Synthesis of trans/cis-3,4-disubstituted 1,2,3,4-tetrahydroisoquinolines by nucleophilic acyl substitution of homophthalic anhydride with aldimines

Article abstract of DOI:10.1002/jhet.1003

The reaction of the functionalized N-protected imines 3 and 7 containing either the chloromethyl or ethyl ester moieties, respectively, attached to the imine carbon with homophthalic anhydride 2 afforded cis/tran-3-subsituted-1-oxo- 1,2,3,4-tetrahydroisoquinoline-4-caboxylic acids appropriate for further synthetic elaboration.

Full text of DOI:10.1002/jhet.1003

114
Synthesis of trans/cis-3,4-Disubstituted 1,2,3,4-Tetrahydroisoquinolines by
Vol 50
Nucleophilic Acyl Substitution of Homophthalic Anhydride with Aldimines
b
Sherif F . Hammada,b and Forrest T. Smith
*
aFaculty of Pharmacy, Helwan University, Egypt
bDepartment of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA
*
E-mail: smithft@auburn.edu
Received March 4, 2011
DOI 10.1002/jhet.1003
View this article online at wileyonlinelibrary.com.
The reaction of the functionalized N-protected imines 3 and 7 containing either the chloromethyl or ethyl ester
moieties, respectively, attached to the imine carbon with homophthalic anhydride 2 afforded cis/tran-3-subsituted-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-caboxylic acids appropriate for further synthetic elaboration.
J. Heterocyclic Chem., 50, 114 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Imine–anhydride condensations have proven to be a valu-
able method for the synthesis of a variety of functionalized
tetrahydroisoquinolines and as such, the reaction has been
utilized for the synthesis of nitidine chloride, corynoline,
6-oxocorynoline, 14-epicorynoline, chelidonine, fagaronine
chloride, and decumbenine, Figure 1 [1–6].
These substituted 1,2,3,4-tetrahydroisoquinolines with
stereogenic centers at C-3 and C-4 exist in both cis and trans
forms that may be obtained as mixtures or as a single
diastereomer depending upon the temperature, the solvent
used, the substituents in positions 2 and 3, and the use of
various catalysts such as Lewis acids. At room temperature,
the reaction is considered as kinetically controlled and
mixtures of cis and trans acids are obtained [7,8].
As part of a project directed at the synthesis of sequence,
selective DNA alkylating agents related to compound 1,
imine–anhydride condensations have been used as a key
reaction in the synthesis of the heterocyclic frame (Fig. 2)
[9–11]. Although this reaction is quite convenient for the
synthesis of these compounds, it is limited due to the syn-
thetic difficulty associated with heterocyclic imines that can
be utilized, which contain additional functionality. In order
to expand the scope of the reaction, it was hoped that functio-
nalized imines could be utilized and could be subsequently
converted into nitrogen containing heterocycles fused to the
isoquinolinic acid that results from the imine–anhydride
condensation. Toward this end, the reaction of compounds
3 and 7 with homophthalic anhydride, 2, have been investi-
gated. Both compounds contain electrophilic functionality
at the alpha carbon of the imine, which may be further
elaborated, as well as removable nitrogen protecting groups.
The reaction of compounds 3a and 3b with homophthalic
anhydride 2 is shown in Scheme 1. The a-chloroimines
were prepared in situ by condensation of the amine with
chloroacetaldehyde in alcohol-free chloroform according to
the procedure reported by Teutsch et al.,[12]. The a-chloroi-
mines are unstable and were therefore not isolated but used
immediately in the subsequent reaction with 2 to afford the
desired isoquinolinic acids 4. The results are presented in
Table 1. The imine anhydride condensation is complete
within 10min to give primarily the cis and trans acids 4a
and 4b with small amounts of the lactones 5. The presence
of the cis and trans acids was determined by GC/MS analysis
that revealed the presence of two peaks (60/40 ratio) with the
same fragmentation pattern showing (M+–CO2–HCl).
Further characterization was not possible however because
of the rapid conversion of the initial products to the lactones.
