A concise synthesis of tetrahydroisoquinoline-1-carboxylic acids using a Petasis reaction and Pomeranz-Fritsch-Bobbitt cyclization sequence

Article abstract of DOI:10.1016/j.tet.2012.02.005

A sequence of two reactions: the Petasis reaction, in which an aminoacetaldehyde acetal was used as the amine component, followed by Pomeranz-Fritsch-Bobbitt cyclization, has been shown to be a convenient and simple method for the synthesis of tetrahydroisoquinoline-1-carboxylic acids. Using this method several acids have been prepared in good to excellent yields and characterized as hydrochloride salts.

Full text of DOI:10.1016/j.tet.2012.02.005

Tetrahedron 68 (2012) 3092e3097
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A concise synthesis of tetrahydroisoquinoline-1-carboxylic acids using a Petasis
reaction and PomeranzeFritscheBobbitt cyclization sequence
*
Maria Chrzanowska, Agnieszka Grajewska, Zofia Meissner, Maria Rozwadowska , Iwona Wiatrowska
ꢀ
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2011
Received in revised form 17 January 2012
Accepted 6 February 2012
Available online 15 February 2012
A sequence of two reactions: the Petasis reaction, in which an aminoacetaldehyde acetal was used as the
amine component, followed by PomeranzeFritscheBobbitt cyclization, has been shown to be a conve-
nient and simple method for the synthesis of tetrahydroisoquinoline-1-carboxylic acids. Using this
method several acids have been prepared in good to excellent yields and characterized as hydrochloride
salts.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydroisoquinoline-1-carboxylic acids
Petasis reaction
PomeranzeFritscheBobbitt cyclization
1. Introduction
A large variety of alkenyl, aryl, and heteroaryl boronic acids,
various primary and secondary amine derivatives (e.g., diamines,
In recent years, the Petasis reaction (the application of a boronic
acid nucleophile in the Mannich reaction)1 has received increasing
attention due to its utility as a powerful and convenient method for
N-hydroxylamines, N-sulfinyl amines, hydrazines) and functional-
ized carbonyl compounds (e.g., -keto acids and -hydroxy alde-
hydes) have been shown to participate in this reaction with
success.1 The reaction can be carried out in many different solvents,
usually DCM, DCE, toluene, alcohols but also in water.6
Herein, we report a novel approach to the synthesis of the tet-
rahydroisoquinoline-1-carboxylic acids featuring a tertiary C-1
carbon center, at a rate which combines the Petasis reaction1 with
the PomeranzeFritscheBobbitt cyclization.7 A substantial feature
of this approach is the use of aminoacetaldehyde acetal or its N-
alkyl derivatives, the reagents characteristic of the Pomeranze-
Fritsch synthesis, as the amine components (Scheme 2).
a
a
the synthesis of functionalized amine derivatives, such as a-amino
carboxylic acids,2
b
-amino alcohols,3 allyl amines,4 various het-
erocyclic compounds,5 just to be mentioned, while new applica-
tions continue to be developed.6
The one step, three-component reaction involves coupling of an
amine, organoboronic acid, and a carbonyl compound functional-
ized at the a-position to give the amine derivative in a short and
experimentally simple process. Along with accessibility of reagents
and mild reaction conditions this approach is an attractive alter-
native to other methodologies.
Scheme 1 illustrates the synthesis of a-amino acids as a typical
example of the Petasis multi-component reaction with the use of
glyoxylic acid as the carbonyl component.
O
OH
OH
B
H
R
R2O OR2
N
O
OH
1a-f
1. 20% HCl
2. H2/Pd-C
DCM, rt
2
R2
R1
N
R1
OH
R1
R
R2
N
R
N
H
HO
O
R1
OR2
OR2
3a-d
O
OH
N
O
R2
R1
HO B R
R
O
OH
R1
H
H
O
N
4-13
14-17
O
OH
OH
OH
O
R B
Scheme 2.
Scheme 1.
2. Results and discussion
To learn the scope and limitations of our method, several Petasis
reaction products (4e13) have been prepared (Table 1) and sub-
jected to the PomeranzeFritscheBobbitt cyclization.
* Corresponding author. Tel.: þ48 61 8291322; fax: þ48 61 8291505; e-mail
address: mdroz@amu.edu.pl (M. Rozwadowska).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.005

M. Chrzanowska et al. / Tetrahedron 68 (2012) 3092e3097
3093
Table 1
The Petasis reaction of aryl boronic acids 1, glyoxylic acid 2, and aminoacetaldehyde acetals 3
R2O OR2
N
O
R1
H
OR2
B(OH)2
DCM
Ar, rt
OH
N
R
R
+
+
H
OR2
R1
O
1
3
4-13
2
O
OH
Entry
1
ArB(OH)2
1
Aminoacetal 3
Aminoacid
Yield (%)
CH3O OCH3
CH3O
CH3O
B(OH)2
H3C
N
OCH3
OCH3
CH3O
CH3O
H
96
N
CH3
OH
3a
1a
4
O
C2H5O OC2H5
CH3O
OC2H5
OC2H5
H2N
3b
2
3
4
5
6
7
8
9
1a
1a
1a
88
94
69
87
57
75
88
52
NH
CH3O
5 O OH
CH3O OCH3
OCH3
OCH3
CH3O
CH3O
C6H5
N
H
N
C6H5
3c
6
O
OH
CH3O OCH3
NH
OCH3
OCH3
CH3O
CH3O
H2N
3d
O
OH
7
CH3O OCH3
B(OH)2
O
O
O
O
3a
3b
3a
3a
3a
N
CH3
1b
O
OH
8
C2H5O OC2H5
O
O
1b
NH
OH
9
O
CH3O OCH3
B(OH)2
N
H3C
CH3
CH3
1c
O
OH
10
CH3O OCH3
B(OH)2
H3C
N
H3C
CH3
1d
11
O
OH
CH3O OCH3
B(OH)2
N
CH3
1e
12
O
OH
CH3O OCH3
B(OH)2
OCH3
N
10
3a
92
CH3
CH3O
13
O
OH
1f

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M. Chrzanowska et al. / Tetrahedron 68 (2012) 3092e3097
We initiated our investigations with the condensation of 3,4-
Similarly, 3,4-methylenedioxyphenyl boronic acid 1b reacted
readily with both aminoacetals 3a, 3b and glyoxylic acid 2,
affording the corresponding arylglycine derivatives 8 and 9, re-
spectively, in satisfactory yield (Table 1, entries 5 and 6). Under the
PomeranzeFritscheBobbitt reaction conditions they were trans-
dimethoxyphenyl boronic acid 1a with glyoxylic acid 2 and N-
methyl aminoacetaldehyde dimethyl acetal 3a. The reaction was
carried out in DCM at rt for 24 h under an argon atmosphere,
supplying Petasis reaction product 4 in a high yield (Table 1, entry
1). Compound 4 was isolated from crude reaction products simply
by crystallization from methanol. Construction of the tetrahy-
droisoquinoline ring system from 4 was easily performed by one-
pot cyclization/hydrogenolysis (20% HCl, H2/5 %PdeC) procedure
to afford tetrahydroisoquinoline-1-carboxylic acid hydrochloride,
14$HCl (Fig. 1). This compound was available in a short synthesis,
involving two simple steps, in 65% overall yield (Scheme 2).
