One-pot synthesis of new substituted 1,2,3,4-tetrahydrocarbazoles via petasis reaction

Article abstract of DOI:10.1021/cc900194k

The one-pot synthesis of a new substituted 1,2,3,4-tetrahydrocarbazoles has been described via Petasis reactions. These tetrahydrocarbazoles exhibits various medicinal importance and might be suitable for elaboration into larger peptides at carboxy termini. The scope and limitations of this method have been examined.

Full text of DOI:10.1021/cc900194k

J. Comb. Chem. 2010, 12, 617–629
617
One-Pot Synthesis of New Substituted 1,2,3,4-Tetrahydrocarbazoles
via Petasis Reaction
Subhasish Neogi, Amrita Roy, and Dinabandhu Naskar*
Syngene International Ltd, Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road,
Bangalore 560 099, India
ReceiVed July 7, 2009
The one-pot synthesis of a new substituted 1,2,3,4-tetrahydrocarbazoles has been described via Petasis
reactions. These tetrahydrocarbazoles exhibits various medicinal importance and might be suitable for
elaboration into larger peptides at carboxy termini. The scope and limitations of this method have been
examined.
Fabio et al.14 and Koppitz et al.15 also reported that
substituted tetrahydrocarbazoles (V and VI, respectively) act
as a new NPY-1 antagonists and as a GPCR antagonists
respectively. Neuropeptide Y (NPY) is a 36-amino acid
peptide isolated fromporcine brain in 1982 by Tatemoto et
al.16 NPY belongs to a family of biologically active polypep-
tides such as peptide YY (PYY) and pancreatic polypeptide
(PP)17 widely distributed in the central and peripheral
nervous system of many mammalian species including
humans.
Introduction
The tetrahydrocarbazole architecture widely exists in
various naturally occurring alkaloids, biologically active
molecules,andsyntheticanaloguesofmedicinalimportance,1-3
some of which can be potentially used as tumor growth
inhibitors and protein kinase C inhibitors.4
It was reported5 by Glennon et al. that 1,2,3,4-tertrahydro
carbazoles (I) act as 5-HT6 serotonin receptor ligands.
Evidence suggests that these receptors could play a role in
certain central disorders, such as schizophrenia and depres-
sion, and more recent information implicates possible
involvement in cognition (but see Lindner et al.),6c convul-
sive disorders, and obesity.6
For this reason, the development of new and efficient
methods for the synthesis of tetrahydrocarbazole deriva-
tives continues to attract considerable attention. Many
elegant methods for the synthesis of various tetrahydro-
carbazole derivatives have been developed in the past
years,18 including reductive cyclization of 2-nitrobi-
phenyl,18q-s Pd-catalyzed oxidation cyclization of 3-(3′-
alkenyl)indoles,18t intramolecular arylation of N,N-diaryl
amines,18u,v and alkyllithium-mediated intramolecular
anionic cyclization.18w However, many of these methods
involve harsh reaction conditions, expensive reagents,
complex handling, and low yields of products. Thus, it
was desirable to develop operationally simple, more
efficient, and practical approaches for the construction of
tetrahydrocarbazoles.
Recently, Gudmundsson et al. reported7 that substituted
tetrahydrocarbazoles (II) act as a potent activity against
human papillomaviruses (HPVs) which are small nonenvel-
oped DNA viruses that cause a wide variety of benign and
premallignant epithelical tumors. Several HPVs infect the
genital mucosa. HPV infection is the most common sexually
transmitted disease throughout the world, with an incidence
roughly twice that of herpes simplex infection.8 There are
over 5.5 million new cases of sexually transmitted HPV
infection that occur in the U.S. each year, with at least 20
million people currently infected.9
Recently, Barf et al. also reported10 that N-substituted-
indolo carboxylic acids (III) act as a potent and selective
adipocyte fatty-acid binding protein (A-FABP) inhibitors
which are tissue-specific, ∼15 KDa cytoplasmic lipid
chaperones, capable of binding and transporting endogenous
fatty acids from the cell surface to the various sites of
metabolism or storage.11 Consequently, the role of fatty-acid
binding proteins (FABPs) is directly linked to lipid-mediated
biology such as signaling pathways, trafficking and mem-
brane synthesis.12
With the recent emergence of combinatorial chemistry
and high-speed parallel synthesis in the lead discovery
arena, the multicomponent reaction (MCR) has witnessed
a resurgence of interest.19 Easily automated one-pot
reactions, such as Ugi,20 Passerini,21 Petasis22 reactions
are powerful tools for producing diverse arrays of
compounds, often in one step and high yield. The Petasis
boronic acid-Mannich reaction that provides a powerful
and convenient method for the preparation of R-amino
acids22 is also quite useful for the synthesis of combina-
torial libraries. In earlier studies, it was shown that
hydrazinecanparticipateinthePetasisboronicacid-Mannich
reaction to afford various R-hydrazinocarboxylic acids.23
Because of our interests in the synthesis of combinatorial
There was a report13 by Brown et al. that 1,2,3,4-
tetrahydorcarbazoles (IV) show relatively good antioxidants
properties.
* To whom correspondence should be addressed. E-mail:
dinabandhu.naskar@syngeneintl.com or dbn70@yahoo.com.
10.1021/cc900194k  2010 American Chemical Society
Published on Web 06/29/2010

618 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
Table 1. Synthesis of 1,2,3,4-Tetrahydro Substituted Carbazole Derivatives
a All yields refer to pure, isolated products; the reactions proceed through the Petasis, removal of the Boc group, coupling, and cyclization in
one pot without purification until the final product (2) is isolated. All compounds have been characterized by LC-MS, 1H NMR, 13C NMR, FAB,
and HRMS.
libraries of heterocycles for drug discovery,24,25 we have
investigated further the scope and limitations of using
substituted hydrazines in the Petasis boronic acid-
Mannich reaction. Within this context, we wished to apply
the strategy more broadly to the preparation of hetero-
cycles, that is, druglike chemical collections, for high-
throughput biological screening. Herein, we report a
practical method for the synthesis of substituted 1,2,3,4-
tetrahydrocarbazoles Via multicomponent condensation
reactions in one pot. However, there is no literature report
available for the synthesis of 1,2,3,4-tetrahydrocarbazoles
2 via Petasis reaction.

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 619
Figure 1. Substituted hydrazines.
Figure 2. Substituted boronic acids.
Scheme 1. Synthesis of 1,2,3,4-Tetrahydro Substituted Carbazoles
The lack of general synthetic method may have precluded
a comprehensive biological evaluation of this interesting
structural class of compounds for these new substituted
1,2,3,4-tetrahydrocarbazoles. Herein, we report an efficient
synthesis of substituted 1,2,3,4-tetrahydrocarbazoles 2 via
multicomponent condensation reactions in one pot (Table
1).
Figure 3. Substituted cyclohexanones.
dro-carbazol-9-yl)-R-phenyl acetic acid derivatives after
purification by column chromatography. It is to be noted
that when R1 ) H, and R2 ) aryl [2(VII)-2(XIII)], these
reactions proceeded in moderate yields affording 21-44%
of the corresponding desired products after purification.
It is also interesting to note that when R1 ) 4-F and R2 )
aryl [2(XIV)-2(XXII)], these reactions proceeded in
moderate yields affording 25-49% of the corresponding
(1,2,3,4-tetrahydro-carbazol-9-yl)-R-phenyl acetic acid
derivatives after purification by column chromatography.
When R1 ) 4-CH3; 2-CH3, 3-CH3, and R2 ) aryl [2(XXIII)-
2(XXXII)], these reactions proceeded in moderate yields
affording 27-32% of the corresponding desired products
after purification. It is noteworthy that the reactions
proceed through the Petasis, followed by removal of the
Boc group and Fischer indole in one pot without purifica-
tion of intermediate until the final product (2) is isolated
(Table 1).
Result and Discussion
A variety of N-1-Boc-N-2-(phenyl substituted)-hydra-
zines23 (1, Figure 1) were subjected to Petasis three-
component condensation reaction in presence of glyoxylic
acid monohydrate and a variety of boronic acids (Figure
2) in DCM (Scheme 1). The resulting mixture was stirred
at ambient temperature for 12 h and then to this reaction
mixture was added cyclohexanone followed by TFA and
stirred at ambient temperature for 24 h. The solvent was
removed under reduced pressure and the crude reaction
mixture was purified by column chromatography using
silica gel to furnish the desired products (Figure 4 and
5). In Table 1, when R1 ) 4-OMe and R2 ) aryl
[2(I)-2(VI)], these reactions proceeded in good yields
affording 38-51% of the corresponding (1,2,3,4-tetrahy-
We explored the diversity at the ketone step with
butanone, pentanone, heptanone, and piperidone to expand
the scope of the reaction, but the reactions gave no
tetrahydrocarbazole products. However, substituted cyl-
cohexanone (Figure 3, Scheme 2) proceeded in moderate
yields affording 30-37% of the corresponding desired

620 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
Figure 4. New substituted 1,2,3,4-tetrahydro substituted carbazoles.
Conclusion
products [3(I)-3(IX)] after purification (Figure 5). It is
noteworthy that the reactions proceed through the Petasis,
followed by removal of the Boc group and Fischer indole
in one pot without purification of intermediate until the
final product (3) is isolated (Table 2).
In summary, we have demonstrated that an efficient synthesis
of substituted 1,2,3,4-tetrahydrocarbazoles have been developed
from N-1-Boc-N-2-(phenyl substituted)-hydrazines utilizing
multicomponent condensation reactions in one pot. All these

