Ring expansion of 1,2,3,4-tetrahydroisoquinolines to dibenzo[c,f]azonines. An unexpected [1,4]-sigmatropic rearrangement of nitrile-stabilized ammonium ylides

Article abstract of DOI:10.1021/jo500749x

When the products of a Strecker reaction of 1,2,3,4-tetrahydroisoquinolines with aromatic aldehydes are quaternized with alkyl triflates and subsequently treated with base, a ring expansion to 6,7,8,13-tetrahydro-5H-dibenzo[c,f] azonine-5-carbonitriles takes place. The nine-membered cyclic products can be obtained in good yields (78-89%) in a process involving the [1,4]-sigmatropic rearrangement of a nitrile-stabilized ammonium ylide. The reaction sequence provides a new, simple, and efficient method for the synthesis of these unusual N-heterocycles.

Full text of DOI:10.1021/jo500749x

Article
pubs.acs.org/joc
Ring Expansion of 1,2,3,4-Tetrahydroisoquinolines to
Dibenzo[c,f]azonines. An Unexpected [1,4]-Sigmatropic
Rearrangement of Nitrile-Stabilized Ammonium Ylides
Julio Cesar Orejarena Pacheco and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: When the products of a Strecker reaction of
1,2,3,4-tetrahydroisoquinolines with aromatic aldehydes are
quaternized with alkyl triflates and subsequently treated with
base, a ring expansion to 6,7,8,13-tetrahydro-5H-dibenzo[c,f ]-
azonine-5-carbonitriles takes place. The nine-membered cyclic
products can be obtained in good yields (78−89%) in a
process involving the [1,4]-sigmatropic rearrangement of a nitrile-stabilized ammonium ylide. The reaction sequence provides a
new, simple, and efficient method for the synthesis of these unusual N-heterocycles.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Azonines are prototypical representatives of medium-sized
saturated N-heterocycles and constitute the backbone of
several natural products.1−5 Their biological properties range
from antihypertensive, antimalarial, and antiproliferative to
analgetic.6−11 In contrast, their [c,f]dibenzo-annulated de-
rivatives have been much less investigated, although they
possess a promising potential as CNS stimulants, anti-
inflammatory drugs, and modulators of NO synthase.12−14
Moreover, they bear similarity to the scaffolds of known
GPCR receptor ligands.
Recently, our research group has developed methodology
which takes advantage of the chemistry of α-aminonitriles and
their conversion to nitrile-stabilized ammonium ylides as
precursors for efficient [1,2]-Stevens rearrangements.17,18
Motivated by these results, we decided to explore the
application of this process in the synthesis of other classes
of N-heterocycles. Thus, we sought to develop a strategy for
the synthesis of 2-substituted benzo[d]azepines (4a) from
1,2,3,4-tetrahydroisoquinolines via Strecker reaction and
subsequent quaternization to the ammonium salts (2a)
which should be followed by [1,2]-Stevens rearrangement of
the nitrile-stabilized ammonium ylides obtained by deproto-
nation (Scheme 1). Related methodologies have been
described using ester derivatives instead of nitriles.19 Soldatova
and co-workers explored α-aminonitrile-derived starting
materials for the ring expansion of 1-benzyl-1,2,3,4-tetra-
hydroisoquinolines but reported only moderate yields.20 We
However, synthetic efforts toward the preparation of
dibenzo[c,f ]azonines are rather limited. The first approach
to this compound class was reported by Zugna and co-
workers, who treated 2,2′-bisbromomethyldiphenylmethane
with sodium cyanamide or benzylamine to give the ring-closed
substitution products.15 Manning and Houlihan patented the
synthesis of dibenzo[c,f ]azonines from isoindolo[1,2-a]iso-
quinolinum salts by reduction with sodium in liquid ammonia
to cleave the central bond between C-12b and nitrogen.12,13
A
Scheme 1. Proposed Synthesis of a Benzo[d]azepine by
Sommelet−Hauser rearrangement of 1-phenyltetrahydroiso-
quinolinium methylides to dibenzo[c,f ]azonines was reported
by Sato et al.16 The latest report on this class of heterocycles
is a patent by Dreux and co-workers describing a sequential
reduction, hydrolysis, and intramolecular cyclocondensation of
ethyl-3-(3-methoxybenzylamino)-4-(3,4-dimethoxyphenyl)-2-
butenoate.14
[1,2]-Stevens Rearrangement
Herein, we report a novel and broadly applicable method
for the preparation of 6,7,8,13-tetrahydro-5H-dibenzo[c,f]-
azonines starting from 1,2,3,4-tetrahydroisoquinolines. To the
best of our knowledge, this represents the first direct ring
expansion of ammonium ylides via [1,4]-sigmatropic rear-
rangement as well as the first efficient protocol for the
preparation of dibenzo[c,f ]azonines from simple starting
materials.
Received: April 1, 2014
© XXXX American Chemical Society
A
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anticipated a better outcome if the negative charge in the
ammonium ylide is stabilized by an adjacent aryl group. This
should increase the acidity of the α-proton and suppress the
competing formation of Hofmann elimination products.
Along these lines, compound 4a should be available in
three steps from 1,2,3,4-tetrahydroisoquinoline (1a). We
found that when 1a and benzaldehyde are treated under
Knoevenagel−Bucherer conditions,21 α-aminonitrile 2a is
obtained in higher yield compared to other reported
methods.22 N-Methylation of 1a with methyl triflate leads to
the formation of tetrahydroisoquinolinium salt 3a in 98%
yield. The use of methyl iodide is not recommended because
halide anions are capable of nucleopilic N-dealkylation.
When compound 3a was treated with KHMDS in THF at
0 °C over 3 h (Scheme 2), the formation of a single product
The surprising formation of aminonitrile 5a indicated that a
[1,4]-sigmatropic rearrangement of the ammonium ylide
derived from tetrahydroisoquinolinium salt 3a had taken
place (Scheme 3). This reaction involves a six-electron
Scheme 3. [1,4]-Sigmatropic Rearrangement of the
Tetrahydroisoquinolinium Salt 3a
Scheme 2. Unexpected [1,4]-Sigmatropic Rearrangement to
Dibenzo[c,f ]azonines 5a
aromatic transition state with suprafacial−suprafacial charac-
teristics.23,24 Migrations of this kind have been observed
before as competing reactions of the common [1,2]- and
[2,3]-sigmatropic rearrangements of ammonium benzylides as
well as of allylic ammonium ylides.24−29
To explore the scope of the reaction, eight new α-
aminonitriles, compounds 2b−i, were prepared via Knoeve-
nagel−Bucherer-type Strecker reaction of 1,2,3,4-tetrahydro-
isoquinoline (1a) or 6,7-dimethoxytetrahydroisoquinoline
(1b) in 80−94% yield. They were quaternized with alkyl
triflates to form 10 new ammonium triflates 3b−j in moderate
to high yields (Table 1).
For the preparation of dibenzo[c,f ]azonines 5, compound
3a was chosen as a model substrate for the optimization of
the reaction conditions (Table 2). Shorter reaction times as
well as higher yields were achieved when DBU was used as a
base in conjunction with acetonitrile as solvent at room
temperature. Recrystallization turned out to be the method of
choice for the purification of the products. Remarkably, no
competing rearrangements were observed as judged by LC-
MS analysis of the reaction mixtures.
was observed. LC-MS analysis indicated a molecular mass
matching that of the expected benzo[d]azepine. Chromato-
graphic purification afforded the corresponding compound in
50% yield. However, NMR analysis revealed that one of the
aromatic proton resonances was missing and showed an
unexpected broadening of the signals in the aliphatic region.
Variable temperature NMR indicated that an optimal
resolution of the signals can be obtained at 70 °C where
ring inversion is fast enough to give sharp resonances (Figure
1).
With this, we were able to identify the product as the
dibenzo[c,f ]azonine carbonitrile 5a. The structure was further
confirmed by X-ray crystallography (see Supporting Informa-
tion).
By applying these optimized reaction conditions to
compounds 3b−j, we prepared nine new dibenzo[c,f ]azonines
1
Figure 1. H and 13C spectra of compound 5a at variable temperatures (K) in C6D6.
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Table 1. Synthesis of 1,2,3,4-Tetrahydroisoquinolinium 3a−j Salts from α-Aminonitriles 2a−i
a
b
Used in the next step without further purification. N-Debenzylation of the aminonitrile with TfOH produced by β-elimination of the electrophile
occurred. The addition of scavenger bases led, however, to problems with the chromatographic workup.
Table 2. Optimization of the Reaction Conditions for
Preparation of Dibenzo[c,f]azonine 5a
Scheme 4. Synthesis of 4-(2,6-Dichlorophenyl)-3-methyl-
2,3-dihydro-1H-benzo[d]azepine 6
entry
base
equiv solvent
temp
time (h)
yield (%)
a
1
2
3
4
5
6
7
KHMDS
KHMDS
KHMDS
DBU
1.2
1.2
1.3
1.2
1.2
1.3
2
THF
THF
PhMe
MeCN
THF
DMF
H2O
0 °C
rt
3
1.5
6
50
a
b
b
c
60
65
87
45
77
reflux
rt
1
DBU
rt
15
1.5
48
b
DBU
rt
KOH
70 °C
no reaction
a
b
Purification by flash chromatography. Purification by recrystalliza-
rearrangement followed by an in situ dehydrocyanation
occurred to produce compound 6 in high yield (Scheme 4).
This class of dibenzo[c,f ]azonines also revealed another
remarkable issue. The crystal structure of compounds 5a and
5h showed that, although both azonine rings adopt a different
conformation, the lone pair at the pyramidal ring nitrogen is
oriented antiperiplanar to the nitrile group in both cases (see
Supporting Information). This should make dibenzazonine
carbonitriles of type 5 suitable candidates for substitutions of
cyanide in elimination/addition reactions, such as the
Bruylants reaction or reductive decyanations.30,31
c
tion. Incomplete consumption of the starting material.
(5b−j) in 78−89% yield (Table 3). It was observed that
substituents in the aryl ring directly involved in the
rearrangement have a strong influence on the rates but not
on the outcome of the reaction. Derivatives with electron-
withdrawing groups reacted faster than derivatives with
electron-donating groups. Whether or not the abstraction of
the α-proton is the rate-determining step remains to be
elucidated.
To test this hypothesis, compound 5a was treated with
LiAlH4 to obtain the decyanated dibenzo[c,f ]azonine 7 in
84% yield (Scheme 5).
When both ortho-positions in the benzylic moiety are
blocked (derivative 3k), the initially expected [1,2]-Stevens
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Table 3. Preparation of Dibenzo[c,f]azonines 5b−j by [1,4]-Sigmatropic Rearrangement
conditions to induce the [1,2]-Stevens rearrangement
selectively.
Scheme 5. Synthesis of 6-Methyl-6,7,8,13-tetrahydro-5H-
dibenzo[c,f ]azonine 7 by Reductive Decyanation
EXPERIMENTAL SECTION
■
Anhydrous reactions were performed in dried glassware under argon
atmosphere. Temperatures ≤0 °C were produced using a water/ice
or a dry ice/acetone cooling bath. All reagents and solvents were
obtained from commercial suppliers without further purification. 6,7-
Dimethoxy-1,2,3,4-tetrahydroisoquinoline (1b) and n-butyl triflate
were synthesized according to known procedures.18,32−34 Anhydrous
THF was distilled from potassium/benzophenone under argon and
collected over activated 4 Å molecular sieves. Anhydrous acetonitrile
was obtained from distillation from P2O5 and collected over activated
4 Å molecular sieves. Melting points were determined in open
capillary tubes and are uncorrected. FTIR spectra were recorded
using a diamond ATR unit and are reported in terms of frequency of
CONCLUSIONS
■
In summary, we have found a novel method for the
straightforward preparation of 6,7,8,13-tetrahydro-5H-dibenzo-
[c,f]azonines from simple starting materials as well as the first
example of a direct ring expansion via [1,4]-sigmatropic
rearrangement. In the case of 2,6-disubstitution of the benzylic
N-substituent, a benzo[b]azepine was formed instead. At
present, we are investigating suitable substrates and reaction
absorption (ν, cm−1). A 400 MHz (400 MHz H and 100.6 MHz
1
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13C) or a 600 MHz (600 MHz 1H and 150.9 MHz 13C)
(ATR) ν = 3067, 3025, 2924, 2818, 2759, 2227, 1670, 1604, 1508,
1
1455, 1226, 1159, 1089, 938, 843, 785, 741 cm−1; H NMR, COSY
spectrometer equipped with 5 mm inverse probeheads with z-
gradient coils were used to record the corresponding NMR spectra.