formed
into
the
unknown
6,7-methylenedioxy-tetrahy-
droisoquinoline-1-carboxylic acids, 16 and 17, respectively (Fig. 1),
compounds that could not be prepared using other methods.15
Next, intermediate amino acids 10e13, differing in the type and
position of substituents at the aromatic ring, were prepared from
boronic acids 1cef, respectively (Table 1, entries 7e10), and sub-
jected to the cyclization process. However, no formation of tetra-
hydroisoquinoline derivatives was observed in reactions in which
compounds 10e13 were used, even with that containing the acti-
vating methyl group (10). Instead, compounds of morpholinone
type, e.g., 18, accompanied by their hydrolysis products, e.g., 19,16
(Fig. 2) were isolated from reaction mixtures, thus limiting our
method to substrates with strongly activating groups. Obviously,
the cyclization step, being a FriedeleCrafts acylation, requires the
presence of electron donating groups at the phenyl ring, and in
positions activating the cyclization site. Moreover, an attack of
carboxyl group on the liberated aldehyde became a competition
process for the aromatic electrophilic substitution, affording mor-
pholinone derivatives and/or the corresponding hydrolysis prod-
ucts. Morpholinone 18 was formed in the synthesis in which the
‘improperly substituted’ o-methoxyphenyl boronic acid 1f was
used as the substrate, while the known hydroxy amino acid 19,16
was isolated in 89% yield from the reaction with phenylboronic
acid 1e. Plausibly, this process involves several steps, such as: hy-
drolysis (of acetal function) and cyclization (to hydroxy morpholi-
none), followed by catalytic hydrogenation.
CH3O
CH3O
CH3O
CH3O
N
NH
OH
CH3
O
OH
O
14
Y = 68%
15 Y = 78%
O
O
O
O
N
NH
CH3
O
OH
O
OH
16
Y = 87%
17
Y = 57%
Fig. 1. Tetrahydroisoquinoline-1-carboxylic acids 14e17.
The success of this synthesis encouraged us to test this method as
a new and simple way to tetrahydroisoquinoline-1-carboxylic acids.
To our surprise, only a few examples of the synthesis of acids with
a tertiary C-1 carbon, a class of important arylglycine derivatives,8,9
could be found in chemical literature. Some of them were prepared
by traditional BischlereNapieralski10 or PicteteSpengler11 cycliza-
tions, in which construction of the tetrahydroisoquinoline ring
system was the key step, others by addition of carbon nucleophiles
to 3,4-dihydroisoquinoline derivatives. In the latter case both Reis-
sert12 and Ugi13 reaction products were used as intermediates. In
comparison with our short synthesis, the above mentioned pro-
cesses involved multi-step transformations such as: initial prepa-
ration of 3,4-dihydroisoquinoline derivatives, reduction and/or
hydrolysis (including enzymatic hydrolysis10a) of intermediates,
others methods gave poor yield.11
OH
CH3
N
CH3O
CH3O
NH
OH
N
CH3
OH
19
CH3O
O
18
O
O
20
Fig. 2. Morpholinone 18, amino acid 19, calycotomine 20.
During our experiments we noticed that the nature and orien-
tation of substituents of aryl boronic acids were crucial for success
of the Petasis reaction. Attempted syntheses with amino-
substituted boronic acids (3-acetamido- and 3-N,N-dimethyla-
mino-), as well as 3-chloro analogues, under the reaction condi-
tions applied (DCM, rt) were unsuccessful. Only small amounts of
the desired product were formed in the Petasis reaction in which 3-
acetamidophenyl boronic acid was heated at reflux in acetonitrile
for 72 h. In this reaction 3-N,N-dimethylaminophenyl boronic acid
decomposed to colour substances, even at rt. Similar problems in
the Petasis reaction with the use of amino-substituted aromatic
boronic acids have been observed earlier.17
3-Chlorophenyl boronic acid was unreactive in this reaction
even after 9 days in DMF.18,19 It may be added that the reaction of
unsubstituted phenylboronic acid 1e with primary amino-
acetaldehyde acetal 3b, in DCM at rt was also unsuccessful, a case
sometimes met in the Petasis reaction with primary amines.1a
In spite of the limitations experienced in the combination of
the two reactions applied, the Petasis synthesis and the Pomer-
anzeFritscheBobbitt cyclization, as well as competitive reaction
of the carboxyl group, our approach may be a convenient and
simple route not only to tetrahydroisoquinoline-1-carboxylic
acids but also to other tetrahydroisoquinoline derivatives. In
particular, it may be useful in the synthesis of isoquinoline al-
kaloids, containing ether substituents at aromatic ring. As
Then, the known tetrahydroisoquinoline derivative 15$HCl
10,13,14
€ €
(Fig. 1), recently intensively studied by Fulop et al.,
was pre-
pared. A reaction between aminoacetaldehyde acetals 3b or 3d,
boronic acid 1a and glyoxylic acid 2 afforded the intermediate
amino acids 5 or 7, respectively (Table 1, entries 2 and 4), which
after cyclization/hydrogenolysis were transformed into tetrahy-
droisoquinoline carboxylic acid hydrochloride 15$HCl in good
overall yield. It precipitated from the reaction mixture on concen-
tration. The melting point of our sample, 134e137 ꢀC, after crys-
tallization from methanol, was different from that reported in lit.13
(mp 159e160 ꢀC) due to the presence of 1 equiv of water of crys-
tallization, which was difficult to remove.
