Scandium(III) triflate mediated intramolecular ring expansion of aziridines: A direct access to 4-aryltetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2014.10.047

A novel, high yielding facile synthesis of 4-substituted tetrahydroisoquinolines has been developed by employing scandium(III) triflate mediated intramolecular ring expansion of aziridines. The meta-substituted electron-donating group on the benzene ring facilitates trapping of an in situ generated benzyl carbenium ion cation leading to the formation of tetrahydroisoquinolines.

Full text of DOI:10.1016/j.tetlet.2014.10.047

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Scandium(III) triflate mediated intramolecular ring expansion of
aziridines: a direct access to 4-aryltetrahydroisoquinolines
⇑
Satyanarayana Tummanapalli , Parthasarathy Muthuraman, Dhanunjaya Naidu Vangapandu,
Supriyo Majumder
Albany Molecular Research Singapore Research Center, 61 Science Park Road, #03-13 The Galen, Singapore Science Park II, Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, high yielding facile synthesis of 4-substituted tetrahydroisoquinolines has been developed
by employing scandium(III) triflate mediated intramolecular ring expansion of aziridines. The
meta-substituted electron-donating group on the benzene ring facilitates trapping of an in situ generated
benzyl carbenium ion cation leading to the formation of tetrahydroisoquinolines.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 20 May 2014
Revised 25 July 2014
Accepted 8 October 2014
Available online xxxx
Keywords:
Intramolecular
Ring expansion
Aziridine
Tetrahydroisoquinoline
Scandium(III) triflate
Tetrahydroisoquinolines have received significant attention due
to their presence in a variety of naturally occurring biologically
active molecules.1 In addition, several synthetic tetrahydroisoquin-
olines have been described which are of pharmaceutical
importance.1 In recent years, 4-aryltetrahydroisoquinolines have
been found to exhibit important biological properties,1–3 for
example, nomifensine (1)2 and dichlorofensine (2)3 are effective
inhibitors of reuptake of central neurotransmitters such as
serotonin, norepinephrine, and dopamine at postsynaptic receptors
(Fig. 1).3,4 Therefore, the development of new synthetic methods for
direct access to tetrahydroisoquinolines is still an active area of
interest. Traditional approaches toward tetrahydroisoquinolines
involve intramolecular cyclization using the ring closure of imini-
um intermediates via the Pictet–Spengler5 or Bischler–Napieralski6
reactions. However, there are not many methods available for the
synthesis of important 4-aryltetrahydroisoquinolines.7
ring-opening of 2-(1-aminoalkyl)epoxides with the H3PO4ÁBF3
complex.9 More recently, Wang et al. reported a scandium(III) tri-
flate catalyzed [3+3] annulation process for the efficient synthesis
of tetrahydroisoquinolines from benzylic alcohols and aziridines.10
Herein, we report the first scandium(III) triflate mediated
intramolecular ring expansion of aziridines leading to 4-substituted
tetrahydroisoquinolines. To examine the hypothesis that
4-substituted tetrahydroisoquinolines 3 could be obtained by trap-
ping carbenium ion 4, which could be generated in situ by treating
Cl
O
Cl
Me
H2N
N
N
H
Me
We envisaged that 4-substituted tetrahydroisoquinolines 3
could be obtained by trapping an in situ generated carbenium
ion 4, which might be generated by treating an N-benzyl aziridine
5 with an appropriate Lewis acid (Scheme 1).
2
1
Figure 1. Structures of nomifensine (1) and dichlorofensine (2).
Aziridine ring-opening has been studied extensively for the syn-
thesis of a variety of different heterocycles.8 However, the direct
use of intramolecular aziridine ring-opening for the synthesis of
tetrahydroisoquinolines has not been described. In 2009, Concellon
et al. reported tetrahydroisoquinoline synthesis via intramoleculer
Ar
Ar
Lewis Acid
NH
N
NH
Ar
5
3
4
⇑
Corresponding author. Tel.: +65 6398 5500; fax: +65 6398 5511.
E-mail address: satyanarayana.tummanapalli@amriglobal.com (T. Satyanarayana).
Scheme 1. Retrosynthetic pathway for the formation of isoquinolines
N-benzyl aziridines 5.
