Niobium pentachloride promoted conversion of carboxylic acids to carboxamides: Synthesis of the 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid structures

Article abstract of DOI:10.1055/s-2003-36823

A practical method for the conversion of carboxylic acids to the corresponding carboxamides mediated by niobium pentachloride under mild conditions is described. The synthesis of the 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid structures was accomplished via benzylic lithiation of N-methyl-3,4-dimethoxy-2-(4′-methoxybenzyl)benzamide.

Full text of DOI:10.1055/s-2003-36823

272
PAPER
Niobium Pentachloride Promoted Conversion of Carboxylic Acids to
Carboxamides: Synthesis of the 4-Aryl-1,2,3,4-tetrahydroisoquinoline
Alkaloid Structures
Conversion of
C
arboxy
a
lic
A
cids
t
r
camides elo S. Nery, Renata P. Ribeiro, Claudio C. Lopes,* Rosangela S. C. Lopes*
Universidade Federal do Rio de Janeiro, Instituto de Química, Departamento de Química Analítica, CT, , Bl. A, 5° andar, s-508, Rio de
Janeiro, RJ, CEP-21949 900, Brazil
Fax +55(21)25627854; E-mail: iqg02022@acd.ufrj.br
Received 21 November 2001; revised 5 October 2002
ials in lithiation reactions aimed at the synthesis of natural
Abstract: A practical method for the conversion of carboxylic ac-
products, such as pancreatistatin10 and substituted 4-hy-
ids to the corresponding carboxamides mediated by niobium pen-
tachloride under mild conditions is described. The synthesis of the
4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid structures was ac-
droxy-coumarins.11 With this as the main objective, we
have developed a practical experimental procedure to ob-
complished via benzylic lithiation of N-methyl-3,4-dimethoxy-2- tain N,N-diethylcarboxamides (2a–l). In addition, it was
(4′-methoxybenzyl)benzamide.
possible to extend the method to the formation of N-butyl-
carboxamides (3a–l) and carboxamides (4a–l) under mild
conditions by the following procedure: a solution of 3.0
equivalents of the appropriate carboxylic acids (1a–l) and
1.0 equivalent of niobium pentachloride was obtained in
dichloromethane or dioxane as solvent and after a certain
period of time with the addition of an excess of diethyl-
amine, butylamine or ammonia (Table 1).
Key words: carboxamides, niobium pentachloride, carboxylic ac-
ids, alkaloid, tetrahydroisoquinoline
Unusual biologically active peptides are isolated from
marine sponges, fungi, bacteria, and other lower animal
forms. Through the use of modern synthetic strategies,
these compounds are synthesized1 by processes involving
as key step the formation of carboxamides under mild
conditions employing reagents such as: 2-oxopiperazine2
derivatives, DCC, HOBt, BOP, isobutylchloroformate,1
etc.
The low yields of oxygenated aromatic acids may be at-
tributed to the formation of stable coordinated species12
with niobium pentachloride and electron donating groups
attached at the aromatic ring instead the formation of cor-
responding acylium species during the course of these re-
actions. Moreover, in the case of piperonylic acid, the low
yield was also related to the cleavage of the methylene-
dioxy ring by coordination of niobium pentachloride with
one oxygen atom, followed by nucleophilic attack of chlo-
ride species on the methylene portion generating catechol
intermediates which form stable coordinating com-
pounds. This type of ring opening is also observed in me-
There also exists a direct approach involving the pyrolytic
dehydration of the appropriate substituted ammonium
carboxylate salts.3 Amines in the vapor phase4 at 270–
290 °C or after a long period of reflux5 with the use of
Lewis acid catalysts,6 aliphatic and aromatic carboxylic
acids can be converted to the desired carboxamides. The
classical two step synthesis involves the conversion of al-
iphatic or aromatic acids to the corresponding acyl chlor-
ides with suitable reagents (SOCl2, PCl5, ClCOCOCl),7
followed by treatment with the appropriate amine.
