Key words isoquinoline - regioexhaustive - cross-coupling - heterocycles - fused-ring systems
- ellipticine
Isoquinoline and 1,2,3,4-tetrahydroisoquinoline are widely present as key structural
motifs in a large number of natural products, pharmaceuticals, and organic materials.[1 ] Owing to their importance, a myriad of synthetic methodologies have been developed
towards the synthesis of this class of compounds. Of particular note are the traditional
Pomeranz–Fritsch, Pictet–Spengler, and Bischler–Napieralski reactions, as they are
still the fundamental gateways to isoquinoline skeletons.[2 ] Despite their utility, each of these approaches has well-known limitations; they
work only well for arenes with electron-donating groups and the commonly required
harsh acidic reaction conditions imply low functional group tolerance. Recently, various
transition-metal-mediated methodologies have emerged as promising alternatives to
construct isoquinolines.[3 ] Although reasonable scopes have been demonstrated, the limited commercial availability
of the starting materials, together with the requisite pre-installation of necessary
functionalities en route to isoquinolines impart certain limitations on these methodologies.
To achieve a more divergent strategy toward functionalized isoquinolines, we envisioned
exploiting the regioexhaustive-functionalization concept, introduced by Schlosser.[4 ] This holistic strategy has been devised to generate structural diversity from a
given aromatic or heteroaromatic core structure via iterative and selective ‘site-silencing’
transformations. The practical realization of this chemistry has relied on site-selective
metalation as a toolbox methodology followed by introduction of protective Cl or TMS
groups.
To demonstrate the utility of the regioexhaustive concept in the realm of isoquinolines,
we set ourselves the goal to use the inexpensive isoquinoline (1 ) as a starting material and attach a phenyl group at any of the four possible vacant
positions of its carbocyclic core. At the outset, owing to the reactivity of isoquinolines,
it appeared worthwhile to use the aromatic electrophilic substitution reaction as
a toolbox methodology instead of metalation chemistry.[5 ] Without an added catalyst, a halogenation at the C-4 position was reported.[6 ] The swamping catalyst effect, however, enables the change of the regioselectivity
of the halogenation reaction from the C-4 position to the benzene ring.[7 ] In these reactions, however, AlCl3 is used in more than one equivalent under forcing reaction conditions. As a result,
these procedures are not easy to handle and not attractive even for laboratory-scale
production. Not surprisingly, practicality and cost issues have spurred efforts to
develop alternative procedures. Recently, it has been demonstrated that strong Brønsted
acids can behave as a swamping catalyst in isoquinoline (1 ) halogenation. Thus, selective monobromination and dichlorination has been achieved
at ambient temperature with N -bromosuccinimide (NBS)[8 ] and 1,3-dichloro-5,5-dimethylhydantoin (DCH).[9 ]
With this in mind, we questioned whether the swamping Brønsted catalysis-based isoquinoline
halogenation could be expanded to a regioexhaustive toolbox which expediently and
selectively produces various bromo- and chloro-substituted isoquinolines. Given the
intrinsic order of reactivity of the carbocyclic core of isoquinoline (5 > 8 > 7 >
6.), we anticipated that gradually functionalizing isoquinoline by chlorine or bromine
would be possible.[5 ] Thus, chlorine or bromine would function as an easily removable ‘site-silencing’
group which allows accesss to less reactive positions (Scheme [1 ]).
Scheme 1 The regioexhaustive strategy for isoquinoline derivatization
First, the most reactive position, C-5 of isoquinoline’s carbocycle was blocked by
selective bromination by using NBS/concd H2 SO4 .[8 ] Slight modification of a previously used workup procedure allowed us to isolate
the desired product 2 in excellent yield in a scalable manner (Scheme [2 ]).
Scheme 2 Transformations of 5-bromoisoquinoline. Reagents and conditions : (a) NBS, H2 SO4 , –20 to –25 °C; (b) TCCA, H2 SO4 , 25 °C; (c) NaBH4 , Pd/C, 2-methyltetrahydrofuran/MeOH, 25 °C; (d) H2 SO4 , 70 °C.
With 2 in hand, a chlorine atom was inserted at position 8 by using trichloroisocyanuric
acid (TCCA) (Scheme [2 ]).[10 ] This 8-chloro-5-bromo compound 12 was then reduced to 8-chloroisoquinoline (13 ). It is worth mentioning that neither the classical Pomeranz–Fritsch method (only
9%) nor multistep deamination protocols (26%) could provide 13 with higher overall yields than this process.[11 ] Next, by using swamping Brønsted acid catalysis, an amidomethylene group was introduced
at position 8. Although the yield of the Tscherniac–Einhorn reaction[12 ] was moderate, the simplicity of the isolation of 14 improved the utility of this transformation.
As bromine has a more restricted area of application than chlorine for site-silencing,
the more valuable 5-chloro compound was targeted. By using TCCA at 10 °C, 15 was produced in moderate yield, high purity, and a scalable manner (Scheme [3 ]).
Scheme 3 Preparation of different chloro- and bromoisoquinoline derivatives. Reagents and conditions : (a) TCCA, H2 SO4 , 10 °C; (b) NBS, H2 SO4 , 25 °C; (c) TCCA, H2 SO4 , 25 °C; (d) DBDMH, H2 SO4 , 25 °C; (e) TCCA, H2 SO4 , 100 °C; (f) BH3 ·SMe2 , THF, 70 °C.
The monochlorination reaction proved to be less selective than the monobromination
reaction, and thus formation of a mixture of 15 , 8-chloroisoquinoline (13 ), and 5,8-dichloroisoquinoline (16 ) was observed. Fortunately, the different basicities of the mono- and dichlorinated
products made it possible to separate them by extractions at different pH, and the
monochlorinated isoquinolines were subsequently purified by recrystallization. Then,
15 was converted into the 8-bromo derivative 4 (88% yield) by using NBS at ambient temperature (Scheme [3 ]).
Next, the same key operations, subsequent chlorination–bromination, were employed
to access C-7 brominated 6 . To this end, the synthesis of the 5,8-dichlorinated 16 had to be accomplished. While the reported method used a 1,3-dichloro-5,5-dimethylhydantoin
reagent in concd H2 SO4 ,[9 ] we employed an even more cost-effective agent, TCCA, with great success (Scheme
[3 ]). For the subsequent bromination reaction, NBS was replaced by the more active 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH). The reaction was conducted between 15 and 20 °C to minimize the decomposition[13 ] of the starting material, and 6 was obtained in 55% yield after precipitation of the crude product (Scheme [3 ]).
The preparation of the remaining C-6 brominated derivative required a multistep synthesis.
First, the more reactive 5-, 7-, and 8-positions were ‘switched off’ by chlorination.
While the direct trichlorination from isoquinoline (1 ) in TCCA/H2 SO4 provided only a trace amount of 17 , its synthesis became possible in a two-step process. Thus, 16 was chlorinated by TCCA at 100 °C (Scheme [3 ]) and the reaction was stopped as soon as the conversion reached 50%. In this manner,
the decomposition of the isoquinoline product was less extensive and a 40% isolated
yield was realized. The unchanged starting material could be recovered and reused.
In the next step, however, 17 failed to react with DBDMH owing to the presence of the large number of deactivating
groups. Therefore, the pyridine ring of isoquinoline in 17 was saturated, forming 18 , by using the borane–dimethyl sulfide complex and then the bromo substituent could
be attached with high yield in the last available position, giving 19 .
Scheme 4 Transformation of the brominated isoquinoline derivatives. Reagents and conditions : (a) PhB(OH)2 , Pd(PPh3 )4 , Na2 CO3 , DME/H2 O, 85 °C; (b) Pd/C, H2 (10 bar), AcOH, MeOH, 25 °C; (c) Boc2 O, EtOAc, 50 °C; (d) Pd/C, H2 (10 bar), Et3 N, MeOH, 25 °C; (e) TFA, H2 O, 25 °C.
With all possible chloro- and bromo-substituted isoquinoline derivatives in hand,
we embarked on their arylation by using phenylboronic acid in the Suzuki reaction.
The appropriate phenylisoquinoline derivatives 20 , 21 , and 22 were isolated in moderate to excellent yields (Scheme [4 ]). Thus, the reactivity difference between bromine and chlorine was sufficient in
cross-coupling reactions to obtain the targeted molecules selectively.
