Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: Concise synthesis and conformational studies

Article abstract of DOI:10.1016/j.tet.2012.01.005

Recent work in our laboratory has shown that the highly substituted, electronically rich 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQ3CA) scaffold is a key building block for a novel class of promising anticoagulants.¹⁰ The synthesis

Full text of DOI:10.1016/j.tet.2012.01.005

Tetrahedron 68 (2012) 2027e2040
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Tetrahedron
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Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid
esters: concise synthesis and conformational studies
*
Rami A. Al-Horani, Umesh R. Desai
Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, 800 East Leigh Street,
Suite 212, P.O. Box 980133, Richmond, VA 23219, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Recent work in our laboratory has shown that the highly substituted, electronically rich 1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid (THIQ3CA) scaffold is a key building block for a novel class of
promising anticoagulants.10 The synthesis of THIQ3CA analogs, especially containing specific, electroni-
cally rich substituents, has been a challenge and essentially no efficient methods have been reported in
the literature. We describe three complementary, glycine donor-based strategies for high yielding syn-
thesis of highly substituted, electronically rich THIQ3CA esters. Three glycine donors studied herein
Received 19 November 2011
Received in revised form 27 December 2011
Accepted 4 January 2012
Available online 10 January 2012
include hydantoin 1, (ꢀ)-Boc-
a-phosphonoglycine trimethyl ester 2, and (ꢀ)-Z-
a-phosphonoglycine
trimethyl ester 3. Although the synthesis of THIQ3CA analogs could be achieved using either of the three,
an optimal, high yielding approach for the desired THIQ3CA esters was best achieved using 3 in three
mild, efficient steps. Using this approach, a focused library of advanced N-arylacyl, N-arylalkyl, and bis-
THIQ3CA analogs was synthesized. Variable temperature and solvent-dependent NMR chemical shift
studies indicated the presence of two major conformational rotamers in 3:1 proportion for N-ar-
ylacyleTHIQ3CA analogs, which were separated by a high kinetic barrier of w17 kcal/mol. In contrast, N-
arylalkyl and bis-THIQ3CA variants displayed no rotamerism, which implicates restricted rotation around
the amide bond as the origin for high-barrier conformational interconversion. This phenomenon is of
major significance because structure-based drug design typically utilizes only one conformation. Overall,
the work presents fundamental studies on the synthesis and conformational properties of highly
substituted, electronically rich THIQ3CA analogs.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
recent work has exploited the THIQ3CA scaffold in the design of
new activators of antithrombin (AT), a plasma glycoprotein and
Nitrogen heterocycles are key building blocks for a large number
of medicinally-relevant molecules and serve as fundamental scaf-
folds for discovering drugs. The 1,2,3,4-tetrahydroisoquinoline
(THIQ) scaffold is an especially useful nitrogen heterocycle in
such efforts for its ability to quickly enhance structural diversity of
a potential library. Recent examples highlight the exploitation of
several THIQ analogs as direct inhibitors of factor Xa (fXa), a key
serine protease of the blood coagulation cascade.1e3 An interesting
variant of the THIQ scaffold is the 1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid (THIQ3CA) structure, which has been utilized in the
design of several pharmacologically relevant molecules.4e7 Our
a key regulator of clotting,8 for accelerated inhibition of fXa.9,10
Several methods are available for synthesis of the THIQ3CA
analogs.11e19 The PicteteSpengler11 and BischlereNapieralski12
reactions, which rely on cyclization of
b-arylethylamine de-
rivatives in presence of a protic or Lewis acid,20e31 are among most
common protocols for this purpose. Several other methods have
also been developed including cycloaddition and enyne metathesis
reactions for the synthesis of 1,2-dihydroisoquinoline-3-carboxylic
acids13 and 5,6-, 6,7-, or 7,8-functionalized THIQ3CA esters.14,15
An interesting method to synthesize THIQ3CA analogs has been
to utilize a,a
0-dibromo-O-xylenes as dielectrophiles in reaction with
a glycine equivalent. The glycine equivalents studied to date include
(2S)-2-isopropyl-3,6-dimethoxy-5-methyl-2,5-dihydropyrazine,32
(R)-di-tert-butyl 2-tert-butyl-4-oxoimidazolidine-1,3-dicarboxylate,33
diethyl acetamidomalonate,34 ethyl acetamidocyano-acetate,35
ethyl 2-(benzylidene amino)acetate,36 (6R)-6-isopropyl-3-methyl-
5-phenyl-3,6-dihydro-2H-1,4-oxazin-2-one,37 and 1,4-diacetyl pi-
perazine-2,5-dione.38 An alternative to using dibromo-O-xylenes as
Abbreviations: AT, antithrombin; fXa, factor Xa; FID, free induction decay; THIQ,
1,2,3,4-tetrahydroisoquinoline; THIQ3CA, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid.
* Corresponding author. Tel.: þ1 804 828 7328; fax: þ1 804 827 3664; e-mail
address: urdesai@vcu.edu (U.R. Desai).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.005

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R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
electrophiles in the reaction with glycine donors is
bromide, which when reacted with (2S,5S)-1-benzoyl-2-tert-butyl-
3,5-dimethyl-imidazolidin-4-one afforded -dimethyl THIQ3CA
a
-methyl benzyl
have been developed primarily for unsubstituted or minimally
substituted THIA3CA esters and are long winding.13e15 Thus, we
realized that developing a facile, concise, high yielding synthesis to
THIQ3CA analogs containing phenolic groups placed at varying
positions was necessary for exploring a library of such molecules as
anticoagulants.
In this work, we describe multiple strategies that yield THIQ3-
CAs containing multiple electron rich methoxy substituents. The
work leads to a major conclusion that highly substituted, electron
rich THIQ3CA analogs can be synthesized in three, mild, and high
yielding steps based on HornereWadswortheEmmons and Pic-
teteSpengler reactions. Interestingly, NMR studies indicate that the
N-arylacyleTHIQ3CA derivatives display two equi-energetic, con-
formational isomers that are separated by a high kinetic barrier of
w17 kcal/mol. This phenomenon is of major significance for
structure-based drug design considering that such efforts typically
utilize only one of the rotamers.
a,b
after PicteteSpengler cyclization.39 At a fundamental level, the
glycine equivalents in these reactions undergo base-mediated,
simultaneous or sequential C- and N-alkylation to afford racemic
or enantiomerically pure products. If alkylation is sequential,
then N-alkylation can be achieved by acid-mediated hydrolytic
cyclization.32,37
We have been interested in developing a THIQ3CA-based library
to gain insight into the mechanism of AT activation by non-
saccharide mimetics of heparin, a highly sulfated polysaccharide.10
The unique highly sulfated nature of the parent biomolecule dic-
tates that the THIQ3CA scaffold contains multiple hydroxyl for
sulfation in the last step.40 Unfortunately, appropriate polyphenolic
THIQ3CA precursors are either not available commercially or their
purported synthesis based on literature reports fails to yield
product in high yields and purity. More specifically, the starting
materials (dimethoxy-b-arylethylamines) for the synthesis of 5,6-
2. Results and discussion
dimethoxy-, 5,8-dimethoxy-, and 6,7-dimethoxyeTHIQ3CA esters
using PicteteSpengler and BischlereNapieralski reactions are not
available. The glycine equivalents approach also is not feasible for
our targeted THIQ3CA derivatives because of the lack of availability
2.1. Glycine donor-based approach to synthesize
electronically rich THIQ3CA esters
of appropriate a,a
0-dibromo-O-xylenes. In fact, a survey of litera-
A quick retro-synthetic analysis of the THIQ3CA core suggested
that the structure could be built using three building blocksda
benzaldehyde, a formaldehyde, and a glycine equivalent moiety
(1e3) (Fig. 1). While the benzaldehyde block is available with many
different electronically rich substituents, which provides a facile
entry to the desired THIQ3CA esters, the glycine block has stringent
requirements. One of the requirements is that the glycine unit
ture shows that each THIQ3CA derivative synthesized to date
through the glycine equivalent approach has not carried any
functionalization on the aromatic ring of THIQ3CA.32,33,37,39 An
added problem has been that these reactions require extended
reflux in strong bases35,36,39 and/or concentrated mineral
acids.32,33,35,37,39 Such strong conditions severely limit the nature of
protecting groups that can be used in the synthesis of polyphenolic
THIQ3CAs. Finally although useful, the cycloaddition approaches
should possess a more nucleophilic
a-carbon than its amine and
carboxylic acid groups. This is satisfied by imidazolidine-2,4-dione
Fig. 1. Retrosynthetic analysis for the synthesis of THIQ3CA scaffold using glycine equivalents.

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2029
1, commonly referred to as hydantoin (Scheme 1). To test its ap-
plicability, we utilized 2,3-dimethoxy and 2,5-dimethoxy benzal-
dehydes (4 and 5) that should yield 5,6-dimethoxy- and 5,8-
dimethoxy-THIQ3CA derivatives, which are not readily accessible
through other competing approaches and form key scaffold of our
novel anticoagulants.10
a predominantly Z-product42 and thus, these glycine donors offered
an excellent opportunity for the synthesis of THIQ3CA esters.43
Trimethyl phosphonate 2 was first treated with 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) at 0 ꢁC in THF and then with either
benzaldehyde 4 or 5 in a dropwise manner to yield the corre-
sponding benzylidene 14 or 15, respectively, in yields of 77e85%.
Catalytic hydrogenation and acidification with equivolume mixture
Reaction of benzaldehyde 4 with 1 at 170 ꢁC gave intermediate
6, which was hydrogenated to imidazolidine-2,4-dione 8 (Scheme
1). The hydantoin moiety of 8 was hydrolyzed and the resulting
crude acid was esterified through sequential treatments with SOCl2
and ethanol to afford 2,3-dimethoxy phenylalanine ethyl ester 10.
PicteteSpengler cyclization of 10 under acidic conditions with
aqueous formaldehyde resulted in 5,6-dimethoxy-THIQ3CA ethyl
ester 12. 5,8-Dimethoxy derivative 13 was also synthesized using
the same protocol.
of TFA and CH2Cl2 gave the a-amino-b-aryl methyl acrylate 18 or 19
in 80e86 % yield. Lastly, PicteteSpengler cyclization using a milder
condition (37% HCHO/TFA in CH2Cl2 at rt) afforded the corre-
sponding THIQ3CA methyl esters 20 and 21 within 5 h and signif-
icantly better yields of 70e80%.
2.2. Further improvement in the glycine donor approach
Although useful, the above protocol was not as high yielding and
efficient as desired. Two other glycine equivalents, namely (ꢀ)-Boc-
Analysis of the approach described in Scheme 1 led to the re-
alization that a significant improvement in the overall efficiency of
the process would be realized if alkene reduction and deprotection
steps can be achieved in one step. Thus, benzyloxycarbonyl (Cbz)
a
-phosphonoglycine trimethyl ester 2 (Scheme 1) and (ꢀ)-Z-
a-
phosphonoglycine trimethyl ester 3 (Scheme 2), were studied to
improve yield and enhance feasibility. It is known that the -proton
a
derivatized a-phosphonoglycine trimethyl ester 3 was treated with
of trimethyl phosphonate is considerably acidic and formation of
a strong OeP bond in the by-product dimethyl phosphate drives
the addition-elimination reaction.41 Thus, we reasoned that glycine
donors 2 and 3 may allow the use of milder conditions to effect
similar transformations than those used for hydantion 1. A further
advantage is likely to arise from the use of 2 and 3 was easier pu-
rification of products because the by-product was known to be
water soluble. In contrast, the hydantoin adduct required hot
methanol for solubilization. The reaction was also expected to yield
either benzaldehyde 4, 5, or 22 to yield benzylidenes 23e25 in
77e85% yield (Scheme 2). The planned simultaneous reduction and
deprotection strategy was employed on benzylidene 23 using cat-
alytic hydrogenation (50 psi H2(g) and 10% Pd/C in ethanol), but
conditions gave poor yield of the desired
a-amino-b-aryl amino
methyl ester 18 (w25%). 1H NMR and mass spectrometry suggested
the formation of N-ethoxycarbonyl amino ester as a major side
product (see Experimental section), which appears to have arisen
from
a
benzyloxy-ethoxy exchange.44 To minimize this side
Scheme 1. Synthesis of 5,6- and 5,8-dimethoxy THIQ3CA esters using 1 and 2 as glycine equivalents.

