Efficient and practical one-pot conversions of n- tosyltetrahydroisoquinolines into isoquinolines and of N-tosyltetrahydro-β- carbolines into β-carbolines through tandem β-elimination and aromatization

Article abstract of DOI:10.1002/ejoc.201001153

An efficient, practical, and general method for conversions of N-tosyltetrahydroisoquinolines (N-tosyl-THIQs) into isoquinolines and of N-tosyltetrahydro-β-carbolines (N-tosyl-THBCs) into β-carbolines is described. Treatment of N-tosyl-THIQs or N-tosyl-THBCs with base in dimethyl sulfoxide afforded dihydroisoquinolines or dihydro-β-carbolines as intermediates, and these were then oxidized in situ by molecular oxygen to furnish isoquinolines or β-carbolines in good to high yields. Both one-pot conversions occurred through tandem β-elimination and aromatization. An efficient method for conversions ofN-tosyltetrahydroisoquinolines (N-tosyl-THIQs) and N-tosyltetrahydro-β-carbolines (N-tosyl-THBCs) into isoquinolines and β-carbolines is described. Treatment ofN-tosyl-THIQs or N-tosyl-THBCs with base affords dihydroisoquinolines or dihydro-β- carbolines. These can be oxidized in situ by molecular oxygen to furnish isoquinolines or β-carbolines. Copyright

Full text of DOI:10.1002/ejoc.201001153

FULL PAPER
DOI: 10.1002/ejoc.201001153
Efficient and Practical One-Pot Conversions of N-Tosyltetrahydroisoquinolines
into Isoquinolines and of N-Tosyltetrahydro-β-carbolines into β-Carbolines
through Tandem β-Elimination and Aromatization
Jing Dong,[a] Xiao-Xin Shi,*[a] Jing-Jing Yan,[a] Jing Xing,[a] Qiang Zhang,[a] and
Sen Xiao[a]
Keywords: Synthetic methods / Heterocycles / Nitrogen heterocycles / Dehydrogenation
An efficient, practical, and general method for conversions
of N-tosyltetrahydroisoquinolines (N-tosyl-THIQs) into iso-
quinolines and of N-tosyltetrahydro-β-carbolines (N-tosyl-
THBCs) into β-carbolines is described. Treatment of N-tosyl-
THIQs or N-tosyl-THBCs with base in dimethyl sulfoxide af-
forded dihydroisoquinolines or dihydro-β-carbolines as inter-
mediates, and these were then oxidized in situ by molecular
oxygen to furnish isoquinolines or β-carbolines in good to
high yields. Both one-pot conversions occurred through tan-
dem β-elimination and aromatization.
(2-arylethyl)-p-toluenesulfonamides and aldehydes. The N-
tosyl-THBCs of type 2 (Table 2, below) were obtained in a
two-step fashion: Pictet–Spengler reactions between trypt-
amine hydrochloride or tryptophan ester hydrochloride and
aldehydes[14] first gave THBCs, which were then trans-
formed into N-tosyl-THBCs in excellent yields on exposure
to p-toluenesulfonyl chloride in the presence of excess po-
tassium carbonate powder and catalytic amounts of pyr-
idine. With the N-tosyl-THIQs 1a–1x and the N-tosyl-
THBCs 2a–2u to hand, we then attempted the conversions
of the N-tosyl-THIQs into isoquinolines and of the N-tosyl-
THBCs into β-carbolines under various sets of conditions.
The results are summarized in Tables 1 and 2, below,
respectively.
As can be seen in Table 1, which shows results for the
treatment of the 24 N-tosyl-THIQs 1a–1x, with different
substituent patterns, with bases in dimethyl sulfoxide
(DMSO), the corresponding isoquinolines 3a–3x were ob-
tained in 70–97% yields. DMSO was found to be the best
solvent for the conversion of N-tosyl-THIQs into isoquinol-
ines; other solvents such as acetonitrile, propanol, butanol,
octanol, 1,2-dimethoxyethane, N,N-dimethylformamide,
and 1,4-dioxane were also tested, but the reactions in all
these solvents were much slower and gave isoquinolines
only in poor or moderate yields. The patterns of the R3 and
R4 groups had a significant impact on the reactions: in the
case of R4 = H, if R3 was an aryl or alkyl group or a hydro-
gen atom, the reactions were best performed at 125 °C with
NaOH as a base (Table 1, Entries 1–16), whereas if one out
of R3 and R4 was an electron-deficient group (COOMe or
COOEt), or both of them were electron-deficient groups
(COOMe), the reactions could be performed at 75 °C, and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was necessary to
prevent hydrolysis of ester groups (Table 1, Entries 17–24).