Then, phenylisoquinolines 20 –22 were transformed into tetrahydroisoquinoline derivatives. In these reactions, 10%
Pd/C was used as catalyst in methanol in the presence of acetic acid, and the corresponding
tetrahydroisoquinoline derivatives 3 , 5 , and 7 were obtained moderate to good yields (Scheme [4 ]).
6-Phenyl-1,2,3,4-tetrahydroisoquinoline (25 ) was synthesized in a similar fashion, except that the NH group had to be protected
before the cross-coupling reaction (Scheme [4 ]). Therefore, 19 was reacted with di-tert -butyl dicarbonate, which gave 23 in good yield (87%). Then 23 was effectively converted into 25 in high yield by using the above-mentioned sequence. Finally, 25 was deprotected by using a TFA/H2 O mixture under an inert atmosphere to avoid partial oxidation, which provided 9 in 70% isolated yield.
To demonstrate the synthetic value of these chloro- and bromo-substituted isoquinolines,
short, concise routes to the core of oxoaporphine[14 ] 10 and ellipticine[15 ] (11 ) were developed (Scheme [5 ] and Scheme [6 ]).
Scheme 5 Synthesis of the oxoaporphine core. Reagents and conditions : (a) 2-OHCC6 H4 B(OH)2 , Pd(PPh3 )4 , Na2 CO3 , DME/H2 O, 85 °C; (b) Et3 N, Pd/alumina, H2 (1 bar), MeOH, 25 °C; (c) TBHP, TFA, DCE, 60 °C.
First, 8-bromo-5-chloroisoquinoline (4 ) was used in a Suzuki reaction with 2-formylphenylboronic acid and 26 was isolated in good yield (Scheme [5 ]). Next, the chlorine atom was removed from position 5 by hydrogen by using Pd on
alumina as catalyst in methanol to provide 27 in 60% yield. Finally, the oxoaporphine framework 10 was formed in 40% yield in a Minisci-type reaction.
Scheme 6 Concise total synthesis of ellipticine (11 ). Reagents and conditions : (a) AlMe3 , Pd(PPh3 )4 , THF, 85 °C; (b) NBS, H2 SO4 , 25 °C; (c) 2-PivNHC6 H4 B(OH)2 , Pd(PPh3 )4 , Na2 CO3 , DME/H2 O, 85 °C; (d) 20% aq H2 SO4 , 120 °C; (e) NaNO2 , NaOAc, NaN3 , HCl, 0–5 °C; (f) 1,2-dichlorobenzene, 190 °C.
The synthesis of ellipticine (11 ), based on an approach by Miller,[15b ] was envisioned to proceed via 7-bromo-5,8-dimethylisoquinoline (29 ) that could be easily accessed from 16 (Scheme [6 ]). Accordingly, 5,8-dichloroisoquinoline (16 ) was transformed into 5,8-dimethylisoquinoline (28 ) by using trimethylaluminum in a cross-coupling reaction in a good yield (88%). Then
28 was brominated with NBS to afford 29 in a selective manner. It is worth mentioning that 28 and its brominated derivative 29 were previously reported, but their synthesis required a multistep, tedious process
starting from p -xylene or its halogenated derivative.[15c ]
[d ]
[e ] Next, the cross-coupling reaction of 29 and the subsequent deprotection of the amine group was realized to afford 31 . The amino group was then smoothly converted into an azido group in 32 in excellent yield. The final ring closure of 32 in 1,2-dichlorobenzene was carried out in a microwave at 190 °C, and ellipticine
(11 ) was isolated in 55% yield.
In summary, we have demonstrated the utility of an exhaustive strategy to deliver
valuable isoquinoline and tetrahydroisoquinoline derivatives, many of which are difficult
to access by other methods. Owing to the operational simplicity of this approach,
one can easily access these derivatives on a multigram scale. We also showed that
these isoquinoline derivatives are valuable starting materials for generating structural
diversity among isoquinolines and they can be utilized for a concise synthesis of
natural products. Further extension of our regioexhaustive method toward new isoquinolines
bearing other substituent patterns and their application in total synthesis is underway.
TLC was performed on Merck Silica gel 60 F254 precoated TLC plates (0.25 mm thickness) and visualization was carried out with short-wavelength
UV light (254 nm). Flash chromatography was carried out by using Teledyne ISCO CombiFlash
Rf200 UV/VIS and Merck Silica gel 60 H. Melting points were recorded on an automatic
melting point apparatus (Jasco SRS Optimelt) and are uncorrected. IR spectra were
recorded on a Varian 2000 ATR-FTIR spectrophotometer. NMR spectra were measured on
400 MHz or 500 MHz instruments at r.t. Chemical shifts (δ) are reported in ppm relative
to residual solvent signals (1 H, CHCl3 : δ = 7.26, DMSO: δ = 2.50; 13 C: CHCl3 : δ = 77.16, DMSO: δ = 39.52). HRMS was carried out on a Q-TOF Premier (Waters Corporation)
spectrometer. GC-MS analysis was conducted on a Shimadzu GC-2010 Plus Ultra instrument.
LC-MS analysis was conducted on a Shimadzu LCMS2020. Isoquinoline (1 ) was redistilled and NBS was recrystallized from H2 O prior to use. The 2-(pivaloylamino)phenylboronic acid was prepared as described
in the literature.[16 ] THF and toluene were freshly distilled from sodium/benzophenone. All other chemicals
were purchased from commercial sources and used as received.
5-Bromoisoquinoline (2)[8 ]
5-Bromoisoquinoline (2)[8 ]
To mechanically stirred concd H2 SO4 (170 mL), isoquinoline (1 ; 21.8 g, 169.2 mmol, 1.0 equiv) was slowly added at 0 °C. The mixture was cooled
to –25 °C and NBS (39.3 g, 220.5 mmol, 1.3 equiv) was added at such a rate that the
reaction temperature was kept between at –25 and –22 °C. The mixture was stirred between
–25 and –20 °C for 2 h and at –18 °C for 2 h. It was then poured onto crushed ice
(600 g) and made alkaline (pH 8–9) by using concd aq NH3 solution with intensive cooling. The alkaline slurry was extracted with Et2 O (3 × 300 mL). The combined organic layer was washed with 1.0 M aq NaOH (2 × 300
mL) and H2 O (300 mL), dried over anhyd Na2 SO4 , filtered, and evaporated to give a brown oil. The crude product was purified by
vacuum distillation (128–130 °C/2 Torr) to give 2 as a white powder.
Yield: 27.8 g (79%); mp 82–83 °C.
IR (ATR): 1580, 1485, 1368, 1263, 1199, 1136, 962, 817, 750, 673, 627, 525 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.23 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H), 7.99–7.94 (m, 3 H), 7.48 (t, J = 7.8 Hz, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 152.7, 144.5, 135.2, 134.2, 129.8, 127.9, 127.6, 121.7, 119.6.
5-Bromo-8-chloroisoquinoline (12)
5-Bromo-8-chloroisoquinoline (12)
5-Bromoisoquinoline (2 ; 5.2 g, 25 mmol, 1.0 equiv) was dissolved in concd H2 SO4 (55 mL) at 0 °C, and addition of TCCA (2.32 g, 10 mmol, 1.2 equiv) followed in small
portions. The mixture was allowed to warm to 25 °C and stirred overnight. Then the
mixture was poured onto crushed ice (ca. 100 g). The precipitate was filtered and
the filtrate was cooled and made alkaline by careful addition of cold concd aq NH3 solution. The slurry was extracted with EtOAc (3 × 60 mL). The combined organic layer
was washed with 1.0 M NaOH (3 × 50 mL), H2 O (3 × 50 mL), and brine (3 × 50 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The residue was dissolved in CH2 Cl2 treated with Tonsil® to remove the contaminants. Removal of the solvent under reduced pressure gave 12 as a white powder.
Yield: 5.31 g (88%); mp 111–114 °C.
IR (ATR): 1886, 1606, 1568, 1479, 1423, 1359, 1256, 1209, 1182, 1045, 979, 831, 815,
792, 694, 630, 565 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.65 (s, 1 H), 8.7 (d, J = 5.9 Hz, 1 H), 7.99 (d, J = 5.9 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 149.9, 145.4, 136.3, 134.0, 132.5, 128.1, 126.7, 120.4, 119.6.