The signals were referenced to the residual solvent signal (CDCl3:
δH = 7.26 ppm, δC = 77.16 ppm; C6D6: δH = 7.16 ppm, δC = 128.06
ppm).35 ESI-HRMS spectra were recorded on a Q-TOF instrument
with a dual source and a suitable external calibrant. Thin-layer
chromatography was carried out on 0.2 mm silica gel plates with a
fluorescence indicator. Substance bands were detected by illumina-
tion with UV light (254 and 360 nm).
General Procedure for the One-Pot Synthesis of α-
Aminonitriles (2a−h). To a turbid solution of the respective
aldehyde (1.0 equiv) in water/methanol (4:1, 7 mL/mmol) was
added NaHSO3 (1.0 equiv) in one portion at room temperature. The
reaction mixture was stirred vigorously for 2 h, and then the
corresponding amine (1.0 equiv) was added, followed by KCN (2.0
equiv) in one portion. The mixture again turned turbid, and the
stirring was continued for an additional 16 h. The reaction mixture
was extracted with CH2Cl2 (3 × 50 mL), and the combined organic
layers were washed with water and brine, dried over Na2SO4, and
filtered. The solvent was removed under reduce pressure, and the
crude products were either purified by recrystallization or used
without further purification where indicated.
(400 MHz, CDCl3) δ = 7.60 (dd, J = 8.7, 5.2 Hz, 2H, H-2′,6′),
7.22−7.07 (m, 5H, H-3′,5′, H-5, H-6, H-7), 7.06−6.98 (m, 1H, H-
8), 5.04 (s, 1H, CHCN), 3.80 (d, J = 14.4 Hz, 1H, H-1), 3.75 (d, J
= 14.4 Hz, 1H, H-1), 3.09−2.74 (m, 4H, 2H-3, 2H-4) ppm; 13C
NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 163.1 (d, J = 248.2
Hz, C4′), 133.7 (C4a), 133.6 (C8a), 129.7 (d, J = 8.2 Hz, 2C,
C2′,6′), 129.0 (d, J = 3.1 Hz, C1′), 128.8 (C5), 126.7 (C8), 126.6
(C6), 126.0 (C7), 115.9 (d, J = 21.7 Hz, 2C, C3′,5′), 115.3 (CN),
61.6 (C−CN), 52.4 (C1), 47.6 (C3), 29.3 (C4) ppm; ESI-MS (m/z)
267.1 (100) [M + H]+; ESI-HRMS calcd for [C17H16FN2]+
267.1298, found 267.1302.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-(4-(trifluoromethyl)-
phenyl)acetonitrile (2d). Following the general procedure,
compound 2d was prepared from 1,2,3,4-tetrahydroisoquinoline 1a
(952 μL, 7.51 mmol), p-trifluoromethylbenzaldehyde (1.03 mL, 7.51
mmol), NaHSO3 (781 g, 7.51 mmol), and KCN (978 mg, 15.02
mmol). The title compound (2.15 g, 6.80 mmol, 90%) was obtained
as a slightly yellow solid after purification by flash column
chromatography (Isolera Flash Purification System, cyclohexane/
EtOAc, gradient 0−28%): Rf = 0.63 (cyclohexane/EtOAc, 3:2); IR
(ATR) ν = 3067, 3026, 2926, 2820, 2227, 1620, 1499, 1413, 1326,
1
1166, 1126, 1092, 1019, 882, 753 cm−1; H NMR, COSY (400 MHz,
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-phenylacetonitrile
(2a). Following the general procedure, compound 2a was prepared
from 1,2,3,4-tetrahydroisoquinoline 1a (952 μL, 7.51 mmol),
benzaldehyde (766 μL, 7.51 mmol), NaHSO3 (781 mg, 7.51
mmol), and KCN (978 mg, 15.02 mmol). The crude product was
recrystallized from methanol to afford the title compound (1.54 g,
6.20 mmol, 83%) as colorless crystals: mp 84.9−85.3 °C (lit.22 mp
77−80 °C); Rf = 0.62 (cyclohexane/EtOAc, 3:2); IR (ATR) ν =
3063, 3028, 2922, 2816, 2756, 2227, 1602, 1585, 1495, 1450, 1091,
CDCl3) δ = 7.78 (d, J = 8.3 Hz, 2H, H-2′,6′), 7.70 (d, J = 8.3 Hz,
2H, H-3′,5′), 7.22−7.11 (m, 3H, H-5, H-6, H-7), 7.06−6.97 (m, 1H,
H-8), 5.12 (s, 1H, CHCN), 3.84 (d, J = 14.4 Hz, 1H, H-1), 3.77 (d,
J = 14.4 Hz, 1H, H-1), 3.06−2.88 (m, 2H, 2H-4), 2.90−2.85 (m,
2H, 2H-3) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ
= 137.2 (C1′), 133.6 (C4a), 133.4 (C8a), 131.5 (q, J = 32.9 Hz,
C4′), 128.9 (C5), 128.2 (2C, C2′,6′), 126.7 (C8), 126.6 (C6), 126.1
(C7), 126.0 (q, J = 3.8 Hz, 2C, C3′,5′), 126.0 (q, J = 272.4 Hz,
CF3), 114.8 (CN), 61.9 (C−CN), 52.6 (C1), 47.7 (C3), 29.3 (C4)
ppm; ESI-MS (m/z) 317.1 (100) [M + H]+; ESI-HRMS calcd for
[C18H15F3N2]+ 317.1266, found 317.1275.
1
937, 740, 711 cm−1; H NMR, COSY (400 MHz, CDCl3) δ = 7.66−
7.59 (m, 2H, H-2′6′), 7.49−7.37 (m, 3H, H-3′,5′, H-4′), 7.19−7.09
(m, 3H, H-5, H-6, H-7), 7.05−6.97 (m, 1H, H-8), 5.09 (s, 1H,
CHCN), 3.82 (d, J = 14.4 Hz, 1H, H-1), 3.77 (d, J = 14.4 Hz, H-1),
3.05−2.79 (m, 4H, 2H-3, 2H-4) ppm; 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3) δ = 133.8 (C4a), 133.7 (C8a), 133.1 (C1′),
129.1 (C4′), 129.0 (2C, C3′,5′), 128.8 (C5), 127.9 (2C, C2′,6′),
126.7 (C8), 126.5 (C6), 125.9 (C7), 115.4 (CN), 62.3 (C−CN),
52.5 (C1), 47.6 (C3), 29.4 (C4) ppm; ESI-MS (m/z) 249.1 (100)
[M + H]+; ESI-HRMS calcd for [C17H17N2]+ 249.1392, found
249.1397.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-(4-methoxyphenyl)-
acetonitrile (2e). Following the general procedure, compound 2e
was prepared from 1,2,3,4-tetrahydroisoquinoline 1a (952 μL, 7.51
mmol), p-anisaldehyde (921 μL, 7.51 mmol), NaHSO3 (781 g, 7.51
mmol), and KCN (978 mg, 15.02 mmol). The crude product was
recrystallized from diethyl ether to afford the title compound (1.94 g,
6.97 mmol, 93%) as colorless crystals: mp 98.5−99.1 °C; Rf = 0.56
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3065, 3023, 2932, 2835,
2757, 2225, 1611, 1585, 1511, 1463, 1250, 1176, 1088, 1032, 937,
2-(4-Chlorophenyl)-2-(3,4-dihydroisoquinolin-2(1H)-yl)-
acetonitrile (2b). Following the general procedure, compound 2b
was prepared from 1,2,3,4-tetrahydroisoquinoline 1a (952 μL, 7.51
mmol), p-chlorobenzaldehyde (1.05 g, 7.51 mmol), NaHSO3 (781
mg, 7.51 mmol), and KCN (978 mg, 15.02 mmol). The crude
product was recrystallized from methanol to afford the title
compound (1.91 g, 6.75 mmol, 90%) as colorless crystals: mp
62.5−63.4 °C; Rf = 0.56 (cyclohexane/EtOAc, 3:2); IR (ATR) ν =
3065, 3025, 2922, 2819, 2758, 2228, 1597, 1490, 1090, 1015, 937,
1
839, 799, 741 cm−1; H NMR, COSY (400 MHz, CDCl3) δ = 7.52
(d, J = 8.6 Hz, 2H, H-2′,6′), 7.20−7.07 (m, 3H, H-5, H-6, H-7),
7.03−6.96 (m, 1H, H-8), 6.94 (d, J = 8.6 Hz, 2H, H-3′,5′), 5.03 (s,
1H, CHCN), 3.84 (s, 3H, OCH3-4′), 3.79 (d, J = 14.8 Hz, 1H, H-
1), 3.75 (d, J = 14.8 Hz, 1H, H-1), 3.11−2.68 (m, 4H, 2H-3, 2H-4)
ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 160.3
(C4′), 133.7 (C4a), 133.6 (C8a), 129.4 (2C, C2′,6′), 128.9 (C5),
126.8 (C8), 126.6 (C6), 126.0 (C7), 124.8 (C1′), 115.6 (CN), 114.3
(2C, C3′,5′), 61.7 (C−CN), 55.5 (OMe-4′), 52.4 (C1), 47.6 (C3),
29.3 (C4) ppm; ESI-MS (m/z) 279.1 (100) [M + H]+; ESI-HRMS
calcd for [C18H19N2O]+ 279.1497, found 279.1498.
1
840, 787, 740 cm−1; H NMR, COSY (400 MHz, CDCl3) δ = 7.57
(d, J = 8.4 Hz, 2H, H-2′,6′), 7.41 (d, J = 8.4 Hz, 2H, H-3′,5′), 7.20−
7.09 (m, 3H, H-5, H-6, H-7), 7.02−6.94 (m, 1H, H-8), 5.06 (s, 1H,
CHCN), 3.81 (d, J = 14.4 Hz, 1H, H-1), 3.75 (d, J = 14.4 Hz, 1H,
H-1), 3.04−2.80 (m, 4H, 2H-3, 2H-4) ppm; 13C NMR, HMBC,
HSQC (100.6 MHz, CDCl3) δ = 135.3 (C4′), 133.6 (C4a), 133.3
(C8a), 131.5 (C1′), 129.4 (2C, C2′,6′), 129.3 (2C, C3′,5′), 128.9
(C5), 126.7 (2C, C6, C8), 126.1 (C7), 115.0 (CN), 61.7 (C−CN),
52.5 (C1″), 47.7 (C3), 29.3 (C4) ppm; ESI-MS (m/z) 283.1 (100)
[M + H]+; ESI-HRMS calcd for [C17H16ClN2]+ 283.1002, found
283.1008.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-(4-fluorophenyl)-
acetonitrile (2c). Following the general procedure, compound 2c
was prepared from 1,2,3,4-tetrahydroisoquinoline 1a (952 μL, 7.51
mmol), p-fluorobenzaldehyde (810 μL, 7.51 mmol), NaHSO3 (781 g,
7.51 mmol), and KCN (978 mg, 15.02 mmol). The title compound
(1.88 g, 7.06 mmol, 94%) was obtained as a yellow oil and was used
without further purification: Rf = 0.79 (cyclohexane/EtOAc, 3:2); IR
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-(3,4,5-trimethoxy-
phenyl)acetonitrile (2f). Following the general procedure,
compound 2f was prepared from 1,2,3,4-tetrahydroisoquinoline 1a
(952 μL, 7.51 mmol), 3,4,5-trimethoxybenzaldehyde (1.47 g, 7.51
mmol), NaHSO3 (781 mg, 7.51 mmol), and KCN (978 mg, 15.02
mmol). The crude product was recrystallized from diethyl ether to
afford the title compound (2.03 g, 6.00 mmol, 80%) as colorless
crystals: mp 126.9−127.5 °C; Rf = 0.51 (cyclohexane/EtOAc, 3:2);
IR (ATR) ν = 3065, 3001, 2938, 2835, 2755, 2228, 1691, 1591,
1
1505, 1456, 1331, 1233, 1125, 1051, 935, 842, 741 cm−1; H NMR,
COSY (400 MHz, CDCl3) δ = 7.21−7.10 (m, 3H, H-5, H-6, H-7),
7.06−7.01 (m, 1H, H-8), 6.84 (s, 2H, H-2′,6′), 5.01 (s, 1H, CHCN),
3.88 (s, 6H, OMe-3′,5′), 3.87 (s, 3H, OMe-4′), 3.84 (d, J = 14.7 Hz,
1H, H-1), 3.79 (d, J = 14.7 Hz, 1H, H-1), 3.02−2.85 (m, 3H, 2H-3,
H-4), 2.85−2.74 (m, 1H, H-4) ppm; 13C NMR, HMBC, HSQC
E
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(100.6 MHz, CDCl3) δ = 153.6 (2C, C3′,5′), 138.4 (C4′), 133.8
(C4a), 133.7 (C8a), 128.9 (C5), 128.7 (C1′), 126.7 (C8), 126.6
(C6), 126.0 (C7), 115.5 (CN), 104.7 (2C, C2′,6′), 62.3 (C−CN),
61.0 (OMe-4′), 56.4 (2C, OMe-3′,5′), 52.8 (C1), 47.3 (C3), 29.4
(C4) ppm; ESI-MS (m/z) 206.0 (100) [M − C9H10N]+, 339.1 (38)
[M + H]+; ESI-HRMS calcd for [C20H23N2O3]+ 339.1709, found
339.1711.
