (m, 1H), 2.90e2.85 (m, 1H),
2.70 (t, J¼7.4 Hz, 2H), 2.04e2.02 (m, 2H), 1.80 (d, J¼6.4 Hz, 3H). 13
C
NMR: CD3OD, 150 MHz,
d
(ppm)¼142.9, 135.5, 134.2, 133.2, 132.1,
131.8 (q, J¼32.0 Hz, 1C), 131.0, 130.4, 128.5, 127.5, 126.6, 126.0 (q,
J¼272.0 Hz, 1C), 125.6 (q. J¼3.5 Hz, 1C), 125.0 (q, J¼3.5 Hz, 1C), 123.1,
54.2, 46.8, 33.2, 28.9, 20.2. MS (EI): 358 (Mþ1), 239, 204, 155, 122.
HRMS calcd for CH23F3N: 358.1783. Found¼358.1819.
TLC stain: ultraviolet and KMnO4. 1H NMR: CDCl3, 500 MHz,
25 ꢀC,
d (ppm): 7.76e7.75 (m, 2H), 7.64e7.62 (m, 2H), 7.17 (d,
J¼8.5 Hz, 2H), 7.07 (d, J¼8.5 Hz, 2H), 6.88 (d, J¼8.5 Hz, 2H), 6.70 (d,
J¼8.5 Hz, 2H), 5.93 (t, J¼6.5 Hz, 1H), 4.39 (d, J¼6.5 Hz, 2H), 3.77 (s,
3H), 3.70 (s, 3H). 13C NMR (ATP): 125 MHz, CDCl3, 25 ꢀC,
d (ppm):
4.3. Synthesis of alverine 7
168.0, 159.2, 158.9, 143.8, 134.5, 133.9, 132.4, 131.2, 131.0, 128.6,
123.1, 120.2, 113.7, 113.4, 55.2, 55.2, 37.7. MS (EI): 400 (Mþ1), 399
4.3.1. N,N-Bis(3-phenylpropyl)acetamide (18).29 To an open round-
bottomed flask (or a test tube) equipped with a magnetic stir bar
were added Pd2(dba)3 (8 mol %, 20 mg), sodium acetate (3 equiv,
0.75 mmol, 0.122 g), and benzonitrile (1.0 mL). To the resulting
suspension was added allylamine derivative 16c (0.25 mmol,
0.06 g) followed by benzenediazonium tetrafluoroborate
(0.60 mmol, 0.114 g). The reaction was stirred at room temperature
for 1 h. Subsequently, the system was purged with hydrogen and
allowed to stir under this atmosphere for 12 h. The reaction mixture
was filtered through a plug of silica gel with ethyl acetate and
concentrated under reduced pressure. The product was purified by
flash chromatography (hexanes/ethyl acetate 80:20 as eluent) to
provide arylated product 18 as a colorless oil. Yield: 0.053 g (72%).
Rf¼0.53. TLC stain: ultraviolet and phosphomolybdic acid. 1H NMR:
(M), 252, 237. HRMS calcd for
C25H21NO4¼399.1471.
Found¼399.1455.
4.4.2. (Z)-2-(2,3-Bis(4-methoxyphenyl)allyl)isoindoline-1,3-dione
(21). TLC stain: ultraviolet and KMnO4. 1H NMR: CDCl3, 500 MHz,
25 ꢀC,
d (ppm): 7.64e7.62 (m, 2H), 7.55e7.53 (m, 2H), 7.41 (d,
J¼8.5 Hz, 2H), 7.30 (d, J¼8.5 Hz, 2H), 6.80 (d, J¼8.5 Hz, 2H),
6.73e6.71 (m, 3H), 4.93 (d, J¼1.0 Hz, 2H), 3.74 (s, 3H), 3.66 (s, 3H).
13C NMR (ATP): 125 MHz, CDCl3, 25 ꢀC,
d (ppm): 168.1, 158.9, 158.4,
135.3, 133.7, 132.3, 131.8, 130.3, 129.8, 128.0, 123.0, 113.7, 113.6, 55.2,
55.1, 37.8. HRMS calcd for C25H21NO4¼399.1471. Found¼399.1475.
