Diprotonative stabilization of ring-opened carbocationic intermediates: conversion of tetrahydroisoquinoline to triarylmethanes

Article abstract of DOI:10.1039/d0cc01969k

Superacid-promoted conversion of tetrahydroisoquinolines to triarylmethanes via tandem reactions of C-N bond scission, Friedel-Crafts alkylation, C-O bond scission, and electrophilic aromatic amidation was developed. Dication formation was important for stabilizing the ring-opened carbocationic intermediate, which is a new role for diprotonation in reaction mechanisms. This journal is

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Diprotonative stabilization of ring-opened carbocationic
intermediate: conversion of tetrahydroisoquinoline to
triarylmethanes
Received 00th January 20xx,
Accepted 00th January 20xx
Hiroaki Kurouchi*a
DOI: 10.1039/x0xx00000x
Superacid-promoted conversion of tetrahydroisoquinolines to the C–N bond, the Pictet-Spengler reaction has been employed
triarylmethanes via tandem reactions of C–N bond scission, Friedel- as a remarkably important method in biological and chemical
Crafts alkylation, C–O bond scission, and electrophilic aromatic syntheses.10 Even a superacid media could be used for
amidation was developed. Dication formation was important for catalyzing the reaction at 120 °C,11 indicating the necessity of
stabilizing the ring-opened carbocationic intermediate, which is a further activation of the C–N bond for its cleavage. Therefore,
new role for diprotonation in reaction mechanisms.
C–N bond scission-initiated electrophilic aromatic substitution
reactions of tetrahydroisoquinoline have not been reported.
Tetrahydroisoquinoline derivatives are major structures found
in various natural products and pharmaceuticals.1 They have
not only unique structures and functions, but also synthetic
utility as precursors to valuable compounds such as
isoquinolines,2 benzazepines,3 and protopines.4 Transformation
of tetrahydroisoquinolines via scission of the C–N bond, while
rare, typically takes place via Hoffmann elimination,4,5 oxidative
hemiaminal formation,4,6 or nucleophilic substitution (Scheme
1).7
Scheme 2. Conversion of tetrahydroisoquinoline compounds to triarylmethanes which
have a dihydroisoquinolone structure (Ar: Aryl group).
In this study, a new series of triarylmethanes 2, which have
a
dihydroisoquinolone structure, were synthesized from
tetrahydroisoquinolines 1 via a tandem reaction sequence
triggered by C–N bond scission using trifluoromethanesulfonic
acid (TfOH) (Scheme 2). A previously developed method for
activating a carbamate at room temperature was utilized to
form the dihydroisoquinolone moiety under mild conditions.12
Historically, diprotonation of substrates has been used to
enhance electrophilicity.13 In this study, however, diprotonation
of the substrate also had an important role in stabilizing the
reactive ring-opened carbocation for successive electrophilic
aromatic substitution. The proposed reaction mechanism is
shown in Figure 1.
Scheme 1. Ring-opening reactions of tetrahydroisoquinoline skeletons: (a) Hoffmann-
type elimination, (b) nucleophilic substitution, and (c) oxidative hemiaminal formation.
Acid-catalyzed activation of the tetrahydroisoquinoline C–N
bond would be expected to generate a carbocation, which is an
important electrophile in synthesizing functionalized aromatic
molecules such as polyaromatic rings and triarylmethanes,8
which are used as medicines, dyes, and fluorophores.9
However, the C–N bond of tetrahydroisoquinoline is relatively
stable under acidic conditions. Because of the acid stability of
Figure 1. Proposed mechanism of the reaction (Ar1: Aryl group).
a. Research Foundation ITSUU Laboratory, C1232 Kanagawa Science Park R & D
Building, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x
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Table 1. Substrate scope of the intramolecular reaction
electrophilic aromatic substitution reactions. The use of
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triphenylmethane (3d) and diphenylDeOthI:e1r0.10(339e/)D0CaCff0o1r9d6e9dK
products 4d and 4e in moderate yields (Entries 4 and 5). Anisole
(3f) and its derivatives (3g-j) also afforded triarylmethanes 4f to
4j in moderate to good yields (Entries 6-10). The possibility of
attack by
a halogen was also examined (Entry 11).