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 621
Scheme 2. Synthesis of 1,2,3,4-Tetrahydro Substituted Carbazoles
compounds are having three points of diversity and these can
be further derivatized at the carboxy terminal to provide more
elaborate peptide. To the best of our knowledge these com-
pounds have not been synthesized previously.
2(I): white solid; mp (Met-Temp) 162°-164 °C (uncor-
rected); analytical HPLC symmetry C18 (4.6 × 75 mm, 3.5
µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.59 min, 98.76%
1
purity; H NMR (DMSO-d6, 400 MHz) δ 0.96-1.02 (m,
Experimental Section
1H), 1.23-1.34 (m, 1H), 1.48-1.51 (m, 1H), 1.68-1.74 (m,
2H), 1.80-1.86 (m, 1H), 2.05-2.08 (m, 1H), 2.31-2.34 (m,
1H), 3.42 (s, 3H), 4.59 (s, 1H), 5.36 (s, 1H), 6.05-6.06 (m,
1H), 6.55-6.64 (m, 4H), 6.97-6.99 (d, J ) 7.92, 1H), 7.16
(s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 18.97, 22.74,
31.82, 33.73, 55.21, 55.54, 79.42, 101.52, 105.32, 108.23,
110.20, 111.57, 112.53, 114.13, 124.90, 127.36, 132.84,
140.82, 147.00, 152.35, 174.61; LCMS (UV) 380.2 (M +
H+); FABMS 380 [calcd for C22H22NO5, 380.41 (M + H+)].
General Procedure for the Synthesis of (1,2,3,4-Tet-
rahydro-substituted carbazol-9-yl)-r-substituted Phen-
yl Acetic Acid Derivatives 2 (Table 1). To a stirred mixture
of glyoxylic acid monohydrate (92 mg, 1 mmol) in DCM (4
mL) was added N-(4-methoxy phenyl)hydrazinecarboxylic
acid tert-butyl ester (238 mg, 1 mmol), followed by 3,4-
(methylenedioxy)phenylboronic acid (166 mg, 1 mmol). The
resulting mixture was stirred at ambient temperature for 12 h
and then to this reaction mixture was added cyclohexanone
(294 mg, 3 mmol) followed by TFA (342 mg, 3 mmol) and
stirred at ambient temperature for 24 h. The solvent was
removed under reduced pressure and the crude reaction
mixture was purified by column chromatography using silica
gel (230-400 mesh) and EtOAc/hexane as eluent to furnish
the desired product 2(I) as white solid (193.5 mg, 51%).
2(II): white solid; mp (Met-Temp) 83°-84 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 0.1%TFA/CH3CN linear
gradient over 12 min, with a flow of 0.8 mL/min, one peak
detected by ELS and UV at Rt ) 4.71 min, 97.48% purity;
1H NMR (CDCl3, 400 MHz) δ 1.25-1.30 (m, 1H), 1.50-1.55
Figure 5. New substituted 1,2,3,4-tetrahydro substituted carbazoles.

622 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
Table 2. Synthesis of 1,2,3,4-tetrahydro substituted carbazole derivatives
a All yields refer to pure, isolated products; the reactions proceed through the Petasis, removal of the Boc group, coupling, and cyclization in one pot
1
without purification until the final product (3) is isolated. All compounds have been characterized by LC-MS, H NMR, and 13C NMR.
(m, 1H), 1.80-1.86 (m, 2H), 1.95-2.03 (m, 2H), 2.24-2.28
(m, 1H), 2.52-2.56 (m, 1H), 3.35 (s, 3H), 5.22 (m, 2H),
6.65 (s, 2H), 7.16-7.18 (d, J ) 7.28, 1H), 7.46-7.50 (m,
1H), 7.53-7.62 (m, 2H), 7.91-7.93 (d, J ) 8.16, 1H),
7.95-7.97 (d, J ) 7.88, 1H), 8.10-8.12 (d, J ) 8.4, 1H);
13C NMR (CDCl3, 100 MHz) δ 20.36, 22.27, 29.69, 33.31,
47.61, 55.63, 110.67, 112.79, 114.83, 122.25, 124.87, 125.63,
126.51, 128.79, 129.37, 129.41, 131.71, 132.31, 133.00,
133.75, 139.53, 153.14, 174.93; LCMS (UV) 386.2 (M +
H+); Anal. Calcd for C25H23NO3 C 77.90, H 6.01, N 3.63;
Found C 77.81, H 6.06, N 3.60.
2(III): white solid; mp (Met-Temp) 79°-80 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 0.1%TFA/CH3CN linear
gradient over 12 min, with a flow of 0.8 mL/min, one peak
detected by ELS and UV at Rt ) 4.69 min, 98.30% purity;
1H NMR (CDCl3, 300 MHz) δ 1.26-1.27 (m, 1H), 1.48-1.51
(m, 2H), 1.71-1.77 (m, 2H), 1.82-1.86 (m, 1H), 2.18 (m,
1H), 2.50 (m, 1H), 3.50 (s, 3H), 3.93 (s, 3H), 4.23 (s, 1H),
5.47 (s, 1H), 6.65 (m, 2H), 6.92-7.03 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 20.14, 22.36, 32.81, 33.23, 51.09,
55.97, 56.27, 104.07, 110.71, 112.53, 112.94, 114.58, 118.76,
118.95, 125.49, 127.00, 131.92, 139.63, 147.49, 150.58,
153.03, 173.75; LCMS (UV) 384.2 (M + H+); Anal. Calcd
for C22H22FNO4 C 68.92, H 5.78, N 3.65; Found C 68.83,
H 5.75, N 3.67.
2(IV): white solid; mp (Met-Temp) 86°-88 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 0.1% TFA/CH3CN linear
gradient over 12 min, with a flow of 0.8 mL/min, one peak
detected by ELS and UV at Rt ) 4.53 min, 96.03% purity;
1H NMR (CDCl3, 400 MHz) δ 1.27 (m, 1H), 1.42-1.48 (m,
1H), 1.57-1.59 (m, 1H), 1.71 (m, 1H), 1.78-1.82 (m, 1H),
1.85-1.86 (m, 1H), 2.19-2.22 (m, 1H), 2.44 (m, 1H), 2.47
(s, 3H), 3.46 (s, 3H), 3.79 (s, 1H), 4.27 (s, 1H), 5.43 (s,
1H), 6.64 (m, 2H), 7.12-7.14 (d, J ) 8.28, 2H), 7.14 (m,
1H), 7.24-7.30 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ
15.81, 20.11, 22.38, 32.86, 33.06, 51.56, 55.61, 104.13,
110.66, 112.40, 114.63, 126.16, 126.46, 129.46, 130.02,
130.18, 131.48, 132.08, 138.66, 139.61, 153.40, 173.97;
LCMS (UV) 382.2 (M + H+); Anal. Calcd for C22H23NO3S
C 69.26, H 6.08, N 3.67; Found C 69.32, H 6.10, N 3.68.
2(V): white solid; mp (Met-Temp) 192°-193 °C (uncor-
rected); analytical HPLC Symmetry C18 (4.6X 75 mm, 3.5
µmparticle size), mobile phase 10 mM. NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.79 min, 99.49%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.26-1.30 (m, 1H),

