Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde and its application in the synthesis of β-(dehydroprenyl)indole-based natural products

Article abstract of DOI:10.1039/a808733d

Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde gives various dehydroprenyl-based indoles. Efficient synthesis of the indole natural products yuehchukene and murrapanine, using this reaction as a key step, is also described.

Full text of DOI:10.1039/a808733d

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Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde and its
application in the synthesis of b-(dehydroprenyl)indole-based natural products
Jyh-Horng Sheu,* Chun-An Chen and Buo-Horng Chen
Department of Marine Resources, National Sun Yat-Sen University, Kaohsing, 804, Taiwan.
E-mail: sheu@mail.nsysu.edu.tw
Received (in Cambridge, UK) 9th November 1998, Accepted 7th December 1998
Reaction of (dimethylvinylidene)carbene with indole-3-car-
baldehyde gives various dehydroprenyl-based indoles. Effi-
cient synthesis of the indole natural products yuehchukene
and murrapanine, using this reaction as a key step, is also
described.
gated the reaction of 1 with indole-3-carbaldehyde. We report
herein the preliminary results of this work directed to the
introduction of a dehydroprenyl unit onto the b-carbon of
indole. Application of this reaction in the synthesis of indole
natural products containing a b-dehydroprenyl group is also
described.
The cyclopropanation of nucleophilic olefins with (dimethylvi-
nylidene)carbene 1, generated by the elimination of hydrogen
halide from propargyl halides or halloallenes (Scheme 1),
Treatment of 3-chloro-3-methylbut-1-yne 2 with aq. KOH, a
catalytic amount of dibenzo-18-crown-6 and THF in the
presence of indole-3-carbaldehyde 3 under reflux gave a
mixture which was separated to afford two bis-indoles,
3-[3-methyl-1-(3-formylindol-1-yl)but-2-enyl]indole 4† (44%)
and 3-[(E)-3-methyl-3-(3-formylindol-1-yl)but-1-enyl]indole
5‡ (6%), and 3-(1,1-dimethylprop-2-ynyl)indole 69 (8%).
Alkyne 6 was considered to be derived from the electrophilic
addition of the carbene 1 at C-3 to the b-carbon of anion 7 and
subsequent decarbonylation. Electrophilic addition of the
carbene at C-1 to the b-carbon of the indolide anion 7 and
subsequent decarbonylation, on the other hand, would lead to
the formation of indole 8, a tautomer of b-(dehydroprenyl)-
indole 9, as the reactive intermediate. Further condensation of
anion 7 at the C-2 and C-4 positions of the side-chain of 8 could
give b-prenylindoles 4 and 5, respectively. The mechanism of
this reaction was proposed as portrayed in Scheme 2. The
formation of 4 and 5 revealed that b-dehydroprenylation of
indole had taken place, but that the product was unstable in the
form of 8 or its tautomer 9 under the above reaction conditions,
and had undergone in situ Michael condensation with anion
7.
Scheme 1
represents an important carbon–carbon bond-forming process,
involving introduction of a dehydroprenyl group into organic
substrates,1–6 and has found use in natural product synthesis.7,8
Interaction of 1 with indole itself9 and a- and/or b-methyl
indoles has been studied,10 however, reaction between 1 and
indoles containing an electron-withdrawing group at C-2 or C-3
has not been investigated. In connection with our previous
studies on the regioselectivity of 1 towards different olefins11
and synthesis of b-(dehydroprenyl)indoles,12 we have investi-
Interaction of carbene 1 with a- and/or b-methylindoles, and
indole itself, has been shown to give mostly ring expansion of
the cyclopropane intermediates, which were assumed to be
formed by addition of carbene to the nucleophilic 2,3-double
bond of indoles, to give 3-vinylquinolines.9,10 However, the
Scheme 2
Chem. Commun., 1999, 203–204
203