The lactones form as a result of further reaction by displace-
ment of the chloride by the initially formed carboxyl group.
Upon standing, or the use of longer reaction times results
in nearly complete conversion to the lactones. To prevent
conversion to the lactones, the acids were immediately
converted to the esters 6a and 6b via reaction with diazo-
methane or NaHCO3/CH3I. Alternatively, Fisher esterifica-
tion could be utilized but this method resulted in increased
lactone formation. Characterization of the esters 6a and 6b
by NMR revealed a coupling constant of J3–4 = 1.6 Hz
between the C-3 and C-4 protons indicating exclusive
formation of the trans isomer. The small coupling constant
is due to the pseudo-axial orientation of the ester and chloro-
methylene groups to minimize steric interaction that gives a
dihedral angle for the C-3 and C-4 protons of approximately
© 2013 HeteroCorporation

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Synthesis of trans/cis-3,4-Disubstituted 1,2,3,4-Tetrahydroisoquinolines
115
by Nucleophilic Acyl Substitution of Homophthalic Anhydride with Aldimines
Figure 1. Natural products synthesized utilizing imine-anhydride condensations as a key step.
combines the anhydride, the aldehyde, and the appropriate
amine in a single pot and utilizes KAl(SO4)2.12H2O (alum)
as the Lewis acid (Scheme 2). This procedure has been
reported for unfunctionalized imines so it was therefore of
interest to determine if it offered any advantages over pre-
forming the imine for these unstable alpha-functionalized
imines. When chloroacetaldehye and benzylamine were uti-
lized in this reaction, the resulting products and yields were
similar to those obtained by pre-forming the imine.(Table 2)
Utilization of the imines 7a and 7b in the condensation
was also investigated as both a means of extending the ver-
satility of the reaction and to investigate the incorporation
of an electron withdrawing ester functionality at the alpha
position of the imine (Scheme 3, Table 2). The imines 7a
and 7b were found to be much more stable than 3a and
3b and were stable upon storage. Reaction times were
longer in the case of 7a and 7b compared with 3a and
3b. In the case of 7a, reaction with homophthalic anhy-
dride gave the isoquinolinic acid 8a in high yield (85%)
exclusively as the cis isomer as revealed from the 6 Hz
Figure 2. Retrosynthetic synthesis of compound 1.
60ꢀ. Molecular mechanics calculations (SYBYL) suggested
the diaxial orientation of the ester and chloromethylene
functions to be 2.0 kcal more stable than the diequatorial
arrangement. The isolation of only the trans isomer occurred
as a result of isomerization of the cis acid to give the more
stable trans isomer during esterification. The lactones
exhibited a coupling constant of J = 7 Hz between C3-H and
C4-H indicating exclusive formation of the cis isomer.
Recently, Lewis acids have been shown to be useful in
promoting imine–anhydride condensations [13]. A proce-
dure reported by Azizian et al. does not pre-form the imine
as was performed in the procedure mentioned earlier but
Scheme 1
Journal of Heterocyclic Chemistry
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116
S. Hammad and F. T. Smith
Vol 50
Table 1
Reaction of Homophthalic anhydride with 3a,b.
Table 2
Reaction of Homophthalic anhydride with 7a,b.
% Yield
Reaction time in minutes
% Yield
Reaction time in hours
Procedure Procedure
Procedure
A
Procedure
B
Procedure Procedure
Procedure
A
Procedure
Compound
A
B
60
–
Compound
A
B
B
6a
6b
5a
5b
70
80
20
15
10 imine + 10
acid
10 imine + 10
acid
10 imine + 10
acid
10 imine + 10
acid
5
–
5
–
8a
8b
9a
9b
85
53
8
85
40
10
0
2
0.5
2
7
8
2
15
0.3
0.3
25
–
9b was formed then completely converted to 8b in case of procedure B.
