An alternative to pictet-gams reaction triggered by hendrickson reagent: Isoquinolines and β-carbolines from amides

Article abstract of DOI:10.1055/s-0029-1217138

The Hendrickson reagent derived from triflic anhydride and triphenylphosphine oxide exhibited high oxophilicity and induced the intramolecular cyclization of β-arylethylamides perfectly. Thus, a one-pot protocol to access isoquinoline and β-carboline was developed involving cyclization followed by oxidative aromatization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1217138

PAPER
587
An Alternative to Pictet–Gams Reaction Triggered by Hendrickson Reagent:
Isoquinolines and b-Carbolines from Amides
S
ynthesis of Isoquinoli
e
nes
a
nd
b
-C
n
arbolinesfr
g
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093,
P. R. of China
Fax +86(25)83317761; E-mail: wangsz@nju.edu.cn
Received 10 September 2009; revised 19 October 2009
temperature. The proposed mechanism is depicted in
Abstract: The Hendrickson reagent derived from triflic anhydride
Scheme 1. As shown, Hedrickson reagent selectively ac-
tivated amide to form imidate, then intramolecular nu-
cleophilic attack took place to afford dihydroisoquinoline
and triphenylphosphine oxide exhibited high oxophilicity and in-
duced the intramolecular cyclization of b-arylethylamides perfect-
ly. Thus, a one-pot protocol to access isoquinoline and b-carboline
was developed involving cyclization followed by oxidative aroma- accompanied by extrusion of Ph3PO and triflic acid. The
tization.
high oxophilicity of Hendrickson reagent attracted us.
Since the cyclization triggered by Hendrickson reagent
occurred perfectly, we envisioned a one-pot protocol for
preparation of isoquinoline and b-carboline compounds
just by combining another aromatization.
Key words: Hendrickson reagent, isoquinoline, b-carboline, b-
arylethylamide, manganese(IV) oxide
Isoquinoline and b-carboline are important scaffolds ex-
isting in various naturally occurring alkaloids and synthet-
ic pharmaceuticals with extensive bioactivities.1,2 In past
decades, considerable efforts have been devoted to the as-
sembly of isoquinoline and b-carboline, and some strate-
gies developed became name reactions.3 Among them,
Pictet–Gams isoquinoline synthesis concerns cascade cy-
clization and dehydration of b-hydroxy-b-arylethyl-
amides promoted by POCl3 or P2O5. Different from the
Pictet–Gams process, an approach was herein explored to
rapidly construct isoquinoline and b-carboline motifs
starting from b-arylethylamides without a hydroxy group.
It involves intramolecular cyclization triggered by Hen-
drickson reagent.
Ph3P
TfO
PPh3
OTf
Hendrickson reagent
MeO
O
MeO
MeO
HN
O
Ph
N
MeO
Ph
OPPh3OTf
1a
– Ph3PO
OTf
MeO
MeO
MeO
N
– TfOH
N
MeO
Pioneered by the discovery that bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate (named as Hendrick-
H
Ph
Ph
son reagent) derived from triphenylphosphine oxide and Scheme 1
triflic anhydride is possessed of high dehydrative ability,4
Kelly revealed the structure by X-ray diffraction and ex-
7
Initially MnO2 was utilized as oxidant and amide 1a was
chosen as a model compound (Scheme 2, Table 1). After
completion of the cyclization promoted by Hendrickson
reagent, oxidant was added and the oxidation reaction was
performed under room temperature in CH2Cl2. To our dis-
appointment, the yield of the desired isoquinoline was
lower than 5% (entry 1). We deduced that the low reaction
temperature impeded the oxidation. Thus, the solvent was
switched to dichloroethane. The cyclization triggered by
Hendrickson reagent in dichloroethane proceeded cleanly
as that in CH2Cl2. When the oxidation was run at 80 °C for
plored its application. By utilizing the O-bridged bis-
phosphonium salt, dipeptides can be converted into thiaz-
olines, oxazolines, and imidazolidines without loss of ste-
reochemical integrity.5 Recently, Yao employed the [4+2]
aza-Diels–Alder strategy promoted by Hendrickson re-
agent as a key step to carry out the total synthesis of camp-
tothecin-family alkaloids.6
During the course of our ongoing program on heterocycle
synthesis, we found that under the action of Hendrickson
reagent generated in situ from 1.5 equivalents of triflic an-
hydride and 3.0 equivalents of triphenylphosphine oxide
in CH2Cl2, amide 1a was converted into 1-phenyl-3,4-di-
hydroisoquinoline in 95% yield within 30 minutes at room
Hendrickson reagent
O
oxidative conditions
H
MeO
MeO
MeO
MeO
N
N
Ph
Ph
SYNTHESIS 2010, No. 4, pp 0587–0592
x
x
.
