Cascade electrophilic iodocyclization: Efficient preparation of 4-iodomethyl substituted tetrahydro-β-carbolines and formal synthesis of oxopropaline G

Article abstract of DOI:10.1021/ol401303f

4-Iodomethyl substituted tetrahydro-β-carbolines, the core structure of numerous natural products and bioactive molecules, are readily prepared via I₂-promoted cascade electrophilic cyclization. The reactivity differences of olefins and alkynes

Full text of DOI:10.1021/ol401303f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cascade Electrophilic Iodocyclization:
Efficient Preparation of 4‑Iodomethyl
Substituted Tetrahydro-β-carbolines and
Formal Synthesis of Oxopropaline G
Hongjian Song, Yongxian Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
wang98h@263.net; wangqm@nankai.edu.cn
Received May 10, 2013
ABSTRACT
4-Iodomethyl substituted tetrahydro-β-carbolines, the core structure of numerous natural products and bioactive molecules, are readily prepared
via I2-promoted cascade electrophilic cyclization. The reactivity differences of olefins and alkynes ensure that the reaction proceeds smoothly.
This methodology was successfully applied to the formal synthesis of oxopropaline G.
Carbolines and tetrahydrocarbolines are common struc-
tural motifs in natural products and pharmaceuticals,1 of
which β-carboline and its saturated analog are particularly
prevalent.2 4-Substituted β-carbolines and tetrahydrocar-
bolines are important motifs in many important natural
products, such as the lavendamycin, (ꢀ)-(S)-brevicolline,
oxopropaline D and G, and neonaucleoside C (Figure 1),
all of which are attractive synthetic targets because of
their biological activities and synthetically challenging
structures.
Various strategies have been developed for the construc-
tion of β-carbolines and tetrahydrocarbolines, including
the PictetꢀSpengler reaction,3a electrocyclic reactions,3b
palladium-catalyzed iminoannulation of internal alkynes,3c
Pd-catalyzed direct dehydrogenative annulation of indole-
carboxamides with alkynes,3d Fisher indolization,3e cataly-
tic nitrene insertion into CꢀH bonds,3f metal catalyzed
domino reactions,3g and [2 þ 2 þ 2] cycloaddition of o,N-
dialkynyl-N-tosylanilides and nitriles.3h However, the de-
velopment of a general synthetic method for the rapid
synthesis of 4-substituted β-carbolines and tetrahydrocar-
bolines in a single operation remains a great challenge.
Cascade reactions constitute a fascinating branch of
organic chemistry4 that offer atom economy,5 as well as
economies of time, labor, resourcemanagement, and waste
generation. During the past few years a rapid increase of
interest in halogen-atom-promoted electrophilic heteroat-
om cyclization has occurred, and it has now become an
(1) (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (b) Maresh,
J. J.; Giddings, L.-A.; Friedrich, A.; Loris, E. A.; Panjikar, S.; Trout,
B. L.; Stockigt, J.; Peters, B.; O’Connor, S. E. J. Am. Chem. Soc. 2008,
130, 710. (c) Luk, L.Y. P.; Bunn, S.; Liscombe, D. K.; Facchini, P. J.;
Tanner, M. E. Biochemistry 2007, 46, 10153.
(2) (a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (b)
Edwankar, C. R.; Edwankar, R. V.; Namjoshi, O. A.; Rallapappi,
S. K.; Yang, J.; Cook, J. M. Curr. Opin. Drug Discovery Dev. 2009, 12,
752. (c) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem.
Heterocycl. Compd. 2009, 45, 889. (d) Bandini, M.; Eichholzer, A.
Angew. Chem. 2009, 121, 9786. Angew. Chem., Int. Ed. 2009, 48, 9608.
(e) Abe, N.; Nakakita, Y.; Nakamura, T.; Enoki, N.; Uchida, H.; Takeo,
S.; Munekata, M. J. Antibiot. 1993, 46, 1672–1677.
(3) (a) Snyder, H. R.; Hansch, C. H.; Katz, L.; Parmerter, S. M.;
Spaeth, E. C. J. Am. Chem. Soc. 1948, 70, 219. (b) Molina, P.; Fresneda,
P. M.; Garcıa-Zafra, S. Tetrahedron Lett. 1995, 36, 3581. (c) Zhang,
´
H. M.; Larock, R. C. Org. Lett. 2001, 3, 3083. (d) Shi, Z. Z.; Cui, Y. X.;
Jiao, N. Org. Lett. 2010, 12, 2908. (e) Narayanan, K.; Schindler, L.;
Cook, J. M. J. Org. Chem. 1991, 56, 359. (f) Pumphrey, A. L.; Dong,
H. J.; Driver, T. G. Angew. Chem. 2012, 124, 6022. Angew. Chem., Int.
Ed. 2012, 51, 5920. (g) Ohta, Y.; Oishi, S.; Ohno, H. Org. Lett. 2009, 11,
1979. (h) Nissen, F.; Richard, V.; Alayrac, C.; Witulski, B. Chem.
Commun. 2011, 47, 6656.
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2006, 118, 7292. Angew. Chem., Int. Ed. 2006, 45, 7134.