(TMS, d 0.00). 13C chemical shifts are reported in d relative to
CDCl3 (center of triplet, d 77.23) or relative to DMSO-d6 (center
of septet, d 39.51). The spin multiplicities are indicated by the
symbols s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). Atlantic Microlabs, Norcross, and
Georgia performed elemental analyses. Reactions were monitored
by thin layer chromatography (TLC) using 0.25 mm E. Merck
silica gel 60-F254 pre-coated silica gel plates with visualization
by the irradiation with Mineralight UVGL-25 lamp or exposure
to iodine vapor. Column chromatography was performed on
Whatman silica gel (average particle size 2–25mm, 60 Å) and
elution with the indicated solvent system. Spinning band
Procedure A involved formation of the imine prior to condensation with
the anhydride. Procedure B involved combining the amine, aldehyde, and
anhydride so that the imine was formed in situ with alum as a catalyst.
coupling constant for the C-3 and C-4 protons. There was
also a small amount of 9a produced as well. Compound
9a apparently arises as a result of breakdown of the imine
during the reaction. In the case of 7b, yields of 8b were
modest (53%) and there was an increased amount of 9b
formed. Utilization of Azizain’s procedure gave similar
yields in the case of 8a along with a small amount of 9a.
In the case of 7b, the yield of 8b was slightly lower and
longer reaction times were necessary. (Scheme 4).
To summarize, these studies have served to show that
functionality can be introduced into the C3 position of the
isoquinolinic-acids that is suitable for further manipulation
with the goal of synthesizing more complex heterocycles
by cyclization of the C3 and C4 positions. The stereochemis-
try of the imine–anhydride cyclization product is dependent
in part upon the functionality present at the alpha carbon of
the imine. The utilization of alum as a Lewis acid did not
prove superior with regard to product yields to pre-forming
the imines in the examples investigated here.
chromatography was performed on
a Chromatotron 8900
(Harrison Research, Palo Alto, CA) sing Merck silica gel 7749
with gypsum binder and fluorescent indicator. Yields refer to
the spectroscopically (1H NMR and 13C NMR) and
chromatographically homogeneous materials. GC-MS was
performed with an HP-5890 GC coupled with an HP-5970 mass
selective detector (Hewlett Packard, Palo Alto, CA) using Helium
(grade 5.0) as carrier gas. The mass spectrometer was operated on
the electron impact (EI) mode using ionization voltage of 70 eV
and a source temperature of 230ꢀC. Samples were dissolved in
HPLC grade acetonitrile (Fisher Scientific, NJ, USA) and
manually introduced (1mL) individually.
Experimental procedures.
Procedure A.
1- General procedure for the synthesis of Imines N-(2-
chloroethylidene)-1-phenylmethanamine (3a) and N-(2-
chloroethylidene)-1-(2,4-dimethoxyphenyl)methanamine (3b)
EXPERIMENTAL
Materials and methods. Melting points were recorded on a
1
Thomas–Hoover melting point apparatus and are uncorrected. H
To chloroacetaldehyde (60 mmoles, 10.5 mL, 1.2 equivalent)
(45% in aqueous solution), 10 ml of water was added and the
resulting solution was stirred in an ice-methanol bath at À5ꢀC.
To this solution, the appropriate amine (50 mmoles, 1 equivalent)
NMR and 13C NMR spectra were recorded on a Varian MR400
(operated at 400 or 100 MHz, respectively). All 1H chemical shifts
are reported in d relative to the internal standard tetramethylsilane
Scheme 2
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Synthesis of trans/cis-3,4-Disubstituted 1,2,3,4-Tetrahydroisoquinolines
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by Nucleophilic Acyl Substitution of Homophthalic Anhydride with Aldimines
Scheme 3
Scheme 4
in one portion was added and the reaction mixture was allowed to
stir for 10 min. After removal of the cooling bath, alcohol-free
chloroform (10 mL) was added twice to extract the imine. The
combined organic extracts were rapidly dried with anhydrous
sodium sulfate and used without further purification in the
next step.
pressure, the product was washed with petroleum ether (25 mL),
and the resulting gum was dried under vacuum. The crude
product contained the acid 4a in the form of a mixture of
diastereomers (60% yield calculated by GC-MS and the lactone
5a in 25% yield) and the crude product was used in the
subsequent esterification step without purification.