x
x
.2
0
1
0
2a
1a
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217138; Art ID: F18709SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

588
M. Wu, S. Wang
PAPER
Tf2O (1.5 equiv), Ph3PO (3.0 equiv)
r.t., 30 min, PhCl; then
MnO2 (3.0 equiv), 130 °C, 4 h
H
MeO
MeO
MeO
N
O
N
R1
MeO
R1
1b–j
2b–j
Scheme 3
erated, providing expedient access to isoquinoline 2b,c
(entries 1, 2). However, the yield of 2b is higher than 2c
and it seems likely that the presence of electron-withdraw-
ing group is more advantageous. Besides nitro and meth-
oxy groups, halo substituents were compatible with the
reaction and good yields of expected isoquinolines 2d,e
were obtained (entries 3, 4). The steric effect on benzoyl
ring was not perceived, since, when sterically demanding
substituent (2-I) was introduced, the yield was almost un-
affected. In addition, 2-propenamide 1f and acetamide 1g
underwent sequential cyclization-oxidative aromatization
smoothly as benzamides did. Isoquinolines 2f and 2g were
prepared, albeit in slightly lower yields (entries 5, 6).
Noteworthy is that isoquinoline 2g is a naturally occurring
alkaloid named nigellimine, which was extracted from an
herbaceous plant.11
Table 1 Different Oxidative Conditions Screened
Entry Oxidative conditionsa
Yield
(%)b
1
2
3
4
5c
6
7
8
MnO2 (3 equiv), CH2Cl2, r.t., 8 h
<5
50
44
18
<5
80
76
80
MnO2 (3 equiv), ClCH2CH2Cl, 80 °C, 8 h
DDQ (2 equiv), ClCH2CH2Cl, 80 °C, 12 h
TPCD (3 equiv), ClCH2CH2Cl, 80 °C, 8 h
Pd/C (10%), O2, ClCH2CH2Cl, 80 °C, 8 h
MnO2 (3 equiv), PhCl, 130 °C, 4 h
MnO2 (3 equiv), PhCl, 130 °C, 8 h
MnO2 (6 equiv), PhCl, 130 °C, 4 h
After screening different amides derived from 2-(3,4-
dimethoxyphenyl)ethylamine, we turned our attention to
tryptamine (Scheme 4, Table 3). However, the cyclization
step of benzamide 3a differed from 1a. Only after per-
forming the reaction at 130 °C for about 30 minutes, could
MnO2 be allowed to add to the reaction system. Other-
wise, no b-carboline 4a could be detected. The experi-
ment result showed that the intermediate generated by the
action of Hendrickson reagent with benzamide 3a is stable
enough at room temperature and is easily destroyed by
MnO2. Accordingly, b-carboline 4a was obtained in 76%
yield (entry 1). Benzamides containing bromo and nitro
group also transformed into the tricyclic products 4b,c in
good yields (entries 2, 3). Furthermore, the process pro-
vides an effective access to prepare b-carboline alkaloids.
Thus, starting from 2-butenamide 3d, acetamide 3e, and
propanamide 3f, different b-carbolines 4d–f were isolated
in yields ranging from 71 to 85% (entries 4–6). Among
them, the b-carboline natural products 4d (vulcanine)12
and 4e (harman),13 and 1-ethyl-b-carboline 4f, which oc-
curs in the wood of Ailanthus malabarica,14 were synthe-
sized.
a Oxidant was added to the reaction mixture after the completion of
cyclodehydration promoted by Hendrickson reagent.
b Isolated yield by flash chromatography.
c Catalytic amount of 10% Pd/C.
