Simple and efficient synthesis of tetrahydro-β-carbolines via the Pictet-Spengler reaction in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)

Article abstract of DOI:10.1039/c4ra03628j

1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) can act as both the solvent and the catalyst to promote the Pictet-Spengler reactions between tryptamine derivatives and aldehydes or activated ketones. For most substrates, removing the low boiling point HFIP by distillation directly afforded tetrahydro-β-carbolines in high yields.

Full text of DOI:10.1039/c4ra03628j

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PAPER
Simple and efficient synthesis of tetrahydro-b-
carbolines via the Pictet–Spengler reaction in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)†
Cite this: RSC Adv., 2014, 4, 30733
*
Li-Na Wang, Su-Li Shen and Jin Qu
Received 21st April 2014
Accepted 30th June 2014
1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) can act as both the solvent and the catalyst to promote the
Pictet–Spengler reactions between tryptamine derivatives and aldehydes or activated ketones. For most
substrates, removing the low boiling point HFIP by distillation directly afforded tetrahydro-b-carbolines
in high yields.
DOI: 10.1039/c4ra03628j
www.rsc.org/advances
According to the mechanism of the Pictet–Spengler reaction,
only when an appropriate amount of Brønsted acid catalyst is
Introduction
used, the reaction can afford product in optimal chemical yield.
If a largely excessive amount of Brønsted acid catalyst is used,
the starting amine may be protonated and loses its nucleophi-
licity. Moreover, in some cases, strong acidic conditions are
incompatible with acid-labile aldehydes. However, when the
amount of the Brønsted acid catalyst is insufficient, conse-
quently the imine is not properly activated and the addition
reaction would be very slow. The frequently used Brønsted acids
are triuoroacetic acid,4a–c acetic acid,4d–f hydrochloric acid,4h
triuoromethanesulfonic acid,4i p-toluenesulfonic acid,4j and
formic acid.4g,k In recent years, Lewis acids5 and some other
miscellaneous reagents6 have also been applied to catalyze the
Pictet–Spengler reaction. In 2003, Ganesan's research group
reported that the reaction could be catalyzed by a variety of
Lewis acids. Among them, Yb(OTf)3 was shown to be highly
effective with the assistance of microwave irradiation.5a In 2006,
Youn's group utilized AuCl3/AgOTf as the catalyst to promote
the Pictet–Spengler reaction, but the imine should be prepared
in advance.5b Although several Brønsted acid catalysts are
capable of mediating the transformation, the kind and the
amount of the acid, as well as the solvent and the temperature
of the reaction should be carefully optimized in order to obtain
a high chemical yield for a given substrate.4c The screening
process inevitably results in a waste of reaction substrates and
heavy labor work. For most of the Lewis acid-catalyzed Pictet–
Spengler reactions, the reactions take rather long reaction time
and microwave irradiation is applied to enhance the reactivity.5a
Also, the usage of Brønsted acid or Lewis acid catalysts gener-
ates waste salt or poisonous metal ion which are harmful to the
environment. Therefore, performing the Pictet–Spengler reac-
tion with a recyclable catalyst and under a mild reaction
condition is still highly desirable.
Tetrahydro-b-carboline is an important structural unit present
in many bioactive natural products such as Fumitremorgin C
and Neonaucleoside A and C.1 The heterocyclic compounds
containing this structural unit have been found to exhibit a
broad spectrum of biological activities such as antiviral and
antitumor activities.2 The Pictet–Spengler reaction is the most
effective method for the direct synthesis of tetrahydro-b-carbo-
lines and therefore has attracted much attention from synthetic
organic chemists.3 The Pictet–Spengler reaction involves two
steps.3c The rst step is the formation of the imine intermediate
(Schiff base) through the dehydration reaction of an electron-
rich b-arylethylamine with an aldehyde or a ketone in the
presence of an acidic catalyst. Then the imine intermediate
undergoes a 6-endo-trig cyclization, which is also catalyzed by an
acidic catalyst (Scheme 1).
Scheme 1 The mechanism and the catalysts of the Pictet–Spengler
reaction. R1, R2 ¼ H, alkyl, aryl; catalysts: Brøsted acid: TFA, AcOH, HCl,
TfOH, p-TsOH, HCOOH, perfluorooctanesulfonic acid, Cl2CHCOOH,
BrCH2COOH, etc.; Lewis acid: Yb(OTf)3, Sc(OTf)3, AuCl3/AgOTf,
Ca(HFIP)2, etc.
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center
of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300071,
China. E-mail: qujin@nankai.edu.cn; Fax: +86-022-23503627
Fluorinated alcohols possess various special properties:7
high polarity (polarity (ENT): HFIP ¼ 1.068, EtOH ¼ 0.654), high
ionizing power (ionizing power (Y): HFIP ¼ 3.82, EtOH ¼ ꢀ1.75),
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for all compounds. See DOI: 10.1039/c4ra03628j
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Table 1 The Pictet–Spengler reactions in HFIP and other solvents
but with very weak nucleophilicity (nucleophilicity (N): HFIP ¼
ꢀ4.23, EtOH ¼ 0). The weak acidic property of HFIP (HFIP: pKa ¼
9.3, EtOH: pKa ¼ 15.9) makes it can act as both the solvent and
the catalyst. In recent years, many reports showed that HFIP
could promote a variety of reactions without additional acid
catalyst.8 In 2010, our group reported that HFIP could efficiently
promote the electrophilic aromatic substitutions between arenes
and epoxides with high regio- and stereo-control.9 Although HFIP
is a relatively expensive organic solvent, it can be easily recovered
by distillation aer the completion of reactions due to its low
boiling point (bp ¼ 58.6 ꢁC) and low viscosity.
without additional catalysta
Yield (%)
Entry Solvent
Temperature (oC) Time (h) 3ab 4ac
In the year of 2005, Professor Zhu's research group observed
that LiCl in the mixed solvent of toluene and HFIP (v:v ¼ 4 : 1)
could promote the Pictet–Spengler reaction between an amine
and ethyl glyoxylate at room temperature. The authors also
observed that without the addition of LiCl, the reaction could
take place at 85 ꢁC but give a substantially low yield of the
desired product.10 In 2007, Saito and Hanzawa reported that the
addition of small amount of HFIP (11.5 v/v%) could consider-
able accelerate the reactions between amine carbamates and
aldehydes when the reactions were catalyzed by per-
uorooctanesulfonic acid (20 mol% in H2O).4l,m The reaction in
dry HFIP proceeded even fast than that in water but the sole use
of HFIP at room temperature did not afford the desired product.