4.4.3. (E)-2-(2,3-Bis(4-methoxyphenyl)allyl)isoindoline-1,3-
dione 22. TLC stain: ultraviolet and KMnO4. 1H NMR: CDCl3,
Please cite this article in press as: Prediger, P.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.014

8
P. Prediger et al. / Tetrahedron xxx (2013) 1e9
500 MHz, 25 ꢀC,
d
(ppm): 7.74e7.72 (m, 2H), 7.63e7.61 (m, 2H), 7.09
with a magnetic stir bar. Next, Pd(OAc)2 (0.03 g, 0.14 mmol) and
CaCO3 (0.20 g, 2.0 mmol) were added. The system was stirred for
2 h; afterward, the mixture was concentrated, and H2O was added
(20 mL). The organic layer was extracted with EtOAc (3ꢁ20 mL).
The combined organic layers were dried over MgSO4 and evapo-
rated under reduce pressure to afford a dark solid. The product was
purified by flash chromatography (hexanes/ethyl acetate 95:5 as
eluent) to furnish compound 29c (E/Z stereoselectivity 92:8) as
a white solid, mp: 119e121 ꢀC. Rf¼0.34. TLC stain: phosphomo-
(d, J¼8.5 Hz, 2H), 6.82 (d, J¼8.5 Hz, 2H), 6.73 (d, J¼8.5 Hz, 2H), 6.63
(d, J¼8.5 Hz, 2H), 6.49 (s, 1H), 4.56 (d, J¼1.35 Hz, 2H), 3.70 (s, 3H),
3.64 (s, 3H). 13C NMR (ATP): 125 MHz, CDCl3, 25 ꢀC,
d (ppm): 167.9,
158.8, 158.2, 134.0, 133.8, 131.9, 130.4, 130.3, 130.1, 129.0, 127.3,
123.2, 114.0, 113.2, 55.0, 55.0, 45.2. HRMS calcd for
C
25H21NO4¼399.1471. Found¼399.1439.
4.4.4. (E)-2-(3-(4-Fluorophenyl)allyl)isoindoline-1,3-dione
(23).13 To a round-bottomed flask (or a test tube) were added
Pd2(dba)3 (4 mol %, 10 mg), sodium acetate (3 equiv, 0.75 mmol,
0.061 g), and benzonitrile (1 mL). To the resulting suspension was
added phthalyl allylamine 19 (1.2 equiv, 0.3 mmol) followed by 4-
lybdic acid. 1H NMR: CDCl3, 400 MHz, 25 ꢀC,
d (ppm): 7.52 (d,
J¼8.5 Hz, 2.5H), 7.25 (d, J¼1.6 Hz, 1.5H), 7.18 (d, J¼8.0 Hz, 1.5H), 7.07
(d, J¼8.4 Hz, 3.5H), 6.34 (s, 1H), 3.63 (s, 3H), 2.37 (s, 3H). 13C NMR:
CDCl3, 100 MHz, 25 ꢀC,
d (ppm): 166.03, 154.50, 139.56, 137.74,
methoxybenzenediazonium
tetrafluoroborate
(0.25
mmol,
131.30, 130.98, 130.83, 128.67, 126.46, 122.79, 17.34, 51.45,
19.95. IR (film, cmꢃ1): 2044, 1719, 1623, 1487, 1431, 1358, 1257,
1153, 1053, 1053, 1012, 873, 828, 775, 687. HRMS calcd
0.055 g). The reaction was stirred at room temperature, while the
reaction progress was monitored by the evolution of N2. After ni-
trogen bubbling stopped, the reaction mixture was filtered through
a plug of silica gel and concentrated under reduced pressure. The
product was purified by flash chromatography (hexanes/ethyl ac-
etate as eluent) to provide the corresponding aryl allylamines
(single spot on TLC). Yield: 0.063 g (91%). Ratio 23/24/25¼95/2/3
C17H15BrClO2¼364.9944.
Found¼364.9940.
Structural
de-
termination of compound 29e was performed using a NMR NOESY
1D experiment. Irradiating the vinylic hydrogen caused increases of
0.83% and 0.49% in the signals corresponding to the aromatic hy-
drogens at the 2 position of the ring bearing the methyl group.