13
thylenedioxy aromatic systems in the presence of AlCl3
and BCl3.14
This procedure described herein contrasts with most liter-
ature procedures3–7 occurring under mild conditions with-
out the generation of free hydrogen chloride gas or other
irritant side products such as sulfur dioxide or phosphorus
oxychloride.
Niobium compounds are useful catalysts for various reac-
tions.8 The compound niobium pentachloride (NbCl5) is a
yellow solid, quickly hydrolyzed by water to the hydrated
pentoxides and hydrochloric acid. Initially, due to its po-
tential as a donor of chloride species, low cost and abun-
The use of niobium pentachloride to promote the forma-
tion of the N,N-diethylcarboxamide of pivalic acid was
achieved in good yield. The same chemical transforma-
tion failed when titanium tetrachloride15 was used as pro-
moter.
Brown and co-workers,16 have published a different ap-
proach for the preparation of acyl chloride, oxoniobium
and oxotitanium carboxylates in moderate yields. The for-
mation of these intermediates occurs at the same time
when a carboxylic acid is submitted to treatment with
TiCl4 or NbCl5. However, the oxotitanium carboxylates
structures formation requires more equivalents of carbox-
ylic acid than oxoniobium carboxylates.16,17 A possible
9
dance in Brazil, NbCl5 was chosen as promoter for the
reactions between carboxylic acids (1a–l) and diethyl-
amine, butylamine or ammonia to obtain the correspond-
ing N,N-diethylcarboxamides (2a–l), N-butylcarbox-
amides (3a–l) or carboxamides (4a–l).
Aromatic N,N-diethylcarboxamides (2a and g) and N,N-
diethylcarbamates have been used as DoM starting mater-
Synthesis 2003, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2003,0,02,0272,0276,ftx,en;M05801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
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Conversion of Carboxylic Acids to Carboxamides
273
Table 1 Conversion of Carboxylic Acids to N,N-Diethylcarboxamides, N-Butylcarboxamides and Carboxamides with Niobium Penta-
chloride
Carboxylic Acids
benzoic acid 1a
Carboxamides
2a, 3a, 4a
2b, 3b, 4b
2c, 3c, 4c
2d, 3d, 4d
2e, 3e, 4e
2f, 3f, 4f
Time (h)
2, 0.5, 0.5
2.5, 0.5, 0.5
2.5, 0.5, 0.5
3, 0.5, 1
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
CH2Cl2
dioxane
CH2Cl2
dioxane
CH2Cl2
Yield (%)
89, 96, 97
85, 93, 95
79, 89, 89
70, 81, 90
84, 88, 96
88, 89, 98
8, 47, 48
m-toluic acid 1b
octanoic acid 1c
crotonic acid 1d
propanoic acid 1e
butyric acid 1f
2.5, 0.5, 1
3, 0.5, 1
piperonylic acid 1g
pivalic acid 1h
2g, 3g, 4g
2h, 3h, 4h
2i, 3i, 4i
5, 0.5, 2
10, 0.5, 1
12, 0.5, 2
5, 0.5, 0.5
10, 0.5, 1
8, 0.5, 3
78, 83, 88
73, 84, 83
63, 93, 93
12, 54, 51
45, 77, 74
nicotinic acid 1i
phenylacetic acid 1j
p-hydroxybenzoic acid 1k
3,4-dimethoxybenzoic acid 1l
2j, 3j, 4j
2k, 3k, 4k
2l, 3l, 4l
explanation could be as follows: When the pivalic acid is The acid (6) was obtained by the same sequence of reac-
used in this procedure, the steric effects contribute to a de- tions described in our previous work.19 By treatment of
crease in the stability of corresponding oxotitanium car- acid (30.0 mmol) (6) under the same conditions as de-
boxylate and consequently generate less amount of scribed in experimental section below, the N-methylbenz-
pivaloyl chloride.
amide (7) was obtained in 86% yield. The interesting
point of this chemical transformation was the addition of
an aqueous solution containing an excess of methylamine
hydrochloride (45%) to quench the oxoniobium carboxy-
late intermediate and furnish the desired product. Tradi-
tionally, standard acylation procedures with aliphatic or
aromatic acyl chlorides require anhydrous free amines to
condense and form the appropriated carboxamides.