Here, we report that in reuxing HFIP and without additional
catalyst, tryptamine derivatives and aldehydes could dehydrate
to the imine intermediates in situ and further react to afford the
cyclization products tetrahydro-b-carbolines. The HFIP-
promoted Pictet–Spengler reactions could avoid the usage of
Brønsted acids or Lewis acids and HFIP could be recovered and
reused.
1
2
3
4
5
6
7
8
HFIP
HFIP
r.t.
12
1
99
99
98
94
16
0
4
0
0
0
0
0
0
0
80
100
94
100
100
100
100
Reux (58.6 ꢁC)
H2O–HFIP (1 : 9) Reux
H2O–HFIP (1 : 4) 70
H2O–HFIP (1 : 1) 70
H2O
TFE
CH3CN
DMF
CH3OH
i-PrOH
19
24
24
24
24
24
24
24
24
Reux
Reux
Reux
100
Reux
Reux
9
10
11
0
a
Reaction conditions: the reactions were performed with tryptamine
b
(0.5 mmol) and aldehyde (0.5 mmol) in solvent (0.8 mL). Isolated
yield. Yield was determined from the 1H NMR spectrum of the crude
c
product.
1
reactions afforded 4a in quantitative yields judging by the H
NMR spectra of the crude products.
In reuxing HFIP, tryptamine (1a) could react with a variety
of aromatic or aliphatic aldehydes or ketones effectively.12 As
shown in Table 2, for aromatic aldehydes, regardless of elec-
tron-withdrawing or electron-donating substituents on the
aromatic ring, the reactions could give the tetrahydro-b-carbo-
line products in excellent yields (compounds 3a–3e, entry 1–5,
Table 2). 1-Naphthaldehyde and 2-thenaldehyde also showed
excellent reactivities and the chemical yields of compounds 3f
and 3g were 95% and 91%, respectively (entry 6 and 7). Aliphatic
aldehydes required longer reaction time but still gave high
chemical yields (compounds 3h–3j, entry 8–10). Compared with
aldehydes, ketones are less reactive and there were fewer liter-
atures reporting the Pictet–Spengler reactions between ketones
and tryptamine and the reactions oen did not proceed well.13
The Pictet–Spengler reactions between tryptamine and ketones
were also attempted in reuxing HFIP. The triuoromethyl
group in triuoroacetophenone enhances the activity of the
carbonyl group and the reaction in reuxing HFIP provided
product 3k in 76% yield aer 24 h (entry 11). Similarly, the
reaction of tryptamine with ethyl pyruvate gave product 3l in
84% yield aer 36 h (entry 12). p-Nitroacetophenone did not
react well, the desired product 3m was obtained in 21% yield
and the imine (43% yield) was formed as the major product
(entry 13). The reaction of 1d with ethyl acetoacetate gave 3n
and the imine in 28% and 68% yields, respectively (entry 14).
We also examined the Pictet–Spengler reactions between
p-nitrobenzaldehyde 2a and 3-hydroxytyramine (dopamine) 1b
or 3-hydroxy-4-methoxy phenethylamine 1c in reuxing
Results and discussion
Our previous studies showed that HFIP presented stronger
catalytic effect at raised temperature. At room temperature in
HFIP, the reaction of tryptamine (1a) and p-nitrobenzaldehyde
(2a) proceeded slowly and 99% yield of the cyclized product 3a
was obtained aer 12 h (entry 1, Table 1). But in HFIP under
reuxing condition, the same reaction provided 99% yield of 3a
within 1 h (entry 2, the same reaction catalyzed by 10% TFA at
room temperature gave 72% yield of 3a aer 36 h,4a or catalyzed
by 1.05 equiv. of HCl at 20 ꢁC under 5 kbar gave 91% yield of 3a
aer 1 h (ref. 4h)). Aer the completion of the reaction, HFIP
was distilled off and the residue was the crude product in nearly
quantitative yield.11 Up to 20% volume percent of water in HFIP
could be tolerated but the reactions were slower compared with
that in pure HFIP (entry 3 and 4). As the amount of water
increased to 50% of volume percent, the yield of 3a decreased
and the reaction gave imine 4a as the major product (entry 5). In
pure water under reuxing condition, the reaction gave the
imine 4a in 100% yield (entry 6). We also examined this reaction
in several other polar organic solvents having relatively high
boiling points (entry 7–11). When the Pictet–Spengler reaction
was carried out in reuxing 1,1,1-triuoroethanol (TFE), the
reaction majorly afforded imine 4a and only 4% yield of 3a was
formed aer 24 h. In CH3CN, DMF, CH3OH, or i-PrOH, the
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Table 2 HFIP-promoted Pictet–Spengler reactions between amines and aldehydes or ketones
Entry
1
Amine
Aldehydes or ketones
Product
Time (h)
1
Yielda (%)
99b
2
3
4
5
1a
1a
1a
1a
3
2
93b
93b
98b
91c
12
24
6
7
8
1a
1a
1a
24
24
48
95c
91c
83c (92)e
9
1a
1a
1a
1a
16
30
24
36
94d
10
11
12
81d (93)e
76d (90)e
84d (92)e
13
1a
48
21d (67)e
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Table 2 (Contd.)
Entry
14
Amine
Aldehydes or ketones
Product
Time (h)
72
Yielda (%)
28d (100)e
1a
15
2a
2a
8
6
93b
16
91b
Isolated yield. b The reactions were performed with amine (0.5 mmol) and aldehyde (0.5 mmol) in HFIP (0.8 mL) under reuxing condition. c The
reactions were performed with tryptamine (0.5 mmol) and aldehyde (0.6 mmol) in HFIP (0.8 mL) under reuxing condition. d The reactions were
a
e
performed with tryptamine (0.5 mmol) and carbonyl compounds (0.75 mmol) in HFIP (0.8 mL) under reuxing condition. Conversion of
tryptamine.
HFIP.5c,6g The reactions gave corresponding tetrahy- 96% yield of desired tetrahydro-b-carboline 3u in 12 hours
droisoquinoline derivatives 3o and 3p in 93% and 91% yields, (entry 6).
respectively (entry 15 and 16). A large-scale Pictet–Spengler
The HFIP-promoted Pictet–Spengler reactions may be
reaction was also performed in HFIP. Reuxing benzylaldehyde explained from several aspects. The weak acidity of HFIP could
(31 mmol, 3.3 g, 3.17 mL) and tryptamine (31 mmol, 5 g) in activate the carbonyl group to form the imine intermediate,
HFIP (15 mL) for 8 h gave the corresponding tetrahydro-b-car- which was also activated by HFIP through the following 6-endo-
boline 3b in 95% isolated yield.
trig cyclization reaction.8d
The previous work from Cook's research group has shown
that owing to the high electrophilicity of the imine generated
from L-tryptophan methyl ester (1d), the Pictet–Spengler reac-
tions between 1d and aldehydes can proceed in benzene under
reuxing condition. These catalyst-free reactions give tetrahy-
dro-b-carbolines with higher chemical yields than those cata-
lyzed by acid catalysts in protic solvents.6d,k We further
examined the Pictet–Spengler reactions between L-tryptophan
methyl ester (1d) and aldehydes in reuxing HFIP (Table 3).