Then N-benzyl amino acid 6 was prepared from boronic acid 1a,
glyoxylic acid 2 and aminoacetal 3c in 94% yield (Table 1, entry 3).
Attempts to purify the oily crude reaction product by crystallization
failed, while chromatographic separation resulted in substantial
reduction in the yield. This compound was found to decompose
slowly when kept in a solution (e.g., during NMR measurements).
Because the cyclization/hydrogenolysis process of 6 led to a mix-
ture of products, an additional step was undertaken to remove the
N-benzyl group (H2/Pd(OH)2/methanol) prior to the cyclization. As
a result, compound 7 was formed in 97% yield, identical to that
prepared from boronic acid 1a, glyoxylic acid 2 and amino-
acetaldehyde methyl acetal 3d (Table 1, entry 4).

M. Chrzanowska et al. / Tetrahedron 68 (2012) 3092e3097
3095
a representative example, calycotomine 20 (Fig. 2), a simple
isoquinoline alkaloid,20 was prepared by BH3$THF reduction of
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
hydrochloride 15$HCl, demonstrating the possibility of synthesis
of other types of alkaloids using these acids as intermediates.
In conclusion, an efficient method for the synthesis of tetra-
hydroisoquinoline-1-carboxylic acids has been developed. It is
based on the coupling of the Petasis reaction and the Pomer-
anzeFritscheBobbitt cyclization and affords tetrahydroisoquino-
line-1-carboxylic acids in two experimentally simple operations,
in good to excellent yields.
103 (100). HRMS: (Mþþ1), found 328.1767. C16H26NO6 requires
328.1755.
3.2.3. N-(2,2-Dimethoxyethyl)-N-benzyl-3,4-dimethoxyphenylgly-
cine (6). Following the general procedure 6 was synthesized from
1a, 2 and 3c in 5 mmol scale. Yield: 94%. Oil. IR (film) cmꢁ1: 2937
(br), 2835,1515. 1H NMR (CDCl3)
(dd, J¼6.0, 14.0 Hz, 1H), 3.25 (s, 3H), 3.33 (s, 3H), 3.73 (d, J¼13.7 Hz
1H), 3.85 (s, 3H), 3.87 (s, 3H), 3.99 (d, J¼13.7 Hz,1H), 4.27 (dd, J¼4.3,
5.8 Hz, 1H), 4.73 (s, 1H), 6.83e6.92 (m 3H), 7.30e7.39 (m, 5H). 13C
d
: 2.64 (dd, J¼4.4,14.0 Hz,1H), 2.85
NMR (CDCl3) d: 52.2 (CH2), 54.3 (CH3), 54.9 (CH3), 55.8 (CH3), 55.9
(CH3), 57.0 (CH2), 69.1 (CH), 102.9 (CH), 110.8 (CH), 112.8 (CH), 122.5
(CH),128.0 (CH),128.4 (CH),128.6 (CH),128.7 (CH),129.1 (CH),136.7
(C), 148.8 (C), 149.1 (C), 172.9 (C). EIMS m/z (%): 357 (13), 314 (20),
313 (57), 298 (12), 255 (100), 240 (20), 224 (15), 179 (12), 178 (22),
150 (21), 117 (16), 92 (15), 91 (59). Anal. found C, 64.59; H, 6.92; N,
3.47. C21H27NO6 requires C, 64.57; H, 7.03; N, 3.62.
3. Experimental section
3.1. General methods
Melting points were determined on a Koffler block and are
uncorrected. IR spectra: Bruker FT-IR IFS 113V. NMR spectra:
Varian Gemini 300, with TMS as the internal standard. Mass
spectra (EI): AM D402. Elemental analysis: Vario EL III. Merck DC-
Alufolien Kieselgel 60 F254 were used for TLC and Kieselgel 60
(70e230 mesh ASTM) for column chromatography. All com-
pounds were purchased from Aldrich Chemical Co. and used as
received.
3.2.4. N-(2,2-Dimethoxyethyl)-3,4-dimethoxyphenylglycine
(7).