Tetrabutylammonium iodide (3k) reacted with the substrate
but did not afford the expected iodine adduct; instead,
reduction of the carbocation afforded 4k.15 Substitution on the
tethered aromatic ring and tetrahydroisoquinoline was also
examined. Substrates 1l-p afforded triarylmethanes 4l-4s in
good to high yields (Entries 12-16). Substrates which had a
halogen atom at the 6-position of the tetrahydroisoquinoline
ring afforded a dihydroisoquinolone moiety with a halogen at
the 8-position, which is difficult to access using other synthetic
methods (Entries 17-19).
Table 2. Substrate scope of the intermolecular reaction
[a] Reaction conditions: TfOH (10 equiv.) was added to a solution of 1 (0.30 mmol)
in dichloromethane (1.5 mL) at 0 °C. The reaction mixture was stirred at 25 °C for
1 h. [b] Isolated yield.
The substrate generality of the reaction was initially verified
with intramolecular cyclization reactions. Dihydroisoquinolones
bearing fluorophores or a fluorophore precursor were obtained
in moderate to high yields (Table 1). Dihydroanthracenes were
successfully introduced to the C-5 carbon of the
dihydroisoquinolone moiety in high yields (Entry 1). Because of
the generation of the carbocationic intermediate by C–N bond
cleavage, 2b was a mixture of cis and trans diastereomers (Entry
2).
A
tetrahydronaphthalene derivative (2c) and
a
dihydrophenanthlene derivative (2d) were also obtained
(Entries 3 and 4). In these reactions, intramolecular cyclization
proceeded less efficiently in comparison with Entries 1 and 2
because aromatic rings at the C-1 position of the
tetrahydroisoquinoline substrates play an important role in
stabilizing the carbocation center to facilitate C–N bond
cleavage. Dihydroisoquinolones bearing fluorene and its
derivatives were also achieved (Entries 5-10). The
intramolecular reaction of a naphthalene moiety was highly
selective (Entries 9 and 10).
The substrate generality of the intermolecular reaction was
also investigated using 2 equivalents of a nucleophile (Table 2).
Various triarylmethane derivatives were obtained in moderate
to good yields. Optimization details are discussed in the ESI.
Benzene (3a), p-xylene (3b), and naphthalene (3c) reacted well
with substrate 1k to afford the corresponding triarylmethanes
(Entries 1-3). Contrary to some previous studies of electrophilic
substitution reactions,14 naphthalene reacted at its 훽-position
rather than 훼-position, presumably for steric reasons as the
electrophile is bulkier than the cations generated in typical
[a] Reaction conditions: TfOH (10 equiv.) was added to a solution of 1k (0.30 mmol)
and 3 (0.60 mmol) in dichloromethane (1.5 mL) at 0 °C. The reaction mixture was
stirred at 25 °C for 30 min. [b] Isolated yield. [c] Excess amount of 3a (57 equiv.)
was used as the solvent instead of CH2Cl2. [d] 5 equiv. of the nucleophile was used.
[e] 15 equiv. of TfOH was used. [f] The ratio was determined by 1H NMR. [g] The
reaction mixture was stirred for 2 h.
Scheme 3. (a) Oxidation of 2a to form anthracene 5. (b) Conversion of
dihydroisoquinolone 4b to isoquinoline 7.
2 | J. Name., 2012, 00, 1-3
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The obtained triarylmethanes could be derivatized (Scheme acids than TfOH such as trifluoroacetic acid (TFA) and
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DOI: 10.1039/D0CC01969K
3). Dihydroanthracene 2a was oxidized to an anthracene 5 methanesulfonic acid (MeSO3H) were also examined. The ring-
(Scheme 3a).16 Dihydroisoquinolone 4b was converted to an opened dication was not observed in these acids even though
isoquinoline derivative 7 via tetrahydroisoquinoline 6 (Scheme the carbonyl carbon shifted to a lower field, indicating
3b).17
monoprotonation or strong hydrogen bond formation (Figure
2c).