339.2 (100) [M + H]+; ESI-HRMS calcd for [C20H23N2O3]+
339.1709, found 339.1712.
2-(2,6-Dichlorophenyl)-2-(3,4-dihydroisoquinolin-2(1H)-yl)-
acetonitrile (2j). Following the general procedure, compound 2j
was prepared from 1,2,3,4-tetrahydroisoquinoline (1a, 952 μL, 7.51
mmol), 2,6-dichlorobenzaldehyde (1.31 g, 7.51 mmol), NaHSO3
(781 g, 7.51 mmol), and KCN (978 mg, 15.02 mmol). The crude
product (1.88 g, 5.93 mmol, 79%) was obtained as a yellow oil and
was used without further purification: Rf = 0.56 (cyclohexane/EtOAc,
3:2); IR (ATR) ν = 3066, 3025, 2922, 2814, 2758, 2243, 1673, 1563,
1202, 1095, 133, 781, 749 cm−1; 1H NMR, COSY (400 MHz,
CDCl3) δ = 7.43−7.38 (m, 2H, H-3′,5′), 7.29 (dd, J = 8.8, 7.3 Hz,
1H, H-4′), 7.15−7.06 (m, 3H, H-5, H-6, H-7), 7.06−6.98 (m, 1H,
H-8), 5.46 (s, 1H, CHCN), 3.96 (d, J = 14.4 Hz, 1H, H-1), 3.85 (d,
J = 14.4 Hz, 1H, H-1), 3.13−2.86 (m, 4H, 2H-3, 2H-4) ppm; 13C
NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 136.6 (2C, C2′,6′),
133.7 (C4a), 133.5 (C8a), 130.9 (C4′), 129.7 (2C, C3′,5′), 129.0
(C1′), 128.8 (C5), 126.8 (C8), 126.6 (C6), 126.0 (C7), 115.5 (CN),
56.7 (C−CN), 52.3 (C1), 48.4 (C3), 29.2 (C4) ppm; ESI-MS (m/z)
317.1 (100) [M + H]+; ESI-HRMS calcd for [C17H15Cl2N2]+
317.0612, found 317.0624.
General Procedure for the Preparation of 2-(Cyano(aryl)-
methyl)-2-alkyl-1,2,3,4-tetrahydroisoquinolin-2-ium Trifluoro-
methanesulfonate (3a−j). Alkyl triflate (1.2−2.0 equiv) was added
to a stirred solution of the corresponding α-aminonitrile 2a−i (1.0
equiv) in dry dichloromethane (6 mL). The stirring was continued at
room temperature for a determined period of time (TLC
monitoring). Removal of the solvent under reduce pressure provided
a crude material which was purified by flash column chromatography
(Isolera Flash Purification System, chloroform/methanol, gradient 0−
16%) to afford the title compouds.
2-(Cyano(phenyl)methyl)-2-methyl-1,2,3,4-tetrahydroiso-
quinolin-2-ium Trifluoromethanesulfonate (3a). According to
the general procedure described above, α-aminonitrile 2a (733 mg,
2.94 mmol) and methyl triflate (387 μL, 3.54 mmol) were allowed
to react overnight in order to obtain compound 3a as a
diastereomeric mixture in a 51:49 ratio (1H NMR) in the form of
a white foam (1.19 g, 2.88 mmol, 98%): Rf = 0.33 (chloroform/
methanol, 10:1); IR (ATR) ν = 3060, 2934, 1588, 1459, 1253, 1224,
1155, 1029, 874, 745, 637 cm−1; (Major diastereomer) 1H NMR,
COSY, NOESY (400 MHz, CDCl3) δ = 7.88 (d, J = 6.8 Hz, 2H, H-
2′,6′), 7.70−7.58 (m, 3H, H-3′,5′ H-4′), 7.41−7.20 (m, 3H, H-5, H-
6, H-7), 7.18 (d, J = 7.6 Hz, 1H, H-8), 6.76 (s, 1H, CHCN), 4.88 (t,
J = 14.7 Hz, 1H, H-1), 4.65 (dd, J = 14.7, 1.8 Hz, 1H, H-1), 4.09−
3.97 (m, 1H, H-3), 3.94−3.86 (m, 1H, H-3), 3.39−3.25 (m, 2H, H-
4), 3.28 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6
MHz, CDCl3) δ = 133.4 (C4′), 132.6 (2C, C2′,6′), 130.4 (2C,
C3′,5″), 129.9 (C5), 129.1 (C6), 128.5 (C7), 128.0 (C4a), 127.7
(C8), 124.5 (C8a), 123.8 (q, J = 319.6 Hz, OTf), 123.3 (C1′), 112.8
(CN), 68.6 (C−CN), 60.4 (C1), 56.4 (C3), 44.0 (N−Me), 23.9
(C4) ppm; (Minor diastereomer) 1H NMR, COSY, NOESY (400
MHz, CDCl3) δ = 7.85 (d, J = 6.8 Hz, 2H, H-2′,6′), 7.70−7.58 (m,
3H, H-3′,5′ H-4′), 7.41−7.21 (m, 3H, H-5, H-6, H-7), 7.15 (d, J =
7.6 Hz, 1H, H-8), 6.65 (s, 1H, CHCN), 4.88 (t, J = 14.7 Hz, 1H, H-
1), 4.54 (dd, J = 14.7, 1.2 Hz, 1H, H-1), 4.28−4.15 (m, 1H, H-3),
3.88−3.75 (m, 1H, H-3), 3.39−3.25 (m, 2H, H-4), 3.26 (s, 3H, N−
Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ =
133.3 (C4′), 132.5 (2C, C2′,6′), 130.4 (2C, C3′,5′), 129.8 (C5),
129.2 (C6), 128.5 (C7), 127.9 (C4a), 127.8 (C8), 124.5 (C8a),
123.8 (q, J = 319.6 Hz, OTf), 123.1 (C1′), 112.7 (CN), 67.7 (C−
CN), 60.2 (C1), 57.0 (C3), 44.4 (N−Me), 23.9 (C4) ppm; ESI-MS
(m/z) 263.1 (100) [M]+; ESI-HRMS calcd for [C18H20N2]+
264.1626, found 264.1617.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-(thiophen-2-yl)aceto-
nitrile (2g). Following the general procedure, compound 2g was
prepared from 1,2,3,4-tetrahydroisoquinoline 1a (952 μL, 7.51
mmol), 2-thiophene carbaldehyde (702 μL, 7.51 mmol), NaHSO3
(781 g, 7.51 mmol), and KCN (978 g, 15.02 mmol). The crude
product was recrystallized from methanol to afford the title
compound (1.66 g, 6.53 mmol, 87%) as a slightly yellow solid:
mp 79.6−80.2 °C; Rf = 0.62 (cyclohexane/EtOAc, 3:2); IR (ATR) ν
= 3066, 3024, 2922, 2819, 2756, 2229, 1584, 1498, 1455, 1355, 1267,
1
1139, 1088, 934, 844, 739, 703 cm−1; H NMR, COSY (400 MHz,
CDCl3) δ = 7.38 (d, J = 5.2 Hz, 1H, H-5′), 7.38−7.32 (m, 1H, H-
3′), 7.21−7.09 (m, 3H, H-5, H-6, H-7), 7.07−6.99 (m, 2H, H-4′, H-
8), 5.23 (s, 1H, CHCN), 3.88 (t, 2H, 2H-1), 3.06−2.93 (m, 3H, 2H-
3, H-4), 2.90−2.75 (m, 1H, H-4) ppm; 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3) δ = 137.0 (C2′), 133.7 (C4a), 133.2 (C8a),
128.9 (C5), 127.7 (C5′), 127.5 (C3′), 126.9 (C4′), 126.7 (2C, C6,
C8), 126.1 (C7), 114.8 (CN), 58.0 (C−CN), 52.7 (C1), 47.4 (C3),
29.3 (C4) ppm; ESI-MS (m/z) 255.1 (100) [M + H]+; ESI-HRMS
calcd for [C15H15N2S]+ 255.0956, found 255.0957.
2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-
phenylacetonitrile (2h). Following the general procedure with a
subtle modification, compound 2h was prepared from 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline 1b (1.00 g, 5.17 mmol, dissolved in 3
mL of methanol before addition), benzaldehyde (527 μL, 5.17
mmol), NaHSO3 (538 mg, 5.17 mmol), and KCN (673 mg, 10.34
mmol). The crude product was recrystallized from diethyl ether to
afford the title compound (1.30 g, 4.21 mmol, 82%) as colorless
crystals: mp 101.6−102.3 °C; Rf = 0.38 (cyclohexane/EtOAc, 3:2);
IR (ATR) ν = 3062, 2998, 2935, 2835, 2225, 1611, 1517, 1463,
1
1257, 1223, 1124, 1013, 980, 855, 726, 697 cm−1; H NMR, COSY
(400 MHz, CDCl3) δ = 7.65−7.57 (m, 2H, H-2′,6′), 7.48−7.37 (m,
3H, H-3′,5′, H-4′), 6.60 (s, 1H, H-5), 6.48 (s, 1H, H-8), 5.07 (s, 1H,
CHCN), 3.84 (s, 3H, OMe-6), 3.81 (s, 3H, OMe-7), 3.72 (d, J =
14.0 Hz, 1H, H-1), 3.67 (d, J = 14.0 Hz, 1H, H-1), 2.95−2.76 (m,
4H, 2H-3, 2H-4) ppm; 13C NMR, HMBC, HSQC (100.6 MHz,
CDCl3) δ = 147.8 (C6), 147.5 (C7), 133.1 (C1′), 129.1 (C4′),
129.0 (2C, C3',5'), 128.0 (2C, C2',6'), 125.6 (C4a), 125.4 (C8a),
115.5 (CN), 111.5 (C5), 109.5 (C8), 62.3 (C−CN), 56.0 (2C,
OMe-6, OMe-7), 52.0 (C1), 47.9 (C3), 29.0 (C4) ppm; ESI-MS
(m/z) 309.1 (100) [M + H]+; ESI-HRMS calcd for [C19H21N2O2]+
309.1603, found 309.1613.