Introduction
Isoquinoline and β-carboline backbones are ubiquitous
in numerous alkaloids.[1,2] Both natural and artificial iso-
quinolines and β-carbolines are of considerable value in me-
dicinal chemistry and organic chemistry, having been seen
to exhibit a variety of biological activities[3,4] and having
also been used as versatile synthetic intermediates.[5]
Syntheses of isoquinolines and β-carbolines are very im-
portant and have therefore attracted much attention from
chemists.[6,7] Because tetrahydroisoquinolines (THIQs) and
tetrahydro-β-carbolines (THBCs) can readily be obtained
through Pictet–Spengler reactions[8] between 2-aryl (or 2-
indolyl) ethylamines and aldehydes, the aromatization of
THIQs and THBCs through dehydrogenation/oxidation
might therefore provide a good approach to isoquinolines
and β-carbolines. Unfortunately, strong oxidants,[9] poison-
ous reagents,[10] and noble metal catalysts[11] are usually
needed during the conversions of THIQs into isoquinolines
and of THBCs into β-carbolines. We wish to report here a
modified and practical method for the above conversions,
in which N-tosyl-THIQs[12] and N-tosyl-THBCs were used
as starting compounds instead of THIQs and THBCs.
Results and Discussion
The N-tosyl-THIQs 1 (Table 1) were directly obtained
through N-sulfonyl Pictet–Spengler reactions[13] between N-
[a] Department of Pharmaceutical Engineering, School of
Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. China
Fax: +86-216-4251033
E-mail: xxshi@ecust.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001153.
Eur. J. Org. Chem. 2010, 6987–6992
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6987

J. Dong, X.-X. Shi, J.-J. Yan, J. Xing, Q. Zhang, S. Xiao
Table 1. Conversion of N-tosyl-THIQs into isoquinolines in DMSO under various sets of conditions.
FULL PAPER
Entry
R1
R2
R3
R4
1
Base
[equiv.]
T
[°C]
t
[h]
3
Yield
[%][a]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
MeO
MeO
MeO
H
H
H
H
MeO
MeO
MeO
MeO
MeO
MeO
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
NaOH (3)
NaOH (3)
NaOH (2)
NaOH (3)
NaOH (3)
NaOH (2)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
DBU[b] (3)
DBU (3)
125
125
125
125
125
125
125
125
125
125
125
125
125
125
125
125
75
75
75
75
75
75
75
75
2
3
1
2
2
1
2
3
3
2
3
3
3
6
7
6
3
2
3
2
1
5
2
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
83
85
87
91
86
92
82
85
97
82
85
81
73
72
70
83
86
92
91
90
85
93
91
4-MeOC6H4
4-ClC6H4
Ph
4-MeOC6H4
2-ClC6H4
Ph
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
3,4-(MeO)2C6H3
2-EtOC6H4
4-MeOC6H4
2-EtOC6H4
H
Me
n-hexyl
H
Ph
4-MeOC6H4
3,4-(MeO)2C6H3
COOMe
H
COOMe
COOMe
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1j
1k
1l
3j
3k
3l
H
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
H
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
H
H
H
H
H
MeO
H
[a] Isolated yield. [b] 1,8-Diazabicyclo[5.4.0]undec-7-ene.
Table 2. Conversion of N-tosyl-THBCs into β-carbolines in DMSO under various sets of conditions.
Entry
R1
R2
2
Base
[equiv.]