The experimental procedure described in this work is a
practical way to produce carboxamides (2, 3, 4a–l) from
carboxylic acids (1a–l) under mild conditions and the HCl
generated is trapped under the form of an ammonium salt,
which together with Nb2O5 can be recycled at the end of
reaction.
A useful synthetic application of this methodology is de-
scribed in Schemes 1 and 2 involving the preparation of
the 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloid struc-
tures related with racemic O-dimethyl latifine (5a), a de-
rivative of the natural product (+)-latifine (5b) isolated
from Crinum latifolium L., which would be expected to
demonstrate potential pharmacological activities of bio-
logical relevance (Figure 1).18
Benzylic lithiation of 7 was carried out in the presence of
3.0 equivalents of BuLi, 1.3 M hexane solution in THF
followed by dropwise addition of a solution of triphos-
gene in THF to afford the N-methylimide 8 in 93% yield.
In our hands, the use of DMF as electrophile20 afforded
poor yields of corresponding 4-aryl-1,2,3,4-tetrahydroiso-
quinoline alkaloid derivative (Scheme 1). Reduction of 8
with a suspension of LiAlH4 in THF gave a complex mix-
ture of products.
Figure 1
Scheme 1 Reagents and conditions:
i) NbCl5/CH2Cl2,,
CH3NH2 HCl/H2O (45% w/v), 0 °C, 86% ii) BuLi/THF (3.0 equiv),
0 °C iii) Triphosgene/THF, 93%.
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274
M. S. Nery et al.
PAPER
Melting points were determined on a Melt-Temp apparatus. 1H and
13C NMR spectra were recorded on Gemini-200 MHz, Bruker AM-
250 MHz and Bruker-300 MHz spectrometers with Me4Si (δ =
0.00) as internal standard in DMSO-d6 or CDCl3 solvents. The fol-
lowing abbreviations are used to describe the multiplicity of signals
(s, singlet; d, doublet; dd, doublet of a doublet; t, triplet; dt, doublet
of a triplet; m, multiplet). Chemical shifts were expressed as δ val-
ues (part per million) from tetramethylsilane. Mass spectra were de-
termined on a Auto Specq EI at 70 eV and HRMS was determined
on a Varian MAT-CH7 instrument at 70 eV by the Department of
Chemistry, Queen’s University, Kingston, Canada. All commercial
chemicals were purchased from Aldrich Co, Sigma and Vetec (Bra-
zilian Chemical Co).
An unexpected result was observed on the benzylic lithia-
tion reaction of amide (7) using methyl chloroformate in-
stead of triphosgene as electrophile. After the same work
up and purification by flash chromatography, the amide
derivative (9) was obtained in 31% yield together with an
imide (10) in 30% yield.
An explanation for these results might be visualized by
the difference of reactivity between triphosgene and me-
thylchloroformate used as eletrophile. Each equivalent of
triphosgene affords 2.0 equivalents of CCl3O– species
which are unstable producing phosgene and LiCl. The
ring closure product 8 with triphosgene produces phos-
gene which is even more reactive than triphosgene. To
complete a ring closure only a third of an equivalent is
necessary since each mole of triphosgene releases 2 addi-
tional phosgenes. However, we obtained best yields in the
formation of N-methylimide 8 using an excess of triphos-
gene. Probably, the N-methylimide 8 is also an
intermediate of the reaction when methyl chloroformate
used as electrophile and the CH3O– species formed can re-
act by two different ways to generate the amide derivative
(9) and the imide (10). The first compound was obtained
by the nucleophilic attack on the carbonyl group at the 3
position and the second by nucleophilic attack at the N-
methyl group of compound 8.
