Efficient synthesis of hexahydrocarbazoles

Article abstract of DOI:10.1080/00397911.2010.492080

Selective reduction of the nitro group in methyl 1-(2-nitrophenyl)-4-oxo- cyclohex- 2-enecarboxylates with zinc-acetic acid forms hexahydrocarbazoles. The reaction is applicable to the corresponding pyridyl analogs to generate azahexahydrocarbazoles. This

Full text of DOI:10.1080/00397911.2010.492080

This article was downloaded by: [Boston College]
On: 01 October 2013, At: 01:11
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of
Hexahydrocarbazoles
Sharada S. Labadie a & Christa Parmer a
a Department of Medicinal Chemistry, Roche Palo Alto LLC, Palo
Alto, California, USA
Published online: 29 Apr 2011.
To cite this article: Sharada S. Labadie & Christa Parmer (2011) Efficient Synthesis of
Hexahydrocarbazoles, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 41:12, 1752-1758, DOI: 10.1080/00397911.2010.492080
To link to this article: http://dx.doi.org/10.1080/00397911.2010.492080
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 1752–1758, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.492080
EFFICIENT SYNTHESIS OF HEXAHYDROCARBAZOLES
Sharada S. Labadie and Christa Parmer
Department of Medicinal Chemistry, Roche Palo Alto LLC,
Palo Alto, California, USA
GRAPHICAL ABSTRACT
Abstract Selective reduction of the nitro group in methyl 1-(2-nitrophenyl)-4-oxo-cyclohex-
2-enecarboxylates with zinc-acetic acid forms hexahydrocarbazoles. The reaction is appli-
cable to the corresponding pyridyl analogs to generate azahexahydrocarbazoles. This pro-
vides an efficient method for the generation of tricyclic framework.
Keywords Azahexahydrocarbazoles; Diels–Alder reaction; hexahydrocarbazoles; zinc-
acetic acid reduction
The hexahydrocarbazole framework occurs in a number of biologically active natural
products, the syntheses of which have been studied extensively.[1,2] Recently reported
syntheses of the hexahydrocarbazole framework indicate that there still is a need for
new, preferably simple, methods for the generation of such entities.[3] As described in
the previous paper,[4] the hexahydrocarbazole 1e was formed unexpectedly from
methyl 1-(3-nitropyridin-2-yl)-4-oxo-cyclohex-2-enecarboxylate 2e in an attempt to
form the spirocycle 3e (Scheme 1). Given this constitutes a simple two-step synthesis
of the tricyclic framework, the scope of this process was further investigated.
The cyclohexenonecarboxylates 2a–h, the required precursors for this synthetic
study, were prepared as described in the previous paper,[4] by a Diels–Alder reaction
of methyl 2-(2-nitroaryl)acrylates 4a–h with trans-1-methoxy-3-trimethylsilyloxy-
1,3-butadiene 5 (Table 1). Whereas the palladium-catalyzed hydrogenation of the
pyridyl compound 2e produced hexahydrocarbazole 1e, catalytic reduction of 2a
Received January 29, 2010.
Current name and affiliation for Christa Parmer: Christa Tatyosian, Bio-Rad Laboratories,
Hercules, California, USA.
Address correspondence to Sharada S. Labadie, Genentech, MS: 18B, 1 DNA Way, So. San
Francisco, CA 94080-4990, USA. E-mail: labadie.sharada@gene.com
1752

SYNTHESIS OF HEXAHYDROCARBONS
1753
Scheme 1. Results of hydrogenation of 2a and 2e.
Table 1. Formation of cyclohexenones as in Scheme 2a
Entry
Acrylate
Cyclohexenone
Yield %
1
87
2
85
3
75
aAll are isolated yields and are not optimized. Synthesis of cyclohexenones 2a–e are described in the
previous paper.[4]

1754
S. S. LABADIE AND C. PARMER
Scheme 2. Synthesis of hexahydrocarbazoles.
gave the spirocyclic oxindole compound 3a. It was therefore essential to effect
selective reduction of the nitro group to ensure exclusive formation of hexahydrocar-
bazoles. This was readily achieved by reduction of 2a–h with zinc in acetic acid sol-
ution (Scheme 2). Under these conditions, the desired hexahydrocarbazoles 1a–d
were obtained in poor (1d) to moderate yields, whereas the corresponding aza
compounds 1e–h were all produced in good yields (Table 2).
It should be noted that ring closure occurred with the formation of a cis-fused
framework, a result for which there is ample literature precedent.[5] This was
confirmed for compound 1b by observation of a strong nuclear Overhauser effect
(NOE) between Ha and the ester methyl group.
Table 2. Formation of hexahydrocarbazoles as in Scheme 2
Entry
Cyclohexenone
Hexahydrocarbazole
Yielda (%)
1
67
2
3
4
47
66
20b
(Continued )