HRMS (ESI): m /z [M + H]+ calcd for C9 H6 ClBrN: 241.9372; found: 241.9380.
8-Chloroisoquinoline (13)[11a ]
8-Chloroisoquinoline (13)[11a ]
A one-necked glass flask was charged with 12 (1.20 g, 4.95 mmol, 1.0 equiv), 2-methyltetrahydrofuran (10 mL), and MeOH (10 mL),
and then N2 gas was bubbled through the mixture. Under an inert atmosphere, 10% Pd/C (530 mg,
0.5 mmol, 0.1 equiv) was added followed by careful addition of NaBH4 (206 mg, 5.45 mmol, 1.1 equiv). The flask was closed by a gas bubbler filled with
silicon oil. The mixture was stirred for 70 min at 25 °C (longer reaction times resulted
in an extensive formation of over-reduced products such as 1,2,3,4-tetrahydroisoquinoline
and 8-chloro-1,2,3,4-tetrahydroisoquinoline), and then quenched with glacial AcOH
(500 μL, 8.74 mmol, 1.75 equiv). The mixture was then stirred for another 10 min,
followed by filtration through Celite. The cake was washed with MeOH and CH2 Cl2 . The filtrate was evaporated and the residue was purified by flash chromatography
(silica gel, hexane–EtOAc, 93:7), which afforded off-white crystals.
Yield: 360 mg (44%); mp 50–55 °C.
IR (ATR): 1620, 1553, 1429, 1379, 1300, 1204, 1038, 970, 827, 748, 686, 634, 534 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.66 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H), 7.73 (d, J = 7.9 Hz, 1 H), 7.69–7.56 (m, 3 H).
13 C NMR (100 MHz, CDCl3 ): δ = 149.4, 143.8, 137.1, 132.5, 130.3, 127.5, 125.6, 125.7, 120.1.
5-Chloroisoquinoline (15)[11b ]
5-Chloroisoquinoline (15)[11b ]
To mechanically stirred concd H2 SO4 (100 mL), isoquinoline (1 ; 12.9 g, 0.1 mol, 1.0 equiv) was slowly added at 0 °C. During intensive stirring
TCCA (12.8 g, 55 mmol, 1.65 equiv) was then added in 4 portions while the reaction
temperature was kept at 10 °C. The mixture was then stirred at 10 °C and followed
by GC-MS. After 24 h the reaction mixture was poured onto crushed ice (ca. 200 g)
and the precipitate was filtered. The pH of the filtrate was adjusted to 2 with concd
aq NH3 solution with extensive cooling. The slurry was then filtered. The filtrate was extracted
with toluene (6 × 75 mL) to remove the side product, 5,8-dichloroisoquinoline (16 ). The aqueous phase was further basified with concd aq NH3 solution until pH 6 was reached. At this point the precipitate was filtered, washed
with H2 O, and dried in air. Finally, the filtrate was recrystallized from methylcyclohexane
to afford 15 .
Yield: 7.60 g (45%); mp 70–72 °C.
IR (ATR): 1580, 1489, 1371, 1267, 1204, 1140, 1065, 984, 822, 750, 687, 628, 536 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.27 (s, 1 H), 8.64 (d, J = 6.0 Hz, 1 H), 8.02 (d, J = 6.0 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.8 Hz, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 152.4, 143.9, 133.7, 131.0, 130.3, 129.4, 127.3, 126.7, 116.9.
8-Bromo-5-chloroisoquinoline (4)
8-Bromo-5-chloroisoquinoline (4)
5-Chloroisoquinoline (15 ; 1.64 g, 10 mmol, 1.0 equiv) was dissolved at 0 °C in concd H2 SO4 (30 mL); then NBS (2.67 g, 15 mmol, 1.5 equiv) was added. The mixture was stirred
at ambient temperature overnight. After that the mixture was poured onto crushed
ice (ca. 50 g). The precipitate was filtered and the filtrate was made alkaline (pH
8–9) by careful addition of cold concd aq NH3 solution with intensive cooling. The slurry was extracted with EtOAc (3 × 50 mL).
The combined organic layer was washed with 1.0 M aq NaOH (3 × 50 mL), H2 O (3 × 50 mL), and brine (3 × 50 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The residue was dissolved in CH2 Cl2 treated with Tonsil® to remove the contaminants, and then filtered. Removal of the solvent under reduced
pressure gave 4 as a white powder.
Yield: 2.06 g (88%); mp 129–132 °C.
IR (ATR) 1608, 1574, 1483, 1425, 1369, 1258, 1213, 1184, 1099, 1045, 979, 835, 815,
813, 694, 629, 573, 534 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.63 (s, 1 H), 8.74 (d, J = 5.8 Hz, 1 H), 8.01 (d, J = 5.8 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H).
13 C NMR (125 MHz, CDCl3 ): δ = 152.5, 145.3, 135.4, 131.3, 131.2, 130.8, 127.7, 121.5, 117.0.
HRMS (ESI): m /z [M + H]+ calcd for C9 H6 BrClN: 241.9372; found: 241.9375.
5,8-Dichloroisoquinoline (16)[9 ]
5,8-Dichloroisoquinoline (16)[9 ]
Isoquinoline (1 ; 24.7 g, 191.3 mmol, 1.0 equiv) was dissolved in concd H2 SO4 (200 mL) at 0 °C, and then TCCA (35.6 g, 153.0 mmol, 2.4 equiv) was added in small
portions to the solution at the same temperature. The reaction mixture was allowed
to warm to r.t. and stirred overnight. It was then poured onto crushed ice and the
precipitate was filtered. The filtrate was made alkaline (pH 8–9) by addition of concd
aq NH3 solution with intensive cooling and extracted with Et2 O (3 × 400 mL). The combined organic layer was washed with 1.0 M NaOH (3 × 200 mL),
H2 O (3 × 200 mL), and brine (1 × 200 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The crude product was recrystallized from CH2 Cl2 –methylcyclohexane to give 16 as a white powder.
Yield: 35.6 g (94%); mp 115–117 °C.
IR (ATR): 1610, 1572, 1483, 1363, 1257, 1186, 1045, 989, 817, 700, 633, 594 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.67 (s, 1 H), 8.73 (d, J = 5.9 Hz, 1 H), 8.03 (d, J = 5.9 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 149.8, 144.9, 135.0, 131.6, 130.4, 130.2, 127.7, 126.4, 117.0.
7-Bromo-5,8-dichloroisoquinoline (6)
7-Bromo-5,8-dichloroisoquinoline (6)
5,8-Dichloroisoquinoline (16 ; 15.0 g, 0.759 mol, 1.0 equiv) was dissolved at 0 °C in concd H2 SO4 (100 mL). The reaction mixture was allowed to warm to 10 °C and 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH; 35.60 g, 0.124 mol, 1.6 equiv) was added at such a rate that the reaction
temperature was kept between 15 and 20 °C. The reaction was followed by GC-MS. When
the reaction was completed, the mixture was poured onto crushed ice (200 g) and the
pH was adjusted to 2 by addition of concd aq NH3 solution with extensive cooling. The slurry was stirred for 15 min then filtered.
The cake was washed with 10% aq NaOH (2 × 100 mL) and H2 O (2 × 100 mL) and first dried in air and then over P2 O5 . Compound 6 was obtained as a white solid.
Yield: 11.7 g (55%); mp 190–191 °C.
IR (ATR): 1600, 1564, 1342, 1217, 1140, 1051, 920, 824, 714, 654, 568 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.70 (s, 1 H), 8.76 (br s, J = 5.2 Hz, 1 H), 8.00 (d, J = 5.8 Hz, 1 H), 7.98 (s, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 149.8, 144.9, 134.2, 134.2, 134.0, 131.7, 130.6, 121.4, 117.1.
HRMS (ESI): m /z [M + H]+ calcd for C9 H5 Cl2 BrN: 275.8982; found: 275.8983.