Synthesis of Carboxamides (2,3,4a–l); General Procedure
In a 100.0 mL round-bottomed flask equipped with a magnetic stir-
rer, argon-inlet, and a reflux condenser NbCl5 (4.71 mmol) was add-
ed followed by addition of a soln in CH2Cl2 or dioxane (30.0 mL),
(see Table 1) of the carboxylic acid (14.13 mmol ) (1a–l). After a
few min of vigorous stirring, a suspension formed and diethyl-
amine, butylamine or ammonia (37.68 mmol) was introduced into
the reaction mixture. In 0.5 h, the temperature was slowly raised to
45–50 °C and the reaction time was maintained as described in
Table 1, for each carboxylic acid. The reaction mixture was cooled
and the solids formed were removed by filtration. The filtrate was
extracted with EtOAc or Et2O (200 mL), washed with a soln of
NaHCO3 (5%, 60 mL), brine (2 × 60 mL), H2O (3 × 60 mL), evap-
orated and distilled to give the desired carboxamides (2,3,4a–l). The
boiling, melting points and other analytical data were compatible
with the chemical structures of carboxamides as described in refer-
ences.3–7 The yields reported in Table 1, were obtained after distil-
lation or recrystallization of the crude materials.
The reduction of 10 with a suspension of LiAlH4 in THF
gave the corresponding 4-aryl-1,2,3,4-tetrahydroisoquin-
oline alkaloid (11) in 71% yield (Scheme 2).
N-Methyl-3,4-dimethoxy-2-(4′-methoxybenzyl)benzamide (7)
In a 100 mL round-bottomed flask equipped with a magnetic stirrer,
argon-inlet, and a reflux condenser NbCl5 (1.0 mmol, 0.270 g) were
added followed by addition of a soln in CH2Cl2 (12.0 mL) of the 3,4-
dimetoxy-2-(4′-methoxybenzyl) benzoic acid (3.0 mmol, 0.905 g)
(1a–l). After a few min of vigorous stirring, the suspension formed
was kept at 0 °C and chloride salt of methylamine (7.0 mmol) 45%
(w/v) were added. In 0.5 h, the temperature was slowly raised to r.t.
and the reaction maintained for 1 h. The reaction mixture was
cooled and the solids formed were removed by filtration. The fil-
trate was introduced into a soln of NaHCO3 (5%, 25.0 mL) and ex-
tracted with CH2Cl2 (80 mL). The organic layer was washed with a
soln of brine (2 × 30 mL), H2O (3 × 30 mL), dried (Na2SO4), the
solvent was evaporated in vacuo, and the brown crude product pu-
rified by fast filtration on silica gel with hexane–EtOAc (2:1) as elu-
ent to give (7) (819 mg, 86%) as an amorphous white solid.
Mp 146–148 °C (lit.20 mp 145–147 °C).
IR (film): 3291, 3074, 3014, 2942, 2841, 1626, 1542, 1512, 1488,
1290, 1251, 1084, 1060, 1032, 1004 cm–1.
1H NMR (CDCl3): δ = 2.80 (d, 3 H, J = 4.6 Hz), 3.72 (s, 3 H), 3.75
(s, 3 H), 3.88 (s, 3 H), 4.15 (s, 2 H), 5.51 (s, 1 H), 6.76 (d, 2 H, J =
8.5 Hz), 6.78 (d, 1 H, J = 8.0 Hz), 7.11 (d, 2 H, J = 8.4 Hz), 7.13 (d,
1 H, J = 7.9 Hz).
Scheme 2: Reagents and conditions: i) BuLi/THF (3.0 equiv), 0 °C
ii) ClCO2CH3/ THF, 9 (31%), 10 (30%) iii) LiAlH4/THF, 71%.
13C NMR (CDCl3): δ = 31.5, 55.3, 55.8, 60.7, 110.0, 113.8, 123.5,
129.7, 130.6, 133.4, 133.7, 147.6, 154.2, 157.9, 170.5.
