Palladium(ii) Catalysed Cascade Strategy for the Synthesis of Dibenzo[5,6:7,8]cycloocta[1,2-: b] indol-10-ols/-10(15 H)-ones: Easy Access to 1,3,5,7-Cyclooctatetraenes (COTs)

Article abstract of DOI:10.1039/d0cc06538b

An atom-economic Pd(ii)-catalysed cascade cyclisation of 2-(biphenylethynyl)anilines tethered to an aldehyde or cyano group leads to the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high yields (up to 95%). The reaction proceeds via amino-palladation of the alkyne followed by nucleophilic addition onto the aldehyde/cyano group. Treatment of 6 with p-TsOH·H2O smoothly provided cyclooctatetraene (COT) derivatives 7. This journal is

Full text of DOI:10.1039/d0cc06538b

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Palladium(II) catalysed cascade strategy for the
synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-
10-ols/-10(15H)-ones: easy access to 1,3,5,7-
cyclooctatetraenes (COTs)†
Cite this:DOI: 10.1039/d0cc06538b
Received 1st October 2020,
Accepted 18th November 2020
Sukanya De,
Moumita Jash
and Chinmay Chowdhury
*
DOI: 10.1039/d0cc06538b
rsc.li/chemcomm
An atom-economic Pd(II)-catalysed cascade cyclisation of 2-(biphe-
Though COTs fused with arenes/hetero-arenes at four8a,14 or
nylethynyl)anilines tethered to an aldehyde or cyano group leads to two4,5a,15 double bonds are well-studied, the synthesis of COTs
the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 fused at three double bonds16 are less in number. Among them,
or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high the synthesis of hybrid COTs, i.e., those fused with an indole
yields (up to 95%). The reaction proceeds via amino-palladation of ring and two arene rings, has not yet been reported, under-
the alkyne followed by nucleophilic addition onto the aldehyde/ lining the urgency for their facile and general synthesis.
cyano group. Treatment of 6 with p-TsOHꢀH2O smoothly provided
cyclooctatetraene (COT) derivatives 7.
In contrast to COTs, 2,4,6-cyclooctatrien-1-ones are less
explored though their synthesis has become an active area of
research in the last century leading to the development of a
Eight-membered carbocyclic rings serve as core structures in several number of reactions.17 The synthesis of the same scaffold fused
important classes of bioactive natural products1a but are relatively with arenes and heteroarenes stimulated more research inter-
difficult to access1b,c using conventional synthetic methods. Among est because of their prevalence in bioactive natural products18
them, 1,3,5,7-cyclooctatetraenes (COTs) find immense applications and synthetic intermediates6b,19 among others. For example,
in diverse fields.2 Besides, they have been identified to serve as a racemosin C (3, Fig. S1, ESI†), isolated from Caulerpa racemosa,
complement motif of cubane, a bioisostere of a phenyl ring, through displayed significant hPTP1B inhibitory activity,18 marginally
validation in a number of pharmaceuticals and agrochemicals.3 lower than that of caulerpin (1a).12a Despite the importance of
COTs fused with other rings give rise to diverse scaffolds which find this field, only a few reports6b,19 on the synthesis of some
potential applications in drug developments,4 and in ligands for specific examples of 2,4,6-cyclooctatrien-1-ones fused with arenes
d- and f-block metals,5 catalysts,5a,6 and molecular devices7 along or other rings are known; this clearly indicates the requirement of
with many uses in materials science.8 In this regard, the degree and a reliable method for their general synthesis.
type of fusion9 in COTs play a critical role in determining their
usefulness.