T
[°C]
t
[h]
4
Yield
[%][a]
1
2
3
4
5
6
7
8
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
4-MeOC6H4
4-EtOC6H4
2-MeOC6H4
2-EtOC6H4
Ph
iPr
Et
Me
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(OCH2O)C6H3
3,4-(OCH2O)C6H3
4-MeOC6H4
4-MeOC6H4
Ph
2-ClC6H4
iPr
Et
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
NaOH (3)
DBU[b] (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
DBU (3)
125
125
125
125
125
125
125
125
125
125
20
20
20
20
20
20
20
20
20
5
4
5
3
4
5
4
5
5
5
4
4
5
5
4
4
3
3
4
5
6
4a
4b
4c
4d
4e
4f
4g
4h
4i
89
86
96
90
95
93
95
85
83
82
91
85
86
92
87
94
89
88
83
85
82
9
H
H
10
11
12
13
14
15
16
17
18
19
20
21
2j
2k
2l
4j
4k
4l
COOEt
COOMe
COOEt
COOMe
COOEt
COOMe
COOMe
COOMe
COOMe
COOEt
COOMe
2m
2n
2o
2p
2q
2r
2s
2t
4m
4n
4o
4p
4q
4r
4s
4t
20
20
Me
2u
4u
[a] Isolated yield. [b] 1,8-Diazabicyclo[5.4.0]undec-7-ene.
6988
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Eur. J. Org. Chem. 2010, 6987–6992

Synthesis of Isoquinolines and β-Carbolines
Scheme 1. A plausible mechanism for the two one-pot conversions.
Scheme 2. Some dihydroisoquinoline and dihydro-β-carboline intermediates.
As can be seen in Table 2, which shows results for the pound 9 was unstable and rapidly changed into the more
treatment of the 21 N-tosyl-THBC derivatives 2a–2u with stable compound 8 through tautomerization.
bases in DMSO, the corresponding β-carbolines 4a–4u were
Oxygen in air was necessary for the both of the above
obtained in 82–96% yields. DMSO was also found to be one-pot conversions: when the reactions were performed
the best solvent for the conversion of N-tosyl-THBCs into under argon the β-elimination took place smoothly, but the
β-carbolines. The reaction conditions depended on the elec- aromatization was sluggish. When compound 1a was
tronic nature of the R2 group: if R2 was a hydrogen atom treated under argon with NaOH (3 equiv.) at 125 °C in
the reactions were best performed at 125 °C with NaOH as DMSO for 2 h, for example, compounds 3a and 5 were ob-
a base (Table 2, Entries 1–10), whereas if R2 was an elec- tained in 9% and 83% yields, respectively.
tron-deficient group (COOMe or COOEt) the reactions
could take place smoothly at room temperature with DBU
as a base (Table 2, Entries 11–21). Other weak bases such as
pyridine, 4-(dimethylamino)pyridine, potassium carbonate,
Conclusions
In conclusion, a mild, practical, and highly efficient
method for one-pot conversions of N-tosyl-THIQ deriva-
tives into isoquinolines and of N-tosyl-THBCs into β-car-
bolines is described. Some advantages such as mild reaction
conditions, good to high yields, ease of manipulation,
cheapness of all reagents, and the use of air as a clean oxi-
dant, as well as the wide scope of these reactions, might
allow this method to be very useful, especially for large-
scale preparations. Because the N-tosyl-THIQ and N-tosyl-
THBC starting compounds are readily available from Pic-
tet–Spengler reactions, the method described here should
provide a good, practical, and general approach to 1-substi-
tuted or 1,3-disubstituted isoquinolines and β-carbolines.
and sodium carbonate were also tried, but only DBU gave
β-carbolines in good to high yields.
A plausible mechanism for both one-pot conversions is
shown in Scheme 1. The N-tosyl-THIQs 1 or N-tosyl-
THBCs 2 would first react with a base to form the anions
A-1 or A-2, and these would then immediately undergo β-
elimination[15] to afford the dihydro intermediates I-1 or I-
2. The dihydro intermediates I-1 or I-2 would then be oxid-
ized in situ by molecular oxygen in air to furnish the final
product isoquinolines 3 or β-carbolines 4.[16] The reaction
pathways would be governed by the acidities of the protons
on C-1 and C-3: if the proton on C-1 was more acidic,
path a would be followed, whereas if the proton on C-3 was
more acidic, path b would be followed.