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R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
Scheme 2. Synthesis of 5,6-, 5,8-, and 6,7-dimethoxy THIQ3CA esters using (ꢀ)-Z-
a
-phosphonoglycine trimethyl ester 3, as glycine equivalent.
reaction, 10% Pd(OH)2 on charcoal in equivolume mixture of CH3OH
and tert-butanol was studied. This modified condition yielded the
desired a-amino-b-aryl amino methyl esters 18, 19, and 26 in good
yields (73e76%, Scheme 2). PicteteSpengler cyclization with
formaldehyde under mild conditions afforded the corresponding
THIQ3CA methyl esters 20, 21, and 27 in high yields.
Overall, using hydantoin 1 as glycine donor led to two THIQ3CA
ethyl esters 12 and 13 in six steps, while using phosphonoglycine
trimethyl ester 2 as a glycine donor gave two di-activated THIQ3CA
methyl esters 20 and 21 in four steps. An alternative strategy in-
volved glycine donor 3, which utilized three mild and efficient steps
for the synthesis of THIQ3CA methyl esters 20, 21, and 27. The
hydantoin-based approach afforded THIQ3CA ethyl esters in
21e30% overall yields, while the phosphonoglycine trimethyl esters
2 and 3 led to yields of 43e58% and 40e52%, respectively. Finally,
the HornereWadswortheEmmons/PicteteSpengler approach for
synthesis of activated THIQ3CA esters is mild, concise, and high
yielding, and also appears to be regioselective.
The synthesis of N-alkylated derivatives was somewhat more
challenging than that described above for N-acylated derivatives.
Several bases (K2CO3, Cs2CO3, Et3N, and DIPEA), solvent systems
(CH3CN, DMF, and their mixtures), and heating methods (conven-
tional refluxing and microwave) were screened to identify high
yielding conditions for N-p-methoxybenzyl THIQ3CA methyl ester
43. A 92% yield of 43 was obtained following microwave-assisted
heating of 1 equiv of THIQ3CA methyl ester 27, 2.5 equiv of
DIPEA,1.1 equiv of p-methoxybenzyl chloride in CH3CN at 150 ꢁC for
30 min. Combining these optimized conditions with search for best
xylene-based electrophile (a,a
0-dichloro or dibromo-m- and p-xy-
lenes) led to a high yielding synthesis of bis-THIQ3CA derivatives 44
and 45. The best dimerization yield (62e66%) was obtained by
refluxing 2 equiv of THIQ3CA 28 with 1 equiv of a xylene derivative
in presence of 4 equiv of Cs2CO3 in equivolume mixture of DMF and
CH3CN.
Overall, a small library of 14 THIQ3CA esters was synthesized
using a combination of HornereWadswortheEmmons/Pictete-
Spengler reactions (Schemes 2 and 3) in near quantitative yields.
These derivatives vary at different structural levels including the
substitution pattern of THIQ3CA (5,6-; 5,8-; or 6,7-disubstituted
moiety); the type of ester at position-2 (methyl or ethyl ester);
the length of the linker (benzyl, benzoyl, acetyl, propanoyl, or
butanoyl); and the type of the linker (amide as in N-arylacyl
THIQ3CA or amine as in N-arylalkyl THIQ3CA); and lastly the
number and pattern of substituents on the aryl moiety (4-
substituted; 2,5-disubstituted; or 3,4,5-trisubstituted moieties).
The library of electronically rich THIQ3CA ester analogs, and their
chemically modified forms including deprotected poly-phenolic or
poly-sulfated derivatives, is likely to be useful in mapping protein
binding site(s) so as to deduce optimal binding and/or selectivity
properties.
2.3. Synthesis of advanced N-arylacyl, N-arylalkyl, and bis-
THIQ3CA analogs
The synthetic protocol developed above (Scheme 2) appeared
very attractive for preparing a library of electronically rich THIQ3CA
derivatives. In particular, (ꢀ)-Z-
a-phosphonoglycine trimethyl es-
ter 3 was especially useful as several novel THIQ3CA-based com-
pounds could be synthesized in near quantitative yields. These
include the N-arylacyl THIQ3CA esters 30e35 and 38e42; the N-
arylalkyl THIQ3CA ester 43 and the bis-THIQ3CA esters 44 and 45
(Scheme 3).
The N-benzoyl and N-acetyl THIQ3CA esters 30e35 were syn-
thesized by direct N-acylation using benzoyl or phenyl acetyl
chloride in the presence of triethylamine. The N-propanoyl and N-
butanoyl THIQ3CA esters 38e42 were prepared using EDCI-
mediated coupling reactions with appropriate propionic or buta-
noic acids in presence of DMAP at rt.
From the perspective of chemical synthesis, several points are
noteworthy regarding synthesis using (ꢀ)-Z-
trimethyl ester 3. First, this approach can be further exploited in
synthesis of many unnatural -amino acids and their correspond-
ing cyclic rigid forms.45 Second, the PicteteSpengler reaction is
a-phosphonoglycine
a

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2031
Scheme 3. Synthesis of N-substituted THIQ3CA-based library.
highly amenable to microwave conditions, which greatly expedites
the construction of a library. Third, it is possible to control chirality
at the 3 position to afford enantiomerically pure THIQ3CA using
rhodium (I) or ruthenium (II)-catalyzed asymmetric hydrogena-
tion.46,47 These advantages are expected to further enhance the
applicability of the THIQ3CA library for drug discovery purposes.
For molecule 35, two sets of nine 1H signals were observed at rt
in CDCl3 (Fig. 2, Table 1). The relative proportion of the two pairs of
peaks was essentially identical across all seven signals and was
approximately 75:25. Likewise, 32 displayed two sets of seven 1H
signals (Table 2). In addition, the number of 13C signals for both 32
and 35 were double the number of carbons, although the fre-
quencies for some atoms could not be measured accurately due to
2.4. NMR studies on N-arylacyl THIQ3CA esters
A
1H NMR spectrum is thought of as a classic reflection of the
purity of a new compound. The N-arylacyl THIQ3CA esters syn-
thesized in this work were highly pure entities as indicated by RP-
HPLC and uPLC-MS analysis, however, each molecule demonstrated
complex 1H NMR and 13C NMR spectra (see Experimental
methods), which could not be analyzed on the basis of a single
conformational entity composition. We reasoned that the com-
plexity of NMR spectra arises from the eNeC(O)e bond at position-
2, which was likely to exhibit partial double-bond character with
cis- and trans-isomers. It was likely that the energy barrier for ro-
tation around the amide bond was large resulting in geometrically
and magnetically nonequivalent N-substituents. This phenomenon
of rotational isomerism has been observed earlier for non-
carboxylated THIQ derivatives.48e52 Considering the medicinal
importance of the carboxylated THIQ derivatives being studied, we
decided to investigate this phenomenon in detail so as to aid de-
velopment of appropriate computational protocols for the in-
teraction of THIQ3CA with proteins. Derivatives 32 and 35 were
chosen as representative THIQ3CA analogs.
Fig. 2. 1H NMR spectrum of THIQ3CA analog 35 in CDCl3 showing duplicity of signals
at ambient temperature. Inset shows 6.0e4.0
d region, assignable to ‘a’ and ‘b’ protons,
for better clarity.

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R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
Table 1
lower resolution. These observations suggested the possibility of
two conformational isomers.
1H NMR-CDCl3 parameters for set of signals that reveal the rotational isomerism in
derivative 35
To understand whether polarity of solvent affects conforma-
tional preferences, the 1H NMR spectrum of 32 was studied in C6D6,
CDCl3, CD3CN, and DMSO-d6 at ambient temperature. The effect
was studied by monitoring Ha, Hd, and He signals (Fig. 3). For proton
He the splitting pattern changed dramatically as the solvent po-
larity increased. The doublet of doublets in C6D6 and CDCl3 merged
into an unresolved multiplet in CD3CN, and gave one doublet of
doublet in DMSO-d6 (Fig. 3A). Protons Ha and Hd belonging to
carbon-3 and methyl ester group, respectively, displayed a gradual
loss of intensity as the signal spread due to increase in solvent
polarity. Whereas the signal spread was 375.7 Hz for Ha in C6D6, it
decreased to 62.0 Hz in DMSO-d6 (Fig. 3C, see Table 3). Likewise, the
spread decreased from 42.6 (C6D6) to 9.7 Hz (DMSO-d6) for Hd
(Fig. 3B, Table 3). This indicates that the two conformers tend to
coalesce with increasing solvent polarity.
Protons
Chemical shift (
d
)
Splitting
Integration
1
Ha, Position-3
5.51e5.49
and 4.94e4.92
4.91e4.60
4.52e4.30
3.76
3.67e3.3.66
3.14e3.00
3.02e2.96
and 2.89e2.84
6.49e6.40
6.56e6.53
dd and dd
Hb, Position-1
Hb, Position-1
Hc, Methylene linker
Hd, Methyl ester
He, Position-4
dd
dd
br s
d
1
1
2
3
1
1
Table 3
dt
The change in Dd for protons Ha and Hd of the two detected conformers of THIQ3CA
derivative 32 in different solvents
He, Position-4
dd and dd
Hf, Position-8
Hg, Position-5
d
d
1
1
Solvents
Ha Dd (Hz)
Hd Dd (Hz)
C6D6
CDCl3
CD3CN
DMSO-d6
374.68
269.22
151.98
61.98
42.64
46.76
19.24
9.68
Table 2
1H NMR-CDCl3 parameters for set of signals that reveal the rotational isomerism in
derivative 32
The influence of temperature on the conformational distribu-
tion of THIQ3CA analog 32 was studied by measuring spectral
changes in DMSO-d6 over the range of 293e373 K. Fig. 4 shows
that the signal spread (Dd) between the signals of Ha (position-3
proton) and Hb (position-1 protons) gradually decreases as the
temperature increases. Both signals retain distinct resonance
positions until 353 K and then start to coalesce on the NMR time
scale. Measurements at 373 K for both Ha and Hb show that the
two conformers have lost their distinction and exhibit a rapidly
equilibrating species. Likewise, two singlets at 3.54 and 3.49
d
corresponding to Hd merge as one singlet at 3.57
doublet of doublet at 2.78e2.72 and 2.55e2.49
to He also coalesce as one doublet at 2.82e2.78
d
and the two
corresponding
(not shown).
Protons
Chemical shift (
d
)
Splitting
Integration
1
d
d
Ha, Position-3
5.64e5.62
and 4.96e4.94
5.02e4.78
4.41e4.14
3.79e3.73
3.54e3.43
3.42e3.37
2.78e2.72
and 2.55e2.49
dd and dd
d
Hb, Position-1
Hb, Position-1
Hc, Methylene linker
Hd, Methyl ester
He, Position-4
dd
dd
d
d
1
1
2
3
1
1
At ambient temperature, the ratio of the major to minor conformer
was approximately 3 to 1, which equalized over the range of
353e373 K.
The variable temperature results can be used to analyze the free
energy of activation promotes the dynamic inter-conversion
between the conformers. The Eyring equation based on detailed
m
He, Position-4
dd and dd
Fig. 3. Solvent-dependent changes in the conformational isomerism of 32. (A) 3.1e2.4 d; (B) 3.9e2.8 d; and (C) 6.2e3.8 d.

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2033
ꢀ
ꢀ
ꢁꢁ
TC
D
Gþþ ¼ aT 9:972 þ log
(1)
D
v
pD
v
pffiffiffi
kc
¼
(2)
2
Using this approach, evaluation of the two singlets at 3.56 and
3.53 , belonging to the methyl ester proton Hd, resulted in values of
16.7ꢀ1.0 kcal/mol and 15.5ꢀ1.9 kcal/mol for
þþ and kc at 353 K,
d
D
G
respectively. This value is significantly higher than a value of
7.8 kcal/mol and 15 kcal/mol for N-acetyl-1-benzyl and N-acetyl-
1,3-dimethyl THIQ derivatives and comparable to the activation
energy range of 17.7e20.1 measured for N-acetyl-1-alkylidene THIQ
(Fig. 5).49e51
Overall, our work reveals that the duplicity of NMR signals
persists for all THIQ3CA derivatives irrespective of groups present
on the scaffold as long as the linker at position 2 is an amide.
Conformational isomerism noted for N-arylacyl THIQ3CA analogs
arises from rotational restrictions around the amide bond at posi-
tion 2 with an estimated D
Gþþ of w17 kcal/mol. Lastly, we expect
that the two corresponding rotational isomers to be equi-energetic
with a calculated energy difference of 0.655 kcal/mol.56
3. Significance
Despite the fact that THIQ3CA scaffold is widely involved in
structures of many medicinal agents, the reported synthetic
options to construct this interesting scaffold are limited. This is
especially true for electronically activated THIQ3CA derivatives.
One of the key reasons is the shortage of availability of appropriate
precursors and/or lengthy scheme involved in precursor synthesis.
The protocol reported herein utilizes commercially available
benzaldehydes and optimized HornereWadswortheEmmons/Pic-
teteSpengler reactions and glycine donor 3. The approach is mild,
expeditious and high yielding. In fact, the approach helped pave the
way for the synthesis of a novel library of bicycliceunicyclic
(30e43) and bicycliceunicyclicebicyclic (44 and 45) methyl-
protected polyphenolic THIQ3CA derivatives in a straightforward
manner. A specific advantage of this protocol is that it is flexible and
is likely to be generally applicable.
Fig. 4. Temperature effect on the conformational isomerism of 32 in DMSO-d6. The
entire 1H NMR spectrum of 32 was recorded but only the 5.6e3.8
d range is shown for
enhanced clarity. 1H NMR spectra at 293, 313, 333 and 353 K were recorded on a Varian
300 MHz instrument, while the spectrum at 373 K was recorded on a Bruker 400 MHz.
line-shape analysis is the most accurate method, although several
other methods have been reported.53e55 Two approximations have
been particularly useful include Eqs. 1 and 2 that afford reliable
estimates of the free energy of inter-conversion (
junction with the rate constant (kc) at the coalescence temperature
(Tc).54,55 In these equations,
is constant with value of
DG
þþ) in con-
a
a
0.004575 kcal/mol, T is the temperature in Kelvin (K), and Dn is the
maximum peak separation in hertz. This approach has been shown
to give reliable estimates for both coalescing singlets and doublets
with different intensities as long as Dn >4 Hz.
NMR spectroscopic studies highlighted an important structural
property of N-arylacyl THIQ3CA derivatives of considerable signif-
icance. Two major rotamersds-trans and s-cisdwere found to be
Fig. 5. THIQ derivatives display a wide range of energy barriers for conformational transitions. The N-arylacyl THIQ3CA esters studied in this work show a distinct high energy
barrier of w17 kcal/mol.