(single spot on TLC). 1H NMR: CDCl3, 250 MHz,
d (ppm): 7.88e7.85
(m, 2H), 7.74e7.71 (m, 2H), 7.34e7.29 (m, 2H), 7.00e6.94 (m, 2H),
4.4.8. Methyl 3-phenyl-3-(p-tolyl)propanoate (30). Cinnamate 28c
(0.48 g, 2.0 mmol), 3-chloro-4-methylbenzenediazonium tetra-
fluoroborate 2c (0.72 g, 3.0 mmol), and MeOH (20 mL) were placed
in a round-bottom flask equipped with a magnetic stir bar. Next,
Pd(OAc)2 (0.03 g, 0.14 mmol) and CaCO3 (0.20 g, 2.0 mmol) were
added. The system was stirred for 2 h before NaHCO3 was added.
The system was purged with H2 and stirred until the reduction of
the HeckeMatsuda product was complete. The mixture was con-
centrated under reduced pressure followed by addition of H2O
(20 mL). The mixture was extracted with EtOAc (3ꢁ20 mL). The
combined organic layers were dried over MgSO4, filtered, and
evaporated under reduce pressure. The crude product was purified
by flash chromatography (hexanes/ethyl acetate 95:5 as eluent) to
provide compound 30 as a yellow oil. Yield: 0.47 g (92%). Rf¼0.28.
TLC stain: phosphomolybdic acid. 1H NMR: CDCl3, 500 MHz, 25 ꢀC,
6.64 (d, J¼16.0 Hz, 1H), 6.22 (dt, J1¼16.0 Hz, J2¼6.5 Hz,1H), 4.44 (dd,
J1¼6.5 Hz, J2¼1.0 Hz, 2H). 13C NMR: CDCl3, 62.5 MHz,
d (ppm): 167.9,
162.4 (d, J¼247.0 Hz, 1C), 134.0, 132.6, 132.4 (d, J¼3.0 Hz, 1C), 132.1,
128.1 (d, J¼8.0 Hz, 1C), 123.3, 122.4, 122.3, 115.6 (d, J¼21 Hz, 1C),
39.5. MS (EI): 282 (Mþ1), 281 (M), 263, 148. HRMS calcd for
C
17H12FNO2¼281.0852. Found: 281.0850. The product was obtained
as a white solid after purification by flash chromatography (hex-
anes/ethyl acetate 4:1 as eluent, Rf¼0.51), mp 167e168 ꢀC. The
reaction was performed on
a 5 mmol scale: 1.05 g of 4-
fluorobenzenediazonium tetrafluoroborate, 6 mmol (1.121 g of al-
lyl phthalimide), 0.2 mmol [0.2 g of Pd2(dba)3], 15 mmol (18.45 g of
NaOAc) dissolved in 5 mL of PhCN were stirred for 1 h at room
temperature. The yield was 91% (1.405 g) for the mixture of isomers
(ratio 23:24:25¼96:2:2). The mixture was dissolved in CHCl3 at
60 ꢀC, and the trans isomer recrystallized in 83% yield upon cooling.
d
(ppm): 7.35e7.05 (m, 9H), 4.52 (t, J¼7.9 Hz, 1H), 3.58 (s, 3H), 3.04
(d, J¼7.9 Hz, 2H), 2.29 (s, 3H). 13C NMR: CDCl3, 125 MHz, 25 ꢀC,
4.4.5. (Z)-2-(3-(4-Methoxyphenyl)allyl)isoindoline-1,3-dione
d (ppm): 172.3, 143.7, 140.5, 136.1, 129.3, 128.5, 127.6, 127.5, 126.5,
(24). 1H NMR: CDCl3, 500 MHz,
d
(ppm): 7.88e7.86 (m, 2H),
51.6, 46.6, 40.6, 21.0.