2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-
methoxyphenyl)acetonitrile (2i). Following the general procedure
with a subtle modification, compound 2i was prepared from 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline 1b (979 mg, 5.07 mmol,
dissolved in 3 mL of methanol before addition), p-anisaldehyde (622
μL, 5.07 mmol), NaHSO3 (527 mg, 5.07 mmol), and KCN (660 g,
10.14 mmol). The crude product was recrystallized from diethyl
ether to afford the title compound (1.44 g, 4.26 mmol, 84%) as
colorless crystals: mp 117.3−117.7 °C; Rf = 0.39 (cyclohexane/
EtOAc, 3:2); IR (ATR) ν = 3059, 2999, 2935, 2836, 2226, 1611,
1585, 1511, 1463, 1250, 1223, 1175, 1123, 1030, 940, 819, 780, 733
1
cm−1; H NMR, COSY (400 MHz, CDCl3) δ = 7.51 (d, J = 8.6 Hz,
2H, H-2′, 6′), 6.94 (d, J = 8.8 Hz, 2H, H-3′,5′), 6.60 (s, 1H, H-5),
6.48 (s, 1H, H-8), 5.01 (s, 1H, CHCN), 3.84 (s, 3H, OMe-6), 3.83
(s, 3H, OMe-7), 3.81 (s, 3H, OMe-4′), 3.70 (d, J = 14.0 Hz, 1H, H-
1), 3.65 (d, J = 14.0 Hz, 1H, H-1), 2.99−2.71 (m, 4H, 2H-3, 2H-4)
ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 160.2
(C4′), 147.8 (C6), 147.5 (C7), 129.3 (2C, C2′,6′), 125.6 (C4a),
125.4 (C8a), 125.0 (C1′), 115.7 (CN), 114.3 (2C, C3′,5′), 111.4
(C5), 109.5 (C8), 61.7 (C−CN), 56.0 (2C, OMe-6, OMe-7), 55.5
(OMe-4′), 51.9 (C1), 47.8 (C3), 28.9 (C4) ppm; ESI-MS (m/z)
2-((4-Chlorophenyl)(cyano)methyl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-2-ium Trifluoromethanesulfonate (3b). Ac-
cording to the general procedure described above, α-aminonitrile 2b
(1.00 g, 3.54 mmol) and methyl triflate (463 μL, 4.24 mmol) were
allowed to react overnight in order to obtain compound 3b as a
diastereomeric mixture in a 52:48 ratio (1H NMR) in the form of a
white foam (1.52 g, 3.40 mmol, 96%): Rf = 0.37 (chloroform/
F
dx.doi.org/10.1021/jo500749x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
methanol, 10:1); IR (ATR) ν = 3057, 2933, 1596, 1495, 1251, 1156,
1), 4.66 (dd, J = 14.7, 2.4 Hz, 1H, H-1), 4.03−3.93 (m, 1H, H-3),
3.94−3.81 (m, 1H, H-3), 3.37−3.21 (m, 2H, H-4), 3.23 (s, 3H, N−
Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ =
135.0 (q, J = 33.1 Hz, C4′), 133.2 (2C, C2′,6′), 129.9 (C5), 129.1
(C6), 128.4 (C7), 128.0 (C4a), 127.8 (C8), 127.3 (q, J = 4.0 Hz,
2C, C3′,5′), 127.1 (C1′), 124.4 (C8a), 123.2 (q, J = 273.2 Hz, CF3),
120.6 (q, J = 319.6 Hz, OTf), 112.3 (CN), 66.8 (C−CN), 60.9
(C1), 57.4 (C3), 44.3 (N−Me), 23.8 (C4) ppm; (Minor
diastereomer) 1H NMR, COSY, NOESY (400 MHz, CDCl3) δ =
8.04 (d, J = 8.3 Hz, 2H, H-2′,6′), 7.84 (d, J = 8.3 Hz, 2H, H-3′,5′),
7.39−7.19 (m, 3H, H-5, H-6, H-7), 7.16 (d, J = 7.6 Hz, 1H, H-8),
6.81 (s, 1H, CHCN), 4.89 (t, J = 14.7 Hz, 1H, H-1), 4.51 (dd, J =
14.7, 2.4 Hz, 1H, H-1), 4.21−3.11 (m, 1H, H-3), 3.94−3.81 (m, 1H,
H-3), 3.37−3.21 (m, 2H, H-4), 3.25 (s, 3H, N−Me) ppm; 13C
NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 135.0 (q, J = 33.1
Hz, C4′), 133.3 (2C, C2′,6′), 129.8 (C5), 129.0 (C6), 128.3 (C7),
127.9 (C4a), 127.7 (C8), 127.3 (q, J = 4.0 Hz, 2C, C3′,5′), 127.0
(C1′), 124.3 (C8a), 123.2 (q, J = 273.2 Hz, CF3), 120.6 (q, J =
319.6 Hz, OTf), 112.2 (CN), 67.6 (C−CN), 60.8 (C1), 57.7 (C3),
44.1 (N−Me), 23.8 (C4) ppm; ESI-MS (m/z) 331.2 (100) [M]+;
ESI-HRMS calcd for [C19H18F3N2]+ 331.1422, found 331.1431.
2-(Cyano(4-methoxyphenyl)methyl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-2-ium Trifluoromethanesulfonate (3e). Ac-
cording to the general procedure described above, α-aminonitrile 2e
(1.00 g, 3.59 mmol) and methyl triflate (471 μL, 4.31 mmol) were
allowed to react overnight in order to obtain compound 3e as a
diastereomeric mixture in a 52:48 ratio (1H NMR) in the form of a
white foam (1.60 g, 3.58 mmol, 99%): Rf = 0.37 (chloroform/
methanol, 10:1); IR (ATR) ν = 3041, 2938, 2844, 1609, 1515, 1254,
1157, 1028, 842, 755, 637 cm−1; (Major diastereomer) 1H NMR,
COSY, NOESY (400 MHz, CDCl3) δ = 7.77 (d, J = 8.8 Hz, 2H, H-
2′,6′), 7.41−7.21 (m, 3H, H-5, H-6, H-7), 7.15 (d, J = 7.7 Hz, 1H,
H-8), 6.61 (s, 1H, CHCN), 4.85 (t, J = 14.7 Hz, 1H, H-1), 4.50 (dd,
J = 14.7, 1.6 Hz, 1H, H-1), 4.03−3.94 (m, 1H, H-3), 3.93−3.82 (m,
1H, H-3), 3.87 (s, 3H, OMe-4′), 3.35−3.24 (m, 2H, H-4), 3.25 (s,
3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
δ = 163.3 (C4′), 134.3 (2C, C2′,6′), 129.9 (C-5), 129.2 (C6), 128.5
(C7), 128.1 (C4a), 127.8 (C8), 124.7 (C8a), 120.7 (q, J = 319.3 Hz,
OTf), 115.7 (2C, C3′,5′), 114.7 (C-1′), 112.9 (CN), 67.7 (C−CN),
59.7 (C1), 55.9 (2C, C3, OMe-4′), 44.1 (N−Me), 23.9 (C4) ppm;
1
1028, 875, 754, 637 cm−1; (Major diastereomer) H NMR, COSY,
NOESY (400 MHz, CDCl3) δ = 7.85 (d, J = 8.6 Hz, 2H, H-2′,6′),
7.58 (d, J = 8.6 Hz, 2H, H-3′,5′), 7.41−7.21 (m, 3H, H-5, H-6, H-
7), 7.14 (d, J = 7.6 Hz, 1H, H-8), 6.73 (s, 1H, CHCN), 4.91 (d, J =
14.5 Hz, 1H, H-1), 4.50 (dd, J = 14.5, 2.3 Hz, 1H, H-1), 4.04−3.95
(m, 1H, H-3), 3.93−3.78 (m, 1H, H-3), 3.36−3.25 (m, 2H, H-4),
3.25 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz,
CDCl3) δ = 140.2 (C4′), 133.7 (2C, C2′,6′), 130.7 (2C, C3′,5′),
129.9 (C5), 129.2 (C6), 128.5 (C7), 127.9 (C4a), 127.8 (C8), 124.4
(C8a), 121.6 (C1′), 120.6 (q, J = 319.7 Hz, OTf), 112.5 (CN), 67.0
(C−CN), 60.4 (C1), 57.1 (C3), 44.2 (N−Me), 23.8 (C4) ppm;
1
(Minor diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3)
δ = 7.84 (d, J = 8.6 Hz, 2H, H-2′,6′), 7.58 (d, J = 8.6 Hz, 2H, H-
3′,5′), 7.41−7.21 (m, 3H, H-5, H-6, H-7), 7.17 (d, J = 7.6 Hz, 1H,
H-8), 6.80 (s, 1H, CHCN), 4.85 (d, J = 14.5 Hz, 1H, H-1), 4.64
(dd, J = 14.5, 2.0 Hz, 1H, H-1), 4.21−4.12 (m, 1H, H-3), 3.93−3.78
(m, 1H, H-3), 3.36−3.25 (m, 2H, H-4), 3.25 (s, 3H, N−Me) ppm;
13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 140.1 (C4′),
134.0 (2C, C2′,6′), 130.7 (2C, C3′,5′), 129.8 (C5), 129.1 (C6),
128.4 (C7), 128.0 (C4a), 127.9 (C8), 124.5 (C8a), 121.8 (C1′),
120.6 (q, J = 319.7 Hz, OTf), 112.5 (CN), 67.8 (C−CN), 60.5
(C1), 56.4 (C3), 43.9 (N−Me), 23.9 (C4) ppm; ESI-MS (m/z)
297.1 (100) [M]+; ESI-HRMS calcd for [C18H18ClN2]+ 297.1159,
found 297.1164.
2-(Cyano(4-fluorophenyl)methyl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-2-ium Trifluoromethanesulfonate (3c). Ac-
cording to the general procedure described above, α-aminonitrile 2c
(1.23 g, 4.62 mmol) and methyl triflate (606 μL, 5.54 mmol) were
allowed to react overnight in order to obtain compound 3c as a
diastereomeric mixture in a 52:48 ratio (1H NMR) in the form of a
slightly yellow foam (1.86 g, 4.32 mmol, 94%): Rf = 0.37
(chloroform/methanol, 10:1); IR (ATR) ν = 3071, 2933, 1606,
1512, 1250, 1164, 1029, 845, 755, 637 cm−1; (Major diastereomer)
1H NMR, COSY, NOESY (400 MHz, CDCl3) δ = 7.94−7.82 (m,
2H, H-2′,6′), 7.35−7.18 (m, 5H, H-5, H-6, H-7, H-3′,5′), 7.11 (d, J
= 7.5 Hz, 1H, H-8), 6.59 (s, 1H, CHCN), 4.84 (t, J = 13.9 Hz, 1H,
H-1), 4.46 (dd, J = 13.9, 2.2 Hz, 1H, H-1), 4.15−4.05 (m, 1H, H-3),
3.98−3.75 (m, 1H, H-3), 3.35−3.23 (m, 2H, H-4), 3.17 (s, 3H, N−
Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ =
165.3 (d, J = 256.5 Hz, C4′), 134.9 (d, J =9.3 Hz, 2C, C2′,4′), 129.7
(C5), 129.1 (C6), 128.3 (C7), 128.1 (C4a), 127.7 (C8), 124.5
(C8a), 120.6 (q, J = 319.7 Hz, OTf), 119.2 (d, J = 3.4 Hz, C1′),
117.7 (d, J = 22.3 Hz, 2C, C3′,5″), 112.6 (CN), 66.9 (C−CN), 60.5
(C1), 57.0 (C3), 44.0 (N−Me), 23.7 (C4) ppm; (Minor
diastereomer) 1H NMR, COSY, NOESY (400 MHz, CDCl3) δ =
7.94−7.82 (m, 2H, H-2′,6′), 7.35−7.18 (m, 5H, H-5, H-6, H-7, H-
3′,5′), 7.15 (d, J = 7.5 Hz, 1H, H-8), 6.66 (s, 1H, CHCN), 4.84 (t, J
= 13.9 Hz, 1H, H-1), 4.62 (dd, J = 13.9, 2.3 Hz, 1H, H-1), 3.98−
3.75 (m, 2H, H-3), 3.35−3.23 (m, 2H, H-4), 3.20 (s, 3H, N−Me)
ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 165.3 (d,
J = 256.5 Hz, C-4′), 134.1 (d, J =9.3 Hz, 2C, C2′,6′), 129.6 (C5),
129.0 (C6), 128.3 (C7), 128.2 (C4a), 127.8 (C8), 124.6 (C8a),
120.6 (q, J = 319.7 Hz, OTf), 119.3 (d, J = 3.4 Hz, C1′), 117.7 (d, J
= 22.3 Hz, 2C, C3′,5′), 112.5 (CN), 67.7 (C−CN), 60.6 (C1), 56.2
(C3), 43.8 (N−CH3), 23.7 (C4) ppm; ESI-MS (m/z) 281.1 (100)
[M]+; ESI-HRMS calcd for [C18H18FN2]+ 281.1454, found 281.1452.