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R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
present in solution arising from hindered rotation around the
amide bond. From the drug design perspective, this observation
carries significant implications. Most structure-based drug design
studies typically utilize only one conformer. The expectation is that
rapid inter-conversion between the different rotamers (or con-
formers) will eventually induce dynamic equilibrium in favor of the
form of that eventually binds to target site.57 This work suggests
that such inter-conversion may not occur for N-arylacyl THIQ3CA
derivatives because of the high rotational barrier of w17 kcal/mol.
Thus, both conformers will have to be explicitly studied in
structure-based drug design.
4.4. Mass spectrometric characterization
The ESI MS characterization of all THIQ3CA derivatives was
performed using a Waters Acquity TDQ mass spectrometer in
positive ion mode. Samples, dissolved in methanol, were infused at
a rate of 20 mL/min and mass scans were collected in the range of
200e700 amu with a scan time of 1 s. The capillary and cone
voltages were varied between 3 and 4 kV and 38e103 V, re-
spectively. The extractor voltage was set to 3 V, the Rf lens voltage
was 0.1 V, the source block temperature was 150 ꢁC, and des-
olvation temperature was set to about 250 ꢁC. Ionization conditions
were optimized for each compound to maximize ionization of the
parent ion.
4. Experimental section
4.5. General procedure for preparation of benzylidene
imidazoline-2,4-dione derivatives 6 and 7
4.1. Chemicals and reagents
Anhydrous CH2Cl2, THF, CH3CN, DMF, and toluene were pur-
chased from SigmaeAldrich (Milwaukee, WI) or Fisher Scientific
(Pittsburgh, PA) and used as such. All other solvents were of reagent
gradient and used as supplied. Other chemical reagents were pur-
chased either from SigmaeAldrich, Fisher Scientific, or Alfa-Aesar
(Ward Hill, MA). Analytical TLC was performed using UNIPLATEÔ
Hydantoin 1 (5.0 g, 50.0 mmol), anhydrous sodium acetate
(8.2 g, 100.0 mmol), and aldehyde (4 or 5) (7.5 g, 45.0 mmol) were
successively added in a solution of glacial acetic acid (15 mL) and
acetic anhydride (2 mL). The mixture was stirred at 170 ꢁC under
nitrogen atmosphere for 3 h. Upon cooling to 110 ꢁC, water
(100 mL) was added drop-wise and the mixture left for stirring
overnight at rt. The orange precipitate of the desired compound
was filtered off and then washed with water to remove acetic acid,
the unreacted hydantoin, and sodium acetate. The orange solid was
then purified by flash chromatography using mobile phase gradient
of 40e100% (EtOAc/hexanes) to afford benzylidene imidazoline-
2,4-dione derivative 6 or 7 as yellow to white solid in 65e72% yield.
silica gel GHLF 250 mm pre-coated plates (ANALTECH, Newark, DE).
TLC was visualized using light of 254 nm. Chemical reactions sen-
sitive to air or moisture were carried out under nitrogen atmo-
sphere in oven-dried glassware. All reagent solutions unless
otherwise noted were handled under an inert nitrogen atmosphere
using syringe techniques. Each chemical reaction was optimized to
afford a yield of more than 65%.
4.5.1. 5-(2,3-Dimethoxybenzylidene)imidazolidine-2,4-dione (6). 1H
NMR (DMSO-d6, 400 MHz):
d
¼11.24 (br, 1H, NH), 10.39 (s, br, 1H,
4.2. Purification of reaction products
NH), 7.25 (d, 1J¼6.9 Hz, 1H, Ar), 7.08 (t, 1J¼8.0 Hz, 1H, Ar), 7.03 (d,
1J¼7.2 Hz, 1H, Ar), 6.62 (s, 1H, CH), 3.81 (s, 3H, CH3), 3.74 (s, 3H,
Flash chromatography was performed using Combiflash RF
CH3). 13C NMR (DMSO-d6, 100 MHz):
d
¼165.5, 155.5, 152.4, 147.1,
from Teledyne Isco (Lincoln, NE) and disposable normal silica
128.7, 126.7, 124.2, 113.3, 102.3, 60.6, 55.7. MS (ESI) calculated for
ꢀ
cartridges of 30e70
m
particle size, 230e400 mesh size and 60 A
C12H12N2O4 [MþH]þ, m/z 249.09, found for [MþNa]þ, m/z 271.20.
pore size. The normal phase silica content of cartridges was
4e24 g (for purification of 250e1000 mg crude samples). Mobile
linear gradients utilized either EtOAc or CH3OH in hexanes or
CH2Cl2, respectively. The flow rate of the mobile phase was in the
range of 18e35 mL/min based on the size of the silica cartridge.
The purity of all compounds was greater than 95% as determined
by uPLC.
4.5.2. 5-(2,5-Dimethoxybenzylidene)imidazolidine-2,4-dione (7). 1H
NMR (DMSO-d6, 400 MHz):
d
¼7.12 (d, 1J¼2.9 Hz, 1H, Ar), 6.96 (d,
1J¼9.0 Hz, 1H, Ar), 6.88e6.85 (dd, 1J¼3.0 Hz, 2J¼9.0 Hz, 1H, Ar), 6.55
(s, 1H, CH), 3.78 (s, 3H, CH3), 3.77 (s, 3H, CH3). 13C NMR (DMSO-d6,
100 MHz):
d
¼166.8,157.1,153.0, 151.4,129.4,122.6,115.1,114.1,112.1,
101.8, 56.0, 55.5. MS (ESI) calculated for C12H12N2O4 [MþH]þ, m/z
249.09, found for [MþNa]þ, m/z 271.23.
4.3. NMR studies
4.6. General procedure for preparation of benzyl imidazoline-
2,4-dione derivatives 8 and 9
The 1H and 13C NMR spectra were recorded on Bruker 400 MHz
spectrometer (unless otherwise noted) in CDCl3, DMSO-d6, CD3OD,
C6D6 or CD3COCD3. Signals, in parts per million (ppm), are either
relative to the internal standard (tetramethyl silane, TMS) or to the
residual peak of the solvent. The NMR data are being reported as:
chemical shift (ppm), multiplicity of signal (s¼singlet, d¼doublet,
t¼triplet, q¼quartet, dd¼doublet of doublet, m¼multiplet,
br¼broad), coupling constants (Hz), and integration.
Benzylidene imidazolidine-2,4-dione derivative (6 or 7) (7.3 g,
29.5 mmol) was dissolved in hot ethanol (100 mL) followed by
addition of 10% Pd/C (0.73 g) after cooling. H2 gas was then pumped
into the reaction vessel to achieve 50 psi at rt. After stirring the
mixture for 5 h, the catalyst was filtered on Celite, which was
washed using a 1:1 mixture of EtOAc and CH3OH. The organic fil-
trate was concentrated in vacuo to afford the corresponding re-
duced product (8 or 9) in w100% yield, which was used without any
further purification.
1H and 13C NMR spectra of compounds were measured using
5e35 mg sample dissolved in 0.6 mL of solvent. For 1H NMR
spectrum, 16 scans were recorded with a spectral width of
8223.685 Hz, a FID resolution of 0.125 Hz, relaxation delay of 1 s,
and acquisition time of 4 s, while the 13C spectra were recorded
using 1024e10,240 scans with a spectral width of 24,038.461 Hz,
FID resolution of 0.367 Hz, acquisition time of 1.5 s, and a relaxation
delay of 2 s. Variable temperature NMR studies were performed on
a Varian 300 MHz in the range of 293e353 K and on a Bruker
400 MHz at temperatures up to 373 K.
4.6.1. 5-(2,3-Dimethoxybenzyl)imidazolidine-2,4-dione (8). 1H NMR
(DMSO-d6, 400 MHz):
d
¼10.58 (s, 1H, NH), 7.76 (s, 1H, NH),
7.00e6.94 (dd, 1J¼8.0 Hz, 2J¼15.6 Hz, 1H, Ar), 6.94e6.91 (dd,
1J¼1.6 Hz, 2J¼8.2 Hz, 1H, Ar), 6.81e6.79 (dd, 1J¼1.6 Hz, 2J¼7.4 Hz,
1H, Ar), 4.26 (t, 1J¼6.5 Hz, 1H, CH), 3.79 (s, 3H, CH3), 3.73 (s, 3H,
CH3), 3.09e3.04 (dd, 1J¼4.9 Hz, 2J¼13.9 Hz, 1H, CH), 2.81e2.76 (dd,
1J¼7.5 Hz, 2J¼13.9 Hz, 1H, CH). 13C NMR (DMSO-d6, 100 MHz):

