Sequential Heck–Heck reactions for the dibenz[a,f]indolizine skeleton: synthetic application to decumbenine B

Article abstract of DOI:10.1016/j.tetlet.2016.10.064

Cyclization of benzamidoacrylate intermediates has been applied for the synthesis of dibenz[a,f]indolizine skeleton. Heck reaction for the 5-membered ring first and the following Heck reaction provided the 6-membered ring next. For the synthetic application properly arranged diiodo-aromatic intermediate has been prepared and subjected to the sequential Heck reactions, and the following decarboxylation provided the known precursor of decumbenine B.

Full text of DOI:10.1016/j.tetlet.2016.10.064

Tetrahedron Letters 57 (2016) 5348–5350
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sequential Heck–Heck reactions for the dibenz[a,f]indolizine
skeleton: synthetic application to decumbenine B
⇑
Bok-Jin Lee, Gil-Pyo Hong, Guncheol Kim
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejon 305-764, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclization of benzamidoacrylate intermediates has been applied for the synthesis of dibenz[a,f]in-
dolizine skeleton. Heck reaction for the 5-membered ring first and the following Heck reaction provided
the 6-membered ring next. For the synthetic application properly arranged diiodo-aromatic intermediate
has been prepared and subjected to the sequential Heck reactions, and the following decarboxylation
provided the known precursor of decumbenine B.
Received 12 September 2016
Revised 8 October 2016
Accepted 18 October 2016
Available online 18 October 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Decumbenine B
Benzamidoacrylate
Heck reaction
Dibenzindolizine
Polycyclic alkaloids frequently encountered in natural products
have shown numerous physiological activities.1 Especially, nitro-
gen fused bicyclic medium rings arranged with aromatic moieties
around have attracted many synthetic chemists’ attention because
of skeletal as well as biological attraction.2,3 As an extension of our
interests on the synthesis of the natural alkaloid products contain-
ing medium sized ring,4 we designed to explore sequential cycliza-
tion reactions using Heck reactions for the construction of dibenzo
6/5-membered ring system (Scheme 1). And we wanted to apply
this approach for the synthesis of 3-arylisoquinoline alkaloid,
decumbenine B (Fig. 1). This alkaloid has been isolated from plant
tubers of Coridalis decumbens Pers,5 which has been used in Chi-
nese folk herbal medicine for the treatment of hypertension, hemi-
plegia, rheumatoid arthritis, and sciatic neuralgia. And it has been
synthesized only by a few groups.6
the following aza-Michael reaction with ethyl propiolate under
Cs2CO3 in DMF in good yields (85% in 2 steps) (Scheme 2).
We hoped that the 2-iodobenzene moiety should undergo Pd-
oxidative insertion faster at the early stage of the process and
the 5-membered ring would be formed favorably via Heck reac-
tion.4d In order to confirm the desired cyclization and find the
optimum condition, we have treated 6 with a palladium reagent
under conventional conditions (Table 1). All the conditions
described in Table 1 provided only a single isomer 7.7 Amine base
such as trimethylamine or diisopropylethylamine (DIEA) provided
less yields (Entries 1 & 2) than inorganic bases such as Cs2CO3,
NaHCO3, or Na2CO3 (Entries 3–7), and the addition of additive
could reduce the reaction time only (Entries 4 and 5). The optimum
condition has been found to be using Pd(OAc)2 and NaHCO3 in
DMF, yielding 79% of 7 (Entry 5). Dibromo-derivative of 6 provided
the same product in less yield under similar conditions along with
5% of an undesired isomer having exchanged 5, 6 membered rings
at the core. On the other hand, the corresponding diiodo-derivative
of 6 provided 7 as a single product in similar yields.
We have used benzamidoacrylate precursors for alkaloid syn-
thesis,4d and we want to construct dibenz[a,f]indolizine skeleton
through consecutive cyclization reactions from intermediate 3:
Heck reaction for 5-membered ring first and the same Heck
reaction for 6-membered ring next. Compound
3
would be
The scope of this reaction has been investigated under the opti-
mized condition found. The desired products have been formed as
a single isomer in various scopes of yields (Table 2). The effect of
position or electronic characters of substituents in each aromatic
ring on yields could not be explained distinctively (cf. 4d, 4f, 4h).
However, electron withdrawing chlorine or nitro group has
afforded lower yield than the corresponding hydrogen or methoxy
group (cf. 4a, 4c, 4i, 4j).
prepared by aza-Michael reaction of amide 2.4d The bicyclic ring
skeleton could be formed by differentiating reactivity in the
cyclization steps (Scheme 1).
For the sequential cyclization, we have prepared amidoacrylate
intermediate 6 from the corresponding aromatic halides through
conventional acid and amine coupling condition using EDCI, and
Although sequential Heck reactions for bi-cyclization have been
⇑
Corresponding author. Tel.: +82 42 821 5475; fax: +82 42 821 8896.
E-mail address: guncheol@cnu.ac.kr (G. Kim).
attempted rarely,8 we consider this route would suggest a practical
http://dx.doi.org/10.1016/j.tetlet.2016.10.064
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

