Iodine-catalyzed aromatization of tetrahydrocarbazoles and its utility in the synthesis of glycozoline and murrayafoline A: A combined experimental and computational investigation

Article abstract of DOI:10.1039/c4ob00635f

A new protocol for the aromatization of tetrahydrocarbazoles has been achieved using a catalytic amount of iodine, giving high yields. The role of iodine in the aromatization has been explained by DFT, and its wide scope is extended to the total synthesis of glycozoline and murrayafoline A. This method has proven to be tolerant of a broad range of functional groups. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00635f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Iodine-catalyzed aromatization of tetrahydro-
carbazoles and its utility in the synthesis of
glycozoline and murrayafoline A: a combined
experimental and computational investigation†
Cite this: Org. Biomol. Chem., 2014,
12, 4832
Received 25th March 2014,
Accepted 24th April 2014
DOI: 10.1039/c4ob00635f
Vivek Humne,a Yuvraj Dangat,b Kumar Vankab and Pradeep Lokhande*a
www.rsc.org/obc
A new protocol for the aromatization of tetrahydrocarbazoles has
The following drawbacks are observed in the aromatization
been achieved using a catalytic amount of iodine, giving high process; (a) Pd/C is often used in a solvent with a high boiling
yields. The role of iodine in the aromatization has been explained point,3 (b) tetrahydrocarbazoles containing carbonyl and cyclo-
by DFT, and its wide scope is extended to the total synthesis of hexanyl groups at the C-1 position show a reduced ability for
glycozoline and murrayafoline A. This method has proven to be aromatization, and possibly produce various side products
tolerant of a broad range of functional groups.
with Pd/C,4 (c) MnO2 requires high temperatures and high stoi-
chiometric proportions,5 (d) chloranil and DDQ are organically
derived reagents capable of effecting the aromatization
process, which require N-protection of the tetrahydrocarba-
zoles.6 In order to avoid the use of these reagents, most
research groups have prepared starting substrates that can
rearrange into the corresponding aromatic products.7 These
materials are, however, unstable and commercially unavail-
able. Therefore, the development of easy, efficient and conven-
tional methods for the aromatization of tetrahydrocarbazole is
exceedingly desirable.
Carbazole is a well-known alkaloid that shows a broad range of
biological and medicinal properties. Various carbazole deriva-
tives are widely used in organic materials of thermal, electrical,
optical and visible light-emitting applications.1 The carbazole
scaffold’s significant features mean that it attracts great atten-
tion in the field of organic synthesis. Fischer–Borsche syn-
thesis is the most common practical method used for the
preparation of carbazole intermediates and their biologically
active compounds.2 In general, this involves the condensation
of phenylhydrazine with cyclohexanone, followed by aromatiza-
tion. The final step, aromatization of tetrahydrocarbazole, is
the most challenging task. To the best of our knowledge, very
few reagents are documented for use in this aromatization
process in the literature (Scheme 1).
Over the last few decades, molecular iodine has been
employed in pharmaceutical and organic syntheses owing
to its inexpensive, non-toxic, and environmentally benign
Table 1 Optimization of the reaction conditions
Entry I2 (mol%) Temp (°C) Time (h) Yield % (2)a Yield % (3)b
a
b
c
d
e
f
10
25
100
10
10
25
Rt
Rt
Rt
48
48
48
48
48
7
NR
NR
NR
NR
53c
93
NR
NR
NR
NR
NR
NR
28
Scheme 1 Different reagents used for the aromatization of
tetrahydrocarbazole.
50
100
100
100
100
aCenter for Advance Studies, Department of Chemistry, University of Pune, Pune,
411007, India. E-mail: vivekhumne@rediffmail.com, pdlokhande@chem.unichem.ac.in
bDivision of Physical Chemistry, CSIR-National Chemical Laboratory, Pune, 411008,
g
h
75
150
10
10
73
NR
89d
India
a,b Isolated products. c Starting substrate was recovered with the
product. d Product was confirmed by NMR and GCMS.