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2035
d
¼175.4, 157.3, 152.2, 147.1, 129.7, 122.4, 111.6, 60.0, 58.0, 55.5, 31.5.
chromatography using the mobile phase of 50% (EtOAc/ hexanes) to
give the desired THIQ3CA ethyl ester (12 or 13) or methyl ester (20,
21 or 27) as yellow oil in 70e82% yield.
MS (ESI) calculated for C12H14N2O4 [MþH]þ, m/z 251.10, found for
[MþNa]þ, m/z 273.24.
4.6.2. 5-(2,5-Dimethoxybenzyl)imidazolidine-2,4-dione (9). 1H NMR
4.8.1. Ethyl 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
(DMSO-d6, 400 MHz):
d
¼10.60 (s, 1H, NH), 7.75 (s, 1H, NH), 6.87 (d,
carboxylate (12). 1H NMR (CDCl3, 400 MHz):
d
¼6.73 (s, 2H, Ar),
1J¼8.6 Hz, 1H, Ar), 6.78 (d, 1J¼3.0 Hz, 1H, Ar), 6.76e6.74 (m, 1H, Ar),
4.26e4.22 (dd, 1J¼5.1 Hz, 2J¼7.2 Hz, 1H, CH), 3.71 (s, 3H, CH3), 3.68
(s, 3H, CH3), 3.08e3.03 (dd, 1J¼4.8 Hz, 2J¼13.8 Hz, 1H, CH),
2.72e2.67 (dd, 1J¼7.6 Hz, 2J¼13.8 Hz, 1H, CH). 13C NMR (DMSO-d6,
4.10e3.80 (m, 5H, CH, 2ꢂ CH2), 3.80 (s, 3H, CH3), 3.79 (s, 3H, CH3),
3.26 (d, 1J¼16.8 Hz, 1H, CH), 3.04e2.94 (dd, 1J¼6.3 Hz, 2J¼17.1 Hz,
1H, CH), 1.15 (t, 1J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
d
¼173.2, 150.5, 146.5, 127.5, 127.0, 121.7, 109.7, 61.1, 55.7, 55.5, 55.3,
100 MHz):
d
¼175.5, 157.4, 152.7, 151.5, 125.4, 117.1, 112.2, 111.5, 57.4,
42.8, 26.2, 14.1. MS (ESI) calculated for C14H19NO4 [MþH]þ, m/z
55.8, 55.2, 32.2. MS (ESI) calculated for C12H14N2O4 [MþH]þ, m/z
266.14, found for [MþH]þ, m/z 266.28.
251.10, found for [MþNa]þ, m/z 273.24.
4.8.2. Ethyl 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
4.7. General procedure for preparation of dimethoxy
phenylalanine ethyl esters 10 and 11
carboxylate (13). 1H NMR (CDCl3, 400 MHz):
d
¼6.58 (d, 1J¼8.9 Hz,
1H, Ar), 6.55 (d, 1J¼8.9 Hz, 1H, Ar), 4.20e4.18 (dd, 1J¼2.3 Hz,
2J¼7.2 Hz, 1H, CH), 4.16e4.14 (dd, 1J¼2.2 Hz, 2J¼7.2 Hz, 1H, CH), 4.13
(d, 1J¼14.2 Hz,1H, CH), 3.80 (d, 1J¼17.0 Hz,1H, CH), 3.71 (s, 3H, CH3),
3.69 (s, 3H, CH3), 3.59e3.55 (dd, 1J¼4.6 Hz, 2J¼10.4 Hz, 1H, CH),
3.07e3.01 (ddd, 1J¼1.0 Hz, 2J¼4.5 Hz, 3J¼17.1 Hz, 1H, CH), 2.64e2.57
A mixture of the benzyl imidazolidine-2,4-dione (8 or 9) (7.0 g,
28.0 mmol), barium hydroxide (14.4 g, 84.0 mmol), and water
(150 mL) was refluxed for 48 h, then filtered hot and the residue
washed with hot water. Following cooling, the filtrate was acidified
to pH 6.5 with 50% H2SO4. The resulting BaSO4 precipitate was
filtered and the pH of the aqueous filtrate adjusted to 9.0 using
NH4OH. The aqueous filtrate was then concentrated, suspended in
ethanol (100 mL), treated with thionyl chloride (20 mL of 2.0 M
solution in CH2Cl2) at 0 ꢁC, and then mixture refluxed for 4 h. Fol-
lowing neutralization with saturated NaHCO3 solution, the reaction
mixture was partitioned between EtOAc and water, and a crude
product obtained from the EtOAc layer. Flash chromatography us-
ing 70% (EtOAc/hexanes) as the mobile phase was used to yield
derivative 10 or 11 as white solid in 43e51% yield.
(dd, 1J¼10.4 Hz, 2J¼17.1 Hz, 1H, CH), 1.24 (t, 1J¼7.2 Hz, 3H, CH3). 13
C
NMR (CDCl3, 400 MHz):
d
¼173.1, 151.2, 150.0, 124.9, 123.6, 107.4,
107.1, 61.1, 55.7, 55.5, 55.3, 42.8, 26.2, 14.1. MS (ESI) calculated for
C14H19NO4 [MþH]þ, m/z 266.14, found for [MþH]þ, m/z 266.28.
4.8.3. Methyl 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (20). 1H NMR (CDCl3, 400 MHz):
d
¼6.68 (s, 2H, Ar),
3.97e3.78 (m, 3H, CH, CH2), 3.75 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.47
(s, 3H, CH3), 3.22e312 (dd, 1J¼4.3 Hz, 2J¼17.4 Hz,1H, CH), 2.97e2.91
(dd, 1J¼9.2 Hz, 2J¼16.4 Hz, 1H, CH). 13C NMR (CDCl3, 100 MHz):
d
¼173.2, 150.5, 146.5, 127.5, 127.0, 121.7, 110.7, 60.1, 56.9, 55.8, 51.3,
49.3, 25.8. MS (ESI) calculated for C13H17NO4 [MþH]þ, m/z 252.12,
4.7.1. Ethyl 2,3-dimethoxy phenylalanine (10). 1H NMR (CDCl3,
found for [MþH]þ, m/z 252.26.
400 MHz):
d
¼6.91 (t, 1J¼7.9 Hz, 1H, Ar), 6.75e6.73 (dd, 1J¼1.4 Hz,
2J¼8.2 Hz, 1H, Ar), 6.70e6.68 (dd, 1J¼1.4 Hz, 2J¼7.6 Hz, 1H, Ar)
4.10e4.04 (q, 1J¼7.2 Hz, 2H, CH2), 3.78 (s, 3H, CH3), 3.76 (s, 3H, CH3),
3.73e3.67 (m, 1H, CH), 3.03e2.99 (dd, 1J¼5.6 Hz, 2J¼13.3 Hz, 1H,
CH), 2.83e2.78 (dd, 1J¼8.3 Hz, 2J¼13.3 Hz, 1H, CH), 1.15 (t, 1J¼7.1 Hz,
4.8.4. Methyl 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylat (21). 1H NMR (CDCl3, 400 MHz):
d
¼6.53 (d, 1J¼3.1 Hz,
1H, Ar), 6.52 (d, 1J¼2.9 Hz, 1H, Ar), 3.94e3.87 (m, 2H, CH2),
3.86e3.81 (dd, 1J¼7.8 Hz, 2J¼16.4 Hz, 1H, CH), 3.69 (s, 3H, CH3), 3.67
(s, 3H, CH3), 3.46 (s, 3H, CH3), 3.12e3.13.06 (dd, 1J¼3.9 Hz,
2J¼17.2 Hz, 1H, CH), 2.86e2.79 (dd, 1J¼10.2 Hz, 2J¼17.4 Hz, 1H, CH).
3H, CH3). 13C NMR (CDCl3, 100 MHz):
123.8, 122.8, 111.3, 60.8, 60.5, 55.7, 55.1, 35.8, 14.1. MS (ESI) calcu-
lated for C13H19NO4 [MþH]þ, m/z 254.14, found for [MþH]þ, m/z
254.30.
d
¼175.1, 152.8, 147.7, 131.2,
13C NMR (CDCl3, 100 MHz):
106.8, 60.1, 56.4, 55.7, 51.2, 45.6, 25.0. MS (ESI) calculated for
d
¼173.5, 151.2, 150.2, 124.7, 123.2, 107.1,
C13H17NO4 [MþH]þ, m/z 252.12, found for [MþH]þ m/z 252.14.
4.7.2. Ethyl 2,5-dimethoxy phenylalanine (11). 1H NMR (CDCl3,
400 MHz): 6.79e6.76 (m, 1H, Ar), 6.74 (d, 1J¼3.0 Hz, 1H, Ar), 6.72 (d,
1J¼1.8 Hz, 1H, Ar), 4.18e4.11 (q, 1J¼7.2 Hz, 2H, CH2), 3.80e3.78 (m,
1H, CH), 3.77 (s, 3H, CH3), 3.74 (s, 3H, CH3), 3.09e3.03 (dd,
1J¼6.0 Hz, 2J¼12.2 Hz,1H, CH), 2.86e2.79 (dd, 1J¼9.0 Hz, 2J¼12.1 Hz,
1H, CH), 1.15 (t, 1J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
4.8.5. Methyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (27). 1H NMR (CDCl3, 400 MHz):
d
¼6.52 (s, 1H, Ar),
6.46 (s, 1H, Ar), 4.08e3.98 (dd, 1J¼15.8 Hz, 2J¼25.6 Hz, 2H, CH2),
3.73e3.79 (m, 1H, CH), 3.78 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.72 (s,
3H, CH3), 3.00e2.95 (dd, 1J¼4.8 Hz, 2J¼16.1 Hz, 1H, CH), 2.91e2.84
(dd, 1J¼9.7 Hz, 2J¼16.0 Hz, 1H, CH). 13C NMR (CDCl3, 100 MHz):
d
¼173.1, 153.5, 151.9, 125.9, 117.4, 112.7, 111.5, 61.2, 56.0, 55.7, 53.8,
33.1, 14.1. MS (ESI) calculated for C13H19NO4 [MþH]þ, m/z 254.14,
d
¼172.7, 147.8, 125.5, 124.4, 111.7, 108.9, 55.9, 55.6, 52.3, 46.4, 30.6.
found for [MþH]þ, m/z 254.30.
MS (ESI) calculated for C13H17NO4 [MþH]þ, m/z 252.12, found for
[MþNa]þ, m/z 274.19.
4.8. General procedure for PicteteSpengler reaction to
synthesize 12, 13, 20, 21, and 27
4.9. General procedure for HornereWadswortheEmmons
reaction for synthesis of 14, 15, 23, 24, and 25
A solution of substituted phenylalanine methyl (18, 19, or 26)
(0.6 g, 2.5 mmol) or ethyl ester (10 or 11) (0.5 g, 2.0 mmol) in CH2Cl2
(10 mL) was treated with formaldehyde (37% aqueous solution,
0.2e0.25 mL, 2.5e3.0 mmol) at rt. Trifluoro-acetic acid (TFA,
3.7e4.6 g, 2.5e3.0 mL, 10.0e12.5 mmol) was then slowly added
over 15 min and the reaction mixture was stirred for 5 h following,
which it was diluted with CH2Cl2 (15 mL) and neutralized with
saturated NaHCO3 solution (20 mL). The organic extracts of the
aqueous solution were combined, the solvent evaporated under
reduced pressure, and the crude mixture was separated by flash
To a solution of (ꢀ)-Boc-
a
a
-phosphono glycine trimethyl ester 2
-phosphonoglycine trimethyl ester 3
(2.0 g, 6.7 mmol) or (ꢀ)-Z-
(2.0 g, 6.0 mmol) in dry THF (3 mL) was added DBU (0.91e1.0 g,
6.0e6.7 mmol) and the mixture stirred for 30 min at 0 ꢁC. A solution
of either 2,3-dimethoxy benzaldehyde 4, 2,5-dimethoxy benzal-
dehyde 5, or 3,4-dimethoxybenzaldehyde 22 (0.83e0.93 g,
5.0e5.6 mmol) in dry THF (3 mL) was then added slowly. The re-
action mixture was allowed to warm to rt, stirred for 5 h and the
solvent evaporated under reduced pressure. The residue was taken