B.-J. Lee et al. / Tetrahedron Letters 57 (2016) 5348–5350
5349
Table 2
Substrate scopes for the cyclizationa
4b 58%
4a 59%
Scheme 1.
4d 10%
4c 85%
Figure 1.
4f 15%
4e 68%
Scheme 2.
4h 99%
4g 59%
Table 1
Heck reaction conditions for the cyclization of 6
4j 35%
4i 20%
Yield of the isolated product.
a
was too unstable to be prepared. So we replaced it with iodo-
benzylamine compound which could be prepared from
Entry
Pd (0.1 equiv)
Conditionsa
Yieldb (%)
9
8
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Et3N, TBAC, 24 h
DIEA, TBAC, 24 h
Cs2CO3, TBAC, 2 h
NaHCO3, TBAC, 2 h
NaHCO3, 5 h
53
26
61
72
79
66
64
through protection of amine with Boc, deprotonation with t-BuLi
at ortho-position followed by iodination, and deprotection with
TFA.9 Diiodo amide 11 could be prepared in 72% yield by a coupling
reaction of 9 with compound 10, which was prepared by oxidation
of the corresponding known aldehyde with AgNO3 and 10% NaOH
in MeCN.10 The amidoacrylate 12 has been prepared from 11 with
ethyl propiolate. Bicyclization under Pd(OAc)2 and NaHCO3 pro-
vided desired 13 in 40% yield, and hydrolysis followed by concur-
rent decarboxylation afforded the known precursor 14 in 40% yield
(Scheme 3).11
Na2CO3, 5 h
NaHCO3, TBAC, 6 h
a
110 °C in DMF, base (2 equiv).
Isolated yield of 7.
b
way to dibenz[a,f]indolizine skeleton and could be applied to a nat-
ural product, decumbenine B. Dibenz[a,f]indolizine intermediate
14 has been a known precursor to the natural alkaloid,6c so we
first tried to prepare intermediate 13 from the corresponding
intermediate 3. And a process including decarboxylation would
convert 13 to 14. The required bromo-derivative of 9, however,
As conversion of 14 to decumbenine B could be repeated as
described in reference (Scheme 4),6c we could perform a formal
synthesis of decumbenine B. In summary, we have developed a
practical way to dibenz[a,f]indolizine skeleton via double Heck
reactions, and the scope including synthesis of a natural alkaloid
has been suggested.

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B.-J. Lee et al. / Tetrahedron Letters 57 (2016) 5348–5350
References and notes
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Scheme 3.
7. Compound 7: 1H NMR (400 MHz, CDCl3) 1.47 (t, 3H, J = 7.2 Hz), 4.58 (q, 2H,
J = 7.2 Hz), 5.11 (s, 2H), 7.27 (t, 1H, J = 5.8 Hz), 7.30–7.56 (m, 3H), 7.56–7.64 (m,
2H), 7.76 (dd, 1H,, J = 7.1, 1.5 Hz), 7.93 (ddd, 1H,, J = 7.1, 1.5, 0.8 Hz). 13C NMR
(100 MHz, CDCl3) 14.10, 42.71, 62.34, 104.32, 123.04, 126.26, 126.63, 127.73,
128.82, 128.93, 130.23, 131.80, 133.20, 133.95, 134.20, 135.20, 140.90, 164.61,
167.58, EIMS 305.11 (M+). When the reaction was quenched earlier, less than 2
hr, starting material 6 and isomers of mono-cyclized product by single Heck
reaction were detected. However, all the intermediates were converted to the
desired product under longer reaction time. None of dehalogenated product
without cyclization has been detected.
Scheme 4.
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Acknowledgment
This work was supported by Research Fund of Chungnam
National University.
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11. Spectral data of the compound obtained were identical to those of the known.6c