5,7,8-Trichloroisoquinoline (17)[7 ]
5,7,8-Trichloroisoquinoline (17)[7 ]
To mechanically stirred concd H2 SO4 (50 mL), 5,8-dichloroisoquinoline (16 ; 10.0 g, 50.4 mmol 1.0 equiv) was slowly added at 0 °C. Then TCCA (11.7 g 50.4 mmol,
3 equiv) was added at 0 °C. The mixture was then rapidly heated to 100–104 °C. The
reaction was followed by GC-MS. When the reaction reached 50% conversion, the mixture
was cooled to r.t. and poured onto crushed ice. (The conversion cannot be increased
further without extensive decomposition of the product). The precipitate was filtered
off and washed with H2 O. The filtrate was made alkaline (pH 8–9) by careful addition of cold concd aq NH3 solution with intensive cooling and the alkaline slurry was filtered. The precipitate
was dissolved in hot EtOAc and treated with Tonsil® , after which it was filtered. The filtrate was allowed to cool to r.t. and was left
to stand overnight; a white precipitate formed. Filtration of the precipitate gave
17 as white crystals.
Yield: 4.60 g (40%); mp 180–182 °C.
IR (ATR): 1566, 1342, 1252, 1147, 1053, 918, 823, 725, 671, 571, 503 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.68 (s, 1 H), 8.74 (d, J = 5.9 Hz, 1 H), 8.00 (d, J = 5.9 Hz, 1 H), 7.83 (s, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 149.5, 145.0, 133.6, 131.5, 131.4, 130.6, 129.4, 126.9, 116.9.
HRMS (ESI): m /z [M + H]+ calcd for C9 H5 Cl3 N: 231.9488; found: 231.9497.
5,7,8-Trichloro-1,2,3,4-tetrahydroisoquinoline (18)
5,7,8-Trichloro-1,2,3,4-tetrahydroisoquinoline (18)
BH3 ·SMe2 (11.4 mL, 120 mmol, 6 equiv) was added to a solution of 17 (4.65 g, 20.0 mmol, 1.0 equiv) in anhyd THF (80 mL) under a N2 atmosphere. The mixture was heated at reflux overnight. After that the reaction mixture
was cooled to 0 °C and then carefully quenched with MeOH (ca. 30 mL), after which
the solvent was evaporated. A H2 O/H2 SO4 solution (1:1; 80 mL) was added to the residue and the mixture was heated at reflux
for 24 h. Then the mixture was cooled to 0 °C, made alkaline (pH 8–9) by using cold
concd aq NH3 solution, and extracted with EtOAc (4 × 50 mL). The combined organic layer was washed
with brine, dried over anhyd Na2 SO4 , and evaporated. The crude product was recrystallized from cyclohexane to give white
crystals.
Yield: 2.65 g (56%); mp 114–116 °C.
IR (ATR): 1572, 1419, 1321, 1188, 1159, 1126, 1095, 979, 945, 878, 804, 727, 532 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 7.38 (s, 1 H), 4.00 (s, 2 H), 3.11 (t, J = 6.0 Hz, 2 H), 2.72 (t, J = 6.0 Hz, 2 H), 1.77 (s, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 137.7, 133.8, 133.3, 130.5, 129.1, 127.9, 47.7, 42.8, 27.4.
HRMS (ESI): m /z [M + H]+ calcd for C9 H9 Cl3 N: 235.9801; found: 235.9807.
6-Bromo-5,7,8-trichloro-1,2,3,4-tetrahydroisoquinoline (19)
6-Bromo-5,7,8-trichloro-1,2,3,4-tetrahydroisoquinoline (19)
Compound 18 (5.30 g, 22.4 mmol, 1.0 equiv) was slowly added to mechanically stirred concd H2 SO4 (51 mL) at 0 °C. Over 20 min, DBDMH (3.84 g, 13.44 mmol, 1.2 equiv) was added slowly;
then the reaction mixture was allowed to warm to r.t. and stirred for 2 h. The solution
was made alkaline (pH 8–9) by using cold concd aq NH3 solution with intensive cooling. The alkaline slurry was extracted with EtOAc (4
× 40 mL). The combined organic layer was washed with 1.0 M aq NaOH (3 × 25 mL) and
H2 O (25 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The crude product was recrystallized from cyclohexane
to give white crystals.
Yield: 6.00 g (85%); mp 156–158 °C.
IR (ATR): 1421, 1358, 1304, 1206, 1132, 981, 883, 777, 731, 698, 636, 517 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 3.97 (s, 2 H), 3.11 (t, J = 6.0 Hz, 2 H), 2.78 (t, J = 6.0 Hz, 2 H), 1.67 (s, 1 H).
13 C NMR (100 MHz, CDCl3 ): δ = 136.3, 135.0, 134.8, 132.1, 130.1, 122.3, 47.8, 43.0, 29.0.
HRMS (ESI): m /z [M + H]+ calcd for C9 H8 Cl3 BrN: 313.8906; found: 313.8908.
6-Bromo-2-tert -butoxycarbonyl-5,7,8-trichloro-1,2,3,4-tetrahydroisoquinoline (23)
6-Bromo-2-tert -butoxycarbonyl-5,7,8-trichloro-1,2,3,4-tetrahydroisoquinoline (23)
Tetrahydroisoquinoline 19 (1.05 g, 3.0 mmol, 1.0 equiv) was suspended in EtOAc (20 mL) and the mixture was
warmed to 50 °C. When the starting material had dissolved, Boc2 O (786 mg, 3.6 mmol, 1.2 equiv) was added and the mixture was stirred overnight. The
reaction was followed by TLC (hexane–EtOAc, 3:1). When the reaction was completed,
the solvent was evaporated and the residue was purified by flash chromatography (silica
gel, hexane–EtOAc, 98:2); this gave 23 as a white solid.
Yield: 1.09 g (87%); mp 148–150 °C.
IR (ATR): 1676, 1417, 1364, 1317, 1242, 1157, 1105, 966, 928, 864, 766, 743, 706,
625, 503 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 4.55 (s, 2 H), 3.65 (t, J = 5.9 Hz, 2 H), 2.88 (t, J = 5.9 Hz, 2 H), 1.49 (s, 9 H).
13 C NMR (100 MHz, CDCl3 ): δ = 154.5, 146.2, 134.6, 134.5, 132.7, 126.1, 122.8, 80.8, 45.3, 45.1, 28.6, 28.5.
HRMS (ESI): m /z [M + Na]+ calcd for C14 H15 BrCl3 NO2 Na: 435.9249; found: 435.9264.
Arylisoquinolines 20–22; General Procedure
Arylisoquinolines 20–22; General Procedure
Into a Schlenk bomb, the appropriate haloisoquinoline (2.40 mmol, 1.0 equiv), PhB(OH)2 (352 mg, 2.9 mmol, 1.2 equiv), Na2 CO3 (510 mg, 4.81 mmol, 2 equiv), DME (10 mL), and distilled H2 O (5 mL) were placed under an inert atmosphere. N2 gas was bubbled through the stirred mixture for 10 min. Then Pd(PPh3 )4 (167 mg, 0.144 mmol, 0.06 equiv) was added. The reaction mixture was heated to 85 °C
and kept at this temperature. The progress of the reaction was monitored by TLC. After
completion, the mixture was cooled to r.t. and diluted with H2 O (16 mL) and EtOAc (27 mL). The aqueous phase was extracted with EtOAc (2 × 15 mL).
The combined organic layer was washed with brine (15 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The residue was purified by flash chromatography (silica
gel, hexane–EtOAc) to give the corresponding phenylisoquinoline derivative.
5-Phenylisoquinoline (20)[17 ]
5-Phenylisoquinoline (20)[17 ]
According to the general procedure, starting from 5-bromoisoquinoline (2 ; 500 mg, 2.40 mmol, 1.0 equiv), the product was obtained after chromatography (silica
gel, hexane–EtOAc, 91:9) as a pale yellow oil.
Yield: 415 mg (84%).
IR (ATR): 1616, 1584, 1485, 1443, 1379, 1029, 829, 754, 700, 629, 532 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.32 (s, 1 H), 8.49 (d, J = 6.0 Hz, 1 H), 8.02–7.99 (q, 1 H), 7.75 (d, J = 6.0 Hz, 1 H), 7.68 (s, 1 H), 7.67 (d, J = 1.2 Hz, 1 H), 7.53–7.47 (m, 5 H).