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 623
1
1.42-1.47 (m, 2H), 1.57-1.71 (m, 2H), 1.78-1.85 (m, 1H),
2.20-2.24 (m, 1H), 2.44-2.48 (m, 1H), 3.37 (s, 3H), 3.78
(s, 3H), 4.59 (s, 1H), 5.24 (s, 1H), 6.54-6.59 (m, 2H),
6.97-6.99 (d, J ) 8.4, 2H), 7.04-7.06 (d, J ) 8.4, 2H),
7.15 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.59, 22.39,
32.89, 33.28, 55.06, 55.35, 55.65, 103.76, 110.56, 112.59,
113.57, 114.45, 124.72, 132.17, 132.32, 139.66, 153.38,
159.45, 174.33; LCMS (UV) 366.2 (M + H+); HRMS
366.1717 [Calcd for C22H24NO4 366.1705 (M + H+)].
2(VI): brown semi solid; moisture sensitive; analytical
HPLC Sunfire C18 (4.6 × 150 mm, 3.5 µmparticle size),
mobile phase 10 mM NH4OAc/CH3CN linear gradient over
30 min, with a flow of 0.7 mL/min, one peak detected by
purity; H NMR (CDCl3, 400 MHz) δ 1.22-1.30 (m, 1H),
1.43-1.50(m, 1H), 1.53-1.60 (m, 1H), 1.70-1.74 (m, 1H),
1.80-1.90 (m, 2H), 2.23-2.27 (m, 1H), 2.46-2.50 (m, 1H),
3.75 (s, 3H), 3.93 (s, 3H), 4.27 (s, 1H), 5.89-5.91 (d, J )
7.52, 1H), 6.54-6.60 (m, 2H), 6.71-6.73 (d, J ) 7.8, 1H),
6.78-6.80 (m, 1H), 6.88-6.90 (d, J ) 8.2, 1H), 7.05-7.09(m,
1H); 13C NMR (CDCl3, 100 MHz) δ 19.56, 22.29, 32.78,
33.35, 51.81, 54.95, 55.92, 103.17, 110.07, 110.62, 114.52,
119.37, 123.40, 125.23, 126.84, 128.46, 131.01, 145.91,
148.37, 148.94, 174.48; LCMS (UV) 366.2 (M + H+); Anal.
Calcd for C22H23NO4 C 72.31, H 6.34, N 3.83; Found C
71.89, H 6.52, N 3.76.
2(X): white solid; mp (Met-Temp) 194°-195 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.31 min, 98.91%
1
ELS and UV at Rt ) 16.89 min, 89.39% purity; H NMR
(CDCl3, 400 MHz) δ 1.27-1.30 (m, 1H), 1.37-1.49 (m,
1H), 1.60 (m, 1H), 1.79-1.89 (m, 3H), 2.51-2.54 (m, 1H),
2.76-2.80 (m, 1H), 3.11 (s, 3H), 4.58 (s, 1H), 5.49 (s, 1H),
6.61-6.67 (m, 2H), 6.89 (s,1H), 7.24-7.34 (m, 2H),
7.53-7.59 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 19.87,
22.28, 33.06, 33.37, 55.04, 55.51, 104.65, 107.66, 110.22,
111.09, 115.22, 121.32, 123.16, 124.44, 128.00, 132.09,
139.10, 150.88, 153.84, 154.36, 170.98; LCMS (UV) 376.2
(M + H+); Anal. Calcd for C23H21NO4 C 73.58, H 5.64, N
3.73; Found C 73.32, H 5.91, N 3.68.
1
purity; H NMR (CDCl3, 400 MHz) δ 1.44-1.48 (m, 1H),
1.52-1.59 (m, 1H), 1.71-1.75 (m, 1H), 1.79-1.87 (m, 2H),
1.91 (m, 1H), 2.21-2.25 (m, 1H), 2.48-2.51 (m, 1H), 3.95
(s, 3H), 4.24 (s, 1H), 5.85-5.87 (d, J ) 7.52, 1H), 6.57-6.61
(m, 1H), 6.73-6.75 (d, J ) 7.8, 1H), 6.90-6.99 (m, 3H),
7.01-7.11 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.52,
22.31, 32.72, 33.42, 54.89, 56.30, 103.55, 110.20, 112.90,
118.85, 119.71, 125.69, 126.32, 126.94, 128.52, 130.80,
145.83, 147.54, 150.59, 153.03, 173.82; LCMS (UV) 354.2
(M + H+); Anal. Calcd for C21H20FNO3 C 71.37, H 5.70, N
3.96; Found C 71.32, H 5.73, N 3.91.
2(VII): white solid; mp (Met-Temp) 194°-195 °C (un-
corrected); analytical HPLC Symmetry C18 (4.6 × 75 mm,
3.5 µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.92 min, 98.21%
2(XI): white solid; mp (Met-Temp) 155°-156 °C (uncor-
rected); analytical HPLC Symmetry C18 (4.6 × 75 mm, 3.5
µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.01 min, 97.24%
purity; 1H NMR (CD3OD, 400 MHz) δ 1.10-1.18 (m, 1H),
1.42-1.45 (m, 1H), 1.63-1.75 (m, 2H), 1.86-1.94 (m, 2H),
2.20-2.24 (m, 1H), 2.45-2.50 (m, 1H), 3.84 (s, 3H), 4.5
(s, 1H), 5.75-5.77 (d, J ) 7.48, 1H), 6.44-6.48 (m, 1H),
6.69-6.71 (d, J ) 7.8, 1H), 6.94-6.96 (d, J ) 8.76, 2H),
7.00-7.04 (m, 1H), 7.08-7.10 (d, J ) 8.56, 2H); 13C NMR
(CD3OD, 100 MHz) δ 20.35, 23.69, 33.08, 34.97, 52.52,
55.74, 110.65, 114.33, 119.58, 126.74, 127.42, 129.35,
133.37, 160.94, 176.2; LCMS (UV) 336.2 (M + H+); Anal.
Calcd for C21H21NO3 C 75.20, H 6.31, N 4.18; Found C
75.68, H 6.59, N 4.21.
1
purity; H NMR (CDCl3, 400 MHz) δ 1.22-1.30 (m, 1H),
1.42-1.57 (m, 2H) 1.69-1.73 (m, 1H), 1.77-1.89 (m, 2H),
2.23-2.26 (m, 1H), 2.45-2.48 (m, 1H), 4.23(s, 1H),
5.95-5.99 (m, 2H), 6.03 (m, 1H), 6.586.68 (m, 3H),
6.71-6.73 (d, J ) 7.76, 1H), 6.83-6.85 (d, J ) 7.92, 1H),
7.06-7.10 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.51,
22.27, 32.36, 33.37, 51.73, 54.91, 101.18, 102.90, 107.96,
110.08, 111.46, 119.63, 124.55, 126.54, 128.42, 130.94,
145.85, 147.38, 174.15; LCMS (UV) 350.2 (M + H+);
FABMS 350 [Calcd for C21H20NO4 350.39 (M + H+)].
2(VIII): white solid; mp (Met-Temp) 175°-176 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1%TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.05 min, 98.53%
1
purity; H NMR (DMSO-d6, 400 MHz) δ 1.60-1.70 (m,
2(XII): white solid; mp (Met-Temp) 103°-104 °C (un-
corrected); analytical HPLC Symmetry C18 (4.6 × 75 mm,
3.5 µmparticle size), mobile phase 10 mM. NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 2.64 min, 96.48%
4H), -2.09-2.14 (m, 1H), 2.59-2.61 (m, 3H), 6.98-7.02
(m, 3H), 7.27-7.31 (m, 2H), 7.38-7.52 (m, 4H), 7.78-7.80
(d, J ) 8.36, 1H), 7.95-7.97 (d, J ) 8.16, 2H), 13.56 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 21.08, 22.75, 23.26,
59.10, 110.13, 110.43, 118.04, 119.39, 121.34, 123.56,
125.50, 126.16, 126.51, 127.24, 127.88, 129.22, 129.67,
131.65, 131.75, 133.82, 136.58, 136.85, 171.50; LCMS (UV)
356.2 (M + H+); Anal. Calcd for C24H21NO2 C 81.10, H
5.96, N 3.94; Found C 81.16, H 5.94, N 3.95.
2(IX): white solid; mp (Met-Temp) 193°-°C (uncor-
rected); analytical HPLC Symmetry C18 (4.6 × 75 mm, 3.5
µmparticle size), mobile phase 10 mM. NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.61 min, 97.67%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.81-1.88(m, 4H),
2.74(m, 2H), 2.81-2.85 (m, 1H), 3.06-3.11(m, 1H), 5.96
(s, 1H), 6.55 (s, 1H), 7.09-7.13 (m, 1H), 7.16-7.29 (m,
4H), 7.44-7.48 (m, 2H), 7.81(broad peak, 1H); 13C NMR
(CDCl3, 100 MHz) δ 22.43, 23.23, 23.48, 23.59, 47.56,
105.79, 109.11, 110.41, 111.17, 119.36, 120.94, 121.16,
122.60, 123.91,.126.18, 128.35, 134.99, 136.07, 155.04,
155.20, 174.76; LCMS (UV) 346.2 (M + H+); Anal. Calcd
for C22H19NO3 C 76.50, H 5.54, N 4.06; Found C 76.12, H
5.34, N 4.08.