8 hours, the yield was improved to 50% (entry 2). Then,
several oxidants other than MnO2 were screened. When
DDQ8 was used, the yield dropped to 44% (entry 3). Me-
tallic oxidant such as TPCD9 [tetrakispyridine cobalt(II)
dichromate] and 10% Pd/C10 showed inferior dehydroge-
native ability (entries 4, 5). Finally, when the oxidation re-
action temperature was elevated to 130 °C by changing
the solvent from dichloroethane to chlorobenzene, the
yield increased to 80% (entry 6). Attempt to either pro-
long the reaction time or increase the amount of oxidant
led to marginal improvements in the yield (entries 7, 8).
With the optimized condition in hand, the scope of the
process was next examined (Scheme 3, Table 2). Differ-
ent benzamides were screened to investigate the electron-
ic and steric effects by switching substituents on benzoyl
moiety, As illustrated, both electron-withdrawing (4-
NO2) and electron-donating (4-OMe) groups are well tol-
i) Tf2O (1.5 equiv), Ph3PO (3.0 equiv), PhCl
r.t., 30 min; then 130 °C, 30 min
ii) MnO2 (3.0 equiv), 130 °C, 4 h
O
HN
N
N
H
N
R2
R2
H
4a–f
3a–f
Scheme 4
Synthesis 2010, No. 4, 587–592 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoquinolines and b-Carbolines from Amides
589
Table 2 Isoquinoline Synthesis by Cyclization–Aromatizationa
Entry
Amide
Isoquinoline
Yield (%)b
MeO
MeO
H
N
MeO
MeO
O
N
1
1b
2b
86
61
NO2
NO2
MeO
MeO
H
N
MeO
MeO
O
N
2
1c
2c
OMe
O
OMe
N
MeO
MeO
H
N
MeO
MeO
3
4
1d
1e
2d
2e
85
87
I
I
MeO
MeO
H
N
MeO
MeO
O
N
Br
Br
MeO
MeO
H
N
MeO
MeO
O
N
5
6
1f
2f
77
75
Ph
Ph
MeO
MeO
H
N
MeO
MeO
O
1g
2g
N
a All reactions were performed at a concentration of 0.05 M.
b Isolated yield by flash chromatography.
Table 3 b-Carboline Synthesis by Cyclization-Aromatizationa
Entry
Amide
b-Carboline
Yield (%)
76
O
O
N
HN
HN
N
H
1
3a
4a
4b
N
H
N
N
H
2
3b
88
N
H
Br
Br
Synthesis 2010, No. 4, 587–592 © Thieme Stuttgart · New York

590
M. Wu, S. Wang
PAPER
Table 3 b-Carboline Synthesis by Cyclization-Aromatizationa (continued)
Entry
3
Amide
b-Carboline
Yield (%)
O
HN
HN
N
N
N
H
3c
4c
65
71
NO2
N
H
NO2
O
4
3d
4d
N
H
N
H
O
O
5
6
3e
3f
4e
4f
82
85
HN
HN
N
N
N
H
N
H
N
H
N
H
a All reactions were performed in 0.05 M concentration.
b Isolated yield by flash chromatography.
13C NMR (75 MHz, CDCl3): d = 158.0, 152.5, 149.8, 141.1, 139.8,
In conclusion, an alternate process for the synthesis of iso-
quinolines/b-carbolines was developed by utilizing the
133.6, 129.4, 128.32, 128.30, 122.3, 118.6, 105.4, 104.8, 55.9, 55.7.
oxophilicity of Hendrickson reagent. The process also MS: m/z (%) = 266 (M + 1, 2), 265 (M+, 100), 264 (M – 1, 90), 250
(66), 235 (35), 234 (13).
was extended successfully to alkaloid synthesis. Further
application of Hendrickson reagent in organic synthesis
will be explored in future.