2036
R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
up in EtOAc (50 mL) and following routine organic extraction and
evaporation procedures a crude product was obtained. The crude
product was then purified by flash chromatography using 30%
(EtOAc/hexanes) as eluent to give 14, 15, or 23e25 as white to
yellow solid in 77e85% yield.
(EtOAc/hexanes) as mobile phase to afford the corresponding
dimethoxy -aryl- -amino methyl ester 18 (oil), 19 (oil), or 26 as
a yellow solid in 73e76% yield.
b
a
4.10.1. Methyl 2-(tert-butoxycarbonylamino)-3-(2,3-dimethoxyphenyl)
propanoate (16). 1H NMR (CDCl3, 400 MHz):
d
¼7.00 (t, 1J¼1.5 Hz, 1H,
1
4.9.1. Methyl-2-(tert-butoxycarbonylamino)-3-(2,3-dimethox-
Ar), 6.82 (d, 1J¼8.2 Hz, 1H, Ar), 6.73 (d, J¼7.6 Hz, 1H, Ar), 5.32 (d,
1J¼7.0 Hz,1H, NH), 4.48e4.43 (dd,1J¼6.8 Hz, 2J¼13.2 Hz,1H, CH), 3.86
(s, 3H, CH3), 3.84 (s, 3H, CH3), 3.71 (s, 3H, CH3), 3.06e3.04 (m, 2H, CH2),
yphenyl)acrylate (14). 1H NMR (CDCl3, 400 MHz):
d
¼7.12 (s, 1H, Ar),
7.06 (d, 1J¼4.3 Hz, 2H, Ar), 6.91e6.89 (dd, 1J¼0.7 Hz, 2J¼4.8 Hz, 1H,
CH), 3.88 (s, 3H, CH3), 3.86 (s, 3H, CH3), 3.80 (s, 3H, CH3), 1.40 (s, 9H,
1.39 (s, 9H, 3ꢂ CH3). 13C NMR (CDCl3,100 MHz):
¼172.8,155.4,152.7,
d
3ꢂ CH3). 13C NMR (CDCl3, 100 MHz):
d
¼166.2, 153.0, 152.9, 147.0,
147.5,130.1,124.0,122.7,111.6, 79.6, 60.6, 55.7, 54.7, 52.2, 32.4, 28.3. MS
(ESI) calculated for C17H25NO6 [MþH]þ, m/z 340.18, found for
[MþNa]þ, m/z 361.82.
128.3, 127.6, 124.2, 121.9, 121.7, 112.7, 80.7, 61.4, 55.9, 52.5, 28.1. MS
(ESI) calculated for C17H23NO6 [MþH]þ, m/z 338.16, found for
[MþH]þ, m/z 338.32.
4.10.2. Methyl 2-(tert-butoxycarbonylamino)-3-(2,5-dimethoxyphenyl)
4.9.2. Methyl-2-(tert-butoxycarbonylamino)-3-(2,5-dimethox-
propanoate (17). 1H NMR (CDCl3, 400 MHz):
d
¼6.70e6.68 (m, 2H,
yphenyl)acrylate (15). 1H NMR (CDCl3, 400 MHz):
d
¼7.21 (s, 1H, Ar),
Ar), 6.61 (d, 1J¼2.8 Hz, 1H, Ar), 5.19 (d, 1J¼7.1 Hz, 1H, NH), 4.45e4.39
7.01 (s, 1H, Ar), 6.78 (t, 1J¼0.9 Hz, 1H, CH), 3.78 (s, 3H, CH3), 3.76 (s,
(dd, 1J¼13.2 Hz, 2J¼7.0 Hz,1H, CH), 3.71 (s, 3H, CH3), 3.67 (s, 3H, CH3),
3H, CH3), 3.68 (s, 3H, CH3), 1.32 (s, 9H, 3ꢂ CH3). 13C NMR (CDCl3,
3.64 (s, 3H, CH3), 2.96 (t, 1J¼4.8 Hz, 2H, CH2), 1.31 (s, 9H, 3ꢂ CH3). 13
C
100 MHz):
d
¼166.1, 153.4, 152.8, 151.5, 126.1, 123.8, 123.5, 116.1,
NMR (CDCl3, 100 MHz):
d
¼172.7, 155.2, 153.5,151.8,125.7, 117.2, 112.7,
114.5, 112.6, 80.7, 56.5, 55.7, 52.4, 28.3. MS (ESI) calculated for
111.3, 79.5, 55.8, 55.6, 54.1, 52.0, 32.9, 28.2. MS (ESI) calculated for
C17H23NO6 [MþH]þ, m/z 338.16, found for [MþNa]þ, m/z 360.18.
C17H25NO6 [MþH]þ, m/z 340.18, found for [MþNa]þ, m/z 361.82.
4.9.3. Methyl-2-(benzyloxycarbonylamino)-3-(2,3-dimethoxyphenyl)
4.10.3. Methyl 3-(2,3-dimethoxyphenyl)-2-(ethoxycarbonylamino)
acrylate (23). 1H NMR (CDCl3, 400 MHz):
d
¼7.32e7.28 (m, 5H, Ar),
7.18 (s, 1H, Ar), 6.96e6.93 (m, 2H, Ar), 6.83e6.81 (m, 1H, CH), 5.00
(s, 2H, CH2), 3.79 (s, 3H, CH3), 3.73 (s, 3H, CH3) 3.69 (s, 3H, CH3). 13
NMR (CDCl3, 100 MHz):
propanoate. 1H NMR (CDCl3, 400 MHz):
d
¼6.97 (t, 1J¼7.9 Hz, 1H,
Ar), 6.86e6.84 (dd, 1J¼1.3 Hz, 2J¼8.2 Hz, 1H, Ar), 6.80e6.78 (dd,
1J¼1.2 Hz, 2J¼7.6 Hz, 1H, Ar), 4.12e4.09 (dd, 1J¼5.4 Hz, 2J¼8.5 Hz,
1H, CH), 3.89 (s, 3H, CH3), 3.86 (s, 3H, CH3), 3.62 (s, 3H, CH3),
3.54e3.50 (dd, 1J¼5.4 Hz, 2J¼13.4 Hz, 1H, CH), 3.35e3.30 (dd,
1J¼8.6 Hz, 2J¼13.4 Hz, 1H, CH), 3.09e3.03 (dd, 1J¼7.2 Hz,
2J¼14.5 Hz, 2H, CH2), 1.44 (t, 1J¼7.2 Hz, 3H, CH3). MS (ESI) calcu-
lated for C15H21NO6 [MþH]þ, m/z 312.34, found for [MþH]þ, m/z
312.30.
C
d
¼165.7, 153.7, 153.0, 146.9, 136.0, 128.5,
128.3, 128.2, 128.0, 127.0, 124.3, 123.7, 121.6, 112.9, 67.3, 61.5, 55.8,
52.6. MS (ESI) calculated for C20H21NO6 [MþH]þ, m/z 372.14, found
for [MþH]þ, m/z 372.28.
4.9.4. Methyl-2-(benzyloxycarbonylamino)-3-(2,5-dimethoxyphenyl)
acrylate (24). 1H NMR (CDCl3, 400 MHz):
d
¼7.34e7.30 (m, 5H, Ar),
6.99 (d, 1J¼2.0 Hz, 1H, Ar), 6.84 (d, 1J¼2.4 Hz, 2H, Ar), 6.77e6.73 (m,
4.10.4. Methyl 2,3-dimethoxy phenylalanine (18). 1H NMR (CDCl3,
1H, CH), 5.08 (s, 2H, CH2), 3.73 (s, 6H, 2ꢂ CH3), 3.59 (s, 3H, CH3). 13
C
400 MHz):
d
¼8.47 (br s, 2H, NH2), 7.00 (t, 1J¼8.0 Hz, 1H, Ar),
NMR (CDCl3, 100 MHz):
d
¼165.7, 153.5, 152.8, 151.4, 136.0, 128.6,
6.86e6.84 (dd,1J¼1.2 Hz, 2J¼8.2 Hz,1H, Ar), 6.77e6.75 (dd,1J¼1.1 Hz,
2J¼7.6 Hz, 1H, Ar), 4.34e4.31 (dd, 1J¼5.4 Hz, 2J¼7.0 Hz, 1H, CH), 3.82
(s, 3H, CH3), 3.81 (s, 3H, CH3), 3.69 (s, 3H, CH3), 3.36e3.31 (dd,
1J¼5.2 Hz, 1J¼14.2 Hz, 1H, CH), 3.23e3.18 (dd, 1J¼5.2 Hz, 2J¼14.2 Hz,
128.4, 128.2, 125.8, 125.0, 123.4, 116.4, 114.4, 112.9, 67.3, 56.6, 55.6,
52.5. MS (ESI) calculated for C20H21NO6 [MþH]þ, m/z 372.14, found
for [MþH]þ, m/z 372.32.
1H, CH).13C NMR (CDCl3,100 MHz):
d¼169.1, 152.7, 147.1, 127.7, 124.7,
4.9.5. Methyl-2-(benzyloxycarbonylamino)-3-(3,4-dimethoxyphenyl)
123.0, 112.5, 60.7, 55.6, 53.7, 53.0, 31.6. MS (ESI) calculated for
acrylate (25). 1H NMR (400 MHz, CDCl3):
7.35e7.30 (m, 4H, Ar), 7.13e7.11 (m, 2H, Ar), 6.90e6.85 (m, 1H, Ar),
6.82 (d, 1J¼8.9 Hz, 1H, CH), 6.26 (br s, 1H, NH), 5.13 (s, 2H, CH2), 3.90
(s, 3H, CH3), 3.81 (s, 3H, CH3), 3.71 (s, 1H, CH3). 13C NMR (CDCl3,
d
¼7.36 (s, 1H, Ar),
C12H17NO4 [MþH]þ, m/z 240.12, found for [MþH]þ, m/z 240.24.
4.10.5. Methyl 2,5-dimethoxy phenylalanine (19). 1H NMR (CDCl3,
400 MHz):
d
¼6.71 (s, 3H, Ar), 4.28e4.25 (dd,1J¼8.0 Hz, 2J¼5.0 Hz,1H,
100 MHz):
d
¼165.9, 150.4, 148.8, 136.0, 133.0, 130.0, 128.5, 128.3,
CH), 3.70 (s, 3H, CH3), 3.66 (s, 3H, CH3), 3.63 (s, 3H, CH3), 3.33e3.28
126.4, 124.2,124.2,122.1,114.2,112.2,110.9, 67.5, 55.9, 55.6, 52.6. MS
(ESI) calculated for C20H21NO6 [MþH]þ, m/z 372.14, found for
[MþH]þ, m/z 372.28.
(dd, 1J¼5.0 Hz, 2J¼14.1 Hz, 1H, CH), 3.03e2.97 (dd, 1J¼8.0 Hz,
2J¼14.1 Hz,1H, CH).13C NMR (CDCl3,100 MHz):
¼169.5,153.4,151.8,
d
123.0, 117.9, 113.9, 111.7, 55.8, 53.0, 52.8, 32.0. MS (ESI) calculated for
C12H17NO4 [MþH]þ, m/z 240.12, found for [MþNa]þ, m/z 262.15.
4.10. General procedure for catalytic hydrogenation of N-Boc
and N-Cbz protected
a
-amino-b-aryl methyl acrylates
4.10.6. Methyl 3,4-dimethoxy phenylalanine (26). 1H NMR (CDCl3,
400 MHz):
d
¼6.73 (d, 1J¼7.8 Hz, 1H, Ar), 6.66 (d, 1J¼7.4 Hz, 1H, Ar),
Method A: Methyl acrylate (14 or 15) (0.5 g, 1.5 mmol) and 10%
Pd/C (0.05 g) were mixed in ethanol (15 mL) and H2 gas pumped
into the reaction mixture at rt. After stirring the solution for 5 h, the
catalyst was filtered on Celite and the organic filtrate concentrated
in vacuo to afford the reduced product (16 or 17) as white solid in
w100% yield.
Method B: N-Cbz protected methyl acrylate 23, 24, or 25 (0.5 g,
1.3 mmol) and 10% Pd(OH)2 (0.05 g) on activated charcoal were
mixed in CH3OH/tert-butanol (1:1) mixture (10 mL) and H2 gas
pumped into the mixture at rt. After stirring overnight, the catalyst
was filtered on Celite, the organic filtrate concentrated in vacuo,
and the residue purified by flash chromatography using 70%
6.65 (s, 1H, Ar), 3.79e3.65 (m, 1H, CH), 3.79 (s, 3H, CH3), 3.78 (s, 3H,
CH3), 3.64 (s, 3H, CH3), 2.99e2.95 (dd, 1J¼4.8 Hz, 2J¼13.6 Hz, 1H,
CH), 2.79e2.74 (dd, 1J¼7.6 Hz, 2J¼13.6 Hz, 1H, CH), 1.86 (br s, 2H,
NH2). 13C NMR (CDCl3, 100 MHz):
d¼175.2, 149.0, 148.0, 129.5, 121.4,
112.4, 111.3, 55.9, 55.8, 55.8, 52.0, 40.4. MS (ESI) calculated for
C12H17NO4 [MþH]þ, m/z 240.12, found for [MþNa]þ, m/z 262.22.
4.11. General procedure for N-Boc deprotection to synthesize
18 and 19
To a solution of N-Boc
a-amino-b-aryl ester (16 or 17) (0.35 g,
1.0 mmol) in CH2Cl2 (5 mL), trifluoro-acetic acid (TFA, 5 mL) was