13 C NMR (125 MHz, CDCl3 ): δ = 152.7, 143.0, 139.5, 139.1, 134.4, 131.3, 130.0, 129.1, 128.7, 128.0, 127.4,
127.1, 118.9.
5-Chloro-8-phenylisoquinoline (21)
5-Chloro-8-phenylisoquinoline (21)
According to the general procedure, starting from 4 (581 mg, 2.40 mmol), the product was obtained after chromatography (silica gel, hexane–EtOAc,
98:2) as an off-white solid.
Yield: 477 mg (83%); mp 75–78 °C.
IR (ATR): 1601, 1558, 1483, 1447, 1369, 1263, 1213, 1171, 1078, 1047, 978, 901, 854,
833, 791, 758, 702, 653, 568, 542, 526 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.75 (s, 1 H), 8.57 (d, J = 6.0 Hz, 1 H), 7.72–7.69 (m, 2 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.57–7.43 (m, 5 H).
13 C NMR (125 MHz, CDCl3 ): δ = 149.7, 143.9, 138.8, 138.3, 135.8, 132.0, 131.0 (2 C), 130.0 (2 C), 128.8,
128.2, 127.3, 126.0, 118.7.
HRMS (ESI): m /z [M + H]+ calcd for C15 H11 ClN: 240.0580; found: 240.0577.
5,8-Dichloro-7-phenylisoquinoline (22)
5,8-Dichloro-7-phenylisoquinoline (22)
According to the general procedure, starting from 6 (666 mg, 2.40 mmol), the product was obtained after chromatography (silica gel, hexane–EtOAc,
97:3) as a white solid.
Yield: 441 mg (67%); mp 147–151 °C.
IR (ATR): 1577, 1483, 1346, 1269, 1215, 1172, 1047, 991, 912, 822, 762, 694, 594,
553 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.82 (s, 1 H), 8.75 (d, J = 5.9 Hz, 1 H), 8.07 (d, J = 5.9 Hz, 1 H), 7.80 (s, 1 H), 7.51–7.45 (m, 5 H).
13 C NMR (100 MHz, CDCl3 ): δ = 150.1, 144.5, 139.8, 138.0, 134.2, 132.9, 129.9, 129.7, 129.2, 128.6, 128.5,
127.0, 116.9.
HRMS (ESI): m /z [M + H]+ calcd for C15 H10 Cl2 N: 274.0190; found: 274.0188.
2-tert -Butoxycarbonyl-5,7,8-trichloro-6-phenyl-1,2,3,4-tetrahydroisoquinoline (24)
2-tert -Butoxycarbonyl-5,7,8-trichloro-6-phenyl-1,2,3,4-tetrahydroisoquinoline (24)
Into a Schlenk bomb, 23 (1.33 g, 3.20 mmol, 1.0 equiv), PhB(OH)2 (780 mg, 6.40 mmol, 2.0 equiv), Cs2 CO3 (2.09 g, 6.410 mmol, 2 equiv), and DME (22 mL) were placed under an inert atmosphere.
N2 gas was bubbled through the stirred mixture for 10 min, and then Pd(PPh3 )4 (167 mg, 0.144 mmol, 0.06 equiv) was added. The reaction mixture was heated to 85 °C
and kept at this temperature for 3 h. The mixture was cooled to r.t., the base Cs2 CO3 was collected by filtration and washed with DME, and the filtrate was evaporated.
The residue was purified by flash chromatography (silica gel, hexane–EtOAc, 98:2).
The crude product was recrystallized from hexane to give 24 as a white solid.
Yield: 1.22 g (92%); mp 108–110 °C.
IR (ATR): 1690, 1402, 1366, 1315, 1238, 1157, 1107, 972, 932, 868, 746, 725, 702,
683, 642, 619, 606, 550, 507 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.47–7.43 (m, 3 H), 7.19 (d, J = 6.8 Hz, 2 H), 4.66 (s, 2 H), 3.70 (t, J = 5.2 Hz, 2 H), 2.89 (t, J = 5.2 Hz, 2 H), 1.52 (s, 9 H).
13 C NMR (125 MHz, CDCl3 ): δ = 154.6, 139.3, 137.9, 134.3, 133.5, 133.4, 131.4, 129.2, 128.5, 128.3, 80.6,
45.5, 40.9, 39.8, 28.6, 27.8.
HRMS (ESI): m /z [M + Na]+ calcd for C20 H20 Cl3 NO2 Na: 434.0457; found: 434.0448.
5-Phenyl-1,2,3,4-tetrahydroisoquinoline (3)
5-Phenyl-1,2,3,4-tetrahydroisoquinoline (3)
5-Phenylisoquinoline (20 ; 400 mg, 1.95 mmol, 1.0 equiv) and glacial AcOH (115 μL, 1.95 mmol, 1.0 equiv) were
dissolved in MeOH (10 mL) in an autoclave. Under an inert atmosphere, 10% Pd/C (213
mg, 0.20 mmol, 0.1 equiv) was then added to the reaction mixture in one portion. The
suspension was stirred under H2 (10 bar) overnight at ambient temperature. The reaction was followed by LC-MS. The
catalyst was removed by filtration on Celite and washed with MeOH and CH2 Cl2 . The filtrate was evaporated under vacuum. The residue was dissolved in CH2 Cl2 (20 mL). The organic layer was washed with 10% aq NaOH (2 × 10 mL) and H2 O (2 × 10 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. Isoquinoline 3 was obtained as a white, amorphous solid.
Yield: 334 mg (89%); mp 95–99 °C.
IR (ATR): 2452, 2325, 1571, 1458, 1422, 1338, 1294, 1253, 1176, 1072, 1029, 948, 781,
762, 729, 704, 648, 599, 568, 546 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.40 (t, J = 7.3 Hz, 2 H), 7.37–7.27 (m, 3 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 7.4 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 4.14 (s, 2 H), 3.09 (t, J = 5.9 Hz, 2 H), 2.68 (t, J = 5.9 Hz, 2 H), 2.64 (br s, 1 H).
13 C NMR (125 MHz, CDCl3 ): δ = 142.5, 141.4, 135.3, 132.3, 129.3 (2 C), 128.3 (2 C), 127.9, 127.1, 125.9,
125.7, 48.4, 44.0, 28.1.
HRMS (ESI): m /z [M + H]+ calcd for C15 H16 N: 210.1283; found: 210.1280.
8-Phenyl-1,2,3,4-tetrahydroisoquinoline (5)
8-Phenyl-1,2,3,4-tetrahydroisoquinoline (5)
5-Chloro-8-phenylisoquinoline (21 ; 168 mg, 0.70 mmol) and glacial AcOH (41 μL, 0.70 mmol, 1.0 equiv) were dissolved
in MeOH (10 mL) in an autoclave. Under an inert atmosphere, 10% Pd/C (75 mg, 0.07
mmol, 0.1 equiv) was then added to the reaction mixture in one portion. The suspension
was stirred under H2 (10 bar) overnight at ambient temperature. The reaction was followed by LC-MS. The
catalyst was removed by filtration on Celite and washed with MeOH and CH2 Cl2 . The filtrate was evaporated under vacuum. The residue was dissolved in CH2 Cl2 (20 mL). The organic layer was washed with 10% aq NaOH (2 × 10 mL) and H2 O (2 × 10 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The product was obtained as a colorless, viscous oil.
Yield: 126 mg (86%).
IR (ATR): 1460, 1431, 839, 783, 756, 723, 700, 675, 665, 637, 611, 596, 571, 540 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.40 (dd, J
1 = 7.9, J
2 = 6.6 Hz, 2 H), 7.35–7.32 (m, 1 H), 7.28–7.26 (m, 2 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.05 (d, J = 7.4 Hz, 1 H), 3.87 (s, 2 H), 3.16 (t, J = 6.1 Hz, 2 H), 2.92 (t, J = 6.1 Hz, 2 H), 2.56 (br s, 1 H).
13 C NMR (125 MHz, CDCl3 ): δ = 142.5, 141.4, 135.3, 132.3, 129.3 (2 C), 128.3 (2 C), 127.9, 127.1, 125.9,
125.7, 48.4, 44.0, 28.1.
HRMS (ESI): m /z [M + H]+ calcd for C15 H16 N: 210.1283; found: 210.1275.