In order to verify this possible mechanism, we tried to
isolate some intermediates (see also Scheme 2) of both one-
pot conversions. When we stopped the conversion of com-
pound 1a into compound 3a at a mid-point, we were able
to isolate the 3,4-dihydroisoquinoline 5. Similarly, the 3,4-
dihydro-β-carboline 6 could be isolated during the conver-
sion of compound 2a into 4a. However, when the conver-
sion of compound 2s into 4s was stopped at the mid-point,
the two intermediate compounds 7 and 8, but little com-
Experimental Section
General Method: 1H NMR and 13C NMR spectra were acquired
with a Bruker AM 500 instrument, chemical shifts are given on the
δ scale as parts per million (ppm) with tetramethylsilane (TMS)
as the internal standard. IR spectra were recorded with a Nicolet
Magna IR-550 instrument. Mass spectra were recorded with a
HP5989A instrument. Column chromatography was performed on
silica gel (Qingdao Ocean Chemical Corp.). All chemicals were an-
pound 9, could be isolated. It was quite possible that com- alytically pure.
Eur. J. Org. Chem. 2010, 6987–6992
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6989

J. Dong, X.-X. Shi, J.-J. Yan, J. Xing, Q. Zhang, S. Xiao
FULL PAPER
Typical Procedure for the Preparation of the N-Tosyl-THIQ Deriva-
tives 1
126.7, 126.5, 122.1, 120.8, 119.3, 118.2, 111.8, 111.0, 110.4, 109.5,
55.80 (OCH3), 55.73 (OCH3), 55.66 (C-1), 39.4 (C-3), 21.3 (C-4),
20.1 (CH3 in Ts) ppm. IR (KBr): ν = 3373 (N–H), 2933, 1597,
˜
1-Phenyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (1a): Boron trifluo-
ride–diethyl ether (10.64 g, 74.97 mmol) was added to a solution of
N-(2-phenylethyl)-p-toluenesulfonamide (13.77 g, 50.01 mmol) and
benzaldehyde (5.35 g, 50.41 mmol) in toluene (150 mL). The solu-
tion was then heated and stirred under N2 at 60 °C for 8 h. After
the solution had cooled down to room temperature, water (150 mL)
was added. Two layers were separated, and the aqueous solution
was extracted twice with toluene (2ϫ 50 mL). The extracts were
combined and dried with anhydrous MgSO4, and the solvent was
removed by distillation under vacuum to give a crude solid that
was recrystallized from ethanol/water (90:10) to afford compound
1a (14.91 g, 41.02 mmol) as white crystals in 82% yield, m.p. 164–
165 °C. 1H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3 in Ts),
2.53–2.57 (m, 1 H, 4-H), 2.62–2.69 (m, 1 H, 4-H), 3.73–3.77 (m, 2
H, 3-H), 6.22 (s, 1 H, 1-H), 6.97–6.98 (m, 2 H, Ar-H), 7.06 (d, J =
8.0 Hz, 2 H, 3,5-H in Ts), 7.09–7.13 (m, 2 H, Ar-H), 7.17–7.18 (m,
2 H, Ar-H), 7.21–7.25 (m, 3 H, Ar-H), 7.53 (d, J = 8.0 Hz, 2 H,
1516, 1464, 1329, 1267, 1155, 1137, 1026, 980, 748, 671 cm–1. MS
(EI): m/z (%) = 462 (12) [M]+, 306 (100), 275 (9), 248 (18), 217 (3),
204 (4), 170 (3), 144 (16). C26H26N2O4S (462.56): calcd. C 67.51,
H 5.67, N 6.06; found C 67.68, H 5.46, N 6.12.