Reuxing 1d and p-nitrobenzaldehyde in HFIP for 3.5 h gave cis/
trans diastereoisomers of 3q in 98% isolated yield. The ratio of
cis- and trans- isomer was 52 : 48, which was parallel with those
reported in the literatures (entry 1, Table 3).6d,k This reaction
could also proceed slowly at room temperature and the ratio of
the cis- and trans- isomer obtained was 55 : 45 (entry 2). The
reaction between 1d and other aromatic aldehydes or aliphatic
aldehydes were also tested in reuxing HFIP. These reactions all
gave very high yields of tetrahydro-b-carbolines (in mixed cis-
and trans- diastereoisomers, entry 3–9). It was worth noting that
the Pictet–Spengler reaction between 1d and salicylaldehyde
(2p) only give the corresponding imine in reuxing benzene
owing to the electron-donating phenolic oxygen on the benzene
ring.6d However, in reuxing HFIP, this reaction could provide
Conclusion
In conclusion, utilizing HFIP as the solvent and also the catalyst
under none strictly anhydrous conditions, the Pictet–Spengler
reactions between tryptamine derivatives and aldehydes or
activated ketones could afford tetrahydro-b-carbolines in high
yields. For most of the substrates, the one-pot reactions did not
need the work-up procedure. Removing solvent HFIP by distil-
lation directly gave the product pure enough for most of further
transformations. HFIP could be recovered and reused, thus no
waste salt was generated in the reaction. The simplicity and the
environmental benign feature of this method ensure its future
application in organic synthesis.
Experimental section
Experimental Details: HFIP was distilled from K2CO3 to get rid
of possible HF contaminates. All of the reactions were carried
out under nitrogen atmosphere. The 1H NMR spectra were
recorded on a 400 MHz NMR machine and 13C NMR spectra
were measured on a 100 MHz NMR machine. Peaks recorded
are relative to the internal standards: TMS (d ¼ 0.00) or DMSO-
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1
Table 3 The Pictet–Spengler reactions of L-tryptophan methyl ester
d6 (d ¼ 2.50) for H NMR; CDCl3 (d ¼ 77.00) or DMSO-d6 (d ¼
39.43) for 13C NMR spectra. High resolution mass spectral
analyses (HRMS) were performed on high resolution ESI-FTICR
mass spectrometer (Varian 7.0 T). Flash column chromatog-
raphy were performed with Qingdao–Haiyang® silica gel (200–
300 mesh).
and aldehydesa
Entry Aldehydes
Product
Time (h) Yieldb (%) cis/transb
General procedure for the preparation of products 3a–3n in
Table 2
1-(4-Nitrophenyl)-1,2,3,4-tetrohydro-b-carboline
(3a).4a
1
3.5
98
52/48
(Table 2, entry 1) The starting material of tryptamine 1a (80 mg,
0.5 mmol) and p-nitrobenzaldehyde 2a (76 mg, 0.5 mmol) were
dissolved in HFIP (0.8 mL) under nitrogen atmosphere. The
resulting solution was reuxed and monitored by TLC. Aer
completion, HFIP was removed by distillation. The residue was
azeotroped with CHCl3 for three times (to get rid of trace
amount of HFIP) to afford 3a (145 mg, 99%) as yellow solid; mp
¼ 172–173 ꢁC (lit.4a mp ¼ 172 ꢁC); 1H NMR (400 MHz, CDCl3): d
¼ 8.15 (d, J ¼ 8.8 Hz, 2H), 7.59 (br s, 1H), 7.56 (d, J ¼ 7.6 Hz, 1H),
7.48 (d, J ¼ 8.4 Hz, 2H), 7.23–7.26 (m, 1H), 7.11–7.19 (m, 2H),
5.26 (s, 1H), 3.25–3.30 (m, 1H), 3.12–3.19 (m, 1H), 2.89–2.97 (m,
1H), 2.80–2.86 (m, 1H), 1.95 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d ¼ 149.3, 147.6, 135.9, 132.6, 129.4, 127.1, 123.9, 122.2,
119.7, 118.4, 110.9, 110.8, 57.1, 42.2, 22.3.
2c
3
2a
3q
12
95
97
55/45
53/47
6
4
24
93
56/44
1-Phenyl-1,2,3,4-tetrahydro-b-carboline (3b).4a Yield 93%;
white solid; mp ¼ 162–163 ꢁC (lit.4a mp ¼ 160–161 ꢁC); 1H NMR
(400 MHz, CDCl3) d ¼ 7.53–7.55 (m, 1H), 7.50 (br s, 1H), 7.30–
7.39 (m, 5H), 7.21–7.24 (m, 1H), 7.09–7.17 (m, 2H), 5.18 (s, 1H),
3.36–3.42 (m, 1H), 3.12–3.18 (m, 1H), 2.90–2.97 (m, 1H), 2.81–
2.86 (m, 1H), 1.82 (br s, 1H); 13C NMR (100 MHz, CDCl3) d ¼
141.5, 135.8, 134.1, 128.6, 128.5, 128.1, 127.1, 121.5, 119.1,
118.0, 110.8, 109.8, 57.7, 42.3, 22.2.
5
6
20
12
92
96
48/52
55/45
1-(4-Chlorophenyl)-1,2,3,4-tetrahydro-b-carboline
(3c).6e,h
Yield 93%; light yellow solid; mp ¼ 206–207 ꢁC; (lit.6e mp ¼ 207–
208 ꢁC).1H NMR (400 MHz, CDCl3) d ¼ 7.57 (d, J ¼ 5.2 Hz, 1H),
7.45 (br s, 1H), 7.34–7.36 (m, 2H), 7.26–7.30 (m, 3H), 7.13–7.20
(m, 2H), 5.18 (s, 1H), 3.37–3.40 (m, 1H), 3.16–3.19 (m, 1H), 2.92–
2.95 (m, 1H), 2.82–2.86 (m, 1H), 1.74 (br s, 1H); 13C NMR (100
MHz, CDCl3) d ¼ 140.3, 135.8, 133.8, 133.7, 129.8, 128.8, 127.2,
121.8, 119.4, 118.2, 110.8, 110.3, 57.2, 42.4, 22.3.