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first via elimination of 3 (recovered quantitatively), followed by
subsequent Diels–Alder reaction (Scheme 3) as described
previously.12 The dehydroprenyl unit of the carbon skeleton of
natural products 11 and 12 were constructed completely from
carbene 1 in this synthesis. It is worth mentioning here that this
is the first synthesis of a dehydroprenylated indole natural
products using (dimethylvinylidene)carbene 1 as the isoprenoid
unit of the carbon skeleton.
In conclusion this is the first reaction of vinylidenecarbene
with indoles having an electron-withdrawing substituent on the
2,3-double bond. The above reaction provides an efficient
method for introducing an appropriate ‘isoprene’ group into the
b-position of indole, making use of inexpensive and readily
available propargyl chloride 2 and indole-3-carbaldehyde 3 as
starting materials. The above result suggests that reaction of
vinylidenecarbene with indoles containing different functional
groups at C-2 and C-3 should be further investigated. The scope
of this chemistry is now being explored in our laboratory.
This work was supported by a grant from the National
Science Council of Republic of China (NSC-87-2113-M-
110-015) awarded to J.-H. S.
Notes and references
† Selected data for 4 : nmax(KBr)/cm21 3256, 1636, 1614, 1386; dH(300
MHz, CDCl3) 1.84 (s, 3 H), 1.86 (s, 3 H), 5.68 (d, 1 H, J 8.4), 6.56 (d, 1 H,
J 8.4), 7.04–8.35 (m, 10 H), 8.38 (br s, 1 H, NH), 9.86 (s, 1 H); m/z 328
(M+).
‡ Selected data for 5 : nmax(KBr)/cm21 3260, 1640, 1612, 1396, 956;
dH(300 MHz, CDCl3) 1.94 (s, 6 H), 6.48 (d, 1 H, J 16.2), 6.70 (d, 1 H, J
16.2), 7.12–8.35 (m, 10 H), 8.41 (br s, 1 H, NH), 10.03 (s, 1 H); m/z 328
(M+).
Scheme 3
reaction of 1 with 3 did not give the expected quinoline 10,
probably due to the stronger acidity of indole-3-carbaldehyde 3
in comparison with a- and/or b-methylindoles and indole itself.
Thus, interaction of indole 3 with base gave indolide anion 7,
which reacted predominantly via nucleophilic attack by C-3
upon carbene 1, and led to the formation of dehydroprenyl-
indoles and/or the following prenylindoles. This study shows
that the presence of an electron-withdrawing group, in this case
the formyl group at the b-position of indole, could prevent the
formation of quinoline and steer the reaction towards b-
alkylation products.
1 H. D. Hartzler, J. Am. Chem. Soc., 1961, 83, 4990.
2 T. B. Patrick, Tetrahedron Lett., 1974, 1407.
3 T. Sasaki, S. Eguchi, M. Ohno and F. Nakata, J. Org. Chem., 1976, 41,
2408.
4 T. Harada, Y. Nozaki and A. Oku, Tetrahedron Lett., 1983, 24, 5665.
5 H. D. Hartzler, J. Am. Chem. Soc., 1961, 83, 4997.
6 H. D. Hartzler, J. Org. Chem., 1964, 29, 1311.
7 R. W. Mills, R. D. H. Murray and R. A. Raphael, J. Chem. Soc., Chem.
Commun., 1971, 555.
8 D. Michelot, G. Linstrumelle and S. Julia, J. Chem. Soc., Chem.
Commun., 1974, 10.
The above reaction provides a new method for the b-
prenylation of indole in a simple and efficient manner.
Furthermore, elimination of 3 from both 4 and 5 to give b-
(dehydroprenyl)indole 9 should be achieved easily as the anion
7 is stable due to delocalisation of the negative charge, and is
considered to be a good leaving group. Thus, the above reaction
may be useful for the synthesis of b-(dehydroprenyl)indole-
base compounds. In order to demonstrate the potential of this
carbon–carbon bond-forming reaction we applied the above
reaction as a key step in the synthesis of two bioactive indole
natural products, yuehchukene 1113,14 and murrapanine 12,15
which were isolated from Murraya species. The structures of
these two compounds reveal that they are derived from b-
(dehydroprenyl)indole 9. We found that heating both 4 and 5 in
a neutral solution of ethylene glycol at 165–170 °C yielded
yuehchukene in 42% yield. Thermal reaction of 4 and 5 with
methoxyquinone 13 (3 equiv.) under the above reaction
conditions afforded murrapanine in 65% yield. The above one-
step reactions are considered to give b-(dehydroprenyl)indole 9
9 E. Wenkert, E. C. Angell, V. F. Ferreira, E. L. Michelotti, S. R. Pittre,
J.-H. Sheu and C. S. Swindell, J. Org. Chem., 1986, 51, 2343.
10 S. R. Landor, V. Rogers and H. R. Sood, J. Chem. Soc., Perkin Trans.
1, 1976, 2103.
11 J.-H. Sheu, C.-F. Yen, Y.-L. Chan and J.-F. Chung, J. Org. Chem., 1990,
55, 5232; J.-H. Sheu, C.-F. Yen, C.-W. Huang and Y.-L. Chan,
Tetrahedron Lett., 1991, 32, 5547; J.-H. Sheu, C.-F. Yen and C.-W.
Huang, J. Chin. Chem. Soc., 1993, 40, 59.
12 J.-H. Sheu, Y.-K. Chen and Y.-L. V. Hong, Tetrahedron Lett., 1991, 32,
1045; J.-H. Sheu, Y.-K. Chen and T.-L. V. Hong, J. Org. Chem., 1993,
58, 5784; J.-H. Sheu, Y.-K. Chen, H.-F. Chung, P.-J. Sung and S.-F. Lin,
Heterocycles, 1996, 43, 1751; J.-H. Sheu, Y.-K. Chen, H.-F. Chung,
S.-F. Lin and P.-J. Sung, J.Chem. Soc., Perkin Trans. 1, 1998, 1959.
13 Y.-C. Kong, K.-F. Cheng, R. C. Cambie and P. G. Waterman, Chem.
Commun., 1985, 47.
14 Y.-C. Kong, K.-H. Ng, K.-H. Wat, A. Wang, I. F. Saxena, H.-F. Cheng,
P. P. H. But and H.-T. Chang, Planta Med., 1985, 44, 304.
15 T.-S. Wu, M.-J. Liou, C.-J. Lee, T.-T. Jong, A. T. McPhail, D. R.
McPhail and K.-H. Lee, Tetrahedron Lett., 1989, 30, 6649.
Communication 8/08733D
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