3
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2
T. Satyanarayana et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
an N-benzyl aziridine 5 with an appropriate Lewis acid (Scheme 1),
we prepared N-benzyl aziridine 5a following the literature
procedure11 and treated it with various Lewis acids (Table 1). When
N-benzyl aziridine 5a was treated with Lewis acids such as BF3ÁEt2O
(entry 1) or AlCl3 (entry 2) at temperatures up to 100 °C in
1,2-dichloroethane, the desired 4-aryltetrahydroisoquinolines
6a/7a were not formed. However, when 5a was treated with
La(OTf)3, Yb(OTf)3, or Zn(OTf)3 at 90 °C, we observed the formation
of 4-aryltetrahydroisoquinoline 6a, albeit with very low conver-
sions (entries 3–5). Interestingly, treatment of N-benzyl aziridine
5a with Sc(OTf)3 at 90 °C provided clean conversion (>99% by
LC–MS analysis) into the desired tetrahydroisoquinoline as a mix-
ture of the two possible regioisomers 6a and 7a (entry 6).12 Based
on 1H NMR and LC–MS analyses of the crude sample, the two
isomers 6a13 and 7a14 were formed in a 76:24 ratio and were sub-
sequently separated by silica gel chromatography.12–14 Lowering
the amount of Sc(OTf)3 to 30 mol % resulted in lower conversion
(50%), even after a prolonged reaction time of 16 h (entry 7).
Encouraged by these results and to further examine the scope
and generality of the Sc(OTf)3-mediated intramolecular aziridine
Lewis acid mediated ring expansion of aziridines resulting in 4-aryltetrahydroiso-
quinolines
Cl
Cl
OMe
OMe
Lewis acid
1,2-DCE,90 °C
N
Cl
NH
NH
MeO
5a
6a
7a
Entry
Lewis acid (equiv)
Time (h)
% Conversiona (6a + 7a)
1
2
3
4
5
6
7
BF3ÁEt2O (1.2)
AlCl3 (3.0)
16
16
16
16
16
1
0
0
La(OTf)3 (1.2)
Yb(OTf)3 (1.2)
Zn(OTf)2 (1.2)
Sc(OTf)3 (1.2)
Sc(OTf)3 (0.3)
10b
<10b
<10b
99c (6a: 73%; 7a: 12%)d
16
50b
a
b
c
Conversions were measured by LC–MS analysis.
Unreacted starting material remained intact.
LC–MS and 1H NMR analyses indicated 6a and 7a were formed in a 76:24 ratio.
d
Isolated yields.
Table 2
Sc(OTf)3-mediated ring expansion of meta-alkoxy substituted aziridines to give 4-aryltetrahydroisoquinolines 6/7
Ar
R
Sc(OTf)3 (1.2 equiv.)
1,2-DCE, 90 oC, 2 h
R
N
NH
6/7
Ar
5
Entry
1
Aziridinea
Cl
Productb,c
MeO
Cl
Cl
OMe
Cl
Cl
N
N
Cl
OMe
N
H
H
7b
(21%)
6b
(70%)
5b
OMe
MeO
OMe
F
2
3
N
F
6c (76%)
OMe
N
5c
H
OMe
OMe
OMe
OMe
MeO
OMe
F
N
F
N
H
6d (70%)
5d
O
O
O
O
O
O
O
F
F
N
F
O
4
N
N
H
5e
6e
H
(72%)
7e
(19%)
Cl
O
O
N
O
5
6
Cl
Cl
O
N
H
N
H
5f
7f
6f
(18%)
(76%)
OMe
MeO
OMe
Cl
N
Cl
6g (84%)
OMe
N
H
5g
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T. Satyanarayana et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2 (continued)
Entry
Aziridinea
Productb,c
OMe
OMe
OMe
OMe
MeO
Cl
OMe
N
7
8
Cl
N
H
5h
6h
(66%)
F
F
MeO
OMe
N
F
N
OMe
F
N
H
H
6i (72%)
5i
7i (22%)
O
O
O
O
N
O
9
F
F
O
6j (78%)
7j (14%)
N
N
5j
H
H
MeO
MeO
F
OMe
F
N
F
10
OMe
N
N
H
5k
H
6k (70%)
7k (25%)
OMe
OMe
F
N
11
F
OMe
N
H
6l
5l
(79%)
a
Aziridines 5b–l were prepared by following the general procedure described in Ref.11
The products were prepared following the general procedure described in Ref.12
Isolated yields after chromatographic purification.