7-Phenyl-1,2,3,4-tetrahydroisoquinoline (7)
7-Phenyl-1,2,3,4-tetrahydroisoquinoline (7)
5,8-Dichloro-7-phenylisoquinoline hydrochloride (22 ·HCl; 168 mg, 0,54 mmol) was dissolved in MeOH (10 mL) in an autoclave. Under an inert
atmosphere, 10% Pd/C (58 mg, 0.05 mmol, 0.1 equiv) was then added to the reaction
mixture in one portion. The suspension was stirred under H2 (10 bar) for 3 h at 70 °C. The reaction was followed by LC-MS. The catalyst was removed
by filtration on Celite and washed with MeOH and CH2 Cl2 . The filtrate was evaporated under vacuum. The residue was dissolved in CH2 Cl2 (20 mL). The organic layer was washed with sat. aq Na2 CO3 (2 × 10 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The product (colorless oil, 170 mg) was stored and characterized
as a hydrochloride salt, therefore it was dissolved in anhyd Et2 O and precipitated with HCl in anhyd Et2 O. Recrystallization of the salt in MeOH gave 7-phenyl-1,2,3,4-tetrahydroisoquinolinium
chloride (7 ·HCl) as an off-white powder.
Yield: 67 mg (50%); mp >220 °C (decomp).
IR (ATR): 1589, 1487, 1454, 1383, 1352, 1178, 1070, 964, 883, 760, 736, 690 cm–1 .
1 H NMR (500 MHz, DMSO): δ = 9.80 (br s, 2 H), 7.64–7.29 (m, 8 H), 4.29 (s, 2 H), 3.34
(s, 2 H), 3.05 (s, 2 H).
13 C NMR (125 MHz, DMSO): δ = 139.3, 138.2, 131.1, 129.4, 129.2, 128.8, 127.3, 126.3,
125.4, 124.8, 43.4, 40.3, 24.2.
HRMS (ESI): m /z [M + H]+ calcd for C15 H16 N: 210.1283; found: 210.1281.
2-tert -Butoxycarbonyl-6-phenyl-1,2,3,4-tetrahydroisoquinoline (25)
2-tert -Butoxycarbonyl-6-phenyl-1,2,3,4-tetrahydroisoquinoline (25)
Tetrahydroisoquinoline 24 (227 mg, 0.55 mmol, 1.0 equiv) and Et3 N (232 μL, 1.65 mmol, 3.0 equiv) were dissolved in MeOH (12 mL) in an autoclave. Under
an inert atmosphere, 10% Pd/C (59 mg, 0.06 mmol, 0.1 equiv) was then added to the
reaction mixture in one portion. The suspension was stirred under H2 (10 bar) for 3 h at 70 °C. The catalyst was removed by filtration on Celite and washed
with MeOH and CH2 Cl2 . The filtrate was evaporated under vacuum. The residue was dissolved in EtOAc (20
mL) and H2 O (20 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic
layer was washed with H2 O (20 mL) and brine (20 mL), dried over anhyd Na2 SO4 , filtered, and evaporated; this gave 25 as a colorless oil.
Yield: 167 mg (98%).
IR (ATR): 1691, 1483, 1418, 1366, 1331, 1238, 1159, 1103, 1045, 986, 935, 906, 860,
760, 729, 696, 646, 534 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.57 (d, J = 7.6 Hz, 2 H), 7.43 (t, J = 7.6 Hz, 3 H), 7.37–7.31 (m, 2 H), 7.19 (t, J = 7.6 Hz, 1 H), 4.62 (s, 2 H), 3.69 (t, J = 6.6 Hz, 2 H), 2.90 (t, J = 6.2 Hz, 2 H), 1.51 (s, 9 H).
13 C NMR (125 MHz, CDCl3 ): δ 155.1, 141.0, 139.6, 135.3, 133.0, 128.9, 127.5, 127.4, 127.2, 126.9, 125.2,
80.0, 45.7, 41.4, 29.3, 28.7.
6-Phenyl-1,2,3,4-tetrahydroisoquinoline (9)
6-Phenyl-1,2,3,4-tetrahydroisoquinoline (9)
Tetrahydroisoquinoline 25 (60 mg, 0.193 mmol, 1.0 equiv) was dissolved in H2 O (1 mL) and TFA (4 mL) under a N2 atmosphere. The reaction mixture was stirred for 3 h at r.t. Then the reaction mixture
was diluted with CH2 Cl2 and extracted with sat. aq NaHCO3 . After that, the aqueous phase was washed with CH2 Cl2 . The combined organic layer was washed with sat. aq NaHCO3 and dried over anhyd Na2 SO4 , filtered, and evaporated; this gave 9 as white crystals.
Yield: 28 mg (70%); mp 91–94 °C.
IR (ATR): 1589, 1487, 1454, 1383, 1352, 1178, 1070, 964, 883, 760, 736, 690 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.42 (t, J = 7.60 Hz, 2 H), 7.37–7.32 (m, 3 H), 7.09 (d, J = 7.60 Hz, 1 H), 4.06 (s, 2 H), 3.18 (t, J = 6.5 Hz, 2 H), 2.87 (t, J = 6.5 Hz, 2 H), 2.10 (s, 1 H).
13 C NMR (125 MHz, CDCl3 ): δ = 141.2, 139.2, 135.2, 135.0, 128.6, 128.1, 127.1, 127.1, 126.8, 124.7, 48.1,
44.0, 29.4.
HRMS (ESI): m /z [M + H]+ calcd for C15 H16 N: 210.1283; found: 210.1264.
2-[(5-Bromoisoquinolin-8-yl)methyl]isoindoline-1,3-dione (14)
2-[(5-Bromoisoquinolin-8-yl)methyl]isoindoline-1,3-dione (14)
5-Bromoisoquinoline (2 ; 1.0 g, 4.8 mmol, 1.0 equiv) and N -(hydroxymethyl)phthalimide (1.7 g, 9.6 mmol, 2.0 equiv) was dissolved at 0 °C in
concd H2 SO4 (10 mL). The mixture was stirred for 1 week at 70 °C. Then the reaction mixture was
poured onto crushed ice and filtered. Recrystallization from EtOAc gave 14 as a white solid.
Yield: 705 mg (40%); mp 212–214 °C.
IR (ATR): 1768, 1713, 1419, 1392, 1373, 1333, 1262, 1111, 748, 714 cm–1 .
1 H NMR (400 MHz, CDCl3 ): δ = 9.8 (s, 1 H), 8.7 (d, J = 5.9 Hz, 1 H), 8.0 (d, J = 5.9 Hz, 1 H), 7.9 (d, J = 7.7 Hz, 1 H), 7.88–7.82 (m, 2 H), 7.76–7.69 (m, 2 H), 7.53 (d, J = 7.7 Hz, 1 H), 5.38 (s, 2 H).
13 C NMR (100 MHz, CDCl3 ): δ = 167.9, 149.1, 144.7, 135.4, 134.3, 133.6, 132.6, 132.0, 129.0, 127.3, 123.6,
122.1, 119.9, 38.3.
HRMS (ESI): m /z [M + H]+ calcd for C18 H12 BrN2 O2 : 367.0082; found: 367.0073.
2-(5-Chloroisoquinolin-8-yl)benzaldehyde (26)
2-(5-Chloroisoquinolin-8-yl)benzaldehyde (26)
8-Bromo-5-chloroisoquinoline 4 (10.0 mmol, 2.43 g, 1.0 equiv), 2-OHCC6 H4 B(OH)2 (1.80 g, 12.0 mmol, 1.2 equiv), Na2 CO3 (2.12 g, 20.0 mmol, 2 equiv), DME (30 mL), and distilled H2 O (15 mL) were placed in a Schlenk bomb under an inert atmosphere. N2 gas was bubbled through the stirred mixture for 10 min. Then Pd(PPh3 )4 (696 mg, 0.6 mmol, 0.06 equiv) was added. The reaction mixture was heated to 85 °C
and kept at this temperature. The progress of the reaction was monitored by TLC (hexane–EtOAc,
2:1). After completion, the mixture was cooled to r.t. and diluted with H2 O (45 mL) and EtOAc (90 mL). The aqueous phase was extracted with EtOAc (2 × 50 mL).