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2037
added drop-wise at 0 ꢁC, and the mixture was warmed to rt. After
stirring for 4 h, the reaction mixture was diluted with CH2Cl2
(25 mL) and neutralized by drop-wise addition of saturated aque-
ous NaHCO3 (20 mL). The organic layer was separated and follow-
ing routine extraction, evaporation procedure gave a crude product,
which was purified by flash chromatography using 70% (EtOAc/
give the desired product (38e42) as colorless or yellow oil in
70e87% yield.
4.13.1. Ethyl 5,6-dimethoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate
(30). 1H
NMR
(CDCl3,
400 MHz):
d¼6.85e6.68 (m, 2H, Ar), 6.64e6.60 (m, 2H, Ar),
hexanes) to give the desired
a
-amino-
b
-aryl ester 18 or 19 as yellow
5.34e5.32 and 4.78e4.76 (m, 1H, CH), 5.08e5.04 and 4.50e4.41 (m,
2H, CH2), 4.13e3.98 (m, 2H, CH2), 3.80e3.74 (m, 15H, 5ꢂ CH3),
3.52e3.48 and 3.37e3.33 (d and dd, 1J¼16.3 Hz and 1J¼3.6 Hz,
2J¼16.3 Hz, 1H, CH), 3.16e3.10 and 2.82e2.77 (dd and dd, 1J¼5.9 Hz,
2J¼16.2 Hz and 1J¼4.8 Hz, 2J¼16.6 Hz, 1H, CH), 1.18 and 1.07 (t and t,
1J¼6.7 Hz and 1J¼8.8 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
oil in 80e86% yield. The NMR spectra for the corresponding prod-
uct are presented above.
4.12. General procedure for step-wise transesterification of
THIQ3CA methyl esters to ethyl esters
d
¼171.5, 170.9, 170.5, 153.5, 153.4, 151.5, 151.0, 146.4, 139.4, 131.1,
126.8, 126.0, 125.7, 125.0, 122.0, 121.1, 111.6, 111.0, 104.4, 103.8, 61.6,
61.4, 60.9, 60.6, 60.4, 56.6, 56.3, 55.9, 52.0, 47.4, 42.9, 25.9, 24.7, 14.1.
MS (ESI) calculated for C24H29NO8 [MþH]þ, m/z 460.20, found for
[MþH]þ, m/z 460.40.
To a stirred solution of dimethoxy THIQ3CA methyl ester (20, 21,
or 27) (0.15 g, 0.6 mmol) in methanol (25 mL), lithium hydroxide
(0.072 g, 3.0 mmol) was added. The mixture was stirred at rt for 5 h
and then concentrated in vacuo, and washed with ethanol
(3ꢂ10 mL). Ethanol (20 mL) was then added to the reaction solid
residue followed by step-wise addition of thionyl chloride (SOCl2,
10 mL of 2 M in CH2Cl2) at 0 ꢁC. The resulting mixture was refluxed
for 4 h, then cooled to rt and neutralized with saturated NaHCO3
solution. The product was extracted with CH2Cl2 (3ꢂ50 mL) fol-
lowed by routine extraction and concentration process to give
a residue that was purified using 45% (EtOAc/hexanes) as eluent of
flash chromatography to give corresponding ethyl ester 12,13, or 28
as yellow oil in 55e72% yield.
4.13.2. Methyl-2-(2-(2,5-dimethoxy phenyl) acetyl)-5,6-dimethoxy-
1,2,3,4-tetrahydro-isoquinoline-3-carboxylate (31). 1H NMR (CDCl3,
400 MHz):
d
¼6.77e6.62 (m, 5H, Ar), 5.38e5.35 and 4.96e4.94 (dd
and dd, 1J¼4.0 Hz, 2J¼6.2 Hz and 1J¼2.5 Hz, 2J¼5.9 Hz, 1H, CH),
4.85e4.56 (dd, 1J¼17.0 Hz, 2J¼101.0 Hz, 1H, CH), 4.49e4.34 (dd,
1J¼15.2 Hz, 2J¼43.2 Hz, 1H, CH), 3.75e3.63 (m, 14H, CH2, 4ꢂ CH3),
3.47 (d, 1J¼52.2 Hz, 3H, CH3), 3.48e3.44 and 3.39e3.34 (dd and dd,
1J¼2.5 Hz, 2J¼16.2 Hz and 1J¼4.0 Hz, 2J¼16.3 Hz, 1H, CH), 2.92e2.86
and 2.67e2.62 (dd and dd, 1J¼6.3 Hz, 2J¼16.3 Hz and 1J¼5.8 Hz,
2J¼16.2 Hz, 1H, CH). 13C NMR (CDCl3, 100 MHz):
¼171.4, 171.3,
d
4.12.1. Ethyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-
171.0, 153.7, 151.4, 151.1, 150.9, 150.5, 146.3, 146.0, 126.7, 125.6, 124.2,
123.8, 122.0, 121.4, 115.8, 113.2, 113.0, 111.5, 111.4, 111.0, 60.5, 60.4,
56.0, 55.8, 55.7, 54.5, 52.3, 52.2, 51.5, 45.3, 43.0, 35.2, 35.0, 25.9,
24.9. MS (ESI) calculated for C23H27NO7 [MþH]þ, m/z 430.19, found
for [MþH]þ, m/z 430.36.
carboxylate (28). 1H NMR (CDCl3, 400 MHz):
d
¼6.52 (s, 1H, Ar),
6.45 (s, 1H, Ar), 4.18e4.13 (q, 1J¼7.1 Hz, 2H, CH2), 3.96 (s, 2H, CH2),
3.80 (s, 3H, CH3), 3.79 (s, 3H, CH3), 3.63e3.60 (dd, 1J¼4.7 Hz,
2J¼10.1 Hz, 1H, CH), 2.94e2.89 (dd, 1J¼4.6 Hz, 2J¼16.0 Hz, 1H, CH),
2
2.83e2.77 (dd, 1J¼10.0 Hz, J¼15.8 Hz, 1H, CH), 2.19 (br s, 1H, NH),
1.23 (t, 1J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
¼173.1,
d
4.13.3. Methyl-2-(2-(2,5-dimethoxy phenyl) acetyl)-5,8-dimethoxy-
147.6, 126.7, 124.9, 111.8, 108.9, 61.0, 55.9, 55.9, 55.9, 47.0, 31.1, 14.2.
MS (ESI) calculated for C14H19NO4 [MþH]þ, m/z 266.14, found for
[MþNa]þ, m/z 288.21.
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (32). 1H NMR (CDCl3,
400 MHz):
d
¼6.82e6.79 (dd, 1J¼2.9 Hz, 2J¼12.0 Hz, 1H, Ar), 6.72 (d,
1J¼8.8 Hz, 1H, Ar), 6.69e6.66 (dd, 1J¼2.8 Hz, 2J¼8.8 Hz, 1H, Ar),
6.60e6.54 (m, 2H, Ar), 5.64e5.62 and 4.96e4.94 (dd and dd,
1J¼2.4 Hz, 2J¼6.8 Hz and 1J¼1.6 Hz, 2J¼6.4 Hz, 1H, CH), 5.02e4.68
(dd, 1J¼18.8 Hz, 2J¼120.8 Hz, 1H, CH), 4.41e4.14 (dd, 1J¼17.1 Hz,
2J¼88.1 Hz, 1H, CH), 3.76 (d, 1J¼23.8 Hz, 2H, CH2), 3.71 (s, 3H, CH3),
3.70 (s, 3H, CH3), 3.67 (s, 3H, CH3), 3.65 (s, 3H, CH3), 3.48 (d,
1J¼46.7 Hz, 3H, CH3), 3.42e3.36 (m, 1H, CH), 2.78e2.72 and
2.55e2.49 (dd and dd, 1J¼6.8 Hz, 2J¼17.0 Hz and 1J¼6.5 Hz,
4.13. General procedure for N-arylacylation of 1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid methyl or ethyl
ester (THIQ3CA ester) and 1,2,3,4-tetrahydroisoquinoline
(THIQ)
Method C: To
a stirred solution of dimethoxy-1,2,3,4-
tetrahydroisoquinoline (12, 13, 20, 21 or 27e29) (0.2 g,
0.8e1.0 mmol) and triethylamine (0.3 g, 3.0 mmol) in anhydrous
CH2Cl2 (10 mL) at 0 ꢁC was added 3,4,5-trimethoxy benzoyl chlo-
ride (0.24 g, 1.05 mmol) or 2,5-dimethoxylphenyl acetyl chloride
(0.24 g, 1.05 mmol). The reaction mixture was allowed to warm to
rt, refluxed for 4 h and then diluted with CH2Cl2 (15 mL). After
routine extraction and concentrations steps, the crude product was
purified by flash chromatography utilizing 50% (EtOAc/hexanes) to
give the desired N-arylacyl THIQ3CA ester (30e35) or N-arylacyl
THIQ (36) as colorless or yellow oil in 85e92% yield.
Method D: To a stirred solution of either propionic or butanoic
acid (0.3 g, 1.4 mmol) in anhydrous CH2Cl2 (5 mL) were added 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 0.3 g,
1.55 mmol) and DMAP (0.17 g, 1.4 mmol) at rt under nitrogen at-
mosphere. Dimethoxy-1,2,3,4-tetrahydroisoquinoline (12, 21 or 27)
(0.4 g, 1.5e1.6 mmol) in anhydrous CH2Cl2 (5 mL) was then added
drop-wise. After stirring overnight, the reaction mixture was par-
titioned between 2 N HCl solution (20 mL) and CH2Cl2 (30 mL), and
the organic layer washed with aqueous solution and concentrated
to give a crude product. The crude product was purified using 50%
(EtOAC/hexanes) as the mobile phase in flash chromatography to
2J¼16.9 Hz, 1H, CH). 13C NMR (100 MHz, CDCl3):
¼171.7, 171.7,
d
171.5,171.0,153.8,153.6,151.3,150.9, 150.6, 150.4, 150.1,149.6,124.4,
123.7, 122.3, 121.9, 121.1, 116.0, 115.6, 113.5, 113.0, 111.6, 111.4, 108.1,
107.7, 107.5, 107.4, 56.1, 56.0, 55.8 (ꢂ2), 55.7 (ꢂ3), 55.4, 54.0, 52.4,
52.2, 49.9, 41.2, 39.2, 35.1, 34.9, 25.2, 24.3. MS (ESI) calculated for
C23H27NO7 [MþH]þ, m/z 430.19, found for [MþNa]þ, m/z 452.30.
4.13.4. Ethyl-2-(2-(2,5-dimethoxy phenyl) acetyl)-5,8-dimethoxy-
1,2,3,4-tetrahydro-isoquinoline-3-carboxylate (33). 1H NMR (CDCl3,
400 MHz):
d
¼6.84e6.80 (dd, 1J¼2.8 Hz, 2J¼14.0 Hz, 1H, Ar),
6.74e6.72 and 6.60e6.54 (m, 3H, Ar), 6.69e6.66 (dd, 1J¼2.9 Hz,
2J¼8.9 Hz, 1H, Ar), 5.61e5.59 and 4.94e4.93 (dd and dd, 1J¼2.1 Hz,
2J¼6.6 Hz and 1J¼1.5 Hz, 2J¼6.4 Hz, 1H, CH), 5.00e4.68 (dd,
1J¼18.7 Hz, 2J¼110.4 Hz, 1H, CH), 4.44e4.19 (dd, 1J¼17.1 Hz,
2J¼81.3 Hz, 1H, CH), 4.06e3.85 (m, 2H, CH2), 3.80e3.58 (m, 12H, 3ꢂ
CH3), 3.57e3.39 (m, 1H, CH), 2.77e2.71 and 2.55e2.49 (dd and dd,
1J¼6.7 Hz, 2J¼17.0 Hz and 1J¼6.5 Hz, 2J¼17.2 Hz, 1H, CH), 1.06 and
0.98 (t and t, 1J¼7.1 Hz and 1J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3,
100 MHz):
d¼171.7, 170.9, 153.8, 153.6, 151.3, 151.0, 150.6, 150.4,
150.2,149.9,124.4,123.7,123.5,122.4,122.0,121.3,117.2,116.0,115.6,
113.5, 113.0, 111.7, 111.4, 108.2, 107.8, 107.6, 61.4, 61.1, 56.2, 56.1, 56.0,