3- General procedure for the synthesis of the esters: methyl 2-benzyl-
3-(chloromethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxyl-
ate (6a) and methyl 3-(chloromethyl)-2-(2,4-dimethoxybenzyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (6b).
2- General procedure for the synthesis of the acids 2-benzyl-3-
(chloromethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic
acid (4a) and 3-(chloromethyl)-2-(2,4-dimethoxybenzyl)-
1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (4b)
and the lactones 4-benzyl-3a,4-dihydrofuro[3,4-c]isoquinoline-
1,5(3H,9bH)-dione (5a) and 4-(2,4-dimethoxybenzyl)-3a,
4-dihydrofuro[3,4-c]isoquinoline-1,5(3H,9bH)-dione (5b).
To a DMF solution (15mL) of the mixture of the acid 4a or 4b
and the lactone 5a or 5b (50 mmoles), respectively, sodium bicar-
bonate (4.3 g, 51mmoles) was added and the formed suspension
was allowed to stir at room temperature for 15 min. To this, methyl
iodide (7.1g, 50mmoles) was added and stirring was continued for
an additional 15min. Brine (5 mL) was added and the product was
extracted with ethyl acetate (3Â 10 mL). The combined organic
extracts were evaporated under vacuum and purified by column
chromatography (silica gel) using petroleum ether and ethyl acetate
in a 4:1 ratio as the eluting system to give esters 6a and 6b in 56.4%
and 65% overall yields, respectively, and the lactones 4a and 4b in
20% and 15% yields, respectively.
The imine 3a or 3b (50 mmoles, 1.2 equivalents) in alcohol-
free chloroform (15 mL) was added to 2 (41 mmoles, 6.64 g,
1 equivalent) suspended in methylene chloride (10 mL) and the
resulting solution was allowed to stir at room temperature for
15 min. The solvents were evaporated under reduced pressure
and the oily residue was washed twice with petroleum ether
(10 mL) to give a brown gum that was further dried under vacuum
to give a yellowish-brown fluffy powder of acid 4a or 4b and the
lactone 5a or 5b, respectively. These were used without further
purification to maximize the yield. The acids 4a and 4b were
characterized in the form of their methyl esters that were obtained
from the next esterification step.
4-Benzyl-3a,4-dihydrofuro[3,4-c]isoquinoline-1,5(3H,9bH)-dione
(5a). This compound was obtained as white crystals, mp:146–148ꢀC;
1H-NMR CDCl3: d 3.97 (dd, 1H,, 2H OCH2a, J=8.02, J=9.2Hz),
4.05 (d, 1H, C4-H, J= 8.41 Hz), 4.09 (dd, 1H, OCH2b, J=6.65,
J= 9.2 Hz), 4.50 (sextet, 1H. C3-H, J=6.65, J= 8.26, 8.30), 4.8–4.95
(dd, 2H, –CH2–Ar, J=15Hz), 7.25–7.35 (m, 5H, Ar–H), 7.45–7.65
(m,3H, Ar–H), 8.3 (d, 1H, Ar–H, J=12Hz); 13C-NMR (CDCl3): d
40.60, 49.77, 55.16, 70.52, 127.29, 127.54, 127.55, 128.13, 128.26,
128.67, 128.70, 128.90, 129.11, 129.17, 133.29, 136.66, 162.16 and
173.51; GC-MS (EI): 293(M+ and100%), 236, 106, 91 and 65. Anal.
Procedure B. A mixture of homophthalic anhydride, 2
(162 mg, 1 mmole), chloroacetaldehyde (45% in aqueous
solution) (1.2 mmoles, 0.21 mL), benzylamine (107 mg,
1
mmole), and alum (0.24 g, 0.5 mmoles) in acetonitrile (10 mL)
in a 25-mL flask was stirred at room temperature for 15 min.
After completion of the reaction (monitored by TLC, ethyl
acetate/pet-ether 1/1), the solvent was evaporated under reduced
Journal of Heterocyclic Chemistry
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S. Hammad and F. T. Smith
Vol 50
Calcd. for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.73; H,
5.15; N, 4.75.