In conclusion, to finish this project, different alkyl groups
will be attached at the nitrogen atom of 5,6-dimethoxy-
4(4′-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (11)
by well known synthetic methodology established by
Brossi and coworkers.21 This involves acylation and fur-
ther reduction to make O-dimethyl latifine (5a) and new
N-aliphatic derivatives whose biological properties will
be evaluated.
MS: m/z (%) = 315 (100), 283 (10), 207 (13).
5,6-Dimethoxy-4-(4′-methoxyphenyl)-2-methyl-4-tetrahydro-
isoquinoline-1,3-dione (8)
The N-methylbenzamide (7) (0.315 g, 1.0 mmol) was dissolved in
THF (20.0 mL) and cooled to 0 °C. A soln of BuLi in hexane (1.3
M, 2.3 mL, 2.3 mmol) was added to generate a deep red soln of the
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PAPER
Conversion of Carboxylic Acids to Carboxamides
275
corresponding dilithiated amide. After 60 min, triphosgene (0.476
g, 1.6 mmol) in THF (6 mL) was added in one portion and the reac-
tion mixture became pale white. The soln was stirred for a further
30 min and NaHCO3 (5 mL, 10%) was added. The reaction mixture
was extracted with EtOAc (120 mL), the organic layer was washed
with H2O (2 × 30 mL) and dried with Na2SO4. The solvent was re-
moved by reduced pressure to give a viscous brown oil which was
purified by flash chromatography using hexane–EtOAc (2:1) as elu-
ent affording 8 (0.317 g, 93%) as a white solid.
stirring was continued for a further 30 min. EtOAc (50.0 mL) was
added, the organic layer washed with H2O (2 × 30 mL) and dried
(Na2SO4). The solvent was removed by reduced pressure evapora-
tion giving a crude residue which after fast filtration on flash silica
gel using hexane–EtOAc (1:1) provided the compound 11 (0.107g,
71%) as a clear white oil.
IR (film): 3439, 3000, 2935, 2935, 2837, 2049, 1609, 1581, 1509,
1458, 1419, 1273, 1246, 1173, 1082, 1032 cm–1.
1H NMR (CDCl3): δ = 3.21 (s, 1 H), 3.64 (s, 3 H), 3.73 (m, 1 H),
3.77 (s, 3 H), 3.86 (s, 3 H), 4.35 (dd, 2 H), 4.67 (d, 1 H), 6.32 (s, 1
H), 6.81 (d, 2 H, J = 8.7 Hz), 6.83 (d, 1 H), 7.01 (d, 1 H, J = 8.4 Hz),
7,22 (d, 2 H, J = 8.7 Hz).
Mp 137–139 °C.
IR (film): 3488, 3000, 2939, 2840, 1759, 1716, 1670, 1602, 1509,
1502, 1453, 1419, 1357, 1285, 1249, 1178, 1155, 1084, 1032, 995,
cm–1.
1H NMR (CDCl3): δ = 3.31 (s, 3 H), 3.71 (s, 6 H), 3.85 (s, 3 H), 6.28
(s, 1 H), 6.77 (d, 1 H, J = 8.6 Hz), 6.97 (d, 2 H, J = 8.0 Hz), 7.09 (d,
2 H, J = 8.1 Hz), 7.62 (d, 1 H, J = 7.9 Hz).
13C NMR (CDCl3): δ = 55.3, 55.8, 61.1, 63.7, 68.1, 69.0, 111.4,
113.6, 126.6, 126.8, 131.7, 136.3, 136.7, 147.3, 152.7, 158.5.
HRMS: m/z calcd for C18H21NO3, 299.3706; found, 299.3711.
13C NMR (CDCl3): δ = 36.7, 55.4, 56.1, 60.6, 77.4, 112.2, 112.6,
116.6, 120.7, 125.3, 131.0, 131.8, 143.6, 156.0, 158.5, 160.0, 161.8.
Acknowledgment
MS: m/z (%) = 341 (19), 313 (100), 285 (15), 249 (22), 179 (23),
176 (24).