2038
R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
55.9, 55.8, 55.7, 55.7, 55.4, 54.2, 50.1, 41.3, 39.3, 35.9, 35.0, 25.3, 24.3,
14.0, 13.9. MS (ESI) calculated for C24H29NO7 [MþH]þ, m/z 444.20,
found for [MþH]þ, m/z 444.34.
4.13.9. Methyl 2-(3-(2,5-dimethoxyphenyl)propanoyl)-5,8-
dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(39). 1H
NMR (CDCl3, 400 MHz):
d¼6.73e6.67 (m, 2H, Ar), 6.63e6.54 (m,
3H, Ar), 5.65e5.63 and 4.96e4.94 (dd and dd, 1J¼2.2 Hz, 2J¼6.8 Hz
and 1J¼1.6 Hz, 2J¼6.4 Hz, 1H, CH), 5.03e4.98 and 4.61e4.56 (dd,
1J¼18.7 Hz, 2J¼168.5 Hz, 1H, CH), 4.43e4.14 (dd, 1J¼17.1 Hz,
2J¼98.6 Hz, 1H, CH), 3.73 (s, 3H, CH3), 3.70 (s, 3H, CH3), 3.69 (s, 3H,
CH3), 3.67 (s, 3H, CH3), 3.55 (s, 3H, CH3), 3.52e3.47 and 3.43e3.38
(dd and dd, 1J¼1.4 Hz, 2J¼17.7 Hz and 1J¼2.0 Hz, 2J¼17.1 Hz, 1H, CH),
2.94e2.85 (m, 2H, CH2), 2.78e2.53 (m, 3H, CH, CH2). 13C NMR
4.13.5. Ethyl 6,7-dimethoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate
(34). 1H
NMR
(CDCl3,
400 MHz):
d
¼6.85e6.60 (m, 4H, Ar), 5.35e5.32 and 4.78e4.75 (m,
1H, CH), 5.10e5.04 and 4.50e4.40 (m, 2H, CH2), 4.13e3.99 (m, 2H,
CH2), 3.81e3.73 (m, 15H, 5ꢂ CH3), 3.52e3.48 and 3.37e3.33 (d and
dd, 1J¼16.3 Hz and 1J¼3.6 Hz, 2J¼16.3 Hz, 1H, CH), 3.16e3.10 and
2.82e2.77 (dd and dd, 1J¼5.9 Hz, 2J¼16.2 Hz and 1J¼4.8 Hz,
2J¼16.7 Hz, 1H, CH), 1.17 and 1.06 (t and t, 1J¼6.7 Hz and 1J¼8.8 Hz,
(CDCl3, 100 MHz):
d
¼173.2, 172.9, 171.6, 171.1, 153.6, 153.5, 151.8,
151.6, 150.9, 150.6, 150.1, 149.6, 130.7, 130.3, 122.4, 122.3, 121.7, 121.1,
116.5, 116.4, 111.8, 111.5, 111.2, 111.1, 108.1, 107.8, 107.6, 107.3, 55.8,
55.8, 55.7 (ꢂ2), 55.4, 55.3, 54.0, 52.6, 52.3, 49.6, 41.0, 38.9, 34.2, 34.1,
27.2, 26.7, 25.3, 24.3. MS (ESI) calculated for C24H29NO7 [MþH]þ, m/
z 444.20, found for [MþNa]þ, m/z 465.97.
3H, CH3). 13C NMR (CDCl3, 400 MHz):
d
¼171.5, 170.9, 170.5, 153.5,
153.4, 151.5,151.0,146.4,139.4, 131.1,126.8,126.0, 125.7,125.0,122.0,
121.1, 111.6, 111.0, 104.4, 103.8, 61.6, 61.4, 60.9, 60.6, 60.4, 56.6, 56.3,
55.9, 52.0, 47.4, 42.9, 25.9, 24.7, 14.1. MS (ESI) calculated for
C24H29NO8 [MþH]þ, m/z 460.20, found for [MþH]þ, m/z 460.34.
4.13.10. Methyl 2-(4-(2,5-dimethoxyphenyl)butanoyl)-5,8-dimethoxy-
4.13.6. Methyl-2-(2-(2,5-dimethoxy phenyl) acetyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (40). 1H NMR (CDCl3,
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (35). 1H NMR (CDCl3,
400 MHz):
d
¼6.70e6.65 (m, 2H, Ar), 6.63e6.55 (m, 3H, Ar),
400 MHz):
d
¼6.80 (d, 1J¼2.6 Hz, 1H, Ar), 6.74 (d, 1J¼8.8 Hz, 1H,
5.63e5.60 and 4.72 (dd and d, 1J¼2.3 Hz, 2J¼6.8 Hz and 1J¼4.9 Hz,
1H, CH), 5.02e4.97 and 4.56e4.53 (dd, 1J¼18.7 Hz, 1J¼181.9 Hz, 1H,
CH), 4.44e4.09 (dd, 1J¼17.0 Hz, 2J¼117.8 Hz, 1H, CH), 3.71 (s, 3H,
CH3), 3.70 (s, 3H, CH3), 3.69 (s, 3H, CH3), 3.67 (s, 3H, CH3), 3.55 (s,
3H, CH3), 3.40e3.37 (dd, 1J¼2.2 Hz, 2J¼17.1 Hz, 1H, CH), 2.75e2.70
(dd, 1J¼6.8 Hz, 2J¼17.0 Hz, 1H, CH), 2.66e2.53 (m, 2H, CH2),
2.51e2.31 (m, 2H, CH2), 1.97e1.89 (m, 2H, CH2). 13C NMR (CDCl3,
Ar), 6.72e6.67 (m, 1H, Ar), 6.54 (d, 1J¼14.1 Hz, 1H, Ar), 6.45 (d,
1J¼34.9 Hz, 1H, Ar), 5.51e5.49 and 4.94e4.92 (dd and dd,
1J¼3.3 Hz, 2J¼6.0 Hz and 1J¼2.3 Hz, 2J¼5.8 Hz, 1H, CH), 4.91e4.60
(dd, 1J¼17.2 Hz, 2J¼108.8 Hz, 1H, CH), 4.52e4.30 (dd, 1J¼15.4 Hz,
2J¼71.5 Hz, 1H, CH), 3.78e3.66 (m, 14H, CH2, 4ꢂ CH3), 3.50 (d,
1J¼51.5 Hz, 3H, CH3), 3.14e3.06 (dt, 1J¼3.4 Hz, 2J¼15.8 Hz, 1H,
CH), 3.02e2.97 and 2.89e2.85 (dd and dd, 1J¼6.0 Hz, 2J¼18.8 Hz
and 1J¼5.8 Hz, 2J¼15.8 Hz, 1H, CH). 13C NMR (CDCl3, 100 MHz):
100 MHz):
d
¼173.4, 173.0, 171.6, 171.0, 153.5, 151.9 (ꢂ2), 150.6, 150.1,
149.6, 131.5, 131.2, 122.5, 122.4, 121.8, 121.1, 116.4, 116.3, 111.5, 111.3,
111.2, 108.2, 107.8, 107.6, 107.4, 55.8, 55.7, 55.4, 53.9, 52.6, 52.3, 49.6,
40.9, 38.8, 33.3, 33.0, 29.9, 29.8, 25.3, 25.1, 24.9, 24.3. MS (ESI)
calculated for C25H31NO7 [MþH]þ, m/z 458.22, found for [MþNa]þ,
m/z 480.40.
d
¼171.5, 171.4 (ꢂ2), 171.2, 153.8, 151.2, 150.6, 148.2, 148.1, 148.0,
147.7, 124.3, 124.2, 123.9, 123.8, 122.8, 115.9, 115.8, 113.3, 112.9,
111.6, 111.4, 111.2, 111.0, 109.3, 109.0, 56.1 (ꢂ2), 56.0 (ꢂ2), 55.9
(ꢂ2), 55.7, 55.0, 52.4, 52.3, 51.3, 45.5, 43.3, 35.3, 35.0, 31.2, 30.3.
MS (ESI) calculated for C23H27NO7 [MþH]þ, m/z 430.19, found for
[MþNa]þ, m/z 452.36.
4.13.11. Methyl 2-(3-(2,5-dimethoxyphenyl)propanoyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (41). 1H NMR (CDCl3,
4.13.7. 1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,5-
400 MHz):
d
¼6.72e6.69 (m, 2H, Ar), 6.67e6.63 (m, 1H, Ar), 6.54 (d,
dimethoxyphenyl) ethanone (36). 1H NMR (CDCl3, 400 MHz):
1J¼9.4 Hz, 1H, Ar), 6.45 (s, 1H, Ar), 5.52e5.50 and 4.87e4.85 (dd and
dd, 1J¼3.0 Hz, 2J¼6.1 Hz and 1J¼2.4 Hz, 2J¼5.8 Hz, 1H, CH), 4.88e4.54
(dd, 1J¼17.0 Hz, 2J¼120.7 Hz, 1H, CH), 4.53e4.30 (dd, 1J¼17.2 Hz,
2J¼74.0 Hz, 1H, CH), 3.78e3.67 (m, 12H, 4ꢂ CH3), 3.55 (d, 1J¼8.5 Hz,
3H, CH3), 3.78e3.09 (m, 1H, CH), 2.99e2.84 (m, 3H, CH, CH2),
d
¼6.78e6.64 (m, 5H, Ar), 4.54 (d, 1J¼48.8 Hz, 2H, CH2), 3.76 (s,
3H, CH3), 3.71(s, 3H, CH3), 3.69 (s, 3H, CH3), 3.67(s, 3H, CH3),
3.63e3.60 (m, 3H, CH, CH2), 3.58e3.54 (m, 1H, CH), 2.78 (t,
1J¼6.0 Hz, 1H, CH), 2.64 (t, 1J¼5.9 Hz, 1H, CH). 13C NMR (CDCl3,
100 MHz):
d¼170.4, 170.2, 153.7, 151.2, 151.0, 150.9, 150.8, 146.6,
2.70e2.67 (m, 2H, CH2). 13C NMR (CDCl3, 100 MHz):
d¼172.8, 172.7,
146.2, 129.4, 128.5, 126.7, 126.2, 124.7, 122.0, 121.2, 117.1, 115.8,
112.9 (ꢂ2), 111.6 (ꢂ2), 111.5, 110.9, 110.7, 60.3, 56.1 (ꢂ2), 56.0,
55.9, 55.7, 55.6, 47.2, 43.9, 43.2, 39.7, 35.9, 35.1, 34.8, 23.6, 22.9.
MS (ESI) calculated for C21H25NO5 [MþH]þ, m/z 372.18, found for
[MþNa]þ, m/z 394.33.
171.6, 171.2, 153.6 (ꢂ2), 151.8, 151.6, 148.3, 148.1 (ꢂ2), 147.8, 130.7,
130.3, 124.5, 124.1, 123.7, 122.9, 116.5 (ꢂ2), 111.7, 111.5, 111.3 (ꢂ2),
111.2, 111.1, 111.0, 109.4, 108.9, 65.8, 55.9 (ꢂ2), 55.8, 55.7, 54.9, 52.6,
52.3, 51.0, 46.9, 45.1, 43.1, 34.2, 30.3, 29.4, 27.1, 26.7, 26.5. MS (ESI)
calculated for C24H29NO7 [MþH]þ, m/z 444.20, found for [MþNa]þ,
m/z 466.04.
4.13.8. Ethyl-2-(2-(2,5-dimethoxy phenyl) butanoyl)-5,6-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (38). 1H NMR (CDCl3,
4.13.12. Methyl 2-(4-(2,5-dimethoxyphenyl)butanoyl)-6,7-dimethoxy-
400 MHz):
d
¼6.79e5.59 (m, 5H, Ar), 5.40e5.37 and 4.67e4.65 (dd
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (42). 1H NMR (CDCl3,
and dd, 1J¼3.6 Hz, 2J¼6.2 Hz and 1J¼2.8 Hz, 2J¼5.8 Hz, 1H, CH),
4.79e4.74 and 4.52e4.48 (dd, 1J¼16.8 Hz, 2J¼107.7 Hz, 1H, CH),
4.47e4.35 (dd, 1J¼15.1 Hz, 2J¼29.7 Hz, 1H, CH), 4.05e3.90 (m, 2H,
CH2), 3.80e3.60 (m, 12H, 4ꢂ CH3), 3.54e3.50 and 3.42e3.37 (dd
and dd, 1J¼2.6 Hz, 2J¼16.1 Hz and 1J¼3.6 Hz, 2J¼16.3 Hz, 1H, CH),
2.86e2.80 (m, 1H, CH), 2.63e2.55 (m, 2H, CH2), 2.43e2.26 (m, 2H,
CH2), 1.98e1.81 (m, 2H, CH2), 1.08 and 1.00 (t and t, 1J¼7.1 Hz,
400 MHz):
d
¼6.71e6.62 (m, 3H, Ar), 6.55 (d, 1J¼6.16 Hz, 1H, Ar), 6.46
(s,1H, Ar), 5.52e5.50 and 4.69e4.67 (dd and dd, 1J¼2.9 Hz, 2J¼5.9 Hz
and 1J¼2.4 Hz, 2J¼5.6 Hz, 1H, CH), 4.86e4.82 and 4.48e4.48 (dd,
1J¼17.0 Hz, 2J¼136.0 Hz, 1H, CH), 4.48e4.25 (dd, 1J¼16.0 Hz,
2J¼75.8 Hz, 1H, CH), 3.78 (s, 3H, CH3), 3.77 (s, 3H, CH3), 3.69 (s, 3H,
CH3), 3.68 (s, 3H, CH3), 3.54 (d, 1J¼3.2 Hz, 3H, CH3), 3.17e3.09 (m,1H,
CH), 3.04e2.93 (m, 1H, CH), 2.64e2.58 (m, 2H, CH2), 2.44e2.40 (m,
2H, CH2), 1.97e1.89 (m, 2H, CH2). 13C NMR (CDCl3, 100 MHz):
1J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz):
¼177.9, 173.1, 171.1,
d
170.6, 153.5, 153.3, 151.9, 151.6, 151.4, 151.0, 146.4, 146.1, 131.3, 131.0,
129.8, 126.8, 126.3, 126.0, 125.5, 122.0, 121.4, 116.4, 116.3, 111.5, 111.2,
111.0, 61.6, 61.1, 60.6, 60.5, 55.9, 55.8, 55.7 (ꢂ2), 54.6, 51.1, 45.0, 42.9,
33.4, 33.1, 29.8, 29.8, 29.5, 26.1, 25.0, 24.9, 24.8, 14.1, 14.0. MS (ESI)
calculated for C26H33NO7 [MþH]þ, m/z 472.23, found for [MþH]þ,
m/z 472.40.
d
¼173.1, 173.0,171.6, 171.1, 153.5, 151.9, 151.8, 148.3,148.1, 147.8, 131.3,
131.2, 124.5, 124.1, 123.6, 122.9, 116.5, 116.4, 111.5, 111.3 (ꢂ2), 111.2
(ꢂ2), 111.0, 109.4, 109.0, 56.6, 56.0, 55.9 (ꢂ2), 55.7, 54.8, 52.6, 52.3,
50.9, 45.2, 43.1, 33.1, 33.0, 31.6, 31.3, 30.9, 30.3, 29.8 (ꢂ2), 28.9, 25.0,
24.8. MS (ESI) calculated for C25H31NO7 [MþH]þ, m/z 458.22, found
for [MþNa]þ, m/z 479.96.