624 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
2(XIII): brown semi solid; moisture sensitive; analytical
HPLC Hypersil BDS C18 (4.6 × 50 mm, 5 µmparticle size),
mobile phase 0.1% TFA/CH3OH linear gradient over 12 min,
with a flow of 0.8 mL/min, one peak detected by ELS and
UV at Rt ) 5.66 min, 96.82% purity; 1H NMR (CDCl3, 400
MHz) δ 1.82-1.89 (m, 4H), 2.44-2.48 (m, 1H), 2.63-2.68
(m, 1H), 2.75-2.76 (m, 2H), 3.75(s, 3H), 6.30 (s, 1H),
6.80-6.81 (m, 2H), 6.85-6.88 (m, 1H), 7.06-7.13 (m, 3H),
7.23-7.25 (m, 1H), 7.48-7.50 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 20.82, 22.80, 23.25, 29.60, 55.18, 55.41, 110.37,
111.32, 112.02, 113.65, 117.81, 119.75, 120.99, 121.92,
123.47, 129.50, 129.95, 136.22, 137.76, 160.12, 192.08;
LCMS (UV) 336.2 (M + H+); Anal. Calcd for C21H21NO3
C 75.20, H 6.31, N 4.18; Found C 74.90, H 6.33, N 4.19.
370.2 (M + H+); Anal. Calcd for C21H20FNO2S C 68.27, H
5.46, N 3.79; Found C 68.35, H 5.49, N 3.76.
2(XVII): white solid; mp (Met-Temp) 196°-198 °C
(uncorrected); analytical HPLC Hypersil BDS C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3OH linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 4.64 min,
1
98.71% purity; H NMR (CDCl3, 400 MHz) δ 1.22-1.30
(m, 1H), 1.42-1.57 (m, 2H) 1.71-1.90 (m, 3H), 2.21-2.25
(m, 1H), 2.43-2.47 (m, 1H), 4.23 (s, 1H), 5.66-5.69 (m,
1H), 6.00-6.04 (m, 2H), 6.61-6.68(m, 3H), 6.76-6.81(m,
1H), 6.85-6.87 (d, J ) 7.8, 1H); 13C NMR (CDCl3, 100
MHz) δ 19.36, 22.18, 32.66, 33.03, 51.42, 55.05, 101.23,
103.45, 108.06, 110.30, 111.19, 113.68, 114.65, 124.39,
125.69, 132.32, 141.74, 147.48, 155.65, 158.00, 173.86;
LCMS (UV) 368.2 (M + H+); Anal. Calcd for C21H18FNO4
C 68.66, H 4.94, N 3.81; Found C 68.40, H 5.21, N 3.77.
2(XIV): white solid; mp (Met-Temp) 197°-198 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1%TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.10 min, 99.54%
2(XVIII): white solid; mp (Met-Temp) 197°-198 °C(un-
corrected); analytical HPLC Symmetry C18 (4.6 × 75 mm,
3.5 µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.07 min, 98.74%
1
purity; H NMR (DMSO-d6, 400 MHz) δ 1.61-1.71 (m,
4H), 2.13 (m, 1H), 2.57-2.65 (m, 3H), 6.79-6.84 (m, 1H),
7.05 (s, 1H), 7.12-7.14 (d, J ) 9.6, 1H), 7.23-7.30 (m,
2H), 7.42-7.53 (m, 3H), 7.75-7.77 (d, J ) 8.36, 1H),
7.96-7.98 (d, J ) 8.16, 2H), 13.61 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 20.63, 22.26, 22.76, 22.94, 58.97,
102.73, 108.25, 110.13, 110.77, 123.28, 125.13, 125.86,
126.08, 126.80, 127.87, 128.79, 129.29, 131.16, 133.12,
133.44, 138.38, 155.87, 158.18, 171.09; LCMS (UV) 374.2
(M + H+); Anal. Calcd for C24H20FNO2 C 77.19, H 5.40, N
3.75; Found C 77.12, H 5.35, N 3.77.
1
purity; H NMR (DMSO-d6, 400 MHz) δ 0.96-1.02 (m,
1H), 1.23-1.31 (m, 1H), 1.49-1.52 (m, 1H), 1.70-1.89 (m,
3H), 2.04-2.08 (m, 1H), 2.32-2.36 (m, 1H), 3.8 (s, 3H),
4.63 (s, 1H), 5.31-5.34 (m, 1H), 6.60-6.64 (m, 1H),
6.80-6.85 (m, 1H), 6.97-6.99 (d, J ) 8.72, 2H), 7.06-7.04
(d, J ) 8.6, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 18.44,
22.17, 31.31, 33.26, 54.73, 55.11, 104.22, 109.47, 112.87,
113.25, 114.29, 125.08, 131.89, 132.93, 143.17, 153.97,
156.28, 158.76, 173.86; LCMS (UV) 354.2 (M + H+);
FABMS 354 [Calcd for C21H21FNO3 354.39 (M + H+)].
2(XIX): white solid; mp (Met-Temp) 180°-181 °C
(uncorrected); analytical HPLC Hypersil BDS C18 (4.6 ×
250 mm, 5 µmparticle size), mobile phase 0.1%TFA/CH3OH
linear gradient over 28 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 12.34 min, 92.74%
2(XV): white solid; mp (Met-Temp) 194°-195 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 10 mM NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.35 min, 94.64%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.23-1.30 (m, 1H),
1.41-1.46 (m, 1H), 1.54-1.58 (m, 1H), 1.72-1.90 (m, 3H),
2.18-2.21 (m, 1H), 2.44-2.47 (m, 1H), 3.94 (s, 3H), 4.23
(s, 1H), 5.55-5.58 (d, J ) 8.8, 1H), 6.61-6.64 (m, 1H),
6.76-6.79 (m, 1H), 6.80-7.02 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 19.42, 22.22, 32.70, 33.15, 50.89, 55.11, 56.32,
103.68, 110.52, 113.06, 114.80, 118.48, 125.07, 126.85,
132.28, 141.88, 147.73, 150.64, 153.09, 155.70, 158.05,
173.53; LCMS (UV) 372.2 (M + H+); Anal. Calcd for
C21H19F2NO3 C 67.92, H 5.16, N 3.77; Found C 67.85, H
5.11, N 3.82.
1
purity; H NMR (CDCl3, 400 MHz) δ 1.22-1.30 (m, 1H),
1.44-1.61 (m, 2H), 1.73-1.92 (m, 3H), 2.21-2.25 (m, 1H),
2.46-2.49 (m, 1H), 3.80 (s, 3H), 3.94 (s, 3H), 4.26 (s, 1H),
5.66-5.69 (m, 1H), 6.64-6.67 (m, 2H), 6.77-6.82 (m, 2H),
6.90-6.92 (d, J ) 8.24, 1H); 13C NMR (CDCl3, 100 MHz)
δ 19.45, 22.20, 32.70, 33.08, 51.58, 55.13, 56.03, 103.43,
110.31, 111.01, 114.89, 122.07, 123.50, 124.66, 132.52,
141.90, 149.31, 155.65, 158.01, 173.95; Anal. Calcd for
C22H22FNO4 C 68.92, H 5.78, N 3.65; Found C 68.66, H
6.02, N 3.61.
2(XVI): yellow solid; mp (Met-Temp) 166°-167 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1% TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.05 min, 92.99%
2(XX): white solid; mp (Met-Temp) 84°-85 °C (uncor-
rected); analytical HPLC Zorbax Extend C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 10 mM. NH4OAc/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 2.93 min, 97.59%
1
1
purity; H NMR (CDCl3, 400 MHz) δ 1.82-1.91 (m, 4H),
purity; H NMR (CDCl3, 400 MHz) δ 1.82-1.86 (m, 4H),
2.34-2.38 (m, 2H), 2.48 (s, 3H), 2.60-2.69 (m, 2H), 6.22
(s, 1H), 6.73-6.78 (m, 1H), 6.92-6.95 (m, 1H), 7.09-7.12
(m, 3H), 7.16-7.26 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 15.37, 20.90, 22.82, 26.92, 41.85, 59.49, 103.22, 108.71,
109.05, 111.24, 111.45, 126.21, 127.74, 128.70, 130.50,
132.41, 137.49, 139.08, 156.25, 159.36, 173.48; LCMS (UV)
2.27 (s, 3H), 2.62-2.67 (m, 4H), 3.79 (s, 3H), 5.49 (s, 1H),
6.72-6.77 (m, 3H), 6.87-6.88 (m, 1H), 7.09-7.12 (d, J )
10.68, 1H), 7.18-7.20 (d, J ) 8.48, 1H); 13C NMR (CDCl3,
100 MHz) δ 19.72, 20.77, 22.96, 23.08, 23.19, 46.19, 55.11,
102.61, 102.93, 110.26, 110.77, 111.14, 116.34, 118.61,
127.42, 127.86, 129.17, 131.84, 136.23, 138.18, 158.69,

