Stereoselective and regioselective intramolecular Friedel-Crafts reaction of aziridinium ions for synthesis of 4-substituted tetrahydroisoquinolines

Article abstract of DOI:10.1021/ol4013537

Optically active 4-substituted tetrahydroisoquinolines were synthesized via intramolecular Friedel-Crafts (FC) reactions of aziridinium ions in a highly regio- and stereoselective manner. Control experiments suggest the formation and ring-opening of aziri

Full text of DOI:10.1021/ol4013537

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Stereoselective and Regioselective
Intramolecular FriedelÀCrafts Reaction
of Aziridinium Ions for Synthesis of
4‑Substituted Tetrahydroisoquinolines
Hyun-Soon Chong* and Yunwei Chen
Department of Biological and Chemical Sciences, Illinois Institute of Technology,
Chicago, Illinois 60616, United States
Chong@iit.edu
Received May 16, 2013; Revised Manuscript Received October 21, 2013
ABSTRACT
Optically active 4-substituted tetrahydroisoquinolines were synthesized via intramolecular FriedelÀCrafts (FC) reactions of aziridinium ions in a
highly regio- and stereoselective manner. Control experiments suggest the formation and ring-opening of aziridinium ions as the key
intermediates in the Lewis acid catalyzed FC reactions.
Aziridinium ions have been utilized as highly reactive
intermediates in the asymmetric synthesis of diverse small
molecules and complex natural products.1À3 Strained
aziridinium ions have been limitedly isolated and
characterized.4À8 Nucleophilic ring opening of substituted
aziridinium ions has been recognized as an efficient syn-
thetic route to chiral precursor molecules including amines,
amino nitriles, amino ethers, and aminoesters.9À12 Despite
synthetic versatility, ring-opening reaction of aziridi-
nium ions remains an underexplored area, while other
three-membered congeners such as aziridines and epoxides
have numerous applications in organic synthesis. Limited
investigations on ring opening of the aziridinium ions in part
stems from difficulty in isolation and characterization of the
labile entities and the lack of general and efficient methods for
the synthesis of aziridinium ions or their precursors with
functionalities. Nucleophilic opening reactions of the aziridi-
nium ions are expected to occur at the two electrophilic
carbons (C2 andC3) undermild conditions. N-Substituents,
C-substituents, or counteranions in the aziridinium ions
are potential nucleophiles that can attack the electrophilic
carbons in intramolecular nucleophilic reactions. With this
potential diverse reactivity, we were interested in the
explorationof azirindium ionsforintramolecularFriedelÀ
Crafts (FC) reaction. FC reaction is a useful synthetic
method for CÀC bond formation in organic synthesis.13,14
We hypothesized that aziridinuim ions containing
an aromatic N-substituent will undergo intramolecular
FC reactions to provide 4-substituted tetrahydroiso-
quinolines (THIQ) in high regio- and stereoselectivity.
THIQ derivatives were reported to possess biological
(1) Metro, T.-X.; Duthion, B.; Pardo, D. G.; Cossy, J. Chem. Soc.
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H. K. J. Org. Chem. 1999, 64, 7323.
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Van Speybroeck, V.; Waroquier, M.; Kim, Y.; Ha, Y.-J. Chem. Com-
mun. 2009, 2508.
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Van Speybroeck, V. J. Org. Chem. 2010, 75, 885.
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2004, 116, 560. Angew. Chem., Int. Ed. 2004, 43, 550.
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York, 1973.
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r
10.1021/ol4013537
XXXX American Chemical Society

functions including anticancer, antibiotic, and dopamine
inhibitory or stimulating activities.15À17 In particular,
4-substituted THIQs such as nomifensine and dichlofen-
sine are known to display dopamine inhibitory or anti-
depressant action.16,17 However, straightforward and
generalsyntheticmethods foroptically active4-substituted
THIQs are rarely reported.18,19 Herein we report a new
synthetic method for enantiomerically enriched 4-substi-
tuted THIQs based on the intramolecular FC reaction of
aziridinium ions. Enantiomerically enriched β-haloamines
1À3 (Table 1) were prepared from β-amino alcohols with
various functionalities and substituents and used as pre-
cursor molecules to generate aziridinium ions in situ for
intramolecular FC reactions.