7
8
24
87
53/47
24
20
91
90
55/45
54/46
1-(2-Fluorophenyl)-1,2,3,4-tetrahydro-b-carboline (3d). Yield
98%; light yellow liquid. 1H NMR (400 MHz, CDCl3) d ¼ 7.77 (br
s, 1H), 7.52–7.54 (m, 1H), 7.25–7.31 (m, 1H), 7.17–7.20 (m, 1H),
7.02–7.14 (m, 5H), 5.54 (s, 1H), 3.24–3.29 (m, 1H), 3.09–3.15 (m,
1H), 2.77–2.91 (m, 2H), 1.94 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d ¼ 160.8 (d, J ¼ 245.0 Hz), 135.8, 132.8, 129.9 (d, J ¼ 4.0
Hz), 129.5 (d, J ¼ 8.0 Hz), 128.6 (d, J ¼ 14.0 Hz), 127.1, 124.1 (d, J
¼ 3.0 Hz), 121.6, 119.2, 118.0, 115.5 (d, J ¼ 21.0 Hz), 110.8,
110.4, 50.1 (d, J ¼ 3.0 Hz), 41.6, 22.2; HRMS (ESI) for C17H15N2F:
calcd for [M + H]+ m/z 267.1298, found 267.1292.
9
a
General procedure: entries 1–7 were performed with L-tryptophan
methyl ester (0.5 mmol) and aldehyde (0.6 mmol) in HFIP (0.8 mL)
under reuxing condition; entry
L-tryptophan methyl ester (0.5 mmol) and aldehyde (0.75 mmol) in
HFIP (0.8 mL) under reuxing condition. Yields are the isolated
yield of the cis/trans isomers, the cis/trans ratio was determined by the
weight of the isolated product. Room temperature.
8 and 9 were performed with
1-(p-Methoxyphenyl)-1,2,3,4-tetrahydro-b-carboline
(3e).6e
b
Yield 91%; light yellow solid; mp ¼ 203–204 ꢁC (lit.6e mp ¼ 205–
206 ꢁC); 1H NMR (400 MHz, CDCl3) d ¼ 7.68 (br s, 1H), 7.52–7.54
(m, 1H), 7.20 (d, J ¼ 8.8 Hz, 2H), 7.16–7.21 (m, 1H), 7.07–7.14
(m, 2H), 6.85 (d, J ¼ 8.8 Hz, 2H), 5.08 (s, 1H), 3.78 (s, 3H),
3.34–3.37 (m, 1H), 3.07–3.14 (m, 1H), 2.87–2.94 (m, 1H),
c
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2.75–2.83 (m, 1H), 1.95 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d ¼ 159.5, 135.8, 134.8, 133.8, 129.6, 127.4, 121.6, 119.3, 118.2,
114.1, 110.8, 110.1, 57.4, 55.3, 42.8, 22.5.
Methyl-(1-methyl-1,2,3,4-tetrahydro-b-carboline-1-yl) carboxy-
late (3l). Yield 84%; light yellow solid; mp ¼ 130–132 ꢁC; 1H NMR
(400 MHz, CDCl3) d ¼ 8.26 (br s, 1H), 7.50 (d, J ¼ 7.6 Hz, 1H), 7.35
(d, J ¼ 8.4 Hz, 1H), 7.18 (t, J ¼ 7.2 Hz, 1H), 7.10 (t, J ¼ 7.2 Hz, 1H),
3.78 (s, 3H), 3.21–3.27 (m, 1H), 3.13–3.19 (m, 1H), 2.75–2.83 (m,
1H), 2.67–2.73 (m, 1H), 2.39 (br s, 1H), 1.71 (s, 3H); 13C NMR (100
MHz, CDCl3) d ¼ 174.8, 136.0, 132.9, 126.8, 122.2, 119.5, 118.5,
110.9, 110.3, 58.9, 52.8, 40.9, 27.2, 22.2.
1-(1-Naphthyl)-1,2,3,4-tetrahydro-b-carboline (3f). Yield
95%; white solid; mp ¼ 167–168 ꢁC; 1H NMR (CDCl3, 400 MHz)
d ¼ 8.24 (br s, 1H), 7.88–7.90 (m, 1H), 7.82 (d, J ¼ 8.0 Hz, 1H),
7.54–7.60 (m, 2H), 7.46–7.53 (m, 2H), 7.36 (t, J ¼ 7.2 Hz, 1H),
7.25 (br s, 1H), 7.10–7.16 (m, 3H), 5.89 (s, 1H), 3.32–3.35 (m,
1H), 3.14–3.21 (m, 1H), 2.93–3.00 (m, 1H), 2.84–2.91 (m, 1H),
1.96 (br s, 1H); 13C NMR (100 MHz, CDCl3) d ¼ 136.8, 135.8,
134.3, 134.1, 131.6, 128.9, 128.7, 127.3, 126.7, 125.8, 125.2,
123.4, 121.6, 119.3, 118.1, 110.8, 110.3, 53.4, 42.5, 22.5; HRMS
(ESI) for C21H18N2: calcd for [M + H]+ m/z 299.1548, found
299.1543.
1-(2-Thienyl)-1,2,3,4-tetrahydro-b-carboline (3g).6i Yield 91%;
light yellow solid; mp ¼ 169–170 ꢁC (lit.6i mp ¼ 172–173 ꢁC); 1H
NMR (CDCl3, 400 MHz) d 7.78 (br s, 1H), 7.53 (d, J ¼ 7.6 Hz, 1H),
7.27 (d, J ¼ 4.8 Hz, 1H), 7.22 (d, J ¼ 8.0 Hz, 1H), 7.08–7.16 (m,
2H), 6.95–7.03 (m, 2H), 5.46 (s, 1H), 3.34–3.39 (m, 1H), 3.11–3.17
(m, 1H), 2.85–2.92 (m, 1H), 2.74–2.81 (m, 1H), 1.99 (br s, 1H);
13C NMR (CDCl3, 100 MHz) d ¼ 145.8, 135.7, 133.9, 127.3, 126.5,
125.7, 125.7, 121.8, 119.4, 118.4, 110.9, 109.6, 52.9, 42.4, 22.3.
1-Cyclohexyl-1,2,3,4-tetrahydro-b-carboline (3h).6h,i Yield
83%; light yellow liquid; 1H NMR (CDCl3, 400 MHz) d ¼ 7.79 (br,
1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.32 (d, J ¼ 7.6 Hz, 1H), 7.07–7.16
(m, 2H), 3.96–4.00 (m, 1H), 3.34–3.41 (m, 1H), 2.94–3.03 (m,
1H), 2.65–2.78 (m, 2H), 1.69–1.86 (m, 5H), 1.62 (br s, 1H), 1.47–
1.55 (m, 1H), 1.40–1.45 (m, 1H), 1.26–1.37 (m, 1H), 1.10–1.23
(m, 3H); 13C NMR (CDCl3, 100 MHz) d ¼ 135.6, 135.3, 127.6,
121.3, 119.2, 117.9, 110.6, 110.0, 57.8, 43.1, 42.3, 30.2, 27.5, 26.8,
26.6, 26.4, 22.8.