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 625
177.72; LCMS (UV) 368.2 (M + H+); Anal. Calcd for
C22H22FNO3 C 71.92, H 6.04, N 3.81; Found C 71.85, H
6.07, N 3.77.
101.11, 102.74, 107.87, 111.46, 119.29, 119.63, 123.92,
124.53, 126.28, 129.35, 130.28, 144.45, 147.26, 147.32,
174.18; LCMS (UV) 364.2 (M + H+); Anal. Calcd for
C22H21NO4 C 72.71, H 5.82, N 3.85; Found C 72.57, H 5.71,
N 3.77.
2(XXI): yellow solid; mp (Met-Temp) 131 °C-132 °C
(uncorrected); analytical HPLC Sunfire C18 (4.6 × 50 mm,
5 µmparticle size), mobile phase 10 mM NH4OAc/CH3OH
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.59 min, 97.24%
2(XXV): white solid; mp (Met-Temp) 232°-233 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3CN linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 3.04 min,
99.78% purity; 1H NMR (DMSO-d6, 400 MHz) δ 1.49-1.52
(m, 1H), 1.62-1.70 (m, 3H), 2.24-2.29 (m, 1H), 2.41 (s,
3H), 2.68 (m, 2H), 2.83-2.87 (m, 1H), 6.24 (s, 1H),
6.62-6.64 (d, J ) 7.4, 1H), 6.75-6.77 (d, J ) 7.44, 1H),
6.99-7.01 (d, J ) 7.12, 1H), 7.38-7.41 (m, 1H), 7.52-7.59
(m, 2H), 7.82-7.84 (d, J ) 8.16, 1H), 7.96-8.00 (m, 2H),
10.68 (s, 1H), 12.70 (s, 1H); 13C NMR (DMSO-d6, 100 MHz)
δ 16.68, 22.23, 22.62, 23.07, 23.37, 50.46, 108.00, 118.51,
118.94, 120.60, 122.87, 125.44, 125.69, 126.35, 126.49,
126.65, 127.42, 128.83, 131.36, 133.49, 134.81, 135.46,
136.13, 174.28; LCMS (UV) 370.2 (M + H+); Anal. Calcd
for C25H23NO2 C 81.27, H 6.27, N 3.79; Found C 81.34, H
6.32, N 3.83.
1
purity; H NMR (CDCl3, 400 MHz) δ 1.82-1.91 (m, 4H),
2.63 (m, 1H), 2.67-2.70 (m, 3H), 3.75(s, 3H), 6.24 (s, 1H),
6.75-6.80(m, 3H), 6.86-6.89(m, 1H), 6.95-6.98 (m, 1H),
7.09-7.12 (m, 1H), 7.24-7.28 (m, 1H); 13C NMR (CDCl3,
100 MHz) δ 20.97, 22.75, 22.85, 23.17, 55.49, 59.86, 103.21,
108.78, 109.04, 111.34, 113.23, 119.65, 121.62, 123.64,
128.74, 129.72, 130.04, 132.54, 137.58, 159.75, 192.27;
LCMS (UV) 354.2 (M + H+); Anal. Calcd for C21H20FNO3
C 71.37, H 5.70, N 3.96; Found C 70.99, H 6.06; N 3.91.
2(XXII): brown semi solid; moisture sensitive; analytical
HPLC Hypersil BDS C18 (4.6 × 250 mm, 5 µmparticle size),
mobile phase 10 mM NH4OAc/CH3OH linear gradient over
12 min, with a flow of 0.8 mL/min, one peak detected by
1
ELS and UV at Rt ) 14.98 min, 89.08% purity; H NMR
(CDCl3, 400 MHz) δ 1.81-1.93 (m, 4H), 2.46-2.50 (m,
1H), 2.62-2.71 (m, 3H), 3.98 (m, 1H), 6.28 (s, 1H),
6.73-6.78 (m, 1H), 6.93-6.96 (m, 1H), 7.10-7.13 (m, 1H),
7.20-7.22 (m, 1H), 7.33-7.39 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 20.92, 22.70, 29.59, 31.54, 59.88, 102.90,
103.13, 108.70, 108.95, 111.18, 127.29, 128.29, 128.60,
132.48, 134.05, 137.56, 174.62; LCMS (UV) 324.2 (M +
H+); Anal. Calcd for C20H18FNO2 C 74.29, H 5.61, N 4.33;
Found C 73.92, H 5.37, N 4.34.
2(XXVI): white solid; mp (Met-Temp) 87°-88 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1%TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.30 min, 96.10%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.84-1.92 (m, 4H),
2.27 (s, 3H), 2.42 (s, 3H), 2.65-2.67 (m, 2H), 2.72-2.75
(m, 2H), 3.77 (s, 3H), 5.24 (s, 1H), 6.67-6.72 (m, 1H),
6.74-6.76 (m, 1H), 6.82 (s, 1H), 7.01-7.03 (d, J ) 8.6,
2H), 7.59 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 16.70,
19.77, 20.09, 21.02, 23.21, 23.26, 53.23, 55.13, 110.95,
111.06, 115.85, 116.20, 116.38, 119.64, 122.82, 127.48,
128.39, 129.52, 129.81, 134.40, 137.85, 158.44, 178.59.
LCMS (UV) 364.2 (M + H+); Anal. Calcd for C23H25NO3
C 76.01, H 6.93, N 3.85; Found C 75.95, H 6.98, N 3.86.
2(XXIII): white solid; mp (Met-Temp) 197°-199 °C
(uncorrected); analytical HPLC Symmetry C18 (4.6 × 75
mm, 3.5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3CN linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 5.25 min,
1
91.77% purity; H NMR (CDCl3, 400 MHz) δ 1.38-1.50
(m, 2H), 1.54-1.61 (m, 1H), 1.70-1.73(m, 1H), 1.79-1.90
(m, 2H), 2.04 (s, 3H), 2.20-2.23 (m, 1H), 2.46-2.50 (m,
1H), 3.87 (s, 3H), 4.26 (s, 1H), 5.63(s, 1H), 6.63-6.65 (d,
J ) 7.88, 1H), 6.87-6.89 (d, J ) 7.88, 1H), 6.92-6.94 (d,
J ) 8.72, 2H), 7.09-7.12 (d, J ) 8.68, 2H); 13C NMR
(CDCl3, 100 MHz) δ 19.62, 20.77, 22.36, 31.92, 32.83,
54.80, 55.38, 103.29, 109.74, 113.39, 124.97, 127.38, 128.63,
128.71, 131.29, 132.23, 143.46, 159.45, 174.54; LCMS (UV)
350.2 (M + H+); Anal. Calcd for C22H23NO3 C 75.62, H
6.63, N 3.99; Found C 75.24, H 6.80, N 3.92.
2(XXVII): white semi solid; moisture sensitive; analytical
HPLC YMC Pack Pro C18 (4.6 × 250 mm, 5 µmparticle
size), mobile phase 0.1%TFA/CH3CN linear gradient over
45 min, with a flow of 0.7 mL/min, one peak detected by
1
ELS and UV at Rt ) 28.57 min, 95.19% purity; H NMR
(CDCl3, 400 MHz) δ 1.37-1.73 (m, 3H), 1.80-1.91 (m,
2H), 2.02-2.08 (m, 1H), 2.19 (s, 3H), 2.21-2.25 (m, 1H),
2.48-2.53 (m, 1H), 3.86 (s, 3H), 4.26 (s, 1H), 5.69-5.71
(d, J ) 7.52, 1H), 6.48-6.52 (m, 1H), 6.89 (s, 1H),
6.91-6.94 (d, J ) 8.6, 2H), 7.09-7.11 (d, J ) 8.52, 2H);
13C NMR (CDCl3, 100 MHz) δ 16.62, 19.60, 22.37, 31.92,
32.91, 55.09, 55.32, 102.72, 113.5, 119.27, 119.60, 124.06,
124.84, 129.34, 130.55, 132.16, 144.54, 159.35, 174.49;
LCMS (UV) 350.4 (M + H+); Anal. Calcd for C22H23NO3
C 75.62, H 6.63, N 4.01; Found C 75.82, H 6.71, N 4.02.
2(XXVIII): brown solid; mp (Met-Temp) 88 °C-89 °C
(uncorrected); analytical HPLC Hypersil BDS C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3CN linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 4.12 min,
2(XXIV): white solid; mp (Met-Temp) 205 °C-206 °C
(uncorrected); analytical HPLC Hypersil BDS C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1%TFA/CH3OH
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 5.44 min, 99.76%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.25-1.30 (m, 1H),
1.42-1.58 (m, 2H) 1.69-1.73 (m, 1H), 1.79-1.90 (m, 2H),
2.18 (s, 3H), 2.23-2.27 (m, 1H), 2.50-2.53 (m, 1H), 4.24
(s, 1H), 5.81-5.83 (d, J ) 7.52, 1H), 5.99-6.03 (m, 2H),
6.52-6.56 (m, 1H), 6.65-6.69 (m, 2H), 6.83-6.85 (d, J )
7.88, 1H),6.90-6.92 (d, J ) 7.48, 1H); 13C NMR (CDCl3,
100 MHz) δ 16.57, 19.49, 22.29, 32.80, 33.30, 51.68, 55.08,
1
93.52% purity; H NMR (CDCl3, 400 MHz) δ 1.42-1.89