194.6 ppm (9a)
10.1 ppm x 2 (9a)
10.3 ppm x 2 (9b)
10.3 ppm x 2 (9c)
190.1 ppm (9b)
191.5 ppm (9c)
(b)
(a)
NH x 2
(rotamer)
X
7.1, 7.3 ppm (9a)
7.2, 7.5 ppm (9b)
7.1, 7.3 ppm (9c)
OH
H
C
7.2
7.1 ppm
7.4
7.3
N
OMe
H
N
TfOH
CH x 2 (rotamer)
C
Scheme 4. Isolation of intermediate 8 and its conversion to 2a.
O
OMe
OH x 2
(rotamer)
9a (X = H)
9b (X = Me) 9a-c-2H+-Open
162.2, 161.5 ppm (9a)
162.1, 161.3 ppm (9b)
162.2, 161.3 ppm (9c)
To verify the mechanism, we tried isolating the initially
formed intermediate and then converting it to 2a. By running
the reaction of 1a at -30 °C for 1 min, intermediate 8 with a
dihydroanthracene ring was obtained in 92% yield, and 8 was
then transformed to 2a in 96% yield (Scheme 4). This is clear
evidence that C–N bond cleavage proceeds prior to C–O bond
cleavage of the carbamate. The rate of the conversion from 1a
to 8, with a half-life presumed to be shorter than 10 s at -30 °C,
indicated that the energy barrier from substrate 1a to 8 is less
than 16 kcal/mol based on Eyring's absolute rate theory.18
To characterize the protonation state of the substrate in the
presence of excess amount of TfOH, model substrates 9a-c were
9c (X = Cl)
(Two rotamers)
X
10.1 ppm
10.3
10.2
Ph
H
(c)
(d)
156.0 ppm (CDCl3)
159.4 ppm (TFA)
159.1 ppm (MeSO3H)
H
H
N
OMe
∆G: +22.8 kcal/mol
9-2H+-Closed
SMD(CH2Cl2)-M06-2X/jul-cc-pVTZ//PCM(CH2Cl2)-M06-2X/6-31G*
X
N
OMe
OH
9-2H+-Open
Ph OH
N
OMe
C
9-H+-Closed
Ph O(H+)
Figure 2. (a) 1H and 13C NMR chemical shifts of 9a-c in TfOH at 0 °C. (b) Observed protons
of the dication 9a-2H+-Open in a mixture of TfOH and SbF5 (89:11 (w/w)). (c) 13C chemical
shift of 9 in CDCl3, TFA, and MeSO3H. (d) Free energy difference of 9-2H+-Open and 9-
2H+-Closed calculated by DFT.
Why does the dication exist as a stable ring-opened
intermediate even though the monocation has a ring-closed
structure? One of the major reasons is electric repulsion
between the protonated carbamate and the benzhydryl cation,
which avoids the formation of a gitonic dication (Figure 2d).13
Density functional theory (DFT) calculations indicated that 9-
2H+-Open is 22.8 kcal/mol more stable in Gibbs free energy than
the closed form (9-2H+-Closed). As a result, the reverse ring-
closing reaction is prohibited by diprotonative stabilization of
the carbocationic intermediate. See ESI for details of the DFT
calculation.
The reaction profile of the transformation of 1a was
calculated to further clarify the reaction mechanism (Figure 3).
The reaction path was initially calculated as the monocation
because the high acidity of TfOH enables complete protonation
of the carbamate group of 1a. (See ESI for details.)