The combined organic layer was washed with brine (50 mL), dried over anhyd Na2 SO4 , and then filtered and evaporated. The residue was purified by flash chromatography
(silica gel, hexane–EtOAc, 80:20) to give 26 as a yellow solid.
Yield: 2.0 g (75%); mp 97–101 °C.
1 H NMR (500 MHz, CDCl3 ): δ = 9.71 (s, 1 H), 8.93 (s, 1 H), 8.69 (d, J = 5.8 Hz, 1 H), 8.17–8.06 (m, 2 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.73 (t, J = 6.9 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.48–7.35 (m, 2 H).
13 C NMR (125 MHz, CDCl3 ): δ = 190.9, 151.2, 144.7, 140.8, 135.9, 135.1, 133.9, 133.8, 132.0, 131.6, 129.5,
129.27, 129.26, 128.8, 128.6, 117.1.
HRMS (ESI): m /z [M + H]+ calcd for C16 H11 ClNO: 268.0529; found: 268.0524.
2-(Isoquinolin-8-yl)benzaldehyde (27)
2-(Isoquinolin-8-yl)benzaldehyde (27)
Benzaldehyde 26 (590 mg, 2.2 mmol, 1.0 equiv) and Et3 N (5.52 mL, 39.6 mmol, 18.0 equiv) were dissolved in MeOH (10 mL). Under an inert
atmosphere 5% Pd on alumina (47 mg, 0.02 mmol, 0.01 equiv) was then added to the reaction
mixture in one portion. The suspension was stirred under H2 (atmospheric pressure) for 4.5 h. The reaction was followed by GC-MS. The catalyst
was removed by filtration on Celite and washed with MeOH and CH2 Cl2 . The filtrate was evaporated under vacuum. The residue was dissolved in Et2 O (30 mL). The organic layer was washed with H2 O (2 × 10 mL) and brine (10 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The crude product was purified by flash chromatography
(silica gel, hexane–EtOAc, 1:1) to give 27 as a yellow oil.
Yield: 307 mg (60%).
1 H NMR (500 MHz, CDCl3 ): δ = 9.69 (s, 1 H), 8.95 (s, 1 H), 8.58 (d, J = 5.3 Hz, 1 H),), 8.13 (d, J = 5.3 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 7.84–7.69 (m, 3 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.52–7.43 (m, 2 H).
13 C NMR (125 MHz, CDCl3 ): δ = 191.3, 150.9, 143.5, 141.9, 136.5, 136.1, 135.1, 133.7, 131.9, 129.6, 129.0,
128.2, 127.9, 127.2, 120.7.
HRMS (ESI): m /z [M + H]+ calcd for C16 H12 NO: 234.0919; found: 234.0911.
7H -Dibenzo[de ,g ]quinolin-7-one (10)[18 ]
7H -Dibenzo[de ,g ]quinolin-7-one (10)[18 ]
In a Schlenk bomb, 27 (205 mg, 0.88 mmol, 1.0 equiv) was dissolved in DCE (4 mL), and then TFA (80 μL,
0.96 mmol, 1.1 equiv) and 5 M TBHP in nonane (1.4 mL, 1.76 mmol, 8.0 equiv) were added.
The mixture was deoxygenated by using the freeze–pump–thaw method, and then heated
to 60 °C and kept at this temperature for 24 h. The reaction was monitored by LC-MS,
and when it was complete, sat. aq NaHCO3 (30 mL) was added to the mixture, which was then extracted with EtOAc (3 × 20 mL).
The combined organic phase was washed with sat. aq NaHCO3 (20 mL) and brine (20 mL), dried over anhyd Na2 SO4 , filtered, and evaporated. The crude product was purified by flash chromatography
(silica gel, hexane–EtOAc, 1:1, then EtOAc) to give 10 as a yellow solid.
Yield: 81 mg (40%); mp 210–214 °C.
1 H NMR (500 MHz, CDCl3 ): δ = 9.05 (d, J = 5.1 Hz, 1 H), 8.53 (d, J = 7.7 Hz, 1 H), 8.41 (d, J = 7.3 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 7.3 Hz, 2 H), 7.84 (t, J = 7.8 Hz, 1 H), 7.76 (t, J = 7.3 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 1 H).
13 C NMR (125 MHz, CDCl3 ): δ = 182.7, 146.9, 145.6, 137.0, 135.0, 134.0, 131.8, 131.1, 129.3, 129.2, 128.8,
128.6, 125.1, 124.75, 124.67, 123.2.
5,8-Dimethylisoquinoline (28)[15d ]
5,8-Dimethylisoquinoline (28)[15d ]
In a flame-dried Schlenk bomb, 16 (7.12 g, 36.0 mmol, 1.0 equiv) was dissolved in anhyd THF (80 mL). N2 was bubbled through the stirred mixture for 10 min. Then Pd(PPh3 )4 (1.8 g, 1.8 mmol, 0.05 equiv) was added. After that, 2.0 M AlMe3 in toluene (66 mL, 72 mmol, 4 equiv) was added slowly to the cooled reaction mixture.
The resulting brown mixture was then stirred overnight at 85 °C. Then the reaction
mixture was cooled to r.t., poured onto crushed ice (ca. 200 g), and made alkaline
(pH 8–9) with 10% aq NaOH. The slurry was extracted with CH2 Cl2 (3 × 50 mL). The combined organic layer was washed with H2 O (50 mL) and brine (50 mL), dried over Na2 SO4 , filtered, and evaporated. The residue (36.8 g, brown oil) was purified by Kugelrohr
distillation under reduced pressure at 160 °C to give a colorless oil. The product
was stored under an inert atmosphere in a freezer, otherwise it easily became brown.
Yield: 5.0 g (88%).
IR (ATR): 1612, 1591, 1580, 1491, 1462, 1441, 1425, 1385, 1279, 1219, 1066, 1029,
831, 804, 719, 640, 549, 542 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.43 (s, 1 H), 8.57 (d, J = 5.8 Hz, 1 H), 7.74 (d, J = 5.8 Hz, 1 H), 7.38 (d, J = 6.7 Hz, 1 H), 7.27 (d, J = 6.7 Hz, 1 H), 2.73 (s, 3 H), 2.61 (s, 3 H).
13 C NMR (125 MHz, CDCl3 ): δ = 149.6, 142.5, 135.7, 133.3, 131.6, 130.6, 127.8, 127.7, 117.5, 18.5, 18.4.
7-Bromo-5,8-dimethylisoquinoline (29)[15d ]
7-Bromo-5,8-dimethylisoquinoline (29)[15d ]
At 0 °C, 28 (1.80 g, 11.5 mmol, 1.0 equiv) was slowly added to intensively stirred concd H2 SO4 (18.0 mL); addition of NBS (2.45 g, 13.8 mmol, 1.2 equiv) followed and the mixture
was stirred at ambient temperature for 6 h. The mixture was poured onto crushed ice
(40 g) and made alkaline (pH 8–9) by using concd aq NH3 with intensive cooling. The alkaline slurry was extracted with EtOAc (3 × 40 mL).
The combined organic layer was washed with H2 O (40 mL) and brine (40 mL), dried over Na2 SO4 , filtered, and evaporated to give a brown solid.
Yield: 1.90 g (70%); mp 98–100 °C.
IR (ATR): 1589, 1562, 1491, 1435, 1379, 1354, 1273, 1213, 1072, 1034, 961, 867, 816,
756, 719, 640, 596, 575, 540, 498 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.47 (s, 1 H), 8.59 (d, J = 5.8 Hz, 1 H), 7.72 (d, J = 5.8 Hz, 1 H), 7.66 (s, 1 H), 2.83 (s, 3 H), 2.61 (s, 3 H).