1-Methyl-1-(4-nitrophenyl)-1,2,3,4-tetrahydro-b-carboline (3m).
Yield 21%; brown liquid; 1H NMR (400 MHz, CDCl3) d ¼ 8.10 (d, J
¼ 8.4 Hz, 2H), 7.88 (br s, 1H), 7.56 (d, J ¼ 7.6 Hz, 1H), 7.50 (d, J ¼
8.8 Hz, 2H), 7.38 (d, J ¼ 8.0 Hz, 1H), 7.23 (t, J ¼ 7.6 Hz, 1H), 7.16 (t,
J ¼ 7.6 Hz, 1H), 3.16–3.20 (m, 1H), 2.79–2.88 (m, 1H), 2.70–2.77
(m, 2H), 1.83 (s, 3H), 1.72 (br s, 1H); 13C NMR (100 MHz, CDCl3) d
¼ 154.0, 146.8, 136.5, 135.8, 127.9, 127.2, 123.3, 122.3, 119.8,
118.6, 111.0, 110.1, 56.8, 39.7, 28.7, 22.6; HRMS (ESI) for
C18H17N3O2: calcd for [M + H]+ m/z 308.1399, found 308.1395.
Ethyl-2-(1-methyl-1,2,3,4-tetrahydro-b-carboline-1-yl) acetate
1
(3n). Yield 28%; brown liquid; H NMR (400 MHz, CDCl3) d ¼
8.83 (br s, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.33 (d, J ¼ 8.0 Hz, 1H),
7.15 (t, J ¼ 7.6 Hz, 1H), 7.08 (t, J ¼ 7.6 Hz, 1H), 4.09–4.20 (m, 2H),
3.14–3.25 (m, 2H), 2.72–2.90 (m, 4H), 1.84 (br s, 1H), 1.60 (s,
3H), 1.22 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d ¼
172.5, 138.1, 135.4, 126.9, 122.7, 119.2, 118.2, 111.0, 108.2, 60.8,
52.0, 45.8, 39.6, 26.6, 22.8, 14.1; HRMS (ESI) for C16H20N2O2:
calcd for [M + H]+ m/z 273.1603, found 273.1602.
General procedure for the preparation of products 3o, 3p in
Table 2
1-(4-Nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol (3o).6g
1-Isopropyl-1,2,3,4-tetrahydro-b-carboline (3i).6h,j Yield 94%; The hydrochloride salt of 3-hydroxytyramine 1b (95 mg, 0.5
light yellow solid; mp ¼ 117–118 ꢁC; (lit.6j mp ¼ 117 ꢁC); 1H mmol) and p-nitrobenzaldehyde 2a (76 mg, 0.5 mmol) were
NMR (400 MHz, CDCl3) d ¼ 7.81 (br s, 1H), 7.49 (d, J ¼ 7.6 Hz, dissolved in HFIP (0.8 mL) under nitrogen atmosphere. Pyri-
1H), 7.31 (d, J ¼ 8.0 Hz, 1H), 7.08–7.17 (m, 2H), 4.02–4.05 (m, dine (40 mL, 0.5 mmol) was added to free the amine. The
1H), 3.39–3.44 (m, 1H), 2.96–3.03 (m, 1H), 2.69–2.78 (m, 3H), resulting solution was reuxed and monitored by TLC. Aer
2.16–2.24 (m, 1H), 1.15 (d, J ¼ 6.8 Hz, 3H), 0.89 (d, J ¼ 7.2 Hz, completion, the reaction mixture was diluted with CH2Cl2
3H); 13C NMR (100 MHz, CDCl3) d ¼ 135.7, 134.7, 127.4, 121.6, (200 mL). The organic phase was washed with saturated
119.3, 118.0, 110.7, 110.0, 58.0, 42.9, 31.6, 22.3, 19.4, 17.0.
sodium bicarbonate solution, water, brine, and dried over
1-Pentyl-1,2,3,4-tetrahydro-b-carboline (3j).6i Yield 81%; light anhydrous MgSO4, and concentrated under reduced pressure.
yellow liquid; 1H NMR (400 MHz, CDCl3) d ¼ 7.69 (br s, 1H), 7.42 The residue was puried by column chromatography (eluent:
(d, J ¼ 7.6 Hz, 1H), 7.25 (d, J ¼ 8.0 Hz, 1H), 7.01–7.10 (m, 2H), 8% MeOH–dichloromethane) to afford 3o (133 mg, 93%) as
3.97–4.03 (m, 1H), 3.31 (dt, J ¼ 4.4, 12.8 Hz, 1H), 2.93–3.00 (m, yellow solid; decomposed at 182 ꢁC; (lit.6g mp ¼ 210–212 ꢁC
1H), 2.61–2.74 (m, 2H), 1.76–1.85 (m, 2H), 1.56–1.66 (m, 1H), (H2O)). 1H NMR (400 MHz, DMSO-d6) d ¼ 8.71 (br s, 1H), 8.55
1.36–1.52 (m, 2H), 1.22–1.33 (m, 4H), 0.83 (t, J ¼ 6.4 Hz, 3H); 13
C
(br s, 1H), 8.18 (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.4 Hz, 2H), 6.49
NMR (100 MHz, CDCl3) d ¼ 136.2, 135.5, 127.4, 121.3, 119.2, (s, 1H), 5.97 (s, 1H), 4.97 (s, 1H), 2.96–3.01 (m, 1H), 2.80–2.86
117.9, 110.6, 108.7, 52.6, 42.5, 34.9, 32.0, 25.5, 22.6, 22.5, 14.0. (m, 1H), 2.69–2.76 (m, 1H), 2.52–2.55 (m, 1H); 13C NMR (100
1-Phenyl-1-triuoromethyl-1,2,3,4-tetrahydro-b-carboline (3k). MHz, DMSO-d6) d ¼ 153.8, 146.4, 143.9, 143.1, 130.0, 127.7,
1
ꢁ
Yield 76%; white solid; mp ¼ 166–167 C; H NMR (400 MHz, 125.8, 123.1, 115.5, 114.4, 59.8, 41.6, 28.3.