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
77.08; H, 5.78; N, 5.38.
6,7-Dimethoxy-1-(4-nitrophenyl)isoquinoline (2b)16
Yellow needles; mp 243–244 °C (EtOH).
IR (KBr): 3008, 1560, 1515, 1508, 1483, 1267, 1238, 853 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.51 (d, J = 5.7 Hz, 1 H), 8.40 (d,
J = 8.7 Hz, 2 H), 7.91 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 5.7 Hz, 1 H),
7.22 (s, 1 H), 7.18 (s, 1 H), 4.07 (s, 3 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.4, 152.9, 150.6, 147.7, 146.3,
141.2, 133.9, 130.6, 123.6, 122.2, 119.8, 105.1, 104.2, 56.1, 55.9.
All melting points were determined on a Yanaco apparatus and are
uncorrected. IR spectra were recorded on a Shimider IDP440 spec-
trometer as KBr pellets, H NMR spectra on a Bruker ACF-300
spectrometer with TMS or residual solvent as internal reference,
and MS spectra on a VG-ZAB-HS mass spectrometer at 70 eV. El-
emental analyses were performed on a PerkinElmer 240C instru-
ment. Petroleum ether (PE) refers to the fraction boiling in the range
60–90 °C.
1
MS: m/z (%) = 311 (M + 1, 3), 310 (M+, 100), 309 (M – 1, 17), 295
(28), 280 (24), 279 (28), 249 (30).
Isoquinolines 2a–g; General Procedure
Triflic anhydride (0.05 mL, 0.3 mmol) was added dropwise by sy-
ringe to a stirred solution of Ph3PO (0.166 g, 0.6 mmol) in anhyd
chlorobenzene (4.0 mL) at 0 °C. After 10 min, the appropriate
amide 1 (0.2 mmol) was added in one portion. Then the reaction
mixture was stirred at r.t. for 30 min. MnO2 (52.0 mg, 0.6 mmol)
was added and the reaction was heated at 130 °C for 4 h. After cool-
ing, the mixture was diluted with CHCl3 (20 mL) and filtered
through Celite to remove insoluble precipitates. The filtrate was
washed successively with aq 10% NaHCO3 (10 mL) and brine (10
mL). The organic layer was dried (MgSO4), filtered, and concen-
trated. The residue was purified by chromatography with EtOAc–
PE (1:2) as eluent to afford the pure product (Table 2).
Anal. Calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03. Found: C,
65.89; H, 4.47; N, 9.07.
6,7-Dimethoxy-1-(4-methoxyphenyl)isoquinoline (2c)17
Colorless solid; mp 114–116 °C (EtOAc–PE).
IR (KBr): 2967, 1513, 1482, 1250, 860, 826 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.46 (d, J = 5.7 Hz, 1 H), 7.69–
7.66 (m, 2 H), 7.46 (d, J = 5.7 Hz, 1 H), 7.41 (s, 1 H), 7.11 (s, 1 H),
7.08–7.05 (m, 2 H), 4.04 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.7, 157.9, 152.5, 149.8, 141.3,
133.7, 132.5, 130.8, 122.4, 118.3, 113.8, 105.6, 104.9, 56.0, 55.8,
55.3.
6,7-Dimethoxy-1-phenylisoquinoline (2a)15
Colorless solid; mp 119–122 °C (EtOH–PE).
IR (KBr): 2993, 1624, 1560, 1507, 1475, 1236, 764 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.47 (d, J = 5.4 Hz, 1 H), 7.71 (d,
J = 7.8 Hz, 2 H), 7.55–7.48 (m, 4 H), 7.37 (s, 1 H), 7.11 (s, 1 H),
4.02 (s, 3 H), 3.85 (s, 3 H).
MS: m/z (%) = 296 (M + 1, 3), 295 (M+, 100), 294 (M – 1, 41), 280
(77), 265 (29), 264 (29).
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
73.11; H, 5.81; N, 4.95.