b
c
Table 3
ring expansion, we prepared various N-benzyl aziridines 5b–l11
and treated them with Sc(OTf)3 (Table 2). All the reactions were
carried out using 1.2 equiv of Sc(OTf)3 and 1,2-dichloroethane as
the solvent. The reactions were heated to 90 °C and monitored by
TLC. The starting materials were completely consumed within
two hours and the desired 4-aryltetrahydroisoquinolines 6/7 were
isolated in fairly good yields after purification (Table 2). We
envisioned that an electron-rich aryl ring (the N-benzyl group)
with at least one electron-donating group (EDG) substituted at
the meta-position might be required for efficient trapping of the
carbenium ion in order to form the tetrahydroisoquinoline under
these conditions. Therefore, the meta-alkoxy-substituted N-benzyl
aziridines 5a–l provided the corresponding 4-aryltetrahydroiso-
quinolines 6a–l with excellent conversions (>99% conversion by
LC–MS) (Table 2).12
To examine the importance of meta-alkoxy substitution we
expanded our study to N-benzyl aziridines lacking a 3-OMe group.
First we treated N-benzyl aziridine 5m with 1.2 equiv of
Sc(OTf)3 in 1,2-dichloroethane under the same reaction conditions.
However, there was no 4-aryltetrahydroisoquinoline formation,
even on heating at an elevated temperature and after a prolonged
reaction time of 16 h. We did however isolate amino alcohol 8a
after usual work-up and purification (entry 1, Table 3).15 Next,
we subjected two electron-rich benzyl aziridines, 5n and 5o con-
taining an ortho and a para- substituted methoxy group, to the
same reaction conditions. Again, after work-up and purification,
we isolated exclusively the corresponding amino alcohols 8b and
8c (entries 2 and 3, Table 3). Aziridine 5p with a Cl group at the
meta-position led to the formation of amino alcohol 8d (entry 4).
A similar result was observed for the amino alcohol 5q containing
an electron-withdrawing group at the para position (entry 5).
These results clearly demonstrate that meta-alkoxy substitution
is essential for the cyclization reaction to occur. These results also
Sc(OTf)3-mediated ring-opening of non meta-alkoxy N-benzyl aziridines into amino
alcohols
R
OH
H
R
N
N
i. Sc(OTf)3
1,2-DCE
90 °C, 3-16 h
ii. Work-up (H2O)
F
5
8
F
Entry Aziridinea
Productb,c
OH
F
H
N
N
1
5m
8a (60%)
F
F
OH
H
N
N
F
2
MeO
OMe
8b (71%)
5n
OMe
OH
OMe
Cl
H
N
N
F
3
5o
8c
(75%)
F
F
F
Cl
Cl
OH
H
N
N
F
4
Cl
5p
8d (76%)
CF3
OH
CF3
H
N
N
F
5
8e
5q
(68%)
a
b
c
Aziridines 5m–q were prepared by followed the general procedure described in Ref.11
Reactions were conducted on 1 mmol scale.
Isolated yields after chromatographic purification.
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4
T. Satyanarayana et al. / Tetrahedron Letters xxx (2014) xxx–xxx
R = an EDG group
Ar
Ar
References and notes
at the meta-
position, e.g.,
3-OMe
R
R
Sc(OTf)3
N
N
N
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Chem. 1986, 29, 1189.
Sc(OTf)3
Ar
MeO
Sc(OTf)3
Carbenium ion A'
Carbenium ion A
5
R = no substitutionor a non
EDG group at the meta-position,
in situ
H2O (work-up)
R
Ar
Ar
H
OH
H
N
aromatization
Ar
NH
N
8
MeO
MeO
Sc(OTf)3
6/7
Carbenium ion A''
Scheme 2. A plausible tentative mechanism for the formation of tetrahydroiso-
quinolines and amino alcohols from N-benzyl aziridines.