4-(2,4-Dimethoxybenzyl)-3a,4-dihydrofuro[3,4-c]isoquinoline-
concentrated under vacuum and crystallized from ethanol/ether/
water in 85% and 53% yields, respectively. All yields were
calculated with respect to 2.
1,5(3H,9bH)-dione (5b). This compound was obtained as a
Procedure B to form the acid 8b. A mixture of 2 (162 mg,
1 mmole), ethyl glyoxalate (123mg, 1.2 mmoles), p-anisidene
(123mg, 1 mmole), and alum (0.24 g, 0.5mmoles) in acetonitrile
(10 mL) in a 25-mL flask was stirred at room temperature for 8 h.
After completion of the reaction (monitored by TLC, ethyl
acetate/pet-ether 1/1), the solvent was evaporated under reduced
pressure, and petroleum ether (25 mL) was added. This resulted in
the formation of a gum from which the petroleum ether was
decanted and the gum was dried under vacuum. The crude
product containing the acid 8b was dissolved in 2N NaHCO3
(5mL) and washed with ethyl acetate. The aqueous solution was
acidified with 0.6N HCl and the precipitated acid was extracted
with ethyl acetate to give the pure acid in the form of a mixture of
diastereomers (50/50) in 40% overall yield.
1
white powder, mp:124–126ꢀC; H-NMR (CDCl3): d 3.81 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 4.01 (d, 1H, C4-H, J = 8.3 Hz), 4.04
(dd,1H, OCH2a, J = 8.02, J = 9.2 Hz), 4.22 (dd, 1H, OCH2b,
J = 6.65, J = 9.2 Hz), 4.57 (sextet, 1H, C3-H, J = 6.65, J = 8.02,
J = 9.2 Hz), 4.75–4.90 (dd, 2H, –CH2–Ph, J = 16Hz), 6.49 (d,2H,
Ar–H), 7.26–7.63 (m,4H, Ar–H) and 8.23 (d,1H, Ar–H,
J = 12Hz); 13C-NMR-4b CDCl3: d 40.67, 43.27, 54.75, 55.40,
55.54, 70.87, 76.68, 77.00, 77.32, 98.54, 104.85, 116.93, 127.19,
127.91, 128.70, 128.72, 128.94, 131.71, 132.94, 158.50, 160.90,
162.03 and 173.91; GC-MS (EI): 353(M+ and100%), 322, 166,
151, 121, 91 and 77. Anal. Calcd. for C20H19NO5: C, 67.98; H,
5.42; N, 3.96. Found: C, 67.80; H, 5.45; N, 3.85.
Methyl 2-benzyl-3-(chloromethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-
4-carboxylate (6a). This compound was obtained as yellow crystals, mp
2-(2,4-Dimethoxybenzyl)-3-(ethoxycarbonyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic acid (8a). This compound was
obtained as a white powder, mp 146–148ꢀC; 1H-NMR (DMSO-d6):
d 1.0 (t, 3H, –CH2–CH3), 3.80 (s, 3H, OCH3), 3.85 (s, 3H, OCH3),
3.90 (q, 2H, –CH2–CH3), 4.53 (d, 1H, C4-H, J=5.5Hz), 4.61
(d, 1H, C3-H, J= 5.7 Hz ), 4.24 and 4.92 (dd, 2H, –CH2–Ar,
J= 15 Hz), 6.48 (d, 1H, Ar–H), 6.57 (s, 1H, Ar–H), 7.2 (d, 1H,
Ar–H), 7.4 (t, 1H, Ar–H), 7.51 (t, 1H, Ar–H), 7.66 (d, 1H, Ar–H)
and 7.92 (d, 1H, Ar–H); 13C-NMR-DMSO-d6: d 13.25, 44.71,
45.43, 55.12, 55.35, 59.55, 60.81, 98.14, 104.56, 116.38, 126.63,
127.12, 127.23, 128.77, 130.88, 131.56, 133.36, 158.37, 160.13,
163.16, 169.01 and 170.12. Anal. Calcd. for C22H23NO7: C, 63.91;
H, 5.61; N, 3.39. Found: C, 63.74; H, 5.62; N, 3.52.