Table 1. Synthesis of THIQ Analogues (R)-5a and (R)-5b
yield
ee
entry substrate
R1
X
time
temp
(%)
(%)
1
2
(R)-1a
(R)-1a
Ph
Ph
Br 1 min
0 °C
81
50
71
79
Br 45 min À 70 to
À20 °C
β-bromoamines (R)-1a (R1 = Ph) and (R)-1b (R1 =
Me) were used for our initial feasibility study on intra-
molecular FC reactions (Table 1). In the presence of AlCl3,
FC reaction of (R)-1a in toluene under mild conditions
(0 °C, 1 min) instantly provided (R)-5a (81% isolated yield,
71% ee) (Table 1, entry 1). The retained stereochemistry at
the benzylic chiral center in (R)-5a suggests that the FC
reaction involved formation of aziridinium ion (S)-4a as
the key intermediate. Opening of aziridinium ion (S)-4a
occurred at the stabilized benzylic position to furnish (R)-
5a as the regiospecific isomer. The same reaction of (R)-1a
at lower temperature (À20 or À70 °C) provided (R)-5a in
similar stereoselectivity but lower isolated yield (Table 1,
entries 2 and 3). (R)-1b (R1 = Me) required a longer
reaction time and heating (0 °C to reflux, 4 h) due to the
inherent lower reactivity of a secondary alkyl substrate
relative to a benzylic substrate toward substitution reac-
tions. It is noteworthy that the reaction gave (R)-5b in ex-
cellent yield and stereoselectivity (90%, 97% ee) (Table 1,
entry 7). Retained stereochemistry at the chiral center in
(R)-5b also suggests formation and ring opening of aziridi-
nium ion (S)-4b. Change of the leaving group (Cl or I) led to
formation of (R)-5a in lower isolated yield and ee (Table 1,
entries 4 and 5). This result suggests that a leaving group plays
a role in the formation of aziridinium ions and THIQs.
Lewis acid catalysts were screened for the formation of
THIQs (R)-5a and (S)-5b (Table 2). Other catalysts weaker
than AlCl3 were surveyed for the reaction of (R)-1a in
toluene. FeBr3 was the most effective catalyst producing
(R)-5a in the highest stereoselectivity (83% ee) (Table 2,
entry 2). The FC reaction using InCl3 and TiCl4 (Table 2,
entries 3 and 4) was significantly slower compared to the
reaction using FeBr3 and provided (R)-5a in a slightly
higher isolated yield and stereoselectivity (72À78%,
77À81% ee). SnCl4 was significantly less efficient (29%)
than other catalysts, although the reaction provided (R)-5a
in high enantioselectivity (81% ee). (S)-1b required a
stronger Lewis acid and provided (S)-5b from the reaction
3
4
5
6
7
(R)-1a
(R)-2a
(R)-3a
(R)-1b
(R)-1b
Ph
Ph
Ph
Br 15 min À20 °C
55
75
72
NR
90
70
63
61
À
Cl
I
1 min
1 min
0 °C
0 °C
0 °C
reflux
CH3 Br 4 h
CH3 Br 4 h
97
Table 2. Effect of Catalyst on the Formation of THIQ
Analogues (R)-5a and (S)-5b
yield
ee
entry
substrate
catalyst
temp
time
(%)
(%)
1
2
3
4
5
6
7
8
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(S)-1b
(S)-1b
(S)-1b
AlCl3
FeBr3
InCl3
TiCl4
SnCl4
AlCl3
FeBr3
InCl3
0 °C
0 °C
rt
1 min
1 min
20 h
15 h
2.5 h
4 h
81
59
78
72
29
93
25
22
71
83
77
81
81
97
85
97
rt
rt
reflux
reflux
reflux
14 h
96 h
using FeBr3 and InCl3 in poor isolated yield (<25%) but
good enantioselectivity. No FC product was obtained
from the reaction of (S)-1b with TiCl4 and SnCl4 under
reflux. The reaction of (R)-1a or (S)-1b was carried out in
different solvents (Table 3). Among the solvents screened
for the reaction of (R)-1a, dichloroethane (DCE) gave the
best result (95%, 78% ee) (Table 3, entry 4). A lower
isolated yield observed with aromatic solvents (toluene,
benzene, xylene, <81%) compared to halogenated sol-
vents (DCE, CHCl3, and CH2Cl2, >91%) is ascribed to
the formation of intermolecular FC products from reac-
tion of (R)-1a with the aromatic solvents. No product was
formed from the reaction of (R)-1a in THF and hydro-
carbon solvents, cyclohexane (Chx) and hexane (Table 3,
entries 7À9). Less reactive (S)-1b was more selective in
solvent. The FC reaction of (S)-1b proceeded only in the
aromatic solvents producing (S)-5b in excellent yield, and
(16) Zhang, J.; Xiong, B.; Zhen, X.; Zhang, A. Med. Res. Rev. 2009,
29, 272.