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00635f
4832 | Org. Biomol. Chem., 2014, 12, 4832–4836
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
nature.8 As part of our continuing efforts to study iodine- in the proportional amount of iodine (25 mol%) at 100 °C, and
mediated transformations,9 we are interested in developing a the corresponding carbazole was isolated with an excellent
novel and efficient protocol for the aromatization of tetra- yield (Table 1, entry f). The addition of 75 mol% of iodine gave
hydrocarbazoles using a catalytic amount of iodine. The method a mixture of the aromatic product 2 and the iodinated pro-
we have developed is extended to the synthesis of natural pro- ducts 3a and b (Table 1, entry g). Moreover, when the amount
ducts such as glycozoline and murrayafoline A.
of iodine was increased to 150 mol%, 3 was obtained as the
We started our experimental strategy with the condensation sole product (Table 1, entry h). Several solvents, such as
of commercially available phenyl hydrazine and cyclohexa- MeOH, AcCN, DCM, DMF and diphenyl ether, were examined
none, which were readily converted to tetrahydrocarbazole by as the reaction medium. Dimethyl sulfoxide was found to be
Fischer indolization. We wished to study the efficacy of the an efficient solvent for the aromatic process.
aromatization of tetrahydrocarbazole by molecular iodine. First,
Under the optimal conditions, our attention shifted to
when 10 mol% of iodine was added to substrate 1a, no remark- exploring the scope of the aromatic process with a variety of
able effect was observed at room temperature (Table 1). The tetrahydrocarbazoles (Scheme 2). In this context, both elec-
process of aromatization was started by a subsequent increase tron-donating and electron-withdrawing substituents were well
Scheme 2 Aromatization of tetrahydrocarbazoles by molecular iodine. aReaction conditions: 4 (2.4 mmol) and I2 (25 mol%) in DMSO (5 mL) at
100 °C. bIsolated yield. cPreparation of substrate 4j–n is given in the ESI.†
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4832–4836 | 4833

View Article Online
Communication
Organic & Biomolecular Chemistry
tolerated. The reaction was clean and smooth, with a cyano compatibility of the developed method is particularly note-
group-containing aromatic product isolated in an excellent worthy, and is not limited to methoxyl, carboxylic acid,
yield (Scheme 2, entry 5a). However, substrate 5b required a halogen and cyano groups. Additionally, we constructed a
higher amount of iodine and high temperature, along with a variety of N-substituted carbazoles using a catalytic amount of
longer reaction time. This may be due to the interaction of iodine (Scheme 2, entry 5j–n). Gratifyingly, all the corres-
iodine with the carboxyl group. On the other hand, 3-methyl- ponding aromatic carbazoles were obtained in good to
tetrahydrocarbazole had an important role in the aromatization excellent yields, while the N-allyl group was found to remain
process (Scheme 2, entry 4g–i). Interestingly, a shorter reaction intact throughout the whole procedure, under the optimal
time and low temperature were enough for the complete conditions.
aromatization of 3-methyltetrahydrocarbazoles by a catalytic
An insight into the mechanism for the aromatization of
amount of molecular iodine (Scheme 2, entry 5g–i).
tetrahydrocarbazole (1a) using molecular iodine was obtained
To exemplify the power of iodine-catalyzed aromatization, using density functional theory (DFT). The PBE/B3LYP/
we carried out a short synthesis of the antibiotic and anti- TZVP11,12 approach was employed for this purpose, with the
fungal natural product glycozoline.10 A catalytic amount of iodine Turbomole 6.4 suite13 of programs. For other information
was added to tetrahydrocarbazole 4h, which afforded glycozo- regarding the calculations, please see the ESI.† The results
line in a good yield (Scheme 2, entry 5h). The functional group obtained are shown in Fig. 1. The mechanism has been found
Fig. 1 The free-energy profile for the conversion of 1a to 2a.
4834 | Org. Biomol. Chem., 2014, 12, 4832–4836
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Scheme 3 A short synthesis of murrayafoline A.