Following the general procedure 7 was synthesized from 1a, 2, and
3d in 5 mmol scale. The crude product was crystallized from
methanol. Yield: 69%. Mp 156e158 ꢀC. IR (KBr) cmꢁ1: 3000 (br),
2838, 1572, 1517. 1H NMR (CD3OD/D2O)
d
: 2.96 (dd, J¼4.9, 13.0 Hz,
1H), 3.06 (dd, J¼5.3,13.0 Hz,1H), 3.39 (s, 3H), 3.40(s, 3H), 3.82(s, 3H),
3.83 (s, 3H), 4.55 (s, 1H), 4.63 (t, J¼5.1 Hz, 1H), 6.97 (d, J¼8.3 Hz, 1H),
7.06 (dd, J¼2.0, 8.3 Hz, 1H), 7.12 (d, J¼2.1 Hz, 1H). 13C NMR (CD3OD/
D2O) d: 48.1 (CH2), 55.3 (CH3), 55.4 (CH3), 56.4 (CH3), 56.5 (CH3), 67.4
3.2. General procedure for synthesis of the Petasis reaction
products 4e13
(CH), 101.6 (CH), 112.8 (CH), 112.9 (CH), 113.0 (CH), 113.1 (CH), 123.3
(CH), 127.1 (C), 150.8 (C), 151.4 (C), 172.3 (C). EIMS m/z (%): 300
(Mþþ1, 3), 255 (22), 254 (57), 236 (12), 222 (27),195 (100),190 (20),
177(11),167(15),166 (56),165 (20),164 (11),139(11), 75(89). HRMS:
(Mþþ1), found 300.14721. C14H22NO6 requires 300.14471.
A round-bottom flask containing glyoxylic acid monohydrate 2,
aryl boronic acid 1 and aminoacetal 3 (in a 1:1:1 molar ratio) in
DCM (5 mL per 1 mmol of substrates) was filled with argon and
sealed. It was then stirred at ambient temperature for 24e72 h
(TLC) and after this time, the solvent and volatile materials were
removed under reduced pressure. The residue was crystallized
from methanol or ethanol, depending on which methyl or ethyl
acetal was used or purified by column chromatography.
3.2.5. N-(2,2-Dimethoxyethyl)-N-methyl-3,4-methylenedioxyphenyl-
glycine (8). Following the general procedure 8 was synthesized
from 1b, 2 and 3a in 5 mmol scale. The crude product was crys-
tallized from methanol. Yield: 87%. Mp 112e114 ꢀC. IR (KBr) cmꢁ1
:
3473 (br), 2493 (br), 1620. 1H NMR (CDCl3)
d: 2.70 (s, 3H), 3.00 (dd,
J¼4.7, 13.4 Hz, 1H), 3.10 (s, 1H, disappears on treatment with D2O),
3.16 (dd, J¼5.6, 13.4 Hz, 1H), 3.40 (s, 3H), 3.41 (s, 3H), 4.59 (s, 1H),
4.71 (t, J¼4.9 Hz, 1H), 5.98 and 5.99 (ABq, J¼1.4 Hz, 2H), 6.81 (d,
J¼8.0 Hz, 1H), 6.99 (dd, J¼1.8, 8.0 Hz, 1H), 7.02 (d, J¼1.7 Hz, 1H). 13C
3.2.1. N-(2,2-Dimethoxyethyl)-N-methyl-3,4-dimethoxyphenylgly-
cine (4). Following the general procedure 4 was synthesized
from 1a, 2 and 3a in 5 mmol scale. The crude product was
crystallized from methanol. Yield: 96%. Mp 126e129 ꢀC. IR
(KBr) cmꢁ1: 3462 (br), 3304 (br), 2648 (br), 1620. 1H NMR
NMR (CDCl3) d: 40.3 (CH3), 54.8 (CH3), 55.1 (CH2), 74.2 (CH), 100.6
(CH), 101.4 (CH2), 108.5 (CH), 109.7 (CH), 124.5 (CH), 125.2 (C), 148.1
(C), 148.6 (C), 169.9 (C). EIMS m/z (%): 298 (Mþþ1, <1), 252 (20), 222
(18), 179 (100), 176 (11), 163 (17), 135 (12). HRMS: (Mþþ1), found
298.1277. C14H20NO6 requires 298.1291.
(DMSO-d6)
d
: 2.31 (s, 3H), 2.46e2.50 (m, 1H), 2.55 (dd, J¼5.4,
13.5 Hz, 1H), 3.19 (s, 3H), 3.22 (s, 3H), 3.74 (s, 3H), 3.75 (s, 3H),
4.16 (s, 1H), 4.45 (t, J¼5.2 Hz, 1H), 6.88 (dd, J¼1.6, 8.3 Hz, 1H),
6.93 (d, J¼8.1 Hz, 1H), 7.02 (d, J¼1.6 Hz, 1H). 13C NMR (DMSO-
d6)
d
: 40.3 (CH3), 53.0 (CH3), 53.2 (CH3), 55.0 (CH3), 55.5 (CH3),
3.2.6. N-(2,2-Diethoxyethyl)-3,4-methylenedioxyphenylglycine
(9). Following the general procedure 9 was synthesized from 1b, 2
and 3b in 5 mmol scale. The crude product was crystallized from
ethanol. Yield: 57%. Mp 129e131 ꢀC. IR (KBr) cmꢁ1: 3442 (br), 2450
72.2 (CH), 102.5 (CH), 111.3 (CH), 112.3 (CH), 121.2 (CH), 128.9
(C), 148.5 (C), 148.6 (C), 172.3 (C). EIMS m/z (%): 314 (Mþþ1, <1),
268 (29), 195 (100). HRMS: Mþ, found 313.1530. C15H23NO6
requires 313.1525.
(br), 1622, 1579. 1H NMR (CDCl3)
d: 1.12e1.18 (m, 6H), 2.70 (dd,
J¼6.2, 12.4 Hz, 1H), 2.98 (dd, J¼4.6, 12.4 Hz, 1H), 3.42e3.52 (m, 2H),
3.2.2. N-(2,2-Diethoxyethyl)-3,4-dimethoxyphenylglycine
(5).