1
128–130ꢀC; H-NMR (CDCl3): d 3.15 (t, 1H, CH–Cl, J=11Hz), 3.39
(s, 3H, –COOCH3), 3.47 (dd, 1H, CH–Cl, J=6.8, J=14Hz), 4.13 (1H,
d, C4-H, J= 1.6 Hz), 4.24 (ddd, 1H, C3-H, J=1.6, J=4.1, J= 10.6 Hz),
4.5–5.1 (dd, 2H, –CH2–Ph, J= 14.8 Hz), 7.25–7.38 (6H, m, Ar–H), 7.45–
7.55 (2H, m, Ar–H), and 8.15 ( d, 1H, Ar–H, J=6.4Hz); 13C-NMR
(CDCl3): d 41.01, 43.85, 48.98, 51.61, 58.04, 126.9, 127.47,127.58,
127.75 (3 carbons), 127.92 (2 carbons), 128.71, 131.01, 131.53, 136.05,
161.78 and 169.55. GC-MS (EI): 343(M+), 394, 248, 91 (100%) and 65.
Anal. Calcd. for C19H18ClNO3: C, 66.38; H, 5.28; N, 4.07. Found: C,
66.15; H, 5.16; N, 4.06.
Methyl 3-(chloromethyl)-2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylate (6b). This compound was
obtained as pinkish-white crystals, mp 125–127ꢀC; 1H-NMR
(CDCl3): d 3.1 (t, 1H, CH–Cl, J= 11 Hz), 3.40 (s, 3H, OCH3), 3.50
(dd, 1H, CH–Cl, J=3.8, J= 11 Hz), 3.80 (s, 3H, OCH3), 3.90 (s,
3H, OCH3), 4.13 ( 1H, d, C4-H, J= 1.6 Hz), 4.36 (ddd, 1H, CH–N,
J=1.6, J=3.6, J=11Hz), 4.5–5.0 (dd, 2H, –CH2–Ph, J=14Hz),
6.5 (2H, d, Ar–H), 7.2–7.6 (4H, m, Ar–H), 8.14( 1H, d, Ar–H,
J=6.4Hz). 13C-NMR (CDCl3): d 42.14, 43.39, 44.74, 52.51,
55.38, 55.44, 58.89, 98.23, 104.56, 117.54, 128.44, 128.58, 128.77,
129.55, 132.08, 132.23, 132.50, 158.73, 160.71, 162.67 and
170.74, GC-MS (EI): 403(M+), 368, 340, 151 (100%), 121, 91 and
77. Anal. Calcd. for C21H22ClNO5: C, 62.45; H, 5.49; N, 3.74; Cl,
8.78. Found: C, 62.53; H, 5.50; N, 3.48; Cl, 8.83.
3-(Ethoxycarbonyl)-2-(4-methoxyphenyl)-1-oxo-1,2,3,4-
tetrahydroisoquinoline-4-carboxylic acid (8b). This compound
was obtained as white crystals, mp 186–188ꢀC; 1H-NMR
(DMSO-d6): d 1.0 (t, 3H, –CH2–CH3), 3.8 (s, 3H, O–CH3), 4.0
(q, 2H, –CH2–CH3), 4.8 (d, 1H, C4-H, J = 6 Hz), 5.0 (d, 1H, C3-
H, J = 5.6Hz), 7.0 (d, 2H, Ar–H), 7.3 (d, 2H, Ar–H), 7.5 (dd, 1H,
Ar–H), 7.6 (dd, 1H, Ar–H), 7.7 (d, 1H, Ar–H), 8.0 (d, 1H, Ar–H)
and 13.35 (s,1H, –COOH); 13C-NMR (DMSO-d6): d 13.53,
45.81, 55.22, 61.02, 63.28, 114.05, 126.38, 127.26, 127.58,
128.09, 128.85, 132.0, 133.81, 134.53, 157.93, 162.81, 169.1 and
170.16. Anal. Calcd. for C20H19NO6: C, 65.03; H, 5.18; N, 3.79.
Found: C, 64.94; H, 5.26; N, 3.83.