(17) Kunstmann, R.; Gerhards, H.; Kruse, H.; Leven, M.; Paulus,
E. F.; Schacht, U.; Schmitt, K.; Witte, P. U. J. Med. Chem. 1987, 30, 798.
ꢀ
(18) Philippe, N.; Levacher, V.; Dupas, G.; Queguiner, G.; Bourguignon,
J. Org. Lett. 2000, 2, 2185.
(19) Yamashita, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc.
2004, 126, 1954.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Effect of Solvents on the Formation of THIQ
Analogues (R)-5a and (S)-5b
Table 4. Substrate Scope for the Synthesis of Various THIQ
Analogues 5
yield
(%)
ee
entry
substrate
solvent
time
temp
(%)
1
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(R)-1a
(S)-1b
(S)-1b
(S)-1b
(S)-1b
toluene
benzene
xylene
(CH2Cl)2
CH2Cl2
CHCl3
Chx
1 min
1 min
1 min
1 min
1 min
1 min
48 h
48 h
48 h
4 h
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
81
71
59
69
78
75
62
À
2
81
3
70
4
95
5
91
6
94
yield
ee
7
NR
NR
NR
93
entry
substrate
temp
solvent
product
(%)
(%)
8
hexane
THF
À
1
2
3
4
5
6
7
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
0 °C
toluene
toluene
toluene
toluene
toluene
DCE
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
(R)-5f
(R)-5g
81
90
79
49
54
41
68
71
97
>99
>99
78
19
2
9
0 °C
À
reflux
reflux
reflux
reflux
À20 °C
À20 °C
10
11
12
13
toluene
benzene
xylene
(CH2Cl)2
reflux
reflux
reflux
reflux
97
>99
98
À
4 h
87
3 h
73
48 h
NR
DCE
no FC product was obtained from the reaction of (S)-1b in
halogenated solvents (DCE, CH2Cl2, CHCl3).
We also investigated the substrate scope for intramolec-
ular FC reactions using β-bromoamines 1aÀg (Table 4). FC
reactions of β-bromoamines 1aÀg were screened for re-
actions using AlCl3. The reaction of (R)-1a and (R)-1b
provided (R)-5a and (R)-5b (71% ee and 97% ee), respec-
tively (Table 4, entries 1 and 2). Replacement of the
C-substituent from methyl to n-propyl (1c) led to formation
of (R)-5c in lower isolated yield but as a nearly exclusive
enantiomer (79%, >99% ee) (Table 4, entry 3). The effect
of N-substitution on the formation of THIQ analogues was
studied. The intramolecular FC reaction was found to be
quite sensitive to N-substitution. The reactions of β-bromoa-
mine (R)-1d containing N-naphthyl groups (1d) provided
(R)-5d in lower isolated yield (49%) but in excellent stereo-
selectivity (Table 4, entry 4). A significant drop in both
isolated yield and ee of (R)-5e was observed from the
reaction of (R)-1e having m-bromobenzyl group (54%,
78% ee) (Table 4, entry 5). In both of the substrates 1d and
1e, FC reactions occurred at the aromatic carbon ortho to
the N-methylene group with exclusive regioselectivity.
Change in the N-substituent from a benzyl (1a) to an allyl
group (1f) led to the formation of (R)-5f in poor isolated yield
and stereoselectivity (41% yield and 19% ee) (Table 4, entry 6).
FC Reaction of (S)-enantiomers of 1aÀf provided
(S)-5aÀf in comparable yield and ee to the enantiomeric
counterparts (Supporting Information).When N-Bn (1a)
was replaced with N-CH3 (1g), the chiral center in 5g was
almost completely racemized (Table 4, entry 7). This result
appears to imply that πÀπ stacking between the nucleo-
philic aromatic ring and the nonreactive N-aromatic ring
or interaction between the aromatic π system and nitrogen
Scheme 1. Proposed Mechanism of the Intramolecular
FriedelÀCrafts Reaction and Confirmation of the
Stereochemistry in the THIQ Analogues (5)
cation in the aziridinium intermediate is essential for the
formation of the FC products in high stereoselectivity.12,20
The stereochemistry in(R)-5aand (R)-5b wasconfirmed
by preparing the known THIQ analogues (R)-7a21 and
(R)-7b22 by N-debenzylation of (R)-5a and (R)-5b (Scheme 1).
The formation and ring opening of aziridinium ions 4 was
proposed as the basis for good to absolute control of
stereochemistry in the synthesis of THIQs 5 as shown in
Scheme 1. The retained stereochemistry at the chiral center
in 5 can be explained by a mechansim wherein an aziridinium
ion 4 was first formed via an intramolecular SN2 reaction
followed by subsequent cleavage of the loose N1ÀC2 bond in
(20) Yamada, S.; Fossey, J. S. Org. Biomol. Chem. 2011, 9, 7275.