In continuation of our work20 on palladium catalysed reactions,
we anticipated that a general synthesis of fused 2,4,6-cyclooctatrien-
Despite the availability of various synthetic variants,10 COTs 1-ols 6 and 2,4,6-cyclooctatrien-1-ones 8 could be achieved in one-
are rare in nature. To date, few indole alkaloids having a COT pot from acetylenic substrates 4 and 5, respectively, employing an
moiety as the core structure [e.g., caulerpin (1a), its analogues 1b appropriate catalyst (Scheme 1). Furthermore, the synthesis of fused
and 1c,11a and jolynamine11b (2)] have been reported (Fig. S1, ESI†). COTs 7 could also be accomplished conveniently by the acid-
Caulerpin exhibits potent inhibitory activity12a (IC50 = 3.77 mM) mediated dehydration of products 6. The synthetic pathways proved
against hPTP1B (human protein tyrosine phosphate 1B), a key to be viable upon the deployment of an appropriate catalyst and
target for the treatment of type II diabetes and obesity,12b in reaction conditions as described herein.
addition to its role as an antitumor agent.12c Nevertheless, there
Initially, we took up the model synthesis of compound 6a
have been limited achievements to date for the efficient construc- (R1 = R2 = R3 = H, PG = Ts) from acetylenic substrate 4a. Thus,
tion of indole-fused COTs.13
carrying out this reaction in 1,4-dioxane employing Pd(OAc)2/
bipyridine (bpy) and D-(+)-camphorsulfonic acid (D-CSA) as an
additive led to product 6a with 27% yield (Table S1 in ESI†,
entry 1). Replacing the catalyst by Pd(OAc)2bpy made it still less
attractive (Table S1, ESI†, entry 2). We, therefore, persisted with
the previous catalytic system but changed the additive to
p-TsOHꢀH2O (Table S1, ESI†, entry 3). Switching to other solvent
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical
Biology, Kolkata-700032, India. E-mail: chinmay@iicb.res.in
† Electronic supplementary information (ESI) available. CCDC 2034270–2034274.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0cc06538b
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Scheme 1 Envisaged route for the synthesis of 6–8.
systems failed to provide the product (Table S1, ESI†, entries 4
and 5) suggesting the importance of 1,4-dioxane in this reac-
tion. We, therefore, reverted to Pd(OAc)2bpy and pursued this
reaction further in 1,4-dioxane; to our surprise, 6a (21%) was
formed together with 20% of COT derivative 7a (Table S1, ESI†,
entry 6). Employment of aliphatic sulphonic acids did not
improve the outcome (Table S1, ESI†, entries 7 and 8). Never-
theless, replacing the additive with benzoic acid was found to
be encouraging, though 2,3-naphthalenedicarboxylic acid
failed to provide 6a (Table S1, ESI†, entries 9 and 10). Next,
switching to low cost acetic acid (2 equiv.) led to 36% yield of
6a; to our delight, increasing the amount of AcOH (i.e., 10% in
Scheme 2 Palladium-catalysed synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]
indol-10-ols 6a–q. Reaction conditions: a mixture of 4 (0.086 mmol) and
Pd(OAc)2bpy (6 mol%) in a solution (1.1 mL) containing AcOH : 1,4-dioxane
(0.1 : 1, v/v) was heated at 100 1C under argon.
1,4-dioxane, v/v) afforded 6a within 3.5 h in 73% yield (Table S1, 6k or 6l to an extent of 60–70%. The reason behind these results is
ESI†, entry 12). But decreasing the catalyst loading had a detri- not very clear at this moment.
mental effect (Table S1, ESI†, entry 13). Employment of other
Interestingly, when a strong EWG (viz., R1 = CO2Me) in ring
Pd(II) catalysts [viz. PdCl2, Pd(MeCN)4(BF4)2 and Pd(MeCN)2Cl2] A and EDG (viz., R2 = OMe) in ring B are simultaneously placed
failed to give the desired product 6a (Table S1, ESI†, entries para to the acetylenic group, product 6m (94%) was formed
14–16). Thus the reaction conditions of entry 12 of Table S1 (ESI†) within 3 h. When the ester group was absent (as in 4n), 6n was
were considered as optimal.
furnished in a somewhat lower yield (81%), while removing the
With the optimised reaction conditions in hand, the general- methoxy group from 4n and incorporating a moderate EDG
ity of the reaction protocol was explored by carrying out the (R2 = Me) as in substrate 4o led to the formation of 6o in 59%
reactions of acetylenic substrates 4a–q (Scheme 2).