to be ionic, leading to the formation of [I–H–I]− and the of the hydroxyl motif of 7 by the alkyl group meant that com-
cationic complex “c” (see Fig. 1). The barrier for this step has patible conditions could not be established. Sissouma16 pro-
been calculated to be 13.0 kcal mol−1. This is followed by the posed the total synthesis of Calothrixin B without protection
abstraction of another proton by [I–H–I]−, leading to the for- of the indole nitrogen using enolate formation, followed by
mation of two HI molecules and the species “d”, which is dehydrogenation. We thought that enolation of substrate 6
exergonically converted to e. This is further converted, with the followed by oxidative dehydrogenation with molecular iodine
aid of I2, to the final species 2a, through two steps which have could achieve product 8. In order to avoid the use of an
barriers below 10.0 kcal mol−1 (see Fig. 1). The slowest step for expensive catalyst, we decided to employ readily available salts
this process was found to have a barrier (ΔG) of 24.7 kcal such as KI and NaI, but these salts did not afford the desired
mol−1, indicating that the reaction would be highly facile at product, while LiBr with molecular iodine gave the expected
elevated temperatures, as observed experimentally (100 °C, as product 8 in a good yield. Phenol 8, upon methylation with
discussed earlier). It is to be noted that the ionic mechanism diazomethane in the presence of methanol, afforded murraya-
was found to be preferred over the homolytic dissociation of foline A (9).17 The spectroscopic data of murrayafoline A is in
I2. The interaction of I2 with 1a was found to lead to a signifi- agreement with that reported in the literature. The overall
cantly endothermic (by 52 kcal mol−1: ΔE value) product when yield of product 9, obtained in 3 steps, was found to be 35%
I2 split homolytically, as opposed to the heterolytic splitting of (Scheme 3).
I2 upon interaction with 1a, where the ionic product was found
To summarize, we have explored a simple and efficient
to be endothermic by only 1.0 kcal mol−1 (ΔE value). This is metal-free method for the aromatization of tetrahydrocarba-
illustrated in Fig. 12.1 of the ESI.† The regeneration from HI of zoles using a catalytic amount of iodine. The current method
I2 during the reaction (after the formation of d – see Fig. 1) is has been successfully applied to the synthesis of glycozoline
seen to be a facile process, having a barrier of only 0.9 kcal and murrayafoline A, and the overall yields have been found to
mol−1 (see Fig. 12.3 in the ESI†).
be 80% and 35% respectively. Overall, the operational simpli-
Encouraged by the findings discussed above, we attempted city and the economic viability of this method have definitely
the total synthesis of murrayafoline A (Scheme 3).14 Phenyl broadened the scope for the further study of aromatization.
hydrazine was added to a boiling solution of 4-methylcyclo-
hexanone in acetic acid, in order to obtain the tetrahydrocarbazole
4i. Our next endeavor was to obtain 1-oxotetrahydrocarbazole 6
Acknowledgements
from substrate 4i. The reaction did not proceed at all with a
VTH is thankful to CSIR, New Delhi, India, for the award of a
variety of oxidants. However, periodic acid was found to be a
senior research fellowship. KV and YD acknowledge the XIIth
befitting oxidant, leading to the desired product 6 in a 69%
Five Year Plan project, MSM, for financial assistance.
yield.15 Substrate 6 was reduced by sodium borohydride in
methanol to yield 7. Thereafter, we were interested in illustrat-
ing the synthetic utility of iodine with tetrahydrocarbazole 7.
The results were quite interesting: product 5i was formed
References
significantly after 5 h, suggesting that dehydration could be
preferable to dehydrogenation in this case. However, protection
1 (a) R. M. Adhikari, D. C. Neckers and B. K. Shah, J. Org.
Chem., 2009, 74, 3341; (b) M. Houssler, J. Z. Liu,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 4832–4836 | 4835

View Article Online
Communication
Organic & Biomolecular Chemistry
R. H. Zheng, J. Wing, Y. Lam, A. J. Qin and
B. Z. Tang, Macromolecules, 2007, 40, 1914; (c) A. V. Dijken,
(e) V. T. Humne and P. D. Lokhande, Tetrahedron Lett.,
2014, 55, 2337.
J. J. A. M. Bastiaansen, N. M. M. Kiggen, B. M. V. Langeveld, 10 (a) D. Kajiyama, K. Inove, Y. Iskikawa and S. Nishiyama,
C. Rothe, A. Monkman, I. Bach, P. Stossel and K. Brunner,
J. Am. Chem. Soc., 2004, 126, 7718.
2 See review (a) A. W. Schmidt, K. R. Reddy and H.-J. Knölker,
Tetrahedron, 2010, 66, 9779; (b) R. Forke, M. P. Krahl,
T. Krause, G. Schlechtinger and H.-J. Knölker, Synlett, 2007,
268.
Chem. Rev., 2012, 112, 3193; (b) H.-J. Knölker and 11 (a) P. A. M. Dirac, Proc. R. Soc. London, A, 1929, 123, 714;
K. R. Reddy, Chem. Rev., 2002, 102, 4303; (c) J. Roy,
A. K. Jana and D. Mal, Tetrahedron, 2012, 68, 6099;
(d) H.-J. Knölker, Chem. Lett., 2009, 38, 8; (e) I. Bauer
and H.-J. Knölker, Top. Curr. Chem., 2012, 309, 203;
(f) H.-J. Knölker, Curr. Org. Chem., 2004, 1, 309.