5. Cox, A. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797–1842.
6. Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183–187.
7. (a) Jacob, J. N.; Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med. Chem. 1981, 24, 1013;
(b) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279; (c) Miller, R. B.;
Svoboda, J. J. Synth. Commun. 1994, 24, 1187; (d) Hu, M.; Guzzo, P. R.; Zha, C.;
Nacro, K.; Yang, Y-L.; Hassler, C.; Liu, S. Tetrahedron Lett. 2012, 53, 846.
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Speybroeck, V.; De Kimpe, N.; Ha, H. J. Chem. Soc. Rev. 2012, 41, 643–665; (b) Lu,
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suggest that the meta-alkoxy group facilitates efficient trapping of
the carbenium ion leading to formation of the tetrahydroisoquino-
line, since all the other differently substituted N-benzyl aziridines
gave amino alcohols upon quenching the reactions with water as
depicted in Scheme 2.
In summary, we have developed the first Lewis acid mediated
ring expansion of aziridines to give 4-aryltetrahydroisoquinolines
in fairly good yields via the trapping of an in situ generated benzyl
carbenium ion.
11. Aziridines 5a–q were prepared following procedures described in (a) Gopinath,
P.; Chandrasekaran, S. J. Org. Chem. 2011, 76, 700; (b) Bera, M.; Pratihar, S.; Roy,
S. J. Org. Chem. 2011, 76, 1475–1478. A typical experimental procedure along
with 1H NMR and MS data for 5a is described in the Supplementary material
Acknowledgments
12. General procedure for the synthesis of tetrahydroisoquinolines: To
a stirred
solution of the aziridine (0.36 mmol) in 1,2-DCE (3 mL) was added Sc(OTf)3
(0.43 mmol) and the mixture was heated at 90 °C for 2 h. Upon completion of
the reaction as judged by TLC, the mixture was diluted with CH2Cl2 (10 mL),
washed with satd NaHCO3 solution and dried over Na2SO4. The organic layer
was concentrated under reduced pressure and purified by silica gel column
chromatography to afford the 4-aryltetrahydroisoquinoline.
We sincerely appreciate the financial support from Albany
Molecular Research Inc. The authors also thank Dr. Chen Zhen Zia
for his support and Dr. Isherwood Matthew for useful discussions
during the preparation of this manuscript.
13. Analytical data for 6a: 1H NMR (400 MHz, CD3OD): d 3.39–3.45 (m, 1H), 3.72–
3.77 (m, 1H), 3.80 (s, 3H), 4.40–4.53 (m, 3H), 6.79–6.86 (m, 3H), 7.16–7.25 (m,
2H), 7.31–7.39 (m, 2H); 13C NMR (100 MHz, CD3OD): d 42.3, 46.4, 49.3, 55.9,
112.2, 116.0, 127.4, 128.6, 129.0, 130.1, 130.9, 131.6, 131.7, 135.9, 144.8,
160.5; ESI-MS: m/z 274 (M+H).
Supplementary data
14. Analytical data for 7a: 1H NMR (400 MHz, CD3OD): d 3.30–3.55 (m, 1H), 3.59 (s,
3H), 3.72–3.76 (m, 1H), 4.36-4.46 (m, 2H), 4.59–4.62 (m, 1H), 6.92–7.07 (m,
5H), 7.26–7.29 (m, 1H), 7.37–7.41 (m, 1H); 13C NMR (100 MHz, CD3OD): d 37.7,
45.8, 49.2, 55.9, 111.6, 119.8, 122.8, 127.2, 128.3, 129.2, 130.4, 131.1, 131.2,
135.5, 145.5, 158.7; ESI-MS: m/z 274 (M+H).
15. Only the amino alcohol 8a was isolated even when the crude reaction mixture,
obtained after solvent evaporation without aqueous work-up, was loaded
directly on the silica gel column and eluted with EtOAc/n-hexanes.
Supplementary data (experimental procedures, 1H NMR and MS
data of 4-aryltetrahydroisoquinolines 6a–l and amino alcohols 8a–
e) associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.10.047.
Please cite this article in press as: Satyanarayana, T.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.10.047