yield. Furthermore, the incorporation of an additional EWG
Interestingly, when the nosyl group (–Ns) was used as an (R1 = CO2Me) in ring A (4p) benefited the reaction by producing
N-protecting group instead of tosyl (–Ts) as in 4b, the reaction product 6p (78%) within 3 h. Surprisingly, the reaction of
required a longer reaction time (i.e., 5.5 h) and the yield of the substrate 4q having an EDG (R3 = OMe) at the para position
product 6b decreased (Scheme 2, product 6a vs. 6b) underlining of the C ring was somewhat sluggish to furnish the product 6q
the importance of the N-tosyl group.
in 61% yield.
Thereafter, we studied the effects of different functional groups
To further probe the synthetic utility of this methodology,
at the meta and para positions (with respect to the acetylenic group) we then attempted to transform the products 6 into COT
in ring A of substrate 4. For the meta position, both moderate derivatives 7 as envisioned previously (Scheme 1). Toward this
electron-withdrawing (i.e., R1 = F/Cl/CF3) and -donating (R1 = Me) goal, we treated 2,4,6-cyclooctatriene-1-ol 6a with a number of
groups performed well, resulting in the formation of products 6c–e Lewis and Brønsted acids; this led to the identification of
and 6f, respectively, within 4.5–5.5 h in 72–81% yields. But a strong p-TsOHꢀH2O as the best acid , allowing the formation of COT
EWG (R1 = CO2Me) or EDG (R1 = OMe) did not favour this reaction 7a in 1,4-dioxane within 4.4 h with an almost quantitative
resulting in lower yields [i.e., 6g (64%), 6h (66%)]. For the para (98%) yield. We then established the generality of this protocol
position, incorporation of a moderate EWG (viz., R1 = F; substrate by applying it to a number of compounds 6 as depicted in
4i) facilitated the reaction affording 6i in 81% yield, compared to an Scheme 3. Substrates 6i/6k bearing an EWG (viz., R1 = F/CO2Me)
EDG (viz., R1 = Me) as in 4j which furnished 6j in a lower yield in ring A meta to the N–Ts group were found to be highly
(68%). These substituent effects are perhaps predictable keeping in reactive, producing the desired COTs 7b/7c within 5.5 h in
view the importance of electrophilicity of the b-carbon (of the triple excellent yields (95–98%), though an EDG (viz., R1 = OMe) at the
bond of 4) for the cyclisation to proceed smoothly. To our surprise, same position furnished the desired product (7d) in a some-
a strong EWG (viz., R1 = CO2Me) or EDG (viz., R1 = OMe) placed at what lower yield (86%). A similar trend of reactivity was
the same position in the substrates (4k or 4l) delivered the product followed when an EWG (R1 = F/Cl) or EDG (R1 = OMe) was
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Scheme 4 Synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-
ones 8a–i. Reaction conditions: a mixture of 5 (0.14 mmol), Pd(OAc)2bpy
(6 mol%) and D-CSA (2.0 equiv.) was heated at 100 1C in NMA (1.5 mL)
under argon.
Scheme 3 Synthesis of 1,3,5,7-cyclooctatetraene (COT) derivatives
7a–7j. Reaction conditions: a mixture of 6 (0.062 mmol) and p-TsOHꢀ
H2O (0.186 mmol) in 1,4-dioxane (1.0 mL) was refluxed under argon.
containing a pyridyl ring (X = N) was still conducive to the
reaction, the product 8i (60%) being formed within 5 h.
Owing to the presence of a free NH group in bioactive
present at the para position, leading to the formation of product compounds,18 we attempted to check the feasibility of N-depro-
7e (95%), 7f (85%) or 7g (83%). For ring B, the placement of an tection of product 8a; to our delight product 9 was formed easily
EDG (viz. R2 = OMe) promoted the reaction furnishing 7h within within 3 h in 82% yield (Scheme S3 in the ESI†).