SYNTHESIS OF HEXAHYDROCARBONS
1755
Table 2. Continued
Entry
Cyclohexenone
Hexahydrocarbazole
Yielda (%)
5
80
6
7
69
66
8
75
aAll are isolated yields and are not optimized.
bIsolated as an HCl salt.
In summary, a simple two-step synthesis of highly functionalized hexahydro-
carbazoles is described. The method tolerates a variety of functionalities and uses
readily accessible starting materials. To our knowledge, this is the first reported
synthesis of azahexahydrocarbazoles.
EXPERIMENTAL
Cyclohexenonecarboxylates 2a–h were synthesiszed as described in the
previous paper.[4] The analytical data for those not reported earlier are as follows.
Methyl 1-(5-Methyl-3-nitropyridin-2-yl)-4-oxo-cyclohex-
2-enecarboxylate 2f
Mp 101–103 (hexane=EtOAc); 1H NMR (300 MHz, CDCl3) d ¼ 8.62
(d, J ¼ 1.5 Hz, 1 H), 8.12 (d, J ¼ 1.5 Hz, 1 H), 7.04 (d, J ¼ 10.2 Hz, 1 H), 6.20 (d,
J ¼ 10.2 Hz, 1 H), 3.72 (s, 3 H), 3.0–2.57 (m, 4 H), 2.48 (s, 3 H). Anal. calcd. for
C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C, 57.98; H, 4.73; N, 9.63.

1756
S. S. LABADIE AND C. PARMER
Methyl 1-(6-Methoxy-2-nitropyridin-2-yl)-4-oxocyclohexen-2-
enecarboxylate 2g
Mp 89–90 (hexane=EtOAc). 1H NMR (300 MHz, CDCl3) d ¼ 8.34 (d, J ¼ 9.0 z,
1 H), 7.06 (d, J ¼ 10.2 Hz, 1 H), 6.83 (d, J ¼ 9.0 Hz, 1 H), 6.20 (d, J ¼ 10.2 Hz, 1 H),
3.99 (s, 3 H), 3.73 (s, 3 H), 3.02–2.50 (m, 4 H). Anal. calcd. for C14H14N2O6: C,
54.90; H, 4.61; N, 9.15. Found: C, 54.76; H, 4.37; N, 9.15.
Methyl 1-(3-Nitropyrid-4-yl)-4-oxo-cyclohexen-2-enecarboxylate 2h
1
Mp 85–87 ꢀC (hexane=EtOAc); H NMR (300 MHz, CDCl3) d ¼ 9.21 (s, 1 H),
8.81–8.79 (m, 0 H), 7.41 (d, J ¼ 4.9 Hz, 1 H), 6.75 (d, J ¼ 10.2 Hz, 1 H), 6.39
(d, J ¼ 10.2 Hz, 1 H), 3.73 (s, 3 H), 3.34–3.16 (m, 1 H), 3.07–2.90 (m, 1 H), 2.39
(d, J ¼ 4.5 Hz, 2 H). Anal. calcd. for C13H12N2O5: C, 56.52; H, 4.38; N, 10.14.
Found: C, 56.21; H, 4.22; N, 9.97.
Synthesis of Hexahydrocarbazoles 1a–h
Hexahydrocarbazole 1a. Acetic acid (0.6 mL) was added to a vigorously
stirred mixture of 2a (0.1 g, 0.36 mmol) and zinc dust (0.6 g) in dichloromethane
(10 mL), and the heterogeneous mixture was stirred for 18 h. Solids were removed
by filtration through a Celite washing well with dichloromethane. The filtrate was
stirred over aqueous NaHCO3 solution (20 mL), and the organic layer was sepa-
rated. The organic layer was washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by flash chromatography (silica gel, 20–60% EtOAc=
hexane) to obtain 1a as an off-white solid (0.07 g): mp 109–110 ꢀC (EtOAc=hexane);
1H NMR (300 MHz, CDCl3): d ¼ 7.38–7.29 (m, 1 H), 7.18–7.03 (m, 1 H), 6.83–6.70
(m, 1 H), 6.66–6.52 (m, 1 H), 4.94–4.84 (m, 1 H), 3.82 (s, 3 H), 2.84–2.56 (m, 2 H),
2.28 (d, 4 H). Anal. calcd. for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.48; N, 6.11; N, 5.78.
The following were obtained in a similar fashion.
Compound 1b. Mp 75–76 ꢀC (EtOAc=hexane); 1H NMR (300 MHz, CDCl3)
d ¼ 7.42 (d, J ¼ 7.9 Hz, 1 H), 7.02 (d, J ¼ 7.9 Hz, 1 H), 6.78 (s, 1 H), 4.93 (d,
J ¼ 3.4 Hz, 1 H), 4.14 (d, J ¼ 2.3 Hz, 1 H), 3.83 (s, 3 H), 2.87–2.56 (m, 2 H),
2.53–1.98 (m, 4 H). Anal. calcd. for C15H14F3NO3: C, 57.51; H, 4.50; N, 4.47.
Found: C, 57.41; H, 4.31; N. 4.58.
Compound 1c. 1H NMR (300 MHz, CDCl3) d ¼ 6.90 (s, 1 H), 6.25 (s, 1 H),
4.87 (t, J ¼ 3.6 Hz, 1 H), 3.94–3.71 (m, 9 H), 2.83–2.55 (m, 2 H), 2.46–2.00 (m, 4 H);
MS (ESI): m=z ¼ 306 (M þ 1).
Compound 1d. 1H NMR (300 MHz, DMSO-d6) d ¼ 6.84–6.68 (m, 1 H),
5.90–5.78 (m, 1 H), 5.78–5.67 (m, 1 H), 5.70–5.60 (m, 1 H), 4.89–4.71 (m, 2 H),
4.71–4.51 (m, 1 H), 3.69 (s, 3 H), 2.50 (d, J ¼ 1.9 Hz, 6 H); MS (ESI): m=z ¼ 261
(M þ 1).
Compound 1e. Mp 149–150 ꢀC (EtOAc=hexane); 1H NMR (300 MHz,
CDCl3) d ¼ 7.99 (dd, J ¼ 1.5, 4.9 Hz, 1 H), 7.00 (dd, J ¼ 4.9, 7.9 Hz, 1 H),