7.75e7.74 (m, 2H), 7.40e7.38 (m, 2H), 7.14 (t, J¼8.5 Hz, 2H), 6.60 (d,
J¼11.0 Hz, 1H), 5.68 (dt, J1¼11.0 Hz, J2¼6.5 Hz, 1H), 4.57 (dd,
4.4.9. 3-Phenyl-3-(p-tolyl)propanoic acid (31). Ester 30 (0.15 g,
0.61 mmol) and KOH (0.27 g, 4.88 mmol) were added to H2O/MeOH
1:4 (7.5 mL) in a round-bottomed flask equipped with a magnetic
stir bar and a condenser. Next, the system was heated to reflux and
left to stir for 3 h. Next, the system was cooled to room temperature
and left to stir overnight. The reaction was concentrated under
reduced pressure before 1 M HCl (20 mL) was added. The product
was extracted with EtOAc (3ꢁ20 mL). The combined organic layers
were dried over MgSO4, filtered, and evaporated under reduce
pressure. The product was purified by flash chromatography
(hexanes/ethyl acetate 90:10 as eluent) to give compound 31 as
a white solid. Yield: 0.12 g (80%). Rf¼0.28, TLC stain: phosphomo-
J1¼6.5 Hz, J2¼1.5 Hz, 2H). 13C NMR: CDCl3, 125 MHz,
d (ppm): 168.0,
161.9 (d, J¼247.0 Hz, 1C), 149.0, 147.0, 134.0, 132.2 (d, J¼3.0 Hz, 1C),
132.0, 130.9, 130.4 (d, J¼8.0 Hz, 1C), 125.7, 123.9, 115.3 (d, J¼21.0 Hz,
1C), 36.3. MS (EI): 282 (Mþ1), 281 (M), 148, 134. HRMS calcd for
C
17H12FNO2¼281.0852. Found. 281.0844.
4.4.6. 2-(2-(4-Methoxyphenyl)allyl)isoindoline-1,3-dione (25).13 1H
NMR: CDCl3, 500 MHz, (ppm): 7.87 (m, 2H), 7.75e7.73 (m, 2H),
d
7.50e7.47 (m, 2H), 7.04 (t, J¼8.5 Hz, 2H), 5.41 (s, 1H), 5.20 (t,
J¼1.5 Hz, 1H), 4.70 (t, J¼1.5 Hz, 2H). 13C NMR: CDCl3, 125 MHz,
d
(ppm): 167.9, 162.5 (d, J¼247.0 Hz, 1C), 141.5, 134.5 (d, J¼3.0 Hz,
1C), 134.0, 131.9, 128.1 (d, J¼8.0 Hz, 1C), 123.4, 115.3 (d, J¼21.0 Hz,
1C), 114.25, 114.24, 41.5. MS (EI): 282 (Mþ1), 281 (M), 263, 160.
HRMS calcd for C17H12FNO2¼281.0852. Found. 281.0856.
Compounds 23e25 were separated by preparative HPLC and
fully characterized. The ratio between the regioisomers was based
on the integrations of the appropriate signals in the 1H NMR
spectra.13
lybdic acid. 1H NMR: CDCl3, 250 MHz, 25 ꢀC,
d (ppm): 7.36e6.95 (m,
9H), 4.47 (t, J¼7.8 Hz, 1H), 3.05 (d, J¼7.9 Hz, 2H), 2.28 (s, 3H). 13
C
NMR: CDCl3, 62.5 MHz, 25 ꢀC,
d (ppm): 177.3, 143.5, 140.2, 136.2,
129.3, 128.6, 127.5, 127.4, 126.5, 46.2, 40.3, 20.9.