Typical Procedure for the Conversion of the N-Tosyl-THIQ Deriva-
tives 1 into Isoquinolines 3 with NaOH as Base
1-Phenylisoquinoline (3a): An aqueous solution of sodium hydrox-
ide (30% w/w, 1.60 g, 12.00 mmol) was added to a solution of com-
pound 1a (1.46 g, 4.02 mmol) in DMSO (12 mL). The mixture was
heated to around 125 °C, and then stirred at this temperature for
2 h. The reaction was monitored by TLC. After the reaction was
complete, the mixture was allowed to cool to room temperature
and diluted with water (60 mL). The aqueous solution was then
extracted twice with ethyl acetate (2ϫ 40 mL). The extracts were
combined and dried with anhydrous MgSO4. Evaporation of the
solvent gave a crude oil which was purified by flash chromatog-
raphy (eluent: EtOAc/hexane 1:5) to furnish compound 3a (0.76 g,
3.70 mmol) as a white solid in 92% yield, m.p. 93–94 °C (ref.[17]
93–94 °C). 1H NMR (500 MHz, CDCl3): δ = 7.46–7.58 (m, 4 H,
Ar-H), 7.65 (d, J = 5.7 Hz, 1 H, 4-H), 7.67–7.73 (m, 3 H, Ar-H),
7.89 (d, J = 8.2 Hz, 1 H, 5-H), 8.11 (d, J = 8.5 Hz, 1 H, 8-H), 8.62
(d, J = 5.7 Hz, 1 H, 3-H) ppm. 13C NMR (125 MHz, CDCl3): δ =
120.40, 127.17, 127.46, 127.65, 128.01, 128.84, 129.06, 130.42,
2,6-H in Ts) ppm. IR (KBr): ν = 2950, 1600, 1450, 1330, 1160,
˜
1090, 820, 700, 670, 630 cm–1. MS (EI): m/z (%) = 363 (46) [M]+,
286 (100), 208 (41), 179 (13), 155 (12), 130 (6), 105 (3), 91 (22), 77
(3).
Typical Procedure for the Preparation of the N-Tosyl-THBC Deriva-
tives 2
1-(3,4-Dimethoxyphenyl)-2-tosyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-
b]indole (2a): 3,4-Dimethoxybenzaldehyde (1.83 g, 11.01 mmol) was
130.45, 137.31, 140.11, 142.73, 161.20 ppm. IR (KBr): ν = 3055,
˜
1619, 1583, 1554, 1441, 1383, 1354, 825, 769, 701 cm–1. MS (EI):
m/z (%) = 205 (75) [M]+, 204 (100), 176 (12), 151 (4), 102 (7), 88
(3), 77 (1), 75 (2).
added to
a solution of tryptamine hydrochloride (1.97 g,
10.02 mmol) in absolute ethanol (30 mL), and the mixture was then
heated at reflux for 20 h under nitrogen. After the reaction was
complete, the solution was then concentrated under reduced pres-
sure. The residue was partitioned between ethyl acetate (50 mL)
and an aqueous solution of potassium carbonate (10% w/v, 25 mL)
and the organic phase was separated and washed twice with brine
(2ϫ 10 mL). After having been dried with anhydrous MgSO4, the
organic solution was concentrated under vacuum to give 1-(3,4-
dimethoxyphenyl)-1,2,3,4-tetrahydro-β-carboline as a crude solid,
which was used for the next step without purification. A solution
of the above crude solid and pyridine (0.24 g, 3.03 mmol) in dichlo-
romethane (60 mL) was cooled to 0 °C with an ice-bath, powdered
K2CO3 (4.15 g, 30.03 mmol) was added, and p-toluenesulfonyl
chloride (2.01 g, 10.54 mmol) was then added in portions over
20 min. After the addition was complete, the ice-bath was removed,
and the mixture was stirred at room temperature for 2 h. Water
(25 mL) was added, and the mixture was transferred into a separat-
ing funnel. The organic phase was separated, and washed success-
ively with aqueous HCl solution (2 n, 15 mL), water (10 mL), and
brine (10 mL). After the organic solution had been dried with an-
hydrous MgSO4, the solvent was removed under vacuum to give a
crude solid that was rinsed with a mixed solvent of ethyl acetate
and hexane (1:3) to afford compound 2a (4.27 g, 9.23 mmol) as an