5.5 h in 96% yield. But the incorporation of an additional EWG
On the basis of the experimental results and the known
(viz. CO2Me) in ring A reduced the yield of the product (7i) to palladium chemistry, a plausible reaction mechanism is out-
74%. On the contrary, an EDG (viz. R3 = OMe) placed in ring lined in Scheme 5. Initially, palladated species A and A0 are
C hindered the reaction to some extent affording the COT generated from the substrates 4 and 5, respectively, through the
derivative 7j within 4.5 h in a moderate yield (60%).
action of the Pd(II) catalyst acting like a Lewis acid. Under acidic
With a view to expanding the scope of this reaction further, conditions, A and A0 would then trigger the heteroannulation via
we replaced the aldehyde group of 4a by a cyano group as in 5a a trans-aminopalladation pathway20a resulting in the formation
which can be synthesised easily in a few steps (see Scheme S2 in of transient cationic palladated species21 B and B0 which are
the ESI†). Initially, we carried out the reaction of 5a under the stabilised through coordination of the tethered nucleophile
optimised reaction conditions for 4a; to our disappointment, (–CHO/–CN) as shown in Scheme 5. Next, species B and B0
the desired product 2,4,6-cyclooctatrien-1-one 8a was formed having the polar C–Pd bond caused by the electron-donating
only in 50% yield. To find the optimised conditions, we therefore effect of the nitrogen atom of the indole ring22a (shown using an
carried out a few more reactions on 5a by changing the catalyst, arrow) could promote nucleophilic 1,2-addition onto the teth-
ligand, additive, solvent, temperature, etc. (see Table S2 in the ered aldehyde and nitrile groups, respectively, resulting in the
ESI†). From this study, the best result was obtained when the generation of palladated species C22b and C0.22c Subsequent
reaction of 5a was carried out at 100 1C for 5.2 h in NMA using protonolysis of C using AcOH would afford the product 6 along
Pd(OAc)2bpy (6 mol%) and D-CSA (2.0 equiv.) leading to the with a Pd(II) species which keeps the catalytic cycle active. On the
generation of 8a in 92% yield (entry 7 of Table S2 in the ESI†).
other hand, protonolysis of C0 with D-CSA would lead to the
With the optimised reaction conditions in hand, we then regeneration of the Pd(II) catalyst in addition to the formation of
established the generality of the reaction for the formation of imine intermediate D0 which upon subsequent hydrolysis under
2,4,6-cyclooctatrien-1-ones 8 (Scheme 4). Substrates 5b/5c bearing acidic conditions would furnish the product 8.
an EDG (R1 = OMe/Me) in ring A meta to the alkyne moiety
In conclusion, we have disclosed an atom economic method
facilitated the reaction, furnishing the products 8b (95%)/8c (87%) for the expedient synthesis of products 6 and 8 via palladium
within 3.5–4.5 h. But 5d/5e having an EWG (R1 = CO2Me/Cl) at the catalysed intramolecular cascade reactions of amino-alkynes 4
same position formed products 8d/8e within 4.4–12 h in lower and 5, respectively. The hallmarks of the synthesis are high
yields (74–85%). Nevertheless, the placement of an EDG (viz., yield (up to 95%), atom-economy, tolerance of functional
R1 = OMe) rather than an EWG (R1 = CO2Me) even at the para groups and formation of two new rings (i.e., cyclooctatriene
position also proved beneficial (substrate 5f vs. 5g) though the and indole) fused to each other. Furthermore, treatment of
former took a longer reaction time (Scheme 4, see 8f vs. 8g). For products 6 with p-TsOHꢀH2O could provide easy access to COT
ring B, when a strong EDG (R2 = OMe) was placed para to the derivatives. Syntheses of higher homologues (i.e., nine and
alkyne moiety (in 5h), the desired product 8h (84%) was formed ten membered rings) of products 6 and 8 are currently
albeit with a longer reaction time (10 h). Interestingly substrate 5i underway.
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Scheme 5 Plausible mechanism for the formation of products 6–8.
J. W. Y. Lam, X. Huang, D. L. Phillips, H. Wang and B. Z. Tang,
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This work was financially supported by CSIR-IICB from
project MLP-116.
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Conflicts of interest
There are no conflicts to declare.
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