2-(Cyano(4-(trifluoromethyl)phenyl)methyl)-2-methyl-
1,2,3,4-tetrahydroisoquinolin-2-ium Trifluoromethane-
sulfonate (3d). According to the general procedure described
above, α-aminonitrile 2d (1.00 g, 3.16 mmol) and methyl triflate
(415 μL, 3.79 mmol) were allowed to react overnight in order to
obtain compound 3d as a diastereomeric mixture in a 51:49 ratio
(1H NMR) and in the form of a white foam (1.38 g, 2.87 mmol,
91%): Rf = 0.39 (chloroform/methanol, 10:1); IR (ATR) ν = 3037,
2935, 2253, 1501, 1457, 1326, 1251, 1164, 1133, 1070, 1029, 851,
1
(Minor diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3)
δ = 7.80 (d, J = 8.9 Hz, 2H, H-2′,6′), 7.41−7.21 (m, 3H, H-5, H-6,
H-7), 7.17 (d, J = 7.9 Hz, 1H, H-8), 6.71 (s, 1H, CHCN), 4.85 (t, J
= 14.7 Hz, 1H, H-1), 4.60 (dd, J = 14.7, 1.9 Hz, 1H, H-1), 4.23−
4.12 (m, 1H, H-3), 3.83−3.71 (m, 1H, H-3), 3.87 (s, 3H, OMe-4′),
3.35−3.24 (m, 2H, H-4), 3.23 (s, 3H, N−Me) ppm; 13C NMR,
HMBC, HSQC (100.6 MHz, CDCl3) δ = 163.3 (C-4′), 134.1 (2C,
C2′,6′), 129.8 (C5), 129.1 (C6), 128.4 (C7), 128.0 (C4a), 127.9
(C8), 124.7 (C8a), 120.7 (q, J = 319.3 Hz, OTf), 115.7 (2C,
C3′,5′), 114.5 (C-1′), 112.9 (CN), 68.5 (C−CN), 60.0 (C1), 56.5
(C3, OMe-4′), 55.9 (OCH3-4′), 43.6 (N−Me), 24.0 (C-4) ppm;
ESI-MS (m/z) 293.2 (100) [M]+; ESI-HRMS calcd for
[C19H21N2O]+ 293.1654, found 293.1653.
2-(Cyano(3,4,5-trimethoxyphenyl)methyl)-2-methyl-1,2,3,4-
tetrahydroisoquinolin-2-ium (3f). According to the general
procedure described above, α-aminonitrile 2f (500 mg, 1.47 mmol)
and methyl triflate (192 μL, 4.31 mmol) were allowed to react
overnight in order to obtain compound 3f as a diastereomeric
mixture in a 51:49 ratio (1H NMR) in the form of a white foam
(708 mg, 1.41 mmol, 96%): Rf = 0.46 (chloroform/methanol, 10:1);
IR (ATR) ν = 3058, 2943, 2843, 1593, 1508, 1466, 1246, 1126,
1
1028, 829, 732, 636 cm−1; (Major diastereomer) H NMR, COSY,
NOESY (400 MHz, CDCl3) δ = 7.39−7.19 (m, 3H, H-5, H-6, H-7),
7.15 (t, J = 7.2 Hz, 1H, H-8), 7.03 (s, 2H, H-2′H-6′), 6.59 (s, 1H,
CHCN), 4.84 (d, J = 14.7 Hz, 1H, H-1), 4.67 (dd, J = 14.7, 2.1 Hz,
1H, H-1), 4.21−4.11 (m, 1H, H-3), 4.02−3.76 (m, 1H, H-3), 3.91
(s, 6H, OMe-3″,5′), 3.87 (s, 3H, OMe-4′), 3.34−3.26 (m, 2H, H-4),
3.26 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz,
CDCl3) δ = 154.3 (2C, C3′,5′), 141.8 (C4′), 129.7 (C5), 129.0
(C6), 128.2 (C7), 128.1 (C4a), 127.8 (C8), 124.7 (C8a), 120.6 (q, J
1
756, 638 cm−1; (Major diastereomer) H NMR, COSY, NOESY (400
MHz, CDCl3) δ = 8.07 (d, J = 8.3 Hz, 2H, H-2′,6′), 7.84 (d, J = 8.3
Hz, 2H, H-3′,5′), 7.39−7.19 (m, 3H, H-5, H-6, H-7), 7.13 (d, J =
7.6 Hz, 1H, H-8), 6.74 (s, 1H, CHCN), 4.89 (t, J = 14.7 Hz, 1H, H-
G
dx.doi.org/10.1021/jo500749x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 319.9 Hz, OTf), 118.0 (C1′), 112.9 (CN), 109.8 (2C, C2′,6′),
69.0 (C−CN), 61.0 (2C, OMe-3′,5′), 60.3 (C1), 56.8 (Me-4″), 56.1
1H, CHCN), 4.79 (d, J = 14.4 Hz, 1H, H-1), 4.42 (d, J = 14.4 Hz,
1H, H-1), 4.0−3.90 (m, 1H, H-3), 3.83 (s, 3H, OMe-6), 3.82−3.67
(m, 1H, H-3), 3.81 (s, 3H, OMe-7), 3.29−3.12 (m, 2H, H-4), 3.22
(s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz,
CDCl3) δ = 150.1 (C6), 149.1 (C7), 133.2 (C4′), 132.4 (2C,
C2′,6′), 130.3 (2C, C3′,5′), 123.2 (C1′), 120.6 (q, J = 319.8 Hz,
OTf), 120.1 (C4a), 116.2 (C8a), 112.7 (CN), 111.0 (C5), 109.7
(C8), 67.4 (C−CN), 60.1 (C1), 56.5 (C3), 56.2 (2C, OMe-6, OMe-
7), 44.2 (N−Me), 23.6 (C4) ppm; ESI-MS (m/z) 323.2 (100) [M]+;
ESI-HRMS calcd for [C20H23N2O2]+ 323.1760, found 323.1764.
2-(Cyano(4-methoxyphenyl)methyl)-6,7-dimethoxy-2-meth-
yl-1,2,3,4-tetrahydroisoquinolin-2-ium Trifluoromethane-
sulfonate (3i). According to the general procedure described
above, α-aminonitrile 2i (500 mg, 1.48 mmol) and methyl triflate
(194 μL, 1.77 mmol) were allowed to react overnight in order to
obtain compound 3i as a diastereomeric mixture in a 51:49 ratio (1H
NMR) in the form of a white foam (650 mg, 1.47 mmol, 99%): Rf =
0.48 (chloroform/methanol, 10:1); IR (ATR) ν = 3008, 2940, 2842,
1610, 1520, 1467, 1258, 1159, 1120, 1029, 842, 811, 638 cm−1;
1
(C3), 44.0 (N−Me), 23.8 (C4) ppm; (Minor diastereomer) H NMR,
COSY, NOESY (400 MHz, CDCl3) δ = 7.39−7.19 (m, 3H, H-5, H-
6, H-7), 7.15 (t, J = 7.2 Hz, 1H, H-8), 7.07 (s, 2H, H-2′,6′), 6.49 (s,
1H, CHCN), 4.91 (d, J = 14.8 Hz, 1H, H-1), 4.50 (dd, J = 14.8, 1.9
Hz, 1H, H-1), 4.02−3.76 (m, 2H, H-3), 3.90 (s, 6H, OMe-3′,5′),
3.88 (s, 3H, OMe-4′), 3.34−3.26 (m, 2H, H-4), 3.25 (s, 3H, N−Me)
ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 154.3
(2C, C3′,5′), 141.8 (C4′), 129.8 (C5), 129.1 (C6), 128.3 (C7),
128.0 (C4a), 127.7 (C8), 124.7 (C8a), 120.6 (q, J = 319.9 Hz, OTf),
117.9 (C1′), 112.7 (CN), 109.8 (2C, C2′, C6′), 68.0 (C−CN), 61.1
(2C, OMe-3′,5′), 60.6 (C-1), 56.9 (OMe-4′), 57.1 (C3), 44.3 (N−
Me), 23.8 (C4) ppm; ESI-MS (m/z) 206.0 (100) [M − C10H13N]+,
353.2 (89) [M]+; ESI-HRMS calcd for [C21H25N2O3]+ 353.1865,
found 353.1864.
2-(Cyano(thiophen-2-yl)methyl)-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-2-ium Trifluoromethanesulfonate (3g). Ac-
cording to the general procedure described above, α-aminonitrile 2g
(501 mg, 1.97 mmol) and methyl triflate (258 μL, 2.36 mmol) were
allowed to react overnight in order to obtain compound 3g as a
diastereomeric mixture in a 53:47 ratio (1H NMR) in the form of a
brown foam (768 mg, 1.83 mmol, 93%): Rf = 0.43 (chloroform/
methanol, 10:1); IR (ATR) ν = 3090, 2921, 1476, 1422, 1248, 1155,
1
(Major diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3)
δ = 7.75 (d, J = 9.0 Hz, 2H, H-2′,6′), 7.06 (dd, J = 9.0, 2.3 Hz, 2H,
H-3′,5′), 6.67 (s, 1H, H-5), 6.59 (s, 1H, H-8), 6.56 (s, 1H, CHCN),
4.78 (t, J = 14.5 Hz, 1H, H-1), 4.41 (d, J = 14.5 Hz, 1H, H-1),
4.14−4.05 (m, 1H, H-3), 3.82−3.65 (m, 1H, H-3), 3.86 (s, 3H,
OMe-6), 3.85 (s, 3H, OMe-7), 3.83 (s, 3H, OMe-4′), 3.31−3.12 (m,
2H, H-4), 3.21 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3) δ = 163.2 (C-4′), 150.1 (C6), 149.2 (C7),
134.1 (2C, C2′, C6′), 120.7 (q, J = 319.7 Hz, OTf), 120.1 (C4a),
116.4 (C8a), 115.7 (2C, C3′, C5′), 114.6 (C1′), 112.9 (CN), 111.0
(C5), 109.7 (C8), 67.3 (C−CN), 59.6 (C1), 56.6 (C3), 56.2 (2C,
OMe-6, OMe-7), 55.8 (OMe-4′), 43.9 (N−Me), 23.6 (C4) ppm;
1
1028, 845, 730, 636 cm−1; (Major diastereomer) H NMR, COSY,
NOESY (400 MHz, CDCl3) δ = 7.82 (dd, J = 3.7, 1.2 Hz, 1H, H-
5′), 7.73 (d, J = 1,2 Hz, 1H, H-3′), 7.38−7.20 (m, 4H, H-4′, H-5, H-
6, H-7), 7.13 (d, J = 7.6 Hz, 1H, H-8), 7.03 (s, 1H, CHCN), 4.94
(d, J = 14.9 Hz, 1H, H-1), 4.52 (dd, J = 14.9, 2.2 Hz, 1H, H-1),
4.03−3.81 (m, 2H, H-3), 3.43−3.25 (m, 2H, H-4), 3.27 (s, 3H, N−
Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ =
137.4 (C5′), 133.4 (C3′), 129.9 (C5), 129.1 (2C, C6, C4′), 128.4
(C7), 128.2 (C4a), 127.8 (C8), 124.5 (C8a), 123.4 (C2′), 120.6 (q,
J = 319.8 Hz, OTf), 112.3 (CN), 62.9 (C−CN), 60.2 (C1), 56.9
1
(Minor diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3)
δ = 7.79 (d, J = 9.0 Hz, 2H, H-2′,6′), 7.06 (dd, J = 9.0, 2.3 Hz, 2H,
H-3′,5′), 6.66 (s, 1H, H-5), 6.64 (s, 1H, CHCN), 6.52 (s, 1H, H-8),
4.78 (t, J = 14.5 Hz, 1H, H-1), 4.52 (dd, J = 14.5, 2.3 Hz, 1H, H-1),
4.00−3.87 (m, 1H, H-3), 3.82−3.65 (m, 1H, H-3), 3.86 (s, 3H,
OMe-6), 3.85 (s, 3H, OMe-7), 3.83 (s, 3H, OMe-4′), 3.31−3.12 (m,
2H, H-4), 3.22 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3) δ = 163.3 (C4′), 150.2 (C6), 149.3 (C7),
134.2 (2C, C2′,6′), 120.7 (q, J = 319.7 Hz, OTf), 119.9 (C4a), 116.5
(C8a), 115.7 (2C, C3′, C5′), 114.8 (C1′), 113.0 (CN), 110.9 (C5),
109.8 (C8), 68.3 (C−CN), 59.8 (C1), 55.9 (C3), 56.2 (2C, OMe-6,
OMe-7), 55.8 (OMe-4′), 43.5 (N−Me), 23.7 (C4) ppm; ESI-MS
(m/z) 353.2 (100) [M]+; ESI-HRMS calcd for [C21H25N2O3]+
353.1865, found 353.1864.