626 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
(m, 5H), 2.04-2.11 (m, 1H), 2.43-2.47 (m, 1H), 2.65 (s,
3H), 2.74 (m, 1H), 3.75 (s, 3H), 6.73-6.78 (m, 2H),
6.84-6.86 (m, 2H), 6.87-6.97 (m, 2H), 7.21-7.24 (m, 1H),
7.35-7.37 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.67,
21.06, 22.72, 23.55, 29.70, 55.27, 60.69, 112.38, 113.10,
113.20, 116.26, 119.40, 119.70, 121.63, 123.65, 125.33,
128.77, 129.58, 136.71, 137.45, 159.71, 192.29; LCMS (UV)
350.2 (M + H+); Anal. Calcd for C22H23NO3 C 75.62, H
6.63, N 4.01; Found C 75.40, H 6.47; N 4.05.
for C22H23NO3 C 75.62, H 6.63, N 4.01; Found C 75.69, H
6.57, N 4.05.
2(XXXII): white solid, mp (Met-Temp) 189°-190 °C
(uncorrected), analytical HPLC Hypersil BDS C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3CN linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 4.30 min,
1
97.73% purity; H NMR (CDCl3, 400 MHz) δ 1.20-1.28
(m, 2H), 1.42-1.46 (m, 1H), 1.52-1.59 (m, 1H), 1.69-1.78
(m, 1H), 1.79-1.89 (m, 1H), 2.21 (m, 1H), 2.24 (s, 3H),
2.45-2.48 (m, 1H), 3.65 (s, 3H), 3.93 (s, 3H), 4.23 (s, 1H),
5.79-5.81 (d, J ) 7.68, 1H), 6.37-6.38 (d, J ) 7.16, 1H),
6.55 (s, 1H), 6.62 (s, 1H), 6.76-6.79 (m, 1H), 6.86-6.88
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.56, 22.43, 22.27,
32.77, 33.36, 51.71, 54.61, 55.85, 103.09, 110.47, 110.78,
114.36, 120.12, 123.35, 125.21, 126.49, 128.19, 138.51,
146.05, 148.25, 148.79, 174.35; LCMS (UV) 380.2 (M +
H+); Anal. Calcd for C23H25NO4 C 72.80, H 6.64, N 3.69;
Found C 72.88, H 6.69, N 3.63.
3(I): white solid; mp (Met-Temp) 142°-144 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (250 × 4.6)
mm, 5 µmparticle size), mobile phase 0.1%. HCOOH in
H2O/CH3OH linear gradient over 38 min, with a flow of 0.8
mL/min, one peak detected by ELS and UV at Rt ) 16.53
min, 99.28% purity; 1H NMR (CDCl3, 300 MHz) δ
1.46-1.51 (m, 1H), 1.78-1.87 (m, 1H), 2.02-2.13 (m, 2H),
2.35-2.45 (m, 1H), 2.52 (s, 3H), 2.60-2.65 (m, 1H),
2.94-3.02 (m, 1H), 4.45 (s, 1H), 5.53-5.57 (d, J ) 8.76,
1H), 6.66-6.70 (m, 1H), 6.78-6.84 (m, 1H), 7.11-7.14 (d,
J ) 8.31, 2H), 7.22-7.36 (m, 7H); 13C NMR (CDCl3, 100
MHz) δ 15.68, 29.82, 33.29, 37.72, 40.96, 51.69, 56.12,
103.10, 110.66, 113.75, 114.00, 114.95, 115.19, 126.22,
126.85, 128.56, 128.76, 131.27, 132.12, 139.25, 141.78,
144.01, 155.76, 158.12, 173.34; LCMS (UV) 446.2 (M +
H+); Anal. Calcd for C27H24FNO2S C 72.78, H 5.43, N 3.14;
Found C, 72.87, H 5.48, N 3.20.
2(XXIX): white solid; mp (Met-Temp) 184°-185 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 10 mM NH4OAc/
CH3CN linear gradient over 12 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 4.69 min,
1
96.93% purity; H NMR (CDCl3, 400 MHz) δ 1.22-1.30
(m, 1H), 1.45-1.58 (m, 2H), 1.71-1.74 (m, 1H), 1.79-1.91
(m, 2H), 2.18 (s, 3H), 2.23 (m, 1H), 2.50-2.53 (m, 1H),
3.93 (s, 3H), 4.24 (s, 1H), 5.69-5.71 (d, J ) 7.52, 1H),
6.49-6.53 (m, 1H), 6.90-6.99 (m, 4H); 13C NMR (CDCl3,
100 MHz) δ 16.59, 19.54, 22.41, 32.78, 33.48, 51.27, 55.19,
56.31, 103.68, 112.88, 118.69, 119.55, 119.87, 123.76,
125.62, 126.96, 129.56, 130.23, 144.41, 147.44, 150.58,
153.02, 174.13; LCMS (UV) 368.2 (M + H+); Anal. Calcd
for C22H22FNO3 C 71.92, H 6.04, N 3.81; Found C 71.98,
H 6.09, N 3.83.
2(XXX): white solid; mp (Met-Temp) 194°-195 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1% TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.57 min, 98.99%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.23-1.29 (m, 1H),
1.44-1.45 (m, 1H), 1.53-1.57 (m, 1H), 1.68 (m, 1H),
1.79-1.87 (m, 2H), 2.20 (m, 1H), 2.25 (s, 3H), 2.44-2.48
(m, 1H), 4.21 (s, 1H), 5.84-5.86 (d, J ) 7.64, 1H),
5.99-6.03 (m, 2H), 6.41-6.43 (d, J ) 7.68, 1H), 6.54-6.57
(m, 2H), 6.64-6.69 (m, 2H), 6.82-6.85 (d, J ) 7.92, 1H);
13C NMR (CDCl3, 100 MHz) δ 19.56, 21.48, 22.32, 32.77,
33.49, 51.78, 54.65, 101.13, 102.68, 107.20, 107.93, 108.39,
110.85, 111.11, 120.42, 124.56, 126.23, 128.17, 128.41,
138.50, 146.09, 147.03, 174.28. LCMS (UV) 364.2 (M +
H+); Anal. Calcd for C22H21NO4 C 72.71, H 5.82, N 3.85;
Found C 72.80, H 5.78, N 3.83.
3(II): white solid; mp (Met-Temp) 251°-252 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (50 × 4.6) mm,
5 µmparticle size, mobile phase 0.1% TFA in H2O/CH3OH
linear gradient over 14 min, with a flow of 1 mL/min, one
peak detected by ELS and UV at Rt ) 5.71 min, 99.39%
1
purity; H NMR (DMSO-d6, 400 MHz) δ 2.38-2.42 (m,
1H), 2.51 (s, 3H), 2.55-2.57 (m, 1H), 2.87-2.91 (m, 1H),
2.97-3.05 (m, 1H), 3.16-3.19 (m, 1H), 3.31-3.35 (m, 1H),
5.21 (s, 1H), 7.05-7.07 (d, J ) 6.32, 1H), 7.21-7.25 (m,
6H), 7.38-7.42 (m, 1H), 7.46-7.49 (m, 2H), 7.63-7.65 (d,
J ) 7.68, 2H), 10.95 (s,1H), 12.75 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 15.23, 21.54, 32.88, 33.84, 42.25,
50.40, 79.65, 102.98, 103.23, 106.34, 111.64, 120.48, 120.66,
123.30, 126.24, 126.32, 126.52, 128.52, 129.46, 129.82,
132.95, 135.28, 135.68, 137.20, 140.56, 154.21, 156.53,
173.74; LCMS (UV) 471.2 (M + H+); Anal. Calcd for
C28H23FN2O2S C 71.47, H 4.93, N 5.95; Found C, 71.52, H
4.95, N 5.97.
2(XXXI): white solid; mp (Met-Temp) 148°-149 °C
(uncorrected); analytical HPLC Zorbax Extend C18 (4.6 ×
50 mm, 5 µmparticle size), mobile phase 0.1% TFA/CH3CN
linear gradient over 12 min, with a flow of 0.8 mL/min, one
peak detected by ELS and UV at Rt ) 4.73 min, 98.14%
1
purity; H NMR (CDCl3, 400 MHz) δ 1.23-1.27 (m, 1H),
1.42-1.45 (m, 1H), 1.54-1.59 (m, 2H), 1.69-1.73 (m, 1H),
1.82-1.90 (m, 1H), 2.20 (m, 1H), 2.46 (s, 3H), 2.49 (m,
1H), 3.86 (s, 3H), 4.24 (s, 1H), 5.73-5.75 (d, J ) 7.64,
1H), 6.37-6.42 (m, 1H), 6.53-6.56 (m, 1H), 6.85-6.87 (d,
J ) 8.68, 1H), 6.91-6.93 (d, J ) 8.68, 1H), 7.06-7.03 (d,
J ) 8.6, 1H), 7.09-7.12 (d, J ) 8.68, 1H); 13C NMR
(CDCl3, 100 MHz) δ 18.49, 19.63, 21.49, 22.44, 32.81,
51.34, 55.33, 107.22, 110.87, 113.50, 114.15, 120.44, 123.17,
124.93, 126.31, 128.44, 132.12, 138.45, 146.05, 146.97,
159.33, 174.46; LCMS (UV) 350.2 (M + H+); Anal. Calcd
3(III): white solid; mp (Met-Temp) 148°-150 °C (uncor-
1
rected); H NMR (DMSO-d6, 300 MHz) δ 2.40-2.48 (m,
1H), 2.49-2.53 (m, 1H), 2.91-2.98 (m, 1H), 3.01 (m, 1H),
3.12-3.16 (m, 1H), 3.29-3.33 (m, 2H), 5.15 (s, 1H), 5.99
(s, 2H), 6.75-6.78 (d, J ) 8.01, 1H), 6.78-6.89 (m, 2H),