SYNTHESIS OF HEXAHYDROCARBONS
1757
6.93–6.79 (m, 1 H), 4.96–4.83 (m, 1 H), 4.01–3.94 (m, 1 H), 3.83 (s, 3 H), 2.78 (d,
J ¼ 3.8 Hz, 1 H), 2.66–2.52 (m, 3 H), 2.41–2.31 (m, 1 H), 1.98 (m, 1 H). Anal. calcd.
for C13H14N2O3: C, 63.40, H, 5.73; N, 11.38. Found: C, 63.50; H, 5.68; N, 11.43.
Compound 1f. Mp 128–129 ꢀC (EtOAc=hexane); 1H NMR (300 MHz,
CDCl3) d ¼ 7.82 (s, 1 H), 6.69 (s, 1 H), 4.88 (t, J ¼ 3.6 Hz, 1 H), 3.81 (s, 3 H),
2.86–2.27 (m, 5 H), 2.88–2.27 (m, 5 H), 2.24 (s, 3 H), 2.23 (s, 3 H), 1.97 (s, 1 H). Anal.
calcd. for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.22; H, 6.06; N,
10.72.
Compound 1g. Mp 140–141 ꢀC (EtOAc=hexane).1H NMR (300 MHz
CDCl3) d ¼ 6.92 (d, J ¼ 8.3 Hz, 1 H), 6.50 (d, J ¼ 8.7 Hz, 1 H), 4.80 (t, J ¼ 3.8 Hz,
1 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 2.80–2.28 (m, 5 H), 2.07–1.91 (m, 1 H). Anal. calcd.
for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.86; H, 5.79; N, 10.17.
Compound 1h. Mp 218–220 ꢀC (EtOAc=hexane). 1H NMR (300 MHz,
DMSO-d6) d ¼ 7.86 (d, J ¼ 4.5 Hz, 1 H), 7.82 (s, 1 H), 7.25 (d, J ¼ 4.9 Hz, 1 H),
6.33 (d, J ¼ 3.0 Hz, 1 H), 4.70–4.65 (m, 1 H), 3.73 (s, 3 H), 2.84 (dd, J ¼ 3.8,
15.9 Hz, 1 H), 2.56–2.39 (m, 3 H), 2.25–2.08 (m, 2 H); MS (ESI) m=z ¼ 247 (M þ 1).
ACKNOWLEDGMENTS
The authors acknowledge Dr. Francisco Talamas and Dr. Josh Taygerly for
their valuable input and the analytical department for providing the spectroscopic
and physical data.
REFERENCES
1. (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker,
K. The total synthesis of strychnine. J. Am. Chem. Soc. 1954, 76, 4749–4751; (b) Saxton,
J. E. In The Alkaloids of the Aspidospermine Group; G. A. Cordell (Ed.); Academic Press:
New York, 1998; vol. 51, p. 1; (c) Ando, M.; Buchi, G.; Ohnuma, T. The total synthesis of
¨
(ꢁ)-vindoline. J. Am. Chem. Soc. 1975, 97, 6880; (d) Zhou, S.-Z.; Bommezijn, S.; Murphy,
J. A. Formal total synthesis of (ꢁ)-vindoline by tandem radical cyclization. Org. Lett. 2002,
4, 443, and references therein; (d) Choi, Y.; Ishikawa, H.; Velcicky, J.; Elliott, G. I.; Miller,
M. M.; Boger, D. L. Total synthesis of (ꢂ)- and ent-(þ)-vindoline. Org. Lett. 2005, 20,
4539–4542; (e) Benchekroun-Mounir, N.; Dugat, D.; Gramain, J. C. A short synthesis of
(ꢁ)-N-benzyl aspidospermidine. Tetrahedron Lett. 1992, 33, 4001–4004.
2. (a) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Organocatalytic asymmetric
Diels–Alder reactions of 3-vinylindoles. Angew. Chem., Int. Ed. 2008, 47, 9236; (b) Fu,
J.-M. Preparation of arylsulphonyl-substituted tetrahydro- and hexahydrocarbazolamines
as 5-HT6 receptor ligands. WO Patent 2003030901, 2003; (c) Fernandez, F.; Garcia-Mera,
X.; Rodriguez, G.; Urrutia, A. New hexahydrocarbazoles and spiro indoles and their affin-
ity for D2 dopamine and 5-HT2A serotonin receptors. Chem. Pharm. Bull. 1999, 47, 1006;
(d) Rodriguez, J. G.; Urrutia, A. Synthesis of sterically hindered 4a,9a-disubstituted
1,2,3,4,4a,9a-hexahydrocarbazoles from 4a-methyl-1,2,3,4-tetrahydro-4aH-carbazole with
organolithium reagents. Tetrahedron 1998, 54, 15613; (d) McCarthy, C.; Jones, K. Indole
alkaloid synthesis: A stereospecific preparation of functionalized cis-hexahydrocarbazoles.
J. Chem. Soc., Chem. Comm. 1989, 22, 1717; (e) Borch, R. F.; Newell, R. G. Novel syn-
thesis of 2-oxo-1,2,3,4-tetrahydrocarbazoles. J. Org. Chem. 1973, 38, 2729–2730.