Synthesis 2010, No. 4, 587–592 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoquinolines and b-Carbolines from Amides
b-Carbolines 4a–f; General Procedure
591
6,7-Dimethoxy-1-(2-iodophenyl)isoquinoline (2d)
Colorless solid; mp 74–78 °C (EtOH–PE).
Triflic anhydride (0.05 mL, 0.3 mmol) was added dropwise by sy-
ringe to a stirred solution of Ph3PO (0.166 g, 0.6 mmol) in anhyd
chlorobenzene (4.0 mL) at 0 °C. After 10 min, the appropriate
amide 3 (0.2 mmol) was added in one portion. The reaction mixture
was stirred at r.t. for 30 min and then heated at 130 °C for another
30 min. MnO2 (52.0 mg, 0.6 mmol) was added and the reaction was
maintained at the same temperature for 4 h. After cooling, the mix-
ture was diluted with CHCl3 (20 mL) and filtered through Celite to
remove insoluble precipitates. The filtrate was washed with aq 10%
NaHCO3 (10 mL) and brine (10 mL) successively. The organic lay-
er was dried (MgSO4), filtered, and concentrated. The residue was
purified by chromatography with EtOAc–PE (1:1) as eluent to af-
ford pure b-carboline (Table 3).
IR (KBr): 2958, 2933, 1621, 1563, 1504, 1477, 1234, 859, 760
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.49 (d, J = 5.4 Hz, 1 H), 8.01 (d,
J = 8.1 Hz, 1 H), 7.59 (d, J = 5.4 Hz, 1 H), 7.54–7.43 (m, 2 H),
7.21–7.16 (m, 2 H), 6.80 (s, 1 H), 4.05 (s, 3 H), 3.81 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 152.9, 150.1, 144.1, 140.8,
139.2, 133.3, 130.3, 129.8, 128.2, 122.5, 119.4, 105.2, 104.9, 97.8,
56.1, 55.9.
MS: m/z (%) = 392 (M + 1, 14), 391 (M+, 100), 264 (65), 220 (13).
Anal. Calcd for C17H14INO2: C, 52.19; H, 3.61; N, 3.58. Found: C,
52.27; H, 3.68; N, 3.74.
1-Phenyl-9H-pyrido[3,4-b]indole (4a)19
Yellow solid; mp 248–250 °C (EtOH).
6,7-Dimethoxy-1-(3-bromophenyl)isoquinoline (2e)
Colorless solid; mp 125–127 °C (EtOH–PE).
IR (KBr): 2928, 1623, 1504, 1475, 1421, 1233, 1221, 854 cm–1.
IR (KBr): 3044, 1624, 1561, 1416, 1235, 737 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.55 (s, 1 H), 8.47 (d, J = 5.4
Hz, 1 H), 8.26 (d, J = 7.8 Hz, 1 H), 8.12 (d, J = 5.1 Hz, 1 H), 8.05
(d, J = 7.2 Hz, 2 H), 7.68–7.50 (m, 5 H), 7.27 (t, J = 7.2 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 142.1, 141.1, 138.31, 138.27,
133.0, 129.2, 128.7, 128.5, 128.4, 128.2, 121.6, 120.8, 119.5, 113.9,
112.4.
1H NMR (300 MHz, CDCl3): d = 8.47 (d, J = 5.4 Hz, 1 H), 7.89 (t,
J = 1.8 Hz, 1 H), 7.66–7.60 (m, 2 H), 7.52 (dd, J = 6.0, 0.6 Hz, 1 H),
7.40 (dt, J = 7.8, 0.6 Hz, 1 H), 7.30 (s, 1 H), 7.13 (s, 1 H), 4.05 (s, 3
H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.4, 152.7, 150.2, 141.9, 141.2,
133.7, 132.6, 131.4, 129.8, 128.1, 122.6, 122.3, 119.1, 104.96,
104.87, 55.0, 55.9.
MS: m/z (%) = 245 (M + 1, 1), 244 (M+, 89), 243 (M – 1, 100).