(21) Kihara, M.; Ikeuchi, M.; Adachi, S.; Nagao, Y.; Moritoki, H.;
Yamaguchi, M.; Taira, Z. Chem. Pharm. Bull. 1995, 43, 1543.
ꢀ
(22) Pedrosa, R.; Andres, C.; Iglesias, J. M.; Obeso, M. A. Tetra-
hedron 2001, 57, 4005.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthesis and Characterization of Optically Active
β-Haloamines 1 and Aziridinium Ions 9
Scheme 4. FriedelÀCrafts Reaction of C-Substituted
Aziridinium Ion 5h
Scheme 3. Lewis Acid Promoted Debenzylation of
β-Bromoamine 10
substitution reaction of β-bromoamines 1 proceeded in an
SN2 pathway to provide aziridinium ions 9 with inverted
stereochemistry. The formation of aziridinium ion 9 was
promoted by sequestration of the halide in 1using AgClO4 or
AgBF4. We then prepared β-bromoamine (S)-10 containing
a tosyl (Ts) group to understand anchimeric participation of
the neighboring nitrogen to form aziridinium ion (Scheme 3).
No neighboring group participation and resultant formation
of aziridinium ion was expected for (S)-10 substituted with
the tosyl group. Reaction of (S)-10 provided only debenzyla-
tion product 11 in 97% yield, and no FC product 12 was
formed. Finally, we investigated whether involvement of the
N-aromatic ring in the FC reaction was more favorable than
that of the aromatic ring in a C-substituent (Scheme 4). The
FC reaction of (()-1h containing a phenylpropyl group gave
only endo-THIQ 5h. No exocyclization products 13 and 14
were formed, and involvement of the phenyl ring linked to the
propyl spacer in the FC reaction was found to be a disfavor-
able process. It should be noted that formation of 14 from a
direct SN2 displacement of bromide by the phenyl group
linked via the propyl chain was not observed. The experi-
mental results described above suggest that intramolecular
FC reaction of β-haloamines 1 for stereoselective synthesis of
THIQs 5 involves formation and opening of aziridinium ions
4, and direct conversion of β-haloamines 1 to THIIQs 5 in a
SN2 pathway is unlikely.
aziridinium ion 4 by the attack of the N-aromatic ring from
the front side in an SNi pathway. This unusual nucleophilic
reaction proceeding with retention at the chiral center ap-
pears to occur due to the nature of the strained aziridinium
ring and the presence of the nonreacting N-aromatic group
which can stabilize the postive charge in C2 of the aziridinium
ion 4 via cationÀπ interaction or interact with the attacking
aromatic ring via πÀπ stacking. A similar mechanism was
proposed for an acid-promoted intramolecular ring opening
of aziridine proceeding with retained stereochemistry at the
chrial center.23À26
The observed high stereoselectivity in the reaction of
(R)-5aÀe rules out a classical SN1 pathway of the FC
reaction of (R)-1aÀe. A direct SN2 inversion at the chiral
center from the intramolecular FC reaction of (R)-1 by
displacement of bromide by the aromatic ring was ex-
cluded, as the obvious N-substitution effect by displace-
ment of bromide by the aromatic ring was observed. As
stated above, a change of the N-substituent from benzyl to
allyl (1f) and methyl (1g) led to a significant or almost
complete loss of stereoselectivity in the respective formation
of (R)-5f and (R)-5g. The FC reaction of β-bromoamines 1f
and 1g are reasonably speculated to proceed via an SN1
pathway involving a more dissociated carbocation that can
be formed from the aziridinium ion (Scheme 1).
In conclusion, we have shown that the reactive aziridinium
ions can be utilized for the synthesis of 4-substituted THIQs in
high yield and enantioselectivity. We have also carried out the
control experiments and demonstrated that the intramolecu-
lar FC reactions proceed via stereoselective and regiospecific
ring opening of the aziridinium ions to produce THIQs.
To further prove the hypothesis based on the formation of
an aziridinium ion as the key reactive intermediate, control
experiments were conducted. First, optically active aziridi-
nium ions 9 were prepared (Scheme 2) and characterized by
1H and 13C NMR and optical rotation. Bromination of β-
amino alcohols 8 using NXS (X = Br, Cl, I) and PPh3
provided β-haloamines 1 from the ring opening of aziridi-
nium ions 4 by the halide counteranion. The intramolecular
Acknowledgment. The authors thank Mr. Chisoo Kang
(Illinois Institute of Technology) for preparation of pre-
cursor molecules for THIQ analogues.
Supporting Information Available. Experimental pro-
cedures and characterization data of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli,
A. Org. Lett. 2000, 2, 1105.
(24) Hori, K.; Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62,
3081.
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(26) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349.
The authors declare no competing financial interest.
D
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