off-white solid in 92% yield over two steps, m.p. 186–187 °C. 1H
NMR (500 MHz, CDCl3): δ = 2.26 (s, 3 H, CH3 in Ts), 2.48–2.67
Typical Procedure for the Conversion of the N-Tosyl-THIQ Deriva-
tives 1 into Isoquinolines 3 with DBU as Base
Methyl 6,7-Dimethoxyisoquinoline-3-carboxylate (3q): DBU (1.84 g,
12.09 mmol) was added to a solution of compound 1q (1.62 g,
4.00 mmol) in DMSO (12 mL). The solution was warmed to
around 75 °C and was then stirred at this temperature for 3 h. The
reaction was monitored by TLC. After the reaction was complete,
the mixture was allowed to cool to room temperature and diluted
with water (60 mL). The aqueous solution was then extracted twice
with ethyl acetate (2ϫ 40 mL). The extracts were combined and
dried with anhydrous MgSO4. Evaporation of the solvent gave a
crude oil that was purified by flash chromatography (eluent:
EtOAc/hexane 1:4) to furnish compound 3q (0.82 g, 3.32 mmol) as
1
a white solid in 83% yield, m.p. 210–211 °C. H NMR (500 MHz,
CDCl3): δ = 4.05 (s, 3 H, OCH3), 4.06 (s, 3 H, OCH3), 4.07 (s, 3
H, OCH3), 7.20 (s, 1 H, 5-H), 7.28 (s, 1 H, 8-H), 8.46 (s, 1 H, 1-
H), 9.12 (s, 1 H, 4-H) ppm. IR (KBr): ν = 3014, 1710, 1616, 1514,
˜
1437, 1287, 1255, 1156, 1005, 852, 604 cm–1. HRMS: calcd. for
C13H13NO4: 247.0845; found 247.0841.
Typical Procedure for the Conversion of the N-Tosyl-THBCs 2 into
the β-Carbolines 4 with NaOH as Base
Preparation of 1-(3,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]indole
(m, 2 H, 3-H), 3.23–3.34 (m, 1 H, 4-H), 3.71 (s, 3 H, OCH3), 3.80 (4a): An aqueous solution of sodium hydroxide (30% w/w, 1.60 g,
(s, 3 H, OCH3), 3.98 (dd, J1 = 14.4, J2 = 5.3 Hz, 1 H, 4-H), 6.21 12.00 mmol) was added to a solution of compound 2a (1.84 g,
(s, 1 H, 1-H), 6.56 (d, J = 8.3 Hz, 1 H, Ar 6Ј-H), 6.64 (d, J = 3.98 mmol) in DMSO (12 mL). The mixture was heated to around
8.3 Hz, 1 H, Ar 5Ј-H), 6.94 (s, 1 H, Ar 2Ј-H), 7.05 (d, J = 8.0 Hz,
2 H, 3,5-H in Ts), 7.07 (dd, J1 = 7.7, J2 = 7.6 Hz, 1 H, 6-H), 7.15
125 °C and was then stirred at this temperature for 5 h. The reac-
tion was monitored by TLC. After the reaction was complete, the
(dd, J1 = 7.6, J2 = 7.8 Hz, 1 H, 7-H), 7.28 (d, J = 7.8 Hz, 1 H, 8- mixture was allowed to cool to room temperature and diluted with
H), 7.38 (d, J = 7.7 Hz, 1 H, 5-H), 7.54 (d, J = 8.0 Hz, 2 H, 2,6-
H in Ts), 8.23 (s, 1 H, indole NH) ppm. 13C NMR (125 MHz,
CDCl3): δ = 148.94, 148.91, 143.2, 138.0, 136.1, 131.9, 130.4, 129.3,
water (60 mL). The precipitate was collected by suction and washed
several times with water. The crude product was then purified by
flash chromatography (eluent: EtOAc/dichloromethane 1:4) to fur-
6990
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nish compound 4a (1.08 g, 3.55 mmol) as white solid in 89% yield,
m.p. 106–107 °C (ref.[18] 104–105 °C). 1H NMR (500 MHz,
CDCl3): δ = 3.98 (s, 3 H, OCH3), 4.00 (s, 3 H, OCH3), 7.06 (d, J
= 8.1 Hz, 1 H, Ar 6Ј-H), 7.32 (dd, J1 = 7.8, J2 = 6.9 Hz, 1 H, 6-
H), 7.48–7.59 (m, 4 H, 7-H, 8-H, Ar 2Ј-H and 5Ј-H), 7.93 (d, J =
5.3 Hz, 1 H, 4-H), 8.17 (d, J = 7.8 Hz, 1 H, 5-H), 8.55 (d, J =
5.3 Hz, 1 H, 3-H), 8.59 (s, 1 H, indole NH) ppm. IR (KBr): ν =
˜
3363 (N–H), 2935, 1626, 1516, 1457, 1409, 1319, 1260, 1235, 1144,
1025, 747 cm–1. MS (EI): m/z (%) = 304 (100) [M]+, 289 (20), 273
(19), 258 (22), 245 (11), 217 (9), 230 (6), 152 (3), 133 (3), 115 (2).