1758
S. S. LABADIE AND C. PARMER
3. (a) Hyde, A. M.; Buchwald, S. L. Palladium-catalyzed c-arylation of b,c-unsaturated
ketones: Application to a one-pot synthesis of tricyclic indolines. Angew. Chem. Int. Ed.
2008, 47, 177–180; (b) Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais, Y. Efficient
synthetic approaches to common indole alkaloids. Org. Lett. 2007, 9, 3913–3916; (c)
Heureux, N.; Wouters, J.; Mark, I. E. Sequential acid=base-catalyzed polycyclization of
the tryptamine derivatives: A rapid access to Buchi’s ketone. Org. Lett. 2005, 7, 5245–
¨
5248; (d) Marcos, I. S.; Moro, R. F.; Costales, I.; Escola, M. A.; Basabe, P.; Diez, D.;
Urones, J. G. Synthesis of hexahydrocarbazoles by cyclisation of 3-(but-3-enyl) indole
derivatives. Tetrahedron 2009, 65, 10235–10242; (e) Majumdar, K. C.; Kundu, U. K.;
Das, U.; Jana, N. K.; Roy, B. N-Iodosuccinimide, an effective reagent for regioselective
heterocyclization of o-cyclohex-20-enylanilines for the synthesis of hexahydrocarbazoles.
Can. J. Chem. 2005, 83, 63–67; (f) Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin, C.
G.; Murphy, J. A. Diethylphosphine oxide (DEPO): High-yielding and facile preparation
of indolones in water. Org. Lett. 2003, 5, 2971–2974.
4. Labadie, S. S.; Parmer, C. Facile synthesis of spirocyclic oxindole, azaoxindole, and
dihydroisoquinolone. Synth. Commun. 2011, 41, 1742–1751.
5. (a) Rupprecht, K. M.; Boger, J.; Hoogsteen, K.; Nachbar, R. B.; Springer, J. P. Controlling
the stereochemistry of the ring junction in hexahydrodibenzofurans. J. Org. Chem. 1991,
56, 6180–6188; (b) Hamilton, C. J.; Fairlamb, A. H.; Egleston, I. M. Regiocontrolled
synthesis of the macrocyclic polyamine alkaloid (ꢁ)-lunarine, a time-dependent inhibitor
of trypanothione reductase. J. Chem. Soc. Perkin Trans. I 2002, 1115–1123.