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 627
7.04-7.06 (d, J ) 6.33, 1H), 7.18-7.21 (d, J ) 11.04, 1H),
7.35-7.48 (m, 3H), 7.61-7.64 (d, J ) 7.68, 2H), 10.92 (s,
1H), 12.65 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 21.06,
32.36, 33.38, 41.78, 49.94, 100.97, 102.41, 102.73, 105.84,
105.89, 108.08, 109.11, 110.97, 120.16, 121.95, 122.73,
125.71, 128.01, 128.95, 132.07, 132.41, 134.75, 140.10,
146.18, 147.25, 153.29, 156.37, 173.31; LCMS (UV) 469.2
(M + H+); Anal. Calcd for C28H21FN2O4 C 71.79, H 4.52,
N 5.98; Found C, 71.66, H 4.59, N 5.91.
3(IV): white solid; mp (Met-Temp) 136°-138 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (250 × 4.6)
mm, 5 µmparticle size), mobile phase 0.1% HCOOH in H2O/
CH3OH linear gradient over 38 min, with a flow of 0.8 mL/
min, one peak detected by ELS and UV at Rt ) 14.91 min,
99.75% purity; 1H NMR (CDCl3, 40 MHz) δ 1.36-1.39 (m,
2H), 1.69-1.71 (m, 2H), 2.01 (m, 1H), 2.27-2.30 (m, 1H),
2.52 (m, 1H), 2.56 (s, 3H), 4.32 (s, 1H), 6.67-6.72 (m, 3H),
6.85-6.91 (m, 2H), 7.12-7.19 (m, 3H), 7.27-7.31 (d, J )
8.32, 2H), 7.39-7.41 (d, J ) 8.8, 2H); 13C NMR (CDCl3,
100 MHz) δ 15.91, 28.14, 34.37, 37.82, 41.25, 55.10, 56.78,
110.38, 110.99, 115.14, 115.38, 126.47, 126.53, 127.04,
128.43, 129.92, 131.06, 137.58, 137.66, 139.18, 140.63,
144.53, 156.83, 159.20, 174.89; LCMS (UV) 446.2 (M +
H+); Anal. Calcd for C27H24FNO2S C 72.78, H 5.43, N 3.14;
Found C, 72.85, H 5.39, N 3.22.
CH3OH linear gradient over 14 min, with a flow of 1 mL/
min, one peak detected by ELS and UV at Rt ) 5.35 min,
94.14% purity; 1H NMR (DMSO-d6, 400 MHz) δ 1.09-1.12
(m, 1H), 1.52-1.61 (m, 1H), 1.81-1.84 (m, 1H), 2.07-2.14
(m, 2H), 2.50 (s, 3H), 2.55 (m, 1H), 3.15-3.21 (m, 1H),
4.91 (s, 1H), 5.33-5.35 (d, J ) 8.88, 1H), 6.67-6.69 (d,
J ) 8.28, 3H), 6.83-6.88 (m, 1H), 7.04-7.11 (m, 4H),
7.33-7.35 (s, J ) 8.12, 2H), 9.19 (s, 1H); 13C NMR (DMSO-
d6, 100 MHz) δ 15.04, 30.15, 32.41, 35.33, 42.38, 50.77,
56.33, 104.49, 110.19, 113.01, 113.34, 114.76, 115.06,
115.66, 125.71, 128.09, 129.98, 131.82, 133.07, 135.56,
138.43, 143.62, 154.15, 156.18, 157.24, 173.88; LCMS (UV)
462.2 (M + H+); Anal. Calcd for C27H24FNO3S C 70.26, H
5.24, N 3.03; Found C, 70.33, H 5.28, N 3.07.
3(VIII): brown solid; mp (Met-Temp) 122°-124 °C
(uncorrected); analytical HPLC Hypersil BDS (250 × 4.6)
mm, 5 µmparticle size, mobile phase 0.1% HCOOH in H2O/
CH3OH linear gradient over 30 min, with a flow of 1.0 mL/
min, one peak detected by ELS and UV at Rt ) 16.67 min,
92.05% purity; 1H NMR (DMSO-d6, 400 MHz) δ 1.92-2.09
(m, 4H), 2.66-2.79 (m, 2H), 2.93-2.96 (m, 1H), 6.84-6.85
(m, 1H), 7.06-7.54 (m, 12H), 7.69-7.83 (m, 1H), 7.94-7.99
(m, 2H), 14.2 (br, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
22.98, 23.46, 29.04, 29.95, 59.56, 79.24, 102.51, 108.53,
109.99, 110.69, 123.24, 123.45, 125.59, 126.09, 126.67,
126.73, 126.96, 127.45, 127.54, 127.63, 128.32, 128.80,
129.16, 131.51, 131.72, 133.51, 138.18, 146.36, 155.85,
158.16, 174.90. LCMS (UV) 450.2 (M + H+); Anal. Calcd
for C30H24FNO2 C 80.16, H 5.38, N 3.12; Found C, 80.25,
H 5.42, N 3.16.
3(VI): white solid; mp (Met-Temp) 131°-132 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (50 × 4.6) mm,
5 µmparticle size, mobile phase 0.1% TFA in H2O/CH3OH
linear gradient over 14 min, with a flow of 1.0 mL/min, one
peak detected by ELS and UV at Rt ) 6.03 min, 99.07%
1
3(IX): white solid; mp (Met-Temp) 138°-140 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (50 × 4.6) mm,
5 µmparticle size, mobile phase 0.1% TFA in H2O/CH3OH
linear gradient over 14 min, with a flow of 1 mL/min, one
peak detected by ELS and UV at Rt ) 5.88 min, 95.62%
purity; H NMR (CDCl3, 400 MHz) δ 2.05-2.22 (m, 2H),
2.72-2.87 (m, 3H), 2.96-3.12 (m, 2H), 5.33 (s, 1H), 5.94
(s, 2H), 6.77-6.87 (m, 3H), 7.07-7.15 (m, 2H), 7.23-7.39
(m, 5H), 7.70 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 23.33,
29.05, 29.62, 30.17, 40.99, 49.74, 101.11, 102.95, 103.20,
108.31, 109.34, 110.71, 110.75, 119.23, 126.27, 126.96,
127.25, 128.47, 131.10, 132.32, 136.02, 146.30, 146.98,
147.89, 154.35, 156.69, 173.02; LCMS (UV) 444.2 (M +
H+); Anal. Calcd for C27H22FNO4 C 73.13, H 5.00, N 3.16;
Found C, 73.01, H 5.05, N 3.13.
3(VI): white solid; mp (Met-Temp) 165°-167 °C (uncor-
rected); analytical HPLC Hypersil BDS C18 (50 × 4.6 mm),
mobile phase 0.1% TFA in H2O/CH3OH linear gradient over
14 min, with a flow of 1 mL/min, one peak detected by ELS
and UV at Rt ) 6.00 min, 94.8% purity; 1H NMR (DMSO-
d6, 400 MHz) δ 2.04 (m, 2H), 2.64-2.67 (m, 1H), 2.72-2.91
(m, 3H), 2.96-2.99 (m, 1H), 3.74 (s, 3H), 5.16 (s, 1H),
6.91-6.93 (d, J ) 8.4, 2H), 6.97-6.99 (m, 1H), 7.08-7.10
(m, 2H), 7.21-7.23 (m, 3H), 7.29-7.33 (m, 5H), 10.72 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 23.00, 29.07, 29.96,
49.59, 55.12, 102.13, 102.37, 108.56, 110.84, 113.87, 119.69,
119.88, 126.01, 126.11, 126.97, 128.39, 129.88, 130.44,
132.34, 136.22, 146.58, 146.61, 153.67, 155.99, 158.27,
173.71; LCMS (UV) 430.2 (M + H+); Anal. Calcd for
C27H24FNO3 C 75.51, H 5.63, N 3.26; Found C, 75.69, H
5.68, N 3.23.
1
purity; H NMR (CDCl3, 400 MHz) δ 1.96-2.07 (m, 4H),
2.71-2.80 (m, 2H), 2.97-3.01 (m, 1H), 6.72-6.92 (m, 4H),
7.07-7.27 (m, 4H), 7.40-7.69 (m, 5H), 7.90-7.95 (m, 2H);
13C NMR (CDCl3, 100 MHz) δ 23.25, 23.69, 29.27, 30.45,
39.24, 59.58, 103.42, 109.16, 109.42, 115.35, 122.56, 124.85,
126.20, 127.00, 127.36, 128.04, 128.50, 129.13, 129.48,
130.07, 131.56, 133.37, 133.52, 133.87, 135.45, 136.77,
137.74, 138.48, 153.82, 156.79, 174.27. LCMS (UV) 466.2
(M + H+); Anal. Calcd for C30H24FNO3 C 77.40, H 5.20, N
3.01; Found C, 77.31, H 5.13, N, 3.08.
Acknowledgment. The authors thank Dr. Ashis Baran
Mandal and gratefully acknowledge Dr. Goutam Das, COO,
Syngene International Ltd., for his invaluable support.
Supporting Information Available. Detailed experimen-
tal procedure and compound characterization. This material
is available free of charge via the Internet at http://
pubs.acs.org.
References and Notes
(1) (a) Knolker, H. J.; Kethiri, R. R. Chem. ReV. 2002, 102, 4303.
(b) Moody, C. J. Synlett 1994, 681. (c) Misra, N.; Luthra, R.;
Singh, K. L.; Kumar, S. ComprehensiVe Natural Products
Chemistry; Kelly, J. W., Ed.; Elsevier: Amsterdam, 1999; Vol.
3(VII): white solid; mp (Met-Temp) 202°-204 °C (un-
corrected); analytical HPLC Hypersil BDS C18 (50 × 4.6)
mm, 5 µmparticle size), mobile phase 0.1% TFA in H2O/