Typical Procedure for the Conversion of the N-Tosyl-THBCs 2 into
the β-Carbolines 4 with DBU as Base
Preparation of Ethyl 1-(3,4-Dimethoxyphenyl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (4k): DBU (1.37 g, 9.00 mmol) was added to
a solution of compound 2k (1.59 g, 2.97 mmol) in DMSO (12 mL).
The solution was then stirred at room temperature for 4 h. The
reaction was monitored by TLC. After the reaction was complete,
the mixture was diluted with water (60 mL). The precipitate was
collected by suction and washed several times with water. The
crude product was then purified by flash chromatography (eluent:
EtOAc/chloroform 1:4) to furnish compound 4k (1.02 g,
2.71 mmol) as a white solid in 91% yield, m.p. 140–141 °C. 1H
NMR (500 MHz, [D6]DMSO): δ = 1.38 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.40 (q, J
= 7.1 Hz, 2 H, OCH2CH3), 7.20 (d, J = 8.6 Hz, 1 H, Ar 5Ј-H),
7.31 (dd, J1 = 7.4, J2 = 7.7 Hz, 1 H, 6-H), 7.50–7.62 (m, 3 H, 7-H,
Ar 2Ј-H and 6Ј-H), 7.69 (d, J = 8.2 Hz, 1 H, 8-H), 8.40 (d, J =
7.7 Hz, 1 H, 5-H), 8.86 (s, 1 H, 4-H), 11.88 (s, 1 H, indole
NH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 165.6 (COOEt),
149.7, 148.8, 142.3, 141.5, 136.8, 134.5, 130.3, 128.9, 128.5, 121.9,
121.3, 120.3, 116.1, 112.8, 112.1, 111.8, 60.6 (OCH2CH3), 55.7
[3]
(OCH ), 55.5 (OCH ), 14.4 (OCH CH ) ppm. IR (KBr): ν = 3423
˜
3
3
2
3
(N–H), 2937, 1709 (C=O), 1626, 1516, 1371, 1348, 1257, 1143,
1025, 746 cm–1. MS (EI): m/z (%) = 376 (37) [M]+, 304 (100), 289
(11), 273 (16), 259 (7), 243 (9), 229 (12), 216 (9), 188 (3), 137 (2).
C22H20N2O4 (376.41): calcd. C 70.20, H 5.36, N 7.44; found C
70.14, H 5.22, N 7.52.
[4]
Supporting Information (see also the footnote on the first page of
this article): Characterization data for compounds 3b–3p, 3r–3x,
4b–4j, 4l–4u, and 5–8. 1H NMR spectra of compounds 3a–3x, 4a–
4u, and 5–8. 13C NMR spectra of compounds 3a, 3g, 3h, 3i, 3j, 3o,
3s, 3t, 3w, 3x, 4b, 4d, 4e, 4f, 4k, 4m, 4o, 4p, 4q, 4s and 7.
Acknowledgments
We thank the National Natural Science Foundation of China
(grant number 20972048) and Shanghai Educational Development
Foundation (Dawn Program, grant number 03SG27) for the finan-
cial support of this work.
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Received: August 16, 2010
Published Online: November 3, 2010
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Eur. J. Org. Chem. 2010, 6987–6992