3.58e3.66 (m, 2H), 4.69 (s, 1H), 4.75 (dd, J¼4.6, 6.0 Hz, 1H), 5.95 (s,
Following the general procedure 5 was synthesized from 1a, 2 and
3b in 5 mmol scale. The crude product was crystallized from eth-
anol. Yield: 88%. Mp 118e122 ꢀC. IR (KBr) cmꢁ1: 3350 (br), 2415
2H), 6.77 (d, J¼8.0 Hz, 1H), 6.99 (m, 2H). 13C NMR (CDCl3)
d: 15.1
(CH3), 45.9 (CH2), 63.4 (CH2), 63.7 (CH2), 64.8 (CH), 98.8 (CH), 101.3
(CH), 108.6 (CH), 108.8 (CH), 123.3 (CH), 126.8 (CH), 148.1 (C), 148.2
(C), 148.2 (C), 171.6 (C). EIMS m/z (%): 312 (Mþþ1, 2), 266 (63), 220
(27), 179 (69), 149 (21), 148 (52), 135 (27), 103 (100). HRMS:
(Mþþ1), found 312.1448. C15H22NO6 requires 312.1442.
(br), 1611, 1573. 1H NMR (DMSO-d6)
d: 1.08e1.14 (m, 6H), 2.50 (s,
1H), 2.55 (dd, J¼5.1, 12.8 Hz, 1H), 2.66 (dd, J¼5.9, 12.5 Hz, 1H),
3.42e3.48 (m, 3H), 3.51e3.61 (m, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 4.27
(s, 1H), 4.61 (t, J¼5.7 Hz, 1H), 6.90 (s, 2H), 6.98 (s, 1H). 13C NMR
(DMSO-d6)
d: 15.2 (CH3), 48.3 (CH2), 55.45 (CH3), 55.5 (CH3), 61.61
3.2.7. N-(2,2-Dimethoxyethyl)-N-methyl-(3-tolyl)glycine
(10).
(CH2), 61.62 (CH2), 64.7 (CH),100.2 (CH),111.4 (CH),111.5 (CH),120.5
(CH), 129.9 (C), 148.5 (C), 148.6 (C), 171.5 (C). EIMS m/z (%): 328
(Mþþ1, 2), 282 (36), 236 (32), 195 (65), 166 (41), 165 (34), 151 (47),
Following the general procedure 10 was synthesized from 1c, 2
and 3a in 5 mmol scale. Yield: 75%. Oil. IR (film) cmꢁ1: 2957 (br),
2836, 1626. 1H NMR (CDCl3)
d: 2.30 (s, 3H), 2.64 (s, 3H), 2.92 (dd,

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M. Chrzanowska et al. / Tetrahedron 68 (2012) 3092e3097
J¼5.1, 13.4 Hz, 1H), 3.08 (dd, J¼4.8, 13.4 Hz, 1H), 3.29 (s, 3H), 3.31
(s, 3H), 4.64e4.66 (m, 2H), 7.12e7.22 (m, 2H), 7.28e7.29 (m, 2H),
8.17 (s, br, 1H, disappears on treatment with D2O). 13C NMR
temperature for 24e48 h (TLC) under an argon atmosphere in the
darkness. After that time it was hydrogenated with hydrogen from
a balloon, in the presence of 5% palladium on carbon (0.2 g per
1 mmol) for 24e48 h (TLC). The catalyst was removed by filtration
and washed with excess of methanol. The filtrate was concentrated
to a partly crystalline residue, which digested with ethyl ether
deposited crystalline, pure hydrochloride salt, that could be crys-
tallized from ethanol.
(CDCl3) d: 21.3 (CH3), 40.6 (CH3), 54.4 (CH3), 54.5 (CH3), 55.3 (CH2),
74.2 (CH), 101.3 (CH), 126.9 (CH), 128.6 (CH), 130.5 (CH), 133.5 (C),
138.4 (C), 171.2 (C). EIMS m/z (%): 267 (Mþ, 4), 222 (45), 192 (100),
149 (84), 132 (24), 75 (67). HRMS: Mþ, found 267.1482. C14H21NO4
requires 267.1471.
3.2.8. N-(2,2-Dimethoxyethyl)-N-methyl-(4-tolyl)glycine
(11).
3.4.1. 6,7-Dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxylic acid hydrochloride (14$HCl). Following the general pro-
cedure 14$HCl was synthesized from 4 in 1 mmol scale. Yield: 68%.
Mp 155e157 ꢀC. IR (KBr) cmꢁ1: 3344 (br), 2526 (br), 1942 (br),
Following the general procedure 11 was synthesized from 1d, 2 and
3a in 5 mmol scale. The crude product was crystallized from
methanol. Yield: 88%. Mp 92e94 ꢀC. IR (KBr) cmꢁ1: 3422 (br), 3197
(br), 3041 (br), 2838, 2711, 1610. 1H NMR (DMSO-d6/D2O)
d
: 2.30 (s,
1725. 1H NMR (DMSO-d6)
d
: 2.86 (s, 3H), 3.03 (s, br, 2H), 3.40e3.46
(m, 1H), 3.72 (s, 3H), 3.75 (s, 3H), 3.78e3.82 (m, 1H), 5.20 (s, 1H),
6.86 (s, 1H), 6.91 (s, 1H). 13C NMR (DMSO-d6)
: 22.9 (CH2), 40.8
3H), 2.35 (s, 3H), 2.69 (dd, J¼5.3, 13.8 Hz, 2H), 3.22 (s, 3H), 3.24 (s,
3H), 4.25 (s, 1H), 4.53 (t, J¼5.0 Hz, 1H), 7.18 (d, J¼7.8 Hz, 2H), 7.26 (d,
d
J¼7.8 Hz, 2H). 13C NMR (DMSO-d6)
d
: 20.7 (CH3), 39.9 (CH3), 52.9
(CH3), 47.4 (CH2), 55.5 (CH3), 55.6 (CH3), 63.5 (CH), 110.2 (CH), 111.6
(CH), 117.5 (C), 123.5 (C), 147.6 (C), 149.1 (C), 168.3 (C). EIMS m/z
(%): 252 (Mþþ1, 2), 207 (33), 206 (100), 193 (7), 192 (31), 191 (23),
190 (23). HRMS: (Mþþ1), found 252.1240. C13H18NO4 requires
252.1236.