CDCl3) d ¼ 8.09 (br s, 1H), 7.59 (d, J ¼ 8.0 Hz, 1H), 7.38–7.43 (m,
1-(4-Nitrophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroiso-
1
3H), 7.30–7.35 (m, 3H), 7.26 (t, J ¼ 7.2 Hz, 1H), 7.17 (t, J ¼ 7.6 Hz, quinoline (3p).5c Yield 91%; yellow solid; mp ¼ 157–158 ꢁC; H
1H), 3.20–3.29 (m, 1H), 2.88–2.96 (m, 2H), 2.71–2.80 (m, 1H), 2.18 NMR (400 MHz, DMSO-d6) d ¼ 8.86 (br s, 1H), 8.17 (d, J ¼ 8.8 Hz,
(br s, 1H); 13C NMR (100 MHz, CDCl3): d ¼ 138.2, 135.9, 128.7, 2H), 7.51 (d, J ¼ 8.8 Hz, 2H), 6.56 (s, 1H), 6.16 (s, 1H), 5.04 (s,
128.5, 127.9, 126.5, 126.2 (q, J ¼ 284 Hz), 122.9, 119.8, 118.8, 1H), 3.51 (s, 3H), 2.90–2.95 (m, 1H), 2.80–2.86 (m, 1H), 2.67–2.74
113.4, 111.2, 64.3 (q, J ¼ 27 Hz), 39.3, 22.0; HRMS (ESI) for (m, 1H), 2.54–2.60 (m, 1H); 13C NMR (100 MHz, DMSO-d6) d ¼
C18H15F3N2: calcd for [M + H]+ m/z 317.1266, found 317.1261.
153.6, 146.3, 145.7, 145.1, 129.9, 127.8, 127.3, 123.1, 115.5,
115.5, 59.5, 55.6, 40.7, 28.3.
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General procedure for the preparation of products 3q–3x in
Table 3
trans-3s. Yield 41%; white solid; mp ¼ 174–175 ꢁC; (lit.4a mp
¼ 175–176 ꢁC); 1H NMR (400 MHz, CDCl3): d ¼ 7.56 (br s, 1H),
7.55 (d, J ¼ 7.6 Hz, 1H), 7.45 (d, J ¼ 8.4 Hz, 2H), 7.24 (d, J ¼ 7.6
Hz, 1H), 7.12–7.19 (m, 4H), 5.38 (s, 1H), 3.94 (t, J ¼ 6.0 Hz, 1H),
3.72 (s, 3H), 3.26 (ddd, J ¼ 0.8, 5.6, 15.6 Hz, 1H), 3.14 (ddd, J ¼
1.2, 6.8, 15.6 Hz, 1H), 2.54 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d ¼ 174.1, 141.0, 136.1, 132.6, 131.8, 130.1, 126.9, 122.1,
122.1, 119.6, 118.3, 110.9, 108.5, 54.3, 52.5, 52.2, 24.5.
1-(2-Fluorophenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-
carboline (3t).4j
1-(p-Nitrophenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-
carboline (3q).4a The starting material of L-tryptophan methyl
ester 1d (91 mg, 0.5 mmol) and p-nitrobenzaldehyde 2a (91 mg,
0.6 mmol) was dissolved in HFIP (0.8 mL) under nitrogen
atmosphere. The resulting solution was reuxed and monitored
by TLC. Aer completion, HFIP was removed by distillation. The
residue was puried by column chromatography to afford the
cis/trans diastereoisomeric mixture of 3q (154 mg, 98%) as
yellow solid.
cis-3t. Yield 44%; white solid; mp ¼ 163–164 ꢁC; 1H NMR (400
MHz, CDCl3): d 7.59 (br s, 1H), 7.52–7.54 (m, 1H), 7.29–7.38 (m,
2H), 7.21–7.24 (m, 1H), 7.09–7.16 (m, 4H), 5.67 (s, 1H), 3.98 (dd,
J ¼ 4.0, 11.2 Hz, 1H), 3.81 (s, 3H), 3.23 (ddd, J ¼ 2.0, 4.0, 15.2 Hz,
1H), 2.96–3.04 (m, 1H), 2.51 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d 173.1, 160.9 (d, J ¼ 244.0 Hz), 136.0, 133.5, 133.0, 129.9
(d, J ¼ 4.0 Hz), 127.6 (d, J ¼ 13.0 Hz), 127.0, 124.8 (d, J ¼ 3.0 Hz),
122.0, 119.6, 118.2, 115.7 (d, J ¼ 21.0 Hz), 110.9, 109.1, 56.7,
52.3, 50.9 (d, J ¼ 4.0 Hz), 25.5.
cis-3q. Yield 51%; yellow solid; mp ¼ 150–151 ꢁC; (lit.4a mp ¼
152–153 ꢁC); 1H NMR (400 MHz, CDCl3) d ¼ 8.21 (d, J ¼ 8.4 Hz,
2H), 7.59 (d, J ¼ 8.8 Hz, 2H), 7.56 (d, J ¼ 7.2 Hz, 1H), 7.44 (br s,
1H), 7.22–7.24 (m, 1H), 7.12–7.19 (m, 2H), 5.38 (s, 1H), 3.98 (dd,
J ¼ 4.0, 11.2 Hz, 1H), 3.83 (s, 3H), 3.26 (ddd, J ¼ 1.6, 4.0, 15.2 Hz,
1H), 2.99–3.06 (m, 1H), 2.61 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d ¼ 172.9, 148.2, 148.0, 136.3, 132.9, 129.6, 126.8, 124.1,
122.4, 119.9, 118.4, 111.0, 109.5, 58.0, 56.5, 52.4, 25.4.
trans-3q. Yield: 47%; yellow solid; mp ¼ 207–208 ꢁC; (lit.4a mp
1
ꢁ
trans-3t. Yield 48%; white solid; mp ¼ 197–198 C; H NMR
(400 MHz, CDCl3): d ¼ 7.76 (br s, 1H), 7.55 (d, J ¼ 7.2 Hz, 1H),
7.24–7.30 (m, 2H), 7.10–7.18 (m, 3H), 6.97–7.03 (m, 2H), 5.79 (s,
1H), 3.92 (dd, J ¼ 5.2, 8.0 Hz, 1H), 3.73 (s, 3H), 3.25 (dd, J ¼ 4.8,
15.2 Hz, 1H), 3.06 (ddd, J ¼ 1.2, 8.0, 15.2 Hz 1H), 2.63 (br s, 1H);
13C NMR (100 MHz, CDCl3): d ¼ 173.8, 160.7 (d, J ¼ 244.0 Hz),
136.1, 131.8, 129.6 (d, J ¼ 13.0 Hz), 129.6, 128.9 (d, J ¼ 14.0 Hz),
126.8, 124.1 (d, J ¼ 3.0 Hz), 122.1, 119.5, 118.2, 115.7 (d, J ¼ 22.0
Hz), 110.9, 109.2, 52.3, 52.2, 48.1 (d, J ¼ 4.0 Hz), 24.9.