studied by 1H and 13C NMR in TfOH at
0 °C. The
tetrahydroisoquinoline structure was completely opened and
two dication rotamers (9a-2H+-Open) with respect to amide
bond rotation were observed (Figure 2a). The proton peaks of
the benzhydryl cation moiety were observed at around 10 ppm
and the carbon peaks were observed at around 190 ppm. These
chemical shifts are in good agreement with the values reported
1
by Olah et al. (9.8 ppm for H and 191.1 ppm for 13C).19 The
carbon peaks of the carbamate also shifted to a lower region
(~162 ppm), indicating further protonation on the carbamate
moiety. Proton exchange of the acid media was suppressed by
the addition of SbF5 to confirm of the protonation state of the
carbamate. The OH group derived from the carbamate was
1
directly observed at 10.3 ppm (Figure 2b), although other H
and 13C chemical shifts did not significantly change. Weaker
Figure 3. Energy profile of the reaction (298.15 K). The free energy values of the monocations are relative to SM-O. The free energy values of the dications are shown
in parenthesis and are relative to INT1-Dication, not to SM-O. See ESI for an explanation of why another standard was used.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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The protonated reactant (1a(H+)) is in equilibrium between
the O-protonated form SM-O and N-protonated form SM-N. C–
N bond cleavage of SM-N proceeds quickly, with a barrier of
16.1 kcal/mol. Because the next transition state of the Friedel-
Crafts cyclization, TS-FC1, has a higher energy barrier than the
reverse reaction of INT1 via TS-CN, the C–N bond cleavage
process for the monoprotonated form is reversible.20
Notes and references
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DOI: 10.1039/D0CC01969K
1
S. Maurice. The isoquinoline alkaloids chemistry and
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3
The Friedel-Crafts cyclization and succeeding proton
transfer process forms INT3. The calculated monocationic
pathway via TS-FC1 has an energy barrier of 22.4 kcal/mol,
which is the highest barrier in the entire process. When
compared with the experimental results shown in Scheme 4,
the DFT-calculated energy barrier is overestimated by more
than 6 kcal/mol. This suggests that a monocationic pathway
does not suitably explain the rate of the Friedel-Crafts
cyclization. As previously seen in the NMR studies, the
carbamate substrate forms a stabilized dication. The open
dication INT1-Dication is expected to be more stable in free
energy than SM-O in the presence of excess TfOH. The reaction
rate of the Friedel-Crafts cyclization should therefore be
assumed from the energy barrier between INT-1-Dication and
TS-FC1-Dication, which is 10.8 kcal/mol. The barrier of the
dicationic pathway is consistent with the experimental reaction
rate. After the dicationic cyclization, deprotonation of INT2-
Dication immediately proceeds to afford monocationic INT3
because the dihydroanthracene moiety cannot be fully
protonated in TfOH.
4
5
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The rate-determining step of the entire process is the
activation of the carbamate moiety to form INT4, which has an
activation free energy from INT3 of 21.9 kcal/mol. This is in
good agreement with a previously reported monocationic
intramolecular hydrogen bond-activated C–O bond cleavage
mechanism.12a The cyclization process then proceeds smoothly
to afford the final product (PD).21
In conclusion, we investigated a new type of transformation
of
tetrahydroisoquinoline
to
functionalized
dihydroisoquinolone derivatives in the presence of TfOH. The
reaction is initiated by carbocation generation via C–N bond
cleavage of the tetrahydroisoquinoline, then diprotonation
prohibits the reverse reaction. The succeeding tandem reaction
then proceeds smoothly. The proposed concept of
diprotonative stabilization is expected to be applicable to the
generation of new types of carbocations from complex
molecules, such as isoquinoline alkaloids.
16 Y. Zou, D. D. Young, A. Cruz-Montanez and A. Deiters, Org.
Lett., 2008, 10, 4661–4664.
17 J. Shi, G. Manolikakes, C. H. Yeh, C. A. Guerrero, R. A. Shenvi,
H. Shigehisa and P. S. Baran, J. Am. Chem. Soc., 2011, 133,
8014–8027.
18 E. V. Anslyn and D. A. Doughtery, Modern Physical Organic
Chemistry, University Science Books, 2006.
19 G. A. Olah, G. K. S. Prakash, G. Liang, P. W. Westerman, K.
Kunde, J. Chandrasekhar and P. V. R. Schleyer, J. Am. Chem.
Soc., 1980, 102, 4485–4492.
Some of the computations were performed at the Research
Center for Computational Science, Okazaki, Japan. This work
was supported by JSPS KAKENHI 18K14205. We are grateful to
Prof. Shuji Akai, Prof. Masayuki Inoue, Prof. Takeo Kawabata,
Prof. Tomohiko Ohwada, Dr. Mitsuaki Ohtani, and Dr. Kin-ichi
Tadano for helpful discussions.
20 The reversibility of C-N bond cleavage of similar compound,
tetrahydro-훽-carboline, in TFA is reported. Further
protonation on amino group on epimerization process is
discussed. see: M. L. Van Linn and J. M. Cook, J. Org. Chem.,
2010, 75, 3587–3599.
Conflicts of interest
There are no conflicts to declare.
21 The discussion about the mechanism is explained in details in
ESI.
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