We thank FAPERJ and FUJB for financial support and CNPq for
the fellowships of Renata P. Ribeiro and Marcelo S. Nery.
HRMS: m/z calcd for C19H19NO5, 341.3647; found, 341.3643.
References
N,N-Carboxymethyl-methyl-3,4-dimethoxy-2-(4′-methoxy-
benzyl)benzamide (9) and 5,6-Dimethoxy-4-(4′-methoxyphen-
yl)-2,4-tetrahydroisoquinoline-1,3-dione (10)
(1) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243.
The same experimental procedure described above for obtaining
compound 8 was used except the electrophile was changed to meth-
yl chloroformate (0.46 mL, 6.0 mmol) instead of triphosgene.
(2) Herrero, S.; Lopez, M. T. G.; Latorre, M.; Cenarruzabeitia,
E.; Del Rio, J.; Herranz, R. J. Org. Chem. 2002, 67, 3866.
(3) (a) Mitchell, J. A.; Reid, E. E. J. Am. Chem. Soc. 1931, 53,
1879. (b) Ruhoff, J. R.; Reid, E. E. J. Am. Chem. Soc. 1937,
59, 401.
9
Yellow pale oil; yield: 0.115 g (31%).
(4) Wagner, R. B. U.S. Patent 2932665, 1960.
(5) Cartwright, C. R. U.S. Patent 2916514, 1959.
(6) Frederick, G.; Stryk, V. Can. Patent 716609, 1965.
(7) (a) Larock, R. C. In Comprehensive Organic
Transformations; VCH Publishers: New York, 1989, 972–
976. (b) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
(c) Khaldi, M.; Chrétien, F.; Chapleur, Y. Bull. Soc. Chim.
Fr. 1996, 133, 7. (d) Lynn, J. W.; English, J. Jr. J. Am.
Chem. Soc. 1951, 73, 4284. (e) Snyder, H. R.; Putnam, R. E.
J. Am. Chem. Soc. 1954, 76, 33. (f) McCabe, E. T.; Barthel,
W. F.; Gertler, S. I.; Hall, S. A. J. Org. Chem. 1954, 45,
2750. (g) Hauser, C. R.; Walker, H. G. Jr. J. Am. Chem. Soc.
1947, 69, 295. (h) Suryanarayama, M. V. S.; Pandey, K. S.;
Shiri, P.; Raghuveeran, C. D.; Dangi, R. S.; Swamy, R. V.;
Rao, K. M. J. Pharm. Sci. 1991, 80, 1055.
IR (film): 3503, 3211, 3068, 3005, 2934, 2840, 2840, 2555, 1762,
1670, 1611, 1570, 1497, 1457, 1342, 1275, 1256, 1178, 1090, 1073,
1029, 970 cm–1.
1H NMR (CDCl3): δ = 3.11 (s, 3 H), 3.52 (s, 3 H), 3.70 (s, 3 H), 3.78
(s, 1 H), 3.84 (s, 3 H), 3.91 (s, 3 H), 6.77 (d, 2 H, J = 8.6 Hz), 7.13
(d, 2 H, J = 9.0 Hz), 7.21 (d, 1 H, J = 8.6 Hz), 8.30 (d, 2 H, J = 9.0
Hz).
13C NMR (CDCl3): δ = 55.4, 56.1, 56.3, 60.6, 106.6, 112.0, 113.0,
119.3, 125.5, 127.6, 130.9, 131.2, 141.9, 144.1, 152.3, 156.6, 158.7,
161.7.
MS m/z (%) = 373 (11), 315 (100), 287 (55), 272 (21).
HRMS: m/z calcd for C20H23NO6, 373.4068; found: 373.4070.
(8) Tanabe, K.; Okazaki, S. Appl. Catal., A 1995, 133, 191.
(9) Niobium pentachloride with purity >99% was a gift kindly
provided by the Brazilian Company of Metallurgy and
Mines (CBMM) Araxá city Minas Gerais state Brazil.