1
(C3), 44.0 (N−Me), 23.9 (C4) ppm; (Minor diastereomer) H NMR,
COSY, NOESY (400 MHz, CDCl3) δ = 7.84 (dd, J = 3.7, 1.2 Hz,
1H, H-5′), 7.74 (d, J = 1,2 Hz, 1H, H-3′), 7.38−7.20 (m, 4H, H-4′,
H-5, H-6, H-7), 7.17 (d, J = 7.6 Hz, 1H, H-8), 7.10 (s, 1H, CHCN),
4.89 (d, J = 14.9 Hz, 1H, H-1), 4.69 (dd, J = 14.9, 2.2 Hz, 1H, H-1),
4.24−4.11 (m, 1H, H-3), 4.03−3.81 (m, 1H, H-3), 3.43−3.25 (m,
2H, H-4), 3.28 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3) δ = 137.7 (C5′), 133.5 (C3′), 129.7 (C5),
129.2 (2C, C6, C4′), 128.3 (C7), 128.1 (C4a), 127.8 (C7), 124.6
(C8a), 123.5 (C2′), 120.6 (q, J = 319.8 Hz, OTf), 112.2 (CN), 63.7
(C−CN), 60.5 (C1), 56.1 (C3), 44.0 (N−Me), 23.9 (C4) ppm; ESI-
MS (m/z) 269.1 (100) [M]+; ESI-HRMS calcd for [C16H17N2S]+
269.1112, found 269.1105.
2-Butyl-2-(cyano(4-methoxyphenyl)methyl)-1,2,3,4-tetra-
hydroisoquinolin-2-ium Trifluoromethanesulfonate (3j). Ac-
cording to the general procedure described above, α-aminonitrile 2e
(1.00 g, 3.59 mmol) and butyl triflate (1.48 g, 7.18 mmol) were
allowed to react over 3 days in order to obtain compound 3j as a
diastereomeric mixture in a 52:48 ratio (1H NMR) in the form of a
slightly yellow foam (463 mg, 955 μmol, 27%): Rf = 0.41
(chloroform/methanol, 10:1); IR (ATR) ν = 3062, 2965, 2878,
2845, 1608, 1515, 1225, 1156, 1029, 838, 754, 637 cm−1; (Major
2-(Cyano(phenyl)methyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinolin-2-ium Trifluoromethanesulfonate (3h).
According to the general procedure described above, α-aminonitrile
2h (848 mg, 2.75 mmol) and methyl triflate (361 μL, 3.30 mmol)
were allowed to react overnight in order to obtain compound 3h as a
diastereomeric mixture in a 51:49 ratio (1H NMR) in the form of a
slightly yellow foam (1.28 g, 2.71 mmol, 98%): Rf = 0.37
(chloroform/methanol, 10:1); IR (ATR) ν = 3061, 2940, 2841,
1613, 1521, 1461, 1252, 1157, 1119, 1028, 730, 700, 636 cm−1;
1
diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3) δ = 7.77
(d, J = 8.9 Hz, 2H, H-2′,6′), 7.39−7.16 (m, 4H, H-5, H-6, H-7, H-
8), 7.05 (d, J = 8.9 Hz, 2H, H-3′,5′), 6.45 (s, 1H, CHCN), 4.70 (d, J
= 15.0 Hz, 1H, H-1), 4.53 (dd, J = 15.0, 2.1 Hz, 1H, H-1), 4.35−
4.24 (m, 1H, H-3), 3.84 (s, 3H, OMe-4′), 3.76−3.54 (m, 1H, H-3),
3.48−3.14 (m, 4H, 2H-4, 2H-1″), 2.18−1.85 (m, 2H, H-2″), 1.39−
1.17 (m, 2H, H-3″), 0.94 (t, J = 7.4 Hz, 3H, H-4″) ppm; 13C NMR,
HMBC, HSQC (100.6 MHz, CDCl3) δ = 163.2 (C-4′), 134.1 (2C,
C2′,6′), 129.7 (C5), 129.1 (C6), 128.5 (C7), 128.3 (C4a), 127.8
(C8), 124.7 (C8a), 120.8 (q, J = 319.8 Hz, OTf), 115.7 (2C,
C3′,5′), 114.5 (C1′), 113.0 (CN), 65.2 (C−CN), 58.7 (C1), 57.9
(C1″), 55.8 (OMe-4″), 53.7 (C3), 24.4 (C2″), 19.8 (C3″), 13.3
(C4″) ppm; (Minor diastereomer) 1H NMR, COSY, NOESY (400
MHz, CDCl3) δ = 7.83 (d, J = 8.8 Hz, 2H, H-2′,6′), 7.39−7.16 (m,
4H, H-5, H-6, H-7, H-8), 7.05 (d, J = 8.8 Hz, 2H, H-3′,5′), 6.52 (s,
1H, CHCN), 4.76 (dd, J = 15.3, 2.4 Hz, 1H, H-1), 4.54 (d, J = 15.3
1
(Major diastereomer) H NMR, COSY, NOESY (400 MHz, CDCl3)
δ = 7.85 (d, J = 7.3 Hz, 2H, H-2′,6′), 7.66−7.53 (m, 3H, H-3′,5′, H-
4′), 6.86 (s, 1H, H-5), 6.63 (s, 1H, CHCN), 6.59 (s, 1H, H-8), 4.79
(d, J = 14.4 Hz, 1H, H-1), 4.54 (d, J = 14.4 Hz, 1H, H-1), 4.10−
4.05 (m, 1H, H-3), 3.82−3.67 (m, 1H, H-3), 3.82 (s, 3H, OMe-6),
3.80 (s, 3H, OMe-7), 3.29−3.12 (m, 2H, H-4), 3.22 (s, 3H, N−Me)
ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ = 150.0
(C6), 149.2 (C7), 133.2 (C4′), 132.6 (2C, C2′,6′), 130.3 (2C,
C3′,5′), 123.3 (C-1′), 120.6 (q, J = 319.8 Hz, OTf), 120.0 (C4a),
116.3 (C8a), 112.7 (CN), 110.9 (C5), 109.8 (C8), 68.5 (C−CN),
60.3 (C1), 57.2 (C3), 56.2 (2C, OMe-6, OMe-7), 43.8 (N−Me),
23.6 (C4) ppm; (Minor diastereomer) 1H NMR, COSY, NOESY
(400 MHz, CDCl3) δ = 7.80 (d, J = 7.5 Hz, 2H, H-2′,6′), 7.66−7.53
(m, 3H, H-3′,5′, H-4′), 6.68 (s, 1H, H-5), 6.58 (s, 1H, H-8), 6.52 (s,
H
dx.doi.org/10.1021/jo500749x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz, 1H, H-1), 4.15−4.04 (m, 1H, H-3), 3.83 (s, 3H, OMe-4′),
3.76−3.54 (m, 1H, H-3), 3.48−3.14 (m, 4H, 2H-4, 2H-1″), 2.18−
1.85 (m, 2H, H-2″), 1.39−1.17 (m, 2H, H-3″), 0.89 (t, J = 7.3 Hz,
3H, H-4″) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3) δ
= 163.1 (C-4′), 134.2 (2C, C2′,6′), 129.6 (C5), 128.8 (C6), 128.4
(C7), 128.2 (C4a), 128.0 (C8), 125.0 (C8a), 120.8 (q, J = 319.8 Hz,
OTf), 115.6 (2C, C3′,5′), 114.7 (C1′), 113.1 (CN), 64.8 (C−CN),
56.9 (C1), 56.8 (C1″), 55.8 (OMe-4′), 55.0 (C3), 24.2 (C2″), 23.8
(C4), 20.0 (C3″), 13.2 (C4″) ppm; ESI-MS (m/z) 335.2 (100)
[M]+; ESI-HRMS calcd for [C22H27N2O]+ 335.2123, found
335.2126.
General Procedure for the Synthesis of Azonines (5a−i).
DBU (1.2 equiv) was added dropwise to a stirred solution of the
corresponding salt 3a−j (1.0 equiv) in dry acetonitrile (26 mL/
mmol) at room temperature. The reaction mixture was stirred for an
estimated period of time (monitoring by TLC). After consumption
of the starting material, the solvent was removed from the reaction
by distillation under reduced pressure and the crude product was
redissolved in dichloromethane. The organic layer was washed two
times with water, and then the water layer was extracted once with
dichloromethane. Combined organic layers were washed with brine,
dried over Na2SO4, and concentrated in vacuo. The respective crude
products were purified by recrystallization.
2802, 2227, 1612, 1589, 1493, 1450, 1246, 1121, 1040, 965, 796, 756
1
cm−1; H NMR, COSY (600 MHz, C6D6, at 70 °C) δ = 7.28 (dd, J
= 8.5, 5.6 Hz, 1H, H-4), 6.98−6.92 (m, 1H, H-10), 6.92−6.86 (m,
3H, H-1, H-11, H-12), 6.79 (d, J = 7.3 Hz, 1H, H-9), 6.61 (td, J =
8.3, 2.8 Hz, 1H, H-3), 4.58 (s, 1H, H-5), 4.01 (br s, 1H, H-13), 3.45
(d, J = 14.1 Hz, 1H, H-1), 2.71−2.53 (m, 2H, H-7, H-8), 2.51−2.36
(m, 1H, H-8), 2.30−2.12 (m, 1H, H-7), 1.86 (s, 3H, N−Me) ppm;
13C NMR, HMBC, HSQC (150.9 MHz, C6D6, at 70 °C) δ = 163.2
(d, J = 247.4 Hz, C2), 143.4 (d, J = 7.2 Hz, C13a), 138.6 (C8a),
138.2 (C12a), 129.9(C12), 129.8 (C9), 129.6 (d, J = 3.0 Hz, C4a),
129.2 (d, J = 8.7 Hz, C4), 127.2 (C11), 127.1 (C10), 118.9 (d, J =
21.7 Hz, C1), 115.2 (CN), 113.0 (d, J = 21.1 Hz, C3), 56.9 (C5),
55.6 (C7), 37.9 (N−Me), 37.6 (C13), 33.8 (C8) ppm; ESI-MS (m/
z) 297.1 (100) [M + H]+; ESI-HRMS calcd for [C18H18FN2]+
281.1454, found 281.1459.