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Chem. 1995, 107, 285. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
r
10.1021/ol401303f
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
ratio
temp
t
entry
solvent
DCM
(6a/I2)
(°C)
(h)
7a0
7a
1
2
3
4
5
6
7
8
1:2
1:2
1:2
1:2
1:1.5
1:1
1:2
1:2
rt
4
30%
58%
60%
ꢀ
ꢀ
DCM
rt
24
12
4
trace
15%
90%
10%
trace
trace
10%
DCM
40
70
70
70
70
70
DCE
DCE
4
85%
92%
60%
80%
Figure 1. Selected examples of 4-substituted carboline alkaloids
and tetrahydrocarboline alkaloids.
DCE
4
acetonitrile
toluene
12
12
a DCM = dichloromethane, DCE = 1,2-dichloroethane.
Scheme 1. Iodine-Mediated Cascade Cyclization of Enynes to
Iodinated Tetrahydro-β-carbolines
Gratifyingly, the tetrahydrocarboline was obtained in
90% yield when dichloromethane was replaced by 1,2-
dichloroethane, and the mixture was heated at70°C for 4 h
(Table 1, entry 4). It was necessary to use a 2-fold amount
of iodine to ensure the target compound was obtained in
a high yield. When the amount of iodine was reduced to
1.5-fold or a molar equivalent, the reaction gave mainly the
indole compound 7a0 (Table 1, entries 5 and 6). The solvent
also greatly influenced the outcome. It was found detri-
mental to generate the carboline compounds when the
solvent was acetonitrile ortoluene, evenwhenthe reactions
were conducted at the same temperature and reaction time
(Table 1, entries 7 and 8).
Encouraged by these initial results, the substrate scope
of this reaction was next examined using different sets of
2-(3-(allylamino)prop-1-ynyl)aniline (their preparation
can be found in the Supporting Information). The trans-
formation was found to be very widely applicable, and the
desired 4-iodomethyl substituted tetrahydro-β-carbolines
were obtained in reasonable yields. First, the electronic
effect of substituents on the benzene ring moiety was in-
vestigated (Table 2, entries 1ꢀ5). Anilines bearing methyl
or methoxy groups(Table 2, entries 3 and 4) aswellasnitro
or chloro groups (Table 2, entries 4 and 5) all produced the
tetrahydro-β-carbolines in good-to-excellent yields. The
substituents on the allylamino group had a crucial impact
on the electrophilic cyclization of the olefin (Table 2,
entries 1, 6, 7). Just like compound 6a, the allylamino-
containing methanesulfonamide 6f underwent electrophi-
lic cyclization smoothly and the total conversion was
almost quantitative (Table 2, entry 6). However, when
the substituent was changed to benzyl, 6g converted to
iodinated indole 7g completely, without affording the
target tetrahydrocarboline (7g0). Compound 7g decom-
posed when the reaction time was prolonged (Table 2,
entry 7). The substrate with a sterically hindered olefin (6h)
was also converted into the target tetrahydrocarboline (7h)
smoothly (Table 2, entry 8). The reaction did not exhibit
extremely active and original field of heterocycle syn-
thesis.6 Larock et al. reported an iodocyclization process
used in the synthesis of indoles.6a We were curious whether
an iodine-mediated domino electrophilic cyclization re-
action of alkynes and alkenes could be applied for the
preparation of 4-iodomethyl substituted tetrahydro-β-
carbolines (Scheme 1). The electrophilic cyclizations of
olefins are more difficult compared with the reactions of
alkynes. While, the difference can be used to generate the
indole ring preferentially, herein, we present first results on
the synthesis of 4-iodomethyl substituted tetrahydro-β-
carbolines via a cascade electrophilic iodocyclization reac-
tion of enynes.
To test the feasibility of this concept, compound 6a
was initially prepared. When 6a was treated with 2 equiv
of iodine in dichloromethane for 4 h at room temperature,
the iodinated indole 7a0 was obtained in 30% yield solely
(Table 1, entry 1). By extending the reaction time to 24 h,
the desired tetrahydrocarboline (7a) was obtained in less
than 5% yield (Table 1, entry 2). When the mixture was
heated at reflux, it gave the tetrahydrocarboline in 15%
yield (Table 1, entry 3), which meant that a higher tem-
perature was favorable for tetrahydrocarboline yield.
(6) (a) Benhur, G.; Ricardo, F. S.; Gilson, Z. Chem. Rev. 2011, 111,
2937. (b) Larock, R. C. Org. Lett. 2004, 6, 1037. (c) Chen, C. C.; Yang,
S. C.; Wu, M. J. J. Org. Chem. 2011, 76, 10269. (d) Ferrara, G.; Jin, T. N.;
Akhtaruzzaman, M.; Islamc, A.; Han, L. Y.; Jiang, H.; Yamamoto, Y.
Tetrahedron Lett. 2012, 53, 1946.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Preparation of 4-Iodomethyl Substituted Tetrahydro-
β-carbolines by Iodine-Mediated Domino Electrophilic Cycli-
zation of Substituted 2-(3-(Allylamino)prop-1-ynyl)anilinesa
Scheme 2. Control Experiment
compound 7a0 was more readily generated and that the
target compound 7a was indeed transformed from the
indole compound 7a0 rather than generated from 6a directly.