Anal. Calcd for C17H12N2: C, 83.58; H, 4.95; N, 11.47. Found: C,
83.67; H, 5.01; N, 11.64.
MS: m/z (%) = 345 (M + 2, 53), 344 (M + 1, 23), 343 (M+, 100), 342
(M – 1, 21), 330 (30), 328 (46), 220 (19).
Anal. Calcd for C17H14BrNO2: C, 59.32; H, 4.10; N, 4.07. Found: C,
59.34; H, 4.21; N, 4.13.
1-(3-Bromophenyl)-9H-pyrido[3,4-b]indole (4b)
Colorless needles; mp 150–151 °C (EtOH–PE).
IR (KBr): 3055, 1625, 1561, 1499, 1456, 1233, 740 cm–1.
6,7-Dimethoxy-1-(2-phenylethenyl)isoquinoline (2f)18
Yellow solid; mp 172–175 °C (acetone–PE).
IR (KBr): 2963, 1626, 1509, 1479, 1418, 1241, 853 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.42 (d, J = 5.4 Hz, 1 H), 7.95 (d,
J = 15.6 Hz, 1 H), 7.81 (d, J = 15.6 Hz, 1 H), 7.70–7.67 (m, 2 H),
7.48 (s, 1 H), 7.44–7.38 (m, 3 H), 7.35–7.30 (m, 1 H), 7.03 (s, 1 H),
4.06 (s, 3 H), 4.01 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 152.5, 152.0, 150.0, 141.3, 137.0,
135.1, 133.6, 128.6, 128.3, 127.3, 123.1, 122.5, 118.8, 105.1, 102.6,
55.93, 55.90.
1H NMR (300 MHz, CDCl3): d = 9.19 (s, 1 H), 8.52 (d, J = 5.1 Hz,
1 H), 8.13 (d, J = 7.8 Hz, 1 H), 8.01 (t, J = 1.8 Hz, 1 H), 7.93 (d,
J = 5.1 Hz, 1 H), 7.77 (td, J = 8.1, 1.2 Hz, 1 H), 7.53–7.44 (m, 3 H),
7.32–7.24 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 141.1, 140.6, 140.3, 139.2, 133.5,
131.6, 131.0, 130.4, 130.2, 128.6, 126.6, 123.1, 121.7, 121.6, 120.3,
114.3, 111.7.
MS: m/z (%) = 324 (M + 2, 79), 323 (M + 1, 13), 322 (M+, 100), 243
(60), 242 (32).
Anal. Calcd for C17H11BrN2: C, 63.18; H, 3.43; N, 8.67. Found: C,
63.11; H, 3.57; N, 8.59.
MS: m/z (%) = 292 (M + 1, 0.4), 291 (M+, 23), 290 (M – 1, 100),
276 (18), 274 (15).
1-(2-Nitrophenyl)-9H-pyrido[3,4-b]indole (4c)20
Yellow needles; mp 208–209 °C (acetone–PE).
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.29; H, 6.03; N, 4.90.
IR (KBr): 3068, 1626, 1524, 1351, 1235, 738 cm–1.
6,7-Dimethoxy-1-methylisoquinoline (2g)11
Colorless solid; mp 142–145 °C (acetone–PE).
1H NMR (300 MHz, DMSO-d6): d = 11.61 (s, 1 H), 8.36 (d, J = 5.4
Hz, 1 H), 8.29 (d, J = 7.8 Hz, 1 H), 8.16 (d, J = 5.7 Hz, 2 H), 7.95–
7.88 (m, 2 H), 7.81–7.75 (m, 1 H), 7.58–7.57 (m, 2 H), 7.31–7.26
(m, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 149.1, 141.0, 139.3, 138.0,
133.5, 133.1, 132.5, 131.5, 129.7, 128.9, 128.4, 124.6, 121.7, 120.7,
119.6, 114.5, 112.1.