(CH3), 53.2 (CH3), 55.2 (CH2), 72.0 (CH), 102.4 (CH), 128.9 (CH), 133.4
(C),137.3 (C),172.3 (C). EIMS m/z (%): 267 (Mþ, 3), 243 (31), 222 (46),
192 (62), 149 (65), 146 (44), 132 (100), 105 (42), 91 (34), 75 (42).
HRMS: Mþ, found 267.1485. C14H21NO4 requires 267.1471.
3.2.9. N-(2,2-Dimethoxyethyl)-N-methylphenylglycine
(12).
3.4.2. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic
acid hydrochloride (15$HCl). Following the general procedure
15$HCl was synthesized from 5 in 1 mmol scale. Yield: 78%. Mp
134e137 ꢀC. IR (KBr) cmꢁ1: 3460 (br), 2552 (br), 1988 (br), 1735.
Following the general procedure 12 was synthesized from 1e, 2 and
3a in 5 mmol scale. The crude product was crystallized from
methanol. Yield: 52%. Mp 124e127 ꢀC. IR (KBr) cmꢁ1: 3424 (br),
2479 (br), 1627. 1H NMR (CDCl3)
d
: 2.74 (s, 3H), 3.02 (dd, J¼4.4,
1H NMR (DMSO-d6)
d: 2.92e2.97 (m, 2H), 3.39e3.48 (m, 2H),
13.3 Hz, 1H), 3.20 (dd, J¼5.0, 13.4 Hz, 1H), 3.38 (s, 3H), 3.39 (s, 4H),
3.90 (s, br, 1H, disappears on treatment with D2O), 4.70 (t, J¼5.0 Hz,
3.73 (s, 3H), 3.75 (s, 3H), 5.15 (s, 1H), 6.83 (s, 1H), 7.03 (s, 1H),
9.40 and 10.66 (2s, br, 1H each, disappear on treatment with
1H), 7.33e7.36 (m, 3H), 7.42e7.48 (m, 2H). 13C NMR (CDCl3)
d: 40.5
D2O). 13C NMR (DMSO-d6)
d: 24.0 (CH2), 38.7 (CH2), 54.8 (CH),
(CH3), 54.8 (CH3), 55.3 (CH2), 74.5 (CH),100.6 (CH), 128.9 (CH),129.5
(CH), 129.9 (CH), 131.7 (C), 169.9 (C). EIMS m/z (%): 253 (Mþþ1, 2),
208 (28), 178 (100), 135 (60), 134 (27), 118 (23). HRMS: Mþ, found
253.1305. C13H15NO4 requires 253.1314.
55.6 (CH3), 55.7 (CH3), 110 (CH), 111.8 (CH), 118.3 (C), 124.7 (C),
147.4 (C), 148.9 (C), 169.0 (C). EIMS m/z (%): 238 (Mþþ1, <1), 237
(Mþ, 1), 193 (38), 192 (100), 176 (25). Anal. found C, 49.25; H,
6.55; N, 4.76. C12H16NO4Cl$H2O requires C, 49.41; H, 6.22;
N, 4.80.
3.2.10. N-(2,2-Dimethoxyethyl)-N-methyl-2-methoxyphenylglycine
(13). Following the general procedure 13 was synthesized from 1f,
2 and 3a in 1 mmol scale. The crude product was purified by col-
umn chromatography (DCM:MeOH 97:3). Yield: 92%. Oil. IR (KBr)
3.4.3. 6,7-Methylenedioxy-N-methyl-1,2,3,4-tetrahydroisoquinoline-
1-carboxylic acid hydrochloride (16$HCl). Following the general
procedure 16$HCl was synthesized from 8 in 1 mmol scale. Yield:
90%. Mp 200e205 ꢀC. IR (KBr) cmꢁ1: 3025e2508 (br), 1748. 1H NMR
cmꢁ1: 3357, 2941 (br), 1635 (br). 1H NMR (CDCl3)
d: 2.62 (s, 3H),
3.01 (ddd, J¼4.9, 13.4, 17.6 Hz, 2H), 3.36 (s, 3H), 3.37 (s, 3H), 3.84 (s,
(DMSO-d6)
1H), 3.68 (s, br, 1H), 5.21 (s, 1H), 6.04 (ABq, J¼1.0 Hz, 2H), 6.85 (s,
1H), 6.89 (s, 1H). 13C NMR (DMSO-d6)
: 23.6 (CH2), 41.3 (CH3), 48.1
(CH2), 65.1 (CH), 101.7 (CH2), 107.6 (CH), 108.5 (CH), 119.6 (C), 125.0
(C), 146.6 (C), 147.8 (C), 168.3 (C). EIMS m/z (%): 236 (Mþþ1, 1), 235
(Mþ, <1), 191 (21), 190 (100), 176 (17). HRMS: (Mþþ1), found
236.0935. C12H14NO4 requires 236.0929.
d
: 2.85 (s, 3H), 2.96 (s, br, 2H), 3.38 (dt, J¼5.5, 11.8 Hz,
3H), 4.71 (t, J¼5.0 Hz, 1H), 5.04 (s, 1H), 6.94 (m, 2H), 7.32 (m, 1H),
7.46 (d, J¼6.9 Hz, 1H). 13C NMR (CDCl3)
d: 40.4 (CH3), 54.5 (CH3),
d
54.6 (CH3), 55.5 (CH3), 55.8 (CH2), 67.7 (CH), 101.1 (CH), 111.0 (CH),
120.9 (CH), 130.4 (CH), 131.3 (CH), 157.9 (C) 170.6 (C). EIMS m/z (%):
283 (Mþ, 2), 252 (9), 238 (42), 208 (79), 165 (100), 135 (20). HRMS:
Mþ, found 283.14019. C14H21NO5 requires 283.14197.