Furthermore, when the reaction time was increased to 7 h,
6a could transform to the target compound 7a exclusively,
with a 1.5-fold amount of iodine (Table 1, entry 5). Thus the
second cyclization is a catalytic process.
According to the above experimental results, a proposed
reaction mechanism is outlined in Scheme 3. First, the
iodine, serving as a Lewis acid, coordinates to the triple
bond to promote cyclization which produces the inter-
mediate 9. Then, one of the alkyl groups is removed by
iodide via an SN2 reaction; this occurs rapidly. Subse-
quently, the second cyclization is promoted by the excess
iodine which coordinates to the double bond of the
iodoindole 7a0 to produce an iminium 11. The iodide could
attack 11 in the manner indicated to give the target
compound 7a and iodine which can then participate in
the next catalytic cycle (Scheme 3).
Scheme 3. Proposed Mechanism
a Experimental procedure is given in the Supporting Information.
b The reaction mixture was heated to reflux for 24 h. c The ratio of the
compounds 7i and 7i0 was determined by 1H NMR, and the determina-
tion of the relative configuration was given in the Supporting Informa-
tion. d The yields given in the table are isolated yields.
significant stereoselectivity (Table 2, entry 9). Alkyne 6j,
with two different alkyl groups (a methyl and benzyl
group) on the nitrogen of the aniline, gave rise to interest-
ing selectivity. Due to the different leaving abilities of the
methyl and benzyl groups in an SN2 reaction, the N-methyl
product 7j was obtained with high selectivity (Table 2,
entry 10).
In order to study the process of the domino electrophilic
cyclization reaction, control experiments were performed.
As mentioned in Table 1 (entries 6) and Scheme 2, 6a was
reacted with 1 equiv of iodine at 70 °C for 4 h to give the
iodinated indole 7a0 exclusively. Then, when 7a0 was re-
acted under the same conditions, by adding another equiva-
lent amount of iodine, it transformed to the tetrahydrocar-
boline 7a smoothly. This finding suggested that the indole
To probe the utility of our method, we used it for a rapid
formal synthesis of the natural product oxopropaline
G, which was isolated from Streptomyces sp. G 324 by
Abe and co-workers in 1993.2 Compound 6a was readily
prepared by Sonogashira coupling of the corresponding
5a and 5b in 70% yield (Scheme 4).7 Treatment of 6a
under our optimized reaction conditions successfully af-
forded the desired 4-iodomethyl substituted tetrahydro-β-
carboline 7a in 90% yield. The iodine was reduced by zinc
(7) Rubin, M.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2005,
127, 10243.
Org. Lett., Vol. XX, No. XX, XXXX
C

In summary, we have developed a new and general
strategy for the construction of 4-iodomethyl substituted
tetrahydro-β-carbolines by an iodine-promoted cascade
electrophilic iodocyclization reaction. This strategy in-
cludes two electrophilic iodocyclization reactions on the
alkyne and alkene successively in one pot. The reactive
differences of olefins and alkynes ensure that the reac-
tion proceeds smoothly. The utility of this method was
demonstrated by a formal synthesis of oxopropaline G.
4-Iodomethyl substituted tetrahydro-β-carbolines con-
taining different substituents can be prepared by using
this method.
Scheme 4. Formal Synthesis of Oxopropaline
Acknowledgment. We are grateful to the National
Key Project for Basic Research (2010CB126100), the
National Natural Science Foundation of China (21132003,
21121002), the National Key Technology Research and
Development Program (2011BAE06B05), and Specialized
Research Fund for the Doctoral Program of Higher
Education (20120031110010) for generous financial sup-
port for our programs.
dust in glacial acetic acid to give 12 in 96% yield.8
Deprotection of the N-tosyl group using sodium/naphthalene
at ꢀ78 °C in anhydrous THF provided 13 in 87% yield.9
Tetrahydrocarboline 13 was oxidized using in the Pd/Cꢀ
maleic acid system in water10 to give β-carboline 14 in 95%
yield, which could be converted to oxopropaline G accord-
ing to reported literature.
(8) Smith, E. C.; Barborak, J. C. J. Org. Chem. 1976, 41, 1433.
(9) Kim, Y. H.; Choi, J. Y. Tetrahedron Lett. 1996, 37, 5543.
(10) Akabori, S.; Saito, K. Beriche der Deutschen Cheischen
Gesellschaft (A and B Series) 1930, 63, 2245.
(11) Rosenau, T.; Hofinger, A.; Potthast, A.; Kosma, P. Org. Lett.
2004, 6, 541.
Supporting Information Available. Detailed experime-
1
tal procedures, copies of H and 13C NMR spectra for
compounds 6aꢀ6j, 7aꢀ7j. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) Choshi, T.; Kuwada, T.; Fukui, M.; Matsuya, Y.; Sugino, E.;
Hibino, S. Chem. Pharm. Bull. 2000, 48, 108.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX