Reaction of 5-aryloxazolidines with arylmagnesium bromides as a new route to N-benzyl-β-hydroxyphenethylamines as starting materials for the preparation of 4-aryl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2013.03.076

Benzaldehydes react smoothly with the non-stabilized azomethine ylide derived from sarcosine and formaldehyde to form 5-aryloxazolidines as intermediates, which undergo ring-opening to give N-benzyl-β- hydroxyphenethylamines in good yields by the action o

Full text of DOI:10.1016/j.tetlet.2013.03.076

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reaction of 5-aryloxazolidines with arylmagnesium bromides
as a new route to N-benzyl-b-hydroxyphenethylamines as starting materials
for the preparation of 4-aryl-1,2,3,4-tetrahydroisoquinolines
⇑
Vladimir S. Moshkin , Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Ural Federal University, prosp. Lenina 51, 620000 Ekaterinburg, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzaldehydes react smoothly with the non-stabilized azomethine ylide derived from sarcosine and
formaldehyde to form 5-aryloxazolidines as intermediates, which undergo ring-opening to give
N-benzyl-b-hydroxyphenethylamines in good yields by the action of arylmagnesium bromides. Their
subsequent acid-catalyzed cyclization into 4-aryl-1,2,3,4-tetrahydroisoquinolines was performed in
moderate to good yields.
Received 26 January 2013
Revised 27 February 2013
Accepted 13 March 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
4-Aryl-1,2,3,4-tetrahydroisoquinolines
5-Aryloxazolidines
Non-stabilized azomethine ylide
[3+2] Cycloaddition
Cyclization reaction
The chemistry of 4-aryl-1,2,3,4-tetrahydroisoquinolines has at-
tracted considerable attention from the synthetic community due
to their distribution in Nature and various biological activities.1
Amaryllidaceae alkaloids such as cherylline (1) and latifine (2) have
been isolated from Crinum latifolium and other Crinum species.2
Nomifensine (3), a serotonin–norepinephrine–dopamine reuptake
inhibitor, was marketed as an antidepressant in the 1970–
1980s.3 Furthermore, a large number of 4-aryltetrahydroisoquino-
lines4 and their hetero analogs5 have been proposed as triple
monoamine reuptake inhibitors, anti-ulcer and antihistamine
drugs, for example, 4-(4-bromophenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (4)6 (Fig. 1).
sec-butyllithium, and subsequent arylation using aryl halides via
aryne intermediates.10
In connection with our interest in the development of azome-
thine ylide chemistry,11 we have developed a convenient, one-pot
method for the preparation of 2-methyl-1,2,3,4-tetrahydroisoquino-
lin-4-ols 5 from aromatic aldehydes bearing electron-donating
substituents and an azomethine ylide derived from sarcosine and
OH
OH
OH
Due to the important applications of this class of compounds,
their synthesis has been studied extensively. There are several
routes for the preparation of 4-aryltetrahydroisoquinolines, with
most of them being completed via the intramolecular cyclization
of N-benzyl-b-hydroxyphenethylamines.4–7 The latter are obtained
by the reaction of phenacyl bromides and benzylamines followed
by a reduction step,4a–d,6,7a or from styrene oxides and benzylam-
ines.7b,c In addition, there are a number of alternative methods
based on Pictet-Spengler cyclization of 2,2-diarylethylamines,8
the addition of lithium benzylamides to acetophenone enols,9 di-
rect deprotonation of C-4 in 1,2,3,4-tetrahydroisoquinolines using
MeO
HO
MeO
N
N
Me
Me
1
2
Br
N
N
Me
Me
NH2
3
4
Figure 1. Some natural alkaloids and drugs containing a 4-aryltetrahydroisoquin-
oline framework.
⇑
Corresponding author. Fax: +7 343 261 59 78.
E-mail address: mvslc@mail.ru (V.S. Moshkin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.076
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2
V. S. Moshkin, V. Ya. Sosnovskikh / Tetrahedron Letters xxx (2013) xxx–xxx
OH
Ar
O
Ar
1) MeNHCH2CO2H
CH2O
2) 6M HCl, 60 °C
O
O
R
R
R
R
N
N
N
Me
Me
Me
5
8a-c
8d,e
N
Me
-H+
H2SO4 (75%)
H2SO4 (96%)
O
O
O
OH
Me
Me
N
OH
OH
N
Me
N
H+
Ar
Ar
7a-c
7d,e
N
6
Me
MgBr
A
O
O
MgBr
1)
2) H+
MgBr
O
R
Me
N
N
OH
Ar
Me
6
H+
-H2O
R
N
Me
MgBr
S
Ar
Scheme 1. One-pot syntheses of substituted tetrahydroisoquinolines.
Me
OH
PPA
N
N
formaldehyde, via a novel aryloxazolidine–tetrahydroisoquinoline
rearrangement.12 In this intramolecular electrophilic substitution
reaction, intermediate iminium cation A reacts with the nucleophilic
arene with formation of the tetrahydroisoquinoline ring system 5.
Taking into account this result, we envisaged that the ring-opening
of oxazolidine 6 by an external nucleophilic arene would produce
the corresponding N-benzyl-b-hydroxyphenethylamine, the key
intermediate for our 4-aryl-1,2,3,4-tetrahydroisoquinoline synthe-
sis. To the best of our knowledge, no such reactions have been
reported to date (Scheme 1).
Ar
S
S
Me
7f
8f
Scheme 2. Synthesis of N-benzyl-b-hydroxyphenethylamines 7 and 4-aryltetrahy-
droisoquinolines 8.
We found that refluxing an aromatic aldehyde (1.0 mmol), sar-
cosine (1.5 mmol), and paraformaldehyde (3.0 mmol), in benzene
or toluene for 6–8 h with azeotropic removal of water, allowed
Table 1
Yields and melting points of N-benzyl-b-hydroxyphenethylamines 7 and 4-aryltetrahydroisoquinolines 8
Amino alcohol
Yield (%)
Tetrahydroisoquinoline
Yielda (%)
Mpb (°C)
Me
OH
N
71
56
167–172c
7a
N
Me
8a
Br
Me
N
OH
Br
82
60
247–252d
7b
N
Me
8b
OMe
Me
OH
MeO
N
76
32
207–215e
7c
N
Me
8c
O
O
Me
OH
N
237–240f
O
58
37
7d
N
O
Me
8d
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V. S. Moshkin, V. Ya. Sosnovskikh / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 1 (continued)
Amino alcohol
Yield (%)
Tetrahydroisoquinoline
Yielda (%)
Mpb (°C)
O
O
OMe
Me
N
OH
MeO
54
39
230–235
7e
O
O
N
Me
8e
Br
Me
N
OH
S
Br
79
65
217–224
7f
N
S
Me
8f
Me
OH
N
65
79
88
—
—
—
—
—
—
—
MeO
7g
Me
N
OH
MeO
MeO
—
—
OMe
OH
7h
Me
N
O
O
7i
a
b
c
d
e
f
Overall yield of the hydrochlorides based on the starting aromatic aldehyde.
Mp of the hydrochlorides, uncorrected.
Mp 169–174 °C (Ref. 7a).
Mp 245–250 °C (Ref. 6b).
This compound was recrystallized from i-PrOH–Et2O; reported in Ref. 10 as a free base.
Mp 237–239 °C (Ref. 7c), 212–214 °C (Ref. 7a).
us to obtain 5-aryloxazolidines 6 in high yields.12,13 The crude oily
products were sufficiently pure according to the 1H NMR spectra,
and were used in the next stage without purification. Arylmagne-
sium bromides were prepared from aryl bromides (1.5 mmol)
and magnesium (1.5 mmol) in THF according to the standard tech-
nique. To our delight, simple addition of oxazolidine 6 to a solution
of the arylmagnesium bromide resulted in full opening of cyclic
aminal 6, and subsequent acidification led to the desired 2-(ben-
zylmethylamino)-1-arylethanols 7a–i (Scheme 2, Table 1).14 The
hydrochlorides of these compounds had different solubilities in
water, so the best technique for their purification involved direct
precipitation as a mixture with the magnesium salt from the
THF–toluene solution, followed by washing to remove non-basic
organic side products, and final basification of the salt mixture
with concentrated aqueous NH3.
bromide led to a three-step synthesis of 4-(4-bromophenyl)-
6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (8f)17 in 65%
yield, as a potential selective 5-HT reuptake inhibitor.5c In this
case, the cyclization step was performed under the action of
PPA7f,g (Scheme 2). It should be noted that the structure of
thienopyridine 8f needed additional confirmation because of the
known possibility of isomerization via a spirocyclic rearrange-
ment.7g This compound was thus identified by comparison of its
1H NMR spectral data with those reported in the literature (the
chemical shift of the H-3 thienyl proton at d 6.52 showing an
upfield shift due to shielding by the phenyl ring).
In a few cases (amino alcohols 7g–i), recognizable products
could not be isolated, presumably due to the stabilizing effect of
the p-alkoxy group on the initial benzylic carbocation intermedi-
ate, which makes cyclization difficult and facilitates intermolecular
side reactions leading to the formation of resinous products. In the
course of this study, N-benzyl-b-hydroxyphenethylamines 7c,e,f
and 4-aryltetrahydroisoquinolines 8e,f have been synthesized for
the first time, while the other compounds were previously known.
The results are compiled in Table 1.
Intramolecular cyclization of N-benzyl-b-hydroxyphenethyl-
amines 7a–c was performed under previously described
conditions (CH2Cl2, RT, H2SO4;6,7a–c for 7c—AlCl3
) to give
4e,f
4-aryltetrahydroisoquinolines 8a–c in moderate to good yields
based on the starting aromatic aldehyde. Similarly, compounds
8d,e bearing an electron-donating methylenedioxy substituent
on the aromatic ring were obtained in 37% and 39% yields, respec-
tively.15,16 Application of this reaction to 2-thienylmagnesium
It is worth noting that compared with the previously known ap-
proaches for the synthesis of 4-aryl-1,2,3,4-tetrahydroisoquino-
lines, the present method does not require the use of a reducing
Please cite this article in press as: Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.076

4
V. S. Moshkin, V. Ya. Sosnovskikh / Tetrahedron Letters xxx (2013) xxx–xxx
Chem. Pharm. Bull. 1996, 44, 1865–1870; (e) Coote, S. J.; Davies, S. G.; Fletcher,
A. M.; Roberts, P. M.; Thomson, J. E. Chem. Asian J. 2010, 5, 589–604; (f)
Maffrand, J. P.; Boigegrain, R.; Courregelongue, J.; Ferrand, G.; Frehel, D. J.
Heterocycl. Chem. 1981, 18, 727–734; (g) Mackay, C.; Waigh, R. D. J. Chem. Soc.,
Chem. Commun. 1982, 793–794; (h) Philippe, N.; Denivet, F.; Vasse, J.-L.;
Sopkova-de Olivera Santos, J.; Levacher, V.; Dupas, G. Tetrahedron 2003, 59,
8049–8056.
agent, and does not involve working with hazardous compounds,
an inert atmosphere, or chromatographic purification of the inter-
mediate liquid products, and thereby greatly facilitates the prepa-
ration of the target tetrahydroisoquinolines.
In conclusion, we have developed a new, three-step route to 4-
aryl-1,2,3,4-tetrahydroisoquinolines from aromatic aldehydes, sar-
cosine, and formaldehyde via a 5-aryloxazolidine intermediate, fol-
lowed by the reaction with an arylmagnesium bromide and final
acid-catalyzed cyclization. This method allows easy access to bio-
logically important tetrahydroisoquinoline derivatives. Further
application of this reaction for the construction of substituted tet-
rahydroisoquinolines and their hetero analogs is underway in our
laboratory and the results will be reported in due course.
8. Ruchirawat, S.; Tontoolarug, S.; Sahakitpichan, P. Heterocycles 2001, 635–640.
9. Crecente-Campo, J.; Vázquez-Tato, M. P.; Seijas, J. A. Tetrahedron 2009, 65,
2655–2659.
10. Singh, K. N.; Singh, P.; Singh, P.; Deol, Y. S. Org. Lett. 2012, 14, 2202–2205.
11. (a) Moshkin, V. S.; Sosnovskikh, V. Y.; Slepukhin, P. A.; Röschenthaler, G.-V.
Mendeleev Commun. 2012, 22, 29–31; (b) Moshkin, V. S.; Sosnovskikh, V. Y.;
Röschenthaler, G.-V. Tetrahedron Lett. 2012, 53, 3568–3572.
12. Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, http://dx.doi.org/
10.1016/j.tetlet.2013.02.087.
13. (a) Nyerges, M.; Fejes, I.; Virányi, A.; Groundwater, P. W.; Töke, L. Synthesis
2001, 1479–1482; (b) Ryan, J. H.; Spiccia, N.; Wong, L. S.-M.; Holmes, A. B. Aust.
J. Chem. 2007, 60, 898–904.
Acknowledgment
14. General procedure for the preparation of 4-aryl-1,2,3,4-tetrahydroisoquinolines 8.
A mixture of the substituted benzaldehyde (1.0 mmol), finely ground sarcosine
(0.13 g, 1.5 mmol), and paraformaldehyde (0.09 g, 3.0 mmol) was refluxed in
dry benzene (3.3 mL), with magnetic stirring and removal of formed water by
means of a Dean–Stark trap, for 6–8 h. The resulting solution was evaporated in
vacuo to give the oily 5-aryl-3-methyloxazolidine 6. This was dissolved in
toluene (1 mL) and quickly added to a solution of ArMgBr prepared from ArBr
(1.5 mmol) and Mg (0.04 g, 1.5 mmol) in THF (2 mL) at 0 °C with vigorous
stirring. The mixture was left overnight at room temperature. Concentrated
HCl (0.25 mL, 3.0 mmol) and toluene (3 mL) were added with stirring to the
cooled solution (À5 °C). The organic layer was decanted and the precipitate
additionally washed with toluene and Et2O. After basification with an excess of
aq NH3, extraction with CH2Cl2 (2 Â 2 mL), drying over Na2SO4, and
This work was supported financially by the RFBR (Grant 12-03-
31036).
References and notes
1. (a)Chemistry of Heterocyclic Compounds: Isoquinolines; Taylor, E. C., Weissberger,
A., Eds.; John Wiley & Sons: New York, 1981, 1990, 1995; Vol. 38, Parts 1–3; (b);
Charifson, P. S. Drugs Future 1989, 14, 1179–1185; (c) Shklyaev, Yu. V.; Kartsev,
V. G. Some 1,2,3,4-tetrahydroisoquinoline alkaloids of the 1-benzylisoquinoline
group. In Nature Isoquinoline Chemistry and Biological Activity; Kartsev, V. G.,
Ed.; IBS Press: Moscow, Russia, 2011; Vol. 8, pp 386–695.
evaporation, the corresponding N-benzyl-b-hydroxyphenethylamine
7 was
obtained. This was dissolved in CH2Cl2 (2 mL) and treated dropwise with concd
H2SO4 (2 mL) (96%—for 7a,b, 75%—for 7d,e) over 5 min. After stirring for 2 h, ice
chips were added and the aq solution made basic with aq NaOH solution. The
mixture was extracted with CH2Cl2 (2 Â 2 mL) and the combined organic
extracts dried over anhydrous Na2SO4, filtered through a thin layer of silica gel
and concentrated in vacuo. Amino alcohols 7c and 7f were cyclized using AlCl3
in CH2Cl2 (4.0 equiv, reflux, 1.5 h) and polyphosphoric acid (1.1 g of PPA—
1 mmol of 7f, 80–90 °C, 1.5 h), respectively. The free bases were converted into
hydrochloride salts with anhydrous ethereal HCl solution generated in situ
from i-PrOH (1.3 equiv) and AcCl (1.1 equiv).
2. (a) Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T. J. Org. Chem.
1970, 35, 1100–1104; (b) Kobayashi, S.; Tokumoto, T.; Taira, Z. J. Chem. Soc.,
Chem. Commun. 1984, 1043–1044.
3. (a) Hoffmann, I.; Ehrhart, G.; Schmitt, K. Arzneim. Forsch. 1971, 21, 1045; (b)
Hunt, P.; Kannengiesser, M. H.; Raynaud, J. P. J. Pharm. Pharmacol. 1974, 26,
370–371.
4. (a) Molino, B. F.; Berkowitz, B.; Cohen, M. US Patent 20060111394, Chem. Abstr.
2006, 144, 488538.; (b) Molino, B. F.; Liu, S.; Berkowitz, B. A.; Guzzo, P.; Beck, J.
P.; Cohen, M. WO Patent 2006020049, Chem. Abstr. 2006, 144, 254149.; (c)
Pechulis, A. D.; Beck, J. P.; Curry, M. A.; Wolf, M. A.; Harms, A. E.; Xi, N.; Opalka,
C.; Sweet, M. P.; Yang, Z.; Vellekoop, A. S.; Klos, A. M.; Crocker, P. J.; Hassler, C.;
Laws, M.; Kitchen, D. B.; Smith, M. A.; Olson, R. E.; Liu, S.; Molino, B. F. Bioorg.
Med. Chem. Lett. 2012, 22, 7219–7222; (d) Deng, X.; Liang, J. T.; Liu, J.;
McAllister, H.; Schubert, C.; Mani, N. S. Org. Process Res. Dev. 2007, 11, 1043–
1050; (e) Jacob, J. N.; Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med. Chem. 1981, 24,
1013–1015; (f) Riggs, R. M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L. J. Med.
Chem. 1987, 30, 1887–1891.
5. (a) Schneider, C. S.; Weber, K. H.; Langbein, A.; Bechtel, W. D.; Boeke, K. DE
Patent 2746443, 1979; Chem. Abstr. 1979, 91, 456978.; (b) Schneider, C. S.;
Weber, K. H.; Langbein, A.; Bechtel, W. D.; Boeke, K. DE Patent 2833378, 1980;
Chem. Abstr. 1980, 93, 426418.; (c) Schneider, C. S.; Weber, K. H.; Daniel, H.;
Bechtel, W. D.; Boeke-Kuhn, K. J. Med. Chem. 1984, 27, 1150–1155; (d) Riggs, R.
M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L.; Glock, D.; Kohli, J. D. J. Med.
Chem. 1987, 30, 1454–1458.
6. (a) Mondeshka, D. M.; Ivanova, N. S.; Ivanov, C. B.; Angelova, I. G.; Boyadjiev, S.
E.; Tancheva, C. N.; Tersiiska, S. A.; Tosheva, M. R.; Parashikov, V. A.; Paskov, V.
D.; Velkov, V. A. EP Patent 400319, 1990; Chem. Abstr. 1992, 116, 6435.; (b)
Mondeshka, D. M.; Angelova, I. G.; Tancheva, C. N.; Ivanov, C. B.; Daleva, L. D.;
Ivanova, N. S. Farmaco 1994, 49, 475–480.
7. (a) Venkov, A. P.; Vodenicharov, D. M. Synthesis 1990, 253–255; (b) Hara, H.;
Shirai, R.; Hoshino, O.; Umezawa, B. Heterocycles 1983, 20, 1945–1950; (c) Hara,
H.; Shirai, R.; Hoshino, O.; Umezawa, B. Chem. Pharm. Bull. 1985, 33, 3107–
3112; (d) Anan, H.; Tanaka, A.; Tsuzuki, R.; Yokota, M.; Yatsu, T.; Fujikura, T.
15. 4-(4-Bromophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline
hydrochloride
(8b„4). White powder, yield 60% (overall yield based on the starting
aromatic aldehyde), mp 247–252 °C (245–250 °C in Ref. 6b).
16. 8-(4-Methoxyphenyl)-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline
hydrochloride (8e). White powder, yield 39%, mp 230–235 °C. 1H NMR
(400 MHz, CDCl3, free base) d 2.40 (s, 3H, MeN), 2.47 (dd, J = 11.3, 8.8 Hz, 1H,
7-CHH), 2.96 (dd, J = 11.3, 5.5 Hz, 1H, 7-CHH), 3.50 (d, J = 14.5 Hz, 1H, 5-CHH),
3.63 (d, J = 14.5 Hz, 1H, 5-CHH), 3.79 (s, 3H, MeO), 4.11 (t, J = 7.0 Hz, 1H, H-8),
5.85 (s, 2H, H-2), 6.32 (s, 1H, H-9), 6.52 (s, 1H, H-4), 6.83 (d, J = 8.6 Hz, 2H, Ar),
7.10 (d, J = 8.6 Hz, 2H, Ar); 13C NMR (126 MHz, DMSO-d6, for the hydrochloride)
d 41.0, 42.2, 53.6, 55.1, 55.9, 101.2, 105.9, 107.8, 114.3, 122.2, 128.8, 130.0,
132.7, 146.3, 146.9, 158.6. Anal. Calcd for C18H20ClNO3Á0.25H2O: C, 63.90; H,
6.11; N, 4.14. Found: C, 63.76; H, 6.20; N, 4.08.
17. 4-(4-Bromophenyl)-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
hydrochloride (8f). Light yellow powder, yield 65%, mp 217–224 °C. 1H NMR
(400 MHz, CDCl3, free base) d 2.46 (s, 3H, MeN), 2.51 (dd, J = 11.6, 8.0 Hz, 1H, 5-
CHH), 3.00 (dd, J = 11.6, 5.5 Hz, 1H, 5-CHH), 3.66 (d, J = 14.5 Hz, 1H, 7-CHH),
3.77 (d, J = 14.5 Hz, 1H, 7-CHH), 4.10 (dd, J = 8.0, 5.5 Hz, 1H, H-4), 6.52 (d,
J = 5.1 Hz, 1H, H-3), 7.04–7.08 (m, 1H, H-2), 7.07 (d, J = 8.2 Hz, 2H, Ar), 7.41 (d,
J = 8.2 Hz, 2H, Ar); 13C NMR (126 MHz, DMSO-d6, for the hydrochloride) d 39.9,
42.3, 50.9, 55.7, 120.8, 125.6, 126.2, 128.0, 130.6, 131.7, 135.3, 139.3. Anal.
Calcd for C14H15BrClNS: C, 48.78; H, 4.39; N, 4.06. Found: C, 49.08; H, 4.36; N,
4.08.
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