628 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Neogi et al.
4, 54. (d) Chakraborty, D. P. Progress in Chemistry Of
Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Eds.; Springer-Verlag: Wien, 1977, 34, 299-371. (e)
Bhattacharyya, P.; Chakraborty, D. P.; Roy, S. Progress in
Chemistry Of Organic Natural Products; Herz, W., Grisebach,
H., Kirby, G. W., Tamm, C., Eds.; Springer-Verlag: Wien,
Germany, 1987, 52, 159-209. (f) Chakraborty, D. P.; Roy,
S. Progress in Chemistry Of Organic Natural Products; Herz,
W., Kirby, G. W., Steglich, G. W., Tamm, C.,. Eds.; Springer-
Verlag: Wien, Germany, 1991, 57, 71-152.
C. P.; Pecunioso, A.; Rumboldt, G.; Spada, S. Bioorg. Med.
Chem. Lett. 2006, 16, 1749.
(15) Koppitz, M.; Reinhardt, G.; Van Lingen, A. Tetrahedron. Lett.
2005, 46, 911.
(16) Tatemoto, K.; Carlquist, M.; Mutt, V. Nature 1982, 296, 659.
(17) Hipskind, P. A.; Gehlert, D. R. Annu. Rep. Med. Chem. 1996,
31, 1.
(18) (a) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase,
Y.; Miyamura, T.; Shirakawa, E. J. Am. Chem. Soc. 2008,
130, 15823. (b) Nair, V.; Nandialath, V.; Abhilash, K. G.;
Suresh, E. Org. Biomol. Chem. 2008, 6, 1738. (c) Ueno, A.;
Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999. (d) Mudadu,
M. S.; Singh, A. N.; Thummel, R. P. J. Org. Chem. 2008,
73, 6513. (e) Gu, R.; Hameurlaine, A.; Dehaen, W. J. Org.
Chem. 2007, 72, 7207. (f) Blechert, S.; Wirth, T. Tetrahedron
Lett. 1992, 33, 6621. (g) Rice, L. M.; Scott, K. R. J. Med.
Chem. 1970, 13, 308. (h) Pindur, U.; Kim, M. Tetrahedron
1989, 45, 6427. (i) Ziegler, F.; Spitzner, E. B.; Wilkins, C. K.
J. Org. Chem. 1971, 36, 1971. (j) Carter, D. S.; Van Vranken,
D. L. J. Org. Chem. 1996, 64, 8537. (k) Mahboobi, S.; Kuhr,
S.; Koller, M. Tetrahedron 1996, 52, 6373. (l) Pecca, J. G.;
Albonico, S. M. J. Med. Chem. 1970, 13, 327. (m) Back, T.;
Pandyra, A.; Wulff, J. E. J. Org. Chem. 2003, 68, 3299. (n)
Noland, W. E.; Kuryla, W. C.; Lange, R. F. J. Am. Chem.
Soc. 1959, 81, 6010. (o) Eitel, M.; Pindur, U. J. Org. Chem.
1990, 55, 5368. (p) Abbiati, G.; Canevari, V.; Facoetti, D.;
Rossi, E. Eur. J. Org. Chem. 2007, 517. (q) Cadogan, J. I. G.;
Cameron-Wood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem.
Soc. 1965, 4831. (r) Smitrovich, J. H.; Davies, I. W. Org.
Lett. 2004, 6, 533. (s) Freeman, A. W.; Urvoy, M.; Criswell,
M. E. J. Org. Chem. 2005, 70, 5014. (t) Kong, A.; Han, X.;
Lu, X. Org. Lett. 2006, 8, 1339. (u) Campeau, L.-C.;
Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857. (v) Liu,
Z.; Larock, R. C. Org. Lett. 2004, 6, 3739. (w) Sanz, R.;
Ferna’ndez, Y.; Castroviejo, M. P.; Pe’rez, A.; Fan˜ana’s, F. J.
J. Org. Chem. 2006, 71, 6291.
(2) (a) Wang, Y. S.; He, H. P; Shen, Y. M.; Hong, X.; Hao, X. J.
J. Nat. Prod. 2003, 66, 416. (b) Ito, C.; Katsuno, S.; Itoigawa,
M.; Ruangrungsi, N.; Mukainaka, T.; Okuda, M.; Kitagawa,
Y.; Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2000,
63, 125. (c) Chakravarty, A. K.; Sarkar, T.; Masuda, K.;
Shiojima, K. Phytochemistry 1999, 50, 1263. (d) Wu, T. S;
Huang, S. C.; Wu, P. L. Chem. Pharm. Bull. 1998, 46, 1459.
(e) Ito, C.; Katsuno, S.; Itoigawa, M.; Ohta, H.; Omura, M.;
Kajura, I.; Furukawa, H. Chem. Pharm. Bull. 1997, 45, 48.
(f) Chakraborty, D. P. Alkaloids 1993, 44, 257. (g) Chakraborty,
D. P.; Roy, S. Prog. Chem. Org. Nat. Prod. 1991, 57, 71.
(3) (a) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1990, 62,
1967. (b) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797.
(c) Saxton, J. E. Nat. Prod. Rep. 1997, 559.
(4) (a) Nikitenko, A.; Evrard, D.; Sabb, A. L.; Vogel, R. L.; Stack,
G.; Young, M.; Lin, M.; Harrison, B. L.; Potoski, J. R. Org.
Process Res. DeV. 2008, 12, 76. (b) Sabb, A. L.; Vogel, R. L.;
Stack, G.; Evrard, D. A.; Failli, A. A.; Krishnan, L.; Chan,
A. W.; Ren, J.; Guinosso, C.; Baudy, R. B.; Sze, J. Y. C.; Li,
Y.; Stanton, C. J.; Nikitenko, A. PCT Int. Appl. WO 2006/
089053, 2006; Chem. Abstr. 2006, 145, 271641. (c) Gopalan,
B.; Joshi, H. V.; Shah, D. M.; Ghorpade, S. R. PCT Int. Appl.
WO 2005/033099, 2005.
(5) Chang-Fong, J.; Rangisetty, J. B; Dukat, M.; Setola, V.;
Raffay, T.; Roth, B.; Glennon, R. A. Bioorg. Med. Chem. Lett.
2004, 14, 1961.
(6) (a) Hoyer, D.; Hannon, J. P; Martin, G. R. Pharmacol.,
Biochem. BehaV. 2002, 71, 533. (b) Russel, M. G. N.; Dias,
R. Curr. Top. Med. Chem. 2002, 2, 643. (c) Lindner, M. D.;
Hodges, D. B., Jr.; Hogan, J. B.; Orie, A. F.; Barten, D. M.;
Polson, C.; Robertson, B. J.; Guss, V. L.; Gillman, K. W.;
Starrett, J. E., Jr.; Gribkoff, V. K. J. Pharmacol. Exp. Ther.
2003, 307, 682. (d) Glennon, R. A. J. Med. Chem. 2003, 46,
2795.
(7) Gudmundsson, K. S.; Sebahar, P. R.; Richardson, L. D.;
Catalano, John G.; Boggs, S. D.; Spaltenstein, A.; Sethna,
P. B.; Brown, K. W.; Harvey, R.; Romines, K. R. Bioorg.
Med. Chem. Lett. 2009, 19, 3489.
(8) (a) Howley, P. M. In Fundamental Virology; Howley, P. M.,
Ed.; Lippincott-Raven: Philadelphia, PA, 1996; p 947. (b)
Kroutsky, L. Am. J. Med. 1997, 102, 3.
(9) (a) Wilson, F. X. Expert Opin. Emerging Drugs 2001, 6, 199.
(b) Department of Health and Human Services Center for
Disease Control and Prevention. Genital HPV infection-CDC
factsheet. www.cdc.gov/std/HPV/STDFact-HPV.htm#common.
(c) Dunne, E. F.; Unger, E. R.; Sternberg, M.; McQuillan,
G.; Swan, D. C.; Patel, S. S.; Markowitz, L. E. J. Am. Med.
Assoc. 2007, 297, 813.
(10) (a) Barf, T.; Lehmann, F.; Hammer, K.; Haile, S.; Axen, E.;
Medina, C.; Uppenberg, J.; Svensson, S.; Rondahl, L.;
Lundback, T. Bioorg. Med. Chem. Lett. 2009, 19, 1745.
(11) (a) Banaszak, L.; Winter, N.; Xu, Z.; Bernlohr, D. A.; Cowan,
S.; Jones, T. A. AdV. Protein Chem. 1994, 45, 89. (b) Bernlohr,
D. A.; Doering, T. L.; Kelly, T. J., Jr.; Lane, M. D. Biochem.
Biophys. Res. Commun. 1985, 132, 50. (c) Zimmerman, A. W.;
Veerkamp, J. H. Cell. Mol. Life. Sci. 2002, 59, 1096.
(12) Furuhashi, M.; Hotamisligil, G. S. Nat. ReV. 2008, 7, 489.
(13) Brown, D. W.; Graupner, P. R.; Sainsbury, M.; Shertzer, H.
Tetrahedron. 1991, 47, 4383.
(19) For two recent excellent reviews, see: (a) Weber, L.; Illgen,
K.; Almstetter, M. Synlett 1999, 3, 366. (b) Dax, S. L.;
McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6,
255.
(20) (a) Ugi, I. Angew, Chem. Int. Ed. Engl. 1962, 1, 8. (b) Ugi,
I.; Steinbruckner, C. Chem Ber. 1961, 94, 734. (c) Ugi, I.;
Domling, A.; Horl, W. EndeaVor 1994, 18, 115. (d) Domling,
A. Comb,. Chem. High Throughput Screen. 1998, 1, 1.
(21) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Gokel,
G.; Ludke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.;
Academic Press: New York, 1971; p 145.
(22) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A.
Tetrahedron 1997, 53, 16463. (c) Hansen, T. K.; Schlienger,
N.; Hansen, B. S.; Andersen, P. H.; Bryce, M. R. Tetrahedron
1999, 40, 3651. (d) Jiang, B.; Yang, C.-G.; Gu, X.-H.
Tetrahedron Lett. 2001, 42, 2545. (e) Koolmeister, T.;
Sodergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5965.
(f) Koolmeister, T.; Sodergren, M.; Scobie, M. Tetrahedron
Lett. 2002, 43, 5969. (g) Thompson, K. A.; Hall, D. G. Chem
Commun. 2000, 2379.
(23) Portlock, D. E.; Naskar, D.; West, L.; Li, M. Tetrahedron
Lett. 2002, 43, 6845.
(24) The Petasis Boronic Acid-Mannich reaction has also been
applied to the synthesis of heterocyclic systems:(a) Batey,
R. A.; MacKay, D. B.; Santhakumar, V. J. J. Am. Chem. Soc.
1999, 121, 5075. (b) Petasis, N. A.; Patel, Z. D. Tetrahedron
Lett. 2000, 41, 9607. (c) Wang, Q.; Finn, M. G. Org. Lett.
2000, 2, 4063. (d) Berree, F.; Debache, A.; Marsac, Y.;
Carboni, B. Tetrahedron Lett. 2001, 42, 3591, and references
cited therein.
(25) (a) Klopfenstein, S. R.; Chen, J. J.; Golebiowski, A.; Li, M.;
Peng, S. X.; Shao, X. Tetrahedron Lett. 2000, 41, 4835. (b)
Golebiowski, A.; Klopfenstein, S. R.; Chen, J. J.; Shao, X.
Tetrahedron Lett. 2000, 41, 4841. (c) Schlienger, N.; Bryce,
(14) Di Fabio, R.; Giovannini, R.; Bertani, B.; Borriello, M.;
Bozzoli, A.; Donati, D.; Falchi, A.; Ghirlanda, D.; Leslie,

Substituted 1,2,3,4-Tetrahydrocarbazoles
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 629
M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. (d)
Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(e) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem.sEur. J. 2000, 6, 3321. (f) Grdner, B.; Nakanishi, H.;
Kahn, M. Tetrahedron 1993, 49, 3433. (g) Naskar, D.; Roy,
A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003,
44, 8865. (h) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock,
D. E. Tetrahedron Lett. 2003, 44, 5819. (i) Naskar, D.; Roy,
A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003,
44, 8861. (j) Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B.
Tetrahedron Lett. 2008, 49, 6762. (k) Portlock, D. E.;
Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003,
44, 603. (l) Portlock, D. E.; Naskar, D.; West, L.; Ostaszewski,
R.; Chen, J. J. Tetrahedron Lett. 2003, 44, 5121. (m) Naskar,
D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett.
2003, 44, 6297. (n) Neogi, S.; Roy, A.; Naskar, D. J. Comb.
Chem. 2010, 12, 75.
CC900194K