3.3. Hydrogenolysis of N-(2,2-dimethoxyethyl)-N-benzyl-3,4-
dimethoxyphenylglycine (6)
3.4.4. 6,7-Methylenedioxy-1,2,3,4-tetrahydroisoquinoline-1-
carboxylic acid hydrochloride (17$HCl). Following the general
procedure 17$HCl was synthesized from 9 in 1 mmol scale. Yield:
85%. Mp 224e226 ꢀC. IR (KBr) cmꢁ1: 3058e2404 (br), 1731. 1H
A solution of amino acid 6 (0.39 g, 1 mmol) in methanol (6 mL)
was hydrogenated with hydrogen from balloon in the presence of
Pd(OH)2 (0.08 g, 20%) for 24 h. The catalyst was then removed by
filtration and washed with methanol (6 mL). The solvent was
evaporated under reduced pressure to deposit TLC-pure com-
pound 7 in 97% yield, identical to those of amino acid 7, previously
prepared from boronic acid 1a, aminoacetal 3d and glyoxylic
acid 2.
NMR (DMSO-d6)
1H), 6.01(s, 1H), 6.03 (s, 1H), 6.81 (s, 1H), 6.98 (s, 1H), 10.00 (s, br,
2H, disappears on treatment with D2O). 13C NMR (DMSO-d6)
d: 2.85e2.97 (m, 2H), 3.31e3.46 (m, 2H), 5.14 (s,
d
:
24.4 (CH2), 38.7 (CH2), 55.1 (CH), 101.3 (CH2), 107.3 (CH), 108.4
(CH), 119.7 (C), 126.1 (C), 146.0 (C), 147.3 (C), 168.8 (C). EIMS m/z
(%): 222 (Mþþ1, <1), 221 (Mþ, <1), 177 (24), 176 (100). Anal.
found C, 50.90; H, 4.92; N, 5.38. C11H12NO4Cl requires C, 51.27; H,
4.69; N, 5.44.
3.4. General procedure for the synthesis of
tetrahydroisoquinoline-1-carboxylic acids 14e17 using the
PomeranzeFritscheBobbitt cyclization
3.4.5. 4-Methyl-3-(2-methoxyphenyl)morpholin-2-one hydrochlo-
ride (18$HCl). Compound 18$HCl was prepared from 13 according
to procedure described in Section 3.4 in 1 mmol scale. The crude
reaction product was digested with petroleum ether and crystal-
lized from ethanol. Yield: 52%. Mp 194e199 ꢀC. IR (KBr) cmꢁ1: 3459
The Petasis addition product was dissolved in 20% hydrochloric
acid (10 mL per 1 mmol) and the solution was stirred at ambient

M. Chrzanowska et al. / Tetrahedron 68 (2012) 3092e3097
3097
(br), 2962, 2869, 1713. 1H NMR (DMSO-d6)
d
: 2.70 (s, 3H), 3.65e3.75
(CH), 55.95 (CH3), 63.9 (CH2), 109.0 (CH), 111.9 (CH), 126.9 (C), 127.5
(m, 2H), 3.84 (s, 3H), 4.66e4.75 (m, 2H), 5.31 (s, br, 1H), 7.04 (t,
J¼7.4 Hz, 1H), 7.13 (d, J¼8.1 Hz, 1H), 7.51 (t, J¼7.7 Hz, 2H), 11.11 (s, br,
(C), 147.4 (C), 147.7 (C). EIMS m/z (%): 223 (Mþ, 2), 192 (100), 176 (25).
1H, disappears on treatment with D2O). 13C NMR (DMSO-d6)
d: 41.9
Acknowledgements
(CH3), 49.5 (CH2), 56.0 (CH3), 64.4 (CH), 64.5 (CH2), 111.8 (CH), 119.3
(C), 120.5 (CH), 132.2 (CH), 133.0 (CH), 156.2 (C), 164.5 (C). EIMS m/z
(%): 221 (Mþ, 87), 177 (52), 162 (100), 147 (84), 119 (84). Anal. found
C, 55.76; H, 6.21; N, 5.43. C12H16ClNO3 requires C, 55.93; H, 6.26; N,
5.43.
This work was supported by the research grant from the Min-
istry of Sciences and High Education (MNI Grant No. N204 032 32/
0794, 2007e2010).
References and notes
3.4.6. 4-Methyl-3-(2-methoxyphenyl)morpholin-2-one
(18).
1. (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Chem. Rev. 2010,110,
6169e6193; (b) Batey, R. A. In Boronic Acids; Hall, D. G., Ed.; Wiley VCH: Wein-
heim, 2008; pp 279e304; (c) Petasis, N. A. Aust. J. Chem. 2007, 60, 795e798.
2. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445e446; (b) Petasis,
N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 48,16463e16470; (c) Hansen,
T. K.; Schlienger, N.; Hansen, B. S.; Andersen, P. H.; Bryce, M. B. Tetrahedron Lett.
1999, 40, 3651e3654; (d) Jiang, B.; Yang, C.-G.; Gu, X.-H. TetrahedronLett. 2001, 42,
2545e2547; (e) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron Lett. 2002,
43, 6845e6847; (f) Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahe-
dron Lett. 2003, 44, 603e605; (g) Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski,
R.; Chen, J. J. Tetrahedron Lett. 2003, 44, 5121e5124; (h) Naskar, D.; Roy, A.; Seibel,
W. L.; Portlock, D. E. TetrahedronLett. 2003, 44, 8865e8868; (i) Lou, S.; Schaus, S. E.
J. Am. Chem. Soc. 2008, 130, 6922e6923.
3. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc.1998,120,11798e11799; (b) Surya
Prakash, G. K.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett. 2000,
2, 3173e3176; (c) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063e4065.
4. (a) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41,
1303e1305; (b) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, W. A. R.