R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
2039
4.14. 2-(2-(2,5-Dihydroxyphenyl)acetyl)-6,7-dihydroxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (37)
the desired xylene-based dimer (44 or 45) as yellow oil in
62e66% yield.
To a stirred solution of THIQ3CA ester 35 (0.45 g, 1.0 mmol) in
anhydrous CH2Cl2 (5 mL), BBr3 (1 M solution in CH2Cl2, 0.4 g,
9 mmol) was added dropwise at ꢃ78 ꢁC under nitrogen atmosphere
over 10 min. After 2 h, the reaction mixture was brought to rt and
allowed to equilibrate overnight. A mixture of methanol/water (1:1
v/v, 2 mL) was then added slowly at 0 ꢁC and vigorously stirred for
10 min to quench the reaction. The reaction mixture was then
concentrated and partitioned between EtOAc (25 mL) and saturated
solution of NH4Cl (15 mL), and aqueous layer further washed with
EtOAc (2ꢂ20 mL). The combined organic layer was concentrated in
vacuo and the crude was purified by 0e25% (CH3OH/CH2Cl2) as
mobile phase gradient in flash chromatography to yield 37 (75%) as
4.16.1. Diethyl 2,20-(1,3-phenylene bis(methylene)) bis(6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate) (44). 1H NMR (CDCl3,
400 MHz):
d
¼7.41 (s, 1H, Ar), 7.30 (s, 3H, Ar), 6.58 (s, 2H, Ar), 6.46 (s,
2H, Ar), 4.19e4.10 (m, 4H, 2ꢂ CH2), 33.99e3.93 (m, 6H, 2ꢂ CH, 2ꢂ
CH2), 3.84 (s, 6H, 2ꢂ CH3), 3.79 (s, 6H, 2ꢂ CH3), 3.76e3.72 (m, 4H, 2ꢂ
CH2), 3.14e3.09 (dd, 1J¼6.0 Hz, 2J¼16.1 Hz, 2H, 2ꢂ CH), 3.05e3.00
(dd, 1J¼4.0 Hz, 2J¼16.0 Hz, 2H, 2ꢂ CH),1.24 (t, 1J¼7.1 Hz, 6H, 2ꢂ CH3).
13C NMR (CDCl3, 100 MHz):
d¼172.7, 147.5, 138.9, 129.4, 128.3, 127.8,
126.1,124.1,111.3,109.3, 60.3, 59.2, 59.0, 55.9, 55.8, 50.7, 31.1,14.4. MS
(ESI) calculated for C36H44N2O8 [MþH]þ, m/z 633.32, found for
[MþH]þ, m/z 633.16.
yellow solid. 1H NMR (acetone-d6, 400 MHz):
d
¼6.65e6.58 (dd,
4.16.2. Diethyl 2,20-(1,4-phenylene bis(methylene)) bis(6,7-dimethoxy-
1J¼2.9 Hz, 2J¼25.1 Hz, 1H, Ar), 6.57e6.55 (dd, 1J¼3.2 Hz, 2J¼7.3 Hz,
1H, Ar), 6.53 (d, 1J¼14.7 Hz, 2H, Ar), 6.47e6.44 (dd, 1J¼2.9 Hz,
1J¼8.6 Hz, 1H, Ar), 5.20e5.18 and 5.15e5.13 (dd and dd, 1J¼3.6 Hz,
2J¼5.9 Hz and 1J¼2.6 Hz, 2J¼5.7 Hz, 1H, CH), 4.79e3.43 (dd and dd,
2H, CH2, and d and d andd, 2H, CH2), 3.07e3.02 and 3.01e2.96 (dd
and dd, 1J¼2.5 Hz, 2J¼15.5 Hz and 1J¼3.6 Hz, 2J¼15.6 Hz, 1H, CH),
1,2,3,4-tetrahydroisoquinoline-3-carboxylate) (45). 1H NMR (CDCl3,
400 MHz):
d
¼7.28 (s, 4H, Ar), 6.52 (s, 2H, Ar), 6.40 (s, 2H, Ar),
4.12e4.05 (m, 4H, 2ꢂ CH2), 3.85e3.93 (m, 6H, 2ꢂ CH, 2ꢂ CH2), 3.77
(s, 6H, 2ꢂ CH3), 3.73 (s, 6H, 2ꢂ CH3), 3.60e3.70 (m, 4H, 2ꢂ CH2),
3.07e3.03 (dd, 1J¼3.5 Hz, 2J¼14.9 Hz, 2H, 2ꢂ CH), 3.00e2.95 (dd,
1J¼4.1 Hz, 2J¼16.0 Hz, 2H, 2ꢂ CH), 1.18 (t, 1J¼7.1 Hz, 6H, 2ꢂ CH3). 13
C
2.88e2.84 (m, 1H, CH). 13C NMR (acetone-d6, 100 MHz):
d¼173.3,
NMR (CDCl3, 100 MHz):
d¼172.7, 147.5, 138.8, 129.0, 126.0, 124.1,
172.2, 151.3, 149.9, 149.5, 145.0, 144.9, 124.7, 124.6, 124.5, 124.0,
123.3, 118.5, 118.0, 117.9, 117.8, 117.7, 115.7, 115.6, 115.5, 115.2, 113.8,
113.7, 56.2, 52.6, 46.5, 43.9, 36.5, 36.1, 31.9, 30.9. MS (ESI) calculated
for C18H17NO7 [MþH]þ, m/z 360.11, found for [MþNa]þ, m/z 382.24.
111.3, 109.2, 60.4, 59.2, 58.7, 55.9, 55.8, 50.7, 30.9, 14.4. MS (ESI)
calculated for C36H44N2O8 [MþH]þ, m/z 633.32, found for [MþH]þ,
m/z 633.23.
Acknowledgements
4.15. Methyl 6,7-dimethoxy-2-(4-methoxybenzyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (43)
This work was supported by grants HL090586, HL099420, and
HL107152 from the National Institutes of Health. We thank Dr. Neil
Scarsdale of Virginia Commonwealth University for help with NMR
experiments.
To
a
stirred solution of methyl 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate 27 (0.1 g, 0.4 mmol) in
CH3CN (2 mL), diisopropylethylamine (DIPEA) (0.15 g, 1.2 mmol)
was slowly added. After 15 min, 4-methoxybenzyl chloride
(0.078 g, 0.5 mmol) was dissolved in CH3CN (1 mL) and was then
added slowly to the reaction mixture. The reaction mixture was
heated up in the microwave (CEM Discover) for 20 min at 150 ꢁC.
The reaction mixture was cooled to rt, diluted with EtOAc (10 mL)
and organic layer worked up as usual to give a crude product,
which was purified using 30% (EtOAc/hexanes) in flash chroma-
tography to yield 43 (yellow oil, 92%). 1H NMR (CDCl3, 400 MHz):
References and notes
1. Ueno, H.; Yokota, K.; Hoshi, J.; Yasue, K.; Hayashi, M.; Hase, Y.; Uchida, I.; Aisaka,
K.; Katoh, S.; Cho, H. J. Med. Chem. 2005, 48, 3586e3604.
2. Ueno, H.; Yokota, K.; Hoshi, J.; Yasue, K.; Hayashi, M.; Uchida, I.; Aisaka, K.;
Hase, Y.; Katoh, S.; Cho, H. Bioorg. Med. Chem. Lett. 2005, 15, 185e189.
3. Watson, N. S.; Adams, C.; Belton, D.; Brown, D.; Burns-Kurtis, C. L.; Chaudry, L.;
Chan, C.; Convery, M. A.; Davies, D. E.; Exall, A. M.; Harling, J. D.; Irvine, S.;
Irving, W. R.; Kleanthous, S.; McLay, I. M.; Pateman, A. J.; Patikis, A. N.; Roethke,
T. J.; Senger, S.; Stelman, G. J.; Toomey, J. R.; West, R. I.; Whittaker, C.; Zhou, P.;
Young, R. J. Bioorg. Med. Chem. Lett. 2011, 21, 1588e1592.
4. Zhang, Y.; Feng, J.; Liu, C.; Zhang, L.; Jiao, J.; Fang, H.; Su, L.; Zhang, X.; Zhang, J.;
Li, M.; Wang, B.; Xu, W. Bioorg. Med. Chem. 2010, 18, 1761e1772.
5. Cheng, S.; Zhang, X.; Wang, W.; Zhao, M.; Zheng, M.; Chang, H. W.; Wu, J.; Peng,
S. Eur. J. Med. Chem. 2009, 44, 4904e4919.
6. Azukizawa, S.; Kasai, M.; Takahashi, K.; Miike, T.; Kunishiro, K.; Kanda, M.;
Mukai, C.; Shirahase, H. Chem. Pharm. Bull. 2008, 56, 335e345.
7. Cai, T. B.; Zou, Z.; Thomas, J. B.; Brieaddy, L.; Navarro, H. A.; Carroll, F. I. J. Med.
Chem. 2008, 51, 1849e1860.
8. Desai, U. R. Med. Res. Rev. 2004, 24, 151e181.
9. Raghuraman, A.; Liang, A.; Krishnasamy, C.; Lauck, T.; Gunnarsson, G. T.; Desai,
d
¼7.29 (d, 1J¼8.6 Hz, 2H, Ar), 6.87 (d, 1J¼8.6 Hz, 2H, Ar), 6.58 (s,
1H, Ar), 6.47 (s, 1H, Ar), 3.95 (d, 1J¼15.2 Hz, 1H, CH), 3.85 (d,
1J¼2.2 Hz, 2H, CH2), 3.84 (s, 3H, CH3), 3.80 (s, 3H, CH3), 3.79 (s,
3H, CH3), 3.77e3.75 (dd, 1J¼4.1 Hz, 2J¼6.0 Hz, 1H, CH), 3.72 (d,
1J¼15.8 Hz, 1H, CH), 3.68 (s, 3H, CH3), 3.14e3.09 (dd, 1J¼6.0 Hz,
2J¼16.1 Hz, 1H, CH), 3.05e3.00 (dd, 1J¼3.8 Hz, 2J¼16.0 Hz, 1H,
CH). 13C NMR (CDCl3, 100 MHz):
d
¼173.2, 158.9, 147.5, 130.6, 130.1,
128.6, 126.1, 124.0, 113.8, 111.3, 109.3, 58.9, 58.4, 55.9, 55.8, 55.3,
51.4, 50.6, 30.9. MS (ESI) calculated for C21H25NO5 [MþH]þ, m/z
372.18, found for [MþH]þ, m/z 372.32.
U. R. Eur. J. Med. Chem. 2009, 44, 2626e2631.
10. Al-Horani, R. A.; Liang, A.; Desai, U. R. J. Med. Chem. 2011, 54, 6125e6138.
11. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797e1842.
12. Whaley, W. M.; Govindachari, T. R. In Organic Reactions; Adams, R., Ed.; Wiley:
New York, NY, 1951; Vol. 6, pp 74e150.
4.16. General procedure for xylene-based dimerization of 6,7-
dimethoxy THIQ3CA ethyl ester
13. Liu, J.-M.; Young, J.-J.; Li, Y.-J.; Sha, C.-K. J. Org. Chem. 1986, 51, 1120e1123.
14. Kotha, S.; Sreenivasachary, N. Bioorg. Med. Chem. Lett. 2000, 10, 1413e1415.
15. Kotha, S.; Sreenivasachary, N. Chem. Commun. 2000, 503e504.
16. Toda, J.; Matsumoto, S.; Saitoh, T.; Sano, T. Chem. Pharm. Bull. 2000, 48, 91e98.
17. Hirsenkorn, R. Tetrahedron Lett. 1991, 32, 1775e1778.
18. Kommidi, H.; Balasubramaniam, S.; Aidhen, I. S. Tetrahedron 2010, 66, 3723e3729.
19. Kihara, M.; Kashimoto, M.; Kobayashi, Y. Tetrahedron 1992, 48, 67e78.
20. Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron Lett. 2001, 42,
8885e8888.
Ethyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carbox-
ylate 28 (0.75 g, 2.8 mmol) was dissolved in DMF/CH3CN (1:1 v/v,
8 mL) and stirred with Cs2CO3 (2.2 g, 11.2 mmol). After 15 min, p- or
m-a,a
0-dibromo xylene (0.37 g, 1.4 mmol) in CH3CN (2 mL) was
slowly added to the reaction mixture and then refluxed for 12 h.
The reaction mixture was cooled, partitioned between EtOAc
(25 mL) and water (25 mL), and the organic layer processed in a
routine manner to prepare a crude product, which was purified
using 30% (EtOAc/hexanes) in flash chromatography to give
21. Connors, R. V.; Zhang, A. J.; Shuttleworth, S. J. Tetrahedron Lett. 2002, 43,
6661e6663.
22. Miles, W. H.; Heinsohn, S. K.; Brennan, M. K.; Swarr, D. T.; Eidam, P. M.; Gelato,
K. A. Synthesis 2002, 1541e1545.
23. Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin. Drug Discovery Dev. 2003, 6,
801e814.

2040
R.A. Al-Horani, U.R. Desai / Tetrahedron 68 (2012) 2027e2040
24. Pal, B.; Jaisankar, P.; Giri, V. S. Synth. Commun. 2003, 33, 2339e2348.
25. Nielsen, T. E.; Meldal, M. J. Org. Chem. 2004, 69, 3765e3773.
26. Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558e10559.
27. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431e1628.
44. Enomoto, T.; Yasui, Y.; Takemoto, Y. J. Org. Chem. 2010, 75, 4876e4879.
45. Un-natural -amino acids including 4-methoxy, 2,3,4-trimethoxy, and 3,4,5-
a
trimethoxy-phenylalanine methyl esters were in fact synthesized and fully
characterized by 1H and 13C NMR. Their syntheses were achieved in quantitative
yields by application of similar conditions of HornereWadswortheEmmons
reaction using glycine donor 3, followed by the catalytic hydrogenation reaction.
46. Knowles, W. S. Angew. Chem., Int. Engl. Ed. 2002, 41, 1998e2007.
47. Wang, W.; Li, H. Tetrahedron Lett. 2004, 45, 8479e8481.
48. Bringmann, G.; Ochse, M.; Michel, M. Tetrahedron 2000, 56, 581e585.
49. Kitamura, M.; Tsukamoto, M.; Takaya, H.; Noyori, R. Bull. Chem. Soc. Jpn. 1996,
69, 1695e1700.
28. Lesma, G.; Danieli, B.; Lodroni, F.; Passarella, D.; Sacchetti, A.; Silvani, A. Comb.
Chem. High Throughput Screening 2006, 9, 691e701.
29. Meutermans, W. D. F.; Alewood, P. F. Tetrahedron Lett. 1995, 36, 7709e7712.
30. Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 2002,
116e121.
31. Judeh, Z. M. A.; Ching, C. B.; Bu, J.; McCluskey, A. Tetrahedron Lett. 2002, 43,
5089e5091.
32. Schollkopf, U.; Hinrchs, R.;Lonsky, R. Angew. Chem., Int. Ed. Engl.1987, 26,143e145.
33. Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann.
Chem. 1989, 12, 1215e1232.
50. Fraenkel, G.; Cava, M. P.; Dalton, D. R. J. Am. Chem. Soc. 1967, 89, 329e332.
51. de Koning, C. B.; van Otterlo, W. A. L.; Michael, J. P. Tetrahedron 2003, 59,
8337e8345.
52. Wouters, J.; Elassad, K.; Norberg, B.; Graulich, A.; Liegeois, J.-F. Eur. J. Med. Chem.
34. Kammermeier, T.; Lerch, U.; Sommer, C. Synthesis 1992, 1157e1160.
35. Wang, C.; Moseberg, H. I. Tetrahedron Lett. 1995, 36, 3623e3626.
36. Mash, E. A.; Williams, L. J.; Pfeiffer, S. S. Tetrahedron Lett. 1997, 38, 6977e6988.
37. Chinchilla, R.; Galindo, N.; Najera, C. Synthesis 1999, 704e717.
38. Fukuyama, T.; Linton, S. D.; Tun, M. M. Tetrahedron Lett. 1990, 31, 5989e5992.
39. Kazmierski, W. M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J. J. Org. Chem. 1994, 59,
1789e1795.
40. Al-Horani, R. A.; Desai, U. R. Tetrahedron 2010, 66, 2907e2918.
41. Singh, R. B.; Rai, D. K. J. Phys. Chem. 1965, 69, 3461e3462.
42. Knor, S.; Laufer, B.; Kessler, H. J. Org. Chem. 2006, 71, 5625e5630.
43. Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53e60.
2010, 45, 3240e3244.
53. Bishop, G. J.; Price, B. J.; Sutherland, I. O. J. Chem. Soc., Chem. Commun. 1967,
672e674.
54. Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74, 961e963.
55. Kost, D.; Carlson, E. H.; Raban, M. J. Chem. Soc., Chem. Commun. 1971,
656e657.
56.
D
G0¼ꢃ2.3RTlogKe, in which
DG
0 is the standard energy difference; R is the gas
constant; T is temperature in Kelvin and Ke is the equilibrium constant, which
was found to be 0.33 based on the NMR study.
57. Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem., Int. Ed.
2009, 48, 6398e6401.