(b) J. C. Slater, Phys. Rev., 1951, 81, 385; (c) J. P. Perdew,
K. Burke and M. Ernzerhof, Chem. Phys. Lett., 1996, 77,
3865; (d) J. P. Perdew and Y. Wang, Phys. Rev. B: Condens.
Matter, 1992, 45, 13244; (e) A. D. Becke, J. Chem. Phys.,
1993, 98, 5648; (f) C. Lee, W. Yang and R. G. Parr, Phys.
Rev. B: Condens. Matter, 1988, 37, 785.
3 M. Hussain, S. M. Toguem, R. Ahmad, D. T. Tung,
I. Knepper, A. Villinger and P. Langer, Tetrahedron, 2011, 12 (a) F. Weigend, Phys. Chem. Chem. Phys., 2002, 4, 4285;
67, 5307.
(b) F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys.,
2005, 7, 3297; (c) A. Schafer, H. Horn and R. Ahlrichs,
J. Chem. Phys., 1992, 97, 2571.
4 K. D. Berlin, P. E. Clark, J. T. Schroeder and D. G. Hopper,
Proc. Okla. Acad. Sci., 1966, 5, 215.
5 M. Ishikura, A. Hino and N. Katagiri, Heterocycles, 2000, 13 R. Ahlrichs, M. Bär, M. Häser, H. Horn and C. Kölmel,
53, 11. Chem. Phys. Lett., 1989, 162, 165.
6 (a) T. P. Lebold and M. A. Kerr, Org. Lett., 2008, 10, 997; 14 (a) G. Bringmann and S. Tasler, Tetrahedron, 2001, 57, 331;
(b) I. K. Park, S. E. Suh, B. Y. Lim and C. G. Cho, Org. Lett.,
2009, 11, 5454; (c) J. T. Vessel, S. Z. Janick and P. A. Petillo,
Org. Lett., 2000, 2, 73.
7 B. Liegault, D. Lee, M. P. Huestis, D. R. Stuart and
K. Fagnau, J. Org. Chem., 2008, 73, 5022.
(b) N. M. Cuong, H. Wilhelm, A. Porzel, N. Arnold and
L. Wessjohann, Nat. Prod. Res., 2008, 22, 1428; (c) H.-J. Knölker
and M. Bauermeister, J. Chem. Soc., Chem. Commun., 1990,
9, 664; (d) H.-J. Knölker and M. Bauermeister, Tetrahedron,
1993, 49, 11221; (e) C. Borger, O. Kataeva and H.-J. Knölker,
Org. Biomol. Chem., 2012, 10, 7269.
8 (a) M. Jereb, D. Vrazic and M. Zupan, Tetrahedron, 2011, 67,
1355; (b) H. Toga and S. Iida, Synlett, 2006, 2159; 15 (a) Y. Ergun, S. Patir and G. Okay, Synth. Commun., 2004,
(c) A. N. French and T. Wirth, Chem. Soc. Rev., 2004, 33,
354.
9 (a) V. T. Humne, S. G. Konda, K. Hasanzadeh and
P. D. Lokhande, Chin. Chem. Lett., 2011, 22, 1435;
34, 435; (b) R. D. Fabio, R. Giovannini, B. Bertani,
M. Borriello, A. Bozzoli, D. Donati, A. Falchi, D. Ghirlanda,
C. P. Leslie, A. Pecunioso, G. Rumboldt and S. Spada,
Bioorg. Med. Chem. Lett., 2006, 16, 1749.
(b) S. G. Konda, V. T. Humne and P. D. Lokhande, Green 16 D. Sissouma, L. Maingot, S. Collet and A. Guingant, J. Org.
Chem., 2011, 13, 2354; (c) V. T. Humne, K. Hasanzadeh and Chem., 2006, 71, 8384.
P. D. Lokhande, Res. Chem. Intermed., 2013, 39, 585; 17 D. P. Chakraborty and B. K. Chowdhary, J. Org. Chem.,
(d) V. Humne and P. Lokahnde, Synth. Commun., 2014, 44, 929; 1968, 33, 1265.
4836 | Org. Biomol. Chem., 2014, 12, 4832–4836
This journal is © The Royal Society of Chemistry 2014