[2-(2,4-Dimethoxy-benzylcarbamoyl)-phenyl]-acetic acid (9a). This
1
compound was obtained as white flakes, mp 150–152ꢀC; H-NMR
Procedure A to form the acids 8a, 8b, 9a, and 9b.
(DMSO-d6): d 3.3 (1H, br.s, NH), 3.74 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.90 (s, 2H, –CO–CH2), 4.15 (d, 2H, –NH–CH2), 6.4 (d, 1H,
Ar–H), 6.52 (s, 1H, Ar–H), 7.08 (d, 1H, Ar–H), 7.3 (dd, 1H, Ar–H),
7.46 (t, 1H, Ar–H), 7.8 (d, 1H, Ar–H) and 8.09 (t, 1H, Ar–H).
13C-NMR (DMSO-d6): d 55.07, 55.25, 98.04, 104.16, 118.87,
126.51, 128.61, 130.03, 131.03, 131.41, 131.58, 136.9, 157.52,
159.52, 168.53 and 169.92. LC-HRMS: calculated for
C18H19NO5 (M-H): 328.1190. Found: 328.1197.
[2-(4-Methoxy-phenylcarbamoyl)-phenyl]-acetic acid (9b). This
compound was obtained as a pale violet powder, mp 174–176ꢀC;
1H-NMR (DMSO-d6): d 3.3 (1H, br. s, NH ), 3.70 (s, 3H, OCH3),
4.05 (s, 2H, –CH2), 6.85 (d, 2H, Ar–H), 7.35 (m, 2H, Ar–H),
7.50 (m, 3H, Ar–H), 7.86 (d, 1H, Ar–H) and 9.93 (s, 1H,–COOH).
13C-NMR (DMSO-d6): d 41.46, 55.04, 113.67 (2 carbons), 120.34
(2 carbons), 126.64, 130.04, 131.10, 131.49, 132.04, 132.56, 136.79,
154.84 and 168.45 (2 overlapped carbonyls).LC-HRMS: calculated
for C16H14NO4 (M-H): 284.0928. Found: 284.0935.
Synthesis of the imines ethyl 2-(2,4-dimethoxybenzylimino)
acetate (7a) and ethyl 2-(4-methoxyphenylimino)acetate (7b). To a
stirred solution of ethyl glyoxalate (12 mmoles, 1.2 equivalents) in
dry methylene chloride (20 mL) in one portion, the amine either 2,4-
dimethoxybenzylamine or p-anisidene (10 mmoles, 1 equivalent) was
added and the reaction mixture was allowed to stir for 3 h in the
presence of molecular sieves. After filtering off the molecular sieves,
the imine dissolved in methylene chloride was added to 2 in the next
reaction without further purification.
2-Synthesis of the acids 8a/ 8b and 9a/9b. To a stirred
suspension of
2 (1.62 g, 10mmoles, 1 equivalent) in dry
methylene chloride (10mL), the imine either 7a or 7b dissolved in
methylene chloride (20 mL) was added and the reaction was
allowed to stir at room temperature for 2 h and the precipitated
acids 9a or 9b were filtered off and dried in 8% and 15%
yields, respectively. The filtrate containing acid 8a or 8b was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis of trans/cis-3,4-Disubstituted 1,2,3,4-Tetrahydroisoquinolines
119
by Nucleophilic Acyl Substitution of Homophthalic Anhydride with Aldimines
[6] Haimova, M. A.; Mollov, N. M.; Ivanova, S. C.; Dimitrova A.
I.; Ognyanov, V. I. Tetrahedron 1977, 33, 331.
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2002, 39, 229.
[8] Stoyanova, M.; Kozekov1, I.; Palamareva, M. D. J Heterocycl
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Acknowledgments. We would like to thank the Egyptian Cultural
and Educational Bureau for the Doctoral Fellow sponsorship of S.F.
Hammad. We would also like to thank Dr. Angela Calderon for the
CHN analysis of some samples.
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