Chem. Commun. 1996, 1953e1954; (c) Petasis, N. A.; Akritopoulou, I. Tetrahedron
Lett. 1993, 34, 583e586.
Compound 18$HCl (100 mg, 0.39 mmol) was dissolved in water
(4 mL) and Na2CO3 (59 mg, 0.56 mmol) was added followed by
ethyl acetate (4 mL). The reaction mixture was stirred at ambient
temperature for 10 min. The phases were separated and the
aqueous one was extracted with ethyl acetate (3ꢂ4 mL). The
combined organic extracts were concentrated under reduced
pressure. The resulting free base 18 was crystallized from diethyl
ether. Yield: 73%. Mp 99e100 ꢀC. IR (KBr) cmꢁ1: 2948, 2802, 1726,
1207. 1H NMR (CDCl3)
d
: 2.23 (s, 3H), 2.73 (ddd, J¼3.1, 11.6,
12.7 Hz, 1H), 2.98 (ddd, J¼2.0, 2.5, 12.7 Hz, 1H), 3.85 (s, 3H), 3.91
(s, 1H), 4.41 (ddd, J¼1.8, 3.0, 10.7 Hz, 1H), 4.69 (ddd, J¼2.8, 10.8,
11.6 Hz, 1H) 6.92e6.96 (m, 2H), 7.22 (dd, J¼1.7, 7.6 Hz, 1H), 7.32
(ddd, J¼1.7, 7.5, 8.3 Hz, 1H). 13C NMR (CDCl3),
d: 43.4 (CH3), 51.2
(CH2), 55.8 (CH3), 67.8 (CH2), 68.7 (CH), 112.0 (CH), 120.4 (CH),
126.4 (C), 129.8 (CH), 131.5 (CH), 156.9 (C), 169.2 (C). EIMS m/z (%):
221 (Mþ, 49), 192 (10), 177 (53), 162 (96), 148 (85), 119 (100).
HRMS: Mþ, found 221.10556. C12H15NO3 requires 221.10519. Anal.
found C, 65.09; H, 7.21; N, 6.24. C12H15NO3 requires C, 65.14; H,
6.83; N, 6.33.
5. (a) Berree, F.; Debache, A.; Marsac, Y.; Carboni, B. Tetrahedron Lett. 2001, 42,
3591e3594; (b) Petasis, N. A.; Patel, Z. D. Tetrahedron Lett. 2000, 41, 9607e9611;
(c) Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M. P. Eur. J. Org. Chem.
2009, 1859e1863.
6. Candeias, N. R.; Cal, P. M. S. D.; Andre, V.; Duarte, M. T.; Veiros, L. F.; Gois, P. M. P.
Tetrahedron 2010, 66, 2736e2745.
7. (a) Shamma, M.; Moniot, L. Isoquinoline Alkaloids Research; Plenum: New York,
NY, 1978; (b) Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601e615; (c)
Bentley, K. W. The Isoquinoline Alkaloids; Harward Academic: Amsterdam, 1998;
(d) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341e3370.
8. Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889e917.
3.5. Calycotomine (20)
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
hydrochloride (15$HCl) (0.14 g, 0.5 mmol) in 1 mL of THF was treated
with BH3$THF complex (1.5 mL,1.5 mmol,1 M solution inTHF) at 0 ꢀC.
The cloudy solution was stirred at rt for 24 h. Then to the solution,
which became clear, methanol (5 mL) and 10% sodium hydroxide
(0.35 mL) were added at 0 ꢀC and the resulting mixturewas stirred for
4 h at rt. Organic solvents were evaporated and the residue was
extracted with DCM. The DCM solution was dried over Na2SO4,
evaporated and the crude product (0.083 g) was crystallized from
benzene to give pure calycotomine 20 as a solid. Mp 127e130 ꢀC (lit.21
9. Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669e1730.
€ €
10. (a) Paal, T. A.; Liljeblad, A.; Kanerva, L. T.; Forro, E.; Fulop, F. Eur. J. Org. Chem.
€ €
2008, 5269e5276; (b) Zalan, Z.; Martinek, T. A.; Lazar, L.; Sillanpaa, R.; Fulop, F.
Tetrahedron 2006, 62, 2883e2891.
11. Hershenson, F. M. J. Org. Chem. 1975, 40, 740e743.
12. Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett 2006, 1595e1597.
€ €
13. Schuster, I.;Sztojkov-Ivanov, A.;Lazar, L.;Fulop, F. Lett. Org. Chem. 2007, 4,102e108.
€ €
14. Paal, T. A.; Forro, E.; Liljeblad, A.; Kanerva, L. T.; Fulop, F. Tetrahedron: Asymmetry
2007, 18, 1428e1433.
15. Schuster, I.; Lazar, L.; Fulop, F. Synth. Commun. 2010, 40, 2488e2498.
€ €
16. Gaillard, R.; Galsomias, J.; Vieles, P. Bull. Soc. Chim. 1974, 294e298.
17. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44,
5819e5821.
mp 138 ꢀC).1H NMR (CDCl3)
d: 2.58 (s, br, 2H, disappearsontreatment
18. Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer, M.; Ross,
G. Synthesis 2008, 4007e4011.
19. Follmann, M.; Graul, F.; Schafer, T.; Kopec, S.; Hamley, P. Synlett 2005,1009e1011.
20. Kaufman, T. S. Synthesis 2005, 339e360.
with D2O), 2.62e2.75 (m, 2H), 3.00e3.12 (m, 2H), 3.63 (t, J¼10.0 Hz,
1H), 3.77 (dd, J¼4.2,10.7 Hz,1H), 3.96e3.99 (m,1H), 6.68 (s,1H), 6.59
(s, 1H). 13C NMR (CDCl3)
d: 29.0 (CH2), 38.7 (CH2), 55.1 (CH3), 55.93
21. For example: See Ref. 12.