IR (KBr): 2968, 1620, 1569, 1508, 1479, 1422, 1234, 1205, 1160,
861, 839 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.28 (d, J = 5.7 Hz, 1 H), 7.38 (d,
J = 5.7 Hz, 1 H), 7.27 (s, 1 H), 7.06 (s, 1 H), 4.04 (s, 3 H), 4.03 (s,
3 H), 2.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.8, 152.4, 149.8, 140.8, 132.6,
123.1, 118.1, 105.2, 103.7, 55.94, 55.90, 22.4.
MS: m/z (%) = 290 (M + 1, 2), 289 (M+, 100), 272 (18), 257 (57),
256 (16), 243 (79), 242 (64).
MS: m/z (%) = 204 (M + 1, 2), 203 (M+, 100), 202 (M – 1, 1), 188
(15), 160 (65), 145 (8), 117 (15).
Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83; N, 14.53. Found: C,
70.51; H, 4.01; N, 14.55.
Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C,
70.87; H, 6.37; N, 6.89.
1-(2-Methylprop-1-en-1-yl)-9H-pyrido[3,4-b]indole (4d)12
Pale yellow solid; mp 162–165 °C (acetone–PE).
Synthesis 2010, No. 4, 587–592 © Thieme Stuttgart · New York

592
M. Wu, S. Wang
PAPER
IR (KBr): 3060, 1660, 1624, 1563, 1505, 1424, 1252, 1241, 746
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.56 (s, 1 H), 8.32 (d, J = 5.4
Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 5.1 Hz, 1 H), 7.60
(d, J = 8.4 Hz, 1 H), 7.52 (td, J = 6.9, 0.6 Hz, 1 H), 7.22 (t, J = 6.9
Hz, 1 H), 6.82 (s, 1 H), 2.25 (s, 3 H), 2.05 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 141.5, 140.9, 140.2, 137.5,
134.0, 127.8, 127.5, 121.5, 121.0, 119.6, 119.2, 112.4, 111.9, 27.4,
20.2.
Heterocyclic Chemistry; Li, J. J.; Corey, E. J., Eds.; Wiley:
Hoboken, NJ, 2005, 376–385. (c) Pictet, A.; Spengler, T.
Ber. Dtsch. Chem. Ges. 1911, 44, 2030. (d) Tinsley, J. M.
Pictet–Gams Isoquinoline Synthesis, In Name Reactions in
Heterocyclic Chemistry; Li, J. J.; Corey, E. J., Eds.; Wiley:
Hoboken, NJ, 2005, 469–479. (e) Pictet, A.; Gams, A. Ber.
Dtsch. Chem. Ges. 1909, 42, 1973. (f) Holsworth, D. D.
Pictet–Gams Isoquinoline Synthesis, In Name Reactions in
Heterocyclic Chemistry; Li, J. J.; Corey, E. J., Eds.; Wiley:
Hoboken, NJ, 2005, 457–465. (g) Pomeranz, C. Monatsh.
Chem. 1893, 14, 116. (h) Hudson, A. Pomeranz–Fritsch
Reaction, In Name Reactions in Heterocyclic Chemistry; Li,
J. J.; Corey, E. J., Eds.; Wiley: Hoboken NJ, 2005, 480–486.
(4) (a) Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron
Lett. 1975, 16, 277. (b) Hendrickson, J. B.; Hussoin, M. S.
J. Org. Chem. 1987, 52, 4137. (c) Hendrickson, J. B.;
Hussoin, M. S. J. Org. Chem. 1989, 54, 1144.
(d) Hendrickson, J. B.; Hussoin, M. S. Synthesis 1989, 217.
(e) Hendrickson, J. B.; Hussoin, M. S. Synlett 1990, 423.
(f) Hendrickson, J. B.; Walker, M. A.; Varvak, A.; Hussoin,
M. S. Synlett 1996, 661.
(5) (a) You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem. Int.
Ed. 2003, 42, 83. (b) You, S.-L.; Kelly, J. W. J. Org. Chem.
2003, 68, 9506. (c) You, S.-L.; Kelly, J. W. Org. Lett. 2004,
6, 1681.
(6) (a) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007,
72, 6270. (b) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett.
2007, 9, 2003.