6-Methyl-2-(trifluoromethyl)-6,7,8,13-tetrahydro-5H-
dibenzo[c,f ]azonine-5-carbonitrile (5d). Following the general
procedure, tetrahydroisoquinolinium salt 3d (100 mg, 208 μmol) was
allowed to react with DBU (37 μL, 250 μmol) during 30 min to
obtain azonine 5d (61 mg, 185 μmol, 89%) as a colorless crystalline
solid after recrystallization from methanol: mp 171.5−172.1 °C; Rf =
0.61 (cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3061, 2947, 2853,
2804, 2228, 1618, 1491, 1465, 1451, 1365, 1218, 1162, 1043, 855,
1
800, 779 cm−1; H NMR, COSY (600 MHz, C6D6, at 70 °C) δ =
6-Methyl-6,7,8,13-tetrahydro-5H-dibenzo[c,f ]azonine-5-car-
bonitrile (5a). Following the general procedure, tetrahydroisoquino-
linium salt 3a (788 mg, 1.91 mmol) was allowed to react with DBU
(342 μL, 2.29 mmol) during 1 h to obtain azonine 5a (435 mg, 1.66
mmol, 87%) as a colorless crystalline solid after recrystallization from
methanol: mp 125.0−126.3 °C; Rf = 0.63 (cyclohexane/EtOAc, 3:2);
IR (ATR) ν = 3060, 2945, 2798, 2226, 1487, 1450, 1039, 936, 808,
7.50 (s, 1H, H-1), 7.34 (d, J = 7.9 Hz, 1H, H-4), 7.17 (dd, J = 7.9,
1.7 Hz, 1H, H-3), 6.97−6.91 (m, 1H, H-10), 6.88−6.84 (m, 2H, H-
11, H-12), 6.78 (d, J = 7.5 Hz, 1H, H-9), 4.59 (s, 1H, H-5), 4.07 (br
s, 1H, H-13), 3.47 (d, J = 14.2 Hz, 1H, H-13), 2.65−2.55 (m, 2H,
H-7, H-8), 2.45−2.35 (m, 1H, H-8), 2.24−2.14 (m, 1H, H-7), 1.82
(s, 3H, N−Me).ppm; 13C NMR, HMBC, HSQC (150.9 MHz, C6D6,
at 70 °C) δ = 142.4 (C13a), 138.5 (C8a), 137.8 (C12a), 137.4
(C4a), 131.3 (q, J = 32.2 Hz, C2), 129.9 (C12), 129.8 (C9), 128.3
(q, J = 3.6 Hz, C1), 128.1 (C4), 127.4 (C10), 127.4 (C11), 126.6
(q, J = 272.3 Hz, CF3), 123.9 (q, J = 3.9 Hz, C1), 114.7 (CN), 57.0
(C5), 55.8 (C7), 37.9 (N−Me), 37.5 (C13), 33.9 (C8) ppm; ESI-
1
744, 619 cm−1; H NMR, COSY (400 MHz, C6D6, at 70 °C) δ =
7.48 (dd, J = 7.5, 1.3 Hz, 1H, H-4), 7.08 (dd, J = 7.6, 1.3 Hz, 1H, H-
2), 7.04 (dd, J = 7.8, 1.6 Hz, 1H, H-12), 7.20−7.12 (m, 1H, H-1),
7.01−6.88 (m, 3H, H-3, H-10, H-11), 6.82 (dd, J = 7.3, 1.8 Hz, 1H,
H-9), 4.73 (s, 1H, H-5), 4.16 (d, J = 14.0 Hz, 1H, H-13), 3.63 (d, J
= 14.0 Hz, 1H, H-13), 2.77−2.57 (m, 2H, H-7, H-8), 2.59−2.42 (m,
1H, H-8), 2.31−2.26 (m, 1H, H-7), 1.92 (s, 3H, N−Me) ppm; 13C
NMR, HMBC, HSQC (100.6 MHz, C6D6, at 70 °C) δ = 141.4
(C13a), 139.2 (C12a), 138.7 (C8a), 133.8 (C4a), 131.7 (C1), 129.9
(C12), 129.8 (C9), 129.0 (C2), 127.8 (C4), 127.1 (C11), 127.0
(C10), 126.9 (C3), 115.4 (CN), 57.4 (C5), 55.9 (C7), 38.0 (N−
Me), 37.8 (C13), 33.9 (C8) ppm; ESI-MS (m/z) 263.1 (100) [M +
H]+; ESI-HRMS calcd for [C18H19N2]+ 263.1548, found 263.1540.
2-Chloro-6-methyl-6,7,8,13-tetrahydro-5H-dibenzo[c,f ]-
azonine-5-carbonitrile (5b). Following the general procedure,
tetrahydroisoquinolinium salt 3b (100 mg, 224 μmol) was allowed to
react with DBU (40 μL, 269 μmol) during 40 min to obtain azonine
5b (56 mg, 189 μmol, 84%) as a colorless crystalline solid after
recrystallization from methanol: mp 165.4−166.2 °C; Rf = 0.63
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3058, 3015, 2945, 2849,
MS (m/z) 331.2 (100) [M
+
H]+; ESI-HRMS calcd for
[C19H17F3N2]+ 331.1422, found 331.1410.
2-Methoxy-6-methyl-6,7,8,13-tetrahydro-5H-dibenzo[c,f ]-
azonine-5-carbonitrile (5e). Following the general procedure,
tetrahydroisoquinolinium salt 3e (100 mg, 226 μmol) was allowed to
react with DBU (40 μL, 271 μmol) during 1 h and 30 min to obtain
azonine 5e (53 mg, 183 μmol, 81%) as a colorless crystalline solid
after recrystallization from methanol: mp 129.6−130.5 °C; Rf = 0.61
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3058, 3014, 2944, 2838,
2798, 2227, 1613, 1578, 1495, 1253, 1037, 756 cm−1; 1H NMR,
COSY (600 MHz, C6D6, at 70 °C) δ = 7.42 (d, J = 8.3 Hz, 1H, H-
4), 7.06 (dd, J = 7.5, 1.5 Hz, 1H, H-12), 6.99−6.93 (m, 2H, H-1, H-
11), 6.91 (td, 1H, J = 7.5, 1.5 Hz, 1H, H-10), 6.82 (dd, J = 7.5, 1.6
Hz, 1H, H-9), 6.49 (dd, J = 8.35, 2.7 Hz, 1H, H-3), 4.58 (s, 1H, H-
5), 4.15 (br s, 1H, H-13), 3.59 (d, J = 14.0 Hz, 1H, H-1), 337 (s,
3H, OMe-2), 2.74−2.58 (m, 2H, H-7, H-8), 2.55−2.41 (m, 1H, H-
8), 2.30−2.24 (m, 1H, H-7), 1.96 (s, 3H, N−Me) ppm; 13C NMR,
HMBC, HSQC (150.9 MHz, C6D6, at 70 °C) δ = 160.7 (C2), 142.7
(C13a), 139.2 (C12a), 138.9 (C8a), 130.1 (C12), 129.8 (C9), 128.9
(C4), 127.2 (C10), 127.1 (C11), 126.3 (C4a), 119.2 (C1), 115.9
(CN), 57.0 (C5), 55.9 (C7), 55.2 (OMe-2), 38.1 (N−Me), 38.0
(C13), 34.1 (C8) ppm; ESI-MS (m/z) 293.1 (100) [M + H]+; ESI-
HRMS calcd for [C19H21N2O]+ 293.1654, found 293.1659.
1,2,3-Trimethoxy-6-methyl-6,7,8,13-tetrahydro-5H-dibenzo-
[c,f ]azonine-5-carbonitrile (5f). Following the general procedure,
tetrahydroisoquinolinium salt 3f (200 mg, 398 μmol) was allowed to
react with DBU (71 μL, 478 μmol) during 3 h and 45 min to obtain
azonine 5f (115 mg, 326 μmol, 82%) as a colorless crystalline solid
after recrystallization from diethyl ether: mp 122.4−122.9 °C; Rf =
0.54 (cyclohexane/EtOAc, 3:2); IR (ATR) ν = 2942, 2836, 2799,
2226, 1600, 1490, 1404, 1332, 1117, 1033, 757 cm−1; 1H NMR,
COSY (600 MHz, C6D6, at 70 °C) δ = 7.51 (d, J = 7.1 Hz, 1H, H-
12), 7.04−6.97 (m, 2H, H-10, H-11), 6.98 (s, 1H, H-4), 6.85 (dd, J
= 7.1, 1.9 Hz, 1H, H-9), 4.83 (s, 1H, H-5), 4.31 (d, J = 14.1 Hz, 1H,
H-1), 3.93−3.84 (m, 1H, H-1), 3.79 (s, 3H, OMe-1), 3.73 (s, 3H,
1
2801, 2227, 1568, 1482, 1143, 1042, 911, 846, 773, 754 cm−1; H
NMR, COSY (600 MHz, C6D6, at 70 °C) δ = 7.23 (d, J = 7.9 Hz,
2H, H-4), 7.22 (s, 1H, H-1), 6.97−6.91 (m, 2H, H-3, H-10), 6.90−
6.86 (m, 2H, H-11, H-12), 6.78 (d, J = 7.5 Hz, 1H, H-9), 4.55 (s,
1H, H-5), 4.00 (br s, 1H, H-13), 3.42 (d, J = 14.1 Hz, 1H, H-13),
2.63−2.55 (m, 2H, H-7, H-8), 2.48−2.34 (m, 1H, H-8), 2.25−2.14
(m, 1H, H-7), 1.85 (s, 3H, N−Me).ppm; 13C NMR, HMBC, HSQC
(150.9 MHz, C6D6, at 70 °C) δ = 143.4 (C13a), 138.7 (C8a), 138.3
(C12a), 135.0 (C2), 132.5 (C4a), 131.9 (C1), 130.1 (C12), 129.9
(C9), 129.1 (C4), 127.4 (C3), 127.0 (C12), 126.9 (2C, C10, C11),
115.2 (CN), 56.9 (C5), 55.9 (C7), 38.1 (N−Me), 37.6 (C13), 34.0
(C8) ppm; ESI-MS (m/z) 297.1 (100) [M + H]+; ESI-HRMS calcd
for [C18H18ClN2]+ 297.1159, found 297.1159.
2-Fluoro-6-methyl-6,7,8,13-tetrahydro-5H-dibenzo[c,f ]-
azonine-5-carbonitrile (5c). Following the general procedure,
tetrahydroisoquinolinium salt 3c (100 mg, 232 μmol) was allowed to
react with DBU (41 μL, 278 μmol) during 40 min to obtain azonine
5c (55 mg, 197 μmol, 85%) as a colorless crystalline solid after
recrystallization from methanol: mp 164.6−165.3 °C; Rf = 0.61
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3059, 3015, 2945, 2848,
I
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Article
OMe-2), 3.42 (s, 3H, OMe-3), 2.71 (dt, J = 13.0, 5.1 Hz, 1H, H-7),
2.67−2.55 (m, 2H, H-8), 2.29 (dt, J = 13.0, 6.4 Hz, 1H, H-7), 1.99
(s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (150.9 MHz, C6D6,
at 70 °C) δ = 153.3 (C1), 152.2 (C2), 143.7 (C3), 140.5 (C12a),
138.7 (C8a), 130.5 (C12), 129.7 (C9), 129.3 (C13a), 127.6 (C4a),
127.2 (C4), 126.2 (C11), 115.8 (CN), 108.4 (C4), 60.9 (OMe-1),
60.5 (OMe-2), 57.3 (C5), 56.0 (2C, C7, OMe-3), 38.4 (N−Me),
33.5 (C8), 28.6 (C13).ppm; ESI-MS (m/z) 353.2 (100) [M + H]+;
ESI-HRMS calcd for [C21H25N2O3]+ 353.1865, found 353.1864.
5-Methyl-5,6,7,12-tetrahydro-4H-benzo[f ]thieno[2,3-c]-
azonine-4-carbonitrile (5g). Following the general procedure,
tetrahydroisoquinolinium salt 3g (200 mg, 478 μmol) was allowed to
react with DBU (86 μL, 573 μmol) during 1 h to obtain azonine 5g
(100 mg, 373 μmol, 78%) as a slightly violet crystalline solid after
recrystallization from methanol: mp 134.4−135.2 °C; Rf = 0.54
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3059, 2945, 2911, 2849,
38.0 (N−Me), 34.1 (C8) ppm; ESI-MS (m/z) 353.2 (100) [M +
H]+; ESI-HRMS calcd for [C21H25N2O3]+ 353.1865, found 353.1850.
6-Butyl-2-methoxy-6,7,8,13-tetrahydro-5H-dibenzo[c,f ]-
azonine-5-carbonitrile (5j). Following the general procedure,
tetrahydroisoquinolinium salt 3j (100 mg, 206 μmol) was allowed
to react with DBU (37 μL, 247 μmol) during 1 h and 30 min to
obtain azonine 5j (55 mg, 165 μmol, 80%) as a colorless crystalline
solid after recrystallization from methanol: mp 101.2−101.8 °C; Rf =
0.69 (cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3014, 2956, 2833,
2225, 1613, 1578, 1495, 1253, 1135, 1040, 754 cm−1; 1H NMR,
COSY (600 MHz, C6D6, at 70 °C) δ = 7.47 (d, J = 8.3 Hz, 1H, H-
4), 7.08 (dd, J = 7.2, 1.8 Hz, 1H, H-12), 7.00−6.88 (m, 3H, H-1, H-
11, H-12), 6.81 (dd, J = 7.1, 1.9 Hz, 1H, H-10), 6.49 (dd, J = 8.3,
2.7 Hz, 1H, H-3), 4.72 (s, 1H, H-5), 4.11 (br s, 1H, H-13), 3.62 (d,
J = 13.9 Hz, 1H, H-13), 3.35 (s, 3H, OMe-2), 2.67−2.55 (m, 3H,
2H-8, H-7), 2.52−2.42 (m, 1H, H-7), 2.41−2.31 (m, 2H,H-1′),
0.98−0.58 (m, 2H,H-2′), 0.61−0.42 (m, 2H,H-3′), 0.43 (t, J = 7.2
Hz, 3H,H-4′) ppm; 13C NMR, HMBC, HSQC (150.9 MHz, C6D6,
at 70 °C) δ = 160.6 (C2), 142.8 (C13a), 139.1 (C12a), 138.9 (C8a),
129.8 (C12), 129.7 (C9), 128.7 (C4), 126.4 (C4a), 119.0 (C1),
116.5 (CN), 110.5 (C3), 56.6 (C5), 55.0 (OMe-2), 52.2 (C7), 50.1
(C1′), 37.8 (C13), 33.9 (C8), 30.2 (C2′), 19.8 (C3′), 13.6 (C4′)
ppm; ESI-MS (m/z) 335.2 (100) [M + H]+; ESI-HRMS calcd for
[C22H27N2O]+ 335.2123, found 335.2120.