4.4.10. N,N-Dimethyl-3-phenyl-3-(p-tolyl)propanamide
(32). Carboxylic acid 31 (0.10 g, 0.43 mmol), dimethylamine (bal-
loon), EDC$HCl (0.11 g, 0.65 mmol), HOBt (0.08 g, 0.65 mmol),
DIPEA (0.17 mL, 1.29 mmol), and dry DCM (5 mL) were placed in
a 25 mL dried flask and stirred for 36 h at room temperature. Af-
terward, the reaction mixture was diluted with brine (20 mL) and
extracted with ethyl acetate (3ꢁ20 mL). The combined organic
4.4.7. (E)-Methyl 3-(4-bromophenyl)-3-(3-chloro-4-methylphenyl)
acrylate (29c). Cinnamate 28c (0.48 g, 2.0 mmol), 3-chloro-4-
methylbenzenediazonium tetrafluoroborate 2f (0.72 g, 3.0 mmol),
and MeOH (20 mL) were placed in a round-bottom flask equipped
Please cite this article in press as: Prediger, P.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.014

P. Prediger et al. / Tetrahedron xxx (2013) 1e9
9
New York, NY, 2002; (d) Tsuji, J. Palladium Reagents and Catalyst; Wiley: Chi-
chester, UK, 2004; (e) The MizorokieHeck Reaction; Oestreich, M., Ed.; Wiley:
Chichester, UK, 2009; (f) Mc Cartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40,
5122; (g) Bellina, F.; Chiappe, C. Molecules 2010, 15, 2211; (h) Heravi, M. M.;
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layers were dried over MgSO4, filtered, and evaporated under
vacuum. The residue was purified by flash column chromatography
(hexanes/ethyl acetate 50:50 as eluent) to afford amide 32 as
a yellow oil. Rf¼0.28. TLC stain: phosphomolybdic acid. 1H NMR:
2. (a) Lundgren, R. J.; Stradiotto, M. Chem.dEur. J. 2012, 18, 9758; (b) Seechurn, C.
C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51,
5062; (c) McGlacken, G. P.; Fairlamb, I. J. S. Eur. J. Org. Chem. 2009, 4011.
CDCl3, 500 MHz, 25 ꢀC,
d
(ppm): 7.03e7.29 (m, 9H), 4.64 (t, J¼7.5 Hz,
1H), 3.02 (d, J¼7.5 Hz, 2H), 2.86 (s, 6H), 2.28 (s, 3H). 13C NMR: CDCl3,
125 MHz, 25 ꢀC,
d (ppm): 170.3, 144.6, 141.3, 135.8, 129.2, 128.4,
~
3. (a) Roglans, A.; Pla-Quitana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622;
(g) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403; (h)
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2815.
127.8, 127.7, 126.3, 46.7, 39.3, 37.3, 35.6, 21.0.
ꢀ
ꢀ
4.4.11. N,N-Dimethyl-3-phenyl-3-(p-tolyl)propan-1-amine
(8). To
4. (a) Salabert, J.; Sebastian, R. M.; Vallribera, A.; Cívicos, J. F.; Najera, C. Tetrahe-
dron 2013, 69, 2655; (b) Gholinejad, M. Appl. Organomet. Chem. 2013, 27, 19.
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a flame dried round-bottomed flask containing THF (4 mL) and
a magnetic stir bar, at 0 ꢀC was added AlCl3 (0.24 mmol, 0.03 g)
under a nitrogen atmosphere. Next, 1.0 M LiAlH4 in THF (8.4 mmol,
0.84 mL of) was added dropwise. Amide 32 was added, and the
reaction mixture was heated at 60 ꢀC for 2 h. Subsequently, 1 mL of
a saturated NH4Cl solution was added, followed by the dropwise
addition of 10 mL of saturated NaHCO3. The product was extracted
with EtOAc (3ꢁ10 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated under reduced pressure. The
product was purified by flash chromatography (hexanes/ethyl ac-
etate, triethylamine 94:5:1 as eluent) to furnish compound 8 as
a colorless oil. Yield: 81%. Rf¼0.15. TLC stain: phosphomolybdic
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6036.
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acid. 1H NMR: CD3OD, 250 MHz, 25 ꢀC,
d (ppm): 7.34e6.94 (m, 9H),
3.88 (t, J¼6.9 Hz, 1H), 2.31e2.13 (m, 10H), 1.91 (s, 3H). 13C NMR:
CD3OD, 125 MHz, 25 ꢀC,
d (ppm): 144.9, 141.6, 135.4, 128.7, 128.0,
127.3, 127.2, 125.8, 57.9, 48.8, 44.0, 32.7, 22.8, 19.6.
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We thank the Research Supporting Foundation of the State of
Sao Paulo (FAPESP, 2011/23832-6) and the Brazilian National Re-
search Council (CNPq, 473832/2010-01) for their financial support
and fellowships.
~
Supplementary data
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Supplementary data associated with this article can be found
online at http://dx.doi.org/10.1016/j.tet.2013.10.014.
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Please cite this article in press as: Prediger, P.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.014