(7) (a) Janin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.;
Decaudin, D.; Monneret, C.; Poupon, M.-F. J. Chem. Soc.,
Perkin Trans. 1 2002, 529. (b) Dehmlow, H.; Aebi, J. D.;
Jolidon, S.; Ji, Y.; von de Mark, E. M.; Himber, J.; Morand,
O. H. J. Med. Chem. 2003, 46, 3354.
MS: m/z (%) = 223 (M + 1, 0.3), 222 (M+, 72), 221 (M – 1, 4), 207
(100), 206 (42).
Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found: C,
81.01; H, 6.36; N, 12.61.
1-Methyl-9H-pyrido[3,4-b]indole (4e)13
Yellow solid; mp 230–232 °C (EtOH–PE).
IR (KBr): 3060, 1624, 1567, 1503, 1321, 1235, 751 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.57 (s, 1 H), 8.21–8.17 (m,
2 H), 7.92 (d, J = 5.1 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.53 (dt,
J = 8.1, 1.2 Hz, 1 H), 7.22 (dt, J = 8.1, 1.2 Hz, 1 H), 2.77 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 142.1, 140.3, 137.5, 134.4,
127.8, 126.8, 121.7, 121.1, 119.2, 112.6, 111.9, 20.4.
MS: m/z (%) = 183 (M + 1, 1), 182 (M+, 100), 181 (M – 1, 11).
Anal. Calcd for C12H10N2: C, 79.10; H, 5.53; N, 15.37. Found: C,
78.93; H, 5.47; N, 15.21.
1-Ethyl-9H-pyrido[3,4-b]indole (4f)14
Brown solid; mp 192–195 °C (acetone–PE).
IR (KBr): 3066, 2966, 1624, 1505, 1324, 1243, 1023, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.57 (s, 1 H), 8.42 (d, J = 5.4 Hz,
1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.85 (d, J = 5.4 Hz, 1 H), 7.55–7.47
(m, 2 H), 7.30–7.25 (m, 1 H), 3.18 (q, J = 7.5 Hz, 2 H), 1.44 (t,
J = 7.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 146.9, 140.4, 138.3, 134.1, 128.7,
128.2, 121.9, 121.7, 119.9, 112.9, 111.6, 27.3, 12.8.
(8) (a) Somei, M.; Sato, H.; Komura, N.; Kaneko, C.
Heterocycles 1985, 23, 1101. (b) Winkler, J. D.; Londregan,
A. T.; Hammann, M. T. Org. Lett. 2006, 8, 2591.
(9) (a) Wei, X.; Hu, Y.; Li, T.; Hu, H. J. Chem. Soc., Perkin
Trans. 1 1993, 2487. (b) Wang, B.; Zhang, X.; Li, J.; Jiang,
X.; Hu, Y.; Hu, H. J. Chem. Soc., Perkin Trans. 1 1999,
1571.
MS: m/z (%) = 197 (M + 1, 0.3), 196 (M+, 759), 195 (M – 1, 100),
168 (12).
(10) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 3955.
(11) Rahman, A.; Malik, S.; Zaman, K. J. Nat. Prod. 1992, 55,
676.
(12) Gozler, T.; Gozler, B.; Linden, A.; Hesse, M.
Anal. Calcd for C13H12N2: C, 79.56; H, 6.16; N, 14.27. Found: C,
79.59; H, 6.17; N, 14.31.
Phytochemistry 1996, 43, 1425.
(13) Blackman, A. J.; Matthews, D. J.; Narkowicz, C. K. J. Nat.
Prod. 1987, 50, 494.
(14) Aono, H.; Koike, K.; Kaneko, J.; Ohmoto, T.
Acknowledgment
This work was financially supported by National Science Founda-
tion of China (20802034) and 973 Program (2007CB936404).
Phytochemistry 1994, 37, 579.
(15) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
(16) Walker, K. A.; Boots, M. R.; Stubbins, J. F.; Rogers, M. E.;
David, C. W. J. Med. Chem. 1983, 26, 174.
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Synthesis 2010, No. 4, 587–592 © Thieme Stuttgart · New York