(10) Heathcock, C. H.; Lopes, R. S. C.; Lopes, C. C. Tetrahedron
Lett. 1992, 33, 6775.
10
White crystaline solid; yield: 0.098 g (30%); mp 172–173 °C.
IR (film): 3503, 3211, 3068, 3005, 2934, 2840, 2840, 2555, 1762,
1670, 1611, 1570, 1497, 1457, 1342, 1275, 1256, 1178, 1090, 1073,
1029, 970, cm–1.
(11) Kalinin, A. V.; Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.;
Snieckus, V. Tetrahedron Lett. 1998, 39, 4995.
(12) (a) Ooi, B. L.; Xu, Q. Y.; Shibahara, T. Inorg. Chim. Acta
1998, 274, 103. (b) Roy, C. N.; Trivedi, S. R. C. J. Indian
Chem. Soc. 1981, 58, 1036.
1H NMR (CDCl3): δ = 3.32 (s, 3 H), 3.72 (s, 3 H), 3.86 (s, 3 H), 6.28
(s, 1 H), 6.79 (d, 2 H, J = 8.7 Hz), 7.02 (d, 1 H, J = 8.3 Hz), 7.12 (d,
2 H, J = 8.7 Hz), 7.59 (d, 1 H, J = 8.3 Hz).
13C NMR (CDCl3): δ = 55.4, 56.4, 60.2, 80.9, 114.1, 114.3, 119.1,
(13) (a) Avery, M. A.; Verlander, M. S.; Goodman, M. J. Org.
Chem. 1980, 45, 2750. (b) Reitz, A.; Avery, M. A.;
Verlander, M. S.; Goodman, M. J. Org. Chem. 1981, 46,
4859.
(14) Schreier, E. Helv. Chim. Acta 1964, 47, 1529.
(15) Wilson, J. D.; Weingarten, H. Can. J. Chem. 1970, 48, 983.
(16) Brown, D. A.; Wallbridge, M. G. H.; Alcock, N. W. J. Chem.
Soc., Dalton Trans. 1993, 2037.
121.9, 128.5, 128.9, 129.9, 142.6, 143.3, 157.6, 160.3, 170.2.
HRMS: m/z calcd for C18H17NO5, 327.3378; found, 327.3381.
5,6-Dimethoxy-4(4′-methoxyphenyl) 1,2,3,4-Tetrahydroiso-
quinoline (11)
To a suspension of LiAlH4 (0.155 g, 4.0 mmol) in THF (8 mL) a
soln of 10 (0.161 g, 0.5 mmol) was added under strong stirring. The
reaction mixture was refluxed for 4 h and after this time it was
cooled to –15 °C. H2O (2.0 mL) was slowly added, and additional
Synthesis 2003, No. 2, 272–276 ISSN 0039-7881 © Thieme Stuttgart · New York

276
M. S. Nery et al.
PAPER
(17) Kapoor, R.; Sharma, R.; Kapoor, P. Indian J. Chem., Sect. A
1985, 24, 761.
(19) (a) Costa, P. R. R.; Lopes, C. C.; Lopes, R. S. C.; Marinho,
M. F. G.; Castro, R. N. Synth. Commun. 1988, 14, 1723.
(b) Lopes, C. C.; Lima, E. L. S.; Silva, A. J. M.; Costa, P. R.
R. Synth. Commun. 1988, 14, 1731.
(20) Gore, V. G.; Narasimhan, N. S. J. Chem. Soc., Perkin Trans.
1 1988, 481.
(18) (a) Kobayashi, S.; Tokumoto, T.; Taira, Z. J. Chem. Soc.,
Chem. Commun. 1984, 1043. (b) Kohli, J. D.; Goldberg, L.
I. J. Pharm. Pharmacol. 1980, 32, 225. (c) Jacob, J. N.;
Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med. Chem. 1981,
24, 1013.
(21) Brossi, A.; Grethe, G.; Teitel, S. J. Org. Chem. 1970, 35,
1100.
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