1-(2-Hydroxyphenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-
b-carboline (3u).4a,6d
1
ꢁ
¼ 205–207 C); H NMR (400 MHz, CDCl3) d ¼ 8.17 (d, J ¼ 8.8
Hz, 2H), 7.60 (br s, 1H), 7.57 (d, J ¼ 7.6 Hz, 1H), 7.49 (d, J ¼ 8.8
Hz, 2H), 7.27 (d, J ¼ 7.6 Hz, 1H), 7.13–7.21 (m, 2H), 5.53 (s, 1H),
3.93 (t, J ¼ 6.0 Hz, 1H), 3.72 (s, 3H), 3.28 (ddd, J ¼ 1.2, 5.6, 15.6
Hz, 1H), 3.16 (ddd, J ¼ 1.2, 6.4, 15.6 Hz, 1H), 2.65 (br s, 1H); 13
C
NMR (100 MHz, CDCl3) d ¼ 173.9, 149.4, 147.3, 136.2, 131.6,
129.2, 126.6, 123.7, 122.3, 119.7, 118.3, 111.0, 108.7, 54.0, 52.3,
52.2, 24.6.
1-Phenyl-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-carboline
(3r).4a
cis-3u. Yield 53%; light yellow solid; mp ¼ 175–176 ꢁC; (lit.4a
mp ¼ 162–164 ꢁC); 1H NMR (400 MHz, CDCl3): d ¼ 10.15 (br s,
1H) 7.49–7.51 (m, 1H), 7.36 (br s, 1H), 7.24–7.28 (m, 2H), 7.17–
7.19 (m, 1H), 7.06–7.14 (m, 2H), 6.90–6.94 (m, 1H), 6.82 (d, J ¼
8.0 Hz, 1H), 5.35 (s, 1H), 3.92 (dd, J ¼ 4.0, 11.2 Hz, 1H), 3.86 (s,
3H), 3.42 (br s, 1H), 3.30 (ddd, J ¼ 1.6, 4.4, 15.2 Hz, 1H), 3.03–
3.10 (m, 1H); 13C NMR (100 MHz, CDCl3): d ¼ 171.9, 157.5,
136.3, 132.2, 130.1, 128.3, 127.0, 123.2, 122.1, 119.7, 119.4,
118.3, 117.8, 111.0, 107.7, 58.7, 56.4, 52.6, 24.7.
trans-3u. Yield 43%; white solid; mp ¼ 164–165 ꢁC; (lit.6d mp ¼
168–169 ꢁC); 1H NMR (400 MHz, CDCl3): d ¼ 10.52 (br s, 1H) 7.51
(d, J ¼ 7.2 Hz, 2H), 7.23 (d, J ¼ 7.6 Hz, 2H), 7.11–7.17 (m, 3H),
6.84–6.89 (m, 2H), 5.59 (s, 1H), 4.13 (t, J ¼ 4.8 Hz, 1H), 3.73 (s, 3H),
3.25–3.36 (m, 2H), 3.12 (br s, 1H); 13C NMR (100 MHz, CDCl3): d ¼
173.3, 157.3, 136.0, 131.3, 129.7, 128.4, 126.9, 124.0, 122.2, 119.6,
119.5, 118.3, 117.5, 111.0, 106.7, 53.9, 53.0, 52.3, 23.6.
cis-3r. Yield 51%; white solid; mp ¼ 221–222 ꢁC; (lit.4a mp ¼
223–224 ꢁC); 1H NMR (400 MHz, CDCl3) d ¼ 7.53–7.55 (m, 1H),
7.44 (br s, 1H), 7.34–7.39 (m, 5H), 7.18–7.21 (m, 1H), 7.09–7.16
(m, 2H), 5.23 (s, 1H), 3.98 (dd, J ¼ 3.6, 11.2 Hz, 1H), 3.81 (s, 3H),
3.23 (ddd, J ¼ 2.0, 4.4, 15.2 Hz, 1H), 2.97–3.04 (m, 1H), 2.46 (br s,
1H); 13C NMR (100 MHz, CDCl3) d ¼ 173.2, 140.5, 136.1, 134.5,
128.9, 128.6, 127.0, 121.9, 119.6, 118.2, 110.9, 108.8, 58.6, 56.8,
52.3, 25.6.
trans-3r. Yield 46%; white solid; mp ¼ 176–177 ꢁC; (lit.4a mp
1
ꢁ
¼ 175–176 C); H NMR (400 MHz, CDCl3) d ¼ 7.66 (br s, 1H),
7.54–7.56 (m, 1H), 7.28–7.34 (m, 3H), 7.23–7.26 (m, 2H), 7.19–
7.22 (m, 1H), 7.10–7.17 (m, 2H), 5.37 (s, 1H), 3.95 (t, J ¼ 5.6 Hz,
1H), 3.70 (s, 3H), 3.26 (dd, J ¼ 5.2, 15.6 Hz, 1H), 3.12 (ddd, J ¼
1.6, 6.8, 15.6 Hz, 1H), 2.48 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d ¼ 174.1, 141.9, 136.1, 133.2, 128.7, 128.4, 128.1, 126.9, 121.9,
119.5, 118.2, 110.9, 108.4, 54.9, 52.5, 52.1, 24.6.
1-(4-Methoxyphenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-
b-carboline (3v).4a
1-(p-Bromophenyl)-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-
carboline (3s).4a
cis-3v. Yield 46%; white solid; mp ¼ 125–126 C; (lit.4a mp ¼
ꢁ
cis-3s. Yield 52%; white solid; mp ¼ 164–165 ꢁC; (lit.4a mp ¼
160–161 ꢁC); 1H NMR (400 MHz, CDCl3): d ¼ 7.53 (d, J ¼ 7.2 Hz,
1H), 7.49 (d, J ¼ 8.0 Hz, 2H), 7.42 (br s, 1H), 7.26 (d, J ¼ 7.6 Hz,
2H), 7.21 (d, J ¼ 7.2 Hz, 1H), 7.10–7.17 (m, 2H), 5.21 (s, 1H), 3.95
(dd, J ¼ 4.0, 10.8 Hz, 1H), 3.81 (s, 3H), 3.23 (ddd, J ¼ 1.6, 4.0,
14.8 Hz, 1H), 2.96–3.03 (m, 1H), 2.47 (br s, 1H); 13C NMR (100
MHz, CDCl3): d ¼ 173.0, 139.8, 136.1, 134.0, 132.1, 130.3, 127.0,
122.5, 122.1, 119.7, 118.3, 110.9, 109.1, 58.1, 56.7, 52.3, 25.6.