13 C NMR (125 MHz, CDCl3 ): δ = 149.4, 142.6, 135.04, 135.02, 133.3, 132.5, 128.5, 123.6, 117.6, 18.2, 17.8.
N -[2-(5,8-Dimethylisoquinolin-7-yl)phenyl]pivalamide (30)
N -[2-(5,8-Dimethylisoquinolin-7-yl)phenyl]pivalamide (30)
Isoquinoline 29 (1.35 g, 5.70 mmol, 1.0 equiv), 2-PivNHC6 H4 B(OH)2 (1.89 g, 8.55 mmol, 1.5 equiv), Na2 CO3 (1.20 g, 11.4 mmol, 2 equiv), DME (18 mL), and distilled H2 O (9 mL) were placed in a Schlenk bomb under an inert atmosphere. N2 gas was bubbled through the stirred mixture for 10 min, and then Pd(PPh3 )4 (223 mg, 0.19 mmol, 0.06 equiv) was added. The reaction mixture was heated to 85 °C
and stirred at this temperature overnight. The reaction was followed by TLC (hexane–EtOAc,
3:1). After completion, the mixture was cooled to r.t. and diluted with H2 O (30 mL). The mixture was extracted with EtOAc (3 × 30 mL). The combined organic
layer was washed with H2 O (50 mL) and brine (50 mL), dried over Na2 SO4 , filtered, and evaporated. The residue was purified by flash chromatography (silica
gel, hexane–EtOAc, 3:2) to give 30 as a white amorphous solid.
Yield: 1.38 g (73%); mp 136–138 °C.
IR (ATR): 1678, 1584, 1518, 1445, 1389, 1306, 1229, 1153, 1083, 922, 885, 853, 822,
752, 598, 565, 542 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.57 (s, 1 H), 8.67 (d, J = 5.9 Hz, 1 H), 8.37 (d, J = 8.2 Hz, 1 H), 7.92–7.86 (m, 1 H), 7.43–7.38 (m, 2 H), 7.20 (s, 2 H), 7.08 (s, 1
H), 2.68 (s, 3 H), 2.53 (s, 3 H), 0.94 (s, 9 H).
13 C NMR (125 MHz, CDCl3 ): δ = 176.3, 149.4, 142.4, 135.9, 135.8, 135.7, 133.3, 132.5, 132.0, 131.1, 129.8,
128.8, 124.1, 121.1, 117.9, 39.8, 27.4, 18.4, 15.0.
HRMS (ESI): m /z [M + H]+ calcd for C22 H25 N2 O: 333.1967; found: 333.1955.
2-(5,8-Dimethylisoquinolin-7-yl)aniline (31)
2-(5,8-Dimethylisoquinolin-7-yl)aniline (31)
Pivalamide 30 (1.16 g, 3.5 mmol) was dissolved in 20% aq H2 SO4 (22 mL) and EtOH (6 mL). The reaction was refluxed for 24 h. The mixture was cooled
and made alkaline by using concd aq NH3 during extensive cooling while a white precipitate formed. The slurry was filtered
and the cake was washed with H2 O and dried on air to give 31 as a white powder.
Yield: 840 mg (97%); mp 168–170 °C.
IR (ATR): 1627, 1599, 1499, 1450, 1381, 1304, 1146, 1036, 959, 889, 854, 816, 743,
664, 594, 532 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.52 (s, 1 H), 8.58 (d, J = 5.6 Hz, 1 H), 7.78 (d, J = 5.6 Hz, 1 H), 7.42 (s, 1 H), 7.21 (d, J
1 = 7.5 Hz, 1 H), 7.05 (d, J
1 = 7.4 Hz), 6.86–6.80 (m, 2 H), 3.81 (br s, 2 H), 2.65 (s, 3 H), 2.57 (s, 3 H).
13 C NMR (125 MHz, CDCl3 ): δ = 149.7, 143.9, 142.3, 137.0, 135.4, 133.6, 131.8, 131.7, 130.4, 128.9, 128.1,
126.8, 118.5, 117.5, 115.3, 18.5, 14.8.
HRMS (ESI): m /z [M + H]+ calcd for C17 H17 N2 : 249.1392; found: 249.1382.
7-(2-Azidophenyl)-5,8-dimethylisoquinoline (32)[15b ]
7-(2-Azidophenyl)-5,8-dimethylisoquinoline (32)[15b ]
Aniline 31 (695 mg, 2.8 mmol, 1.0 equiv) was dissolved in concd HCl (16.5 mL). The mixture was
cooled to 0 °C. Then a solution of NaNO2 (445 mg, 6.44 mmol, 2.3 equiv) in H2 O (14 mL) was carefully added at such a rate that the temperature was kept under 5 °C.
(During addition the colorless solution became yellow.) After the mixture had stirred
for 2 h at 0 °C, a solution of NaOAc (5.84 g, 42.7 mmol, 13.3 equiv) and NaN3 (419 mg, 6.44 mmol, 2.3 equiv) in H2 O (14 mL) was added while the temperature was maintained under 5 °C; then the mixture
was stirred for another hour. The reaction progress was followed by TLC (hexane–EtOAc,
3:1). When the reaction was complete, it was quenched and the pH was adjusted to 7
with sat. aq Na2 CO3 . The mixture was extracted with CHCl3 (3 × 30 mL). The combined organic layer was washed with H2 O, dried over anhyd Na2 SO4 , and evaporated to give a brown oil.
Yield: 700 mg (91%).
IR (ATR): 2122, 2099, 1598, 1576, 1487, 1443, 1384, 1283, 1096, 1038, 962, 891, 820,
748, 691, 644, 594, 532 cm–1 .
1 H NMR (500 MHz, CDCl3 ): δ = 9.56 (s, 1 H), 8.62 (d, J = 5.7 Hz, 1 H), 7.80 (d, J = 5.7 Hz, 1 H), 7.48–7.45 (m, 1 H), 7.33 (s, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.27–7.24 (m, 2 H), 2.66 (s, 3 H), 2.54 (s, 3 H).
13 C NMR (125 MHz, CDCl3 ): δ = 150.0, 142.6, 138.3, 136.3, 135.5, 133.3, 133.1, 131.6, 131.3, 131.1, 129.3,
127.9, 124.9, 118.6, 117.5, 18.5, 15.2.
Ellipticine (11)[15 ] and 5,6a-Dimethyl-6aH -pyrido[3,4-a ]carbazole (33)
Ellipticine (11)[15 ] and 5,6a-Dimethyl-6aH -pyrido[3,4-a ]carbazole (33)
Azide 32 (36 mg, 0.13 mmol) was dissolved in 1,2-dichlorobenzene (2 mL). The mixture was heated
in a microwave reactor at 190 °C for 1 h. Two products formed according to TLC. The
mixture was concentrated under reduced pressure and purified by flash chromatography
(hexane–EtOAc, 1:1, then hexane–EtOAc, 1:4) to give 11 (55%) as a yellow powder and 33 (45%) as an orange powder.
Ellipticine (11)
Yield: 18 mg (55%); mp 306–308 °C.
1 H NMR (50 MHz, DMSO): δ = 11.36 (s, 1 H), 9.70 (s, 1 H), 8.47–8.31 (m, 2 H), 7.92
(d, J = 5.6 Hz, 1 H), 7.61–7.49 (m, 2 H), 7.26 (t, J = 7.0 Hz, 1 H), 3.27 (s, 3 H), 2.80 (s, 3 H).
13 C NMR (125 MHz, DMSO): δ = 149.6, 142.6, 140.51, 140.45, 132.4, 128.0, 127.0, 123.7,
123.4, 123.1, 121.9, 119.1, 115.8, 110.6, 108.0, 14.3, 11.8.
5,6a-Dimethyl-6aH -pyrido[3,4-a ]carbazole (33)
5,6a-Dimethyl-6aH -pyrido[3,4-a ]carbazole (33)
Yield: 13 mg (45%); mp 117–122 °C.
1 H NMR (500 MHz, CDCl3 ): δ = 9.20 (s, 1 H), 8.72 (d, J = 5.22 Hz, 1 H), 7.71 (d, J = 8.67 Hz, 1 H), 7.44 (d, J = 7.17 Hz, 1 H), 7.38 (t, J = 8.36 Hz, 1 H), 7.27 (t, J = 8.16 Hz, 1 H), 7.21 (d, J = 5.03 Hz, 1 H), 6.55 (br s, 1 H), 2.08 (br s, 3 H), 1.41 (s, 3 H).
13 C NMR (125 MHz, CDCl3 ): δ = 182.4, 154.6, 153.0, 146.4, 144.5, 141.7, 135.4, 130.2, 128.5, 126.2, 124.2,
121.9, 121.7, 118.6, 57.2, 27.6, 19.0.