1
2799, 2227, 1539, 1464, 1117, 1087, 754, 686, 659 cm−1; H NMR,
COSY (400 MHz, C6D6) δ = 7.01−6.92 (m, 3H, H-9, H-10, H-11),
6.77−6.69 (m, 1H, H-8), 6.64 (d, J = 5.0 Hz, 1H, H-2), 6.61 (d, J =
5.0 Hz, 1H, H-1), 4.53 (s, 1H, H-4), 3.72 (d, J = 14.0 Hz, 1H), 3.66
(d, J = 14.2 Hz, 1H), 2.43 (dt, J = 12.6, 5.8 Hz, 1H, H-6), 2.36 (t, J
= 5.5 Hz, 2H, H-7), 2.19 (dt, J = 12.6, 5.0 Hz, 1H, H-6), 2.08 (s,
3H, N−Me) ppm; 13C NMR, HMBC, HSQC (100.6 MHz, C6D6) δ
= 140.4 (C12a), 139.3 (C7a), 138.3 (C11a), 130.6 (C11), 130.4
(2C, C2, C7), 130.2 (C2a), 127.1 (C10), 127.0 (C9), 116.4 (CN),
54.8 (C6), 53.1 (C4), 39.2 (N−Me), 33.0 (C12), 32.0 (C7) ppm;
ESI-MS (m/z) 260.1 (100) [M − CN + H2O]+; ESI-HRMS calcd
for [C15H18NOS]+ 260.1109, found 260.1099.
10,11-Dimethoxy-6-methyl-6,7,8,13-tetrahydro-5H-
dibenzo[c,f ]azonine-5-carbonitrile (5h). Following the general
procedure, tetrahydroisoquinolinium salt 3h (100 mg, 212 μmol) was
allowed to react with DBU (38 μL, 254 μmol) during 1 h to obtain
azonine 5h (57 mg, 178 μmol, 84%) as a colorless crystalline solid
after recrystallization from methanol: mp 173.9−174.5 °C; Rf = 0.33
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 2940, 2829, 2797, 2224,
1607, 1515, 1450, 1268, 1223, 1096, 743 cm−1; 1H NMR, COSY
(600 MHz, C6D6, at 70 °C) δ = 7.53 (d, J = 7.5 Hz, 1H, H-4),
7.22−7.15 (m, 1H, H-1), 7.09 (td, J = 7.4, 1.4 Hz, 1H, H-2), 6.99
(td, J = 7.5, 1.5 Hz, 1H, H-3), 6.62 (s, 1H, H-12), 6.43 (s, 1H, H-9),
4.85 (s, 1H, H-5), 4.30 (d, J = 14.1 Hz, 1H, H-13), 3.63 (d, J = 14.1
Hz, 1H, H-13), 3.51 (s, 3H, OMe-11), 3.35 (s, 3H, OMe-10), 2.80−
2.63 (m, 2H, H-7, H-8), 2.48−2.38 (m, 1H, H-8), 2.37−2.26 (m,
1H, H-7), 2.02 (s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC
(150.9 MHz, C6D6, at 70 °C) δ = 149.3 (C11), 149.2 (C10), 141.1
(C13a), 133.4 (C4a), 131.1 (C1), 130.9 (C12a), 130.7 (C8a), 128.4
(C2), 127.3 (C4), 126.4 (C3), 115.0 (CN), 114.8 (C12), 114.6 (C-
9), 57.1 (C5), 56.0 (C7), 55.7 (OMe-11), 55.3 (OMe-10), 37.6
(C13), 37.5 (N−Me), 33.6 (C8) ppm; ESI-MS (m/z) 323.2 (100)
[M + H]+; ESI-HRMS calcd for [C20H23N2O2]+ 323.1760, found
323.1765.
2,10,11-Trimethoxy-6-methyl-6,7,8,13-tetrahydro-5H-
dibenzo[c,f ]azonine-5-carbonitrile (5i). Following the general
procedure, tetrahydroisoquinolinium salt 3i (200 mg, 452 μmol) was
allowed to react with DBU (81 μL, 542 μmol) during 2 h to obtain
azonine 5i (132 mg, 375 μmol, 83%) as a colorless crystalline solid
after recrystallization from diethyl ether: mp 143.9−144.2 °C; Rf =
0.32 (cyclohexane/EtOAc, 3:2); IR (ATR) ν = 2939, 2836, 2225,
1610, 1578, 1515, 1464, 1268, 1095, 1037, 735 cm−1; 1H NMR,
COSY (400 MHz, C6D6, at 70 °C) δ = 7.47 (d, J = 8.3 Hz, 1H, H-
4), 6.97 (d, J = 2.6 Hz, 1H, H-1), 6.64 (s, 1H, H-12), 6.50 (dd, J =
8.4, 2.7 Hz, 1H, H-3), 6.42 (s, 1H, H-9), 4.82 (s, 1H, H-5), 4.31 (br
s, 1H, H-13), 3.60 (d, J = 14.1 Hz, 1H, H-13), 3.49 (s, 3H, OMe-
11), 3.37 (s, 3H, OMe-2), 3.31 (s, 3H, OMe-10), 2.82−2.62 (m, 2H,
H-7, H-8), 2.48−2.38 (m, 1H, H-8), 2.37−2.29 (m, 1H, H-7), 2.07
(s, 3H, N−Me) ppm; 13C NMR, HMBC, HSQC (150.9 MHz, C6D6,
at 70 °C) δ = 160.6 (C2), 149.6 (C11), 149.5 (C10), 143.0 (C13a),
131.1 (C12a), 131.0 (C8a), 128.9 (C4), 126.3 (C4a), 119.1 (C1),
115.8 (CN), 115.0 (C12), 114.8 (C9), 110.5 (C3), 57.1 (C5), 56.3
(OMe-11), 56.0 (OMe-10), 55.6 (C7), 55.0 (OMe-2), 38.1 (C13),
4-(2,6-Dichlorophenyl)-3-methyl-2,3-dihydro-1H-benzo[d]-
azepine (6). Following the same general procedure for the synthesis
of dibenzo[c,f ]azonines, tetrahydroisoquinolinium salt 3k (200 mg,
415 μmol) was allowed to react with DBU (74 μL, 499 μmol)
during 1.5 h to obtain benzazepine 6 (100 mg, 329 μmol, 79%) as a
yellow oil after purification by flash column chromatography (Isolera
Flash Purification System, cyclohexane/EtOAc, gradient 0−18%): Rf
= 0.63 (cyclohexane/EtOAc, 10:1); IR (ATR) ν = 3012, 2926, 2795,
1
1608, 1558, 1487, 1438, 1222, 775, 747 cm−1; H NMR, COSY (400
MHz, CDCl3) δ = 7.37 (d, J = 8.0 Hz, 2H, H-3′, H-5′), 7.21 (dd, J
= 8.6, 7.5 Hz, 1H, H-4′), 7.15−7.06 (m, 3H, H-6, H-7, H-8), 7.04−
6.95 (m, 1H, H-9), 5.26 (s, 1H, H-1), 3.58−3.33 (m, 2H, H-4),
3.23−2.99 (m, 2H, H-5), 2.64 (s, 3H, N−Me) ppm; 13C NMR,
HMBC, HSQC (100.6 MHz, CDCl3) δ = 142.2 (C2), 138.9 (C5a),
138.3 (C9a), 137.3 (C1′), 135.7 (2C, C2′,6′), 129.7 (C6), 129.3 (C-
4′), 128.9 (C7), 128.0 (2C, C3′,5′), 126.1 (C8), 123.4 (C9), 104.8
(C1), 54.3 (C4), 41.0 (N−Me), 37.2 (C5) ppm; ESI-MS (m/z)
304.1 (100) [M + H]+; ESI-HRMS calcd for [C17H16NCl2]+
304.0660, found 304.0667.
Reductive Decyanation: Synthesis of 6-Methyl-6,7,8,13-
tetrahydro-5H-dibenzo[c,f ]azonine (7). To a solution of azonine
5a (50 mg, 190 μmol) in dry THF (3 mL) was added dropwise
LiAlH4 (THF solution 2M, 104 μL, 209 μmol) at 0 °C. After 10 min
of stirring at this temperature, the mixture was allowed to reach
room temperature and the stirring was continued overnight. The
reaction was quenched with 10 mL of water and extracted with
dichloromethane (3 × 20 mL). The combined organic layers were
washed with brine (50 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by flash column
chromatography (cyclohexane/EtOAc 3:2) to obtain compound 7
as a slightly yellow oil (38 mg, 160 μmol, 84%): Rf = 0.17
(cyclohexane/EtOAc, 3:2); IR (ATR) ν = 3059, 3013, 2934, 2832,
1
2787, 1600, 1489, 1364, 1046, 741, 624 cm−1; H NMR, COSY (400
MHz, CDCl3) δ = 7.44 (d, J = 7.4 Hz, 1H, H-4), 7.31−7.21 (m, 2H,
H-3, H-12), 7.19−7.02 (m, 5H, H-1, H-2, H-9, H-10, H-11), 4.26 (s,
2H, H-13), 3.50 (s, 1H, H-5), 3.07 (t, J = 5.7 Hz, 2H, C-8)), 2.73 (t,
J = 5.7 Hz, 1H, H-7), 2.30 (s, 3H, N−Me) ppm; 13C NMR, HMBC,
HSQC (100.6 MHz, CDCl3) δ = 141.7 (C13a), 139.6 (2C, C8a,
C12a) 137.3 (C4a), 130.7 (C4), 130.3 (C1), 129.9 (C12), 129.5
(C9), 127.7 (C13), 126.7 (C2), 126.5 (C11), 126.3 (C10), 58.1
(C5), 57.0 (C7), 44.3 (N−Me), 37.4 (C13), 32.6 (C8) ppm; ESI-
MS (m/z) 238.2 (100) [M + H]+; ESI-HRMS calcd for [C17H20N]+
238.1596, found 238.1593. The spectroscopic data are in accordance
with those reported in the literature.16
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The Journal of Organic Chemistry
Article
(23) Jemison, R. W.; Laird, T.; Ollis, W. D.; Sutherland, I. O. J.
Chem. Soc., Perkin Trans. 1 1980, 1436.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra of all synthesized compounds as well as the
crystallographic data (.cif) for compounds 5a and 5g. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(24) Jon
(25) Jon
́
́
493.
(26) Zdrojewski, T.; Jon
(27) Jonczyk, A.; Zdrojewski, T.; Grzywaca, P.; Balcerzak, P. J.
́
czyk, A. Tetrahedron Lett. 1995, 36, 1355.
́
Chem. Soc., Perkin Trans. 1 1996, 2919.
AUTHOR INFORMATION
Corresponding Author
*E-mail: opatz@uni-mainz.de.
Notes
(28) Jemison, R. W.; Ollis, W. D. J. Chem. Soc. D: Chem. Commun.
1969, 294.
(29) Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O. J. Chem.
Soc., Perkin Trans. 1 1983, 1049.
(30) Mattalia, J.-M.; Marchi-Delapierre, C.; Hazimeh, H.; Chanon,
M. ARKIVOC 2006, 90.
■
The authors declare no competing financial interest.
(31) Miyano, S.; Yamashita, O.; Sumoto, K.; Shima, K.;
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ACKNOWLEDGMENTS
■
The authors express their gratitude to Dr. J. C. Liermann
(Mainz) for NMR spectroscopy, Dr. D. Schollmeyer for X-ray
crystallography, and Dr. N. Hanold (Mainz) for mass
spectrometry.
DEDICATION
■
Dedicated to Professor Hans-Ulrich Reissig on the occasion of
his 65th birthday.
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