1
ꢁ
125–127 C); H NMR (400 MHz, CDCl3): d ¼ 7.52–7.54 (m, 1H),
7.46 (br s, 1H), 7.28 (d, J ¼ 8.4 Hz, 2H), 7.19–7.22 (m, 1H), 7.09–
7.16 (m, 2H), 6.89 (d, J ¼ 8.8 Hz, 2H), 5.19 (s, 1H), 3.97 (dd, J ¼ 4.0,
11.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.22 (ddd, J ¼ 1.6, 4.0, 15.2
Hz, 1H), 2.96–3.03 (m, 1H), 2.41 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d ¼ 173.2, 159.7, 136.0, 135.0, 132.7, 129.7, 127.1, 121.8,
119.5, 118.1, 114.2, 110.9, 108.8, 58.0, 56.9, 55.3, 52.2, 25.7.
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trans-3v. Yield 41%; white solid; mp ¼ 188–189 ꢁC; (lit.4a mp
¼ 189–190 ꢁC); 1H NMR (400 MHz, CDCl3): d ¼ 7.69 (br s, 1H),
7.55 (d, J ¼ 6.8 Hz, 1H), 7.10–7.22 (m, 5H), 6.84 (d, J ¼ 8.4 Hz,
2H), 5.34 (s, 1H), 3.95 (t, J ¼ 6.0 Hz, 1H), 3.78 (s, 3H), 3.70 (s,
3H), 3.26 (dd, J ¼ 5.2, 15.2 Hz, 1H), 3.11 (dd, J ¼ 6.8, 15.2 Hz,
1H), 2.28 (br s, 1H); 13C NMR (100 MHz, CDCl3): d ¼ 174.1,
159.3, 136.1, 134.0, 133.5, 129.5, 126.9, 121.8, 119.4, 118.2,
114.0, 110.9, 108.2, 55.3, 54.2, 52.4, 52.1, 24.6.
T. Annable and L. M. Greenberger, Cancer Res., 1998, 58,
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1-Pentyl-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-carboline
(3w).4j
cis-3w. Yield 50%; yellow liquid; 1H NMR (400 MHz, CDCl3) d
¼ 7.79 (br s, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), d 7.32 (d, J ¼ 8.0 Hz,
1H), 7.16 (t, J ¼ 7.2 Hz, 1H), 7.11 (t, J ¼ 7.2 Hz, 1H), 4.17–4.22 (m,
1H), 3.83 (s, 3H), 3.79 (dd, J ¼ 8.0, 11.2 Hz, 1H), 3.15 (ddd, J ¼
1.6, 4.0, 14.8 Hz, 1H), 2.78–2.85 (m, 1H), 2.08 (br s, 1H), 1.91–
1.95 (m, 1H) 1.67–1.75 (m, 1H), 1.44–1.56 (m, 2H), 1.33–1.40 (m,
4H), 0.90 (t, J ¼ 3.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d ¼
173.7, 135.9, 135.7, 127.2, 121.7, 119.6, 118.0, 110.8, 108.1, 56.5,
52.7, 52.2, 34.9, 32.1, 26.0, 25.0, 22.5, 14.1.
3 (a) A. Pictet and T. Spengler, Ber. Dtsch. Chem. Ges., 1911, 44,
2030–2036; (b) G. J. Tatsui, J. Pharm. Soc. Jpn., 1928, 48, 92;
¨
For reviews of Pictet–Spengler reaction: (c) J. Stokigt,
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trans-3w. Yield 41%; yellow liquid; 1H NMR (400 MHz, CDCl3)
d ¼ 7.76 (br s, 1H), 7.48 (d, J ¼ 7.6 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz,
1H), 7.08–7.17 (m, 2H), 4.21–4.24 (m, 1H), 3.98 (dd, J ¼ 5.2, 7.2
Hz, 1H), 3.75 (s, 3H), 3.12 (ddd, J ¼ 1.2, 5.2, 15.6 Hz, 1H), 2.99
(ddd, J ¼ 1.2, 7.2, 15.2 Hz, 1H), 1.90 (br s, 1H), 1.70–1.82 (m, 2H),
1.44–1.58 (m, 2H), 1.28–1.40 (m, 4H), 0.91 (t, J ¼ 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) d ¼ 174.3, 135.8, 135.7, 127.1, 121.6,
119.4, 118.0, 110.7, 106.9, 52.6, 52.1, 50.3, 35.7, 31.9 25.9, 25.0,
22.6, 14.1.
1-Isopropyl-3-methoxycarbonyl-1,2,3,4-tetrahydro-b-carbo-
line (3x).4j
cis-3x. Yield 49%; light yellow liquid; 1H NMR (400 MHz,
CDCl3) d ¼ 7.83 (br s, 1H), 7.49 (d, J ¼ 8.0 Hz, 1H), 7.32 (d, J ¼ 8.0
Hz, 1H), 7.16 (t, J ¼ 6.8 Hz, 1H), 7.11 (t, J ¼ 6.8 Hz, 1H), 4.15–4.18
(m, 1H), 3.82 (s, 3H), 3.75 (dd, J ¼ 4.4, 11.6 Hz, 1H), 3.12 (ddd, J
¼ 1.6, 4.0, 14.8 Hz, 1H), 2.75–2.82 (m, 1H), 2.18–2.25 (m, 1H),
1.99 (br s, 1H), 1.16 (d, J ¼ 6.8 Hz, 3H), 0.88 (d, J ¼ 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d ¼ 173.8, 135.9, 135.0, 127.2, 121.6,
119.5, 117.9, 110.7, 109.2, 57.8, 56.3, 52.1, 31.7, 25.9, 19.0, 16.4.
1
trans-3x. Yield 41%; light yellow liquid; H NMR (400 MHz,
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916–917; (b) S. W. Youn, J. Org. Chem., 2006, 71, 2521–
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CDCl3) d ¼ 7.76 (br s, 1H), 7.49 (d, J ¼ 7.6 Hz, 1H), 7.30 (d, J ¼ 7.6
Hz, 1H), 7.08–7.17 (m, 2H), 4.12 (d, J ¼ 4.8 Hz, 1H), 4.02 (t, J ¼
5.6 Hz, 1H), 3.70 (s, 3H), 3.01–3.13 (m, 2H), 2.01–2.11 (m, 2H),
1.11 (d, J ¼ 6.8 Hz, 3H), 0.92 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) d ¼ 174.6, 135.8, 134.6, 127.1, 121.5, 119.3, 118.0,
110.6, 107.9, 55.3, 53.5, 52.0, 32.9, 24.6 19.5, 17.8.
¨
6 (a) A. Hegedus and Z. Hell, Tetrahedron Lett., 2004, 45, 8553–
Acknowledgements
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This work was nancially supported by the NSFC (21072098,
21372119), the National Natural Science Foundation of China
Innovation Group (21121002) and the Tianjin Natural Science
Foundation (14JCYBJC20200).
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